NELSON 4251 4720 Merged

Nelson
TEXTBOOK of
PEDIATRICS
EDITION 20
Robert M. Kliegman, MD
Professor and Chair Emeritus
Department of Pediatrics
Medical College of Wisconsin
Milwaukee, Wisconsin
Bonita F. Stanton, MD Nina F. Schor, MD, PhD

Vice-Dean of Research William H. Eilinger Professor and Chair
Professor of Pediatrics Department of Pediatrics
Wayne State University School of Medicine Professor
Detroit, Michigan Department of Neurology
Pediatrician-in-Chief
Joseph W. St Geme III, MD Golisano Children’s Hospital
Chair, Department of Pediatrics University of Rochester Medical Center
Professor of Pediatrics and Microbiology Rochester, New York
Perelman School of Medicine at the University of
Pennsylvania Editor Emeritus
Physician-in-Chief
Leonard and Madlyn Abramson Endowed Chair in Richard E. Behrman, MD
Pediatrics Nonprofit Healthcare and Educational
Children’s Hospital of Philadelphia Consultants to Medical Institutions
Philadelphia, Pennsylvania Santa Barbara, California
1600 John F. Kennedy Blvd.
Ste. 1800
Philadelphia, PA 19103-2899
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PART
The Nervous System XXVII
Historical markers of neurologic dysfunction include full-term infants
who are unable to breathe spontaneously; have poor, uncoordinated
Chapter 590 sucks; need an inordinate amount of time to feed; or require gavage
feeding. Again, it is important to consider the developmental context,
Neurologic Evaluation because all of these issues would be expected in premature infants,
particularly those with a very-low birthweight. Double-checking the
state newborn screening results may provide a clue to abnormal neu-
Rebecca K. Lehman and Nina F. Schor rologic manifestation in an infant.
The most important component of a neurologic history is the devel-
opmental assessment (see Chapters 9-14 and 16). Careful evaluation
of a child’s social, cognitive, language, fine motor, and gross motor
HISTORY skills is required to distinguish normal development from either iso-
A detailed history is the cornerstone of any neurologic assessment. lated or global (i.e., in 2 or more domains) developmental delay. An
Although parents may be the primary informants, most children older abnormality in development from birth suggests an intrauterine or
than 3-4 yr are capable of contributing to their history and should be perinatal cause, but a loss of skills (regression) over time strongly sug-
questioned directly. gests an underlying degenerative disease of the CNS, such as an inborn
The history should begin with the chief complaint, as well as a error of metabolism. The ability of parents to recall the precise timing
determination of the complaint’s relative significance within the of their child’s developmental milestones is extremely variable. It is
context of normal development (see Chapters 9-16). The latter step is often helpful to request old photographs of the child or to review the
critical because a 13 mo old who cannot walk may be perfectly normal, baby book, where the milestones may have been dutifully recorded. In
whereas a 4 yr old who cannot walk might have a serious neurologic general, parents are aware when their child has a developmental
condition. problem, and the physician should show appropriate concern. Table
Next, the history of present illness should provide a chronological 590-1 outlines the upper limits of normal for attaining specific devel-
outline of the patient’s symptoms, with attention paid to location, opmental milestones. Chapter 16 includes a comprehensive review of
quality, intensity, duration, associated features, and alleviating or exac- developmental screening tests and their interpretation.
erbating factors. It is essential to perform a review of systems, because Family history is extremely important in the neurologic evaluation
abnormalities of the central nervous system (CNS) often manifest with of a child. Most parents are extremely cooperative in securing medical
vague, nonfocal symptoms that may be misattributed to other organ information about family members, particularly if it might have rel-
systems (e.g., vomiting, constipation, urinary incontinence). A detailed evance for their child. The history should document the age and
history might suggest that vomiting is as a result of increased intracra- history of neurologic disease, including developmental delay, epilepsy,
nial pressure (ICP) rather than gastritis or that constipation and migraine, stroke, and inherited disorders, for all 1st- and 2nd-degree
urinary incontinence are caused by a spinal cord tumor rather than relatives. It is important to inquire directly about miscarriages or fetal
behavioral stool withholding. In addition, a systemic illness may deaths in utero and to document the sex of the embryo or fetus, as
produce CNS manifestations such as lupus erythematosus (seizures, well as the gestational age at the time of demise. When available, the
psychosis, demyelination) or mitochondrial disorders (developmental results of postmortem examinations should be obtained, as they can
delay, strokes, hypotonia). have a direct bearing on the patient’s condition. The parents should
Following the chief complaint and history of present illness, the be questioned about their ethnic backgrounds, because some genetic
physician should obtain a complete birth history, particularly if a con- disorders occur more commonly within specific populations (e.g.,
genital disorder is suspected. The birth history should begin with a Tay-Sachs disease in the Ashkenazi Jewish population). They should
review of the pregnancy, including specific questions about common also be asked if there is any chance that they could be related to each
complications, such as pregnancy-induced hypertension, preeclamp- other, because the incidence of metabolic and degenerative disorders
sia, gestational diabetes, vaginal bleeding, infections, and falls. It is of the CNS is increased significantly in children of consanguineous
important to quantify any cigarette, alcohol, or drug (prescription, marriages.
herbal, illicit) use. Inquiring about fetal movement might provide clues The social history should detail the child’s current living environ-
to an underlying diagnosis, because decreased or absent fetal activity ment, as well as the child’s relationship with other family members.
can be associated with chromosomal anomalies and CNS or neuro- It is important to inquire about recent stressors, such as divorce,
muscular disorders. Finally, any abnormal ultrasound or amniocente- remarriage, birth of a sibling, or death of a loved one, because they
sis results should be noted. can affect the child’s behavior. If the child is in daycare or school,
A labor history should address the gestational age at delivery and one should document the child’s academic and social performance,
mode of delivery (spontaneous vaginal, vacuum- or forceps-assisted, paying particular attention to any abrupt changes. Academic perfor-
cesarean section) and should comment on the presence or absence of mance can be assessed by asking about the child’s latest report card,
fetal distress. If delivery was by cesarean section, it is essential to record and peer relationships can be evaluated by having the child name his
the indication for surgery. or her “best friends.” Any child who is unable to name at least 2
The birth weight, length, and head circumference provide useful or 3 playmates might have abnormal social development. In some
information about the duration of a given problem, as well as insights cases, discussions with the daycare worker or teacher provide useful
into the uterine environment. Parents can usually provide a reliable ancillary data.
history of their child’s postnatal course; however, if the patient was
resuscitated or had a complicated hospital stay, it is often helpful to NEUROLOGIC EXAMINATION
obtain the hospital records. The physician should inquire about the The neurologic examination begins at the outset of the interview. Indi-
infant’s general well-being, feeding and sleeping patterns, activity level, rect observation of the child’s appearance and movements can yield
and the nature of the infant’s cry. If the infant had jaundice, it is impor- valuable information about the presence of an underlying disorder. For
tant to determine both the degree of jaundice and how it was managed. instance, it may be obvious that the child has dysmorphic facies, an
2791
2792 Part XXVII ◆ The Nervous System
Table 590-1 Screening Scheme for Developmental Delay: Upper Range

AGE (mo) GROSS MOTOR FINE MOTOR SOCIAL SKILLS LANGUAGE
3 Supports weight on forearms Opens hands spontaneously Smiles appropriately Coos, laughs
6 Sits momentarily Transfers objects Shows likes and dislikes Babbles
9 Pulls to stand Pincer grasp Plays pat-a-cake, peek-a-boo Imitates sounds
12 Walks with 1 hand held Releases an object on Comes when called 1-2 meaningful words
command
18 Walks upstairs with assistance Feeds from a spoon Mimics actions of others At least 6 words
24 Runs Builds a tower of 6 blocks Plays with others 2-3–word sentences
unusual posture, or an abnormality of motor function manifested by a

hemiparesis or gait disturbance. The child’s behavior while playing and
interacting with his or her parents may also be telling. A normal child
usually plays independently early in the visit, but then engages in the
interview process. A child with attention-deficit/hyperactivity disorder
might display impulsive behavior in the examining room, and a child
with neurologic impairment might exhibit complete lack of awareness
of the environment. Finally, note should be made of any unusual odors
about the patient, because some metabolic disorders produce charac-
teristic scents (e.g., the “musty” smell of phenylketonuria or the “sweaty
feet” smell of isovaleric acidemia). If such an odor is present, it is
important to determine whether it is persistent or transient, occurring
only with illnesses.
The examination should be conducted in a nonthreatening, child-
friendly setting. The child should be allowed to sit where the child is
most comfortable, whether it be on a parent’s lap or on the floor of the
examination room. The physician should approach the child slowly, Figure 590-1 Congenital hydrocephalus. Note the enlarged cranium
reserving any invasive or painful tests (e.g., measurement of head and prominent scalp veins.
circumference, gag reflex) for the end of the examination. In the end,
the more that the examination seems like a game, the more the child
will cooperate. Because the neurologic examination of an infant premature infant is 0.5 cm in the 1st 2 wk, 0.75 cm in the 3rd wk, and
requires a somewhat modified approach from that of an older child, 1.0 cm in the 4th wk and every week thereafter until the 40th wk of
the 2 groups are considered separately (see Chapters 9, 10, and 94 vs development. The head circumference of an average term infant mea-
Chapters 11-14). sures 34-35 cm at birth, 44 cm at 6 mo, and 47 cm at 1 yr of age (see
Chapters 9 and 10).
Mental Status If the brain is not growing, the skull will not grow; therefore, a small
Age aside, the neurologic examination should include an assessment head frequently reflects a small brain, or microcephaly. Conversely, a
of the patient’s mental status in terms of both level of arousal and large head may be associated with a large brain, or macrocephaly,
interaction with the environment. Premature infants born at <28 wk which is most commonly familial but may be from a disturbance of
of gestation do not have consistent periods of alertness, whereas growth, neurocutaneous disorder (e.g., neurofibromatosis), chromo-
slightly older infants arouse from sleep with gentle physical stimula- somal defect (e.g., Klinefelter syndrome), or storage disorder. Alterna-
tion. Sleep–wake patterns are well developed at term. Because the level tively, the head size may be increased secondary to hydrocephalus (Fig.
of alertness of a neonate depends on many factors, including the time 590-1) or chronic subdural hemorrhages. In the latter case, the skull
of the last feeding, room temperature, and gestational age, serial exami- tends to assume a square or box-like shape, because the long-standing
nations are critical when evaluating for changes in neurologic function. presence of fluid in the subdural space causes enlargement of the
Older children’s mental status can be assessed by watching them play. middle fossa.
Having them tell a story, draw a picture, or complete a puzzle can also The shape of the head should be documented carefully. Plagioceph-
be helpful in assessing cognitive function. Memory can be evaluated aly, or flattening of the skull, can be seen in normal infants but may be
informally as patients recount their personal information, as well as particularly prominent in hypotonic or weak infants, who are less
more formally by asking them to register and recall 3 objects or mobile. A variety of abnormal head shapes can be seen when cranial
perform a digit span. sutures fuse prematurely, as in the various forms of inherited cranio-
synostosis (see Chapter 591.12).
Head An infant has 2 fontanels at birth: a diamond-shaped anterior fon-
Correct measurement of the head circumference is important. It tanel at the junction of the frontal and parietal bones that is open at
should be performed at every visit for patients younger than 3 yr and birth, and a triangular posterior fontanel at the junction of the parietal
should be recorded on a suitable head growth chart. To measure, a and occipital bones that can admit the tip of a finger or may be closed
nondistensible plastic measuring tape is placed over the mid-forehead at birth. If the posterior fontanel is open at birth, it should close over
and extended circumferentially to include the most prominent portion the ensuing 6-8 wk; its persistence suggests underlying hydrocephalus
of the occiput. If the patient’s head circumference is abnormal, it or congenital hypothyroidism. The anterior fontanel varies greatly in
is important to document the head circumferences of the parents size, but it usually measures approximately 2 × 2 cm. The average time
and siblings. Errors in the measurement of a newborn skull are of closure is 18 mo, but the fontanel can close normally as early as
common owing to scalp edema, overriding sutures, and the presence 9 mo. A very small or absent anterior fontanel at birth might indicate
of cephalohematomas. The average rate of head growth in a healthy craniosynostosis or microcephaly, whereas a very large fontanel can
Chapter 590 ◆ Neurologic Evaluation 2793
signify a variety of problems. The fontanel is normally slightly depressed fair coloring. This normal finding can cause confusion and can lead to
and pulsatile and is best evaluated by holding the infant upright while the improper diagnosis of optic atrophy.
the infant is asleep or feeding. A bulging fontanel is a potential indica- Disc edema refers to swelling of the optic disc, and papilledema
tor of increased ICP, but vigorous crying can cause a protuberant specifically refers to swelling that is secondary to increased ICP. Pap-
fontanel in a normal infant. illedema rarely occurs in infancy because the skull sutures can separate
Inspection of the head should include observation of the venous to accommodate the expanding brain. In older children, papilledema
pattern, because increased ICP and thrombosis of the superior sagittal may be graded according to the Frisen scale (Fig. 590-2). Disc edema
sinus can produce marked venous distention. Dysmorphic facial fea- must be differentiated from papillitis, or inflammation of the optic
tures can indicate a neurodevelopmental aberration. Likewise, cutane- nerve. Both conditions manifest with enlargement of the blind spot,
ous abnormalities, such as cutis aplasia or abnormal hair whorls, can but visual acuity and color vision tend to be spared in early papill-
suggest an underlying brain malformation or genetic disorder. edema in contrast to what occurs in optic neuritis.
Palpation of a newborn’s skull characteristically reveals molding of Retinal hemorrhages occur in 30-40% of all full-term newborn
the skull accompanied by overriding sutures—a result of the pressures infants. The hemorrhages are more common after vaginal delivery than
exerted on the skull during its descent through the pelvis. Marked after Cesarean section and are not associated with birth injury or with
overriding of the sutures beyond the early neonatal period is cause for neurologic complications. They disappear spontaneously by 1-2 wk of
alarm, because it suggests an underlying brain abnormality. Palpation age. The presence of retinal hemorrhages beyond the early neonatal
additionally might reveal bony bridges between sutures (craniosynos- period should raise a concern for nonaccidental trauma.
tosis), cranial defects, or, in premature infants, softening of the parietal
bones (craniotabes). Vision
Auscultation of the skull is an important adjunct to the neurologic At 28 wk of corrected gestational age, a premature infant blinks in
examination. Cranial bruits may be noted over the anterior fontanel, response to a bright light, and at 32 wk, the infant maintains eye
temporal region, or orbits, and are best heard using the diaphragm of closure until the light source is removed. A normal 37 wk infant turns
the stethoscope. Soft symmetric bruits may be discovered in normal the head and eyes toward a soft light, and a term infant is able to fix
children younger than 4 yr of age or in association with a febrile illness. on and follow a target, such as the examiner’s face. Optokinetic nys-
Demonstration of a loud or localized bruit is usually significant and tagmus (OKN), which is conjugate nystagmus that occurs during
warrants further investigation, because they may be associated with attempted fixation on a series of rapidly moving objects, can also be
severe anemia, increased ICP, or arteriovenous malformations of the used as a crude assessment of the visual system in infants. OKN is
middle cerebral artery or vein of Galen. It is important to exclude elicited by moving an OKN tape—usually a strip of material with
murmurs arising from the heart or great vessels, because they may be alternating 2-inch black and white strips—across the patient’s visual
transmitted to the cranium. field. Although OKN responses can be tested monocularly in neonates,
they do not become symmetric until 4-6 mo of age.
Cranial Nerves Visual fields can be tested in an infant or young child by advancing
Olfactory Nerve (Cranial Nerve I) a brightly colored object from behind the patient’s head into the
Anosmia, loss of smell, most commonly occurs as a transient abnor- peripheral visual field and noting when the patient first looks at
mality in association with an upper respiratory tract infection or aller- the object. Suspension of the object by a string prevents the patient
gies. Permanent causes of anosmia include head trauma with damage from focusing on the examiner’s hand and arm. The examiner should
to the ethmoid bone or shearing of the olfactory nerve fibers as they be certain that the patient is responding to seeing, not hearing, the
cross the cribriform plate, tumors of the frontal lobe, intranasal drug object.
use, and exposure to toxins (acrylates, methacrylates, cadmium). Visual acuity in term infants approximates 20/150 and reaches the
Occasionally, a child who recovers from purulent meningitis or devel- adult level of 20/20 by about 6 mo of age. Children who are too young
ops hydrocephalus has a diminished sense of smell. Rarely, anosmia is to read the standard letters on a Snellen eye chart may learn the “E
congenital, in which case it can occur as an isolated deficit or as part game,” which entails pointing to indicate the direction that the E is
of Kallmann syndrome, a familial disorder characterized by hypogo- facing. Children as young as 2.5-3 yr of age can identify the objects on
nadotropic hypogonadism and congenital anosmia. Although not a a pediatric eye chart (Allen chart) at a distance of 15-20 ft.
routine component of the examination, smell can be tested reliably as The pupil reacts to light by 29-32 wk of corrected gestational age;
early as the 32nd wk of gestation by presenting a stimulus and observ- however, the pupillary response is often difficult to evaluate, because
ing for an alerting response, withdrawal, or both. Care should be taken premature infants resist eye opening and have poorly pigmented irises.
to use appropriate stimuli, such as coffee or peppermint, as opposed Pupillary size, symmetry, and reactivity may be affected by drugs,
to strongly aromatic substances (e.g., ammonia inhalants) that stimu- space-occupying brain lesions, metabolic disorders, and abnormalities
late the trigeminal nerve. Each nostril should be tested individually by of the optic nerves and midbrain. A small pupil may be seen as part of
pinching shut the opposite side. the Horner syndrome—characterized by ipsilateral ptosis (droopy
eyelid), miosis (constricted pupil), and anhidrosis (lack of sweating)
Optic Nerve (Cranial Nerve II) of the face. Horner syndrome may be congenital or may be caused
Assessment of the optic disc and retina is a critical component of the by a lesion of the sympathetic pathway in the hypothalamus, brain-
neurologic examination. Although the retina is best visualized by dilat- stem, cervical spinal cord, or sympathetic plexus. Localization of the
ing the pupil, most physicians do not have ready access to mydriatic lesion within the sympathetic nervous system may be obvious given
agents at the bedside; therefore, it may be necessary to consult an the other signs present or may be uncertain. In the latter case, serial
ophthalmologist in some cases. Mydriatics should not be administered testing with cocaine drops followed by hydroxyamphetamine drops
to patients whose pupillary responses are being followed as a marker may be helpful.
for impending herniation or to patients with cataracts. When mydriat- During the examination of the pupil, any abnormalities of the iris
ics are used, both eyes should be dilated, because unilateral papillary should also be noted (e.g., heterochromia, Brushfield spots). The physi-
fixation and dilation can cause confusion and worry in later examiners cian should also assess the posterior segment of the eye using the red
unaware of the pharmacologic intervention. Examination of an infant’s reflex test, which is performed in a darkened room using a direct
retina may be facilitated by providing a nipple or soother and by ophthalmoscope held close to the examiner’s eye and 12-18 inches
turning the head to one side. The physician gently strokes the patient from the infant’s eyes. If the posterior segment of the eye is normal,
to maintain arousal, while examining the closer eye. An older child the examiner should see symmetric reddish-pink retinal reflections.
should be placed in the parent’s lap and should be distracted by bright The absence of any red reflex or the presence of a blunted reflex, white
objects or toys. The color of the optic nerve is salmon-pink in a child reflex (leukocoria), or red reflex with dark spots all signal pathology
but may be gray-white in a newborn, particularly if the newborn has and should prompt referral to an ophthalmologist.
A B C
D E F
Figure 590-2 Stages of papilledema (Frisen scale). A, Stage 0: Normal optic disc. B, Stage 1: Very early papilledema with obscuration of the
nasal border of the disc only, without elevation of the disc borders. C, Stage 2: Early papilledema showing obscuration of all borders, elevation
of the nasal border, and a complete peripapillary halo. D, Stage 3: Moderate papilledema with elevation of all borders, increased diameter of the
optic nerve head, obscuration of vessels at the disc margin, and a peripapillary halo with finger-like extensions. E, Stage 4: Marked papilledema
characterized by elevation of the entire nerve head and total obscuration a segment of a major blood vessel on the disc. F, Stage 5: Severe
papilledema with obscuration of all vessels and obliteration of the optic cup. Note also the nerve fiber layer hemorrhages and macular exudate.
(A-C courtesy Dr. Deborah Friedman; D-F courtesy Flaum Eye Institute, University of Rochester.)
Oculomotor (Cranial Nerve III), Trochlear (Cranial globe during activities such as reading and walking downstairs. Patients
Nerve IV), and Abducens Nerves (Cranial Nerve VI) with an isolated paralysis of the trochlear nerve often have a compensa-
The globe is moved by 6 extraocular muscles, which are innervated by tory head tilt away from the affected side, which helps to alleviate their
the oculomotor, trochlear, and abducens nerves. These muscles and diplopia. The abducens nerve innervates the lateral rectus muscle; its
nerves can be assessed by having the patient follow an interesting toy paralysis causes medial deviation of the eye with an inability to abduct
or the examiner’s finger in the 6 cardinal directions of gaze. The physi- beyond the midline. Patients with increased ICP often respond posi-
cian observes the range and nature (conjugate vs dysconjugate, smooth tively when questioned about double vision (diplopia) and exhibit
vs choppy or saccadic) of the eye movements, particularly noting the incomplete abduction of the eyes on lateral gaze as a result of partial
presence and direction of any abnormal eye movements. Premature VIth nerve palsies. This false-localizing sign occurs because CN VI has
infants older than 25 wk of gestational age and comatose patients can a long intracranial course, making it particularly susceptible to being
be evaluated using the oculocephalic (doll’s eye) maneuver, in which stretched. Internuclear ophthalmoplegia, caused by a lesion in the
the patient’s head is quickly rotated to evoke reflex eye movements. If medial longitudinal fasciculus of the brainstem, that functionally
the brainstem is intact, rotating the patient’s head to the right causes serves conjugate gaze by connecting CN VI on one side to CN III on
the eyes to move to the left and vice versa. Similarly, rapid flexion and the other, results in paralysis of medial rectus function in the adducting
extension of the head elicits vertical eye movement. eye and nystagmus in the abducting eye.
Disconjugate gaze can result from extraocular muscle weakness; When there is a subtle eye movement abnormality, the red glass test
cranial nerve (CN) III, IV, or VI palsies; or brainstem lesions that may be helpful in localizing the lesion. To perform this test, a red glass
disrupt the medial longitudinal fasciculus. Infants who are younger is placed over one of the patient’s eyes and the patient is instructed to
than 2 mo old can have slightly disconjugate gaze at rest, with 1 eye follow a white light in all directions of gaze. The child sees 1 red/white
horizontally displaced from the other by 1 or 2 mm (strabismus). light in the direction of normal muscle function but notes a separation
Vertical displacement of the eyes requires investigation, as it can indi- of the red and white images that is greatest in the plane of action of
cate trochlear nerve (CN IV) palsy or skew deviation (supranuclear the affected muscle.
ocular malalignment that is often associated with lesions of the poste- In addition to gaze palsies, the examiner might encounter a variety
rior fossa). Strabismus is discussed further in Chapter 623. of adventitious movements. Nystagmus is an involuntary, rapid move-
The oculomotor nerve innervates the superior, inferior, and medial ment of the eye that may be subclassified as being pendular, in which
recti, as well as the inferior oblique and the levator palpebrae superioris the 2 phases have equal amplitude and velocity, or jerk, in which there
muscles. Complete paralysis of the oculomotor nerve causes ptosis, is a fast and slow phase. Jerk nystagmus can be further characterized
dilation of the pupil, displacement of the eye outward and downward, by the direction of its fast phase, which may be left-, right-, up-, or
and impairment of adduction and elevation. The trochlear nerve sup- downbeating; rotatory; or mixed. Many patients have a few beats of
plies the superior oblique muscle, which depresses and intorts the nystagmus with extreme lateral gaze (end-gaze nystagmus), which is
of no consequence. Pathologic horizontal nystagmus is most often unobstructed. In an obtunded or comatose patient, 30-50 mL of ice
congenital, drug-induced (e.g., alcohol, anticonvulsants), or a result of water is then delivered by syringe into the external auditory canal with
vestibular system dysfunction. By contrast, vertical nystagmus is often the patient’s head elevated 30 degrees. If the brainstem is intact, the
associated with structural abnormalities of the brainstem and cerebel- eyes deviate toward the irrigated side. A much smaller quantity of ice
lum. Ocular bobbing is characterized by a downward jerk followed by water (2 mL) is used in awake, alert patients to avoid inducing nausea.
a slow drift back to primary position and is associated with pontine In normal subjects, introduction of ice water produces eye deviation
lesions. Opsoclonus describes involuntary, chaotic oscillations of the toward the stimulated labyrinth followed by nystagmus with the fast
eyes, which are often seen in the setting of neuroblastoma or viral component away from the stimulated labyrinth.
infection. Because hearing is integral to normal language development, the
physician should inquire directly about hearing problems. Parents’
Trigeminal Nerve (Cranial Nerve V) concern is often a reliable indicator of hearing impairment and war-
The 3 divisions of the trigeminal nerve—ophthalmic, maxillary, and rants a formal audiologic assessment with either audiometry or brain-
mandibular—convey information about facial protopathic (pain, tem- stem auditory evoked potential testing (see Chapter 637). Even in the
perature) and epicritic (vibration, proprioception) sensation. Each absence of parents’ concern, certain children warrant formal testing
modality should be tested and compared to the contralateral side. In within the 1st mo of life, including those with a family history of early
patients who are uncooperative or comatose, the integrity of the tri- life or syndromic deafness or a personal history of prematurity, severe
geminal nerve can be assessed by the corneal reflex, elicited by touch- asphyxia, exposure to ototoxic drugs, hyperbilirubinemia, congenital
ing the cornea with a small pledget of cotton and observing for anomalies of the head or neck, bacterial meningitis, and congenital
symmetric eye closure, and nasal tickle, obtained by stimulating the TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus,
nasal passage with a cotton swab and observing for symmetric grimace. herpes simplex virus) infections. For all other infants and children, a
An absent reflex may be because of a sensory defect (trigeminal nerve) simple bedside assessment of hearing is usually sufficient. Newborns
or a motor deficit (facial nerve). The motor division of the trigeminal might have subtle responses to auditory stimuli, such as changes in
nerve can be tested by examining the masseter, pterygoid, and tempo- breathing, cessation of movement, or opening of the eyes and/or
ralis muscles during mastication, as well as by evaluation of the mouth. If the same stimulus is presented repeatedly, normal neonates
jaw jerk. cease to respond, a phenomenon known as habituation. By 3-4 mo of
age, infants begin to orient to the source of sound. Hearing-impaired
Facial Nerve (Cranial Nerve VII) toddlers are visually alert and appropriately responsive to physical
The facial nerve is a predominantly motor nerve that innervates the stimuli but might have more frequent temper tantrums and abnormal
muscles of facial expression, buccinator, platysma, stapedius, stylohy- speech and language development.
oid, and posterior belly of the digastric. It also has a separate division,
called the chorda tympani, that contains sensory, special sensory Glossopharyngeal Nerve (Cranial Nerve IX)
(taste), and parasympathetic fibers. Because the portion of the facial The glossopharyngeal nerve conveys motor fibers to the stylopharyn-
nucleus that innervates the upper face receives bilateral cortical input, geus muscle; general sensory fibers from the posterior third of the
lesions of the motor cortex or corticobulbar tract have little effect on tongue, pharynx, tonsil, internal surface of the tympanic membrane,
upper face strength. Rather, such lesions manifest with flattening of the and skin of the external ear; special sensory (taste) fibers from the
contralateral nasolabial fold or drooping of the corner of the mouth. posterior third of the tongue; parasympathetic fibers to the parotid
Conversely, lower motor neuron or facial nerve lesions tend to involve gland; and general visceral sensory fibers from the carotid bodies.
upper and lower facial muscles equally. Facial strength can be evaluated The nerve is tested by stimulating 1 side of the lateral oropharynx
by observing the patient’s spontaneous movements and by asking the or soft palate with a tongue blade and observing for symmetric eleva-
patient to mimic a series of facial movements (e.g., smiling, raising the tion of the palate (gag reflex). An isolated lesion of CN IX is rare,
eyebrows, inflating the cheeks). A facial nerve palsy may be congenital; because it runs in close proximity to CN X. Potential causes of injury
idiopathic (Bell palsy); or secondary to trauma, demyelination (Guil- and/or dysfunction include birth trauma, ischemia, mass lesions,
lain-Barré syndrome), infection (Lyme disease, herpes simplex virus, motor neuron disease, retropharyngeal abscess, and Guillain-Barré
HIV), granulomatous disease, neoplasm, or meningeal inflammation syndrome.
or infiltration. Facial nerve lesions that are proximal to the junction
with the chorda tympani will result in an inability to taste substances Vagus Nerve (Cranial Nerve X)
with the anterior two-thirds of the tongue. If necessary, taste can be The vagus nerve has 10 terminal branches: meningeal, auricular, pha-
tested by placing a solution of saline or glucose on 1 side of the ryngeal, carotid body, superior laryngeal, recurrent laryngeal, cardiac,
extended tongue. Normal children can identify the test substance in pulmonary, esophageal, and gastrointestinal. The pharyngeal, superior
<10 sec. Other findings that may be associated with facial nerve palsy laryngeal, and recurrent laryngeal branches contain motor fibers that
include hyperacusis, resulting from stapedius muscle involvement, and innervate all of the muscles of the pharynx and larynx, with the excep-
impaired tearing. tion of the stylopharyngeus (CN IX) and tensor veli palatini (CN V)
muscles. Thus, unilateral injury of the vagus nerve results in weakness
Vestibulocochlear Nerve (Cranial Nerve VIII) of the ipsilateral soft palate and a hoarse voice; bilateral lesions can
The vestibulocochlear nerve has 2 components within a single trunk: produce respiratory distress as a result of vocal cord paralysis, as well
the vestibular nerve, which innervates the semicircular canals of the as nasal regurgitation of fluids, pooling of secretions, and an immobile,
inner ear and is involved with equilibrium, coordination, and orienta- low-lying soft palate. Isolated lesions to the vagus nerve may be a
tion in space, and the cochlear nerve, which innervates the cochlea and complication of thoracotomies or may be seen in neonates with type
subserves hearing. II Chiari malformations. If such a lesion is suspected, it is important
Dysfunction of the vestibular system results in vertigo, the sensation to visualize the vocal cords. In addition to motor information, the
of environmental motion. On examination, patients with vestibular vagus nerve carries somatic afferents from the pharynx, larynx, ear
nerve dysfunction typically have nystagmus, in which the fast compo- canal, external surface of the tympanic membrane, and meninges of
nent is directed away from the affected nerve. With their arms out- the posterior fossa; visceral afferents; taste fibers from the posterior
stretched and eyes closed, their limbs tend to drift toward the injured pharynx; and preganglionic parasympathetics.
side. Likewise, if they march in place, they slowly pivot toward the
lesion (Fukuda stepping test). On Romberg and tandem gait testing, Accessory Nerve (Cranial Nerve XI)
they tend to fall toward the abnormal ear. Vestibular function can be The accessory nerve innervates the sternocleidomastoid (SCM) and
further evaluated with caloric testing. Before testing, the tympanic trapezius muscles. The left SCM acts to turn the head to the right side
membrane should be visualized to ensure that it is intact and and vice versa; acting together, the SCMs flex the neck. The trapezius
acts to elevate the shoulder. Lesions to the accessory nerve result in that has been replaced by fat and connective tissue, giving it a bulky
atrophy and paralysis of the ipsilateral SCM and trapezius muscles, appearance with a paradoxical reduction in strength, as in Duchenne
with resultant depression of the shoulder. Because several cervical muscular dystrophy.
muscles are involved in head rotation, unilateral SCM paresis might
not be evident unless the patient is asked to rotate the head against Tone
resistance. Skull base fractures or lesions, motor neuron disease, myo- Muscle tone, which is generated by an unconscious, continuous, partial
tonic dystrophy, and myasthenia gravis commonly produce atrophy contraction of muscle, creates resistance to passive movement of a
and weakness of these muscles; congenital torticollis is associated with joint. Tone varies greatly based on a patient’s age and state. At 28 wk
SCM hypertrophy. of gestation, all 4 extremities are extended and there is little resistance
to passive movement. Flexor tone is visible in the lower extremities at
Hypoglossal Nerve (Cranial Nerve XII) 32 wk and is palpable in the upper extremities at 36 wk; a normal-term
The hypoglossal nerve innervates the tongue. Examination of the infant’s posture is characterized by flexion of all 4 extremities.
tongue includes assessment of its bulk and strength, as well as observa- There are 3 key tests for assessing postural tone in neonates: the
tion for adventitious movements. Malfunction of the hypoglossal traction response, vertical suspension, and horizontal suspension (Fig.
nucleus or nerve produces atrophy, weakness, and fasciculations of the 590-3; see Chapters 94 and 97). To evaluate the traction response, the
tongue. If the injury is unilateral, the tongue deviates toward the side physician grasps the infant’s hands and gently pulls the infant to a
of the injury; if it is bilateral, tongue protrusion is not possible and the sitting position. Normally, the infant’s head lags slightly behind the
patient can have difficulty swallowing (dysphagia). Werdnig-Hoffmann infant’s body and then falls forward upon reaching the sitting position.
disease (infantile spinal muscular atrophy, or spinal muscular atrophy To test vertical suspension, the physician holds the infant by the
type 1) and congenital anomalies in the region of the foramen magnum axillae without gripping the thorax. The infant should remain sus-
are the principal causes of hypoglossal nerve dysfunction. pended with the infant’s lower extremities held in flexion; a hypotonic
infant will slip through the physician’s hands. With horizontal suspen-
Motor Examination sion, the physician holds the infant prone by placing a hand under the
The motor examination includes assessment of muscle bulk, tone, and infant’s abdomen. The head should rise and the limbs should flex, but
strength, as well as observation for involuntary movements that might a hypotonic infant will drape over the physician’s hand, forming a U
indicate central or peripheral nervous system pathology. shape. Assessing tone in the extremities is accomplished by observing
the infant’s resting position and passively manipulating the infant’s
Bulk limbs. When the upper extremity of a normal-term infant is pulled
Decreased muscle bulk (atrophy) may be secondary to disuse or to gently across the chest, the elbow does not quite reach the mid-sternum
diseases of the lower motor neuron, nerve root, peripheral nerve, or (scarf sign), whereas the elbow of a hypotonic infant extends beyond
muscle. In most cases, neurogenic atrophy is more severe than myo- the midline with ease. Measurement of the popliteal angle is a useful
genic atrophy. Increased muscle bulk (hypertrophy) is usually physi- method for documenting tone in the lower extremities. The examiner
ologic (e.g., body builders). Pseudohypertrophy refers to muscle tissue flexes the hip and extends the knee. Normal-term infants allow
A B
C D
Figure 590-3 Normal tone in a full-term neonate. A, Flexed resting posture. B, Traction response. C, Vertical suspension. D, Horizontal
suspension.
extension of the knee to approximately 80 degrees. Similarly, tone can floppy and often assumes a frog-leg posture at rest. Hypotonia can
be evaluated by flexing the hip and knee to 90 degrees and then inter- reflect pathology of the cerebral hemispheres, cerebellum, spinal cord,
nally rotating the leg, in which case the heel should not pass the anterior horn cell, peripheral nerve, neuromuscular junction, or
umbilicus. muscle.
Abnormalities of tone include spasticity, rigidity, and hypotonia.
(Paratonia, which is rarely seen in the pediatric population, is not Strength
discussed here.) Spasticity is characterized by an initial resistance to Older children are usually able to cooperate with formal strength
passive movement, followed by a sudden release, referred to as the testing, in which case muscle power is graded on a scale of 0-5 as
clasp-knife phenomenon. Because spasticity results from upper motor follows: 0 = no contraction; 1 = flicker or trace of contraction; 2 = active
neuron dysfunction, it disproportionately affects the upper-extremity movement with gravity eliminated; 3 = active movement against
flexors and lower-extremity extensors and tends to occur in conjunc- gravity; 4 = active movement against gravity and resistance; 5 = normal
tion with disuse atrophy, hyperactive deep tendon reflexes, and exten- power. An examination of muscle power should include all muscle
sor plantar reflexes (Babinski sign). In infants, spasticity of the lower groups, including the neck flexors and extensors and the muscles of
extremities results in scissoring of the legs upon vertical suspension. respiration. It is important not only to assess individual muscle groups,
Older children can present with prolonged commando crawling or but also to determine the pattern of weakness (i.e., proximal vs distal;
toe-walking. Rigidity, seen with lesions of the basal ganglia, is charac- segmental vs regional). Testing for pronator drift can be helpful in
terized by resistance to passive movement that is equal in the flexors localizing the lesion in a patient with weakness. This test is accom-
and extensors regardless of the velocity of movement (lead pipe). plished by having the patient extend his or her arms away from the
Patients with either spasticity or rigidity might exhibit opisthotonos, body with the palms facing upward and the eyes closed. Together,
defined as severe hyperextension of the spine caused by hypertonia of pronation and downward drift of an arm indicate a lesion of the contra-
the paraspinal muscles (Fig. 590-4), although similar posturing can be lateral corticospinal tract.
seen in patients with Sandifer syndrome (gastroesophageal reflux or Because infants and young children are not able to participate in
hiatal hernia associated with torsional dystonia). Hypotonia refers to formal strength testing, they are best assessed with functional mea-
abnormally diminished tone and is the most common abnormality of sures. Proximal and distal strength of the upper extremities can be
tone in neurologically compromised neonates. A hypotonic infant is tested by having the child reach overhead for a toy and by watching
the child manipulate small objects. In infants younger than 2 mo old,
the physician can also take advantage of the palmar grasp reflex in
assessing distal power and the Moro reflex in assessing proximal power.
Infants with decreased strength in the lower extremities tend to have
diminished spontaneous activity in their legs and are unable to support
their body weight when held upright. Older children may have diffi-
culty climbing or descending steps, jumping, or hopping. They might
also use their hands to “climb up” their legs when asked to rise from a
prone position, a maneuver called Gowers sign (Fig. 590-5).
Involuntary Movements
Patients with lower motor neuron or peripheral nervous system lesions
might have fasciculations, which are small, involuntary muscle con-
tractions that result from the spontaneous discharge of a single motor
unit and create the illusion of a “bag of worms” under the skin. Because
most infants have abundant body fat, muscle fasciculations are best
observed in the tongue in this age group.
Most other involuntary movements, including tics, dystonia, chorea,
Figure 590-4 Opisthotonus in a brain-injured infant. and athetosis, stem from disorders of the basal ganglia. Tremor seems
A B C D
Figure 590-5 A-D, Gowers sign in a boy with hip girdle weakness because of Duchenne muscular dystrophy. When asked to rise from a prone
position, the patient uses his hands to walk up his legs to compensate for proximal lower-extremity weakness.
Table 590-2 Timing of Selected Primitive Reflexes

REFLEX ONSET FULLY DEVELOPED DURATION
Palmar grasp 28 wk gestation 32 wk gestation 2-3 mo postnatal
Rooting 32 wk gestation 36 wk gestation Less prominent after 1 mo postnatal
Moro 28-32 wk gestation 37 wk gestation 5-6 mo postnatal
Tonic neck 35 wk gestation 1 mo postnatal 6-7 mo postnatal
Parachute 7-8 mo postnatal 10-11 mo postnatal Remains throughout life
to be an exception, as it is thought to be mediated by cerebellothala- because they are mediated by several competing reflexes and can be
mocortical pathways. Further detail on the individual movement dis- either flexor or extensor, depending on how the foot is positioned.
orders is provided in Chapter 597. Asymmetry of the reflexes or plantar response is a useful lateralizing
sign in infants and children.
Sensory Examination
The sensory examination is difficult to perform on an infant or unco- Primitive Reflexes
operative child and has a relatively low yield in terms of the informa- Primitive reflexes appear and disappear at specific times during devel-
tion that it provides. A gross assessment of sensory function can be opment (Table 590-2), and their absence or persistence beyond those
achieved by distracting the patient with an interesting toy and then times signifies CNS dysfunction. Although many primitive reflexes
touching the patient with a cotton swab in different locations. Normal have been described, the Moro, grasp, tonic neck, and parachute
infants and children indicate an awareness of the stimulus by crying, reflexes are the most clinically relevant. The Moro reflex is elicited by
withdrawing the extremity, or pausing briefly; however, with repeated supporting the infant in a semierect position and then allowing the
testing, they lose interest in the stimulus and begin to ignore the exam- infant’s head to fall backwards onto the examiner’s hand. A normal
iner. It is critical, therefore, that any areas of concern are tested effi- response consists of symmetric extension and abduction of the fingers
ciently and, if necessary, reexamined at an appropriate time. and upper extremities, followed by flexion of the upper extremities and
Fortunately, isolated disorders of the sensory system are less common an audible cry. An asymmetric response can signify a fractured clavicle,
in the very young pediatric population than in the adult population, so brachial plexus injury, or hemiparesis. Absence of the Moro reflex in a
detailed sensory testing is rarely warranted. Furthermore, most patients term newborn is ominous, suggesting significant dysfunction of the
who are old enough to voice a sensory complaint are also old enough to CNS. The grasp response is elicited by placing a finger in the open
cooperate with formal testing of light touch, pain, temperature, vibra- palm of each hand; by 37 wk of gestation, the reflex is strong enough
tion, proprioception, and corticosensation (e.g., stereognosis, 2-point that the examiner can lift the infant from the bed with gentle traction.
discrimination, extinction to double simultaneous stimulation). A The tonic neck reflex is produced by manually rotating the infant’s
notable exception is when the physician suspects a spinal cord lesion in head to 1 side and observing for the characteristic fencing posture
an infant or young child and needs to identify a sensory level. In such (extension of the arm on the side to which the face is rotated and
situations, observation might suggest a difference in color, temperature, flexion of the contralateral arm). An obligatory tonic neck response, in
or perspiration, with the skin cool and dry below the level of injury. which the infant becomes “stuck” in the fencing posture, is always
Lightly touching the skin above the level can evoke a squirming move- abnormal and implies a CNS disorder. The parachute reflex, which
ment or physical withdrawal. Other signs of spinal cord injury include occurs in slightly older infants, can be evoked by holding the infant’s
decreased anal sphincter tone and strength and absence of the superfi- trunk and then suddenly lowering the infant as if he or she were falling.
cial abdominal, anal wink, and cremasteric reflexes. The arms will spontaneously extend to break the infant’s fall, making
this reflex a prerequisite to walking.
Reflexes
Deep Tendon Reflexes and the Plantar Response Coordination
Deep tendon reflexes are readily elicited in most infants and children. Ataxia refers to a disturbance in the smooth performance of voluntary
In infants, it is important to position the head in the midline when motor acts and is usually the result of cerebellar dysfunction. Lesions
assessing reflexes, because turning the head to 1 side can alter reflex to the cerebellar vermis result in unsteadiness while sitting or standing
tone. Reflexes are graded from 0 (absent) to 4+ (markedly hyperactive), (truncal ataxia). Affected patients might have a wide-based gait or
with 2+ being normal. Reflexes that are 1+ or 3+ can be normal as may be unable to perform tandem gait testing. Lesions of the cerebellar
long as they are symmetrical. Sustained clonus is always pathologic, hemispheres cause appendicular ataxia, which may be apparent as the
but infants younger than 3 mo old can have 5-10 beats of clonus, patient reaches for objects and performs finger-to-nose and heel-to-
and older children can have 1-2 beats of clonus, provided that it is shin movements. Other features of cerebellar dysfunction include
symmetrical. errors in judging distance (dysmetria), inability to inhibit a muscular
The ankle jerk is hardest to elicit, but it can usually be obtained by action (rebound), impaired performance of rapid alternating move-
passively dorsiflexing the foot and then tapping on either the Achilles ments (dysdiadochokinesia), intention tremor, nystagmus, scanning
tendon or the ball of the foot. The knee jerk is evoked by tapping the dysarthria, hypotonia, and decreased deep tendon reflexes. Acute
patellar tendon. If this reflex is exaggerated, extension of the knee may ataxia suggests an infectious or postinfectious, endocrinologic, toxic,
be accompanied by contraction of the contralateral adductors (crossed traumatic, vascular, or psychogenic process, and chronic symptoms
adductor response). Hypoactive reflexes reflect lower motor neuron suggest a metabolic, neoplastic, or degenerative process.
or cerebellar dysfunction, whereas hyperactive reflexes are consistent
with upper motor neuron disease. The plantar response is obtained by Station and Gait
stimulation of the lateral aspect of the sole of the foot, beginning at the Observation of a child’s station and gait is an important aspect of the
heel and extending to the base of the toes. The Babinski sign, indicat- neurologic examination. Normal children can stand with their feet
ing an upper motor neuron lesion, is characterized by extension of the close together without swaying; however, children who are unsteady
great toe and fanning of the remaining toes. Too vigorous stimulation may sway or even fall. On gait testing, the heels should strike either
may produce withdrawal, which may be misinterpreted as a Babinski side of an imaginary line, but children with poor balance tend to walk
sign. Plantar responses have limited diagnostic utility in neonates, with their legs farther apart to create a more stable base. Tandem gait
testing forces patients to have a narrow base, which highlights subtle opening pressures are 90-120 mm H2O in newborns, 60-180 mm H2O
balance difficulties. in young children, and 12-120 mm H2O in older children and adults.
There are a variety of abnormal gaits, many of which are associated The 90th percentile in children has been reported to be 250 mm of
with a specific underlying etiology. Patients with a spastic gait appear H2O. The most common cause of an elevated opening pressure is an
stiff-legged like a soldier. They may walk on tiptoe as a result of tight- agitated patient. Sedation and high body mass index can also increase
ness or contractures of the Achilles tendons, and their legs may scissor the opening pressure.
as they walk. A hemiparetic gait is associated with spasticity and cir- Contraindications to performing a lumbar puncture include sus-
cumduction of the leg, as well as decreased arm swing on the affected pected mass lesion of the brain, especially in the posterior fossa or
side. Cerebellar ataxia results in a wide-based, reeling gait like a drunk above the tentorium and causing shift of the midline; suspected mass
person, whereas sensory ataxia results in a wide-based steppage gait, lesion of the spinal cord; symptoms and signs of impending cerebral
in which the patient lifts the legs up higher than usual in the swing herniation in a child with probable meningitis; critical illness (on rare
phase and then slaps the foot down. A myopathic, or waddling, gait is occasions); skin infection at the site of the lumbar puncture; and
associated with hip girdle weakness. Affected children often develop a thrombocytopenia with a platelet count <20 × 109/L. If disc edema or
compensatory lordosis and have other signs of proximal muscle weak- focal findings suggest a mass lesion, a head CT should be obtained
ness, such as difficulty climbing stairs. During gait testing, the exam- before proceeding with lumbar puncture to prevent uncal or cerebellar
iner might also note hypotonia or weakness of the lower extremities; herniation as the CSF is removed. In the absence of these findings,
extrapyramidal movements, such as dystonia or chorea; or orthopedic routine head imaging is not warranted. The physician should also be
deformities, such as pelvic tilt, genu recurvatum, varus or valgus defor- alert to clinical signs of impending herniation, including alterations in
mities of the knee, pes cavus (high arches) or pes planus (flat feet), and the respiratory pattern (e.g., hyperventilation; Cheyne-Stokes respira-
scoliosis. tions, ataxic respirations, respiratory arrest), abnormalities of pupil size
and reactivity, loss of brainstem reflexes, and decorticate or decerebrate
GENERAL EXAMINATION posturing. If any of these signs are present or the child is so ill that the
Examination of other organ systems is essential because myriad sys- lumbar puncture might induce cardiorespiratory arrest, blood cultures
temic diseases affect the nervous system. Dysmorphic features can should be drawn and supportive care, including antibiotics, should be
indicate a genetic syndrome (see Chapter 108). Heart murmurs may initiated. Once the patient has stabilized, it may be possible to perform
be associated with rheumatic fever (Sydenham chorea), cardiac rhab- a lumbar puncture safely.
domyoma (tuberous sclerosis), cyanotic heart disease (cerebral abscess Normal CSF contains up to 5/mm3 white blood cells, and a newborn
or thrombosis), and endocarditis (cerebral vascular occlusion). Hepa- can have as many as 15/mm3. Polymorphonuclear cells are always
tosplenomegaly can suggest an inborn error of metabolism, storage abnormal in a child, but 1-2/mm3 may be present in a normal neonate.
disease, HIV, or malignancy. Cutaneous lesions may be a feature of a An elevated polymorphonuclear count suggests bacterial meningitis or
neurocutaneous syndrome (see Chapter 596). the early phase of aseptic meningitis (see Chapter 603). CSF lympho-
cytosis can be seen in aseptic, tuberculous, or fungal meningitis; demy-
SPECIAL DIAGNOSTIC PROCEDURES elinating diseases; brain or spinal cord tumor; immunologic disorders,
Lumbar Puncture and Cerebrospinal including collagen vascular diseases; and chemical irritation (following
Fluid Examination myelogram, intrathecal methotrexate).
Examination of the cerebrospinal fluid (CSF) and measurement of the Normal CSF contains no red blood cells; thus, their presence indi-
pressure it creates in the subarachnoid space are essential in confirm- cates a traumatic tap or a subarachnoid hemorrhage. Progressive clear-
ing the diagnosis of meningitis, encephalitis, and idiopathic intracra- ing of the blood between the first and last samples indicates a traumatic
nial hypertension (previously referred to as pseudotumor cerebri), and tap. Bloody CSF should be centrifuged immediately. A clear superna-
it is often helpful in assessing subarachnoid hemorrhage; demyelinat- tant is consistent with a bloody tap, whereas xanthochromia (yellow
ing, degenerative, and collagen vascular diseases; and intracranial neo- color that results from the degradation of hemoglobin) suggests a sub-
plasms. Having an experienced assistant who can position, restrain, arachnoid hemorrhage. Xanthochromia may be absent in bleeds <12 hr
and comfort the patient is critical to the success of the procedure. old, particularly when laboratories rely on visual inspection rather than
The patient should be situated in a lateral decubitus or seated posi- spectroscopy. Xanthochromia can also occur in the setting of hyper-
tion with the neck and legs flexed to enlarge the intervertebral spaces. bilirubinemia, carotenemia, and markedly elevated CSF protein.
As a rule, sick neonates should be maintained in a seated position to The normal CSF protein is 10-40 mg/dL in a child and as high as
prevent problems with ventilation and perfusion. Regardless of the 120 mg/dL in a neonate. The CSF protein falls to the normal childhood
position chosen, it is important to make sure that the patient’s shoul- range by 3 mo of age. The CSF protein may be elevated in many pro-
ders and hips are straight to prevent rotating the spine. cesses, including infectious, immunologic, vascular, and degenerative
Once the patient is situated, the physician identifies the appropriate diseases, blockage of CSF flow, as well as tumors of the brain (primary
interspace by drawing an imaginary line from the iliac crest downward CNS tumors, systemic tumors metastatic to the CNS, infiltrative acute
perpendicular to the vertebral column. In adults, lumbar punctures are lymphoblastic leukemia) and spinal cord. With a traumatic tap, the
usually performed in the L3-L4 or L4-L5 interspaces. Next, the physi- CSF protein is increased by approximately 1 mg/dL for every 1,000 red
cian dons a mask, gown, and sterile gloves. The skin is thoroughly blood cells/mm3. Elevation of CSF immunoglobulin G, which nor-
prepared with a cleansing agent, and sterile drapes are applied. The skin mally represents approximately 10% of the total protein, is observed in
and underlying tissues are anesthetized by injecting a local anesthetic subacute sclerosing panencephalitis, in postinfectious encephalomyeli-
(e.g., 1% lidocaine) at the time of the procedure or by applying a eutec- tis, and in some cases of multiple sclerosis. If the diagnosis of multiple
tic mixture of lidocaine and prilocaine (EMLA) to the skin 30 minutes sclerosis is suspected, the CSF should be tested for the presence of
before the procedure. A 22-gauge, 1.5-3.0 in, sharp, beveled spinal oligoclonal bands.
needle with a properly fitting stylet is introduced in the midsagittal The CSF glucose content is approximately 60% of the blood glucose
plane and directed slightly cephalad. The physician should pause fre- in a healthy child. To prevent a spuriously elevated blood:CSF glucose
quently, remove the stylet, and assess for CSF flow. Although a pop can ratio in a case of suspected meningitis, it is advisable to collect the
occur as the needle penetrates the dura, it is more common to experi- blood glucose before the lumbar puncture when the child is relatively
ence a subtle change in resistance. calm. Hypoglycorrhachia is found in association with diffuse menin-
Once CSF has been detected, a manometer and 3-way stopcock can geal disease, particularly bacterial and tubercular meningitis. Wide-
be attached to the spinal needle to obtain an opening pressure. If the spread neoplastic involvement of the meninges, subarachnoid
patient was seated as the spinal needle was introduced, the patient hemorrhage, disorders involving the glucose transporter protein type
should be moved carefully to a lateral decubitus position with the 1, fungal meningitis, and, occasionally, aseptic meningitis can produce
head and legs extended before the manometer is attached. Normal low CSF glucose as well.
A Gram stain of the CSF is essential if there is a suspicion for bacte- child in the acute setting. MRI can be used to evaluate for congenital
rial meningitis; an acid-fast stain and India ink preparation can be used or acquired brain lesions, migrational defects, dysmyelination or
to assess for tuberculous and fungal meningitis, respectively. CSF is demyelination, posttraumatic gliosis, neoplasms, cerebral edema, and
then plated on different culture media depending on the suspected acute stroke (see Table 590-3). Paramagnetic MR contrast agents (e.g.,
pathogen. When indicated by the clinical presentation, it can also be gadolinium-diethylenetriaminepentaacetic acid [DTPA]) are effica-
helpful to assess for the presence of specific antigens (e.g., latex agglu- cious in identifying areas of disruption in the blood–brain barrier, such
tination for Neisseria meningitidis, Haemophilus influenzae type b, or as those occurring in primary and metastatic brain tumors, meningitis,
Streptococcus pneumoniae) or to obtain antibody or polymerase chain cerebritis, abscesses, and active demyelination. MR angiography and
reaction studies (e.g., herpes simplex virus-1 and -2, West Nile virus, MR venography provide detailed images of major intracranial vascu-
enteroviruses). In noninfectious cases, levels of CSF metabolites, such lature structures and assist in the diagnosis of conditions such as
as lactate, amino acids, and enolase, can provide clues to the underlying stroke, vascular malformations, and cerebral venous sinus thrombosis.
metabolic disease. MR angiography is the procedure of choice for infants and young
children owing to the lack of ionizing radiation and contrast; however,
Neuroradiologic Procedures CT angiography may be preferable in older children because it is faster
Skull roentgenograms have limited diagnostic utility. They can dem- and can eliminate the need for sedation; it is particularly useful for
onstrate fractures, bony defects, intracranial calcifications, or indirect looking at blood vessels in the neck, where there is less interference
evidence of increased ICP. Acutely increased ICP causes separation of from bone artifact than in the skull-encased brain.
the sutures, whereas chronically increased ICP is associated with Functional MRI is a noninvasive technique used to map neuronal
erosion of the posterior clinoid processes, enlargement of the sella activity during specific cognitive states and/or sensorimotor functions.
turcica, and increased convolutional markings. Data are usually based on blood oxygenation, although they can also
Cranial ultrasonography is the imaging method of choice for be based on local cerebral blood volume or flow. Functional MRI is
detecting intracranial hemorrhage, periventricular leukomalacia, and useful for presurgical localization of critical brain functions and has
hydrocephalus in infants with patent anterior fontanels. Ultrasound is several advantages over other functional imaging techniques. Specifi-
less sensitive than either CT or MRI for detecting hypoxic–ischemic cally, functional MRI produces high-resolution images without expo-
injury, but the use of color Doppler or power Doppler sonography, sure to ionizing radiation or contrast, and it allows coregistration of
both of which show changes in regional cerebral blood flow, improve functional and structural images.
its sensitivity. In general, ultrasound is not a useful technique in older Proton MR spectroscopy (MRS) is a molecular imaging technique
children, although it can be helpful intraoperatively when placing in which the unique neurochemical profile of a preselected brain
shunts, locating small tumors, and performing needle biopsies. region is displayed in the form of a spectrum. Many metabolites can
CT is a valuable diagnostic tool in the evaluation of many neurologic be detected, the most common of which are N-acetylaspartate, creatine
emergencies, as well as some nonemergent conditions. It is a noninva- and phosphocreatine, choline, myoinositol, and lactate. Changes in
sive, rapid procedure that can usually be performed without sedation. the spectral pattern of a given area can yield clues to the underlying
CT scans use conventional x-ray techniques, meaning that they pathology, making MRS useful in the diagnosis of inborn errors
produce ionizing radiation. Because children younger than 10 yr of age of metabolism, as well as the preoperative and posttherapeutic assess-
are several times more sensitive to radiation than adults, it is important ment of intracranial tumors. MRS can also detect areas of cortical
to consider the whether imaging is actually indicated and, if it is, dysplasia in patients with epilepsy, because these patients have low
whether an ultrasound or MRI might be the more appropriate study. N-acetylaspartate:creatine ratios. Finally, MRS may be useful in detect-
In the emergency setting, a noncontrast CT scan can demonstrate skull ing hypoxic–ischemic injury in newborns in the 1st day of life, because
fractures, pneumocephalus, intracranial hemorrhages, hydrocephalus, the lactate peak enlarges and the N-acetylaspartate peak diminishes
and impending herniation. If the noncontrast scan reveals an abnor- before MRI sequences become abnormal.
mality and an MRI cannot be performed in a timely fashion, nonionic Catheter angiography is the gold standard for diagnosing vascular
contrast should be used to highlight areas of breakdown in the blood– disorders of the CNS, such as arteriovenous malformations, aneu-
brain barrier (e.g., abscesses, tumors) and/or collections of abnormal rysms, arterial occlusions, and vasculitis. A 4-vessel study is accom-
blood vessels (e.g., arteriovenous malformations). CT is less useful for plished by introducing a catheter into the femoral artery and then
diagnosing acute infarcts in children, because radiographic changes injecting contrast media into each of the internal carotid and vertebral
might not be apparent for up to 24 hr. Some subtle signs of early arteries. Because catheter angiography is invasive and requires general
(<24 hr) infarction include sulcal effacement, blurring of the gray– anesthesia, it is typically reserved for treatment planning of endovas-
white junction, and the hyperdense middle cerebral artery sign cular or open procedures and for cases in which noninvasive imaging
(increased attenuation in the middle cerebral artery that is often associ- results are not diagnostic.
ated with thrombosis). In the routine setting, CT imaging can be used Positron emission tomography provides unique information on
to demonstrate intracranial calcifications or, with the addition of brain metabolism and perfusion by measuring blood flow, oxygen
3-dimensional reformatting, to evaluate patients with craniofacial uptake, and/or glucose consumption. Positron emission tomography is
abnormalities or craniosynostosis. Although other pathologic pro- an expensive technique that is gaining a following in some pediatric
cesses may be visible on CT scan, MR is generally preferred because it centers, particularly those with active epilepsy surgery programs.
provides a more-detailed view of the anatomy without exposure to ion- Single-photon emission CT using 99mTc hexamethylpropyleneamine
izing radiation (Table 590-3). oxime is a sensitive and inexpensive technique to study regional cere-
CT angiography is a useful tool for visualizing vascular structures bral blood flow. Single-photon emission CT is particularly useful in
and is accomplished by administering a tight bolus of iodinated con- assessing for vasculitis, herpes encephalitis, dysplastic cortex, and
trast through a large-bore intravenous catheter and then acquiring CT recurrent brain tumors. Positron emission tomography MRI is only
images as the contrast passes through the arteries. available in a few pediatric centers in the United States; it provides
MRI is a noninvasive procedure that is well suited for detecting a better resolution and tissue definition than single-photon emission CT.
variety of abnormalities, including those of the posterior fossa and
spinal cord. MR scans are highly susceptible to patient motion artifact; Electroencephalography
consequently, many children younger than age 8 yr require sedation to An electroencephalogram (EEG) provides a continuous recording of
ensure an adequate study. (The need for sedation is beginning to electrical activity between reference electrodes placed on the scalp.
change in some centers as MRI technology improves and allows for Although the genesis of the electrical activity is not certain, it likely
faster performance of studies.) Because the American Academy of originates from postsynaptic potentials in the dendrites of cortical
Pediatrics recommends that infants be kept nothing by mouth (NPO) neurons. Even with amplification of the electrical activity, not all
for 4 hr or longer and older children for 6 hr or longer before deep potentials are recorded because there is a buffering effect of the
sedation, it is often difficult to obtain an MRI on an infant or young scalp, muscles, bone, vessels, and subarachnoid fluid. EEG waves are
Table 590-3 Preferred Imaging Procedures in Neurologic Diseases

ISCHEMIC INFARCTION OR TRANSIENT ISCHEMIC ATTACK HEADACHE
CT/CTA (head and neck) ± CT perfusion for patients who are unstable CT with and without contrast or MRI with and without gadolinium if a
or are potential candidates for tissue plasminogen activator or other structural disorder is suspected (MRI is preferred in nonemergent
acute interventions situations as it does not involve ionizing radiation and provides a
Otherwise, MRI/MRA (head and neck) with and without gadolinium better view of the parenchyma)
and with diffusion-weighted images
If the examination findings localize to the anterior circulation, carotid HEAD TRAUMA
ultrasound should be performed rather than neck CTA or MRA CT without contrast initially
Obtain an MRV if the infarct does not follow an arterial distribution MRI after initial assessment and treatment if clinically indicated.
CT or MRI can detect infarcts more than 24 hr old, although MRI is Diffusion tensor imaging and/or diffusion kurtosis sequences may be
generally preferred to avoid exposure to ionizing radiation useful to detect subtle white matter abnormalities
INTRAPARENCHYMAL HEMORRHAGE EPILEPSY

CT if <24 hr; MRI if >24 hr MRI with and without gadolinium. Thin slices through the mesial
MRI and MRA to assess for underlying vascular malformation, tumor, temporal lobes may be helpful if a temporal focus is suspected
etc. PET
Catheter angiography if MRA is nondiagnostic Interictal SPECT
ARTERIOVENOUS MALFORMATION BRAIN TUMOR

CT for acute hemorrhage; MRI and MRA with and without gadolinium MRI with and without gadolinium
as early as possible MRS
Catheter angiography if noninvasive imaging is nondiagnostic PET
CEREBRAL ANEURYSM MULTIPLE SCLEROSIS

CT without contrast for acute subarachnoid hemorrhage MRI with and without gadolinium
MRA or CTA to identify the aneurysm Obtain sagittal FLAIR images
Catheter angiography may be necessary in some cases MENINGITIS OR ENCEPHALITIS
TCD to detect vasospasm CT without and with contrast before lumbar puncture if there are
HYPOXIC–ISCHEMIC BRAIN INJURY signs of increased ICP on examination
Ultrasound in infants MRI with and without gadolinium after initial assessment and
If ultrasound is negative or there is a discrepancy between the clinical treatment for patients with complicated meningitis or encephalitis
course and the sonogram, obtain an MRI BRAIN ABSCESS
In older children, CT if unstable; otherwise, MRI MRI with and without gadolinium
MRS can show a lactate peak even in the absence of structural Diffusion-weighted images and MRS can help to differentiate abscess
abnormalities and can be useful for prognostication purposes from necrotic tumor
METABOLIC DISORDERS If the patient is unstable, CT with and without contrast followed by
MRI, particularly T2-weighted and FLAIR images MRI with and without contrast when feasible
Diffusion-weighted images may be useful in distinguishing acute and MOVEMENT DISORDERS
chronic changes MRI with and without gadolinium
MRS, SPECT, and PET may be useful in certain disorders PET
HYDROCEPHALUS DaTscan (SPECT scan using ioflupane iodine-123 as the contrast agent
Ultrasound (in infants), CT with and without contrast, or MR with and for detecting dopamine transporters in suspected parkinsonian
without gadolinium for diagnosis of communicating hydrocephalus syndromes)
MR with and without gadolinium for diagnosis of noncommunicating
hydrocephalus
Ultrasound (in infants) or CT to follow ventricular size in response to
treatment
CTA, computed tomographic angiography; FLAIR, fluid-attenuated inversion recovery; ICP, intracranial pressure; MRA, magnetic resonance angiography;
MRS, magnetic resonance spectroscopy; MRV, magnetic resonance venography; PET, positron emission tomography; SPECT, single-photon emission computed
tomography; TCD, transcranial Doppler ultrasonography.
classified according to their frequency as delta (1-3/sec), theta (4-7/ EEG abnormalities can be divided into 2 general categories: epilep-
sec), alpha (8-12/sec), and beta (13-20/sec). These waves are altered by tiform discharges and slowing. Epileptiform discharges are paroxysmal
many factors, including age, level of alertness, eye closure, drugs, and spikes or sharp waves, often followed by slow waves, which interrupt
disease states. the background activity. They may be focal, multifocal, or generalized.
The normal waking EEG is characterized by the posterior dominant Focal discharges are often associated with cerebral dysgenesis or irrita-
rhythm—a sinusoidal, 8-12 Hz rhythm that is most prominent over tive lesions, such as cysts, slow-growing tumors, or glial scar tissue;
the occipital region in a state of relaxed wakefulness with the eyes generalized discharges typically occur in children with structurally
closed. This rhythm first becomes apparent at 3-4 mo old, and most normal brains. Generalized discharges can occur as an epilepsy trait
children have achieved the adult frequency of 8-12 Hz by age 8 yr. in children who have never had a seizure and, by themselves, are not
Normal sleep is divided into 3 stages of non–rapid eye movement an indication for treatment. Epileptiform activity may be enhanced
sleep—designated N1, N2, and N3—and rapid eye movement sleep. by activation procedures, including hyperventilation and photic
N1 corresponds to drowsiness, and N3 represents deep, restorative, stimulation.
slow-wave sleep. Rapid eye movement sleep is rarely captured during As with epileptiform discharges, slowing can be either focal or
a routine EEG but may be seen on an overnight recording. The diffuse. Focal slowing should raise a concern for an underlying func-
American Electroencephalography Society Guideline and Technical tional or structural abnormality, such as an infarct, hematoma, or
Standards states that “sleep recordings should be obtained whenever tumor. Diffuse slowing is the hallmark of encephalopathy and is usually
possible”; however, it appears that sleep deprivation—not sleep during secondary to a widespread disease process or toxic–metabolic insult.
the EEG—is what increases the yield of the study, particularly in chil- Long-term video EEG monitoring provides precise characteriza-
dren with 1 or more clinically diagnosed seizures and in children older tion of seizure types, which allows specific medical or surgical manage-
than 3 yr of age. ment. It facilitates more accurate differentiation of epileptic seizures
from paroxysmal events that mimic epilepsy, including psychogenic
nonepileptiform attacks. Long-term EEG monitoring can also be
useful during medication adjustments.
Evoked Potentials
An evoked potential is an electrical signal recorded from the CNS fol-
lowing the presentation of a specific visual, auditory, or sensory stimu-
lus. Stimulation of the visual system by a flash or patterned stimulus,
such as a black-and-white checkerboard, produces visual evoked
potentials (VEPs), which are recorded over the occiput and averaged
in a computer. Abnormal VEPs can result from lesions to the visual
pathway anywhere from the retina to the visual cortex. Many demye-
linating disorders and neurodegenerative diseases, such as Tay-Sachs,
Krabbe, or Pelizaeus-Merzbacher disease, or neuronal ceroid lipofus-
cinoses, show characteristic VEP abnormalities. Flash VEPs can also
be helpful in evaluating infants who have sustained an anoxic injury;
however, detection of an evoked potential does not necessarily mean
that the infant will have functional vision.
Brainstem auditory evoked responses (BAERs) provide an objec-
tive measure of hearing and are particularly useful in neonates and in
children who have failed, or are uncooperative with, audiometric
testing. BAERs are abnormal in many neurodegenerative diseases of
childhood and are an important tool in evaluating patients with sus-
pected tumors of the cerebellopontine angle. BAERs can be helpful in
assessing brainstem function in comatose patients, because the wave-
forms are unaffected by drugs or by the level of consciousness; however,
they are not accurate in predicting neurologic recovery and outcome.
Somatosensory evoked potentials (SSEPs) are obtained by stimu-
lating a peripheral nerve (peroneal, median) and then recording the
electrical response over the cervical region and contralateral parietal
somatosensory cortex. SSEPs determine the functional integrity of the
dorsal column–medial lemniscal system and are useful in monitoring
spinal cord function during operative procedures for scoliosis, aortic
coarctation, and myelomeningocele repair. SSEPs are abnormal in
many neurodegenerative disorders and are the most accurate evoked
potential in the assessment of neurologic outcome following a severe
CNS insult.
Bibliography is available at Expert Consult.

Chapter 590 ◆ Neurologic Evaluation 2802.e1
Bibliography Chiappa KH: Evoked potentials in clinical medicine, ed 3, Philadelphia, 1997,

Avery RA, Shah SS, Licht DJ, et al: Reference range for cerebrospinal fluid opening Lippincott–Raven.
pressure in children, N Engl J Med 363:891–893, 2010. DeRoos ST, Chillag KL, Keeler M, et al: Effects of sleep deprivation on the
Barkovich JA: Pediatric neuroimaging, ed 5 rev., Philadelphia, 2011, Lippincott pediatric electroencephalogram, Pediatrics 123:703–708, 2009.
Williams & Wilkins. Jan MMS: Neurological examination of difficult and poorly cooperative children,
Beitzke D, Simbrunner J, Riccabona M: MRI in paediatric hypoxic-ischemic J Child Neurol 22:1209–1213, 2007.
disease, metabolic disorders, and malformations—a review, Eur J Radiol Portnoy JM, Olson LC: Normal cerebrospinal fluid values in children: another
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Campbell WW: DeJong’s the neurologic examination, ed 7, Philadelphia, 2012,
Lippincott Williams & Wilkins.
paced our understanding of the epigenetic and environmental mecha-

nisms causing these malformations.
These disorders are heterogeneous in their presentation. Common
presentations and clinical problems include disorders of head size and/
or shape; hydrocephalus; fetal ultrasonographic brain abnormalities;
neonatal encephalopathy and seizures; developmental delay, cognitive
impairment, and intellectual disability; hypotonia, motor impairment,
and cerebral palsy; seizures, epilepsy, and drug-resistant epilepsy;
cranial nerve dysfunction; and spinal cord dysfunction.
591.1 Neural Tube Defects

Stephen L. Kinsman and Michael V. Johnston
Neural tube defects (NTDs) account for the largest proportion of con-
genital anomalies of the CNS and result from failure of the neural tube
to close spontaneously between the 3rd and 4th wk of in utero develop-
ment. Although the precise cause of NTDs remains unknown, evi-
dence suggests that many factors, including hyperthermia, drugs
(valproic acid), malnutrition, low red cell folate levels, chemicals,
maternal obesity or diabetes, and genetic determinants (mutations in
folate-responsive or folate-dependent enzyme pathways) can adversely
affect normal development of the CNS from the time of conception.
In some cases, an abnormal maternal nutritional state or exposure to
radiation before conception increases the likelihood of a congenital
CNS malformation. The major NTDs include spina bifida occulta,
meningocele, myelomeningocele, encephalocele, anencephaly, caudal
regression syndrome, dermal sinus, tethered cord, syringomyelia, dia-
stematomyelia, and lipoma involving the conus medullaris and/or
filum terminale and the rare condition iniencephaly.
The human nervous system originates from the primitive ectoderm
that also develops into the epidermis. The ectoderm, endoderm, and
mesoderm form the three primary germ layers that are developed by
the 3rd wk. The endoderm, particularly the notochordal plate and the
intraembryonic mesoderm, induces the overlying ectoderm to develop
the neural plate in the 3rd wk of development (Fig. 591-1A). Failure
of normal induction is responsible for most of the NTDs, as well as
disorders of prosencephalic development. Rapid growth of cells within
the neural plate causes further invagination of the neural groove and
differentiation of a conglomerate of cells, the neural crest, which
migrate laterally on the surface of the neural tube (Fig. 591-1B). The
notochordal plate becomes the centrally placed notochord, which acts
Chapter 591 as a foundation around which the vertebral column ultimately devel-
ops. With formation of the vertebral column, the notochord undergoes
Congenital Anomalies of involution and becomes the nucleus pulposus of the intervertebral
disks. The neural crest cells differentiate to form the peripheral nervous
system, including the spinal and autonomic ganglia and the ganglia of
the Central Nervous cranial nerves V, VII, VIII, IX, and X. In addition, the neural crest
forms the leptomeninges, as well as Schwann cells, which are respon-
System sible for myelination of the peripheral nervous system. The dura is
thought to arise from the paraxial mesoderm. In the region of the
embryo destined to become the head, similar patterns exist. In this
Stephen L. Kinsman and region, the notochord is replaced by the prechordal mesoderm.
Michael V. Johnston In the 3rd wk of embryonic development, invagination of the neural
groove is completed and the neural tube is formed by separation from
the overlying surface ectoderm (see Fig. 591-1C). Initial closure of the
Central nervous system (CNS) malformations are grouped into neural neural tube is accomplished in the area corresponding to the future
tube defects and associated spinal cord malformations; encephaloceles; junction of the spinal cord and medulla and moves rapidly both cau-
disorders of structure specification (gray matter structures, neuronal dally and rostrally. For a brief period, the neural tube is open at both
migration disorders, disorders of connectivity, and commissure and ends, and the neural canal communicates freely with the amniotic
tract formation); disorders of the posterior fossa, brainstem, and cer- cavity (see Fig. 591-1D). Failure of closure of the neural tube allows
ebellum; disorders of brain growth and size; and disorders of skull excretion of fetal substances (α-fetoprotein [AFP], acetylcholinester-
growth and shape. Classification of these conditions into syndromic, ase) into the amniotic fluid, serving as biochemical markers for a NTD.
nonsyndromic, and single-gene etiologies is also important. These dis- Prenatal screening of maternal serum for AFP in the 16th-18th wk of
orders can also be seen as isolated findings or as being a consequence gestation is an effective method for identifying pregnancies at risk for
of environmental exposures. Elucidation of single-gene causes has out- fetuses with NTDs in utero. Normally, the rostral end of the neural
2802.e2 Chapter 591 ◆ Congenital Anomalies of the Central Nervous System
Bibliography Stothard J, Tennant PW, Bell R, et al: Maternal overweight and obesity and the risk
Aradhya S, Manning MA, Splendore A, et al: Whole-genome array-CGH identifies of congenital anomalies: a systematic review and meta-analysis, JAMA
novel contiguous gene deletions and duplications associated with developmental 301:636–650, 2009.
delay, mental retardation, and dysmorphic features, Am J Med Genet A
143A:1431–1441, 2007.
Qiao Y, Tyson C, Hrynchak M, et al: Clinical application of 2.7M cytogenetics
array for CNV detection in subjects with idiopathic autism and/or intellectual
disability, Clin Genet 83:145–154, 2013.
Chapter 591 ◆ Congenital Anomalies of the Central Nervous System 2803
tube closes on the 23rd day and the caudal neuropore closes by a ways of progenitor cell generation and migration are also being eluci-
process of secondary neurulation by the 27th day of development, dated. It is likely that microglia originate from mesenchymal cells at a
before the time that many women realize they are pregnant. later stage of fetal development when blood vessels begin to penetrate
The embryonic neural tube consists of 3 zones: ventricular, mantle, the developing nervous system.
and marginal (see Fig. 591-1E). The ependymal layer consists of plu-
ripotential, pseudostratified, columnar neuroepithelial cells. Specific
neuroepithelial cells differentiate into primitive neurons or neuroblasts 591.2 Spina Bifida Occulta
that form the mantle layer. The marginal zone is formed from cells in
the outer layer of the neuroepithelium, which ultimately becomes the (Occult Spinal Dysraphism)
white matter. Glioblasts, which act as the primitive supportive cells of Stephen L. Kinsman and Michael V. Johnston
the CNS, also arise from the neuroepithelial cells in the ependymal
zone. They migrate to the mantle and marginal zones and become Spina bifida occulta is a common anomaly consisting of a midline
future astrocytes and oligodendrocytes. The importance of other path- defect of the vertebral bodies without protrusion of the spinal cord or
meninges. Most patients are asymptomatic and lack neurologic signs,
and the condition is usually of no consequence. Some consider the
Neural groove
Surface ectoderm Neural fold term spina bifida occulta to denote merely a posterior vertebral body
Neural plate fusion defect. This simple defect does not have an associated spinal
cord malformation. Other clinically more significant forms of this
closed spinal cord malformation are more correctly termed occult
spinal dysraphism. In most of these cases, there are cutaneous manifes-
tations such as a hemangioma, discoloration of the skin, pit, lump,
Intraembryonic Notochordal Neural
dermal sinus, or hairy patch (Fig. 591-2). A spine roentgenogram in
mesoderm plate groove
Yolk sac simple spina bifida occulta shows a defect in closure of the posterior
A Rostral vertebral arches and laminae, typically involving L5 and S1; there is no
neuropore abnormality of the meninges, spinal cord, or nerve roots. Occult spinal
dysraphism is often associated with more significant developmental
Neural groove
Somites
abnormalities of the spinal cord, including syringomyelia, diastemato-
myelia, lipoma, fatty filum, dermal sinus, and/or a tethered cord. A
Neural crest spine x-ray in these cases might show bone defects or may be normal.
All cases of occult spinal dysraphism are best investigated with MRI
(Fig. 591-3). Initial screening in the neonate may include ultrasonog-
Somite
raphy, but MRI is more accurate at any age.
A dermoid sinus usually forms a small skin opening, which leads
B Notochord into a narrow duct, sometimes indicated by protruding hairs, a hairy
patch, or a vascular nevus. Dermoid sinuses occur in the midline
Caudal at the sites where meningoceles or encephaloceles can occur: the
Developing
neuropore lumbosacral region or occiput, respectively and occasionally in the
epidermis cervical or thoracic area. Dermoid sinus tracts can pass through
the dura, acting as a conduit for the spread of infection. Recurrent
meningitis of occult origin should prompt careful examination for
Neural tube Developing D a small sinus tract in the posterior midline region, including the
spinal ganglion back of the head. Lower back sinuses are usually above the gluteal
fold and are directed cephalad. Tethered spinal cord syndrome may
also be an associated problem. Diastematomyelia commonly has bony
abnormalities that require surgical intervention along with untether-
C Neural canal ing of the spinal cord.
An approach to imaging of the spine in patients with cutaneous
lesions is noted in Table 591-1.
Mantle zone
Table 591-1 Cutaneous Lesions Associated with Occult

Central canal Spinal Dysraphism
IMAGING INDICATED
Ventricular zone Subcutaneous mass or lipoma
Hairy patch
Dermal sinus
Atypical dimples (deep, >5 mm, >25 mm from anal verge)
Marginal zone Vascular lesion, e.g., hemangioma or telangiectasia
Skin appendages or polypoid lesions, e.g., skin tags, tail-like
appendages
Scar-like lesions
IMAGING UNCERTAIN
Hyperpigmented patches
E Deviation of the gluteal fold
Figure 591-1 Diagrammatic illustration of the developing nervous IMAGING NOT REQUIRED
system. A, Transverse sections of the neural plate during the 3rd wk.
Simple dimples (<5 mm, <25 mm from anal verge)
B, Formation of the neural groove and the neural crest. C, The neural
Coccygeal pits
tube is developed. D, Longitudinal drawing showing the initial closure
of the neural tube in the central region. E, Cross-sectional drawing of From Williams H: Spinal sinuses, dimples, pits and patches: what lies beneath?
the embryonic neural tube (primitive spinal cord). Arch Dis Child Educ Pract Ed 91:ep75–ep80, 2006.
A B
C D
Figure 591-2 Clinical aspects of congenital median lumbosacral cutaneous lesions. A, Midline sacral hemangioma in a patient with an occult
lipomyelomeningocele. B, Capillary malformation with a subtle patch of hypertrichosis in a patient with a dermal sinus. C, Human tail with underly-
ing lipoma in an infant with lipomyelomeningocele. D, Midline area of hypertrichosis (faun tail) overlying a patch of hyperpigmentation. (A-C from
Kos L, Drolet BA: Developmental abnormalities. In Eichenfield LF, Frieden IJ, Esterly NB, editors: Neonatal dermatology, ed 2, Philadelphia, 2008,
WB Saunders. D from Spine and spinal cord: developmental disorders. In Schapira A, editor: Neurology and clinical neuroscience, Philadelphia,
2007, Mosby.)
A B C D E
Figure 591-3 Clinical features and imaging findings associated with occult spinal dysraphism. A, Lumbosacral lipoma. The subcutaneous lipoma
is in continuity with the spinal cord via a defect in the underlying muscles bone and dura. B, Sagittal T1-weighted image shows huge intradural
lipoma, merging with the conus medullaris superiorly. C, Lipoma and central dermal sinus. D and E, Dermal sinus with dermoid on an 8 yr old
girl. Slightly parasagittal T2-weighted image shows sacral dermal sinus coursing obliquely downward in subcutaneous fat (arrow) (D). Midsagittal
T2-weighted image shows huge dermoid in the thecal sac (arrowheads), extending upward to the tip of the conus medullaris (E). The mass gives
a slightly lower signal than cerebrospinal fluid and is outlined by a thin low-signal rim. (A from Thompson DNP: Spinal dysraphic anomalies: clas-
sification, presentation and management. Paed Child Health 24:431–438, 2014, Fig. 4; B, D, and E from Rossi A, Biancheri R, Cama A, et al:
Imaging in spine and spinal cord malformations, Eur J Radiol 50(2):177–200, 2004, Fig. 9a; and C, from Jaiswal AK, Garg A, Mahapatra AK: Spinal
ossifying lipoma, J Clin Neurosci 12:714–717, 2005, Fig. 1.)
a role in the pathogenesis of meningomyelocele. These enzymes include

591.3 Meningocele 5,10-methylenetetrahydrofolate reductase, cystathionine β-synthase,
Stephen L. Kinsman and Michael V. Johnston and methionine synthase. An association between a thermolabile
variant of 5,10-methylenetetrahydrofolate reductase and mothers of
A meningocele is formed when the meninges herniate through a defect children with NTDs might account for up to 15% of preventable NTDs.
in the posterior vertebral arches or the anterior sacrum. The spinal cord Maternal periconceptional use of folic acid supplementation reduces
is usually normal and assumes a normal position in the spinal canal, the incidence of NTDs in pregnancies at risk by at least 50%. To be
although there may be tethering of the cord, syringomyelia, or diaste- effective, folic acid supplementation should be initiated before concep-
matomyelia. A fluctuant midline mass that might transilluminate tion and continued until at least the 12th wk of gestation, when neu-
occurs along the vertebral column, usually in the lower back. Most rulation is complete. The mechanisms by which folic acid prevents
meningoceles are well covered with skin and pose no immediate threat NTDs remain poorly understood.
to the patient. Careful neurologic examination is mandatory. Ortho-
pedic and urologic examination should also be considered. In asymp- PREVENTION
tomatic children with normal neurologic findings and full-thickness The U.S. Public Health Service has recommended that all women of
skin covering the meningocele, surgery may be delayed or sometimes childbearing age and who are capable of becoming pregnant take
not performed. 0.4 mg of folic acid daily. If, however, a pregnancy is planned in high-
Before surgical correction of the defect, the patient must be thor- risk women (previously affected child), supplementation should be
oughly examined with the use of plain x-rays, ultrasonography, started with 4 mg of folic acid daily, beginning 1 mo before the time
and MRI to determine the extent of neural tissue involvement, if any, of the planned conception. The modern diet provides about half the
and associated anomalies, including diastematomyelia, lipoma, and daily requirement of folic acid. To increase folic acid intake, fortifica-
possible clinically significant tethered spinal cord. Urologic evaluation tion of flour, pasta, rice, and cornmeal with 0.15 mg folic acid per
usually includes cystometrogram to identify children with neurogenic 100 g was mandated in the United States and Canada in 1998. The
bladder who are at risk for renal deterioration. Patients with leaking added folic acid is insufficient to maximize the prevention of prevent-
cerebrospinal fluid (CSF) or a thin skin covering should undergo able NTDs. Therefore, informative educational programs and folic
immediate surgical treatment to prevent meningitis. A CT scan or MRI acid vitamin supplementation remain essential for women planning a
of the head is recommended for children with a meningocele because pregnancy and possibly for all women of childbearing age. In addi-
of the association with hydrocephalus in some cases. An anterior tion, women should also strive to consume food folate from a varied
meningocele projects into the pelvis through a defect in the sacrum. diet. Certain drugs, including drugs that antagonize folic acid, such
Symptoms of constipation and bladder dysfunction develop due to the as trimethoprim and the anticonvulsants carbamazepine, phenytoin,
increasing size of the lesion. Female patients might have associated phenobarbital, and primidone, increase the risk of myelomeningocele.
anomalies of the genital tract, including a rectovaginal fistula and The anticonvulsant valproic acid causes NTDs in approximately 1-2%
vaginal septa. Plain x-rays demonstrate a defect in the sacrum, and CT of pregnancies when administered during pregnancy. Some epilepsy
scanning or MRI outlines the extent of the meningocele and any asso- clinicians recommend that all female patients of childbearing poten-
ciated anomalies. tial who take anticonvulsant medications also receive folic acid sup-
plements. There may be a threshold for ideal red blood cell folate
levels (900-1,000 nmol/L), which is associated with a markedly
reduced risk of NTDs.
591.4 Myelomeningocele
Stephen L. Kinsman and Michael V. Johnston CLINICAL MANIFESTATIONS
Myelomeningocele produces dysfunction of many organs and struc-
Myelomeningocele represents the most severe form of dysraphism, a tures, including the skeleton, skin, and gastrointestinal and genitouri-
so-called aperta or open form, involving the vertebral column and nary tracts, in addition to the peripheral nervous system and the CNS.
spinal cord, which occurs with an incidence of approximately 1 in A myelomeningocele may be located anywhere along the neuraxis, but
4,000 live births. the lumbosacral region accounts for at least 75% of the cases. The
extent and degree of the neurologic deficit depend on the location of
ETIOLOGY the myelomeningocele and the associated lesions. A lesion in the low
The cause of myelomeningocele is unknown, but as with all neural tube sacral region causes bowel and bladder incontinence associated with
closure defects, including anencephaly, a genetic predisposition exists; anesthesia in the perineal area but with no impairment of motor func-
the risk of recurrence after 1 affected child is 3-4% and increases to tion. Newborns with a defect in the midlumbar or high lumbothoracic
10% with 2 prior affected children. Both epidemiologic evidence and region typically have either a sac-like cystic structure covered by a thin
the presence of substantial familial aggregation of anencephaly, myelo- layer of partially epithelialized tissue (Fig. 591-4) or an exposed flat
meningocele, and craniorachischisis indicate heredity, on a polygenic
basis, as a significant contributor to the etiology of NTDs. Nutritional
and environmental factors have a role in the etiology of myelomenin-
gocele as well.
Folate is intricately involved in the prevention and etiology of
NTDs. Folate functions in single-carbon transfer reactions and
exists in many chemical forms. Folic acid (pteroylmonoglutamic acid),
which is the most oxidized and stable form of folate, occurs rarely in
food but is the form used in vitamin supplements and in fortified food
products, particularly flour. Most naturally occurring folates (food
folate) are pteroylpolyglutamates, which contain 1-6 additional gluta-
mate molecules joined in a peptide linkage to the γ-carboxyl of gluta-
mate. Folate coenzymes are involved in DNA synthesis, purine
synthesis, generation of formate into the formate pool, and amino
acid interconversion; the conversion of homocysteine to methionine
provides methionine for the synthesis of S-adenosylmethionine (SAMe,
an agent important for in vivo methylation). Mutations in the genes Figure 591-4 A lumbar myelomeningocele is covered by a thin layer
encoding the enzymes involved in homocysteine metabolism may play of skin.
neural placode without overlying tissues. When a cyst or membrane is and bladder pressure that prevents urinary tract infections and reflux
present, remnants of neural tissue are visible beneath the membrane, leading to pyelonephritis, hydronephrosis, and bladder damage. Latex-
which occasionally ruptures and leaks CSF. free catheters and gloves must be used to prevent development of latex
Examination of the infant shows a flaccid paralysis of the lower allergy. Periodic urine cultures and assessment of renal function,
extremities, an absence of deep tendon reflexes, a lack of response to including serum electrolytes and creatinine as well as renal scans,
touch and pain, and a high incidence of lower-extremity deformities vesiculourethrograms, renal ultrasonography, and cystometrograms,
(clubfeet, ankle and/or knee contractures, and subluxation of the hips). are obtained according to the risk status and progress of the patient
Some children have constant urinary dribbling and a relaxed anal and the results of the physical examination. This approach to urinary
sphincter. Other children do not leak urine and in fact have a high- tract management has greatly reduced the need for urologic diversion-
pressure bladder and sphincter dyssynergy. Thus, a myelomeningocele ary procedures and significantly decreased the morbidity and mortality
above the midlumbar region tends to produce lower motor neuron associated with progressive renal disease in these patients. Some chil-
signs because of abnormalities and disruption of the conus medullaris dren can become continent with surgical implantation of an artificial
and above spinal cord structures. urinary sphincter (these are used less often) or bladder augmentation
Infants with myelomeningocele typically have increased neurologic at a later age.
deficit as the myelomeningocele extends higher into the thoracic Although incontinence of fecal matter is common and is socially
region. These infants sometimes have an associated kyphotic gibbus unacceptable during the school years, it does not pose the same organ-
that requires neonatal orthopedic correction. Patients with a myelome- damaging risks as urinary dysfunction, but occasionally fecal impac-
ningocele in the upper thoracic or cervical region usually have a very tion and/or megacolon develop. Many children can be bowel-trained
minimal neurologic deficit and, in most cases, do not have hydro- with a regimen of timed enemas or suppositories that allows evacua-
cephalus. They can have neurogenic bladder and bowel. tion at a predetermined time once or twice a day. Special attention to
Hydrocephalus in association with a type II Chiari malformation low anorectal tone and enema administration and retention is often
develops in at least 80% of patients with myelomeningocele. Generally, required. Appendicostomy for antegrade enemas may also be helpful
patients with sacral myelomeningocele have a very low risk of hydro- (see Chapter 23.4).
cephalus. The possibility of hydrocephalus developing after the neona- Functional ambulation is the wish of each child and parent and
tal period should always be considered, no matter what the spinal level. may be possible, depending on the level of the lesion and on intact
Ventricular enlargement may be indolent and slow growing or may be function of the iliopsoas muscles. Almost every child with a sacral or
rapid causing a bulging anterior fontanel, dilated scalp veins, setting- lumbosacral lesion obtains functional ambulation; approximately half
sun appearance of the eyes, irritability, and vomiting in association the children with higher defects ambulate with the use of braces, other
with an increased head circumference. Approximately 15% of infants orthotic devices, and canes. Ambulation is often more difficult as ado-
with hydrocephalus and Chiari II malformation develop symptoms of lescence approaches and body mass increases. Deterioration of ambu-
hindbrain (brainstem) dysfunction, including difficulty feeding, latory function, particularly during earlier years, should prompt
choking, stridor, apnea, vocal cord paralysis, pooling of secretions, and referral for evaluation of tethered spinal cord and other neurosurgical
spasticity of the upper extremities, which, if untreated, can lead to issues.
death. This Chiari crisis is caused by downward herniation of the In utero surgical closure of a spinal lesion has been successful in a
medulla and cerebellar tonsils through the foramen magnum, as well few centers. Preliminary reports suggest a lower incidence of hind-
as endogenous malformations in the cerebellum and brainstem, brain abnormalities and hydrocephalus (fewer shunts) as well as
causing dysfunction. improved motor outcomes. This suggests that the defects may be pro-
gressive in utero and that prenatal closure might prevent the develop-
TREATMENT ment of further loss of function. In utero diagnosis is facilitated by
Management and supervision of a child and family with a myelome- maternal serum AFP screening and by fetal ultrasonography (see
ningocele require a multidisciplinary team approach, including sur- Chapter 96).
geons, other physicians, and therapists, with 1 individual (often a
pediatrician) acting as the advocate and coordinator of the treatment PROGNOSIS
program. The news that a newborn child has a devastating condition For a child who is born with a myelomeningocele and who is treated
such as myelomeningocele causes parents to feel considerable grief and aggressively, the mortality rate is 10-15%, and most deaths occur before
anger. They need time to learn about the condition and its associated age 4 yr, although life-threatening complications occur at all ages. At
complications and to reflect on the various procedures and treatment least 70% of survivors have normal intelligence, but learning problems
plans. A knowledgeable individual in an unhurried and nonthreaten- and seizure disorders are more common than in the general popula-
ing setting must give the parents the facts, along with general prognos- tion. Previous episodes of meningitis or ventriculitis adversely affect
tic information and management strategies and timelines. If possible, intellectual and cognitive function. Because myelomeningocele is a
discussions with other parents of children with NTDs are helpful in chronic disabling condition, periodic and consistent multidisciplinary
resolving important questions and issues. follow-up is required for life. Renal dysfunction is one of the most
Surgery is often done within a day or so of birth but can be important determinants of mortality.
delayed for several days (except when there is a CSF leak) to allow
the parents time to begin to adjust to the shock and to prepare for Bibliography is available at Expert Consult.
the multiple procedures and inevitable problems that lie ahead. Evalu-
ation of other congenital anomalies and renal function can also be
initiated before surgery. Most pediatric centers aggressively treat the
majority of infants with myelomeningocele. After repair of a myelo- 591.5 Encephalocele
meningocele, most infants require a shunting procedure for hydro- Stephen L. Kinsman and Michael V. Johnston
cephalus. If symptoms or signs of hindbrain dysfunction appear,
early surgical decompression of the posterior fossa is indicated. Club- Two major forms of dysraphism affect the skull, resulting in protru-
feet can require taping or casting, and dislocated hips may require sion of tissue through a bony midline defect, called cranium bifidum.
operative procedures. A cranial meningocele consists of a CSF-filled meningeal sac only, and
Careful evaluation and reassessment of the genitourinary system are a cranial encephalocele contains the sac plus cerebral cortex, cerebel-
some of the most important components of the management. Teaching lum, or portions of the brainstem. Microscopic examination of the
the parents, and, ultimately, the patient, to regularly catheterize a neu- neural tissue within an encephalocele often reveals abnormalities. The
rogenic bladder is a crucial step in maintaining a low residual volume cranial defect occurs most commonly in the occipital region at or
Chapter 591 ◆ Congenital Anomalies of the Central Nervous System 2806.e1
Bibliography Fichter MA, Dornseifer U, Henke J, et al: Fetal spina bifida repair—current trends
Adzick NS, Thom EA, Spong CY, et al: A randomized trial of prenatal versus and prospects of intrauterine neurosurgery, Fetal Diagn Ther 23:271–286, 2008.
postnatal repair of myelomeningocele, N Engl J Med 364:993–1004, 2011. Guggisberg D, Hadj-Rabia S, Viney C, et al: Skin markers of occult spinal
Bauer SB: Neurogenic bladder: etiology and assessment, Pediatr Nephrol dysraphism in children, Arch Dermatol 140:1109–1115, 2004.
23:541–551, 2008. Ickowicz V, Ewin D, Maugay-Laulom B, et al: Meckel-Gruber syndrome,
Bitsko RH, Reefhuis J, Romitti PA, et al: Periconceptional consumption of vitamins sonography and pathology, Ultrasound Obstet Gynecol 27:296–300, 2006.
containing folic acid and risk for multiple congenital anomalies, Am J Med Joseph DB: Current approaches to the urologic care of children with spina bifida,
Genet 143A:2397–2405, 2007. Curr Urol Rep 9:151–157, 2008.
Cameron M, Moran P: Prenatal screening and diagnosis of neural tube defects, Madden-Fuentes RJ, McNamara ER, Lloyd JC, et al: Variation in definitions of
Prenat Diagn 29:402–411, 2009. urinary tract infections in spina bifida patients: a systematic review, Pediatrics
Centers for Disease Control and Prevention: CDC Grand Rounds: additional 132:132–139, 2013.
opportunities to prevent neural tube defects with folic acid fortification, Safra N, Bassil AG, Ferguson PJ, et al: Genome-wide association mapping in dogs
MMWR Morb Mortal Wkly Rep 59:980–984, 2010. enables identification of the homeobox gene, NKX2-8, as a genetic component
Centers for Disease Control and Prevention: Investigation of a cluster of neural of neural tube defects in humans, PLoS Genet 9:e1003646, 2014.
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62:728–729, 2013. spina bifida: a review of the literature, J Urol 180:2323–2329, 2008.
Chescheir NC: Maternal-fetal surgery: where are we and how did we get here?, Shin M, Kucik JE, Siffel C, et al: Improved survival among children with spina
Obstet Gynecol 113:717–731, 2009. bifida in the United States, J Pediatr 161:1132–1137, 2012.
Clarke R, Bennett D: Folate and prevention of neural tube defects, BMJ 349:g4810, Stevenson RE, Allen WP, Pai GS, et al: Decline in prevalence of neural tube defects
2014. in a high-risk region of the United States, Pediatrics 106:677–683, 2000.
Cochrane DD: Cord untethering for lipomyelomeningocele: expectation after Tubbs RS, Bui CJ, Loukas M, et al: The horizontal sacrum as an indicator of the
surgery, Neurosurg Focus 23:1–7, 2007. tethered spinal cord in spina bifida aperta and occulta, Neurosurg Focus 23:1–4,
de Jong TP, Chrzan R, Klijn AJ, et al: Treatment of the neurogenic bladder in spina 2007.
bifida, Pediatr Nephrol 23:889–896, 2008. U.S. Preventive Services Task Force: Recommendation statement: folic acid for the
Dicianno BE, Kurowski BG, Yang JM, et al: Rehabilitation and medical prevention of neural tube defects, Ann Intern Med 150:626–631, 2009.
management of the adult with spina bifida, Am J Phys Med Rehabil 87:1027– Williams H: Spinal sinuses, dimples, pits and patches: what lies beneath?, Arch Dis
1050, 2008. Child 91:ep75–ep80, 2006.
below the inion, but in certain parts of the world, frontal or nasofron-
tal encephaloceles (transethmoidal, sphenoethmoidal, sphenomaxil- 591.7 Disorders of Neuronal Migration
lary, sphenoorbital, transsphenoidal) are more common. Some frontal Stephen L. Kinsman and Michael V. Johnston
lesions are associated with a cleft lip and palate. These abnormalities
are one-tenth as common as neural tube closure defects involving the Disorders of neuronal migration can result in minor abnormalities
spine. The etiology is presumed to be similar to that for anencephaly with little or no clinical consequence (small heterotopia of neurons)
and myelomeningocele; examples of each are reported in the same or devastating abnormalities of CNS structure and/or function (intel-
family. lectual disability, seizures, lissencephaly, and schizencephaly, particu-
Infants with a cranial encephalocele are at increased risk for devel- larly the open-lip form) (Fig. 591-5). One of the most important
oping hydrocephalus because of aqueductal stenosis, Chiari malfor- mechanisms in the control of neuronal migration is the radial glial
mation, or the Dandy-Walker syndrome. Examination might show a fiber system that guides neurons to their proper site. Migrating
small sac with a pedunculated stalk or a large cyst-like structure that neurons attach to the radial glial fiber and then disembark at prede-
can exceed the size of the cranium. The lesion may be completely termined sites to form, ultimately, the precisely designed 6-layered
covered with skin, but areas of denuded lesion can occur and require cerebral cortex. Another important mechanism is the tangential
urgent surgical management. Transillumination of the sac can indicate migration of progenitor neurons destined to become cortical inter-
the presence of neural tissue. A plain x-ray of the skull and cervical neurons. The severity and the extent of the disorder are related to
spine is indicated to define the anatomy of the cranium and vertebrae. numerous factors, including the timing of a particular insult and a
Ultrasonography is most helpful in determining the contents of the sac. host of environmental and genetic contributors. Some cortical malfor-
MRI or CT further helps define the spectrum of the lesion. Children mations may be from somatic mutations, as exemplified by kinesin
with a cranial meningocele generally have a good prognosis, whereas gene mutations in patients with pachygyria.
patients with an encephalocele are at risk for vision problems, micro-
cephaly, intellectual disability, and seizures. Generally, children with LISSENCEPHALY
neural tissue within the sac and associated hydrocephalus have the Lissencephaly, or agyria, is a rare disorder that is characterized by the
poorest prognosis. absence of cerebral convolutions and a poorly formed sylvian fissure,
Cranial encephalocele is often part of a syndrome. Meckel-Gruber giving the appearance of a 3-4 mo fetal brain. The condition is probably
syndrome is a rare autosomal recessive condition that is characterized a result of faulty neuroblast migration during early embryonic life and
by an occipital encephalocele, cleft lip or palate, microcephaly, is usually associated with enlarged lateral ventricles and heterotopias
microphthalmia, abnormal genitalia, polycystic kidneys, and polydac- in the white matter. In some forms, there is a 4-layered cortex, rather
tyly. Determination of maternal serum AFP levels and ultrasound mea- than the usual 6-layered one, with a thin rim of periventricular white
surement of the biparietal diameter, as well as identification of the matter and numerous gray heterotopias visible by microscopic exami-
encephalocele itself, can diagnose encephaloceles in utero. Fetal MRI nation. Milder forms of lissencephaly also exist.
can help define the extent of associated CNS anomalies and the degree
of brain herniated into the encephalocele.
591.6 Anencephaly
An anencephalic infant presents a distinctive appearance with a large

defect of the calvarium, meninges, and scalp associated with a rudi-
mentary brain, which results from failure of closure of the rostral
neuropore, the opening of the anterior neural tube. The primitive
brain consists of portions of connective tissue, vessels, and neuroglia.
The cerebral hemispheres and cerebellum are usually absent, and
only a residue of the brainstem can be identified. The pituitary gland
is hypoplastic, and the spinal cord pyramidal tracts are missing
owing to the absence of the cerebral cortex. Additional anomalies
include folding of the ears, cleft palate, and congenital heart defects
in 10-20% of cases. Most anencephalic infants die within several days
of birth.
The incidence of anencephaly approximates 1 in 1,000 live births;
the greatest incidence is in Ireland, Wales, and Northern China. The
recurrence risk is approximately 4% and increases to 10% if a couple
has had 2 previously affected pregnancies. Many factors, in addition to
genetics, are implicated as a cause of anencephaly, including low socio-
economic status, nutritional and vitamin deficiencies, and a large
number of environmental and toxic factors. It is very likely that several
noxious stimuli interact on a genetically susceptible host to produce
anencephaly. The incidence of anencephaly has been decreasing since
the 1990s. Approximately 50% of cases of anencephaly have associated
polyhydramnios. Couples who have had an anencephalic infant should Figure 591-5 T1-weighted MRI scan demonstrating band heteroto-
have successive pregnancies monitored, including amniocentesis, pia. A thin layer of white matter (black arrow) lies between the band of
determination of AFP levels, and ultrasound examination between the heterotopic gray matter and the cortical surface. Failure of cortical
14th and 16th wk of gestation. Prenatal folic acid supplementation organization with lissencephaly is present in both frontal lobes (white
decreases the risk of this condition. arrow).
Bibliography Leitch CC, Zaghloul NA, Davis EE, et al: Hypomorphic mutations in syndromic
France D, Alonso N, Ruas R, et al: Transsphenoidal meningoencephalocele encephalocele genes are associated with Bardet-Biedl syndrome, Nat Genet
associated with cleft lip and palate: challenges for diagnosis and surgical 40:443–448, 2008.
treatment, Childs Nerv Syst 25:1455–1458, 2009.
Joó JG, Papp Z, Berkes E, et al: Non-syndromic encephalocele: a 26-year
experience, Dev Med Child Neurol 50:958–960, 2008.
These infants present with failure to thrive, microcephaly, marked Several genes have been identified that are a cause of these
developmental delay, and a severe seizure disorder. Ocular abnormali- conditions.
ties are common, including hypoplasia of the optic nerve and microph-
thalmia. Lissencephaly can occur as an isolated finding, but it is POLYMICROGYRIAS
associated with Miller-Dieker syndrome in approximately 15% of Polymicrogyria is characterized by an augmentation of small con-
cases. These children have characteristic facies, including a prominent volutions separated by shallow enlarged sulci. Epilepsy, including
forehead, bitemporal hollowing, anteverted nostrils, a prominent drug-resistant forms, is a common feature. Truncation of the KBP
upper lip, and micrognathia. Approximately 70% of children with gene has been implicated in a family with multiple members with
Miller-Dieker syndrome have visible or submicroscopic chromosomal polymicrogyria.
deletions of 17p13.3.
The gene LIS-1 (lissencephaly 1) that maps to chromosome region
17p13.3 is deleted in patients with Miller-Dieker syndrome. CT and
MRI scans typically show a smooth brain with an absence of sulci
(Fig. 591-6). Doublecortin is an X chromosome gene that causes lis-
sencephaly when mutated in males and subcortical band heterotopia
when mutated in females. Other important forms of lissencephaly
include the Walker-Warburg variant and other cobblestone cortical
malformations.
SCHIZENCEPHALY
Schizencephaly is the presence of unilateral or bilateral clefts within
the cerebral hemispheres owing to an abnormality of morphogenesis
(Fig. 591-7). The cleft may be fused or unfused and, if unilateral and
large, may be confused with a porencephalic cyst. Not infrequently, the
borders of the cleft are surrounded by abnormal brain, particularly
microgyria. MRI is the study of choice for elucidating schizencephaly
and associated malformations.
When the clefts are bilateral, many patients are severely intellectually
challenged, with seizures that are difficult to control, and microce-
phalic, with spastic quadriparesis. Some cases of bilateral schizenceph-
aly are associated with septooptic dysplasia and endocrinologic
disorders. Unilateral schizencephaly is a common cause of congenital
hemiparesis. It remains controversial whether genetic causes of
schizencephaly exist. Some gene mutations are seen in cases of familial
schizencephaly.
NEURONAL HETEROTOPIAS
Subtypes of neuronal heterotopias include periventricular nodular het- Figure 591-6 MRI of an infant with lissencephaly. Note the absence
erotopias, subcortical heterotopia (including band-type), and marginal of cerebral sulci and the maldeveloped sylvian fissures associated with
glioneuronal heterotopias. Intractable seizures are a common feature. enlarged ventricles.
Figure 591-7 Unilateral schizencephaly shown on axial MR images of the brain. Example of an open-lip schizencephaly with a cleft communicat-
ing between the ventricle and the extraaxial cranial space (arrow on left panel). Many of these clefts are lined with abnormal gray matter (arrow
on right panel).
Figure 591-8 Agenesis of the corpus callosum shown on MR images of the brain. Sagittal (left panel) and coronal (right panel) views of an infant
show the total absence of a midsagittal white matter structure (left panel, arrows). The coronal view (right panel) demonstrates (despite some
motion artifact) the absence of a structure bridging the 2 hemispheres (area under arrow).
FOCAL CORTICAL DYSPLASIAS signaling that specifies and organizes this area during early embryo-
Focal cortical dysplasias consist of abnormal cortical lamination in a genesis causes agenesis of the corpus callosum.
discrete area of cortex. High-resolution, thin-section MRI can reveal It is often said that the outcome of agenesis of the corpus callosum
these areas sometimes in the setting of drug-resistant epilepsy. is dictated by the company it keeps. When agenesis of the corpus cal-
losum is an isolated phenomenon, the patient may be normal. When
PORENCEPHALY it is accompanied by brain anomalies from cell migration defects, such
Porencephaly is the presence of cysts or cavities within the brain that as heterotopias, polymicrogyria, and pachygyria (broad, wide gyri),
result from developmental defects or acquired lesions, including infarc- patients often have significant neurologic abnormalities, including
tion of tissue. True porencephalic cysts are most commonly located in intellectual disability, microcephaly, hemiparesis, diplegia, and
the region of the sylvian fissure and typically communicate with the seizures.
subarachnoid space, the ventricular system, or both. They represent The anatomic features of agenesis of the corpus callosum are best
developmental abnormalities of cell migration and are often associated depicted on MRI or CT scan and include widely separated frontal
with other malformations of the brain, including microcephaly, abnor- horns with an abnormally high position of the third ventricle between
mal patterns of adjacent gyri, and encephalocele. Affected infants tend the lateral ventricles. MRI precisely outlines the extent of the corpus
to have many problems, including intellectual disability, spastic hemi- callosum defect.
paresis or quadriparesis, optic atrophy, and seizures. Absence of the corpus callosum may be inherited as an X-linked
Several risk factors for porencephalic cyst formation have been iden- recessive trait or as an autosomal dominant trait and on occasion as an
tified, including hemorrhagic venous infarctions; various thrombo- autosomal recessive trait. The condition may be associated with specific
philias such as protein C deficiency and factor V Leiden mutations; chromosomal disorders, particularly trisomy 8 and trisomy 18. Single-
perinatal alloimmune thrombocytopenia; von Willebrand disease; gene mutations have also been identified, usually in association with
maternal warfarin use; maternal cocaine use; congenital infections; other anomalies. Agenesis of the corpus callosum is also seen in some
trauma such as amniocentesis; and maternal abdominal trauma. Muta- metabolic disorders (Table 591-2).
tions in the COL4A1 gene have been described in cases of familial Aicardi syndrome represents a complex disorder that affects many
porencephaly. systems and is typically associated with agenesis of the corpus cal-
Pseudoporencephalic cysts characteristically develop during the losum, distinctive chorioretinal lacunae, and infantile spasms. Patients
perinatal or postnatal period and result from abnormalities (infarction, are almost all female, suggesting a genetic abnormality of the X
hemorrhage) of arterial or venous circulation. These cysts tend to be chromosome (it may be lethal in males during fetal life). Seizures
unilateral, do not communicate with a fluid-filled cavity, and are not become evident during the 1st few mo and are typically resistant to
associated with abnormalities of cell migration or CNS malformations. anticonvulsants. An electroencephalogram shows independent activ-
Infants with pseudoporencephalic cysts present with hemiparesis and ity recorded from both hemispheres as a result of the absent corpus
focal seizures in the 1st yr of life and sometimes present with neonatal callosum and shows often hemihypsarrhythmia. All patients have
encephalopathy or as a floppy newborn or infant. severe intellectual disability and can have abnormal vertebrae that
may be fused or only partially developed (hemivertebra). Abnormali-
Bibliography is available at Expert Consult. ties of the retina, including circumscribed pits or lacunae and colo-
boma of the optic disc, are the most characteristic findings of Aicardi
syndrome.
Colpocephaly refers to an abnormal enlargement of the occipital
591.8 Agenesis of the Corpus Callosum horns of the ventricular system and can be identified as early as the
Stephen L. Kinsman and Michael V. Johnston fetal period. It is often associated with agenesis of the corpus callosum,
but it can occur in isolation. It is also associated with microcephaly. It
Agenesis of the corpus callosum consists of a heterogeneous group can also be seen in anatomic megalencephaly, such as is associated with
of disorders that vary in expression from severe intellectual and neu- Sotos syndrome.
rologic abnormalities to the asymptomatic and normally intelligent
patient (Fig. 591-8). The corpus callosum develops from the commis- HOLOPROSENCEPHALY
sural plate that lies in proximity to the anterior neuropore. Either a Holoprosencephaly is a developmental disorder of the brain that
direct insult to the commissural plate or disruption of the genetic results from defective formation of the prosencephalon and
Bibliography Jamuar SS, Lam ATN, Kircher M, et al: Somatic mutations in cerebral cortical
Abdel Razek AAK, Kandell AY, Elsorogy LG, et al: Disorders of cortical formation: malformations, N Engl J Med 371:733–742, 2014.
MR imaging features, AJNR Am J Neuroradiol 30:4–11, 2009. Kerjan G, Gleeson JG: Genetic mechanisms underlying abnormal neuronal
Almgren M, Schalling M, Lavebratt C: Idiopathic megalencephaly—possible cause migration in classical lissencephaly, Trends Genet 23:623–630, 2007.
and treatment opportunities: from patient to lab, Eur J Paediatr Neurol Sharif U, Kuban K: Prenatal intracranial hemorrhage and neurologic complications
12:438–445, 2008. in alloimmune thrombocytopenia, J Child Neurol 16:838–842, 2001.
Breedveld G, de Coo IF, Lequin MH, et al: Novel mutations in three families Sherlock RL, Synnes AR, Grunau RE, et al: Long-term outcome after neonatal
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43:490–495, 2006. Neonatal Ed 96:F127–F131, 2008.
Gould DB, Phalan FC, Breedveld GJ, et al: Mutations in Col4a1 cause perinatal Spalice A, Parisi P, Nicita F, et al: Neuronal migration disorders: clinical,
cerebral hemorrhage and porencephaly, Science 308:1167–1171, 2005. neuroradiologic and genetics aspects, Acta Paediatr 98:421–433, 2009.
Guerrini R, Dobyns WB, Barkovich AJ: Abnormal development of the human van der Knaap MS, Smit LME, Barkhof F, et al: Neonatal porencephaly and adult
cerebral cortex: genetics, functional consequences and treatment options, Trends stroke related to mutations in collagen IV A1, Ann Neurol 59:504–511, 2006.
Neurosci 31:154–162, 2008. Wynshaw-Boris A: Lissencephaly and LIS1: insights into the molecular
Hayashi N, Tsutsumi Y, Barkovich AJ: Polymicrogyria without porencephaly/ mechanisms of neuronal migration and development, Clin Genet 72:296–304,
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2002.
Table 591-2 Disorders Associated with Agenesis of the Corpus Callosum*

DISORDER SALIENT FEATURES
WITH IDENTIFIED GENES†
Andermann syndrome (KCC3) ACC, progressive neuropathy, and dementia
Donnai-Barrow syndrome (LRP2) Diaphragmatic hernia, exomphalos, ACC, deafness
Frontonasal dysplasia (ALX1) ACC, bilateral extreme microphthalmia, bilateral oblique facial cleft
XLAG (ARX) Lissencephaly, ACC, intractable epilepsy
Microcephaly (TBR2) ACC, polymicrogyria
Microcephaly with simplified gyral pattern and ACC (WDR62)
Mowat-Wilson syndrome (ZFHX1B) Hirschsprung disease, ACC
Pyridoxine-dependent epilepsy (ALDH7A1) ACC, seizures, other brain malformations
Pyruvate dehydrogenase deficiency (PDHA1, PDHB, PDHX) ACC with other brain changes
ACC with fatal lactic acidosis (MRPS16) Complexes I and IV deficiency, ACC, brain malformations
HSAS/MASA syndromes (L1CAM) Hydrocephalus, adducted thumbs, ACC, MR
ACC SEEN CONSISTENTLY (NO GENE YET IDENTIFIED)
Acrocallosal syndrome ACC, polydactyly, craniofacial changes, MR
Aicardi syndrome ACC, chorioretinal lacunae, infantile spasms, MR
Chudley-McCullough syndrome Hearing loss, hydrocephalus, ACC, colpocephaly
FG syndrome MR, ACC, craniofacial changes, macrocephaly
Genitopatellar syndrome Absent patellae, urogenital malformations, ACC
Temtamy syndrome ACC, optic coloboma, craniofacial changes, MR
Toriello-Carey syndrome ACC, craniofacial changes, cardiac defects, MR
Vici syndrome ACC, albinism, recurrent infections, MR
ACC SEEN OCCASIONALLY (PARTIAL LIST)‡
ACC with spastic paraparesis (SPG11; SPG15) Progressive spasticity and neuropathy, thin corpus callosum
Craniofrontonasal syndrome Coronal craniosynostosis, facial asymmetry, bifid nose
Fryns syndrome CDH, pulmonary hypoplasia, craniofacial changes
Marden-Walker syndrome Blepharophimosis, micrognathia, contractures, ACC
Meckel-Gruber syndrome Encephalocele, polydactyly, polycystic kidneys
Nonketotic hyperglycinemia (GLDC, GCST, GCSH) ACC, cerebral and cerebellar atrophy, myoclonus, progressive
encephalopathy
Microphthalmia with linear skin defects Microphthalmia, linear skin markings, seizures
Opitz G syndrome Pharyngeal cleft, craniofacial changes, ACC, MR
Orofaciodigital syndrome Tongue hamartoma, microretrognathia, clinodactyly
Pyruvate decarboxylase deficiency Lactic acidosis, seizures, severe MR and spasticity
Rubinstein-Taybi syndrome Broad thumbs and great toes, MR, microcephaly
Septooptic dysplasia (de Morsier syndrome) Hypoplasia of septum pellucidum and optic chiasm
Sotos syndrome Physical overgrowth, MR, craniofacial changes
Warburg micro syndrome Microcephaly, microphthalmia, microgenitalia, MR
Wolf-Hirschhorn syndrome Microcephaly, seizures, cardiac defects, 4p−
*Reliable incidence data are unavailable for these very rare syndromes.
†
Gene symbols in parentheses.
‡
Many of these also may consistently have a thin of dysplastic corpus callosum, such as Sotos’ syndrome or agenesis of the corpus callosum (ACC) with spastic
paraparesis (SPG11). The overlap between ACC and these conditions is still under investigation. Other gene symbols are omitted from this section.
4p−, deletion of the terminal region of the short arm of chromosome 4, defines the genotype for Wolf-Hirschhorn patients; ACC, agenesis of the corpus callosum;
ARX, Aristaless-related homeobox gene; CDH, congenital diaphragmatic hernia; HSAS/MASA, X-linked hydrocephalus/mental retardation, aphasia, shuffling gait, and
adducted thumbs; KCC3, KCl cotransporter 3; L1CAM, L1 cell adhesion molecule; MR, mental retardation; MRPS16, mitochondrial ribosomal protein S16; SPG11,
spastic paraplegia 11; XLAG, X-linked lissencephaly with absent corpus callosum and ambiguous genitalia; ZFHX1B, zinc finger homeobox 1b.
From Sherr EH, Hahn JS: Disorders of forebrain development. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s pediatric neurology, 5th ed.
Philadelphia, 2012, WB Saunders, Table 23-2.
inadequate induction of forebrain structures. The abnormality, which Affected children with the alobar type have high mortality rates, but
represents a spectrum of severity, is classified into 3 groups: alobar, some live for years. Mortality and morbidity with milder types are
semilobar, and lobar, depending on the degree of the cleavage abnor- more variable, and morbidity is less severe. Care must be taken not to
mality (Fig. 591-9). A fourth type, the middle interhemispheric fusion prognosticate severe outcomes in all cases. The incidence of holopros-
variant or syntelencephaly, involves a segmental area of noncleavage, encephaly ranges from 1 in 5,000-16,000 live births. A prenatal diag-
actually a nonseparation, of the posterior frontal and parietal lobes. nosis can be confirmed by ultrasonography after the 10th wk of
Facial abnormalities, including cyclopia, synophthalmia, cebocephaly, gestation for more severe types, but fetal MRI at later gestational ages
single nostril, choanal atresia, solitary central incisor tooth, and pre- gives far greater anatomic, and therefore diagnostic, precision.
maxillary agenesis are common in severe cases, because the pre- The cause of holoprosencephaly is often not identified. There appears
chordal mesoderm that induces the ventral prosencephalon is also to be an association with maternal diabetes. Chromosomal abnormali-
responsible for induction of the median facial structures. Milder facial ties, including deletions of chromosomes 7q and 3p, 21q, 2p, 18p, and
abnormalities are seen in milder forms. Alobar holoprosencephaly is 13q, as well as trisomy 13 and 18, account for upwards of 50% of all
characterized by a single ventricle, an absent falx, and nonseparated cases. Mutations in the sonic hedgehog gene at 7q have been shown to
deep cerebral nuclei. Care must be taken not to overdiagnose holo- cause holoprosencephaly. Gene Reviews lists 14 single-gene causes.
prosencephaly based on ventricular abnormalities alone. Evidence of Clinically, it is important to look for associated anomalies, because
nonseparated midline deep-brain structures, such as caudate, many syndromes are associated with holoprosencephaly.
putamen, globus pallidus, and hypothalamus, is the critical element
for diagnosis. Bibliography is available at Expert Consult.
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Bedeschi MF, Bonaglia MC, Grasso R, et al: Agenesis of the corpus callosum: migration in classical lissencephaly, Trends Genet 23:623–630, 2007.
clinical and genetic study in 63 young patients, Pediatr Neurol 34:186–193, Miller SP, Shevell MI, Patenaude Y, et al: Septo-optic dysplasia plus: a spectrum of
2006. malformations of cortical development, Neurology 54:1701–1703, 2000.
Bendavid C, Dubourg C, Gicquel I, et al: Molecular evaluation of foetuses with Moes P, Schilmoeller K, Schilmoeller G: Physical, motor, sensory and
holoprosencephaly shows high incidence of microdeletions in the HPE genes, developmental features associated with agenesis of the corpus callosum, Child
Hum Genet 119:1–8, 2006. Care Health Dev 35:656–672, 2009.
Cohen MM: Holoprosencephaly: clinical, anatomic, and molecular dimensions, Neidich JA, Nussbaum RL, Packer RJ, et al: Heterogeneity of clinical severity and
Birth Defects Res A Clin Mol Teratol 76:658–673, 2006. molecular lesions in Aicardi syndrome, J Pediatr 116:911–917, 1990.
Dubourg C, Lazaro L, Pasquier L, et al: Molecular screening of SHH, ZIC2, SIX3, Passos-Bueno MR, et al: Genetics of craniosynostosis: genes, syndromes, mutations
and TGIF genes in patients with features of holoprosencephaly spectrum: and genotype-phenotype correlations, Front Oral Biol 12:107–143, 2008.
mutation review and genotype-phenotype correlations, Hum Mutat 24:43–51, Polizzi A, Pavone P, Iannetti P, et al: Septo-optic dysplasia complex: a
2004. heterogeneous malformation syndrome, Pediatr Neurol 34:66–71, 2006.
Glass HC, Shaw GM, Ma C, et al: Agenesis of the corpus callosum in California Schell-Apacik CC, Wagner K, Bihler M, et al: Agenesis and dysgenesis of the
1983–2003: a population-based study, Am J Med Genet 146A:2495–2500, 2008. corpus callosum: clinical, genetic and neuroimaging findings in a series of 41
Goetzinger KR, Stamilio DM, Dicke JM, et al: Evaluating the incidence and patients, Am J Med Genet 146A:2501–2511, 2008.
likelihood ratios for chromosomal abnormalities in fetuses with common Smith T, Tekes A, Boltshauser E, et al: Commissural malformations: beyond the
central nervous system malformations, Am J Obstet Gynecol 199(285):e1–e6, corpus callosum, J Neuroradiol 35:301–303, 2008.
2008. Tang PH, Bartha AI, Norton ME, et al: Agenesis of the corpus callosum: an MR
Griffiths PD, Batty R, Connolly DA, et al: Effects of failed commissuration on the imaging analysis of associated abnormalities in the fetus, AJNR Am J
septum pellucidum and fornix: implications for fetal imaging, Neuroradiology Neuroradiol 30:257–263, 2009.
51:347–356, 2009. Volpe P, Campobasso G, De Robertis V, et al: Disorders of prosencephalic
Herman-Sucharska I, Bekiesinska-Figatowska M, Urbanik A: Fetal central nervous development, Prenat Diagn 29:340–354, 2009.
system malformations on MR images, Brain Dev 31:185–199, 2009.
innervation by the oculomotor nerve of the lateral rectus muscle.

Abnormalities of cranial nerve development have been demonstrated
in this condition.
Less common than Duane retraction syndrome and Möbius syn-
drome are the group of disorders known as congenital fibrosis of the
extraocular muscles. Congenital fibrosis of the extraocular muscles is
characterized by severe restriction of eye movements and ptosis from
abnormal oculomotor and trochlear nerve development and/or from
abnormalities of extraocular muscle innervation.
BRAINSTEM AND CEREBELLAR DISORDERS

Disorders of the posterior fossa structures include abnormalities of not
only the brainstem and cerebellum, but also the CSF spaces. Com-
monly encountered malformations include Chiari malformation,
Dandy-Walker malformation, arachnoid cysts, mega cisterna magna,
persisting Blake pouch, Joubert syndrome, rhombencephalosynapsis,
Lhermitte-Duclos disease, and the pontocerebellar hypoplasias.
Chiari malformation is the most common malformation of the
posterior fossa and hindbrain. It consists of herniation of the cerebellar
tonsils though the foramen magnum. Often, there is also an associated
developmental abnormality of the bones of the skull base leading to a
small posterior fossa. Cases can be either asymptomatic or symptom-
atic. When symptoms develop, they often do not do so until late child-
hood. Symptoms include headaches that are worse with straining and
other maneuvers that increase intracranial pressure. Symptoms of
brainstem compression such as diplopia, oropharyngeal dysfunction,
spasticity, tinnitus, and vertigo can occur. Obstructive hydrocephalus
Figure 591-9 Lobar holoprosencephaly. T1-weighted MRI scan dem- and/or syringomyelia can also occur.
onstrates failure of separation of the hemispheres and a persistent Dandy-Walker malformation is part of a continuum of posterior
fused ventricle. fossa anomalies that include cystic dilation of the fourth ventricle,
hypoplasia of the cerebellar vermis, hydrocephalus, and an enlarged
posterior fossa with elevation of the lateral venous sinuses and the
591.9 Agenesis of the Cranial Nerves and tentorium. Extracranial anomalies are also seen. Variable degrees of
neurologic impairment are usually present. The etiology of Dandy-
Dysgenesis of the Posterior Fossa Walker malformation includes chromosomal abnormalities, single
Stephen L. Kinsman and Michael V. Johnston gene disorders, and exposure to teratogens.
Arachnoid cysts of the posterior fossa can be associated with hydro-
Classification of disorders of cranial nerve, brainstem, and cerebellum cephalus. Mega cisterna magna is characterized by an enlarged CSF
development remains anatomic, but future classification systems will space inferior and dorsal to the cerebellar vermis and when present in
likely be based on the molecular biology of brain development based isolation may be considered a normal variant. Persisting Blake pouch
on the genes involved and the roles they play in orchestrating brain is a cyst that obstructs the subarachnoid space and is associated with
architecture. hydrocephalus.
Joubert syndrome is an autosomal recessive disorder (ciliopathy)
CONGENITAL CRANIAL DYSINNERVATION with significant genetic heterogeneity that is associated with cerebellar
DISORDERS vermis hypoplasia and the pontomesencephalic molar tooth sign (a
Absence of the cranial nerves or the corresponding central nuclei has deepening of the interpeduncular fossa with thick and straight superior
been described in several conditions and includes the optic nerve cerebellar peduncles) (Fig. 591-10). It is associated with hypotonia,
defects, congenital ptosis, Marcus Gunn phenomenon (sucking jaw ataxia (as toddler), characteristic breathing abnormalities including
movements causing simultaneous eyelid blinking; this congenital syn- episodic apnea and hyperpnea (which improves with age), global
kinesis results from abnormal innervation of the trigeminal and ocu- developmental delay, nystagmus, strabismus, ptosis, and oculomotor
lomotor nerves), trigeminal and auditory nerves defects, and cranial apraxia. There can be many associated systemic features (Joubert syn-
nerves IX, X, XI, and XII defects. Increased understanding of these drome and related disorders) including progressive retinal dysplasia
disorders and their genetic causes has led to the term congenital cranial (Leber congenital amaurosis), coloboma, congenital heart disease,
dysinnervation disorders. microcystic kidney disease, liver fibrosis, polydactyly, tongue protru-
Optic nerve hypoplasia can occur in isolation or as part of the sep- sion, and soft tissue tumors of the tongue (Fig. 591-11).
tooptic dysplasia complex (de Morsier syndrome). Septooptic dyspla- Rhombencephalosynapsis is an absent or small vermis associated
sia can be caused by a mutation in the HESX1 gene. with a nonseparation or fusion of the deep midline cerebellar struc-
Möbius syndrome is characterized by bilateral facial weakness, tures. Ventriculomegaly or hydrocephalus is often seen. There is vari-
which is often associated with paralysis of the abducens nerve. Hypo- able clinical presentation from normal to cognitive and language
plasia or agenesis of brainstem nuclei, as well as absent or decreased impairments, epilepsy, and spasticity. Lhermitte-Duclos disease is a
numbers of muscle fibers, has been reported. Affected infants present dysplastic gangliocytoma of the cerebellum leading to focal enlarge-
in the newborn period with facial weakness, causing feeding difficulties ment of the cerebellum and macrocephaly, cerebellar signs, and
owing to a poor suck. The immobile, dull facies might give the incor- seizures.
rect impression of intellectual impairment; the prognosis for normal Pontocerebellar hypoplasias are a group of disorders characterized
development is excellent in most cases. The facial appearance of by impairment of cerebellar and pontine development together with
Möbius syndrome has been improved by facial surgery. histopathologic features of neuronal death and glial replacement. Clin-
Duane retraction syndrome is characterized by congenital limita- ical features tend to be nonspecific and include hypotonia, feeding
tion of horizontal globe movement and some globe retraction on difficulties, developmental delay, and breathing difficulties. Classifica-
attempted adduction and is believed to be the result of abnormal tion, associations, and causes include type I (with features of anterior
A B C D
Figure 591-10 Neuroimaging findings in a 2-yr-old child with pure Joubert syndrome (upper panels) compared to a healthy control (lower
panels). A, Parasagittal T1-weighted image shows the thickened, elongated, and horizontally orientated superior cerebellar peduncles (white arrow).
B, Midsagittal T1-weighted image demonstrates a moderate hypoplasia and dysplasia of the cerebellar vermis (white arrows) with secondary
distortion and enlargement of the fourth ventricle with rostral shifting of the fastigium (white arrowhead). A deepened interpeduncular fossa is
also noted. C, Axial T1-weighted image at the level of the pontomesencephalic junction shows the molar tooth sign with a deepened interpedun-
cular fossa (white arrowhead) and elongated, thickened, and horizontally orientated superior cerebellar peduncles (white arrows). Additionally, the
cerebellar vermis appears to be hypoplastic and its remnants dysplastic. D, Coronal T1-weighted image reveals the thickened superior cerebellar
peduncles (white arrows). (From Romani M, Micalizzi A, Valente EM: Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet
Neurol 12:894–905, 2013, Fig. 1.)
Figure 591-11 Spectrum of organ involvement in Joubert syndrome and classification in clinical subgroups (in bold). Chorioretinal colobomas
are more frequently found in the subgroup of Joubert syndrome with liver involvement but can be present also in other subgroups. Similarly,
polydactyly (especially if preaxial or mesoaxial) is invariably present in the Orofaciodigital type VI subgroup, but postaxial polydactyly is frequently
observed also in association with other Joubert syndrome phenotypes. Other clinical features outside the circles occur more rarely, without a
specific association to a clinical subgroup. CNS, central nervous system; COR, cerebello oculorenal; K, kidney involvement; L, liver involvement;
MTS, molar tooth sign; OFDVI, orofaciodigital type VI syndrome. (From Romani M, Micalizzi A, Valente EM: Joubert syndrome: congenital cerebel-
lar ataxia with the molar tooth. Lancet Neurol 12:894–905, 2013, Fig. 3.)
horn cell involvement), type II (with extrapyramidal features, seizures, Although there are many causes of microcephaly, abnormalities in
and acquired microcephaly), Walker-Warburg syndrome, muscle-eye- neuronal migration during fetal development, including heterotopias
brain disease, congenital disorders of glycosylation type 1A, mitochon- of neuronal cells and cytoarchitectural derangements, are often found.
drial cytopathies, teratogen exposure, congenital cytomegalovirus Microcephaly may be subdivided into 2 main groups: primary (genetic)
infection, 3-methylglutaconic aciduria, PEHO syndrome (progressive microcephaly and secondary (nongenetic) microcephaly. A precise
encephalopathy with edema, hypsarrhythmia, and optic atrophy), diagnosis is important for genetic counseling and for prediction for
autosomal recessive cerebellar hypoplasia in the Hutterite population, future pregnancies.
lissencephaly with cerebellar hypoplasia, and other subtypes of ponto-
cerebellar hypoplasia. ETIOLOGY
Primary microcephaly refers to a group of conditions that usually have
Bibliography is available at Expert Consult. no associated malformations and follow a mendelian pattern of inheri-
tance or are associated with a specific genetic syndrome. Affected
infants are usually identified at birth because of a small head circumfer-
ence. The more common types include familial and autosomal domi-
591.10 Microcephaly nant microcephaly and a series of chromosomal syndromes that are
Stephen L. Kinsman and Michael V. Johnston summarized in Table 591-3. Primary microcephaly is also associated
with at least 7 gene loci, and 7 single etiologic genes have been identi-
Microcephaly is defined as a head circumference that measures more fied. It is known as autosomal recessive primary microcephaly and
than 3 SD below the mean for age and sex. This condition is relatively has autosomal inheritance. Many X-linked causes of microcephaly
common, particularly among developmentally delayed children. are caused by gene mutations that lead to severe structural brain
Table 591-3 Causes of Microcephaly

CAUSES CHARACTERISTIC FINDINGS
PRIMARY (GENETIC)
Familial (autosomal Incidence 1 in 40,000 live births
recessive) Typical appearance with slanted forehead, prominent nose and ears; severe mental retardation and
prominent seizures; surface convolutional markings of the brain, poorly differentiated and disorganized
cytoarchitecture
Autosomal dominant Nondistinctive facies, upslanting palpebral fissures, mild forehead slanting, and prominent ears
Normal linear growth, seizures readily controlled, and mild or borderline mental retardation
Syndromes
Down (trisomy 21) Incidence 1 in 800 live births
Abnormal rounding of occipital and frontal lobes and a small cerebellum; narrow superior temporal gyrus,
propensity for Alzheimer neurofibrillary alterations, ultrastructure abnormalities of cerebral cortex
Edward (trisomy 18) Incidence 1 in 6,500 live births
Low birthweight, microstomia, micrognathia, low-set malformed ears, prominent occiput, rocker-bottom
feet, flexion deformities of fingers, congenital heart disease, increased gyri, heterotopias of neurons
Cri-du-chat (5 p-) Incidence 1 in 50,000 live births
Round facies, prominent epicanthic folds, low-set ears, hypertelorism, characteristic cry
No specific neuropathology
Cornelia de Lange Prenatal and postnatal growth delay; synophrys; thin, downturning upper lip
Proximally placed thumb
Rubinstein-Taybi Beaked nose, downward slanting of palpebral fissures, epicanthic folds, short stature, broad thumbs and
toes
Smith-Lemli-Opitz Ptosis, scaphocephaly, inner epicanthic folds, anteverted nostrils
Low birthweight, marked feeding problems
SECONDARY (NONGENETIC)
Congenital Infections
Cytomegalovirus Small for dates, petechial rash, hepatosplenomegaly, chorioretinitis, deafness, mental retardation, seizures
Central nervous system calcification and microgyria
Rubella Growth retardation, purpura, thrombocytopenia, hepatosplenomegaly, congenital heart disease,
chorioretinitis, cataracts, deafness
Perivascular necrotic areas, polymicrogyria, heterotopias, subependymal cavitations
Toxoplasmosis Purpura, hepatosplenomegaly, jaundice, convulsions, hydrocephalus, chorioretinitis, cerebral calcification
Drugs
Fetal alcohol Growth retardation, ptosis, absent philtrum and hypoplastic upper lip, congenital heart disease, feeding
problems, neuroglial heterotopia, disorganization of neurons
Fetal hydantoin Growth delay, hypoplasia of distal phalanges, inner epicanthic folds, broad nasal ridge, anteverted nostrils
Other Causes
Radiation Microcephaly and mental retardation most severe with exposure before 15th wk of gestation
Meningitis/encephalitis Cerebral infarcts, cystic cavitation, diffuse loss of neurons
Malnutrition Controversial cause of microcephaly
Metabolic Maternal diabetes mellitus and maternal hyperphenylalaninemia
Hyperthermia Significant fever during 1st 4-6 wk has been reported to cause microcephaly, seizures, and facial anomalies
Pathologic studies show neuronal heterotopias
Further studies show no abnormalities with maternal fever
Hypoxic–ischemic Initially diffuse cerebral edema; late stages characterized by cerebral atrophy and abnormal signals on MRI
encephalopathy
Bibliography Romani M, Micalizzi A, Valente EM: Joubert syndrome: congenital cerebellar

Bolduc M, Limperopoulos C: Neurodevelopmental outcomes in children with ataxia with the molar tooth, Lancet Neurol 12:894–905, 2013.
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51:256–267, 2009. series of 24 pediatric patients and evaluation of associated anomalies, incidence
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2009. of syndromes with congenital limitation of eye movements, Trans Am
Jaspan T: New concepts on posterior fossa malformations, Pediatr Radiol Ophthalmol Soc 102:373–389, 2004.
38:S409–S414, 2008.
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Prenat Diagn 26:707–710, 2006.
malformations such as lissencephaly, holoprosencephaly, polymicro-

gyria, cobblestone dysplasia, neuronal heterotopia, pontocerebellar Table 591-4 Causes of Hydrocephalus
hypoplasia; these should be sought on MRI. Secondary microcephaly COMMUNICATING
results from a large number of noxious agents that can affect a fetus in Achondroplasia
utero or an infant during periods of rapid brain growth, particularly Basilar impression
the 1st 2 yr of life. Benign enlargement of subarachnoid space
Acquired microcephaly can be seen in conditions such as Rett, Choroid plexus papilloma
Seckel, and Angelman syndromes and in encephalopathy syndromes Meningeal malignancy
associated with severe seizure disorders. Meningitis
Posthemorrhagic
CLINICAL MANIFESTATIONS AND DIAGNOSIS NONCOMMUNICATING
A thorough family history should be taken, seeking additional cases of Aqueductal stenosis
microcephaly or disorders affecting the nervous system. It is important Infectious*
to measure a patient’s head circumference at birth to diagnose micro- X-linked
cephaly as early as possible. A very small head circumference implies Mitochondrial
Autosomal recessive
a process that began early in embryonic or fetal development. An insult
Autosomal dominant
to the brain that occurs later in life, particularly beyond the age of 2 yr, L1CAM mutations
is less likely to produce severe microcephaly. Serial head circumference Chiari malformation
measurements are more meaningful than a single determination, par- Dandy-Walker malformation
ticularly when the abnormality is minimal. The head circumference of Klippel-Feil syndrome
each parent and sibling should be recorded. Mass lesions
Laboratory investigation of a microcephalic child is determined by Abscess
the history and physical examination. If the cause of the microcephaly Hematoma
is unknown, the mother’s serum phenylalanine level should be deter- Tumors and neurocutaneous disorders
Vein of Galen malformation
mined. High phenylalanine serum levels in an asymptomatic mother
Walker-Warburg syndrome
can produce marked brain damage in an otherwise normal nonphe-
nylketonuric infant. A karyotype and/or array comparative genomic HYDRANENCEPHALY
hybridization study is obtained if a chromosomal syndrome is sus- Holoprosencephaly
pected or if the child has abnormal facies, short stature, and additional Massive hydrocephalus
congenital anomalies. MRI is useful in identifying structural abnor- Porencephaly
malities of the brain such as lissencephaly, pachygyria, and polymicro- *Toxoplasmosis, neurocysticercosis mumps.
gyria, and CT scanning is useful to detect intracerebral calcification. From Fenichel GM: Clinical pediatric neurology, ed 5, Philadelphia, 2005,
Additional studies include a fasting plasma and urine amino acid Elsevier, p. 354.
analysis; serum ammonia determination; toxoplasmosis, rubella,
cytomegalovirus, and herpes simplex (TORCH) titers as well as HIV innervate the choroid plexus. Stimulation of the adrenergic system
testing of the mother and child; and a urine sample for the culture of diminishes CSF production, whereas excitation of the cholinergic
cytomegalovirus. Single-gene mutations as a cause of both primary nerves may double the normal CSF production rate. In a normal child,
microcephaly and syndromic microcephaly are being increasingly approximately 20 mL/hr of CSF is produced. The total volume of CSF
identified. approximates 50 mL in an infant and 150 mL in an adult. Most of the
CSF is extraventricular. The choroid plexus forms CSF in several stages;
TREATMENT through a series of intricate steps, a plasma ultrafiltrate is ultimately
Once the cause of microcephaly has been established, the physician processed into a secretion, the CSF.
must provide accurate and supportive genetic and family counseling. CSF flow results from the pressure gradient that exists between the
Because many children with microcephaly are also intellectually chal- ventricular system and venous channels. Intraventricular pressure may
lenged, the physician must assist with placement in an appropriate be as high as 180 mm H2O in the normal state, whereas the pressure
program that will provide for maximal development of the child (see in the superior sagittal sinus is in the range of 90 mm H2O. Normally,
Chapter 36). CSF flows from the lateral ventricles through the foramina of Monro
into the 3rd ventricle. It then traverses the narrow aqueduct of Sylvius,
Bibliography is available at Expert Consult. which is approximately 3 mm long and 2 mm in diameter in a child,
to enter the fourth ventricle. The CSF exits the fourth ventricle through
the paired lateral foramina of Luschka and the midline foramen of
Magendie into the cisterns at the base of the brain. Hydrocephalus
591.11 Hydrocephalus resulting from obstruction within the ventricular system is called
Stephen L. Kinsman and Michael V. Johnston obstructive or noncommunicating hydrocephalus. The CSF then cir-
culates from the basal cisterns posteriorly through the cistern system
Hydrocephalus is not a specific disease; it represents a diverse group and over the convexities of the cerebral hemispheres. CSF is absorbed
of conditions that result from impaired circulation and/or absorption primarily by the arachnoid villi through tight junctions of their endo-
of CSF or, in rare circumstances, from increased production of CSF by thelium by the pressure forces that were noted earlier. CSF is absorbed
a choroid plexus papilloma (Table 591-4). Because megalencephaly is to a much lesser extent by the lymphatic channels directed to the
often discovered as part of an evaluation for hydrocephalus in children paranasal sinuses, along nerve root sleeves, and by the choroid plexus
with macrocephaly, it is included in this section. itself. Hydrocephalus resulting from obliteration of the subarachnoid
cisterns or malfunction of the arachnoid villi is called nonobstructive
PHYSIOLOGY or communicating hydrocephalus.
The CSF is formed primarily in the ventricular system by the choroid
plexus, which is situated in the lateral, third, and fourth ventricles. PATHOPHYSIOLOGY AND ETIOLOGY
Although most CSF is produced in the lateral ventricles, approximately Obstructive or noncommunicating hydrocephalus develops most com-
25% originates from extrachoroidal sources, including the capillary monly in children because of an abnormality of the aqueduct of Sylvius
endothelium within the brain parenchyma. There is active neurogenic or a lesion in the fourth ventricle. Aqueductal stenosis results from an
control of CSF formation because adrenergic and cholinergic nerves abnormally narrow aqueduct of Sylvius that is often associated with
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branching or forking. In a small percentage of cases, aqueductal steno-

sis is inherited as a sex-linked recessive trait. These patients occasion-
ally have minor neural tube closure defects, including spina bifida
occulta. Rarely, aqueductal stenosis is associated with neurofibromato-
sis. Aqueductal gliosis can also give rise to hydrocephalus. As a result
of neonatal meningitis or a subarachnoid hemorrhage in a premature
infant, the ependymal lining of the aqueduct is interrupted and a brisk
glial response results in complete obstruction. Intrauterine viral infec-
tions can also produce aqueductal stenosis followed by hydrocephalus,
and mumps meningoencephalitis has been reported as a cause in a
child. A vein of Galen malformation can expand to become large and,
because of its midline position, obstruct the flow of CSF. Lesions or
malformations of the posterior fossa are prominent causes of hydro-
cephalus, including posterior fossa brain tumors, Chiari malformation,
and the Dandy-Walker syndrome.
Nonobstructive or communicating hydrocephalus most commonly
follows a subarachnoid hemorrhage, which is usually a result of intra-
ventricular hemorrhage in a premature infant. Blood in the subarach-
noid spaces can cause obliteration of the cisterns or arachnoid villi and
obstruction of CSF flow. Pneumococcal and tuberculous meningitis
have a propensity to produce a thick, tenacious exudate that obstructs
the basal cisterns, and intrauterine infections can also destroy the CSF
pathways. Leukemic infiltrates can seed the subarachnoid space and
produce communicating hydrocephalus. *
CLINICAL MANIFESTATIONS
The clinical presentation of hydrocephalus is variable and depends on
many factors, including the age at onset, the nature of the lesion
causing obstruction, and the duration and rate of increase of the intra-
cranial pressure (ICP). In an infant, an accelerated rate of enlargement
of the head is the most prominent sign. In addition, the anterior fon-
Figure 591-12 Sagittal MR scan of a patient with Chiari malforma-
tanel is wide open and bulging, and the scalp veins are dilated. The tion type I. Cerebellar tonsils are displaced through the foramen
forehead is broad, and the eyes might deviate downward because of magnum (white bar) to the lower aspect of C2 with clear crowding at
impingement of the dilated suprapineal recess on the brainstem tectum, the foramen. A syrinx (white asterisk) is visible extending from C3 to
producing the setting-sun eye sign. Long-tract signs, including brisk T2. (From Yassari R, Frim D: Evaluation and management of the Chiari
tendon reflexes, spasticity, clonus (particularly in the lower extremi- malformation type 1 for the primary care pediatrician, Pediatr Clin
ties), and Babinski sign, are common owing to stretching and disrup- North Am 51:477–490, 2004.)
tion of the corticospinal fibers originating from the leg region of the
motor cortex. In an older child, the cranial sutures are less accommo-
dating so that the signs of hydrocephalus may be subtler. Irritability, (Fig. 591-13). Approximately 10% of type II malformations produce
lethargy, poor appetite, and vomiting are common to both age groups, symptoms during infancy, consisting of stridor, weak cry, and apnea,
and headache is a prominent symptom in older patients. A gradual which may be relieved by shunting or by decompression of the poste-
change in personality and deterioration in academic productivity rior fossa. A more indolent form consists of abnormalities of gait,
suggest a slowly progressive form of hydrocephalus. With regard to spasticity, and increasing incoordination (including the arms and
other clinical signs, serial measurements of the head circumference hands) during childhood.
often indicate an increased velocity of growth. Percussion of the skull Plain skull radiographs show a small posterior fossa and a widened
might produce a cracked pot sound or Macewen sign, indicating sepa- cervical canal. CT scanning with contrast and MRI display the cerebel-
ration of the sutures. A foreshortened occiput suggests Chiari malfor- lar tonsils protruding downward into the cervical canal and the hind-
mation, and a prominent occiput suggests the Dandy-Walker brain abnormalities. The anomaly is treated by surgical decompression,
malformation. Papilledema, abducens nerve palsies, and pyramidal but asymptomatic or mildly symptomatic patients may be managed
tract signs, which are most evident in the lower extremities, are appar- conservatively.
ent in many cases. The Dandy-Walker malformation consists of a cystic expansion of
Chiari malformation consists of 2 major subgroups. Type I typically the fourth ventricle in the posterior fossa and midline cerebellar hypo-
produces symptoms during adolescence or adult life and is usually not plasia, which results from a developmental failure of the roof of the
associated with hydrocephalus. Patients complain of recurrent head- fourth ventricle during embryogenesis (Fig. 591-14). Approximately
ache, neck pain, urinary frequency, and progressive lower-extremity 90% of patients have hydrocephalus, and a significant number of chil-
spasticity. The deformity consists of displacement of the cerebellar dren have associated anomalies, including agenesis of the posterior
tonsils into the cervical canal (Fig. 591-12). Syrinx of the spinal cord, cerebellar vermis and corpus callosum. Infants present with a rapid
especially the cervical region should be looked for on MRI imaging. increase in head size and a prominent occiput. Transillumination of
Although the pathogenesis is unknown, a prevailing theory suggests the skull may be positive. Most children have evidence of long-tract
that obstruction of the caudal portion of the fourth ventricle during signs, cerebellar ataxia, and delayed motor and cognitive milestones,
fetal development is responsible. Other theories include tethering of probably due to the associated structural anomalies. The Dandy-
the cord or additional anomalies (syrinx). Walker malformation is managed by shunting the cystic cavity (and on
The type II Chiari malformation is characterized by progressive occasion the ventricles as well) in the presence of hydrocephalus.
hydrocephalus with a myelomeningocele. This lesion represents an
anomaly of the hindbrain, probably owing to a failure of pontine DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
flexure development during embryogenesis, and results in elongation Investigation of a child with hydrocephalus begins with the history.
of the fourth ventricle and kinking of the brainstem, with displacement Familial cases suggest X-linked or autosomal hydrocephalus secondary
of the inferior vermis, pons, and medulla into the cervical canal to aqueductal stenosis. A past history of prematurity with intracranial
hemorrhage, meningitis, or mumps encephalitis is important to inspected for abnormal midline skin lesions, including tufts of hair,
ascertain. Multiple café-au-lait spots and other clinical features of lipoma, or angioma that might suggest spinal dysraphism. The pres-
neurofibromatosis point to aqueductal stenosis as the cause of ence of a prominent forehead or abnormalities in the shape of the
hydrocephalus. occiput can suggest the pathogenesis of the hydrocephalus. A cranial
Examination includes careful inspection, palpation, and ausculta- bruit is audible in association with many cases of vein of Galen arte-
tion of the skull and spine. The occipitofrontal head circumference is riovenous malformation. Transillumination of the skull is positive with
recorded and compared with previous measurements. The size and massive dilation of the ventricular system or in the Dandy-Walker
configuration of the anterior fontanel are noted, and the back is syndrome. Inspection of the eyegrounds is mandatory because the
finding of chorioretinitis suggests an intrauterine infection, such as
toxoplasmosis, as a cause of the hydrocephalus. Papilledema is observed
in older children but is rarely present in infants because the cranial
sutures separate as a result of the increased pressure.
Plain skull films typically show separation of the sutures, erosion of
the posterior clinoids in an older child, and an increase in convolu-
tional markings (beaten-silver appearance) on the inside of the skull
with long-standing increased ICP. The CT scan and/or MRI along with
ultrasonography in an infant are the most important studies to identify
the specific cause and severity of hydrocephalus.
The head might appear enlarged (and can be confused with hydro-
cephalus) secondary to a thickened cranium resulting from chronic
anemia, rickets, osteogenesis imperfecta, and epiphyseal dysplasia.
Chronic subdural collections can produce bilateral parietal bone
prominence. MRI has revealed the common occurrence of benign
external hydrocephalus, a growth-limited condition where interven-
tion is rarely required. Various metabolic and degenerative disorders
of the CNS produce megalencephaly as a result of abnormal storage
of substances within the brain parenchyma. These disorders include
lysosomal diseases (Tay-Sachs disease, gangliosidosis, and the muco-
polysaccharidoses), the aminoacidurias (maple syrup urine disease),
and the leukodystrophies (metachromatic leukodystrophy, Alexander
disease, Canavan disease). In addition, cerebral gigantism (Sotos syn-
drome), other overgrowth syndromes and neurofibromatosis are char-
acterized by increased brain mass. Familial megalencephaly is inherited
Figure 591-13 A midsagittal T1-weighted MRI of a patient with type as an autosomal dominant trait and is characterized by delayed motor
II Chiari malformation. The cerebellar tonsils (white arrow) have milestones and hypotonia but normal or near-normal intelligence.
descended below the foramen magnum (black arrow). Note the small, Measurement of parents’ head circumferences is necessary to establish
slitlike fourth ventricle, which has been pulled into a vertical position. the diagnosis.
A B C
Figure 591-14 Dandy-Walker cyst. A, Axial CT scan (preoperative) showing large posterior fossa cyst (Dandy-Walker cyst; large arrows) and
dilated lateral ventricles (small arrows), a complication secondary to cerebrospinal fluid (CSF) pathway obstruction at the fourth ventricular outlet.
B, Same patient, with a lower axial CT scan showing splaying of the cerebellar hemispheres by the dilated fourth ventricle (Dandy-Walker cyst).
The dilated ventricles proximal to the fourth ventricle again show CSF obstruction caused by the Dandy-Walker cyst. C, MRI of the same patient
showing decreased size of the Dandy-Walker cyst and temporal horns (arrows) after shunting. The incomplete vermis (small arrow) now becomes
recognizable.
MEGALENCEPHALY The cause of hydranencephaly is unknown, but bilateral occlusion of

Megalencephaly is an anatomic disorder of brain growth defined as the internal carotid arteries during early fetal development would
a brain weight : volume ratio >98th percentile for age (or ≥2 SD explain most of the pathologic abnormalities. Affected infants can have
above the mean) that is usually accompanied by macrocephaly (an a normal or enlarged head circumference at birth that grows at an
occipitofrontal circumference >98th percentile). Various storage and excessive rate postnatally. Transillumination shows an absence of the
degenerative diseases are associated with megalencephaly, but ana- cerebral hemispheres. The child is irritable, feeds poorly, develops sei-
tomic and genetic causes exist as well. The most common cause of zures and spastic quadriparesis, and has little or no cognitive develop-
anatomic megalencephaly is benign familial megalencephaly. This con- ment. A ventriculoperitoneal shunt prevents massive enlargement of
dition is easily diagnosed by careful family history and measurement the cranium.
of the parents’ head circumferences (occipitofrontal circumferences).
On the other hand, macrocephaly is a known feature of more than TREATMENT
100 syndromes. Therapy for hydrocephalus depends on the cause. Medical manage-
Anatomic megalencephaly is usually apparent at birth, and head ment, including the use of acetazolamide and furosemide, can provide
growth continues to run parallel to the upper percentiles. Sometimes, temporary relief by reducing the rate of CSF production, but long-term
in some syndromes, increased occipitofrontal circumference is the pre- results have been disappointing. Most cases of hydrocephalus require
senting sign. Neuroimaging is critical in identifying the various struc- extracranial shunts, particularly a ventriculoperitoneal shunt. Endo-
tural and gyral abnormalities seen in syndromic macrocephaly and scopic third ventriculostomy has evolved as a viable approach and
determining whether anatomic megalencephaly exists. criteria have been developed for its use, but the procedure might need
Common megalencephaly-associated macrocephaly syndromes to be repeated to be effective. Ventricular shunting may be avoided
include syndromes with prenatal and/or postnatal somatic over- with this approach. The major complications of shunting are occlusion
growth such as Sotos, Simpson-Golabi-Behmel, fragile X, Weaver, (characterized by headache, papilledema, emesis, mental status
macrocephaly-cutis marmorata telangiectatica congenita, and changes) and bacterial infection (fever, headache, meningismus),
Bannayan-Ruvalcaba-Riley syndromes, and syndromes without usually caused by Staphylococcus epidermidis. With meticulous prepa-
somatic overgrowth such as FG, Greig cephalopolysyndactyly, acrocal- ration, the shunt infection rate can be reduced to <5%. The results of
losal, and Gorlin. intrauterine surgical management of fetal hydrocephalus have been
Sotos syndrome (cerebral gigantism) is the most common megalen- poor (possibly because of the high rate of associated cerebral malfor-
cephalic syndrome, with 50% of patients having prenatal macrocephaly mations in addition to the hydrocephalus) except for some promise in
and 100% of patients having macrocephaly by age 1 yr. Early postnatal cases of hydrocephalus associated with fetal meningomyelocele.
overgrowth normalizes by adulthood. Facial features include high fore-
head with frontal bossing, sparse hair in the frontoparietal region, PROGNOSIS
downslanting palpebral fissures, apparent hypertelorism, long narrow Prognosis depends on the cause of the dilated ventricles and not on
face, prominent mandible, and malar flushing. Hypotonia, poor coor- the size of the cortical mantle at the time of operative intervention,
dination, and speech delay are common. Most children show cognitive except in cases in which the cortical mantle has been severely com-
impairment, ranging from mild to severe. pressed and stretched. Hydrocephalic children are at increased risk for
various developmental disabilities. The mean intelligence quotient is
HYDRANENCEPHALY reduced compared with the general population, particularly for per-
Hydranencephaly may be confused with hydrocephalus. The cerebral formance tasks as compared with verbal abilities. Many children have
hemispheres are absent or represented by membranous sacs with rem- abnormalities in memory function. Vision problems are common,
nants of frontal, temporal, or occipital cortex dispersed over the mem- including strabismus, visuospatial abnormalities, visual field defects,
brane. The midbrain and brainstem are relatively intact (Fig. 591-15). and optic atrophy with decreased acuity secondary to increased ICP.
The visual evoked potential latencies are delayed and take some time
to recover after correction of the hydrocephalus. Although most hydro-
cephalic children are pleasant and mild mannered, some children show
aggressive and delinquent behavior. Accelerated pubertal development
in patients with shunted hydrocephalus or myelomeningocele is rela-
tively common, possibly because of increased gonadotropin secretion
in response to increased ICP. It is imperative that hydrocephalic chil-
dren receive long-term follow-up in a multidisciplinary setting.
591.12 Craniosynostosis
Craniosynostosis is defined as premature closure of the cranial sutures

and is classified as primary or secondary. It is associated with varying
types of abnormal skull shape. Primary craniosynostosis refers to
closure of 1 or more sutures owing to abnormalities of skull develop-
ment, whereas secondary craniosynostosis results from failure of brain
growth and expansion and is not discussed here. The incidence of
primary craniosynostosis approximates 1 in 2,000 live births. The cause
is unknown in the majority of children; however, genetic syndromes
account for 10-20% of cases. Deformational forces appear important
in occipital and frontal plagiocephaly in many cases. Early detection
Figure 591-15 Hydranencephaly. MRI scan showing the brainstem of posterior skull shape is critical and allows successful intervention to
and spinal cord with remnants of the cerebellum and the cerebral be offered in the form of physical therapy for torticollis and other
cortex. The remainder of the cranium is filled with cerebrospinal fluid. positional asymmetries that lead to plagiocephaly.
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Acakpo-Satchivi L, Shannon CN, Tubbs RS, et al: Death in shunted hydrocephalic Parisi MA, Dobyns WB: Human malformations of the midbrain and hindbrain:
children: a follow-up study, Childs Nerv Syst 24:197–201, 2008. review and proposed classification scheme, Mol Genet Metab 80:36–53, 2003.
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with cerebrospinal fluid shunt malfunction, J Neurosurg Pediatr 6:318–324, 1999–2002: epidemiology, outcome and ophthalmological findings, Childs Nerv
2010. Syst 23:1111–1118, 2007.
Drake JM: The surgical management of pediatric hydrocephalus, Neurosurgery Putoux A, Thomas S, Coene KIM, et al: KIF7 mutations cause fetal hydrolethalus
62(Suppl 2):633–640, 2008. and acrocallosal syndromes, Nat Genet 43:601–606, 2011.
Greene M, Benacerraf B, Crawford J: Hydranencephaly: US appearance during in Sacko O, Boetto S, Lauwers-Cances V, et al: Endoscopic third ventriculostomy:
utero evolution, Radiology 156:779–780, 1985. overcome analysis in 368 procedures, J Neurosurg Pediatr 5:68–74, 2010.
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J Neurosurg 61:515–522, 1984. Focus 16:E5, 2004.
Kandasamy J, Jenkinson MD, Mallucci CL: Contemporary management and recent Tuan TJ, Thorell EA, Hamblett NM, et al: Treatment and microbiology of repeated
advances in paediatric hydrocephalus, BMJ 343:d4191, 2011. cerebrospinal fluid shunt infections in children, Pediatr Infect Dis J 30:731–735,
Long A, Moran P, Robson S: Outcome of fetal cerebral posterior fossa anomalies, 2011.
Prenat Diagn 26:707–710, 2006. Van Landingham M, Nguyen TV, Roberts A, et al: Risk factors of congenital
Novegno F, Caldarelli M, Massa A, et al: The natural history of the Chiari type I hydrocephalus: a 10 year retrospective study, J Neurol Neurosurg Psychiatry
anomaly, J Neurosurg Pediatr 2:179–187, 2008. 80:213–217, 2009.
DEVELOPMENT AND ETIOLOGY CLINICAL MANIFESTATIONS

The bones of the cranium are well developed by the 5th mo of gestation AND TREATMENT
(frontal, parietal, temporal, and occipital) and are separated by sutures Most cases of craniosynostosis are evident at birth and are character-
and fontanels. The brain grows rapidly in the 1st several yr of life and ized by a skull deformity that is a direct result of premature suture
is normally not impeded because of equivalent growth along the suture fusion. Palpation of the suture reveals a prominent bony ridge, and
lines. The cause of craniosynostosis is unknown, but the prevailing fusion of the suture may be confirmed by plain skull roentgenograms,
hypothesis suggests that abnormal development of the base of the skull CT scan, or bone scan in ambiguous cases (Table 591-6).
creates exaggerated forces on the dura that act to disrupt normal Premature closure of the sagittal suture produces a long and narrow
cranial suture development. Genetic factors have been identified for skull, or scaphocephaly, the most common form of craniosynostosis.
some isolated and for many syndromic causes of craniosynostosis Scaphocephaly is associated with a prominent occiput, a broad fore-
(Table 591-5). head, and a small or absent anterior fontanel. The condition is sporadic,
is more common in males, and often causes difficulties during labor
because of cephalopelvic disproportion. Scaphocephaly does not
produce increased ICP or hydrocephalus, and results of neurologic
Table 591-5 Commonly Used Clinical Genetic examination of affected patients are normal.
Classifications of Craniosynostoses Frontal plagiocephaly is the next most common form of craniosyn-
ostosis and is characterized by unilateral flattening of the forehead,
DISORDER CAUSE elevation of the ipsilateral orbit and eyebrow, and a prominent ear on
ISOLATED CRANIOSYNOSTOSIS the corresponding side. The condition is more common in females and
Morphologically described Unknown, uterine constraint, or is the result of premature fusion of a coronal and sphenofrontal suture.
FGFR3 mutation Surgical intervention produces a cosmetically pleasing result. When
SYNDROMIC CRANIOSYNOSTOSIS imaging does not reveal a closed suture, positional factors are of
Antler-Bixler syndrome Unknown primary importance.
Apert syndrome Usually 1 of 2 mutations in FGFR2 Occipital plagiocephaly is most often a result of positioning during
Beare-Stevenson syndrome Mutation in GFGR2 or FGFR3 infancy and is more common in an immobile child or a child with a
Baller-Gerold syndrome Mutation in TWIST heterogenous disability, but fusion or sclerosis of the lambdoid suture can cause
Carpenter syndrome Unknown unilateral occipital flattening and bulging of the ipsilateral frontal
Craniofrontonasal dysplasia Unknown gene at Xp22 bone. Trigonocephaly is a rare form of craniosynostosis caused by
Crouzon syndrome Numerous different mutations at premature fusion of the metopic suture. These children have a keel-
FGFR2 shaped forehead and hypotelorism and are at risk for associated devel-
Crouzonomesodermoskeletal Mutation in FGFR3
syndrome
opmental abnormalities of the forebrain. Milder forms of metopic
Jackson-Weiss syndrome Mutation in FGFR2 ridging are more common. Turricephaly refers to a cone-shaped head
Muenke syndrome Mutation in FGFR3 from premature fusion of the coronal, and often sphenofrontal and
Pfeiffer syndrome Mutation in FGFR1 or numerous frontoethmoidal, sutures. The kleeblattschädel deformity is a pecu-
mutation in FGFR2 liarly shaped skull that resembles a cloverleaf. Affected children have
Saethre-Chotzen syndrome Mutation in TWIST very prominent temporal bones, and the remainder of the cranium is
Shprintzen-Goldberg Mutation in FBEN1 constricted. Hydrocephalus is a common complication.
syndrome Premature fusion of only 1 suture rarely causes a neurologic deficit.
From Ridgway EB, Weiner HL: Skull deformities, Pediatr Clin North Am In this situation, the sole indication for surgery is to enhance the child’s
51:359–387, 2004. cosmetic appearance, and the prognosis depends on the suture involved
Table 591-6 Epidemiology and Clinical Characteristics of the Common Craniosynostoses

TYPE EPIDEMIOLOGY SKULL DEFORMITY CLINICAL PRESENTATION
Sagittal Most common CSO affecting a Dolicocephaly or Frontal bossing, prominent occiput, palpable keel
single suture, 80% male scaphocephaly (boat-shaped) ridge. OFC normal and reduced biparietal diameter
Coronal 18% of CSO, more common in girls Unilateral: plagiocephaly Unilateral: flattened forehead on affected side, flat
Associated with Apert syndrome Bilateral: brachycephaly, checks, nose deviation on normal side; higher
(with syndactyly) and Crouzon acrocephaly supraorbital margin leading to harlequin sign on
disease, which includes abnormal radiograph and outward rotation of orbit can result
sphenoid, orbital, and facial in amblyopia
bones (hypoplasia of the Bilateral: broad, flattened forehead. In Apert
midface) syndrome accompanied by syndactyly and in
Crouzon disease by hypoplasia of the midface and
progressive proptosis
Lambdoid 10-20% of CSO, M : F ratio 4 : 1 Lambdoid/occipital Unilateral: flattening of occiput, indentation along
plagiocephaly; right side synostotic suture, bulging of ipsilateral forehead
affected in 70% of cases leading to rhomboid skull, ipsilateral ear is anterior
and inferior
Bilateral: brachycephaly with bilateral anteriorly and
inferiorly displaced ears
Metopic Association with 19p chromosome Trigonocephaly Pointed forehead and midline ridge, hypotelorism
abnormality
Multiple Oxycephaly Tower skull with undeveloped sinuses and shallow
orbits, and elevated intercranial pressure
CSO, craniosynostosis; OFC, occipital-frontal circumference.
From Ridgway EB, Weiner HL: Skull deformities, Pediatr Clin North Am 51:359–387, 2004.
and on the degree of disfigurement. Neurologic complications, includ-
ing hydrocephalus and increased ICP, are more likely to occur when 2
or more sutures are prematurely fused, in which case operative inter-
vention is essential. The role of early repositioning efforts and therapy
for torticollis and the use of cranial molding devices are beyond the
scope of this review.
The most prevalent genetic disorders associated with craniosyn-
ostosis include Crouzon, Apert, Carpenter, Chotzen, and Pfeiffer
syndromes. Crouzon syndrome is characterized by premature
craniosynostosis and is inherited as an autosomal dominant trait. The
shape of the head depends on the timing and order of suture fusion
but most often is a compressed back-to-front diameter or brachy-
cephaly resulting from bilateral closure of the coronal sutures. The
orbits are underdeveloped, and ocular proptosis is prominent. Hypo-
plasia of the maxilla and orbital hypertelorism are typical facial
features.
Apert syndrome has many features in common with Crouzon syn-
drome. Apert syndrome is usually a sporadic condition, although auto-
somal dominant inheritance can occur. It is associated with premature
fusion of multiple sutures, including the coronal, sagittal, squamosal,
and lambdoid sutures. The facies tend to be asymmetric, and the eyes
are less proptotic than in Crouzon syndrome. Apert syndrome is char-
acterized by syndactyly of the 2nd, 3rd, and 4th fingers, which may be
joined to the thumb and the 5th finger. Similar abnormalities often
occur in the feet. All patients have progressive calcification and fusion
of the bones of the hands, feet, and cervical spine.
Carpenter syndrome is inherited as an autosomal recessive condi-
tion, and the many fusions of sutures tend to produce the kleeblatt-
schädel skull deformity. Soft tissue syndactyly of the hands and feet is
always present, and intellectual disability is common. Additional but
less common abnormalities include congenital heart disease, corneal
opacities, coxa valga, and genu valgum.
Chotzen syndrome is characterized by asymmetric craniosynostosis
and plagiocephaly. The condition is the most prevalent of the genetic
syndromes and is inherited as an autosomal dominant trait. It is associ-
ated with facial asymmetry, ptosis of the eyelids, shortened fingers, and
soft tissue syndactyly of the 2nd and 3rd fingers.
Pfeiffer syndrome is most often associated with turricephaly. The
eyes are prominent and widely spaced, and the thumbs and great toes
are short and broad. Partial soft-tissue syndactyly may be evident. Most
cases appear to be sporadic, but autosomal dominant inheritance has
been reported.
Mutations of the fibroblast growth factor receptor (FGFR) gene
family have been shown to be associated with phenotypically specific
types of craniosynostosis. Mutations of the FGFR1 gene located on
chromosome 8 result in Pfeiffer syndrome; a similar mutation of the
FGFR2 gene causes Apert syndrome. Identical mutations of the FGFR2
gene can result in both Pfeiffer and Crouzon phenotypes.
Each of the genetic syndromes poses a risk of additional anomalies,
including hydrocephalus, increased ICP, papilledema, optic atrophy
resulting from abnormalities of the optic foramina, respiratory prob-
lems secondary to a deviated nasal septum or choanal atresia, and
disorders of speech and deafness. Craniectomy is mandatory for
management of increased ICP, and a multidisciplinary craniofacial
team is essential for the long-term follow-up of affected children.
Craniosynostosis may be surgically corrected with good outcomes and
relatively low morbidity and mortality, especially for nonsyndromic
infants.

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Chapter 592 ◆ Deformational Plagiocephaly 2819
Chapter 592
Deformational
Plagiocephaly
René P. Myers, Aubrey N. Duncan,
and John A. Girotto
Deformational plagiocephaly (DP), also known as positional plagio-

cephaly, is the development of cranial flattening and asymmetry in the
infant as a result of extrinsic molding forces placed on the skull, such as
consistently sleeping on the same area of the head. Since the suggestion
to place sleeping infants on their backs to sleep for the prevention of
the sudden infant death syndrome, the incidence of DP has risen
dramatically, and this has caused concern for parents and clinicians in
the primary care setting.
EPIDEMIOLOGY AND ETIOLOGY

Incidence
The incidence is frequent at 6 wk of age (16%), greatest at 4 mo of age
(up to 20%), and then decreases over the next 3 yr (7% at 12 mo and
3.3% at 24 mo). It generally resolves completely by 2-3 yr of age. The
American Academy of Pediatrics started a campaign in the 1990s that
resulted in the recommendation to place infants on their backs or sides
while sleeping, which resulted in a 40% decrease in sudden infant death
syndrome cases. Within 4 yr, craniofacial centers and primary care
offices reported a 600% increase in referrals for plagiocephaly, which
was previously reported to be approximately 1 in 300 infants. This may
be a result of increasing awareness or early referral, as point prevalence
has not changed in the past 40 yr.
Infants cannot reposition their heads in the 1st few wk of life and
are not able to hold their own heads up until about 4 mo of age. It is
for this reason that DP is most severe around 4 mo of age. It is also
during this time that an infant’s head circumference is rapidly increas-
ing: about 2 cm/month in the 1st 3 mo, 1 cm/month from 4-6 mo of
age, and 0.5 cm/month after 6 mo of age. Around 6 mo of age, an
infant has developed head control, and this ability to actively reposition
their own head allows for the gradual improvement of the cranial shape
because of pressure offloading and continued brain growth.
Risk Factors
Congenital torticollis, positional preference when sleeping, and lower
levels of activity are especially prominent in patients with DP. Table
592-1 delineates other risk factors. Many of these risk factors cannot
be prevented, but sleeping supine with the head always turned to
the same side has been found to predict DP independent of the
other factors, and this can be prevented. There may be an association
between developmental delay and DP. Although not causal, studies
have found significant differences in gross motor development such as
sitting up, crawling, and rolling back to side, between babies with and
without DP.
Table 592-1 Factors That Increase Risk for

Deformational Plagiocephaly
Male
Firstborn child
Limited passive neck rotation at birth (e.g., congenital torticollis)
Developmental delay
Sleep position is supine at birth and at 6 weeks
Bottle feeding only
Tummy time <3 times/day
Lower activity level, slower milestone achievement
Sleeping with head to same side, positional preference
Causes rule out craniosynostosis as a primary cause for cranial asymmetry in

Prenatal causes of DP include uterine compression and intrauterine infants, as management of this condition is very different from that of
constraint, such as occurs with oligohydramnios or multifetus gesta- DP and requires immediate referral to a craniofacial surgeon for evalu-
tion. Postnatal causes of DP include infant sleeping position and con- ation (see Chapter 591.12). Craniosynostosis occurs in approximately
genital muscular torticollis. 1 in 2,000 live births and results in plagiocephaly as a consequence of
Muscular torticollis is a condition that is present in as many as 1 the early closure of skull sutures. Craniosynostosis must be distin-
in 6 newborns and causes continuous tightening of muscles in the neck guished from DP because the management is different. Lambdoidal
preventing passive rotation. It is thought that this condition typically craniosynostosis, although extremely rare (1 in 300,000 live births),
precedes the development of cranial deformity. However, head position presents with features most similar to those of DP. It can be distin-
preference may result from cervical asymmetry that leads to torticollis guished from DP by a variety of historical and physical findings. Bilat-
and later flattening of a side of the skull from acquired positional eral coronal synostosis also presents very similarly to posterior DP.
preference (see Chapter 680.1).
Sleeping position plays a major role in the incidence of DP. When History and Physical Exam
an infant continuously sleeps with the same part of the skull resting on Tables 592-2 and 592-3 outline the key components of history and
a flat surface, a continuous force is placed in this area. During this time physical examination.
of rapid skull development, the growth is inhibited at the area where Observation of the cranial shape as well as ear displacement are
it rests on a hard surface, causing a “flat spot.” Because of this inhibi- the first steps. It is critical to observe the child anteriorly, laterally, and
tion, growth is increased in opposite directions causing a deformation from a vertex view. When cranial shape is viewed from above, DP
that can be distinguished from other types of plagiocephaly. typically looks like a parallelogram, and the ear on the same side of
the flat or bald spot is displaced anteriorly. In lambdoidal craniosyn-
EXAMINATION AND DIFFERENTIATING ostosis, the head has a trapezoid shape and the ear on the same side as
BETWEEN DEFORMATIONAL the flat spot is posteriorly displaced (Fig. 592-1).
PLAGIOCEPHALY AND CRANIOSYNOSTOSIS Palpation will help to differentiate these 2 conditions. Craniosynos-
Abnormal head shape in an infant is distressing for parents. DP is a tosis presents with palpable ridges along the suture, whereas DP does
clinical diagnosis. Management also requires accurate counseling not. Additionally, patients with craniosynostosis will not have mobile
about its cause and treatment. It is especially important to be able to calvarial bones. This can be tested by applying gentle pressure on 2
Table 592-2 Important Historical and Physical Factors in the Evaluation of a Patient with Plagiocephaly
DEFORMATIONAL SYNOSTOTIC
Birth history • Intrauterine compression • Typically no complications
• Firstborn child
Head shape at birth • Typically normal • Can be irregular
Age first noticed shape irregularity • Usually in 1st few mo of life • Can be at birth
How patient prefers to sleep • Same side, same position • Variable
• Same even during naps
Bald spot • Yes • No
Motor development for age • If age atypical for deformational plagiocephaly, • Varies depending on presence of
typically slow motor development for age concomitant syndrome
• Torticollis present
• History of limited activity or mobility
Tummy time • Decreased • Suggested time
Signs/symptoms of increasing • No • Possible
intracranial pressure
Table 592-3 Key Differences Between Synostotic (Craniosynostosis) and Deformational Plagiocephaly
DEFORMATIONAL PLAGIOCEPHALY CRANIOSYNOSTOSIS
Causes External forces applied to the skull Premature fusion of 1 or more cranial
• Prenatal: uterine compression, intrauterine constrained sutures
• Postnatal: congenital torticollis, sleeping position
Common types • Lateral • Bilateral coronal
• Posterior • Sagittal
• Metopic
Common distinguishing features • Normal round head shape at birth • Can have abnormal head shape at birth
• Parallelogram shape to head • Trapezoid shape to head
• Ipsilateral ear anteriorly displaced • Ipsilateral ear posteriorly displaced
• No palpable bony ridges • Palpable bony ridges
Management • Repositioning • Surgery
• Physical therapy • Helmet in some cases
• Helmet in some cases
Adapted from Nield LS, Brunner MD, Kamat D: The infant with a misshapen head. Clin Pediatr (Phila) 46:292–298, 2007, Tables 1 and 2.
Chapter 592 ◆ Deformational Plagiocephaly 2821
Positional molding Unilateral lambdoid synostosis
Figure 592-1 Differentiating physical find-

ings between deformational plagiocephaly
and craniosynostosis. Vertex views. A, Right-
sided deformational plagiocephaly exhibit-
ing a parallelogram head shape. B, Right- Ipsilateral
sided lambdoid craniosynostosis exhibiting ear displaced Ipsilateral ear
anteriorly Parietal Flattening displaced
a trapezoid-like head shape. (From Lin AY, Contralateral bossing posteriorly
Flattening
Losee JE: Pediatric plastic surgery. In Zitelli BJ, occipital (variable)
McIntire SC, Norwalk AJ, editors: Zitelli and bossing Ipsilateral
Davis’ atlas of pediatric physical diagnosis, occipitomastoid
ed 6, Philadelphia, 2012, Elsevier, Fig. 22-5.)
A B bossing
L R
Figure 592-2 Cranial measurements. (Modified from

Looman WS, Flannery AB: Evidence-based care of the child
with deformational plagiocephaly, part I: assessment and Width Length Transcranial
diagnosis. J Pediatr Health Care 26:242–250, 2012, Table 1.) diagonal difference
adjacent skull bones separated by a suspected synostotic suture. If the ◆ Cranial vault asymmetry: Ratio of oblique measurements. This is
plates do not move relative to each other, then the suspicion for cra- difficult to implement because different physicians and authors
niosynostosis is raised. propose varying points to use for these measurements
Verifying neck muscle tone and range of motion is a key part of One technology for the evaluation of the severity and improvement
the exam because it helps in evaluating motor development and in over time of DP is the 3-dimensional photographic system. Advantages
diagnosing congenital torticollis. Resistance to passive motion raises of this system include an easy and comfortable ability to image in an
the concern for torticollis. Decreased tone should prompt further unbiased manner. Similarly, the use of laser scanners for the prefabrica-
evaluation of motor development. Infants do not gain the muscle tion scans for helmets is frequently employed by orthotists.
control to turn or lift their heads until approximately 4 mo of age, and After observations and measurements the clinician can determine
delays in motor development could increase the infant’s risk of DP at the type and severity of the DP (Table 592-4 and Fig. 592-3). For lateral
later ages than those at which it usually occurs. Decreased range of DP, bossing of the occiput occurs opposite the flattened deformity and
motion can also be seen in cervical spine abnormalities, although this the ear on the same side as the flat area can be anteriorly displaced.
is rare. Early recognition of these conditions is critical in treatment, This type of DP is typically associated with infants who have torticollis
management, and outcome. or a head position preference to 1 side. Transdiagonal diameter is typi-
Accurate and consistent measurements will help to distinguish eti- cally abnormal in this type of plagiocephaly, and this measurement is
ologies and manage infants presenting with an abnormal-shape skull. the gold standard for determining severity.
Along with the usual head circumference measurements, the clinician In posterior DP, the occiput is uniformly flattened, temporal bossing
should also measure cranial width, length, and transcranial diameter can occur, and the ears are normal. It is usually associated with large
(as shown in Figure 592-2), which is best performed with calipers. head size and a history of limited activity or mobility. Cephalic index
These measurements allow the clinician to diagnose, determine sever- is increased with posterior DP.
ity, and monitor the plagiocephaly. Time and accurate exam records can help in management. If defor-
◆ Cranial length: Distance from the most prominent point between mation is worsening when DP typically begins to demonstrate improv-
the eyebrows to the most prominent point of the occiput ing head shape, craniosynostosis should be suspected.
◆ Width: Maximum transverse diameter, horizontal
◆ Cephalic index (cranial index): Ratio of the cranial width to the TREATMENT
cranial length Prevention
◆ Occipital-frontal transcranial diameter: Find the points on either Sleep position should be monitored and varied. Alternating the infant’s
side of the head where the deformation is the worst (2 on the head to face the head and foot of the crib on alternate nights will allow
right, 2 on the left), then measure the diagonal distances between the infant to sleep facing into the room without always lying on the
these points same side of the head. Consistently alternating sleeping position early
◆ Transdiagonal difference (transcranial diagonal difference): The on allows the infant to have equal time on both sides of the occiput,
difference between 2 transcranial diameters and this will become a pattern the infant is used to. Infants who have
Table 592-4 Diagnostic Guide for Determining Type and Severity of Lateral and Posterior Deformational Plagiocephaly
TYPE
POSTERIOR DEFORMATIONAL
CLINICAL FINDINGS LATERAL DEFORMATIONAL PLAGIOCEPHALY PLAGIOCEPHALY (BRACHYCEPHALY)
Occiput (vertex view) Ipsilateral occipital flattening; contralateral Uniform occipital flattening
occipital bossing
Ear position (vertex view) Ipsilateral ear may be anteriorly displaced Normal
Face, forehead (anterior, lateral, May be normal; more-severe cases may present Temporal bossing, increase in vertical height in
and vertex views) with the following: mandibular asymmetry, severe cases
ipsilateral frontal bossing, contralateral forehead
flattening, ipsilateral cheek anteriorly displaced
Other Torticollis, head position preference Large size, history of limited activity or limited
mobility
SEVERITY
POSTERIOR DEFORMATIONAL
LATERAL DEFORMATIONAL PLAGIOCEPHALY PLAGIOCEPHALY (BRACHYCEPHALY)
Mild TDD 3-10 mm Type I Flattening restricted to the back CI: 0.82-0.9 Central posterior deformity
of the skull (“ping-pong ball depression”)
Moderate TDD 10-12 mm Type II Malposition of ear CI: 0.9-1.0 Central posterior deformity and
Type III Forehead deformity widening of posterior skull
Severe TDD >12 mm Type IV Malar deformity CI: >1.0 Vertical head, head growth, or
Type V Vertical or temporal skull growth temporal bossing
CI, cephalic index (cranial index); TDD, transcranial diameter difference.
Figure 592-3 Types of deformational plagiocephaly. (From Looman WS, Flannery AB: Evidence-based care of the child with deformational
plagiocephaly, part I: assessment and diagnosis. J Pediatr Health Care 26:242–250, 2012, Fig. 1.)
an obvious positional preference to a particular side will take more usually developmentally normal, healthy children. This is in contrast
time and effort in purposefully repositioning them counter to their to craniosynostosis, in which increases in intracranial pressure may
preference. Parents must be counseled in the benefit of this strategy have deleterious effects on central nervous system function.
in preventing bald spots or flat spots that can progress to cranial
deformity. Bibliography is available at Expert Consult.
“Tummy time” is the term used to describe the infant’s awake time
spent lying on their stomach. The suggested amount of tummy time is
10-15 minutes at least 3 times a day. Reassure parents that sleep is
the only time during which the prone position should be avoided, and
educate the parents as to the benefits for the infant of awake prone
positioning to help progression of motor development.
Treatment Options
Cranial asymmetry from DP does not usually spontaneously improve,
nor do the more-severe manifestations of facial and ear asymmetry
disappear. Once a flat spot develops, it is unlikely that the infant will
be able to overcome the pull to lie on the same spot in time to allow
for reversal of the asymmetry.
“Watch-and-wait” management is not recommended in infants
with DP. Evidence suggests that, at a minimum, repositioning and
physiotherapy should be initiated as soon as asymmetry is observed.
Repositioning and physiotherapy (RPPT) include the counseling
and teaching for parents as to positional changes and tummy time in
their child as well as referral to physical therapy in the case of con-
genital torticollis. RPPT is the optimal treatment choice for patients
younger than 4 mo of age who have mild or moderately severe DP. The
earliest types of behavioral modifications can be as simple as increasing
tummy time, or repositioning the infant’s crib such that everything
interesting in the room is on the side opposite the DP.
Molding therapy (helmet therapy) is the use of an orthotic helmet
to promote the resolution of cranial asymmetry while the infant’s head
is still rapidly growing. Orthotic helmets do not actively mold the skull;
rather, they protect the areas that are flat and allow the child to “grow
into” the flat spot. Studies have shown helmet therapy to achieve cor-
rection 3 times faster and better than repositioning alone. This therapy
is still debated because of its expense, time requirements, coverage and
side effects (irritation, rashes, and pressure sores). The most recent
studies suggest that combined treatment with helmet therapy and
RPPT is the most beneficial management of infants older than 4 mo
with severe DP or with worsening of mild/moderate DP trialed on
RPPT. Infants with severe DP should be considered for helmet therapy
at any age.
Studies suggest helmet therapy should be started for significant DP
between 4 and 8 mo and continued for 7-8 mo. Parents should be
counseled on the commitment involved in this treatment as helmets
need to be worn more than 20 hr a day.
Patients with craniosynostosis require surgery. Sometimes, a
molding helmet can be used as an adjunctive therapy after surgery but
never as monotherapy.
OUTCOMES
Outcomes may be better when helmet therapy is started before 6 mo
of age, and infants starting therapy later than that do not achieve the
same degree of normal head measurements as those whose helmet
therapy is started before 6 mo of age do. Significant improvements in
asymmetry are usually obvious at 4-11 wk after initiation of helmet
therapy.
Studies in patients with a median follow-up age of 9 yr old found
that 75% of cases had a what both parents and patients considered to
be a normal head appearance. Nine percent of patients and 4% of
parents noted residual asymmetry that they considered significant.
Cognitive and academic outcomes may be different depending on
the side of deformity. Poorer academic performance and greater speech
abnormalities were found in patients with left-sided deformities com-
pared to those with right-sided deformities. This manifested as double
the number of patients with expressive speech abnormalities and triple
the number of special education needs. It is unclear what the underly-
ing mechanism is; treatment differences were apparently not a factor.
In general, children with DP and without comorbid conditions are
Chapter 592 ◆ Deformational Plagiocephaly 2823.e1
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American Academy of Pediatrics: American Academy of Pediatrics Task Force a cohort study, Pediatrics 132:298–304, 2013.
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Bialocerkowski AE, Vladusic SL, Wei Ng C: Prevalence, risk factors, and natural Nuysink J, Eijsermans MJC, van Haastert IC, et al: Clinical course of asymmetric
history of positional plagiocephaly: a systematic review, Dev Med Child Neurol motor performance and deformational plagiocephaly in very preterm infants,
50(8):577–586, 2008. J Pediatr 163:658–665, 2013.
Collett BR: Helmet therapy for positional plagiocephaly and brachycephaly, BMJ Rogers GF, Oh AK, Mulliken JB: The role of congenital muscular torticollis in the
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26(4):242–250, 2012.
Chapter 593 ◆ Seizures in Childhood 2823
Chapter 593
Seizures in Childhood
Mohamad A. Mikati and Abeer J. Hani
A seizure is a transient occurrence of signs and/or symptoms resulting

from abnormal excessive or synchronous neuronal activity in the
brain. The International Classification of Epileptic Seizures divides
epileptic seizures into 2 large categories: In focal (formerly known
as partial) seizures, the first clinical and electroencephalographic
(EEG) changes suggest initial activation of a system of neurons limited
to part of 1 cerebral hemisphere. The term simple partial seizures is
an outdated classification that refers to focal seizures with no altera-
tion in consciousness whereas complex partial seizures, currently also
referred to as focal dyscognitive, denote focal seizures with altered
awareness of the surroundings. In generalized seizures, the first clini-
cal and EEG changes indicate synchronous involvement of all of both
hemispheres (Table 593-1). Approximately 30% of patients who have
a first afebrile seizure have later epilepsy; the risk is approximately
20% if neurologic exam, EEG, and neuroimaging are normal. Febrile
seizures are a separate category. Acute symptomatic seizures occur
secondary to an acute problem affecting brain excitability such as
electrolyte imbalance. Most children with these types of seizures do
well. However, sometimes these seizures signify major structural,
inflammatory, or metabolic disorders of the brain, such as meningitis,
encephalitis, acute stroke, or brain tumor. Consequently, the prognosis
depends on the underlying disorder, including its reversibility or treat-
ability and the likelihood of developing epilepsy from it. An unpro-
voked seizure is one that is not an acute symptomatic seizure. Remote
symptomatic seizure is one that is considered to be secondary
to a distant brain injury, such as an old stroke. Reflex seizures are
usually precipitated by a sensory stimulus such as flashing lights (see
Chapter 593.9).
Epilepsy is a disorder of the brain characterized by an enduring
predisposition to generate seizures and by the neurobiologic, cognitive,
psychologic, and social consequences of this condition. The clinical
diagnosis of epilepsy usually requires the occurrence of at least 1
unprovoked epileptic seizure with either a second such seizure or
enough EEG and clinical information to convincingly demonstrate an
enduring predisposition to develop recurrences. For epidemiologic
and commonly for clinical purposes, epilepsy is considered to be
present when 2 or more unprovoked seizures occur in a time frame of
longer than 24 hr. Approximately 4-10% of children experience at least
1 seizure (febrile or afebrile) in the 1st 16 yr of life. The cumulative
lifetime incidence of epilepsy is 3%, and more than half of the cases
start in childhood. The annual prevalence is 0.5-1.0%. Thus, the occur-
rence of a single seizure or of febrile seizures does not necessarily imply
the diagnosis of epilepsy. Seizure disorder is a general term that is
usually used to include any 1 of several disorders, including epilepsy,
febrile seizures, and possibly single seizures and symptomatic seizures
secondary to metabolic, infectious, or other etiologies (e.g., hypocal-
cemia, meningitis).
An epileptic syndrome is a disorder that manifests 1 or more
specific seizure types and has a specific age of onset and a specific
prognosis. Several types of epileptic syndromes can be distinguished
Table 593-1 Types of Epileptic Seizures

SELF-LIMITED SEIZURE TYPES CONTINUOUS SEIZURE TYPES
Focal Seizures Generalized Status Epilepticus
Focal sensory seizures Generalized tonic-clonic status epilepticus
• With elementary sensory symptoms (e.g., occipital and parietal lobe Clonic status epilepticus
seizures) Absence status epilepticus
• With experiential sensory symptoms (e.g., temporoparietooccipital Tonic status epilepticus
junction seizures) Myoclonic status epilepticus
Focal motor seizures Focal Status Epilepticus
• With elementary clonic motor signs Epilepsia partialis continua of Kojevnikov
• With asymmetrical tonic motor seizures (e.g., supplementary motor Aura continua
seizures) Limbic status epilepticus (psychomotor status)
• With typical (temporal lobe) automatisms (e.g., mesial temporal Hemiconvulsive status with hemiparesis
lobe seizures)
• With hyperkinetic automatisms PRECIPITATING STIMULI FOR REFLEX SEIZURES
• With focal negative myoclonus Visual stimuli
• With inhibitory motor seizures • Flickering light—color to be specified when possible
Gelastic seizures • Patterns
Hemiclonic seizures • Other visual stimuli
Secondarily generalized seizures Thinking
Reflex seizures in focal epilepsy syndromes Music
Generalized Seizures Eating
Tonic-clonic seizures (includes variations beginning with a clonic or Praxis
myoclonic phase) Somatosensory
Clonic seizures Proprioceptive
• Without tonic features Reading
• With tonic features Hot water
Typical absence seizures Startle
Atypical absence seizures
Absence with special features:
• Eyelid myoclonia
• Myoclonic absence
Tonic seizures
Myoclonic seizures
Myoclonic atonic seizures
Negative myoclonus
Atonic seizures
Reflex seizures in generalized epilepsy syndromes
Unknown
Epileptic Spasms
Modified from Berg AT, Berkovic SF, Brodie MJ et al: Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission
on Classification and Terminology, 2005–2009. Epilepsia 51(4):676–685, 2010.
(Tables 593-2 to 593-5). This classification has to be distinguished from is referred to as the unknown epilepsy, designating that the underlying
the classification of epileptic seizures that refers to single events rather cause of the epilepsy is as yet unknown.
than to clinical syndromes. In general, seizure type is the primary
determinant of the type of medications the patient is likely to respond EVALUATION OF THE FIRST SEIZURE
to, and the epilepsy syndrome determines the type of prognosis one Initial evaluation of an infant or child during or shortly after a sus-
could expect. An epileptic encephalopathy is an epilepsy syndrome pected seizure should include an assessment of the adequacy of the
in which there is a severe EEG abnormality which is thought to result airway, ventilation, and cardiac function, as well as measurement of
in cognitive and other impairments in the patient. Idiopathic epilepsy temperature, blood pressure, and glucose concentration. For acute
is an older term that refers to an epilepsy syndrome that is genetic or evaluation of the first seizure, the physician should search for poten-
presumed genetic and in which there is no underlying disorder affect- tially life-threatening causes of seizures such as meningitis, systemic
ing development or other neurologic function (e.g., petit mal epilepsy). sepsis, unintentional or nonaccidental intentional head trauma, and
In the International League Against Epilepsy (ILAE) classification of ingestion of drugs of abuse or accidental ingestion of drugs or of other
etiology of epilepsy, idiopathic epilepsy was replaced by the term toxins. The history should attempt to define factors that might have
genetic epilepsy, which implies that the epilepsy syndrome is the promoted the convulsion and to provide a detailed description of the
direct result of a known or presumed genetic defect(s) in which the seizure and the child’s postictal state (see Chapter 593.9). Most parents
genetic defect is not causative of a brain structural or metabolic disor- vividly recall their child’s initial convulsion and can describe it in
der other than the epilepsy. Symptomatic epilepsy is also an older detail.
term referring to an epilepsy syndrome caused by an underlying brain The subsequent step in an evaluation is to determine whether the
disorder that may or may not be genetic (e.g., epilepsy secondary to seizure has a focal onset or is generalized. Focal seizures may be char-
tuberous sclerosis or to an old stroke); this is referred to as structural/ acterized by motor or sensory symptoms, which could include forceful
metabolic epilepsy, which would be caused by a distinct structural or turning of the head and eyes to 1 side, unilateral clonic movements
metabolic entity that increases the risk for seizures and causes the beginning in the face or extremities, or a sensory disturbance, such as
epilepsy. The older terms of cryptogenic epilepsy or of presumed paresthesias or pain localized to a specific area. Focal seizures in an
symptomatic epilepsy refer to an epilepsy syndrome in which there is adolescent or adult usually indicate a localized lesion, whereas these
a presumed underlying brain disorder causing the epilepsy and affect- seizures during childhood are often, but not always, secondary to a
ing neurologic function, but the underlying disorder is not known; this Text continued on p. 2829
Table 593-2 Classification for Epilepsy Syndromes with an Indication of Age of Onset, Duration of Active Epilepsy,
Prognosis, and Therapeutic Options
SPECIFIC AGE AT AGE AT MONOTHERAPY POSSIBLE
SYNDROMES ONSET REMISSION PROGNOSIS OR ADD-ON* ADD-ON† SURGERY†
EPILEPSIES OF UNKNOWN CAUSE OF INFANCY AND CHILDHOOD
Benign infantile Infant Infant Good PB — No
seizures (nonfamilial)
Benign childhood 3-13 yr 16 yr Good CBZ, LEV, OXC, — No
epilepsy with VPA
centrotemporal
spikes
Early and late-onset 2-8 yr; 6-17 yr 12 yr or Good CBZ, LEV, OXC, — No
idiopathic occipital younger; VPA
epilepsy 18 yr
FAMILIAL (AUTOSOMAL DOMINANT) EPILEPSIES
Benign familial Newborn to Newborn to Good PB — No
neonatal convulsions young infant young infant
Benign familial Infant Infant Good CBZ, PB — No
infantile convulsions
Autosomal dominant Childhood Variable CBZ, GBP, OXC, CLB, LEV, PB, No
nocturnal frontal PHT, TPM PHT
lobe epilepsy
Familial lateral Childhood to Variable CBZ, GBP, OXC, CLB, LEV, PB, No
temporal lobe adolescence PHT, TPM, VPA PHT
epilepsy
Generalized Childhood to Variable ESM, LTG, TPM, CLB, LEV No
epilepsies with adolescence VPA
febrile seizures plus
STRUCTURAL–METABOLIC FOCAL EPILEPSIES
Limbic Epilepsy
Mesial temporal lobe School-age or Long lasting Variable CBZ, LEV, OXC, CLB, GBP, LAC, Temporal resection
epilepsy with earlier TPM, VPA PB, PHT, ZON
hippocampal
sclerosis
Mesial temporal lobe Variable Long lasting Variable CBZ, LEV, OXC, CLB, GBP, LAC, Temporal resection
epilepsy defined by TPM, VPA PB, PHT, ZON
specific causes
Other types defined Variable Long lasting Variable CBZ, LEV, OXC, CLB, FBM, GBP, Lesionectomy ±
by location and TPM, VPA LAC, PB, PHT, temporal resection
causes ZON
Neocortical Epilepsies
Rasmussen syndrome 6-12 yr Progressive Ominous Plasmapheresis, CBZ, LAC, PB, Functional
immunoglobulins PHT, TPM hemispherectomy
Hemiconvulsion- 1-5 yr Chronic Severe CBZ, LEV, OXC, CLB, GBP, LAC, Functional
hemiplegia TPM, VPA PB, PHT, ZON hemispherectomy
syndrome
Other types defined Variable Long lasting Variable CBZ, LEV, OXC, PHT, PB, CLB, Lesionectomy ±
by location and TPM, VPA GBP, LAC, ZON cortical resection
cause
Migrating partial Infant No remission Ominous Bromides, CBZ, BDZ, LAC, ZON No
seizures of early LEV, PB, PHT,
infancy TPM, VPA
GENERALIZED EPILEPSIES OF UNKNOWN CAUSE
Benign myoclonic 3 mo-3 yr 3-5 yr Variable LEV, TPM, VPA BDZ, ZON No
epilepsy in infancy
Epilepsy with 3-5 yr Variable Variable ESM, TPM, VPA BDZ, ketogenic No
myoclonic astatic diet, LEV, LTG,
seizures steroids, ZON
Childhood absence 5-6 yr 10-12 yr Good ESM, LTG, VPA Acetazolamide, No
epilepsy ketogenic diet,
ZON
Epilepsy with 1-12 yr Variable Guarded ESM, VPA BDZ, ZON No
myoclonic absences
*Reflects current trends in practice, which may be off-label and may not be FDA approved for that indication. See Table 593-10 for FDA indications.
†
May apply to selected cases only. Vagus nerve stimulation has been used for all types of refractory seizures and epilepsy types.
ACTH, adrenocorticotropic hormone; BDZ, benzodiazepine; CBZ, carbamazepine; CLB, clobazam; DZP: diazepam; ESM, ethosuximide; FBM: felbamate; GBP,
gabapentin; IVIG, intravenous immunoglobulin; LAC, lacosamide; LEV, levetiracetam; LTG, lamotrigine; n/a, not applicable; OXC: oxcarbazepine; PB, phenobarbital;
PHT, phenytoin; PRM, primidone; RFD, rufinamide; TPM, topiramate; VGB: vigabatrin; VPA, valproic acid; ZON, zonisamide.
Continued
Table 593-2 Classification for Epilepsy Syndromes with an Indication of Age of Onset, Duration of Active Epilepsy,
Prognosis, and Therapeutic Options—cont’d
SPECIFIC AGE AT AGE AT MONOTHERAPY POSSIBLE
SYNDROMES ONSET REMISSION PROGNOSIS OR ADD-ON* ADD-ON† SURGERY†
GENERALIZED EPILEPSIES OF UNKNOWN CAUSE WITH VARIABLE PHENOTYPES
Juvenile absence 10-12 yr Usually Good ESM, LTG, VPA BDZ No
epilepsy lifelong
Juvenile myoclonic 12-18 yr Usually Good LEV, TPM, VPA BDZ, LTG, PB, No
epilepsy lifelong PRM, ZON
Epilepsy with 12-18 yr Usually Good LEV, LTG, TPM, BDZ, CBZ, ZON No
generalized lifelong VPA
tonic-clonic seizures
only
REFLEX EPILEPSIES
Idiopathic 10-12 yr Unclear Variable VPA BDZ, LEV, LTG, No
photosensitive ZON
occipital lobe
epilepsy
Other visual sensitive 2-5 yr Unclear Variable VPA BDZ, LEV, LTG, No
epilepsies ZON
Startle epilepsy Variable Long lasting Guarded CBZ, GBP, OXC, CLB, LEV, PB, Lesionectomy ±
PHT, TPM, VPA PHT, ZON cortical resection
in some
EPILEPTIC ENCEPHALOPATHIES
Early myoclonic Newborn- Poor, Ominous PB, steroids, VGB BDZ, ZON No
encephalopathy and infant Ohtahara
Ohtahara syndrome syndrome
evolves into
West
syndrome
West syndrome Infant Variable Variable ACTH, steroids, BDZ, FBM, IVIG, Lesionectomy ±
VGB TPM, ZON cortical resection
Dravet syndrome Infant No remission Severe CLB, stiripentol, BDZ, ZON No
(severe myoclonic TPM, VPA
epilepsy in infancy)
Lennox-Gastaut 3-10 yr No remission Severe CLB, LTG, RFD, BDZ, FBM, IVIG, Callosotomy
syndrome TPM, VPA steroids, ZON
Landau-Kleffner 3-6 yr 8-12 yr Guarded LEV, nocturnal BDZ, ESM, IVIG, Multiple subpial
syndrome DZP, steroids, LTG transections, rarely
VPA lesionectomy
Epilepsy with 4-7 yr 8-12 yr Guarded LEV, nocturnal BDZ, ESM, IVIG, No
continuous spike DZP, steroids, LTG
waves during VPA
slow-wave sleep
PROGRESSIVE MYOCLONUS EPILEPSIES
Unverricht-Lundborg, Late infant to Progressive Ominous TPM, VPA, ZON BDZ, PB No
Lafora, ceroid adolescent
lipofuscinoses, etc.
OTHER EPILEPSIES AND SEIZURE DISORDERS OF UNKNOWN OR OTHER CAUSES
Benign neonatal Newborn Newborn Good LEV, PB — No
seizures
Febrile seizures 3-5 yr 3-6 yr Good PB or VPA if — No
repeated and
prolonged
Reflex seizures Variable n/a LEV, VPA LTG, ZON No
Drug or other Variable n/a Withdraw — No
chemically induced offending agent
seizures
Immediate and early Variable n/a LEV, PHT — No
posttraumatic
seizures
Modified from Guerrini R: Epilepsy in children, Lancet 367:499–524, 2006; and Parisi P, Verrotti A, Paolino MC, et al. “Electro-clinical syndromes” with onset in the
pediatric age group: the highlights of the clinical-EEG, genetic and therapeutic advances. Ital J Pediatr 37:58, 2011.
Table 593-3 Identified Genes for Epilepsy Syndromes*†

EPILEPSY TYPE GENE PROTEIN
INFANTILE ONSET
Benign familial neonatal seizures KCNQ2 Potassium voltage-gated channel
KCNQ3 Potassium voltage-gated channel
Benign familial neonatal infantile seizures SCN2A Sodium channel protein type 2α
Early familial neonatal infantile seizures SCN2A Sodium channel protein type 2α
Early infantile epileptic encephalopathy (EIEE) CDKL5 (EIEE2) Cyclin-dependent kinase-like 5
ARX (EIEE1) Aristaless-related homeobox
TSC1 Hamartin
TSC2 Tuberin
SCN1A (EIEE6) Sodium channel protein type 1α
PCDH19(EIEE9) Protocadherin-19
KCNQ2 (EIEE7) Potassium voltage-gated channel
STXBP1 (EIEE4) Syntaxin binding protein 1
SLC2A1 Solute carrier family 2, facilitated glucose
transporter member 1
ALDH7A1 α-Aminoadipic semialdehyde dehydrogenase
(antiquitin)
POLG DNA polymerase subunit gamma-1
SCN2A (EIEE11) Sodium channel protein type 2α
PLCβ1 (EIEE12) Phospholipase C β1
ATP6AP2 Renin receptor
SPTAN1 (EIEE5) α2-Spectrin
SLC25A22 (EIEE3) Mitochondrial glutamate carrier 1
PNPO Pyridoxine-5′-phosphate oxidase
Generalized epilepsy with febrile seizures plus SCN1A Sodium channel protein type 1α
(early onset) SCN1B Sodium channel protein type 1β
GABRG2 γ-Aminobutyric acid receptor subunit γ2
SCN2A Sodium channel protein type 1α
CHILDHOOD ONSET
Childhood onset epileptic encephalopathies SCN1A Sodium channel protein type 1α
PCDH19 Protocadherin-19
SLC2A1 Solute carrier family 2, facilitated GTM1
POLG DNA polymerase subunit γ1
Early onset absence seizures, refractory GLUT-1 deficiency syndrome, SLC2A1gene Solute carrier family 2, facilitated GTM1
epilepsy of multiple types at times with
movement disorder
Generalized epilepsy with febrile seizure plus SCN1A Sodium channel protein type 1α
SCN1B Sodium channel protein type 1β
GABRG2 γ-Aminobutyric acid receptor subunit γ2
Juvenile myoclonic epilepsy (more commonly EFHC1 EF-hand domain-containing protein 1
presents in adolescence) CACNB4 Voltage-dependent L-type calcium channel
GABRA1 γ-Aminobutyric acid receptor subunit α1
Progressive myoclonic epilepsy (different EPM2A Laforin
forms present from infancy through NHLRC1 NHL repeat-containing protein 1 (Malin)
adulthood) CSTB Cystatin-B
PRICKLE1 Prickle-like protein 1
PPT1, TPP1,CLN3, CLN5, CLN6, CLN8, CTSD, Multiple proteins causing neuronal ceroid
DNAJC5, MFSD8 lipofuscinosis
Autosomal dominant nocturnal frontal lobe CHRNA4 Neuronal acetylcholine receptor α4
epilepsies (presents in childhood through CHRNB2 Neuronal acetylcholine receptor β2
adulthood) CHRNA2 Neuronal acetylcholine receptor α2
ADOLESCENT ONSET
Juvenile myoclonic epilepsy (JME) See Childhood Onset JME
Progressive myoclonic epilepsy (PME) See Childhood Onset PME
Autosomal dominant nocturnal frontal lobe See Childhood Onset AD-NFLE
epilepsies (AD-NFLE)
Autosomal dominant lateral temporal lobe See Childhood Onset AD-LTLE
epilepsy (AD-LTLE)
Autosomal dominant lateral temporal lobe LGI1 Leucine-rich glioma-inactivated protein 1
epilepsy (usually presents in adulthood)
*Note that the same gene (different mutations) often appears as causing different epilepsy syndromes.
†
Most of these genes can be tested for through commercially available targeted single-gene sequencing or through commercially available gene panels or though
exome sequencing (http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=genetests).
Table 593-4 Identified Genes for Syndromic Epilepsy Syndromes*

SYNDROME GENE PROTEIN
Rett/atypical Rett syndromes MECP2 Methyl CpG binding protein 2
CDKL5 Cyclin-dependent kinase-like 5
FOXG1 Forkhead box protein G1
MBD5 Methyl-CpG-binding domain protein 5
MEF2C Myocyte-specific enhancer factor 2C
Angelman/Angelman-like/Pitt-Hopkins UBE3A Ubiquitin protein ligase E3A
syndromes SLC9A6 Sodium/hydrogen exchanger 6
MBD5 Methyl-CpG-binding domain protein 5
TCF4 Transcription factor 4
NRXN1 Neurexin-1
CNTNAP2 Contactin-associated protein-like 2
Mowat-Wilson syndrome ZEB2 Zinc finger E-box-binding homeobox 2
Creatine deficiency syndromes GAMT Guanidinoacetate N-methyltransferase
GATM Glycine amidinotransferase, mitochondrial
Neuronal ceroid lipofuscinosis (NCL) PPT1 (CLN1) Palmitoyl-protein thioesterase 1
TPP1 (CLN2) Tripeptidyl-peptidase 1
CLN3 Battenin
CLN5 Ceroid-lipofuscinosis neuronal protein 5
MFSD8 (CLN7) Major facilitator superfamily domain-containing protein 8
CTSD (CLN10) Cathepsin D
KCTD7 (CLN14) BTB/POZ domain-containing protein KCTD7
Adenosuccinate lyase deficiency ADSL Adenylosuccinate lyase
Cerebral folate deficiency FOLR1 Folate receptor alpha
Epilepsy with variable learning and GRIN2A Glutamate receptor ionotropic, N-methyl-D-aspartate (NMDA) 2A
behavioral disorders SYN1 Synapsin-1
17q21.31 microdeletion syndrome KANSL1 KAT8 regulatory nonspecific lethal (NSL) complex subunit 1
Microcephaly with early-onset intractable PNKP Bifunctional polynucleotide phosphatase/kinase
seizures and developmental delay (MCSZ)
*Most of these genes can be tested for through commercially available targeted single-gene sequencing or through commercially available gene panels or though
exome sequencing.
Table 593-5 Childhood Epileptic Syndromes with Generally Good Prognosis

SYNDROME COMMENT
Benign neonatal familial convulsions Dominant, may be severe and resistant for a few days
Febrile or afebrile seizures (benign) occur later in a minority
Infantile familial convulsions Dominant; seizures often in clusters
Febrile convulsions plus syndromes Febrile and afebrile generalized convulsions, absence and myoclonic seizures occur in
(see Table 593-2) different members. Seizures usually generalized (GEFS+) but in some families may
be focal
Benign myoclonic epilepsy of infancy Often seizures during sleep; 1 rare variety with reflex myoclonic seizures (touch, noise)
Partial idiopathic epilepsy with rolandic spikes Seizures with falling asleep or on awakening; focal sharp waves with centrotemporal
(benign epilepsy with centrotemporal spikes) location on EEG
Idiopathic occipital partial epilepsy Early childhood form with seizures during sleep and ictal vomiting; can occur as
status epilepticus
Later form with occipital spikes that block on eye opening; migrainous symptoms and
seizures; not always benign
Petit mal absence epilepsy Cases with absences only; some have generalized seizures
In most cases, absences disappear on therapy but there are resistant cases
(unpredictable); 60-80% full remission
Juvenile myoclonic epilepsy Adolescence onset, with early morning myoclonic seizures and generalized seizures
during sleep or upon awakening; often history of absences in childhood
EEG, electroencephalogram; GEFS+, generalized epilepsy with febrile seizures plus.
Modified from Deonna T: Management of epilepsy, Arch Dis Child 90:5–9, 2005; and Seneviratne U: The prognosis of idiopathic generalized epilepsy, Epilepsia
53(12):2079–2090, 2012.
lesion or the result of a genetic, idiopathic, epilepsy. Focal seizures in recurrent within a 24-hr period. A complex febrile seizure is more
a neonate may be seen because of focal lesions like perinatal stroke or prolonged (>15 min), is focal, and/or reoccurs within 24 hr. Febrile
because of a metabolic abnormality like hypocalcemia caused by status epilepticus is a febrile seizure lasting longer than 30 min. Some
immaturity of the brain connections. Focal and generalized motor use the term simple febrile seizure plus for those with recurrent
seizures may be tonic–clonic, tonic, clonic, myoclonic, or atonic. Tonic febrile seizures within 24 hr. Most patients with simple febrile seizures
seizures are characterized by increased tone or rigidity, and atonic have a very short postictal state and usually return to their baseline
seizures are characterized by flaccidity or lack of movement during a normal behavior and consciousness within minutes of the seizure.
convulsion. Clonic seizures consist of rhythmic fast muscle contrac- Between 2% and 5% of neurologically healthy infants and children
tions and slightly longer relaxations; myoclonus is a “shock-like” con- experience at least 1, usually simple, febrile seizure. Simple febrile
traction of a muscle of <50 msec that is often repeated. The duration seizures do not have an increased risk of mortality even though they
of the seizure and state of consciousness (retained or impaired) should are, understandably, concerning to the parents when they first witness
be documented. The history should determine whether an aura pre- them. Complex febrile seizures may have an approximately 2-fold
ceded the convulsion and the behavior of the child immediately pre- long-term increase in mortality, as compared to the general popula-
ceding the seizure. The most common aura experienced by children tion, over the subsequent 2 yr, probably secondary to coexisting
consists of epigastric discomfort or pain and a feeling of fear. The pathology. There are no long-term adverse effects of having 1 or more
posture of the patient, presence or absence and distribution of cyano- simple febrile seizures. Compared with age-matched controls, patients
sis, vocalizations, loss of sphincter control (particularly of the urinary with febrile seizures do not have any increase in the incidence of
bladder), and postictal state (including sleep, headache, and hemipa- abnormalities of behavior, scholastic performance, neurocognitive
resis) should be noted. function, or attention. Children who develop later epilepsy, however,
In addition to the assessment of cardiorespiratory and metabolic might experience such difficulties. Febrile seizures recur in approxi-
status, examination of a child with a seizure disorder should be geared mately 30% of those experiencing a first episode, in 50% after 2 or more
toward the search for an organic cause. The child’s head circumference, episodes, and in 50% of infants younger than 1 yr old at febrile seizure
length, and weight are plotted on a growth chart and compared with onset. Several factors affect recurrence risk (Table 593-6). Although
previous measurements. A careful general and neurologic examination approximately 15% of children with epilepsy have had febrile seizures,
should be performed. The eyegrounds must be examined for the pres- only 2-7% of children who experience febrile seizures proceed to
ence of papilledema, optic neuritis, retinal hemorrhages, uveitis, cho- develop epilepsy later in life. There are several predictors of epilepsy
rioretinitis, coloboma, or macular changes, as well as retinal phakoma. after febrile seizures (Table 593-7).
The finding of unusual facial features or of associated physical findings
such as hepatosplenomegaly point to an underlying metabolic or GENETIC FACTORS
storage disease as the cause of the neurologic disorder. The presence The genetic contribution to the incidence of febrile seizures is mani-
of a neurocutaneous disorder may be indicated by the presence of fested by a positive family history for febrile seizures in many patients.
vitiliginous ash leaf–type lesions using an ultraviolet light (Wood In some families, the disorder is inherited as an autosomal dominant
lamp), of adenoma sebaceum, shagreen patches, or of retinal phako-
mas (tuberous sclerosis), of multiple café-au-lait spots (neurofibroma-
tosis), or of V1 or V2 distribution nevus flammeus (Sturge-Weber Table 593-6 Risk Factors for Recurrence of Febrile
syndrome). Seizures
Localizing neurologic signs, such as a subtle hemiparesis with
MAJOR
hyperreflexia, an equivocal Babinski sign, and a downward-drifting of
Age <1 yr
an extended arm with eyes closed, might suggest a contralateral hemi- Duration of fever <24 hr
spheric structural lesion, such as a slow-growing glioma, as the cause Fever 38-39°C (100.4-102.2°F)
of the seizure disorder. Unilateral growth arrest of the thumbnail, hand,
or extremity in a child with a focal seizure disorder suggests a chronic MINOR
condition, such as a porencephalic cyst, arteriovenous malformation, Family history of febrile seizures
Family history of epilepsy
or cortical atrophy of the opposite hemisphere. Complex febrile seizure
After the initial acute investigation, which often includes metabolic Daycare
and CT scanning, depending on the clinical presentation in emergency Male gender
room, in a child with a first nonfebrile seizure, it is recommended to Lower serum sodium at time of presentation
obtain an EEG to help predict the risk of seizure recurrence. Subse-
Having no risk factors carries a recurrence risk of approximately 12%; 1 risk
quent imaging studies with MRI should be seriously considered in any factor, 25-50%; 2 risk factors, 50-59%; 3 or more risk factors, 73-100%.
child with a significant cognitive or motor impairment of unknown
etiology, unexplained abnormalities on neurologic or psychiatric
examination, a seizure of focal onset with or without secondary gen- Table 593-7 Risk Factors for Occurrence of
eralization, an EEG that does not represent a benign partial epilepsy Subsequent Epilepsy After a Febrile
of childhood or primary generalized epilepsy, or in children younger Seizure
than 1 year of age. Other laboratory tests or lumbar punctures may be
pursued depending on the specific clinical settings. Further details RISK FOR SUBSEQUENT
regarding the approach to a first seizure are included in Chapter 593.2. RISK FACTOR EPILEPSY
Simple febrile seizure 1%
Recurrent febrile seizures 4%
593.1 Febrile Seizures Complex febrile seizures (more 6%
Mohamad A. Mikati and Abeer J. Hani than 15 min duration or recurrent
within 24 hr)
Febrile seizures are seizures that occur between the age of 6 and 60 mo Fever <1 hr before febrile seizure 11%
with a temperature of 38°C (100.4°F) or higher, that are not the result
of central nervous system infection or any metabolic imbalance, and Family history of epilepsy 18%
that occur in the absence of a history of prior afebrile seizures. A Complex febrile seizures (focal) 29%
simple febrile seizure is a primary generalized, usually tonic–clonic,
Neurodevelopmental abnormalities 33%
attack associated with fever, lasting for a maximum of 15 min, and not
trait, and multiple single genes that cause the disorder have been iden- • History
tified in such families. However, in most cases the disorder appears to
be polygenic, and the genes predisposing to it remain to be identified. • Exam
Identified single genes include FEB 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 genes • Manage acute febrile seizure and acute illness (first aid,
on chromosomes 8q13-q21, 19p13.3, 2q24, 5q14-q15, 6q22-24, midazolam, diazepam, diagnostic tests) as needed.
18p11.2, 21q22, 5q34, 3p24.2-p23, and 3q26.2-q26.33. Only the func- • Determine risk factors for recurrence and estimate risk of
tion of FEB 2 is known: it is a sodium channel gene, SCN1A. recurrence of the febrile seizures (Table 593-6).
Almost any type of epilepsy can be preceded by febrile seizures, and
a few epilepsy syndromes typically start with febrile seizures. These are
generalized epilepsy with febrile seizures plus (GEFS+), severe myo- Counsel parents about risk of recurrence and
clonic epilepsy of infancy (also called Dravet syndrome), and, in how to provide first aid and manage fever.
many patients, temporal lobe epilepsy secondary to mesial temporal
sclerosis.
GEFS+ is an autosomal dominant syndrome with a highly variable Determine risk factors for later epilepsy
phenotype. Onset is usually in early childhood and remission is usually (Table 593-7)
in mid-childhood. It is characterized by multiple febrile seizures and
by several subsequent types of afebrile generalized seizures, including
generalized tonic–clonic, absence, myoclonic, atonic, or myoclonic
astatic seizures with variable degrees of severity. A focal febrile seizures Low risk Intermediate or high risk
plus epilepsy variant, in which the seizures are focal rather than gen- No therapy or 1. Consider EEG and imaging
eralized, has also been described. investigations 2. Consider intermittent oral
Dravet syndrome is the most severe of the phenotypic spectrum of are necessary diazepam or, in exceptional
febrile seizure-associated epilepsies. It constitutes a distinct entity in cases that recur, continuous
the onset of which is in infancy. Its onset is characterized by febrile and therapy
afebrile unilateral clonic seizures recurring every 1 or 2 mo. These early
seizures are typically induced by fever, but they differ from the usual Figure 593-1 Management of febrile seizures. (Modified from
Mikati MA, Rahi A: Febrile seizures: from molecular biology to clinical
febrile convulsions in that they are more prolonged, are more frequent,
practice, Neurosciences (Riyadh) 10:14–22, 2004.)
are focal and come in clusters. Seizures subsequently start to occur with
lower fevers and then without fever. During the 2nd yr of life, myoc-
lonus, atypical absences, and partial seizures occur frequently and with antibiotics. In patients presenting with febrile status epilepticus in
developmental delay usually follows. This syndrome is usually caused the absence of a central nervous system infection, a nontraumatic lumbar
by a de novo mutation, although rarely it is inherited in an autosomal puncture rarely shows cerebrospinal fluid (CSF) pleocytosis (96% have
dominant manner. The mutated gene is located on 2q24-31 and <3 nucleated cells in the CSF) and the CSF protein and glucose are
encodes for SCN1A, the same gene mutated in GEFS+ spectrum. usually normal.
However, in Dravet syndrome the mutations lead to loss of function
and thus to a more severe phenotype. There are several milder variants Electroencephalogram
of Dravet syndrome that manifest some but not all of the above features If the child is presenting with the first simple febrile seizure and is
and that are referred to as Dravet syndrome spectrum or Borderland. otherwise neurologically healthy, an EEG need not normally be per-
Mutations in other genes may also cause Dravet syndrome or GEFS+ formed as part of the evaluation. An EEG would not predict the future
phenotypes. recurrence of febrile seizures or epilepsy even if the result is abnormal.
The majority of patients who had prolonged febrile seizures and Spikes during drowsiness are often seen in children with febrile sei-
encephalopathy after vaccination and who had been presumed to have zures, particularly those older than age 4 yr, and these do not predict
suffered from vaccine encephalopathy (seizures and psychomotor later epilepsy. EEGs performed within 2 wk of a febrile seizure often
regression occurring after vaccination and presumed to be caused by have nonspecific slowing, usually posteriorly. Thus, in many cases, if
it) turn out to have Dravet syndrome mutations, indicating that their an EEG is indicated, it is delayed until or repeated after more than 2 wk
disease is caused by the mutation and not secondary to the vaccine. have passed. An EEG should, therefore, generally be restricted to
This has raised doubts about the very existence of the entity termed special cases in which epilepsy is highly suspected, and, generally, it
vaccine encephalopathy. should be used to delineate the type of epilepsy rather than to predict
its occurrence. If an EEG is done, it should be performed for at least
EVALUATION 20 min in wakefulness and in sleep according to international guide-
Figure 593-1 delineates the general approach to the patient with febrile lines to avoid misinterpretation and drawing of erroneous conclusions.
seizures. Each child who presents with a febrile seizure requires a At times, if the patient does not recover immediately from a seizure,
detailed history and a thorough general and neurologic examination. then an EEG can help distinguish between ongoing seizure activity and
Febrile seizures often occur in the context of otitis media, roseola and a prolonged postictal period, sometimes termed a nonepileptic twi-
human herpesvirus (HHV) 6 infection, shigella, or similar infections, light state. EEG can also be helpful in patients who present with febrile
making the evaluation more demanding. In patients with febrile status, status epilepticus because the presence of focal slowing present on the
HHV-6B (more frequently) and HHV-7 infections were found to EEG obtained within 72 hr of the status has been shown to be highly
account for one-third of the cases. Several laboratory studies need to associated with MRI evidence of acute hippocampal injury.
be considered in evaluating the patient with febrile seizures.
Blood Studies
Lumbar Puncture Blood studies (serum electrolytes, calcium, phosphorus, magnesium,
Meningitis should be considered in the differential diagnosis, and and complete blood count) are not routinely recommended in the
lumbar puncture should be performed for all infants younger than work-up of a child with a first simple febrile seizure. Blood glucose
6 mo of age who present with fever and seizure, or if the child is ill- should be determined in children with prolonged postictal obtunda-
appearing or at any age if there are clinical signs or symptoms of tion or with poor oral intake (prolonged fasting). Serum electrolyte
concern. A lumbar puncture is an option in a child 6-12 mo of age who values may be abnormal in children after a febrile seizure, but this
is deficient in Haemophilus influenzae type b and Streptococcus pneu- should be suggested by precipitating or predisposing conditions elic-
moniae immunizations or for whom immunization status is unknown. ited in the history and reflected in abnormalities of the physical exami-
A lumbar puncture is an option in children who have been pretreated nation. If clinically indicated (e.g., in a history or physical examination
suggesting dehydration), these tests should be performed. A low probe for previous signs or symptoms of other seizures in the preced-
sodium level is associated with higher risk of recurrence of the febrile ing weeks, or longer, that the parents may have overlooked and did not
seizure within the following 24 hr. report. In some instances, if the events have been going on for a time
and there is a question about their nature (e.g., sleep myoclonus vs
Neuroimaging seizures), then the family could video record the patient and make the
A CT or MRI is not recommended in evaluating the child after a first video available to the healthcare provider. Having the parents imitate
simple febrile seizure. The work-up of children with complex febrile the seizure can also be helpful. Seizure patterns (e.g., clustering), pre-
seizures needs to be individualized. This can include an EEG and cipitating conditions (e.g., sleep or sleep deprivation, television, visual
neuroimaging, particularly if the child is neurologically abnormal. patterns, mental activity, stress), exacerbating conditions (e.g., men-
Approximately 11% of children with febrile status epilepticus are strual cycle, medications), frequency, duration, time of occurrence,
reported to have (usually) unilateral swelling of their hippocampus and other characteristics need to be carefully documented (see Chapter
acutely, which is followed by subsequent long-term hippocampal 593.9). Parents often overlook, do not report, or underreport absence,
atrophy. Whether these patients will ultimately develop temporal lobe complex partial, or myoclonic seizures. A history of personality change
epilepsy remains to be determined. or symptoms of increased intracranial pressure can suggest an intra-
cranial tumor. Similarly, a history of cognitive regression can suggest
TREATMENT a degenerative or metabolic disease. Certain medications such as stim-
In general, antiepileptic therapy, continuous or intermittent, is not ulants or antihistamines, particularly sedating ones, can precipitate
recommended for children with 1 or more simple febrile seizures. seizures. A history of prenatal or perinatal distress or of developmental
Parents should be counseled about the relative risks of recurrence of delay can suggest etiologic congenital or perinatal brain dysfunction.
febrile seizures and recurrence of epilepsy, educated on how to handle Details of the spells can suggest nonepileptic paroxysmal disorders that
a seizure acutely, and given emotional support. If the seizure lasts for mimic seizures (see Chapter 594).
longer than 5 min, acute treatment with diazepam, lorazepam, or mid-
azolam is needed (see Chapter 593.8 for acute management of seizures DIFFERENTIAL DIAGNOSIS
and status epilepticus). Rectal diazepam is often prescribed to be given This involves consideration of nonepileptic paroxysmal events (see
at the time of reoccurrence of a febrile seizure lasting longer than 5 min Chapter 594), determination of the seizure type, as classified by the
(see Table 593-12 for dosing). Alternatively, buccal or intranasal mid- new ILAE system (see Table 593-1) and consideration of potential
azolam may be used and is often preferred by parents. Intravenous underlying etiologies. Some seizures might begin with auras, which
benzodiazepines, phenobarbital, phenytoin, or valproate may be are sensory experiences reported by the patient and not observed
needed in the case of febrile status epilepticus. If the parents are very externally. These can take the form of visual (e.g., flashing lights or
anxious concerning their child’s seizures, intermittent oral diazepam seeing colors or complex visual hallucinations), somatosensory (tin-
(0.33 mg/kg every 8 hr during fever) or intermittent rectal diazepam gling), olfactory, auditory, vestibular, or experiential (e.g., déjà vu, déjà
(0.5 mg/kg administered as a rectal suppository every 8 hr), can be vécu feelings) sensations, depending upon the precise localization of
given during febrile illnesses. Intermittent oral nitrazepam, clobazam, the origin of the seizures.
and clonazepam (0.1 mg/kg/day) have also been used. Such therapies Motor seizures can be tonic (sustained contraction), clonic (rhyth-
help reduce, but do not eliminate, the risks of recurrence of febrile mic contractions), myoclonic (rapid shock-like contractions, usually
seizures. Other therapies have included continuous phenobarbital <50 msec in duration, that may be isolated or may repeat but usually
(4-5 mg/kg/day in 1 or 2 divided doses), and continuous valproate are not rhythmic), atonic, or astatic. Astatic seizures often follow
(20-30 mg/kg/day in 2 or 3 divided doses). In the vast majority of cases, myoclonic seizures and cause a very momentary loss of tone with a
it is not justified to use continuous therapy owing to the risk of side effects sudden fall. Atonic seizures, on the other hand, are usually longer and
and lack of demonstrated long-term benefits, even if the recurrence rate the loss of tone often develops more slowly. Sometimes it is difficult to
of febrile seizures is expected to be decreased by these drugs. distinguish among tonic, myoclonic, atonic, or astatic seizures based
Antipyretics can decrease the discomfort of the child but do not on the history alone when the family reports only that the patient
reduce the risk of having a recurrent febrile seizure, probably because “falls”; in such cases, the seizure may be described as a drop attack.
the seizure often occurs as the temperature is rising or falling. Chronic Loss of tone or myoclonus in only the neck muscles results in a milder
antiepileptic therapy may be considered for children with a high seizure referred to as a head drop. Tonic, clonic, myoclonic, and atonic
risk for later epilepsy. Currently available data indicate that the possi- seizures can be focal (including 1 limb or 1 side only), focal with sec-
bility of future epilepsy does not change with or without antiepileptic ondary generalization, or primary generalized. Epileptic spasms (axial
therapy. Iron deficiency is associated with an increased risk of febrile spasms, these terms being preferred over infantile spasms because they
seizures, and thus screening for that problem and treating it appears can occur beyond infancy) consist of flexion or extension of truncal
appropriate. and extremity musculature that is sustained for 1-2 sec, shorter than
what is seen in tonic seizures, which last longer than 2 sec. Focal motor
Bibliography is available at Expert Consult. clonic and/or myoclonic seizures that persist for days, months, or even
longer are termed epilepsia partialis continua.
Absence seizures are generalized seizures consisting of staring,
unresponsiveness, and eye flutter lasting usually for few seconds.
593.2 Unprovoked Seizures Typical absences are associated with 3 Hz spike–and–slow-wave dis-
Mohamad A. Mikati and Abeer J. Hani charges and with petit mal epilepsy, which has a good prognosis.
Atypical absences are associated with 1-2 Hz spike–and–slow-wave
HISTORY AND EXAMINATION discharges, and with head atonia and myoclonus during the seizures.
Acute evaluation of a first seizure includes assessment of vital signs and They occur in Lennox-Gastaut syndrome, which has a poor prognosis.
respiratory and cardiac function, and institution of measures to nor- Juvenile absences are similar to typical absences but are associated
malize and stabilize them as needed. Signs of head trauma, abuse, with 4-5 Hz spike-and-slow waves and occur in juvenile myoclonic
drug intoxication, poisoning, meningitis, sepsis, focal abnormalities, epilepsy. Seizure type and other EEG and clinical manifestations deter-
increased intracranial pressure, herniation, neurocutaneous stigmata, mine the type of epilepsy syndrome with which a particular patient is
brainstem dysfunction, and/or focal weakness should all be sought afflicted (Table 593-8; see Chapter 593.3 and 593.4).
because they could suggest an underlying etiology for the seizure. Family history of certain forms of epilepsy, like benign neonatal
The history should also include details of the seizure manifestations, seizures, can suggest the specific epilepsy syndrome. More often,
particularly those that occurred at its initial onset. These could give however, different members of a family with a positive history of epi-
clues to the type and brain localization of the seizure. One should also lepsy have different types of epilepsy. Head circumference can indicate
Chapter 593 ◆ Seizures in Childhood 2831.e1
Bibliography Nordli DR Jr, Moshé SL, Shinnar S, et al; FEBSTAT Study Team: Acute EEG
American Academy of Pediatrics: Clinical practice guideline for the long-term findings in children with febrile status epilepticus: results of the FEBSTAT
management of the child with simple febrile seizures, Pediatrics 121:1281–1286, study, Neurology 79(22):2180–2186, 2012.
2008. Nørgaard M, Ehrenstein V, Mahon BE, et al: Febrile seizures and cognitive
American Academy of Pediatrics: Clinical practice guideline—febrile seizures: function in young adult life: a prevalence study in Danish conscripts, J Pediatr
guideline for the neurodiagnostic evaluation of the child with a simple febrile 155:404–409, 2009.
seizure, Pediatrics 127:389, 2011. Offringa M, Newton R: Prophylactic drug management for febrile seizures in
Berg AT, Berkovic SF, Brodie MJ, et al: Revised terminology and concepts for children, Cochrane Database Syst Rev (4):CD003031, 2012.
organization of seizures and epilepsies: report of the ILAE Commission on Oluwabusi T, Sood SK: Update on the management of simple febrile seizures:
Classification and Terminology, 2005–2009, Epilepsia 51(4):676–685, 2010. emphasis on minimal intervention, Curr Opin Pediatr 24:259–265, 2012.
Epstein LG, Shinnar S, Hesdorffer DC, et al: Human herpesvirus 6 and 7 in febrile Patel AD, Vidaurre J: Complex febrile seizures: a practical guide to evaluation and
status epilepticus: The FEBSTAT study, Epilepsia 53:1481–1488, 2012. treatment, J Child Neurol 28:762–767, 2013.
Frank LM, Shinnar S, Hesdorffer DC, et al; FEBSTAT Study Team: Cerebrospinal Shinnar S, Bello JA, Chan S, et al; FEBSTAT Study Team: MRI abnormalities
fluid findings in children with fever-associated status epilepticus: results of following febrile status epilepticus in children: the FEBSTAT study, Neurology
the consequences of prolonged febrile seizures (FEBSTAT) study, J Pediatr 79(9):871–877, 2012.
161(6):1169–1171, 2012. Strengell T, Uhari M, Tarkka R, et al: Antipyretic agents for preventing recurrences
Graves RC, Oehler K, Tingle LE: Febrile seizures: risks, evaluation, and prognosis, of febrile seizures, Arch Pediatr Adolesc Med 163:799–804, 2009.
Am Fam Physician 85(2):149–153, 2012. Sun Y, Christensen J, Hviid A, et al: Risk of febrile seizures and epilepsy after
Grill MF, Ng YT: “Simple febrile seizures plus (SFS +)”: more than one febrile vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus,
seizure within 24 hours is usually okay, Epilepsy Behav 27:472–475, 2013. and Haemophilus Influenzae type b, JAMA 307:823–831, 2012.
Hartfield DS, Tan J, Yager JY, et al: The association between iron deficiency and
febrile seizures in childhood, Clin Pediatr (Phila) 48:420–426, 2009.
Kimia AA, Ben-Joseph E, Prabhu S, et al: Yield of emergent neuroimaging among
children presenting with a first complex febrile seizure, Pediatr Emerg Care
28:316–321, 2012.
Table 593-8 Selected Epilepsy Syndromes by Age Table 593-9 Proposed Diagnostic Scheme for People
of Onset with Epileptic Seizures and with Epilepsy
NEONATAL PERIOD Epileptic seizures and epilepsy syndromes are to be described
Benign familial neonatal seizures (BFNS) and categorized according to a system that uses standardized
Early myoclonic encephalopathy (EME) terminology and that is sufficiently flexible to take into account
Ohtahara syndrome the practical and dynamic aspects of epilepsy diagnosis:
• Axis 1: Ictal phenomenology, used to describe ictal events with
INFANCY any degree of detail needed.
Epilepsy of infancy with migrating focal seizures • Axis 2: Seizure type, from the List of types of Epileptic Seizures.
West syndrome Localization within the brain and precipitating stimuli for reflex
Myoclonic epilepsy in infancy (MEI) seizures should be specified when appropriate.
Benign infantile seizures • Axis 3: Syndrome, from the List of Epilepsy Syndromes, with the
Benign familial infantile epilepsy understanding that a syndromic diagnosis may not always be
Dravet syndrome possible.
Myoclonic encephalopathy in nonprogressive disorders • Axis 4: Etiology, from a Classification of Diseases Frequently
CHILDHOOD Associated with Epileptic Seizures or Epilepsy Syndromes when
Febrile seizures plus (FS+) (can start in infancy; this can be with possible, genetic defects, or specific pathologic substrates for
generalized [GEFS+] or with focal seizures) symptomatic focal epilepsies.
Early-onset benign childhood occipital epilepsy (Panayiotopoulos • Axis 5: Impairment; this is often useful to make sure one does not
type) overlook the consequences of epilepsy, such as medication side
Epilepsy with myoclonic atonic (previously astatic) seizures effects, and learning and socialization difficulties.
Benign epilepsy with centrotemporal spikes (BCECTS) Modified from Engel J. A proposed diagnostic scheme for people with epileptic
Late-onset childhood occipital epilepsy (Gastaut type) seizures and with epilepsy: report of the ILAE task force on classification and
Autosomal dominant nocturnal frontal lobe epilepsy (AD-NFLE) terminology. Epilepsia. 2001;42:796–803.
Epilepsy with myoclonic absences
Lennox-Gastaut syndrome
Epileptic encephalopathy with continuous spike-and-wave during lesions (sometimes associated with tuberous sclerosis and detected
sleep (CSWS) more reliably by viewing the skin under UV light), or other neurocu-
Landau-Kleffner syndrome taneous manifestations such as Shagreen patches and adenoma seba-
Childhood absence epilepsy (CAE) ceum (associated with tuberous sclerosis), or whorl-like hypopigmented
ADOLESCENCE–ADULT areas (hypomelanosis of Ito, associated with hemimegalencephaly).
Juvenile absence epilepsy (JAE) Subtle asymmetries on the exam such as drift of 1 of the extended arms,
Juvenile myoclonic epilepsy (JME) posturing of an arm on stress gait, slowness in rapid alternating move-
Epilepsy with generalized tonic–clonic seizures alone ments, small hand or thumb and thumb nail on 1 side, or difficulty in
Progressive myoclonus epilepsies (PME) hopping on 1 leg relative to the other can signify a subtle hemiparesis
Autosomal dominant epilepsy with auditory features (ADEAF) associated with a lesion on the contralateral side of the brain.
Other familial temporal lobe epilepsies Guidelines on the evaluation of a first unprovoked nonfebrile
AGE-RELATED (AGE OF ONSET LESS SPECIFIC) seizure include a careful history and physical examination and brain
Familial focal epilepsy with variable foci (childhood to adult) imaging by head CT or MRI. Emergency head CT in the child present-
Reflex epilepsies ing with a first unprovoked nonfebrile seizure is often useful for acute
SEIZURE DISORDERS THAT ARE NOT TRADITIONALLY GIVEN management of the patient. Laboratory studies are recommended in
THE DIAGNOSIS OF EPILEPSY specific clinical situations: Spinal tap is considered in patients with
Benign neonatal seizures (BNS) suspected meningitis or encephalitis, in children without brain swell-
Febrile seizures (FS) ing or papilledema, and in children in whom a history of intracranial
EPILEPTIC ENCEPHALOPATHIES bleeding is suspected without evidence of such on head CT. In the
EME second of these, examination of the CSF for xanthochromia is essential.
Ohtahara syndrome Electrocardiography (ECG) to rule out long QT or other cardiac dys-
Migrating partial seizures of infancy rhythmias and other tests directed at disorders that could mimic sei-
West syndrome zures may be needed (see Chapter 594). EEG is highly recommended
Dravet syndrome to assess for focal abnormalities and predict seizure recurrence.
Myoclonic encephalopathy in nonprogressive disorders
Epilepsy with myoclonic astatic seizures LONG-TERM APPROACH TO THE PATIENT
Lennox-Gastaut syndrome AND ADDITIONAL TESTING
Epileptic encephalopathy with CSWS
Landau-Kleffner syndrome
The approach to the patient with epilepsy is based on the diagnostic
scheme proposed by the ILAE Task Force on Classification and Termi-
OTHER SECONDARY GENERALIZED EPILEPSIES nology and presented in Table 593-9. This emphasizes the total
Generalized epilepsy secondary to neurodegenerative disease approach to the patient, including identification, if possible, of the
Progressive myoclonus epilepsies underlying etiology of the epilepsy and the impairments that result
Modified from Berg AT, Berkovic SF, Bordie MJ, et al. Revised terminology from it. The impairments are very often just as important as, if not
and concepts for organization of seizures and epilepsies: report of the more important than, the seizures themselves. Most epilepsy syn-
ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia dromes are potentially caused by any 1 of multiple underlying or still
51:676–685, 2010.
undetermined etiologies. However, in addition, there are many epi-
lepsy syndromes that are associated with specific gene mutations (see
the presence of microcephaly or of macrocephaly. Eye exam may show Table 593-2). Different mutations of the same gene can result in differ-
optic disc edema, retinal hemorrhages, chorioretinitis, colobomata ent epilepsy syndromes, and mutations of different genes can cause the
(associated with brain malformations), a cherry-red spot, optic atrophy, same epilepsy syndrome phenotype. The clinical use of gene testing in
macular changes (associated with genetic neurodegenerative and the diagnosis and management of childhood epilepsy has been limited
storage diseases), or phakomas (associated with tuberous sclerosis). to patients manifesting specific underlying malformational, metabolic,
Skin exam could show a trigeminal V1 distribution capillary heman- or degenerative disorders, patients with severe named epilepsy syn-
gioma (associated with Sturge-Weber syndrome), hypopigmented dromes (such as West and Dravet syndromes and progressive
myoclonic epilepsies), and to patients with syndromes of mendelian Most patients do not require a work-up anywhere near the above
inheritance (see Table 593-2). described extensive testing. The pace and extent of the work-up must
Patients with recurrent seizures, specifically with 2 seizures spaced depend critically upon the clinical epileptic and nonepileptic features,
apart by longer than 24 hr, warrant further work-up directed at the the family and antecedent personal history of the patient, the medica-
underlying etiology. In patients with drug-resistant epilepsy, or in tion responsiveness of the seizures, the likelihood of identifying a
infants with new-onset epilepsy in whom the initial testing did not treatable condition, and the wishes and need of the family to assign a
reveal an underlying etiology, a full metabolic work-up, including specific diagnosis to the child’s illness.
amino acids, organic acids, biotinidase, and CSF studies, is needed.
Additional testing can include, depending on the case, some or most Bibliography is available at Expert Consult.
of the following:
1. Measurement of serum lactate, pyruvate, acyl carnitine profile,
creatine, very-long-chain fatty acids, and guanidino-acetic acid. 593.3 Partial Seizures and Related Epilepsy
2. Blood and serum sometimes need to be tested for white blood
cell lysosomal enzymes, serum coenzyme Q levels, and serum Syndromes
copper and ceruloplasmin levels (for Menkes syndrome). Mohamad A. Mikati and Abeer J. Hani
3. Serum immune isoelectric focusing is performed for
carbohydrate-deficient transferrin. Partial (now referred to as focal) seizures account for approximately
4. CSF glucose testing looks for glucose transporter deficiency, and 40% of seizures in children and can be divided into simple partial
CSF can be examined for cells and proteins (for parainfectious seizures (currently referred to in the most recent ILAE classification
and postinfectious syndromes, and for Aicardi-Goutières as focal seizures without impairment of consciousness), in which
syndrome, which also shows cerebral calcifications and has a consciousness is not impaired, and complex partial seizures (cur-
specific gene defect test available). rently referred to as focal seizures with impairment of consciousness,
5. Other laboratory studies include immunoglobulin (Ig) G index, also called focal dyscognitive seizures), in which consciousness is
NMDA (N-methyl-d-aspartate) receptor antibodies, and measles affected. Simple and complex partial seizures can each occur in isola-
titers. tion, one can temporally lead to the other (usually simple to complex),
6. CSF tests can also confirm with, the appropriate clinical and/or each can progress into secondary generalized seizures (tonic,
setup, the diagnosis of cerebral folate deficiency, pyridoxine clonic, atonic, or most often tonic–clonic).
dependency, pyridoxal dependency, mitochondrial disorders,
nonketotic hyperglycinemia, neopterin/biopterin metabolism FOCAL SEIZURES WITHOUT IMPAIRMENT
disorders, adenylosuccinate lyase deficiency, and OF CONSCIOUSNESS
neurotransmitter deficiencies. In infants who do not respond These can take the form of sensory seizures (auras) or brief motor
immediately to antiepileptic therapy, vitamin B6 (100 mg seizures, the specific nature of which gives clues as to the location of
intravenously) is given as a therapeutic trial to help diagnose the seizure focus. Brief motor seizures are the most common and
pyridoxine-responsive seizures, with precautions to guard against include focal tonic, clonic, or atonic seizures. Often there is a motor
possible apnea. The trial is best done with continuous EEG (jacksonian) march from face to arm to leg, adversive head and eye
monitoring, including a preadministration baseline recording movements to the contralateral side, or postictal (Todd) paralysis that
period. Prior to the vitamin B6 trial, a pipecolic acid level and can last minutes or hours, and sometimes longer. Unlike tics, motor
urine and CSF α-aminoadipic acid semialdehyde levels should seizures are not under partial voluntary control; seizures are more
be drawn, because they often elevated in this rare syndrome and often stereotyped and less likely than tics to manifest different types in
the therapeutic trial result may not be definitive. Some patients a given patient.
are pyridoxal phosphate, rather than pyridoxine, dependent.
Also patients with cerebral folate deficiency can have intractable FOCAL SEIZURES WITH IMPAIRMENT
seizures. Thus trials of pyridoxal phosphate given orally (up to OF CONSCIOUSNESS
50 mg/kg) and folinic acid (up to 3 mg/kg) over several weeks These seizures usually last 1-2 min and are often preceded by an aura,
can help diagnose these rare disorders while waiting for the such as a rising abdominal feeling, déjà vu or déjà vécu, a sense of fear,
definitive diagnosis from CSF or genetic testing for these complex visual hallucinations, micropsia or macropsia (temporal lobe),
disorders. Certain EEG changes such as continuous spike–and– generalized difficult-to-characterize sensations (frontal lobe), focal
slow-wave seizure activity and burst-suppression patterns may sensations (parietal lobe), or simple visual experiences (occipital lobe).
also suggest these vitamin-responsive syndromes. Children younger than 7 yr old are less likely than older children to
7. Urine may also need to be tested for urinary sulfites indicating report auras, but parents might observe unusual preictal behaviors that
molybdenum cofactor deficiency and for oligosaccharides and suggest the experiencing of auras. Subsequent manifestations consist of
mucopolysaccharides. MR spectroscopy is performed for lactate decreased responsiveness, staring, looking around seemingly purpose-
and creatine peaks to rule out mitochondrial disease and lessly, and automatisms. Automatisms are automatic semipurposeful
creatine transporter deficiency. movements of the mouth (oral, alimentary such as chewing) or of the
8. Gene testing looks for specific disorders that can manifest extremities (manual, such as manipulating the sheets; leg automatisms
with seizures, including SCN1A mutations in Dravet syndrome; such as shuffling, walking). Often there is salivation, dilation of the
ARX gene for West syndrome in boys; MECP2, CDKL5, and pupils, and flushing or color change. The patient might appear to react
protocadherin 19 for Rett syndrome and similar presentations; to some of the stimulation around him or her but does not later recall
syntaxin binding protein for Ohtahara syndrome; and the epileptic event. At times, walking and/or marked limb flailing and
polymerase G for West syndrome and other seizures in infants. agitation occur, particularly in patients with frontal lobe seizures.
Gene testing can also be performed for other dysmorphic or Frontal lobe seizures often occur at night and can be very numerous and
metabolic syndromes. brief, but other complex partial seizures from other areas in the brain
9. Muscle biopsy can be performed for mitochondrial enzymes and can also occur at night, too. There is often contralateral dystonic postur-
coenzyme Q10 levels, and skin biopsy for inclusion bodies seen ing of the arm and, in some cases, unilateral or bilateral tonic arm
in neuronal ceroid lipofuscinosis and Lafora body disease is stiffening. Some seizures have these manifestations with minimal or no
sometimes needed. automatisms. Others consist of altered consciousness with contralateral
10. Genetic panels are available that include multiple genes that can motor, usually clonic, manifestations. After the seizure, the patient can
cause epilepsy at specific ages; whole-exome sequencing is also have postictal automatisms, sleepiness, and/or other transient focal
available. These can be helpful in selected patients. deficits such as weakness (Todd paralysis) or aphasia.
Bibliography Moseley BD, Wirrell EC, Nickels K, et al: Electrocardiographic and oximetric
AAN summary of evidence-based guideline for clinicians: evaluating an apparent changes during partial complex and generalized seizures, Epilepsy Res
unprovoked first seizure in adults, Continuum (Minneap Minn) 16(3):255–256, 95:237–245, 2011.
2010. Muthugovindan D, Hartman AL: Pediatric epilepsy syndromes, Neurologist
Alam S, Lux AL: Epilepsies in infancy, Arch Dis Child 97:985–992, 2012. 16:223–237, 2010.
Hess CP, Barkovich AJ: Seizures: emergency neuroimaging, Neuroimaging Clin N Russ SA, Larson K, Halfon N: A national profile of childhood epilepsy and seizure
Am 20:619–637, 2010. disorder, Pediatrics 129:256–264, 2012.
Kullmann DM: Neurological channelopathies, Annu Rev Neurosci 33:151–172, Sharma S, Prasad AN: Genetic testing of epileptic encephalopathies of infancy: an
2010. approach, Can J Neurol Sci 40(1):10–16, 2013.
Kurian MA, Gissen P, Smith M, et al: The monoamine neurotransmitter disorders: Wilden JA, Cohen-Gadol AA: Evaluation of first nonfebrile seizures, Am Fam
an expanding range of neurological syndromes, Lancet Neurol 10:721–733, Physician 86(4):334–340, 2012.
2011.
Michelucci R, Pasini E, Riguzzi P, et al: Genetics of epilepsy and relevance to
current practice, Curr Neurol Neurosci Rep 12(4):445–455, 2012.
SECONDARY GENERALIZED SEIZURES tions, medial temporal sclerosis, arteriovenous malformations, inflam-
Seizures of this type were previously known as focal seizures with matory pathologies, or tumors (Fig. 593-3).
impairment of consciousness evolving to bilateral convulsive seizures.
Secondary generalized seizures can start with generalized clinical phe- BENIGN EPILEPSY SYNDROMES
nomena (from rapid spread of the discharge from the initial focus), or WITH FOCAL SEIZURES
as simple or complex partial seizures with subsequent clinical general- The most common such syndrome is benign childhood epilepsy
ization. There is often adversive eye and head deviation to the side with centrotemporal spikes which typically starts during childhood
contralateral to the side of the seizure focus followed by generalized (ages 3-10 yr) and is outgrown in adolescence. The child typically
tonic, clonic, or tonic–clonic activity. Tongue biting, urinary and stool wakes up at night owing to a focal (simple partial) seizure causing
incontinence, vomiting with risk of aspiration, and cyanosis are buccal and throat tingling and tonic or clonic contractions of 1 side of
common. Fractures of the vertebrae or humerus are rare complications. the face, with drooling and inability to speak but with preserved con-
Most such seizures last 1-2 min. Tonic focal or secondary generalized sciousness and comprehension. Dyscognitive focal (complex partial)
seizures often manifest adversive head deviation to the contralateral and secondary generalized seizures can also occur. EEG shows typical
side, or fencing, hemi- or full figure-of-four arm, or Statue of Liberty broad-based centrotemporal spikes that are markedly increased in fre-
postures. These postures often suggest frontal origin, particularly when quency during drowsiness and sleep. MRI is normal. Patients respond
consciousness is preserved during them, indicating that the seizure very well to antiepileptic drugs (AEDs) such as carbamazepine. In
originated from the medial frontal supplementary motor area. some patients who only have rare and mild seizures treatment might
EEG in patients with focal/partial seizures usually shows focal spikes not be needed.
or sharp waves in the lobe where the seizure originates. A sleep- Benign epilepsy with occipital spikes can occur in early childhood
deprived EEG with recording during sleep increases the diagnostic (Panayiotopoulos type) and manifests with complex partial seizures
yield and is advisable in all patients whenever possible (Fig. 593-2). with ictal vomiting, or they appear in later childhood (Gastaut type)
Despite that, approximately 15% of children with epilepsy initially have with complex partial seizures, visual auras, and migraine headaches.
normal EEGs because the discharges are relatively infrequent or the Both are typically outgrown in a few years. Manifestations may include
focus is deep. If repeating the test does not detect paroxysmal findings, visual hallucinations and postictal headache (epilepsy–migraine
then longer recordings in the laboratory or using ambulatory EEG or sequence).
even inpatient 24-hr video EEG monitoring may be helpful. The latter In infants, several less-common benign infantile familial convul-
is particularly helpful if the seizures are frequent enough, because it sion syndromes have been reported. For some of these, the corre-
then can allow visualization of the clinical events and the correspond- sponding gene mutation and its function are known (see Tables 593-2
ing EEG tracing. and 593-5), but for others, the genetic underpinnings are yet to be
Brain imaging is critical in patients with focal seizures. In general, determined. Specific syndromes include benign infantile familial con-
MRI is preferable to CT, which misses subtle but occasionally poten- vulsions with parietooccipital foci linked to chromosomal loci 19q
tially clinically significant lesions. MRI can show pathologies such as and 2q, benign familial infantile convulsions with associated choreo-
changes as a result of previous strokes or hypoxic injury, malforma- athetosis linked to chromosomal locus 16p12-q12, and benign
(i) (i)
Cz-C3 Fp1-A1
F7-A1
C3-T3
(ii)
C3-Sp1 P3-PZ
Sp1-Sp2 PZ-P4
P4-T6
Sp2-T4
T5-01
T4-C4
(iii)
T4-CZ
Fp1-F7
F7-T3
(ii)
T3-T5
T3-C3 T5-O1
C3-CZ (iv)
Fp1-F3
CZ-C4 F3-C3
C3-P3
P3-O1
C4-T4 Fp2-F4
F4-C4
A B
Figure 593-2 A, Representative EEG associated with partial seizures: (i) Spike discharges from the left temporal lobe (arrow) in a patient with
complex partial seizures caused by mesial temporal sclerosis; (ii) left central-parietal spikes (arrow) characteristic of benign partial epilepsy with
centrotemporal spikes. B, Representative EEGs associated with generalized seizures: (i) 3/sec spike-and-wave discharge of absence seizures
with normal background activity; (ii) 1-2/sec interictal slow spike waves in a patient with Lennox-Gastaut syndrome; (iii) hypsarrhythmia with an
irregular multifocal high-voltage spike and wave activity with chaotic high-voltage slow background; (iv) juvenile myoclonic epilepsy EEG showing
4-6/sec spike and waves enhanced by photic stimulation.
A B
Figure 593-3 A, Coronal fluid-attenuated inversion-recovery (FLAIR) MRI scan of a 13 yr old with intractable seizures and mesial temporal sclerosis
(MTS). The arrow points at the hippocampus with the high-intensity signal characteristic of MTS. B, Axial FLAIR MRI of a 7 yr old with intractable
seizures and right frontal cortical dysplasia. The arrows point at the high-intensity signal corresponding to the dysplasia. (A from Lee JYK, Adelson
PD: Neurosurgical management of pediatric epilepsy, Pediatr Clin North Am 51:441–456, 2004.)
infantile familial convulsions with hemiplegic migraine linked to chro- Temporal lobe epilepsy can be caused by any temporal lobe lesion.
mosome 1. A number of benign infantile nonfamilial syndromes A common cause is mesial (also termed medial) temporal sclerosis,
have been reported, including dyscognitive focal (complex partial) a condition often preceded by febrile seizures and, rarely, genetic in
seizures with temporal foci, secondary generalized tonic–clonic sei- origin. Pathologically, these patients have atrophy and gliosis of the
zures with variable foci, tonic seizures with midline foci, and partial hippocampus and, in some, of the amygdala. It is the most common
seizures in association with mild gastroenteritis. All of these have a cause of surgically remediable partial epilepsy in adolescents and
good prognosis and respond to treatment promptly, often necessitat- adults. Occasionally, in patients with other symptomatic or crypto-
ing only short-term (e.g., 6 mo), if any, therapy. Nocturnal autosomal genic partial or generalized epilepsies, the focal discharges are so con-
dominant frontal lobe epilepsy has been linked to acetylcholine- tinuous that they cause an epileptic encephalopathy. Activation of
receptor gene mutations and manifests with nocturnal seizures with temporal discharges in sleep can lead to loss of speech and verbal audi-
dystonic posturing and agitation, screaming, kicking that respond tory agnosia (Landau-Kleffner epileptic aphasia syndrome). Activa-
promptly to carbamazepine. Several other less-frequent familial tion of frontal and secondary generalized discharges in sleep leads to
benign epilepsy syndromes with different localizations have also been more global delay secondary to the syndrome of continuous spike
described, some of which occur exclusively or predominantly in adults waves in slow-wave sleep (>85% of slow-wave sleep recording domi-
(see Table 593-2). nated by discharges).
The syndrome of Rasmussen encephalitis is a form of chronic
SEVERE EPILEPSY SYNDROMES encephalitis that manifests with unilateral intractable partial seizures,
WITH FOCAL SEIZURES epilepsia partialis continua, and progressive hemiparesis of the affected
Symptomatic structural/metabolic epilepsy secondary to focal brain side, with progressive atrophy of the contralateral hemisphere. The
lesions has a higher chance of being severe and refractory to therapy etiology is usually unknown. Some cases have been attributed to cyto-
than idiopathic genetic epilepsy. It is important to note that many megalovirus and others to anti-NMDA receptor autoantibodies.
patients with focal lesions, for example, old strokes or brain tumors,
either never have seizures or have well-controlled epilepsy. In infants,
drug-resistant epilepsy with focal seizures is often caused by severe 593.4 Generalized Seizures and Related
metabolic problems, hypoxic–ischemic injury, or congenital malfor-
mations. In addition, in this age group, a syndrome of multifocal severe Epilepsy Syndromes
partial seizures with progressive mental regression and cerebral atrophy Mohamad A. Mikati and Abeer J. Hani
called migrating partial seizures of infancy has been described. In
infants and older children, several types of lesions, which can occur in ABSENCE SEIZURES
any lobe, can cause intractable epilepsy and seizures and some cases Typical absence seizures usually start at 5-8 yr of age and are often,
may be secondary to mutations in the calcium sensitive potassium owing to their brevity, overlooked by parents for many months even
channel KCNT1. Brain malformations causing focal epilepsy include though they can occur up to hundreds of times per day. Unlike complex
focal cortical dysplasia, hemimegalencephaly, Sturge-Weber heman- partial seizures they do not have an aura, usually last for only a few
gioma, tuberous sclerosis, and congenital tumors such as gangliogli- seconds, and are accompanied by eye lid flutter or upward rolling of
oma, and dysembryoplastic neuroepithelial tumors, as well as others. the eyes but typically not by the usually more florid automatisms of
The intractable seizures can be simple partial, complex partial, second- complex partial seizures (absence seizures can have simple automa-
ary generalized, or combinations thereof. If secondary generalized tisms like lip-smacking or picking at clothing and the head can mini-
seizures predominate and take the form of absence-like seizures and mally fall forward). Absence seizures do not have a postictal period
drop attacks, the clinical picture can mimic the generalized epilepsy and are characterized by immediate resumption of what the patient
syndrome of Lennox-Gastaut syndrome and has been termed by some was doing before the seizure. Hyperventilation for 3-5 min can pre-
pseudo–Lennox-Gastaut syndrome. cipitate the seizures and the accompanying 3 Hz spike–and–slow-wave
discharges. The presence of periorbital, lid, perioral or limb myoclonic wave discharges. There are other forms of generalized epilepsies such
jerks with the typical absence seizures usually predicts difficulty in as photoparoxysmal epilepsy, in which generalized tonic–clonic,
controlling the seizures with medications. Early onset absence seizures absence or myoclonic generalized seizures are precipitated by photic
(before the age of 4 yr) should trigger evaluation for glucose trans- stimuli such as strobe lights, flipping through TV channels and viewing
porter defect that is often associated with low CSF glucose levels and video games. Other forms of reflex (i.e., stimulus-provoked) epilepsy
an abnormal sequencing test of the transporter gene. can occur; associated seizures are usually generalized, although some
Atypical absence seizures have associated myoclonic components may be focal (see Table 593-1 and Chapter 593.9).
and tone changes of the head (head drop) and body and are also usually
more difficult to treat. They are precipitated by drowsiness and are SEVERE GENERALIZED EPILEPSIES
usually accompanied by 1-2 Hz spike–and–slow-wave discharges. Severe generalized epilepsies are associated with intractable seizures
Juvenile absence seizures are similar to typical absences but occur and developmental delay. Early myoclonic infantile encephalopathy
at a later age and are accompanied by 4-6 Hz spike–and–slow- starts during the 1st 2 mo of life with severe myoclonic seizures and
wave and polyspike–and–slow-wave discharges. These are usually burst suppression pattern on EEG. It is usually caused by inborn errors
associated with juvenile myoclonic epilepsy (see “Benign Generalized of metabolism such as non-ketotic hyperglycinemia. Early infantile
Epilepsies”). epileptic encephalopathy (Ohtahara syndrome) has similar age of
onset and EEG but manifests tonic seizures and is usually caused by
GENERALIZED MOTOR SEIZURE brain malformations or syntaxin binding protein 1 mutations. Severe
The most common generalized motor seizures are generalized tonic– myoclonic epilepsy of infancy (Dravet syndrome) starts as focal
clonic seizures that can be either primarily generalized (bilateral) or febrile status epilepticus or focal febrile seizures and later manifests
secondarily generalized (as described in Chapter 593.3) from a unilat- myoclonic and other seizure types (see Chapter 593.1).
eral focus. If there is no partial component, then the seizure usually West syndrome starts between the ages of 2 and 12 mo and consists
starts with loss of consciousness and, at times, with a sudden cry, of a triad of infantile epileptic spasms that usually occur in clusters
upward rolling of the eyes, and a generalized tonic contraction with (particularly in drowsiness or upon arousal), developmental regres-
falling, apnea, and cyanosis. In some, a clonic or myoclonic component sion, and a typical EEG picture called hypsarrhythmia (see Fig. 593-2).
precedes the tonic stiffening. The tonic phase is followed by a clonic Hypsarrhythmia is a high-voltage, slow, chaotic background with mul-
phase that, as the seizure progresses, shows slowing of the rhythmic tifocal spikes. Patients with cryptogenic (sometimes called idiopathic,
contractions until the seizure stops usually 1-2 min later. Incontinence now referred to as unknown etiology) West syndrome have normal
and a postictal period often follow. The latter usually lasts for 30 min development before onset, while patients with symptomatic West syn-
to several hours with semicoma or obtundation and postictal sleepi- drome have preceding developmental delay owing to perinatal enceph-
ness, weakness, ataxia, hyper- or hyporeflexia, and headaches. There is alopathies, malformations, underlying metabolic disorders, or other
a risk of aspiration and injury. First aid measures include positioning etiologies (see Chapter 593.2). In boys, West syndrome can also be
the patient on his or her side, clearing the mouth if it is open, loosening caused by ARX gene mutations (often associated with ambiguous geni-
tight clothes or jewelry, and gently extending the head and, if possible, talia and cortical migration abnormalities). West syndrome, especially
insertion of an airway by a trained professional. The mouth should not in cases of unknown etiology (cryptogenic cases, i.e., cases that are not
be forced open with a foreign object (this could dislodge teeth, causing symptomatic of metabolic or structural brain disorder), is a medical
aspiration) or with a finger in the mouth (this could result in serious emergency because diagnosis delayed for 3 wk or longer can affect
injury to the examiner’s finger). Many patients have single idiopathic long-term prognosis. The spasms are often overlooked by parents and
generalized tonic–clonic seizures that may be associated with inter- by physicians, being mistaken for startles caused by colic or for other
current illness or with a cause that cannot be ascertained (see Chapter benign paroxysmal syndromes (see Chapter 594).
593.2). Generalized tonic, atonic, and astatic seizures often occur in Lennox-Gastaut syndrome typically starts between the ages of 2
severe generalized pediatric epilepsies. Generalized myoclonic seizures and 10 yr and consists of a triad of developmental delay, multiple
can occur in either benign or difficult-to-control generalized epilepsies seizure types that as a rule include atypical absences, myoclonic,
(see “Benign Generalized Epilepsies” and “Severe Generalized astatic, and tonic seizures. The tonic seizures occur either in wakeful-
Epilepsies”). ness (causing falls and injuries) or also, typically, in sleep. The third
component is the EEG findings (see Fig. 593-2): 1-2 Hz spike–and–
BENIGN GENERALIZED EPILEPSIES slow waves, polyspike bursts in sleep, and a slow background in wake-
Petit mal epilepsy typically starts in mid-childhood, and most patients fulness. Patients commonly have myoclonic, atonic, and other seizure
outgrow it before adulthood. Approximately 25% of patients also types that are difficult to control, and most are left with long-term
develop generalized tonic–clonic seizures, half before and half after the cognitive impairment and intractable seizures despite multiple thera-
onset of absences. Benign myoclonic epilepsy of infancy consists of pies. Some, but not all, patients start with Ohtahara syndrome, develop
the onset of myoclonic and other seizures during the 1st yr of life, with West syndrome, and then progress to Lennox-Gastaut syndrome.
generalized 3 Hz spike–and–slow-wave discharges. Often, it is initially Myoclonic astatic epilepsy is a syndrome similar to, but milder than,
difficult to distinguish this type from more-severe syndromes, but Lennox-Gastaut syndrome that usually does not have tonic seizures or
follow-up clarifies the diagnosis. Febrile seizures plus syndrome polyspike bursts in sleep. The prognosis is more favorable than that for
manifests febrile seizures and multiple types of generalized seizures in Lennox-Gastaut syndrome. Another syndrome characterized by atonic
multiple family members, and at times different individuals within the seizures causing head nodding as well as tonic, clonic and stimulus
same family manifest different generalized and febrile seizure types sensitive seizures is the nodding syndrome, which is a recently
(see Chapter 593.1). described epidemic type of epilepsy seen in some African countries
Juvenile myoclonic epilepsy (Janz syndrome) is the most common and often associated with encephalopathy, stunted growth, and vari-
generalized epilepsy in young adults, accounting for 5% of all epilep- able degrees of cognitive deficits. The underlying etiology is unknown.
sies. It has been linked to mutations in many genes including CACNB4; Progressive myoclonic epilepsies are a group of epilepsies charac-
CLNC2; EJM2, 3, 4, 5, 6, 7, 9; GABRA1; GABRD; and Myoclonin1/ terized by progressive dementia and worsening myoclonic and other
EFHC1 (see Table 593-2). Typically, it starts in early adolescence with seizures. Type I or Unverricht-Lundborg disease (secondary to a cys-
1 or more of the following manifestations: myoclonic jerks in the tatin B mutation) is more slowly progressive than the other types and
morning, often causing the patient to drop things; generalized tonic– usually starts in adolescence. Type II or Lafora body disease can have
clonic or clonic–tonic–clonic seizures upon awakening; and juvenile an early childhood onset but usually starts in adolescence, is more
absences. Sleep deprivation, alcohol (in older patients), and photic quickly progressive, and is usually fatal within the 2nd or 3rd decade.
stimulation, or, rarely, certain cognitive activities can act as precipi- It can be associated with photosensitivity, manifests periodic acid–
tants. The EEG usually shows generalized 4-5 Hz polyspike–and–slow- Schiff-positive Lafora inclusions on muscle or skin biopsy (in eccrine
sweat gland cells), and has been shown to be caused by laforin (EPM2A) supplementation in addition to pyridoxine use. Cerebral folate defi-
or malin (EPM2B) gene mutations. Other causes of progressive myo- ciency, which also responds to high doses of folinic acid (2-3 mg/kg/
clonic epilepsy include myoclonic epilepsy with ragged red fibers, siali- day), may manifest with epilepsy, intellectual disability, developmental
dosis type I, neuronal ceroid lipofuscinosis, juvenile neuropathic regression, dyskinesias, and autism. CSF 5-methyltetrahydrofolate
Gaucher disease, dentatorubral-pallidoluysian atrophy, and juvenile levels are decreased with normal plasma and red blood cell folate
neuroaxonal dystrophy. levels. There are usually mutations in the folate receptor (FOLR1)
Myoclonic encephalopathy in nonprogressive disorders is an epi- gene or blocking autoantibodies against membrane-associated folate
leptic encephalopathy that occurs in some congenital disorders affect- receptors of the choroid plexus. Tetrahydrobiopterin deficiencies
ing the brain, such as Angelman syndrome, and consists of almost with or without hyperphenylalaninemia may present with epilepsies,
continuous and difficult-to-treat myoclonic and, at times, other and symptoms resulting from deficiencies of dopamine (parkinsonism,
seizures. dystonia), noradrenaline (axial hypotonia), serotonin (depression,
Landau-Kleffner syndrome is a rare condition of unknown cause insomnia, temperature changes) and folate (myelin formation, basal
characterized by loss of language skills attributed to auditory agnosia ganglia calcifications, and seizures). Treatment is by substitution
in a previously normal child. At least 70% have associated clinical therapy with tetrahydrobiopterin and neurotransmitter precursors
seizures, but some do not. The seizures when they occur are of several started as early as possible. Creatine deficiency syndromes present
types, including focal, generalized tonic–clonic, atypical absence, typically with developmental delay, seizures, autistic features, and
partial complex, and, occasionally, myoclonic seizures. High-amplitude movement disorders and are diagnosed by abnormal levels of urine
spike-and-wave discharges predominate and tend to be bitemporal. In creatine and guanidinoacetic acid and/or, depending on the type of
the later evolutionary stages of the condition, the EEG findings may underlying genetic etiology, with absent creatine peak on MR spectros-
be normal. The spike discharges are always more apparent during copy of the brain. Use of creatine monohydrate and dietary restrictions
non–rapid eye movement sleep; thus, a child in whom Landau-Kleffner are helpful. Biotinidase deficiency presenting as developmental delay,
syndrome is suspected should have an EEG during sleep, particularly seizures, ataxia, alopecia, and skin rash and often associated with inter-
if the awake record is normal. CT and MRI studies typically yield mittent metabolic acidosis and organic profile of lactic and propionic
normal results. In the related but clinically distinct epilepsy syndrome acidemia, responds to the use of biotin. Serine biosynthesis defects
with continuous spike waves in slow-wave sleep, the discharges are with low serine levels in plasma or CSF amino acids often present
more likely to be frontal or generalized and the delays more likely to with congenital microcephaly, intractable seizures, and psychomotor
be global. The approach and therapy to the 2 syndromes are similar. retardation and respond to supplemental serine and glycine use.
Valproic acid is often the anticonvulsant that is used first to treat the Developmental delay, epilepsy, and neonatal diabetes is caused by
clinical seizures and may help the aphasia. Some children respond to activating mutations in the adenosine triphosphate-sensitive potas-
clobazam, to the combination of valproic acid and clobazam, or to sium channels. Sulfonylurea drugs that block the potassium channel
levetiracetam. For therapy of the aphasia, nocturnal diazepam therapy treat the neonatal diabetes and probably also favorably affect the
(0.2-0.5 mg/kg PO at bedtime for several months) is often used as central nervous system (CNS) symptoms and affect seizures. Hyperin-
first- or second-line therapy, as are oral steroids. Oral prednisone is sulinism-hyperammonemia syndrome is caused by activating muta-
started at 2 mg/kg/24 hr for 1 mo and decreased to 1 mg/kg/24 hr for tions of the glutamate dehydrogenase encoded by the GLUD1 gene.
an additional month. With clinical improvement, the prednisone is Patients present with hypoglycemic seizures after a protein-rich meal
reduced further to 0.5 mg/kg/24 hr for up to 6-12 mo. Long-term with hyperammonemia (ammonia levels 80-150 µmol/L). They are
therapy is often needed irrespective of what the patient responds to. If managed with a combination of protein restriction, AEDs, and diazox-
the seizures and aphasia persist after diazepam and steroids trials, then ide (a potassium channel agonist that inhibits insulin release). GLUT-1
a course of intravenous immunoglobulins should be considered. It is deficiency syndrome classically presents with infantile-onset epilepsy,
imperative to initiate speech therapy and maintain it for several years, developmental delay, acquired microcephaly, and complex movement
because improvement in language function occurs over a prolonged disorders. It causes impaired glucose transport to the brain typically
period. diagnosed by genetic testing or finding of low CSF lactate and CSF
Amenably treatable metabolic epilepsies are becoming increas- glucose, or low CSF to serum glucose ratios (less than 0.4). The mani-
ingly recognized. Pyridoxine-dependent epilepsy typically presents as festations of the disease are usually responsive to ketogenic diet.
neonatal encephalopathy shortly after birth with, at times, report of
increased fetal movements (seizure) in utero. There are associated gas-
trointestinal symptoms with emesis and abdominal distention, neuro-
logic irritability, sleepless and facial grimacing along with recurrent 593.5 Mechanisms of Seizures
partial motor seizure, generalized tonic seizures, and myoclonus. Sei- Mohamad A. Mikati and Abeer J. Hani
zures are usually refractory and may progress to status epilepticus if
no pyridoxine is used. Some cases start in infancy or in childhood. One can distinguish in the pathophysiology of epilepsy 4 distinct, often
Diagnosis is confirmed by the presence of elevated plasma, urine and sequential, mechanistic processes. First is the underlying etiology,
CSF α-aminoadipic semialdehyde and elevated plasma and CSF pipe- which is any pathology or pathologic process that can disrupt neuronal
colic acid levels. The presence of either homozygous or compound function and connectivity and that eventually leads to the second
heterozygous mutations in ALDH7A1 alleles (which encode the process (epileptogenesis) which makes the brain epileptic. The under-
protein antiquitin) confirms the diagnosis. The use of pyridoxine lying etiologies of epilepsy are diverse and include, among other enti-
100 mg daily orally (up to 600 mg/day) or intravenously helps stop the ties, brain tumors and malformations, strokes, scarring, or mutations
seizures. Pyridoxal phosphate responsive neonatal epileptic enceph- of specific genes. These mutations can involve voltage-gated channels
alopathy (Pyridox[am]ine 5′-phosphate oxidase [PNPO] deficiency) (Na+, K+, Ca2+, Cl−, and HCN [hydrogen cyanide]), ligand-gated chan-
may present similarly in the absence of gastrointestinal symptoms. nels (nicotinic acetylcholine and γ-aminobutyric acid A receptors
Diagnostically, there are reduced pyridoxal phosphate levels in the CSF [GABAA]) or other proteins. In some but not in all such mutations, the
with increased levels of CSF levodopa and 3-methoxytyrosine along molecular and cellular deficits caused by the mutations have been
with decreased CSF homovanillic acid and 5-hydroxyindolacetic acid. identified. For example, in Dravet syndrome, the loss of function muta-
The EEG may show a burst suppression pattern and treatment is by tion in the SCN1A gene causes decreased excitability in inhibitory
enteral administration of pyridoxal phosphate (up to 60 mg/kg/day). GABAergic interneurons, leading to increased excitability and epi-
Folinic acid–responsive seizures may also present with neonatal epilepsy. In human cortical dysplasia, the expression of the NR2B subunit
leptic encephalopathy and intractable seizures. These patients have a of the NMDA receptor is increased, leading to excessive depolarizing
similar diagnostic profile as pyridoxine-dependent epilepsy patients currents. In many other epileptic conditions, a clear etiology is still
and are caused by the same gene mutations but respond to folinic acid lacking and in others the etiology may be known, but it is still not
known how the identified underlying genetic etiology or brain insult epilepticus. Many such patients show acute swelling in the hippocam-
results in epileptogenesis. pus and long-term hippocampal atrophy with sclerosis on MRI. None-
Second, epileptogenesis is the mechanism through which the brain, theless in most patients with seizure-related MRI abnormalities, the
or part of it, turns epileptic. The presence of this process explains why findings are transient. In experimental models, the mechanisms of
some patients with the above pathologies develop epilepsy and some such injuries have been shown to involve both apoptosis and necrosis
do not. Kindling is an animal model for human focal epilepsy in which of neurons in the involved regions. There is evidence from surgically
repeated electrical stimulation of selected areas of the brain with a resected epileptic tissue that apoptotic pathways are activated in foci
low-intensity current initially causes no apparent changes but with of intractable epilepsy.
repeated stimulation results in epilepsy. This repetitive stimulation can In infantile spasms, recently developed animal models suggest that
lead to temporal lobe epilepsy, for example, through activation of increases in stress-related corticotropin-releasing hormone, sodium
metabotropic and ionotropic glutamate receptors (by glutamate), as channel blockade, and NMDA receptor stimulation are contributing
well as the tropomyosin-related kinase B receptor (by brain-derived mechanisms. Prior positron emission tomography data suggest that an
neurotrophic factor and neurotrophin-4). This leads to an increase interaction between focal cortical lesions and the brainstem raphe
in the intraneuronal calcium, which, in turn, activates calcium nuclei is important at least in some infantile spasms patients.
calmodulin–dependent protein kinase and calcineurin, a phosphatase,
resulting eventually in calcium-dependent epileptogenic gene expres- Bibliography is available at Expert Consult.
sion (e.g., c-fos) and promotion of mossy fiber sprouting. Mossy fibers
are excitatory fibers that connect the granule cells to the CA3 region
within the hippocampus, and their pathologic sprouting underlies
increased excitability in medial temporal lobe epilepsy associated with 593.6 Treatment of Seizures and Epilepsy
mesial temporal sclerosis in humans and in animal models. The cell Mohamad A. Mikati and Abeer J. Hani
loss in the CA3 region that is a characteristic of mesial temporal scle-
rosis (presumably resulting from an original insult such as a prolonged DECIDING ON LONG-TERM THERAPY
febrile status epilepticus episode or hypoxia) leads to a pathologic After a first seizure, if the risk of recurrence is low, such as when the
attempt at compensation by sprouting of the excitatory mossy fibers. patient has normal neurodevelopmental status, EEG, and MRI (risk
Consequently, mossy fiber sprouting, which has been demonstrated in approximately 20%), then treatment is usually not started. If the patient
humans also, leads to increased excitability and to epilepsy. Complex has abnormal EEG, MRI, development, and/or neurologic exam, and/
febrile seizures in rats induce hyperactivation of, paradoxically or a positive family history of epilepsy, then the risk is higher and often
excitatory, GABAA receptors leading to granule cell ectopia and to treatment is started. Other considerations are also important, such as
subsequent temporal lobe epilepsy. Possibly similar yet to be fully motor vehicle driving status and type of employment in older patients
characterized epileptogenesis mechanisms may underlie other focal or the parents’ ability to deal with recurrences or AED drug therapy in
epilepsies. children. The decision is therefore always individualized. All aspects of
Lately, the role of large-scale molecular cell signaling pathways in this decision-making process should be discussed with the family.
epileptogenesis, namely the mammalian target of rapamycin (mTOR), Figure 593-4 presents an overview of the approach to the treatment of
the Ras/ERK, and repressor element 1 (RE1)-silencing transcription seizures and epilepsy.
factor (REST; also known as neuron-restrictive silencer factor) path-
ways have been implicated in the mechanisms leading to epilepsy. The COUNSELING
mTOR pathway in tuberous sclerosis, hemimegalencephaly and corti- An important part of the management of a patient with epilepsy is
cal dysplasia-related epilepsies, Ras/ERK in a number of syndromes, educating the family and the child about the disease, its management,
and REST in epileptogenesis after acute neuronal injury. and the limitations it might impose and how to deal with them. It is
The third process is the resultant epileptic state of increased excit- important to establish a successful therapeutic alliance. Restrictions on
ability that is present in all patients irrespective of the underlying etiol- driving (in adolescents) and on swimming are usually necessary (Table
ogy or mechanism of epileptogenesis. In a seizure focus, each neuron 593-10). In most states, the physician is not required to report the
has a stereotypic synchronized response called paroxysmal depolar- epileptic patient to the motor vehicle registry; this is the responsibility
ization shift that consists of a sudden depolarization phase, resulting of the patient. The physician then is requested to complete a specific
from glutamate and calcium channel activation, with a series of action form for patients who are being cleared to drive. Also in most states,
potentials at its peak followed by an after-hyperpolarization phase, a seizure-free period of 6 mo, and in some states longer, is required
resulting from activation of potassium channels and GABA receptors before driving is allowed. Often swimming in rivers, lakes, or sea, and
that open chloride channels. When the after-hyperpolarization is dis- underwater diving are prohibited, but swimming in swimming pools
rupted in a sufficient number of neurons, the inhibitory surround is may be allowable. When swimming, even patients with epilepsy that
lost and a population of neurons fire at the same rate and time, result- is under excellent control should be under the continuous supervision
ing in a seizure focus. In childhood absence epilepsy, the discharging of an observer who is aware of their condition and capable of lifeguard-
neurons also develop a paroxysmal depolarization shift similar to the level rescue.
one found in partial epilepsy. However, the mechanism of paroxysmal The physician, parents, and child should jointly evaluate the risk
depolarization shift generation is different because it involves thalamo- of involvement in athletic activities. To participate in athletics, proper
cortical connections bilaterally. T-type calcium channels on thalamic medical management, good seizure control, and proper supervision
relay neurons are activated during hyperpolarization by GABAergic are crucial to avoid significant risks. Any activity where a seizure
interneurons in the reticular thalamic nucleus, which results in might cause a dangerous fall should be avoided; these activities include
enhancement of synchronization in the thalamocortical loop and con- rope climbing, use of the parallel bars, and high diving. Participation
sequently in the typical generalized spike-wave pattern. In tumor- in collision or contact sports depends on the patient’s condition. Epi-
related epilepsy, particularly in that related to oligodendroglioma, the leptic children should not automatically be banned from participating
voltage-gated sodium channels are present on the surface of tumor in hockey, baseball, basketball, football, or wrestling. Rather, indi-
cells at a higher density than on normal cells, and their inactivation is vidual consideration should be based on the child’s specific case (see
impaired by the alkaline pH present in this condition. In hypothalamic Table 593-10).
hamartoma causing gelastic seizures, clusters of GABAergic interneu- Counseling is helpful to support the family and to educate them
rons spontaneously fire, thus synchronizing the output of the hypotha- about the resources available in the community. Educational and, in
lamic hamartoma neurons projecting to the hippocampus. some cases, psychologic evaluation may be necessary to evaluate for
The fourth process is seizure-related neuronal injury as demon- possible learning disabilities or abnormal behavioral patterns that
strated by MRI in patients after prolonged febrile and afebrile status might coexist with the epilepsy. Epilepsy does carry a risk of increased
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Did the child have a seizure?
NO YES
Benign paroxysmal Initial Seizure Recurrent Seizures

vertigo Fasting blood sugar, Drug compliance?
Breath holding calcium, metabolic Improper dose?
Cough syncope studies dictated by Incorrect drug?
Familial choreoathetosis history and physical; Metabolic disorder?
Hereditary chin trembling EEG? CT scan? MRI? Underlying structural lesion?
Shuddering attacks CSF examination? Drug interaction?
Narcolepsy CNS degenerative disease?
Night terror Intractable seizures?
Pseudoseizures
Rage attack
Benign myoclonus of
infancy
Tics Studies and Examination
Abnormal Normal Normal (except EEG)

Symptomatic Seizures Isolated first seizure Consider drug therapy
Treat underlying cause with normal EEG
(hypoglycemia, urea Negative family history
cycle abnormality, No continuous drug
meningitis, temporal treatment Follow-up
lobe tumor, etc.) Close observation
Antiepileptic drugs if Prescribe rescue
necessary medications (rectal
diazepam) for
seizures longer than
5 min
Good Control Poor Control
Regular follow-up Consider hospitalization
Antiepileptic drug levels Prolonged EEG
Monitor toxicity (CBC, recording and video
liver function, monitoring for
behavioral, learning) possible epilepsy
EEG as indicated surgery candidacy
Readjust medication
Reconsider underlying
pathology with
reinvestigation with
CT or MRI
Frequent follow-up
Figure 593-4 Approach to the child with a suspected convulsive disorder.
mortality (2 or more times the standardized mortality rates of the

Table 593-10 Sports and Special Considerations for the general population) and of sudden unexpected death. This is mostly
Child with Epilepsy* related to the conditions associated with or underlying the epilepsy
SPORTS TYPE SPECIAL CONSIDERATIONS (e.g., tumor, metabolic diseases), to poor seizure control (e.g., in
patients with severe epileptic encephalopathies, or drug-resistant sei-
Body contact If there are more than occasional seizures, zures), and to poor compliance with prescribed therapies. Thus, family
sports physician evaluation of benefits and risks of members can usually be informed about this increased risk without
participation should be made based on the
child’s condition. No contraindications in
inappropriately increasing their anxiety. Many family members feel
general except for boxing. they need to observe the patient continuously in wakefulness and sleep
and have the patient sleep in the parents’ room to detect seizures. There
Noncontact Generally recommended. Anxiety and fatigue are currently advertised seizure-detection equipment that use motion
sports can cause a problem in some children. sensors placed under the mattress to detect seizures. Some are disap-
Individualization based on clinical history
must be the rule.
pointing and ineffective in detecting seizures, whereas data from other
equipment are encouraging in that they were useful in detecting a
Gymnastics A fall can result if the child experiences a majority of generalized tonic–clonic seizures during sleep (see bibliog-
sudden seizure, especially with trampolines, raphy for details). Whether such measures can reduce sudden unex-
parallel bars, and rope climbing, which pected death in epilepsy (SUDEP) risk remains to be seen and the
should be avoided.
Individual consideration remains the basic
parents need to guard against being overprotective to avoid adversely
determinant. affecting the psychology of the child. Education about what to do in
case of seizures, the choices of treatment or no treatment and of medi-
Swimming The child should always be under cations and their side effects, and potential complications of epilepsy
supervision, and scuba diving should be should be provided to the parents and, if the child is old enough, to
discouraged in poorly controlled epileptics.
the child.
*Specific advice should be individualized depending on the patient’s clinical
condition. Many patients actually have fewer seizures when they are active than MECHANISMS OF ACTION
when they are idle.
Modified from Committee on Children with Handicaps: The epileptic child
OF ANTIEPILEPTIC DRUGS
and competitive school athletics, Pediatrics 42:700–702, 1968; and Knowles BD: AEDs reduce excitability by interfering with the sodium, potassium or
Athletes with seizure disorders, Curr Sports Med Rep 11(1):16–20, 2012, Table 1. calcium ion channels, by reducing excitatory neurotransmitter release
Figure 593-5 Mechanisms of action of antiepileptic drugs, which act by diverse mechanisms, mainly involving modulation of voltage activated
ion channels, potentiation of GABA, and inhibition of glutamate. Approved antiepileptic drugs have effects on inhibitory (left hand side) and
excitatory (right hand side) nerve terminals. The antiepileptic efficacy in trials of most of these drugs as initial add-on does not differ greatly,
indicating that seemingly similar antiseizure activity can be obtained by mechanisms aimed at diverse targets. However, putative mechanisms of
action were determined only after discovering the antiseizure effects; mechanism driven drug discovery has been largely ignored. AMPA, α-amino-
3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GAT-1, sodium-dependent and chloride-dependent GABA transporter
1; SV2A, synaptic vesicle glycoprotein 2A. (From Schmidt D, Schachter SC: Drug treatment of epilepsy in adults. BMJ, 348:bmj.g254, 2014.)
or function, or by enhancing GABAergic inhibition (Fig. 593-5). Most propionic acid)/kainate receptors. Topiramate also blocks AMPA/
medications have multiple mechanisms of action, and the exact mecha- kainate receptors. Levetiracetam binds to the presynaptic vesicle
nism responsible for their activity in human epilepsy is usually not fully protein SV2A found in all neurotransmitter vesicles and possibly
understood. Often, medications acting on sodium channels are effec- results in inhibition of presynaptic neurotransmitter release in a use-
tive against partial seizures, and medications acting on T-type calcium dependent manner. Perampanel blocks glutamate AMPA receptors.
channels are effective against absence seizures. Voltage-gated sodium
channels are blocked by felbamate, valproate, topiramate, carbamaze- CHOICE OF DRUG ACCORDING TO SEIZURE
pine, oxcarbazepine, lamotrigine, phenytoin, rufinamide, lacosamide, TYPE AND EPILEPSY SYNDROME
and zonisamide. T-type calcium channels, found in the thalamus area, Drug therapy should be based on the type of seizure and the epilepsy
are blocked by valproate, zonisamide, and ethosuximide. Voltage-gated syndrome as well as on other individual factors. In general, the drugs
calcium channels are inhibited by gabapentin, pregabalin, lamotrigine, of first choice for focal seizures and epilepsies are oxcarbazepine and
and felbamate. N-type calcium channels are inhibited by levetiracetam. carbamazepine; for absence seizures, ethosuximide; for juvenile myo-
Ezogabine/retigabine opens KCNQ/Kv7 voltage-gated potassium clonic epilepsy, valproate and lamotrigine; for Lennox-Gastaut syn-
channels. drome, clobazam, valproate, topiramate, lamotrigine, and, most
GABAA receptors are activated by phenobarbital, benzodiazepines, recently, as add on, rufinamide; and for infantile spasms, adrenocorti-
topiramate, felbamate, and levetiracetam. Tiagabine, by virtue of its cotropic hormone (ACTH). There is significant controversy about
binding to GABA transporters 1 (GAT-1) and 3 (GAT-3), is a GABA these choices, and therapy should always be individualized (see Choice
reuptake inhibitor. GABA levels are increased by vigabatrin via its of Drug: Other Considerations below and Table 593-10).
irreversible inhibition of GABA transaminases. Valproate inhibits West syndrome is best treated with ACTH. There are several pro-
GABA transaminases, acts on GABAB presynaptic receptors (also done tocols that range in dose from high to intermediate to low. The recom-
by gabapentin), and activates glutamic acid decarboxylase (the enzyme mended regimen of ACTH (80 mg/mL) is a daily dose of 150 units/m2
that forms GABA). (divided into twice-daily intramuscular injections of 75 units/m2, the
Glutaminergic transmission is decreased by felbamate that blocks lot number is recorded) administered over a 2-wk period with a sub-
NMDA and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole- sequent gradual taper over a 2-wk period (30 units/m2 in the morning
for 3 days; 15 units/m2 in the morning for 3 days; 10 units/m2 in the Very rare cases of patients who have neonatal, infantile, or early
morning for 3 days; and 10 units/m2 every other morning for 6 days, childhood seizures who have pyridoxine-dependent epilepsy (dem-
then stop). The increase in price of ACTH gel in the United States has onstrated to be caused by antiquitin gene mutation) respond to pyri-
led many physicians to use the lower-dose regimen because it may be doxine 10-100 mg/day orally (up to 600 mg/day has been used) within
just as effective (initial: 20 units/day for 2 wk, if patient responds, taper 3-7 days of the initiation of oral therapy and almost immediately if
and discontinue over a 1-wk period; if patient does not respond, given parenterally. Some patients have seizures that are intractable
increase dose to 30 units/day for 4 wk then taper and discontinue over from onset, but others have seizures that show an initial but transient
a 1-wk period). Response is usually observed within the 1st 7 days; response to traditional AEDs. Some of these patients also require con-
however, if no response is observed within 2 wk, the lot is changed. current folinic acid (5-15 mg/day). Other patients require the active
During the tapering period of any regimen, and especially in symp- form of vitamin B6, specifically, pyridoxal phosphate (50 mg/day initial
tomatic patients, relapse can occur. Remediation entails increasing the dose that can be increased gradually up to 15 mg/kg every 6 hr) owing
dose to the previously effective dose for 2 wk and then beginning the to their deficiency of PNPO. In both the PNPO-deficient/pyridoxal
taper again. Synthetic ACTH has also been used: Synacthen Depot phosphate–dependent and the pyridoxine-dependent forms, hypoto-
intramuscular 0.25 mg/mL or 1 mg/mL is used; 1 mg is considered to nia and hypopnea can occur after initiation of vitamin therapy. Pyri-
have the potency of 100 IU in stimulating the adrenal gland. doxine has also been used by some, specifically in Japan, early in the
Awake and asleep EEGs are often done 1, 2, and 4 wk after the initia- treatment of West syndrome. Patients with cerebral folate deficiency
tion of ACTH to monitor the patient’s response, with the aim of clear- can respond to folinic acid supplementation (usually at doses of 2-3 mg/
ing the EEG from hypsarrhythmia and of stopping the seizures. Side kg/day). Traditionally these entities have been diagnosed by giving the
effects, more common with the higher doses, include hypertension, vitamin B6 or folinic acid in therapeutic trials, but currently laboratory
electrolyte imbalance, infections, hyperglycemia and/or glycosuria, testing is available to confirm the diagnosis (see Chapter 593.4).
and gastric ulcers. All should be carefully monitored for and prophy- Absence seizures are most often initially treated with ethosuximide,
lactic therapy for ulcers is desirable. ACTH is generally thought to offer which is, as effective as, but less toxic than, valproate and more effective
an added advantage, particularly in cryptogenic cases, over vigabatrin than lamotrigine. Alternative drugs of first choice are lamotrigine and
and possibly over prednisone and other steroids. valproate, especially if generalized tonic–clonic seizures coexist with
Vigabatrin is considered by some as a drug of second choice for absence seizures, as these 2 medications are effective against the latter
infantile spasms and by some even as an alternative to ACTH as a drug seizures whereas ethosuximide is not. Patients resistant to ethosuxi-
of first choice. Its principal side effect is retinal toxicity that is seen in mide might still respond to valproate or to lamotrigine. In absence
approximately 30% of the patients, with resultant visual field defects seizures, the EEG is usually helpful in monitoring the response to
that persist despite withdrawal of the drug. The level of evidence for therapy and is often more sensitive than the parents’ observations in
its efficacy is weaker than that for ACTH but stronger than that of detecting these seizures. The EEG often normalizes when complete
other alternative medications, including valproate, benzodiazepines seizure control is achieved. This is usually not true for partial epilep-
like nitrazepam and clonazepam, topiramate, lamotrigine, zonisamide, sies. Other medications that could be used for absence seizures include
pyridoxine, ketogenic diet, and intravenous gamma globulin (IVIG). acetazolamide, zonisamide, or clonazepam.
None of these alternative drugs offers uniformly satisfactory results. Benign myoclonic epilepsies are often best treated with valproate,
However, they are useful for decreasing the frequency and severity of particularly when patients have associated generalized tonic–clonic
seizures in patients with symptomatic infantile spasms and as adjunc- and absence seizures. Benzodiazepines, clonazepam, lamotrigine, and
tive therapy in patients with cryptogenic infantile spasms who do not topiramate are alternatives for the treatment of benign myoclonic epi-
respond completely to ACTH or vigabatrin. lepsy. Severe myoclonic epilepsies are treated with medications effec-
Lennox-Gastaut syndrome is another difficult-to-treat epilepsy tive for Lennox-Gastaut syndrome such topiramate, clobazam, and
syndrome. Treatment of seizures in Lennox-Gastaut syndrome varies valproate, as well as zonisamide. Levetiracetam may also have efficacy
according to the preponderant seizure type. For drop attacks (tonic, in myoclonic epilepsies.
atonic, or myoclonic astatic seizures), valproate, lamotrigine, topira- Partial and secondary generalized tonic and clonic seizures can
mate, clobazam, felbamate, and rufinamide are considered to be effec- be treated with oxcarbazepine, levetiracetam, carbamazepine, pheno-
tive. Felbamate is used as a last resort medication because of its barbital, topiramate, valproic acid, lamotrigine, clobazam, or clonaze-
potential toxicity. These drugs might control other types of seizures pam (see Table 593-8). Oxcarbazepine, levetiracetam, carbamazepine
(partial, generalized tonic–clonic, atypical absence, other tonic, myo- (United States), or valproate (Europe) are often being used first. One
clonic) as well. For patients who have a preponderance of atypical study favored lamotrigine as initial monotherapy for partial seizures
absence seizures, lamotrigine or ethosuximide are often suitable drugs and valproate for generalized seizures. Almost any of these medica-
to try because they are relatively less toxic than many of the alternative tions has been used as first or second choice. depending on the indi-
drugs. Valproate is helpful against these seizures, too. Clonazepam is vidualization of the therapy.
often helpful but produces significant sedation, hyperactivity, and
drooling, and often tolerance to its antiepileptic effects develops in a CHOICE OF DRUG: OTHER CONSIDERATIONS
few months. Consequently, clonazepam is often used as a rescue medi- Because there are many options for each patient, the choice of which
cation for clusters of seizures (disintegrating tablet preparation). In drug to use is always an individualized decision based on comparative
resistant cases of Lennox-Gastaut syndrome and related epilepsies, effectiveness data from randomized controlled trials and on several
zonisamide, levetiracetam, acetazolamide, methsuximide, corticoste- other considerations delineated below.
roids, ketogenic diet, or IVIG can be used. Comparative effectiveness (Table 593-11) and potential for para-
Dravet syndrome is usually treated with valproate and benzodiaz- doxical seizure aggravation by some AEDs (e.g., precipitation of
epines such as clobazam or clonazepam. The ketogenic diet can also myoclonic seizures by lamotrigine in Dravet syndrome and exacerba-
be useful in patients with this syndrome, including cases with refraction of absence seizures by carbamazepine and tiagabine) must be
tory status. Stiripentol, which is available in some countries, is useful, considered.
particularly if used in combination with valproate and clobazam, but ◆ Comparative tolerability (see Table 593-14): Adverse effects can
doses need to be adjusted, since stirpentol can increase clobazam levels vary according to the profile of the patient. The most prominent
and valproate can increase stirpentol levels. Other medications include example is the increased risk of liver toxicity for valproate therapy
zonisamide and topiramate. Lamotrigine, carbamazepine, and phe- in children who are younger than 2 yr of age, on polytherapy,
nytoin are reported to exacerbate seizures. Barbiturate use during and/or have metabolic disorders. Thus, if metabolic disorders are
status epilepticus in this syndrome is suspected to be associated with suspected, other drugs should be considered first and valproate
adverse outcomes; consequently, alternative acute therapies in such should not be started until the metabolic disorders are ruled out
cases need to be considered. by normal amino acids, organic acids, acylcarnitine profile, lactate,
Table 593-11 Comparison of Recommendations for the Treatment of Pediatric Epilepsy

PEDIATRIC PEDIATRIC
SEIZURE EXPERT EXPERT
TYPE OR CONSENSUS CONSENSUS
EPILEPSY FDA SURVEY (NORTH SURVEY
SYNDROME APPROVED SIGN (2005) NICE (2012) AAN (2004) ILAE (2013)* AMERICA–2005) (EUROPE–2007)
Partial-onset CBZ, CBZ, CLB, CBZ, LEV, LTG, CBZ, GBP, A: OXC CBZ, OXC CBZ, OXC
ezogabine, LTG, OXC, OXC, VPA LTG, OXC, B: None
lacosamide, PHT, TPM, PB, PHT, C: CBZ, PB, PHT,
LEV, LTG, VGB, VPA TPM TPM, VGB, VPA
OXC, PB, D: CLB, CZP,
perampanel, LTG, ZNS
PHT, TPM,
VGB
BCECT None Not CBZ, LEV, LTG, Not surveyed A, B: None CBZ, OXC VPA
specifically OXC, VPA C: CBZ, VPA
mentioned D: GBP, LEV,
OXC, STM
Childhood ESM, VPA ESM, LTG, ESM, LTG, VPA LTG A: ESM, VPA ESM VPA
absence VPA B: None
epilepsy C: LTG
D: None
Juvenile LEV, LTG, TPM VPA LEV, LTG, TPM, Not surveyed A, B, C: None LTG, VPA VPA
myoclonic VPA D: TPM, VPA
epilepsy
Lennox- CLB, FLB, LTG, CLB, LTG, VPA Not surveyed Not reviewed LTG, VPA VPA
Gastaut rufinamide VPA
syndrome (atonic), TPM
Infantile VGB Nitrazepam, Corticosteroids, ACTH, VGB Not reviewed ACTH, VGB VGB
spasms TPM, VGB, VGB (updated IS
VPA guidelines
2012)
Primary LEV, LTG, TPM TPM, VPA LTG, TPM, VPA No evidence A: None
generalized given B: None
tonic-clonic C: CBZ, PB, PHT,
seizures TPM, VPA
D: OXC
*ILAE recommendations are listed according to levels of evidence supporting the efficacy of the options. Level A: ≥1 class I randomized controlled trial (RCT) or ≥2
class II RCTs; Level B: 1 class II RCT or ≥2 class III RCTs; Level C: ≥2 class III RCTs; Level D: 1 class III double-blind or open-label study or 1 class IV clinical study or
data from expert committee reports, opinions from experienced clinicians.
AAN, American Academy of Neurology; ACTH, adrenocorticotropic hormone; BCECT, benign childhood epilepsy with centrotemporal spikes; CBZ, carbamazepine;
CLB, clobazam; CZP, clonazepam; ESM, ethosuximide; FDA, Food and Drug Administration; FLB, felbamate; GBP, gabapentin; ILAE, International League against
Epilepsy; LEV, levetiracetam; LTG, lamotrigine; NICE, National Institute for Clinical Excellence; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; SIGN,
Scottish Intercollegiate Guidelines Network; STM, sulthiame; TPM, topiramate; VGB, vigabatrin; VPA, valproic acid; ZNS, zonisamide.
Modified and updated from Wheless JW, Clarke DF, Arzimanoglou A, et al: Treatment of pediatric epilepsy: European expert opinion, Epileptic Disord 9:353–412,
2007; and Perucca E, Tomson T; ILAE Subcommission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial
monotherapy for epileptic seizures and syndromes. Epilepsia 54(3):551–563, 2013.
pyruvate, liver function tests, and perhaps other tests. The choice ◆ Ease of initiation of the AED: Medications that are started very
of an AED can also be influenced by the likelihood of occurrence gradually such as lamotrigine and topiramate should not be
of nuisance side effects such as weight gain (valproate, chosen in situations when there is a need to achieve a therapeutic
carbamazepine), gingival hyperplasia (phenytoin), alopecia level quickly. In such situations, medications that have intravenous
(valproate), hyperactivity (benzodiazepines, barbiturates, preparations or that can be started and titrated more quickly, such
levetiracetam, valproate, gabapentin). Children with behavior as valproate, phenytoin, or levetiracetam, should be considered
problems and/or with attention-deficit disorder can become instead.
particularly hyperactive with GABAergic drugs mentioned above. ◆ Drug interactions and presence of background medications: An
This often affects the choice of medications. example is the potential interference of enzyme-inducing drugs
◆ Cost and availability: The cost of the newer AEDs often precludes with many chemotherapeutic agents. In those cases, medications
their use, particularly in developing countries where cost is a like gabapentin or levetiracetam are used. Also, valproate inhibits
major issue. Also, many drugs are not available in many countries the metabolism and increases the levels of lamotrigine,
either because they are too expensive, because, paradoxically, they phenobarbital, and felbamate. It also displaces protein-bound
are too inexpensive (lower profit margin), or because of regulatory phenytoin from protein-binding sites, increasing the free fraction,
restrictions. AEDs have a narrow therapeutic range and thus and, thus, the free and not the total level needs to be checked when
switching from brand name to generic formulations, or from one both medications are being used together. Enzyme inducers like
generic to another, can result in changes in levels that could result phenobarbital, carbamazepine, phenytoin, and primidone reduce
in breakthrough seizures or side effects. Thus, generic substitution levels of lamotrigine, valproate, and, to a lesser extent, topiramate
is generally best avoided, particularly in fragile patients, if a brand and zonisamide. Medications exclusively excreted by the kidney like
name drug has already proved efficacious. levetiracetam and gabapentin are not subject to such interactions.
Table 593-12 Teratogenesis and Perinatal Outcomes of Antiepileptic Drugs

LEVEL OF
FINDING RECOMMENDATION RECOMMENDATION
VPA as part of polytherapy and possibly If possible, avoidance of valproate polytherapy during B
monotherapy probably contributes to the the 1st trimester of pregnancy should be considered
development of major congenital malformations so as to decrease the risk of major congenital
and adverse cognitive outcome malformations and adverse cognitive outcome
AED polytherapy, as compared to monotherapy, If possible, avoidance of AED polytherapy during the B
regimens probably contribute to the 1st trimester of pregnancy should be considered to
development of major congenital malformations decrease the risk of major congenital malformations
and to adverse cognitive outcomes and adverse cognitive outcome
Monotherapy exposure to phenytoin or If possible, avoidance of phenytoin and phenobarbital C
phenobarbital possibly increases the likelihood during pregnancy may be considered to prevent
of adverse cognitive outcomes adverse cognitive outcomes
Neonates of women with epilepsy taking AEDs Pregnancy risk stratification should reflect that the C
probably have an increased risk of being small offspring of women with epilepsy taking AEDs are
for gestational age and possibly have an probably at increased risk for being small for
increased risk of a 1 min Apgar score of <7 gestational age (level B) and possibly at increased
risk of 1 min Apgar scores of <7
Levels of recommendation: A: strongest recommendation; based on class 1 evidence; B and C: lower levels of recommendations.
Types of malformations: Prior studies had reported the occurrence of spina bifida with valproate and carbamazepine therapy, and of cardiac malformation and cleft
palate after carbamazepine, phenytoin, and phenobarbital exposure. There is variability from study to study. However, in general the relative incidence of major
malformations of approximately 10% for valproate monotherapy, higher with valproate polytherapy, and in the range of 5% for monotherapy with the other above 3
AEDs and higher with polytherapy.
FDA categories: Valproate, phenobarbital, carbamazepine, and phenytoin are classified by the FDA as category D. Ethosuximide, felbamate, gabapentin,
lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide are category C. Category C: Animal studies have shown an adverse effect and there
are no adequate and well-controlled studies in pregnant women or no animal studies have been conducted and there are no adequate and well-controlled studies in
pregnant women. Category D: Studies, adequate, well-controlled, or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits
of therapy might outweigh the potential risk.
AED, antiepileptic drug; VPA, valproate.
Data from Harden CI, Meador KJ, Pennell PB, et al: Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-
based review): teratogenesis and perinatal outcomes. Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the
American Academy of Neurology and American Epilepsy Society, Neurology 73(2):133–141, 2009.
◆ The presence of comorbid conditions: For example, the presence sodium channels). A number of medications, such as lamotrigine
of migraine in a patient with epilepsy can lead to the choice of a and valproate or topiramate and lamotrigine, are reported to have
medication that is effective against both conditions such as synergistic effects, possibly because they have different
valproate or topiramate. In an obese patient, a medication such as mechanisms of action.
valproate might be avoided, and a medication that decreases ◆ Ease of use: Medications that are given once or twice a day are
appetite such as topiramate might be used instead. In adolescent easier to use than medications that are given 3 or 4 times a day.
girls of child-bearing potential, enzyme-inducing AEDs are often Availability of a pediatric liquid preparation, particularly if
avoided because they can interfere with birth control pills; other palatable, also plays a role.
AEDs, particularly valproate, can increase risks for fetal ◆ Ability to monitor the medication and adjust the dose: Some
malformations (Table 593-12). Valproic acid may unmask or medications are difficult to adjust and to follow, requiring frequent
exacerbate certain underlying metabolic disorders; these include blood levels. The prototype of such medications is phenytoin, but
nonketotic hyperglycinemia, DNA polymerase γ mutations many of the older medications also require blood level monitoring
(POLG) with mitochondrial DNA depletion (also known as for optimal titration. However, monitoring in itself can represent a
Alpers-Huttenlocher syndrome), other mitochondrial disorders practical or patient satisfaction disadvantage for the older drugs as
(Leigh syndrome; mitochondrial myopathy, encephalopathy, compared to the newer AEDs, which generally do not require
lactic acidosis, and stroke-like episodes [MELAS]; myoclonic blood-level monitoring except to check for compliance.
epilepsy with ragged red fibers; myoclonic epilepsy-myopathy- ◆ Patient’s and family’s preferences: All things being equal, the
sensory ataxia syndrome), and hyperammonemic choice between 2 or more acceptable alternative AEDs might also
encephalopathies. Manifestations may include hepatotoxicity depend on the patient’s or family’s preferences. For example, some
or encephalopathy. patients might want to avoid gingival hyperplasia and hirsutism as
◆ Coexisting seizures: In a patient with both absence and side effects but might tolerate weight loss, or vice versa.
generalized tonic–clonic seizures, a drug that has a broad ◆ Genetics and genetic testing: A genetic predisposition to
spectrum of antiseizure effects such as lamotrigine or valproate developing AED-induced side effects is another factor that may be
could be used rather than medications that have a narrow a consideration. For example, there is a strong association between
spectrum of efficacy, such as phenytoin and ethosuximide. the human leukocyte antigen HLA-B*1502 allele and severe
◆ History of prior response to specific AEDs: For example, if a cutaneous reactions induced by carbamazepine, phenytoin, or
patient or a family member with the same problem had previously lamotrigine in Chinese Han patients and, to a lesser extent,
responded to carbamazepine, carbamazepine could be a desirable South East Asian populations; hence these AEDs should be
choice. avoided in genetically susceptible persons after testing for the
◆ Mechanism of drug actions: At present, the current allele. The testing for other alleles that predispose to such allergies
understanding of the pathophysiology of epilepsy does not allow in other populations is not yet clinically useful. Mutations of the
specific choice of AEDs based on the assumed pathophysiology of SCN1A sodium channel gene indicating Dravet syndrome could
the epilepsy. However, in general, it is believed that it is better to also lead to avoiding lamotrigine, carbamazepine, and phenytoin,
avoid combining medications that have similar mechanisms of and to the use of the more appropriate valproate, clobazam, or
action, such as phenytoin and carbamazepine (both work on stiripentol.
◆ Teratogenic profiles: Some AEDs, including valproate and to a counseled about potential adverse effects, and these should be moni-
lesser extent carbamazepine, phenobarbital, and phenytoin, are tored during follow-up visits (Table 593-14).
associated with teratogenic effects (see Table 593-12).
Some of these considerations can be addressed by resorting to Titration
expert opinion surveys (see Table 593-11) or to guidelines developed Levels of many AEDs should usually be determined after initiation to
by concerned societies such as the ILAE, National Institute for Clinical ensure compliance and therapeutic concentrations. Monitoring is most
Excellence (NICE) in England, Scottish Intercollegiate Guidelines helpful for the older AEDs such as phenytoin, carbamazepine, valpro-
Network (SIGN), or the American Academy of Neurology (AAN). ate, phenobarbital, and ethosuximide. After starting the maintenance
Some guidelines are totally evidence based (AAN, ILAE), and others dosage or after any change in the dosage, a steady state is not reached
(NICE, SIGN) incorporate other considerations as well. However, no until 5 half-lives have elapsed, which, for most AEDs, is 2-7 days (half-
guideline is able to incorporate all the considerations relevant to each life: 6-24 hr). For phenobarbital, it is 2-4 wk (mean half-life: 69 hr).
patient. For zonisamide it is 14 days during monotherapy and less than that
during polytherapy with enzyme inducers (half-life: 63 hr in mono-
INITIATING AND MONITORING THERAPY therapy and 27-38 hr during combination therapy with enzyme induc-
In nonemergency situations, or when loading is not necessary, the ers). If a therapeutic level has to be achieved faster, a loading dose may
maintenance dose of the chosen AED is started (Table 593-13). With be used for some drugs, usually with a single dose that is twice the
some medications (e.g., carbamazepine and topiramate), even smaller average maintenance dose per half-life. For valproate it is 25 mg/kg,
doses are initially started then gradually increased up to the mainte- for phenytoin it is 20 mg/kg, and for phenobarbital it is 10-20 mg/kg.
nance dose to build tolerance to adverse effects such as sedation. For A lower loading dosage of phenobarbital is sometimes given in older
example, the starting dose of carbamazepine is usually 5-10 mg/kg/day. children (5 mg/kg, which may be repeated once or more in 24 hr), to
Increments of 5 mg/kg/day can be added every 3 days until a thera- avoid excessive sedation.
peutic level is achieved and a therapeutic response is established or Only 1 drug should be used initially and the dose increased until
until unacceptable adverse effects occur. With other medications such complete control is achieved or until side effects prohibit further
as zonisamide, phenobarbital, phenytoin, or valproate, starting at the increases. Then, and only then, may another drug be added and the
maintenance dose is usually tolerated. With some, such as levetirace- initial drug subsequently tapered. Control with 1 drug (monotherapy)
tam and gabapentin, either approach can be used. Patients should be should be the goal, although some patients eventually need to take
Table 593-13 Dosages of Selected Antiepileptic Drugs

MAINTENANCE ORAL
DOSAGE (mg/kg/day)
FDA APPROVAL UNLESS OTHERWISE USUAL THERAPEUTIC
MEDICATION (AGE APPROVED) SPECIFIED DOSING LEVELS PREPARATIONS
Acetazolamide Absence seizures 1-12 mo; 10 <1 yr: 20-30 bid or tid 10-15 mg/L 125, 250, 500 mg tabs
(adults)
Bromide 50-100 bid or qd 10-15 mEq/L Supplied as triple
bromide soln (240 mg/
mL of bromide salt)
Carbamazepine* Partial and GTC (all 10-20 tid or qid 3-12 mg/L 150, 300 mg ER caps
ages) SR usually bid 100, 200, 400 mg ER tabs
100 mg chewable tabs
200 mg tabs
100 mg/5 mL susp
Clobazam† LGS (all ages above 10-20 mg/day bid or tid 60-200 µg/L 5 mg, 10 mg, 20 mg tabs
2 yr) 2.5 mg/mL soln
Clonazepam† Absence sz, LGS, 0.05-0.2 bid or tid 25-85 µg/L 0.5, 1, 2 mg tabs
myoclonic sz (all 0.125, 0.25, 0.5 mg orally
ages) disintegrating tabs
Diazepam Partial sz (all ages 0.25-1.5 bid or tid 100-700 µg/L 2, 5, 10 mg tabs
>6 mo) 0.01-0.25 IV 5 mg/mL, 5 mg/5 mL soln
0.2-0.5 mg/kg rectal Rectal gel that can be
(according to age; see dialed to dispense 2.5,
Table 593-15) 5, 7.5, 10, 12.5, 15, 17.5,
20 mg
Ethosuximide Absence sz (>3 yr) 20-30 bid or tid 40-100 mg/L 250 mg caps
250 mg/5 mL syrup, soln
Ezogabine Partial sz (adults) No pediatric dose tid — 50, 200, 300, 400 mg tabs
approved
Felbamate LGS (>2 yr) Partial sz 15-45 bid or tid 50-110 mg/L 400, 600 mg tabs
(>14 yr) 600 mg/5 mL susp
Gabapentin‡ Partial sz (>3 yr) 30-60 tid 2-20 mg/L 100, 300, 400 mg caps,
600, 800 mg tabs
Lacosamide Partial sz (>17 yr) No FDA approved bid <= 15 µg/L 50, 100, 150, 200 mg tabs
dose. 10 mg/mL oral soln
4-12
Table 593-13 Dosages of Selected Antiepileptic Drugs—cont’d

MAINTENANCE ORAL
DOSAGE (mg/kg/day)
FDA APPROVAL UNLESS OTHERWISE USUAL THERAPEUTIC
MEDICATION (AGE APPROVED) SPECIFIED DOSING LEVELS PREPARATIONS
§
Lamotrigine LGS, partial and 5-15 tid 1-15 mg/L 25, 100, 150, 200 mg tabs
tonic–clonic sz (age 1-5¶ bid 5, 25 mg chewable
>2 yr) dispersible tabs
25, 50, 100, 200 mg ODTs
25, 50, 100, 200, 250,
300 mg ER tabs
Levetiracetam† Myoclonic, partial and 20-40 bid or tid 6-20 mg/L 250, 500, 750 mg tabs
tonic–clonic sz (age 100 mg/mL soln
>4-6 yr) 500, 750 mg SR (ER) tabs
Lorazepam Status epilepticus (all 0.05-0.1 bid or tid 20-30 µg/L 0.5, 1, 2 mg tabs
ages) 2 mg/mL soln
Methsuximide (or Absence sz (children 10-30 bid or tid 10-50 mg/L 150, 300 mg caps
methsuximide) and older)
Nitrazepam – 0.25-1 bid or tid <200 µg/L 5 mg tabs
Oxcarbazepine* Partial sz (>2 yr) 20-40 bid 13-28 mg/L 150, 300, 600 mg tabs
300 mg/5 mL susp
Perampanel Partial sz (>12 yr) 2-12 mg per day (older qhs - 2 mg, 4 mg, 6 mg, 8 mg,
than 12 yr) 10 mg, 12 mg tabs
Phenobarbital Myoclonic, partial, and <5 yr, 3-5 bid or qd 10-40 mg/L 15, 30, 60, 90, 100 mg
tonic–clonic sz and >5 yr, 2-3 tabs
status (all ages) 4 mg/mL soln
Phenytoin Partial, tonic–clonic sz <3 yr, 8-10 tabs, susp: tid 5-20 mg/L 50 mg tabs
and status (all ages) >3 yr, 4-7 caps: qd 30,100 mg caps
125 mg/5 mL susp
Pregabalin Partial sz (adults) 2-14 bid Up to 25, 50, 75, 100, 150, 200,
10 µg/mL 225, 300 mg caps
20 mg/mL soln
Primidone Partial and tonic– 10-20 bid or tid 4-13 mg/L 50, 250 mg tabs, susp
clonic sz (all ages)
Rufinamide† LGS (age >4 yr) 30-45 bid <60 µg/mL 200, 400 mg tabs
‖
Sulthiame 5-15 bid or tid 1.5-20 µg/mL 50, 200 mg caps
Not available in all
countries
Tiagabine Partial sz (age >2 yr) 0.5-2 bid, tid, qid 80-450 µg/L 2, 4, 12, 16 mg tabs
Topiramate† LGS, partial and 3-9, slow titration bid or tid 2-25 mg/L 25, 100, 200 mg tabs
tonic–clonic sz (all 15, 25 mg sprinkle caps
ages)
Valproate Absence, myoclonic, 15-40. Higher doses are Sprinkle caps: 50-100 mg/L 250 mg caps
partial and tonic– used if the patient is bid 125 mg sprinkle caps
clonic sz (age >2 yr) on enzyme inducers Soln: tid 125, 250, 500 mg tabs
(up to 60 kg/day) 250 mg/5 mL soln
Vigabatrin Infantile spasms and 50-150 bid 20-160 µg/mL 500 mg tabs
partial sz (age 500 mg powder for soln
>1 mo)
Zonisamide Partial sz (age >16 yr) 4-8 bid or qd 10-40 mg/L 100 mg caps
Unless specified otherwise, as above, one would usually target the lower range of therapeutic dose then adjust as needed depending on response and/or levels.
Dosing schedule (e.g., bid or tid) can depend on if a sustained release preparation is available and if the patient is on enzyme inducers (e.g., carbamazepine) or
inhibitors (e.g., valproic acid) that could affect that drug (as indicated in the dosing in the table and in the text).
*Usually start by one-fourth maintenance dose and increase by one-fourth every 2-3 days to full dose.
†
Usually start with one-fourth maintenance dose and increase by one-fourth every 7 days to full dose.
‡
Usually start with one-fourth maintenance dose and increase by one-fourth every day to full dose.
§
Child on enzyme inducers.
‖
Available in some European countries.
¶
Child on valproate.
cap, capsule; ER, extended release; GTC, generalized tonic–clonic; LGS, Lennox-Gastaut syndrome; ODT, orally disintegrating tablet; soln, solution; SR, sustained
release; susp, suspension; sz, seizure(s); tab, tablet.
Table 593-14 Some Common Adverse Effects of Antiepileptic Drugs*

ANTIEPILEPTIC DRUG SIDE EFFECT(S)
Acetazolamide Nuisance: dizziness, polyuria, electrolyte imbalance
Serious: Stevens-Johnson syndrome
Benzodiazepines Nuisance: dose-related neurotoxicity (drowsiness, sedation, ataxia), hyperactivity, drooling, increased secretions
Serious: apnea
Bromide Nuisance: irritability, spurious hyperchloremia (falsely high chloride owing to bromide)
Serious: psychosis, rash, toxicity developing slowly owing to the very long half-life
Carbamazepine Nuisance: tics, transient leukopenia; hyponatremia, weight gain, nausea; dizziness
Serious: Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, liver toxicity
Ezogabine Nuisance: dizziness, somnolence tremor, abnormal coordination, disturbance in attention, memory impairment,
blurred vision, gait disturbance, and dysarthria
Serious: blue discoloration of the skin and retinal pigmentation that requires close ophthalmologic monitoring
in follow up, urinary retention
Felbamate Nuisance: anorexia, vomiting, insomnia, hyperactivity, dizziness
Serious: major risks for liver and hematologic toxicity requiring close monitoring (1 in 500 in children >2 yr with
complex neurological disorders)
Gabapentin In children: acute onset of aggression, hyperactivity
In adults: euphoria and behavioral disinhibition, weight gain
Lacosamide Nuisance: diplopia, headache, dizziness, nausea
Serious: possibly cardiac arrhythmias (if predisposed)
Lamotrigine Nuisance: CNS side effects: headache, ataxia, dizziness, tremor, but usually less than other AEDs
Serious: Stevens-Johnson syndrome, rarely liver toxicity
Levetiracetam CNS adverse events: somnolence, asthenia, dizziness, but usually less than other AEDs
In children: behavioral symptoms are common
In adults: depressive mood
Oxcarbazepine Somnolence, headache, dizziness, nausea, apathy, rash, hypertrichosis, gingival hypertrophy, hyponatremia
Perampanel Dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, and
balance disorder
Phenobarbital and Nuisance: neurotoxicity, insomnia, hyperactivity, signs of distractibility, fluctuation of mood, aggressive outbursts
other barbiturates Serious: liver toxicity, Stevens-Johnson syndrome
Phenytoin and other Nuisance: gingival hyperplasia, coarsening of the facies, hirsutism, cerebellovestibular symptoms (nystagmus
hydantoins and ataxia)
Serious: Stevens-Johnson syndrome, liver toxicity
Pregabalin Nuisance: dizziness, peripheral edema, blurred vision, weight gain, thrombocytopenia
Serious: hypersensitivity reactions, rhabdomyolysis
Primidone Nuisance: CNS toxicity (dizziness, slurred speech, giddiness, drowsiness, depression)
Serious: liver toxicity, Stevens-Johnson syndrome
Rufinamide Nuisance: somnolence, vomiting
Serious: contraindicated in familial short QT interval
Succinimides Nuisance: nausea, abdominal discomfort, anorexia, hiccups
Serious: Stevens-Johnson syndrome, drug-induced lupus
Tiagabine Nuisance: dizziness, somnolence, asthenia, headache and tremor, precipitation of absence or myoclonic seizures
Serious: precipitation of nonconvulsive status epilepticus
Topiramate Nuisance: cognitive dysfunction, weight loss, renal calculi, hypohidrosis, fever
Serious: precipitation of glaucoma
Valproic acid Nuisance: weight gain; hyperammonemia tremor, alopecia, menstrual irregularities
Serious: hepatic and pancreatic toxicity
Vigabatrin Nuisance: hyperactivity
Serious: irreversible visual field deficits, retinopathy that requires frequent ophthalmologic evaluations and
follow up
Zonisamide Fatigue, dizziness, anorexia, psychomotor slowing, ataxia, rarely hallucinations, hypohidrosis and fever
*Essentially all AEDs can cause CNS toxicity and potentially rashes and serious allergic reactions.
AED, antiepileptic drug; CNS, central nervous system.
multiple drugs. When appropriate, levels should also be checked upon double the usual maintenance doses. On the other hand, if the patient
addition (or discontinuation) of a second drug because of potential is on valproate, the doses of phenobarbital or lamotrigine are approxi-
drug interactions. During follow-up, repeating the EEG every few mately half of what is usually needed. Thus, changes in the dosing of
months may be helpful to evaluate changes in the predisposition to the background medication are often done as the interacting medica-
seizures. This is especially true in situations where tapering off of tion is being started. Genetic variability in enzymes that metabolize
medication is contemplated in any seizure type and during follow-up AEDs, and in the presence of inducible multidrug resistance genes,
to assess response for absence seizures, as the EEG mirrors response pharmacogenomics, might account for some of the variation among
in such patients. individuals in responding to certain AEDs. Although numerous vari-
ants of the cytochrome P450 enzymes have been characterized and
Monitoring although several multidrug resistance genes have been identified, the
For the older AEDs, before starting treatment, baseline laboratory use of this new knowledge is currently largely restricted to research
studies, including complete blood count, platelets, liver enzymes, and investigations, and it has yet to be applied in routine clinical practice.
possibly kidney function tests and urinalysis, are often obtained and
repeated periodically. Laboratory monitoring is more relevant early on, Additional Treatments
because idiosyncratic adverse effects such as allergic hepatitis and The principles of monotherapy indicate that a second medication
agranulocytosis are more likely to occur in the 1st 3-6 mo of therapy. needs to be considered after the first either is pushed as high as toler-
These laboratory studies are usually initially checked once or twice ated and still does not control the seizures or results in intolerable
during the 1st mo, then every 3-4 mo thereafter. Serious concerns have adverse effects. In those cases, a second drug is started and the first is
been raised about the real usefulness of routine monitoring (in the tapered and then discontinued. The second drug is then again pushed
absence of clinical signs) because the yield of significant adverse effects to the dose that controls the seizure or that results in intolerable side
is low and the costs may be high. There are currently many advocates effects. If the second drug fails, monotherapy with a third drug or dual
of less-frequent routine monitoring. (combination) therapy is considered.
In approximately 10% of patients, a reversible dose-related leukope- Patients with drug-resistant (previously referred to as intractable or
nia may occur in patients on carbamazepine or on phenytoin. This refractory) epilepsy (those who have failed at least 2 fair trials of
adverse effect responds to decreasing the dose or to stopping the medi- appropriate medications) warrant a careful diagnostic reevaluation to
cation and should be distinguished from the much-less-common idio- look for degenerative, metabolic, or inflammatory underlying disor-
syncratic aplastic anemia or agranulocytosis. One exception requiring ders (e.g., mitochondrial disease, Rasmussen encephalitis; see Chapter
frequent (even weekly) monitoring of liver function and of blood 593.2) and to investigate them for candidacy for epilepsy surgery.
counts throughout the therapy is felbamate, owing to the high inci- Treatable metabolic disorders that can manifest as intractable epilepsy
dence of liver and hematologic toxicity (1 in 500 children under 2 yr include pyridoxine-dependent and pyridoxal-responsive epilepsy;
of age with complex neurological disorders who are on the drug). The folinic acid–responsive seizures (demonstrated to be the same disorder
gum hyperplasia that is seen with phenytoin necessitates good oral as pyridoxine-dependent epilepsy); cerebral folate deficiency; neu-
hygiene (brushing teeth at least twice per day and rinsing the mouth rotransmitter disorders; biotinidase deficiency; glucose transporter 1
after taking the phenytoin); in a few cases, it may be severe enough to deficiency (responds to the ketogenic diet); serine synthesis defects;
warrant surgical reduction and/or change of medication. Allergic rash creatine deficiency syndromes; untreated phenylketonuria; develop-
can occur with any medication, but is probably most common with mental delay, epilepsy and neonatal diabetes; and hyperinsulinemia–
lamotrigine, carbamazepine, and phenytoin. hyperammonia. Often patients who do not respond to AEDs are
candidates for steroids, IVIG, or the ketogenic diet.
SIDE EFFECTS Steroids, usually given as ACTH (see the discussion of West
During follow-up the patient should be monitored for side effects. syndrome in “Severe Generalized Epilepsies” in Chapter 593.4) or as
Occasionally, a Stevens-Johnson–like syndrome develops, probably prednisone 2 mg/kg/day (or equivalent), are often used in epileptic
most commonly with lamotrigine; it also has been found to be particu- encephalopathies such as West, Lennox-Gastaut, myoclonic astatic,
larly common in Chinese patients who have the allele HLA-B*1502 continuous spike-waves in slow-wave sleep, and Landau-Kleffner syn-
and are taking carbamazepine and lamotrigine. dromes. The course usually is for 2-3 mo with a taper over a similar
Other potential side effects are rickets from phenytoin, phenobarbi- period. Because relapses occur commonly during tapering, and in such
tal, primidone, and carbamazepine (enzyme inducers that reduce syndromes as Landau-Kleffner and continuous spike-waves in slow-
25-hyrdroxy-vitamin D level by inducing its metabolism) and hyper- wave sleep, therapy for longer than 1 yr is often needed.
ammonemia from valproate. Skeletal monitoring is warranted in IVIG has also been reported to be similarly effective in non–
patients on chronic AED therapy because it is often associated with immunodeficient patients with West, Lennox-Gastaut, Landau-
vitamin D abnormalities (low bone density, rickets, and hypocalcemia) Kleffner, and continuous spike-waves in slow-wave sleep syndromes
in children and adults, particularly those on enzyme-inducing medica- and may also have efficacy in partial seizures. One should check the
tions. Thus, counseling the patient about sun exposure and vitamin D IgA levels before starting the infusions (to assess the risk for allergic
intake, monitoring its levels, and, in most cases, vitamin D supplemen- reactions, because these are increased in patients with complete IgA
tation are recommended. There is currently no consensus on the dose deficiency) and guard against allergic reactions during the infusion.
to be used for supplementation or prophylaxis, but starting doses of Low IgA, low IgG2, and male sex are reported to possibly predict favor-
400-2,000 IU/day with follow-up of the levels are reasonable. able response. The usual regimen is 2 g/kg divided over 4 consecutive
Irreversible hepatic injury and death are particularly feared in young days followed by 1 g/kg once a month for 6 mo. The mechanism of
children (<2 yr old) who are on valproate in combination with other action of steroids and of IVIG are not known but is presumed to be
AEDs, particularly those who might have inborn errors of metabolism antiinflammatory, because it has been demonstrated that seizures
such as acidopathies and mitochondrial disease. Virtually all AEDs can increase cytokines and that these, in turn, increase neuronal excitabil-
produce sleepiness, ataxia, nystagmus, and slurred speech with toxic ity by several mechanisms, including activation of glutamate receptors.
levels. Steroids and ACTH might also stimulate brain neurosteroid receptors
The FDA has determined that the use of AEDs may be associated that enhance GABA activity and might reduce corticotrophin-releasing
with an increased risk of suicidal ideation and action and has recom- hormone, which is known to be epileptogenic.
mended counseling about this side effect before starting these medica- The ketogenic diet is believed to be effective in glucose transporter
tions. This is obviously more applicable to adolescents and adults. protein 1 deficiency, pyruvate dehydrogenase deficiency, myoclonic–
When adding a new AED, the doses used are often affected by the astatic epilepsy, tuberous sclerosis complex, Rett syndrome, severe
background medications. For example, if the patient is on enzyme myoclonic epilepsy of infancy (Dravet syndrome), and infantile
inducers, the doses needed of valproate and lamotrigine are often spasms. There is also suggestion of possible efficacy in selected
mitochondrial disorders—glycogenosis type V, Landau-Kleffner syn- of seizures, decrease in medication requirements, and meaningful
drome, Lafora body disease, and subacute sclerosing panencephalitis. improvements in the patient’s quality of life in approximately half or
The diet is absolutely contraindicated in carnitine deficiency (primary); more of eligible patients.
carnitine palmitoyltransferase I or II deficiency; carnitine translocase
deficiency; β-oxidation defects; medium-chain acyl dehydrogenase DISCONTINUATION OF THERAPY
deficiency; long-chain acyl dehydrogenase deficiency; short-chain Discontinuation of AEDs is usually indicated when children are
acyl dehydrogenase deficiency; long-chain 3-hydroxyacyl-coenzyme A free of seizures for at least 2 yr. In more-severe syndromes, such
deficiency; medium-chain 3-hydroxyacyl-coenzyme A deficiency; as temporal lobe epilepsy secondary to mesial temporal sclerosis,
pyruvate carboxylase deficiency; and porphyrias. Thus, an appropriate Lennox-Gastaut syndrome, or severe myoclonic epilepsy, a prolonged
metabolic work-up, depending on the clinical picture, usually needs to period of seizure freedom on treatment is often warranted before
be performed before starting the diet (e.g., acyl carnitine profile, total AEDs are withdrawn, if withdrawal is attempted at all. In self-limited
and free carnitine levels). The diet has been used for refractory seizures (benign) epilepsy syndromes, the duration of therapy can often be as
of various types (partial or generalized) and consists of an initial period short as 6 mo.
of fasting followed by a diet with a 3 : 1 or 4 : 1 fat : nonfat ratio, with Many factors should be considered before discontinuing medica-
fats consisting of animal fat, vegetable oils, or medium-chain triglyc- tions, including the likelihood of remaining seizure-free after drug
erides. Many patients do not tolerate it owing to diarrhea, vomiting, withdrawal based on the type of epilepsy syndrome and etiology; the
hypoglycemia, dehydration, or lack of palatability. Diets such as the risk of injury in case of seizure recurrence (e.g., if the patient drives);
low-glycemic-index diet and the Atkins diet are easier to institute, do and the adverse effects of AED therapy. Most children who have not
not require hospitalization, and are also useful, but it is not known yet had a seizure for 2 yr or longer and who have a normal EEG when
if they are as effective as the classic diet. AED withdrawal is initiated, remain free of seizures after discontinuing
medication, and most relapses occur within the 1st 6 mo.
APPROACH TO EPILEPSY SURGERY Certain risk factors can help the clinician predict the prognosis
If a patient has failed 3 drugs, the chance of achieving seizure freedom after AED withdrawal. The most important risk factor for seizure
using AEDs is generally <10%. Therefore, proper evaluation for surgery relapse is an abnormal EEG before medication is discontinued. Chil-
is necessary as soon as patients fail 2 or 3 AEDs, usually within 2 yr of dren who have remote structural (symptomatic) epilepsy are less
the onset of epilepsy and often sooner than 2 yr. Performing epilepsy likely to be able to stop AEDs than are children who have a benign
surgery in children at an earlier stage (e.g., <5 yr of age) allows transfer genetic (idiopathic) epilepsy. In patients with absences or in patients
of function in the developing brain. Candidacy for epilepsy surgery treated with valproate for primary generalized epilepsy, the risk of
requires proof of resistance to AEDs used at maximum, tolerably non- relapse might still be high despite a normal EEG because valproate
toxic doses; absence of expected unacceptable adverse consequences of can normalize EEGs with generalized spike-wave abnormalities. Thus,
surgery, and a properly defined epileptogenic zone (area that needs to in these patients, repeating the EEG during drug taper can help iden-
be resected to achieve seizure freedom). The epileptogenic zone is tify recurrence of the EEG abnormality and associated seizure risk
identified by careful analysis, by an expert team of epilepsy specialists before clinical seizures recur. Older age of epilepsy onset, longer dura-
in an epilepsy center, of the following parameters: seizure semiology, tion of epilepsy, presence of multiple seizure types, and need to use
interictal EEG, video-EEG long-term monitoring, neuropsychologic more than 1 AED are all factors associated with a higher risk of
profile, and MRI. Other techniques, such as invasive EEG (depth elec- seizure relapse after AED withdrawal.
trodes, subdurals), single-photon emission CT, magnetoencephalogra- AED therapy should be discontinued gradually; often over a period
phy, and positron emission tomography are also often needed when of 3-6 mo. Abrupt discontinuation can result in withdrawal seizures
the epileptogenic zone is difficult to localize or when it is close to or status epilepticus. Withdrawal seizures are especially common with
eloquent cortex. To avoid resection of eloquent cortex, several tech- phenobarbital and benzodiazepines; consequently, special attention
niques can be used, including the Wada test. In this test, intracarotid must be given to a prolonged tapering schedule during the withdrawal
infusion of amobarbital is used to anesthetize 1 hemisphere to of these AEDs. Seizures that occur more than 2-3 mo after AEDs are
lateralize memory and speech by testing them during that unilateral completely discontinued indicate relapse, and resumption of treatment
anesthesia. Other tests to localize function include functional MRI, is usually warranted.
magnetoencephalography, and subdural electrodes with cortical stim- The decision to attempt AED withdrawal must be assessed mutually
ulation. Developmental delay or psychiatric diseases must be consid- among the clinician, the parents, and the child depending on the child’s
ered in assessing the potential impact of surgery on the patient. The age. Risk factors should be identified and precautionary measures
usual minimal presurgical evaluation includes EEG monitoring, should be taken. The patient and family should be counseled fully on
imaging, and age-specific neuropsychologic assessment. what to expect, what precautions to take (including cessation of driving
Epilepsy surgery is often used to treat refractory epilepsy of a for a period of time), and what to do in case of relapse. A prescription
number of etiologies, including cortical dysplasia, tuberous sclerosis, for rectal diazepam or of intranasal midazolam to be given at the time
polymicrogyria, hypothalamic hamartoma, Landau-Kleffner syn- of seizures that might occur during and after tapering is usually war-
drome, and hemispheric syndromes, such as Sturge-Weber syndrome, ranted (see Table 593-12 for dosing).
hemimegalencephaly, and Rasmussen encephalitis. Patients with
intractable epilepsy resulting from metabolic or degenerative problems Sudden Unexpected Death in Epilepsy
are not candidates for resective epilepsy surgery. Focal resection of the SUDEP is the most common epilepsy related mortality in patients
epileptogenic zone is the most common procedure. Hemispherectomy with chronic epilepsy; the incidence is unknown but ranges from 1-5
is used for diffuse hemispheric lesions; multiple subpial transection, per 1,000 people with epilepsy. Although the precise etiology is
a surgical technique in which the horizontal connections of the epilep- unknown, risk factors include polypharmacology, poorly controlled
tic focus are partially cut without resecting it, is sometimes used for generalized tonic–clonic seizures, male gender, age younger than
unresectable foci located in eloquent cortex such as in Landau-Kleffner 16 yr, long duration of epilepsy, and frequent seizures. Patients are
syndrome. In Lennox-Gastaut syndrome, corpus callosotomy is used usually found dead in their bed in a prone position with evidence sug-
for drop attacks. Vagal nerve stimulation is often used for intractable gesting a recent seizure. Potential mechanisms of SUDEP include
epilepsies of various types and for seizures of diffuse focal or multifocal respiratory arrest or dysfunction, drug-induced cardiac toxicity, CNS
anatomic origin that do not yield themselves to resective surgery. Focal dysfunction (hypoventilation, arrhythmia, suppression of brain elec-
resection and hemispherectomy result in a high rate (50-80%) of trical activity), or pulmonary edema. Table 593-15 lists possible pre-
seizure freedom. Corpus callosotomy and vagal nerve stimulation ventive measures.
result in lower rates (5-10%) of seizure freedom; however, these pro-
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sive GABA depolarization and avert the neuronal hyperexcitability

Table 593-15 Measures in Clinical Practice to Reduce underlying neonatal seizures. It also prevents, in rats, complex febrile
the Risk of SUDEP seizure induced hyperactivation of excitatory GABAA receptors and
• Reduction of tonic–clonic seizures: optimum treatment, good the resultant granule cell ectopia and temporal lobe epilepsy.
drug compliance, lifestyle advice (e.g., alcohol intake, sleep Although it is susceptible to developing seizures, the immature brain
deprivation) appears to be more resistant to the deleterious effects of seizures than
• Treatment changes: change in a gradual staged manner; when the mature brain, as a result of increases in calcium binding proteins
switching drugs, introduce the new drug before withdrawing the that buffer injury-related increases in calcium, increased extracellular
old drug; the patients should have access to immediate advice in space, decreased levels of the second messenger inositol triphosphate,
the event of worsening seizures during periods of change and the immature brain’s ability to tolerate hypoxic conditions by
• Supervision at night for patients at high risk: attendance, use of resorting to anaerobic energy metabolism.
alarms (balancing the benefits of independent living and the
Many animal studies indicate that seizures are detrimental to the
penalties of intrusive monitoring)
• Choice of drugs: caution with antiepileptic drugs with potential immature brain. Human studies also suggest harmful effects of seizures
cardiorespiratory adverse effects as shown by MRI and by the association of worse prognosis in neonates
• Act on ictal warning signs: tonic–clonic seizures that are with seizures even when correcting for confounding factors. Even elec-
prolonged, associated with marked cyanosis, severe bradycardia trographic seizures without clinical correlates have been shown to be
or apnea, and postictal EEG suppression; complex partial associated with worse prognosis. However, it is not definite that this
seizures with marked atonia (drop attacks); seizure in those with association is causal: It is difficult in human studies to distinguish
preexisting cardiac or respiratory impairment among effects of seizures, of the underlying insult responsible for the
• Supervision after a tonic–clonic seizure: continuous attendance seizures (clinical or electrographic), and of the AEDs used to stop the
until full consciousness is restored; call emergency services for
seizures. Most physicians currently believe that it is favorable to control
high-risk seizures
• Counseling on the risks: lifestyle and treatment decisions are the clinical as well as electrographic seizures.
patient’s prerogative and the physician’s role is to provide a
risk-vs-benefit analysis TYPES OF NEONATAL SEIZURES
There are 5 main neonatal seizure types: subtle, clonic, tonic, spasms,
EEG, electroencephalogram; SUDEP, sudden unexpected death in epilepsy.
From Shorvan S, Tomson T: Sudden unexpected death in epilepsy. Lancet
and myoclonic. Spasms, focal clonic, focal tonic, and generalized myo-
378:2028–2036, 2011. clonic seizures are, as a rule, associated with electrographic discharges
(epileptic seizures), whereas motor automatisms, the subtle, general-
ized tonic and multifocal myoclonic episodes are frequently not associ-
ated with discharges and thus are thought to often represent release
593.7 Neonatal Seizures phenomena with abnormal movements secondary to brain injury
Mohamad A. Mikati and Abeer J. Hani rather than true epileptic seizures (Table 593-16). To determine clini-
cally whether such manifestations are seizures or release phenomena
Seizures are possibly the most important and common indicator of is often difficult, but precipitation of such manifestations by stimula-
significant neurologic dysfunction in the neonatal period. Seizure inci- tion and aborting them by restraint or manipulation would suggest that
dence is higher during this period than in any other period in life: 57.5 they are not seizures. One needs to keep in mind, however, that epi-
per 1,000 in infants with birth weights <1,500 g and 2.8 per 1,000 in leptic seizures can also be induced by stimulation. Thus, in many cases,
infants weighing between 2,500 and 3,999 g have seizures. specifically in sick neonates with history of neurologic insults, continu-
ous bedside EEG monitoring helps make this distinction. Such moni-
PATHOPHYSIOLOGY toring has become the standard of care in most intensive care
The immature brain has many differences from the mature brain that nurseries.
render it more excitable and more likely to develop seizures. Based
predominantly on animal studies, these are delay in Na+, K+-adenosine Subtle Seizures
triphosphatase maturation and increased NMDA and α-amino-3- Subtle seizures include transient eye deviations, nystagmus, blinking,
hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor density. In mouthing, abnormal extremity movements (rowing, swimming, bicy-
addition, the specific types of these receptors that are increased are cling, pedaling, and stepping), fluctuations in heart rate, hypertension
those that are permeable to calcium (GLUR2 AMPA receptors). This episodes, and apnea. Subtle seizures occur more commonly in prema-
contributes to increased excitability and to the long-term consequences ture than in full-term infants.
associated with seizures, particularly those resulting from perinatal
hypoxia. Medications that block AMPA receptors, such as topiramate, Clonic Seizures
may thus prove useful in this clinical setup. Clonic seizures can be focal or multifocal. Multifocal clonic seizures
Another difference is delay in the development of inhibitory GAB- incorporate several body parts and are migratory in nature. The migra-
Aergic transmission. In fact, GABA in the immature brain has an tion follows a nonjacksonian trend; for example, jerking of the left arm
excitatory function as the chloride gradient is reversed relative to the can be associated with jerking of the right leg. Generalized clonic
mature brain, with higher concentrations of chloride being present seizures that are bilateral, symmetric, and synchronous are uncommon
intracellularly than extracellularly. Thus, opening of the chloride chan- in the neonatal period presumably due to decreased connectivity asso-
nels in the immature brain results in depolarizing the cell and not in ciated with incomplete myelination at this age.
hyperpolarizing it. This phenomenon appears to be more prominent
in male neonates, perhaps explaining their greater predisposition to Tonic Seizures
seizures. The reason for this is that the Cl− transporter, NKCC1, is Tonic seizures can be focal or generalized (generalized are more
predominantly expressed in the neonatal period, leading to transport common). Focal tonic seizures include persistent posturing of a limb
of Cl− into the cell at rest, and then to cellular depolarization upon or posturing of trunk or neck in an asymmetric way often with persis-
activation of GABAA receptors and opening of Cl− channels with chlo- tent horizontal eye deviation. Generalized tonic seizures are bilateral
ride efflux. This is important for neuronal development but renders the tonic limb extension or tonic flexion of upper extremities often associ-
neonatal brain hyperexcitable. With maturation, expression of NCCK1 ated with tonic extension of lower extremities.
decreases and KCC2 increases. KCC2 transports Cl− out of the cell,
resulting in reduction of intracellular chloride concentration so that Spasms
when GABAA receptors are activated, Cl− influx and hyperpolarization Spasms are sudden generalized jerks lasting 1-2 sec that are distin-
occur. Bumetanide, a diuretic that blocks NKCC1, can prevent exces- guished from generalized tonic spells by their shorter duration and by
Table 593-16 Clinical Characteristics, Classification, and Presumed Pathophysiology of Neonatal Seizures
CLASSIFICATION CHARACTERIZATION
Focal clonic Repetitive, rhythmic contractions of muscle groups of the limbs, face, or trunk
May be unifocal or multifocal
May occur synchronously or asynchronously in muscle groups on 1 side of the body
May occur simultaneously but asynchronously on both sides
Cannot be suppressed by restraint
Pathophysiology: epileptic
Focal tonic Sustained posturing of single limbs
Sustained asymmetrical posturing of the trunk
Sustained eye deviation
Cannot be provoked by stimulation or suppressed by restraint
Generalized tonic Sustained symmetrical posturing of limbs, trunk, and neck
May be flexor, extensor, or mixed extensor/flexor
May be provoked or intensified by stimulation
May be suppressed by restraint or repositioning
Presumed pathophysiology: nonepileptic
Myoclonic Random, single, rapid contractions of muscle groups of the limbs, face, or trunk
Typically not repetitive or may recur at a slow rate
May be generalized, focal, or fragmentary
May be provoked by stimulation
Presumed pathophysiology: may be epileptic or nonepileptic
Spasms May be flexor, extensor, or mixed extensor/flexor
May occur in clusters
Cannot be provoked by stimulation or suppressed by restraint
Motor automatisms
Ocular signs Random and roving eye movements or nystagmus (distinct from tonic eye deviation)
May be provoked or intensified by tactile stimulation
Oral-buccal-lingual movements Sucking, chewing, tongue protrusions
Progression movements Rowing or swimming movements
Pedaling or bicycling movements of the legs
May be suppressed by restraint or repositioning
Complex purposeless movements Sudden arousal with transient increased random activity of limbs
From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia, 1998, Lippincott-Raven. Tab 4, p. 21.
the fact that spasms are usually associated with a single, very brief, the other hand, generally do not end with tactile or motor suppression.
generalized discharge. Jitteriness, unlike most seizures, is usually induced by a stimulus. Also
unlike jitteriness, seizures often involve eye deviation and autonomic
Myoclonic Seizures changes.
Myoclonic seizures are divided into focal, multifocal, and generalized
types. Myoclonic seizures can be distinguished from clonic seizures by ETIOLOGY
the rapidity of the jerks (<50 msec) and by their lack of rhythmicity. Table 593-17 lists causes of neonatal seizures.
Focal myoclonic seizures characteristically affect the flexor muscles of
the upper extremities and are sometimes associated with seizure activ- Hypoxic–Ischemic Encephalopathy
ity on EEG. Multifocal myoclonic movements involve asynchronous This is the most common cause of neonatal seizures, accounting for
twitching of several parts of the body and are not commonly associated 50-60% of patients. Seizures secondary to this encephalopathy occur
with seizure discharges on EEG. Generalized myoclonic seizures within 12 hr of birth.
involve bilateral jerking associated with flexion of upper and occasion-
ally lower extremities. The latter type of myoclonic jerks is more com- Vascular Events
monly correlated with EEG abnormalities than the other types. These include intracranial bleeds and ischemic strokes and account for
10-20% of patients. Three types of hemorrhage can be distinguished:
Seizures vs Jitteriness primary subarachnoid hemorrhage, germinal matrix–intraventricular
Jitteriness can be defined as rapid motor activities, such as a tremor or hemorrhage, and subdural hemorrhage. Patients with arterial strokes
shake, that can be ended by flexion or holding the limb. Seizures, on or venous sinus thrombosis can present with seizure and these can be
Brain Malformations
Table 593-17 Causes of Neonatal Seizures According Brain malformations account for 5-10% of neonatal seizure cases. An
to Common Age of Presentation example is Aicardi syndrome, which affects girls only and consists of
AGES 1-4 DAYS retinal lacunae, agenesis of the corpus callosum, and severe seizures
Hypoxic–ischemic encephalopathy including subsequent infantile spasms with hypsarrhythmia that is
Drug withdrawal, maternal drug use of narcotic or barbiturates sometimes initially unilateral on EEG.
Drug toxicity: lidocaine, penicillin
Intraventricular hemorrhage Metabolic Disturbances
Acute metabolic disorders Metabolic disturbances include disturbances in glucose, calcium, mag-
• Hypocalcemia nesium, other electrolytes, amino acids, or organic acids and pyridox-
• Sepsis ine dependency.
• Maternal hyperthyroidism, or hypoparathyroidism
Hypoglycemia can cause neurologic disturbances and is very
• Hypoglycemia
• Perinatal insults, prematurity, small for gestational age common in small neonates and neonates whose mothers are diabetic
• Maternal diabetes or prediabetic. The duration of hypoglycemia is very critical in deter-
• Hyperinsulinemic hypoglycemia mining the incidence of neurologic symptoms.
• Hypomagnesemia Hypocalcemia occurs at 2 peaks. The first peak corresponds to low-
• Hyponatremia or hypernatremia birthweight infants and is evident in the 1st 2-3 days of life. The second
• Iatrogenic or inappropriate antidiuretic hormone secretion peak occurs later in neonatal life and often involves large, full-term
Inborn errors of metabolism babies who consume milk that has an unfavorable ratio of phosphorus
• Galactosemia to calcium and phosphorus to magnesium. Hypomagnesemia is often
• Hyperglycinemia
associated with hypocalcemia. Hyponatremia can cause seizures and
• Urea cycle disorders
Pyridoxine deficiency and pyridoxal-5-phosphate deficiency (must is often secondary to inappropriate antidiuretic hormone secretion.
be considered at any age) Local anesthetic intoxication seizures can result from neonatal
intoxication with local anesthetics administered into the infant’s scalp.
AGES 4-14 DAYS Neonatal seizures can also result from disturbances in amino acid
Infection
or organic acid metabolism. These are usually associated with acidosis
• Meningitis (bacterial)
• Encephalitis (enteroviral, herpes simplex) and/or hyperammonemia. However, even in the absence of these find-
Metabolic disorders ings, if a cause of the seizures is not immediately evident, then ruling
• Hypocalcemia out metabolic causes requires a full metabolic work-up (see Chapter
• Diet, milk formula 593.2) including examination of serum amino acids, acyl carnitine
• Hypoglycemia, persistent profile, lactate, pyruvate, ammonia, very-long-chain fatty acids (for
• Inherited disorders of metabolism neonatal adrenoleukodystrophy and Zellweger syndrome), examina-
• Galactosemia tion of urine for organic acids, α-aminoadipic acid semialdehyde and
• Fructosemia sulfocysteine, as well as examination of CSF for glucose, protein, cells,
• Leucine sensitivity
amino acids, lactate, pyruvate, α-aminoadipic acid semialdehyde,
• Hyperinsulinemic hypoglycemia, hyperinsulinism,
hyperammonemia syndrome pyridoxal phosphate, 5-MTHF (5-methyltetrahydrofolate), succinyl-
• Anterior pituitary hypoplasia, pancreatic islet cell tumor adenosine, and CSF neurotransmitter metabolites. This is because
• Beckwith syndrome many inborn errors of metabolism, such as nonketotic hyperglycin-
Drug withdrawal, maternal drug use of narcotics or barbiturates emia, can manifest with neonatal seizures (often mistaken initially for
Benign neonatal convulsions, familial and nonfamilial hiccups that these patients also have) and can be detected only by
Kernicterus, hyperbilirubinemia performing these tests. Definitive diagnosis of nonketotic hypergly-
Developmental delay, epilepsy, neonatal diabetes syndrome cinemia, for example, requires measuring the ratio of CSF glycine to
AGES 2-8 WK plasma glycine.
Infection Pyridoxine and pyridoxal dependency disorders can cause severe
• Herpes simplex or enteroviral encephalitis seizures. These seizures, which are often multifocal clonic, usually start
• Bacterial meningitis during the 1st few hr of life. Cognitive impairment is often associated
Head injury if therapy is delayed (see Chapter 593.6).
• Subdural hematoma
• Child abuse Drug Withdrawal
Inherited disorders of metabolism
• Aminoacidurias
Seizures can rarely be caused by the neonate’s passive addiction and
• Urea cycle defects then drug withdrawal. Such drugs include narcotic analgesics, sedative–
• Organic acidurias hypnotics, and others. The associated seizures appear during the 1st 3
• Neonatal adrenoleukodystrophy days of life.
Malformations of cortical development
• Lissencephaly Neonatal Seizure Syndromes
• Focal cortical dysplasia Seizure syndromes include benign idiopathic neonatal seizures (fifth
Tuberous sclerosis day fits), which are usually apneic and focal motor seizures that start
Sturge-Weber syndrome around the fifth day of life. Interictal EEG shows a distinctive pattern
called theta pointu alternant (runs of sharp 4-7 Hz activity), and ictal
EEG shows multifocal electrographic seizures. Patients have a good
response to medications and a good prognosis. Autosomal dominant
diagnosed by neuroimaging. Venous sinus thrombosis could be missed benign familial neonatal seizures have onset at 2-4 days of age and
unless MR or CT venography studies are requested. usually remit at 2-15 wk of age. The seizures consist of ocular devia-
tion, tonic posturing, clonic jerks, and, at times, motor automatisms.
Intracranial Infections Interictal EEG is usually normal. These are caused by mutations in the
Bacterial and nonbacterial infections account for 5-10% of the cases of KCNQ2 and KCNQ3 genes. Approximately 16% of patients develop
neonatal seizures and include bacterial meningitis, TORCH (toxoplas- later epilepsy. Early myoclonic encephalopathy and early infantile
mosis, other infections, rubella, cytomegalovirus, herpes simplex virus) epileptic encephalopathy (Ohtahara syndrome) are discussed in
infections, particularly herpes simplex encephalitis. Chapter 593.4.
Miscellaneous Conditions A lumbar puncture is indicated in virtually all neonates with sei-
Miscellaneous conditions include benign neonatal sleep myoclonus zures, unless the cause is obviously related to a metabolic disorder such
and hyperekplexia, which are nonepileptic conditions (see Chapter as hypoglycemia or hypocalcemia. The latter infants are normally alert
594). interictally and usually respond promptly to appropriate therapy. The
CSF findings can indicate a bacterial meningitis or aseptic encephalitis.
DIAGNOSIS Prompt diagnosis and appropriate therapy improve the outcome for
Some cases can be correctly diagnosed by simply taking the prenatal these infants. Bloody CSF indicates a traumatic tap or a subarachnoid
and postnatal history and performing an adequate physical examina- or intraventricular bleed. Immediate centrifugation of the specimen
tion. Depending on the case, additional tests or procedures can be can assist in differentiating the 2 disorders. A clear supernatant sug-
performed. EEG is considered the main tool for diagnosis. It can show gests a traumatic tap, and a xanthochromic color suggests a subarach-
paroxysmal activity (e.g., sharp waves) in between the seizures and noid bleed. Mildly jaundiced normal infants can have a yellowish
electrographic seizure activity if a seizure is captured. However, some discoloration of the CSF that makes inspection of the supernatant less
neonatal seizures might not be associated with EEG abnormalities as reliable in the newborn period.
noted above either because they are “release phenomena” or alterna- Many inborn errors of metabolism cause generalized convulsions
tively because the discharge is deep and is not detected by the scalp in the newborn period. Because these conditions are often inherited in
EEG. Additionally, electrographic seizures can occur without observed an autosomal recessive or X-linked recessive fashion, it is imperative
clinical signs (electroclinical dissociation). This is presumed to be that a careful family history be obtained to determine if there is con-
caused by the immaturity of cortical connections, resulting, in many sanguinity or whether siblings or close relatives developed seizures or
cases, in no or minimal motor manifestations. Continuously monitor- died at an early age. Serum ammonia determination is useful for
ing the EEG at the bedside in the neonatal intensive care unit for screening for the hypoglycemic hyperammonemia syndrome and for
neonates at risk for neonatal seizures and brain injury is part of routine suspected urea cycle abnormalities. In addition to having generalized
clinical practice in most centers, providing real-time measurements of clonic seizures, these latter infants present during the 1st few days of
the brain’s electrical activity and identifying seizure activity. Many life with increasing lethargy progressing to coma, anorexia and vomit-
centers apply EEG monitoring to at-risk babies even before seizures ing, and a bulging fontanel. If the blood gases show an anion gap and
develop, which is often desirable; others monitor patients who have a metabolic acidosis with the hyperammonemia, urine organic acids
manifested or are suspected of having seizures. In addition, there are should be immediately determined to investigate the possibility of
currently attempts to develop methods for continuous monitoring of methylmalonic or propionic acidemia.
cerebral activity with automated detection and background analysis Maple syrup urine disease should be suspected when a metabolic
of neonatal seizures, similar to the continuous ECG monitoring in acidosis occurs in association with generalized clonic seizures, vomit-
intensive care facilities. In infants started on hypothermia protocols ing, bulging fontanel, and muscle rigidity during the 1st wk of life. The
following suspected hypoxic–ischemic injuries, it is recommended to result of a rapid screening test using 2,4-dinitrophenylhydrazine that
continuously monitor the EEG during the cooling and rewarming identifies keto derivatives in the urine is positive in maple syrup urine
periods to detect clinical and subclinical events in this high-risk popu- disease.
lation. The American Clinical Neurophysiology Society recommends Additional metabolic causes of neonatal seizures include nonketotic
continuous EEG monitoring in the neonatal intensive care unit to hyperglycinemia, an intractable condition characterized by markedly
monitor evolution of EEG background to help with prognostication, elevated plasma and CSF glycine levels, prominent hiccups, persistent
to guide titration of anticonvulsant therapy for infants with established generalized seizures, and lethargy rapidly leading to coma; ketotic
seizures, to screen for seizures among infants deemed to be at risk hyperglycinemia in which seizures are associated with vomiting, fluid
(hypoxic ischemic encephalopathy, stroke, meningitis, intraventricular and electrolyte disturbances, and a metabolic acidosis; and Leigh
hemorrhage, metabolic disorders, and congenital cerebral malforma- disease suggested by elevated levels of serum and CSF lactate or an
tions), to screen for seizures among infants who are paralyzed, to increased lactate : pyruvate ratio. Biotinidase deficiency should also be
characterize clinical events suspected to represent seizures, and to considered. A comprehensive description of the diagnosis and man-
detect impending cerebral ischemia or hemorrhage. agement of these metabolic diseases is discussed in Part XI, Metabolic
Careful neurologic examination of the infant might uncover the Disorders.
cause of the seizure disorder. Examination of the retina might show Unintentional injection of a local anesthetic into a fetus during
the presence of chorioretinitis, suggesting a congenital TORCH infec- labor can produce intense tonic seizures. These infants are often
tion, in which case titers of mother and infant are indicated. The thought to have had a traumatic delivery because they are flaccid at
Aicardi syndrome is associated with coloboma of the iris and retinal birth, have abnormal brainstem reflexes, and show signs of respiratory
lacunae. Inspection of the skin might show hypopigmented lesions depression that sometimes require ventilation. Examination may show
characteristic of tuberous sclerosis (seen best on UV light examination) a needle puncture of the skin or a perforation or laceration of the scalp.
or the typical crusted vesicular lesions of incontinentia pigmenti; both An elevated serum anesthetic level confirms the diagnosis. The treat-
neurocutaneous syndromes are often associated with generalized myo- ment consists of supportive measures and promotion of urine output
clonic seizures beginning early in life. An unusual body or urine odor by administering intravenous fluids with appropriate monitoring to
suggests an inborn error of metabolism. prevent fluid overload.
Blood should be obtained for determinations of glucose, calcium, Benign familial neonatal seizures, an autosomal dominant condi-
magnesium, electrolytes, and blood urea nitrogen. If hypoglycemia is tion, begins on the 2nd-3rd day of life, with a seizure frequency of
a possibility, serum glucose testing is indicated so that treatment can 10-20/day. Patients are normal between seizures, which stop in 1-6 mo.
be initiated immediately. Hypocalcemia can occur in isolation or in These are caused by mutations in the voltage-sensitive potassium
association with hypomagnesemia. A lowered serum calcium level is channel genes Kv7.2, and Kv7.3 (KCNQ2 and KCNQ3). Other muta-
often associated with birth trauma or a CNS insult in the perinatal tions in the Kv7.2 gene cause severe neonatal epileptic encephalopathy.
period. Additional causes include maternal diabetes, prematurity, Fifth-day fits occur on day 5 of life (4-6 days) in normal-appearing
DiGeorge syndrome, and high-phosphate feedings. Hypomagnesemia neonates. The seizures are multifocal and are often present for <24 hr.
(<1.5 mg/dL) is often associated with hypocalcemia and occurs par- The diagnosis requires exclusion of other causes of seizures and
ticularly in infants of malnourished mothers. In this situation, the sequencing of the above genes. The prognosis is good for the benign
seizures are resistant to calcium therapy but respond to intramuscular form.
magnesium, 0.2 mL/kg of a 50% solution of MgSO4. Serum electrolyte Pyridoxine dependency, a rare disorder, must be considered when
measurement can indicate significant hyponatremia (serum sodium seizures begin shortly after birth with signs of fetal distress in utero
<115 mEq/L) or hypernatremia (serum sodium >160 mEq/L) as a and are resistant to conventional anticonvulsants such as phenobarbi-
cause of the seizure disorder. tal or phenytoin. The history may suggest that similar seizures
occurred in utero. When pyridoxine-dependent seizures are sus- often require assisted ventilation after receiving intravenous or oral
pected, 100-200 mg of pyridoxine or pyridoxal phosphate should be loading doses of AEDs, and thus precautions for observations and for
administered intravenously during the EEG, which should be needed interventions are necessary.
promptly performed once the diagnosis is considered. The seizures
abruptly cease, and the EEG often normalizes in the next few hours or Lorazepam
longer. Not all cases of pyridoxine dependency respond dramatically The initial drug used to control acute seizures is usually lorazepam.
to the initial bolus of IV pyridoxine. Therefore, a 6-wk trial of oral Lorazepam is distributed to the brain very quickly and exerts its anti-
pyridoxine (100-200 mg/day) or preferably pyridoxal phosphate (as convulsant effect in <5 min. It is not very lipophilic and does not clear
pyridoxine does not help infants with the related but distinct syn- out from the brain very rapidly. Its action can last 6-24 hr. Usually, it
drome of pyridoxal dependency) is recommended for infants in does not cause hypotension or respiratory depression. The dose is
whom a high index of suspicion continues after a negative response 0.05 mg/kg (range: 0.02-0.10 mg/kg) every 4-8 hr.
to IV pyridoxine. Measurement of serum pipecolic acid and
α-aminoadipic acid semialdehyde (elevated) and CSF pyridoxal-5- Diazepam
phosphate (decreased) needs to be performed before initiation of the Diazepam can be used as an alternative initial drug. It is highly lipo-
trials without delay. These children require lifelong supplementation philic, so it distributes very rapidly into the brain and then is cleared
of oral pyridoxine (100 mg/day at times with folinic acid) or pyridoxal very quickly out, carrying the risk of recurrence of seizures. Like other
phosphate (15-60 mg/kg/day). Cerebral folate deficiency should also intravenous benzodiazepines, it carries a risk of apnea and hypoten-
be ruled out by medication trial (folinic acid 1-3 mg/kg/day) and by sion, particularly if the patient is also on a barbiturate, so patients need
CSF levels of 5-methyltetrahydrofolate assay. Gene sequencing can to be observed for 3-8 hr after administration. The usual dose is
confirm the diagnosis (see Chapter 593.4). The earlier the therapy is 0.1-0.3 mg/kg IV over 3-5 min, given every 15-30 min to a maximum
initiated in these vitamin responsive disorders, the more favorable the total dose of 2 mg. However, because of the respiratory and blood
outcome. pressure limitations and because the intravenous preparation contains
Drug-withdrawal seizures can occur in the newborn nursery but can sodium benzoate and benzoic acid, it is currently not recommended
take several weeks to develop because of prolonged excretion of the as a first-line agent.
drug by the neonate. The incriminated drugs include barbiturates,
benzodiazepines, heroin, and methadone. The infant may be jittery, Midazolam
irritable, and lethargic, and can have myoclonus or frank clonic sei- Midazolam can be used as an initial drug as a bolus or as a second- or
zures. The mother might deny the use of drugs; a serum or urine drug third-line drug as a continuous drip for patients who did not respond
screen might identify the responsible agent. to phenobarbital and/or to phenytoin. The doses used have been in the
Infants with focal seizures, suspected stroke or intracranial hemor- range of 0.05-0.1 mg/kg IV initial bolus, with a continuous infusion of
rhage, and severe cytoarchitectural abnormalities of the brain 0.5-1 µg/kg/min IV that can then be gradually titrated upward, if toler-
(including lissencephaly and schizencephaly) who clinically may ated, every 5 min or longer, to a maximum of approximately 33 µg/kg/
appear normal or microcephalic should undergo MRI or CT scan. min (2 mg/kg/hr).
Indeed, it is appropriate to recommend imaging of all neonates with
seizures unexplained by serum glucose, calcium, or electrolyte disor- Phenobarbital
ders. Infants with chromosome abnormalities and adrenoleukodystro- Phenobarbital is considered by many as the first choice long-acting
phy are also at risk for seizures and should be evaluated with drug in neonatal seizures. Whether to use a benzodiazepine first
investigation of a karyotype and serum very-long-chain fatty acids, depends on the clinical situation. The usual loading dose is 20 mg/kg.
respectively. If this dosage is not effective, then additional doses of 5-10 mg/kg can
be given until a dose of 40 mg/kg is reached. Respiratory support may
PROGNOSIS be needed after phenobarbital loading. Twenty-four hours after start-
Over the last few decades, prognosis of neonatal seizures has improved ing the loading dose, maintenance dosing can be started at 3-6 mg/kg/
owing to advancements in obstetric and intensive neonatal care. Mor- day usually administered in 2 separate doses. Phenobarbital is metabo-
tality has decreased from 40% to 20%. The correlation between EEG lized in the liver and is excreted through kidneys. Thus, any abnormal-
and prognosis is very clear. Although neonatal EEG interpretation is ity in the function of these organs alters the drug’s metabolism and can
very difficult, EEG was found to be highly associated with the outcome result in toxicity. In infants with acidosis or critical illness that might
in premature and full-term infants. An abnormal background is a alter serum protein content, free (i.e., not protein bound) levels of the
powerful predictor of less-favorable later outcome. In addition, prodrug should be followed carefully.
longed electrographic seizures (>10 min/hr), multifocal periodic elec-
trographic discharges, and spread of the electrographic seizures to the Phenytoin and Fosphenytoin
contralateral hemisphere also correlate with poorer outcome. The For ongoing seizures, if a total loading dose of 40 mg/kg of pheno-
underlying etiology of the seizures is the main determinant of outcome. barbital was not effective, then a loading dose of 15-20 mg/kg of
For example, patients with seizures secondary to hypoxic–ischemic phenytoin can be administered intravenously. The rate at which the
encephalopathy have a 50% chance of developing normally, whereas dose should be given must not exceed 0.5-1.0 mg/kg/min so as to
those with seizures caused by primary subarachnoid hemorrhage or prevent cardiac problems, and the medication needs to be avoided in
hypocalcemia have a much better prognosis. patients with significant heart disease. Heart rate should be monitored
while administrating the drug. It is not possible to mix phenytoin or
TREATMENT fosphenytoin with dextrose solutions. Owing to its reduced solubility,
A mainstay in the therapy of neonatal seizures is the diagnosis and potentially severe local cutaneous reactions, interaction with other
treatment of the underlying etiology (e.g., hypoglycemia, hypocalce- drugs, and possible cardiac toxicity, intravenous phenytoin is not
mia, meningitis, drug withdrawal, trauma), whenever one can be iden- widely used.
tified. There are conflicting approaches regarding the control of Fosphenytoin, which is a phosphate ester prodrug, is preferable. It
neonatal seizures. Most experts advocate complete control of clinical is highly soluble in water, and can be administered very safely intrave-
as well electrographic seizures. Others argue for treating clinical sei- nously and intramuscularly, without causing injury to tissues. Fosphe-
zures only. Most centers favor the first approach. An important con- nytoin is administered in phenytoin equivalents (PE). The usual
sideration before starting anticonvulsants is deciding, based on the loading dose of fosphenytoin is 15-20 PE/kg administered over 30 min.
severity duration and frequency of the seizures if the patient needs to Maintenance doses of 4-8 PE/kg/day can be given. As is the case for
receive intravenous therapy and loading with an initial bolus or can phenobarbital, free levels of the drug should be monitored in neonates
simply be started on maintenance doses of a long-acting drug. Patients whose serum pH or protein content might not be normal.
Other Medications aggressiveness catatonia, and or psychotic symptoms. It should be con-

Approximately 45% of neonates respond to the first drug used if it is sidered in any of these situations, especially in an unresponsive or
phenobarbital or phenytoin and an additional 15% respond to the encephalopathic child. Epilepsia partialis continua has been defined
second agent. Levetiracetam (which can be given intravenously with previously and can be caused by tumor, vascular etiologies, mitochon-
later convenient conversion to oral solution) and topiramate (oral) are drial disease (mitochondrial myopathy, encephalopathy, lactic acidosis,
reported to be the drugs of second and third choice for approximately and stroke-like episodes [MELAS]), and Rasmussen encephalitis.
half of surveyed pediatric neurologists and some have used them Refractory status epilepticus is status epilepticus that has failed to
even before phenobarbital or phenytoin in selected cases. The dosages respond to therapy, usually with at least 2 (such as a benzodiazepine
used are 10-30 mg/kg/day of levetiracetam, at times higher, and up to and another medication) medications. Currently, the trend is not to
20 mg/kg/day of topiramate. Bumetanide has been used as an adjunct assign a minimum duration, whereas in the past a minimum duration
drug, particularly with phenobarbital, because of its effect on the chlo- of 30 min, 60 min, or even 2 hr was cited. New-onset refractory status
ride gradient, as discussed above. Lidocaine is another medication epilepticus has been identified as a distinct entity that can be caused
used for resistant cases. Primidone, carbamazepine, valproate, and by almost any of the causes of status epilepticus in a patient without
lamotrigine use, although reported in some studies, is rarely war- prior epilepsy. It also is often of unknown etiology, presumed to be
ranted. Valproate, for example, is more likely to be toxic in children encephalitic or postencephalitic, can last several weeks or longer, and
younger than 2 yr of age than in older children. often, but not always, has a poor prognosis. Devastating epileptic
encephalopathy in school-age children, also called fever-induced
Duration of Therapy refractory epileptic encephalopathy in school age children (FIRES)
Duration of therapy is related to the risk of developing later epilepsy is a syndrome of refractory status epilepticus that is associated with
in infants suffering from neonatal seizures, which ranges from 10-30% acute febrile infections, appears to be parainfectious in nature, and to
and depends on the individual neurologic examination, the etiology of be highly drug resistant but responsive to the ketogenic diet.
the seizures, and the EEG at the time of discharge from the hospital.
In general, if the EEG at the time of discharge does not show evidence ETIOLOGY
of epileptiform activity, then medications are usually tapered at that Etiologies include new-onset epilepsy of any type; drug intoxication
time. If the EEG remains paroxysmal, then the decision is usually (e.g., tricyclic antidepressants) in children and drug and alcohol abuse
delayed for several months after discharge. in adolescents; drug withdrawal or overdose in patients on AEDs;
hypoglycemia; hypocalcemia; hyponatremia; hypomagnesemia; acute
Bibliography is available at Expert Consult. head trauma; encephalitis; meningitis; autoimmune encephalitis (such
as anti-NMDA receptor and anti–voltage-gated potassium channel
complex antibody syndromes); ischemic (arterial or venous) stroke;
intracranial hemorrhage; folinic acid and pyridoxine and pyridoxal
593.8 Status Epilepticus phosphate dependency (these usually present in infancy but childhood
Mohamad A. Mikati and Abeer J. Hani onset is also possible); inborn errors of metabolism (see Chapter 593.2)
such as nonketotic hyperglycinemia in neonates and mitochondrial
Status epilepticus is a medical emergency that should be anticipated encephalopathy with lactic acidosis (MELAS) in infants, children, and
in any patient who presents with an acute seizure. It is defined as con- adolescents; ion channel–related epilepsies (e.g., sodium and potas-
tinuous seizure activity or recurrent seizure activity without regaining sium channel mutations reviewed in the sections above); hypoxic–
of consciousness lasting for more than 5 min as part of an operational ischemic injury (e.g., after cardiac arrest); systemic conditions (such as
definition put forth within the past few years. In the past, the cutoff hypertensive encephalopathy, posterior reversible encephalopathy,
time was 30 min, but this has been reduced to emphasize the risks renal or hepatic encephalopathy); brain tumors; and any other disor-
involved with the longer durations. The ILAE defines status epilepticus ders that can cause epilepsy (such as brain malformations, neurode-
as “a seizure which shows no clinical signs of arresting after a duration generative disorders, different types of progressive myoclonic epilepsy,
encompassing the great majority of seizures of that type in most storage diseases).
patients or recurrent seizures without resumption of baseline central A rare condition called hemiconvulsion-hemiplegia-epilepsy syn-
nervous system function interictally.” The measures used to treat status drome consists of prolonged febrile status epilepticus presumably
epilepticus have to be started in any patient with acute seizures that caused by focal acute encephalitis with resultant atrophy in the involved
do not stop within a few minutes. The most common type is convulsive hemisphere, contralateral hemiplegia, and chronic epilepsy. It should
status epilepticus (generalized tonic, clonic, or tonic–clonic), but be suspected early on to attempt to control the seizures as early as
other types do occur, including nonconvulsive status (complex partial, possible. This and the somewhat similar condition mentioned above
absence), myoclonic status, epilepsia partialis continua, and neonatal called FIRES are likely to be have a parainfectious-autoimmune etiol-
status epilepticus. The incidence of status epilepticus ranges between ogy. Rasmussen encephalitis often causes epilepsia partialis continua
10 and 60 per 100,000 population in various studies. Status epilepticus (see Chapter 593.3) and sometimes convulsive status epilepticus.
is most common in children younger than 5 yr of age, with an inci- Several types of infections are more likely to cause encephalitis with
dence in this age group of >100 per 100,000 children. status epilepticus, such as herpes simplex (complex partial and convul-
Approximately 30% of patients presenting with status epilepticus are sive status), Bartonella (particularly nonconvulsive status), Epstein-
having their first seizure, and approximately 40% of these later develop Barr virus, and mycoplasma (postinfectious encephalomyelitis with
epilepsy. Febrile status epilepticus is the most common type of status any type of status epilepticus). Postinfectious encephalitis and acute
epilepticus in children. In the 1950s and 1960s, mortality rates of disseminated encephalomyelitis are common causes of status epilepti-
6-18% were reported after status epilepticus; currently, with the recog- cus, including refractory status epilepticus. HHV6 can cause a distinct
nition of status epilepticus as a medical emergency, a lower mortality epileptic syndrome with limbic status epilepticus in immune-
rate of 4-5% is observed, most of it secondary to the underlying etiol- suppressed patients.
ogy rather than to the seizures. Status epilepticus carries an approxi-
mately 14% risk of new neurologic deficits, most of this (12.5%) MECHANISMS
secondary to the underlying pathology. The mechanisms leading to the establishment of sustained seizure
Nonconvulsive status epilepticus manifests as a confusional state, activity seen in status epilepticus appear to involve (1) failure of desen-
dementia, hyperactivity with behavioral problems, fluctuating impair- sitization of AMPA glutamate receptors, thus persistence of increased
ment of consciousness with at times unsteady sitting or walking, fluc- excitability, and (2) reduction of GABA-mediated inhibition as a result
tuating mental status, confusional state, hallucinations, paranoia, of intracellular internalization of GABAA receptors. This explains the
Bibliography Pisani F, Piccolo B, Cantalupo G, et al: Neonatal seizures and postneonatal

Abend NS, Wusthoff CJ: Neonatal seizures and status epilepticus, J Clin epilepsy: a 7-y follow-up study, Pediatr Res 72:186–192, 2011.
Neurophysiol 29(5):441–448, 2012. Sivaswamy L: Approach to neonatal seizures, Clin Pediatr (Phila) 51(5):415–425,
Chapman KE, Raol YH, Brooks-Kayal A: Neonatal seizures: controversies and 2012.
challenges in translating new therapies from the lab to the isolette, Eur J Thibeault-Eybalin MP, Lortie A, Carmant L: Neonatal seizures: do they damage the
Neurosci 35(12):1857–1865, 2012. brain? Pediatr Neurol 40:175–180, 2009.
Gillam-Krakauer M, Carter BS: Neonatal hypoxia and seizures, Pediatr Rev
33(9):387–396, 2012.
Lawrence R, Mathur A, Tich SNT, et al: A pilot study of continuous limited-
channel aEEG in term infants with encephalopathy, J Pediatr 154:835–841,
2009.
clinical observation that status epilepticus is often less likely to stop in depending on clinical suspicion and need. EEG is helpful in ruling out
the next specific period of time the longer the seizure has lasted and pseudo–status epilepticus (psychologic conversion reaction mimick-
why benzodiazepines appear to be decreasingly effective the longer ing status epilepticus) or other movement disorders (chorea, tics),
seizure activity lasts. During status epilepticus there is increased cere- rigors, clonus with stimulation, and decerebrate/decorticate posturing.
bral metabolic rate and a compensatory increase in cerebral blood flow The EEG can also be helpful in identifying the type of status epilepticus
that, after approximately 30 min, is not able to keep up with the (generalized vs focal), which can guide further testing for the underly-
increases in cerebral metabolic rate. This leads to a transition from ing etiology and further therapy. EEG can also help distinguish between
adequate to inadequate cerebral oxygen tensions and, together with postictal depression and later stages of status epilepticus in which the
other factors, contributes to neuronal injury resulting from status epi- clinical manifestations are subtle (e.g., minimal myoclonic jerks) or
lepticus. Status epilepticus can cause both neuronal necrosis and apop- absent (electroclinical dissociation), and can help in monitoring the
tosis. The mechanisms of apoptosis are thought to be related to therapy, particularly in patients who are paralyzed and intubated. Neu-
increases in intracellular calcium and proapoptotic factors such as roimaging must be considered after the child has been stabilized, espe-
ceramide, Bax, and apoptosis-inducing factor. In addition, inflamma- cially if it is indicated by the clinical manifestations, by an asymmetric
tion through the cytokines (such as interleukin-1β) released during or focal nature of the EEG abnormalities, or by lack of knowledge of
seizure activity can modify neuronal excitability by modifying neu- the underlying etiology. The EEG manifestations of status epilepticus
rotransmitter function in a number of ways, such as through phos- show several stages that consist of initial distinct electrographic sei-
phorylation of the NR2B subunit rendering the NMDA receptors more zures (stage I) followed by waxing and waning electrographic seizures
permeable to calcium influx, increased expression of highly calcium- (stage II), continuous electrographic seizures (stage III; many patients
permeable AMPA receptors, and induction of endocytosis of GABAA start with this directly), continuous ictal discharges punctuated by
receptors. Prostaglandins (such as prostaglandin E2) can increase glu- flat periods (stage IV), and periodic epileptiform discharges on flat
tamate release and reduce potassium currents leading to increased background (stage V). The last 2 stages are often associated with
excitability. subtle clinical manifestations and with a lower chance of response to
medications.
THERAPY The initial emergent therapy usually involves intravenous diazepam,
Status epilepticus is a medical emergency that requires initial and lorazepam, or midazolam. Diazepam is at least as effective as intrave-
continuous attention to securing airway, breathing, and circulation nous lorazepam but has fewer side effects (Table 593-18). The use of
(with continuous monitoring of vital signs including ECG) and deter- midazolam autoinjector as initial therapy for acute seizures was found
mination and management of the underlying etiology (e.g., hypogly- to be at least as useful and safe as the use intravenous lorazepam and
cemia). Laboratory studies, including glucose, sodium, calcium, results in earlier response. If intravenous access is not available, buccal
magnesium, complete blood count, basic metabolic panel, CT scan, or intranasal midazolam, intranasal lorazepam, or rectal diazepam are
and continuous EEG, are needed for all patients. Blood and spinal fluid effective options. Intramuscular midazolam is equally effective as intra-
cultures, toxic screens, and tests for inborn errors of metabolism are venous lorazepam. With all options, respiratory depression is a poten-
often needed. AED levels need to be determined in all patients known tial side effect for which the patient should be monitored and managed
already to be taking these drugs. Lumbar puncture, comprehensive as needed. In some infants, a trial of pyridoxine may be warranted. The
toxicologic screens, MRI, and other laboratory tests are performed strongest evidence for initial and emergent therapy is for diazepam or
Table 593-18 Doses of Commonly Used Antiepileptic Drugs in Status Epilepticus

DRUG* ROUTE DOSAGE
Lorazepam Intravenous 0.1 mg/kg up to 4 mg total, may repeat in 5-10 min
Intranasal 0.1 mg/kg
Midazolam Intravenous 0.2 mg/kg up to 10 mg total dose, may repeat in 5-10 min
0.08-0.23 mg/kg/hr maintenance
Intramuscular 0.2 mg/kg
Intranasal 0.2 mg/kg
Buccal 0.5 mg/kg
Diazepam Intravenous 0.15 mg/kg up to a max total dose of 10 mg, may repeat in 5-10 min
Rectal 2-5 yr: 0.5 mg/kg
6-11 yr: 0.3 mg/kg
≥12 yr: 0.2 mg/kg
Fosphenytoin Intravenous 20 mg/kg PE, then 3-6 mg/kg/24 hr, loading rate up to 50 mg PE per min
†
Phenobarbital Intravenous 5-20 mg/kg
Pentobarbital coma† Intravenous 13.0 mg/kg, then 1-5 mg/kg/hr
†
Propofol Intravenous 1 mg/kg (bolus), then 1-15 mg/kg/hr (infusion)
Thiopental† Intravenous 5 mg/kg/1st hr, then 1-2 mg/kg/hr
†
Valproate Intravenous Loading: 25 mg/kg, then 30-60 mg/kg/24 hr
Lacosamide† Intravenous Loading: 4 mg/kg then 4-12 mg/kg/24 hr
Levetiracetam Intravenous 20-60 mg/kg
Topiramate Enterally 5-10 mg/kg/24 hr (loading dose) then same or lower for maintenance
*Reflects current trends in use which may not be FDA approved. For FDA indications, see Table 593-13.
†
May cause PR prolongation.
PE, phenytoin sodium equivalents.
lorazepam, followed by phenytoin/fosphenytoin and phenobarbital, autoimmune encephalitides), immunoglobulins, and plasma exchange
then valproate and levetiracetam. (e.g., in Rasmussen or other autoimmune encephalitides), ketogenic
After the emergent therapy usually with a benzodiazepine, the sub- diet (in patients with FIRES and Landau-Kleffner syndrome), vagus
sequent urgent therapy medication is usually fosphenytoin, and the nerve stimulation in catastrophic epilepsy in infants, hypothermia,
loading dose is usually 15-20 PE/kg. A level is usually taken 2 hr later electroconvulsive therapy, magnetic transcranial stimulation, and sur-
to ensure achievement of a therapeutic concentration. Depending gical management with focal resection. Another potential therapy
on the level, maintenance dose can be started right away or, more under study for convulsive status epilepticus is induction of acidosis
commonly, in 6 hr. With phenytoin and phenobarbital, each 1 mg/kg (e.g., by hypercapnia), which could reduce neuronal excitability.
(1 PE/kg for fosphenytoin) increases the serum concentration by For nonconvulsive status epilepticus and epilepsia partialis conti-
approximately 1 µg/mL; for valproate, each 1 mg/kg increases the nua, therapy needs to be tailored according to the clinical manifesta-
serum concentration by approximately 4 µg/mL. Precautions about the tions and often consists of trials of sequential oral or sometimes
rate of infusion of fosphenytoin and phenytoin (not >0.5-1.0 mg/kg/ parenteral AEDs without resorting to barbiturate coma or overmedica-
min) and the other medications need to be followed because side tion that could result in respiratory compromise. The approach to
effects often depend on infusion rate. The subsequent medication is complex partial status epilepticus is sometimes similar to the approach
often phenobarbital. The dose used in neonates is usually 20 mg/kg to convulsive status epilepticus and sometimes intermediate between
loading dose, but in infants and children the dose is often 5-10 mg/kg the approach for epilepsia partialis and that for convulsive status,
(to avoid respiratory depression), with the dose repeated if there is not depending on severity. Long-term consequences after complex partial
an adequate response. Current evidence for the urgent therapy is stron- status epilepticus do occur, but the complications are often less severe
gest for valproate, followed by phenytoin/fosphenytoin and midazolam than those after convulsive status epilepticus of similar duration. Pro-
continuous infusion, followed by phenobarbital and levetiracetam, the longed nonconvulsive complex partial status epilepticus can last for as
last of which are currently being increasingly used. long as 12 wk, with patients manifesting psychotic symptoms and con-
After the second or third medication is given, and sometimes before fusional states. These cases can be resistant to therapy. Despite that,
that, the patient might need to be intubated. All patients with status patients still can have a full recovery. Some of these cases appear to
epilepticus, even the ones who respond, need to be admitted to the improve with the use of steroids or IVIG, which are used if an autoim-
ICU for completion of therapy and monitoring. Ideally, emergent and mune, parainfectious etiology is suspected.
urgent therapies should have been received within less than 30 min so
as to initiate the subsequent therapy soon, thus reducing the chances Bibliography is available at Expert Consult.
of sequelae. For refractory status epilepticus treatment, an intrave-
nous bolus followed by continuous infusion of midazolam, propofol,
pentobarbital, or thiopental is used. This is done in the ICU. Subsequent
boluses and adjustment of the rate of the infusion are usually made 593.9 Reflex Seizures
depending on clinical and EEG responses. Because most of these
patients need to be intubated and paralyzed, the EEG becomes the (Stimulus Precipitated Seizures)
method of choice by which to follow them. The goal is to stop electro- Robert M. Kliegman
graphic seizure activity before reducing the therapy. Usually this implies
achievement of complete flattening of the EEG. Some consider that Many patients with epilepsy can identify precipitating or provoking
achieving a burst suppression pattern may be enough, and the periods events that predispose them to having a seizure. Common events in
of flattening in such a case need to be 8-20 sec to ensure interruption patients with epilepsy include stress, lack of sleep, fever, or fatigue.
of electrographic seizure activity. However, this is an area that is in There is another group of patients who have seizures in response to
need of further study. Currently, the level of the evidence for refractory a very specific, identifiable sensory stimulus or activity and are consid-
treatment is strongest for midazolam and valproate, followed by ered to have reflex seizures. Although no known “reflex” may be
propofol and pentobarbital/thiopental, followed by levetiracetam, involved, more appropriate terms may be sensory precipitated or stim-
phenytoin/fosphenytoin, lacosamide, topiramate, and phenobarbital. ulus sensitive seizures (see Table 593-1). Stimuli may be external (light,
Patients on these therapies require careful attention to blood pres- patterns, music, brushing teeth) or internal (math, reading, thinking,
sure and to systemic complications, and some develop multiorgan self-induced). Reflex seizures may be generalized, partial, nonconvul-
failure. It is not unusual for patients put into pentobarbital coma to sive, absence or myoclonic. One common pattern is photomyoclonic
have to be on multiple pressors to maintain their blood pressure during seizures characterized by forehead muscle twitching or repetitive eye
therapy. opening or closing.
The choice among the above options to treat refractory status epi- Photosensitive or pattern-induced seizures are a well-recognized
lepticus often depends on the experience of the specific center. Mid- disorder stimulated by bright or flashing lights (TV, video games, dis-
azolam probably has fewer side effects, but is less effective, and cotheques, concert light shows) or by patterns (TV, video games, lines
barbiturate coma is more effective, but carries a higher risk of side on the road while traveling). Visual sensitivity may occur in 0.3-3% of
effects. On propofol, some patients develop a propofol infusion syn- the population, while photosensitive or pattern-induced seizures may
drome with lactic acidosis, hemodynamic instability, and rhabdomy- occur in 1 in 4,000 people in the at-risk age group of 5-25 yr. When
olysis with higher infusion rates (>67 µg/kg/min). Thus electrolytes, Japanese children were exposed to a Pokémon cartoon that induced
creatine phosphokinase, and organ function studies need to be moni- seizures, only 24% had a history of spontaneous seizures. Patients tend
tored. Often, barbiturate coma and similar therapies are maintained to outgrow photosensitive or pattern-induced seizures in their 30s.
for 1 or more days before it is possible to gradually taper the therapy, Photoparoxysmal responses, with an abnormal EEG response to photic
usually over a few days. However, in some cases, including cases of stimulation may be more common than photic-induced seizures. There
new-onset refractory status epilepticus (new-onset refractory status are some photo-induced responses that do not demonstrate EEG
epilepticus), such therapies need to be maintained for several weeks or abnormalities (nonconvulsive).
even months. Even though the prognosis in new-onset refractory For patients with isolated photosensitive or pattern-induced sei-
status epilepticus cases is often poor and many patients do not survive, zures, avoidance or modification of stimuli is the initial approach. Such
meaningful recovery despite a prolonged course is still possible. This activities may include blue or polarized sunglasses, avoiding high-
also appears to apply to the FIRES syndrome. Occasionally, inhala- contrast flashing-light video games, avoiding discotheques, use a TV
tional anesthetics are useful. Probably isoflurane is preferable because remote or watch TV in a well-lit room at a distance of >8 feet, and
halothane can increase intracranial pressure and enflurane can induce covering 1 eye when in a provocative situation.
seizures. Other therapies have included ketamine, corticosteroids
(e.g., for Rasmussen encephalitis, Hashimoto encephalopathy, or other Bibliography is available at Expert Consult.
Bibliography Nabbout R, Mazzuca M, Hubert P, et al: Efficacy of ketogenic diet in severe

Brophy GM, Bell R, Claassen J, et al; Neurocritical Care Society Status Epilepticus refractory status epilepticus initiating fever induced refractory epileptic
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of status epilepticus, Neurocrit Care 17(1):3–23, 2012. 2010.
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2856.e2 Chapter 593 ◆ Seizures in Childhood
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Table 593-19 Consensus Case Definition and Modified Consensus Case Definition for Nodding Syndrome—Uganda,
2012-2013*
TYPE OF CASE CONSENSUS CASE DEFINITION MODIFIED CONSENSUS CASE DEFINITION
Suspected case Reported head nodding (repetitive involuntary drops of Reported head nodding (repetitive involuntary drops of
the head toward the chest on 2 or more occasions) in a the head toward the chest on 2 or more occasions) in
previously normal person a previously normal person
Probable case Suspected case of head nodding, with both major criteria: Suspected case of head nodding, with 1 major criterion:
• Age of onset of nodding ranging from 3-18 yr • Age of onset of nodding ranging from 3-18 yr
• Frequency of nodding 5-20 per minute
Plus at least 1 of the following minor criteria: Plus at least 1 of the following minor criteria:
• Other neurologic abnormalities (cognitive decline, • Other neurologic abnormalities (cognitive decline,
school dropout because of cognitive or behavioral school dropout because of cognitive or behavioral
problems, other seizures or neurologic abnormalities) problems, other seizures or neurologic abnormalities)
• Clustering in space or time with similar cases • Clustering in space or time with similar cases
• Triggering by food or cold weather • Triggering by food or cold weather
• Stunting or wasting • Stunting or wasting
• Delayed sexual or physical development • Psychiatric symptoms
• Psychiatric symptoms
Confirmed case Probable case, with documented nodding episode Probable case, with documented nodding episode
• Observed and recorded by a trained healthcare worker, • Observed and recorded by a trained healthcare
or worker, or
• Videotaped nodding episode, or • Videotaped nodding episode, or
• Video/EEG/EMG documenting head nodding as atonic • Video/EEG/EMG documenting head nodding as
seizures atonic seizures
*The consensus case definition was drafted at the first International Scientific Meeting on Nodding Syndrome, held July 30–August 1, 2012, in Kampala, Uganda.
Meeting report available at http://www.who.int/neglected_diseases/diseases/Nodding_syndrom_Kampala_Report_2012.pdf. The modified consensus case definition
was developed during the March 2013 single-stage cluster survey conducted by Centers for Disease Control and Prevention (CDC) and the Ugandan Ministry of
Health to assess prevalence of nodding syndrome in Uganda.
EEG, electroencephalographic; EMG, electromyographic.
From Iyengar PJ, Wamala J, Ratto J, et al: Prevalence of nodding syndrome–Uganda, 2012-2013. MMWR Morb Mortal Wkly Rep 63:603–606, 2014, Table 1.
593.10 Nodding Syndrome

Robert M. Kliegman
Nodding syndrome appears to be an epidemic progressive epilepsy

encephalopathy syndrome of unknown etiology seen predominantly
in Uganda, Liberia, Tanzania, and the southern Sudan, with a preva-
lence of approximately 6.8 per 1,000 children. Age of onset is 6-13 yr.
Nodding episodes are characterized by at least daily, rapid, paroxysmal
forward head bobbling spells lasting several minutes; some patients are
unresponsive whereas others may respond to commands or continue
what they were doing before the episode. Children were previously
healthy, although there may be a family history of seizures. In addition
to episodes of nodding, there may be associated definable generalized
tonic–clonic or absence seizures. Furthermore, patients go on to dem-
onstrate severe and global cognitive impairment (see Table 593-19 for
case definitions).
The EEG demonstrates a disorganized slow background and inter-
ictal generalized 2.5-3.0 Hz spike and slow waves. During a nodding
episode, the EEG demonstrates generalized electrodecrement and
paraspinal electromyography dropout suggestive of an atonic seizure.
Cerebral spinal fluid analysis is usually negative, while the MRI shows
cerebral and cerebellar atrophy.
Nodding episodes may be triggered during meals while eating hot
foods or drinking cold liquids; cold environmental temperature may
also trigger a nodding episode.
Treatment of seizures are indicated; however, the response to treat-
ment is poor.

Bibliography Tumwine JK, Vandemaele K, Chungong S, et al: Clinical and epidemiological

Dowell SF, Sejvar JJ, Riek L, et al: Nodding syndrome, Emerg Infect Dis 19:1374– characteristics of nodding syndrome in Mundri County, southern Sudan,
1384, 2013. Afr Health Sci 12:242–248, 2012.
Iyengar PJ, Wamala J, Ratto J, et al: Prevalence of nodding syndrome–Uganda, Winkler AS, Friedrich K, Konig R, et al: The head nodding syndrome–clinical
2012-2013, MMWR Morb Mortal Wkly Rep 63:603–606, 2014. classification and possible causes, Epilepsia 49:2008–2015, 2008.
Sejvar JJ, Kakooza AM, Foltz JL, et al: Clinical, neurological, and
electrophysiological features of nodding syndrome in Kitgum, Uganda: an
observational case series, Lancet Neurol 12:166–174, 2013.
Chapter 594 ◆ Conditions That Mimic Seizures 2857
Chapter 594
Conditions That Mimic
Seizures
Mohamad A. Mikati and Makram M. Obeid
The misdiagnosis of epilepsy is estimated to be as high as 5-40%, imply-

ing that many patients may be subjected to unnecessary therapy and
tests. Often all that is needed to differentiate nonepileptic paroxysmal
disorders from epilepsy is a careful and detailed history in addition to
a thorough exam; but sometimes an electroencephalogram (EEG) or
more advanced testing may be necessary. The ready availability of
video recording on mobile phones and other devices at home or at
school can provide invaluable information. Nonepileptic paroxysmal
disorders can be classified according to the age of presentation and the
clinical manifestations: (1) syncope and other generalized paroxysms,
(2) movement disorders and other abnormal movements and postures,
(3) oculomotor abnormalities and visual hallucinations, and (4) sleep-
related disorders (Table 594-1).
SYNCOPE AND OTHER GENERALIZED

PAROXYSMS
Apnea
Apneic episodes in neonates are usually associated with bradycardia as
is usually apnea resulting from brainstem compression. In contrast,
apnea associated with seizures is usually accompanied by tachycardia.
Of note, exceptions do occur as bradycardia can occur during epileptic
seizures, and severe apnea of any cause can be followed by anoxic
seizures.
Table 594-1 Conditions That Mimic Seizures According to Age of Presentation

SYNCOPE AND OTHER MOVEMENT DISORDERS AND
GENERALIZED OTHER ABNORMAL OCULOMOTOR
AGE PAROXYSMS MOVEMENTS ABNORMALITIES SLEEP DISORDERS
Neonate Apnea Jitteriness Paroxysmal tonic up gaze Benign neonatal sleep
Paroxysmal extreme pain Hyperekplexia Alternating hemiplegia myoclonus
disorder Paroxysmal dystonic choreoathetosis of childhood Sleep transition disorders
Infants Reflex anoxic seizures Jitteriness Paroxysmal tonic upgaze Non-REM partial arousal
Breath-holding spells Sandifer Oculomotor apraxia disorders
Benign paroxysmal vertigo Paroxysmal dystonic choreoathetosis Spasmus nutans REM sleep disorders
Paroxysmal extreme pain Benign myoclonus of early infancy Opsoclonus myoclonus Narcolepsy
disorder Pathologic startle syndrome Sleep transition disorders
Shuddering attacks (somnambulism,
Benign paroxysmal torticollis somniloquy)
Psychologic disorders
Alternating hemiplegia of childhood
Jactatio capitis head banging
Drug reactions
Children and Benign paroxysmal vertigo Tics Daydreaming Non-REM partial-arousal
adolescents Compulsive Valsalva Tremor Drug reactions disorders
Familial hemiplegic Pathologic startle REM sleep disorders
migraine Paroxysmal dyskinesias Narcolepsy
Syncope (long QT, Alternating hemiplegia of childhood Sleep transition disorders
vasovagal, vagovagal, Benign paroxysmal torticollis (somnambulism,
orthostatic, migraine- Episodic ataxia somniloquy)
induced) Psychologic disorders including Sleep myoclonus
Psychogenic seizures factitious disorder imposed on Restless legs syndrome
Transient global amnesia another, malingering
Hyperventilation spells Masturbation
Psychogenic seizures
Cataplexy
Jactatio capitis (head banging)
Episodic rage
Drug reactions
REM, rapid eye movement.
From Obeid M, Mikati MA: Expanding spectrum of paroxysmal events in children: potential mimickers of epilepsy, Pediatr Neurol 37(5):309–316, 2007.
Breath-Holding Spells this case, true breath-holding occurs, and it usually lasts for approxi-
The term breath-holding spells is actually a misnomer, as these are not mately 10 sec during inspiration. Some clinicians advocate the use of
self-induced, but result from the immaturity of the autonomic system naloxone in such cases.
and occur in 2 different forms. The first type is the pallid breath-
holding spell, which is caused by reflex vagal–cardiac bradycardia and Neurally Mediated Syncope
asystole. The second type is the cyanotic, or “blue,” breath-holding Syncope can present with drop attacks and can also lead to generalized
spell, which does not occur during inspiration, but results from pro- convulsions, termed anoxic seizures. These convulsions, triggered by a
longed expiratory apnea and intrapulmonary shunting. Episodes sudden reduction of oxygen to the brain, are clinically similar to and
usually start with a cry (often, in the case of the pallid type, a “silent” can be misdiagnosed as generalized epileptic seizures. Vasovagal (neu-
cry with marked pallor), and progress to apnea and cyanosis. Spells rocardiogenic) syncope is one of the most common mimickers of
usually begin between 6 and 18 mo of age. Syncope, tonic posturing, generalized tonic–clonic seizures and is usually triggered by dehydra-
and even reflex anoxic seizures may follow the more-severe episodes, tion, heat, standing for a long time without movement, hot showers,
particularly in breath-holding spells of the pallid type. Injury, anger, the sight of blood, pain, swallowing, vomiting, and or sudden stress.
and frustration, particularly with surprise, are common triggers. Edu- History is usually the clue to distinguishing syncope from epileptic
cation and reassurance of the parents is usually all that is needed, as seizures: There is initially pallor and sweating followed by blurring of
these episodes are, as a rule, self-limited and are outgrown within a few vision, dizziness, nausea, and then gradual collapse with loss of con-
years. However, treatment of coexisting iron deficiency is needed if it sciousness. These symptoms are present in most, although not neces-
is present as the spells are made worse by iron-deficiency anemia. sarily all patients with syncope and can sometimes be manifestations
Anticholinergic drugs (e.g., atropine sulfate 0.01 mg/kg/24 hr in of complex partial seizures. Much more important is the fact that such
divided doses with a maximum daily dose of 0.4 mg), or antiepileptic prodromal features have an insidious onset and build up gradually,
drug therapy for coexisting anoxic seizures that are recurrent and not often arising from a state of malaise when they precede syncope.
responding to other measures may, rarely, be needed. It is important However when they precede an epileptic convulsion, such features
also to educate parents on how to handle more-severe spells by first-aid usually start suddenly are short in duration, paroxysmal and are fol-
measures, or even basic CPR when needed. In severe cases of asystole, lowed by other manifestations of complex partial seizures such as
a cardiac pacemaker implantation may be needed. All parents should stereotyped automatisms. Abdominal pain, a common aura in tempo-
be taught not to provide secondary gain when the episodes occur, ral lobe epilepsy, occurs in vasovagal syncope, and can be a trigger or
because this can reinforce the episodes. Also, preparation for unpleas- a consequence of that process (intestinal vagal discharge). Urinary
ant experiences (such as receiving a shot) rather than surprising the incontinence and a brief period of convulsive jerks are not uncommon
child with them, can help limit the number of spells (see Chapter 69). in vasovagal syncope. These occur with a frequency of 10% and 50%,
respectively. Postictal confusion only rarely occurs, and the rule is the
Compulsive Valsalva occurrence of only brief postictal tiredness with a subsequent remark-
In children with intellectual disability, including Rett syndrome, syn- able ability to resume planned activities. Most children with vasovagal
copal convulsions may be self-induced by maneuvers like Valsalva. In syncope have an affected 1st-degree relative; reports demonstrate
autosomal dominant inheritance at least in some families. The EEG is or directly at the end (usually valvular) and, if suspected, warrants
normal and the tilt test has been used for diagnostic purposes in an echocardiogram.
selected cases. In most cases with typical history, this test is not needed.
Vagovagal syncope can progress to convulsive seizure if the asystole Other Causes of Syncope
is sufficiently prolonged. Sudden cold exposure to the face or to the Syncope that is not neurally mediated or cardiac in origin is caused by
body can also trigger vagal syncope. Syncope has been reported (rarely) a decrease in blood volume, or a mechanical disruption of brain perfu-
to occur in association with cough, tight hair braiding, and hair sion. Systemic diseases that lead to syncope by affecting blood volume
combing. Orthostatic hypotension and orthostatic intolerance man- (e.g., adrenal insufficiency) are usually first brought to medical atten-
ifest symptoms that develop during upright standing and can be tion by other accompanying signs and symptoms. In stretch syncope,
relieved by recumbence. Postural tachycardia syndrome, the patho- which occurs mostly in adolescents while stretching the neck and the
physiology of which presumably involves an excessive sympathetic trunk backward and the arms outward, or during flexion of the neck,
discharge resulting in increased heart rate and vasoconstriction that the presumed mechanism is mechanical disruption of brain perfusion
can lead to decreased peripheral perfusion, is usually a disease of ado- caused by compression of the vertebral arteries. In some cases, this may
lescent females that is characterized by upright syncope/near syncope, be associated with an abnormally prolonged stylomastoid process
and tachycardia with normal or even increased blood pressure during compressing the carotids. If the latter condition is suspected, then
the episode. Primary autonomic failure is rare in children, and familial neuroimaging (CT, MRI) is required for proper diagnosis of the stylo-
dysautonomia is the only relatively common form. Familial dysauto- mastoid anomaly.
nomia is a disease common in Ashkenazi Jews and is characterized
by absence of overflow emotional tears, depressed patellar reflexes, and Sporadic and Familial Hemiplegic Migraine
lack of a flare reaction following intradermal histamine. Dopamine This is a rare type of migraine with a motor aura of weakness. Attacks
β-hydroxylase deficiency is a very rare cause of primary autonomic begin as early as 5-7 yr of age. In a genetically susceptible person,
failure, and is characterized by a complicated perinatal course (hypo- attacks may be precipitated by head trauma, exertion, or emotional
tension, hypotonia, hypothermia), ptosis, highly arched palate, hyper- stress. The 3 genes so far identified are SCN1A (neuronal sodium
flexible joints, impaired ejaculation, and nocturia. The tilt test causes channel subunit), CACNA1A (neuronal calcium channel subunit),
a drop in both blood pressure and heart rate in patients with classic and ATP1A2 (sodium potassium adenosine triphosphatase subunit).
vasovagal syncope. It results in a blood pressure drop with minimal However at least a quarter of the affected families, and most of the
change in heart rate in autonomic failure, and in blood pressure drop sporadic cases do not carry a mutations in these 3 genes. Headaches
and an increase in heart rate in postural tachycardia syndrome. Man- occur in all attacks in most patients. The presence of negative phe-
agement of syncope centers on avoidance of precipitating factors nomena (e.g., numbness, visual scotomas) in addition to positive
(maintenance of hydration, avoidance of standing still, rising slowly phenomena (pins and needles, flickering lights), and the progressive
from sitting, first-aid measures, raising of the legs, positioning) and and successive occurrence of visual, sensory, motor, aphasic, and
treatment of any accompanying or underlying medical conditions basilar signs and symptoms, in that order, help differentiate these
(anemia, adrenal insufficiency, cardiac, etc.). In addition, salt supple- attacks from epileptic seizures. Persistent cerebellar deficits (e.g.,
mentation (2-4 g/day), β-blockers (e.g., metoprolol at a starting dose nystagmus, ataxia) may be present. Verapamil, acetazolamide, and
of 1-2 mg/kg once per day up to a maximum of 6 mg/kg/day), or fluo- lamotrigine have been successfully used to prevent attacks and vera-
rohydrocortisone (0.05-0.1 mg/day) therapy may be needed in selected pamil and ketamine have been used for the acute episode, while ergot
cases. derivatives, nimodipine, Midrin (isometheptene mucate, dichloral-
phenazone, and paracetamol), and probably triptans and propranolol
Cardiac Syncope are to be avoided because of concerns of exacerbating the attacks.
See Chapter 435.5. Interestingly, the co-occurrence of epileptic seizures has been reported
Long QT syndromes (LQT) can cause life-threatening “pallid” or in a minority of patient with hemiplegic migraine. It is important
white syncope. Accompanying this are ventricular arrhythmias, also to note that recurrent attacks akin to hemiplegic migraine can
usually torsades de pointes or even ventricular fibrillation. There are be symptomatic of Sturge-Weber syndrome or various metabolic dis-
more than 10 types of prolonged QT syndrome. When accompanied eases (e.g., mitochondrial encephalopathy with lactic acidosis and
by congenital deafness, it is part of the autosomal recessive Jervell stroke-like episodes).
and Lange-Nielson syndrome (type 1, LQT 1, associated with KvLQT1
potassium channel mutation). The Romano-Ward syndrome is an Benign Paroxysmal Vertigo of Childhood
autosomal dominant syndrome with incomplete penetrance that is This is a common migraine equivalent that consists of brief seconds-
characterized by episodes of lying still like a dead body for several to-minutes episodes of vertigo that is often accompanied by postural
seconds before the anoxic convulsive episode (LQT 2 associated with imbalance and nystagmus. It is important to note that vertigo does not
an HERG potassium channel mutation). LQT 3 is associated with an always refer to a spinning motion; it can also refer to a backward or
SCN1A sodium channel mutation, LQT 4 with ankyrin protein muta- forward motion (vertigo titubant) where children sometimes report
tion, LQT 5 (milder form) with KCNE1 mutations, LQT 6 with that objects are moving toward them. The child appears frightened
KCNE2 potassium gene mutations, LQT 9 with caveolin sodium during the episode. Diaphoresis, nausea, vomiting, and, rarely, tinnitus
channel–related protein mutations, and LQT 10 with SCN4B sodium may be present. Episodes usually remit by 6 yr of age. MRI and EEG
channel mutations. LQT 7 and LQT 8 are of particular interest are normal, but caloric testing, if done, can show abnormal vestibular
because of associated clinical and neurologic manifestations. LQT 7 function. Diphenhydramine, 5 mg/kg/day (maximum of 300 mg/day)
(Andersen-Tawil) syndrome is associated with periodic paralysis, may be used for a cluster of attacks. Preventive therapy with cyprohep-
skeletal developmental abnormalities, clinodactyly, low-set ears, and tadine may be rarely needed for frequent attacks.
micrognathia (mutations in KCNJ2 gene). LQT 8 or the Timothy
syndrome (mutations in the calcium channel gene CACNA1c) mani- Cyclic Vomiting Syndrome
fests congenital heart disease, autism, syndactyly, and immune defi- This syndrome is another related periodic migraine variant that can
ciency. All family members of an affected LQT syndrome individual respond to antimigraine or antiepileptic drugs. This and other periodic
should be investigated. Affected individuals need insertion of cardiac syndromes have been associated with mutations that also can cause
defibrillators, and their families should be taught CPR. As a rule, hemiplegic migraine.
children with new-onset seizure disorder should get an electrocardio-
gram to rule out LQT syndrome masquerading as seizure disorder. The “Alice in Wonderland” Syndrome
Cardiac syncope is usually sudden without the gradual onset and the This is the episodic experience of transient distortions of body image
symptoms that accompany vagal syncope. Aortic stenosis can cause or visual images that, most often, constitute a migraine equivalent. It
sudden syncope at the height of the exercise (usually hypertrophic), also can be an epileptic phenomenon.
Migraine-Induced Syncope response is often incomplete. Gain-of-function Na(v)1.7 mutations are

Migraine, usually of the basilar variety, can trigger vasovagal syncope known to cause two neuropathic pain syndromes: inherited erythro-
and, less commonly, epileptic seizures. Careful elicitation of the history melalgia and paroxysmal extreme pain syndrome. These syndromes
of a migrainous prelude to the syncope helps in identifying these are inherited in a dominant trait; they usually begin in childhood or
phenomena. infancy, and are characterized by attacks of severe neuropathic pain
accompanied with autonomic symptoms. In addition, small fiber neu-
Psychologic Disorders ropathy and chronic nonparoxysmal pain have been described in
Psychogenic nonepileptic seizures are conversion reactions that are patients harboring gain-of-function mutations in Na(v)1.7 channel.
usually suspected clinically based on the characteristics of the spells Loss-of-function mutations in Na(v)1.7 are extremely rare and invari-
(Table 594-2). The diagnosis can be confirmed by video EEG with ably cause congenital inability to perceive pain.
capture of an episode to eliminate any residual doubts about their
nature, as they can often occur in patients who also have epileptic sei- Autonomic Storms (Diencephalic Seizures)
zures. They are best managed acutely by reassurance about their rela- Spells of hyperhidrosis, changes in blood pressure, temperature and
tively benign nature and by a supportive attitude while at the same autonomic instability occur in patients with severe diffuse brain injury
time avoiding positive reinforcement of the episodes. Psychiatric evalu- or localized hypothalamic injury and have been termed autonomic
ation and follow-up are needed to uncover underlying psychopathol- storms. The term diencephalic seizures is discouraged as these are not
ogy, and to establish continued support as psychogenic seizures can truly seizures. Therapy is difficult and has included, with mixed results,
persist over long periods of time. Malingering and factitious disorder clonidine, anticonvulsants, cyproheptadine, morphine, and sympa-
imposed on another (formerly called Munchausen syndrome by thectomy. Serotonin syndrome caused by antidepressants, stimulants,
proxy) are often difficult to diagnose but an approach similar to that for opioids, certain herbs like St. John’s Wart and some other medications
psychogenic seizures, including video-EEG monitoring, is often helpful. can produce similar symptoms, and if not recognized, can at times be
fatal as can be the similar neuroleptic malignant syndrome caused by
Paroxysmal Extreme Pain Disorder antipsychotic medications.
Paroxysmal extreme pain disorder was previously called familial rectal
pain syndrome. This syndrome (caused by the SCN9A sodium channel MOVEMENT DISORDERS AND OTHER
gene mutation) usually starts in the neonatal period or infancy and ABNORMAL MOVEMENTS AND POSTURES
persists throughout life. Autonomic manifestations predominate ini- Neonatal Jitteriness and Clonus
tially, with skin flushing in all cases and harlequin color change and Jitteriness consists of equal backward and forward movements of
tonic attacks in most. Dramatic syncope with bradycardia and some- limbs, occurring spontaneously, or triggered by touch or loud sounds.
times asystole are common. Later, the disorder is characterized by Movement suppression by stimulus removal or by relaxing the affected
attacks of excruciating deep burning pain often in the rectal, ocular, or limbs, the lack of autonomic symptoms, and the clear difference
jaw areas, but also diffusely in some. Attacks are triggered by defeca- from the 2-phased (fast contraction, slow relaxation) clonic activity
tion, cold, wind, eating, and emotion. Carbamazepine is used, but the and the very quick myoclonic jerks, point to a nonepileptic event.
Table 594-2 Comparison of Generalized Seizures and Some Disorders That Can Mimic Them
PRECIPITANTS (MAY
NOT APPLY TO ALL POSTICTAL
CONDITION PATIENTS) PRODROME ICTAL SYMPTOMS SYMPTOMS
Generalized seizures Sleep deprivation, Rarely irritability or Usually 2-3 min Delayed recovery with
television, video games, nonspecific Consciousness might be postictal depression,
visual patterns, and behavioral preserved if atonic, or in incontinence (may be
photic stimulation changes some, tonic seizures ictal also)
Synchronous bilateral
movements
Tongue biting
Syncope: vasovagal Fatigue, emotional stress, Blurring of vision, Loss of consciousness for Rapid recovery with no
dehydration, vomiting, tinnitus, dizziness seconds, pallor and rarely postictal depression
choking, swallowing Crying in reflex anoxic seizures
Syncope with reflex Minor bump to head, breath-holding
anoxic seizures upsetting surprises spells
Syncope: trigeminal vagal Cold water on face
Syncope: orthostatic Standing up, bathing,
awakening
Hyperekplexia Auditory and tactile None Tonic stiffening, cyanosis if Depending on
stimuli severe, nonfatigable nose- severity, may have
tap–induced startles postictal depression
Cardiac Exercise None Loss of consciousness, often Rarely
only few seconds, pallor
Psychogenic Suggestion, stress None Eyes closed No postictal
Asynchronous flailing limb depression
movements that vary between
attacks
No injury, closed eyelids
May respond to suggestion
during “loss of consciousness”
Usually longer than 2-3 min
Adapted from Obeid M, Mikati MA: Expanding spectrum of paroxysmal events in children: potential mimickers of epilepsy, Pediatr Neurol 37(5):309–316, 2007.
Hypocalcemia, hypoglycemia, drug withdrawal, and hypoxic–ischemic Paroxysmal Dyskinesias and

encephalopathy are possible etiologies. Clonus as a result of cortico- Other Movement Disorders
spinal tract injury usually occurs in later infancy and childhood and These disorders are characterized by sudden attacks that consist of
can be stopped by change in position. choreic, dystonic, ballistic, or mixed movements (Table 594-3). A sen-
sation of fatigue or weakness confined to 1 side may herald an attack.
Hyperekplexia (Stiff Baby Syndrome) Consciousness is preserved and patients may be able perform a motor
and Pathologic Startles activity, like walking, despite the attack. The variability in the pattern
Hyperekplexia is a rare, sporadic or dominantly inherited disorder of severity and localization between different attacks may also help in
with neonatal onset of life-threatening episodes of tonic stiffening that differentiating them from seizures. The frequency of attacks increases
precipitate apnea and convulsive hypoxic seizures. in adolescence, and steadily decreases in the 3rd decade. Neurologic
Stiffness may result in difficulty in swallowing, choking spells, hip exam between attacks, EEG, laboratory investigations, and imaging
dislocations, umbilical or inguinal hernias, and delayed motor devel- studies are normal. These dyskinesias often respond to phenytoin, car-
opment. Stiffness in the neonatal form improves by 1 yr of age and may bamazepine, clonazepam, or to antidopaminergic drugs such as halo-
disappear during sleep. peridol. Drug reactions can result in abnormal movements such as
The genetic cause is a defect in the α or β subunits of the oculogyric crisis with many antiemetics, choreoathetosis with phe-
strychnine-sensitive glycine receptors. It is characterized by a triad of nytoin, dystonia and facial dyskinesias with antidopaminergic drugs,
generalized stiffness, nocturnal myoclonus, and later a pathologic and tics with carbamazepine. Strokes, focal brain lesions, connective
startle reflex. A specific diagnostic sign can be elicited by tapping the tissue disorders (e.g., systemic lupus erythematosus), vasculitis, or
nose, which produces a nonfatigable startle reflex with head retrac- metabolic and genetic disorders can also cause movement disorders.
tion. Bathing, sudden awakening, and auditory or tactile stimuli can Mutations of the glucose transporter 1 (GLUT1/SLC2AI) gene have
induce attacks. The differential diagnosis includes congenital stiff been described in patients with exercise-induced dyskinesia.
person syndrome, startle epilepsy, myoclonic seizures, neonatal tetany,
phenothiazine toxicity, and Schwartz-Jampel syndrome. Making a Motor Tics
prompt diagnosis is extremely important to initiate treatment with These are movements that are under partial control, and are associated
clonazepam as hypoxic brain injury can result from a prolonged with an urge to do them and with a subsequent relief. They are usually
episode. Other antiepileptics have also been effective. Repeatedly exacerbated by emotions, and often change in character over time. In
flexing the baby at the neck and hips (the Vigevano maneuver) can patients with tics who have Tourette syndrome, there is often a family
abort the episodes. history of tics and/or obsessive compulsive disorder or personality
In other children after brain injury, and in many patients with cere- traits.
bral palsy, an exaggerated startle reflex can occur. This is more common
than hyperekplexia. In Tay-Sachs disease and similar gangliosidoses, Episodic Ataxias
exaggerated startle to sound occurs and has been, inappropriately, Episodic ataxia encompasses 7 clinically and genetically heterogeneous
interpreted as hyperacusis. syndromes, only 2 of which (types 1 and 2) have been described in a
large number of families. Type 1 is caused by mutations in the voltage-
Benign Paroxysmal Torticollis of Infancy gated potassium channel Kv1.1. It consists of brief episodes (seconds
This condition typically presents as morning episodes of painless ret- to minutes) of cerebellar ataxia, and occasional partial seizures with
rocollis, and later, torticollis, often triggered by changes in posture. interictal myokymia as a main diagnostic feature. Type 2 is character-
Attacks may start with abnormal ocular movements, and progress to ized by longer attacks (minutes to hours) and interictal cerebellar signs.
stillness in an abnormal posture. This usually lasts for minutes or hours It is caused by mutations in the voltage-gated calcium channel gene
and, at times, days. Neurologic exam between attacks, EEG, and neu- CACNA1A. This type is more responsive than type 1 to acetazolamide
roimaging are normal. It affects girls more than boys (3 : 1), often that reduces the frequency and severity of attacks, but not the interictal
begins before 3 mo of age, and spontaneously remits before the age of signs and symptoms.
5 yr. Medical therapy is not needed. It is considered to be a migraine
equivalent and cosegregates with migraine in families. Benign Myoclonus of Early Infancy, Shuddering
Attacks, and Chin Trembling
Sandifer Syndrome Benign myoclonus consists of myoclonic jerks of the extremities in
Gastroesophageal reflux in infants may cause paroxysmal episodes of wakefulness and sometimes also in sleep. It has been suggested by some
generalized stiffening and opisthotonic posturing that may be accom- that these attacks are in the same spectrum as shuddering attacks.
panied by apnea, staring, and minimal jerking of the extremities. Epi- Shuddering attacks are characterized by rapid tremor of the head,
sodes often occur 30 min after a feed. In older children, this syndrome shoulder, and trunk, lasting a few seconds, often associated with eating,
manifests with episodic dystonic or dyskinetic movements consisting and recurring many times a day. Others have considered shuddering
of latero-, retro-, or torticollis, the exact pathophysiology of which as an early manifestation of essential tremor as family history of essen-
remains elusive. tial tremor is often present. The clinical events in either of these can
be mistaken for infantile spasms, but ictal and interictal EEG, MRI,
Alternating Hemiplegia of Childhood and development are normal. Spontaneous remission occurs in both
This is a rare, often severe, disorder that consists of attacks of flaccid usually within a few months. Hereditary chin trembling at a fre-
hemiplegia affecting 1 or both sides lasting minutes to days, starting quency faster than 3 Hz starting shortly after birth and precipitated by
in the 1st 18 mo of life. Earlier manifestations include paroxysmal stress has been described in several families.
nystagmus, which is often monocular and ipsilateral to the hemiplegia. A novel type of nonepileptic attack with infantile onset characterized
Dystonic and tonic spells often occur and can be confused with sei- in 3 patients as clusters of repeated head drops, mimicking epileptic
zures and the hemiplegia with Todd paralysis. Attacks can be triggered negative myoclonus of the neck, accompanied by crying. The episodes
by bathing, cold, fatigue, hyperthermia, and emotional stress, and they occurred for 5 or 6 mo and disappeared by the end of the 1st yr. Lan-
remit during sleep and for about 15 minutes or so after waking up. guage and cognition were normal This is a different form of myoclonic
Most cases are caused by mutations in the ATP1A3 gene while, rarely, activity that may complicate the diagnosis of infantile spasms and West
a similar clinical picture can occur as a result of mutations in ATP1A2 syndrome; thorough EEG investigation is needed in such cases.
or in the glucose transporter 1 (GLUT1/SLC2AI) gene mutations. Flu-
narizine 2.5-15 mg/day reduces the frequency of the attacks. Most Brainstem Dysfunction
children ultimately develop ataxia, developmental delay, and persistent Decorticate or decerebrate posturing that mimics epileptic tonic
choreoathetosis. seizures may be secondary to decompensated hydrocephalus,
Table 594-3 Differential Diagnoses of Various Types of Paroxysmal Dyskinesia

Features PKD PNKD PNKD PED PHD
MR1+ MR1−
Nomenclature PKC PDC, FPC PDC, FPC PEDt ADNFLE
Inheritance AD–16q AD–2q35 AD–2q13 AD/AR AD–20q13, 15q24,
1q21, 8p21
Age at onset (yr) 1-20 <1-12 1-23 Usually childhood Usually childhood
Triggers Sudden whole-body Coffee, alcohol, Exercise After 10-15 minutes Sleep
movement stress of exercise
Clinical features Chorea, athetosis, Chorea, athetosis, Chorea, athetosis, Mainly leg dystonia Wakes up with
ballismus, dystonia dystonia, ballismus dystonia, ballismus dystonic posture
Usual duration <1-5 min 10 min to 1 hr 10 min to 2-3 hr 10-15 min <1 min
Frequency 1-20/day 1/week 1/week Unclear Several/night
Associations Infantile seizures, Migraine Epilepsy RE-PED-WC
migraine, writer’s
cramp, essential
tremor
Medication Carbamazepine Clonazepam Clonazepam Acetazolamide Carbamazepine
Phenytoin Benzodiazepine Benzodiazepine L-DOPA Oxcarbazepine
Oxcarbazepine
Prognosis Excellent Excellent, worse Minimally worse Poor medication Excellent
than PKD than PNKD MR1+ response
AD, autosomal-dominant; ADNFLE, autosomal-dominant nocturnal frontal lobe epilepsy; AR, autosomal-recessive; FPC, familial paroxysmal choreoathetosis; MR1+,
myofibrillogenesis regulator 1-positive; MR1−, myofibrillogenesis regulator 1-negative; PDC, paroxysmal dystonic choreoathetosis; PED, paroxysmal exercise-induced
dyskinesia; PEDt, paroxysmal exercise-induced dystonia; PHD, paroxysmal hypnogenic dyskinesia; PKC, paroxysmal kinesigenic choreoathetosis; PKD, paroxysmal
kinesigenic dyskinesia; PNKD, paroxysmal nonkinesigenic dyskinesia; RE-PED-WC, rolandic epilepsy–paroxysmal exercise-induced dystonia–writer’s cramp.
From Friedman NR, Ghosh D, Moodley M: Syncope and paroxysmal disorders other than epilepsy. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors:
Swaiman’s pediatric neurology, ed 5, Philadelphia, 2012, WB Saunders, Table 65-1.
hemorrhage, or other causes of sudden rises in intracranial pressure Hyperventilation spells can be precipitated by anxiety and are associ-
that lead to brainstem dysfunction. In addition, crowding of the ated with dizziness, tingling, and, at times, carpopedal spasm. Tran-
posterior fossa and near herniation, the so-called cerebellar fits can sient global amnesia consists of isolated short-term memory loss for
also lead to abnormal extensor posturing, drop attacks, and varying minutes to hours that occurs mostly in the elderly. The etiology can be
degrees of altered consciousness and respiratory compromise. Histori- epileptic, vascular, or drug related.
cally secondary to undiagnosed posterior fossa tumors in the preneu-
roimaging era, “cerebellar fits” mostly occur in the context of Chiari I OCULOMOTOR ABNORMALITIES AND
malformations. VISUAL HALLUCINATIONS
Paroxysmal Tonic Upgaze of Childhood
Psychologic Disorders This usually starts before 3 mo of age, and consists of protracted attacks
Many psychologic disorders can be mistaken for epileptic seizures. (hours to days) of continuous or episodic upward gaze deviation,
Pleasurable behavior similar to masturbation may occur from infancy during which horizontal eye movements are preserved. A downbeating
onward, and may consist of rhythmical rocking movement in a sitting nystagmus occurs on downward gaze. Symptoms are reduced or
or lying position, or rhythmic hip flexion and adduction. Masturba- relieved by sleep, exacerbated by fatigue and infections, and spontane-
tion may occur in girls 2-3 yr of age and is often associated with ously remit after a few years. Up to 50% of patients may have psycho-
perspiration, irregular breathing, and grunting, but no loss of con- motor and language delay. Imaging, laboratory, and neuropsychologic
sciousness. Occasionally this is associated with child abuse or with examinations are usually nonrevealing. Therapy with low-dose
other psychopathology. Stereotypies, or repetitive movements that are levodopa/carbidopa may be helpful.
more complex than tics and do not change and wax and wane like tics
(e.g., head banging, head rolling, body rocking, and hand flapping), Oculomotor Apraxia and Saccadic Intrusions
usually occur in neurologically impaired children. A mannerism is a In oculomotor apraxia saccadic eye movements are impaired. Sudden
pattern of socially acceptable, situational behavior that is seen in par- head turns compensating for lateral gaze impairment mimic seizures.
ticular situations such as gesturing when talking. Mannerisms should This disorder may be idiopathic (Cogan oculomotor apraxia) or may
not be confused with stereotypies which are generally pervasive over occur in the context of ataxia telangiectasia or lysosomal storage dis-
almost every other activity such as head-shaking or hand-flapping in eases. Genetic defects in DNA repair mechanisms have been impli-
multiple situations. Stereotypies, unlike mannerisms, increase with cated in at least 4 spinocerebellar ataxia disorders that are accompanied
stress. Unlike tics and mannerisms, stereotypies usually start before the by oculomotor apraxia. A selective loss of Purkinje cells required to
age of 3 yr, involve more body parts, are more rhythmic and most suppress omnipause neurons and initiate saccadic eye movement is
importantly occur with engrossment with an object or activity of inter- believed to occur in those disorders. Saccadic intrusions are involun-
est and do not have a premonitory urge that increases with attempts tary sudden conjugate eye movements away from the desired eye posi-
to suppress them as children rarely try to suppress stereotypies. Panic tion. These are not necessarily pathologic.
and anxiety attacks have been described in children; at times, these
may be clinically indistinguishable from actual epileptic seizures, and Spasmus Nutans
therefore may necessitate video-EEG monitoring. Rage attacks usually This disorder presents with a triad of nystagmus, head tilt, and head
occur in patients with personality disorder and are usually not seizures nodding. If diurnal fluctuation occurs, symptoms may look like epi-
although rare cases of partial seizures can manifest as rage attacks. leptic seizures. Brain MRI should be performed, as the triad has been
associated with masses in the optic chiasm and third ventricle. Retinal usually last for 10-15 min. Night terrors similarly occur a few hours
disease should also be ruled out. In the absence of these associations, after going to sleep in stage 3 or 4 of sleep, most often at 2-7 yr of age
remission occurs before 5 yr of age. and more so in boys. The child screams; appears terrified; has dilated
pupils, tachycardia, tachypnea, unresponsiveness, agitation, and
Opsoclonus Myoclonus Syndrome thrashing that increase with attempts to be consoled; is difficult to
The so-called dancing eyes refers to continuous, random, irregular, and arouse; and may have little or no vocalization. In older children with
conjugate eye movements that may fluctuate in intensity. They usually persistent night terrors, an underlying psychologic etiology may be
accompany myoclonus and ataxia (“dancing feet”). Encephalitis and present. Diagnosis is based on the history. However, rarely, video EEG
neuroblastoma are possible causes. Therapy is by treating the underly- monitoring may be needed. At times, the use of bedtime diazepam
ing etiology, but adrenocorticotropic hormone (ACTH), corticoste- (0.2-0.3 mg/kg) or clonazepam (0.01 mg/kg) may help control the
roids, and clonazepam may be needed. Rituximab has been studied and problem while psychologic factors are being investigated. Restless leg
preliminary trials suggest it may be effective as well. syndrome can cause painful leg dysesthesias that cause nocturnal
arousals and insomnia. It can be either genetic or associated with iron
Daydreaming and Behavioral Staring deficiency, systemic illness, or some drugs. Therapy depends upon
Staring may be a manifestation of absence seizures, which should be treating the underlying cause and, if needed, on dopaminergic drugs
differentiated from daydreaming, behavioral staring because of fatigue, such as levodopa/carbidopa, or antiepileptics like gabapentin.
and inattention. Episodes of staring only in certain settings (e.g.,
school) are unlikely to be seizures. In addition, responsiveness to stim- Rapid Eye Movement Sleep Disorders
ulation such as touch and lack of interruption of playing activity char- Nightmares and sleep paralysis are common disorders. Unlike night
acterizes nonepileptic staring. terrors, nightmares tend to occur later during the night and the child
has a memory of the event.
Visual Hallucinations
Visual perceptions in the absence of external stimuli, or visual hallu- Sleep Transition Disorders
cinations, are usually accompanied by other neurologic signs and Nocturnal head banging (jactatio capitis nocturna), rolling, or body
symptoms when they occur in the context of seizures. An exception is rocking often occurs in infants and toddlers as they are trying to fall
occipital seizures, which can manifest with isolated and unformed asleep. These usually remit spontaneously by 5 yr of age. No specific
visual hallucinations and may be accompanied by headache and therapy is needed.
nausea, making them difficult to differentiate from migraine. However,
occipital seizures are characterized by colorful, shapes, circles and Narcolepsy-Cataplexy Syndrome
spots lasting seconds and confined to 1 hemifield, while migrainous Narcolepsy is characterized by excessive daytime sleepiness, cataplexy,
auras usually last minutes, and consist of black-and-white lines, scoto- sleep paralysis, hypnogogic hallucinations, and disturbed nighttime
mas, and or fortification spectra that start in the center of vision. Hal- sleep. The persistence of rapid eye movement sleep atonia upon awak-
lucinations can also be secondary to drug exposure, midbrain lesions, ening or its intrusion during wakefulness lead to sleep paralysis or
and psychiatric illnesses. In addition, retinal-associated hallucinations cataplexy, respectively. Loss of tone in cataplexy occurs in response to
can occur in the form of flashes of light in the context of inflammatory strong emotions, and spreads from the face downwards leading to a
etiologies, trauma, or optic nerve edema. fall in a series of stages rather than a sudden one. Consciousness is
maintained in cataplexy. A selective loss of hypocretin-secreting
SLEEP DISORDERS neurons in the hypothalamus is at the origin of this disorder. The fact
Paroxysmal nonepileptic sleep events are more common in epileptic that DQB1*0602 is a predisposing HLA allele identified in 85-95% of
patients than in the general population, which makes their diagnosis patients with narcolepsy-cataplexy suggests an autoimmune-mediated
difficult. Semiology, timing of events, and if needed video-EEG and neuronal loss. Diagnosis is based on the multiple sleep latency test,
polysomnography help in distinguishing epileptic from nonepileptic and therapy relies on scheduled naps, amphetamines, methylpheni-
events. Parasomnias typically occur less than once or twice a night; date, tricyclic antidepressants, and counseling about precautions in
more frequent episodes suggest epileptic seizures. Of note, the EEG work and driving.
pattern of frontal lobe epileptic seizures may be similar to the one seen
in a normal arousals, making their diagnosis challenging, especially Bibliography is available at Expert Consult.
that they have nonspecific hypermotor manifestations such as thrash-
ing, body rocking, kicking, boxing, pedaling, bending, running, and
various vocalizations. The diagnosis of such epileptic seizures is made
on the basis of highly stereotyped events arising several times a night
from nonrapid eye movement sleep.
Benign Sleep Myoclonus and

Neonatal Sleep Myoclonus
Neonatal sleep myoclonus consists of repetitive, usually bilateral rhyth-
mic jerks involving the upper and lower limbs during nonrapid eye
movement sleep, sometimes mimicking clonic seizures. A slow (1 Hz)
rocking of the infant in a head-to-toe direction is a specific diagnostic
test that may reproduce the myoclonus. The lack of autonomic changes,
occurrence only in sleep, and suppression by awakenings may help in
differentiating these events from epileptic seizures. Remission is spon-
taneous at 2-3 mo of age. In older children and adults, sleep myoclonus
consists of random myoclonic jerks of the limbs.
Nonrapid Eye Movement Partial

Arousal Disorders
Brief nocturnal confusional arousals occurring 1-2 hr after sleep in
stage 4 sleep are normal in children. Such episodes can vary from
chewing, sitting up, and mumbling to agitated sleep walking, and
Chapter 594 ◆ Conditions That Mimic Seizures 2863.e1
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Abriel H, Zaklyazminskaya EV: Cardiac channelopathies: genetic and molecular channel mutations, Curr Neurol Neurosci Rep 12(1):76–83, 2012.
mechanisms, Gene 517(1):1–11, 2013. DiMario FJ Jr: Paroxysmal nonepileptic events of childhood, Semin Pediatr Neurol
Armangue T, Petit-Pedrol M, Dalmau J: Autoimmune encephalitis in children, 13:208–221, 2006.
J Child Neurol 27(11):1460–1469, 2012. Dreissen YE, Tijssen MA: The startle syndromes: physiology and treatment,
Capovilla G, Montagnini A, Peruzzi C, et al: Head atonic attacks: a new type of Epilepsia 53(Suppl 7):3–11, 2012.
benign non-epileptic attack in infancy strongly mimicking epilepsy, Epileptic Heinzen EL, Swoboda KJ, Hitomi Y, et al: De novo mutations in ATP1A3 cause
Disord 15(1):44–48, 2013. alternating hemiplegia of childhood, Nat Genet 44(9):1030–1034, 2012.
Crompton DE, Berkovic SF: The borderland of epilepsy: clinical and molecular Kotagal S, Chopra A: Pediatric sleep-wake disorders, Neurol Clin 30(4):1193–1212,
features of phenomena that mimic epileptic seizures, Lancet Neurol 8(4):370– 2012.
381, 2009. Vendrame M, Kothare SV: Epileptic and nonepileptic paroxysmal events out of
Cross JH: Differential diagnosis of epileptic seizures in infancy including the sleep in children, J Clin Neurophysiol 28(2):111–119, 2011.
neonatal period, Semin Fetal Neonatal Med 18:192–195, 2013.
Chapter 595 ◆ Headaches 2863
Chapter 595
Headaches
Andrew D. Hershey,
Marielle A. Kabbouche, and
Hope L. O’Brien
Headache is a common complaint in children and adolescents. Head-

aches can be a primary problem or occur as a symptom of another
disorder, representing a secondary problem. Recognizing this differ-
ence is essential for choosing the appropriate evaluation and treatment
to ensure successful management of the headache. Primary headaches
are most often recurrent, episodic headaches and for most children are
sporadic in their presentation.
The most common forms of primary headache of childhood are
migraine and tension-type headaches (Table 595-1). Other forms of
Table 595-1 Classification of Headaches (ICHD-3 Beta Code Diagnosis)

MIGRAINE HEADACHE ATTRIBUTED TO CRANIAL OR CERVICAL
Migraine with or without aura VASCULAR DISORDER
Migraine with typical aura (with or without headache) Headache attributed to ischemic stroke or transient ischemic attack
Migraine with brainstem aura Headache attributed to nontraumatic intracerebral hemorrhage
Hemiplegic migraine (sporadic or familial types 1, 2, 3, or other Headache attributed to nontraumatic subarachnoid hemorrhage (SAH)
genetic loci) Headache attributed to nontraumatic acute subdural hemorrhage
Retinal migraine (ASDH)
Chronic migraine Headache attributed to unruptured vascular malformation
Complications of Migraine Headache attributed to unruptured saccular aneurysm
Status migrainosus Headache attributed to arteriovenous malformation (AVM)
Persistent aura without infarction Headache attributed to dural arteriovenous fistula (DAVF)
Migrainous infarction Headache attributed to cavernous angioma
Migraine aura-triggered seizure Headache attributed to encephalotrigeminal or leptomeningeal
Episodic Syndromes That May Be Associated with Migraine angiomatosis (Sturge-Weber syndrome)
Recurrent gastrointestinal disturbance Headache attributed to arteritis
Cyclical vomiting syndrome Headache attributed to giant cell arteritis (GCA)
Abdominal migraine Headache attributed to primary angiitis of the central nervous system
Benign paroxysmal vertigo (PACNS)
Benign paroxysmal torticollis Headache attributed to secondary angiitis of the central nervous
system (SACNS)
TENSION-TYPE HEADACHE (TTH) Headache attributed to cervical carotid or vertebral artery disorder
Infrequent episodic tension-type headache associated with or without Headache or facial or neck pain attributed to cervical carotid or
pericranial tenderness vertebral artery dissection
Frequent episodic tension-type headache associated with or without Post-endarterectomy headache
pericranial tenderness Headache attributed to carotid or vertebral angioplasty
Chronic tension-type headache associated with or without pericranial Headache attributed to cerebral venous thrombosis (CVT)
tenderness Headache attributed to other acute intracranial arterial disorder
Probable tension-type headaches Headache attributed to an intracranial endovascular procedure
TRIGEMINAL AUTONOMIC CEPHALALGIAS (TACS) Angiography headache
Cluster headache (episodic or cluster) Headache attributed to reversible cerebral vasoconstriction syndrome
Paroxysmal hemicrania (episodic or cluster) (RCVS)
Short-lasting unilateral neuralgiform headache attacks with or without Headache attributed to intracranial arterial dissection
conjunctival injection and tearing (SUNCT) Headache attributed to genetic vasculopathy
Episodic SUNCT Cerebral autosomal dominant arteriopathy with subcortical infarcts
Chronic SUNCT and leukoencephalopathy (CADASIL)
Short-lasting unilateral neuralgiform headache attacks with or without Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
cranial autonomic symptoms (SUNA) (MELAS)
Episodic SUNA Headache attributed to another genetic vasculopathy
Chronic SUNA Headache attributed to pituitary apoplexy
Hemicrania continua HEADACHE ATTRIBUTED TO NONVASCULAR INTRACRANIAL
Probable trigeminal autonomic cephalalgias DISORDER
OTHER PRIMARY HEADACHE DISORDERS Headache attributed to increased cerebrospinal fluid pressure
Primary cough headache Headache attributed to idiopathic intracranial hypertension (IIH)
Primary exercise headache Headache attributed to intracranial hypertension secondary to
Primary headache associated with sexual activity metabolic, toxic, or hormonal causes
Primary thunderclap headache Headache attributed to intracranial hypertension secondary to
Cold-stimulus headache (external application, ingestion, or inhalation) hydrocephalus
External-pressure headache Headache attributed to low cerebrospinal fluid pressure
External-compression headache Postdural puncture headache
External-traction headache Cerebrospinal fluid fistula headache
Primary stabbing headache Headache attributed to spontaneous intracranial hypotension
Nummular headache Headache attributed to noninfectious inflammatory disease
Hypnic headache Headache attributed to neurosarcoidosis
New daily persistent headache (NDPH) Headache attributed to aseptic (noninfectious) meningitis
Headache attributed to other noninfectious inflammatory disease
HEADACHE ATTRIBUTED TO TRAUMA OR INJURY TO Headache attributed to lymphocytic hypophysitis
THE HEAD AND/OR NECK Syndrome of transient headache and neurological deficits with
Acute headache attributed to traumatic (mild, moderate, or severe) cerebrospinal fluid lymphocytosis (HaNDL)
injury to the head Headache attributed to intracranial neoplasm
Persistent headache attributed to traumatic (mild, moderate, or Headache attributed to colloid cyst of the third ventricle
severe) injury to the head Headache attributed to carcinomatous meningitis
Acute or persistent headache attributed to whiplash Headache attributed to hypothalamic or pituitary hyper- or
Acute or persistent headache attributed to craniotomy hyposecretion
Headache attributed to intrathecal injection
Headache attributed to epileptic seizure
Hemicrania epileptica
Postictal headache
Headache attributed to Chiari malformation type I (CM1)
Headache attributed to other nonvascular intracranial disorder
Table 595-1 Classification of Headaches (ICHD-3 Beta Code Diagnosis)—cont’d

HEADACHE ATTRIBUTED TO A SUBSTANCE OR ITS WITHDRAWAL HEADACHE OR FACIAL PAIN ATTRIBUTED TO DISORDER OF THE
Headache attributed to use of or exposure to a substance CRANIUM, NECK, EYES, EARS, NOSE, SINUSES, TEETH, MOUTH,
Nitric oxide (NO) donor-induced headache OR OTHER FACIAL OR CERVICAL STRUCTURE
Phosphodiesterase (PDE) inhibitor-induced headache Headache attributed to disorder of cranial bone
Carbon monoxide (CO)-induced headache Headache attributed to retropharyngeal tendonitis
Alcohol-induced headache Headache attributed to craniocervical dystonia
Monosodium glutamate (MSG)-induced headache Headache attributed to acute glaucoma
Cocaine-induced headache Headache attributed to refractive error
Histamine-induced headache Headache attributed to heterophoria or heterotropia (latent or
Calcitonin gene-related peptide (CGRP)-induced headache persistent squint)
Headache attributed to exogenous acute pressor agent Headache attributed to ocular inflammatory disorder
Headache attributed to occasional or long-term use of nonheadache Headache attributed to trachelitis
medication Headache attributed to disorder of the ears
Headache attributed to exogenous hormone Headache attributed to acute or chronic or recurring rhinosinusitis
Medication-Overuse Headache (MOH) Headache attributed to temporomandibular disorder (TMD)
Ergotamine-overuse headache Head or facial pain attributed to inflammation of the stylohyoid
Triptan-overuse headache ligament
Simple analgesic-overuse headache Headache or facial pain attributed to other disorder of cranium, neck,
Paracetamol (acetaminophen)-overuse headache eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical
Acetylsalicylic acid-overuse headache structure
Other non-steroidal antiinflammatory drug (NSAID)-overuse headache
HEADACHE ATTRIBUTED TO PSYCHIATRIC DISORDER
Opioid-overuse headache
Combination analgesic-overuse headache Headache attributed to somatization disorder
Headache attributed to psychotic disorder
Headache Attributed to Substance Withdrawal
Caffeine-withdrawal headache PAINFUL CRANIAL NEUROPATHIES AND OTHER FACIAL PAINS
Opioid-withdrawal headache Classical trigeminal neuralgia
Estrogen-withdrawal headache Classical trigeminal neuralgia, purely paroxysmal or with concomitant
persistent facial pain
HEADACHE ATTRIBUTED TO INFECTION
Painful trigeminal neuropathy
Acute or chronic headache attributed to bacterial meningitis or
Painful trigeminal neuropathy attributed to acute herpes zoster
meningoencephalitis
Postherpetic trigeminal neuropathy
Persistent headache attributed to past bacterial meningitis or
Painful posttraumatic trigeminal neuropathy
meningoencephalitis
Painful trigeminal neuropathy attributed to multiple sclerosis (MS)
Acute or chronic headache attributed to intracranial fungal or other
plaque
parasitic infection
Painful trigeminal neuropathy attributed to space-occupying lesion
Headache attributed to brain abscess
Painful trigeminal neuropathy attributed to other disorder
Headache attributed to subdural empyema
Glossopharyngeal neuralgia
Headache attributed to systemic infection (acute or chronic)
Classical nervus intermedius (facial nerve) neuralgia
HEADACHE ATTRIBUTED TO DISORDER OF HOMEOSTASIS Nervus intermedius neuropathy attributed to herpes zoster
Headache attributed to hypoxia and/or hypercapnia Occipital neuralgia
High-altitude headache Optic neuritis
Headache attributed to airplane travel Headache attributed to ischemic ocular motor nerve palsy
Diving headache Tolosa-Hunt syndrome
Sleep apnea headache Paratrigeminal oculosympathetic (Raeder) syndrome
Dialysis headache Recurrent painful ophthalmoplegic neuropathy
Headache attributed to arterial hypertension Burning mouth syndrome (BMS)
Headache attributed to pheochromocytoma Persistent idiopathic facial pain (PIFP)
Headache attributed to hypertensive crisis with or without Central neuropathic pain
hypertensive encephalopathy Central neuropathic pain attributed to multiple sclerosis (MS)
Headache attributed to preeclampsia or eclampsia Central post-stroke pain (CPSP)
Headache attributed to autonomic dysreflexia
Headache attributed to hypothyroidism
Headache attributed to fasting
Cardiac cephalalgia
Headache attributed to other disorder of homoeostasis
From Headache Classification Committee on the International Headache Society (IHS): The International Classification of Headache Disorders, ed 3 (beta version).
Cephalalgia 33(9):629–808, 2013.
primary headache, including the trigeminal autonomic cephalalgias, when 2 or more common conditions occur in close temporal associa-
occur much less commonly. Primary headache can progress to very tion. This frequently leads to the misdiagnosis of a primary headache
frequent or even daily headaches with chronic migraine and chronic as a secondary headache. This is, for example, the case when migraine
tension-type headaches being increasingly recognized. These more fre- is misdiagnosed as a sinus headache. In general, the key components
quent headaches can have an enormous impact on the life of the child of a secondary headache are the likely direct cause-and-effect relation-
and adolescent, as reflected in school absences and decreased school ship between the headache and the precipitating condition, and the
performance, social withdrawal, and changes in family interactions. To lower likelihood in a specific patient and circumstance of the head-
reduce this impact, a treatment strategy that incorporates acute treat- aches being the result of a recurrent headache disorder. In addition,
ments, preventive treatments, and biobehavioral therapies must be once the underlying suspected cause is treated, the secondary headache
implemented. should resolve. If this does not occur, either the diagnosis must be
Secondary headache involves headaches that are a symptom of an reevaluated or the effectiveness of the treatment reassessed. One key
underlying illness (see Table 595-1). The underlying illness should be clue that additional investigation is warranted is the presence of an
clearly present as a direct cause of the headaches. This is often difficult abnormal neurologic examination or unusual neurologic symptoms.
595.1 Migraine Table 595-4 Migraine with Brainstem Aura

Andrew D. Hershey, Marielle A. Kabbouche,
A. At least 2 attacks fulfilling criteria B to D
and Hope L. O’Brien B. Aura consisting of visual, sensory and/or speech/language
symptoms, each fully reversible, but no motor or retinal
Migraine is the most frequent type of recurrent headache that is symptoms
brought to the attention of parents and primary care providers, but it C. At least 2 of the following brainstem symptoms:
remains underrecognized and undertreated, particularly in children. 1. Dysarthria
Migraine is characterized by episodic attacks that may be moderate to 2. Vertigo
severe in intensity, focal in location on the head, have a throbbing 3. Tinnitus
4. Hypacusis
quality, and may be associated with nausea, vomiting, light sensitivity,
5. Diplopia
and sound sensitivity. Compared to adults, pediatric migraine is 6. Ataxia
shorter in duration and has a bilateral, often bifrontal, location. 7. Decreased level of consciousness
Migraine can also be associated with an aura that may be typical D. At least 2 of the following 4 characteristics:
(visual, sensory, or dysphasic) or atypical (i.e., hemiplegic, “Alice 1. At least 1 aura symptom spreads gradually over 5 or more
in Wonderland” syndrome) (Tables 595-2 to 595-6). In addition, a minutes, and/or 2 or more symptoms occur in succession
number of migraine variants have been described and, in children, 2. Each individual aura symptom lasts 5-60 minutes
include abdominal related symptoms without headache, and compo- 3. At least 1 aura symptom is unilateral
nents of the painless periodic syndromes of childhood (see Table 595- 4. The aura is accompanied, or followed within 60 minutes, by
headache
1). Treatment of migraine requires the incorporation of an acute
E. Not better accounted for by another ICHD-3 diagnosis, and
treatment plan, a preventive treatment plan if the migraine occurs transient ischemic attack has been excluded.
frequently or is disabling, and a biobehavioral plan to help cope with
both the acute attacks and frequent or persistent attacks if present. From Headache Classification Committee on the International Headache
Society (IHS): The International Classification of Headache Disorders, ed 3 (beta
version). Cephalalgia 33(9):629–808, 2013, Table 7.
EPIDEMIOLOGY
Up to 75% of children report having a significant headache by the time
they are 15 yr old. Recurrent headaches are less common, but remain
highly frequent. Migraine has been reported to occur in up to 10.6%
of children between the ages of 5 and 15 yr, and up to 28% of older
Table 595-5 Vestibular Migraine with Vertigo
A. At least 5 episodes fulfilling criteria C and D
Table 595-2 Migraine Without Aura B. A current or past history of 1.1 Migraine without aura or 1.2
Migraine with aura
A. At least 5 attacks fulfilling criteria B to D C. Vestibular symptoms of moderate or severe intensity, lasting
B. Headache attacks lasting 4-72 hr (untreated or unsuccessfully between 5 min and 72 hr
treated) D. At least 50% of episodes are associated with at least 1 of the
C. Headache has at least 2 of the following 4 characteristics: following 3 migrainous features:
1. Unilateral location 1. Headache with at least 2 of the following 4 characteristics:
2. Pulsating quality a. Unilateral location
3. Moderate or severe pain intensity b. Pulsating quality
4. Aggravation by or causing avoidance of routine physical c. Moderate or severe intensity
activity (e.g., walking or climbing stairs) d. Aggravation by routine physical activity
D. During headache at least 1 of the following: 2. Photophobia and phonophobia
1. Nausea and/or vomiting 3. Visual aura
2. Photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis or by
E. Not better accounted for by another ICHD-3 diagnosis another vestibular disorder
From Headache Classification Committee on the International Headache From Headache Classification Committee on the International Headache
Society (IHS): The International Classification of Headache Disorders, ed 3 (beta Society (IHS): The International Classification of Headache Disorders, ed 3 (beta
version). Cephalalgia 33(9):629–808, 2013, Table 4. version). Cephalalgia 33(9):629–808, 2013 (Table 8).
Table 595-3 Migraine with Typical Aura Table 595-6 Chronic Migraine
A. At least 2 attacks fulfilling criteria B and C A. Headache (tension-type-like and/or migraine-like) on 15 or
B. Aura consisting of visual, sensory and/or speech/language more days per month for more than 3 mo and fulfilling criteria B
symptoms, each fully reversible, but no motor, brainstem or and C
retinal symptoms B. Occurring in a patient who has had at least 5 attacks fulfilling
C. At least 2 of the following 4 characteristics: criteria B to D for 1.1 Migraine without aura and/or criteria B and
1. At least 1 aura symptom spreads gradually over 5 or more C for 1.2 Migraine with aura
minutes, and/or 2 or more symptoms occur in succession C. On 8 or more days per month for more than 3 mo, fulfilling any
2. Each individual aura symptom lasts 5-60 minutes of the following:
3. At least 1 aura symptom is unilateral 1. Criteria C and D for 1.1 Migraine without aura
4. The aura is accompanied, or followed within 60 minutes, by 2. Criteria B and C for 1.2 Migraine with aura
headache 3. Believed by the patient to be migraine at onset and relieved
D. Not better accounted for by another ICHD-3 diagnosis, and by a triptan or ergot derivative
transient ischemic attack has been excluded D. Not better accounted for by another ICHD-3 diagnosis
From Headache Classification Committee on the International Headache From Headache Classification Committee on the International Headache
Society (IHS): The International Classification of Headache Disorders, ed 3 Society (IHS): The International Classification of Headache Disorders, ed 3
(beta version). Cephalalgia 33(9):629–808, 2013, Table 6. (beta version). Cephalalgia 33(9):629–808, 2013, Table 9.
adolescents. When the headaches become frequent, they convert into diagnosis of a gastrointestinal disorder is no longer appropriate. When
chronic daily headaches in up to 1% of children. When headaches are headache is present, vomiting raises the concern of a secondary head-
occurring more than 15 days a month the risk of conversion to a daily ache, particularly related to increased intracranial pressure. One of the
headache becomes more prominent. This explains the necessity to treat red flags for this is the daily or near daily early morning vomiting, or
the headaches aggressively or prevent the headaches altogether, trying headaches waking the child up from sleep. When the headaches associ-
to block transformation to chronic daily headaches. ated with vomiting episodes are sporadic and not worsening, it is more
Migraine can impact a patient’s life through school absences, limita- likely that the diagnosis is migraine. Vomiting and headache caused by
tion of home activities, and restriction of social activities. As headaches increased intracranial pressure are frequently present on first awaken-
become more frequent, their negative impact increases in magnitude. ing and remit with maintenance of upright posture. In contrast, if a
This can lead to further complications including anxiety and school migraine is present on first awakening (a relatively infrequent occur-
avoidance, requiring a more extensive treatment plan. rence in children), getting up and going about normal, upright activities
usually makes the headache and vomiting worse.
CLASSIFICATION AND CLINICAL As the child matures, light and sound sensitivity (photophobia and
MANIFESTATIONS phonophobia) may become more apparent. This is either by direct
Criteria have been established to guide the clinical and scientific study report of the patient, or the interpretation by the parents of the child’s
of headaches; these are summarized in The International Classification activity. These symptoms are likely a component of the hypersensitivity
of Headache Disorders, 3rd edition (ICHD-3 beta). Table 595-1 con- that develops during an acute migraine attack and may also include
trasts the different clinical types of migraine; Tables 595-2 to 595-6 list smell sensitivity (osmophobia) and touch sensitivity (cutaneous allo-
the specific criteria for migraine types. dynia with central sensitization). Although only the photophobia and
phonophobia are components of the ICHD-3 beta criteria, these other
Migraine Without Aura symptoms are helpful in confirming the diagnosis and may be helpful
Migraine without aura is the most common form of migraine in both in understanding the underlying pathophysiology and determining the
children and adults. The ICHD-3 beta (see Table 595-2) requires this response to treatment. The final ICHD-3 beta requirement is the exclu-
to be recurrent (at least 5 headaches that meet the criteria, but there is sion of causes of secondary headaches, and this should be an integral
no time limit over which this must occur). The recurrent episodic component of the headache history.
nature helps differentiate this from a secondary headache, as well as Migraine typically runs in families with reports up to 90% of chil-
separates migraine from tension-type headache, but may limit the diag- dren having a 1st- or 2nd-degree relative with recurrent headaches.
nosis in children as they may just be beginning to have headaches. Given the underdiagnosis and misdiagnosis in adults, this is often not
The duration of the headache is defined as 4-72 hr for adults. It recognized by the family and a headache family history is required.
has been recognized that children may have shorter-duration head- When a family history is not identified, this may be the result of either
aches, so an allowance has been made to reduce this duration to a lack of awareness of migraine within the family or an underlying
2-72 hr or 1-72 hr with diary confirmation. Note that this duration secondary headache in the child. Any child whose family, upon close
is for the untreated or unsuccessfully treated headache. Furthermore, and both direct and indirect questioning, does not include individuals
if the child falls asleep with the headache, the entire sleep period is with migraine or related syndromes (e.g., motion sickness, cyclic vom-
considered part of the duration. These duration limits help differenti- iting, menstrual headache) should have an imaging procedure per-
ate migraine from both short-duration headaches, including the formed to look for anatomic etiologies for headache.
trigeminal autonomic cephalalgias, and prolonged headaches, like In addition to the classifying features, there may additional markers
those caused by idiopathic intracranial hypertension (pseudotumor of a migraine disorder. These include such things as triggers (skipping
cerebri). Some prolonged headaches may still be migraine, but a meals, inadequate or irregular sleep, dehydration and weather changes
migraine that persists beyond 72 hr is classified as a variant termed are the most common), pattern recognition (associated with menstrual
status migrainosus. periods in adolescents or Monday-morning headaches resulting from
The quality of migraine pain is often, but not always, throbbing or changes in sleep patterns over the weekend and nonphysiologic early
pounding. This may be difficult to elicit in young children and draw- waking on Monday mornings for school), and premonitory symptoms
ings or demonstrations may help confirm the throbbing quality. (a feeling of irritability, tiredness, and food cravings prior to the start
The location of the pain has classically been described as unilateral of the headache). Although these additional features may not be con-
(hemicrania); in young children it is more commonly bilateral. A sistent, they do raise the index of suspicion for migraine and provide
more appropriate way to think of the location would therefore be a potential mechanism of intervention. In the past, food triggers were
focal, to differentiate it from the diffuse pain of tension-type head- considered widely common, but the majority have either been discred-
aches. Of particular concern is the exclusively occipital headache ited with scientific study or represent such a small number of patients
because although these can be migraines, they are more frequently that they only need to be addressed when consistently triggering the
secondary to another more proximate etiology such as posterior fossa headache.
abnormalities.
Migraine, when allowed to fully develop, often worsens in the face Migraine with Aura
of and secondarily results in altered activity level. For example, worsen- The aura associated with migraine is a neurologic warning that a
ing of the pain occurs classically in adults when going up or down migraine is going to occur. In the common forms this can be the start
stairs. This history is often not elicited in children. A change in the of a typical migraine or a headache without migraine, or it may even
child’s activity pattern can be easily observed as a reduction in play or occur in isolation. For a typical aura, the aura needs to be visual,
physical activity. Older children may limit or restrict their sports activ- sensory, or dysphasic, lasting longer than 5 min and less than 60 min
ity or exercise during a headache attack. with the headache starting within 60 min (see Table 595-3). The
Migraine may have a variety of associated symptoms. In younger importance of the aura lasting longer than 5 min is to differentiate the
children, nausea and vomiting may be the most obvious symptoms and migraine aura from a seizure with a postictal headache, while the
often outweigh the headache itself. This often leads to the overlap with 60 min maximal duration is to separate migraine aura from the pos-
several of the gastrointestinal periodic diseases, including recurrent sibility of a more prolonged neurologic event such as a transient isch-
abdominal pain, recurrent vomiting, cyclic vomiting, and abdominal emic attack.
migraine. The common feature among all of these related conditions The most common type of visual aura in children and adolescents
is an increased propensity among children with them for the later is photopsia (flashes of light or light bulbs going off everywhere). These
development of migraine. Oftentimes, early childhood recurrent vom- photopsias are often multicolored and when gone, the child may report
iting may in fact be migraine, but the child is not asked about or is not being able to see where the flash occurred. Less likely in children
unable to describe headache pain. Once this becomes clear, the earlier are the typical adult auras including fortification spectra (brilliant white
zigzag lines resembling a starred pattern castle) or shimmering scotoma sleep disorders (sleepwalking, sleeptalking, and night terrors), unex-
(sometimes described as a shining spot that grows or a sequined plained recurrent fevers, and even seizures.
curtain closing). In adults, the auras typically involve only half the The gastrointestinal symptoms span the spectrum from the relatively
visual field, whereas in children they may be randomly dispersed. mild (motion sickness on occasional long car rides) to severe episodes
Blurred vision is often confused as an aura but is difficult to separate of uncontrollable vomiting that may lead to dehydration and the need
from photophobia or difficulty concentrating during the pain of the for hospital admission to receive fluids. These latter episodes may occur
headache. on a predictable time schedule and hence have been called cyclic vom-
Sensory auras are less common. They typically occur unilaterally. iting. During these attacks, the child may appear pale and frightened
Many children describe this sensation as insects are worms crawling but does not lose consciousness. After a period of deep sleep, the child
from their hand, up their arm to their face with a numbness following awakens and resumes normal play and eating habits as if the vomiting
this sensation. Once the numbness occurs, the child may have difficulty had not occurred. Many children with cyclic vomiting have a positive
using the arm as they have lost sensory input, and a misdiagnosis of family history of migraine, and as they grow older have a higher than
hemiplegic migraine may be made. average likelihood of developing migraine. Cyclic vomiting may be
Dysphasic auras are the least-common type of typical aura and have responsive to migraine-specific therapies with careful attention to fluid
been described as an inability or difficulty to respond verbally. The replacement if the vomiting is excessive. Cyclic vomiting of migraine
patient afterwards will describe an ability to understand what is being must be differentiated from gastrointestinal disorders including intes-
asked, but cannot answer back. This may be the basis of what in the tinal obstruction (malrotation, intermittent volvulus, duodenal web,
past has been referred to as confusional migraine and special attention duplication cysts, superior mesenteric artery compression, and internal
needs to be paid to asking the child about this possibility and their hernias), peptic ulcer, gastritis, giardiasis, chronic pancreatitis, and
degree of understanding during the initial phases of the attack. Most Crohn disease. Abnormal gastrointestinal motility and pelviureteric
of the time, these episodes are described as a motor aphasia and they junction obstruction can also cause cyclic vomiting. Metabolic causes
are often associated with sensory or motor symptoms. include disorders of amino acid metabolism (heterozygote ornithine
Much less commonly, atypical forms of aura can occur, including transcarbamylase deficiency), organic acidurias (propionic acidemia,
hemiplegia (true weakness, not numbness, and may be familial), methylmalonic acidemia), fatty acid oxidation defects (medium-chain
vertigo or lower cranial nerve symptoms (basilar-type, formerly acyl-coenzyme A dehydrogenase deficiency), disorders of carbohy-
thought to be caused by basilar artery dysfunction, now thought to be drate metabolism (hereditary fructose intolerance), acute intermittent
more brainstem based) (see Table 595-4), and distortion (“Alice in porphyria, and structural central nervous system lesions (posterior
Wonderland” syndrome). Whenever these rarer forms of aura are fossa brain tumors, subdural hematomas or effusions). The diagnosis
present, further investigation is warranted. Not all motor auras can be is a diagnosis of exclusion and children will need a full work up prior
classified as hemiplegic migraine spectrum and they should be differ- to be labeled of cyclic vomiting syndrome. Cyclic vomiting syndrome
entiated from those very specific migrainous events, as the diagnosis is more frequent in younger children and will gradually transform into
of hemiplegic migraine has genetic, pathophysiologic, and therapeutic a typical migraine attack by puberty.
implications. The diagnosis of abdominal migraine can be confusing but can be
Hemiplegic migraine is one of the better known forms of rare auras. thought of as a migraine without the headache. Like a migraine, it is
This transient unilateral weakness usually lasts only a few hours but an episodic disorder characterized by midabdominal pain with pain-
may persist for days. Both familial and sporadic forms have been free periods between attacks. At times this pain is associated with
described. The familial hemiplegic migraine is an autosomal dominant nausea and vomiting (thus crossing into the recurrent abdominal pain
disorder with mutations described in 3 separate genes: (1) CACNA1A, or cyclic vomiting spectrum). The pain is usually described as “dull”
(2) ATP1A2, and (3) SCN1A. Some patients with familial hemiplegic and may be moderate to severe. The pain may persist from 1-72 hr and,
migraine have other yet-to-be-identified genetic mutations. Multiple although usually midline, may be periumbilical or poorly localized by
polymorphisms have been described for these genes. Hemiplegic the child. To meet the criteria of abdominal migraine, the child must
migraines may be triggered by minor head trauma, exertion, or emo- complain at the time of the abdominal pain of at least 2 of the follow-
tional stress. The motor weakness is usually associated with another ing: anorexia, nausea, vomiting, or pallor. As with cyclic vomiting, a
aura symptom and may progress slowly over 20-30 min first with visual thorough history and physical examination with appropriate labora-
and then followed in sequence by sensory, motor, aphasic, and then tory studies must be completed to rule out an underlying gastrointes-
basilar auras. Headache is present in more than 95% of patients and tinal disorder as a cause of the abdominal pain. Careful questioning
usually begins during the aura; headache may be unilateral or bilateral about the presence of headache or head pain needs to be addressed
and may have no relationship to the motor weakness. Some patients directly with the child, as many times this is truly a migraine, but in
may develop attacks of coma with encephalopathy, cerebrospinal fluid the child’s mind (as well as the parents’ observation) the abdominal
(CSF) pleocytosis, and cerebral edema. Long-term complications may symptoms are paramount.
include seizures, repetitive daily episodes of blindness, cerebellar signs
with the development of cerebellar atrophy, and mental retardation. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Basilar-type migraine was formerly considered a disease of the A thorough history and physical examination including a neurologic
basilar artery as many of the unique symptoms were attributed to examination with special focus on headache has been shown to be the
dysfunction in this area of the brainstem. Some of the symptoms most sensitive indicator of an underlying etiology. The history needs
described include vertigo, tinnitus, diplopia, blurred vision, scotoma, to include a thorough evaluation of the premonitory symptoms, any
ataxia, and an occipital headache. The pupils may be dilated, and ptosis potential triggering events or timing of the headaches, associated neu-
may be evident. rologic symptoms, and a detailed characterization of the headache
Syndrome of transient headache and neurological deficits with attacks, including frequency, severity, duration, associated symptoms,
CSF lymphocytosis (HaNDL) describes transient headaches associ- use of medication, and disability. The disability assessment should
ated with neurologic deficits, and CSF showing pleocytosis. It is con- include the impact on school, home, and social activities and can easily
sidered a self-limited migraine-like syndrome, and is rarely reported be assessed with tools such as PedMIDAS. Family history of headaches
in the pediatric population. and any other neurologic, psychiatric, and general health conditions is
Childhood periodic syndromes are a group of potentially related also important both for identification of migraine within the family as
symptoms that occur with increased frequency in children with well as the identification of possible secondary headache disorders. The
migraine. The hallmark of these symptoms is the recurrent episodic familial penetrance of migraine is so robust that the absence of a family
nature of the events. Some of these have included gastrointestinal- history of migraine or its equivalent phenomena should trigger obtain-
related symptoms (motion sickness, recurrent abdominal pain, recur- ing of an imaging procedure. When headaches are refractory, a history
rent vomiting including cyclic vomiting, and abdominal migraine), of potential comorbid conditions, which includes mood disorders and
illicit substance use, especially in teenagers, that may influence adher- 4. Avoidance of acute headache medication escalation
ence and acceptability of the treatment plan, may also need to be 5. Education and enabling of patients to manage their disease to
addressed. enhance personal control of their migraine
Neuroimaging is warranted when the neurologic examination is 6. Reduction of headache-related distress and psychologic
abnormal or unusual neurologic features occur during the migraine; symptoms
when the child has headaches that awaken the child from sleep or that
are present on first awakening and remit with upright posture; when
the child has brief headaches that only occur with cough or bending
over; when the headache is mostly in the occipital area; and when the Table 595-7 Indications for Neuroimaging in a Child
child has migrainous headache with an absolutely negative family with Headaches
history of migraine or its equivalent (e.g., motion sickness, cyclic vom-
iting; Table 595-7). In this case, an MRI is the imaging of choice as it Abnormal neurologic examination
Abnormal or focal neurologic signs or symptoms
provides the highest sensitivity for detecting posterior fossa lesions and
• Focal neurologic symptoms or signs developing during a
does not expose the child to radiation. headache (i.e., complicated migraine)
In the child with a headache that is instantaneously at its worst at • Focal neurologic symptoms or signs (except classic visual
onset, a CT scan looking for blood is the best initial test; and, if it is symptoms of migraine) develop during the aura, with fixed
negative, a lumbar puncture should be done looking especially for laterality; focal signs of the aura persisting or recurring in the
xanthochromia of the CSF. There is no evidence that laboratory studies headache phase
or an electroencephalogram is beneficial in a typical migraine without Seizures or very brief auras (<5 min)
aura or migraine with aura. Unusual headaches in children
• Atypical auras including basilar-type, hemiplegic
• Trigeminal autonomic cephalalgia including cluster headaches in
TREATMENT child or adolescent
Table 595-8 outlines the drugs used to manage migraine headaches in • An acute secondary headache (i.e., headache with known
children. underlying illness or insult)
The American Academy of Neurology established useful practice Headache in children younger than 6 yr old or any child who cannot
guidelines for the management of migraine as follows: adequately describe his or her headache
1. Reduction of headache frequency, severity, duration, and Brief cough headache in a child or adolescent
disability Headache worst on first awakening or that awakens the child from
2. Reduction of reliance on poorly tolerated, ineffective, or unwanted sleep
acute pharmacotherapies Migrainous headache in the child with no family history of migraine
or its equivalent
3. Improvement in quality of life
Table 595-8 Drugs Used in the Management of Migraine Headaches in Children

DRUG DOSE MECHANISM SIDE EFFECTS COMMENTS
ACUTE MIGRAINE
Analgesics
Acetaminophen 15 mg/kg/dose Analgesic effects Overdose, fatal hepatic Effectiveness limited in
necrosis migraine
Ibuprofen 7.5-10 mg/kg/dose Antiinflammatory GI bleeding stomach Avoid overuse (2-3 times per
and analgesic upset, kidney injury wk)
Triptans
Almotriptan* (ages 12.5 mg 5-HT1b/1d agonist Vascular constriction, Avoid overuse (more than 4-6
12-17 yr) serotonin symptoms times per mo)
such as flushing,
paresthesias,
somnolence, GI
discomfort
Eletriptan 40 mg Same Same Avoid overuse (more than 4-6
times per mo)
Frovatriptan 2.5 mg Same Same May be effective for menstrual
migraine prevention
Avoid overuse (more than 4-6
times per mo)
Naratriptan 2.5 mg Same Same May be effective for menstrual
migraine prevention
Avoid overuse (more than 4-6
times per mo)
Rizatriptan* (ages 5 mg for child weighing Same Same Available in tablets and melts
6-17 yr) <40 kg, 10 mg Avoid overuse (more than 4-6
times per mo)
Sumatriptan Oral: 25 mg, 50 mg, Same Same Avoid overuse (more than 4-6
100 mg times per mo)
Nasal: 10 mg
SC: 6 mg
Zolmitriptan Oral: 2.5 mg, 5 mg Same Same Available in tablets and melts
Nasal: 5 mg Avoid overuse (more than 4-6
times per mo)
Continued
Table 595-8 Drugs Used in the Management of Migraine Headaches in Children—cont’d

DRUG DOSE MECHANISM SIDE EFFECTS COMMENTS
PROPHYLAXIS (NONE APPROVED BY FDA FOR CHILDREN)
Calcium Channel Blockers
Flunarizine† 5 mg hs Calcium channel Headache, lethargy, May ↑ to 10 mg hs
blocking agent dizziness
Anticonvulsants
Valproic acid 20 mg/kg/24 hr (begin ↑ Brain GABA Nausea, pancreatitis, ↑ 5 mg/kg every 2 wk
5 mg/kg/24 hr) fatal hepatotoxicity
Topiramate 100-200 mg divided bid ↑ Activity of Fatigue, nervousness Increase slowly over 12-16 wk
GABA
Levetiracetam 20-60 mg/kg divided bid Unknown Irritability, fatigue Increase every 2 wk starting at
20 mg/kg divided bid
Gabapentin 900-1800 mg divided bid Unknown Somnolence, fatigue Begin 300 mg, ↑ 300 mg/wk
aggression, weight gain
Antidepressants
Amitriptyline 1 mg/kg/day ↑ CNS serotonin Cardiac conduction, Increase by 0.25 mg/kg every
and abnormalities and dry 2 wk
norepinephrine mouth, constipation, Morning sleepiness reduced by
drowsiness, confusion administration at dinnertime
Antihistamines
Cyproheptadine 0.2-0.4 mg/kg divided H1-receptor and Drowsiness, thick Preferred in children who
bid; max: 0.5 mg/ serotonin bronchial secretions cannot swallow pills; not well
kg/24 hr agonist tolerated in adolescents
Antihypertensive
Propranolol 10-20 mg tid Nonselective Dizziness, lethargy Begin 10 mg/24 hr ↑ 10 mg/wk
β-adrenergic (contraindicated in asthma
blocking agent and depression)
Others
Coenzyme Q10 1-3 mg/kg/day Increases fatty No adverse effects Fat soluble; ensure brand
acid oxidation in reported contains small amount of
mitochondria vitamin E to help absorption
Riboflavin 50-400 mg daily Cofactor in energy Bright yellow urine,
metabolism polyuria and diarrhea
Magnesium 9 mg/kg divided tid Cofactor in energy Diarrhea or soft stool
metabolism
Butterbur 50-150 mg daily May act similar to Burping
a calcium
channel blocker
OnabotulinumtoxinA 100 units (age 11-17 yr) Inhibits Ptosis, blurred vision, Used off label in children
acetylcholine hematoma at injection
release from site
nerve endings
SEVERE INTRACTABLE
Prochlorperazine 0.15 mg/kg/IV; max dose Dopamine Agitation, drowsiness, May have increased
10 mg antagonist muscle stiffness, effectiveness when combined
akinesia and akathisia with ketorolac and fluid
hydration
Metoclopramide 0.2 mg/kg IV; 10 mg max Dopamine Drowsiness, urticaria, Caution in asthma patients
dose antagonist agitation, akinesia and
akathisia
Ketorolac 0.5 mg/kg IV; 15 mg max Antiinflammatory GI upset, bleeding
dose and analgesic
Valproate sodium 15 mg/kg IV: 1,000 mg ↑ Brain GABA Nausea, vomiting, Would avoid in hepatic disease
injection max dose somnolence,
thrombocytopenia
Dihydroergotamine 0.5 mg/dose every 8 hr Nausea, vomiting, Dose may need to be adjusted
IV (<40 kg) vascular constriction, for side effects (decrease) or
1.0 mg/dose every 8 hr phlebitis limited effectiveness
(>40 kg) (increase).
Nasal spray 0.5-1.0 mg/dose
0.5 mg/spray
*FDA approved in the pediatric population.
†
Available in Europe.
↑, Increase; CNS, central nervous system; GABA, γ-aminobutyric acid; GI, gastrointestinal; hs, at night; SC, subcutaneous.
To accomplish these goals, 3 components need to be incorporated severe, or attacks that have failed NSAID use, restricting to not more
into the treatment plan: than 4-6 attacks per month. For an acute attack, the NSAIDs can be
1. An acute treatment strategy should be developed for stopping a repeated once in 3-4 hr if needed for that specific attack, and the trip-
headache attack on a consistent basis with return to function as tans can be repeated once in 2 hr if needed. It is important to consider
soon as possible with the goal being 2 hr maximum. the various formulations available and a discussion of these options
2. A preventive treatment strategy should be considered when the should be made with pediatric patients and their parents, especially if
headaches are frequent (1 or more per week) and disabling. a child is unable to swallow pills or take an oral dose because of
3. Biobehavioral therapy should be started, including a discussion of nausea.
adherence, elimination of barriers to treatment, and healthy habit As vascular dilation is a common feature of migraine that may be
management. responsible for some of the facial flushing followed by paleness and the
lightheaded feeling accompanying the attacks, fluid hydration should
Acute Treatment be integrated into the acute treatment plan. For oral hydration this can
Management of an acute attack is to provide headache freedom as include the sports drinks that combine electrolytes and sugar to
quickly as possible with return to normal function. This mainly provide the intravascular rehydration.
includes 2 groups of medicines: nonsteroidal antiinflammatory drugs Antiemetics were used for acute treatment of the nausea and vomit-
(NSAIDs) and triptans. Most migraine headaches in children will ing. Further study has identified that their unique mechanism of effec-
respond to appropriate doses of NSAIDs when administered at the tiveness in headache treatment is related to their antagonism of
onset of the headache attack. Ibuprofen has been well documented to dopaminergic neurotransmission. Therefore, the antiemetics with the
be effective at a dose of 7.5-10.0 mg/kg and is often preferred; however, most robust dopamine antagonism (i.e., prochlorperazine and meto-
acetaminophen (15 mg/kg) can be effective in those with a contrain- clopramide) have the best efficacy. These can be very effective for status
dication to NSAIDs. Special concern for the use of ibuprofen or other migrainosus or a migraine that is unresponsive to the NSAIDs and
NSAIDs includes ensuring that the children can recognize and respond triptans. They require intravenous administration, as other forms of
to onset of the headache. This means discussing with the child the administration of these drugs are less effective than the NSAIDs or
importance of telling the teacher when the headache starts at school triptans. When combined with ketorolac and intravenous fluids in the
and ensuring that proper dosing guidelines and permission have been emergency department or an acute infusion center, intravenous anti-
provided to the school. In addition, overuse needs to be avoided, limit- emetics can be very effective. When they are not effective, further
ing the NSAID (or any combination of nonprescription analgesics) to inpatient treatment may be required using dihydroergotamine (DHE)
not more than 2-3 times per week. The limitation of any analgesic to which will mean an admission to an inpatient unit for more aggressive
not more than 3 headaches a week is necessary to prevent the trans- therapy of an intractable attack.
formation of the migraines into medication overuse headaches. If a
patient has maximized the weekly allowance of analgesics, the patient’s Emergency Department Treatments for Intractable
next step is to only use hydrating fluids for the rest of the week as an Headaches
abortive approach. If ibuprofen is not effective, naproxen sodium also When an acute migraine attack does not respond to an outpatient
may be tried in similar doses. Aspirin is also a reasonable option but regimen and is disabling, other therapeutic approaches are available
is usually reserved for older children (older than age 15 yr). Use of and may be necessary to prevent further increases in the frequency of
other NSAIDs have yet to be studied in pediatric migraine. The goal headaches. These migraines fall into the classification of status migrain-
of the primary acute medication should be headache relief within 1 hr osus and need infusion therapy and admission to the emergency room
with return to function in 10 of 10 headaches. department or to an inpatient unit.
When a migraine is especially severe, NSAIDs alone may not be Available specific treatments for migraine headache in an emergency
sufficient. In this case, a triptan may be considered. Multiple studies room setting include the following: antidopaminergic medications
have demonstrated their effectiveness and tolerability. There are cur- such as prochlorperazine and metoclopramide; NSAIDs such as ketor-
rently 2 triptans that are approved by the FDA for the treatment of olac and DHE; antiepileptic drugs such as sodium valproate; and
episodic migraine in the pediatric population. Almotriptan is approved triptans.
for the treatment of acute migraine in adolescents (ages 12-17 yr). Antidopaminergic Drugs: Prochlorperazine and
Rizatriptan is approved for the treatment of migraine in children as Metoclopramide. The use of these medications is not limited to
young as age 6 yr. The combination of naproxen sodium and sumat- controlling the nausea and vomiting often present during a migraine
riptan has been studied and may be effective in children. Controlled headache. Their potential pharmacologic effect may be a result of their
clinical trials demonstrate that intranasal sumatriptan is safe and effec- antidopamine property and the underlying pathologic process involv-
tive in children older than age 8 yr with moderate to severe migraine. ing the dopaminergic system during a migraine attack. Prochlorpera-
At present, pediatric studies showing the effectiveness of oral sumat- zine is very effective in aborting an attack in the emergency room when
riptan are lacking and there is insufficient evidence to support the use given intravenously with a bolus of IV fluid. Results show a 75%
of subcutaneous sumatriptan in children. For most adolescents, dosing improvement with 50% headache freedom at 1 hr and 95% improve-
is the same as for adults; a reduction in dose is made for children ment with 60% headache freedom at 3 hr. Prochlorperazine may be
weighing less than 40 kg. The triptans vary by rapidity of onset and more effective than metoclopramide. The average dose of metoclo-
biologic half-life. This is related to both their variable lipophilicity and pramide use is 0.13-0.15 mg/kg with a maximum dose of 10 mg given
dose. Clinically, 60-70% of patients respond to the first triptan tried, intravenously over 15 min. The average dose of prochlorperazine is
with 60-70% of the patients who did not respond to the first triptan 0.15 mg/kg with a maximum dose of 10 mg. These medications are
responding to the next triptan. Therefore, in the patient who does usually well tolerated, but extrapyramidal reactions are more frequent
not respond to the first triptan in the desired way (rapid reproducible in children compared to the older population. An acute extrapyramidal
response without relapse or side effects), it is worthwhile to try a dif- reaction can be controlled in the emergency room with 25-50 mg of
ferent triptan. The most common side effects of the triptans are caused diphenhydramine given IV.
by their mechanism of action—tightness in the jaw, chest, and fingers Nonsteroidal Antiinflammatory Drugs: Ketorolac. It
as a result of vascular constriction and a subsequent feeling of groggi- is known that an aseptic inflammation occurs in the central nervous
ness and fatigue from the central serotonin effect. The vascular con- system as a result of the effect of multiple reactive peptides in patients
striction symptoms can be alleviated through adequate fluid hydration with migraines. Ketorolac is often used in the emergency department
during an attack. as monotherapy for a migraine attack or in combination with other
The most effective way to administer abortive treatment is to use drugs. In monotherapy, the response to ketorolac is 55.2% improve-
NSAIDs first in mild to severe cases, restricting their use to fewer ment. When combined to prochlorperazine, the response rate jumps
than 2-3 attacks per week, and adding the triptan for moderate to to 93%.
Antiepileptic Drugs: Sodium Valproate. Antiepileptic of 1,000 mg), followed by 5 mg/kg every 8 hr until headache freedom
drugs have been used as prophylactic treatment for migraine headache or up to a maximum of 10 doses. Always give an extra dose after head-
for years with adequate double-blinded, controlled studies on their ache ceases. This protocol was studied in adults with chronic daily
efficacy in adults. The mechanism in which sodium valproate acutely headaches and showed an 80% improvement. It is well tolerated and is
aborts migraine headaches is not well understood. Sodium valproate useful in children when DHE is ineffective, contraindicated, or not
is given as a bolus of 15-20 mg/kg push (over 10 min). This intravenous tolerated.
load is followed by an oral dose (15-20 mg/day) in the 4 hr after the
injection. Patients may benefit from a short-term preventive treatment Preventive Therapy
with an extended release form after discharge from the emergency When the headaches are frequent (more than 1 headache/wk) or there
room. Sodium valproate is usually well tolerated. Patients should be are more than 1 disabling headache a month (missing school, home,
receiving a fluid load during the procedure to prevent a possible hypo- or social activities, or a PedMIDAS score higher than 20), preventive
tensive episode. or prophylactic therapy is warranted. The goal of this therapy should
Triptans. Subcutaneous sumatriptan (0.06 mg/kg) has an overall to be to reduce frequency (1-2 headaches or fewer per month) and
efficacy of 72% at 30 min and 78% at 2 hr, with a recurrence rate of disability (PedMIDAS score <10). Prophylactic agents should be given
6%. Because children tend to have a shorter duration of headache, a for at least 4-6 mo at an adequate dose and then weaned over several
recurrence rate of 6% would seem appropriate for this population. weeks. Evidence in adult studies has begun to demonstrate that persis-
DHE, if recommended for the recurrences, should not be given in the tent frequent headaches foreshadow an increased risk of progression
24 hr after triptan use. Triptans are contraindicated in patients treated with decreased responsiveness and increased risk of refractoriness in
with ergotamine within 24 hr and within 2 wk of treatment with the future. It is unclear whether this also occurs in children and/or
monoamine oxidase inhibitors. Triptans may potentially produce a adolescents and whether early treatment of headache in childhood
serotonin syndrome in patients taking a serotonin syndrome reuptake prevents development of refractory headache in adulthood.
inhibitor. Both triptans and ergotamine are contraindicated in hemi- Multiple preventive medications have been utilized for migraine
plegic migraines. prophylaxis in children. When analyzed as part of a practice parameter,
Dihydroergotamine. DHE is an old migraine medication only 1 medication, flunarizine (a calcium channel blocking agent),
used as a vasoconstrictor to abort the vascular phase of migraine head- demonstrated a level of effectiveness viewed as substantial; it is not
ache. The effectiveness is discussed in detail in the section “Inpatient available in the United States. Flunarizine is typically dosed at 5 mg
Management of Intractable Migraine and Status Migrainosus” below. orally daily and increased after 1 mo to 10 mg orally daily, with a
One dose of DHE can be effective for abortive treatment in the emer- month off of the drug every 4-6 mo.
gency department. Emergency room treatment of migraine shows a The most commonly used preventive therapy for headache and
recurrence rate of 29% at 48-72 hr, with 6% who need more aggressive migraine is amitriptyline. Typically, a dose of 1 mg/kg daily at dinner
therapy in an inpatient unit. or in the evening is effective. However, this dose needs to be reached
slowly (i.e., over weeks: with an increase every 2 wk until goal is
Inpatient Management of Intractable Migraine and reached) to minimize side effects and improve tolerability. The most
Status Migrainosus common side effects are sleepiness and those related to amitriptyline’s
Six percent to 7% of patients fail acute treatment in the emergency anticholinergic activity. Weight gain has been observed in adults using
department. These patients are usually admitted for a 3-5 day stay and amitriptyline but is a less frequent occurrence in children. Amitripty-
receive extensive parenteral treatment. A child should be admitted to line does have the potential to exacerbate prolonged QT syndrome, so
the hospital for a primary headache when the child is in status migrain- it should be avoided in patients with this diagnosis and looked for in
ous, has an exacerbation of a chronic severe headache, or is in an patients on the drug who complain of rapid or irregular heart rate.
analgesic rebound headache. The goal of inpatient treatment is to Antiepileptic medications are also used for migraine prophylaxis,
control a disabling headache that has been unresponsive to other abor- with topiramate, valproic acid, and levetiracetam having been demon-
tive therapy and is disabling to the child. Treatment protocols include strated to be effective in adults. There are limited studies in children
the use of DHE, antiemetics, sodium valproate and other drugs. for migraine prevention, but all of these medications have been assessed
Dihydroergotamine. Ergots are one of the oldest treatments for safety and tolerability in children with epilepsy.
for migraine headache. DHE is a parenteral form used for acute exac- Topiramate has become widely used for migraine prophylaxis in
erbations. Its effect is because of the 5HT1A-1B-1D-1F receptor agonist adults. Topiramate was also demonstrated to be effective in an adoles-
affinity and central vasoconstriction. DHE has a greater α-adrenergic cent study. This study demonstrated that a 25 mg dose twice a day was
antagonist activity and is less vasoconstrictive peripherally. Before ini- equivalent to placebo, whereas a 50 mg dose twice a day was superior.
tiation of an IV ergot protocol, a full history and neurologic examina- Thus it appears that the adult dosing schedule is also effective in ado-
tion should be obtained. Girls of childbearing age should be evaluated lescents with an effective dosage range or 50 mg twice a day to 100 mg
for pregnancy before administering ergots. twice a day. This dose needs to be reached slowly to minimize the
The DHE protocol consists of the following: Patients are premedi- cognitive slowing associated with topiramate use. Additional side
cated with 0.13-0.15 mg/kg of prochlorperazine 30 min prior to the effects include weight loss, paresthesias, kidney stones, lowered bicar-
DHE dose (maximum of 3 prochlorperazine doses to prevent extrapy- bonate levels, decreased sweating, and rarely glaucoma and changes in
ramidal syndrome, then other types of antiemetics should be used, serum transaminases. In addition, in adolescent girls taking birth
such as ondansetron). A dose of 0.5-1.0 mg of DHE is used (depending control pills, the lowering of the effectiveness of the birth control by
on age and tolerability) every 8 hr until headache freedom. When topiramate needs to be discussed.
headache ceases, an extra dose is given in an attempt to prevent recur- Valproic acid has long been used for epilepsy in children and has
rence after discharge. The response to this protocol is a 97% improve- been demonstrated to be effective in migraine prophylaxis in adults.
ment and 77% headache freedom. Response starts being noticeable by The effective dose in children appears to be 10 mg/kg orally twice a
the fifth dose and can reach its maximum effects after the 10th dose. day. Side effects of weight gain, ovarian cysts, and changes in serum
Side effects of DHE include nausea, vomiting, abdominal discomfort, transaminases and platelet counts need to be monitored. Other anti-
flushed face, increased blood pressure. The maximum dose used in this epileptics, including lamotrigine, levetiracetam, zonisamide, gabapen-
protocol is 15 mg total of DHE. During the hospital admission the tin, and pregabalin, are also used for migraine prevention.
patient is usually started on migraine prophylaxis depending on the β-Blockers have long been used for migraine prevention. The studies
patient’s history and comorbid problems. on β-blockers have a mixed response pattern with variability both
Sodium Valproate. Sodium valproate is used when DHE is between β-blockers and between patients with a given β-blocker. Pro-
contraindicated or has been ineffective. One adult study recommends pranolol is the best studied for pediatric migraine prevention with
the use of valproate sodium as follows: Bolus with 15 mg/kg (maximum unequivocally positive results. The contraindication for use of
propranolol in children with asthma or allergic disorders or diabetes over the headaches and may further help the child cope with frequent
and the increased incidence of depression in adolescents using pro- headaches.
pranolol limit its use somewhat. It may be very effective for a mixed
subtype of migraine (basilar-type migraine with postural orthostatic Bibliography is available at Expert Consult.
tachycardia syndrome). This syndrome has been reported to be respon-
sive to propranolol. α-Blockers and calcium channel blockers, aside
from flunarizine, also have been used in pediatric migraine; their effec-
tiveness, however, remains unclear. 595.2 Secondary Headaches
In very young children, cyproheptadine may be effective in preven- Andrew D. Hershey, Marielle A. Kabbouche,
tion of migraine or the related variants. Young children tend to tolerate and Hope L. O’Brien
the increased appetite induced by the cyproheptadine and tend not to
be subject to the lethargy seen in older children and adults; the weight Headaches can be a common symptom of other underlying illnesses.
gain is limiting once children start to enter puberty. Typical dosing is In recognition of this, the ICHD-3 beta has classified the potential
0.1-0.2 mg/kg orally twice a day. secondary headaches (see Table 595-1). The key to the diagnosis of a
Nutraceuticals have become increasingly popular over the past few secondary headache is to recognize the underlying cause and demon-
years, especially among families who prefer a more “natural” approach strate a direct cause and effect. Until this has been demonstrated the
to headache treatment. Despite studies showing success of these thera- diagnosis is speculative. This is especially true when the suspected
pies in adults, few studies have shown effectiveness in pediatric head- etiology is common.
aches. Riboflavin (vitamin B2), at doses ranging from 25-400 mg, is the Common causes or suspected causes of secondary headaches in
most widely studied with good results. Side effects are minimal and children include the sequelae of head trauma and sinusitis. Posttrau-
include bright yellow urine, diarrhea, and polyuria. Coenzyme Q10 matic headaches sometimes occur in children who have not had a
supplementation may be effective in reducing migraine frequency at prior history of headaches and are temporally related to the initiating
doses of 1-2 mg/kg/day. Butterbur is also effective in reducing head- head injury. Frequently, though, these children have a family history
aches with minimal side effects, including burping. Use in children has of migraine or its equivalent. The head injury may be minor or major
been limited to avoid the potential toxicity of butterbur containing and the subsequent headache may be acute (resolves within 3 mo, most
pyrrolizidine alkaloids, which are naturally contained and are a known typically within 10 days) or chronic (longer than 15 days per month
carcinogen and toxic to the liver. for more than 3 mo). Bed rest appears to be the most effective treat-
OnabotulinumtoxinA is the first medication FDA-approved for ment for acute posttraumatic headache; magnesium supplementation
chronic migraine in adults. There are studies in children indicating its and migraine prophylaxis may also be effective. When a child has a
effectiveness; use in children is considered off-label. The limited avail- history of episodic headaches, the head trauma or the overuse of daily
able studies revealed the following: Average dose used was 188.5 units medications may lead to status migrainosus or chronic migraine and
± 32 units with a minimum dose of 75 units and maximum of 200 the diagnosis may be difficult to sort out.
units. The average age of patients receiving the treatment was 16.8 ± Sinus headache is the most overdiagnosed form of recurrent head-
2.0 yr (minimum: 11; maximum: 21 yr old). OnabotulinumtoxinA aches. Although no studies have evaluated the frequency of misdiag-
injections improved disability scores (PedMIDAS) and headache fre- nosis of an underlying migraine as a sinus headache in children, in
quency in pediatric chronic daily headache patients and chronic adults, it has been found that up to 90% of adults diagnosed as having
migraine in this age group. OnabotulinumtoxinA not only had a posi- a sinus headache by either themselves or their physician appear to have
tive effect on the disability scoring for these young patients with head- migraine. When headaches are recurrent and respond within hours to
ache, but was also able to transform the headaches from chronic daily analgesics, migraine should be considered first. In the absence of puru-
to intermittent headache in more than 50% of the patients. lent nasal discharge, fever, or chronic cough, the diagnosis of sinus
headache should not be made.
Biobehavioral Therapy Medication overuse headaches frequently complicate primary and
Biobehavioral evaluation and therapy is essential for effective migraine secondary headaches. A medication overuse headache is defined as a
management. This includes identification of behavioral barriers to headache present for more than 15 days/mo for longer than 3 mo and
treatment, like a child’s shyness or limitation in notifying a teacher of intake of a simple analgesic on more than 15 days/mo and/or prescrip-
the start of a migraine or a teacher’s unwillingness to accept the need tion medications including triptans or combination medications on
for treatment. Additional barriers include a lack of recognition of the more than 10 days/mo. Some of the signs that should raise suspicion
significance of their headache problem and reverting to “bad habits” of medication overuse are the increasing use of analgesics (nonpre-
once the headaches have responded to treatment. Adherence is equally scription or prescription) with either decreased effectiveness or fre-
important for acute and preventive treatment. The need to have a quently wearing off (i.e., analgesic rebound). This can be worsened
sustained response for long enough to prevent relapse (i.e., to stay on by using ineffective medications and underdosing or misdiagnosing
preventive medication) is often difficult when the child starts to feel the headache. Patients should be cautioned against the frequent use
better. Establishing a defined treatment goal (1-2 or fewer headaches of antimigraine medications, including combination analgesics or
per month for 4-6 mo) helps with acceptance. triptans.
As many of the potential triggers for frequent migraines (skipping Serious causes of secondary headaches are likely to be related to
meals, dehydration, decreased or altered sleep) are related to a child’s increased intracranial pressure. This can be caused by a mass (tumor,
daily routine, a discussion of healthy habits is a component of biobe- vascular malformation, cystic structure) or an intrinsic increase in
havioral therapy. This should include adequate fluid intake without pressure (idiopathic intracranial hypertension also known as pseudo-
caffeine, regular exercise, not skipping meals and making healthy food tumor cerebri). In the former case, the headache is caused by the mass
choices, and adequate (8-9 hr) sleep on a regular basis. Sleep is often effect and local pressure on the dura; in the latter case, the headache
difficult in adolescents, as middle and high schools often have very is caused by diffuse pressure on the dura. The etiology of idiopathic
early start times, and the adolescent’s sleep architecture features a shift intracranial hypertension may be the intake of excessive amounts of
to later sleep onset and waking. This has been one of the explanations fat-soluble compounds (e.g., vitamin A, retinoic acid, and minocy-
for worsening headaches during the school year in general and at the cline), hormonal changes (increased incidence in females) or blockage
beginning of the school year and week. of venous drainage (as with inflammation of the transverse venous
Biofeedback-assisted relaxation and cognitive behavioral therapy sinus from mastoiditis). When increased pressure is suspected, either
(usually in combination with amitriptyline) are effective for both acute by historical suspicion or the presence of papilledema, an MRI with
and preventive therapy and may be incorporated into this multiple magnetic resonance angiography and magnetic resonance venography
treatment strategy. This provides the child with a degree of self-control should be performed, followed by a lumbar puncture if no mass or
Chapter 595 ◆ Headaches 2873.e1
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vascular anomaly is noted. The lumbar puncture can be diagnostic and Evaluation of patients with suspected TTHs requires a detailed
therapeutic of idiopathic intracranial hypertension but must be per- headache history and complete general and neurologic examination.
formed with the patient in a relaxed recumbent position with legs This is to establish the diagnosis and ensure exclusion of secondary
extended, as abdominal pressure can artificially raise intracranial pres- etiologies. When secondary headaches are suspected, further, directed
sure. If headache persists or there are visual field changes, pharmaceu- evaluation is indicated.
tical treatment with a carbonic anhydrase inhibitor, optic nerve Treatment of TTHs can require acute therapy to stop attacks, pre-
fenestration, or a shunt needs to be considered. ventive therapy when frequent or chronic, and behavioral therapy. It is
Additional causes of secondary headaches in children that may not often suspected that there may be underlying psychologic stressors
be associated with increased intracranial pressure include arteriove- (hence the misnomer as a “stress” headache), but this is often difficult
nous malformations, berry aneurysm, collagen vascular diseases to identify in children, and although it may be suspected by the parents,
affecting the central nervous system, hypertensive encephalopathy, it cannot be confirmed in the child. Studies of and conclusive evidence
infectious or autoimmune etiologies, acute subarachnoid hemorrhage, to guide the treatment of TTH in children are lacking, but the same
and stroke. The management of secondary headache depends on the general principles and medications used in migraine can be applied to
cause. Helpful laboratory tests and neuroradiologic procedures depend children with TTHs (see Chapter 595.1). Oftentimes, simple analgesics
on the clues provided by the history and physical examination. By (ibuprofen or acetaminophen) can be effective for acute treatment.
definition, a secondary headache has a specific cause and should Flupirtine is a nonopioid analgesic that has been approved in Europe
resolve once this cause is treated. If the headache persists, the diagnosis for the treatment of TTH in children as young as age 6 yr, but is not
and treatment should be questioned as either the diagnosis, which may available in the United States. Amitriptyline has the most evidence of
include a primary headache, and/or treatment may be incorrect. effective prevention of TTH; biobehavioral intervention, including
biofeedback-assisted relaxation training and coping skills, can be
Bibliography is available at Expert Consult. useful as well.

595.3 Tension-Type Headaches
Andrew D. Hershey, Marielle A. Kabbouche, and
Hope L. O’Brien
Tension-type headaches (TTHs) may be very common in children and

adolescents with prevalence in some studies shown as high as 48%,
with those having a combination of migraine and TTH around 20%.
Because of their mild to moderate nature, relative lack of associated
symptoms and lower degree of associated disability they are often
ignored or have a minimal impact. The ICHD-3 beta subclassifies
TTHs as infrequent (<12 times/yr) (Table 595-9), frequent (1-15 times/
mo), and chronic (>15 headaches/mo). They can further be separated
into headaches with or without pericranial muscle tenderness. The
classification of TTH can be likened to the opposite of migraine.
Whereas migraines are typically moderate to severe, are focal in loca-
tion, are worsened by physical activity or limit physical activity, and
have a throbbing quality, TTH are mild to moderate in severity, are
diffuse in location, are not affected by activity (although the patient
may not feel like being active), and are nonthrobbing (often described
as a constant pressure). TTH is much less frequently associated with
nausea, photophobia, or phonophobia and is never associated with
more than 1 of these at a time or with vomiting. TTH must be recur-
rent, but at least 10 headaches are required and the duration can be
30 min to 7 days. Secondary headaches with other underlying etiolo-
gies must be ruled out.
Table 595-9 Infrequent Episodic Tension-Type

Headache
A. At least 10 episodes of headache occurring on <1 day per
month on average (<12 days per year) and fulfilling criteria B
to D
B. Lasting from 30 min to 7 days
C. At least 2 of the following 4 characteristics:
1. Bilateral location
2. Pressing or tightening (nonpulsating) quality
3. Mild or moderate intensity
4. Not aggravated by routine physical activity such as walking or
climbing stairs
D. Both of the following:
1. No nausea or vomiting
2. No more than 1 of photophobia or phonophobia
E. Not better accounted for by another ICHD-3 beta diagnosis
From Headache Classification Committee on the International Headache
Society (IHS): The International Classification of Headache Disorders, ed 3
(beta version). Cephalalgia 33(9):629–808, 2013, Table 10.
Chapter 595 ◆ Headaches 2874.e1
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headache, JAMA 302:2451–2457, 2009. pediatric idiopathic stabbing headache, Pediatrics 133:e245–e247, 2014.
Crock C, Orsini F, Lee KJ, et al: Headache after lumbar puncture: randomized Lambru G, Matharu M: Management of trigeminal autonomic cephalalgias in
crossover trial of 22-gauge versus 25-gauge needles, Arch Dis Child 99:203–207, children and adolescents, Curr Pain Headache Rep 17:323, 2013.
2014. Leroux E, Valade D, Taifas I, et al: Suboccipital steroid injections for transitional
Dafer RM, Jay WM: Headache and the eye, Curr Opin Ophthalmol 20:520–524, treatment of patients with more than two cluster headache attacks per day: a
2009. randomized, double-blind, placebo-controlled trial, Lancet Neurol 10:891–897,
DeVries A, Young PC, Wall E, et al: CT scan utilization patterns in pediatric 2011.
patients with recurrent headache, Pediatrics 132:e1–e8, 2013. Massano D, Julliand S, Kanagarajah L, et al: Headache with focal neurologic signs
Ducros A, Bousser MG: Thunderclap headache, BMJ 345:e8557, 2012. in children at the emergency department, J Pediatr 165:376–382, 2014.
Friedman BW, Adewunmi V, Campbell C, et al: A randomized trial of intravenous Nesbitt AD, Goadsby PJ: Cluster headache, BMJ 344:e2407, 2012.
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2874.e2 Chapter 595 ◆ Headaches
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Chapter 596
Neurocutaneous
Syndromes
Mustafa Sahin
The neurocutaneous syndromes include a heterogeneous group of dis-

orders characterized by abnormalities of both the integument and
central nervous system. Many of the disorders are familial and believed
to arise from a defect in differentiation of the primitive ectoderm.
Disorders classified as neurocutaneous syndromes include neurofibro-
matosis, tuberous sclerosis, Sturge-Weber syndrome, von Hippel-
Lindau disease, PHACE (posterior fossa malformations, hemangiomas,
arterial anomalies, coarctation of aorta, cardiac defects, eye abnormali-
ties) syndrome, ataxia telangiectasia, linear nevus syndrome, hypomel-
anosis of Ito, and incontinentia pigmenti.
596.1 Neurofibromatosis
Mustafa Sahin
Neurofibromatoses are autosomal dominant disorders that cause

tumors to grow on nerves and result in other abnormalities such as
skin changes and bone deformities. It was believed that there were 2
types of neurofibromatosis (type 1 and type 2), but it is recognized that
they are clinically and genetically distinct diseases and should be con-
sidered separate entities: neurofibromatosis type 1 (NF-1) and neuro-
fibromatosis type 2 (NF-2).
CLINICAL MANIFESTATIONS AND DIAGNOSIS

NF-1 is the most prevalent type, with an incidence of 1 in 3,000 live
births, and is caused by dominant loss-of-function mutations in the
NF-1 gene. The disease is clinically diagnosed when any 2 of the
following 7 features are present: (1) six or more café-au-lait macules
larger than 5 mm in greatest diameter in prepubertal individuals and
larger than 15 mm in greatest diameter in postpubertal individuals
(Fig. 596-1). Café-au-lait spots are the hallmark of neurofibromatosis
Chapter 596 ◆ Neurocutaneous Syndromes 2875
A B
Figure 596-1 A and B, Multiple café-au-lait spots over the back. Note the dermal neurofibromas below the right scapula and right side of
the lower back. (From Hersh JH, Committee on Genetics: Health supervision for children with neurofibromatosis, Pediatrics 121:633–642, 2008,
Fig. 1.)
Table 596-1 Diseases Associated with Multiple Café-Au-Lait Spots

DISEASE MAJOR FEATURES
Ataxia telangiectasia Progressive ataxia, lymphoreticular malignancy
Bannayan-Riley-Ruvalcaba syndrome Macrosomia, megalencephaly, lipomas, intestinal polyps
Basal cell nevus syndrome Multiple basal cell epitheliomas, jaw cysts, skeletal anomalies
Bloom syndrome Short stature, photosensitivity, chromosome breaks, malignancy
Fanconi anemia Limb anomalies, renal anomalies, pancytopenia
Gaucher disease Jewish predilection, ataxia, mental retardation
Hunter syndrome Thickened skin, coarse facies, skin papules, joint contractures
Jaffe-Campanacci syndrome Fibromas of long bones, hypogonadism, mental retardation, ocular/cardiac anomalies
Maffucci syndrome Venous malformations, enchondromas
McCune-Albright syndrome Polyostotic fibrous dysplasia, precocious puberty
Multiple lentigines syndrome Multiple lentigines, hypertelorism, pulmonic stenosis
Multiple mucosal neuroma syndrome Mucosal neuromas, thyroid carcinoma, pheochromocytoma, parathyroid adenoma, dysautonomia
Neurofibromatosis Neurofibromas, central nervous system tumors, iris hamartomas, axillary freckles, skeletal anomalies
Russell-Silver syndrome Short stature, asymmetry, limb anomalies
Tuberous sclerosis White macules, multiple hamartomas, central nervous system anomalies
Watson syndrome Pulmonic stenosis, axillary freckles, low intelligence
Legius syndrome Axillary freckling macrocephaly, a Noonan-like facial dysmorphism, lipomas
From Marcoux DA, Duran-McKinster C, Baselga E, et al: Pigmentary abnormalities. In: Schachner LA, Hansen RC, editors: Pediatric dermatology, ed 4, Philadelphia,
2011, Mosby, Table 10-2.
and are present in almost 100% of patients. They are present at birth NF-1 but are not a characteristic of NF-2. The prevalence of Lisch
but increase in size, number, and pigmentation, especially during the nodules increases with age, from only 5% of children younger than 3 yr
1st few yr of life. The spots are scattered over the body surface, with of age, to 42% among children 3-4 yr of age, and virtually 100% of
predilection for the trunk and extremities but sparing the face. (2) adults older than 21 yr of age. (4) Two or more neurofibromas or 1
Axillary or inguinal freckling consisting of multiple hyperpigmented plexiform neurofibroma. Neurofibromas typically involve the skin, but
areas 2-3 mm in diameter. Skinfold freckling usually appears between they may be situated along peripheral nerves and blood vessels and
3 and 5 yr of age. The frequency of axillary and inguinal freckling is within viscera including the gastrointestinal tract. These lesions appear
reported to be >80% by 6 yr of age. Café-au-lait macules are not spe- characteristically during adolescence or pregnancy, suggesting a hor-
cific for NF-1; they may be seen in Noonan syndrome, constitutional monal influence. They are usually small, rubbery lesions with a slight
mismatch repair deficiency syndrome, Legius syndrome, Peutz-Jeghers purplish discoloration of the overlying skin. Plexiform neurofibromas
syndrome, Carney complex, and those diseases listed in Table 596-1. are usually evident at birth and result from diffuse thickening of nerve
(3) Two or more iris Lisch nodules. Lisch nodules are hamartomas trunks that are frequently located in the orbital or temporal region of
located within the iris and are best identified by a slit-lamp examina- the face. The skin overlying a plexiform neurofibroma may be hyper-
tion (Fig. 596-2). They are present in more than 74% of patients with pigmented to a greater degree than a café-au-lait macule. Plexiform
Figure 596-2 Neurofibromatosis type 1 (NF-1). Pigmented hamarto-

mas of the iris (Lisch nodules). (From Zitelli BJ, McIntire S, Nowalk AJ,
editors: Zitelli and Davis’ atlas of pediatric physical diagnosis, ed 6,
Philadelphia, 2012, Mosby, Fig. 15-9.)
Figure 596-4 T2-weighted MRI scan of a patient with NF-1. Note

the high-signal areas (unidentified bright objects) in the basal ganglia
(black arrows).
thalamus, internal capsule, and cerebellum (Fig. 596-4). These signals,

“unidentified bright objects,” tend to disappear with age; most have
disappeared by 30 yr of age. It is unclear what the unidentified
bright objects represent pathologically, and there is disagreement as to
the relationship between the presence and number of unidentified
bright objects and the occurrence of learning disabilities, attention-
deficit disorders, behavioral and psychosocial problems, and abnor-
malities of speech among affected children. Therefore, imaging
studies such as brain MRIs should be reserved for patients with clinical
symptoms only.
One of the most common complications is learning disability affect-
ing approximately 30% of children with NF-1. Seizures are observed
in approximately 8% of NF-1 patients. The cerebral vessels may develop
aneurysms or stenosis resulting in moyamoya syndrome (see Chapter
Figure 596-3 Optic glioma. Sagittal T1-weighted MRI scan of a 601). Neurologic sequelae of these vascular abnormalities include tran-
patient with NF-1 shows thickening of the optic nerve (arrow). sient cerebrovascular ischemic attacks, hemiparesis, and cognitive
defects. Precocious puberty may become evident in the presence or
absence of lesions of the optic pathway tumors. Malignant neoplasms
neurofibromas may produce overgrowth of an extremity and a defor- are also a significant problem in patients with NF-1, affecting approxi-
mity of the corresponding bone. (5) A distinctive osseous lesion such mately 3% of patients. A neurofibroma occasionally differentiates into
as sphenoid dysplasia (which may cause pulsating exophthalmos) or a malignant peripheral nerve sheath tumor. The incidence of pheo-
cortical thinning of long bones with or without pseudoarthrosis (e.g., chromocytoma, rhabdomyosarcoma, leukemia, and Wilms tumor is
tibia). (6) Optic gliomas are present in approximately 15% of patients higher than in the general population. Scoliosis is a common complica-
with NF-1 and represent mostly low-grade astrocytomas. They are the tion found in approximately 10% of the patients. Patients with NF-1
main central nervous system tumor with a marked increased frequency are at risk for hypertension, which may result from renal vascular
in NF-1. Because of their growth, it is recommended that all children stenosis or a pheochromocytoma.
age 10 yr or younger with NF-1 undergo annual ophthalmologic exam-
inations. When they progress, visual symptoms occur because the MANAGEMENT
tumors enlarge and put pressure on the optic nerves and chiasm result- Because of the diverse and unpredictable complications associated
ing in impaired visual acuity and visual fields. Extension into the hypo- with NF-1, close multidisciplinary follow-up is necessary. Patients with
thalamus can lead to endocrine deficiencies or failure to thrive. The NF-1 should have regular clinical assessments at least yearly, focusing
MRI findings of an optic glioma include diffuse thickening, localized the history and examination on the potential problems for which they
enlargement, or a distinct focal mass originating from the optic nerve are at increased risk. These assessments include yearly ophthalmologic
or chiasm (Fig. 596-3). (7) A 1st-degree relative with NF-1 whose examination, neurologic assessment, blood pressure monitoring, and
diagnosis was based on the aforementioned criteria. scoliosis evaluation. Neuropsychologic and educational testing should
Children with NF-1 are susceptible to neurologic complications. be considered as needed. The National Institutes of Health (NIH) Con-
MRI studies of selected children have shown abnormal hyperintense sensus Development Conference has advised against routine imaging
T2-weighted signals in the optic tracts, brainstem, globus pallidus, studies of the brain and optic tracts because treatment in these
Table 596-2 Frequency of Lesions Associated with 596.2 Tuberous Sclerosis

Neurofibromatosis Type 2 Mustafa Sahin
FREQUENCY OF
ASSOCIATION WITH NF-2 Tuberous sclerosis complex (TSC) is inherited in an autosomal domi-
nant manner with variable expression and a prevalence of 1 in 6,000
NEUROLOGIC LESIONS newborns. Spontaneous genetic mutations occur in 65% of the cases.
Bilateral vestibular schwannomas 90-95%
Molecular genetic studies have identified 2 foci for TSC: the TSC1 gene
Other cranial nerve schwannomas 24-51%
Intracranial meningiomas 45-58% is located on chromosome 9q34, and the TSC2 gene is on chromosome
Spinal tumors 63-90% 16p13. The TSC1 gene encodes a protein called hamartin, while the
Extramedullary 55-90% TSC2 gene encodes the protein tuberin. Within a cell, these 2 proteins
Intramedullary 18-53% bind to one another and work together. Consequently, a mutation in
Peripheral neuropathy Up to 66% either the TSC1 gene or the TSC2 gene results in a similar disease in
OPHTHALMOLOGIC LESIONS
patients. The TSC1 and TSC2 genes are tumor-suppressor genes. The
Cataracts 60-81% loss of either tuberin or hamartin protein results in the formation of
Epiretinal membranes 12-40% numerous benign tumors (hamartomas). Tuberin and hamartin are
Retinal hamartomas 6-22% involved in a key pathway in the cell that regulates protein synthesis
and cell size. One of the ways cells regulate their growth is by control-
CUTANEOUS LESIONS
ling the rate of protein synthesis. A protein called mTOR (mammalian
Skin tumors 59-68%
Skin plaques 41-48% target of rapamycin) was identified as one of the master regulators of
Subcutaneous tumors 43-48% cell growth. mTOR, in turn, is controlled by rheb, a small cytoplasmic
Intradermal tumors Rare guanosine triphosphatase. When rheb is activated, the protein synthe-
sis machinery is turned on, most likely via mTOR, and the cell grows
From Asthagiri AR, Parry DM, Butman JA, et al: Neurofibromatosis type 2, in size. Of interest in TSC, rheb is activated by the protein complex
Lancet 373:1974–1984, 2009, Table 1.
formed by hamartin and tuberin.
TSC is an extremely heterogeneous disease with a wide clinical
spectrum varying from severe intellectual disability and intractable
asymptomatic NF-1 children is rarely required. However, all symptom- epilepsy to normal intelligence and a lack of seizures; this variation is
atic cases (i.e., those with visual disturbance, proptosis, increased intra- often seen within the same family, thus with individuals carrying the
cranial pressure) must be studied without delay. same mutation. The disease affects many organ systems other than the
skin and brain, including the heart, kidney, eyes, lungs, and bone
GENETIC COUNSELING (Fig. 596-5).
Although NF-1 is an autosomal dominant disorder, more than half the
cases are sporadic, representing de novo mutations. The NF-1 gene on CLINICAL MANIFESTATIONS AND DIAGNOSIS
chromosome region 17q11.2 encodes for a protein also known as neu- Definite TSC is diagnosed when at least 2 major or one major plus 2
rofibromin. Neurofibromin acts as an inhibitor of the oncogene Ras. minor features are present (Tables 596-3 and 596-4 list the major and
The diagnosis of NF-1 is based on the clinical features. However, minor features).
molecular testing for the NF-1 gene mutations is available and can be The hallmark of TSC is the involvement of the central nervous
useful in a number of cases. Some scenarios in which genetic testing system. Retinal lesions consist of two types: hamartomas (elevated
is helpful include for patients who meet only 1 of the criteria for clinical mulberry lesions or plaque-like lesions; Fig. 596-6) and white depig-
diagnosis, those with unusually severe disease, and those seeking mented patches (similar to the hypopigmented skin lesions). The
prenatal/preimplantation diagnosis. characteristic brain lesion is a cortical tuber (Fig. 596-7). Brain MRI is
NF-2 is a rarer condition, with an incidence of 1 in 25,000 births, the best way of identifying cortical tubers, which can form before
and may be diagnosed when 1 of the following 4 features is present: birth.
(1) bilateral vestibular schwannomas; (2) a parent, sibling, or child with Subependymal nodules are lesions found along the wall of the lateral
NF-2 and either unilateral vestibular schwannoma or any 2 of the fol- ventricles where they undergo calcification and project into the ven-
lowing: meningioma, schwannoma, glioma, neurofibroma, posterior tricular cavity, producing a candle-dripping appearance. These lesions
subcapsular lenticular opacities; (3) unilateral vestibular schwannoma do not cause any problems; however, in 5-10% of cases, these benign
and any 2 of the following: meningioma, schwannoma, glioma, neuro- lesions can grow into subependymal giant cell astrocytomas (SEGAs).
fibroma, posterior subcapsular lenticular opacities; or (4) multiple These tumors can grow and block the circulation of cerebrospinal fluid
meningiomas (2 or more) and unilateral vestibular schwannoma or around the brain and cause hydrocephalus, which requires immediate
any 2 of the following: schwannoma, glioma, neurofibroma, cataract. neurosurgical intervention. Thus, it is recommended that all asymp-
Symptoms of tinnitus, hearing loss, facial weakness, headache, or tomatic TSC patients undergo brain MRI every 1-3 yr to monitor for
unsteadiness may appear during childhood, although signs of a cere- new occurrence of SEGA. Patients with large or growing SEGA, or with
bellopontine angle mass are more commonly present in the 2nd and SEGA causing ventricular enlargement but yet are still asymptomatic,
3rd decades of life. Although café-au-lait macules and skin neurofibro- should undergo MRI scans more frequently and the patients and their
mas are classic findings in NF-1, they are much less common in NF-2. families should be educated regarding the potential of new symptoms
Posterior subcapsular lens opacities are identified in approximately due to increased intracranial pressure. Surgical resection should be
50% of patients with NF-2. The NF-2 gene (which codes for a protein performed for acutely symptomatic SEGA. For growing but otherwise
known as merlin or schwannomin) is located on chromosome 22q1.11. asymptomatic SEGA, either surgical resection or medical treatment
Table 596-2 notes the frequency of lesions in NF-2. with an mTOR inhibitor may be used. Presymptomatic treatment with
Legius syndrome (caused by SPRED1 mutations) resembles a mild everolimus is effective in slowing the growth or even reducing the size
form of NF-1. Patients with Legius syndrome present with multiple of SEGAs. Everolimus is also effective in treating refractory seizures
café-au-lait macules and macrocephaly, with and without skinfold and reducing the volume of renal angiomyolipomas and lymphangi-
freckling. However, other typical features of NF-1, such as Lisch oleiomyomatosis as well as facial angiofibromas.
nodules, neurofibromas, optic nerve gliomas, and malignant periph- The most common neurologic manifestations of TSC consist of epi-
eral nerve sheath tumors, are not seen with SPRED1 mutations. lepsy, cognitive impairment, and autism spectrum disorders. TSC may
present during infancy with infantile spasms and a hypsarrhythmic
Bibliography is available at Expert Consult. electroencephalogram pattern. However, it is important to remember
Chapter 596 ◆ Neurocutaneous Syndromes 2877.e1
Bibliography Hyman SL, Shores A, North KN: The nature and frequency of cognitive deficits in
Baser ME, R Evans DG, Gutmann DH: Neurofibromatosis 2, Curr Opin Neurol children with neurofibromatosis type 1, Neurology 65(7):1037–1044, 2005.
16(1):27–33, 2003. Isaacs H Jr: Perinatal neurofibromatosis: Two case reports and review of the
Blakeley JO, Evans DG, Adler J, et al: Consensus recommendations for current literature, Am J Perinatol 27:285–292, 2010.
treatments and accelerating clinical trials for patients with neurofibromatosis Koss M, Scott RM, Irons MB, et al: Moyamoya syndrome associated with
type 2, Am J Med Genet A 158(1):24–41, 2012. neurofibromatosis type 1: perioperative and long-term outcome after surgical
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supervision for children with neurofibromatosis, Pediatrics 121(3):633–642,
2008.
A B C
RVOT
Tumour
TV
PV
RA
AOV PA
LA
D E F
Figure 596-5 Dermatologic, cardiac, and pulmonary manifestations of tuberous sclerosis. A, Hypomelanotic macules. B, Facial angiofibromas.
C, Shagreen patch. D, Hyperechoic rhabdomyoma detected by echocardiography. E, Retinal hamartoma. F, Lymphangioleiomyomatosis. (From
Curatolo P, Bombardieri R, Jozwiak S: Tuberous sclerosis, Lancet 372:657–668, 2008, Fig. 7.)
Table 596-3 Major Features of TSC

Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Facial angiofibroma or forehead plaque
Ungual or periungual fibroma (non-traumatic)
Hypomelanotic macules (>3)
Shagreen patch
Multiple retinal hamartomas
Cardiac rhabdomyoma
Renal angiomyolipoma
Pulmonary lymphangioleiomyomatosis
Table 596-4 Minor Features of TSC

Cerebral white matter migration lines
Figure 596-6 A mulberry lesion involving the superior part of the
optic nerve in a patient with tuberous sclerosis. (From Yanoff M,
Multiple dental pits
Sassani JW: Ocular pathology, ed 7, Philadelphia, 2015, WB Saunders,
Gingival fibromas
Fig. 2-7.)
Bone cysts
Retinal achromatic patch
Confetti skin lesions
Nonrenal hamartomas SKIN LESIONS
Multiple renal cysts More than 90% of patients show the typical hypomelanotic macules
Hamartomatous rectal polyps
that have been likened to an ash leaf on the trunk and extremities.
Visualization of the hypomelanotic macule is enhanced by the use
of a Wood ultraviolet lamp (see Chapter 653). To count as a major
that you can have infantile spasms without hypsarrhythmia in TSC feature, at least three hypomelanotic macules must be present (see
patients. The seizures may be difficult to control and, at a later age, they Fig. 596-5). Facial angiofibromas develop between 4 and 6 yr of age;
may develop into myoclonic epilepsy (see Chapter 593). Vigabatrin is they appear as tiny red nodules over the nose and cheeks and are
the first-line therapy for infantile spasms. ACTH can be used if treat- sometimes confused with acne (see Fig. 596-5). Later, they enlarge,
ment with vigabatrin fails. Anticonvulsant therapy of other seizure coalesce, and assume a fleshy appearance. A shagreen patch is also
types in TSC should generally follow that of other epilepsies, and epi- characteristic of TSC and consists of a roughened, raised lesion with
lepsy surgery should be considered for medically refractory TSC an orange-peel consistency located primarily in the lumbosacral region
patients. (see Fig. 596-5). During adolescence or later, small fibromas or nodules
A B
Figure 596-7 Tuberous sclerosis. A, CT scan with subependymal calcifications characteristic of tuberous sclerosis. B, The MRI demonstrates
multiple subependymal nodules in the same patient (black arrow). Parenchymal tubers are also visible on both the CT and the MRI scan as low-
density areas in the brain parenchyma.
The current recommendation is to follow the angiomyolipoma by

yearly imaging, and when the size of the lesion reaches more than
4 cm, to use transcatheter tumor embolization for treatment. Single or
multiple renal cysts are also commonly present in TSC. Lymphangi-
oleiomyomatosis is the classical pulmonary lesion in TSC and only
affects women after the age of 20 yr.
Diagnosis of TSC relies on a high index of suspicion when assessing
a child with infantile spasms. A careful evaluation for the typical skin
and retinal lesions should be completed in all patients with a seizure
disorder or autism spectrum disorder. Brain MRI confirms the diag-
nosis in most cases. Genetic testing for TSC1 and TSC2 mutations is
available and may be considered when the individual patient does not
meet all the clinical criteria. Prenatal testing may be offered when a
known TSC mutation exists in that family.
Figure 596-8 Periungual fibroma in a patient tuberous sclerosis MANAGEMENT

complex (TSC). As for routine follow-up of individuals with TSC, the following are
recommended in addition to physical examination: brain MRI every
1-3 yr, renal imaging (US, CT or MRI) every 1-3 yr and neurode-
of skin may form around fingernails or toenails in 15-20% of the TSC velopmental testing at the time of beginning 1st grade. Based on
patients (Fig. 596-8). the complications of the disease, additional follow-up testing may
be required for each individual. Symptoms and signs of increased
OTHER ORGAN INVOLVEMENT intracranial pressure suggest obstruction of the foramen of Monro
Approximately 50% of children with TSC have cardiac rhabdomyomas, by a SEGA and warrant immediate investigation and surgical
which may be detected in the fetus at by an echocardiogram. The intervention.
rhabdomyomas may be numerous or located at the apex of the left
ventricle, and although they can cause congestive heart failure and Bibliography is available at Expert Consult.
arrhythmias in a minority of patients, they tend to slowly resolve spon-
taneously. In 75-80% of patients older than 10 yr of age, the kidneys
display angiomyolipomas that are usually benign tumors. Angiomyo-
lipomas begin in childhood in many individuals with TSC, but they 596.3 Sturge-Weber Syndrome
may not be problematic until young adulthood. By the third decade of Mustafa Sahin
life, they may cause lumbar pain and hematuria from slow bleeding,
and rarely they may result in sudden retroperitoneal bleeding. Embo- Sturge-Weber syndrome (SWS) is a sporadic vascular disorder and
lization followed by corticosteroids is first-line therapy for angiomyo- consists of a constellation of symptoms and signs including a facial
lipoma presenting with acute hemorrhage. Nephrectomy should be capillary malformation (port-wine stain), abnormal blood vessels of
avoided. For asymptomatic, growing angiomyolipomas measuring the brain (leptomeningeal angioma) and abnormal blood vessels of the
larger than 3 cm in diameter, an mTOR inhibitor, everolimus, is FDA- eye leading to glaucoma. Patients present with seizures, hemiparesis,
approved for treatment. Selective embolization or kidney-sparing stroke-like episodes, headaches, and developmental delay. Approxi-
resection is alternative therapies for asymptomatic angiomyolipoma. mately 1 in 50,000 live births are affected with SWS.
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J Urol 174(5):1764–1766, 2005.
ETIOLOGY least 50% in later childhood, probably the result of intractable epilepsy
The sporadic incidence and focal nature of SWS suggests the presence and increasing cerebral atrophy.
of somatic mutations. Whole-genome sequencing from affected and
unaffected skin of 3 patients with SWS identified a single-nucleotide DIAGNOSIS
variant (c.548G→A, p.Arg183Gln) in the GNAQ gene. This mutation MRI with contrast is the imaging modality of choice for demonstrating
has been confirmed in samples of affected tissue from 88% of a larger the leptomeningeal angioma in SWS (Fig. 596-10). White matter
cohort of SWS patients as well as 92% of the participants with appar- abnormalities are common and are thought to be a result of chronic
ently nonsyndromic port-wine stains. Brain tissue from SWS patients hypoxia. Often, atrophy is noted ipsilateral to the leptomeningeal angi-
also demonstrated the same change in the GNAQ gene. These results omatosis. Calcifications can be seen best with a head CT (Fig. 596-11).
strongly suggest that SWS occurs as a result of mosaic mutations
in GNAQ.
The condition is thought to result from anomalous development of
the embryonic vascular bed in the early stages of facial and cerebral
development. There are hypotheses about aberrant sympathetic inner-
vation, increased vascular growth factors and defects in extracellular
matrix, but these remain to be tested. Low flow angiomatosis of the
leptomeninges appears to result in a chronic hypoxic state leading to
cortical atrophy and calcifications.
The facial port-wine stain is present at birth, tends to be unilateral, and
always involves the upper face and eyelid, in a distribution consistent
with the ophthalmic division of the trigeminal nerve (Fig. 596-9). The
capillary malformation may also be evident over the lower face, trunk,
and in the mucosa of the mouth and pharynx. It is important to note
that not all children with facial port-wine stain have SWS even though
the genetic defect appears to be the same. In fact, the overall incidence
of SWS has been reported to be 8-33% in those with a port-wine stain.
Buphthalmos and glaucoma of the ipsilateral eye are common compli-
cations. The incidence of epilepsy in patients with SWS is 75-90%,
and seizures develop in most patients in the 1st yr of life. They are
typically focal tonic–clonic and contralateral to the side of the facial
capillary malformation. The seizures may become refractory to anti-
convulsants and are associated with a slowly progressive hemiparesis
in many cases. Transient stroke-like episodes or visual defects persist-
ing for several days and unrelated to seizure activity are common and
probably result from thrombosis of cortical veins in the affected region. Figure 596-10 Gadolinium-enhanced axial T1 fluid-attenuated inver-
Although neurodevelopment appears to be normal in the 1st yr of life, sion recovery (FLAIR) images of a 15 mo old with Sturge-Weber syn-
intellectual disability or severe learning disabilities are present in at drome shows leptomeningeal enhancement in left hemisphere.
Figure 596-11 CT scan of a patient with Sturge-Weber syndrome

Figure 596-9 Port-wine stain involving both V1 and V2 dermatomes. showing unilateral calcification and underlying atrophy of a cerebral
(Courtesy of Dr. Anne W. Lucky, Cincinnati Children’s Hospital.) hemisphere.
Ophthalmologic evaluation examining for glaucoma is also necessary.

Based on the involvement of the brain and the face, there are 3 types 596.5 Linear Nevus Syndrome
of SWS according to the Roach Scale: Mustafa Sahin
1. Type I—Both facial and leptomeningeal angiomas; may have
glaucoma This sporadic condition is characterized by a facial nevus and neuro-
2. Type II—Facial angioma alone (no central nervous system developmental abnormalities. The nevus is located on the forehead and
involvement); may have glaucoma nose and tends to be midline in its distribution. It may be quite faint
3. Type III—Isolated leptomeningeal angiomas; usually no during infancy but later becomes hyperkeratotic, with a yellow-brown
glaucoma appearance. Two thirds of the patients with linear nevus syndrome
demonstrate associated neurologic findings, including cortical dyspla-
MANAGEMENT sia, glial hamartomas, and low-grade gliomas. Cerebral and cranial
Management of SWS is symptomatic and multidisciplinary but not anomalies, predominantly hemimegalencephaly and enlargement of
well studied by prospective studies. It is aimed at seizure control, treat- the lateral ventricles, were reported in 72% of cases. The incidence of
ment of headaches, and prevention of stroke-like episodes, as well as epilepsy has been reported as high as 75% and intellectual disability as
monitoring of glaucoma and laser therapy for the cutaneous capillary high as 60%. Focal neurologic signs including hemiparesis and hom-
malformations. Seizures beginning in infancy are not always associated onymous hemianopia may also be seen.
with a poor neurodevelopmental outcome. For patients with well-
controlled seizures and normal or near-normal development, manage- Bibliography is available at Expert Consult.
ment consists of anticonvulsants and surveillance for complications
including glaucoma, buphthalmos, and behavioral abnormalities. If the
seizures are refractory to anticonvulsant therapy, especially in infancy
and the 1st 1-2 yr, and arise from primarily 1 hemisphere, most medical 596.6 PHACE Syndrome
centers advise a hemispherectomy. Because of the risk of glaucoma, Mustafa Sahin
regular measurement of intraocular pressure is indicated. The facial
port-wine stain is often a target of ridicule by classmates, leading to See also Chapter 650.
psychologic trauma. Pulsed-dye laser therapy often provides excellent The syndrome denotes posterior fossa malformations, hemangio-
clearing of the port-wine stain, particularly if it is located on the mas, arterial anomalies, coarctation of the aorta and other cardiac
forehead. defects, and eye abnormalities. It is also referred to as PHACES syn-
drome when ventral developmental defects, including sternal clefting
Bibliography is available at Expert Consult. and/or a supraumbilical raphe, are present. Large facial hemangiomas
may be associated with a Dandy-Walker malformation, vascular anom-
alies (coarctation of aorta, aplasia or hypoplastic carotid arteries, aneu-
rysmal carotid dilation, aberrant left subclavian artery), glaucoma,
cataracts, microphthalmia, optic nerve hypoplasia, and ventral defects
596.4 Von Hippel-Lindau Disease (sternal clefts). The facial hemangioma is typically ipsilateral to the
Mustafa Sahin aortic arch. The Dandy-Walker malformation is the most common
developmental abnormality of the brain. Other anomalies include
von Hippel-Lindau disease affects many organs, including the cerebel- hypoplasia or agenesis of the cerebellum, cerebellar vermis, corpus
lum, spinal cord, retina, kidney, pancreas, and epididymis. Its inci- callosum, cerebrum, and septum pellucidum. Cerebrovascular anoma-
dence is around 1 in 36,000 newborns. It results from an autosomal- lies can result in acquired, progressive vessel stenosis and acute isch-
dominant mutation affecting a tumor suppressor gene, VHL. emic stroke. According to a case series of 29 children with PHACE
Approximately 80% of individuals with von Hippel-Lindau syndrome syndrome, 44% had language delay, 36% gross motor delay, and 8%
have an affected parent, and approximately 20% have a de novo gene fine motor delay; 52% had an abnormal neurologic exam, with speech
mutation. Molecular testing is available and detects mutations in abnormalities as the most common finding. Overall, there is a female
almost 100% of probands. predominance. The underlying pathogenesis of PHACE syndrome
The major neurologic features of the condition include cerebellar remains unknown. Propranolol is starting to be used for treatment of
hemangioblastomas and retinal angiomas. Patients with cerebellar the infantile hemangiomas associated with PHACE syndrome.
hemangioblastoma present in early adult life with symptoms and
signs of increased intracranial pressure. A smaller number of patients Bibliography is available at Expert Consult.
have hemangioblastoma of the spinal cord, producing abnormalities
of proprioception and disturbances of gait and bladder dysfunction.
A CT or MRI scan typically shows a cystic cerebellar lesion with
a vascular mural nodule. Total surgical removal of the tumor is 596.7 Incontinentia Pigmenti
curative. Mustafa Sahin
Approximately 25% of patients with cerebellar hemangioblastoma
have retinal angiomas. Retinal angiomas are characterized by small This rare, heritable, multisystem ectodermal disorder features derma-
masses of thin-walled capillaries that are fed by large and tortuous tologic, dental, and ocular abnormalities. The phenotype is produced
arterioles and venules. They are usually located in the peripheral retina by functional mosaicism caused by random X-inactivation of an
so that vision is unaffected. Exudation in the region of the angiomas X-linked dominant gene that is lethal in males (IKBKG [inhibitor of
may lead to retinal detachment and visual loss. Retinal angiomas are kappa B kinase gamma, previously NEMO] gene). The paucity of
treated with photocoagulation and cryocoagulation, and both have affected males, the occurrence of female-to-female transmission, and
produced good results. an increased frequency of spontaneous abortions in carrier females
Cystic lesions of the kidneys, pancreas, liver, and epididymis as well support this supposition.
as pheochromocytoma are frequently associated with von Hippel-
Lindau disease. Renal carcinoma is the most common cause of death. CLINICAL MANIFESTATIONS AND DIAGNOSIS
Regular follow-up and appropriate imaging studies are necessary to This disease has 4 phases, not all of which may occur in a given patient.
identify lesions that may be treated at an early stage. The 1st phase is evident at birth or in the 1st few wk of life and
consists of erythematous linear streaks and plaques of vesicles (Fig.
Bibliography is available at Expert Consult. 596-12) that are most pronounced on the limbs and circumferentially
Bibliography Shirley MD, Tang H, Gallione CJ, et al: Sturge-Weber syndrome and port-wine
Comi AM: Advances in Sturge-Weber syndrome, Curr Opin Neurol 19(2):124–128, stains caused by somatic mutation in GNAQ, N Engl J Med 368(21):1971–1979,
2006. 2013.
Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Tan OT, Sherwood K, Gilchrest BA: Treatment of children with port-wine stains
Sturge-Weber syndrome worldwide, Neurology 59:1735–1738, 2002. using the flashlamp-pulsed tunable dye laser, N Engl J Med 320:416–421, 1989.
2881.e2 Chapter 596 ◆ Neurocutaneous Syndromes
Bibliography Maher ER, Neumann HP, Richard S: von Hippel-Lindau disease: a clinical and
Latif F, Tory K, Gmarra J, et al: Identification of the von Hippel-Lindau disease scientific review, Eur J Hum Genet 19:617–623, 2011.
tumor suppressor gene, Science 260:1317–1320, 1993.
Maher ER, Kaelin WG Jr: von Hippel-Lindau disease, Medicine (Baltimore)
76:381–391, 1997.
Bibliography
Menascu S, Donner EJ: Linear nevus sebaceous syndrome: case reports and review
of the literature, Pediatr Neurol 38(3):207–210, 2008.
2881.e4 Chapter 596 ◆ Neurocutaneous Syndromes
Bibliography Poetke M, Frommeld T, Berlien HP: PHACE Syndrome: new views on diagnostic
Drolet BA, Frommelt PC, Chamlin SL, et al: Initiation and use of propranolol for criteria, Eur J Pediatr Surg 12:366–374, 2002.
infantile hemangioma: report of a consensus conference, Pediatrics 131:128– Tangtiphaiboontana J, Hess CP, Bayer M, et al: Neurodevelopmental Abnormalities
140, 2013. in Children with PHACE Syndrome, J Child Neurol 28:608–614, 2013.
Metry DW, Dowd CF, Barkovich AJ, et al: The many faces of PHACE syndrome,
J Pediatr 139:117–123, 2001.
detected. Differential diagnosis includes hypomelanosis of Ito, which
presents with similar skin manifestations and is often associated with
chromosomal mosaicism.
MANAGEMENT
The choice of investigative studies and the plan of management depend
on the occurrence of particular noncutaneous abnormalities since the
skin lesions are benign. The high incidence of associated major anoma-
lies warrants genetic counseling.
Figure 596-12 Whorled vesicular phase of incontinentia pigmenti.
on the trunk. The lesions may be confused with those of herpes

simplex, bullous impetigo, or mastocytosis, but the linear configura-
tion is unique. Histopathologically, epidermal edema and eosinophil-
filled intraepidermal vesicles are present. Eosinophils also infiltrate the
adjacent epidermis and dermis. Blood eosinophilia as high as 65% of
the white blood cell count is common. The 1st stage generally resolves
by 4 mo of age, but mild, short-lived recurrences of blisters may
develop during febrile illnesses. In the 2nd phase, as blisters on the
distal limbs resolve, they become dry and hyperkeratotic, forming ver-
rucous plaques. The verrucous plaques rarely affect the trunk or face
and generally involute within 6 mo. Epidermal hyperplasia, hyperkera-
tosis, and papillomatosis are characteristic. The 3rd or pigmentary
stage is the hallmark of incontinentia pigmenti. It generally develops
over weeks to months and may overlap the earlier phases, be evident
at birth, or, more commonly, begin to appear in the 1st few wk of
life. Hyperpigmentation is more often apparent on the trunk than the
limbs and is distributed in macular whorls, reticulated patches, flecks,
and linear streaks that follow Blaschko lines. The axillae and groin are
invariably affected. The sites of involvement are not necessarily those
of the preceding vesicular and warty lesions. The pigmented lesions,
once present, persist throughout childhood. They generally begin to
fade by early adolescence and often disappear by age 16 yr. Occasion-
ally, the pigmentation remains permanently, particularly in the groin.
The lesion, histopathologically, shows vacuolar degeneration of the
epidermal basal cells and melanin in melanophages of the upper
dermis as a result of incontinence of pigment. In the 4th stage, hairless,
anhidrotic, hypopigmented patches or streaks occur as a late manifes-
tation of incontinentia pigmenti; they may develop, however, before
the hyperpigmentation of stage 3 has resolved. The lesions develop
mainly on the flexor aspect of the lower legs and less often on the arms
and trunk.
Approximately 80% of affected children have other defects. Alope-
cia, which may be scarring and patchy or diffuse, is most common on
the vertex and occurs in up to 40% of patients. Hair may be lusterless,
wiry, and coarse. Dental anomalies, which are present in up to 80% of
patients and are persistent throughout life, consist of late dentition,
hypodontia, conical teeth, and impaction. Central nervous system
manifestations, including seizures, intellectual disability, hemiplegia,
hemiparesis, spasticity, microcephaly, and cerebellar ataxia, are found
in up to 30% of affected children. Ocular anomalies, such as neovas-
cularization, microphthalmos, strabismus, optic nerve atrophy, cata-
racts, and retrolenticular masses, occur in >30% of children.
Nonetheless, >90% of patients have normal vision. Less common
abnormalities include dystrophy of nails (ridging, pitting) and skeletal
defects.
Diagnosis of incontinentia pigmenti is made on clinical grounds,
although major and minor criteria have been established to aid in
diagnosis. Wood’s lamp examination may be useful in older children
and adolescents to highlight pigmentary abnormalities. Clinical
molecular testing is available, and in 80% of the affected patients a
deletion that removes exons 4 through 10 of IKBKG gene can be
Bibliography Smahi A, Courtois G, Vabres P, et al: Genomic rearrangement in NEMO impairs

Bruckner AL: Incontinentia pigmenti: A window to the role of NF-kappaB NF-kappaB activation and is a cause of incontinentia pigmenti. The
function, Semin Cutan Med Surg 23:116–124, 2004. International Incontinentia Pigmenti (IP) Consortium, Nature 405:466–472,
Meuwissen ME, Mancini GM: Neurological findings in incontinentia pigmenti; a 2000.
review, Eur J Med Genet 55:323–331, 2012.
Minić S, Trpinac D, Obradović M: Systematic review of central nervous system
anomalies in incontinentia pigmenti, Orphanet J Rare Dis 8:25, 2013.
Chapter 597
Movement Disorders
Jonathan W. Mink
Movement disorders are characterized by abnormal or excessive invol-

untary movements that may result in abnormalities in posture, tone,
balance, or fine motor control. Most movement disorders in children
are characterized by involuntary movements. These involuntary move-
ments can represent the sole disease manifestation, or they may be one
of many signs and symptoms.
Evaluation of movement disorders begins with a comprehensive
history and careful neurologic examination. It is often difficult for
children and caregivers to describe abnormal movements, which
makes observation of the movements by the clinician an essential
component of the evaluation. If the movements are not apparent at the
time of the examination, video examples from home or school can be
invaluable. With the increasing availability of high quality video capa-
bility on cellular phones, obtaining a short video is feasible for most
families. Resources are available to guide families in gathering useful
video data.
There is no specific diagnostic test to differentiate among movement
disorders. The category of movement assists in localizing the pathologic
process, whereas the onset, age, and degree of abnormal motor activity
and associated neurologic findings help organize the investigation.
When considering the type of movement disorder, the following
questions concerning the history and examination of the movement
are helpful.
◆ What is the distribution of the movements across body parts?
◆ Are the movements symmetric?
◆ What is the speed of the involuntary movements? Are they rapid
and fast or slow and sustained?
◆ When do the movements occur? Are they present at rest? Are they
present with maintained posture or with voluntary actions?
◆ Are the movements seen in relation to certain postures or boy
positions?
◆ Do the abnormal movements occur only with specific tasks?
◆ Can the child voluntarily suppress the movements, even for a
short time?
◆ Are the movements stereotyped?
◆ Are the movements rhythmic?
◆ What is the temporal pattern of the movements? Are they
continuous or intermittent? Do they occur in discrete episodes?
◆ Are the involuntary movements preceded by an urge to make the
movement?
◆ Do the movements persist during sleep?
◆ Are the movements associated with impairment of motor
function?
◆ What factors aggravated or alleviate the movements?
Chapter 597 ◆ Movement Disorders 2883
Table 597-1 Selected Types of Involuntary Movement in Childhood

TYPE CHARACTERISTICS
Stereotypies (see Chapter 24) Involuntary, patterned, coordinated, repetitive, rhythmic movements that occur in the same fashion with
each repetition
Tics (see Chapter 24) Involuntary, sudden, rapid, abrupt, repetitive, nonrhythmic, simple or complex motor movements or
vocalizations (phonic productions). Tics are usually preceded by an urge that is relieved by carrying out
the movement
Tremor Oscillating, rhythmic movements about a fixed point, axis, or plane
Dystonia (see Chapter 597.3) Intermittent and sustained involuntary muscles contractions that produce abnormal postures and
movements of different parts of the body, often with a twisting quality
Chorea (see Chapter 597.2) Involuntary, continual, irregular movements or movement fragments with variable rate and direction that
occur unpredictably and randomly
Ballism Involuntary, high amplitude, flinging movements typically occurring proximally. Ballism is essentially a large
amplitude chorea
Athetosis Slow, writhing, continuous, involuntary movements
Myoclonus Sudden, quick, involuntary muscle jerks
The first decision to be made is whether the movement disorder is Joubert syndrome, but only approximately 50% of cases have a dem-
“hyperkinetic”(characterized by excessive and involuntary move- onstrated causal mutation (see Chapter 591).
ments) or “hypokinetic” (characterized by slow voluntary movements The major infectious causes of ataxia include cerebellar abscess,
and a general paucity of movement). Hyperkinetic movement disor- acute labyrinthitis, and acute cerebellar ataxia. Acute cerebellar ataxia
ders are much more common than hypokinetic disorders in children. occurs primarily in children 1-3 yr of age and is a diagnosis of exclu-
Once the category of movement disorder is recognized, etiology can sion. The condition often follows a viral illness, such as varicella virus,
be considered. Clinical history, including birth history, medication/ coxsackievirus, or echovirus infection by 2-3 wk and is thought to
toxin exposure, trauma, infections, family history, progression of the represent an autoimmune response to the viral agent affecting the
involuntary movements, developmental progress, and behavior should cerebellum (see Chapters 250, 253, and 603). The onset is sudden, and
be explored as the underlying cause is established. Table 597-1 lists the truncal ataxia can be so severe that the child is unable to stand or
types and clinical characteristics of selected hyperkinetic movement sit. Vomiting may occur initially, but fever and nuchal rigidity are
disorders. absent. Horizontal nystagmus is evident in approximately 50% of cases
and, if the child is able to speak, dysarthria may be impressive. Exami-
nation of the cerebrospinal fluid is typically normal at the onset of
ataxia but a mild lymphocytic pleocytosis (10-30/mm3) is not unusual.
597.1 Ataxias Later in the course, the cerebrospinal fluid protein undergoes a moder-
Denia Ramirez-Montealegre and Jonathan W. Mink ate elevation. The ataxia begins to improve in a few weeks but may
persist for as long as 3 mo and rarely longer than that. The incidence
Ataxia is the inability to make smooth, accurate, and coordinated of acute cerebellar ataxia appears to have declined with increased rates
movements, usually because of a dysfunction of the cerebellum, its of vaccination against varicella. The prognosis for complete recovery
inputs or outputs, sensory pathways in the posterior columns of the is excellent; a small number have long-term sequelae, including behav-
spinal cord, or a combination of these. Ataxias may be generalized or ioral and speech disorders as well as ataxia and incoordination. Acute
primarily affect gait or the hands and arms or trunk; they may be acute cerebellitis in contrast is a more severe form of cerebellar ataxia dem-
or chronic; acquired or genetic (Tables 597-2 to 597-5). onstrating abnormal MRI scans, more severe symptoms, and a poorer
Signs and symptoms of ataxia include clumsiness, difficulty walking long-term prognosis. Infectious agents include Epstein-Barr virus,
or sitting, falling to 1 side, slurred speech, hypotonia, intention tremor, mycoplasma, mumps, and influenza virus, although in many the etiol-
dizziness, and delayed motor development. Genetic or chronic causes ogy is unknown; autoimmune cerebellitis may represent some of these
of cerebellar ataxia are often characterized by a long duration of symp- unknown cases. Patients may present with ataxia, increased intracra-
toms, a positive family history, muscle weakness and abnormal gait, nial pressure from obstructive hydrocephalus, headache and fever.
abnormal tone and strength, abnormal deep tendon reflexes, pes cavus, Acute labyrinthitis may be difficult to differentiate from acute cerebel-
and sensory defects. Distinguishing ataxia from vestibular dysfunction lar ataxia in a toddler. The condition is associated with middle-ear
may be difficult; however, labyrinth disorders are often characterized infections and presents with intense vertigo, vomiting, and abnormali-
by severe vertigo, nausea and vomiting, position-induced vertigo, and ties in labyrinthine function.
a severe sense of unsteadiness. Toxic causes of ataxia include alcohol, thallium (which is used
Congenital anomalies of the posterior fossa, including the Dandy- occasionally in homes as a pesticide), and the anticonvulsants, particu-
Walker malformation, Chiari malformation, and encephalocele, are larly phenytoin and carbamazepine when serum levels exceed the usual
prominently associated with ataxia because of their destruction or therapeutic range.
replacement of the cerebellum (see Chapter 591.9). MRI is the method Brain tumors (see Chapter 497), including tumors of the cerebellum
of choice for investigating congenital abnormalities of the cerebellum, and frontal lobe, as well as peripheral nervous system neuroblastoma,
vermis, and related structures. Agenesis of the cerebellar vermis pres- may present with ataxia. Cerebellar tumors cause ataxia because of
ents in infancy with generalized hypotonia and decreased deep-tendon direct disruption of cerebellar function or indirectly because of
reflexes. Delayed motor milestones and truncal ataxia are typical. increased intracranial pressure from compression of the fourth ven-
Joubert syndrome and related disorders are autosomal recessive dis- tricle. Frontal lobe tumors may cause ataxia as a consequence of
orders marked by developmental delay, hypotonia, abnormal eye destruction of the association fibers connecting the frontal lobe with
movements, abnormal respirations, and a distinctive malformation of the cerebellum or because of increased intracranial pressure. Neuro-
the cerebellum and brainstem that manifests as the “molar tooth sign” blastoma (see Chapter 498) may be associated with a paraneoplastic
on MRI. Mutations in more than 21 different genes are associated with encephalopathy characterized by progressive ataxia, myoclonic jerks,
Table 597-2 Selected Causes of Ataxia in Childhood

CONGENITAL METABOLIC
• Agenesis of vermis of the cerebellum • Abetalipoproteinemia
• Aplasia or dysplasia of the cerebellum • Argininosuccinic aciduria
• Basilar impression • Ataxia with vitamin E deficiency (AVED)
• Cerebellar dysplasia with microgyria, macrogyria, or agyria • Congenital disorders of glycosylation
• Cervical spinal bifida with herniation of the cerebellum (Chiari • GM2 gangliosidosis (late)
malformation type 3) • Hartnup disease
• Chiari malformation • Hyperalaninemia
• Dandy-Walker syndrome • Hyperammonemia I and II (urea cycle defects)
• Encephalocele • Hypoglycemia
• Hydrocephalus (progressive) • Kearns-Sayre syndrome
• Hypoplasia of the cerebellum • Leigh disease
• Maple syrup urine disease (intermittent)
DEGENERATIVE AND/OR GENETIC
• Myoclonic epilepsy with ragged red fibers (MERRF)
• Acute intermittent cerebellar ataxia
• Metachromatic leukodystrophy
• Ataxia, retinitis pigmentosa, deafness, vestibular abnormality, and
• Mitochondrial complex defects (I, III, IV)
intellectual deterioration
• Multiple carboxylase deficiency (biotinidase deficiency)
• Ataxia-telangiectasia
• Neuronal ceroid-lipofuscinosis
• Biemond posterior column ataxia
• Neuropathy, ataxia, retinitis pigmentosa (NARP)
• Cerebellar ataxia with deafness, anosmia, absent caloric responses,
• Niemann-Pick disease (late infantile)
nonreactive pupils, and hyporeflexia
• 5-Oxoprolinuria
• Cockayne syndrome
• Pyruvate decarboxylase deficiency
• Dentate cerebellar ataxia (dyssynergia cerebellaris progressiva)
• Refsum disease
• Familial ataxia with macular degeneration
• Sialidosis
• Friedreich ataxia
• Triose-phosphate isomerase deficiency
• Hereditary cerebellar ataxia, intellectual retardation,
• Tryptophanuria
choreoathetosis, and eunuchoidism
• Wernicke encephalopathy
• Hereditary cerebellar ataxia with myotonia and cataracts
• Hypertrophic interstitial neuritis NEOPLASTIC
• Marie ataxia • Frontal lobe tumors
• Marinesco-Sjögren syndrome • Hemispheric cerebellar tumors
• Multiple-system atrophy • Midline cerebellar tumors
• Pelizaeus-Merzbacher disease • Neuroblastoma
• Periodic attacks of vertigo, diplopia, and ataxia–autosomal- • Pontine tumors (primarily gliomas)
dominant inheritance • Spinal cord tumors
• Posterior and lateral column difficulties, nystagmus, and muscle
atrophy PRIMARY PSYCHOGENIC
• Progressive cerebellar ataxia and epilepsy • Conversion reaction
• Ramsay Hunt syndrome (myoclonic seizures and ataxia) TOXIC
• Roussy-Lévy disease • Alcohol
• Spinocerebellar ataxia (SCA); olivopontocerebellar ataxias • Benzodiazepines
• Vanishing white matter syndrome • Carbamazepine
ENDOCRINOLOGIC • Clonazepam
• Acquired hypothyroidism • Lead encephalopathy
• Cretinism • Neuroblastoma
• Phenobarbital
INFECTIOUS, POSTINFECTIOUS, INFLAMMATORY • Phenytoin
• Acute cerebellar ataxia • Primidone
• Acute disseminated encephalomyelitis • Tic paralysis poisoning
• Autoimmune (anti-glutamic acid decarboxylase, anti–γ-aminobutyric
acidB receptor antibodies) TRAUMATIC
• Cerebellar abscess • Acute cerebellar edema
• Cerebellitis • Acute frontal lobe edema
• Coxsackievirus VASCULAR
• Diphtheria • Angioblastoma of cerebellum
• Echovirus • Basilar migraine
• Fisher syndrome • Cerebellar embolism
• Infectious mononucleosis (Epstein-Barr virus infection) • Cerebellar hemorrhage
• Infectious polyneuropathy • Cerebellar thrombosis
• Japanese B encephalitis • Posterior cerebellar artery disease
• Mumps encephalitis • Vasculitis
• Mycoplasma pneumonia • von Hippel-Lindau disease
• Paraneoplastic (opsoclonus-myoclonus-ataxia syndrome)
• Pertussis
• Polio
• Postbacterial meningitis
• Rubeola
• Tuberculosis
• Typhoid
• Varicella
Modified from Jafar-Nejad P, Maricich SM, Zoghbi HY: The cerebellum and the hereditary ataxias. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors:
Swaiman’s pediatric neurology, ed 5, Philadelphia, 2012, WB Saunders, Box 67-1.
Table 597-3 Treatable Causes of Inherited Ataxia

DISTINGUISHING CLINICAL
DISORDER METABOLIC ABNORMALITY FEATURES TREATMENT
Acute disseminated Demyelination Positive MRI findings Steroids, IVIG, rituximab
encephalomyelitis
Ataxia with vitamin E Mutation in α-tocopherol Ataxia, areflexia, retinopathy Vitamin E
deficiency transfer protein
Bassen-Kornzweig syndrome Abetalipoproteinemia Acanthocytosis, retinitis Vitamin E
pigmentosa, fat malabsorption
Hartnup disease Tryptophan malabsorption Pellagra rash, intermittent ataxia Niacin
Familial episodic ataxia type 1 Mutations in potassium channel Episodic attacks, worse with Acetazolamide
and type 2 (KCNA1) and α1A voltage-gated pregnancy or birth control pills
calcium channel, respectively
Multiple carboxylase deficiency Biotinidase deficiency Alopecia, recurrent infections, Biotin
variable organic aciduria
Mitochondrial complex defects Complexes I, III, IV Encephalomyelopathy Possibly riboflavin, CoQ10,
dichloroacetate
Opsoclonus-myoclonus-ataxia Paraneoplastic or spontaneous Underlying neuroblastoma or Steroids, IVIG, rituximab
syndrome autoimmune autoantibodies
Pyruvate dehydrogenase Block in E-M and Krebs cycle Lactic acidosis, ataxia Ketogenic diet, possibly
deficiency interface dichloroacetate
Refsum disease Phytanic acid, α-hydroxylase Retinitis pigmentosa, Dietary restriction of
cardiomyopathy, hypertrophic phytanic acid
neuropathy, ichthyosis
Urea cycle defects Urea cycle enzymes Hyperammonemia Protein restriction, arginine,
benzoate, α-ketoacids
CoQ10, Coenzyme Q10; E-M, mitochondrial electron transport; IVIG, intravenous immunoglobulin.
Modified from Stumpf DA: The inherited ataxias. Pediatr Neurol 1:129-133, 1985, Table 1; and from Jafar-Nejad P, Maricich SM, Zoghbi HY: The cerebellum and the
hereditary ataxias. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s pediatric neurology, ed 5, Philadelphia, 2012, WB Saunders, Table 67-1.
Table 597-4 Autosomal-Recessive Cerebellar Ataxias

ATAXIA CHROMOSOME GENE GENE PRODUCT MECHANISM AGE OF ONSET (yr)
Friedreich ataxia 9q13 X25 Frataxin GAA repeat 2-51
Friedreich ataxia 2 9p23–p11 Unknown Unknown Unknown 5-20
AVED 8q13 TTP1 TTPA Missense mutation, 2-52
deletion, insertion
Ataxia-telangiectasia 11q22.3 ATM ATM Missense and deletion Infancy
mutations
ATLD 11q21 hMRE11 MRE11A Missense and deletion 9-48 mo
mutations
Ataxia-ocular apraxia 1 9p13.3 APTX Aprataxin Frameshift, missense, 2-18
nonsense mutations
SCAR1 9q34 SETX Senataxin Frameshift, missense, 9-22
nonsense mutations
SCAR2 9q34–qter Unknown Unknown Unknown Congenital
SCAR3 6p23–p21 Unknown Unknown Unknown 3-52
SCAR4 1p36 Unknown Unknown Unknown 23-39
SCAR5 15q24–q26 Unknown Unknown Unknown 1-10
SCAR6 20q11–q13 Unknown Unknown Unknown Infancy
SCAR7 11p15 Unknown Unknown Unknown Childhood
SCAR8 11p15 SYNE1 SYNE1 Splice site mutation, 17-46
nonsense mutations
Continued
Table 597-4 Autosomal-Recessive Cerebellar Ataxias—cont’d

ATAXIA CHROMOSOME GENE GENE PRODUCT MECHANISM AGE OF ONSET (yr)
SCAR9 1q41 ADCK3 ADCK3 Splice site mutation, 3-11
missense, nonsense
mutations
Ataxia, Cayman type 19q13.3 ATCAY Caytaxin Missense mutation Birth
IOSCA 10q24 C10orf2 Twinkle Missense, silent mutations 9-24 mo
Progressive myoclonic epilepsy 21q22.3 CST6 Cystatin B 5′ dodecamer repeat 6–13
ARSACS 13q12 SACS Sacsin Frameshift and nonsense 1–20
mutations
Congenital disorders of Multiple Multiple Multiple Birth
glycosylation
ARSACS, autosomal-recessive spastic ataxia of Charlevoix-Saguenay; ATLD, ataxia-telangiectasia-like disorder; AVED, ataxia with vitamin E deficiency; IOSCA,
infantile-onset spinocerebellar ataxia; SCAR, spinocerebellar ataxia, autosomal-recessive.
From Jafar-Nejad P, Maricich SM, Zoghbi HY: The cerebellum and the hereditary ataxias. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s
pediatric neurology, ed 5, Philadelphia, 2012, WB Saunders, Table 67-2.
Table 597-5 Autosomal-Dominant Cerebellar Ataxias

DURATION
GENE AGE OF NORMAL EXPANDED OF
ATAXIA CHROMOSOME GENE PRODUCT MECHANISM ONSET (yr) REPEAT REPEAT EPISODES
POLYGLUTAMINE EXPANSION
SCA1 6p23 SCA1 Ataxin-1 CAG repeat 6-60 6-44* 39-82*
SCA2 12q24 SCA2 Ataxin-2 CAG repeat 2-65 15-24 35-59
SCA3/MJD 14q24.3-q31 MJD1 Ataxin-3 CAG repeat 11-70 13-47* 45-84*
SCA6 19q13 CACNA1A CACNA1A CAG repeat 16-v73 4-20 21-33
SCA7 3p21.1-p12 SCA7 Ataxin-7 CAG repeat Birth-53 4-35 37-460
SCA17 6q27 SCA17 TBP CAG repeat 3-48 25-42 45-66
DRPLA 12p13.31 DRPLA Atrophin-1 CAG repeat 4-55 mo 7-34 53-93
NONCODING EXPANSION
SCA8 13q21 SCA8 SCA8 RNA CTG repeat in 18-72 2-91* 110-155*
3′ UTR
SCA10 22q13 SCA10 Ataxin-10 ATTCT repeat 14-45 10-29 750-4500
in intron 9
SCA12 5q31-q33 SCA12 P2R2B CAG repeat in 8-55 7-32 55-78
5′ UTR
SCA31 16q22.1 BEAN/TK2 BEAN/TK2 TGGAA repeat 45-72 Rarely 2.5-3.8 kb
insertion in (0.23%)
intron of 1.5-2.0 kb
BEAN and TK
OTHER MUTATIONS
SCA14 19q13.4 PKC-γ PKC-γ Missense 10-69
mutation
SCA27 13q34 FGF14 FGF14 Fibroblast 15-20
growth factor
deficiency
SCA5 11p11-q11 SPTBN2 β-3 Deletion, 10-68
spectrin missense
mutations
SCA11 15q14-q21.3 TTBK2 TTBK2 Truncation 15-43
mutation
SCA13 19q13.3-q13.4 KCNC3 KCNC3 Missense <1-60
mutations
SCA15 3p24.2-3pter ITPR1 ITPR1 Deletion, Child–adult
missense
mutation
SCA28 18p11.22-q11.2. AFG3L2 AFG3L2 Missense 12-36
mutations
Table 597-5 Autosomal-Dominant Cerebellar Ataxias—cont’d

DURATION
GENE AGE OF NORMAL EXPANDED OF
ATAXIA CHROMOSOME GENE PRODUCT MECHANISM ONSET (yr) REPEAT REPEAT EPISODES
MUTATION UNKNOWN
SCA4 16q22 Unknown Unknown Unknown 19-59
SCA18/SMNA 7q31-q32 Unknown Unknown Unknown 12-25
SCA19 1p21-q21 Unknown Unknown Unknown 10-45
SCA20 11 Unknown Unknown Unknown 19-64
SCA21 7p21.3–p15.1 Unknown Unknown Unknown 6-30
SCA22 1p21-q23 Unknown Unknown Unknown 10-46
SCA23 20p13-p12.2 Unknown Unknown Unknown 43-56
SCA25 2p Unknown Unknown Unknown 1.5-39
SCA26 19p13.3 Unknown Unknown Unknown 26-60
SCA30 4q34.3-q35.1 Unknown Unknown Unknown 45-76
SAX1 12p13 Unknown Unknown Unknown Early
childhood
to early 20s
SPAR Unknown Unknown Unknown Unknown 15-35
EPISODIC ATAXIA
EA1 12p13 EA1 KCNA1 Channelopathy Early Secs to mins
childhood
EA2/FHM 19p13 CACNA1A CACNA1A Channelopathy: 4-30 Hours
missense and
nonsense
mutations
EA3 1q42 Unknown Unknown Unknown 1-42 1 min to 6 h
EA4 Unknown Unknown Unknown Unknown 23-42 Short to
constant
EA5 2q22-q23 CACNB4 CACNB4 Channelopathy: Juvenile Hours
missense and
nonsense
mutations
EA6 5p13 SLC1A3 EAAT1 Missense 5 Hours to days
mutation
EA7 19q13 Unknown Unknown Unknown <20 Hours to days
*Some overlap of pathogenic and nonpathogenic repeat length.
DRPLA, dentatorubral-pallidoluysian atrophy; EA, episodic ataxia; FHM, familial hemiplegic migraine; MJD, Machado-Joseph disease; SAX, spastic ataxia;
SCA, spinocerebellar ataxia; SMNA, sensorimotor neuropathy with ataxia; SPAR, spastic paraplegia, ataxia, and mental retardation; TBP, TATA-binding protein,
UTR, untranslated region.
From Jafar-Nejad P, Maricich SM, Zoghbi HY: The cerebellum and the hereditary ataxias. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s
pediatric neurology, ed 5, Philadelphia, 2012, WB Saunders, Table 67-3.
and opsoclonus (nonrhythmic, conjugate horizontal and vertical oscil- nystagmus. Ataxia-telangiectasia may present with chorea (see Chapter
lations of the eyes). 597.2) rather than ataxia. The telangiectasia becomes evident by mid-
Several metabolic disorders are characterized by ataxia, including childhood and is found on the bulbar conjunctiva, over the bridge of
abetalipoproteinemia, arginosuccinic aciduria, and Hartnup disease. the nose, and on the ears and exposed surfaces of the extremities.
Abetalipoproteinemia (Bassen-Kornzweig disease) begins in child- Examination of the skin shows a loss of elasticity. Abnormalities of
hood with steatorrhea and failure to thrive (see Chapters 86.3 and immunologic function that lead to frequent sinopulmonary infections
600). A blood smear shows acanthocytosis. Serum chemistries reveal include decreased serum and secretory immunoglobulin (Ig) A as well
decreased levels of cholesterol and triglycerides; serum β-lipoproteins as diminished IgG2, IgG4, and IgE levels in more than 50% of patients.
are absent. Neurologic signs become evident by late childhood and Children with ataxia-telangiectasia have a 50-100–fold increased risk
consist of ataxia, retinitis pigmentosa, peripheral neuritis, abnormali- of developing lymphoreticular tumors (lymphoma, leukemia, and
ties of position and vibration sense, muscle weakness, and intellectual Hodgkin disease) as well as brain tumors. Additional laboratory abnor-
disability. Vitamin E is undetectable in the serum of patients with malities include an increased incidence of chromosome breaks, par-
neurologic symptoms. ticularly of chromosome 14, and elevated levels of α-fetoprotein. Death
Degenerative diseases of the central nervous system represent an results from infection or tumor dissemination.
important group of ataxic disorders of childhood because of the genetic Friedreich ataxia is inherited as an autosomal-recessive disorder
consequences and poor prognosis. Ataxia-telangiectasia, an autoso- involving the spinocerebellar tracts, dorsal columns in the spinal cord,
mal recessive condition, is the most common of the degenerative the pyramidal tracts, and the cerebellum and medulla. The majority of
ataxias and is heralded by ataxia beginning at approximately age 2 yr patients are homozygous for a GAA repeat expansion in the noncoding
and progressing to loss of ambulation by adolescence. Ataxia- region of the gene coding for the mitochondrial protein frataxin. Muta-
telangiectasia is caused by mutations in the ATM gene located at tions cause oxidative injury associated with excessive iron deposits in
11q22-q23. ATM is a phosphytidylinositol-3 kinase that phosphory- mitochondria. The onset of ataxia is somewhat later than in ataxia-
lates proteins involved in DNA repair and cell-cycle control. Oculomo- telangiectasia, but usually occurs before age 10 yr. The ataxia is slowly
tor apraxia of horizontal gaze, defined as difficulty shifting gaze from progressive and involves the lower extremities to a greater degree
one object to another and overshooting the target with lateral move- than the upper extremities. The Romberg test result is positive; the
ment of the head, followed by refixating the eyes, is a frequent finding, deep-tendon reflexes are absent (particularly at the ankle), and the
as is strabismus, hypometric saccade pursuit abnormalities, and plantar response is typically extensor (Babinski sign). Patients develop
a characteristic explosive, dysarthric speech, and nystagmus is present

in most children. Although patients may appear apathetic, their intel- Table 597-6 Etiologic Classification of Choreic
ligence is preserved. They may have significant weakness of the distal Syndromes
musculature of the hands and feet. Marked loss of vibration and joint GENETIC CHOREAS
position sense is common and is caused by degeneration of the poste- Huntington disease (rarely presents with chorea in childhood)
rior columns. Friedreich ataxia is also characterized by skeletal abnor- Huntington disease–like 2 and other Huntington disease –like
malities, including high-arched feet (pes cavus) and hammertoes, syndromes
as well as progressive kyphoscoliosis. Results of electrophysiologic Dentatorubropallidoluysian atrophy
studies, including visual, auditory brainstem, and somatosensory- Neuroacanthocytosis
evoked potentials, are often abnormal. Hypertrophic cardiomyopathy Leigh syndrome and other mitochondrial disorders
with progression to intractable congestive heart failure is the cause of Ataxia telangiectasia
Benign hereditary chorea
death for most patients.
Wilson disease
Several forms of spinocerebellar ataxia are similar to Friedreich Spinocerebellar ataxia (types 2, 3, or 17)
ataxia but are less common. Roussy-Levy disease has, in addition to Pantothene kinase–associated neurodegeneration (PKAN)
ataxia, atrophy of the muscles of the lower extremity with a pattern of Paroxysmal kinesigenic choreoathetosis
wasting similar to that observed in Charcot-Marie-Tooth disease; Paroxysmal nonkinesigenic choreoathetosis
Ramsay Hunt syndrome has an associated myoclonic epilepsy. Fahr syndrome
There are more than 20 dominantly inherited spinocerebellar Rett syndrome
ataxias, some of which present in childhood. These include those asso- STRUCTURAL BASAL-GANGLIA LESIONS
ciated with CAG (polyglutamine) repeats and noncoding microsatellite Vascular chorea in stroke, vasculitis, Moyamoya disease
expansions. Dominantly inherited episodic ataxias caused by potas- Mass lesions (e.g., central nervous system lymphoma, metastatic
sium or calcium channel dysfunction present as episodes of ataxia and brain tumors)
muscle weakness. Some of these disorders may respond to acetazol- Joubert syndrome and related disorders
amide. The dominantly inherited olivopontocerebellar atrophies Multiple sclerosis plaques
include ataxia, cranial nerve palsies, and abnormal sensory findings in Extrapontine myelinolysis
Trauma
the 2nd or 3rd decade, but can present in children with rapidly progres-
sive ataxia, nystagmus, dysarthria, and seizures. PARAINFECTIOUS AND AUTOIMMUNE DISORDERS
Additional degenerative ataxias include Pelizaeus-Merzbacher Sydenham chorea
disease, neuronal ceroid lipofuscinoses, and late-onset GM2 ganglio- Systemic lupus erythematosus
sidosis (see Chapters 86.4 and 600). Rare forms of progressive cerebel- Chorea gravidarum
lar ataxia have been described in association with vitamin E deficiency. Antiphospholipid antibody syndrome
Postinfectious or postvaccinal encephalitis
A number of autosomal-dominant progressive spinocerebellar ataxias Anti–N-methyl-D-aspartate (NMDA)–receptor antibody syndrome
have been defined at the molecular level, including those caused by (Limbic encephalitis)
unstable trinucleotide repeat expansions. Paraneoplastic choreas
INFECTIOUS CHOREA
HIV encephalopathy
597.2 Chorea, Athetosis, Tremor Toxoplasmosis
Cysticercosis
Rebecca K. Lehman and Jonathan W. Mink Diphtheria
Bacterial endocarditis
Chorea, meaning “dance-like” in Greek, refers to rapid, chaotic Neurosyphilis
movements that seem to flow from 1 body part to another. Affected Scarlet fever
individuals exhibit motor impersistence, with difficulty keeping the Viral encephalitis (mumps, measles, varicella)
tongue protruded (“darting tongue”) or maintaining grip (“milkmaid METABOLIC DRUG OR TOXIC ENCEPHALOPATHIES
grip”). Chorea tends to occur both at rest and with action. Patients Acute intermittent porphyria
often attempt to incorporate the involuntary movements into more Hypo-/hypernatremia
purposeful movements, making them appear fidgety. Chorea increases Hypocalcemia
with stress and disappears in sleep. Chorea can be divided into primary Hyperthyroidism
(i.e., disorders in which chorea is the dominant symptom and the etiol- Hypoparathyroidism
ogy is presumed to be genetic) and secondary forms, with the vast Hepatic/renal failure
Carbon monoxide poisoning
majority of pediatric cases falling into the latter category (Tables 597-6
Manganese poisoning
and 597-7). Mercury poisoning
Sydenham chorea (St. Vitus dance) is the most common acquired Organophosphate poisoning
chorea of childhood. It occurs in 10-20% of patients with acute rheu- Pheochromocytoma
matic fever, typically weeks to months after a group A β-hemolytic
DRUG-INDUCED CHOREA (see Table 597-8)
streptococcal infection (see Chapter 183.1). Peak incidence is at age
8-9 yr, with a female predominance of 2 : 1. There is evidence that Modified from Cardoso F, Seppi K, Mair KJ, et al: Seminar on choreas, Lancet
group A β-hemolytic streptococci promote the generation of cross- Neurol 5:589–602, 2006.
reactive or polyreactive antibodies through molecular mimicry
between streptococcal and host antigens. Specifically, antibodies be abrupt. Most patients have generalized chorea but the majority have
against the N-acetyl-β-d-glucosamine epitope (GlcNAc) of streptococ- asymmetric manifestations and up to 20% have hemichorea. Hypoto-
cal group A carbohydrate target intracellular β-tubulin and extracel- nia manifests with the “pronator sign” (arms and palms turn outward
lular lysoganglioside GM1 in human caudate-putamen preparations. when held overhead) and the “choreic hand” (spooning of the extended
These antibodies are also capable of directing calcium/calmodulin– hand by flexion of the wrist and extension of the fingers). When chorea
dependent protein kinase II activation, which may cause the neuro- and hypotonia are severe, the child may be incapable of feeding, dress-
logic manifestations of Sydenham chorea by increasing dopamine ing, or walking without assistance. Speech is often involved, sometimes
release into the synapse. to the point of being unintelligible. Periods of uncontrollable crying
The clinical hallmarks of Sydenham chorea are chorea, hypotonia, and extreme mood swings are characteristic and may precede the onset
and emotional lability. Onset of the chorea is usually insidious but may of the movement disorder.
Table 597-7 Genetic Choreas

MODE OF GENE, PROTEIN USUAL AGE AT
INHERITANCE LOCATION PRODUCT ONSET (yr) CLINICAL SIGNS
HDL2* AD† JPH3, 16q Junctophilin-3 20-40 Huntington disease phenotype,
sometimes acanthocytosis; almost
exclusively African ethnicity
SCA17 AD† TBP, 6q TBP 10-30 Cerebellar ataxia, chorea, dystonia,
hyperreflexia, cognitive decline
DRPLA AD† DRPLA, 12p Atrophin-1 About 20 Variable phenotypic picture including
chorea, ataxia, seizures, psychiatric
disturbances, dementia; more
common in Japan than in Europe
or United States
SCA3/MJD AD† MJD, 14q Ataxin-3 35-40 Wide phenotypic variability with
cerebellar ataxia, protruded eyes,
chorea, dystonia, parkinsonian
features, neuropathy, pyramidal
tract features
SCA2 AD† Ataxin-2, 12q Ataxin-2 30-35 Cerebellar ataxia, chorea, markedly
reduced velocity of saccadic eye
movements, hyporeflexia
Chorea- AR VPS13A Chorein 20-50 Orofacial self-mutilation, dystonia,
acanthocytosis (formerly neuropathy, myopathy, seizures,
CHAC), 9q acanthocytosis
McLeod syndrome X-linked, XK, Xp XK-protein 40-70 Dystonia, neuropathy, myopathy,
recessive cardiomyopathy, seizures,
acanthocytosis, raised creatine
kinase, weak expression of Kell
antigen
Neuroferritinopathy AD FTL, 19q FTL 20-55 Chorea, dystonia, parkinsonian
features; usually reduced serum
ferritin; MR abnormalities with cyst
formation and increased T2 signal
in globus pallidus and putamen
AT and ATLD AR ATM, 11q (AT) ATM (AT) MRE11 Childhood Ataxia, neuropathy, oculomotor
MRE11, 11q (ATLD) apraxia, other extrapyramidal
(ATLD) manifestations including chorea,
dystonia, and myoclonus
In AT: oculocutaneous
telangiectasias; predisposition to
malignancies, IgA and IgG
deficiency, high α-fetoprotein in
serum and high concentrations of
carcinoembryonic antigen
AOA 1 and 2 AR APTX, 9p (AOA Aprataxin (AOA 1) Childhood or Ataxia, neuropathy, oculomotor
1) SETX, 9q Senataxin adolescence apraxia, other extrapyramidal
(AOA 2) (AOA 2) (later onset in manifestations including chorea
AOA 2) and dystonia; ataxia with
oculomotor apraxia type 1:
hypoalbuminemia and
hypercholesterolemia; ataxia with
oculomotor apraxia type 2: raised
α-fetoprotein in serum
Pantothenate kinase AR PANK2, 20p Pantothenate Childhood, but Chorea, dystonia, parkinsonian
associated kinase 2 also adult- features, pyramidal tract features;
neurodegeneration onset subtype MR abnormalities with decreased
(formerly T2 signal in the globus pallidus and
Hallervorden-Spatz substantia nigra, “eye of the tiger”
syndrome) sign (hyperintense area within the
hypointense area); sometimes
acanthocytosis, abnormal
cytosomes in lymphocytes
Continued
Table 597-7 Genetic Choreas—cont’d

MODE OF GENE, PROTEIN USUAL AGE AT
INHERITANCE LOCATION PRODUCT ONSET (yr) CLINICAL SIGNS
Lesch-Nyhan X-linked, HPRT, Xq Hypoxanthine- Childhood Chorea, dystonia, hypotonia,
syndrome recessive guanine self-injurious behavior with biting of
phosphoribosyl- fingers and lips, mental retardation;
transferase short stature, renal calculi,
hyperuricemia
Wilson disease AR ATP7B, 13q Copper <40 Parkinsonian features, dystonia,
transporting tremor, rarely chorea, behavioral
P-type adenosine and cognitive change, corneal
triphosphatase Kayser-Fleischer rings, liver disease
(ATPase)
PKC syndrome and AD Unknown, 16p Unknown <1-40 Paroxysmal movement disorders
ICCA syndrome presenting with recurrent brief
episodes of abnormal involuntary
movements with dramatic response
to low-dose carbamazepine (PKC);
recurrent brief episodes of
abnormal involuntary movements in
association with infantile
convulsions (ICCA)
Benign hereditary AD TITF-1, 14q; Thyroid Childhood Chorea, mild ataxia; genetically
chorea other transcription heterogeneous
factor 1
*HDL1, HDL3, and HDL4 are very rare conditions (only 1 family known) and therefore not included in the table.
†
Disorders based on expanded CAG repeats (HDL2 based on CAG/CTG repeats; SCA 17 based on CAG/CAA repeats); age of symptom onset inversely related to
repeat size.
AD, autosomal dominant; AOA, ataxia with oculomotor apraxia (types 1 or 2); AR, autosomal recessive; AT, ataxia telangiectasia; ATLD, ataxia telangiectasia–like
disorder; DRPLA, dentatorubropallidoluysian atrophy; ICCA, infantile convulsions and paroxysmal choreoathetosis syndrome; MJD, Machado-Joseph disease; PKC,
paroxysmal kinesigenic choreoathetosis; SCA, spinocerebellar ataxia (types 2, 3, or 17).
Modified from Cardoso F, Seppi K, Mair KJ, et al: Seminar on choreas, Lancet Neurol 5:589–602, 2006.
Sydenham chorea is a clinical diagnosis; a combination of acute and

convalescent serum antistreptolysin O titers may help to confirm an Table 597-8 Drugs That Can Induce Chorea
acute streptococcal infection. Negative titers do not exclude the diag- DOPAMINE RECEPTOR CALCIUM CHANNEL
nosis. All patients with Sydenham chorea should be evaluated for car- BLOCKING AGENTS (UPON BLOCKERS
ditis and started on long-term antibiotic prophylaxis (e.g., penicillin G WITHDRAWAL OR AS A Cinnarizine
benzathine 1.2 million units IM every 4 wk or penicillin V 250 mg PO TARDIVE SYNDROME) Flunarizine
twice daily) to decrease the risk of rheumatic heart disease with recur- Phenothiazines Verapamil
rence. For patients with chorea that is impairing, treatment options Butyrophenones
OTHERS
include valproate, carbamazepine, and dopamine receptor antagonists. Benzamides
Lithium
Historically, there have been conflicting data regarding the efficacy of ANTIPARKINSONIAN DRUGS Baclofen
prednisone, intravenous immunoglobulin, and other immunomodula- L-DOPA Digoxin
tory agents in Sydenham chorea, making it difficult to recommend Dopamine agonists Tricyclic antidepressants
their routine use. A more recent randomized, double-blinded study of Anticholinergics Cyclosporine
37 children with Sydenham chorea compared high-dose prednisone Steroids/oral contraceptives
ANTIEPILEPTIC DRUGS
(2 mg/kg/day, max: 60 mg) for 4 wk vs a placebo and found that ste- Theophylline
Phenytoin
roids significantly reduced time to remission (54.3 days vs 119.9 days Propofol
Carbamazepine
in controls). There is no evidence that treatment with prednisone alters Valproic acid
recurrence rate or long-term outcome. PSYCHOSTIMULANTS
Sydenham chorea usually resolves spontaneously within 6-9 mo, Amphetamines
although it can persist for up to 2 yr and, in rare cases, can remain a Methylphenidate
lifelong condition. Relapse in the 1st few yr is relatively common, Cocaine
occurring in 37.9% of patients in 1 series. Remote recurrence of chorea
Modified from Cardoso F, Seppi K, Mair KJ, et al: Seminar on choreas, Lancet
is rare, but may be provoked by streptococcal infections, pregnancy Neurol 5:589–602, 2006.
(chorea gravidarum), or oral contraceptive use.
Although much rarer than Sydenham chorea, systemic lupus ery-
thematosus (see Chapter 158) is a well-known cause of chorea in Additional causes of secondary chorea include metabolic (hyperthy-
children. In some cases, chorea may be the presenting sign of systemic roidism, hypoparathyroidism), infectious (Lyme disease), immune-
lupus erythematosus. A recent retrospective study of a large pediatric mediated (systemic lupus erythematosus; anti–N-methyl-d-aspartate
lupus cohort examined the prevalence of antiphospholipid antibodies receptor antibody syndrome), vascular (stroke, moyamoya disease),
and evaluated their association with neuropsychiatric symptoms. heredodegenerative disorders (Wilson disease), and drugs (Table 597-8).
There was a significant association between a persistently positive Although chorea is a hallmark of Huntington disease in adults, chil-
lupus anticoagulant and chorea (p = 0.02); however, only 2 of the 137 dren who develop Huntington disease tend to present with rigidity and
patients in the cohort had chorea. Regardless, a child with chorea of bradykinesia (Westphal variant) or dystonia rather than chorea.
unknown cause should be investigated for the presence of antiphos- Athetosis is characterized by slow, continuous, writhing movements
pholipid antibodies. that repeatedly involve the same body part(s), usually the distal
extremities, face, neck, or trunk. Like chorea, athetosis may occur at

rest and is often worsened by voluntary movement. Because athetosis Table 597-9 Selected Causes of Tremor in Children
tends to co-occur with other movement disorders, such as chorea BENIGN
(choreoathetosis) and dystonia, it is often difficult to distinguish as a Enhanced physiologic tremor
discrete entity. Choreoathetosis is associated with cerebral palsy, ker- Shuddering attacks
nicterus, and other forms of basal ganglia injury; therefore, it is often Jitteriness
seen in conjunction with rigidity—increased muscle tone that is equal Spasmus nutans
in the flexors and extensors in all directions of passive movement STATIC INJURY/STRUCTURAL
regardless of the velocity of the movement. This is to be differentiated Cerebellar malformation
from spasticity, a velocity-dependent (“clasp-knife”) form of hyperto- Stroke (particularly in the midbrain or cerebellum)
nia that is seen with upper motor neuron dysfunction. As with chorea, Multiple sclerosis
athetosis/choreoathetosis can also be seen with hypoxic-ischemic
HEREDITARY/DEGENERATIVE
injury and dopamine-blocking drugs. Familial essential tremor
Tremor is a rhythmic, oscillatory movement around a central point Fragile X premutation
or plane that results from the action of antagonist muscles. Tremor can Wilson disease
affect the extremities, head, trunk, or voice and can be classified by Huntington disease
both its frequency (slow [4 Hz], intermediate [4-7 Hz], and fast Juvenile parkinsonism (tremor is rare)
[>7 Hz]) and by the context in which it is most pronounced. Rest Pallidonigral degeneration
tremor is maximal when the affected body part is inactive and sup- METABOLIC
ported against gravity, whereas postural tremor is most notable when Hyperthyroidism
the patient sustains a position against gravity. Action tremor occurs Hyperadrenergic state (including pheochromocytoma and
with performance of a voluntary activity and can be subclassified into neuroblastoma)
simple kinetic tremor, which occurs with limb movement, and inten- Hypomagnesemia
tion tremor, which occurs as the patient’s limb approaches a target and Hypocalcemia
is a feature of cerebellar disease. Hypoglycemia
Essential tremor (ET) is the most common movement disorder in Hepatic encephalopathy
Vitamin B12 deficiency
adults, and 50% of persons diagnosed with ET report an onset in child- Inborn errors of metabolism
hood; thus ET may be the most common tremor disorder in children Mitochondrial disorders
as well. Clinical experience in pediatric movement disorders clinic
suggests that ET is more common in the pediatric population than the DRUGS/TOXINS
literature would suggest. ET is an autosomal-dominant condition with Valproate, phenytoin, carbamazepine, lamotrigine, gabapentin,
lithium, tricyclic antidepressants, stimulants (cocaine,
variable expressivity but complete penetrance by the age of 60 yr. amphetamine, caffeine, thyroxine, bronchodilators), neuroleptics,
Although the genetics of ET are not fully understood, at least 3 differ- cyclosporine, toluene, mercury, thallium, amiodarone, nicotine,
ent genes—EMT1 on chromosome 3q13, EMT2 on chromosome 2p22- lead, manganese, arsenic, cyanide, naphthalene, ethanol, lindane,
25, and LINGO1 on chromosome 15q24—are linked to the condition. serotonin reuptake inhibitors
Based on functional imaging studies, the defect is thought to localize
PERIPHERAL NEUROPATHIES
to cerebellar circuits.
ET is characterized by a slowly progressive, bilateral, 4-9 Hz postural PSYCHOGENIC
tremor that involves the upper extremities and occurs in the absence
of other known causes of tremor. Mild asymmetry is common, but ET
is rarely unilateral. ET may be worsened by actions, such as trying to
pour water from cup to cup. Affected adults may report a history of course, and association with selective but not task-specific disabilities.
ethanol responsiveness. Most young children present for evaluation In some cases, tremor may even occur as a manifestation of another
because a parent, teacher, or therapist has noticed the tremor, rather movement disorder, as is seen with position- or task-specific tremor
than because the tremor causes impairment. Most children with ET do (e.g., writing tremor), dystonic tremor, and myoclonic tremor.
not require pharmacologic intervention. If they are having difficulty When evaluating a child with tremor, it is important to screen for
with their handwriting or self-feeding, an occupational therapy evalu- common metabolic disturbances, including electrolyte abnormalities
ation and/or assistive devices, such as wrist weights and weighted sil- and thyroid disease, assess the child’s caffeine intake, and review the
verware, may be helpful. Teenagers tend to report more impairment child’s medication list for known tremor-inducing agents. It is also
from ET. Teenagers who do require pharmacotherapy usually respond critical to exclude Wilson disease in teenagers with characteristic
to the same medications that are used in adults—propranolol and “wing-beating” tremor, as this is a treatable condition.
primidone. Propranolol, which is generally considered the first-line
treatment, can be started at 20–40 mg daily and titrated to effect, with
most patients responding to doses of 60-80 mg/day. Propranolol
should not be used in patients with reactive airway disease. Primidone 597.3 Dystonia
can be started at 12.5-25 mg at bedtime and increased gradually in a Erika F. Augustine and Jonathan W. Mink
twice daily schedule. Most patients respond to doses of 50-200 mg/day.
Other treatments options for ET reported in the adult literature include Dystonia is a disorder of movement characterized by sustained muscle
atenolol, gabapentin, topiramate, and alprazolam. Surgical treatments, contraction, frequently causing twisting and repetitive movements or
which include deep brain stimulation of the thalamus and unilateral abnormal postures. Major causes of dystonia include primary general-
thalamotomy, are generally reserved for adults with medically refrac- ized dystonia, medications, metabolic disorders, and perinatal asphyxia
tory disabling tremor. (Tables 597-10 and 597-11).
In addition to ET, there are numerous secondary etiologies of tremor
in children (Table 597-9). Holmes tremor, previously referred to as INHERITED PRIMARY DYSTONIAS
midbrain or rubral tremor, is characterized by a slow frequency, high- Primary generalized dystonia, also referred to as primary torsion dys-
amplitude tremor that is present at rest and with intention. It is a tonia or dystonia musculorum deformans, is caused by a group of
symptomatic tremor, which usually results from lesions of the brain- genetic disorders with onset in childhood. One form, which occurs
stem, cerebellum, or thalamus. Psychogenic tremor is distinguished more commonly in the Ashkenazi Jewish population, is caused by a
by its variable appearance, abrupt onset and remission, nonprogressive dominant mutation in the DYT1 gene coding for the adenosine
Table 597-10 Causes of Dystonia in Childhood

STATIC INJURY/STRUCTURAL DISORDERS DRUGS/TOXINS
Cerebral palsy Neuroleptic and antiemetic medications (haloperidol, chlorpromazine,
Hypoxic–ischemic injury olanzapine, risperidone, prochlorperazine)
Kernicterus Calcium channel blockers
Head trauma Stimulants (amphetamine, cocaine, ergot alkaloids)
Encephalitis Anticonvulsants (carbamazepine, phenytoin)
Tumors Thallium
Stroke in the basal ganglia (which may be a result of vascular Manganese
abnormalities or varicella) Carbon monoxide
Congenital malformations Ethylene glycol
Cyanide
HEREDITARY/DEGENERATIVE DISORDERS
Methanol
DYT1 (9q34, encodes torsinA)
Wasp sting
DYT2 (autosomal-recessive)
DYT3 (X-linked dystonia-parkinsonism syndrome of Lubag–Xq13) PAROXYSMAL DISORDERS
DYT4 Paroxysmal kinesigenic choreoathetosis (PKC)
DYT5 (14q22.1-2, encodes GTP cyclohydrolase I, leading to dopa- Paroxysmal nonkinesigenic choreoathetosis (PNKC)
responsive dystonia or Segawa disease) Exercise-induced dystonia
DYT6 (8p21-q22) Complex migraine
DYT7 (18p) Alternating hemiplegia of childhood (AHC)
DYT8 (2q33-q35, causing paroxysmal nonkinesigenic choreoathetosis Paroxysmal torticollis of infancy
[PNKC])
DYT9 (1p, causing paroxysmal nonkinesigenic dyskinesia [PNKD] and DISORDERS THAT MIMIC DYSTONIA
spasticity) Tonic seizures (including paroxysmal nocturnal dystonia caused by
DYT10 (16p11.2-q12.1, causing paroxysmal kinesigenic nocturnal frontal lobe seizures)
choreoathetosis [PKC]) Arnold-Chiari malformation type II
DYT11 (heterogeneous, causing familial myoclonus-dystonia) Atlantoaxial subluxation
Rapid-onset dystonia-parkinsonism (DYT12) Syringomyelia
Fahr disease (often caused by hypoparathyroid disease) Posterior fossa mass
Pantothenate kinase-associated neurodegeneration (PKAN; neuronal Cervical spine malformation (including Klippel-Feil syndrome)
brain iron accumulation type 1, formerly Hallervorden-Spatz disease, Skew deviation with vertical diplopia causing neck twisting
caused by mutations in PANK2) Juvenile rheumatoid arthritis
Huntington disease (particularly the Westphal variant, IT15-4p16.3) Sandifer syndrome (associated with hiatal hernia in infants)
Spinocerebellar ataxias (SCAs, including SCA3/Machado-Joseph Spasmus nutans
disease) Tics
Neuronal ceroid-lipofuscinoses (NCL) Infant masturbation
Rett syndrome Spasticity
Striatal necrosis Myotonia
Leigh disease Rigidity
Neuroacanthocytosis Stiff-person syndrome
HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis Isaac syndrome (neuromyotonia)
pigmentosa, and pallidal degeneration) Startle disease (hyperekplexia)
Ataxia-telangiectasia Neuroleptic malignant syndrome
Tay-Sachs disease Central herniation with posturing
Sandhoff’s disease Psychogenic dystonia
Niemann-Pick type C
GM1 gangliosidosis
Metachromatic leukodystrophy (MLD)
Lesch-Nyhan disease
METABOLIC DISEASE
Glutaric aciduria types 1 and 2
Acyl-coenzyme A (CoA) dehydrogenase deficiencies
Dopa-responsive dystonia (tyrosine hydroxylase deficiency, guanosine
triphosphate [GTP] cyclohydrolase 1 deficiency, DYT5)
Dopamine agonist-responsive dystonia (aromatic l-amino acid
decarboxylase deficiency, aminolevulinic acid dehydrase [ALAD])
Biotin responsive basal ganglia disease
Mitochondrial disorders
Wilson disease
Vitamin E deficiency
Homocystinuria
Methylmalonic aciduria
Tyrosinemia
From Sanger TD, Mink JW: Movement disorders. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s pediatric neurology: principles and practice,
ed 5, Philadelphia, 2012, WB Saunders, Box 68-2.
Table 597-11 Examples of Primary and Secondary Dystonia in Childhood

DIAGNOSIS ADDITIONAL CLINICAL FEATURES DIAGNOSIS ADDITIONAL CLINICAL FEATURES
Aicardi-Goutières Encephalopathy, developmental Leigh syndrome Motor delays, weakness, hypotonia
syndrome regression Ataxia, tremor
Acquired microcephaly Elevated lactate
Sterile pyrexias MRI: bilateral symmetric hyperintense
Lesions on the digits, ears (chilblain) lesions in the basal ganglia or
Epilepsy thalamus
CT: calcification of the basal ganglia
Lesch-Nyhan syndrome Male
Alternating hemiplegia Episodic hemiplegia/quadriplegia (X-linked) Self-injurious behavior
of childhood Abnormal ocular movements Hypotonia
Autonomic symptoms Oromandibular dystonia, inspiratory
Epilepsy stridor
Global developmental impairment Oculomotor apraxia
Environmental triggers for spells Cognitive impairment
Elevated uric acid
Aromatic amino acid Developmental delay
decarboxylase Oculogyric crises Myoclonus dystonia Myoclonus
deficiency (AADC) Autonomic dysfunction Head, upper limb involvement
Hypotonia
Niemann-Pick type C Hepatosplenomegaly
ARX gene mutation Male Hypotonia
(X-linked) Cognitive impairment Supranuclear gaze palsy
Infantile spasms, epilepsy Ataxia, dysarthria
Brain malformation Epilepsy
Psychiatric symptoms
Benign paroxysmal Episodic
torticollis of infancy Cervical dystonia only Neuroacanthocytosis Oromandibular and lingual dystonia
Family history of migraine
Neurodegeneration with Cognitive impairment
Complex regional pain Lower limb involvement brain iron accumulation Retinal pigmentary degeneration, optic
syndrome Prominent pain atrophy
Dopa-responsive Diurnal variation Rapid onset dystonia Acute onset
dystonia (DRD) parkinsonism (DYT12) Distribution face > arm > leg
Prominent bulbar signs
Drug-induced dystonia
Rett syndrome Female
Dystonia-deafness optic Sensorineural hearing loss in early Developmental regression following a
neuropathy syndrome childhood period of normal development
Psychosis Stereotypic hand movements
Optic atrophy in adolescence Acquired microcephaly
DYT1 dystonia Lower limb onset followed by Epilepsy
generalization Spinocerebellar ataxia 17 Ataxia
Glutaric aciduria type 1 Macrocephaly (SCA17) Dementia, psychiatric symptoms
Encephalopathic crises Parkinsonism
MRI: striatal necrosis Tics Stereotyped movements
GM1 gangliosidosis Short stature, skeletal dysplasia Premonitory urge, suppressible
type 3 Orofacial dystonia Tyrosine hydroxylase Infantile encephalopathy, hypotonia
Speech/swallowing disturbance deficiency Oculogyric crises, ptosis
Parkinsonism Autonomic symptoms
MRI: putaminal hyperintensity Less diurnal fluctuation than DRD
Huntington disease Parkinsonism
Epilepsy
Family history of Huntington disease
Kernicterus Jaundice in infancy
Hearing loss
Impaired upgaze
Enamel dysplasia
MRI: hyperintense lesions in the globus
pallidus
triphosphate (ATP) binding protein torsinA. The initial manifestation should still be considered, given the intrafamilial variability in clinical
of DYT1 dystonia is often intermittent unilateral posturing of a lower expression.
extremity, which assumes an extended and rotated position. Ulti- More than a dozen loci for genes for torsion dystonia have been
mately, all 4 extremities and the axial musculature can be affected, but identified (DYT1-DYT24). One is the autosomal dominant disorder
the dystonia may also remain localized to one limb. Cranial involve- dopa-responsive dystonia (DRD, DYT5a), also called Segawa syn-
ment can occur in DYT1 dystonia, but it is uncommon compared to drome. The gene for DRD codes for guanosine triphosphate cyclohy-
non-DYT1 dystonias. There is a wide clinical spectrum, varying even drolase 1, the rate-limiting enzyme for tetrahydrobiopterin synthesis,
within families. If a family history of dystonia is absent, the diagnosis which is a cofactor for synthesis of the neurotransmitters dopamine
and serotonin. Thus, the genetic mutation results in dopamine defi- CEREBRAL PALSY
ciency. The hallmark of the disorder, particularly in adolescents and See Chapter 598.
adults, is diurnal variation: symptoms worsen as the day progresses and
may transiently improve with sleep. Early-onset patients, who tend to METABOLIC DISORDERS
present with delayed or abnormal gait from dystonia of a lower extrem- Disorders of monamine neurotransmitter metabolism, of which
ity, can easily be confused with patients with dystonic cerebral palsy. DRD is one, present in infancy and early childhood with dystonia,
It should be noted that in the presence of a progressive dystonia, hypotonia, oculogyric crises, and/or autonomic symptoms. The more
diurnal fluctuation, or if loss of previously achieved motor skills occurs, common disorders among this group of rare diseases include DRD,
a prior diagnosis of cerebral palsy should be reexamined. DRD tyrosine hydroxylase deficiency, and aromatic amino acid decarboxyl-
responds dramatically to small daily doses of levodopa. The respon- ase deficiency. Abnormalities of the dopamine transporter (DAT)
siveness to levodopa is a sustained benefit, even if the diagnosis is can also present in infancy with dystonia. Detailed discussion is
delayed several years, as long as contractures have not developed. beyond the scope of this chapter; reviews, however, are available for
Myoclonus dystonia (DYT11), caused by mutations in the epsilon- reference.
sarcoglycan (SCGE) gene, is characterized by dystonia involving the Wilson disease is an autosomal recessive inborn error of copper
upper extremities, head, and/or neck, as well as myoclonic movements transport characterized by cirrhosis of the liver and degenerative
in these regions. Although a combination of myoclonus and dystonia changes in the central nervous system, particularly the basal ganglia
typically occurs, each manifestation can present in isolation. When (see Chapter 357.2). It has been determined that there are multiple
repetitive, the myoclonus may take on a tremor-like appearance, mutations in the Wilson disease gene (WND), accounting for the vari-
termed dystonic tremor. Improvement in symptoms following alcohol ability in presentation of the condition. The neurologic manifestations
ingestion, reported by affected adult family members, may be a helpful of Wilson disease rarely appear before age 10 yr, and the initial sign
clue to this diagnosis. is often progressive dystonia. Tremors of the extremities develop, uni-
Common to the inherited dystonias, there is considerable intrafa- laterally at first, but they eventually become coarse, generalized, and
milial variability in clinical manifestations, distribution, and severity incapacitating. Other neurologic signs of Wilson disease relate to pro-
of dystonia. In primary dystonias, although the main clinical features gressive basal ganglia disease, such as parkinsonism, dysarthria, dys-
are motor, there may be an increased risk for major depression. Anxiety, phonia, and choreoathetosis. Less frequent are ataxia and pyramidal
obsessive-compulsive disorder, and depression have all been reported signs. The MRI or CT scan shows ventricular dilation in advanced
in the myoclonus–dystonia syndrome. Screening for psychiatric cases with atrophy of the cerebrum, cerebellum, and/or brainstem,
comorbidities cannot be overlooked in this population. along with signal intensity change in the basal ganglia, thalamus, and/
or brainstem, particularly the midbrain.
DRUG-INDUCED DYSTONIAS Pantothenate kinase–associated neurodegeneration (formerly
A number of medications are capable of inducing involuntary move- known as Hallervorden-Spatz disease) is a rare autosomal recessive
ments, drug-induced movement disorders, in children and adults. neurodegenerative disorder. Many patients have mutations in panto-
Dopamine-blocking agents, including antipsychotics (e.g., haloperi- thenate kinase 2 (PANK2) localized to mitochondria in neurons. The
dol) and antiemetics (e.g., metoclopramide, prochlorperazine), as well condition usually begins before 6 yr of age and is characterized by
as atypical antipsychotics (e.g., risperidone) can produce acute dys- rapidly progressive dystonia, rigidity, and choreoathetosis. Spasticity,
tonic reactions or delayed (tardive) drug-induced movement disor- extensor plantar responses, dysarthria, and intellectual deterioration
ders. Acute dystonic reactions, occurring in the 1st days of exposure, become evident during adolescence, and death usually occurs by early
typically involve the face and neck, manifesting as torticollis, retrocol- adulthood. MRI shows lesions of the globus pallidus, including low
lis, oculogyric crisis, or tongue protrusion. Life-threatening presenta- signal intensity in T2-weighted images (corresponding to iron pig-
tions with laryngospasm and airway compromise can also occur, ments) and an anteromedial area of high signal intensity (tissue necro-
requiring prompt recognition and treatment of this entity. Intravenous sis and edema), or “eye-of-the-tiger” sign (Fig. 597-1). Neuropathologic
diphenhydramine, 1-2 mg/kg/dose, may rapidly reverse the drug- examination indicates excessive accumulation of iron-containing pig-
related dystonia. The high potency of the dopamine blocker, young age, ments in the globus pallidus and substantia nigra. More recently, similar
and prior dystonic reactions may be predisposing factors. Acute dys- disorders of high brain iron content without PANK2 mutations, includ-
tonic reactions have also been described with cetirizine. ing infantile neuroaxonal dystrophy, neuroferritinopathy, and acerulo-
Severe rigidity combined with high fever, autonomic symptoms plasminemia, have been grouped as disorders of neurodegeneration
(tachycardia, diaphoresis), delirium, and dystonia are signs of neuro- with brain iron accumulation. Patterns of iron deposition visualized by
leptic malignant syndrome, which typically occurs a few days after brain MRI have shown utility in differentiating these disorders.
starting or increasing the dose of a neuroleptic drug, or in the setting Biotin-responsive basal ganglia disease manifests with episodes
of withdrawal from a dopaminergic agent. In contrast to acute dystonic of acute dystonia, external ophthalmoplegia and encephalopathy.
reactions, which take place within days, neuroleptic malignant syn- SLC19A3 is the responsible mutated gene. MRI demonstrates involve-
drome occurs within a month of medication initiation or dose increase. ment of the basal ganglia, with vasogenic edema and the “bat-wing”
Delayed onset involuntary movements, tardive dyskinesias, develop sign (Fig. 597-2). Treatment with biotin and thiamine results in
in the setting of chronic (>3 mo duration) neuroleptic use. Involve- improvement in 2-4 days.
ment of the face, particularly the mouth, lips, and/or jaw with chewing Although dystonia may present in isolation as the first sign of a
or tongue thrusting is characteristic. The risk of tardive dyskinesia, metabolic or neurodegenerative disorder, this group of diseases should
which is much less frequent in children compared to adults, increases be considered mainly in those who demonstrate signs of systemic
as medication dose and duration of treatment increase. There are data disease, (e.g., organomegaly, short stature, hearing loss, vision impair-
to suggest that children with autism spectrum disorders may also be ment, epilepsy), those with episodes of severe illness, evidence of
at increased risk for this drug-induced movement disorders. Unlike regression, or cognitive impairment. Table 597-11 outlines additional
acute dystonic reactions and neuroleptic malignant syndrome, discon- features suggestive of specific disorders.
tinuation of the offending agent may not result in clinical improve-
ment. In these patients, use of dopamine-depletors, such as reserpine OTHER DISORDERS
or tetrabenazine, may prove helpful. Although uncommon, movement disorders, including dystonia, may
Therapeutic doses of phenytoin or carbamazepine rarely cause probe part of the presenting symptoms of complex regional pain syn-
gressive dystonia in children with epilepsy, particularly in those who drome. Onset of involuntary movements within 1 yr of the traumatic
have an underlying structural abnormality of the brain. event, affected lower limb, pain disproportionate to inciting event, and
During evaluation of new onset dystonia, a careful history of pre- changes in the overlying skin and blood flow to the affected area
scriptions and potential medication exposures is critical. suggest complex regional pain syndrome. Although sustained dystonia
A B
Figure 597-1 Pantothenate kinase–associated neurodegeneration (PKAN). A, Axial T2-weighted image showing symmetric hypointensity in the
bilateral globi pallidi with central hyperintensity (“eye-of-the-tiger sign,” arrows). B, Axial susceptibility-weighted image (SWI) image showing
hypointensity in the globi pallidi representing increased iron accumulation (arrows). (From From Bosemani T, Meoded A, Poretti A: Susceptibility-
weighted imaging in pantothenate kinase-associated neurodegeneration. J Pediatr 164:212, 2014.)
A B C
Figure 597-2 Biotin-responsive basal ganglia disease. An initial brain MRI showed high-signal intensity alterations on T2-weighted images bilat-
erally involving the (A) cerebellum (arrows), (B) basal ganglia (white arrows), and medial nucleus of the thalamus (open arrows), and (B, C) cerebral
cortex (black arrows). (Modified from Tabarki B, Al-Sheikh F, Al-Shahwan S, Zuccoli G: Bilateral external ophthalmoplegia in biotin-responsive basal
ganglia disease. J Pediatr 162:1291–1292, 2013.)
can produce pain or discomfort, complex regional pain syndrome patients are also affected by episodes of dystonia, ranging from minutes
should be considered in those who have a prominent component of to days in duration. On average, both features of the disorder com-
pain and recent history of trauma to the affected limb. mence at approximately 6 mo of age. Episodic abnormal eye move-
There are disorders unique to childhood that warrant exploration in ments are observed in a large proportion of patients (93%) with onset
this section. Benign paroxysmal torticollis of infancy is characterized as early as the 1st wk of life. Alternating hemiplegia of childhood is
by recurrent episodes of cervical dystonia beginning in the 1st few mo associated with mutations in the ATP1A2 and ATP1A3 genes. Alternat-
of life. The torticollis may alternate sides from 1 episode to the next ing hemiplegia of childhood can similarly be triggered by fluctuations
and may also persist during sleep. Associated signs and symptoms in temperature, certain foods, or water exposure. Over time, epilepsy
include irritability, pallor, vomiting, vertigo, ataxia, and occasionally and cognitive impairment emerge, and the involuntary movements
limb dystonia. Family history is often notable for migraine and/or change from episodic to constant. Infantile onset and the paroxysmal
motion sickness in 1st-degree relatives. Despite the high frequency of nature of symptoms early in the disease course are key features to this
spells, imaging studies are normal, and the outcome is uniformly diagnosis.
benign with resolution by 3 yr of age. Finally, although a diagnosis of exclusion, the presence of odd move-
In alternating hemiplegia of childhood, episodic hemiplegia affect- ments or selective disability may indicate a psychogenic dystonia in
ing either side of the body is the hallmark of the disorder. However, older children. There is considerable overlap in features of organic and
psychogenic movement disorders, making the diagnosis difficult to
establish. For instance, both organic and psychogenic movement dis-
orders have the potential to worsen in the setting of stress and may
dissipate with relaxation or sleep. History should include review of
recent stressors, psychiatric symptoms, and exposure to others with
similar disorders. On examination, a changing movement disorder,
inconsistent motor or sensory exam, or response to suggestion, are
supportive of a possible psychogenic movement disorder. Early recog-
nition of this disorder may lessen morbidity caused by unnecessary
diagnostic and interventional procedures.
TREATMENT
Children with generalized dystonia, including those with involvement
of the muscles of swallowing, may respond to the anticholinergic agent
trihexyphenidyl (Artane). Titration occurs slowly over the course of
months in an effort to limit untoward side effects, such as urinary
retention, mental confusion, or blurred vision. Additional drugs that
have been effective include levodopa and diazepam. Segmental dysto-
nia, such as torticollis, often responds well to botulinum toxin injec-
tions. Intrathecal baclofen delivered through implantable constant
infusion pump may be helpful in some patients. Deep brain stimula-
tion with leads implanted in the globus pallidus is most helpful for
children with severe primary generalized dystonia. Recent data suggest,
however, that deep brain stimulation may also be of benefit in children
with secondary dystonias, such as cerebral palsy.
In the case of drug-induced dystonias, removal of the offending agent
and treatment with intravenous diphenhydramine typically suffices.
For neuroleptic malignant syndrome, dantrolene may be indicated.

Chapter 597 ◆ Movement Disorders 2896.e1
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Paz JA, Silva CAA, Marques-Dias MJ: Randomized double-blind study with
prednisone in Sydenham’s chorea, Pediatr Neurol 34(4):264–269, 2006.
EPIDEMIOLOGY AND ETIOLOGY

CP is the most common and costly form of chronic motor disability
that begins in childhood; data from the Centers for Disease Control
and Prevention indicate that the incidence is 3.6 per 1,000 children
with a male : female ratio of 1.4 : 1. The Collaborative Perinatal Project,
in which approximately 45,000 children were regularly monitored
from in utero to the age of 7 yr, found that most children with CP had
been born at term with uncomplicated labors and deliveries. In 80%
of cases, features were identified pointing to antenatal factors causing
abnormal brain development. A substantial number of children with
CP had congenital anomalies external to the central nervous system
(CNS). Fewer than 10% of children with CP had evidence of intrapar-
tum asphyxia. Intrauterine exposure to maternal infection (chorioam-
nionitis, inflammation of placental membranes, umbilical cord
inflammation, foul-smelling amniotic fluid, maternal sepsis, tempera-
ture >38°C [100.4°F] during labor, urinary tract infection) was associ-
ated with a significant increase in the risk of CP in normal birthweight
infants. Elevated levels of inflammatory cytokines have been reported
in heelstick blood collected at birth from children who later were
identified with CP. Genetic factors may contribute to the inflammatory
cytokine response, and a functional polymorphism in the interleukin-6
gene is associated with a higher rate of CP in term infants.
The prevalence of CP has increased somewhat as a result of the
enhanced survival of very premature infants weighing <1,000 g, who
go on to develop CP at a rate of approximately 15 per 100. However,
the gestational age at birth-adjusted prevalence of CP among 2 yr
old former premature infants born at 20-27 wk of gestation has
decreased over the past decade. The major lesions that contribute to
CP in preterm infants are intracerebral hemorrhage and periven-
tricular leukomalacia (PVL). Although the incidence of intracerebral
hemorrhage has declined significantly, PVL remains a major problem.
PVL reflects the enhanced vulnerability of immature oligodendroglia
in premature infants to oxidative stress caused by ischemia or
infectious/inflammatory insults. White matter abnormalities (loss of
Chapter 598 volume of periventricular white matter, extent of cystic changes, ven-
tricular dilation, thinning of the corpus callosum) present on MRI at
Encephalopathies 40 wk of gestational age among former preterm infants are a predictor

of later CP.
In 2006, the European Cerebral Palsy Study examined prenatal and
Michael V. Johnston perinatal factors as well as clinical findings and results of MRI in a
contemporary cohort of more than 400 children with CP. In agreement
with the Collaborative Perinatal Project study, more than half the chil-
Encephalopathy is a generalized disorder of cerebral function that may dren with CP in this study were born at term, and less than 20% had
be acute or chronic, progressive, or static. The etiologies of the enceph- clinical or brain imaging indicators of possible intrapartum factors
alopathies in children include infectious, toxic (carbon monoxide, such as asphyxia. The contribution of intrapartum factors to CP is
drugs, lead), metabolic, genetic, and ischemic causes. Hypoxic– higher in some underdeveloped regions of the world. Also in agree-
ischemic encephalopathy is discussed in Chapter 99.5. ment with earlier data, antenatal infection was strongly associated with
CP and 39.5% of mothers of children with CP reported having an
infection during the pregnancy, with 19% having evidence of a urinary
tract infection and 11.5% reporting taking antibiotics. Multiple preg-
598.1 Cerebral Palsy nancy was also associated with a higher incidence of CP and 12% of
Michael V. Johnston the cases in the European CP study resulted from a multiple pregnancy,
in contrast to a 1.5% incidence of multiple pregnancy in the study.
See Chapters 36, 97.2, and 597.3. Other studies have also documented a relationship between multiple
Cerebral palsy (CP) is a diagnostic term used to describe a group of births and CP, with a rate in twins that is 5-8 times greater than in
permanent disorders of movement and posture causing activity limita- singleton pregnancies and a rate in triplets that is 20-47 times greater.
tion, that are attributed to nonprogressive disturbances in the in the Death of a twin in utero carries an even greater risk of CP that is 8
developing fetal or infant brain. The motor disorders are often accom- times that of a pregnancy in which both twins survive and approxi-
panied by disturbances of sensation, perception, cognition, communi- mately 60 times the risk in a singleton pregnancy. Infertility treatments
cation, and behavior as well as by epilepsy and secondary musculoskeletal are also associated with a higher rate of CP, probably because these
problems. CP is caused by a broad group of developmental, genetic, treatments are often associated with multiple pregnancies. Among chil-
metabolic, ischemic, infectious, and other acquired etiologies that dren from multiple pregnancies, 24% were from pregnancies after
produce a common group of neurologic phenotypes. CP has histori- infertility treatment compared with 3.4% of the singleton pregnancies
cally been considered a static encephalopathy, but some of the neuro- in the study. CP is more common and more severe in boys compared
logic features of CP, such as movement disorders and orthopedic to girls and this effect is enhanced at the extremes of body weight. Male
complications, including scoliosis and hip dislocation, can change or infants with intrauterine growth retardation and a birthweight less
progress over time. Many children and adults with CP function at a than the 3rd percentile are 16 times more likely to have CP than males
high educational and vocational level, without any sign of cognitive with optimal growth, and infants with weights above the 97th percen-
dysfunction. tile are 4 times more likely to have CP.
Chapter 598 ◆ Encephalopathies 2897
Table 598-1 Classification of Cerebral Palsy and Major Causes

MOTOR SYNDROME (APPROX. % OF CP) NEUROPATHOLOGY/MRI MAJOR CAUSES
Spastic diplegia (35%) Periventricular leukomalacia Prematurity
Periventricular cysts or scars in white matter, Ischemia
enlargement of ventricles, squared off posterior Infection
ventricles Endocrine/metabolic (e.g., thyroid)
Spastic quadriplegia (20%) Periventricular leukomalacia Ischemia, infection
Multicystic encephalomalacia Endocrine/metabolic, genetic/
Cortical malformations developmental
Hemiplegia (25%) Stroke: in utero or neonatal Thrombophilic disorders
Focal infarct or cortical, subcortical damage Infection
Cortical malformations Genetic/developmental
Periventricular hemorrhagic infarction
Extrapyramidal (athetoid, dyskinetic) (15%) Asphyxia: symmetric scars in putamen and thalamus Asphyxia
Kernicterus: scars in globus pallidus, hippocampus Kernicterus
Mitochondrial: scaring globus pallidus, caudate, Mitochondrial
putamen, brainstem Genetic/metabolic
No lesions: ? dopa-responsive dystonia
CLINICAL MANIFESTATIONS immature white matter during the vulnerable period of immature oli-
CP is generally divided into several major motor syndromes that differ godendroglia between 20-34 wk of gestation. However, approximately
according to the pattern of neurologic involvement, neuropathology, 15% of cases of spastic diplegia result from in utero lesions in infants
and etiology (Table 598-1). The physiologic classification identifies the who go on to delivery at term. The first clinical indication of spastic
major motor abnormality, whereas the topographic taxonomy indi- diplegia is often noted when an affected infant begins to crawl. The
cates the involved extremities. CP is also commonly associated with a child uses the arms in a normal reciprocal fashion but tends to drag
spectrum of developmental disabilities, including intellectual impair- the legs behind more as a rudder (commando crawl) rather than using
ment, epilepsy, and visual, hearing, speech, cognitive, and behavioral the normal 4-limbed crawling movement. If the spasticity is severe,
abnormalities. The motor handicap may be the least of the child’s application of a diaper is difficult because of the excessive adduction
problems. of the hips. If there is paraspinal muscle involvement, the child may be
Infants with spastic hemiplegia have decreased spontaneous move- unable to sit. Examination of the child reveals spasticity in the legs with
ments on the affected side and show hand preference at a very early brisk reflexes, ankle clonus, and a bilateral Babinski sign. When the
age. The arm is often more involved than the leg and difficulty in hand child is suspended by the axillae, a scissoring posture of the lower
manipulation is obvious by 1 yr of age. Walking is usually delayed until extremities is maintained. Walking is significantly delayed, the feet are
18-24 mo, and a circumductive gait is apparent. Examination of the held in a position of equinovarus, and the child walks on tiptoe. Severe
extremities may show growth arrest, particularly in the hand and spastic diplegia is characterized by disuse atrophy and impaired growth
thumbnail, especially if the contralateral parietal lobe is abnormal, of the lower extremities and by disproportionate growth with normal
because extremity growth is influenced by this area of the brain. Spas- development of the upper torso. The prognosis for normal intellectual
ticity refers to the quality of increased muscle tone, which increases development for these patients is good, and the likelihood of seizures
with the speed of passive muscle stretching and is greatest in antigrav- is minimal. Such children often have learning disabilities and deficits
ity muscles. It is apparent in the affected extremities, particularly at the in other abilities, such as vision, because of disruption of multiple white
ankle, causing an equinovarus deformity of the foot. An affected child matter pathways that carry sensory as well as motor information.
often walks on tiptoe because of the increased tone in the antigravity The most common neuropathologic finding in children with spastic
gastrocnemius muscles, and the affected upper extremity assumes a diplegia is PVL, which is visualized on MRI in more than 70% of cases.
flexed posture when the child runs. Ankle clonus and a Babinski sign MRI typically shows scarring and shrinkage in the periventricular
may be present, the deep tendon reflexes are increased, and weakness white matter with compensatory enlargement of the cerebral ventri-
of the hand and foot dorsiflexors is evident. About one-third of patients cles. However, neuropathology has also demonstrated a reduction in
with spastic hemiplegia have a seizure disorder that usually develops oligodendroglia in more widespread subcortical regions beyond the
in the 1st yr or 2; approximately 25% have cognitive abnormalities periventricular zones, and these subcortical lesions may contribute to
including mental retardation. MRI is far more sensitive than CT for the learning problems these patients can have. MRI with diffusion
most lesions seen with CP, although a CT scan may be useful for detect- tensor imaging is being used to map white matter tracks more precisely
ing calcifications associated with congenital infections. In the Euro- in patients with spastic diplegia, and this technique has shown that
pean CP study, 34% of children with hemiplegia had injury to the white thalamocortical sensory pathways are often injured as severely as
matter that probably dated to the in utero period and 27% had a focal motor corticospinal pathways (Fig. 598-1). These observations have led
lesion that may have resulted from a stroke. Other children with hemi- to greater interest in the importance of sensory deficits in these
plegic CP had had malformations from multiple causes including patients, which may be important for designing rehabilitative
infections (e.g., cytomegalovirus), lissencephaly, polymicrogyria, techniques.
schizencephaly, or cortical dysplasia. Focal cerebral infarction (stroke) Spastic quadriplegia is the most severe form of CP because of
secondary to intrauterine or perinatal thromboembolism related to marked motor impairment of all extremities and the high association
thrombophilic disorders, like the presence of anticardiolipin antibod- with intellectual disability and seizures. Swallowing difficulties are
ies, is an important cause of hemiplegic CP (see Chapter 601). Family common as a result of supranuclear bulbar palsies, often leading to
histories suggestive of thrombosis and inherited clotting disorders, aspiration pneumonia. The most common lesions seen on pathologic
such as factor V Leiden mutation, may be present and evaluation of examination or on MRI scanning are severe PVL and multicystic corti-
the mother may provide information valuable for future pregnancies cal encephalomalacia. Neurologic examination shows increased tone
and other family members. and spasticity in all extremities, decreased spontaneous movements,
Spastic diplegia is bilateral spasticity of the legs that is greater than brisk reflexes, and plantar extensor responses. Flexion contractures of
in the arms. Spastic diplegia is strongly associated with damage to the the knees and elbows are often present by late childhood. Associated
Lateral Posterior thalamic

radiation
Fibers penetrating
the posterior limb
of internal capsule
AP
Left
superior
oblique
Figure 598-1 Diffusion tensor image of white matter pathways in the brains of 2 patients with spastic diplegia on the right compared to a normal
child on the far left. Yellow fibers are corticospinal pathways projected from the motor cerebral cortex at the top downward into the brainstem,
whereas the red fibers are thalamocortical sensory fibers projected from the thalamus upward to the cortex. In the children with spastic diplegia,
both the corticospinal and thalamocortical pathways are reduced in size, but the ascending thalamocortical pathways are more affected. (From
Nagae LM, Hoon AH Jr, Stashinko E, et al: Diffusion tensor imaging in children with periventricular leukomalacia: variability of injuries to white
matter tracts, AJNR Am J Neuroradiol 28:1213–1222, 2007.)
developmental disabilities, including speech and visual abnormalities, disorders such as mitochondrial disorders and glutaric aciduria. MRI
are particularly prevalent in this group of children. Children with scanning and possibly metabolic testing are important in the evalua-
spastic quadriparesis often have evidence of athetosis and may be clas- tion of children with extrapyramidal CP to make a correct etiologic
sified as having mixed CP. diagnosis. In patients with dystonia who have a normal MRI, it is
Athetoid CP, also called choreoathetoid, extrapyramidal, or dys- important to have a high level of suspicion for dihydroxyphenylalanine
kinetic CP, is less common than spastic CP and makes up approxi- (DOPA)-responsive dystonia (Segawa disease), which causes promi-
mately 15-20% of patients with CP. Affected infants are characteristically nent dystonia that can resemble CP. These patients typically have
hypotonic with poor head control and marked head lag and develop diurnal variation in their signs with worsening dystonia in the legs
variably increased tone with rigidity and dystonia over several years. during the day; however, this may not be prominent. These patients
The term dystonia refers to the abnormality in tone in which muscles can be tested for a response to small doses of L-dopa and/or cerebro-
are rigid throughout their range of motion and involuntary contrac- spinal fluid can be sent for neurotransmitter analysis.
tions can occur in both flexors and extensors leading to limb position- Associated comorbidities are common and include pain (in 75%),
ing in fixed postures. Unlike spastic diplegia, the upper extremities are cognitive disability (50%), hip displacement (30%), seizures (25%),
generally more affected than the lower extremities in extrapyramidal behavioral disorders (25%), sleep disturbances (20%), visual impair-
CP. Feeding may be difficult, and tongue thrust and drooling may be ment (19%), and hearing impairment (4%).
prominent. Speech is typically affected because the oropharyngeal
muscles are involved. Speech may be absent or sentences are slurred, DIAGNOSIS
and voice modulation is impaired. Generally, upper motor neuron A thorough history and physical examination should preclude a pro-
signs are not present, seizures are uncommon, and intellect is pre- gressive disorder of the CNS, including degenerative diseases, meta-
served in many patients. This form of CP is also referred to in Europe bolic disorders, spinal cord tumor, or muscular dystrophy. The
as dyskinetic CP and is the type most likely to be associated with birth possibility of anomalies at the base of the skull or other disorders
asphyxia. In the European CP study, 76% of patients with this form of affecting the cervical spinal cord needs to be considered in patients
CP had lesions in the basal ganglia and thalamus. Extrapyramidal CP with little involvement of the arms or cranial nerves. An MRI scan of
secondary to acute intrapartum near-total asphyxia is associated with the brain is indicated to determine the location and extent of structural
bilaterally symmetric lesions in the posterior putamen and ventrolat- lesions or associated congenital malformations; an MRI scan of the
eral thalamus. These lesions appear to be the correlate of the neuro- spinal cord is indicated if there is any question about spinal cord
pathologic lesion called status marmoratus in the basal ganglia. pathology. Additional studies may include tests of hearing and visual
Athetoid CP can also be caused by kernicterus secondary to high levels function. Genetic evaluation should be considered in patients with
of bilirubin, and in this case the MRI scan shows lesions in the globus congenital malformations (chromosomes) or evidence of metabolic
pallidus bilaterally. Extrapyramidal CP can also be associated with disorders (e.g., amino acids, organic acids, MR spectroscopy). In addi-
lesions in the basal ganglia and thalamus caused by metabolic genetic tion to the genetic disorders mentioned earlier that can present as CP,
the urea cycle disorder arginase deficiency is a rare cause of spastic ments. The function of the affected extremities in children with hemi-
diplegia and a deficiency of sulfite oxidase or molybdenum cofactor plegic CP can often be improved by therapy in which movement of
can present as CP caused by perinatal asphyxia. Tests to detect inher- the good side is constrained with casts while the impaired extremities
ited thrombophilic disorders may be indicated in patients in whom an perform exercises which induce improved hand and arm functioning.
in utero or neonatal stroke is suspected as the cause of CP. This constraint-induced movement therapy is effective in patients of
Because CP is usually associated with a wide spectrum of develop- all ages.
mental disorders, a multidisciplinary approach is most helpful in the Several drugs have been used to treat spasticity, including the
assessment and treatment of such children. benzodiazepines and baclofen. These medications have beneficial
effects in some patients but can also cause side effects such as sedation
TREATMENT for benzodiazepines and lowered seizure threshold for baclofen.
Some progress has been made in both prevention of CP before it occurs Several drugs can be used to treat spasticity, including oral diazepam
and treatment of children with the disorder. Preliminary results from (0.01-0.3 mg/kg/day, divided bid or qid), baclofen (0.2-2 mg/kg/day,
controlled trials of magnesium sulfate given intravenously to mothers divided bid or tid) or dantrolene (0.5-10 mg/kg/day, bid). Small doses
in premature labor with birth imminent before 32 wk gestation showed of levodopa (0.5-2 mg/kg/day) can be used to treat dystonia or DOPA-
significant reduction in the risk of CP at 2 yr of age. Nonetheless, one responsive dystonia. Artane (trihexyphenidyl, 0.25 mg/day, divided
study that followed preterm infants whose mothers received magne- bid or tid and titrated upward) is sometimes useful for treating dysto-
sium sulfate demonstrated no benefit in terms of the incidence of CP nia and can increase use of the upper extremities and vocalizations.
and abnormal motor, cognitive, or behavioral function at school age. Reserpine (0.01-0.02 mg/kg/day, divided bid to a maximum of 0.25 mg
Furthermore, several large trials have shown that cooling term infants daily) or tetrabenazine (12.5-25.0 mg, divided bid or tid) can be useful
with hypoxic–ischemic encephalopathy to 33.3°C (91.9°F) for 3 days, for hyperkinetic movement disorders including athetosis or chorea.
starting within 6 hr of birth, reduces the risk of dyskinetic or spastic Intrathecal baclofen delivered with an implanted pump has been
quadriplegia form of CP. used successfully in many children with severe spasticity, and can be
For children who have a diagnosis of CP, a team of physicians, useful because it delivers the drug directly around the spinal cord
including neurodevelopmental pediatricians, pediatric neurologists, where it reduces neurotransmission of afferent nerve fibers. Direct
and physical medicine and rehabilitation specialists, as well as occupa- delivery to the spinal cord overcomes the problem of CNS side effects
tional and physical therapists, speech pathologists, social workers, edu- caused by the large oral doses needed to penetrate the blood–brain
cators, and developmental psychologists, is important to reduce barrier. This therapy requires a team approach and constant follow-up
abnormalities of movement and tone and to optimize normal psycho- for complications of the infusion pumping mechanism and infection.
motor development. Parents should be taught how to work with their Botulinum toxin injected into specific muscle groups for the manage-
child in daily activities such as feeding, carrying, dressing, bathing, and ment of spasticity shows a very positive response in many patients.
playing in ways that limit the effects of abnormal muscle tone. They Botulinum toxin injected into salivary glands may also help reduce the
also need to be instructed in the supervision of a series of exercises severity of drooling, which is seen in 10-30% of patients with CP and
designed to prevent the development of contractures, especially a tight has been traditionally treated with anticholinergic agents. Patients with
Achilles tendon. Physical and occupational therapies are useful for rigidity, dystonia, and spastic quadriparesis sometimes respond to
promoting mobility and the use of the upper extremities for activities levodopa, and children with dystonia may benefit from carbamazepine
of daily living. Speech language pathologists promote acquisition of a or trihexyphenidyl. Hyperbaric oxygen has not been shown to improve
functional means of communications. These therapists help children the condition of children with CP.
to achieve their potential and often recommend further evaluations Communication skills may be enhanced by the use of Bliss symbols,
and adaptive equipment. talking typewriters, electronic speech generating devices, and specially
Children with spastic diplegia are treated initially with the assistance adapted computers including artificial intelligence computers to
of adaptive equipment, such as walkers, poles, and standing frames. If augment motor and language function. Significant behavior problems
a patient has marked spasticity of the lower extremities or evidence of may substantially interfere with the development of a child with CP;
hip dislocation, consideration should be given to performing surgical their early identification and management are important, and the assis-
soft-tissue procedures that reduce muscle spasm around the hip girdle, tance of a psychologist or psychiatrist may be necessary. Learning and
including an adductor tenotomy or psoas transfer and release. A rhi- attention deficit disorders and mental retardation are assessed and
zotomy procedure in which the roots of the spinal nerves are divided managed by a psychologist and educator. Strabismus, nystagmus, and
produces considerable improvement in selected patients with severe optic atrophy are common in children with CP; an ophthalmologist
spastic diplegia (Fig. 598-2). A tight heel cord in a child with spastic should be included in the initial assessment. Lower urinary tract dys-
hemiplegia may be treated surgically by tenotomy of the Achilles function should receive prompt assessment and treatment.
tendon. Quadriplegia is managed with motorized wheelchairs, special
feeding devices, modified typewriters, and customized seating arrange- Bibliography is available at Expert Consult.
A
B
Figure 598-2 Schematic of the technique of selected dorsal rhizotomy. A, After laminectomy, the dura is opened and the dorsal spinal rootlets
are exposed. The rootlets are stimulated so that abnormal rootlet activity can be identified. B, A proportion of rootlets are transected. (From
Koman LA, Smith BP, Shilt JS: Cerebral palsy, Lancet 363:1619–1631, 2004. Reproduced with permission from Wake Forest University Orthopaedic
Press.)
Chapter 598 ◆ Encephalopathies 2899.e1
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598.2 Mitochondrial Encephalomyopathies consequence of high mutation rates for mitochondrial DNA (mtDNA),
and the severity of disease varies from person to person.
Michael V. Johnston Mitochondrial diseases can be caused by mutations of nuclear DNA
(nDNA) or mtDNA (see Chapters 80, 86, and 87). Oxidative phos-
See Chapters 87.4 and 611.4. phorylation in the respiratory chain is mediated by 4 intramitochon-
Mitochondrial encephalomyopathies are a heterogeneous group of drial enzyme complexes (complexes I-IV) and 2 mobile electron
clinical syndromes caused by genetic lesions that impair energy pro- carriers (coenzyme Q and cytochrome c) that create an electrochemi-
duction through oxidative phosphorylation. The signs and symptoms cal proton gradient utilized by complex V (adenosine triphosphate
of these disorders reflect the vulnerability of the nervous system, [ATP] synthase) to create the ATP required for normal cellular func-
muscles, and other organs to energy deficiency. Signs of brain and tion. The maintenance of oxidative phosphorylation requires coordi-
muscle dysfunction (seizures, weakness, ptosis, external ophthalmo- nated regulation of nuclear DNA and mtDNA genes. Human mtDNA
plegia, psychomotor regression, hearing loss, movement disorders, and is a small (16.6 kb), circular, double-stranded molecule that has been
ataxia) in association with lactic acidosis are prominent features of completely sequenced and encodes 37 genes including 13 structural
mitochondrial disorders. Cardiomyopathy and diabetes mellitus can proteins, all of which are subunits of the respiratory chain complexes,
also result from mitochondrial disorders. as well as 2 ribosomal RNAs and 22 transfer RNAs (tRNAs) needed
Children with mitochondrial disorders often have multifocal signs for translation. The nuclear DNA is responsible for synthesizing
that are intermittent or relapsing–remitting, often in association with approximately 70 subunits, transporting them to the mitochondria via
intercurrent illness. Many of these disorders were described as clinical chaperone proteins, ensuring their passage across the inner mitochon-
syndromes before their genetics were understood. Children with mito- drial membrane, and coordinating their correct processing and assem-
chondrial encephalomyopathy with lactic acidosis and stroke-like epi- bly. Diseases of mitochondrial oxidative phosphorylation can be
sodes (MELAS) present with developmental delay, weakness, and divided into 3 groups: (1) defects of mtDNA, (2) defects of nDNA, and
headaches, as well as focal signs that suggest a stroke. Brain imaging (3) defects of communication between the nuclear and mitochondrial
indicates that injury does not fit within the usual vascular territories. genome. mtDNA is distinct from nDNA for the following 4 reasons:
Children with myoclonic epilepsy with ragged red fibers (MERRF) (1) its genetic code differs from nDNA, (2) it is tightly packed with
present with myoclonus and myoclonic seizures as well as intermittent information because it contains no introns, (3) it is subject to sponta-
muscle weakness. The ragged red fibers referred to in the name of this neous mutations at a higher rate than nDNA, (4) it has less efficient
disorder are clumps of abnormal mitochondria seen within muscle repair mechanisms.
fibers in sections from a muscle biopsy stained with Gomori trichrome Inheritance of mutations present on mtDNA is nonmendelian and
stain. NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa), can be complex. At fertilization, mtDNA is present in hundreds or
Kearns-Sayre syndrome (KSS; ptosis, ophthalmoplegia, heart block), thousands of copies per cell and is transmitted by maternal inheritance
Leigh disease (subacute necrotizing encephalomyelopathy), and Leber from her oocyte to all her children, but only her daughters can pass it
hereditary optic neuropathy (LHON) are also defined as relatively on to their children. Through the process called heteroplasmy or
homogeneous clinical subgroups (Table 598-2). It is important to keep threshold effect, mtDNA containing mutations can be distributed
in mind that mitochondrial disorders can be difficult to diagnose. They unequally between cells in specific tissues. Some cells receive few or
often present with novel combinations of signs and symptoms as a no mutant genomes (normal or wild-type homoplasmy), whereas
Table 598-2 Clinical Manifestations of Mitochondrial Encephalomyopathies

TISSUE SYMPTOMS/SIGNS MELAS MERRF NARP KSS LEIGH LHON
CNS Regression + + + +
Seizures + +
Ataxia + + + +
Cortical blindness +
Deafness + +
Migraine +
Hemiparesis +
Myoclonus + +
Movement disorder + +
Nerve Peripheral neuropathy + + + +
Muscle Ophthalmoplegia +
Weakness + + + + +
RRF on muscle biopsy + + +
Ptosis +
Eye Pigmentary retinopathy + +
Optic atrophy + + +
Cataracts
Heart Conduction block + +
Cardiomyopathy +
Blood Anemia +
Lactic acidosis + + +
Endocrine Diabetes mellitus +
Short stature + + +
Kidney Fanconi syndrome + + +
KSS, Kearns-Sayre syndrome; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes;
MERRF, myoclonic epilepsy with ragged red fibers; NARP, neuropathy, ataxia and retinitis pigmentosa; RRF, ragged red fibers.
others receive a mixed population of mutant and wild-type mtDNAs rolandic lesions and epilepsia partialis continua associated with
(heteroplasmy), and still others receive primarily or exclusively mtDNA mutations at 10158T>C and 10191T>C. MELAS is a progres-
mutant genomes (mutant homoplasmy). The important implications sive disorder that has been reported in siblings. However, most mater-
of maternal inheritance and heteroplasmy are as follows: (1) inheri- nal relatives of MELAS patients are mildly affected or unaffected.
tance of the disease is maternal, but both sexes are equally affected; (2) MELAS is punctuated with episodes of stroke leading to dementia (see
phenotypic expression of an mtDNA mutation depends on the relative Chapter 611.4).
proportions of mutant and wild-type genomes, with a minimum criti- Regional cerebral hypoperfusion can be detected by single-photon
cal number of mutant genomes being necessary for expression (thresh- emission CT studies and MR spectroscopy can detect focal areas of
old effect); (3) at cell division, the proportional distribution may shift lactic acidosis in the brain. Neuropathology may show cortical atrophy
between daughter cells (mitotic segregation), leading to a correspond- with infarct-like lesions in both cortical and subcortical structures,
ing phenotypic change; and (4) subsequent generations are affected at basal ganglia calcifications, and ventricular dilation. Muscle biopsy
a higher rate than in autosomal dominant diseases. The critical number specimens usually show RRF. Mitochondrial accumulations and
of mutant mtDNAs required for the threshold effect may vary, depend- abnormalities have been shown in smooth muscle cells of intramuscu-
ing on the vulnerability of the tissue to impairments of oxidative lar vessels and of brain arterioles and in the epithelial cells and blood
metabolism as well as on the vulnerability of the same tissue over time vessels of the choroid plexus, producing a mitochondrial angiopathy.
that may increase with aging. In contrast to maternally inherited dis- Muscle biochemistry shows complex I deficiency in many cases;
orders caused by mutations in mtDNA, diseases resulting from defects however, multiple defects have also been documented involving com-
in nDNA follow mendelian inheritance. Mitochondrial diseases caused plexes I, III, and IV. Targeted molecular testing for specific mutations
by defects in nDNA include defects in substrate transport (plasmalem- or sequence analysis and mutation scanning are generally used to make
mal carnitine transporter, carnitine palmitoyltransferases I and II, car- a diagnosis of MELAS when clinical evaluation suggests the diagnosis.
nitine acylcarnitine translocase defects), defects in substrate oxidation Because the number of mutant genomes is lower in blood than in
(pyruvate dehydrogenase complex, pyruvate carboxylase, intramito- muscle, muscle is the preferable tissue for examination. Inheritance is
chondrial fatty acid oxidation defects), defects in the Krebs cycle maternal, and there is a highly specific, although not exclusive, point
(α-ketoglutarate dehydrogenase, fumarase, aconitase defects), and mutation at nt 3243 in the tRNALeu(UUR) gene of mtDNA in approxi-
defects in the respiratory chain (complexes I-V), including defects of mately 80% of patients. An additional 7.5% have a point mutation at
oxidation/phosphorylation coupling (Luft syndrome), and defects in nt 3271 in the tRNALeu(UUR) gene. A third mutation has been identified
mitochondrial protein transport. at nt 3252 in the tRNALeu(UUR) gene. The prognosis in patients with the
Diseases caused by defects in mtDNA can be divided into those full syndrome is poor. Therapeutic trials reporting some benefit have
associated with point mutations that are maternally inherited (e.g., included corticosteroids, coenzyme Q10, nicotinamide, carnitine, cre-
LHON, MELAS, MERRF, and NARP syndromes) and those caused by atine, riboflavin and various combinations of these; l-arginine and
deletions or duplications of mtDNA that reflect altered communication preclinical studies reported some success with resveratrol.
between the nucleus and the mitochondria (KSS; Pearson syndrome,
a rare severe encephalopathy with anemia and pancreatic dysfunction; MYOCLONUS EPILEPSY AND RAGGED
and progressive external ophthalmoplegia). These disorders can be RED FIBERS
inherited by sporadic, autosomal dominant or recessive mechanisms MERRF syndrome is characterized by progressive myoclonic epilepsy,
and mutations in multiple genes, including mitochondrial mtDNA mitochondrial myopathy, and cerebellar ataxia with dysarthria and
polymerase γ catalytic subunit (POLG), have been identified. POLG nystagmus. Onset may be in childhood or in adult life, and the course
mutations have also been identified in patients with Alpers- may be slowly progressive or rapidly downhill. Other features include
Huttenlocher syndrome, which causes a refractory seizure disorder dementia, sensorineural hearing loss, optic atrophy, peripheral neu-
and hepatic failure as well as autosomal dominant and recessive pro- ropathy, and spasticity. Because some patients have abnormalities of
gressive external ophthalmoplegia, childhood myocerebrohepatopathy deep sensation and pes cavus, the condition may be confused with
spectrum disorders, myoclonic epilepsy myopathy sensory ataxia syn- Friedreich ataxia. A significant number of patients have a positive
drome, and POLG-related ataxia neuropathy spectrum disorders. family history and short stature. This condition is maternally
Other genes that regulate the supply of nucleotides for mtDNA syn- inherited.
thesis are associated with severe encephalopathy and liver disease, and Pathologic findings include elevated serum lactate concentrations,
new disorders are being identified that result from defects in the inter- RRF on muscle biopsy, and marked neuronal loss and gliosis affecting,
actions between mitochondria and their milieu in the cell. in particular, the dentate nucleus and inferior olivary complex with
some dropout of Purkinje cells and neurons of the red nucleus. Pallor
MITOCHONDRIAL MYOPATHY, of the posterior columns of the spinal cord and degeneration of the
ENCEPHALOPATHY, LACTIC ACIDOSIS, gracile and cuneate nuclei occur. Muscle biochemistry has shown vari-
AND STROKELIKE EPISODES able defects of complex III, complexes II and IV, complexes I and IV,
Children with MELAS may be normal for the 1st several yr, but or complex IV alone. More than 80% of cases are caused by a hetero-
they gradually display delayed motor and cognitive development and plasmic G to A point mutation at nt 8344 of the tRNALys gene of
short stature. The clinical syndrome is characterized by (1) recurrent mtDNA. Additional patients have been reported with a T to C muta-
stroke-like episodes of hemiparesis or other focal neurologic signs with tion at nt 8356 in the tRNALys gene. Targeted mutation analysis or
lesions most commonly seen in the posterior temporal, parietal, and mutation analysis after sequencing of the mitochondrial genome is
occipital lobes (CT or MRI evidence of focal brain abnormalities); (2) used to diagnosis MERRF.
lactic acidosis, ragged red fibers (RRF), or both; and (3) at least 2 of There is no specific therapy, although coenzyme Q10 appeared to be
the following: focal or generalized seizures, dementia, recurrent beneficial in a mother and daughter with the MERRF mutation. The
migraine headaches, and vomiting. In 1 series, onset was before age anticonvulsant levetiracetam is reported to help reduce myoclonus and
15 yr in 62% of patients, and hemianopia or cortical blindness was the myoclonic seizures in this disorder.
most common manifestation. Cerebrospinal fluid protein is often
increased. The MELAS 3243 mutation on mtDNA is the most common NEUROPATHY, ATAXIA, AND RETINITIS
mutation to produce MELAS and can also be associated with different PIGMENTOSA SYNDROME
combinations of exercise intolerance, myopathy, ophthalmoplegia, pig- This maternally inherited disorder presents with either Leigh syn-
mentary retinopathy, hypertrophic or dilated cardiomyopathy, cardiac drome or with neurogenic weakness and NARP syndrome, as well as
conduction defects, deafness, endocrinopathy (diabetes mellitus), and seizures. It is caused by a point mutation at nt 8993 within the ATPase
proximal renal tubular dysfunction. A number of other mutations have subunit 6 gene. The severity of the disease presentation appears to have
been reported, and 2 patients have been described with bilateral close correlation with the percentage of mutant mtDNA in leukocytes.
Two clinical patterns are seen in patients with NARP syndrome: (1) present within the 1st few wk of life with hypotonia, severe muscle
neuropathy, ataxia, retinitis pigmentosa, dementia, and ataxia, and (2) weakness, and very elevated serum lactate levels, and they often require
severe infantile encephalopathy resembling Leigh syndrome with mechanical ventilation. However, feeding and psychomotor develop-
lesions in the basal ganglia on MRI. ment are not affected. Muscle biopsies taken from these children in the
neonatal period show RRF and deficient COX activity, but these find-
LEBER HEREDITARY OPTIC NEUROPATHY ings disappeared within 5-20 mo when the infants recovered spontane-
LHON is characterized by onset usually between the ages of 18 and ously. It is difficult to distinguish these infants from those with lethal
30 yr of acute or subacute visual loss caused by severe bilateral optic mitochondrial disorders without waiting for them to improve. The
atrophy, although children as young as 5 yr have been reported to have mechanism for this recovery is not established, but it may reflect a
LHON. Three mtDNA mutations account for most cases of LHON and developmental switch in mitochondrial RNAs later in infancy. This
at least 85% of patients are young men. An X-linked factor may modu- reversible disorder is observed only in COX deficiency associated with
late the expression of the mtDNA point mutation. The classic ophthal- the 14674T>C mt-tRNAGlu mutation, so it is suggested that infants with
mologic features include circumpapillary telangiectatic microangiopathy this type of severe weakness in the neonatal period be tested for this
and pseudoedema of the optic disc. Variable features may include mutation to help with prognosis.
cerebellar ataxia, hyperreflexia, Babinski sign, psychiatric symptoms,
peripheral neuropathy, or cardiac conduction abnormalities (preexci- LEIGH DISEASE (SUBACUTE NECROTIZING
tation syndrome). Some cases are associated with widespread white ENCEPHALOMYOPATHY)
matter lesions as seen with multiple sclerosis. Lactic acidosis and RRF Leigh disease is a progressive degenerative disorder presenting in
tend to be conspicuously absent in LHON. More than 11 mtDNA point infancy with feeding and swallowing problems, vomiting, and failure
mutations have been described, including a usually homoplasmic G to to thrive associated with lactic acidosis and lesions seen in the brain-
A transition at nt 11,778 of the ND4 subunit gene of complex I. The stem and/or basal ganglia on MRI (Table 598-3). There are several
latter leads to replacement of a highly conserved arginine residue by genetically determined causes of Leigh disease that result from nuclear
histidine at the 340th amino acid and accounts for 50-70% of cases in DNA mutations in genes that code for components of the respiratory
Europe and more than 90% of cases in Japan. Certain LHON pedigrees chair: pyruvate dehydrogenase complex deficiency, complex I or II
with other point mutations are associated with complex neurologic deficiency, complex IV (COX) deficiency, complex V (ATPase) defi-
disorders and may have features in common with MELAS syndrome ciency, and deficiency of coenzyme Q10. These defects may occur
and with infantile bilateral striatal necrosis. One family has been sporadically or be inherited by autosomal recessive transmission, as in
reported with pediatric onset of progressive generalized dystonia with the case of COX deficiency; by X-linked transmission, as in the case of
bilateral striatal necrosis associated with a homoplasmic G14459A pyruvate dehydrogenase E1α deficiency; or by maternal transmission,
mutation in the mtDNA ND6 gene, which is also associated with as in complex V (ATPase 6 nt 8993 mutation) deficiency. Approxi-
LHON alone and LHON with dystonia. mately 30% of cases are caused by mutations in mtDNA. Delayed
motor and language milestones may be evident, and generalized
KEARNS-SAYRE SYNDROME seizures, weakness, hypotonia, ataxia, tremor, pyramidal signs, and
KSS is a characteristic multiorgan disorder involving external ophthal- nystagmus are prominent findings. Intermittent respirations with asso-
moplegia, heart block, and retinitis pigmentosa with onset before age ciated sighing or sobbing are characteristic and suggest brainstem dys-
20 yr caused by single deletions in mtDNA. There must also be at least function. Some patients have external ophthalmoplegia, ptosis, retinitis
1 of the following: heart block, cerebellar syndrome, or cerebrospinal pigmentosa, optic atrophy, and decreased visual acuity. Abnormal
fluid protein >100 mg/dL. Other nonspecific but common features results on CT or MRI scan consist of bilaterally symmetric areas of low
include dementia, sensorineural hearing loss, and multiple endocrine attenuation in the basal ganglia and brainstem as well as elevated lactic
abnormalities, including short stature, diabetes mellitus, and hypo- acid on MR spectroscopy (Fig. 598-3). Pathologic changes consist of
parathyroidism. The prognosis is guarded, despite placement of a pace- focal symmetric areas of necrosis in the thalamus, basal ganglia, teg-
maker, and progressively downhill, with death resulting by the 3rd or mental gray matter, periventricular and periaqueductal regions of the
4th decade. Unusual clinical presentations can include renal tubular brainstem, and posterior columns of the spinal cord. Microscopically,
acidosis and Lowe syndrome. There are also a few overlap cases of these spongiform lesions show cystic cavitation with neuronal loss,
children with KSS and stroke-like episodes. Muscle biopsy shows RRF demyelination, and vascular proliferation. Elevations in serum lactate
and variable cytochrome c oxidase (COX)-negative fibers. Most levels are characteristic and hypertrophic cardiomyopathy, hepatic
patients have mtDNA deletions, and some have duplications. These failure and rental tubular dysfunction can occur. The overall outlook
may be new mutations accounting for the generally sporadic nature of is poor, but a few patients experience prolonged periods of remission.
KSS. A few pedigrees have shown autosomal dominant transmission. There is no definitive treatment for the underlying disorder, but a range
Patients should be monitored closely for endocrine abnormalities, of vitamins including riboflavin, thiamine, and coenzyme Q are often
which can be treated. Coenzyme Q is reported anecdotally to have given to try to improve mitochondrial function. Biotin, creatine, suc-
some beneficial effect; a positive effect of folinic acid for low folate cinate, and idebenone, as well as a high-fat diet have also been used,
levels also is reported. A report of positive effects of a cochlear implant but phenobarbital and valproic acid should be avoided because of their
for deafness is also reported. inhibitory effect on the mitochondrial respiratory chain.
Sporadic progressive external ophthalmoplegia with ragged red
fibers is a clinically benign condition characterized by adolescent or REYE SYNDROME
young adult–onset ophthalmoplegia, ptosis, and proximal limb girdle This encephalopathy, which has become uncommon, is associated with
weakness. It is slowly progressive and compatible with a relatively pathologic features characterized by fatty degeneration of the viscera
normal life. The muscle biopsy material demonstrates RRF and COX- (microvesicular steatosis) and mitochondrial abnormalities and bio-
negative fibers. Approximately 50% of patients with progressive exter- chemical features consistent with a disturbance of mitochondrial
nal ophthalmoplegia have mtDNA deletions, and there is no family metabolism (see Chapter 361).
history. Recurrent Reye-like syndrome is encountered in children with
genetic defects of fatty acid oxidation, such as deficiencies of the plas-
REVERSIBLE INFANTILE CYTOCHROME C malemmal carnitine transporter, carnitine palmitoyltransferases I and
OXIDASE DEFICIENCY MYOPATHY II, carnitine acylcarnitine translocase, medium- and long-chain acyl-
Mutations in mtDNA are also responsible for a reversible form of coenzyme A dehydrogenase, multiple acyl-coenzyme A dehydroge-
severe neuromuscular weakness and hypotonia in infants that is the nase, and long-chain L-3 hydroxyacyl-coenzyme A dehydrogenase or
result of a maternally inherited homoplasmic m.14674T>C mt-tRNAGlu trifunctional protein. These disorders are manifested by recurrent
mutation associated with a deficiency of COX. Affected children hypoglycemic and hypoketotic encephalopathy, and they are inherited
Table 598-3 Clinical Features of Congenital Leigh Syndrome or Leigh-Like Syndrome

NEUROLOGIC MANIFESTATIONS NONNEUROLOGIC MANIFESTATIONS
Brainstem Dysmorphic Features
Bradypnea, hypopnea, episodes of apnea Lip cleft
Bradycardia Short distal phalanges
Tetraparesis Single palmar crease
Hypotonia (floppy infant) Rostral vertebrae
Failure to thrive, poor sucking Round face
Swallowing difficulties, dysphagia, poor feeding, poor sucking Frontal bossing
Vomiting Flat nasal root
Spasticity, brisk tendon reflexes Microcephaly
Dysphasia, dysarthria Thin lips
Squint Small chin
Absence of optic or acoustic blink Long, featureless philtrum
Other Cerebral Manifestations Hypospadia
Stroke-like episodes Others
Delay of developmental milestones Inguinal hernia
Paralysis of vertical gaze Stiff neck
Myoclonic jerks of limbs or eyelids Retinal dystrophy, retinopathy
Hypothermia Deafness, hypoacusis
Drowsiness, dizziness Hypertrophic, dilated cardiomyopathy
Psychomotor (mental) retardation Pancreatitis
Ataxia, tremor Diarrhea
Seizures, convulsions Urinary excretion of Krebs-cycle intermediates
Growth retardation Intrauterine growth retardation
Dystonia Hypertrichosis
Clumsiness, dullness Villous atrophy
Nystagmus, uncoordinated eye movement, slow saccades Nephrotic syndrome
Optic atrophy Nephropathy
Visual loss Hyperhidrosis
Facial dyskinesia Scoliosis
Ocular apraxia
Drooling
Gaze fixation difficulty
Peripheral Nervous System Manifestations
Cranial nerve palsies
Generalized wasting
Bilateral ptoses
Chronic progressive external ophthalmoplegia, strabismus
Reduced tendon reflexes
Polyneuropathy
Muscle weakness
Myopathy
From Finsterer J: Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 39:223–235, 2008, Table 1.
A B C
Figure 598-3 Leigh syndrome. Axial T2-weighted magnetic resonance images (TR/TE/NEX = 3,000/120/1 msec) of 8 mo old girl with Leigh syn-
drome because of a SURF1 mutation indicate hyperintense lesions in substantia nigra and medial thalamic nuclei (A, B). Follow-up images (TR/TE/
NEX = 2,028/120/2 msec) at age 26 mo (C) indicate hyperintense putamina and hyperintense left caudate nucleus. (From Farina L, Chiapparini L,
Uziel G, et al: MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations, AJNR Am J Neuroradiol 23:1095–1100, 2002, Fig. 2.)
in an autosomal recessive pattern. Other potential inborn errors of

metabolism presenting with Reye syndrome include urea cycle defects Table 598-4 Diagnostic Criteria for Acute Necrotizing
(ornithine transcarbamylase, carbamyl phosphate synthetase) and Encephalopathy of Childhood
certain of the organic acidurias (glutaric aciduria type I), respiratory 1. Acute encephalopathy following (1-3 days) a febrile disease.
chain defects, and defects of carbohydrate metabolism (fructose Rapid deterioration in the level of consciousness. Seizures.
intolerance). 2. No cerebrospinal fluid pleocytosis. Increase in cerebrospinal fluid
protein.
Bibliography is available at Expert Consult. 3. CT or MRI evidence of symmetric, multifocal brain lesions.
Involvement of the bilateral thalami. Lesions also common in the
cerebral periventricular white matter, internal capsule, putamen,
upper brainstem tegmentum and cerebellar medulla. No
598.3 Other Encephalopathies involvement of other central nervous system regions.
4. Elevation of serum aminotransferases of variable degrees. No
Michael V. Johnston
increase in blood ammonia.
5. Exclusion of resembling diseases.
HIV ENCEPHALOPATHY A. Differential diagnosis from clinical viewpoints.
Encephalopathy is an unfortunate and common manifestation in Overwhelming bacterial and viral infections, and fulminant
infants and children with HIV infection (see Chapter 276). hepatitis; toxic shock, hemolytic uremic syndrome, and other
toxin-induced diseases; Reye syndrome, hemorrhagic shock
LEAD ENCEPHALOPATHY and encephalopathy syndrome, and heat stroke.
See Chapter 721. B. Differential diagnosis from radiologic viewpoints.
Leigh encephalopathy and related mitochondrial cytopathies;
glutaric acidemia, methylmalonic acidemia, and infantile
BURN ENCEPHALOPATHY bilateral striatal necrosis; Wernicke encephalopathy and
An encephalopathy develops in approximately 5% of children with carbon monoxide poisoning; acute disseminated
significant burns in the 1st several wk of hospitalization (see Chapter encephalomyelitis, acute hemorrhagic leukoencephalitis,
75). There is no single cause of burn encephalopathy but rather a other types of encephalitis, and vasculitis; arterial or venous
combination of factors that include anoxia (smoke inhalation, carbon infection, and the effects of severe hypoxia or head trauma
monoxide poisoning, laryngospasm), electrolyte abnormalities, bacte- Modified from Hoshino A, Saitoh M, Oka, et al: Epidemiology of acute
remia and sepsis, cortical vein thrombosis, a concomitant head injury, encephalopathy in Japan, with emphasis on the association of viruses and
cerebral edema, drug reactions, and emotional distress. Seizures are syndromes. Brain Dev 34:337–343, 2012, Table 1.
the most common clinical manifestation of burn encephalopathy, but
altered states of consciousness, hallucinations, and coma may also
occur. Management of burn encephalopathy is directed to a search for
the underlying cause and treatment of hypoxemia, seizures, specific
electrolyte abnormalities, or cerebral edema. The prognosis for com- reducing the cerebral edema and reversing the neurologic signs. Late-
plete neurologic recovery is generally excellent, particularly if seizures radiation encephalopathy is characterized by headaches and slowly
are the primary abnormality. progressive focal neurologic signs, including hemiparesis and seizures.
Exposure of the brain to radiation for treatment of childhood cancer
HYPERTENSIVE ENCEPHALOPATHY increases the risk of later cerebrovascular disease, including stroke,
Hypertensive encephalopathy is most commonly associated with renal moyamoya disease, aneurysm, vascular malformations, mineralizing
disease in children, including acute glomerulonephritis, chronic pyelo- microangiopathy, and stroke-like migraines. Some children with acute
nephritis, and end-stage renal disease (see Chapters 445 and 535). In lymphocytic leukemia treated with a combination of intrathecal meth-
some cases, hypertensive encephalopathy is the initial manifestation of otrexate and cranial irradiation develop neurologic signs months or
underlying renal disease. Marked systemic hypertension produces years later; signs consist of increasing lethargy, loss of cognitive abili-
vasoconstriction of the cerebral vessels, which leads to vascular perme- ties, dementia, and focal neurologic signs and seizures (see Chapter
ability, causing areas of focal cerebral edema and hemorrhage. The 494). The CT scan shows calcifications in the white matter, and the
onset may be acute, with seizures and coma, or more indolent, with postmortem examination demonstrates a necrotizing encephalopathy.
headache, drowsiness and lethargy, nausea and vomiting, blurred This devastating complication of the treatment of leukemia has
vision, transient cortical blindness, and hemiparesis. Examination of prompted re-evaluation and reduction in the use of cranial radiation
the eyegrounds may be nondiagnostic in children, but papilledema and in the treatment of these children.
retinal hemorrhages may occur. MRI often shows increased signal
intensity in the occipital lobes on T2-weighted images, which is known ACUTE NECROTIZING ENCEPHALOPATHY
as posterior reversible leukoencephalopathy (PRES) and may be Acute necrotizing encephalopathy is a rare, severe encephalopathy
confused with cerebral infarctions. These high signal areas may appear seen more commonly in Asian countries. It is thought to be triggered
in other regions of the brain as well. PRES may also be seen in children by a viral infection (influenza, HHV-6) in a genetically susceptible
without hypertension. In all circumstances, PRES manifests with gen- host. Table 598-4 lists the diagnostic criteria. The elevation of hepatic
eralized motor seizures, headache, mental status changes, and visual enzymes without hyperammonemia is a unique feature. A familial or
disturbances. CT may be normal in PRES; MRI is the study of choice. recurrent form is associated with mutations in the RANBP2 gene and
Treatment is directed at restoration of a normotensive state and control is designated ANE1. MRI finding are characterized by symmetric
of seizures with appropriate anticonvulsants. lesions that must be present in the thalami (Fig. 598-4). The prognosis
is usually poor, however some patients have responded to steroids and
RADIATION ENCEPHALOPATHY intravenous immunoglobulin (IVIG).
Acute radiation encephalopathy is most likely to develop in young
patients who have received large daily doses of radiation. Excessive CYSTIC LEUKOENCEPHALOPATHY
radiation injures vessel endothelium, resulting in enhanced vascular An autosomal recessive disorder caused by mutations of RNASET2
permeability, cerebral edema, and numerous hemorrhages. The child proteins produces a brain MRI study that closely resembles congenital
may suddenly become irritable and lethargic, complain of headache, cytomegalovirus infection. Cystic leukoencephalopathy is manifest as
or present with focal neurologic signs and seizures. Patients occasion- a static encephalopathy without megalencephaly.
ally develop hemiparesis as the result of an infarct secondary to vascu-
lar occlusion of the cerebral vessels. Steroids are often beneficial in Bibliography is available at Expert Consult.
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Children’s Oncology Group report, Leukemia 24:285–297, 2010. syndrome in children with cancer, Pediatr Blood Cancer 48:152–159, 2007.
Henneke M, Dickmann S, Ohlenbusch A, et al: RNASET2-deficient cystic Neilson DE: The interplay of infection and genetics in acute necrotizing
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Nat Genet 41:773–775, 2009. Nielson DE, Adams MD, Orr C, et al: Infection-triggered familial or recurrent
Hoshino A, Saitoh M, Oka A, et al: Epidemiology of acute encephalopathy in cases of acute necrotizing encephalopathy caused by mutation in a component
Japan, with emphasis on the association of viruses and syndromes, Brain Dev of the nuclear pore, RANBP2, Am J Hum Genet 84:44–51, 2009.
34:337–343, 2012. Onder AM, Lopez R, Teomete U, et al: Posterior reversible encephalopathy
Kastrup O, Gerwig M, Frings M, et al: Posterior reversible encephalopathy syndrome in the pediatric renal population, Pediatr Nephrol 22:1921–1929,
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A B C
D E F
Figure 598-4 Acute necrotizing encephalopathy. MRI at presentation. A, Axial diffusion-weighted image; B, axial apparent diffusion coefficient
(ADC) map; C, axial T2-weighted image; D, axial fluid-attenuated inversion recovery (FLAIR) image; E, contrast-enhanced axial T1-weighted image;
F, axial susceptibility weighted image. Diffusion-weighted images (A) and corresponding ADC map (B) clearly show multiple areas of restricted
diffusion against a background of increased diffusion involving both thalami, which are swollen. On T2-weighted (C) and FLAIR (D) images, the
thalami are markedly swollen and hyperintense. On T1-weighted images obtained after intravenous gadolinium chelate injection (E), multiple
necrotic portions are well delineated by peripheral faint, linear enhancement. Incidental choroid plexus cysts are detected. Susceptibility weighted
image (F) shows multiple hypointense spots, consistent with petechial hemorrhage. (From Bergamino L, Capra V, Biancheri R, et al: Immunomodu-
latory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful? Brain Dev 34:384–391, 2012, Fig. 1.)
The identification of these disorders provides a definitive diagnosis

598.4 Autoimmune Encephalitis to many cases of encephalitis previously considered idiopathic, infec-
Thaís Armangué and Josep O. Dalmau tious, or postinfectious, although no causative agents were found.
Because the etiology and pathogenic mechanisms were unknown,
Autoimmune encephalitis comprises an expanding group of clinical some of these disorders were previously defined with descriptive terms.
syndromes that can occur at all ages (<1 yr to adult) but preferentially More than half of cases under the ill-defined term “encephalitis lethar-
affect younger adults and children (Table 598-5). These disorders asso- gica” and some cases of “choreoathetosis post–herpes simplex enceph-
ciate with antibodies against neuronal cell surface proteins and synap- alitis” are known to be anti–N-methyl-d-aspartate receptor (NMDAR)
tic receptors involved in synaptic transmission, plasticity, or neuronal encephalitis.
excitability. The syndromes vary according to the associated antibody The mechanisms that trigger the production of the antibodies are
with phenotypes that resemble those in which the function of the target unknown. In a small subgroup of adolescent or young adult patients,
antigen is pharmacologically or genetically modified. the presence of a tumor that expresses the target neuronal antigen
Most of these disorders are severe and potentially fatal but patients likely contributes in triggering the immune response. In addition, the
frequently respond to immunotherapy with good outcomes. Moreover, high prevalence of prodromal viral-like symptoms has suggested that
because of the broad spectrum of symptoms—including alterations of nonspecific viral infections may contribute to breaking immune toler-
behavior, psychosis, catatonia, memory deficits, seizures, abnormal ance and increase the permeability of the blood–brain barrier to anti-
movements, and autonomic dysregulation—patients usually require a bodies. Nonetheless in many of these disorders the blood–brain barrier
multidisciplinary treatment approach often in an intensive care unit. appears intact and there is evidence that the autoantibodies are
Table 598-5 Autoimmune Encephalitis in Children
TUMOR TREATMENT/
MECHANISMS ASSOCIATION SYNDROME ANCILLARY TEST PROGNOSIS
DEMONSTRATED IMMUNE MECHANISMS
Anti-NMDAR Antibodies against Age and gender Psychiatric symptoms, EEG: almost always 80% complete recovery
encephalitis NR1 subunit of related: 41% in seizures, orofacial abnormal; it may show after immunotherapy
NMDAR, disrupt females older dyskinesias and “extreme delta brush” and tumor removal
function by than 12 yr; <6% other abnormal pattern (if appropriate).
crosslinking and in girls younger movements, Brain MRI: nonspecific Frequently second-
internalization of than 12 yr. No autonomic findings in ~35% line drug*
receptors tumors identified dysfunction CSF: pleocytosis and/or immunotherapy is
in young boys increased protein in required. Relapses in
>80% ~15% of patients
Limbic Antibodies against Extremely rare in Severe short-term EEG: temporal lobe If autoantigens are
encephalitis intraneuronal children (see memory loss, epileptic activity; focal intracellular, poor
antigens: Hu, Ma2, text) seizures or generalized slowing response to
amphiphysin, GAD MRI: increased T2 and immunotherapy
Antibodies against FLAIR signal in limbic If autoantigens are on
synaptic antigens: region the cell surface,
GABABR, mGluR5 CSF: pleocytosis and ~80% are responsive
increased proteins to immunotherapy
STRONGLY SUSPECTED IMMUNE MECHANISMS
Opsoclonus- Most patients do not Neuroblastoma Opsoclonus often CSF abnormalities Partial response to
myoclonus and have detectable occurs in 50% of accompanied by suggesting B-cell immunotherapy in
other cerebellar- antibodies (a few children <2 year irritability, ataxia, activation neuroblastoma-
brainstem patients have Hu old; teratoma in falling, myoclonus, MRI: in some cases related opsoclonus
encephalitis antibodies) teenagers and tremor, and cerebellar atrophy High response to
young adults drooling immunotherapy in
teratoma-associated
opsoclonus
Bickerstaff GQ1b antibodies No tumor Ophthalmoplegia, MRI: abnormal in ~30% Often good outcome
encephalitis association ataxia, hyperreflexia. (T2-signal with steroids, IVIG
May overlap with abnormalities in the and/or plasma
Miller-Fisher brainstem, thalamus, exchange
syndrome and cerebellum)
Nerve conduction
studies: abnormal in
~44% (predominant
axonal degeneration,
less frequent
demyelination)
Hashimoto TPO antibodies No tumor Stroke-like symptoms, 48% hypothyroidism, Steroid-responsive.
encephalitis association tremor, myoclonus, MRI often normal Partial responses are
aphasia, sleep and EEG: slow activity frequent
behavioral problems CSF: elevated protein
seizures, ataxia
Rasmussen Most likely immune No tumor Progressive refractory MRI: progressive Limited response to
encephalitis mediated (unclear association partial seizures, unilateral hemispheric immunotherapy.
mechanism) cognitive decline, atrophy Patients may need
focal deficits, and functional
brain hemiatrophy hemispherectomy
Basal ganglia Antibodies to D2R in No tumor Abnormal movement Variable basal ganglia Mostly monophasic,
encephalitis some cases association and behavior T2/FLAIR abnormalities can relapse
disorder
POSSIBLE IMMUNE MECHANISMS
CLIPPERS No antibodies No tumor Episodic diplopia or MRI: symmetric Steroid-responsive but
association facial paresthesias curvilinear gadolinium may require chronic
with subsequent enhancement steroid or other
development of peppering the pons immunosuppressive
symptoms of and extending variably therapy
brainstem and into the medulla,
occasionally spinal brachium pontis,
cord dysfunction cerebellum, midbrain,
and, occasionally,
spinal cord
ROHHAD Unknown. Neural crest tumor Rapid onset obesity, Brain MRI, usually Symptomatic; in some
Autoimmune and in ~50% of hyperphagia, normal patients limited
genetic origin cases† abnormal behavior, response to
postulated. autonomic immunotherapy
dysfunction, and
central
hypoventilation
*Includes rituximab and cyclophosphamide.
†
Exact frequency is unknown.
CLIPPERS, Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CSF, cerebrospinal fluid; D2R, dopamine 2 receptor;
EEG, electroencephalography; FLAIR, fluid-attenuated inversion recovery; GABABR, γ-aminobutyric acid-B receptor, GAD, glutamic acid decarboxylase; IVIG,
intravenous immunoglobulin; mGluR5, metabotropic glutamate receptor 5; MRI, magnetic resonance imaging; NMDAR, N-methyl-D-aspartate receptor; ROHHAD,
rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation; TPO, thyroid peroxidase.
synthesized within the CNS by plasma cells that form part of local
brain and meningeal inflammatory infiltrates.
ANTI-N-METHYL-D-ASPARTATE RECEPTOR
ENCEPHALITIS
In this disorder, the antibodies target the NR1 subunit of the NMDA
receptor. The exact frequency of this syndrome is unknown but it is
considered the second most common cause of autoimmune encepha-
litis after acute disseminated encephalomyelitis in children and adoles-
cents. Overall, the disorder predominates in females (80%), although
in patients younger than 12 yr the frequency of males is higher (40%).
The resulting syndrome is highly predictable and usually evolves in
stages. In teenagers and young adults, the disorder usually presents
with prominent psychiatric manifestations that may include rapidly
progressive anxiety, agitation, delusional thoughts, bizarre behavior,
labile affect, mood disturbances (mania), catatonic features, memory Figure 598-5 Electroencephalogram showing a pattern named
deficit, language disintegration, aggression, and insomnia or other “extreme delta brush” in a 14 yr old girl with anti–N-methyl-D-aspar-
sleep disturbances. In many cases, these symptoms had been preceded tate receptor (NMDAR) encephalitis. This pattern has been found to
by a few days of prodromal headache, fever or viral-like symptoms. As be characteristic of anti-NMDAR encephalitis. It consists of a nearly
a result of this symptom presentation, patients are often misdiagnosed continuous combination of delta activity with superimposed fast activ-
ity, usually in the beta range, symmetrically involving all head regions,
with new-onset psychosis or a primary psychiatric disorder. However, with a frontal preference in patients who are not under effects of seda-
in a few days or weeks, additional symptoms occur, including a tion or anesthetics. (From Armangue T, Titulaer MJ, Málaga I, et al:
decreased level of consciousness, seizures (including status epilepti- Pediatric anti-N-methyl-D-aspartate receptor encephalitis—clinical
cus), limb or oral dyskinesias, choreoathetoid movements, and auto- analysis and novel findings in a series of 20 patients. J Pediatr 162:850–
nomic instability which usually includes tachycardia, bradycardia, 856, 2012, Fig. 2.)
fluctuations of blood pressure, hypoventilation, hyperthermia and sial-
orrhea. In rare instances, bradycardia and cardiac pauses occur, at
times requiring the transient use of a pacemaker. The disorder also In a small number of patients, anti-NMDAR encephalitis occurs
occurs in toddlers and infants (the youngest patient identified to date simultaneously or after infections with a variety of pathogens, includ-
was 6 mo old), and although the evolution of the syndrome is similar ing Mycoplasma pneumoniae, human herpes simplex viruses 1 and 6
to that of adults, young patients more frequently present with motor (HSV), enterovirus, and influenza. A pathogenic link with most of
or complex seizures and movement disorders. Because of their age, the these infections has not established; there is evidence that some
psychiatric–behavioral features may be missed. In this young age patients with HSV encephalitis develop antibodies against the NR1
group, behavior changes include irritability, new-onset temper tan- subunit of the NMDAR. These patients may progress to develop relaps-
trums, agitation, aggression, reduced speech, mutism, and autistic-like ing neurologic symptoms post-HSV encephalitis. In a subgroup of
regression. Moreover, compared with adults some children also develop patients with noninfectious relapsing neurologic symptoms post-HSV
cerebellar ataxia and hemiparesis; in contrast, autonomic dysfunction encephalitis, or “choreoathetosis post-HSV encephalitis,” the disor-
is usually milder and less severe in children. There is often an abrupt der is in fact anti-NMDAR encephalitis (see Videos 598-1, 598-2,
on–off phenomenon in alterations of responsiveness or level of and 598-3).
consciousness. Although no prospective clinical trials have been done, there is
Brain MRI is abnormal in approximately 35% of cases, usually evidence that tumor removal, when appropriate, and prompt immu-
showing nonspecific cortical and subcortical T2–fluid-attenuated notherapy improve outcome. Most children receive first-line immuno-
inversion recovery (FLAIR) signal abnormalities, sometimes with tran- therapies, including corticosteroids, IVIG, or plasma exchange.
sient cortical or meningeal enhancement; nonspecific white matter However, because these treatments fail in almost 50% of patients, and
abnormalities are common. Lesions may also involve the spinal cord with an increasing number of reports showing that rituximab can be
producing symptoms of myelitis. The cerebrospinal fluid (CSF) is ini- effective, this treatment is increasingly being used in combination with
tially abnormal in approximately 80% of cases, showing moderate lym- IVIG and steroids, or after first-line immunotherapies. Cyclophospha-
phocytic pleocytosis and less frequently increased protein synthesis mide can be effective when there has been no response to these
and oligoclonal bands. The electroencephalogram (EEG) is abnormal treatments.
in virtually all patients, and usually shows focal or diffuse slow activity Although anti-NMDAR encephalitis has a mortality rate of 7%,
in the delta and theta range, which does not correlate with abnormal approximately 80% of patients have substantial or full recovery. Recov-
movements. In addition, many patients develop epileptic activity, ery is usually slow and can take as long as 2 yr after symptom onset.
requiring video-monitoring for adequate clinical management. A char- The last symptoms to improve are social interactions, and language and
acteristic EEG pattern called “extreme delta brush” characterized by executive functions. Relapses occur in approximately 15% of patients;
beta-delta complexes occurs in 30% of adults and has been described they can develop as partial syndromes, are usually milder than the
in children (Fig. 598-5). initial episode and respond equally to immunotherapy. Initial compre-
The diagnosis of the disorder is established by demonstrating hensive immunotherapy appears to prevent or reduce the number of
NMDAR antibodies in CSF or serum. The sensitivity is higher in CSF relapses. The efficacy of chronic immunosuppression with drugs such
compared with serum (100% vs 85%), and the levels of antibodies in as azathioprine or mycophenolate mofetil in preventing relapses is
CSF appear to correlate better with outcome. Antibodies may remain unknown.
detectable, albeit at lower titers, after patients recover. The differential diagnosis of anti-NMDAR encephalitis is extensive
The presence of an underlying tumor, mostly teratomas, is age and and varies according to the stage of the disease (Table 598-6). The most
sex dependent. Whereas 40% of females older than 12 yr have an frequently considered disorders are viral encephalitis, neuroleptic
underlying teratoma of the ovary, less than 6% of females younger than malignant syndrome, acute psychosis, and drug abuse.
12 yr have a tumor. In young boys with anti-NMDAR encephalitis, the
presence of an underlying tumor is exceptional; in young adults, the LIMBIC ENCEPHALITIS
presence of a testicular teratoma is also rare (<15% of cases). In chil- This disorder refers to an inflammatory process of the limbic system
dren, MRI of abdomen and pelvis and abdominal and testicular ultra- including, the medial temporal lobes, amygdala, and cingulate gyri. In
sound are the preferred tumor screening tests. adults, the most frequent immune-mediated limbic encephalitis occurs
Table 598-6 Differential Diagnosis of Anti-NMDAR Encephalitis in Children

DISORDER COMMENTS
Viral encephalitis Viral encephalitis is often suggested by the acute onset of symptoms, CSF pleocytosis, and
hyperthermia. Most viral encephalitides (except rabies) occur with higher levels of CSF pleocytosis and
protein concentration. Psychosis and dyskinesias are significantly less frequent in viral encephalitis
than in anti-NMDAR encephalitis.
Relapsing post–herpes Occurs ~4-6 wk after successful treatment of herpes simplex encephalitis. This may represent a true viral
simplex virus encephalitis relapse of encephalitis (CSF PCR-positive, progression of necrotic MRI changes, response to acyclovir),
or an autoimmune disorder (CSF PCR-negative, no new necrotic lesions on MRI, lack of response to
acyclovir). In a proportion of the latter patients, the disorder is anti-NMDAR encephalitis.
New-onset psychosis Because most patients with anti-NMDAR encephalitis present with psychosis, a primarily psychiatric
disorder is frequently considered. As the disease evolves, the development of neurological symptoms
usually reveals the diagnosis.
Drugs/toxins The acute development of personality and behavioral changes, and symptoms suggesting involvement
of dopaminergic pathways (rigidity, dystonia, orofacial movements) usually leads to a suspicion of
drug abuse (e.g., ketamine, phencyclidine, among others). Carbon monoxide.
Neuroleptic malignant The occurrence of altered level of consciousness, episodes of rigidity, hyperthermia, and autonomic
syndrome instability often suggest NMS. In addition, some patients with anti-NMDAR encephalitis have elevated
serum creatine kinase and rhabdomyolysis (in the absence of antipsychotic medication). The frequent
use of neuroleptics to control the abnormal behavior adds further confusion between both syndromes.
The presence of dyskinesias and catatonia suggest anti-NMDAR encephalitis.
Limbic encephalitis Criteria of LE are well defined. Patients with LE do not have dyskinesias or central hypoventilation; the
MRI usually shows abnormalities restricted to the medial temporal lobes, and the EEG findings
(epileptic or slow activity) are largely restricted to the temporal lobes.
Encephalitis lethargica This is an ill-defined entity, likely representing multiple disorders. Criteria include: acute or subacute
encephalitis with at least 3 of the following: signs of basal ganglia involvement; oculogyric crises;
ophthalmoplegia; obsessive-compulsive behavior; akinetic mutism; central respiratory irregularities;
and somnolence and/or sleep inversion. Approximately, 50% of patients categorized as encephalitis
lethargica hyperkinetica have anti-NMDAR encephalitis.
Childhood disintegrative Children with anti-NMDAR encephalitis often show cognitive regression, rapid loss of language
disorder/late-onset autism function, autistic features, and seizures, suggesting a childhood disintegrative disorder. While the
prognosis of CDD is poor, most patients with anti-NMDAR encephalitis respond to immunotherapy
and have substantial clinical recovery.
Kleine-Levin syndrome Symptoms of hypersomnia, compulsive hyperphagia, hypersexuality, apathy, and child-like behavior,
which are typical components of Kleine-Levin syndrome, may occur transiently during the process of
recovery of anti-NMDAR encephalitis, or as permanent sequelae.
Inborn errors of metabolism Glutaric aciduria type I can present in previously asymptomatic patients as episodes of encephalopathy
with dystonia, coinciding with an infection or febrile process. Several inborn errors of metabolism can
also occur with acute or subacute encephalopathy with extrapyramidal signs, including
3-methylglutaconic aciduria, creatine transport deficiency, mitochondrial disorders (Leigh syndrome),
Wilson, and Lesch-Nyhan syndromes. Pantothenate kinase associated neurodegeneration, porphyria,
and urea cycle defects should also be considered.
Monoamine neurotransmitter Deficiency of dopamine, serotonin or both can result in encephalopathy, epilepsy, and pyramidal and
disorders extrapyramidal symptoms. The diagnosis is established by examining the CSF for levels of these
neurotransmitters.
Demyelinating disorders Acute disseminated encephalomyelitis and neuromyelitis optica are immune-mediated inflammatory
and demyelinating disorders of the central nervous system. These disorders should be considered in
the differential diagnosis of multifocal neurologic abnormalities and encephalopathy in children. As
with anti-NMDAR encephalitis these disorders may be preceded by an infection and can show
pleocytosis. The diagnosis is suggested by the MRI findings. In NMO the presence of aquaporin 4
antibodies in serum or CSF is associated with relapses and poor prognosis.
CNS vasculitis CNS vasculitis results in neurologic deficits and psychiatric manifestations. The diagnosis is established
by angiography in large vessel angiitis, and brain biopsy in small vessel angiitis. In the latter, serum
inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, Complement 3, von
Willebrand factor antigen) are usually elevated, and the MRI shows FLAIR/T2 abnormalities in the
white and/or gray matter, not restricted to vascular territories with frequent leptomeningeal and/or
local enhancement.
Systemic rheumatic disorders Systemic lupus erythematosus and other rheumatic disorders can result in encephalopathy and
multifocal neurologic and psychiatric manifestations. These disorders are usually suggested by the
presence of signs and symptoms of involvement of systemic organs: skin, joints, kidneys, blood-
forming cells, and blood vessels.
CDD, childhood disintegrative disorder; CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalography; FLAIR, fluid-attenuated inversion
recovery; LE, limbic encephalitis; MRI, magnetic resonance imaging; NMDAR, N-methyl-D-aspartate receptor; NMO, neuromyelitis optica; NMS, neuroleptic malignant
syndrome; PCR, polymerase chain reaction.
in association with antibodies against proteins that were once thought neuroblastoma. The child often presents with irritability, ataxia, falling,
to be voltage-gated potassium channels (VGKC), but which, in myoclonus, tremor, and drooling. Additional symptoms may include
fact, target a secreted neuronal protein called leucine-rich glioma- refusal to walk or sit, speech problems, hypotonia, and the typical
inactivated 1 (LGI1), and a protein called Caspr2 expressed in brain features of opsoclonus characterized by rapid, chaotic, multidirectional
and juxtaparanodal regions of myelinated nerves. Patients with LGI1 eye movements without saccadic intervals. Because opsoclonus may be
antibody associated limbic encephalitis often develop hyponatremia; in absent at symptom presentation, patients may initially be diagnosed
some patients the disorder is preceded by short-lasting episodes of with acute cerebellitis or labyrinthitis. Typically CSF abnormalities
distinctive dystonic or myoclonic-like movements, described as facio- suggest B-cell activation, and the presence of antibodies against neu-
brachial dystonic seizures, but with EEG features of tonic seizures. ronal proteins has been demonstrated in several studies, although the
Patients with antibodies to Caspr2 usually develop Morvan syndrome, identification of a specific autoantigen has been elusive.
which includes encephalopathy, seizures, autonomic dysfunction, and Immunosuppressive treatment, including corticosteroids, IVIG,
neuromyotonia. How the clinical significance of antibodies called rituximab, and cyclophosphamide often improves the abnormal eye
“VGKC-complex proteins” differs from LGI1 and Caspr2 is unknown. movements, but residual behavioral, language, and cognitive problems
Other less frequent types of autoimmune limbic encephalitis in persist in the majority of patients, often requiring special education. In
adults are paraneoplastic and may occur with antibodies against intra- addition, insomnia and abnormal response to pain are common.
cellular antigens (e.g., Hu, CRMP5, Ma2) or neuronal cell surface and Relapses occur in 50% of the patients, usually as a result of an intercur-
synaptic proteins (e.g., AMPA, GABAB receptor, mGluR5). While the rent infection or drug tapering. Delay in treatment appears to associate
disorders associated with antibodies against intracellular antigens with a poorer neurologic outcome; therefore, in cases with neuroblas-
appear to be mediated by cytotoxic T-cell responses and are poorly toma, removal of the tumor should not delay the start of
responsive to treatment, those associated with antibodies to cell surface immunotherapy.
and synaptic antigens are likely mediated by the antibodies and treat- In teenagers and young adults, opsoclonus–myoclonus and
ment responsive. brainstem–cerebellar encephalitis without opsoclonus are often con-
In children, autoimmune or paraneoplastic limbic encephalitis is sidered “idiopathic” or “postinfectious”; however, there is evidence that
exceptional. Unfortunately, any type of encephalopathy resulting in some of these patients have an underlying teratoma, usually in the
seizures and alteration of memory and behavior is frequently labeled ovaries. These patients do not harbor NMDAR antibodies, and com-
as “limbic encephalitis,” making data based on literature searches using pared with those with anti-NMDAR encephalitis are less likely to ini-
the term “limbic encephalitis” unreliable. Fewer than 30 children with tially present with psychosis and behavioral changes, and rarely develop
limbic encephalitis have been described in the English literature, some dyskinesias. Although these patients do not appear to have neuronal
of them with antibodies against intracellular or cell surface antigens antibodies, the CSF often shows pleocytosis and elevated protein
(Hu, Ma2, GAD, amphiphysin, GABAB, and VGKC-complex proteins concentration. Identification of this subphenotype of opsoclonus–
different from LGI1 and Caspr2). In some cases an underlying tumor myoclonus is important because patients usually have full recovery
was identified and included, leukemia, ganglioneuroblastoma, neuro- after treatment with immunotherapy (corticosteroids, IVIG, and/or
blastoma, and small-cell carcinoma of the ovary. plasma exchange) and if present, removal of the ovarian teratoma. The
The Ophelia syndrome is a form of limbic encephalitis that occurs prognosis of this disorder seems better than that of neuroblastoma-
in association with Hodgkin’s lymphoma and predominantly affects associated opsoclonus, or the paraneoplastic opsoclonus of older
young adults, teenagers or children. Some patients develop antibodies patients, usually related to breast, ovarian, or lung cancer.
against mGluR5, a receptor involved in learning and memory; symp-
toms are usually responsive to chemotherapy. BICKERSTAFF ENCEPHALITIS
This term is used to describe patients with subacute progressive oph-
HASHIMOTO ENCEPHALOPATHY thalmoplegia and ataxia in addition to drowsiness or hyperreflexia.
Hashimoto encephalopathy is defined by the detection of thyroid per- Although this entity has been described more frequently in adults,
oxidase (TPO) antibodies in patients with acute or subacute encepha- children as young as 3 yr old have been identified. Most patients are
litis that responds to corticosteroids. Since almost 50% of patients treated with steroids, IVIG, and/or plasma exchange, and often have
have normal thyroid function and not all patients respond to steroids, good outcome. Serum GQ1b immunoglobulin G antibodies are found
the term “encephalopathy associated with autoimmune thyroid in 66% of patients. Brain MRI abnormalities occur in 30% of the
disease” is considered more accurate than the previous term “steroid- patients and usually include increased T2-signal abnormalities in the
responsive encephalopathy associated with autoimmune thyroiditis.” brainstem, thalamus, cerebellum, and sometimes cerebral white matter.
Clinical features are not specific and may include stroke-like symp- Some patients develop hyporeflexia and limb weakness, with predomi-
toms, tremor, myoclonus, transient aphasia, sleep and behavior abnor- nant axonal involvement, overlapping with symptoms of the Miller-
malities, hallucinations, seizures, and ataxia. The CSF usually shows Fisher syndrome and the axonal subtype of the Guillain-Barré
elevated protein level with less-frequent pleocytosis. EEG studies syndrome.
almost always are abnormal frequently showing generalized slowing.
Brain MRI is usually normal, although it may show diffuse white CHRONIC LYMPHOCYTIC INFLAMMATION
matter abnormalities and meningeal enhancement that can resolve WITH PONTINE PERIVASCULAR
with steroid therapy. As TPO antibodies occur in approximately 10% ENHANCEMENT RESPONSIVE TO STEROIDS
of asymptomatic children (nonencephalopathic and most cases euthy- This is a clinically and radiologically distinct pontine-predominant
roid), as well as in patients who have more relevant antibody- encephalomyelitis. To date fewer than 30 patients have been reported
associated disorders, such as GABAB, LGI1, or NMDAR antibodies, and two of them were children (13 and 16 yr). Patients usually
TPO antibodies should be viewed as a marker of autoimmunity rather present with episodic diplopia or facial paresthesias with subsequent
than a neurologic disease-specific or pathogenic antibody. Impor- development of symptoms of brainstem and occasionally spinal cord
tantly the presence of TPO antibodies should not prevent testing for dysfunction. Brain MRI shows symmetric curvilinear gadolinium
more relevant antibodies. enhancement peppering the pons and extending variably into the
medulla, brachium pontis, cerebellum, midbrain and occasionally
OPSOCLONUS–MYOCLONUS AND OTHER spinal cord. The clinical and radiological findings usually respond to
BRAINSTEM–CEREBELLAR ENCEPHALITIDES high dose steroids but may worsen after the steroid taper, requiring
Opsoclonus-myoclonus occurs in infants, teenagers and adults, chronic steroid or other immunosuppressive therapy. The differential
although it probably represents different diseases and pathogenic diagnosis is extensive and includes infections, granulomatous disease,
mechanisms. In infants, the syndrome usually develops in the 1st 2 yr lymphoma or vasculitis. Biopsy studies may be needed to exclude
of life (mean: 20 mo), and at least 50% of patients have an underlying these and other conditions.
AUTOIMMUNE ENCEPHALOPATHIES However, no mutations in PHOX2B and other candidate genes have
ASSOCIATED WITH EPILEPSY AND STATUS been found in patients with ROHHAD.
EPILEPTICUS The term basal ganglia encephalitis is used to describe patients with
Rasmussen encephalitis is an inflammatory encephalopathy charac- predominant or isolated involvement of the basal ganglia. These
terized by progressive refractory partial seizures, cognitive deteriora- patients typically have abnormal movements and neuropsychiatric
tion, and focal deficits that occur with gradual atrophy of 1 brain disease. Although these disorders probably have multiple etiologies,
hemisphere. The disorder frequently presents in 6-8 yr old children, including metabolic, toxic, genetic, and infectious processes, an
although adolescents and adults can be affected. The etiology is immune-mediated etiology has been postulated in some patients.
unknown and, therefore, multiple theories are proposed, including There have been no clinical trials, but case reports and small noncon-
the presence of antibodies against the GluR3 subunit of the AMPA trolled case series describe the potential benefit of immunotherapy.
receptor and T-cell mediated mechanisms triggered by a viral infec- Antibodies against the dopamine-2 receptor have been identified in
tion. None of these mechanisms satisfactorily explains the unilateral some of these patients as well as in patients with Sydenham chorea and
brain involvement characteristic of the disorder. Treatment with high- Tourette syndrome.
dose steroids, plasma exchange, or IVIG can ameliorate symptoms in Pseudomigraine syndrome with CSF pleocytosis (PMP) or head-
early stages of the disease. Rituximab and intraventricular γ-interferon ache with neurologic deficits and CSF lymphocytosis (HaNDL) is an
have been effective in a few isolated cases. In a small series, patients ill-defined entity that predominantly affects young male adults with a
treated with tacrolimus showed better outcomes of neurologic func- family history of migraine, although adolescents can be affected. This
tion and slower progression of cerebral hemiatrophy, but not improved syndrome is characterized by repeated episodes of severe headache
seizure control. The only definitive treatment is functional hemispher- with transient neurologic deficits, accompanied by aseptic CSF lym-
ectomy that consists in surgical disconnection of the affected phocytosis and normal brain MRI. Patients frequently show high CSF
hemisphere. opening pressure, elevated CSF protein concentration, and focal EEG
The discovery of treatment-responsive encephalitis associated with slowing, which normalize after the episodes of headache. Because of
antibodies against cell surface or synaptic proteins has resumed the the inflammatory characteristics of the CSF and the high prevalence
interest for a potential autoimmune basis of several devastating of prodromal viral-like symptoms, an infectious-autoimmune medi-
encephalopathies with refractory seizures. Some well-defined autoim- ated mechanism has been proposed. Other theories include spreading
mune encephalitis such as anti-NMDAR encephalitis can present in cortical depression and trigeminal-vascular activation.
children with refractory seizures or status epilepticus. In these patients, An immune-mediated mechanism and trigeminal-vascular activa-
the development over a short period of time of the characteristic spec- tion are also considered as possible mechanisms of ophthalmoplegic
trum of symptoms (altered behavior, orofacial dyskinesias, and auto- migraine, also named recurrent cranial neuralgia. This disorder pre-
nomic dysfunction) and demonstration of NMDAR antibodies leads dominantly affects young children and is characterized by recurrent
to the correct diagnosis and initiation of immunotherapy. bouts of head pain in addition to cranial nerves III, IV, and/or VI
A devastating epileptic encephalopathy associated with fever involvement. In contrast to PMP/HaNDL, CSF studies do not show
named fever-induced refractory epileptic encephalopathy syn- pleocytosis, and in approximately 75% of cases, the MRI shows focal
drome, among other terms, is suspected to be an infection-triggered nerve thickening and contrast enhancement. Observational data
autoimmune process because of its biphasic clinical course and the suggest that treatment with steroids may be beneficial. In this syn-
occasional finding of neuronal antibodies in a few patients. However, drome, as well as in PMP/HaNDL, the differential diagnosis includes
the lack of response to most treatments including immunotherapy, structural, neoplastic, traumatic, metabolic, and infectious disorders.
and the rare and inconsistent association to different types of anti
bodies cast doubts on an autoimmune pathogenesis. Other investiga- Bibliography is available at Expert Consult.
tors suggest a genetic error in metabolism.
Antibodies to VGKC-complex proteins different from LGI1 and
Caspr2 have been described in a few children with encephalitis with
or without status epilepticus. Given that the target antigens are
unknown and the response to immunotherapy is unpredictable, the
significance of these antibodies is unclear.
OTHER SUSPECTED AUTOIMMUNE

ENCEPHALITIDES
Demyelinating disorders, vasculitis of the CNS, and rheumatic diseases
associate with autoimmune mechanisms can result in encephalitis.
Rapid onset obesity with hypothalamic dysfunction, hypoventila-
tion, and autonomic dysregulation (ROHHAD) usually affects chil-
dren who had normal development until 2-4 yr of age and then
develop rapid onset of hyperphagia, weight gain, and abnormal behav-
ior (social disinhibition, irascibility, impulsivity, lethargy, outburst of
euphoria and laughing, impaired concentration), followed by auto-
nomic dysfunction (abnormal pupillary responses, thermal dysregula-
tion, gastrointestinal dysmotility), and central hypoventilation. An
autoimmune or paraneoplastic etiology of ROHHAD syndrome is sup-
ported by the frequent association to neural crest tumors, the identifi-
cation in some patients of genetic factors predisposing to autoimmunity,
and the finding of intrathecal oligoclonal bands and infiltrates of lym-
phocytes and histiocytes in the hypothalamus of some patients. Fur-
thermore, responses to immunotherapy have been described in a few
patients. A possible genetic origin is suggested because of the similari-
ties of this syndrome with the congenital central hypoventilation syn-
drome (Ondine curse) related to a PHOX2B mutation, which presents
in the neonatal period and also associates with autonomic problems
(Hirschsprung disease) and neural crest tumors (see Chapter 418.2).
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Chapter 599
Neurodegenerative
Disorders of Childhood
Jennifer M. Kwon
Neurodegenerative disorders of childhood encompass a large, hetero-

geneous group of diseases that result from specific genetic and bio-
chemical defects, chronic viral infections, and varied unknown causes.
Children with suspected neurodegenerative disorders were once sub-
jected to brain and rectal (neural) biopsies, but with modern neuro-
imaging techniques and specific biochemical and molecular diagnostic
tests, these invasive procedures are rarely necessary. The most impor-
tant component of the diagnostic investigation continues to be a
thorough history and physical examination. The hallmark of a neuro-
degenerative disease is regression and progressive deterioration
of neurologic function with loss of speech, vision, hearing, or locomo-
tion, often associated with seizures, feeding difficulties, and impair-
ment of intellect. The age of onset, rate of progression, and principal
Chapter 599 ◆ Neurodegenerative Disorders of Childhood 2911
Table 599-1 Neurometabolic Conditions Associated with Developmental Regression

AGE AT ONSET (yr) CONDITIONS COMMENTS
<2 with Fructose intolerance Vomiting, hypoglycemia, poor feeding, failure to thrive
hepatomegaly (when given fructose)
Galactosemia Lethargy, hypotonia, icterus, cataract, hypoglycemia (when
given lactose)
Glycogenosis (glycogen storage disease) types I-IV Hypoglycemia, cardiomegaly (type II)
Mucopolysaccharidosis types I and II Coarse facies, stiff joints
Niemann-Pick disease, infantile type Gray matter disease, failure to thrive
Tay-Sachs disease Seizures, cherry-red macula, edema, coarse facies
Zellweger syndrome Hypotonia, high forehead, flat facies
Gaucher disease (neuronopathic form) Extensor posturing, irritability
Carbohydrate-deficient glycoprotein syndromes Dysmyelination, cerebellar hypoplasia
<2, without Krabbe disease Irritability, extensor posturing, optic atrophy, and blindness
hepatomegaly Rett syndrome Girls with deceleration of head growth, loss of hand skills,
hand wringing, impaired language skills, gait apraxia
Maple syrup urine disease Poor feeding, tremors, myoclonus, opisthotonos
Phenylketonuria Light pigmentation, eczema, seizures
Menkes kinky hair disease Hypertonia, irritability, seizures, abnormal hair
Subacute necrotizing encephalopathy of Leigh disease White matter disease
Canavan disease White matter disease, macrocephaly
Neurodegeneration with brain iron accumulation White matter disease, movement disorder
disease
2-5 Niemann-Pick disease types III and IV Hepatosplenomegaly, gait difficulty
Wilson disease Liver disease, Kayser-Fleischer ring; deterioration of
cognition is late
Gangliosidosis type II Gray matter disease
Neuronal ceroid lipofuscinosis Gray matter disease
Mitochondrial encephalopathies (e.g., myoclonic Gray matter disease
epilepsy with ragged red fibers [MERRF])
Ataxia-telangiectasia Basal ganglia disease
Huntington disease (chorea) Basal ganglia disease
Neurodegeneration with brain iron accumulation Basal ganglia disease
syndrome
Metachromatic leukodystrophy White matter disease
Adrenoleukodystrophy White matter disease, behavior problems, deteriorating
school performance, quadriparesis
5-15 Adrenoleukodystrophy Same as for adrenoleukodystrophy in 2-5 yr olds
Multiple sclerosis White matter disease
Neuronal ceroid lipofuscinosis, juvenile and adult Gray matter disease
(Spielmeyer-Vogt and Kufs disease)
Schilder disease White matter disease, focal neurologic symptoms
Refsum disease Peripheral neuropathy, ataxia, retinitis pigmentosa
Sialidosis II, juvenile form Cherry-red macula, myoclonus, ataxia, coarse facies
Subacute sclerosing panencephalitis Diffuse encephalopathy, myoclonus; may occur years after
measles
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, WB Saunders, p. 542.
neurologic findings determine whether the disease affects primarily

the white or the gray matter. Upper motor neuron signs and progres- 599.1 Sphingolipidoses
sive spasticity are the hallmarks of white matter disorders; convulsions Jennifer M. Kwon
and intellectual and visual impairments that occur early in the disease
course are the hallmarks of gray matter disorders. A precise history The sphingolipidoses are characterized by intracellular storage of lipid
confirms regression of developmental milestones, and the neurologic substrates resulting from defective catabolism of the sphingolipids
examination localizes the process within the nervous system. Although comprising cellular membranes (Fig. 599-1). The sphingolipidoses are
the outcome of a neurodegenerative condition is usually fatal and subclassified into 6 categories: Niemann-Pick disease, Gaucher disease,
available therapies are often limited in effect, it is important to make GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease, and meta-
the correct diagnosis so that genetic counseling may be offered chromatic leukodystrophy. Niemann-Pick disease and Gaucher disease
and prevention strategies can be implemented. Bone marrow trans- are discussed in Chapter 86.4.
plantation and other novel therapies may prevent the progression of
disease in certain individuals who are either presymptomatic or very GANGLIOSIDOSES
early in their disease course. For all conditions in which the specific See also Chapter 86.4.
enzyme defect is known, prevention by prenatal diagnosis (chorionic Gangliosides are glycosphingolipids, normal constituents of the
villus sampling or amniocentesis) is possible. Carrier detection is also neuronal and synaptic membranes. The basic structure of GM1 gan-
often possible by enzyme assay. Table 599-1 summarizes selected glioside consists of an oligosaccharide chain attached to a hydroxyl
inherited neurodegenerative and metabolic disorders by their usual age group of ceramide and sialic acid bound to galactose. The gangliosides
of onset. are catabolized by sequential cleavage of the sugar molecules
Gal-GalNAc
Gal Glc-Ceramide (GM1 Ganglioside)
NANA Neurodegeneration,
GM1 gangliosidoses
HSM, CRS,
skeletal deformities
Gal
-Galactosidase GalNac-Gal-Gal-Glc-Ceramide (Globoside)
GalNAc
Gal Glc-Ceramide (GM2) Sandhoff disease Similar to Tay-Sachs,
may have HSM,
NANA Tay-Sachs Disease Neurodegeneration, dysostosis multiplex
CRS, large head,
acoustic startle GalNac
GalNAc -Hexosaminidase A & B
-Hexosaminidase A
Gal-Gal-Glc-Ceramide
NANA Gal Glc-Ceramide (GM3) Fabry disease Angiokeratomas,
kidney/heart disease,
Gal burning dysesthesias
Neuraminidase NANA -Galactosidase
Gal Glc-Ceramide
(Lactosyl Ceramide)
-Galactosidase
Sphingomyelinase Gal
Phosphorylcholine-Ceramide Glc-Ceramide
Gaucher disease Most common
HSM, osteoporosis,
Choline P
CNS disease rare
-Glucosidase
Niemann-Pick A/B
Glc
Neurodegeneration Ceramide
HSM Painful joint deformities,
Gal Farber disease
subcutaneous lipid
nodules, hoarse cry
Ceramidase
-Galactosidase Fatty Acid
Sphingosine
Krabbe Spasticity, irritability,
blindness, failure to thrive
Gal-Ceramide
SO3H
Arylsulfatase A
MLD Spasticity, dementia,

areflexia
SO3H-Gal-Ceramide
Figure 599-1 Sphingolipid degradation pathway showing the sites of enzyme deficiencies and their associated disorders. Sphingolipids are
composed of a ceramide backbone with oligosaccharide side chains. CRS, cherry-red spot (retinal); Gal-, galactosyl-; GalNAc, N-acetyl-galactose;
Glc-, glucosyl-; HSM, hepatosplenomegaly; MLD, metachromatic leukodystrophy; NANA, N-acetyl-neuraminic acid.
by specific exoglycosidases. Abnormalities in catabolism result in an Development is globally delayed, and generalized seizures are promi-
accumulation of the ganglioside within the cell. Defects in ganglioside nent. The phenotype is striking and shares many characteristics with
degradation can be classified into 2 groups: the GM1 gangliosidoses Hurler syndrome. The facial features are coarse, the forehead is promi-
and the GM2 gangliosidoses. nent, the nasal bridge is depressed, the tongue is large (macroglossia),
and the gums are hypertrophied. Hepatosplenomegaly is present early
GM1 Gangliosidoses in the course as a result of accumulation of foamy histiocytes, and
The 3 subtypes of GM1 gangliosidoses are classified according to age kyphoscoliosis is evident because of anterior beaking of the vertebral
at presentation: infantile (type 1), juvenile (type 2), and adult (type 3). bodies. The neurologic examination is dominated by apathy, progres-
The condition is inherited as an autosomal recessive trait and results sive blindness, deafness, spastic quadriplegia, and decerebrate rigidity.
from a marked deficiency of acid β-galactosidase. This enzyme may be A cherry-red spot in the macular region is visualized in approximately
assayed in leukocytes and cultured fibroblasts. The acid β-galactosidase 50% of cases. The cherry-red spot is characterized by an opaque ring
gene has been mapped to chromosome 3p14.2. Prenatal diagnosis (sphingolipid-laden retinal ganglion cells) encircling the normal red
is possible by measurement of acid β-galactosidase in cultured fovea (Fig. 599-2). Children rarely survive beyond age 2-3 yr, and death
amniotic cells. may be from aspiration pneumonia.
Infantile GM1 gangliosidosis presents at birth or during the neo- Juvenile GM1 gangliosidosis has a delayed onset beginning about
natal period with anorexia, poor sucking, and inadequate weight gain. 1 yr of age. The initial symptoms consist of incoordination, weakness,
dases A and B in serum and leukocytes. Children usually die by 3 yr

of age. Sandhoff disease is caused by mutations in the HEXB gene
located on chromosome 5q13.
Juvenile GM2 gangliosidosis develops in mid-childhood, initially
with clumsiness followed by ataxia. Signs of spasticity, athetosis, loss
of language, and seizures gradually develop. Progressive visual loss is
associated with optic atrophy, but cherry-red spots rarely occur in
juvenile GM2 gangliosidosis. A deficiency of hexosaminidase is vari-
able (total deficiency to near normal) in these patients. Death occurs
around 15 yr of age.
Adult GM2 gangliosidosis is characterized by a myriad neurologic
signs, including slowly progressive gait ataxia, spasticity, dystonia,
proximal muscle atrophy, and dysarthria. Generally, visual acuity and
intellectual function are unimpaired. Hexosaminidase A activity alone
or hexosaminidases A and B activity is reduced significantly in the
serum and leukocytes.
Figure 599-2 A cherry-red spot in a patient with GM1 gangliosidosis. Krabbe Disease (Globoid Cell Leukodystrophy)
Note the whitish ring of sphingolipid-laden ganglion cells surrounding
the fovea. (From Leavitt JA, Kotagal S: The “cherry red” spot. Pediatr Krabbe disease (KD) is a rare autosomal recessive neurodegenerative
Neurol 37(1):74–75, 2007, Fig. 1.) disorder characterized by severe myelin loss and the presence of
globoid bodies in the white matter. The gene for KD (GALC) is located
on chromosome 14q24.3-q32.1. The disease results from a marked
deficiency of the lysosomal enzyme galactocerebroside β-galactosidase.
ataxia, and regression of language. Thereafter, convulsions, spasticity, KD is a disorder of myelin destruction rather than abnormal myelin
decerebrate rigidity, and blindness are the major findings. Unlike the formation. Normally, myelination begins in the 3rd trimester, corre-
infantile type, this type is not usually marked by coarse facial features sponding with a rapid increase of galactocerebroside β-galactosidase
and hepatosplenomegaly. Radiographic examination of the lumbar activity in the brain. In patients with KD, galactocerebroside cannot be
vertebrae may show minor beaking. Children rarely survive beyond metabolized during the normal turnover of myelin because of defi-
10 yr of age. Adult GM1 gangliosidosis is a slowly progressive disease ciency of galactocerebroside β-galactosidase. When galactocerebroside
consisting of spasticity, ataxia, dysarthria, and a gradual loss of cogni- is injected into the brains of experimental animals, a globoid cell reac-
tive function. tion ensues. It is postulated that a similar phenomenon occurs in
humans; nonmetabolized galactocerebroside stimulates the formation
GM2 Gangliosidoses of globoid cells that reflect the destruction of oligodendroglial cells.
The GM2 gangliosidoses are a heterogeneous group of autosomal reces- Because oligodendroglial cells are responsible for the elaboration of
sive inherited disorders that consist of several subtypes, including Tay- myelin, their loss results in myelin breakdown, thus producing addi-
Sachs disease (TSD), Sandhoff disease, juvenile GM2 gangliosidosis, tional galactocerebroside and causing a vicious circle of myelin
and adult GM2 gangliosidosis. TSD is most prevalent in the Ashkenazi destruction.
Jewish population and has an approximate carrier rate of 1 in 30 Jews The symptoms of KD become evident in the 1st few mo of life
in the United States. TSD is caused by mutations in the HEXA gene and include excessive irritability and crying, unexplained episodes of
located on chromosome 15q23-q24. Affected infants appear normal hyperpyrexia, vomiting, and difficulty feeding. In the initial stage of
until approximately 6 mo of age, except for a marked startle reaction KD, children are often treated for colic or milk allergy with frequent
to noise that is evident soon after birth. Affected children then begin formula changes. Generalized seizures may appear early in the course
to lag in developmental milestones and, by 1 yr of age, they lose the of the disease. Alterations in body tone with rigidity and opisthotonos
ability to stand, sit, and vocalize. Early hypotonia develops into pro- and visual inattentiveness as a result of optic atrophy become apparent
gressive spasticity, and relentless deterioration follows, with convul- as the disease progresses. In the later stages of the illness, blindness,
sions, blindness, deafness, and cherry-red spots in almost all patients deafness, absent deep-tendon reflexes, and decerebrate rigidity consti-
(see Fig. 599-2). Macrocephaly becomes apparent by 1 yr of age and tute the major physical findings. Most patients die by 2 yr of age. MRI
results from the 200-300–fold normal content of GM2 ganglioside and magnetic resonance spectroscopy are useful for evaluating the
deposited in the brain. Few children live beyond 3-4 yr of age, and extent of demyelination in KD. Umbilical cord blood (stem cell) trans-
death is usually associated with aspiration or bronchopneumonia. A plantation from unrelated donors in asymptomatic babies may favor-
deficiency of the isoenzyme hexosaminidase A is found in tissues of ably alter the natural history but will not help patients who already
patients with TSD. Mass screening for prenatal diagnosis of TSD is a have neurologic symptoms.
reliable and cost-effective method of prevention because the condition Late-onset KD has been described beginning in childhood or ado-
occurs most frequently in a defined population (Ashkenazi Jews). Tar- lescence. Patients present with optic atrophy and cortical blindness,
geted screening is responsible for the fact that currently, the rare chil- and their condition may be confused with adrenoleukodystrophy.
dren with TSD born in the United States are most commonly born to Slowly progressive gait disturbances, including spasticity and ataxia,
non-Jewish parents who are not routinely screened. An accurate and are prominent. As with classic KD, globoid cells are abundant in the
inexpensive carrier detection test is available (serum or leukocyte hex- white matter, and leukocytes are deficient in galactocerebroside
osaminidase A), and the disease can be reliably diagnosed by chorionic β-galactosidase. An examination of the cerebrospinal fluid shows an
villus sampling in the 1st trimester of pregnancy in couples at risk elevated protein content, and the nerve conduction velocities are mark-
(heterozygote parents). edly delayed as a result of segmental demyelination of the peripheral
Sandhoff disease is very similar to TSD in the mode of presentation, nerves. The VEPs decrease gradually in amplitude with no response in
including progressive loss of motor and language milestones beginning the late stages of the disease, and the auditory brainstem responses are
at 6 mo of age. Seizures, cherry-red spots, macrocephaly, and doll-like characterized by the presence of only waves I and II. CT scans and MRI
facies are present in most patients; however, children with Sandhoff studies highlight the marked decrease in white matter, especially of the
disease may also have splenomegaly. The visual evoked potentials cerebellum and centrum semiovale, with sparing of the subcortical U
(VEPs) are normal early in the course of Sandhoff disease and TSD, fibers. Prenatal diagnosis is possible by the assay of galactocerebroside
but become abnormal or absent as the disease progresses. The auditory β-galactosidase activity in chorionic villi or in cultured amniotic fluid
brainstem responses show prolonged latencies. The diagnosis of Sand- cells. Newborn screening may identify patients at risk for late onset
hoff disease is established by finding deficient levels of hexosamini- disease.
Metachromatic Leukodystrophy Deterioration in school performance and alterations in personality

This disorder of myelin metabolism is inherited as an autosomal reces- may herald the onset of the disease. This is followed by incoordination
sive trait and is characterized by a deficiency of arylsulfatase A activity. of gait, urinary incontinence, and dysarthria. Muscle tone becomes
The ARSA gene is located on chromosome 22q13-13qter. The absence increased, and ataxia, dystonia, or tremor may be present. In the ter-
or deficiency of arylsulfatase A leads to accumulation of cerebroside minal stages, generalized tonic–clonic convulsions are prominent and
sulfate within the myelin sheath of the central nervous system (CNS) are difficult to control. Patients rarely live beyond mid-adolescence.
and peripheral nervous system because of the inability to cleave sulfate Adult MLD occurs from the 2nd to 6th decade. Abnormalities in
from galactosyl-3-sulfate ceramide. The excessive cerebroside sulfate is memory, psychiatric disturbances, and personality changes are promi-
thought to cause myelin breakdown and destruction of oligodendrog- nent features. Slowly progressive neurologic signs, including spasticity,
lia. Prenatal diagnosis of metachromatic leukodystrophy (MLD) is dystonia, optic atrophy, and generalized convulsions, lead eventually
made by assaying of arylsulfatase A activity in chorionic villi or cul- to a bedridden state characterized by decorticate postures and
tured amniotic fluid cells. Cresyl violet applied to tissue specimens unresponsiveness.
produces metachromatic staining of the sulfatide granules, giving the
disease its name. Some individuals with low arylsulfatase A enzyme Bibliography is available at Expert Consult.
activity are clinically normal and have a pseudodeficiency state that
can only be confirmed by additional genetic or biochemical tests.
Those affected with MLD are generally classified according to age of
onset: late infantile, juvenile, and adult. 599.2 Neuronal Ceroid Lipofuscinoses
Late infantile MLD begins with insidious onset of gait disturbances Jennifer M. Kwon
between 1 and 2 yr of age. The child initially appears awkward and
frequently falls, but locomotion is gradually impaired significantly and The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited,
support is required to walk. The extremities are hypotonic, and the neurodegenerative, lysosomal storage disorders characterized by visual
deep-tendon reflexes are absent or diminished. Within the next several loss, progressive dementia, seizures, motor deterioration, and early
months, the child can no longer stand, and deterioration in intellectual death. The NCLs are so named because of the intracellular accumula-
function becomes apparent. The speech is slurred and dysarthric, and tion of fluorescent lipopigments, ceroid and lipofuscin. They comprise
the child appears dull and apathetic. Visual fixation is diminished, a genetically and phenotypically heterogeneous group of disorders
nystagmus is present, and examination of the retina shows optic (currently there are at least 9 NCL types) that have traditionally been
atrophy. Within 1 yr from the onset of the disease, the child is unable subclassified by age of onset, among other clinical features. They differ
to sit unsupported, and progressive decorticate postures develop. from one another in the associated ultrastructural patterns of the inclu-
Feeding and swallowing are impaired because of pseudobulbar palsies, sions as seen by electron microscopy. Evaluation of neuronal biopsies
and a feeding gastrostomy is required. Patients ultimately become stu- (either brain, rectal, conjunctival, or skin) was once required for diag-
porous and die of aspiration or bronchopneumonia by age 5-6 yr. nosis. With the advent of enzymatic and molecular testing methods,
Neurophysiologic evaluation shows slowing of peripheral nerve con- clinicians can make specific NCL diagnoses using less-invasive methods
duction velocities and progressive changes in the VEPs, auditory brain- (Table 599-2).
stem responses, and somatosensory evoked potentials. CT and MRI Infantile-type neuronal ceroid lipofuscinose (INCL, Haltia-
images of the brain indicate diffuse symmetric attenuation of the cer- Santavuori) begins in the 1st yr of life with myoclonic seizures, intel-
ebellar and cerebral white matter, and examination of the cerebrospinal lectual deterioration, and blindness. Optic atrophy and brownish
fluid shows an elevated protein content. Bone marrow transplantation discoloration of the macula are evident on examination of the retina,
is a promising experimental therapy for the management of late infan- and cerebellar ataxia is prominent. The electroretinogram typically
tile MLD, and early trials of enzyme replacement are being conducted. shows small-amplitude or absent waveforms. Death occurs during
As with KD, favorable outcomes have been reported only in patients childhood. The infantile form is caused by recessive mutations of the
treated with less-severe disease or those identified very early in the gene for the lysosomal enzyme palmitoyl-protein thioesterase-1
course of the disease. (PPT1) on chromosome 1p32. A number of cell types in INCL patients
Juvenile MLD has many features in common with late infantile show characteristic intracellular fine granular osmiophilic deposits
MLD, but the onset of symptoms is delayed to 5-10 yr of age. discernible by electron microscopy.
Table 599-2 Clinical and Genetic Characteristics of the Neuronal Ceroid Lipofuscinoses (NCL)
NCL TYPE GENE* PROTEIN AGE OF ONSET CLINICAL PRESENTATION
‡
Congenital CLN10 Cathepsin Birth (but can Severe seizures, blindness, rigidity, early death
present later) Can also present similar to late infantile forms
Infantile CLN1 Palmitoyl-protein 6-24 months Early onset, often rapid progression of seizures;
thioesterase-1 (PPT1)‡ cognitive and motor decline with visual loss
Variant infantile CLN1 3 yr to adulthood Chronic course
Initial visual loss followed then by slow mental and
motor decline and seizures
Late infantile CLN2 Tripeptidyl peptidase-1 (TPP1)‡ 2-8 yr Seizures, often severe and intractable; cognitive and
CLN5 Partially soluble protein motor decline; and visual loss
CLN6 Membrane protein
CLN7 Membrane protein
CLN8 Membrane protein 5-10 yr Severe epilepsy, progressive with mental retardation
Juvenile CLN3 Membrane protein 4-10 yr Visual loss is usually the initial presenting complaint
Also have mental, motor disorder and seizures
*Note that all the NCL genes have the prefix CLN. The adult form (also called Kufs disease, with locus CLN4, caused by mutations in DNAJC5) is not well
characterized and is not included in the table.
†
Direct genetic testing is available for all.
‡
Enzyme testing available.
Chapter 599 ◆ Neurodegenerative Disorders of Childhood 2914.e1
Bibliography Kohlschutter A, Eichler F: Childhood leukodystrophies: a clinical perspective,

Batzios SP, Zafeiriou DI: Developing treatment options for metachromatic Expert Rev Neurother 11(10):1485–1496, 2011.
leukodystrophy, Mol Genet Metab 105:56–63, 2012. Schiffmann R, van der Knaap MS: Invited Article: An MRI-based approach to the
Brunetti-Pierri N, Scaglia F: GM1 gangliosidosis: review of clinical, molecular, and diagnosis of white matter disorders, Neurology 72:750–759, 2009.
therapeutic aspects, Mol Genet Metab 94:391–396, 2008. Smith NJ, Winstone AM, Stellitano L, et al: GM2 gangliosidosis in a UK study of
Duffner PK, Granger C, Lyon N, et al: Developmental and functional outcomes in children with progressive neurodegeneration: 73 cases reviewed, Dev Med Child
children with a positive newborn screen for Krabbe disease: a pilot study of a Neurol 54(2):176–182, 2012.
phone-based interview surveillance technique, J Pediatr 161:258–263, 2012.
A subset of children with PPT1 enzyme deficiency has a much less- with cherry-red spot myoclonus syndrome. Myoclonus of the extremi-
severe course with clinical features resembling those of the juvenile- ties is gradually progressive and often debilitating and eventually
onset NCL patients. Clinically, these variant INCL patients have a renders patients nonambulatory. The myoclonus is triggered by volun-
course that is often quite distinct from the typical, classic rapidly tary movement, touch, and sound and is not controlled with anticon-
degenerating infantile form. Yet they have PPT1 deficiency and granu- vulsants. Generalized convulsions responsive to antiepileptic drugs
lar osmiophilic deposits on pathology. There is no clear CLN1 genotype occur in most patients.
that predicts severity of phenotype. Sialidosis type II patients present at a younger age and have cherry-
Late infantile-type neuronal ceroid lipofuscinose (LINCL, Jansky- red spots and myoclonus, as well as somatic involvement, including
Bielschowsky) generally presents with myoclonic seizures beginning coarse facial features, corneal clouding (rarely), and dysostosis multi-
between 2 and 4 yr of age in a previously normal child. Dementia and plex, producing anterior beaking of the lumbar vertebrae. Type II
ataxia are combined with a progressive loss of visual acuity and micro- patients may be further subclassified into congenital and infantile
cephaly. Examination of the retina shows marked attenuation of (childhood) forms, depending on the age at presentation. Examination
vessels, peripheral black bone spicule pigmentary abnormalities, optic of lymphocytes shows vacuoles in the cytoplasm, biopsy of the liver
atrophy, and a subtle brown pigment in the macular region. The elec- demonstrates cytoplasmic vacuoles in Kupffer cells, and membrane-
troretinogram and VEP are abnormal early in the course of disease. bound vacuoles are found in Schwann cell cytoplasm, all attesting to
The autofluorescent material is deposited in neurons, fibroblasts, the multiorgan nature of sialidosis type II. No distinctive neuroimaging
and secretory cells. Electron microscopic examination of the storage findings or abnormalities in electrophysiologic studies are noted in this
material in skin or conjunctival biopsy material typically shows group of disorders. Patients with sialidosis have been reported to live
curvilinear profiles. LINCL can be caused by autosomal recessive beyond the 5th decade.
mutations of several different genes: CLN2 gene, which codes for a Some cases of what appears to be sialidosis type II are the result of
tripeptidyl peptidase-1 (TPP1) that is essential for the degradation of combined deficiencies of β-galactosidase and α-neuraminidase result-
cholecystokinin-8, as well as the CLN5, CLN6, and CLN8 genes that ing from deficiency of protective protein/cathepsin A that prevents
code for membrane proteins that have not been completely character- premature intracellular degradation of these 2 enzymes. These patients
ized. CLN8 is also known as the locus of Northern epilepsy syndrome, have galactosialidosis and they are clinically indistinguishable from
which is often called progressive epilepsy with mental retardation. those with sialidosis type II. Consequently, patients who have features
Juvenile type neuronal ceroid lipofuscinose (JNCL, Spielmeyer- of sialidosis type II with marked urinary excretion of oligosaccharides
Vogt or Batten disease) is the most common form of NCL disease should be tested for protective protein/cathepsin A deficiency as well
and is generally caused by autosomal-recessive mutations in CLN3. as sialidase deficiency.
(Patients who present clinically with JNCL but have PPT1 or TPP1
deficiency are said to have variant INCL or LINCL, respectively.) Chil- Bibliography is available at Expert Consult.
dren affected with JNCL tend to develop normally for the 1st 5 yr of
life. Their initial symptom is usually progressive visual loss and their
retinal pigmentary changes often results in an initial diagnosis of reti-
nitis pigmentosa. The funduscopic changes are similar to those for the 599.5 Miscellaneous Disorders
late infantile type. After disease onset, there may be rapid decline with Jennifer M. Kwon
changes in cognition and personality, motor incoordination, and sei-
zures. Myoclonic seizures are not as prominent as in LINCL, but par- PELIZAEUS-MERZBACHER DISEASE
kinsonism can develop and impair ambulation. Patients die in their Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder
late twenties to early thirties. In JNCL caused by CLN3, the electron characterized by nystagmus and abnormalities of myelin. PMD is
microscopy of tissues show deposits called fingerprint profiles, and caused by mutations in the proteolipid protein (PLP1) gene, on chro-
routine light microscopy of a peripheral blood smear may show lym- mosome Xq22, which is essential for CNS myelin formation and oli-
phocyte vacuoles. godendrocyte differentiation. Mutations in the same gene can cause
familial spastic paraparesis (progressive spastic paraparesis type 2,
Bibliography is available at Expert Consult. SPG2). PLP1 mutations causing disease include point mutations, dele-
tions, gene duplications, and other gene dosage changes.
Clinically, classic PMD is recognized by nystagmus and roving eye
movements with head nodding during infancy. Developmental mile-
599.3 Adrenoleukodystrophy stones are delayed; ataxia, choreoathetosis, and spasticity ultimately
Jennifer M. Kwon develop. Optic atrophy and dysarthria are associated findings, and
death occurs in the 2nd or 3rd decade. The major pathologic finding
See Chapter 86.2. is a loss of myelin with intact axons, suggesting a defect in the function
of oligodendroglia. An MRI scan shows a symmetric pattern of delayed
myelination. Multimodal-evoked potential studies demonstrate early
in the course a pattern consisting of loss of waves III-V on the auditory
599.4 Sialidosis brainstem response. This finding is useful in the investigation of nys-
Jennifer M. Kwon tagmus in infant boys. VEPs show prolonged latencies, and somato-
sensory evoked potentials show absent cortical responses or delayed
Sialidosis is the result of lysosomal sialidase deficiency, secondary to latencies. It is now recognized that a broad spectrum of phenotypes,
autosomal recessive mutations in the sialidase (α-neuraminidase, including SPG2 and peripheral nerve abnormalities, can also result
NEU1) gene on chromosome 6p21.3. The accumulation of sialic acid– from mutations in the PLP1 gene.
oligosaccharides with markedly increased urinary excretion of sialic There is a PMD-like syndrome caused by autosomal recessive muta-
acid–containing oligosaccharides is associated with clinical presentations in the gap junction protein alpha 12 (GJA12, or connexin 47).
tions that range from the milder sialidosis type I to the more severe Individuals with GJA12 mutations have a clinical and radiologic phe-
sialidosis type II associated with both neurologic and somatic notype like PMD including hypomyelinating leukodystrophy.
features.
Sialidosis type I, the cherry-red spot myoclonus syndrome, usually ALEXANDER DISEASE
presents in the 2nd decade of life, when a patient complains of visual This is a rare disorder that causes progressive macrocephaly and leu-
deterioration. Inspection of the retina shows a cherry-red spot, but, kodystrophy. Alexander disease is caused by dominant mutations in
unlike patients with TSD, visual acuity declines slowly in individuals the glial fibrillary acidic protein (GFAP) gene, on chromosome 17q21
Bibliography
Kohlschütter A, Schulz A: Towards understanding the neuronal ceroid
lipofuscinoses, Brain Dev 31:499–502, 2009.
Mole SE, Williams RE, Goebel HH, editors: The neuronal ceroid lipofuscinoses,
ed 2, Oxford, 2011, Oxford University Press.
2915.e2 Chapter 599 ◆ Neurodegenerative Disorders of Childhood
Bibliography Ramachandran N, Girard JM, Turnbull J, et al: The autosomal recessively inherited
Caciotti A, Di Rocco M, Filocamo M, et al: Type II sialidosis: review of the clinical progressive myoclonus epilepsies and their genes, Epilepsia 50(Suppl 5):29–36,
spectrum and identification of a new splicing defect with chitotriosidase 2009.
assessment in two patients, J Neurol 256:1911–1915, 2009.
A B
Figure 599-3 Alexander disease. MRI of the index patient at the age of 15 mo. A, Axial T2-weighted sequences (TR/TE: 4000/99) at the basal
ganglia and thalamus level demonstrating diffuse bilateral, symmetric increased signal predominantly of the frontal periventricular, but also of the
subcortical white matter and of the basal ganglia. B, Significant periventricular rim after intravenous gadolinium infusion (T1-weighted sequences;
TR/TE: 400/88). (From Zafeiriou DI, Dragoumi P, Vargiami E: Alexander disease. J Pediatr 162:648, 2013.)
and cases are usually sporadic in their families. Pathologic examination mutations in the protein are associated with low serum copper and
of the brain discloses deposition of eosinophilic hyaline bodies called ceruloplasmin levels, as well as a defect in intestinal copper absorption
Rosenthal fibers in astrocyte processes. These accumulate in a perivas- and transport. Symptoms begin in the 1st few mo of life and include
cular distribution throughout the brain. In the classic infantile form of hypothermia, hypotonia, and generalized myoclonic seizures. The
Alexander disease, degeneration of white matter is most prominent facies are distinctive, with chubby, rosy cheeks and kinky, colorless,
frontally. Diagnosis may be suggested by MRI (Fig. 599-3) and MR friable hair. Microscopic examination of the hair shows several abnor-
spectroscopy demonstrating abnormal metabolic substrates. Affected malities, including trichorrhexis nodosa (fractures along the hair shaft)
children develop progressive loss of intellect, spasticity, and unrespon- and pili torti (twisted hair). Feeding difficulties are prominent and lead
sive seizures causing death by 5 yr of age. However, there are milder to failure to thrive. Severe mental retardation and optic atrophy are
forms that present later in life and that may not have the characteristic constant features of the disease. Neuropathologic changes include tor-
frontal predominance or megalencephaly. tuous degeneration of the gray matter and marked changes in the
cerebellum with loss of the internal granule cell layer and necrosis of
CANAVAN SPONGY DEGENERATION the Purkinje cells. Death occurs by 3 yr of age in untreated patients.
See Chapter 85.15. Copper-histidine therapy may be effective in preventing neurologic
deterioration in some patients with Menkes disease, particularly when
OTHER LEUKODYSTROPHIES treatment is begun in the neonatal period or, preferably, with the fetus.
Metabolic and degenerative disorders can present with significant cere- These presymptomatic children are currently identified because of a
bral white matter changes, such as some mitochondrial disorders (see family history of an affected brother. Copper is essential in the early
Chapters 86.1 and 598.2) and glutaric aciduria type 1 (see Chapter stages of CNS development, and its absence probably accounts for the
85.14). In addition, the broader use of MRI has brought to light new neuropathologic changes. Infants diagnosed presymptomatically in the
leukodystrophies. One example is vanishing white matter disease or 1st 10 days of life can be started on an experimental protocol of daily
childhood ataxia with CNS hypomyelination characterized by ataxia copper-histidine subcutaneous injections (as of 2015, only available at
and spasticity. Some patients also have optic atrophy, seizures, and NIH under a program supervised by Dr. Stephen Kaler). Optimal
cognitive deterioration. The age of presentation and the rapidity of response to copper-histidine injection treatment appears to occur only
decline can be quite variable. In the early-onset forms, decline is usually in patients who are identified in the newborn period and whose muta-
rapid and followed quickly by death; in the later-onset forms, mental tions permit residual copper-transport activity.
decline is usually slower and milder. Interestingly, acute demyelination The occipital horn syndrome, a skeletal dysplasia caused by differ-
in these disorders can be triggered by fever or fright. The diagnosis of ent mutations in the same gene as that involved in Menkes disease, is
vanishing white matter disease or childhood ataxia with CNS hypomy- a relatively mild disease. The 2 diseases are often confused, because the
elination is based on clinical findings, characteristic abnormalities on biochemical abnormalities are identical. Resolution of the uncertainty
cranial MRI, and autosomal recessive mutations in 1 of 5 causative about treatment of patients with Menkes disease will require careful
genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the 5 genotype-phenotype correlation, along with further clinical trials of
subunits of the eucaryotic translation initiation factor, eIF2B. copper therapy.
MENKES DISEASE RETT SYNDROME

Menkes disease (kinky hair disease) is a progressive neurodegenerative This syndrome is not strictly speaking a degenerative disease, but
condition inherited as a X-linked recessive trait. The Menkes gene a disorder of early brain development marked by a period of develop-
codes for a copper-transporting, P-type adenosine triphosphatase, and mental regression and deceleration of brain growth after a relatively
Figure 599-4 Clinical and radiographic approach to neurodegeneration with brain iron accumulation. NBIA, neurodegeneration with brain iron
accumulation; SENDA, static encephalopathy of childhood with neurodegeneration in adulthood. (From Kruer MC, Boddaert N: Neurodegenera-
tion with brain iron accumulation: a diagnostic algorithm. Semin Pediatr Neurol 19:67–74, 2012, Fig. 1.)
normal neonatal course. It occurs predominantly in girls. The fre- reported cases has decreased dramatically to 0.06 cases/million popu-
quency is approximately 1 in 15,000-22,000 children. Rett syndrome is lation, paralleling the decline in reported measles cases. The initial
caused by mutations in MeCP2, a transcription factor that binds to clinical manifestations include personality changes, aggressive behav-
methylated CpG islands and silences transcription. Development may ior, and impaired cognitive function in individuals who have been
proceed normally until 1 yr of age, when regression of language and exposed to natural measles virus in early childhood. Myoclonic sei-
motor milestones and acquired microcephaly become apparent. An zures soon dominate the clinical picture. Later, generalized tonic–
ataxic gait or fine tremor of hand movements is an early neurologic clonic convulsions, hypertonia, and choreoathetosis become evident,
finding. Most children develop peculiar sighing respirations with inter- followed by progressive bulbar palsy, hyperthermia, and decerebrate
mittent periods of apnea that may be associated with cyanosis. The postures. Funduscopic examination early in the course of the disease
hallmark of Rett syndrome is repetitive hand-wringing movements reveals papilledema in approximately 20% of the cases. Optic atrophy,
and a loss of purposeful and spontaneous use of the hands; these fea- chorioretinitis, and macular pigmentation are observed in most
tures may not appear until 2-3 yr of age. Autistic behavior is a typical patients. The diagnosis is established by the typical clinical course and
finding in all patients. Generalized tonic-clonic convulsions occur in 1 of the following: (1) measles antibody detected in the cerebrospinal
the majority and are usually well controlled by anticonvulsants. Feeding fluid, (2) a characteristic electroencephalogram consisting of bursts of
disorders and poor weight gain are common. After the initial period high-voltage slow waves interspersed with a normal background that
of neurologic regression, the disease process appears to plateau, with occur with a constant periodicity in the early stages of the disease, and
persistence of the autistic behavior. Cardiac arrhythmias may result in (3) typical histologic findings in the brain biopsy or postmortem speci-
sudden, unexpected death at a rate that is higher than the general men. Treatment with a series of antiviral agents has been attempted
population. Generally girls survive into adulthood. without success. Death occurs usually within 1-2 yr from the onset of
Postmortem studies show significantly reduced brain weight (60-80% symptoms.
of normal) with a decrease in the number of synapses, associated with
a decrease in dendritic length and branching. The phenotype may be NEURODEGENERATION WITH BRAIN
related to failure to suppress expression of genes that are normally silent IRON ACCUMULATION
in the early phases of postnatal development. Although very few males Neurodegeneration with brain iron accumulation represents multiple,
survive with the classic Rett syndrome phenotype, genotyping of boys age-of-onset-dependent disorders characterized by extrapyramidal
without the classic Rett syndrome phenotype but with intellectual dis- symptoms, intellectual deterioration and regression, with iron depo-
ability and other atypical neurologic features has detected a significant sition in the basal ganglia. There is significant phenotype variability
number with mutations in MeCP2. Mutations in MeCP2 have been of these disorders; however, a characteristic finding on MRI dem-
demonstrated in normal female carriers, females with Angelman syn- onstrates symmetric T2 signal homogeneous hypointensity. Common
drome, and in males with fatal encephalopathy, Klinefelter (47 XXY) neurodegeneration with brain iron accumulation disorders are dis-
syndrome, and familial X-linked mental retardation. tinguished in Table 599-3 and an approach to their diagnosis is
Some girls have an atypical Rett phenotype associated with severe noted in Figure 599-4. Clinical features, which are highly variable,
myoclonic seizures in infancy, slowing of head growth, and develop- may include dystonia, parkinsonism, ataxia, spasticity, psychiatric
mental arrest and have mutations in another X-linked gene encoding symptoms, and intellectual impairment. Treatment should focus on
for cyclin-dependent kinase–like 5 (CDKL5), which may interact with the specific disorder and is usually symptomatic relief rather than
MeCP2 and other proteins regulating gene expression. curative. Iron chelation has been attempted without major long-term
benefit.
SUBACUTE SCLEROSING PANENCEPHALITIS
This is a rare, progressive neurologic disorder caused by persistent
measles virus infection of the CNS (see Chapter 246). The number of Bibliography is available at Expert Consult.
Bibliography Messing A, Brenner M, Feany MB, et al: Alexander disease, J Neurosci

Campbell H, Andrews N, Brown KE, et al: Review of the effect of measles 32(15):5017–5023, 2012.
vaccination on the epidemiology of SSPE, Int J Epidemiol 36:1334–1348, 2007. Percy AK: Rett syndrome: exploring the autism link, Arch Neurol 68(8):985–989,
Gadoth N: Subacute sclerosing panencephalitis (SSPE) the story of a vanishing 2011.
disease, Brain Dev 34(9):705–711, 2012. Sawaishi Y: Review of Alexander disease: beyond the classical concept of
Gutierrez J, Issacson RS, Koppel BS: Subacute sclerosing panencephalitis: an leukodystrophy, Brain Dev 31:493–498, 2009.
update, Dev Med Child Neurol 52(10):901–907, 2010. Schiffmann R, van der Knaap MS: Invited article: an MRI-based approach to the
Hobson GM, Garbern JY: Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like diagnosis of white matter disorders, Neurology 72:750–759, 2009.
disease 1, and related hypomyelinating disorders, Semin Neurol 32(1):62–67, Schneider SA, Zorzi G, Nardocci N: Pathophysiology and treatment of
2012. neurodegeneration with brain iron accumulation in the pediatric population,
Kaler SG: ATP7A-related copper transport diseases-emerging concepts and future Curr Treat Options Neurol 15:652–667, 2013.
trends, Nat Rev Neurol 7(1):15–29, 2011. Staretz-Chacham O, Lang TC, LaMarca ME, et al: Lysosomal storage disorders in
Kohlschutter A, Eichler F: Childhood leukodystrophies: a clinical perspective, the newborn, Pediatrics 123:1191–1207, 2009.
Expert Rev Neurother 11(10):1485–1496, 2011. Zafeiriou DI, Dragoumi P, Vargiami E: Alexander disease, J Pediatr 162:648, 2013.
Kruer MC, Boddaert N: Neurodegeneration with brain iron accumulation: a
diagnostic algorithm, Semin Pediatr Neurol 19:67–74, 2012.
2918 Part XXVII
◆
Table 599-3 Overview of Neurodegeneration with Brain Iron Accumulation Conditions and Genes (if Known)
CHILDHOOD-ONSET VARIANT LATE-ONSET VARIANT
CONDITION CHROMOSOMAL LB AGE OF CLINICAL CLINICAL
(ACRONYM) SYNONYM GENE POSITION PATHOLOGY ONSET PRESENTATION AGE OF ONSET PRESENTATION
PKAN NBIA1 PANK2 20p13 No Early Typical PKAN Teens or early Atypical PKAN
childhood, adulthood
around age 3
PLAN NBIA2, PLA2G6 22q12 √ Infancy Infantile neuroaxonal Teens or early Dystonia parkinsonism
PARK14 dystrophy adulthood
The Nervous System
FAHN SPG35 FA2H 16q23 Not known Childhood Leukodystrophy, Adulthood (age May resemble idiopathic
hereditary spastic range up to PD
paraplegia 30 yr)
MPAN — C19orf12 19q12 √ — Pyramidal
extrapyramidal
syndrome
Kufor-Rakeb PARK9 ATP13A2 1p36 √ Childhood- Parkinsonism,
disease teens pyramidal tract
signs, eye
movement disorder
BPAN SENDA WDR45 Xp11.23 Not known Childhood Encephalopathy with Then: 20s to 30s Sudden onset
syndrome psychomotor progressive dystonia
regression, then parkinsonism
static
Aceruloplasminemia — CP 3q23 No — — 50s (range: 16-70) Extrapyramidal,
diabetes, dementia
Neuroferritinopathy — FTL 19q13 No — — 40s Chorea, dystonia,
dementia
Idiopathic late- — Probably Probably Heterogeneous — — Heterogeneous Parkinsonism, in may
onset cases heterogeneous heterogeneous resemble idiopathic PD
√, Present; BPAN, beta-propeller associated neurodegeneration; CP, ceruloplasmin; FA2H, fatty acid 2-hydroxylase; FAHN, fatty acid 2-hydroxylase-associated neurodegeneration; FTL, ferritin light chain; MPAN,
mitochondrial membrane-associated neurodegeneration; NBIA, neurodegeneration with brain iron accumulation; PANK2, pantothenate kinase 2; PD, Parkinson disease; PKAN, pantothenate kinase-associated
neurodegeneration; PLA2G6, phospholipase A2; PLAN, PLA2G6-associated neurodegeneration; SENDA, static encephalopathy of childhood with neurodegeneration in adulthood; SPG, spastic paraplegia.
From Schneider SA, Zorzi G, Nardocci N: Pathophysiology and treatment of neurodegeneration with brain iron accumulation in the pediatric population, Curr Treat Option Neurol 15:652-667, 2013, Table 1.
Chapter 600 ◆ Demyelinating Disorders of the Central Nervous System 2919
Table 600-1 Differential Diagnosis of Demyelinating

Disorders
Chapter 600
Acute disseminated encephalomyelitis (ADEM)
Demyelinating Disorders Multiple sclerosis (including tumefactive MS)

Acute hemorrhagic leukoencephalopathy
Clinically isolated syndrome (CIS)
of the Central Nervous Neuromyelitis optica spectrum disorder
N-methyl-D-aspartate receptor (NMDAR) antibody and other
System autoimmune encephalitis

Vasculitis/angiopathies
Hashimoto encephalitis (anti–thyroid peroxidase [TPO] antibody)
Jayne M. Ness Familial hemophagocytic lymphohistiocytosis
Langerhans cell histiocytosis
Lymphoma
Gliomatosis cerebri
Glioma
Acquired demyelinating disorders of the central nervous system Sarcoidosis
(CNS) result in neurologic dysfunction caused by immune-mediated Mitochondrial disorders (Leigh syndrome)
attacks on white matter insulating the brain, optic nerves and spinal Vitamin E deficiency
cord. The white matter insulation is formed by myelin contained Vitamin B12 deficiency
Celiac disease
within oligodendrocytes wrapping around nerve axons. In contrast
Herpes simplex virus (HSV), enterovirus, arbovirus, Powassan and
to genetically determined leukodystrophies (sometimes called dys- other viral encephalitides
myelinating disorders) that produce disrupted white matter, acquired Rabies
demyelinating disorders generally target normally formed white Subacute sclerosing pan-encephalitis (SSPE) (chronic measles)
matter. Pediatric demyelinating syndromes are characterized clinically Charcot-Marie-Tooth syndrome
by (1) localization of neurologic deficits (i.e., single site, such as Leukoencephalopathies (Aicardi-Goutières syndrome)
spinal cord [transverse myelitis], optic nerves [optic neuritis] or Vanishing white matter disease
brainstem, vs polyregional demyelination); (2) the presence vs Schilder disease (possibly an adrenoleukodystrophy)
absence of encephalopathy; and (3) disease course (i.e., monophasic X-linked adrenoleukodystrophy
Griscelli syndrome type 2
vs repeated attacks involving either the same or new CNS regions).
Major demyelinating disorders in childhood include acute dissemi-
nated encephalomyelitis (ADEM), typically a self-limited disorder,
and relapsing–remitting multiple sclerosis (MS). MRI of brain and CLINICAL MANIFESTATIONS
spine is useful to initially characterize symptomatic and clinically Presenting symptoms in pediatric MS include hemiparesis or parapa-
silent demyelinating lesions, but serial MRI is often required to dis- resis; unilateral or, less often, bilateral optic neuritis; focal sensory
tinguish self-limited vs chronic demyelinating syndromes, especially loss; ataxia; diplopia; dysarthria; or bowel/bladder dysfunction (Table
in the younger child. Additional studies, such as cerebrospinal fluid 600-3). Polyregional symptoms are reported in 30% of patients.
(CSF) analysis, autoimmune and genetic testing, and sometimes even Encephalopathy is less common and suggests consideration of ADEM
brain biopsy, may be required to evaluate for mimickers of demyelin- or possibly neuromyelitis optica (NMO).
ation, such as neoplasm, infection, systemic rheumatologic disorders,
isolated CNS angiitis, mitochondrial disease, and leukodystrophies LABORATORY FINDINGS
(Tables 600-1 and 600-2). Cranial MRI exhibits discrete T2 lesions in cerebral white matter, par-
ticularly periventricular regions as well as brainstem, cerebellum, and
juxtacortical and deep gray matter. Alternatively, large tumefactive T2
lesions may be seen. Spine MRI typically shows partial-width cord
lesions restricted to 1-2 spine segments. CSF may be normal or exhibit
600.1 Multiple Sclerosis mild pleocytosis, particularly in younger children. Abnormal MS pro-
Jayne M. Ness files (increased immunoglobulin [Ig] G index, and/or CSF oligoclonal
bands) increase likelihood of MS but may be negative in 10-60% of
Pediatric MS is a chronic demyelinating disorder of the brain, spinal pediatric MS patients, particularly prepubertal children; they also may
cord, and optic nerves characterized by a relapsing–remitting course be occasionally positive in ADEM or autoimmune encephalitis (Fig.
of neurologic events without encephalopathy separated in time and 600-1). Abnormal evoked potential studies can localize disruptions in
space. visual, auditory, or somatosensory pathways.
EPIDEMIOLOGY DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Pediatric MS is rare, with an estimated 2-5% of MS patients experienc- Pediatric MS can usually be diagnosed following 2 demyelinating epi-
ing their first symptoms before age 18 yr. Pediatric MS has a slight male sodes without encephalopathy localizing to distinct CNS regions,
predominance when disease onset is before age 6 yr, but by age 12 yr, lasting longer than 24 hr and separated by more than 30 days, provided
females outnumber males 2 : 1. no other plausible explanation exists. Current MS diagnostic criteria
use MRI to serve as a surrogate for recurrent demyelination, enabling
PATHOGENESIS MS diagnosis after the first event. For adults and children >12 yr, the
A complex interplay of environmental, infectious, and genetic factors initial MRI may be sufficient to diagnose MS if it demonstrates dis-
influence MS susceptibility. Immune system dysregulation involving T semination in space (≥2 T2 lesions involving juxtacortical, periven-
and B lymphocytes triggers inflammation, axonal demyelination, tricular, infratentorial, or spine regions) and time (presence of
axonal loss, and regeneration within both white and gray matter. asymptomatic gadolinium-enhancing lesion and nonenhancing T2
Inflammatory infiltrates within actively demyelinating lesions of lesion in same scan). Alternatively, MS can be diagnosed with a
relapsing-remitting MS are targets for disease modifying agents follow-up MRI at any time interval exhibiting accumulation of T2 or
(DMAs). Neurodegenerative changes predominate in progressive gadolinium-enhancing lesions in the brain or spine. Challenges arise
forms of MS. in distinguishing pediatric MS from other acquired demyelinating
Table 600-2 IPMSSG 2012 Definitions for Pediatric Acute Demyelinating Disorders of the Central Nervous System
DISORDER IPMSSG 2012
CIS • A first monofocal or multifocal CNS demyelinating event; encephalopathy is absent, unless caused by fever
Monophasic ADEM • A first polyfocal clinical CNS event with presumed inflammatory cause
• Encephalopathy that cannot be explained by fever is present
MRI typically shows diffuse, poorly demarcated, large, >1-2 cm lesions involving predominantly the
cerebral white matter; T1 hypointense white matter lesions are rare; deep gray-matter lesions (e.g.,
thalamus or basal ganglia) can be present
• No new symptoms, signs or MRI findings after 3 mo of the incident ADEM
Recurrent ADEM • See multiphasic ADEM
Multiphasic ADEM • New event of ADEM 3 mo or more after the initial event that can be associated with new or reemergence
of prior clinical and MRI findings. Timing in relation to steroids is no longer pertinent
MS Any of the following:
• Two or more nonencephalopathic CNS clinical events separated by more than 30 days, involving more than
1 area of the CNS
• Single clinical event and MRI features rely on 2010 Revised McDonald criteria for DIS and DIT (but criteria
relative for DIT for a single attack and single MRI only apply to children ages 2-12 yr and only apply to
cases without an ADEM onset)
NMO All are required:
• Optic neuritis
• Acute myelitis
At least 2 of 3 supportive criteria
• Contiguous spinal cord MRI lesion S3 vertebral segments
• Brain MRI not meeting diagnostic criteria for MS
• Anti–aquaporin-4 immunoglobulin G–seropositive status
• ADEM followed 3 mo later by a nonencephalopathic clinical event with new lesions on brain MRI consistent
with MS
The 2001 McDonald MRI criteria for DIS require 3 of the following 4 MRI features: 29 T2 lesions or 1 gadolinium-enhancing lesion; 23 periventricular lesions; 21
infratentorial lesion(s); 21 juxtacortical lesion(s). The DIT criteria require subsequent white-matter lesions whose timing depends on the temporal relation of the initial
MRI with the onset of the clinical symptoms.
The 2010 Revised McDonald MRI criteria for DIS require the presence of at least 2 of the following 4 criteria: 21 lesions in each of the 4 locations; periventricular,
juxtacortical, infratentorial, and spinal cord. The 2010 Revised McDonald MRI criteria for DIT can be satisfied either by the emergence of newT2 lesions (with or
without enhancement) on serial scan(s) or can be met on a single baseline scan if there exists simultaneous presence of a clinically silent gadolinium-enhancing lesion
and a nonenhancing lesion.
ADEM, acute disseminated encephalomyelitis; CIS, clinically isolated syndrome; CNS, central nervous system; DIS, dissemination in space; DIT, dissemination in
time; IPMSSG, International Pediatric Multiple Sclerosis Study Group; MS, multiple sclerosis; NMO, neuromyelitis optica.
Modified from Krupp LB, Tardieu M, Amato MP, et al: International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-
mediated central nervous system demyelinating disorders: revision to the 2007 definitions. Mult Scler 19(10):1261–1267, 2013, Appendix 1, p. 1266.
Table 600-3 Symptoms and Signs of Multiple Sclerosis by Site

SYMPTOMS SIGNS
Cerebrum Cognitive impairment Deficits in attention, reasoning, and executive function (early);
dementia (late)
Hemisensory and motor Upper motor neuron signs
Affective (mainly depression)
Epilepsy (rare)
Focal cortical deficits (rare)
Optic nerve Unilateral painful loss of vision Scotoma, reduced visual acuity, color vision, and relative
afferent papillary defect
Cerebellum and Tremor Postural and action tremor, dysarthria
cerebellar pathways Clumsiness and poor balance Limb incoordination and gait ataxia
Brainstem Diplopia, oscillopsia Nystagmus, internuclear and other complex ophthalmoplegias
Vertigo
Impaired swallowing Dysarthria
Impaired speech and emotional lability Pseudobulbar palsy
Paroxysmal symptoms
Spinal cord Weakness Upper motor neuron signs
Stiffness and painful spasms Spasticity
Bladder dysfunction
Erectile impotence
Constipation
Other Pain
Fatigue
Temperature sensitivity and exercise intolerance
Modified from Compston A, Coles A: Multiple sclerosis, Lancet 372:1502–1517, 2008, p. 1503.
Diagnosis of
Clincal episodes? MRI CSF
multiple sclerosis
Yes
Delayed MRI

Yes
Yes
CSF Serum
Yes
Figure 600-1 Criteria for the diagnosis of multiple sclerosis. The principle is to establish dissemination in time and place of lesions, meaning
that episodes affecting separate sites within the central nervous system have occurred at least 30 days apart. MRI can substitute for 1 of these
clinical episodes. Dissemination in time of magnetic resonance lesions requires simultaneous presence of asymptomatic gadolinium-enhancing
and asymptomatic lesions or followup MRI showing accumulation of a new gadolinium-enhancing lesion or T2 lesion. Criteria for MRI definition
of dissemination in space require 2 or more lesions in periventricular, juxtacortical, or infratentorial regions or spine. Primary progressive MS is
very rare in childhood but can be diagnosed after 1 yr of a progressive deficit and 2 of the following: (1) a positive brain MRI; (2) a positive spinal
cord MRI; and (3) positive oligoclonal bands. Patients having an appropriate clinical presentation but who do not meet all of the diagnostic criteria
can be classified as having possible MS. CSF, cerebrospinal fluid. (From Compston A, Coles A: Multiple sclerosis, Lancet 372:1502–1517, 2008,
Fig. 1.)
syndromes such as ADEM or NMO, especially in the prepubertal child. TREATMENT

ADEM is a self-limited syndrome characterized by encephalopathy, Relapses causing functional disability may be treated with methylpred-
polyregional neurologic deficits, and diffuse multifocal MRI T2 abnor- nisolone, 20-30 mg/kg/day (max: 1,000 mg/day) for 3-5 days, with or
malities followed by subsequent clinical improvement and resolution without prednisone taper. DMAs reduce relapse frequency and T2
of MRI T2 lesions (see Tables 600-1, 600-2, 600-4, and 600-5). However, lesion load, mainly by targeting the inflammatory response that pre-
a subset of pediatric MS patients (10-25%) presents with an ADEM dominates during the relapsing-remitting phase of MS (Table 600-6).
phenotype and then experiences multiple relapses with accumulation There are 4 injectable DMAs, 3 oral DMAs, and 2 infused DMAs
of MRI T2 lesions. NMO, traditionally thought of as a combined myeli- approved by the FDA for adult MS, but to date, none of these agents
tis and optic neuritis with normal brain MRI, now has a broader has a pediatric MS indication. Injectable agents, first approved in the
phenotype with the identification of the NMO antibody against the mid-1990s (interferon-beta1α SC or IM or interferon-beta1β SC; glat-
CNS water channel aquaporin-4 and MRI lesions in the brain. The iramer acetate SC) have some side effects such as flu-like side effects
NMO spectrum includes isolated bilateral optic neuritis or longitudi- and risk of transaminase elevation with interferon-beta or requirement
nally extensive transverse myelitis even in the presence of brain MRI for daily injections with glatiramer acetate but otherwise have an excel-
abnormalities or encephalopathy. lent safety record so are still recommended as first-line therapy in
pediatric MS. Three oral DMAs (fingolimod, teriflunomide, dimethyl
COMPLICATIONS fumarate) have been FDA-approved since 2010, but despite ease of oral
Similar to adults with MS, pediatric MS patients can acquire fixed administration, enthusiasm is tempered by reports of severe side effects
neurologic deficits affecting vision and other cranial nerves, motor and or even death from reactivation of latent viruses (fingolimod, dimethyl
sensory function, balance, and bowel/bladder function. Cognitive fumarate) and potential of severe birth defects (teriflunomide). Intra-
impairment can impede academic achievement. venous DMAs (natalizumab, mitoxantrone) are second-line agents
used only after failure of first-line injectable or oral agents. Natali- 600.2 Neuromyelitis Optica
zumab therapy is associated with the risk of developing progressive
multifocal encephalopathy (CNS infection with human polyomavirus Jayne M. Ness
JC). Mitoxantrone has a lifetime dose limit because of cardiotoxicity
and is associated with subsequent development of acute myelogenous NMO (Devic disease) is a demyelinating disorder characterized by
lymphoma in 2 of 802 MS patients (0.25%). monophasic or polyphasic episodes of optic neuritis and/or transverse
myelitis. It was once thought that NMO was a variant of MS; but iden-
PROGNOSIS tification of the NMO antibody against the aquaporin-4 water channel
Retrospective studies of patients diagnosed with MS prior to wide- has broadened the spectrum of NMO to include brainstem syndromes
spread dimethyltryptamine use suggest slower disease progression in and recurrent forms of optic neuritis and transverse myelitis (see Table
pediatric MS patients compared to adults. Despite a longer time to 600-2). NMO spectrum disorder frequently involves symptomatic or
irreversible disability (20-30 yr), pediatric MS patients acquire irre- silent MRI lesions demonstrating demyelination of the cerebral cortex
versible disability at a younger age than adults. and other regions of the brain.
Bibliography is available at Expert Consult. EPIDEMIOLOGY

NMO has an age of onset of 31.2 ± 11 yr. In 1 study, in monophasic
patients, the range of age of onset was 1-54 yr; in polyphasic patients,
the range was 6-72 yr. NMO is more common in females than in males;
Table 600-4 Clinical Features That May Distinguish 65% of monophasic and 80-85% of polyphasic NMO patients are
ADEM from First Attack of MS female. It is also more common in Asians than in blacks or whites and
appears to have a higher mortality rate in individuals of African
ADEM MS descent than in others.
Age <10 yr >10 yr
PATHOGENESIS
Stupor/coma + − NMO is associated with IgG antibodies against the aquaporin-4 water
Encephalopathy + − channel, which is most abundant on astrocyte foot processes within
periventricular regions, brainstem, optic nerves, and spinal cord. Anti-
Fever/vomiting + −
body binding to aquaporin-4 activates the classical complement
Family history No 20% pathway with C5b-C9 components leading to leukocytes attraction and
Sensory complaints + +
degranulation, causing astrocyte death. Chemokines from dying astro-
cytes and activated leukocytes attract macrophages, leading to death of
Optic neuritis Bilateral Unilateral oligodendrocytes and neurons with subsequent necrosis or even cavi-
Manifestations Polysymptomatic Monosymptomatic tation in affected tissues. Although most cases of NMO are idiopathic
and only occasional familial cases have been reported, there have been
CSF Pleocytosis Oligoclonal bands reports of postinfectious NMO. HIV, syphilis, chlamydia, varicella,
(lymphocytosis)
cytomegalovirus, and Epstein-Barr virus are associated with subse-
Response to steroids + + quent development of NMO. Aquaporin-4 antibody–positive NMO
Follow-up No new lesions New lesions may follow or occur simultaneously with N-methyl-d-aspartate recep-
tor antibody autoimmune encephalitis.
Some features that may help distinguish an initial acute episode of
demyelination from a first attack of MS in children. Final diagnosis of MS is
based on follow-up evaluation and possibly MRI.
+, More likely to be present; −, less likely to be present; ADEM, acute NMO presents with optic neuritis or transverse myelitis or brainstem
disseminated encephalomyelitis; CSF, cerebrospinal fluid; MS, multiple sclerosis. symptoms such as intractable vomiting or hiccups, diplopia, facial
Table 600-5 MRI Characteristics for Dissemination in Space That Increase the Likelihood of a Pediatric Multiple
Sclerosis Diagnosis
POLMAN (2010
MIKAELOFF CALLEN (MS VS CALLEN VERHEY REVISED MCDONALD
BARKHOF* (KIDMUS)† ADEM)‡ (DIAGNOSTIC MS)§ (DIFFERENTIAL)‖ CRITERIA)¶
3 of 4: 1 of 2: 2 of 3: 2 of 3: 2 of 2: 2 of 4:
≥9 T2 lesions or Lesions perpendicular Absence of a diffuse ≥5 Lesions on ≥1 Periventricular ≥1 Periventricular
1 gadolinium to long axis of the bilateral lesion T2-weighted images lesions ≥1 Juxtacortical
enhancing corpus callosum pattern 2 Periventricular ≥1 Hypointense ≥1 Infratentorial
≥3 Periventricular Sole presence of Presence of black lesions lesions on T1 ≥1 Spinal cord
≥1 Infratentorial well-defined lesions holes ≥1 Brainstem lesions images
≥1 Juxtacortical ≥2 Periventricular
lesions
*Barkhof F, Filippi M, Miller DH, et al: Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 120:2059–
2069, 1997.
†
Mikaeloff Y, Adamsbaum C, Husson HM, et al: MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain 127:1942–1947,
2004.
‡
Callen DJ, Shroff MM, Branson HM, et al: Role of MRI in the differentiation of ADEM from MS in children. Neurology 72:968–973, 2009.
§
Callen DJ, Shroff MM, Branson HM, et al: MRI in the diagnosis of pediatric multiple sclerosis. Neurology 72:961–967, 2009.
‖
Verhay LH, Branson HM, Shroff MM, et al: MRI parameters for prediction of multiple sclerosis diagnosis in children with acute CNS demyelination: a prospective
national cohort study. Lancet Neurol 10:1065–1073, 2011.
¶
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302, 2011.
ADEM, acute disseminated encephalomyelitis; MS, multiple sclerosis.
From Krupp LB, Tardieu M, Amato MP, et al: International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated
central nervous system demyelinating disorders: revision to the 2007 definitions. Mult Scler 19(10):1261–1267, 2013, Appendix 3, p. 1267.
Chapter 600 ◆ Demyelinating Disorders of the Central Nervous System 2922.e1
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Table 600-6 Overview of Available and Emerging Therapies in Pediatric Multiple Sclerosis
STUDIES DESCRIBING
MEDICATION DRUG EFFICACY IN
MEDICATION CLASS MECHANISM IN MS SIDE EFFECTS PEDIATRIC MS
FIRST-LINE THERAPIES
Interferon-α or β Immunomodulator Modulates T cells and Flu-like symptoms; transaminitis; Retrospective
cytokine production leukopenia; tissue necrosis at Prospective multicenter
injection site (rare)
Glatiramer Immunomodulator Modulates T cells and Flushing, lipodystrophy at Prospective single center
acetate* reduces antigen injection sites Prospective multicenter
presentation
SECOND-LINE THERAPIES
Natalizumab* Monoclonal Targets α4-integrin; Overall PML rate ~1 in 500 Retrospective
antibody prevents T-cell migration patients, but lower in subgroups; Prospective multicenter
into CNS and other immune reconstitution syndrome
tissues after discontinuation; melanoma;
infusion reaction; transaminitis
(rare)
Cyclophosphamide Chemotherapeutic DNA alkylation; effects Hemorrhagic cystitis; bladder Retrospective multicenter
include cytotoxic immune cancer; late-onset malignancy;
cell depletion infection; infertility
Mitoxantrone* Chemotherapeutic Disrupts DNA synthesis; Significant long-term safety risks, Retrospective single center
effects include cytotoxic including cardiotoxicity (1 in 200
immune cell depletion patients) and secondary
leukemia (1 in 125 patients);
opportunistic infections
Daclizumab Monoclonal Targets/inactivates Glucose intolerance; pulmonary Retrospective multicenter
antibody interleukin-2 receptor; edema; infusion reaction;
inhibits activated T cells gastrointestinal upset; skin
reactions
Rituximab Monoclonal Targets CD20, a marker of PML (rate undefined); infusion- No efficacy assessments
antibody immature B cells; depletes related side effects available in pediatric MS
B-cell populations
Azathioprine Chemotherapeutic Disrupts purine metabolism; Transaminitis; leukopenia; No efficacy assessments
effects include cytotoxic lymphoma available in pediatric MS
immune cell depletion
Fingolimod*† Immunomodulator Sphingosine-1-phosphate Systemic viral infection; cardiac FDA approved for adult MS
agonist; causes T-cell arrhythmia; macular edema; in September 2010; no
sequestration in lymphoid transaminitis reports of use in pediatric
compartments MS to date
Teriflunomide*† Immunomodulator Impairs immune cell Infections; headaches; diarrhea; FDA approved for adult MS
proliferation via transaminitis; alopecia; in September 2012; no
pyrimidine synthesis teratogenicity reports of use in pediatric
inhibition MS to date
EMERGING THERAPIES
Vitamin D† Vitamin/hormone Modulates immune cell Hypercalcemia and kidney stones Prospective trials in
expression at a serum 25(OH) vitamin D pediatric and adult MS
level >100 ng/mL are currently underway
Ocrelizumab Monoclonal Targets CD20, a marker of Headache; infusion-related side Recently completed phase
antibody immature B cells; depletes effects; theoretical risk of PML III trial in adult MS; no
B-cell populations (undefined) use in pediatric MS to
date
Dimethyl fumarate† Immunomodulator Neuroprotectant; Flushing reaction; gastrointestinal FDA approved for adult MS
antioxidant upset; headache in March 2013; no use in
pediatric MS to date
Alemtuzumab Monoclonal Anti-CD52 antibody target; Opportunistic infection, Recently completed phase
antibody depletes mature T cells autoimmune thyroiditis (20-30% III trial in adult MS; no
risk), immune thrombocytopenia use in pediatric MS to
(1%) date
Laquinimod† Immunomodulator Modulates T cell and Transaminitis Recently completed phase
cytokine production III trial in adult MS; no
use in pediatric MS to
date
*FDA approved for the treatment of adult MS.
†
Orally administered therapy.
CNS, central nervous system; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy.
weakness or numbness or dysphagia. Optic neuritis or transverse disrupted puberty. The symptoms and signs of transverse myelitis
myelitis may occur simultaneously or may be separated in time by depend on the spinal level and completeness of the inflammatory
weeks or even years. Some present with an encephalopathy mimicking changes. NMO differs from MS in that recovery of visual and spinal
ADEM. Others exhibit endocrinopathies such as the syndrome of cord function is generally not as complete after each episode; optic
inappropriate antidiuretic hormone secretion, diabetes insipidus, or neuritis is more frequently bilateral in NMO than in MS.
LABORATORY FINDINGS PATHOGENESIS

CSF in patients with NMO often has 50 or more white blood cells Molecular mimicry induced by infectious exposure or vaccine may
per microliter. Unlike MS, it is devoid of oligoclonal bands. Serum trigger production of CNS autoantigens. Many patients experience a
positivity for anti–aquaporin-4 antibodies (so-called NMO antibod- transient febrile illness in the month prior to ADEM onset. Preceding
ies) has a sensitivity of 73% and a specificity of 91% for NMO. Neu- infections associated with ADEM include influenza, Epstein-Barr
roimaging studies should include the entire spine, optic nerves as well virus, cytomegalovirus, varicella, enterovirus, measles, mumps, rubella,
as the cortex that may reveal lesions in the brainstem or thalami or herpes simplex, and Mycoplasma pneumoniae. Postvaccination ADEM
hazy ill-defined lesions in the hemispheres in contrast to the discrete, has been reported following immunizations for rabies, smallpox,
well-defined oval lesions in the periventricular white matter seen measles, mumps, rubella, Japanese encephalitis B, pertussis, diphtheria-
in MS. polio-tetanus, and influenza.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS CLINICAL MANIFESTATIONS

Clinical diagnosis of NMO currently requires optic neuritis and trans- Initial symptoms of ADEM may include lethargy, fever, headache,
verse myelitis plus at least 2 of 3 supporting criteria: (1) brain MRI not vomiting, meningeal signs, and seizures, including status epilepticus.
diagnostic of MS, (2) seropositivity for anti–aquaporin-4 antibody, or Encephalopathy is a hallmark of ADEM, ranging from ongoing confu-
(3) spine MRI with longitudinally extensive transverse myelitis involv- sion to persistent irritability to coma. Focal neurologic deficits can be
ing at least 3 spinal segments (see Table 600-2). NMO spectrum dis- difficult to ascertain in the obtunded or very young child but common
order may be diagnosed in relapsing forms of transverse myelitis or neurologic signs in ADEM include visual loss, cranial neuropathies,
optic neuritis with aquaporin-4 seropositivity. The differential diagno- ataxia, motor and sensory deficits, plus bladder/bowel dysfunction
sis includes MS; ADEM (see Chapter 600.3); rheumatologic etiologies with concurrent spinal cord demyelination.
producing transverse myelitis, and/or optic neuritis, including sys-
temic lupus erythematosus, Behçet disease, and neurosarcoidosis NEUROIMAGING
(usually accompanied by other nonneurologic manifestations); idio- Head CT may be normal or show hypodense regions. Cranial MRI, the
pathic transverse myelitis, tropical spastic paraparesis, and viral imaging study of choice, typically exhibits large, multifocal and some-
encephalomyelitis (none of which have NMO antibodies in the serum times confluent or large edematous mass-like tumefactive T2 lesions
or CSF); and metabolic and idiopathic causes of isolated optic neuritis with variable enhancement within white and often gray matter of the
or other acute monocular or binocular visual loss (see Chapter 631). cerebral hemispheres, cerebellum, and brainstem (Fig. 600-2). Deep
Additional considerations depending on the location of the lesions gray-matter structures (thalami, basal ganglia) are often involved,
include lymphoma, Langerhans cell histiocytosis, tuberculosis, and although this may not be specific to ADEM. Spinal cord may have
vitamin B12 or E deficiencies. abnormal T2 signal or enhancement, with or without clinical signs of
myelitis. MRI lesions of ADEM typically appear to be of similar age
COMPLICATIONS but their evolution may lag behind the clinical presentation. Serial MRI
Similar to adults with NMO, pediatric NMO patients often are left imaging 3-12 mo following ADEM shows improvement and often
with fixed neurologic deficits affecting visual acuity, visual fields, complete resolution of T2 abnormalities, although residual gliosis may
color vision, motor and sensory function, balance, and bowel/bladder remain.
function.
TREATMENT
Initial episodes and relapses may be treated acutely with methylpred-
nisolone, 20-30 mg/kg/day (max: 1,000 mg/day) for 3-5 days, followed
by a slow prednisone taper. Rituximab is effective in preventing relapses
of NMO and NMO spectrum disorder. Preliminary evidence suggests
that eculizumab also reduced recurrences and may improve disability
in patients with severe NMO spectrum disorder.
PROGNOSIS
The prognosis is generally poor for patients with NMO. In 1 study,
approximately 20% remained functionally blind (i.e., 20/200 vision
or worse) in at least 1 eye and 31% had permanent monoplegia
or paraplegia. Five-year survival of the patients with paraplegia is
approximately 90%.
600.3 Acute Disseminated

Encephalomyelitis
Jayne M. Ness
ADEM is an initial inflammatory, demyelinating event with multifocal

neurologic deficits, typically accompanied by encephalopathy (see
Table 600-2).
EPIDEMIOLOGY Figure 600-2 Axial T2-weighted fluid-attenuated inversion recovery

ADEM can occur at any age but most series report a mean age MRI of the brain in a child with acute disseminated encephalomyelitis.
between 5 and 8 yr with a slight male predominance. Reported inci- High signal (white) lesions in the T2-weighted image reflect areas of
dence ranges from 0.07-0.4 per 100,000 per year in the pediatric demyelination and edema in deep subcortical and periventricular white
population. matter as well as the basal ganglia and thalamus on the left side.
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A B C D
Figure 600-3 MRI findings in acute disseminated encephalomyelitis. Multiple scattered T2 hyperintensities are appreciated on fluid-attenuated
inversion recovery images (A) with evidence of hemorrhage on susceptibility-weighted images (B), contrast enhancement on T1 postgadolinium
images (C), and without diffusion restriction on diffusion-weighted imaging (D). (From Virmani T, Agarwal A, Klawiter EC: Clinical reasoning: a
young adult presents with focal weakness and hemorrhagic brain lesions. Neurology 76:e105–e109, 2011, Fig. 2.)
Severe involvement may progress to an acute hemorrhagic leuko-

encephalopathy (Hurst disease) with large lesions, edema, mass affect,
and a polymorphonucleated cell pleocytosis (in contrast to lympho-
cytic pleocytosis in the CSF noted in typical ADEM) (Fig. 600-3).
LABORATORY FINDINGS
There is no biologic marker for ADEM and laboratory findings can
vary widely. CSF studies often exhibit pleocytosis with lymphocytic or
monocytic predominance. CSF protein can be elevated, especially on
repeat studies. Up to 10% of patients with ADEM have oligoclonal
bands in the CSF and/or elevated CSF immune globulin production.
Patients with ADEM may occasionally demonstrate antibodies against
myelin oligodendrocyte glycoprotein, or anti–N-methyl-d-aspartate
receptor antibodies. Electroencephalograms often show generalized
slowing, consistent with encephalopathy, although polyregional demy-
elination of ADEM can also cause focal slowing or epileptiform
discharges.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for ADEM is broad but can be narrowed
by careful history, appropriate laboratory evaluations, and MRI
(see Table 600-1). Empirical antibiotic and antiviral treatment should
be considered while infectious evaluations are pending. Follow-up
MRI examinations 3-12 mo after ADEM should show improvement;
new or enlarging T2 lesions should prompt reevaluation for other
etiologies such as MS, leukodystrophies, tumor, vasculitis, or mito-
chondrial, metabolic, or rheumatologic disorders (see Table 600-1 and
Table 600-5).
TREATMENT
Although there are no randomized controlled trials to compare acute
treatments for ADEM or other demyelinating disorders of childhood,
high-dose intravenous steroids are commonly employed (typically
methylprednisolone 20-30 mg/kg per day for 5 days with a maximum
dose of 1,000 mg per day). An oral prednisone taper over 1 mo may
prevent relapse. Other treatment options include intravenous immune
globulin (usually 2 g/kg administered over 2-5 days) or plasmapheresis
(typically 5-7 exchanges administered every other day). In severe cases
of suspected ADEM, rituximab or cyclophosphamide have been used.
There is no consensus about timing of these treatments for ADEM.
PROGNOSIS
Many children experience full recovery after ADEM but some are left
with residual motor and/or cognitive deficits. ADEM is usually a
monophasic illness but demyelinating symptoms can fluctuate for
several months. Repeated bouts of demyelination more than 3 mo after
ADEM later raise the question of MS vs repeated ADEM.

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2010.
Chapter 601 ◆ Pediatric Stroke 2925
Chapter 601
Pediatric Stroke
Adam Kirton and Gabrielle A. deVeber
Stroke is an important cause of acquired brain injury in newborns and

children. The ischemic varieties of arterial ischemic stroke (AIS) and
cerebral sinovenous thrombosis (CSVT) are more common than brain
malignancy (incidence approximately 5 in 100,000 children per year).
Perinatal stroke is even more common and is the leading cause of
hemiparetic cerebral palsy. A similar number of children suffer from
hemorrhagic stroke (HS) and other forms of cerebrovascular disease.
Acute stroke is a neurologic emergency; however, delays in recognition
are common and delayed treatment worsens outcomes. In contrast to
stroke in adults, there are a diverse group of disorders producing stroke
in neonates and children.
601.1 Arterial Ischemic Stroke

Adam Kirton and Gabrielle A. deVeber
Arterial blood reaches the brain via the anterior (internal carotid) and
posterior (vertebrobasilar) circulations, converging at the circle of
Willis. Strokes most often involve the middle cerebral artery territory
but can occur in any cerebral artery of any size. AIS is the focal brain
infarction that results from occlusion of these arteries and is a leading
cause of acquired brain injury in children with the perinatal period
carrying the highest risk.
The diagnosis of stroke in children is frequently delayed. This is a
consequence of subtle and nonspecific clinical presentations, poor
awareness by primary care pediatric physicians, a complicated differ-
ential diagnosis (see Chapter 601.4), and a high frequency (>50%) of
negative initial CT scan. The acute onset of a focal neurologic deficit
in a child is stroke until proven otherwise. The most common focal
presentation is hemiparesis, but acute visual, speech, sensory, or
balance deficits also occur. Children with these presentations require
urgent neuroimaging and consultation with a child neurologist, as
emergency interventions may be indicated. AIS is a clinical and radio-
graphic diagnosis. Although CT imaging can demonstrate mature AIS
and exclude hemorrhage, MRI is required to identify early and small
infarcts. Diffusion-weighted MRI demonstrates AIS within minutes
of onset and up to 7 days postonset; MR angiography can confirm
vascular occlusion and suggest possible arteriopathy (Fig. 601-1).
Diffusion-weighted MRI can also demonstrate wallerian degeneration
A B C
D E F
Figure 601-1 Arterial ischemic stroke. A healthy 3 yr old boy had sudden onset of left-sided weakness. Examination also demonstrated left-sided
hemisensory loss and neglect. A to C, Diffusion-weighted MRI shows focal increased signal in the right temporal–parietal region in the territory of the
middle cerebral artery (MCA). D, Apparent diffusion coefficient map confirms restricted diffusion consistent with infarction (ischemic stroke). E, MR
angiogram shows decreased flow in the corresponding branch of the MCA. F, Follow-up MRI at 3 mo shows atrophy and gliosis in the same region.
in the descending corticospinal tract, which correlates with chronic of surface vessels. Arterial dissection can be spontaneous or post-
hemiparesis. traumatic and can affect extra- or intracranial arteries. Moyamoya
Many possible risk factors for AIS are recognized (Table 601-1), syndrome may be idiopathic or associated with other conditions
although the specific pathophysiologic mechanisms are often poorly (neurofibromatosis type 1, trisomy 21, Alagille syndrome, sickle cell
understood. Three main categories of etiology should be considered: anemia, chromosomal microdeletions/microduplications, postirradia-
arteriopathy, cardiac, and hematologic; full investigation, however, tion) and demonstrates progressive occlusion of the distal internal
often reveals multiple risk factors per individual. carotid arteries. Congenital malformations of the craniocervical arteries,
Arteriopathy refers to disorders of the cerebral arteries and is a including PHACES (posterior fossa abnormalities, hemangioma, and
leading cause of childhood AIS, present in more than 50% of children. arterial, cardiac, eye, and sternal abnormalities) syndrome, or fibromus-
A common syndrome affecting healthy school-age children features cular dysplasia may predispose to AIS. Vasospasm as occurs in migraine,
unilateral irregular stenosis of the proximal middle cerebral artery and subarachnoid hemorrhage or reversible cerebral vasoconstriction syn-
neighboring arteries presenting with basal ganglia infarction. The drome (sometimes called Call-Fleming syndrome) can cause AIS.
description of this entity has been published under multiple names— Cardioembolic stroke makes up approximately 25% of childhood
transient cerebral arteriopathy, postvaricella angiopathy, nonpro- AIS with maximal embolic risk concurrent with catheterization,
gressive childhood primary angiitis of the central nervous system, surgical repair, or ventricular assistive device use. AIS complicates
and focal cerebral arteriopathy—reflecting uncertainty regarding the approximately 0.5% of pediatric cardiac surgeries and reoperation
pathogenesis. increases the risk. Although complex congenital heart diseases
This entity may represent focal inflammation or intracranial dissec- are most frequently associated with AIS, acquired conditions, includ-
tion or early moyamoya disease, although it is nearly always self-limited. ing arrhythmia, cardiomyopathy, and infective endocarditis, also
Diffuse, bilateral, progressive vasculitis is rare and can represent pro- should be considered. A patent foramen ovale provides the possibility
gressive childhood primary angiitis of the central nervous system or be of paradoxical venous thromboembolism but is not likely an indepen-
associated with systemic vasculitides (Table 601-2). Cranial infections dent risk factor. All children with suspected AIS require thorough
(e.g., bacterial meningitis) also produce arteritis and thrombophlebitis cardiovascular examination, electrocardiogram, and echocardiogram.
Table 601-1 Risk Factors for Arterial Ischemic Stroke in Children

MAJOR CATEGORY EXAMPLES
Arteriopathy Transient cerebral arteriopathy (TCA) (synonyms: childhood primary angiitis of the central nervous system
[cPACNS]; focal cerebral arteriopathy [FCA])
Postvaricella and other viruses angiopathy (PVA)
Systemic/secondary vasculitis (e.g., Takayasu arteritis)
Moyamoya disease/syndrome
Arterial infection (e.g., bacterial meningitis, tuberculosis)
Fibromuscular dysplasia
Traumatic or spontaneous carotid or vertebral artery dissection
Vasospasm (e.g., Call-Fleming syndrome)
Migraine (migrainous infarction?)
Congenital arterial hypoplasia (e.g., PHACES syndrome)
Cardiac Complex congenital heart diseases (cyanotic ≫ acyanotic)
Cardiac catheterization/procedure (e.g., balloon atrial septostomy)
Ventricular assistive device use
Cardiac surgery
Arrhythmia
Valvular heart disease
Endocarditis
Cardiomyopathy, severe ventricular dysfunction
Intracardiac lesions (e.g., atrial myxoma)
Septal defects (atrial septal defect, ventricular septal defect, patent foramen ovale [possible paradoxical emboli])
Hematologic Sickle cell anemia
Iron-deficiency anemia
Inherited prothrombotic (e.g., factor V Leiden, prothrombin gene mutation 20210A)
Acquired prothrombotic (e.g., protein C/S deficiency, antithrombin III deficiency, lipoprotein a, antiphospholipid
antibodies, oral contraceptives, pregnancy)
Other including Acute systemic illness (e.g., dehydration, sepsis, diabetic ketoacidosis)
metabolic/genetic Chronic systemic illness (e.g., systemic lupus erythematosus, leukemia)
etiologies Illicit drugs and toxins (e.g., cocaine)
Extracorporeal membrane oxygenation (ECMO)
Hereditary dyslipoproteinemia
Familial hypoalphalipoproteinemia
Familial hypercholesterolemia
Type IV, type III hyperlipoproteinemia
Tangier disease
Progeria
Fabry disease (α-galactosidase A deficiency)
Subacute necrotizing encephalomyelopathy (Leigh disease)
Sulfite oxidase deficiency
11β-Ketoreductase deficiency
17α-Hydroxylase deficiency
Purine nucleoside phosphorylase deficiency
Ornithine transcarbamylase deficiency
Neurofibromatosis type 1
HERNS
Heritable disorders of connective tissue
Ehlers-Danlos syndrome (type IV)
Marfan syndrome
Pseudoxanthoma elasticum
Homocystinuria (cystathionine β-synthase deficiency, or 5,20-methylenetetrahydrofolate reductase)
Menkes syndrome
Organic acidemias
Methylmalonic academia
Propionic academia
Isovaleric academia
Glutaric aciduria type II
Mitochondrial encephalomyopathies
MELAS
MERRF
MERRF/MELAS overlap syndrome
Kearns-Sayre syndrome
See also: stroke mimics (see Chapter 601.4)
HERNS, hereditary endotheliopathy with retinopathy, nephropathy, and stroke; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like
episodes; MERRF, myoclonic epilepsy with ragged red fibers; PHACES, posterior fossa abnormalities, hemangioma, and arterial, cardiac, eye, and sternal
abnormalities.
Modified from Roach ES, Golomb MR, Adams R, et al: Management of stroke in infants and children. Stroke 39:2644–2691, 2008, Table 2, p. 6.
Prothrombotic coagulation disorders and infection at index stroke

Table 601-2 Classification of Cerebral Vasculitis increase stroke recurrence risk.
Infectious vasculitis Hematologic disorders associated with AIS include sickle cell
Bacterial, fungal, parasitic anemia, in which stroke risk is increased 400-fold, although effective
Spirochetal (syphilis, Lyme disease, leptospirosis) screening (transcranial Doppler) and treatments (transfusions) have
Viral, rickettsial, mycobacterial, free-living amebae, cysticercosis, reduced the incidence. Iron-deficiency anemia also increases the risk
other helminths and is easily treatable. Coagulation disorders are associated with child-
Necrotizing vasculitides hood AIS. They include hereditary (e.g., factor V Leiden) and acquired
Classic polyarteritis nodosa (e.g., antiphospholipid antibodies, lipoprotein-a elevation) prothrom-
Wegener granulomatosis botic states and prothrombotic medications, including oral contra-
Allergic angiitis and granulomatosis (Churg-Strauss syndrome)
ceptives and asparaginase chemotherapy. Additional AIS risk factors
Necrotizing systemic vasculitis overlap syndrome
Lymphomatoid granulomatosis include migraine, acute childhood illnesses, chronic systemic illnesses,
Vasculitis associated with collagen vascular disease illicit drugs and toxins, and rare inborn errors of metabolism.
Systemic lupus erythematosus Treatment of childhood AIS is multifaceted and multiple consensus-
Rheumatoid arthritis based guidelines are available. Given the inadequate safety data, emer-
Scleroderma gency thrombolysis is not recommended for children, but safety studies
Sjögren syndrome are underway. Early initiation of antithrombotic strategies is para-
Vasculitis associated with other systemic diseases mount to prevent early reinfarction. Depending on the suspected
Behçet disease cause, this includes anticoagulation with heparins or antiplatelet strate-
Ulcerative colitis
gies, usually aspirin. Hyperacute neuroprotective strategies are essen-
Sarcoidosis
Relapsing polychondritis tial to initiate with suspected stroke as they prevent progressive
Kohlmeier-Degos disease ischemic brain injury. These include control of blood glucose, tempera-
Takayasu arteritis ture and seizures and maintenance of cerebral perfusion pressure.
Hypersensitivity vasculitides Early malignant cerebral edema is life-threatening, more common
Henoch-Schönlein purpura in children and predictable, and emergency surgical decompression
Drug-induced vasculitides can be life-saving. Disease-specific treatments include transfusion
Chemical vasculitides therapy in sickle cell disease, immunosuppression in vasculitis, and
Essential mixed cryoglobulinemia revascularization surgery in moyamoya. Long-term treatment goals
Miscellaneous
include secondary stroke prevention, including antiplatelet therapy in
Vasculitis associated with neoplasia
Vasculitis associated with radiation arteriopathy and anticoagulation in cardiogenic causes. Multimodal,
Cogan syndrome family-centered rehabilitation programs are required for most survi-
Dermatomyositis-polymyositis vors, targeting motor deficits, language and intellectual impairments,
X-linked lymphoproliferative syndrome behavioral and social disabilities, and epilepsy. Long-term attention to
Kawasaki disease arterial health lifestyle factors may also be important. Outcomes after
Primary central nervous system vasculitis
childhood stroke include recurrent stroke ranging from 10-50%
From Roach ES, Golomb MR, Adams R, et al: Management of stroke in depending on cause and preventative treatment, death in 6-10%, neu-
infants and children, Stroke 39:2644–2691, 2008, Table 5, p. 8. rologic deficits in 60-70%, and seizure disorders in up to 30%.
PERINATAL ARTERIAL ISCHEMIC STROKE

Perinatal stroke is very common, differs from childhood stroke, and has
2 distinct clinical presentations. Acute symptomatic neonatal AIS pres-
ents with focal seizures at 24-28 hr of life (Fig. 601-2). MRI diffusion
A B
Figure 601-2 Perinatal arterial ischemic stroke. A term newborn developed focal right-sided seizures at 16 hr of life. A, Diffusion-weighted MRI
on day 2 diagnoses neonatal arterial ischemic stroke by demonstrating restricted diffusion in the left middle cerebral artery territory. B, Repeat
MRI at 12 mo shows cystic encephalomalacia and scarring in the same territory, a similar appearance to children diagnosed with presumed perinatal
arterial ischemic stroke later in infancy.
abnormalities in an arterial territory confirm recent infarction. Alter- seizures. Children may present with symptoms mimicking idiopathic
natively, infants are asymptomatic at birth and present in later infancy intracranial hypertension, including progressive headache, papill-
with signs of early hand preference and congenital hemiparesis. Hand edema, diplopia secondary to 6th nerve palsy, or with acute focal defi-
dominance within the 1st yr of life is abnormal and may be the result of cits. Seizures, lethargy, and confusion are common. Diagnosis requires
perinatal stroke. Imaging reveals focal encephalomalacia in an arterial a high clinical suspicion and purposeful imaging of the cerebral venous
territory, typically large middle cerebral artery lesions. system. Nonenhanced CT is very insensitive for CSVT, and contrast
In acute neonatal AIS, seizure control is important, but antithrom- CT venography or MR venography is necessary to demonstrate filling
botic agents are rarely required (exception: cardiac embolism). Patho- defects in the cerebral venous system (Fig. 601-3). MRI offers superior
physiology is complex and poorly understood. Most are idiopathic, parenchymal imaging compared to CT.
although established causes include congenital heart disease, throm- Table 601-3 lists the risk factors for CSVT. Prothrombotic states
botic placentopathy, and other prothrombotic disorders and meningi- associated with childhood CSVT include inherited (e.g., prothrombin
tis. Many other maternal, prenatal, perinatal, obstetrical, and neonatal gene 20210A mutation) and acquired (e.g., antiphospholipid antibod-
factors have been investigated with several strong associations found ies) conditions, prothrombotic medications (asparaginase, oral contra-
(e.g., infertility, primiparity, multiple gestation). Outcomes are poor, ceptives) and common childhood illnesses including otitis media,
with most children having lifelong disability. Perinatal stroke accounts iron-deficiency anemia, and dehydration. Systemic diseases associ-
for most cases of hemiparetic cerebral palsy (congenital hemiplegia, ated with increased CSVT risk include leukemia, inflammatory bowel
see Chapter 598.1). Additional morbidity, seen in approximately 25%, disease, and nephrotic syndrome.
includes disorders of language, learning, cognition, and behavior and Head and neck disorders can directly involve cerebral veins and
longer-term epilepsy. Stroke recurrence rates for both the child and sinuses causing CSVT. Common infections, including meningitis,
subsequent pregnancies are extremely low. otitis media, and mastoiditis, can cause septic thrombophlebitis of
venous channels. CSVT can complicate head trauma especially adja-
Bibliography is available at Expert Consult. cent to skull fractures. Neurosurgical procedures in proximity to cere-
bral venous structures may lead to injury and CSVT. Finally, obstruction
of the jugular veins and proximal stasis may result in CSVT. In neo-
nates, the unfused status of cranial sutures enables mechanical distor-
601.2 Cerebral Sinovenous Thrombosis tion of underlying venous sinuses during delivery, or postnatally
Adam Kirton and Gabrielle A. deVeber occipital bone compression of the posterior sagittal sinus during supine
lying predisposing to CSVT.
Cerebral venous drainage occurs via the cerebral sinovenous system. Anticoagulation therapy plays an important role in childhood
This includes superficial (cortical veins, superior sagittal sinus) and CSVT treatment. Substantial indirect evidence has led to consensus to
deep (internal cerebral veins, straight sinus) systems that converge at recommend anticoagulation with unfractionated or low-molecular-
the torcula to exit via the paired transverse and sigmoid sinuses and weight heparins in most children. Hemorrhagic transformation of
jugular veins. In CSVT, thrombotic occlusion of these venous struc- venous infarcts is not an absolute contraindication. Treatment is
tures can create increased intracranial pressure, cerebral edema, and, usually planned for 6 mo, although if reimaging at 3 mo confirms
in 50% of cases, venous infarction or hemorrhage (stroke). CSVT may recanalization, treatment is usually discontinued. However anticoagu-
be more common in children than in adults, and risk is greatest risk lation of neonates is more controversial and guidelines differ. Evidence
in the neonatal period. suggests that 30% of untreated neonates and children will extend their
Clinical presentations are typically gradual, variable, and nonspecific thrombosis in the 1st wk postdiagnosis and additional venous infarc-
compared to AIS. Neonates often present with encephalopathy and tion can result. Therefore, if anticoagulation is withheld, early (e.g., 5-7
A B
Figure 601-3 Cerebral sinovenous thrombosis. A 9 yr old girl presented with fever and progressive right-sided headache. She complained of
double vision and had papilledema on examination. Axial (A) and coronal (B) CT venography demonstrates a large thrombus in the right transverse
sinus that fails to opacify with contrast (full arrows). Note normal filling in superior sagittal and in smaller left transverse sinuses (empty arrows,
right) and opacification of the mastoid air cells (hatched arrow, left). Cause was otitis media/mastoiditis with septic thrombophlebitis of transverse
sinus.
Chapter 601 ◆ Pediatric Stroke 2929.e1
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medical treatment for secondary stroke prevention, Stroke 43:422–431, 2012. and areas of research, J Pediatr 162:227–235, 2013.
Mackay MT, Wiznitzer M, Benedict SL, et al: Arterial ischemic stroke risk factors: Zhou Q, Yang D, Ombrello AK, et al: Early-onset stroke and vasculopathy
the international pediatric stroke study, Ann Neurol 69:130–140, 2011. associated with mutations in ADA2, N Engl J Med 370:911–920, 2014.
Marshman LAG, Ball L, Jadun CK: Spontaneous bilateral carotid and vertebral
artery dissections associated with multiple disparate intracranial aneurysms,
Table 601-3 Common Risk Factors for Cerebral Sinovenous Thrombosis in Children
MAJOR CATEGORIES EXAMPLES
Blood coagulation Prothrombotic conditions
Factor V Leiden, prothrombin gene mutation 20210A, protein C deficiency, protein S deficiency, antithrombin
III deficiency, lipoprotein a, antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies),
pregnancy/puerperium
Dehydration (e.g., gastroenteritis, neonatal failure to thrive)
Iron-deficiency anemia
Drugs and toxins (e.g., L-asparaginase, oral contraceptives)
Acute systemic illness (e.g., sepsis, disseminated intravascular coagulation)
Chronic systemic illness (e.g., inflammatory bowel disease, systemic lupus erythematosus, leukemia)
Nephrotic syndrome
Inborn errors of metabolism (e.g., homocystinuria)
Blood vessel Infection/thrombophlebitis
Otitis media, mastoiditis, bacterial meningitis, sinusitis, dental abscess, pharyngitis
Lemierre syndrome
Sepsis
Trauma: skull fractures, closed hear trauma
Compression: birth, occipital bone compression in neonates in supine lying
Iatrogenic: neurosurgery, jugular lines, extracorporeal membrane oxygenation
Venous malformations (e.g., dural arteriovenous fistulas)
days) repeat venous imaging is paramount. Protocols supporting initial apparent history of trauma. Subtle scalp, suborbital, or ear bruising;
anticoagulation recommend shorter treatment durations (i.e., 6 wk to retinal hemorrhages in multiple layers; and chronic failure to thrive
3 mo) in neonates. Children with persistent risk factors may require should always be sought, and in infants with subdural bleeds, x-rays
prophylactic long-term anticoagulation. At initial diagnosis, support- performed to rule out fractures. Epidural hematoma is nearly always
ive interventions include management of infection, detection and caused by trauma, including middle meningeal artery injury typically
treatment of seizures, and neuroprotective measures (normothermia, associated with skull fracture. Subdural hematoma can occur sponta-
normotension, normovolemia, normoglycemia). Optic neuropathy neously in children with brain atrophy because of stretching of bridg-
secondary to increased intracranial pressure is an important and easily ing veins.
missed complication of CSVT. Regular funduscopic examination by an Causes of and risk factors for HS (Table 601-4) include vascular
ophthalmologist and measures to reduce intracranial pressure (e.g., malformations and systemic disorders. Arteriovenous malformations
acetazolamide, serial lumbar puncture) may be required to avoid visual
loss. Most neurologic morbidity is suffered by those incurring venous
infarction and children with bilateral venous infarction can be devas- Table 601-4 Potential Risk Factors for Hemorrhagic
tated. Consistent with other forms of childhood stroke, a comprehen- Stroke in Children
sive neurorehabilitation program is required.
MAJOR
Bibliography is available at Expert Consult. CATEGORIES EXAMPLES
Vascular Arteriovenous malformations
disorder Cavernous malformations (“cavernomas”)
Venous angiomas and other venous anomalies
601.3 Hemorrhagic Stroke Hereditary hemorrhagic telangiectasia
Adam Kirton and Gabrielle A. deVeber Intracranial aneurysm
Choroid plexus angiomas (pure intraventricular
HS includes nontraumatic intracranial hemorrhage and is classified by hemorrhage)
Moyamoya disease/syndrome
the intracranial compartment containing the hemorrhage. Intraparen- Inflammatory vasculitis (see Chapter 601.1)
chymal bleeds may occur in any location, whereas intraventricular Neoplastic lesions with unstable vasculature
hemorrhage may be isolated or an extension of intraparenchymal hem- Drugs/toxins (cocaine, amphetamine)
orrhage. Bleeding outside the brain may occur in the subarachnoid, Cerebral sinovenous thrombosis
subdural, or epidural spaces.
Blood disorder Idiopathic thrombocytopenic purpura
Clinical presentations vary according to location, cause, and rate of Hemolytic uremic syndrome
bleeding. Acute hemorrhages may feature instantaneous or thunder- Hepatic disease/failure coagulopathy
clap headache, loss of consciousness, and nuchal rigidity in addition Vitamin K deficiency (hemorrhagic disease of
to focal neurologic deficits and seizures. HS can be rapidly fatal. In the newborn)
bleeds associated with vascular malformations, pulsatile tinnitus, Disseminated intravascular coagulopathy
cranial bruit, macrocephaly, and high-output heart failure may be
Trauma Middle meningeal artery injury (epidural
present. Diagnosis relies on imaging and CT is highly sensitive to acute hematoma)
HS. However, lumbar puncture may be required to exclude subarach- Bridging vein injury (subdural hematoma)
noid hemorrhage. MRI is highly sensitive to even small amounts of Subarachnoid hemorrhage
both acute and chronic hemorrhage and offers improved diagnostic Hemorrhagic contusions (coup and contrecoup)
accuracy (Fig. 601-4). Angiography by CT, MR, or conventional cath- Nonaccidental trauma (subdural hematomas of
eter means is often required to exclude underlying vascular abnormali- different ages)
ties (e.g., vascular malformations, aneurysms). Iatrogenic (neurosurgical procedures,
Abusive head trauma with intracranial bleeding in children may angiography)
Rupture of arachnoid cyst
present as primary subdural or parenchymal hemorrhage with no
Bibliography Monagle P, Chan AK, Goldenberg NA, et al: Antithrombotic therapy in neonates
Berfelo FJ, Kersbergen KJ, van Ommen CH, et al: Neonatal cerebral sinovenous and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
thrombosis from symptom to outcome, Stroke 41:1382–1388, 2010. American College of Chest Physicians Evidence-Based Clinical Practice
deVeber G, Andrew M: Canadian Pediatric Ischemic Stroke Study Group. Cerebral Guidelines, Chest 141:e737S–e801S, 2012.
sinovenous thrombosis in children, N Engl J Med 345:417–423, 2001. Sebire G, Tabarki B, Saunders DE, et al: Cerebral venous sinus thrombosis in
Jackson BF, Porcher FK, Zapton DT, et al: Cerebral sinovenous thrombosis in children: risk factors, presentation, diagnosis and outcome, Brain 128:477–489,
children, Pediatr Emerg Care 27:874–882, 2011. 2005.
Moharir MD, Shroff M, Stephens D, et al: Anticoagulants in pediatric cerebral
sinovenous thrombosis: a safety and outcome study, Ann Neurol 67:590–599,
2010.
A B C
D E F
Figure 601-4 Hemorrhagic stroke. A healthy 1 mo old presented with sudden-onset irritability followed by focal left body seizures. Plain
CT head demonstrates a large hyperdense lesion in the right parietal region with surrounding edema consistent with acute hemorrhage (A). Axial
(B) and sagittal (C) contrast CT scans suggest an abnormal cluster of vessels in the center of the hemorrhage consistent with an AVM. T2-weighted
MRI differentiates the acute hemorrhage from surrounding edema (D). Gradient echo MRI, both acutely (E) and at 3 mo (F), demonstrates the
presence of blood product.
are the most common cause of childhood subarachnoid and intrapa- lant therapy (with, for example, vitamin K, fresh-frozen plasma) may
renchymal HS and may occur anywhere. Neonates with vein of Galen be required, but the role of other medical interventions, such as factor
malformations may present with heart failure, progressive macroceph- VII, are unstudied in children. Recurrence risk for those with struc-
aly, or, rarely, hemorrhage. In older children with arteriovenous mal- tural lesions is significant and serial imaging may be required. Defini-
formations, the risk of bleeding is approximately 2-4% per year tive repair or removal of the vascular malformation may require a
throughout life. Other vascular malformations leading to HS include combined approach with interventional endovascular methods or
cavernous angiomas (“cavernomas”), dural arteriovenous fistulas, and neurosurgery. Outcomes from childhood HS are not well studied but
vein of Galen malformations. Cerebral aneurysms are an uncommon likely depend on lesion size, location, and etiology. Compared with
cause of subarachnoid hemorrhage in children and may suggest an ischemic stroke, HS mortality is higher while long-term deficits are
underlying disorder (e.g., polycystic kidney disease, infective endocar- less common.
ditis). A common cause for HS is bleeding from a preexisting brain Neonatal HSs have unique features. Cranial ultrasound can detect
tumor. Arterial diseases that usually cause ischemic stroke, including many neonatal parenchymal bleeds, especially In the preterm infant
fibromuscular dysplasia, vasculitis, and moyamoya, can also predis- where bleeds are located centrally within the cranium and include
pose to HS. Additional causes of parenchymal HS include hypertensive germinal matrix bleeding and intraventricular hemorrhage (see
hemorrhage and hematologic disorders such as thrombocytopenic Chapter 99.3). Germinal matrix injury or bleeding may also occur in
purpura, hemophilia, acquired coagulopathies (e.g., disseminated utero, resulting in periventricular venous infarction that becomes
intravascular coagulopathy, liver failure), anticoagulant therapy (e.g., symptomatic in later infancy as congenital hemiparesis. Subarachnoid
warfarin), or illicit drug use. Ischemic infarcts may undergo hemor- and subdural blood may be imaged in up to 25% of normal term new-
rhagic transformation, particularly in CSVT, and may be difficult to borns. Term HS is poorly studied and includes the etiologies listed
differentiate from primary HS. above, although HS may be idiopathic in more than 50% of cases. Term
Management of acute childhood HS may require emergent neuro- intraventricular bleeding is often secondary to deep CSVT with spe-
surgical intervention for large or rapidly expanding hemorrhage. The cific management implications.
same principles of neuroprotection for vulnerable brain suggested in
the ischemic stroke sections also apply to HS. Reversal of anticoagu- Bibliography is available at Expert Consult.
Bibliography Mark DG, Hung YY, Offerman SR, et al: Nontraumatic subarachnoid hemorrhage
Beslow LA, Abend NS, Gindville MC, et al: Pediatric intracerebral hemorrhage: in the setting of negative cranial computed tomography results: external
acute symptomatic seizures and epilepsy, JAMA Neurol 70:448–454, 2013. validation of a clinical and imaging prediction rule, Ann Emerg Med 62:1–10.e1,
Cress M, Kestle JRW, Holubkov R, et al: Risk factors for pediatric arachnoid cyst 2013.
ruprute/hemorrhage: a case-control study, Neurosurgery 72:716–722, 2013. Meyer-Heim AD, Boltshauser E: Spontaneous intracranial haemorrhage in
Gaberel T, Magheru C, Parienti JJ, et al: Intraventricular fibrinolysis versus external children: aetiology, presentation and outcome, Brain Dev 25:416–421, 2003.
ventricular drainage alone in intraventricular hemorrhage—a meta analysis, Morita A, Kirino T, Hashi K, et al: The natural course of unruptured cerebral
Stroke 42:2776–2781, 2011. aneurysms in a Japanese cohort, N Engl J Med 366:2474–2482, 2012.
Gregson BA, Broderick JP, Auer LM, et al: Individual patient data subgroup Perry JJ, Stiell IG, Sivilotti MLA, et al: Clinical decision rules to rule out
meta-analysis of surgery for spontaneous supratentorial intracerebral subarachnoid hemorrhages for acute headache, JAMA 310:1248–1254, 2013.
hemorrhage, Stroke 43:1496–1504, 2012. Salman RA, White PM, Counsell CE, et al: Outcome after conservative
Gupta SN, Kechli AM, Kanamalla US: Intracranial hemorrhage in term newborns: management or intervention for unruptured brain arteriovenous malformations,
management and outcomes, Pediatr Neurol 40:1–12, 2009. JAMA 311:1661–1668, 2014.
Hoang S, Choudhri O, Edwards M, et al: Vein of Galen malformation, Neurosurg Smith ER, Scott M: Cavernous malformations, Neurosurg Clin N Am 21:483–490,
Focus 27:1–7, 2009. 2010.
Khan NR, Tsivgoulis G, Lee SL, et al: Fibrinolysis for intraventricular Tsutsumi Y, Kosaki R, Itoh Y, et al: Vein of Galen aneurysmal malformation
hemorrhage-an updated meta-analysis and systematic review of the literature, associated with an endoglin gene mutation, Pediatrics 128:e1307–e1310, 2011.
Stroke 45:2662–2669, 2014. van Beijnum J, van der Worp HB, Buis DR, et al: Treatment of brain arteriovenous
Knopman J, Stieg PE: Management of unruptured brain arteriovenous malformations, JAMA 306:2011–2019, 2011.
malformations, Lancet 383:581–583, 2014. White PM, Lewis SC, Gholkar A, et al: Hydrogel-coated coils versus bare platinum
Liang JT, Huo LR, Bao YH, et al: Intracranial aneurysms in adolescents, Childs coils for the endovascular treatment of intracranial aneurysms (HELPS): a
Nerv Syst 27:1101–1107, 2011. randomised controlled trial, Lancet 377:1655–1662, 2011.
Lo WD: Childhood hemorrhagic stroke: an important but understudied problem, Zhou X, Chen J, Li Q, et al: Minimally invasive surgery for spontaneous
J Child Neurol 26:1174–1185, 2011. supratentorial intracerebral hemorrhage, Stroke 43:2923–2930, 2012.
Lo WD, Hajek C, Pappa C, et al: Outcomes in children with hemorrhagic stroke,
JAMA Neurol 70:66–71, 2013.
601.4 Differential Diagnosis Migraine can also (rarely) cause a stroke, referred to as migrainous
infarction.
of Stroke-Like Events
Adam Kirton and Gabrielle A. deVeber SEIZURE
Prolonged focal seizure activity is frequently followed by a period of
The diagnosis of stroke in childhood requires a high index of suspicion focal neurologic deficit (“Todd’s paresis”) which typically resolves
balanced with awareness of the differential diagnosis for stroke-like within an hour. Very rarely, focal seizures can manifest with only “nega-
events (Table 601-5). Acute onset of a focal neurologic deficit should tive” symptoms producing acute onset, focal neurologic deficits. A
be considered stroke until proven otherwise and assessed with neuro- history of clonic jerks or tonic posturing at onset, a known past history
imaging. However, pediatric stroke must be differentiated from other of seizures, and electroencephalogram findings may be helpful. Imaging
stroke-like disorders that may require their own urgent specific is required in all new cases of seizure with persisting Todd’s paresis
treatment. because stroke in children is often associated with seizures at onset.
MIGRAINE INFECTION
Careful history and examination can often suggest migraine as the Life-threatening and treatable brain infections, including bacterial
cause of acute focal deficits. Migraine auras should last between 5 and meningitis and herpes encephalitis, can be mistaken for stroke.
60 min and resolve completely. Neurologic deficits associated with However, symptom onset in primary central nervous system infection
migraine typically evolve slowly compared with stroke, with sensory is typically more gradual and less focal with fever as a consistent
disturbance or weakness “marching” across body areas over minutes. feature. Children with bacterial meningitis are at risk for both venous
Although evolution into a migrainous headache is expected, headache and arterial stroke.
may also accompany acute infarction. Furthermore, a group of uncom-
mon migraine subtypes can occur without headache and can more DEMYELINATION
closely mimic stroke in children. These include familial hemiplegic Acute disseminated encephalomyelitis, clinically isolated syndrome,
migraine, basilar migraine, and migraine aura without headache. multiple sclerosis, and other demyelinating conditions can present
Table 601-5 Differential Diagnosis of Stroke-Like Episodes in Children

DISORDER CLINICAL DISTINCTION FROM STROKE IMAGING DISTINCTION FROM STROKE
Migraine Evolving or “marching” symptoms, short duration, Typically normal
complete resolution, headache, personal or family Migrainous infarction is rare
history of migraine
Seizure Positive symptoms, Todd paralysis is postseizure Normal or may identify source of seizures (e.g.,
and limited malformation, old injury, etc.)
Infection Fever, encephalopathy, gradual onset, meningismus Normal or signs of encephalitis/cerebritis, which
are typically diffuse and bilateral. Arterial
ischemic stroke and cerebral sinovenous
thrombosis can occur in bacterial meningitis
Demyelination Gradual onset, multifocal symptoms, Multifocal lesions, characteristic appearance (e.g.,
encephalopathy patchy in acute disseminated encephalomyelitis,
Accompanying optic neuritis or transverse myelitis ovoid in multiple sclerosis), typical locations
(e.g., pericallosal in multiple sclerosis), less likely
to show restricted diffusion
Hypoglycemia Risk factor (e.g., insulin therapy), related to meals, Bilateral, symmetrical
additional systemic symptoms May see restricted diffusion
Posterior dominant pattern
Watershed infarction caused Risk factor (e.g., hypotension, sepsis, heart disease), Bilateral, symmetric restricted diffusion in border
by global hypoxic–ischemic bilateral deficits zones between major arteries (watershed zones)
encephalopathy
Hypertensive encephalopathy Documented hypertension, bilateral visual Posterior dominant, bilateral, patchy lesions
(posterior reversible symptoms, encephalopathy involving gray and white matter, usually no
leukoencephalopathy) restricted diffusion
Inborn errors of metabolism Preexisting delays/regression, multisystem disease, May have restricted diffusion lesions but bilateral,
abnormal biochemical profiles symmetrical, not within vascular territories. MR
spectroscopy changes (e.g., high lactate in
mitochondrial myopathy, encephalopathy, lactic
acidosis, and stroke-like episodes)
Vestibulopathy Symptoms limited to vertigo, imbalance (i.e., no Normal
weakness). Gradual onset
Acute cerebellar ataxia Sudden-onset bilaterally symmetric ataxia; postviral Normal
Channelopathy Syndromic cluster of symptoms not localizing to Normal
single lesion. Gradual onset, progressive evolution
Alternating hemiplegia History contralateral events Normal
Choreoathetosis/dystonia
with acute focal neurologic deficits. Symptom onset and initial progres-
sion is more gradual (typically hours or days) compared with stroke
onset (minutes). Multifocal deficits, or concurrent encephalopathy in
the case of acute disseminated encephalomyelitis, would decrease the
probability of stroke.
HYPOGLYCEMIA
Acute lowering of blood glucose levels can produce focal deficits
mimicking stroke. New-onset hypoglycemia in otherwise healthy
children is rare, but predisposing conditions include insulin-
dependent diabetes, adrenal insufficiency, steroid withdrawal, and
ketogenic diet.
GLOBAL HYPOXIC–ISCHEMIC
ENCEPHALOPATHY
Generalized decreases in cerebral perfusion can produce focal areas of
watershed brain infarction which can be asymmetric and mimic
stroke. Watershed ischemic injury should be accompanied by recog-
nized hypotension or conditions predisposing to low cerebral perfu-
sion such as sepsis, dehydration, or cardiac dysfunction. Clinical
presentations would involve more generalized and bilateral cerebral
dysfunction compared to stroke and the anatomic location of the
infarct is in typical bilateral watershed zones rather than a single arte-
rial territory.
HYPERTENSIVE ENCEPHALOPATHY
The posterior reversible leukoencephalopathy syndrome is seen in chil-
dren with hypertension, often in the context of an acute rise in blood
pressure. Posterior regions are selectively involved, possibly resulting
in symptoms of bilateral cortical visual dysfunction in addition to
encephalopathy and seizures.
INBORN ERRORS OF METABOLISM

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-
like episodes (MELAS; see Chapter 598.2) are the classic examples,
though other mitochondrial disease can mimic stroke. Features favor-
ing MELAS would include a history of developmental regression, pos-
terior (and often bilateral) lesions not respecting vascular territories on
MRI, and elevated serum or cerebrospinal fluid lactate (MR spectros-
copy). In contrast to these types of “metabolic infarction,” children
with Fabry disease (see Chapter 613.6) and homocystinuria (see
Chapter 85.4) are at risk of true ischemic stroke.
VESTIBULOPATHY/ATAXIA
Acute onset vertigo and/or ataxia can be confused with brainstem or
cerebellar stroke. Simple bedside tests of vestibular function with oth-
erwise intact brainstem functions are reassuring. This differential diag-
nosis includes acute vestibular neuronopathy, viral labyrinthitis, and
the benign paroxysmal vertigos as well as acute cerebellar ataxia and
episodic ataxias.
CHANNELOPATHIES
An increasing number of nervous system ion channel mutations
are described that feature sudden focal neurological deficits thereby
mimicking stroke. These include the migraine syndromes men-
tioned above as well as a growing list of episodic ataxias. A strong
family history raises suspicion but most require additional
investigation.
ALTERNATING HEMIPLEGIA OF CHILDHOOD

Alternating hemiplegia of childhood typically presents in infancy with
acute intermittent episodes of hemiplegia that alternate from 1 side of
the body to the other. The hemiplegia persists for minutes to weeks and
then resolves spontaneously. Choreoathetosis and dystonic movements
are commonly observed in the hemiparetic extremity. Signs spontane-
ously regress with sleep but recur with awakening. Neuroimaging
including MRA should be completed to exclude moyamoya disease.
Alternating hemiplegia of childhood is linked to mutations in the
ATP1A3 gene.
Chapter 602 ◆ Central Nervous System Vasculitis 2933
Chapter 602
Central Nervous System
Vasculitis
Heather A. Van Mater, William B. Gallentine,
and Susanne M. Benseler
Autoimmune-mediated inflammatory brain diseases are recognized as

an etiology for neurologic and neuropsychiatric symptoms in children
and adults and include primary central nervous system (CNS) vascu-
litis, secondary CNS vasculitis, and autoimmune encephalitis (Fig.
602-1; see Chapter 598.4).
Primary angiitis of the CNS (PACNS) is recognized as the underly-
ing etiology of a broad spectrum of neurologic and psychiatric symp-
toms in children. Criteria characteristic of childhood CNS vasculitis
(cPACNS) include (1) newly acquired focal and/or diffuse neurologic
deficits and/or psychiatric symptoms in a child 18 yr of age or younger,
plus (2) angiographic and/or histologic evidence of vasculitis in the
absence of (3) a systemic underlying condition known to cause or
mimic the findings. Two broad categories of cPACNS are recognized
based on the predominant vessel size affected: large/medium-vessel
cPACNS and small-vessel cPACNS. Large/medium-vessel cPACNS is
diagnosed on angiography demonstrating features of vessel wall
inflammation, wall swelling and edema, and resulting luminal stenosis.
Based on the clinical course and the corresponding distribution of
vessel stenosis within the vascular tree of the CNS, children with large/
medium-vessel cPACNS are classified as a monophasic, nonprogressive
(NPcPACNS) or a progressive subtype (PcPACNS). The latter is char-
acterized by chronic, progressive vessel wall inflammation affecting
both proximal and distal vessel segments in 1 or both hemispheres. In
contrast, NPcPACNS is a monophasic illness; vessel inflammation
occurs in a characteristic distribution and is limited to the proximal
vessel segments of the anterior and/or middle cerebral artery and/or
distal internal carotid artery of 1 hemisphere. Small vessel cPACNS
(SVcPACNS) is considered a progressive illness; the diagnosis is con-
firmed on brain biopsies because angiography is normal.
Secondary childhood CNS vasculitis can affect all cerebral vessel
segments and can occur in the context of infections, rheumatic or other
inflammatory conditions or as a result of systemic or local vascular
irritation (Table 602-1). The neuropsychiatric manifestations of sec-
ondary CNS vasculitis are the same as those of primary CNS vasculitis.
Secondary CNS vasculitis is distinguished from primary CNS vasculi-
tis largely by the non-CNS manifestations of the underlying systemic
vasculitic disease.
EPIDEMIOLOGY
The incidence and prevalence of primary CNS vasculitis is undeter-
mined. In the past, the majority of children have been diagnosed at
autopsy. Increased physician awareness, improved diagnostic markers,
sensitive neuroimaging techniques, and brain biopsies have led to dra-
matically increased recognition and decreased mortality. Exploring the
epidemiology of primary CNS vasculitis remains a challenge: the
disease has many names including isolated angiitis of the CNS, tran-
sient cerebral angiitis, postvaricella angiopathy, and focal cerebral arte-
riopathy. Furthermore, children are frequently diagnosed with their
presenting clinical phenotype, such as stroke, movement disorder, hal-
lucination, or cognitive decline. Within clinical phenotypes, such as
arterial ischemic stroke or status epilepticus in children without preex-
isting epilepsy, cPACNS should be considered an important etiology.
Recognition of childhood CNS vasculitis requires a very high level of
suspicion; any neurologic or psychiatric presentation can be the result
Inflammatory brain disease
Primary CNS Secondary CNS Antibody-mediated

Vasculitis Vasculitis encephalitis
Angiography Angiography See Table 602-1 Intracellular Receptor/Cell

positive negative antigen surface antigen
Brain biopsy
positive
Progressive Non-progressive
Figure 602-1 CNS vasculitis within the spectrum of immune-mediated inflammatory brain diseases.
is a disconnection between the clinical presentation and the child’s

Table 602-1 Causes of Secondary CNS Vasculitis electroencephalogram findings. In many centers, refractory status epi-
VIRAL INFECTIONS lepticus is increasingly recognized as the presenting phenotype of
Varicella zoster virus, HIV, hepatitis C virus, cytomegalovirus, SVcPACNS. Optic neuritis and spinal cord disease are also recognized
parvovirus B19 in SVcPACNS.
Constitutional features of fever or fatigue may point toward an
BACTERIAL INFECTIONS
underlying systemic illness causing a secondary CNS vasculitis. All
Treponema pallidum, Borrelia burgdorferi, Mycobacterium
tuberculosis, Mycoplasma pneumoniae, Bartonella henselae, children with suspected or confirmed CNS vasculitis require a careful
Rickettsia spp. assessment for a systemic illness.
FUNGAL INFECTIONS DIAGNOSIS
Aspergillosis, mucormycosis, coccidioidomycosis, candidosis
The first step is considering vasculitis as a possible underlying etiology
PARASITIC INFECTIONS of newly acquired neurologic deficits and/or psychiatric symptoms
Cysticercosis (Table 602-2). The likelihood of CNS vasculitis in general and a specific
SYSTEMIC VASCULITIDES subtype of CNS vasculitis in particular depends on the demographic
Wegener granulomatosis, Churg-Strauss syndrome, Behçet disease, characteristics of the patient, the CNS and non-CNS features of the
polyarteritis nodosa, Henoch-Schönlein purpura, Kawasaki clinical presentation, the preceding symptoms, and the mode of onset
disease, giant-cell arteritis, Takayasu arteritis of the disease. SVcPACNS is more commonly seen in girls of all ages,
CONNECTIVE TISSUE DISEASES
whereas large/medium cPACNS has a clear male preponderance. Sei-
Systemic lupus erythematosus, rheumatoid arthritis, Sjögren zures are a hallmark of SVcPACNS, whereas strokes often reflect large/
syndrome, dermatomyositis, mixed connective tissue disease medium-vessel inflammation. Laboratory markers of vasculitis typi-
cally include C-reactive protein, erythrocyte sedimentation rate, and
MISCELLANEOUS complete blood counts. But inflammatory markers lack sensitivity and
Antiphospholipid antibodies syndrome, Hodgkin and non-Hodgkin
specificity in cPACNS, particularly when the CNS is involved in isola-
lymphomas, neurosarcoidosis, inflammatory bowel disease,
graft-versus-host disease, bacterial endocarditis, acute bacterial tion. More than 50% of children with large/medium-vessel cPACNS
meningitis, drug-induced CNS vasculitis (cocaine, amphetamine, have normal inflammatory markers at diagnosis. In contrast, the
ephedrine, phenylpropanolamine) majority of children with SVcPACNS present with mild-moderately
raised markers. Von Willebrand factor antigen, an endothelial cell–
From Salvarani C, Brown Jr. RD, Hunder GG: Adult primary central nervous
system vasculitis. Lancet 380:767–776, 2012, Panel, p. 768.
derived protein, is a proposed biomarker of vasculitis correlating
closely with disease activity in cPACNS. It may be of particular impor-
tance for distinguishing SVcPACNS from demyelinating diseases.
of an underlying CNS vasculitis. The clinical phenotype may provide Cerebrospinal fluid (CSF) analysis is abnormal in up to 90% of
clues to the size of the primarily affected vessel segments and resulting SVcPACNS patients and less than half of large/medium-vessel cPACNS.
cPACNS subtype: the majority of children with large/medium cPACNS Within the latter group, children with the progressive subtype have a
present with arterial ischemic stroke features. Focal neurologic deficits, higher likelihood of presenting with abnormal CSF findings, including
such as hemiparesis, facial droop, aphasia or any other distinct gross high opening pressure, raised CSF cell count, typically with lympho-
or fine motor deficits, may be the result of large vessel inflammation cyte predominance, and raised CSF protein. Oligoclonal bands are seen
causing stenosis and decreased blood supply to the specific functional in 20% of children with SVcPACNS. They are rarely seen in other
areas of the brain. Initially, these focal deficits wax and wane; they may subtypes. Autoimmune encephalitis (see Chapter 598.4) is one of the
even briefly resolve without therapeutic intervention and can therefore key differential diagnoses of SVcPACNS.
be easily overlooked. Headaches are a symptom of vascular disease in Neuroimaging is a valuable diagnostic modality for cPACNS. Paren-
general and are commonly reported in cPACNS. New onset of vascular- chymal lesions may be inflammatory or ischemic in nature and are best
type (e.g., migraine) headaches in children without any family history viewed on MRI including T2/fluid attenuated inversion recovery
of migraine can serve as a diagnostic clue. Cognitive dysfunction in (FLAIR) sequences and diffusion-weighted images (DWI) (Fig. 602-2).
cPACNS often includes loss of higher executive function, concentra- CNS lesions in children with large/medium-vessel cPACNS are pre-
tion difficulties, learning and memory problems, atypical behavior or dominantly ischemic in nature and restricted to large vascular territo-
personality changes, and loss of social and emotional control. Seizures ries. In contrast, MRI lesions in children with SVcPACNS are not
are a hallmark of SVcPACNS, as more than 80% of children with restricted to major vascular territories; lesions are primarily inflam-
SVcPACNS present with seizures; all seizure types are seen. Often there matory and may enhance with contrast. In this subtype, focal or
Chapter 602 ◆ Central Nervous System Vasculitis 2935
Table 602-2 Proposed Diagnostic Evaluation of

Suspected Childhood Primary CNS
Vasculitis
1. Clinical evaluation: Newly acquired symptom or deficit in a
previously healthy child
• Focal neurologic deficit: hemiparesis, hemisensory loss,
aphasia, ataxia, movement abnormality, paresthesia, facial
droop, ataxia, vision loss, spinal cord symptoms, others
• Seizures or (refractory) seizure status
• Diffuse neurologic deficit including cognitive decline with loss
of higher executive function, concentration difficulties, learning
or memory problems, behavior or personality changes, loss of
social skills or emotional/impulse control, others
• Headaches
• Meningitis symptoms, abnormal level of consciousness
• Psychiatric symptoms including hallucinations, pseudoseizures
Differential diagnosis approach:
• Underlying illness known to cause, be associated or mimic
CNS vasculitis: check all potential clinical features
2. Laboratory tests A
• Blood inflammatory markers: C-reactive protein, erythrocyte
sedimentation rate and complete blood counts
• Endothelial markers: von Willebrand factor (vWF) antigen
• Cerebrospinal fluid (CSF) inflammatory markers: opening
pressure, cell count, protein, oligoclonal bands
Differential diagnosis approach:
• Infections/postinfectious inflammation: cultures, serologies,
Gram stains
• Autoimmune encephalitis: check neuronal antibodies in CSF
and blood
• Systemic inflammation/rheumatic disease: characteristic
laboratory markers such as complement, autoantibodies
• Thromboembolic conditions: procoagulatory profile
3. Neuroimaging
• Parenchymal imaging on MRI:
• Inflammatory lesions: T2/fluid attenuated inversion recovery
sequences plus gadolinium contrast (lesion enhancement)
• Ischemic lesions: diffusion-weighted images/apparent
diffusion coefficient mapping
• Vessel imaging
4. Brain biopsy B
generalized meningeal enhancement is commonly seen if children are

imaged prior to immunosuppressive therapy. Spinal cord parenchy-
mal imaging is challenging; defining the nature of lesions is often
difficult.
Evidence of vessel stenosis confirms the diagnosis in large/medium-
vessel cPACNS subtypes; brain biopsies are not required. Important
information about the disease activity can be obtained from post–
gadolinium contrast studies of the vascular wall. The vessel wall of an
inflamed cerebral vessel in active large/medium-vessel cPACNS sub-
types is thickened and enhances contrast. Conventional angiography
when compared to MR angiography has a higher sensitivity in detect-
ing vessel stenosis in the distal vessel segments, the posterior circula-
C D
tion, and in very young children. Vessel wall imaging is often normal Figure 602-2 Imaging of patients with primary CNS vasculitis.
in children with SVcPACNS, sometimes mandating an elective brain A, Cerebral angiogram shows alternating stenosis and dilation of the
biopsy to definitively make the diagnosis. Studies of regional blood distal middle cerebral artery (arrows) and the anterior cerebral artery
flow or therapeutic trials of antiinflammatory or immunosuppressive (arrowheads). B, Magnetic resonance angiography of the brain shows
agents are nonsurgical alternatives that do not afford specific diagnos- a short-segment stenosis of the anterior cerebral artery (green arrow)
tic information. Biopsies should target low-risk, nonfunctional areas and stenosis of the distal middle cerebral artery (white arrow). C, Fluid
identified on MRI. In the appropriate clinical context, nonlesional attenuation inversion recovery–weighted MRI shows a large abnormal-
biopsies have a high yield for confirming the diagnosis of SVcPACNS. ity within the right cerebral hemisphere consistent with ischemia
(arrowheads). D, MRI shows diffuse, asymmetric, nodular, and linear
Characteristic findings in SVcPACNS include an intramural and/or
leptomeningeal enhancement, with dura only slightly affected. (From
perivascular mononuclear infiltrate, evidence of endothelial activation, Salvarani C, Brown Jr. RD, Hunder GG: Adult primary central nervous
and reactive astrocyte activation. Gliosis and perivascular demyelin- system vasculitis. Lancet 380:767–776, 2012, Fig. 2.)
ation are hallmarks of long-standing disease. Findings typically seen
in adult PACNS, including granulomas or vessel wall necrosis, are
rarely seen in children with SVcPACNS. In children, the diagnostic
yield of brain biopsies is 70%. Biopsy-related complications are
rarely seen.
Table 602-3 Characteristics of Primary CNS Vasculitis and Reversible Cerebral Vasoconstriction Syndrome
PCNSV RCVS
Precipitating factor None Postpartum onset or onset after exposure to
vasoactive substances
Onset More insidious, progressive course Acute onset followed by a monophasic course
Headaches Chronic and progressive Acute, thunderclap type
CSF findings Abnormal (leucocytosis and high total protein concentration) Normal to near normal
MRI Abnormal in almost all patients Normal in 70% of patients
Angiography Possibly normal; otherwise, diffuse abnormalities are often Always abnormal, strings of beads
indistinguishable from RCVS; irregular and asymmetrical appearance of cerebral arteries;
arterial stenoses or multiple occlusions are more abnormalities reversible within 6-12 wk
suggestive of PCNSV; abnormalities might be irreversible
Cerebral biopsy Vasculitis No vasculitic changes
Drug treatment Prednisone with or without cytotoxic agents Nimodipine
CSF, cerebrospinal fluid; PCNSV, primary CNS vasculitis; RCVS, reversible cerebral vasoconstriction syndrome.
From Salvarani C, Brown Jr. RD, Hunder GG: Adult primary central nervous system vasculitis. Lancet 380:767–776, 2012, Table 2.
Disorders that may be seen in adolescents and young adults that

produce the reversible vasoconstriction syndrome must also be con-
sidered. These include migraine, drug-induced vasospasm, and post-
partum angiopathy. Differentiating vasculitis is important for therapy
and prognosis (Table 602-3).
TREATMENT
Corticosteroids are the mainstay of acute immunosuppressive manage-
ment of cPACNS. Usually IV pulse therapy is initially given. Anti-
thrombotic therapy is equally important, particularly in large/
medium-vessel cPACNS subtypes, because children are at high risk for
recurrent ischemic events. For the distinct cPACNS subtypes, different
treatment regimens should be considered. Nonprogressive cPACNS is
a monophasic inflammatory attack with the highest risk of poor neu-
rologic outcome. Vessel wall inflammation causes severe proximal ste-
nosis and a high restroke risk. High-dose corticosteroid pulses are
commonly given followed by a 6-12 wk course of oral steroids at taper-
ing doses. Second-line immunosuppressive agents are uncommonly
used. All children require antithrombotic therapy. No unifying regimen
exists. Many centers initially use low-molecular-weight heparin fol-
lowed by long-term antiplatelet therapy. When reimaged at 3 mo
follow-up, children should have stable or improved vessel disease, no
newly affected vessel segments, and no evidence of contrast wall
enhancement. At this point the immunosuppressive therapy is com-
monly discontinued and children are only kept on antiplatelet agents.
Progressive cPACNS and SVcPACNS are considered chronic pro-
gressive vasculitis subtypes requiring a prolonged course of combina-
tion immunosuppression. High-dose corticosteroids are initially used
followed by long-term oral corticosteroids with slow taper. Many
centers use an induction-maintenance protocol adding IV cyclophos-
phamide to the corticosteroids as the induction medication, followed
by mycophenolate mofetil or other oral second-line agents during
maintenance therapy. Symptomatic therapy is essential including anti-
convulsants or psychotropic medication if required. Supportive therapy
includes bone protection with calcium and vitamin D, prophylaxis
against pneumocystis pneumonia, and gastric mucosal protection as
required.
PROGNOSIS
The mortality rate of cPACNS has significantly improved. Some treat-
ment protocols for SVcPACNS report a good outcome, defined as no
functional neurologic deficits in two-thirds of children. Children pre-
senting with status epilepticus and SVcPACNS have the poorest cogni-
tive outcome.

Chapter 602 ◆ Central Nervous System Vasculitis 2936.e1
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8 new cases, review of the literature, and proposal for diagnostic criteria, Lanthier S, Armstrong D, Domi T, et al: Post-varicella arteriopathy of childhood:
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Chapter 603
Central Nervous System
Infections
Charles G. Prober, Nivedita S. Srinivas,
and Roshni Mathew
Infection of the central nervous system (CNS) is the most common

cause of fever associated with signs and symptoms of CNS disease in
children. Many microorganisms can cause infection. Nonetheless, spe-
cific pathogens are identifiable and are influenced by the age and
immune status of the host and the epidemiology of the pathogen. In
general, viral infections of the CNS are much more common than
bacterial infections, which, in turn, are more common than fungal and
parasitic infections. Infections caused by rickettsiae (Rocky Mountain
spotted fever, Ehrlichia) are relatively uncommon but assume impor-
tant roles under certain epidemiologic circumstances. Mycoplasma
spp. can also cause infections of the CNS, although their precise con-
tribution is often difficult to determine.
Regardless of etiology, most patients with CNS infection have similar
clinical manifestations. Common symptoms include headache,
nausea, vomiting, anorexia, restlessness, altered state of consciousness,
and irritability; most of these symptoms are nonspecific. Common
signs of CNS infection, in addition to fever, include photophobia, neck
pain and rigidity, obtundation, stupor, coma, seizures, and focal neu-
rologic deficits. The severity and constellation of signs are determined
by the specific pathogen, the host, and the area of the CNS affected.
Infection of the CNS may be diffuse or focal. Meningitis and enceph-
alitis are examples of diffuse infection. Meningitis implies primary
involvement of the meninges, whereas encephalitis indicates brain
parenchymal involvement. Because these anatomic boundaries are
often not distinct, many patients have evidence of both meningeal and
parenchymal involvement and should be considered to have meningo-
encephalitis. Brain abscess is the best example of a focal infection of
the CNS. The neurologic expression of this infection is determined by
the site and extent of the abscess(es) (see Chapter 604).
The diagnosis of diffuse CNS infections depends on examination of
cerebrospinal fluid (CSF) obtained by lumbar puncture (LP). Table
603-1 provides an overview of the expected CSF abnormalities with
various CNS disorders.
Chapter 603 ◆ Central Nervous System Infections 2937
Table 603-1 Cerebrospinal Fluid Findings in Central Nervous System Disorders

PRESSURE PROTEIN GLUCOSE
CONDITION (mm H2O) LEUKOCYTES (mm3) (mg/dL) (mg/dL) COMMENTS
Normal 50-80 <5, ≥75% Lymphocytes 20-45 >50 (or 75%
serum glucose)
COMMON FORMS OF MENINGITIS
Acute bacterial Usually elevated 100-10,000 or more; usually Usually Decreased, Organisms usually seen on
meningitis (100-300) 300-2,000; PMNs 100-500 usually <40 (or Gram stain and recovered
predominate <50% serum by culture
glucose)
Partially treated Normal or 5-10,000; PMNs usual but Usually Normal or Organisms may be seen on
bacterial meningitis elevated mononuclear cells may 100-500 decreased Gram stain
predominate if pretreated Pretreatment may render
for extended period of CSF sterile. Antigen may
time be detected by
agglutination test
Viral meningitis or Normal or slightly Rarely >1,000 cells. Eastern Usually 50-200 Generally normal; HSV encephalitis is
meningoencephalitis elevated equine encephalitis and may be suggested by focal seizures
(80-150) lymphocytic decreased to or by focal findings on CT
choriomeningitis may <40 in some or MRI scans or EEG.
have cell counts of several viral diseases, Enteroviruses and HSV
thousand. PMNs early but particularly infrequently recovered
mononuclear cells mumps (15-20% from CSF. HSV and
predominate through of cases) enteroviruses may be
most of the course detected by PCR of CSF
UNCOMMON FORMS OF MENINGITIS
Tuberculous Usually elevated 10-500; PMNs early, but 100-3,000; may <50 in most cases; Acid-fast organisms almost
meningitis lymphocytes predominate be higher in decreases with never seen on smear.
through most of the presence of time if Organisms may be
course block treatment is not recovered in culture of
provided large volumes of CSF.
Mycobacterium
tuberculosis may be
detected by PCR of CSF
Fungal meningitis Usually elevated 5-500; PMNs early but 25-500 <50; decreases Budding yeast may be seen.
mononuclear cells with time if Organisms may be
predominate through treatment is not recovered in culture.
most of the course. provided Cryptococcal antigen (CSF
Cryptococcal meningitis and serum) may be positive
may have no cellular in cryptococcal infection
inflammatory response
Syphilis (acute) and Usually elevated 50-500; lymphocytes 50-200 Usually normal Positive CSF serology.
leptospirosis predominate Spirochetes not
demonstrable by usual
techniques of smear or
culture; dark-field
examination may be
positive
Amebic (Naegleria) Elevated 1,000-10,000 or more; PMNs 50-500 Normal or slightly Mobile amebas may be seen
meningoencephalitis predominate decreased by hanging-drop
examination of CSF at
room temperature
BRAIN ABSCESSES AND PARAMENINGEAL FOCUS
Brain abscess Usually elevated 5-200; CSF rarely acellular; 75-500 Normal unless No organisms on smear or
(100-300) lymphocytes predominate; abscess culture unless abscess
if abscess ruptures into ruptures into ruptures into ventricular
ventricle, PMNs ventricular system
predominate and cell system
count may reach >100,000
Subdural empyema Usually elevated 100-5,000; PMNs 100-500 Normal No organisms on smear or
(100-300) predominate culture of CSF unless
meningitis also present;
organisms found on tap of
subdural fluid
Cerebral epidural Normal to slightly 10-500; lymphocytes 50-200 Normal No organisms on smear or
abscess elevated predominate culture of CSF
Spinal epidural Usually low, with 10-100; lymphocytes 50-400 Normal No organisms on smear or
abscess spinal block predominate culture of CSF
Chemical (drugs, Usually elevated 100-1,000 or more; PMNs 50-100 Normal or slightly Epithelial cells may be seen
dermoid cysts, predominate decreased within CSF by use of
myelography dye) polarized light in some
children with dermoids
Continued
Table 603-1 Cerebrospinal Fluid Findings in Central Nervous System Disorders—cont’d

PRESSURE PROTEIN GLUCOSE
CONDITION (mm H2O) LEUKOCYTES (mm3) (mg/dL) (mg/dL) COMMENTS
NONINFECTIOUS CAUSES
Sarcoidosis Normal or 0-100; mononuclear 40-100 Normal No specific findings
elevated slightly
Systemic lupus Slightly elevated 0-500; PMNs usually 100 Normal or slightly No organisms on smear or
erythematosus with predominate; lymphocytes decreased culture. Positive neuronal
CNS involvement may be present and ribosomal P protein
antibodies in CSF
Tumor, leukemia Slightly elevated 0-100 or more; mononuclear 50-1,000 Normal to Cytology may be positive
to very high or blast cells decreased
(20-40)
Acute disseminated Normal or ~100 lymphocytes Normal to Normal MRI adds to diagnosis
encephalomyelitis elevated elevated
Autoimmune Normal ~100 lymphocytes Normal to Normal Anti-NMDAR antibody–
encephalitis elevated positive
CSF, cerebrospinal fluid; EEG, electroencephalogram; HSV, herpes simplex virus; NMDAR, N-methyl-D-aspartate receptor; PCR, polymerase chain reaction;
PMN, polymorphonuclear neutrophils.
603.1 Acute Bacterial Meningitis Beyond bacteremia; the odds ratio is greater for meningococcus (85 times) and
H. influenzae type b (12 times) relative to that for pneumococcus.
the Neonatal Period Specific host defense defects as a result of altered immunoglobulin
Charles G. Prober and Roshni Mathew production in response to encapsulated pathogens may be responsible
for the increased risk of bacterial meningitis in Native Americans and
Bacterial meningitis is one of the most potentially serious infections Eskimos. Defects of the complement system (C5-C8) are associated
occurring in infants and older children. This infection is associated with recurrent meningococcal infection, and defects of the properdin
with a high rate of acute complications and risk of long-term morbid- system are associated with a significant risk of lethal meningococcal
ity. The incidence of bacterial meningitis is sufficiently high in febrile disease. Splenic dysfunction (sickle cell anemia) or asplenia (caused by
infants that it should be included in the differential diagnosis of trauma or congenital defect) is associated with an increased risk of
those with altered mental status and other evidence of neurologic pneumococcal, H. influenzae type b (to some extent), and, rarely,
dysfunction. meningococcal sepsis and meningitis. T-lymphocyte defects (congeni-
tal or acquired by chemotherapy, AIDS, or malignancy) are associated
ETIOLOGY with an increased risk of L. monocytogenes infections of the CNS.
The most common causes of bacterial meningitis in children older than A congenital or acquired CSF leak across a mucocutaneous barrier,
1 mo of age in the United States are Streptococcus pneumoniae and such as a lumbar dural sinus, cranial or midline facial defects (cribri-
Neisseria meningitidis. Bacterial meningitis caused by S. pneumoniae form plate), and middle ear (stapedial foot plate) or inner ear fistulas
and Haemophilus influenzae type b has become much less common in (oval window, internal auditory canal, cochlear aqueduct), or CSF
developed countries since the introduction of universal immunization leakage through a rupture of the meninges as a result of a basal skull
against these pathogens beginning at 2 mo of age. Demonstrating the fracture into the cribriform plate or paranasal sinus, is associated with
importance of vaccination, invasive H. influenzae disease was reported an increased risk of pneumococcal meningitis. The risk of bacterial
in Minnesota in 2008 in 5 children with no relationship to one another meningitis, caused by S. pneumoniae, in children with cochlear
and who were partially or not immunized. It is the largest number of implants, used for the treatment of hearing loss, is more than 30 times
children with invasive H. influenzae in Minnesota since 1992. Infection the risk in the general U.S. population. Lumbosacral dermal sinus and
caused by S. pneumoniae or H. influenzae type b must be considered meningomyelocele are associated with staphylococcal, anaerobic, and
in incompletely vaccinated individuals or those in developing coun- Gram-negative enteric bacterial meningitis. CSF shunt infections
tries. Those with certain underlying immunologic (HIV infection, increase the risk of meningitis caused by staphylococci (especially
immunoglobulin [Ig] G subclass deficiency) or anatomic (splenic dys- coagulase-negative species) and other low-virulence bacteria that typi-
function, cochlear defects or implants) disorders also may be at cally colonize the skin.
increased risk of infection caused by these bacteria.
Alterations of host defense resulting from anatomic defects or Streptococcus pneumoniae
immune deficits also increase the risk of meningitis from less-common See Chapter 182.
pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, The 7-valent pneumococcal protein polysaccharide conjugate
coagulase-negative staphylococci, Salmonella spp., anaerobes, and Lis- vaccine (PCV7) was introduced into the routine vaccination schedule
teria monocytogenes. in 2000 and contained the serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.
These serotypes caused most of the invasive pneumococcal infections
EPIDEMIOLOGY in the United States at that time. The vaccine led to a dramatic decrease
A major risk factor for meningitis is the lack of immunity to specific in rates of invasive pneumococcal disease. However, an increase in
pathogens associated with young age. Additional risks include recent invasive disease caused by serotypes not contained in the original
colonization with pathogenic bacteria, close contact (household, vaccine, such as serotype 19A, was observed. As a result, a 13-valent
daycare centers, college dormitories, military barracks) with individu- pneumococcal polysaccharide-protein conjugate vaccine (PCV13) was
als having invasive disease caused by N. meningitidis or H. influenzae licensed in the United States in February 2010. PCV13 contains the
type b, crowding, poverty, black or Native American race, and male serotypes in PCV7 plus serotypes 1, 3, 5, 6A, 7F, and 19A. This vaccine
gender. The mode of transmission is probably person-to-person is recommended for routine administration to all children 2-59 mo of
contact through respiratory tract secretions or droplets. The risk of age. The PCV13 vaccine is given as a 4-dose series at 2, 4, 6, and
meningitis is increased among infants and young children with occult 12-15 mo of age. The incidence of invasive pneumococcal infections
peaks in the 1st 2 yr of life, reaching rates of 228 per 100,000 in chil- of identifiable thrombosis have been described at autopsy. Cerebral
dren 6-12 mo of age. Children with anatomic or functional asplenia infarction, resulting from vascular occlusion because of inflammation,
secondary to sickle cell disease and those infected with HIV have infec- vasospasm, and thrombosis, is a frequent sequela. Infarct size ranges
tion rates that are 20-100–fold higher than in those of healthy children from microscopic to involvement of an entire hemisphere.
in the 1st 5 yr of life. Additional risk factors for contracting pneumo- Inflammation of spinal nerves and roots produces meningeal signs,
coccal meningitis include otitis media, sinusitis, pneumonia, CSF otor- and inflammation of the cranial nerves produces cranial neuropathies
rhea or rhinorrhea, the presence of a cochlear implant, and chronic of optic, oculomotor, facial, and auditory nerves. Increased intracranial
graft-versus-host disease following bone marrow transplantation. pressure (ICP) also produces oculomotor nerve palsy because of the
presence of temporal lobe compression of the nerve during tentorial
Neisseria meningitidis herniation. Abducens nerve palsy may be a nonlocalizing sign of ele-
See Chapter 191. vated ICP.
Five serogroups of meningococcus—A, B, C, Y, and W-135—are Increased ICP is a result of cell death (cytotoxic cerebral edema),
responsible for disease. Meningococcal meningitis may be sporadic or cytokine-induced increased capillary vascular permeability (vasogenic
may occur in epidemics. In the United States, serogroups B, C, and Y cerebral edema), and, possibly, increased hydrostatic pressure (inter-
each account for approximately 30% of cases, although serogroup dis- stitial cerebral edema) after obstructed reabsorption of CSF in the
tribution varies by location and time. Epidemic disease, especially in arachnoid villus or obstruction of the flow of fluid from the ventricles.
developing countries, is usually caused by serogroup A. Cases occur ICP may exceed 300 mm H2O; cerebral perfusion may be further com-
throughout the year but may be more common in the winter and promised if the cerebral perfusion pressure (mean arterial pressure
spring and following influenza virus infections. Nasopharyngeal car- minus ICP) is <50 cm H2O as a result of systemic hypotension with
riage of N. meningitidis occurs in 1-15% of adults. Colonization may reduced cerebral blood flow. The syndrome of inappropriate antidi-
last weeks to months; recent colonization places nonimmune younger uretic hormone secretion (SIADH) may produce excessive water reten-
children at greatest risk for meningitis. The incidence of disease occur- tion and potentially increase the risk of elevated ICP (see Chapter 559).
ring in association with an index case in the family is 1%, a rate that Hypotonicity of brain extracellular spaces may cause cytotoxic edema
is 1,000-fold the risk in the general population. The risk of secondary after cell swelling and lysis. Tentorial, falx, or cerebellar herniation does
cases occurring in contacts at daycare centers is approximately 1 in not usually occur because the increased ICP is transmitted to the entire
1,000. Most infections of children are acquired from a contact in a subarachnoid space and there is little structural displacement. Further-
daycare facility, a colonized adult family member, or an ill patient with more, if the fontanels are still patent, increased ICP is not always
meningococcal disease. Children younger than 5 yr have the highest dissipated.
rates of meningococcal infection. A second peak in incidence occurs Hydrocephalus can occur as an acute complication of bacterial
in persons between 15 and 24 yr of age. College freshmen living in meningitis. It most often takes the form of a communicating hydro-
dormitories have an increased incidence of infection compared to cephalus caused by adhesive thickening of the arachnoid villi around
non–college-attending, age-matched controls. the cisterns at the base of the brain. Thus, there is interference with the
The Centers for Disease Control and Prevention (CDC) recom- normal resorption of CSF. Less often, obstructive hydrocephalus devel-
mends vaccination against meningococcus (types A, C, W, and Y) with ops after fibrosis and gliosis of the aqueduct of Sylvius or the foramina
1 dose of a quadrivalent conjugate meningococcal vaccine between the of Magendie and Luschka.
ages of 11 and 12 yr and for persons 2 mo to 18 yr who are at increased Raised CSF protein levels are partly a result of increased vascular
risk for meningococcal disease. The CDC also has specific recommen- permeability of the blood–brain barrier and the loss of albumin-rich
dations for meningococcal vaccination of infants at high risk of menin- fluid from the capillaries and veins traversing the subdural space. Con-
gococcal infection as a consequence of complement pathway tinued transudation may result in subdural effusions, usually found in
deficiencies. College freshmen living in dormitories who have not been the later phase of acute bacterial meningitis. Hypoglycorrhachia
previously vaccinated should also be vaccinated. (reduced CSF glucose levels) is attributable to decreased glucose trans-
port by the cerebral tissue.
Haemophilus influenzae Type B Damage to the cerebral cortex may be a result of the focal or diffuse
See Chapter 194. effects of vascular occlusion (infarction, necrosis, lactic acidosis),
Before universal H. influenzae type b vaccination in the United hypoxia, bacterial invasion (cerebritis), toxic encephalopathy (bacterial
States, approximately 70% of cases of bacterial meningitis occurring in toxins), elevated ICP, ventriculitis, and transudation (subdural effu-
the 1st 5 yr of life were caused by this pathogen. Invasive infections sions). These pathologic factors result in the clinical manifestations of
occurred primarily in infants 2 mo to 2 yr of age; peak incidence was impaired consciousness, seizures, cranial nerve deficits, motor and
at 6-9 mo of age, and 50% of cases occurred in the 1st yr of life. The sensory deficits, and later psychomotor retardation.
risk to children was markedly increased among family or daycare
center contacts of patients with H. influenzae type b disease. Incom- PATHOGENESIS
pletely vaccinated individuals, those in underdeveloped countries who Bacterial meningitis most commonly results from hematogenous dis-
are not vaccinated, and those with blunted immunologic responses semination of microorganisms from a distant site of infection; bacte-
to vaccine (such as children with HIV infection) remain at risk for remia usually precedes meningitis or occurs concomitantly. Bacterial
H. influenzae type b meningitis. colonization of the nasopharynx with a potentially pathogenic micro-
organism is the usual source of the bacteremia. There may be pro-
PATHOLOGY AND PATHOPHYSIOLOGY longed carriage of the colonizing organisms without disease or, more
A meningeal purulent exudate of varying thickness may be distributed likely, rapid invasion after recent colonization. Prior or concurrent viral
around the cerebral veins, venous sinuses, convexity of the brain, and upper respiratory tract infection may enhance the pathogenicity of
cerebellum, and in the sulci, sylvian fissures, basal cisterns, and spinal bacteria producing meningitis.
cord. Ventriculitis with bacteria and inflammatory cells in ventricular N. meningitidis and H. influenzae type b attach to mucosal epithelial
fluid may be present (more often in neonates), as may subdural effu- cell receptors by pili. After attachment to epithelial cells, bacteria
sions and, rarely, empyema. Perivascular inflammatory infiltrates also breach the mucosa and enter the circulation. N. meningitidis may be
may be present, and the ependymal membrane may be disrupted. transported across the mucosal surface within a phagocytic vacuole
Vascular and parenchymal cerebral changes characterized by polymor- after ingestion by the epithelial cell. Bacterial survival in the blood-
phonuclear infiltrates extending to the subintimal region of the small stream is enhanced by large bacterial capsules that interfere with
arteries and veins, vasculitis, thrombosis of small cortical veins, occlu- opsonic phagocytosis and are associated with increased virulence.
sion of major venous sinuses, necrotizing arteritis producing subarach- Host-related developmental defects in bacterial opsonic phagocytosis
noid hemorrhage, and, rarely, cerebral cortical necrosis in the absence also contribute to the bacteremia. In young, nonimmune hosts, the
defect may be from an absence of preformed IgM or IgG anticapsular Alterations of mental status are common among patients with
antibodies, whereas in immunodeficient patients, various deficiencies meningitis and may be the consequence of increased ICP, cerebritis, or
of components of the complement or properdin system may interfere hypotension; manifestations include irritability, lethargy, stupor,
with effective opsonic phagocytosis. Splenic dysfunction may also obtundation, and coma. Comatose patients have a poor prognosis.
reduce opsonic phagocytosis by the reticuloendothelial system. Additional manifestations of meningitis include photophobia and
Bacteria gain entry to the CSF through the choroid plexus of the tache cérébrale, which is elicited by stroking the skin with a blunt
lateral ventricles and the meninges and then circulate to the extrace- object and observing a raised red streak within 30-60 sec.
rebral CSF and subarachnoid space. Bacteria rapidly multiply because
the CSF concentrations of complement and antibody are inadequate to DIAGNOSIS
contain bacterial proliferation. Chemotactic factors then incite a local The diagnosis of acute pyogenic meningitis is confirmed by analysis of
inflammatory response characterized by polymorphonuclear cell infil- the CSF, which typically reveals microorganisms on Gram stain and
tration. The presence of bacterial cell wall lipopolysaccharide (endo- culture, a neutrophilic pleocytosis, elevated protein, and reduced
toxin) of Gram-negative bacteria (H. influenzae type b, N. meningitidis) glucose concentrations (see Table 603-1). LP should be performed
and of pneumococcal cell wall components (teichoic acid, peptidogly- when bacterial meningitis is suspected. Contraindications for an
can) stimulates a marked inflammatory response, with local produc- immediate LP include (1) evidence of increased ICP (other than a
tion of tumor necrosis factor, interleukin 1, prostaglandin E, and other bulging fontanel), such as 3rd or 6th cranial nerve palsy with a
inflammatory mediators. The subsequent inflammatory response is depressed level of consciousness, or hypertension and bradycardia with
characterized by neutrophilic infiltration, increased vascular permea- respiratory abnormalities (see Chapter 590); (2) severe cardiopulmo-
bility, alterations of the blood–brain barrier, and vascular thrombosis. nary compromise requiring prompt resuscitative measures for shock
Meningitis-associated brain injury is not simply caused by viable bac- or in patients in whom positioning for the LP would further compro-
teria but occurs as a consequence of the host reaction to the inflam- mise cardiopulmonary function; and (3) infection of the skin overlying
matory cascade initiated by bacterial components. the site of the LP. Thrombocytopenia is a relative contraindication for
Rarely, meningitis may follow bacterial invasion from a contiguous LP. If an LP is delayed, empirical antibiotic therapy should be initiated.
focus of infection such as paranasal sinusitis, otitis media, mastoiditis, CT scanning for evidence of a brain abscess or increased ICP should
orbital cellulitis, or cranial or vertebral osteomyelitis or may occur after not delay therapy. LP may be performed after increased ICP has been
introduction of bacteria via penetrating cranial trauma, dermal sinus treated or a brain abscess has been excluded.
tracts, or meningomyeloceles. Blood cultures should be performed in all patients with suspected
meningitis. Blood cultures reveal the responsible bacteria in up to
CLINICAL MANIFESTATIONS 80-90% of cases of meningitis. Elevations of the C-reactive protein,
The onset of acute meningitis has 2 predominant patterns. The more erythrocyte sedimentation rate, and procalcitonin have been used
dramatic and, fortunately, less common presentation is sudden onset to differentiate bacterial (usually elevated) from viral causes of
with rapidly progressive manifestations of shock, purpura, dissemi- meningitis.
nated intravascular coagulation, and reduced levels of consciousness
often resulting in progression to coma or death within 24 hr. More Lumbar Puncture
often, meningitis is preceded by several days of fever accompanied by See Chapter 590.
upper respiratory tract or gastrointestinal symptoms, followed by non- The CSF leukocyte count in bacterial meningitis usually is elevated
specific signs of CNS infection, such as increasing lethargy and to >1,000/mm3 and, typically, there is a neutrophilic predominance
irritability. (75-95%). Turbid CSF is present when the CSF leukocyte count
The signs and symptoms of meningitis are related to the nonspecific exceeds 200-400/mm3. Normal healthy neonates may have as many
findings associated with a systemic infection and to manifestations of as 30 leukocytes/mm3 (usually <10), but older children without
meningeal irritation. Nonspecific findings include fever, anorexia and viral or bacterial meningitis have <5 leukocytes/mm3 in the CSF;
poor feeding, headache, symptoms of upper respiratory tract infection, in both age groups there is a predominance of lymphocytes or
myalgias, arthralgias, tachycardia, hypotension, and various cutaneous monocytes.
signs, such as petechiae, purpura, or an erythematous macular rash. A CSF leukocyte count <250/mm3 may be present in as many as 20%
Meningeal irritation is manifested as nuchal rigidity, back pain, Kernig of patients with acute bacterial meningitis; pleocytosis may be absent
sign (flexion of the hip 90 degrees with subsequent pain with extension in patients with severe overwhelming sepsis and meningitis and is a
of the leg), and Brudzinski sign (involuntary flexion of the knees and poor prognostic sign. Pleocytosis with a lymphocyte predominance
hips after passive flexion of the neck while supine). In children, par- may be present during the early stage of acute bacterial meningitis;
ticularly in those younger than 12-18 mo, Kernig and Brudzinski signs conversely, neutrophilic pleocytosis may be present in patients in the
are not consistently present. Indeed fever, headache, and nuchal rigid- early stages of acute viral meningitis. The shift to lymphocytic-
ity are present in only 40% of adults with bacterial meningitis. Increased monocytic predominance in viral meningitis invariably occurs within
ICP is suggested by headache, emesis, bulging fontanel or diastasis 8-24 hr of the initial LP. The Gram stain is positive in 70-90% of
(widening) of the sutures, oculomotor (anisocoria, ptosis) or abducens patients with untreated bacterial meningitis.
nerve paralysis, hypertension with bradycardia, apnea or hyperventila- A diagnostic conundrum in the evaluation of children with sus-
tion, decorticate or decerebrate posturing, stupor, coma, or signs of pected bacterial meningitis is the analysis of CSF obtained from chil-
herniation. Papilledema is uncommon in uncomplicated meningitis dren already receiving antibiotic (usually oral) therapy. This is an
and should suggest a more chronic process, such as the presence of an important issue, because 25-50% of children being evaluated for bacte-
intracranial abscess, subdural empyema, or occlusion of a dural venous rial meningitis are receiving oral antibiotics when their CSF is obtained.
sinus. Focal neurologic signs usually are a result of vascular occlusion. CSF obtained from children with bacterial meningitis, after the initia-
Cranial neuropathies of the ocular, oculomotor, abducens, facial, and tion of antibiotics, may be negative on Gram stain and culture. Pleo-
auditory nerves may also be the result of focal inflammation. Overall, cytosis with a predominance of neutrophils, elevated protein level, and
approximately 10-20% of children with bacterial meningitis have focal a reduced concentration of CSF glucose usually persist for several days
neurologic signs. after the administration of appropriate intravenous antibiotics. There-
Seizures (focal or generalized) caused by cerebritis, infarction, or fore, despite negative cultures, the presumptive diagnosis of bacterial
electrolyte disturbances occur in 20-30% of patients with meningitis. meningitis can be made. Some clinicians test CSF for the presence of
Seizures that occur on presentation or within the 1st 4 days of onset bacterial antigens if the child has been pretreated with antibiotics and
are usually of no prognostic significance. Seizures that persist after the the diagnosis of bacterial meningitis is in doubt. These tests have tech-
4th day of illness and those that are difficult to treat may be associated nical limitations. Polymerase chain reactions using broad-based bacte-
with a poor prognosis. rial 16S ribosomal RNA gene patterns may be useful in diagnosing the
cause of culture-negative meningitis because of prior antibiotic therapy and other signs of increased ICP suggest a focal lesion, such as a brain
or the presence of a nonculturable fastidious pathogen. or epidural abscess, or subdural empyema. Under these circumstances,
A traumatic LP may complicate the diagnosis of meningitis. Repeat antibiotic therapy should be initiated before LP and CT scanning. If
LP at a higher interspace may produce less hemorrhagic fluid, but signs of increased ICP and/or focal neurologic signs are present, CT
this fluid usually also contains red blood cells. Interpretation of CSF scanning should be performed first to determine the safety of perform-
leukocytes and protein concentration are affected by LPs that are ing an LP.
traumatic, although the Gram stain, culture, and glucose level may
not be influenced. Although methods for correcting for the presence Initial Antibiotic Therapy
of red blood cells have been proposed, it is prudent to rely on the The initial (empirical) choice of therapy for meningitis in immuno-
bacteriologic results rather than attempt to interpret the CSF leuko- competent infants and children is primarily influenced by the antibi-
cyte and protein results of a traumatic LP. Children with seizure, otic susceptibilities (Table 603-4) of S. pneumoniae. Selected antibiotics
particularly those with fever associated status epilepticus do not have should achieve bactericidal levels in the CSF. Although there are sub-
a CSF pleocytosis in the absence of CNS infection or inflammatory stantial geographic differences in the frequency of resistance of S. pneu-
disease. moniae to antibiotics, rates are increasing throughout the world. In the
United States, 25-50% of strains of S. pneumoniae are currently resis-
Differential Diagnosis tant to penicillin; relative resistance (minimal inhibitory concentration
In addition to S. pneumoniae, N. meningitidis, and H. influenzae type = 0.1-1.0 µg/mL) is more common than high-level resistance (minimal
b, many other microorganisms can cause generalized infection of the inhibitory concentration = 2.0 µg/mL). Resistance to cefotaxime and
CNS with similar clinical manifestations. These organisms include less- ceftriaxone is also evident in up to 25% of isolates. In contrast, most
typical bacteria, such as Mycobacterium tuberculosis, Nocardia spp., strains of N. meningitidis are sensitive to penicillin and cephalosporins,
Treponema pallidum (syphilis), and Borrelia burgdorferi (Lyme disease); although rare resistant isolates have been reported. Approximately
fungi, such as those endemic to specific geographic areas (Coccidioides, 30-40% of isolates of H. influenzae type b produce β-lactamases and,
Histoplasma, and Blastomyces) and those responsible for infections in therefore, are resistant to ampicillin. These β-lactamase–producing
compromised hosts (Candida, Cryptococcus, and Aspergillus); para- strains are sensitive to the extended-spectrum cephalosporins.
sites, such as Toxoplasma gondii and those that cause cysticercosis and, Based on the substantial rate of resistance of S. pneumoniae to
most frequently, viruses (see Chapter 603.2; Table 603-2). Focal infec- β-lactam drugs, vancomycin (60 mg/kg/24 hr, given every 6 hr) is rec-
tions of the CNS including brain abscess and parameningeal abscess ommended as part of initial empirical therapy. Because of the efficacy
(subdural empyema, cranial and spinal epidural abscess) may also be of third-generation cephalosporins in the therapy of meningitis caused
confused with meningitis. In addition, noninfectious illnesses can by sensitive S. pneumoniae, N. meningitidis, and H. influenzae type b,
cause generalized inflammation of the CNS. Relative to infections, cefotaxime (300 mg/kg/24 hr, given every 6 hr) or ceftriaxone (100 mg/
these disorders are uncommon and include malignancy, collagen vas- kg/24 hr administered once per day or 50 mg/kg/dose, given every
cular syndromes, and exposure to toxins (Table 603-2). 12 hr) should also be used in initial empirical therapy. Patients allergic
Determining the specific cause of CNS infection is facilitated by to β-lactam antibiotics and >1 mo of age can be treated with chloram-
careful examination of the CSF with specific stains (Kinyoun carbol phenicol, 100 mg/kg/24 hr, given every 6 hr. Another option for
fuchsin for mycobacteria, India ink for fungi), cytology, antigen detec- patients with allergy to β-lactam antibiotics is a combination of van-
tion (Cryptococcus), serology (syphilis, West Nile virus, arboviruses), comycin and rifampin. Alternatively, patients can be desensitized to
viral culture (enterovirus), and polymerase chain reaction (herpes the antibiotic (see Chapter 152).
simplex, enterovirus, and others). Other potentially valuable diagnos- If L. monocytogenes infection is suspected, as in young infants or
tic tests include blood cultures, CT or MRI of the brain, serologic tests, those with a T-lymphocyte deficiency, ampicillin (200 mg/kg/24 hr,
and, rarely, meningeal or brain biopsy. A unique MRI finding in given every 6 hr) also should also be given because cephalosporins
patients suspected of CNS infection is pachymeningitis (Fig. 603-1). are inactive against L. monocytogenes. Intravenous trimethoprim-
In addition to bacterial, tuberculous, or fungal infection (Fig. 603-1), sulfamethoxazole is an alternative treatment for L. monocytogenes.
the differential diagnosis also includes immune or inflammatory dis- If a patient is immunocompromised and Gram-negative bacterial
eases such as Sweet syndrome, CNS vasculitis, sarcoidosis, lymphoma, meningitis is suspected, initial therapy might include ceftazidime and
and neonatal-onset multisystem inflammatory disease. an aminoglycoside or meropenem.
Acute viral meningoencephalitis is the most likely infection to be
confused with bacterial meningitis (see Tables 603-2 and 603-3). DURATION OF ANTIBIOTIC THERAPY
Although, in general, children with viral meningoencephalitis appear Therapy for uncomplicated penicillin-sensitive S. pneumoniae menin-
less ill than those with bacterial meningitis, both types of infection gitis should be for 10-14 days with a third-generation cephalosporin
have a spectrum of severity. Some children with bacterial meningitis or intravenous penicillin (400,000 units/kg/24 hr, given every 4-6 hr).
may have relatively mild signs and symptoms, whereas some with viral If the isolate is resistant to penicillin and the third-generation cepha-
meningoencephalitis may be critically ill. Although classic CSF profiles losporin, therapy should be completed with vancomycin. Intravenous
associated with bacterial vs viral infection tend to be distinct (see Table penicillin (300,000 units/kg/24 hr) for 5-7 days is the treatment of
603-1), specific test results may have considerable overlap. choice for uncomplicated N. meningitidis meningitis. Uncomplicated
H. influenzae type b meningitis should be treated for 7-10 days. Patients
TREATMENT who receive intravenous or oral antibiotics before LP and who do not
The therapeutic approach to patients with presumed bacterial menin- have an identifiable pathogen, but do have evidence of an acute bacte-
gitis depends on the nature of the initial manifestations of the illness. rial infection on the basis of their CSF profile, should continue to
A child with rapidly progressing disease of less than 24 hr duration, in receive therapy with ceftriaxone or cefotaxime for 7-10 days. If focal
the absence of increased ICP, should receive antibiotics as soon as pos- signs are present or the child does not respond to treatment, a para-
sible after an LP is performed. If there are signs of increased ICP or meningeal focus may be present and a CT or MRI scan should be
focal neurologic findings, antibiotics should be given without perform- performed.
ing an LP and before obtaining a CT scan. Increased ICP should be A routine repeat LP is not indicated in all patients with uncompli-
treated simultaneously (see Chapter 68). Immediate treatment of asso- cated meningitis caused by antibiotic-sensitive S. pneumoniae, N. men-
ciated multiple organ system failure, shock (see Chapter 70), and acute ingitidis, or H. influenzae type b. Repeat examination of CSF is indicated
respiratory distress syndrome (see Chapter 71) is also indicated. in some neonates, in all patients with Gram-negative bacillary menin-
Patients who have a more protracted subacute course and become gitis, or in infection caused by a β-lactam–resistant S. pneumoniae. The
ill over a 4-7 day period should also be evaluated for signs of increased CSF should be sterile within 24-48 hr of initiation of appropriate anti-
ICP and focal neurologic deficits. Unilateral headache, papilledema, biotic therapy.
Table 603-2 Clinical Conditions and Infectious Agents Associated with Aseptic Meningitis
VIRUSES PARASITES (NONEOSINOPHILIC)
Enteroviruses (coxsackievirus, echovirus, poliovirus, enterovirus) Toxoplasma gondii (toxoplasmosis)
Arboviruses: Eastern equine, Western equine, Venezuelan equine, Acanthamoeba spp.
St. Louis encephalitis, Powassan and California encephalitis, West Naegleria fowleri
Nile virus, Colorado tick fever Malaria
Parechovirus
Herpes simplex (types 1, 2) POSTINFECTIOUS
Human herpesvirus type 6 Vaccines: rabies, influenza, measles, poliovirus
Varicella-zoster virus Demyelinating or allergic encephalitis
Epstein-Barr virus SYSTEMIC OR IMMUNOLOGICALLY MEDIATED
Parvovirus B19 Acute Disseminated Encephalomyelitis (ADEM)
Cytomegalovirus Autoimmune Encephalitis
Adenovirus Bacterial endocarditis
Variola (smallpox) Kawasaki disease
Measles Systemic lupus erythematosus
Mumps Vasculitis, including polyarteritis nodosa
Rubella Sjögren syndrome
Influenza A and B Mixed connective tissue disease
Parainfluenza Rheumatoid arthritis
Rhinovirus Behçet syndrome
Rabies Wegener granulomatosis
Lymphocytic choriomeningitis Lymphomatoid granulomatosis
Rotaviruses Granulomatous arteritis
Coronaviruses Sarcoidosis
Human immunodeficiency virus type 1 Familial Mediterranean fever
BACTERIA Vogt-Koyanagi-Harada syndrome
Mycobacterium tuberculosis (early and late) MALIGNANCY
Leptospira species (leptospirosis) Leukemia
Treponema pallidum (syphilis) Lymphoma
Borrelia species (relapsing fever) Metastatic carcinoma
Borrelia burgdorferi (Lyme disease) Central nervous system tumor (e.g., craniopharyngioma, glioma,
Nocardia species (nocardiosis) ependymoma, astrocytoma, medulloblastoma, teratoma)
Brucella species
Bartonella species (cat-scratch disease) DRUGS
Rickettsia rickettsii (Rocky Mountain spotted fever) Intrathecal infections (contrast media, serum, antibiotics,
Rickettsia prowazekii (typhus) antineoplastic agents)
Ehrlichia canis Nonsteroidal antiinflammatory agents
Coxiella burnetii OKT3 monoclonal antibodies
Mycoplasma pneumoniae Carbamazepine
Mycoplasma hominis Azathioprine
Chlamydia trachomatis Intravenous immune globulins
Chlamydia psittaci Antibiotics (trimethoprim-sulfamethoxazole, sulfasalazine,
Chlamydia pneumoniae ciprofloxacin, isoniazid)
Partially treated bacterial meningitis MISCELLANEOUS
BACTERIAL PARAMENINGEAL FOCUS Heavy metal poisoning (lead, arsenic)
Sinusitis Foreign bodies (shunt, reservoir)
Mastoiditis Subarachnoid hemorrhage
Brain abscess Postictal state
Subdural-epidural empyema Postmigraine state
Cranial osteomyelitis Mollaret syndrome (recurrent)
Intraventricular hemorrhage (neonate)
FUNGI Familial hemophagocytic syndrome
Coccidioides immitis (coccidioidomycosis) Postneurosurgery
Blastomyces dermatitidis (blastomycosis) Dermoid–epidermoid cyst
Cryptococcus neoformans (cryptococcosis) Headache, neurologic deficits
Histoplasma capsulatum (histoplasmosis) CSF lymphocytosis (syndrome of transient headache and neurologic
Candida species deficits with cerebrospinal fluid lymphocytosis [HaNDL])
Other fungi (Alternaria, Aspergillus, Cephalosporium, Cladosporium,
Drechslera hawaiiensis, Paracoccidioides brasiliensis, Petriellidium
boydii, Sporotrichum schenckii, Ustilago spp., Zygomycetes)
PARASITES (EOSINOPHILIC)
Angiostrongylus cantonensis
Gnathostoma spinigerum
Baylisascaris procyonis
Strongyloides stercoralis
Trichinella spiralis
Toxocara canis
Taenia solium (cysticercosis)
Paragonimus westermani
Schistosoma spp.
Fasciola spp.
Compiled from Cherry JD: Aseptic meningitis and viral meningitis. In Feigin RD, Cherry JD, editors: Textbook of pediatric infectious diseases, ed 4, Philadelphia,
1998, WB Saunders, p. 450; Davis LE: Aseptic and viral meningitis. In Long SS, Pickering LK, Prober CG, editors: Principles and practice of pediatric infectious disease,
New York, 1997, Churchill Livingstone, p. 329; and Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis therapy, ed 2, Philadelphia, 2004,
Elsevier, p. 961.
A B
Figure 603-1 Cerebral MRI. Three-dimensional T1 sequence with fast-spoiled gradient-echo gadolinium injection. A, Day 11 following menin-
gococcal infection. B, Day 9 following meningococcal infection. (From Toubiana J, Heilbronner C, Gitiaux C, et al: Pachymeningitis after menin-
gococcal infection. Lancet 381:1596–1597, 2013.)
Meningitis caused by Escherichia coli or P. aeruginosa requires respiratory rate should be monitored frequently. Neurologic assess-
therapy with a third-generation cephalosporin active against the isolate ment, including pupillary reflexes, level of consciousness, motor
in vitro. Most isolates of E. coli are sensitive to cefotaxime or ceftriax- strength, cranial nerve signs, and evaluation for seizures, should be
one, and most isolates of P. aeruginosa are sensitive to ceftazidime. made frequently in the 1st 72 hr, when the risk of neurologic complica-
Gram-negative bacillary meningitis should be treated for 3 wk or for tions is greatest. Important laboratory studies include an assessment of
at least 2 wk after CSF sterilization, which may occur after 2-10 days blood urea nitrogen; serum sodium, chloride, potassium, and bicar-
of treatment. bonate levels; urine output and specific gravity; complete blood and
Side effects of antibiotic therapy of meningitis include phlebitis, platelet counts; and, in the presence of petechiae, purpura, or abnormal
drug fever, rash, emesis, oral candidiasis, and diarrhea. Ceftriaxone bleeding, measures of coagulation function (fibrinogen, prothrombin,
may cause reversible gallbladder pseudolithiasis, detectable by abdom- and partial thromboplastin times).
inal ultrasonography. This is usually asymptomatic but may be associ- Patients should initially receive nothing by mouth. If a patient is
ated with emesis and upper right quadrant pain. judged to be normovolemic, with normal blood pressure, intravenous
fluid administration should be restricted to one-half to two-thirds of
Corticosteroids maintenance, or 800-1,000 mL/m2/24 hr, until it can be established
Rapid killing of bacteria in the CSF effectively sterilizes the meningeal that increased ICP or SIADH is not present. Fluid administration may
infection but releases toxic cell products after cell lysis (cell wall endo- be returned to normal (1,500-1,700 mL/m2/24 hr) when serum sodium
toxin) that precipitate the cytokine-mediated inflammatory cascade. levels are normal. Fluid restriction is not appropriate in the presence
The resultant edema formation and neutrophilic infiltration may of systemic hypotension because reduced blood pressure may result in
produce additional neurologic injury with worsening of CNS signs and reduced cerebral perfusion pressure and CNS ischemia. Therefore,
symptoms. Therefore, agents that limit production of inflammatory shock must be treated aggressively to prevent brain and other organ
mediators may be of benefit to patients with bacterial meningitis. dysfunction (acute tubular necrosis, acute respiratory distress syn-
Data support the use of intravenous dexamethasone, 0.15 mg/kg/ drome). Patients with shock, a markedly elevated ICP, coma, and
dose given every 6 hr for 2 days, in the treatment of children older refractory seizures require intensive monitoring with central arterial
than 6 wk with acute bacterial meningitis caused by H. influenzae and venous access and frequent vital signs, necessitating admission to
type b. Among children with meningitis caused by H. influenzae a pediatric intensive care unit. Patients with septic shock may require
type b, corticosteroid recipients have a shorter duration of fever, fluid resuscitation and therapy with vasoactive agents such as dopa-
lower CSF protein and lactate levels, and a reduction in sensorineural mine and epinephrine. The goal of such therapy in patients with men-
hearing loss. Data in children regarding benefits, if any, of cortico- ingitis is to avoid excessive increases in ICP without compromising
steroids in the treatment of meningitis caused by other bacteria are blood flow and oxygen delivery to vital organs.
inconclusive. Early steroid treatment of adults with bacterial men- Neurologic complications include increased ICP with subsequent
ingitis, especially those with pneumococcal meningitis, results in herniation, seizures, and an enlarging head circumference because of
improved outcome. a subdural effusion or hydrocephalus. Signs of increased ICP should
Corticosteroids appear to have maximum benefit if given 1-2 hr be treated emergently with endotracheal intubation and hyperventila-
before antibiotics are initiated. They also may be effective if given tion (to maintain the pCO2 at approximately 25 mm Hg). In addition,
concurrently with or soon after the first dose of antibiotics. Complica- intravenous furosemide (Lasix, 1 mg/kg) and mannitol (0.5-1.0 g/kg)
tions of corticosteroids include gastrointestinal bleeding, hypertension, osmotherapy may reduce ICP (see Chapter 68). Furosemide reduces
hyperglycemia, leukocytosis, and rebound fever after the last dose. brain swelling by venodilation and diuresis without increasing intra-
cranial blood volume, whereas mannitol produces an osmolar gradient
Supportive Care between the brain and plasma, thus shifting fluid from the CNS to the
Repeated medical and neurologic assessments of patients with bacte- plasma, with subsequent excretion during an osmotic diuresis. Another
rial meningitis are essential to identify early signs of cardiovascular, approach to treating reductions of cerebral perfusion pressure caused
CNS, and metabolic complications. Pulse rate, blood pressure, and by elevations of intracranial pressure is to increase systemic blood
Table 603-3 Classification of Encephalitis by Cause and Source

I. INFECTIONS: VIRAL III. PARAINFECTIOUS: POSTINFECTIOUS, ALLERGIC, AUTOIMMUNE
A. Spread: person to person only Patients in whom an infectious agent or 1 of its components plays a
1. Mumps: frequent in an unimmunized population; often contributory role in etiology, but the intact infectious agent is not
mild isolated in vitro from the nervous system; it is postulated that in this
2. Measles: may have serious sequelae group, the influence of cell-mediated antigen–antibody complexes
3. Enteroviruses: frequent at all ages; more serious in plus complement is especially important in producing the observed
newborns tissue damage
4. Parechovirus A. Associated with specific diseases (these agents may also cause
5. Rubella: uncommon; sequelae rare except in congenital direct CNS damage; see I and II)
rubella Measles
6. Herpesvirus group Rickettsial infections
a. Herpes simplex (types 1 and 2, possibly 6): relatively Rubella
common; sequelae frequent; devastating in newborns Influenzas A and B
b. Varicella-zoster virus: uncommon; serious sequelae not Mumps
rare Varicella-zoster
c. Cytomegalovirus, congenital or acquired: may have M. pneumoniae
delayed sequelae in congenital type B. Associated with vaccines
d. Epstein-Barr virus (infectious mononucleosis): not Rabies
common Measles
7. Pox group Vaccinia
a. Vaccinia and variola: uncommon, but serious CNS Yellow fever
damage occurs C. Autoimmune encephalitis
8. Parvovirus (erythema infectiosum): not common D. Acute disseminated encephalomyelitis (ADEM)
9. Influenzas A and B Paraneoplastic
10. Adenovirus Idiopathic
11. Other: reoviruses, respiratory syncytial, parainfluenza, IV. HUMAN SLOW-VIRUS DISEASES
hepatitis B Accumulating evidence that viruses frequently acquired earlier in life,
B. Arthropod-borne agents not necessarily with detectable acute illness, participate in later
C. Arboviruses: spread to humans by mosquitoes or ticks; chronic neurologic disease (similar events also known to occur in
seasonal epidemics depend on ecology of the insect vector; animals)
the following occur in the United States: A. Subacute sclerosing panencephalitis; measles; rubella?
Eastern equine California B. Creutzfeldt-Jakob disease (spongiform encephalopathy)
Western equine Powassan C. Progressive multifocal leukoencephalopathy
Venezuelan equine Dengue D. Kuru (Fore tribe in New Guinea only)
St. Louis Colorado tick fever E. Human immunodeficiency virus
West Nile V. UNKNOWN: COMPLEX GROUP
D. Spread by warm-blooded mammals This group constitutes more than two-thirds of the cases of
1. Rabies: saliva of many domestic and wild mammalian encephalitis reported to the Centers for Disease Control and
species Prevention, Atlanta, Georgia; the yearly epidemic curve of these
2. Herpesvirus simiae (“B” virus): monkeys’ saliva undiagnosed cases suggests that the majority are probably caused
3. Lymphocytic choriomeningitis: rodents’ excreta by enteroviruses and/or arboviruses.
II. INFECTIONS: NONVIRAL There is also a miscellaneous group that is based on clinical criteria:
A. Rickettsial: in Rocky Mountain spotted fever and typhus; Reye syndrome is 1 current example; others include the extinct von
encephalitic component from cerebral vasculitis Economo encephalitis (epidemic during 1918-1928); myoclonic
B. Mycoplasma pneumoniae: interval of some days between encephalopathy of infancy; retinomeningoencephalitis with
respiratory and CNS symptoms papilledema and retinal hemorrhage; recurrent encephalomyelitis (?
C. Bacterial: tuberculous and other bacterial meningitis; often has allergic or autoimmune); pseudotumor cerebri; and epidemic
encephalitic component neuromyasthenia (Iceland disease).
D. Spirochetal: syphilis, congenital or acquired; leptospirosis; An encephalitic clinical pattern may follow ingestion or absorption of
Lyme disease a number of known and unknown toxic substances; these include
E. Cat-scratch disease ingestion of lead and mercury, and percutaneous absorption of
F. Fungal: immunologically compromised patients at special risk: hexachlorophene as a skin disinfectant and gamma benzene
cryptococcosis; histoplasmosis; aspergillosis; mucormycosis; hexachloride as a scabicide.
candidosis; coccidioidomycosis
G. Protozoal: Plasmodium, Trypanosoma, Naegleria, and
Acanthamoeba spp.; Toxoplasma gondii
H. Metazoal: trichinosis; echinococcosis; cysticercosis;
schistosomiasis
CNS, central nervous system.

Modified from Behrman RE, editor: Nelson textbook of pediatrics, ed 14, Philadelphia, 1992, WB Saunders, p. 667. From Kliegman RM, Greenbaum LA, Lye PS:
Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, Elsevier, p. 967.
pressure using fluids (normal saline) and vasopressor agents (dopa- kg loading dose, 5 mg/kg/24 hr maintenance) to reduce the likelihood
mine, norepinephrine). This method reduces the risk of systemic hypo- of recurrence. Phenytoin is preferred to phenobarbital because it pro-
tension and may improve survival and reduce disability. duces less CNS depression and permits assessment of a patient’s level
Seizures are common during the course of bacterial meningitis. of consciousness. Serum phenytoin levels should be monitored to
Immediate therapy for seizures includes intravenous diazepam (0.1- maintain them in the therapeutic range (10-20 µg/mL).
0.2 mg/kg/dose) or lorazepam (0.05-0.10 mg/kg/dose), and careful
attention paid to the risk of respiratory suppression. Serum glucose, COMPLICATIONS
calcium, and sodium levels should be monitored. After immediate During the treatment of meningitis, acute CNS complications
management of seizures, patients should receive phenytoin (15-20 mg/ can include seizures, increased ICP, cranial nerve palsies, stroke,
Table 603-4 Antibiotics Used for the Treatment of Bacterial Meningitis*

Neonates
DRUGS 0-7 DAYS 8-28 DAYS INFANTS AND CHILDREN
†‡
Amikacin 15-20 divided q12h 30 divided q8h 20-30 divided q8h
Ampicillin 150 divided q8h 200 divided q6h or q8h 300 divided q6h
Cefotaxime 100-150 divided q8h or q12h 150-200 divided q6h or q8h 225-300 divided q6h or q8h
Ceftriaxone§ — — 100 divided q12h or q24h
Ceftazidime 100-150 divided q8h or q12h 150 divided q8h 150 divided q8h
Gentamicin†‡ 5 divided q12h 7.5 divided q8h 7.5 divided q8h
Meropenem — — 120 divided q8h
Nafcillin 75 divided q8h or q12h 100-150 divided q6h or q8h 200 divided q6h
Penicillin G 150,000 divided q8h or q12h 200,000 divided q6h or q8h 300,000 divided q4h or q6h
Rifampin — 10-20 divided q12h 10-20 divided q12h or q24h
†‡
Tobramycin 5 divided q12h 7.5 divided q8h 7.5 divided q8h
Vancomycin†‡ 20-30 divided q8h or q12h 30-45 divided q6h or q8h 60 divided q6h
*Dosages in mg/kg (units/kg for penicillin G) per day.
†
Smaller doses and longer dosing intervals, especially for aminoglycosides and vancomycin for very-low-birthweight neonates, may be advisable.
‡
Monitoring of serum levels is recommended to ensure safe and therapeutic values.
§
Use in neonates is not recommended because of inadequate experience in neonatal meningitis.
Adapted from Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 39(9):1267–1284, 2004,
Table 6.
cerebral or cerebellar herniation, and thrombosis of the dural venous The highest mortality rates are observed with pneumococcal meningi-
sinuses. tis. Severe neurodevelopmental sequelae may occur in 10-20% of
Collections of fluid in the subdural space develop in 10-30% of patients recovering from bacterial meningitis, and as many as 50%
patients with meningitis and are asymptomatic in 85-90% of patients. have some, albeit subtle, neurobehavioral morbidity. The prognosis is
Subdural effusions are especially common in infants. Symptomatic poorest among infants younger than 6 mo and in those with high
subdural effusions may result in a bulging fontanel, diastasis of sutures, concentrations of bacteria/bacterial products in their CSF. Those with
enlarging head circumference, emesis, seizures, fever, and abnormal seizures occurring more than 4 days into therapy or with coma or focal
results of cranial transillumination. CT or MRI scanning confirms the neurologic signs on presentation have an increased risk of long-term
presence of a subdural effusion. In the presence of increased ICP or a sequelae. There does not appear to be a correlation between duration
depressed level of consciousness, symptomatic subdural effusion of symptoms before diagnosis of meningitis and outcome.
should be treated by aspiration through the open fontanel (see Chap- The most common neurologic sequelae include hearing loss, cogni-
ters 68 and 590). Fever alone is not an indication for aspiration. tive impairment, recurrent seizures, delay in acquisition of language,
SIADH occurs in some patients with meningitis, resulting in hypo- visual impairment, and behavioral problems. Sensorineural hearing
natremia and reduced serum osmolality. This may exacerbate cerebral loss is the most common sequela of bacterial meningitis and, usually,
edema or result in hyponatremic seizures (see Chapter 55). is already present at the time of initial presentation. It is a result of
Fever associated with bacterial meningitis usually resolves within cochlear infection and occurs in as many as 30% of patients with
5-7 days of the onset of therapy. Prolonged fever (>10 days) is noted pneumococcal meningitis, 10% with meningococcal, and 5-20% of
in approximately 10% of patients. Prolonged fever is usually caused by those with H. influenzae type b meningitis. Hearing loss may also be
intercurrent viral infection, nosocomial or secondary bacterial infec- caused by direct inflammation of the auditory nerve. All patients with
tion, thrombophlebitis, or drug reaction. Secondary fever refers to the bacterial meningitis should undergo careful audiologic assessment
recrudescence of elevated temperature after an afebrile interval. Noso- before or soon after discharge from the hospital. Frequent reassessment
comial infections are especially important to consider in the evaluation on an outpatient basis is indicated for patients who have a hearing
of these patients. Pericarditis or arthritis may occur in patients being deficit.
treated for meningitis, especially that caused by N. meningitidis.
Involvement of these sites may result either from bacterial dissemina- PREVENTION
tion or from immune complex deposition. In general, infectious peri- Vaccination and antibiotic prophylaxis of susceptible at-risk contacts
carditis or arthritis occurs earlier in the course of treatment than does represent the 2 available means of reducing the likelihood of bacterial
immune-mediated disease. meningitis. The availability and application of each of these approaches
Thrombocytosis, eosinophilia, and anemia may develop during depend on the specific infecting bacteria.
therapy for meningitis. Anemia may be a result of hemolysis or bone
marrow suppression. Disseminated intravascular coagulation is most Neisseria meningitidis
often associated with the rapidly progressive pattern of presentation Chemoprophylaxis is recommended for all close contacts of patients
and is noted most commonly in patients with shock and purpura. The with meningococcal meningitis regardless of age or immunization
combination of endotoxemia and severe hypotension initiates the status. Close contacts should be treated with rifampin 10 mg/kg/dose
coagulation cascade; the coexistence of ongoing thrombosis may every 12 hr (maximum dose of 600 mg) for 2 days as soon as possible
produce symmetric peripheral gangrene. after identification of a case of suspected meningococcal meningitis or
sepsis. Close contacts include household, daycare center, and nursery
PROGNOSIS school contacts, and healthcare workers who have direct exposure to
Appropriate antibiotic therapy and supportive care have reduced the oral secretions (mouth-to-mouth resuscitation, suctioning, intuba-
mortality of bacterial meningitis after the neonatal period to <10%. tion). Exposed contacts should be treated immediately on suspicion of
infection in the index patient; bacteriologic confirmation of infection agents. The CSF is characterized by pleocytosis and the absence of
should not be awaited. In addition, all contacts should be educated microorganisms on Gram stain and routine bacterial culture. In most
about the early signs of meningococcal disease and the need to seek instances, the infections are self-limited. In some cases, substantial
prompt medical attention if these signs develop. morbidity and mortality occur.
Two quadrivalent (A, C, Y, W-135), conjugated vaccines (MCV-4;
Menactra and Menveo) are licensed by the FDA. The Advisory Com- ETIOLOGY
mittee on Immunization Practices (ACIP) to the CDC recommends Enteroviruses are the most common cause of viral meningoencepha-
routine administration of this vaccine to 11-12 yr old adolescents. litis. As of 2014, more than 70 serotypes of these small RNA viruses
Menactra is licensed for use in infants older than 9 mo of age, and have been identified. The severity of infection caused by enteroviruses
Menveo for use in children older than 2 yr of age. There is also a biva- ranges from mild, self-limited illness with primarily meningeal involve-
lent meningococcal polysaccharide protein conjugate vaccine that pro- ment to severe encephalitis resulting in death or significant sequelae.
vides protection against serogroups C and Y along with H. influenzae Human enterovirus 68 has been associated with neurologic symptoms
type b. This vaccine is licensed for use in children ages 6 wk through including flaccid paralysis. Parechoviruses may be an important cause
18 mo. High-risk patients include those with anatomic or functional of aseptic meningitis or encephalitis in infants. The clinical manifesta-
asplenia or deficiencies of terminal complement proteins. Use of tions are similar to that of the enteroviruses with the exception of more
meningococcal vaccine should be considered for college freshmen, severe MRI lesions of the cerebral cortex and at times an absence of a
especially those who live in dormitories, because of an observed CSF pleocytosis.
increased risk of invasive meningococcal infections compared to the Arboviruses are arthropod-borne agents, responsible for some cases
risk in non–college-attending, age-matched controls. of meningoencephalitis during summer months. Mosquitoes and ticks
are the most common vectors, spreading disease to humans and other
Haemophilus influenzae Type B vertebrates, such as horses, after biting infected birds or small animals.
Rifampin prophylaxis should be given to all household contacts of Encephalitis in horses (“blind staggers”) may be the first indication of
patients with invasive disease caused by H. influenzae type b, if any an incipient epidemic. Although rural exposure is most common,
close family member younger than 48 mo has not been fully immu- urban and suburban outbreaks also are frequent. The most common
nized or if an immunocompromised person, of any age, resides in the arboviruses responsible for CNS infection in the United States are West
household. A household contact is one who lives in the residence of Nile virus (WNV), La Crosse, Powassan, and St. Louis encephalitis
the index case or who has spent a minimum of 4 hr with the index case viruses (see Chapter 267). WNV made its appearance in the Western
for at least 5 of the 7 days preceding the patient’s hospitalization. Family hemisphere in 1999. It has gradually made its way from the east to the
members should receive rifampin prophylaxis immediately after the west coast over successive summers. Cumulatively, from 1999 through
diagnosis is suspected in the index case because >50% of secondary 2008, a total of 47 states reported roughly 30,000 human infections
family cases occur in the 1st wk after the index patient has been caused by WNV. WNV may also be transmitted by blood transfusion,
hospitalized. organ transplantation, or vertically across the placenta. Most children
The dose of rifampin is 20 mg/kg/24 hr (maximum dose of 600 mg) with WNV are either asymptomatic or have a nonspecific viral-like
given once each day for 4 days. Rifampin colors the urine and perspira- illness. Approximately 1% develop CNS disease; adults are more
tion red-orange, stains contact lenses, and reduces the serum concen- severely affected than children.
trations of some drugs, including oral contraceptives. Rifampin is Several members of the herpes family of viruses can cause menin-
contraindicated during pregnancy. goencephalitis. Herpes simplex virus (HSV) type 1 is an important
The most striking advance in the prevention of childhood bacterial cause of severe, sporadic encephalitis in children and adults. Brain
meningitis followed the development and licensure of conjugated vac- involvement usually is focal; progression to coma and death occurs in
cines against H. influenzae type b. Three conjugate vaccines are licensed 70% of cases without antiviral therapy. Severe encephalitis with diffuse
in the United States. Although each vaccine elicits different profiles of brain involvement is caused by HSV type 2 in neonates who usually
antibody response in infants immunized at 2-6 mo of age, all result contract the virus from their mothers at delivery. A mild transient form
in protective levels of antibody with an efficacy rate against invasive of meningoencephalitis may accompany genital herpes infection in
infections after primary series at 93%. Efficacy is not as consistent in sexually active adolescents; most of these infections are caused by HSV
Native American populations, a group recognized as having an espe- type 2. Varicella-zoster virus may cause CNS infection in close tempo-
cially high incidence of disease. All children should be immunized ral relationship with chickenpox. The most common manifestation of
with H. influenzae type b conjugate vaccine beginning at 2 mo of age CNS involvement is cerebellar ataxia, and the most severe is acute
(see Chapter 172). encephalitis. After primary infection, varicella-zoster virus becomes
latent in spinal and cranial nerve roots and ganglia, expressing itself
Streptococcus pneumoniae later as herpes zoster, sometimes with accompanying mild meningo-
Routine administration of conjugate vaccine against S. pneumoniae is encephalitis. Cytomegalovirus infection of the CNS may be part of
recommended for children younger than 5 yr of age. The initial dose congenital infection or disseminated disease in immunocompromised
is given at about 2 mo of age. Children who are at high risk of invasive hosts, but it does not cause meningoencephalitis in normal infants and
pneumococcal infections, including those with functional or anatomic children. Epstein-Barr virus is associated with myriad CNS syndromes
asplenia and those with underlying immunodeficiency (such as infec- (see Chapter 254). Human herpes virus 6 can cause encephalitis, espe-
tion with HIV, primary immunodeficiency, and those receiving immu- cially among immunocompromised hosts.
nosuppressive therapy) should also receive the vaccine. Mumps is a common pathogen in regions where mumps vaccine is
not widely used. Mumps meningoencephalitis is mild, but deafness
Bibliography is available at Expert Consult. from damage of the 8th cranial nerve may be a sequela. Meningoen-
cephalitis is caused occasionally by respiratory viruses (adenovirus,
influenza virus, parainfluenza virus), rubeola, rubella, or rabies; it
may follow live virus vaccinations against polio, measles, mumps, or
603.2 Viral Meningoencephalitis rubella.
Charles G. Prober and Nivedita S. Srinivas
EPIDEMIOLOGY
Viral meningoencephalitis is an acute inflammatory process involving The epidemiologic pattern of viral meningoencephalitis is primarily
the meninges and, to a variable degree, brain tissue. These infections determined by the prevalence of enteroviruses, the most common
are relatively common and may be caused by a number of different etiology. Infection with enteroviruses is spread directly from person
Chapter 603 ◆ Central Nervous System Infections 2946.e1
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to person, with a usual incubation period of 4-6 days. Most cases studies (CT or MRI) may show swelling of the brain parenchyma. Focal
in temperate climates occur in the summer and fall. Epidemiologic seizures or focal findings on EEG, CT, or MRI, especially involving the
considerations in aseptic meningitis due to agents other than entero- temporal lobes, suggest HSV encephalitis.
viruses also include season, geography (travel), climatic conditions,
animal exposures, mosquito or tick bites, and factors related to the Differential Diagnosis
specific pathogen. A number of clinical conditions that cause CNS inflammation mimic
viral meningoencephalitis (see Table 603-2). The most important
PATHOGENESIS AND PATHOLOGY group of alternative infectious agents to consider is bacteria. Most
Neurologic damage is caused by direct invasion and destruction of children with acute bacterial meningitis appear more critically ill than
neural tissues by actively multiplying viruses or by a host reaction to those with CNS viral infection. Parameningeal bacterial infections,
viral antigens. Tissue sections of the brain generally are characterized such as brain abscess or subdural or epidural empyema, may have
by meningeal congestion and mononuclear infiltration, perivascular features similar to viral CNS infections. Infections caused by M. tuber-
cuffs of lymphocytes and plasma cells, some perivascular tissue necro- culosis, T. pallidum (syphilis), B. burgdorferi (Lyme disease), and Bar-
sis with myelin breakdown, and neuronal disruption in various stages, tonella henselae, the bacillus associated with cat scratch disease, tend
including, ultimately, neuronophagia and endothelial proliferation or to result in indolent courses. Analysis of CSF and appropriate serologic
necrosis. A marked degree of demyelination with preservation of tests are necessary to differentiate these various pathogens.
neurons and their axons is considered to represent predominantly Infections caused by fungi, rickettsiae, mycoplasma, protozoa, and
“postinfectious” or an autoimmune encephalitis. other parasites may also need to be included in the differential diag-
The cerebral cortex, especially the temporal lobe, is often severely nosis. Consideration of these agents usually arises as a result of accom-
affected by HSV; the arboviruses tend to affect the entire brain; rabies panying symptoms, geographic locality of infection, or host immune
has a predilection for the basal structures. Involvement of the spinal factors.
cord, nerve roots, and peripheral nerves is variable. Various noninfectious disorders may be associated with CNS inflam-
mation and have manifestations overlapping with those associated with
CLINICAL MANIFESTATIONS viral meningoencephalitis. Some of these disorders include malig-
The progression and severity of disease are determined by the relative nancy, autoimmune diseases, intracranial hemorrhage, and exposure
degree of meningeal and parenchymal involvement, which, in part, is to certain drugs or toxins. Attention to history and other organ involve-
determined by the specific etiology. The clinical course resulting from ment usually allow elimination of these diagnostic possibilities. Auto-
infection with the same pathogen varies widely. Some children may immune encephalitis owing to anti–N-methyl-d-aspartate receptor
appear to be mildly affected initially, only to lapse into coma and die antibodies is an important cause of noninfectious encephalitis in chil-
suddenly. In others, the illness may be ushered in by high fever, violent dren. Detection of these antibodies in the serum or CSF confirms this
convulsions interspersed with bizarre movements, and hallucinations diagnosis. Acute disseminated encephalomyelitis may also initially be
alternating with brief periods of clarity, followed by complete confused with encephalitis.
recovery.
The onset of illness is generally acute, although CNS signs and symp- Laboratory Findings
toms are often preceded by a nonspecific febrile illness of a few days’ The CSF contains from a few to several thousand cells per cubic mil-
duration. The presenting manifestations in older children are headache limeter. Early in the disease, the cells are often polymorphonuclear;
and hyperesthesia, and in infants, irritability and lethargy. Headache is later, mononuclear cells predominate. This change in cellular type is
most often frontal or generalized; adolescents frequently complain of often demonstrated in CSF samples obtained as little as 8-12 hr apart.
retrobulbar pain. Fever, nausea and vomiting, photophobia, and pain The protein concentration in CSF tends to be normal or slightly ele-
in the neck, back, and legs are common. As body temperature increases, vated, but concentrations may be very high if brain destruction is
there may be mental dullness, progressing to stupor in combination extensive, such as that accompanying HSV encephalitis. The glucose
with bizarre movements and convulsions. Focal neurologic signs may level is usually normal, although with certain viruses, for example,
be stationary, progressive, or fluctuating. WNV and nonpolio entero- mumps, a substantial depression of CSF glucose concentrations may
viruses may cause anterior horn cell injury and a flaccid paralysis. For be observed. The CSF may be normal with parechovirus and in those
those reported with WNV, encephalitis is more common than aseptic who have encephalitis in the absence of meningeal involvement.
meningitis; acute flaccid paralysis may be noted in approximately 5% The success of isolating viruses from the CSF of children with viral
of patients. Nonetheless, many patients have a nonspecific febrile meningoencephalitis is determined by the time in the clinical course
illness “West Nile fever” and may never seek medical attention. Loss that the specimen is obtained, the specific etiologic agent, whether the
of bowel and bladder control and unprovoked emotional outbursts infection is a meningitic as opposed to a localized encephalitic process,
may occur. and the skill of the diagnostic laboratory staff. Isolating a virus is most
Exanthems often precede or accompany the CNS signs, especially likely early in the illness, and the enteroviruses tend to be the easiest
with echoviruses, coxsackieviruses, varicella-zoster virus, measles, to isolate, although recovery of these agents from the CSF rarely
rubella, and, occasionally, WNV. Examination often reveals nuchal exceeds 70%. To increase the likelihood of identifying the putative viral
rigidity without significant localizing neurologic changes, at least at the pathogen, specimens for culture should also be obtained from naso-
onset. pharyngeal swabs, feces, and urine. Although isolating a virus from 1
Specific forms or complicating manifestations of CNS viral infection or more of these sites does not prove causality, it is highly suggestive.
include Guillain-Barré syndrome, transverse myelitis, hemiplegia, and Detection of viral DNA or RNA by polymerase chain reaction is the test
cerebellar ataxia. of choice in the diagnosis of CNS infection caused by HSV, parechovirus
and enteroviruses, respectively. CSF serology is the diagnostic test of
DIAGNOSIS choice for WNV.
The diagnosis of viral encephalitis is usually made on the basis of the A serum specimen should be obtained early in the course of illness
clinical presentation of nonspecific prodrome followed by progressive and, if viral cultures are not diagnostic, again 2-3 wk later for serologic
CNS symptoms. The diagnosis is supported by examination of the CSF, studies. Serologic methods are not practical for diagnosing CNS infec-
which usually shows a mild mononuclear predominance (see Table tions caused by the enteroviruses because there are too many serotypes.
603-1). Other tests of potential value in the evaluation of patients with This approach may be useful, however, in confirming that a case is
suspected viral meningoencephalitis include an electroencephalogram caused by a known circulating serotype. Serologic tests may also be of
(EEG) and neuroimaging studies. The EEG typically shows diffuse value in determining the etiology of nonenteroviral CNS infection,
slow-wave activity, usually without focal changes. Neuroimaging such as arboviral infection.
TREATMENT
With the exception of the use of acyclovir for HSV encephalitis 603.3 Eosinophilic Meningitis
(see Chapter 252), treatment of viral meningoencephalitis is support- Charles G. Prober and Nivedita S. Srinivas
ive. Treatment of mild disease may require only symptomatic relief.
Headache and hyperesthesia are treated with rest, non–aspirin- Eosinophilic meningitis is defined as 10 or more eosinophils/mm3 of
containing analgesics, and a reduction in room light, noise, and visi- CSF. The most common cause worldwide of eosinophilic pleocytosis is
tors. Acetaminophen is recommended for fever. Opioid agents and CNS infection with helminthic parasites. In countries such as the
medications to reduce nausea may be useful, but if possible, their use United States, where helminthic infestation is uncommon, however,
in children should be minimized because they may induce misleading the differential diagnosis of CSF eosinophilic pleocytosis is broad.
signs and symptoms. Intravenous fluids are occasionally necessary
because of poor oral intake. More-severe disease may require hospital- ETIOLOGY
ization and intensive care. Although any tissue-migrating helminth may cause eosinophilic
It is important to monitor patients with severe encephalitis closely meningitis, the most common cause is human infection with the rat
for convulsions, cerebral edema, inadequate respiratory exchange, dis- lungworm, Angiostrongylus cantonensis (see Chapter 297). Other
turbed fluid and electrolyte balance, aspiration and asphyxia, and parasites that can cause eosinophilic meningitis include Gnathostoma
cardiac or respiratory arrest of central origin. In patients with evidence spinigerum (dog and cat roundworm) (see Chapter 297), Baylisascaris
of increased ICP, placement of a pressure transducer in the epidural procyonis (raccoon roundworm), Ascaris lumbricoides (human round-
space may be indicated. The risks of cardiac and respiratory failure or worm), Trichinella spiralis, Toxocara canis, T. gondii, Paragonimus
arrest are high with severe disease. All fluids, electrolytes, and medica- westermani, Echinococcus granulosus, Schistosoma japonicum, Oncho-
tions are initially given parenterally. In prolonged states of coma, par- cerca volvulus, and Taenia solium. Eosinophilic meningitis may also
enteral alimentation is indicated. SIADH is common in acute CNS occur as an unusual manifestation of more common viral, bacterial,
disorders; monitoring of serum sodium concentrations is required for or fungal infections of the CNS. Noninfectious causes of eosinophilic
early detection (see Chapter 559). Normal blood levels of glucose, meningitis include multiple sclerosis, malignancy, hypereosinophilic
magnesium, and calcium must be maintained to minimize the likeli- syndrome, or a reaction to medications or a ventriculoperitoneal
hood of convulsions. If cerebral edema or seizures become evident, shunt.
vigorous treatment should be instituted.
EPIDEMIOLOGY
PROGNOSIS A. cantonensis is found in Southeast Asia, the South Pacific, Japan,
Supportive and rehabilitative efforts are very important after patients Taiwan, Egypt, Ivory Coast, and Cuba. Infection is acquired by eating
recover from the acute phase of illness. Motor incoordination, convul- raw or undercooked freshwater snails, slugs, prawns, or crabs contain-
sive disorders, total or partial deafness, and behavioral disturbances ing infectious 3rd-stage larvae. Gnathostoma infections are found in
may follow viral CNS infections. Visual disturbances from chorioreti- Japan, China, India, Bangladesh, and Southeast Asia. Gnathostomiasis
nopathy and perceptual amblyopia may also occur. Special facilities is acquired by eating undercooked or raw fish, frog, bird, or
and, at times, institutional placement may become necessary. Some snake meat.
sequelae of infection may be very subtle. Therefore, neurodevelopmen-
tal and audiologic evaluations should be part of the routine follow-up CLINICAL MANIFESTATIONS
of children who have recovered from viral meningoencephalitis. When eosinophilic meningitis results from helminthic infestation,
Most children completely recover from viral infections of the CNS, patients become ill 1-3 wk after exposure. This reflects the transit time
although the prognosis depends on the severity of the clinical illness, for parasites to migrate from the gastrointestinal tract to the CNS.
the specific causative organism, and the age of the child. If the clinical Common concomitant findings include fever, peripheral eosinophilia,
illness is severe and substantial parenchymal involvement is evident, vomiting, abdominal pain, creeping skin eruptions, or pleurisy. Neu-
the prognosis is poor, with potential deficits being intellectual, motor, rologic symptoms may include headache, meningismus, ataxia, cranial
psychiatric, epileptic, visual, or auditory in nature. Severe sequelae nerve palsies, and paresthesias. Paraparesis or incontinence can result
should also be anticipated in those with infection caused by HSV. from radiculitis or myelitis.
Although some literature suggests that infants who contract viral
meningoencephalitis have a poorer long-term outcome than older DIAGNOSIS
children, most other data refute this observation. Approximately The presumptive diagnosis of helminth-induced eosinophilic menin-
10% of children younger than 2 yr of age with enteroviral CNS gitis is most often based on travel and exposure history in the presence
infections suffer an acute complication such as seizures, increased of typical clinical and laboratory findings. Direct visualization of hel-
ICP, or coma. Almost all have favorable long-term neurologic minths in CSF is affected by the relatively low organism burden, result-
outcomes. ing in limited diagnostic sensitivity. Serologic assays for helminthic
infections are also of limited utility because they are not readily avail-
PREVENTION able commercially and there is substantial cross-reactivity between
Widespread use of effective viral vaccines for polio, measles, mumps, different helminth species.
rubella, and varicella has almost eliminated CNS complications from
these diseases in the United States. The availability of domestic animal TREATMENT
vaccine programs against rabies has reduced the frequency of rabies Treatment is supportive, because infection is self-limited and anthel-
encephalitis. Control of encephalitis caused by arboviruses has been mintic drugs do not appear to influence the outcome of infection.
less successful because specific vaccines for the arboviral diseases that Analgesics should be given for headache and radiculitis, and CSF
occur in North America are not available. Control of insect vectors by removal or shunting should be performed to relieve hydrocephalus, if
suitable spraying methods and eradication of insect breeding sites, present. Steroids may decrease the duration of headaches in adults with
however, reduces the incidence of these infections. Furthermore, mini- eosinophilic meningitis.
mizing mosquito bites through the application of N,N-diethyl-3-
methylbenzamide (DEET)-containing insect repellents on exposed PROGNOSIS
skin and wearing long-sleeved shirts, long pants, and socks when out- The prognosis is good; 70% of patients improve sufficiently to leave the
doors, especially at dawn and dusk, reduces the risk of arboviral hospital in 1-2 wk. Mortality associated with eosinophilic meningitis
infection. is <1%.
Bibliography is available at Expert Consult. Bibliography is available at Expert Consult.

Chapter 603 ◆ Central Nervous System Infections 2948.e1
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Communities in the United States, N Engl J Med 367:1604–1713, 2012. Markoula S, Giannopoulos S, Pelidou SH, et al: MRI deterioration in herpes
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Centers for Disease Control and Prevention (CDC): Investigational drug available 39:1484–1492, 2004.
directly from CDC for the treatment of infections with free-living amebae, Ramirez-Avila L, Slome S, Schuster FL, et al: Eosinophilic meningitis due to
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Chapter 604 ◆ Brain Abscess 2949
Chapter 604
Brain Abscess
Charles G. Prober and Roshni Mathew
Brain abscesses can occur in children of any age but are most
common in children between 4 and 8 yr old and in neonates.
The causes of brain abscess include embolization as a result of con-
genital heart disease with right-to-left shunts (especially tetralogy of
Fallot), endocarditis, meningitis, chronic otitis media and mastoiditis,
sinusitis, soft-tissue infection of the face or scalp, orbital cellulitis,
dental infections, severe complicated pneumonia, penetrating head
injuries, immunodeficiency states, and infection of ventriculoperito-
neal shunts.
PATHOLOGY
Cerebral abscesses are evenly distributed between the 2 hemispheres,
and 80% of cases are divided equally between the frontal, parietal, and
temporal lobes. Brain abscesses in the occipital lobe, cerebellum, and
brainstem account for approximately 20% of the cases. Most brain
abscesses are single, but 30% are multiple and may involve more than
1 lobe. The pathogenesis is undetermined in 10-15% of cases. An
abscess in the frontal lobe is often caused by extension from sinusitis
or orbital cellulitis, whereas abscesses located in the temporal lobe or Figure 604-1 CT with contrast. Note the large, wall-enhancing
cerebellum are frequently associated with chronic otitis media and abscess in the left frontal lobe causing a shift of the brain to the right.
mastoiditis. Abscesses resulting from penetrating injuries tend to be The patient had no neurologic signs until just before the CT scan
singular and caused by Staphylococcus aureus, whereas those resulting because the abscess is located in the frontal lobe, a “silent” area of
from septic emboli, congenital heart disease, or meningitis often have the brain.
several causal organisms.
ETIOLOGY
The predominant organisms causing brain abscesses in children are may be minimally elevated or normal, and the glucose level may be
aerobic and anaerobic streptococci (60-70% of the cases) with Strepto- low. Cerebrospinal fluid cultures are rarely positive; culture of pus from
coccus milleri gp (Streptococcus anginosus, Streptococcus constellatus, the neurosurgical drainage is the key to establishing a bacteriologic
and Streptococcus intermedius) being increasingly isolated from surgi- diagnosis. However, the culture can be sterile in a substantial number
cally drained brain abscesses. Other important streptococci include of cases and 16S bacterial ribosomal RNA polymerase chain reaction
group A and B streptococci, Streptococcus pneumoniae, and Enterococ- amplification and sequencing may be used to identify unculturable
cus faecalis. Other bacteria isolated from brain abscesses include anaer- bacteria in brain abscesses. Because examination of the cerebrospinal
obic organisms (Gram-positive cocci, Bacteroides spp., Fusobacterium fluid is seldom useful and a lumbar puncture may cause herniation of
spp., Prevotella spp., Actinomyces spp.) and Gram-negative aerobic the cerebellar tonsils, the procedure should not be undertaken in a
bacilli (Haemophilus aphrophilus, Haemophilus parainfluenzae, Hae- child suspected of having a brain abscess. The electroencephalogram
mophilus influenzae, Enterobacter, Escherichia coli, Proteus spp.). Citro- shows corresponding focal slowing, and the radionuclide brain scan
bacter is most common in neonates. One organism is cultured in indicates an area of enhancement caused by disruption of the blood–
70% of abscesses, 2 in 20%, and 3 or more in 10% of cases. Abscesses brain barrier in more than 80% of cases. CT with contrast and MRI
associated with mucosal infections (sinusitis) frequently have anaero- are the most reliable methods of demonstrating cerebritis and abscess
bic bacteria. Fungi (Aspergillus, Candida), Nocardia, Mycobacterium, formation (Fig. 604-1). MRI is the diagnostic test of choice. The CT
and Listeria spp. are more common in children with impaired host findings of cerebritis are characterized by a parenchymal low-density
defenses. lesion, and MRI T2-weighted images indicate increased signal inten-
sity. An abscess cavity shows a ring-enhancing lesion by contrast CT,
CLINICAL MANIFESTATIONS and the MRI also demonstrates an abscess capsule with gadolinium
The early stages of cerebritis and abscess formation are associated with administration.
nonspecific symptoms, including low-grade fever, headache, and leth-
argy. The significance of these symptoms is generally not recognized, TREATMENT
and an oral antibiotic is often prescribed with resultant transient relief. The initial management of a brain abscess includes prompt diagnosis
As the inflammatory process proceeds, vomiting, severe headache, and institution of an antibiotic regimen that is based on the probable
seizures, papilledema, focal neurologic signs (hemiparesis), and coma pathogenesis and the most likely organism. When the cause is
may develop. A cerebellar abscess is characterized by nystagmus, ipsi- unknown, the combination of vancomycin, a third-generation cepha-
lateral ataxia and dysmetria, vomiting, and headache. If the abscess losporin, and metronidazole is commonly used. The same regimen is
ruptures into the ventricular cavity, overwhelming shock and death initiated when otitis media, sinusitis, or mastoiditis is the likely cause.
usually ensue. If there is a history of penetrating head injury, head trauma, or neuro-
surgery, vancomycin plus a third-generation cephalosporin is appro-
DIAGNOSIS priate. When cyanotic congenital heart disease is the predisposing
The peripheral white blood cell count can be normal or elevated, and factor, ampicillin-sulbactam alone or a third-generation cephalosporin
the blood culture is positive in 10% of cases. Examination of the cere- plus metronidazole may be used. Meropenem has good activity against
brospinal fluid shows variable results; the white blood cells and protein Gram-negative bacilli, anaerobes, staphylococci, and streptococci,
including most antibiotic-resistant pneumococci, and may be used
alone to replace the combination of metronidazole and a β-lactam in
the previous regimens. Notably, meropenem does not provide activity
against methicillin-resistant S. aureus and may have decreased activity
against penicillin-resistant strains of S. pneumoniae, indicating that
vancomycin should remain a part of the initial regimen when these
organisms are suspected. Abscesses secondary to an infected ventricu-
loperitoneal shunt may be initially treated with vancomycin and cef-
tazidime. When Citrobacter meningitis (often in neonates) leads to
abscess formation, a third-generation cephalosporin is used, typically
in combination with an aminoglycoside. Listeria monocytogenes may
cause a brain abscess in the neonate and if suspected, ampicillin should
be added to the cephalosporin. In immunocompromised patients,
broad-spectrum antibiotic coverage is used, and amphotericin B
therapy should be considered.
A brain abscess can be treated with antibiotics without surgery if the
abscess is <2 cm in diameter, the illness is of short duration (<2 wk),
there are no signs of increased intracranial pressure, and the child is
neurologically intact. If the decision is made to treat with antibiotics
alone, the child should have follow-up neuroimaging studies to ensure
the abscess is decreasing in size. An encapsulated abscess, particularly
if the lesion is causing a mass effect or increased intracranial pressure,
should be treated with a combination of antibiotics and aspiration.
Surgical excision of an abscess is rarely required, because the procedure
may be associated with greater morbidity compared with aspiration of
a cavity. Surgery is indicated when the abscess is >2.5 cm in diameter,
gas is present in the abscess, the lesion is multiloculated, the lesion is
located in the posterior fossa, or a fungus is identified. Associated
infectious processes, such as mastoiditis, sinusitis, or a periorbital
abscess, may require surgical drainage. The duration of antibiotic
therapy depends on the organism and response to treatment but is
usually 4-6 wk.
PROGNOSIS
Mortality rates prior to 1980s ranged from 11-53%. More recent mor-
tality rates accompanying wider use of CT and MRI, improved micro-
biologic techniques and prompt antibiotic and surgical management,
range from 5-10%. Factors associated with high mortality rate at the
time of admission include age younger than 1 yr, multiple abscesses
and coma. Long-term sequelae occur in about one-third of the survi-
vors and include hemiparesis, seizures, hydrocephalus, cranial nerve
abnormalities, and behavior and learning problems.

Chapter 604 ◆ Brain Abscess 2950.e1
Bibliography Sáez-Llorens X, Nieto Guevara J: Parameningeal infections. In Feigin RD, Cherry

Arora P, Kalra VK, Pappas A: Multiple brain abscesses in a neonate after blood JD, Demmler-Harrison GJ, et al, editors: Feigin and Cherry’s textbook of
stream infection with methicillin-resistant Staphylococcus aureus, J Pediatr pediatric infectious diseases, ed 6, Ch. 38. Philadelphia, 2009, Saunders Elsevier.
161:563, 2012. Saez-Lloreus XJ, Umana NA, Odio CN, et al: Brain abscesses in infants and
Brouwer MC, Tunkel AR, McKhann IIGM, et al: Brain abscess, N Engl J Med children, Pediatr Infect Dis J 8:449–458, 1989.
371:447–456, 2014. Shachor-Meyouhas Y, Bar-Joseph G, et al: Brain abscess in children–epidemiology,
Cole TS, Clark ME, et al: Pediatric focal intracranial suppuration: a UK predisposing factors and management in the modern medicine era, Acta
single-center experience, Childs Nerv Syst 28:2109–2114, 2012. Paediatr 99:1163–1167, 2010.
Goodkin HP, Harper MB, Pomeroy SL: Intracranial abscess in children: historical Smith RR: Neuroradiology of intracranial infection, Pediatr Neurosurg 18:92–104,
trends at Children’s Hospital Boston, Pediatrics 113:1765–1770, 2004. 1992.
Keller PM, Rampini SK, Bloemberg GV: Detection of mixed infection in a Yogev R, Bar-Meir M: Management of brain abscesses in children, Pediatr Infect
culture-negative brain abscess by broad-spectrum bacterial 16S rRNA gene Dis J 23:157–159, 2004.
PCR, J Clin Microbiol 48(6):2250, 2010.
Chapter 605
Idiopathic Intracranial
Hypertension/
Pseudotumor Cerebri
Misha L. Pless
Idiopathic intracranial hypertension, also known as pseudotumor

cerebri, is a clinical syndrome that mimics brain tumors and is char-
acterized by increased intracranial pressure ≥280 mm Hg in sedated
or obese children; ≥250 mm Hg in nonobese, nonsedated children with
a normal cerebrospinal fluid (CSF) cell count and protein content and
normal to slightly decreased ventricular size, and normal ventricular
anatomy and position documented by MRI. Papilledema is universally
present in children old enough to have a closed fontanel (Fig. 605-1).
ETIOLOGY
Table 605-1 lists the many causes of pseudotumor cerebri. There are
many explanations for the development of pseudotumor cerebri,
including alterations in CSF absorption and production, subtle
cerebral edema, abnormalities in vasomotor control and cerebral
blood flow, and venous obstruction. The causes of pseudotumor are
numerous and include metabolic disorders (galactosemia, hypopara-
thyroidism, pseudohypoparathyroidism, hypophosphatasia, prolonged
corticosteroid therapy or rapid corticosteroid withdrawal, possibly
growth hormone treatment, refeeding of a significantly malnourished
child, hypervitaminosis A, severe vitamin A deficiency, Addison
disease, obesity, menarche, oral contraceptives, and pregnancy), infec-
tions (roseola infantum, sinusitis, chronic otitis media and mastoiditis,
Guillain-Barré syndrome), drugs (nalidixic acid, doxycycline, minocy-
cline, tetracycline, nitrofurantoin, isotretinoin used for acne therapy
especially when combined with tetracycline), hematologic disorders
(polycythemia, hemolytic and iron-deficiency anemias [see Fig. 605-1],
Figure 605-1 Optic nerve photos of the right and left eyes, respectively, demonstrating grade 5 optic nerve head edema with characteristics,
including (A) total obscuration of the optic cup; (B) total obscuration of a segment of a major blood vessel; (C) total obscuration of disc margin;
and (D) macular star. (From Vickers AL, El-Dairi MA: Subacute vision loss in young, obese female. J Pediatr 163:1518–1519, 2013, Fig. 1.)
Chapter 605 ◆ Idiopathic Intracranial Hypertension/Pseudotumor Cerebri 2951
Wiskott-Aldrich syndrome), obstruction of intracranial drainage by

Table 605-1 Etiology of Childhood Pseudotumor venous thrombosis (lateral sinus or posterior sagittal sinus thrombo-
Cerebri sis), head injury, and obstruction of the superior vena cava. When a
HEMATOLOGIC NUTRITIONAL cause is not identified, the condition is classified as idiopathic intra-
Wiskott-Aldrich syndrome Hypovitaminosis A cranial hypertension.
Iron-deficiency anemia Vitamin A intoxication
Aplastic anemia Hyperalimentation in CLINICAL MANIFESTATIONS
Sickle cell disease malnourished patient The most frequent symptom is chronic (weeks to months), progressive,
Polycythemia? Vitamin D–dependent rickets frontal headache that may worsen with postural changes or a Valsalva
Bone marrow transplantation maneuver, and although vomiting also occurs, the vomiting is rarely
and associated treatments? CONNECTIVE TISSUE
DISORDERS as persistent and insidious as that associated with a posterior fossa
Prothrombotic states tumor. Transient visual obscuration lasting seconds and diplopia (sec-
Fanconi anemia Antiphospholipid antibody
syndrome ondary to dysfunction of the abducens nerve) may also occur as may
INFECTIONS Systemic lupus erythematosus? pulsatile tinnitus. Most patients are alert and lack constitutional symp-
Acute sinusitis Behçet disease toms. Examination of the infant with pseudotumor cerebri character-
Otitis media (lateral sinus istically reveals a bulging fontanel and a “cracked pot sound” or
thrombosis) ENDOCRINE
Menarche Macewen sign (percussion of the skull produces a resonant sound)
Mastoiditis
Polycystic ovarian syndrome resulting from separation of the cranial sutures. Papilledema with an
Tonsillitis
Measles Hypothyroidism enlarged blind spot is the most consistent sign in a child beyond
Roseola Hypoparathyroidism/ infancy. Papilledema may be absent or mild in infants with pseudotu-
Varicella, recurrent varicella- hyperparathyroidism mor cerebri because high CSF pressure may be transmitted to the soft
zoster virus infection Congenital adrenal hyperplasia fontanels earlier than the optic nerves. Early optic nerve edema may
Lyme disease? Addison disease be noted with orbit ultrasonography. Inferior nasal or peripheral visual
Recombinant growth hormone
HIV or associated treatment field defects may be detected on formal tangent screen testing. The
complications? OTHER presence of focal neurologic signs should prompt an investigation to
DRUGS Dural sinus thrombosis uncover a process other than pseudotumor cerebri. Any patient sus-
Tetracyclines Obesity (in pubertal patients) pected of pseudotumor cerebri should undergo an MRI. MR
Sulfonamides Bariatric surgery angiography/MR venography should be considered in patients sus-
Head trauma
Nalidixic acid pected of having dural sinus thrombosis.
Fluoroquinolones Superior vena cava syndrome
Corticosteroid therapy and Arteriovenous malformation
Sleep apnea TREATMENT
withdrawal The key objective in management is recognition and treatment of the
Nitrofurantoin Guillain-Barré syndrome
Crohn disease underlying cause. There are no randomized clinical trials to guide the
Cytarabine
Cyclosporine Ulcerative colitis? treatment of pseudotumor cerebri. Pseudotumor cerebri can be a self-
Phenytoin Turner syndrome limited condition, but optic atrophy and blindness are the most signifi-
Mesalamine POSSIBLE ASSOCIATIONS cant complications of untreated pseudotumor cerebri (Fig. 605-2). The
Isotretinoin Cystic fibrosis obese patient should be treated with a weight-loss regimen, and if a
Amiodarone? Cystinosis drug is thought to be responsible, it should be discontinued. For most
1-Deamino-8-D-arginine Down syndrome patients old enough to participate in such testing, serial monitoring of
vasopressin (DDAVP)? Hypomagnesemia–hypercalciuria visual function is required. Serial determination of visual acuity, color
Lithium? Galactokinase deficiency vision, and visual fields is critical in this disease. Serial optic nerve
Levonorgestrel implants? Galactosemia examination is essential as well. Optical coherence tomography is
Oral contraceptive pills Atrial septal defect repair useful to serially follow changes in papilledema. Serial visual-evoked
Moebius syndrome
RENAL potentials are useful if the visual acuity cannot be reliably documented.
Sarcoidosis?
Nephrotic syndrome The initial lumbar tap that follows a CT or MRI scan is diagnostic and
Chronic renal insufficiency? may be therapeutic. The spinal needle produces a small rent in the dura
Post–renal transplantation? that allows CSF to escape the subarachnoid space, thus reducing the
Peritoneal dialysis?
intracranial pressure. Several additional lumbar taps and the removal
Figure 605-2 Bilateral optic atrophy is evident upon resolution of the papilledema, 1 mo after bilateral optic nerve sheath fenestrations. (From
Vickers AL, El-Dairi MA: Subacute vision loss in young, obese female. J Pediatr 163:1518–1519, 2013, Fig. 2.)
of sufficient CSF to reduce the opening pressure by 50% occasionally
lead to resolution of the process. Acetazolamide, 10-30 mg/kg/24 hr, is
an effective regimen. Corticosteroids are not routinely administered,
although they may be used in a patient with severe intracranial pres-
sure elevation who is at risk of losing visual function and is awaiting a
surgical decompression. Sinus thrombosis is typically addressed by
anticoagulation therapy. Rarely, a ventriculoperitoneal shunt or sub-
temporal decompression is necessary, if the aforementioned approaches
are unsuccessful and optic nerve atrophy supervenes. Some centers
perform optic nerve sheath fenestration to prevent visual loss. Any
patient whose intracranial pressure proves to be refractory to treatment
warrants consideration for repeat neuroradiologic studies. A slow-
growing tumor or obstruction of a venous sinus may become evident
by the time of reinvestigation.

Chapter 605 ◆ Idiopathic Intracranial Hypertension/Pseudotumor Cerebri 2952.e1
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Kesler A, Bassan H: Pseudotumor cerebri—idiopathic intracranial hypertension in hypertension (IIH) in children and adolescents, Curr Neurol Neurosci Rep
the pediatric population, Pediatr Endocrinol Rev 3(4):387–392, 2006. 13:336–342, 2013.
Matthews YY: Drugs used in childhood idiopathic or benign intracranial
hypertension, , Arch Dis Child Educ Pract Ed 93(1):19–25, 2008.
Chapter 606
Spinal Cord Disorders
Harold L. Rekate
606.1 Tethered Cord Figure 606-1 Sagittal MRI showing thickening of the filum terminale
in a patient with a symptomatic tethered spinal cord. (Used with permis-
Harold L. Rekate
sion from Barrow Neurological Institute.)
Beyond infancy the spinal cord in humans ends in the conus medul-
laris at about the level of L1. The position of the conus below L2 is
consistent with a congenital tethered spinal cord. For normal humans
as the spine flexes and extends, the spinal cord is free to move up and
down within the spinal canal. If the spinal cord is fixed at any point,
this movement is restricted and the spinal cord and nerve roots become
stretched. This fixing of the spinal cord, regardless of the underlying
cause of the fixation, is called a tethered cord. When severe pain or
neurologic deterioration occurs in response to the fixation, it is called
the tethered cord syndrome.
In its simplest form the tethered cord syndrome results from a thick-
ened filum terminale, which normally extends as a thin, very mobile
structure from the tip of the conus to the sacrococcygeal region where
it attaches. When this structure is thickened and shortened, the conus
is found to end at levels below L2. This stretching between 2 points is
likely to cause symptoms later in life. Fatty infiltration is often seen in
the thickened filum (Fig. 606-1).
Any condition that fixes the spinal cord can be the cause of the
tethered cord syndrome. Conditions that are well established to cause
symptomatic tethering include various forms of occult dysraphism Figure 606-2 Child with a lipomyelomeningocele demonstrating
such as lipomyelomeningocele, myelocystocele, and diastematomyelia. an extraspinal mass and an asymmetry of the gluteal fold indicative
These conditions are associated with cutaneous manifestations such as of underlying occult dysraphism. (Used with permission from Barrow
midline lipomas often with asymmetry of the gluteal fold (Fig. 606-2), Neurological Institute.)
and hairy patches called hypertrichosis (Fig. 606-3). Probably the most
common type of symptomatic tethered cord involves patients who had
previously undergone closure of an open myelomeningocele and later of the filum terminale in the context of normal radiology. This concept
become symptomatic with pain or neurologic deterioration. Tethered will require a randomized controlled trial to evaluate the efficacy of
cord syndrome can also be associated with attachment of the spinal this approach.
cord in patients who undergo surgical procedures that disrupt the pial
surface of the spinal cord. CLINICAL MANIFESTATIONS
It is possible that a patient can be suffering from a tethered cord with Patients at risk for the subsequent development of the tethered cord
the conus medullaris in a completely normal position. Although this syndrome can often be identified at birth by the presence of an open
concept remains controversial, recent reports suggest that half of chil- myelomeningocele or by cutaneous manifestations of dysraphism. It is
dren with new onset of incontinence found to be neurologic in nature important to examine the back of the newborn for cutaneous midline
by urodynamic measurements can be successfully treated by sectioning lesions (lipoma, dermal sinus, tail, or hairy patch) that may signal an
Chapter 606 ◆ Spinal Cord Disorders 2953
TREATMENT
There are no nonsurgical options for the management of tethered cord
syndrome. Because the presence of tethering is most likely to be at least
suspected in the newborn, prophylactic surgery to prevent late deterio-
ration has been advocated by some neurosurgeons. This strategy
remains controversial and depends to some extent on a careful assess-
ment of the risks compared to the benefits. If surgical intervention is
chosen, microsurgical dissection with release of the spinal cord attach-
ment to the overlying dura is the goal of treatment.
OUTCOME
The outcome of releasing a thickened filum terminale or detethering
of patients with diastematomyelia is routinely good, and the chance of
recurrent symptoms is very low. Patients with symptomatic tethered
cord who undergo repair of a myelomeningocele or a lipomyelomenin-
gocele have a significant possibility of recurrent tethering and recur-
rent symptoms.
Figure 606-3 Hairy patch or hypertrichosis usually associated with

diastematomyelia. (Used with permission from Barrow Neurological 606.2 Diastematomyelia
Institute.) Harold L. Rekate
DIASTEMATOMYELIA: SPLIT-CORD
MALFORMATION
Diastematomyelia is a relatively rare form of occult dysraphism in
which the spinal cord is divided into 2 halves. In type 1 split-cord
malformation, there are 2 spinal cords, each in its own dural tube and
separated by a spicule of bone and cartilage (Fig. 606-5A). In a type 2
split-cord malformation, the 2 spinal cords are enclosed in a single
dural sac with a fibrous septum between the 2 spinal segments (Fig.
606-5B). In both cases the anatomy of the outer half of the spinal cord
is essentially normal while the medial half is extremely underdevel-
oped. Undeveloped nerve roots and dentate ligaments terminate medi-
ally into the medial dural tube in type 1 cases and terminate in the
membranous septum in type 2 cases. Both types have an associated
defect in the bony spinal segment. In the case of type 2 lesions, this
defect can be quite subtle.
Figure 606-4 Example of the neuroorthopedic syndrome involving a
larger left foot than right foot, a high arch, and absent ankle jerk fre-
quently associated with tethered cord regardless of the etiology. (Used
with permission from Barrow Neurological Institute.) Patients with both type 1 and type 2 split-cord malformations may have
subtle signs of neurologic involvement such as unilateral calf atrophy
and a high arch to 1 or both feet early in life, but they are more likely
to be neurologically normal. These patients are tethered by the adher-
underlying form of occult dysraphism. Dermal sinuses are usually ence of the spinal cord to the median membrane or dural sac. Later
located above the gluteal fold. Cutaneous abnormalities are not found they may develop progressive loss of bowel and bladder function and
in patients with an isolated thickened filum terminale. Patients who sensory and motor difficulties in the lower extremities. Back pain is a
become symptomatic later in life often exhibit an asymmetry of the common symptom in adolescents and adults with split-cord malfor-
feet (i.e., 1 is smaller than the other). The smaller foot will show a high mation but is uncommon in small children.
arch and clawing of the toes (Fig. 606-4). Characteristically, there is no Cutaneous manifestations of dysraphism are present in 90% of
ankle jerk on the involved side and the calf is atrophied. This condition patients with split-cord malformations. Large, hairy, midline patches
is termed the neuroorthopedic syndrome. called hypertrichosis, the most common cutaneous manifestations, are
Three clinical syndromes can occur at the time of deterioration. The present in approximately 60% of the cases.
most likely clinical presentation is increasing urinary urgency and,
finally, incontinence. Deterioration of motor and sensory function in DIAGNOSTIC EVALUATION
the lower extremities is a compelling reason for intervention. Finally, MRI, the study of choice, shows the 2 spinal cords. The frequent asso-
severe generalized back pain, often radiating into the lower extremities, ciation of bony abnormalities in this condition may require further
can occur, particularly in older adolescents and adults. evaluation with radiography or computed tomography.
DIAGNOSTIC EVALUATION TREATMENT

When patients present with symptoms related to the tethered cord The treatment of split-cord malformations is surgical. This abnormality
syndrome, a thorough motor and sensory examination of the patient is a form of tethered cord syndrome, and its treatment is to release the
must be documented. Assessment of bladder function with an ultra- spinal cord to move freely with movement of the spine. In type 1 split-
sound of the bladder and urodynamic studies is useful in analyzing cord malformations, the 2 half cords are in separate dural sacs with
bladder innervation. MRI is the diagnostic study of choice to reflect medial attachment to the dura and bony septum. In this case the dura
the anatomy of the tethering lesion and to provide information about needs to be opened, the bony septum removed, the medial attachments
the risks of surgical intervention. to the dura lysed, and a single dural tube created. For type 2 lesions,
Chapter 606 ◆ Spinal Cord Disorders 2953.e1
Bibliography
Selden NR: Minimal tethered cord syndrome: what’s necessary to justify new
surgical indication, Neurosurg Focus 23(2):E1, 2007.
Wehby MC, O’Holleren PS, Abtin K, et al: Occult tight filum syndrome: results of
surgical untethering, Pediatr Neurosurg 40:51–57, discussion 58, 2007.
Yamada S, Won DJ: What is the true tethered cord syndrome? Childs Nerv Syst
23:371–375, 2007.
A B
Figure 606-5 A, T2-weighted axial MRI of a type 1 split cord malformation showing the 2 spinal cords within 2 separate dural compartments.
B, Type 2 split cord malformation with 2 spinal cords sharing a single dural compartment. (A and B used with permission from Barrow Neurological
Institute.)
the membranous septum should be lysed. An attachment of this mem-

brane to the anterior dura should be explored and lysed as well.
Retethering of this type is rare as there is no reason to disrupt the pial
layer of the spinal cord.
606.3 Syringomyelia
Harold L. Rekate
Syringomyelia is a cystic distention of the spinal cord caused by

obstruction of the flow of spinal fluid from within the spinal cord to
its point of absorption. There are 3 recognized forms of syringomyelia
depending on the underlying cause. Communicating syringomyelia
implies that cerebrospinal fluid (CSF) from within the ventricles com-
municates with the fluid within the spinal cord and is assumed to be
the source of the CSF that distends the spinal cord. Noncommunicat-
ing syringomyelia implies that ventricular CSF does not communicate
with the fluid within the spinal cord. It primarily occurs in the context
of intramedullary tumors and obstructive lesions. In the final form of
syringomyelia, that is, posttraumatic syringomyelia, spinal cord injury
results in damage and subsequent softening of the spinal cord. This
softening, combined with the scarring of the surrounding spinal cord
tissue, results in progressive distention of the cyst. Syringomyelia has
been associated with Chiari anomalies and in patients with Ehlers-
Danlos syndrome; most are isolated findings unassociated with
syndromes.
Figure 606-6 Sagittal MRI of patient with a Chiari I malformation and
Signs and symptoms of syringomyelia develop insidiously over years a holocord syrinx. (Used with permission from Barrow Neurological
or decades. The classic presentation is the central cord syndrome. In Institute.)
this situation the patient develops numbness beginning in the shoulder
in a cape-like distribution followed by the development of atrophy and
weakness in the upper extremities. Trophic ulcers of the hands are distention above the level of the initial injury. There is also an ascend-
characteristic of advanced cases. The central cord syndrome results ing level of motor and sensory dysfunction.
from damage to the central spinal cord and the orientation of spinal
tracts from proximal to distal leading to selective involvement of the DIAGNOSTIC EVALUATION
upper rather than the lower extremities. MRI is the radiologic study of choice (Figs. 606-6 and 606-7). The study
Other forms of presentation include scoliosis that may be rapidly should include the entire spine and should include gadolinium-
progressive and often can be presumed from the absence of superficial enhanced sequences. Specific attention should be paid to the cranio-
abdominal reflexes. Urgency and bladder dysfunction as well as lower vertebral junction because of the frequent association of syringomyelia
extremity spasticity also may be part of the presentation. with Chiari I and II malformations. Obstruction to the flow of CSF
In patients with syringomyelia related to spinal cord injury, the from the fourth ventricle can cause syringomyelia; therefore, most
presentation is usually severe pain in the area of the spinal cord patients also should undergo imaging of the brain.
Bibliography
Pang D: Split cord malformation: part II: clinical syndrome, Neurosurgery
31:481–500, 1992.
Proctor MR, Scott RM: Long-term outcome for patients with split cord
malformation, Neurosurg Focus 10:e5, 2001.
TREATMENT shunt tubing is 1 form of treatment. Syrinx-to-pleural or syrinx-to-

The treatment of syringomyelia should be tailored to the underlying peritoneal shunting is more likely to result in improvement in the
cause. If that cause can be removed or ameliorated, the syrinx should radiographic appearance of the syrinx. In patients with syringomyelia
improve. Traumatic syrinxes result from hematomyelia in the sub- that extends to the conus medullaris, remnants of the central canal can
stance of the spinal cord coupled with severe arachnoidal scarring be found in the filum terminale. Lysis of this structure near the conus
around the circumference of the spinal cord. When progressive this can provide effective drainage.
form of syringomyelia is treated by exploration and lysis of the adhe- Some children who show no testable neurologic findings are being
sions that fix the spinal cord to the overlying dura. In cases of complete referred to pediatric neurosurgeons with the diagnosis of syringomy-
spinal cord injury, as is usually found in the thoracic spinal cord, the elia. Many of these children were scanned because of back pain or as
most effective treatment is the transection of the spinal cord, which part of a screening for scoliosis. They are found on MRI to have a
would both drain the syrinx and detether the spinal cord. Doing so persistent central canal and the diagnosis of syringomyelia is made.
drains the fluid from the spinal cord. In cases of incomplete spinal cord Some have been scanned sequentially for follow up and banned from
injury, functioning neurologic elements must be protected. Micro- athletic activities. These syrinxes are 1-3 mm in diameter and extend
scopic lysis of the scar surrounding the spinal cord at the point of over 2 segments (see Fig. 606-7). There is no distortion of the spinal
injury allows the spinal cord to collapse and prevents it from being cord in the region and no change in signal of the surrounding spinal
distorted by a hydrostatic column. cord. These syrinxes have been called “idiopathic” syrinxes. Follow-up
Communicating syringomyelia is most frequently seen in the of significant numbers of such children has shown them to be benign
context of abnormalities at the craniovertebral junction caused by in nature and probably represent a normal variant. There does not seem
inflammatory conditions such as chronic meningitis as seen in tuber- to be a need for routine follow-up imaging without new symptoms.
culosis or meningeal carcinomatosis. There is frequently a causative They need no treatment and do not require limitations of activity.
association with hindbrain herniation as in Chiari malformations (see
Fig. 606-6). In such cases decompression of the craniovertebral junc- Bibliography is available at Expert Consult.
tion is usually effective in the management of the syringomyelia. In the
context of the Chiari II malformation associated with spina bifida,
syringomyelia usually results from an insidious failure of the shunt
used to treat the hydrocephalus. This distention of the spinal cord 606.4 Spinal Cord Tumors
results in a rapid development of scoliosis and occasionally spasticity Harold L. Rekate
in the lower extremities. Repair of the shunt is effective treatment.
Noncommunicating syringomyelia results from blocking the flow of Tumors of the spine and spinal cord are rare in children. Different types
spinal cord extracellular fluid or CSF within the central canal by an of tumors have different relationships with the spinal cord, meninges,
intramedullary spinal cord tumor or severe external compression of and bony elements of the spine (Fig. 606-8). Intramedullary spinal cord
the spinal cord. In such cases, management should be directed to tumors arise within the substance of the spinal cord itself (Fig. 606-9).
tumor resection or to decompression of constricting elements. They represent between 5% and 15% of primary central nervous
Drainage procedures can result in symptomatic and radiographic system tumors. This percentage may well reflect the total volume of
improvement. Syrinx-to-subarachnoid shunting with a small piece of spinal cord as opposed to brain. Approximately 10% of intramedullary
spinal cord tumors are malignant astrocytic tumors, but most are
World Health Organization grade I or II tumors of glial or ependymal
origin. In children, low-grade astrocytomas and gangliogliomas repre-
sent the most common tumor types with ependymomas being less
common than in adults. Ependymomas in children are frequently asso-
ciated with neurofibromatosis (NF-2).
Except in the context of NF-1 and NF-2, intradural extramedullary
tumors are extremely rare in children. Most are nerve sheath tumors,
Dura
Extramedullary, Intramedullary Extramedullary,

extradural tumor tumor intradural tumor
Figure 606-8 Diagram of the relationship of various tumors to the

Figure 606-7 T1-weighted MRI scan of upper spinal cord showing an spine, nerve roots, and spinal cord. (Used with permission from Barrow
extensive syringomyelia (arrow). Neurological Institute.)
Bibliography
Magge SN, Smyth MD, Governale LS, et al: Idiopathic syrinx in the pediatric
populations: a combined center experience, J Neurosurg Pediatr 7(1):30–36,
2011.
Milhorat TH: Classification of syringomyelia, Neurosurg Focus 8:E1, 2000.
present with symptoms and signs relative to the nerve root involved.
Pain in a band-like distribution around the chest or into an extremity
is the most common presenting complaint. Tumor growth eventually
leads to spinal cord compression and involvement of adjacent nerve
roots.
Tumors rarely arise in the fat of the epidural space; most epidural
tumors arise in the bony compartment of the spine. They can present
abruptly with severe pain and neurologic deficit at the time of patho-
logic fracture of the vertebral body. Benign tumors such as giant cell
tumors and aneurysmal bone cysts present more insidiously as the
tumor slowly grows and begins to compress neural structures.
DIAGNOSTIC EVALUATION
MRI with and without gadolinium enhancement of the spinal cord is
the diagnostic study of choice and is essential in the diagnosis of spinal
cord tumors, especially intramedullary spinal cord tumors. Most astro-
cytic tumors of the spinal cord and most ependymomas show diffuse
enhancement and will distend the spinal cord focally. These tumors
may involve the entire length of the spinal cord (holocord astrocyto-
mas). MRI also shows the relationship between the normal spinal cord
and tumor embedded within spinal cord tissue. These tumors are fre-
quently associated with a syrinx, which is usually distal to the tumor.
Nerve sheath tumors characteristically enhance and are focal. They
may exit through the neural foramen and distend the canal as can be
seen on MRI. They also may be visualized on plain radiographs of the
Figure 606-9 T1-weighted MRI scan of a spinal cord tumor (arrow). affected area of the spine.
The fusiform expansion of the cervical cord enhances after intravenous Plain radiographs of the spine are helpful in defining the relationship
gadolinium injection. of extradural tumors to the bony spine and in documenting evidence
of instability in the case of pathologic compression fractures. When a
pathologic fracture occurs, CT is essential to determine the effect of
either schwannomas or, in the case of NF-2, neurofibromas. Intraspinal the tumor on the bone. Because many of these tumors occur as meta-
meningiomas in children are essentially found only in patients with static lesions, a general staging of the extent of disease is essential. In
NF-2. The intradural extramedullary compartment is also a site for the case of Langerhans cell histiocytosis, a thorough bone survey
metastatic tumors from primary cancers such as leukemia or primitive should be conducted to look for other lesions. Radionucleotide bone
neuroectodermal tumors. scanning is also useful in determining the extent of the disease.
Extradural spinal tumors characteristically begin in the bones of the
spine. Primary tumors in this location include aneurysmal bone cysts, TREATMENT
Langerhans cell histiocytosis (formerly called eosinophilic granuloma), The primary treatment of both intramedullary and extramedullary
and giant cell tumors. In infants, the extradural space is often the site intradural tumors is surgical removal. For both low-grade astrocyto-
of neuroblastomas or ganglioneuroblastomas, which tend to be present mas and ependymomas, microsurgical removal with the intent of total
in the epidural space and in the paraspinous tissue through the inter- removal is the treatment of choice. This goal should be attainable in all
vertebral foramen. In older patients, the bones of the spine may be the patients with ependymomas and in most patients with low-grade
site of multiple myeloma and metastases from common malignant astrocytomas and gangliogliomas. Adjunctive treatment of these
tumors. tumors is unwarranted in patients treated with adequate surgical resec-
tion. Likewise, schwannomas should be resectable. Occasionally,
CLINICAL MANIFESTATIONS however, the nerve root must be resected. Doing so may be of no
With the exception of the uncommon malignant glial tumors of the consequence in the thoracic spinal cord, but an attempt to remove the
spinal cord, which tend to present precipitously, intramedullary spinal tumor while salvaging the motor root in the cervical and lumbosacral
cord tumors present in a very insidious manner. Back pain related to region is critical to preserve movement. Malignant astrocytic tumors
the level of the tumor is a common presenting complaint. It is likely cannot be resected without major morbidity and, in any case, carry an
that this pain will awaken the child from sleep and improve as the day extremely poor prognosis. In the case of grades III and IV astrocyto-
progresses. Before the use of MRI became routine, the time from the mas of the spinal cord, decompression and biopsy followed by radia-
first onset of symptoms to diagnosis of the tumor could be as long tion therapy and possibly chemotherapy are utilized.
as 9 yr. Weakness, gait disturbance, and sensory deficits are usually The diagnosis and treatment of extramedullary spinal cord tumors
minor and are often found when formal neurologic examinations are must be individualized. Patients with distention of the vertebral body
performed. Scoliosis, urinary urgency, and incontinence may be the or with unstable pathologic fractures benefit from extensive resection
presenting complaints associated with intramedullary spinal cord of the involved vertebral bodies and will likely need fusion. For extra-
tumors. medullary tumors with soft-tissue components such as neuroblasto-
Extramedullary extradural tumors have a propensity to cause an mas, treatment is determined by the nature of the tumor and degree
acute block of the CSF pathways owing to rapid growth within a con- of spinal cord compression, and directed following needle biopsy of
fined space. Such children present with a flaccid paraplegia, urinary the lesion. In the absence of significant neurologic compression, surgi-
retention, and a patulous anus. Some extramedullary tumors produce cal intervention is rarely indicated.
the Brown-Séquard syndrome, which consists of ipsilateral weakness,
spasticity, and ataxia, with contralateral loss of pain and temperature OUTCOME
sensation. Papilledema is observed in a few patients, usually in associa- The prognosis for patients with benign intramedullary spinal cord
tion with markedly elevated CSF protein levels that presumably inter- tumors depends, to some extent, on the patient’s condition at the time
fere with normal CSF flow dynamics. of surgical intervention. It is very unlikely that nonambulatory patients
Nerve sheath tumors primarily arise from the sensory rootlet of will improve after surgery. If, however, patients are ambulatory at the
the exiting spinal nerve. They are very slow-growing tumors and time of surgery, they may experience increased weakness after surgery.
They are likely to recover at least their preoperative level of function. The mildest injury to the spinal cord is transient quadriparesis
Malignant spinal cord tumors are usually lethal with death resulting evident for seconds or minutes with complete recovery in 24 hr. This
from diffuse metastases via the CSF pathways. Successful resection of injury follows a concussion of the cord.
nerve sheath tumors should be curative. In the context of neurofibro- A transverse injury in the high cervical cord level (C1-C2) causes
matosis, however, many more tumors can be found at other levels or respiratory arrest and death in the absence of ventilatory support.
can be expected to develop later in life. Surgical intervention in the Fracture dislocations at the C5-C6 level resulting in spinal cord
context of neurofibromatoses should be performed only on clearly injuries are characterized by flaccid quadriparesis, loss of sphincter
symptomatic lesions. function, and a sensory level corresponding to the upper sternum.
The outcome of treatment of extramedullary tumors depends on the Fractures or dislocations in the low thoracic (T12-L1) region may
cell type and, in most cases, on the efficacy of nonsurgical, adjunctive produce the conus medullaris syndrome, which includes a loss of
therapies. For aneurysmal bone cysts and giant cell tumors, resection urinary and rectal sphincter control, flaccid weakness, and sensory
of the tumor and fusion of the spine are the treatments of choice. disturbances of the legs. A central cord lesion may result from contu-
The significant majority of spinal cord tumors in children are benign sion and hemorrhage and typically involves the upper extremities
(World Health Organization grades 2 and 3). The intramedullary low- to a greater degree than the legs. There are lower motor neuron
grade glial tumors for the most part act the same as the same histology signs in the upper extremities and upper motor neuron signs in
in the brain. The evidence would point to the fact that intramedullary the legs, bladder dysfunction, and loss of sensation caudal to the
ependymomas act in a more benign fashion than they do in the fourth lesion. There may be considerable recovery, particularly in the lower
ventricle. Gross total removal without adjuvant treatment is the pre- extremities.
ferred method of treatment and carries not only much longer progres- Thoracolumbar injuries are usually fracture–dislocations such as
sion free survival but improved quality of life as well. occur in severe motor vehicle accidents when children are wearing lap
belts but not shoulder harnesses. These injuries lead to a conus medul-
Bibliography is available at Expert Consult. laris syndrome. These patients exhibit a loss of bowel and bladder
function and lower motor neuron injuries involving the innervation of
the lower extremities.
606.5 Spinal Cord Injuries in Children CLEARING THE CERVICAL SPINE
Harold L. Rekate IN CHILDREN
The management of children following major trauma is challenging.
Spine and spinal cord injuries are very rare in children, particularly in Clearing the cervical spine in children carries some of the same issues
young children. The spine of a small child is very mobile, and fractures as it does in comatose adults in that with small children you cannot
of the spine are exceedingly rare. This increased mobility is not always count on their cooperation with positioning for radiographs and com-
a positive feature. Transfer of energy leading to spinal distortion can plaints of pain are difficult to assess. There has been an increasing
maintain the structural integrity of the spine but lead to significant emphasis on the use of MRI for the evaluation of potential cervical
injuries of the spinal cord. Spinal cord injury without radiographic spine instability but in small children this study requires sedation and,
bone (vertebral) abnormalities, called SCIWORA, is more common in in most centers, the presence of an anesthesiologist. Despite the radia-
children than adults. There seem to be 2 distinct forms. The infantile tion dose, it is clear that the CT scan is the most important study with
form involves severe injury of the cervical or thoracic spine. These 100% sensitivity and 95% specificity. A multiply injured child is likely
patients have a poor likelihood of complete recovery. In older children to be in the scanner having other anatomic studies done in any case
and adolescents, SCIWORA is more likely to cause a less-severe injury and no other study has been shown to be better for detection of unsta-
and the likelihood of complete recovery over time is high. The adoles- ble cervical spine injury. This test detects all significant injuries to the
cent form is assumed to be a spinal cord concussion or mild contusion cervical spine and has very few false-positives as opposed to MRI scan-
as opposed to the severe spinal cord injury related to the mobility of ning, which overcalls the injury 1 in 4 times.
the spine in small children.
Although the mechanisms of spinal cord injury in children include TREATMENT
birth trauma, falls, and child abuse, the major cause of morbidity and The initial management of spine and spinal cord injuries in children is
mortality remains motor vehicle injuries. Although the mechanisms of similar to that in adults. The cervical spine should be immobilized
injury and diagnosis are distinct in very small children, adolescents in the field by the emergency medical technicians. In cases of acute
incur spinal cord injuries with epidemiology similar to that of adults, spinal cord injury, some data support the acute infusion of a bolus
including significant male predominance and a high likelihood of frac- of high-dose (30 mg/kg) methylprednisolone followed by a 23 hr
ture dislocations of the lower cervical spine or thoracolumbar region. infusion (5.4 mg/kg/hr). The data for this treatment in children are
In infants and children younger than age 5 yr, fractures and mechani- controversial.
cal disruption of spinal elements are limited to the upper cervical spine Surgical management of unstable spinal injuries must be tailored to
between the occiput and C3. the patient’s age. For occipitocervical dislocations, early surgery with
fusion from the occiput to C2 or C3 should be performed, even in
CLINICAL MANIFESTATIONS babies older than 6 mo. Fixation of the subaxial spine must be tailored
One in 3 patients with significant trauma to the spine and spinal cord to the size of the pedicles and other osseus structures of the developing
will have a concomitant severe head injury, which makes early diagno- axial skeleton.
sis challenging. For these patients clinical evaluation may be difficult.
They need to be maintained in a protective environment such as a PREVENTION
collar until the appropriate radiographs can be obtained. A careful The most important aspect of the care of spinal cord injuries in chil-
neurologic examination is necessary for infants with suspected spinal dren relates to injury prevention. In this regard, the use of appropriate
cord injuries. Complete spinal cord injury will lead to spinal shock child restraints in automobiles is the most important precaution. In
with early areflexia. Severe cervical spinal cord injuries will usually lead older children and adolescents, rules against spear tackling in football
to paradoxical respiration in patients who are breathing spontaneously. and the “Feet First, First Time Program” from the Think First Founda-
Paradoxical respiration occurs when the diaphragm functions because tion aimed at adolescents diving into swimming pools and natural
the phrenic nerves from C3, C4, and C5 are functioning normally but water areas are important ways to help prevent severe cervical spinal
the intercostal musculature innervated by the thoracic spinal cord is cord injuries.
paralyzed. In this situation, inspiration fails to expand of the chest wall
but distends the abdomen. Bibliography is available at Expert Consult.
Bibliography Wilne S, Walker D: Spine and spinal cord tumours in children: a diagnostic and
McGirt MJ, Chaichana KL, Atiba A, et al: Resection of intramedullary spinal therapeutic challenge to healthcare, Arch Dis Child Educ Pract Ed 95:47–54,
cord tumors in children: assessment of long-term motor and sensory deficits, 2010.
J Neurosurg Pediatr 1:63–67, 2008.
Scheinemann K, Bartels U, Huang A, et al: Survival and functional outcomes of
childhood low-grade gliomas. Clinical article, J Neurosurg Pediatr 4(3):254–261,
2009.
2957.e2 Chapter 606 ◆ Spinal Cord Disorders
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Brockmeyer DL, Ragel BT, Kestle JR: The pediatric cervical spine instability study. 338:881–884, 2009.
A pilot study assessing the prognostic value of four imaging modalities in Polk-Williams A, Carr BG, Blinman TA, et al: Cervical spine injury in young
clearing the cervical spine for children with severe traumatic injuries, Childs children: a National Trauma Data Bank review, J Pediatr Surg 43:1718–1721,
Nerv Syst 28(5):699–705, 2012. 2008.
Garton HJ, Hammer MR: Detection of pediatric cervical spine injury, Neurosurgery
62:700–708, 2008.
606.6 Transverse Myelitis reflexia and clonus. Rarely is the weakness unilateral. Urinary retention
is an early finding; incontinence occurs later in the course. Most have
Harold L. Rekate sensory loss manifest as anesthesia, paresthesia, or allodynia. Other
findings may include priapism and vision loss (neuromyelitis optica),
Transverse myelitis (TM) is a condition characterized by rapid devel- as well as spinal shock and subsequent autonomic dysreflexia.
opment of both motor and sensory deficits at any level of the spinal The differential diagnosis includes demyelinating disorders, overt
cord. TM presents acutely as either partial or complete cord involve- meningitis, spinal cord infarction, or mass lesions such as bony distor-
ment and is defined as evidence of spinal cord inflammation by an tion, abscess, and spine and spinal cord tumors (Table 606-1).
MRI-documented enhancing lesion, or CSF pleocytosis (>10 cells), or
increased immunoglobulin G index. The progression is rapid and the DIAGNOSTIC EVALUATION
time to maximal disability is more than 4 hr and fewer than 21 days. MRI with and without contrast enhancement is essential to rule out a
It has multiple causes and tends to occur in 2 distinct contexts. Small mass lesion requiring neurosurgical intervention. In both conditions,
children, 3 yr of age and younger, develop spinal cord dysfunction over T1-weighted images of the spine at the anatomic level of involvement
hours to a few days. They have a history of an infectious disease, usually may be normal or may show distention of the spinal cord. In the
of viral origin, or of an immunization within the few weeks preceding infantile form, T2-weighted images show high signal intensity that
the development of their neurologic difficulties. The clinical loss of extends over multiple segments. In the adolescent form, the high signal
function is often severe and may seem complete. Although a slow intensity may be limited to 1 or 2 segments. A limited degree of con-
recovery (weeks to months) is common in these cases, it is likely to be trast enhancement after the administration of gadolinium is expected,
incomplete. The likelihood of independent ambulation in these small especially in the infantile form, and denotes an inflammatory condi-
children is approximately 40%. The pathologic findings of perivascular tion (Fig. 606-10). MRI of the brain is also indicated and shows evi-
infiltration with mononuclear cells imply an infectious or inflamma- dence of other foci of demyelination in at least 30% of patients; in these
tory basis. Overt necrosis of spinal cord may rarely be seen. patients and those with encephalopathy, acute disseminated encepha-
In older children, the syndrome is somewhat different. Although lomyelitis must be considered (Fig. 606-11).
the onset is also rapid with a nadir in neurologic function occurring After a mass lesion associated with spinal cord compression or com-
between 2 days and 2 wk, recovery is more rapid and more likely plete subarachnoid column block from spinal cord swelling have been
to be complete. Pathologic or imaging examination shows acute ruled out, a lumbar puncture is indicated. In both forms of disease, the
demyelination. number of mononuclear cells is usually elevated. The level of CSF
protein maybe elevated or normal. CSF should be analyzed for myelin
CLINICAL MANIFESTATIONS basic protein and immunoglobulin levels, which are usually elevated
TM is often preceded within the previous 1-3 wk by a mild nonspecific in TM. The presence of inflammatory cells is essential for the diagnosis
illness, minimal trauma, or perhaps an immunization. In both forms of TM.
the patient shows or complains of discomfort or overt pain in the neck Because one of the most important possibilities for this condition is
or back, depending on the level of the lesion. The most common neuromyelitis optica (NMO; Devic syndrome) the serum of all patients
involved segments are in the thoracic region. Depending on its severity, should be analyzed for the NMO antibody. This test is positive in most
the condition progresses to numbness, anesthesia, ataxia, areflexia, and patients with NMO (see Chapter 600.2). NMO is associated with bilat-
motor weakness in the truncal and appendicular musculature at or eral optic neuritis and recurrent or long segment TM (≥3 segments).
distal to the lesion. Paralysis begins as flaccidity (paraparesis, tetrapa- NMO may involve any spinal segment in addition to the brainstem or
resis), but over a few weeks spasticity develops and is evident by hyper- conus medullaris and cauda equina (myeloradiculitis). As in adults with
Table 606-1 Clinical and Radiologic Mimics of Transverse Myelitis

EXTRAAXIAL COMPRESSION DISEASE SPINAL CORD DISORDERS
1. Vertebral spine disorders 1. Congenital malformation
a. Trauma a. Neurenteric cysts
i. Blunt b. Spinal cord tethering
ii. Penetrating 2. Infection
iii. Surfing a. Nonpolio enteroviruses
b. Atlantoaxial subluxation b. West Nile virus
i. Trisomy 21 c. Human T-lymphocyte virus 1
ii. Mucopolysaccharidosis type IV d. Neurocysticercosis
iii. Grisel syndrome 3. Vascular disorders
c. Destructive lesions a. Arteriovenous malformation
i. Tuberculosis b. Cavernomas
ii. Lymphoma c. Cobb syndrome
iii. Langerhans cell histiocytosis d. Fibrocartilaginous embolization
d. Scheuermann disease e. Spinal cord infarction
2. Epidural disease 4. Vasculitis
a. Tumor a. Systemic lupus erythematosus
i. Neuroblastoma b. Behçet disease
ii. Wilms tumor 5. Nutritional disorders
iii. Ewing sarcoma a. Vitamin B12 deficiency (Subacute combined degeneration)
b. Abscess 6. Toxic injury
i. Associated dermal sinus, vertebral body infection a. Chemotherapy (e.g., methotrexate)
c. Hematoma b. Radiation
3. Arachnoiditis 7. Immune mediated
a. Tuberculosis a. Acute disseminated encephalomyelitis
b. Cryptococcosis b. Neuromyelitis optica
c. Carcinomatous infiltration c. Multiple sclerosis
4. Spinal nerve root inflammation
a. Guillain-Barré syndrome
Modified from Thomas T, Branson HM: Childhood transverse myelitis and its mimics. Neuroimaging Clin N Am 23:267–278, 2013, Box 11.
A B C
Figure 606-10 Transverse myelitis. A, Sagittal T2-weighted image demonstrates a longitudinal hyperintense spinal cord lesion spanning three
vertebral segments (arrows). B, On an axial T2-weighted image, the lesion involves more than two-thirds of the cord’s cross-sectional area (arrow).
C, Sagittal T1-weighted postcontrast image shows an enhancing area within the lesion (arrow). (From Ajtai B, Lindzen E, Masdeu JC: Structural
imaging: magnetic resonance imaging and computed tomography. In Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, editors: Bradley’s neurol-
ogy in clinical practice, ed 6. Philadelphia, 2012, WB Saunders, Fig. 33A.96.)
decreasing the severity and duration of the condition. The use of

high-dose steroids, particularly methylprednisolone, is the initial
approach to treatment of childhood forms of TM. If there is a poor
response to high-dose steroids, other therapeutic approaches include
intravenous immunoglobulin, plasma exchanges, rituximab, and
cyclophosphamide.
Follow-up of children with TM often reveals poor ambulation, con-
tinued bowel or bladder symptoms and dysesthesias.
606.7 Spinal Arteriovenous Malformations

Harold L. Rekate
Arteriovenous malformations of the spinal cord are rare lesions in

children. Only about 60 patients younger than age 18 yr are treated in
the United States each year. These lesions are complex. Despite their
rarity there are multiple subtypes, which require different treatment
strategies. Patients commonly present with back or neck pain, depend-
ing on the segments of the spinal cord involved, and they may experi-
ence the insidious onset of motor and sensory disturbances. Sudden
onset of paraplegia secondary to hemorrhage has been reported. Occa-
sionally, patients present with subarachnoid hemorrhage without overt
neurologic deficits, similar to the presentation associated with cerebral
aneurysms. In some cases, bruits are audible upon auscultation over
the bony spine.
DIAGNOSTIC EVALUATION
When a spinal arteriovenous malformation is suspected, MRI of the
Figure 606-11 Acute disseminated encephalomyelitis. Sagittal
T2-weighted image shows a diffuse hyperintense lesion spanning the
spinal cord is first needed to make the diagnosis and to obtain a general
length of the cervical cord (arrows). Note the enlarged caliber of the idea of the location of the lesion. MR angiography or CT angiography
cord, which is a result of swelling. (From Ajtai B, Lindzen E, Masdeu may provide further information, but formal catheter angiography of
JC: Structural imaging: magnetic resonance imaging and computed the spinal cord is needed to obtain an adequate understanding of the
tomography. In Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, complex anatomy of the lesion and to plan the intervention.
editors: Bradley’s neurology in clinical practice, ed 6. Philadelphia,
2012, WB Saunders, Fig. 33A.95.) TREATMENT
Open microsurgery had been the mainstay of treatment for spinal cord
TM, older children with the condition should have serum studies sent arteriovenous fistulas and arteriovenous malformations. With the
for autoimmune disorders, especially systemic lupus erythematosus. rapid development of interventional techniques, the percentage of
patients undergoing microsurgery has decreased from 70% to approxi-
TREATMENT mately 30%. Stereotactic radiosurgery may be used adjunctively. Treat-
There are no standards for the treatment of TM. Available evidence ment of these complex lesions requires the commitment of an organized
suggests that modulation of the immune response may be effective in neurovascular treatment program.
Bibliography Scott TF, Frohman EM, De Seze J, et al: Evidence-based guideline: clinical
Frohman EM, Wingerchuk DM: Transverse myelitis, N Engl J Med 363:564–572, evaluation and treatment of transverse myelitis, Neurology 77:2128–2134, 2011.
2010. Thomas T, Branson HM: Childhood transverse myelitis and its mimics,
Pawate S, Sriram S: Isolated longitudinal myelitis: a report of six cases, Spinal Cord Neuroimaging Clin N Am 23:267–278, 2013.
47:257–261, 2009. Wolf VL, Lupo PJ, Lotze TE: Pediatric acute transverse myelitis overview and
Pidcock FS, Krishnan C, Crawford TO, et al: Acute transverse myelitis in differential diagnosis, J Child Neurol 27:1426–1436, 2012.
childhood, Neurology 68:1474–1480, 2007.
Sato DK, Lana-Peixoto A, Fujihara K, et al: Clinical spectrum and treatment of
neuromyelitis optica spectrum disorders: evolution and current status, Brain
Pathol 23:647–660, 2013.
Neuromuscular Disorders XXVIII
PART
confused: Passive tone is range of motion around a joint; active tone

Chapter 607 is physiologic resistance to movement. Head lag when an infant is
pulled to a sitting position from supine is a sign of weakness, not of
Evaluation and low tone. Hypotonia may be associated with normal strength or with
weakness; enlarged muscles may be weak or strong; thin, wasted
muscles may be weak or have unexpectedly normal strength. The dis-
Investigation tribution of these components is of diagnostic importance. In general,
myopathies follow a proximal distribution of weakness and muscle
Harvey B. Sarnat wasting (with the notable exception of myotonic muscular dystrophy);
neuropathies are generally distal in distribution (with the notable
exception of juvenile spinal muscular atrophy; Table 607-1). Involve-
ment of the face, tongue, palate, and extraocular muscles provides an
The term neuromuscular disease defines disorders of the motor unit important distinction in the differential diagnosis. Tendon stretch
and excludes influences on muscular function from the brain, such as reflexes are generally lost in neuropathies and in motor neuron dis-
spasticity. The motor unit has 4 components: a motor neuron in the eases and are diminished but preserved in myopathies (Table 607-1).
brainstem or ventral horn of the spinal cord; its axon, which together A few specific clinical features are important in the diagnosis of
with other axons forms the peripheral nerve; the neuromuscular junc- some neuromuscular diseases. Fasciculations of muscle, which are
tion; and all muscle fibers innervated by a single motor neuron. The often best seen in the tongue, are a sign of denervation. Sensory abnor-
size of the motor unit varies among different muscles and with the malities indicate neuropathy. Fatigable weakness is characteristic of
precision of muscular function required. In large muscles, such as neuromuscular junctional disorders. Myotonia is specific for a few
the glutei and quadriceps femoris, hundreds of muscle fibers are myopathies.
innervated by a single motor neuron; in small, finely tuned muscles, Some features do not distinguish myopathy from neuropathy.
such as the stapedius or the extraocular muscles, a 1 : 1 ratio can prevail. Muscle pain or myalgias are associated with acute disease of either
The motor unit is influenced by suprasegmental or upper motor myopathic or neurogenic origin. Acute dermatomyositis and acute
neuron control that alters properties of muscle tone, precision of move- polyneuropathy (Guillain-Barré syndrome) are characterized by myal-
ment, reciprocal inhibition of antagonistic muscles during movement, gias. Muscular dystrophies and spinal muscular atrophies are not asso-
and sequencing of muscle contractions to achieve smooth, coordinated ciated with muscle pain. Myalgias also occur in several metabolic
movements. Suprasegmental impulses also augment or inhibit the diseases of muscle and in ischemic myopathy, including vascular dis-
monosynaptic stretch reflex; the corticospinal tract is inhibitory upon eases such as dermatomyositis. Myalgias denote the acuity, rather than
this reflex. the nature, of the process, so that progressive but chronic diseases, such
Diseases of the motor unit are common in children. These neuro- as muscular dystrophy and spinal muscular atrophy, are not painful
muscular diseases may be genetically determined, congenital or but acute stages of inflammatory myopathies and acute denervation of
acquired, acute or chronic, and progressive or static. Because specific muscle often do present with muscular pain and tenderness to palpa-
therapy is available for many diseases and because of genetic and tion. Contractures of muscles, whether present at birth or developing
prognostic implications, precise diagnosis is important; laboratory later in the course of an illness, occur in both myopathic and neuro-
confirmation is required for most diseases because of overlapping clini- genic diseases.
cal manifestations. Infant boys who are weak in late fetal life and in the neonatal period
Many chromosomal loci are identified with specific neuromuscular often have undescended testes. The testes are actively pulled into the
diseases as a result of genetic linkage studies and the isolation and scrotum from the anterior abdominal wall by a pair of cords that
cloning of a few specific genes. In some cases, such as Duchenne mus- consist of smooth and striated muscle called the gubernacula. The
cular dystrophy, the genetic defect is a deletion of nucleotide sequences gubernacula are weakened in many congenital neuromuscular dis-
and is associated with a defective protein product, dystrophin. In other eases, including spinal muscular atrophy, myotonic muscular dystro-
cases, such as myotonic muscular dystrophy, the genetic defect is an phy, and many congenital myopathies.
expansion or repetition, rather than a deletion, in a codon (a set of 3 The thorax of infants with congenital neuromuscular disease often
consecutive nucleotide repeats that encodes for a single amino acid), has a funnel shape, and the ribs are thin and radiolucent as a result of
with many copies of a particular codon (in this example they are also intercostal muscle weakness during intrauterine growth. This phenom-
associated with abnormal messenger RNA). Some diseases manifest as enon is characteristically found in infantile spinal muscular atrophy
autosomal dominant and autosomal recessive traits in different pedi- but also occurs in myotubular myopathy, neonatal myotonic dystrophy,
grees; these distinct mendelian genotypes can result from different and other disorders (Fig. 607-1). Because of the small muscle mass,
genetic mutations on different chromosomes (nemaline myopathy) or birthweight may be low for gestational age.
from small differences in the same gene at the same chromosomal Generalized hypotonia and motor developmental delay are the
locus (myotonia congenita), despite many common phenotypic fea- most common presenting manifestations of neuromuscular disease
tures and shared histopathologic findings in a muscle biopsy specimen. in infants and young children (Table 607-2). These features can
Among the several clinically defined mitochondrial myopathies, spe- also be expressions of neurologic disease, endocrine and systemic
cific mitochondrial DNA deletions and transfer RNA point mutations metabolic diseases, and Down syndrome, or they may be non-
are recognized. The inheritance patterns and chromosomal and mito- specific neuromuscular expressions of malnutrition or chronic sys-
chondrial loci of common neuromuscular diseases affecting infants temic illness (Table 607-3). A prenatal history of decreased fetal
and children are summarized in Table 608-1 in Chapter 608. movements and intrauterine growth retardation is often found in
patients who are symptomatic at birth. Developmental disorders
CLINICAL MANIFESTATIONS tend to be of slow onset and are progressive. Acute flaccid paralysis
Examination of the neuromuscular system includes an assessment of in older infants and children has a different differential diagnosis
muscle bulk, tone, and strength. Tone and strength should not be (Table 607-4).
2960
Chapter 607 ◆ Evaluation and Investigation 2961
LABORATORY FINDINGS muscle, MB for cardiac muscle, and BB for brain. Serum CK determi-
Serum Enzymes nation is not a universal screening test for neuromuscular disease
Several lysosomal enzymes are released by damaged or degenerating because many diseases of the motor unit are not associated with ele-
muscle fibers and may be measured in serum. The most useful of these vated enzymes. The CK level is characteristically elevated in certain
enzymes is creatine kinase (CK), which is found in only 3 organs and diseases, such as Duchenne muscular dystrophy, and the magnitude of
may be separated into corresponding isozymes: MM for skeletal increase is characteristic for particular diseases.
Table 607-1 Distinguishing Features of Disorders of the Motor System

WEAKNESS
DEEP
LOCUS OF Proximal– TENDON ELECTRO- MUSCLE
LESION Face Arms Legs Distal REFLEXES MYOGRAPHY BIOPSY OTHER
Central 0 + + ≥ Normal or Normal Normal Seizures, hemiparesis, and
↑ delayed development
Ventral horn Late ++++ ++++ ≥ 0 Fasciculations and Denervation Fasciculations (tongue)
cell fibrillations pattern
Peripheral 0 +++ +++ < ↓ Fibrillations Denervation Sensory deficit, elevated
nerve pattern cerebrospinal fluid
protein, depressed
nerve biopsy
Neuromuscular +++ +++ +++ = Normal Decremental response Normal Response to neostigmine
junction (myasthenia); or edrophonium
incremental (myasthenia);
response and BSAP constipation and fixed
(botulism) pupils (botulism)
Muscle Variable ++ + > ↓ Short duration, Myopathic Elevated muscle enzyme
(+ to small-amplitude pattern* levels (variable)
++++) motor unit potentials
and myopathic
polyphasic potentials
*Can also show unique features, such as in central core disease, nemaline myopathy, myotubular myopathy, and congenital fiber type disproportion.
+ to ++++, varying degrees of severity; BSAP, brief duration, small amplitude, overly abundant motor unit potentials.
From Volpe J: Neurology of the newborn, ed 4, Philadelphia, 2001, WB Saunders, p. 706.
Figure 607-1 Type 1 spinal muscular atrophy

(Werdnig-Hoffmann disease). Characteristic postures
in 6 wk old (A) and 1 yr old (B) infants with severe
weakness and hypotonia from birth. Note the frogleg
posture of the lower limbs and internal rotation (“jug
handle”) (A) or external rotation (B) at the shoulders.
Note also intercostal recession, especially evident
in B, and normal facial expressions. (From Volpe J:
Neurology of the newborn, ed 4, Philadelphia, 2001, A B
WB Saunders, p. 645.)
2962 Part XXVIII ◆ Neuromuscular Disorders
Table 607-2 Pattern of Weakness and Localization in the Floppy Infant

ANATOMIC REGION OF HYPOTONIA CORRESPONDING DISORDERS PATTERN OF WEAKNESS AND INVOLVEMENT
Central nervous system Chromosomal disorders Central hypotonia
Inborn errors of metabolism Axial hypotonia more prominent
Cerebral dysgenesis Hyperactive reflexes
Cerebral, spinal cord trauma
Motor neuron Spinal muscular atrophy Generalized weakness; often spares the diaphragm,
facial muscles, pelvis, and sphincters
Nerve Peripheral neuropathies Distal muscle groups involved
Weakness with wasting
Neuromuscular junction Myasthenia syndromes Bulbar, oculomotor muscles exhibit greater degree of
Infantile botulism involvement
Muscle Congenital myopathies Weakness is prominent
Metabolic myopathies Proximal musculature
Congenital muscular dystrophy Hypoactive reflexes
Congenital myotonic dystrophy Joint contractures
From Prasad AN, Prasad C: The floppy infant: contribution of genetic and metabolic disorders, Brain Dev 27:457–476, 2003.
Molecular Genetic Markers origin. MRI is the study of choice to image the spinal cord, if a tumor
Many DNA markers of hereditary myopathies, including the muscular or other structural lesion of the spinal cord is suspected as the cause
dystrophies, and neuropathies are available from leukocytes in blood of muscular dysfunction, and nerve roots and plexus (e.g., brachial
samples. If the clinical manifestations suggest a particular disease, plexus). Brain MRI is indicated in some myopathies, such as the con-
these tests can provide a definitive diagnosis and not subject the child genital muscular dystrophies, in which cerebral malformations often
to more-invasive procedures, such as muscle biopsy. Other molecular accompany the myopathy because the mutated gene responsible is
markers are available only in muscle biopsy tissue. expressed in both muscle and the developing brain.
Nerve Conduction Velocity Muscle Biopsy

Motor and sensory nerve conduction velocity may be measured elec- The muscle biopsy is traditionally the most important and specific
trophysiologically by using surface electrodes. Neuropathies of various diagnostic study of most neuromuscular disorders, if the definitive
types are detected by decreased conduction. The site of a traumatic diagnosis of a hereditary disease is not provided by molecular genetic
nerve injury may also be localized. The nerve conduction value at birth testing in blood. Not only are neurogenic and myopathic processes
is about half of the mature value achieved by age 2 yr. Tables are avail- distinguished, but also the type of myopathy and specific enzymatic
able for normal values at various ages in infancy, including for preterm deficiencies may be determined. The vastus lateralis (quadriceps
infants. Because the nerve conduction velocity study measures only the femoris) is the muscle that is most commonly sampled. The deltoid
fastest conducting fibers in a nerve, 80% of the total nerve fibers must muscle should be avoided in most cases because it normally has a
be involved before slowing in conduction is detected. 60-80% predominance of type I fibers so that the distribution patterns
of fiber types are difficult to recognize. Muscle biopsy is a simple out-
Electromyography patient procedure that may be performed under local anesthesia with
Electromyography (EMG) requires insertion of a needle into the belly or without femoral nerve block. Needle biopsies are preferred in some
of a muscle and recording of the electric potentials in various states of centers but are not percutaneous and require an incision in the skin
contraction. It is less useful in pediatrics than in adult medicine, in similar to open biopsy; numerous samples must be taken to conduct
part because of technical difficulties in recording these potentials in an adequate examination of the tissue, and they provide inferior speci-
young children and in part because the best results require the patient’s mens. The volume of tissue from a needle biopsy is usually not ade-
cooperation for full relaxation and maximal voluntary contraction of quate for all required studies, including supplementary biochemical
a muscle. Many children are too frightened to provide such coopera- studies, such as mitochondrial respiratory chain enzymes; a small,
tion. Characteristic EMG patterns distinguish denervation from myo- clean, open biopsy is therefore advantageous.
pathic involvement. The specific type of myopathy is not usually Histochemical studies of frozen sections of the muscle are obligatory
definitively diagnosed, but certain specialized myopathic conditions, in all pediatric muscle biopsies because many congenital and metabolic
such as myotonia, may be demonstrated. An EMG can transiently raise myopathies cannot be diagnosed from paraffin sections using conven-
the serum CK level. tional histologic stains. Immunohistochemistry is a useful supplement
EMG combined with repetitive electrical stimulation of a motor in some cases, such as for demonstrating dystrophin in suspected
nerve supplying a muscle to produce tetany is useful in demonstrating Duchenne muscular dystrophy or merosin in congenital muscular dys-
myasthenic decremental responses. Small muscles, such as the abduc- trophy. A portion of the biopsy specimen should be fixed for potential
tor digiti quinti of the hypothenar eminence, are used for such studies. electron microscopy, but ultrastructure has additional diagnostic value
Additional specialized tests, such as single myofiber EMG, may provide only in selected cases. Interpretation of muscle biopsy samples is
supplementary evidence in selected cases, but are performed only in complex and should be performed by an experienced pathologist. A
large neuromuscular centers. portion of frozen muscle tissue should also be routinely saved for pos-
sible biochemical analysis (mitochondrial cytopathies, carnitine pal-
Imaging of Muscle and Central Nervous System mitoyltransferase, acid maltase).
Ultrasonography, CT scans, and, more often, MRI are used to image Immunocytochemical reactivities can be applied to formalin-fixed,
muscle in many neuromuscular diseases. Although these methods are paraffin-embedded sections and do not require frozen sections. Some
not always definitively diagnostic, in experienced hands, they provide reactivities, such as slow and fast myosin, can distinguish fiber
a supplementary means of following the progression of disease over types and hence substitute for myofibrillar adenosine triphosphatase
time. MRI is quite useful in identifying inflammatory myopathies of histochemical stains in frozen sections. An increasing number of sar-
immune (dermatomyositis) or infectious (viral, bacterial, parasitic) colemmal regional proteins can be demonstrated that are specific for
Chapter 607 ◆ Evaluation and Investigation 2963
Table 607-3 Differential Diagnosis of Infantile Table 607-4 Differential Diagnosis of Acute Flaccid
Hypotonia Paralysis
Cerebral hypotonia Brainstem stroke
• Benign congenital hypotonia Brainstem encephalitis
• Chromosome disorders Acute anterior poliomyelitis
• Prader-Willi syndrome • Caused by poliovirus
• Trisomy • Caused by other neurotropic viruses
• Chronic nonprogressive encephalopathy Acute myelopathy
• Cerebral malformation • Space-occupying lesions
• Perinatal distress • Acute transverse myelitis
• Postnatal disorders Peripheral neuropathy
• Peroxisomal disorders • Guillain-Barré syndrome
• Cerebrohepatorenal syndrome (Zellweger syndrome) • Post–rabies vaccine neuropathy
• Neonatal adrenoleukodystrophy • Diphtheritic neuropathy
• Other genetic defects • Heavy metals, biologic toxins, or drug intoxication
• Familial dysautonomia • Acute intermittent porphyria
• Oculocerebrorenal syndrome (Lowe syndrome) • Vasculitic neuropathy
• Other metabolic defects • Critical illness neuropathy
• Acid maltase deficiency (see “Metabolic Myopathies”) • Lymphomatous neuropathy
• Infantile GM gangliosidosis Disorders of neuromuscular transmission
Spinal cord disorders • Myasthenia gravis
Spinal muscular atrophies • Biologic or industrial toxins
• Acute infantile • Tic paralysis
• Autosomal dominant Disorders of muscle
• Autosomal recessive • Hypokalemia
• Cytochrome-c oxidase deficiency • Hypophosphatemia
• X-linked • Inflammatory myopathy
• Chronic infantile • Acute rhabdomyolysis
• Autosomal dominant • Trichinosis
• Autosomal recessive • Familial periodic paralyses (normokalemic, hypokalemic,
• Congenital cervical spinal muscular atrophy hyperkalemic)
• Infantile neuronal degeneration
From Hughes RAC, Camblath DR: Guillain-Barré syndrome, Lancet 366:1653–
• Neurogenic arthrogryposis
1666, 2005.
Polyneuropathies
• Congenital hypomyelinating neuropathy
• Giant axonal neuropathy
• Hereditary motor-sensory neuropathies Nerve Biopsy
Disorders of neuromuscular transmission The most commonly sampled nerve is the sural nerve, a pure sensory
• Familial infantile myasthenia nerve that supplies a small area of skin on the lateral surface of the
• Infantile botulism foot. Whole or fascicular biopsy specimens of this nerve may be taken.
• Transitory myasthenia gravis
When the sural nerve is severed behind the lateral malleolus of the
Fiber-type disproportion myopathies
• Central core disease ankle, regeneration of the nerve occurs in more than 90% of cases, so
• Congenital fiber-type disproportion myopathy that permanent sensory loss is not experienced. The sural nerve is often
• Myotubular (centronuclear) myopathy involved in many neuropathies whose clinical manifestations are pre-
• Acute dominantly motor.
• Chronic Electron microscopy is performed on most nerve biopsy specimens
• Nemaline (nemaline rod) myopathy because many morphologic alterations cannot be appreciated at the
• Autosomal dominant resolution of a light microscope. Teased fiber preparations are some-
• Autosomal recessive times useful in demonstrating segmental demyelination, axonal swell-
Metabolic myopathies
ings, and other specific abnormalities, but these time-consuming
• Acid maltase deficiency (Pompe disease)
• Cytochrome-c oxidase deficiency procedures are not done routinely. Special stains may be applied to
• Other mitochondrial disorders ordinary frozen or paraffin sections of nerve biopsy material to dem-
• Muscular dystrophies onstrate myelin, axoplasm, and metabolic products.
• Bethlem myopathy The molecular genetic identification of the specific mutation in
• Congenital dystrophinopathy many of the hereditary motor and sensory neuropathies, determined
• Congenital muscular dystrophy from blood samples, has rendered the nerve biopsy much less often
• Merosin deficiency primary performed than in the past, but it retains a great value in selected cases
• Merosin deficiency secondary for which the etiology remains elusive despite genetic and electrophysi-
• Merosin positive
ological testing.
• Congenital myotonic dystrophy
From Fenichel GM: The hypotonic infant. In Fenichel GM, editor: Clinical Cardiac Assessment
pediatric neurology: a signs and symptoms approach, ed 5, Philadelphia, 2005, Cardiac evaluation is important if myopathy is suspected because of
Saunders, p. 150.
involvement of the heart in muscular dystrophies and in inflammatory
and metabolic myopathies. Electrocardiography often detects early
cardiomyopathy or conduction defects that are clinically asymptomatic.
each of the various muscular dystrophies and include the dystrophins, At times, a more complete cardiac work-up, including echocardiogra-
merosin, sarcoglycans, and dystroglycans. Ryanodine receptors, phy and consultation with a pediatric cardiologist, is indicated. Serial
important in myasthenia gravis and in malignant hyperthermia, also pulmonary function tests also should be performed in muscular dys-
now can be demonstrated. In addition, immunocytochemical reactivi- trophies and in other chronic or progressive diseases of the motor unit.
ties can distinguish the various types of inflammatory cells in autoim-
mune myopathies, including T and B lymphocytes and macrophages. Bibliography is available at Expert Consult.
Chapter 607 ◆ Evaluation and Investigation 2963.e1
Bibliography Perreault S, Birca A, Piper D, et al: Transient creatine phosphokinase elevations in

Fardeau M, Desguerre I: Diagnostic workup for neuromuscular disease. In Dulac children: a single-center experience, J Pediatr 159:682–689, 2011.
O, Lassonde M, Sarnat HB, editors: Handbook of clinical neurology, vol 113, 3rd Prasad AN, Prasad C: The floppy infant: contribution of genetic and metabolic
series, Edinburgh, 2013, Elsevier, pp 1291–1297. disorders, Brain Dev 27:457–476, 2003.
Fenichel GM: Clinical pediatric neurology: a signs and symptoms approach, ed 5, Tuysuz B, Kartal N, Erener-Ercan T, et al: Prevalence of Prader-Willi syndrome
Philadelphia, 2005, Elsevier Saunders. among infants with hypotonia, J Pediatr 164:1064–1067, 2014.
sporadic. Although clinical features, including phenotype, can raise a

strong suspicion of a congenital myopathy, the definitive diagnosis is
Chapter 608 determined by the histopathologic findings in the muscle biopsy speci-
men. In conditions for which the defective gene has been identified,
Developmental Disorders the diagnosis may be established by the specific molecular analysis
of the suspected gene expressed in lymphocytes. The morphologic
and histochemical abnormalities differ considerably from those of the
of Muscle muscular dystrophies, spinal muscular atrophies, and neuropathies.
Many are reminiscent of the embryologic development of muscle,
Harvey B. Sarnat thus suggesting possible defects in the genetic regulation of muscle
development.
Congenital myopathies often show closer genetic relationships than
previously appreciated between entities that have quite distinct patho-
logic phenotypes in the muscle biopsy and also distinctiveness in clini-
A heterogeneous group of congenital neuromuscular disorders is cal expression with a degree of overlap. For example, mutation of the
known as the congenital myopathies (Tables 608-1 and 608-2). Most tropomyosin-3 (TPM3) gene is one of the well-documented etiologies of
of these disorders have subcellular abnormalities that can be demon- nemaline myopathy, but identical genetic mutations of this gene are
strated only by muscle biopsy, by means of histochemistry and electron more recently also shown to be capable of causing isolated congenital
microscopy. In others, the muscle biopsy abnormality is not a subcel- fiber-type disproportion without nemaline rods, cap myopathy, centro-
lular anatomic defect but an aberration in the ratio and sizes of specific nuclear (“myotubular”) myopathy, and central core/minicore disease.
myofiber types. A genetic basis is demonstrated in many of the con-
genital myopathies, and molecular genetic testing from blood samples MYOGENIC REGULATORY GENES AND
may confirm the diagnosis without muscle biopsy. GENETIC LOCI OF INHERITED DISEASES
Most congenital myopathies are nonprogressive conditions, but OF MUSCLE
some patients show slow clinical deterioration accompanied by addi- A family of 4 myogenic regulatory genes shares encoding transcription
tional changes in their muscle histology. In some congenital myopa- factors of “basic helix-loop-helix” proteins associated with common
thies, such as severe neonatal nemaline myopathy, the clinical DNA nucleotide sequences. These genes direct the differentiation of
expression can be life-threatening because of dysphagia and respira- striated muscle from any undifferentiated mesodermal cell. The earliest
tory and/or cardiac insufficiency. Cardiomyopathy develops in some basic helix-loop-helix gene to program the differentiation of myoblasts
patients with congenital myopathies (Table 608-3). Most of the diseases is myogenic factor 5 (MYF5). The second gene, myogenin, promotes
in the category of congenital myopathies are hereditary; others are Text continued on p. 2970
Table 608-1 Classification of Muscular Dystrophies

OMIM GENE MAIN
INHERITANCE NUMBER LOCUS SYMBOL PROTEIN LOCALIZATION
Duchenne or Becker X-R 310200 Xq21⋅2 DMD Dystrophin Sarcolemma-
muscular dystrophy (Duchenne); associated protein
300376
(Becker)
LIMB-GIRDLE MUSCULAR DYSTROPHY
Type 1A AD 159000 5q31 MYOT Myotilin Sarcomere-
associated protein
(Z disc)
Type 1B AD 159001 1q21⋅2 LMNA Lamin A/C Nuclear lamina-
associated protein
Type 1C AD 607780 3p25 CAV3 Caveolin-3 Sarcolemma-
associated protein
Type 1D AD 603511 7q DNAJB6 Co-chaperone DNAJB6 Sarcomere-
associated protein
(Z disc)
Type 1E AD 602067 6q23 DES Desmin Intermediate
filament protein
Type 1F AD 608423 7q32 Unknown Unknown Unknown
Type 1G AD 609115 4p21 Unknown Unknown Unknown
Type 1H AD 613530 3p23–p25 Unknown Unknown Unknown
Type 2A AR 253600 15q15⋅1 CAPN3 Calpain-3 Myofibril-associated
proteins
Type 2B AR 253601 2p13 DYSF Dysferlin Sarcolemma-
associated protein
Type 2C AR 253700 13q12 SGCG γ-Sarcoglycan Sarcolemma-
associated protein
Type 2D AR 608099 17q12– SGCA α-Sarcoglycan Sarcolemma-
q21⋅33 associated protein
Type 2E AR 604286 4q12 SGCB β-Sarcoglycan Sarcolemma-
associated protein
Type 2F AR 601287 5q33 SGCD δ-Sarcoglycan Sarcolemma-
associated protein
Chapter 608 ◆ Developmental Disorders of Muscle 2965
Table 608-1 Classification of Muscular Dystrophies—cont’d

OMIM GENE MAIN
Type 2G AR 601954 17q12 TCAP Titin cap (telethonin) Sarcomere-
associated protein
(Z disc)
Type 2H AR 254110 9q31–q34 TRIM32 Tripartite motif- Sarcomeric-
containing 32 associated protein
(ubiquitin ligase) (Z disc)
Type 2I AR 607155 19q13⋅3 FKRP Fukutin-related protein Putative
glycosyltransferase
enzymes
Type 2J AR 608807 2q31 TTN Titin Sarcomeric protein
Type 2K AR 609308 9q34 POMT1 Protein-1-O- Glycosyltransferase
mannosyltransferase 1 enzymes
Type 2L AR 611307 11p14⋅3 ANO5 Anoctamin 5 Transmembrane
protein, possible
sarcoplasmic
reticulum
Type 2M AR 611588 9q31 FKTN Fukutin Putative
glycosyltransferase
enzymes
Type 2N AR 613158 14q24 POMT2 Protein-O- Glycosyltransferase
mannosyltransferase 2 enzymes
Type 2O AR 613157 1p34 POMGNT1 Protein-O-linked Glycosyltransferase
mannose β 1,2-N- enzymes
aminyltransferase 1
Type 2P AR 613818 3p21 DAG1 Dystrophin-associated Sarcomeric-
glycoprotein 1 associated protein
Type 2Q AR 613723 8q24 PLEC1 Plectin 1 Sarcolemma-
associated protein
(Z disc)
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY
Type 1 AD 158900 4q35 Unknown DUX4 and chromatin Nuclear
rearrangement
Type 2 AD 158901 18 Unknown SMCHD1 Structural
maintenance of
chromosome’s
flexible hinge
domain containing
1
EMERY-DREIFUSS MUSCULAR DYSTROPHY
X-linked type 1 X-R 310300 Xq28 EMD Emerin Nuclear membrane
protein
X-linked type 2 X-R 300696 Xq27⋅2 FHL1 Four and a half LIM Sarcomere and
domain 1 sarcolemma
Autosomal dominant AD 2181350 1q21⋅2 LMNA Lamin A/C Nuclear membrane
protein
Autosomal recessive AR 604929 1q21⋅2 LMNA Lamin A/C Nuclear membrane
protein
With nesprin-1 defect AD 612998 6q25 SYNE1 Spectrin repeat Nuclear membrane
containing, nuclear protein
envelope 1 (nesprin-
1)
With nesprin-2 defect AD 5612999 4q23 SYNE2 Spectrin repeat Nuclear membrane
containing, nuclear protein
envelope 2 (nesprin-
2)
Congenital muscular AR 607855 6q2 LAMA2 Laminin α2 chain of Extracellular matrix
dystrophy with merosin merosin proteins
deficiency (MDC1A)
Congenital muscular AR 604801 1q42 Unknown Unknown Unknown
dystrophy
Congenital muscular AR 606612 19q13 FKRP Fukutin-related protein Putative
dystrophy and abnormal glycosyltransferase
glycosylation of enzymes
dystroglycan (MDC1C)
Congenital muscular AR 608840 22q12 LARGE Like-glycosyl Putative
dystrophy and abnormal transferase glycosyltransferase
glycosylation of enzymes
dystroglycan (MDC1D)
Fukuyama congenital AR 253800 9q31–q33 FCMD Fukutin Putative
muscular dystrophy glycosyltransferase
enzymes
Continued
Table 608-1 Classification of Muscular Dystrophies—cont’d

OMIM GENE MAIN
WALKER–WARBURG SYNDROME
With fukutin defect AR 236670 9q31–q33 FCMD Fukutin Putative
glycosyltransferase
enzymes
With protein-O- AR 236670 9q34 POMT1 Protein-1-O- Glycosyltransferase
mannosyltransferase 1 mannosyltransferase 1 enzymes
defect
With protein-O- AR 236670 14q24 POMT2 Protein-O- Glycosyltransferase
defect
With protein-O-linked AR 236670 1p34 POMGNT1 Protein-O-linked Glycosyltransferase
mannose β 1,2-N- mannose β 1,2-N- enzymes
aminyltransferase 1 aminyltransferase 1
defect
With fukutin-related AR 236670 19q13 FKRP Fukutin-related protein Putative
protein defect glycosyltransferase
enzymes
MUSCLE-EYE-BRAIN DISEASE
With protein-O-linked AR 253280 1p34 POMGNT1 Protein-O-linked Glycosyltransferase
mannose β 1,2-N- mannose β 1,2-N- enzymes
aminyltransferase 1 aminyltransferase 1
defect
With fukutin-related AR 253280 19q13 FKRP Fukutin-related protein Putative
protein defect glycosyltransferase
enzymes
With protein-O- AR 253280 14q24 POMT2 Protein-O- Glycosyltransferase
defect
Congenital muscular AR NA 9q34⋅1 DPM2 Dolichyl-phosphate Glycosyltransferase
dystrophy caused by mannosyltransferase enzymes
glycosylation disorder polypeptide 2
Congenital muscular AR NA 1q21⋅3 DPM3 Dolichyl-phosphate Glycosyltransferase
dystrophy caused by mannosyltransferase enzymes
glycosylation disorder polypeptide 3
Congenital muscular mtDNA 602541 22q13 CHKB Choline kinase Sarcolemmal and
dystrophy with mitochondrial
mitochondrial structural membrane
abnormalities
Congenital muscular AR 602771 1p36 SEPN1 Selenoprotein N1 Endoplasmic
dystrophy with rigid reticulum protein
spine syndrome
ULLRICH SYNDROME
With collagen type VI AR 254090 21q22⋅3 COL6A1 Collagen type VI, Extracellular matrix
subunit α1 defect subunit α1 proteins
With collagen type VI AR 254090 21q22⋅3 COL6A2 Collagen type VI, Extracellular matrix
With collagen type VI AR 254090 2q37 COL6A3 Collagen type VI, Extracellular matrix
Congenital muscular AR 613204 12q13 ITGA7 Integrin α7 External
dystrophy with integrin sarcolemmal
α7 defect protein
Congenital muscular AR NA 3p21⋅3 ITGA9 Integrin α9 External
dystrophy with integrin sarcolemmal
α9 defect protein
Muscular dystrophy with AR NA 17q21– PTRF Polymerase I and T tubules and
generalized q23 transcript release sarcolemma
lipodystrophy factor (cavin-1)
Oculopharyngeal AD or AR 164300 14q11⋅2 PABPN1 Polyadenylate-binding Unknown
muscular dystrophy protein nuclear 1
AD, autosomal dominant; AR, autosomal recessive; NA, not assigned; OMIM, Online Mendelian Inheritance in Man; X-R, X-linked recessive.
From Mercuri E, Muntoni F: Muscular dystrophies. Lancet 381:845–858, 2013, Table 1.
Table 608-2 Clinical Signs of Muscular Dystrophy
DISTRIBUTION RIGID RESPIRATORY DISEASE INCREASED
MOTOR FUNCTION OF WEAKNESS SPINE CARDIOMYOPATHY IMPAIRMENT COURSE CK OTHER SIGNS
CONGENITAL-ONSET MUSCULAR DYSTROPHY
Congenital muscular Independent ambulation Upper limbs > – Not frequent ++ Slowly progressive ++ White matter
dystrophy with merosin generally not achieved lower limbs changes on brain
deficiency in patients with absent MRI
merosin
Congenital muscular Independent ambulation Upper limbs > – Not frequent + Slowly progressive ++ Frequent structural
dystrophy and generally not achieved lower limbs brain changes
abnormal glycosylation
of dystroglycan
(Walker-Warburg
syndrome, muscle-eye-
brain disease,
congenital muscular
dystrophy type 1C, etc.)
Congenital muscular Ambulation achieved Axial muscles > ++ – Early respiratory Progression of N or + Scoliosis
dystrophy with rigid limbs failure respiratory signs
spine syndrome type 1 > motor signs
(SEPN1)
Ullrich syndrome Ambulation achieved in Proximal and ++ – Early respiratory Progression of N or + Distal laxity
~50% but lost by axial failure respiratory and
middle teens motor signs
FROM EARLY-ONSET TO CHILDHOOD-ONSET MUSCULAR DYSTROPHY
Chapter 608
Duchenne muscular Independent ambulation Proximal > distal – ++ ++ Progression of ++ Mental retardation
◆
dystrophy achieved, but lost (pattern A) motor, cardiac, in 30%

before age of 13 yr and respiratory
signs
Emery-Dreifuss muscular Ambulation achieved in Scapuloperoneal ++ ++ In adulthood in Slowly progressive + (+) Frequent
dystrophy with lamin all cases except for (pattern B) the typical association with
AC deficiency (type 2) rare cases with form, but also Dunningham-type
congenital onset in childhood lipodystrophy
(congenital
variants)
Limb-girdle muscular Independent ambulation Proximal > distal + ++ In adulthood Progression of + (+) None
dystrophy with lamin achieved, variable (pattern A) cardiac signs >
AC deficiency (type 1B) progression motor signs
Limb-girdle muscular Ambulation achieved Proximal > distal + – Not frequent Slow progression ++ None
dystrophy with calpain (pattern A)
deficiency (type 2A)
Continued
Developmental Disorders of Muscle 2967
Table 608-2 Clinical Signs of Muscular Dystrophy—cont’d
DISTRIBUTION RIGID RESPIRATORY DISEASE INCREASED
MOTOR FUNCTION OF WEAKNESS SPINE CARDIOMYOPATHY IMPAIRMENT COURSE CK OTHER SIGNS
2968 Part XXVIII
CHILDHOOD-ONSET AND ADULTHOOD-ONSET MUSCULAR DYSTROPHY

◆
Becker muscular Independent ambulation Proximal > distal – ++ Not frequent Progressive with ++ None
dystrophy achieved, variable (pattern A) substantial
progression variability
Limb-girdle muscular Independent ambulation Proximal > distal – ++ ++ Progression of ++ None
dystrophy with achieved, generally (pattern A) motor, cardiac,
sarcoglycan deficiency lost in the 2nd decade and respiratory
(types 2C, 2D, 2E, 2F) signs
Limb-girdle muscular Independent ambulation Proximal > distal – ++ +(+) Progressive ++ Mental retardation
dystrophy with achieved, variable (pattern A) reported in some
abnormal glycosylation progression cases
of dystroglycan (types
2I, 2K, 2L, 2M, 2N, 2O)
Limb-girdle muscular Independent ambulation Both pattern A – – – Progressive in ++ None
dystrophy with dysferlin always achieved and pattern E adulthood
Neuromuscular Disorders
deficiency (type 2B)

Limb-girdle muscular Independent ambulation Proximal > distal – + + Progressive in + (+) None
dystrophy with achieved, generally (pattern A); in adulthood
telethonin deficiency lost in the 4th decade some pattern
(type 2G) B
Limb-girdle muscular Independent ambulation Proximal > distal – – – Roughly half lose ++ None
dystrophy with titin achieved (pattern A) but ambulation in
deficiency (type 2J) also pattern E adulthood
Facioscapulohumeral Independent ambulation Pattern D – – Uncommon and Slowly progressive N or + Neurosensory
dystrophy achieved, variable mild hearing loss and
progression retinal
degeneration
Emery-Dreifuss muscular Independent ambulation Scapuloperoneal + ++ Not frequent Progression of + (+) None
dystrophy with merin achieved, variable (pattern B) cardiac signs >
deficiency (type 1) progression motor signs
ADULT-ONSET MUSCULAR DYSTROPHY
Limb-girdle muscular Onset in adulthood, 8 : 1 Mainly lower – – – Slowly progressive ++ None
dystrophy with ratio of men to women limbs pattern in adulthood
anoctamin deficiency A, rarely
(type 2L) pattern E
Limb-girdle muscular Independent ambulation Proximal > distal – – – Generally slowly + Dysarthria in some
dystrophy type 1A achieved (pattern A) progressive in cases
(myotilin) adulthood
Limb-girdle muscular Independent ambulation Proximal and – + – Slowly progressive, ++ Cramps, rippling,
dystrophy with caveolin achieved; rippling distal variable percussion-
deficiency (type 1C) might be seen before induced repetitive
weakness contractions
–, Absent; +, mild; ++, severe; +(+), variable; CK, creatine kinase; N, normal.
Table 608-3 Cardiac Involvement in Muscular Dystrophies

ONSET AND FIRST
SIGNS PROGRESSION CARDIAC DEATH SURVEILLANCE
Duchenne muscular Dilated cardiomyopathy Dilated cardiomyopathy Congestive heart failure Echocardiography every
dystrophy with reduced left- in almost all patients by or sudden death in 20% 2 yr in the 1st decade of
ventricular ejection 18 yr of age. Ventricular of patients, although life and annually after
fraction after 10 yr of dysrhythmias occur in the contribution of 10 yr of age (or more
age older patients heart to death of frequently if
ventilated patients is abnormalities are
now well established identified)
Becker muscular Dilated cardiomyopathy, Present in 40% of patients Death from congestive Echocardiography at least
dystrophy generally after 10 yr of older than 18 yr and heart failure and every 5 yr
age more than 80% of those arrhythmias is estimated
older than 40 yr. Most to occur in up to 50% of
patients develop dilated cases. Cardiac
cardiomyopathy transplants reported
followed by ventricular
arrhythmias
Myotonic dystrophy Cardiac abnormalities can Conduction deficits occur 20-30% of patients; mean ECG yearly. Holter
occur as early as the in about 65% of adult 54 yr of age. Sudden monitoring is
2nd decade of life patients death is mainly caused recommended in
by conduction blocks, patients with ECG
but ventricular abnormalities to detect
tachyarrhythmias are asymptomatic
also a possible cause of conduction blocks and
death arrhythmias
EMERY-DREIFUSS MUSCULAR DYSTROPHY
X-linked recessive Conduction disturbances Ventricular myocardium Sudden death is by far ECG and yearly Holter
Emery-Dreifuss generally in the 2nd might become involved, the most common monitoring are
muscular dystrophy decade leading to mild cause of death and can indicated. Pacemaker
(type 1) ventricular dilation and be very unpredictable implantation should be
low-to-normal systolic considered if sinus node
function or atrioventricular node
disease develops.
Defibrillator might be
needed in some patients
Emery-Dreifuss Conduction disease and Dysrhythmias (sinus Sudden death reported ECG and yearly Holter
muscular dystrophy cardiac failure bradycardia, also in patients with monitoring are
2 and limb-girdle atrioventricular pacemaker. Rare death indicated. Defibrillator
muscular dystrophy conduction block, or with defibrillator also implantation should be
1B atrial arrhythmias) reported. Cardiac considered as
present in 92% of failure. Cardiac pacemaker does not
patients older than 30 yr transplants reported have a substantial effect
on mortality
LIMB-GIRDLE MUSCULAR DYSTROPHY
Sarcoglycanopathies ECG and/or Severe dilated Typically by cardiac No evidence-based
echocardiographic cardiomyopathy and failure. Cardiac standards of care exist,
abnormalities reported lethal ventricular transplants reported but experts have made
in 20-30% of patients arrhythmias might occur recommendations
(especially β and δ in patients with
variants; less common in Duchenne muscular
α variant) dystrophy–like
dystrophy
Limb-girdle muscular Cardiac involvement Symptomatic cardiac Cardiac failure. Cardiac No evidence-based
dystrophy 2I reported in 29-62% of failure over time, at a transplants reported standards of care exist,
limb-girdle muscular mean age of 38 yr but experts have made
dystrophy 2I. Dilated (range: 18-58 yr) recommendations
cardiomyopathy may
start in teenage yr
Limb-girdle muscular Dilated, restrictive, Major cardiac signs, such Life-threatening cardiac No evidence-based
dystrophy 1E hypertrophic as atrioventricular block, complications in roughly standards of care exist,
cardiomyopathies and can be the presenting 50% of patients, at a but experts have made
arrhythmias. Cardiac symptom or occur mean age of 40 yr, recommendations
involvement can within a decade of including sudden death,
precede muscle onset of muscle end-stage heart failure,
weakness in some weakness atrioventricular block,
patients and syncope
Continued
Table 608-3 Cardiac Involvement in Muscular Dystrophies—cont’d

ONSET AND FIRST
SIGNS PROGRESSION CARDIAC DEATH SURVEILLANCE
CONGENITAL MUSCULAR DYSTROPHY
Congenital muscular Occasional reports of Not well characterized Rare by cardiac failure No evidence-based
dystrophy merosin reduced left ventricular standards of care exist,
muscular dystrophy systolic function but experts have made
type C1A recommendations
Fukuyama Systolic left-ventricular Symptomatic cardiac Death from congestive No evidence-based
congenital dysfunction may failure over time heart failure might standards of care exist,
muscular dystrophy develop in the 2nd occur by the age of but experts have made
decade 20 yr recommendations
Muscular dystrophy Dilated cardiomyopathy Not well characterized Not reported No evidence-based
type C1C reported in young standards of care exist,
children but experts have made
recommendations
Facioscapulohumeral Uncommon Not well characterized Not reported No evidence-based
muscular dystrophy standards of care exist,
but experts have made
recommendations
ECG, electrocardiogram.
fusion of myoblasts to form myotubes. Herculin (also known as MYF6) development at 8-15 wk of gestation. It was based on the morpho-
and MYOD1 are the other 2 myogenic genes. Myf5 cannot support logic appearance of myofibers as a row of central nuclei and mito-
myogenic differentiation without myogenin, MyoD, and MYF6. Each chondria within a core of cytoplasm, with contractile myofibrils
of these 4 genes can activate the expression of at least 1 other and, forming a cylinder around this core (Fig. 608-1). These morphologi-
under certain circumstances, can autoactivate as well. Another recently cally abnormal myofibers are not true fetal myotubes, however; hence
discovered gene known as myomaker also facilitates myoblast fusion. the more neutral and descriptive term centronuclear myopathy is
The expression of MYF5 and of herculin is transient in early ontogen- preferred.
esis but returns later in fetal life and persists into adult life.
The human locus of the MYOD1 gene is on chromosome 11, very PATHOGENESIS
near to the domain associated with embryonal rhabdomyosarcoma. The common pathogenesis involves loss of myotubularin protein,
The genes Myf5 and herculin are on chromosome 12, and myogenin is leading to structural and functional abnormalities in the organization
on chromosome 1. of T-tubules and sarcoplasmic reticulum and defective excitation-
The myogenic genes are activated during muscle regeneration, reca- contraction coupling.
pitulating the developmental process; MyoD in particular is required
for myogenic stem cell (satellite cell) activation in adult muscle. PAX3, CLINICAL MANIFESTATIONS
PAX7, and WNT3a genes also play important roles in myogenesis Fetal movements can decrease in late gestation. Polyhydramnios is a
and interact with each of the 4 basic genes mentioned above. Another common complication because of pharyngeal weakness of the fetus
gene, myostatin, is a negative regulator of muscle development by pre- and inability to swallow amniotic fluid.
venting myocytes from differentiating. The precise integrative roles of At birth, affected infants have a thin muscle mass involving axial,
the myogenic genes in developmental myopathies are not yet fully limb girdle, and distal muscles; severe generalized hypotonia; and
defined. diffuse weakness. Respiratory efforts may be ineffective, requiring ven-
The myogenic genes are important not only for fetal myogenesis but tilatory support. Gavage feeding may be required because of weakness
also for regeneration of muscle at any age, particularly in degenerative of the muscles of sucking and deglutition. The testes are often unde-
diseases such as muscular dystrophies and autoimmune inflammatory scended. Facial muscles may be weak, but infants do not have the
myopathies and in injuries of muscle secondary to trauma or to toxins. characteristic facies of myotonic dystrophy. Ptosis may be a prominent
Satellite cells in mature muscle that mediate regeneration have the feature. Ophthalmoplegia is observed in a few cases. The palate may
same somitic origin as embryonic muscle progenitor cells, but the be high. The tongue is thin, but fasciculations are not seen. Tendon
genes that regulate them differ. Pax3 and Pax7 mediate the migration stretch reflexes are weak or absent.
of primitive myoblast progenitors from the myotomes of the somites Myotubular myopathy is not associated with cardiomyopathy
to their peripheral muscle sites in the embryo, but only 1 of 2 Pax7 (mature cardiac muscle fibers normally have central nuclei), but one
genes continues to act postnatally for satellite cell survival. Then it, too, report describes complete atrioventricular block without cardiomy-
no longer is required after the juvenile period for muscle satellite (i.e., opathy in a patient with confirmed X-linked myotubular myopathy.
stem) cells to become activated for muscle regeneration. Congenital anomalies of the central nervous system or of other systems
are not associated. A single patient with progressive dementia was
Bibliography is available at Expert Consult. reported, who had a mutation removing the start signal of exon 2.
Patients with much milder symptoms or a much later age of onset with
mutations in the same gene are now known. Some of these are mani-
608.1 Myotubular Myopathy festing carriers.
(Centronuclear Myopathy) LABORATORY FINDINGS
Harvey B. Sarnat Serum levels of creatine kinase (CK) are normal. Electromyography
does not show evidence of denervation; results are usually normal
The term myotubular myopathy is a misnomer because it implies or show minimal nonspecific myopathic features in early infancy.
maturational arrest of fetal muscle during the myotubular stage of Nerve conduction velocity may be slow but is usually normal. The
Chapter 608 ◆ Developmental Disorders of Muscle 2970.e1
Bibliography Romero NB, Mezmezian M, Fidziańska A: Main steps of skeletal muscle

Bentzinger CF, Wang YX, Rudnicki MA: Building muscle: molecular regulation of development in the human. Morphological analysis and ultrastructural
myogenesis, Cold Spring Harb Perspect Biol 4(2):2012. characteristics of developing human muscle, Handb Clin Neurol 113:1299–1310,
Finsterer J, Stollberger C, Wahbi K: Cardiomyopathy in neurological disorders, 2013.
Cardiovasc Pathol 22:389–400, 2013. von Maltzahn J, Chang NC, Bentzinger CF, et al: Wnt signalling in myogenesis,
Mercuri E, Muntoni F: Muscular dystrophies, Lancet 381:845–858, 2013. Trends Cell Biol 22:602–609, 2012.
Millay DP, O’Rourke JR, Sutherland LB, et al: Myomaker is a membrane activator von Maltzahn J, Jones AE, Parks RJ, et al: Pax7 is critical for the normal function
of myoblast fusion and muscle formation, Nature 499:301–315, 2013. of satellite cells in adult skeletal muscle, Proc Natl Acad Sci U S A 110:16474–
Price F, Rudnicki MA: Satellite cells and the muscle stem cell niche, Physiol Rev 16479, 2013.
93:23–67, 2013.
Relaix F, Rocancourt D, Mansouri A, et al: A Pax3/Pax7-dependent population of
skeletal muscle progenitor cells, Nature 435:948–953, 2005.
Histochemical stains for oxidative enzymatic activity and glycogen

reveal a central distribution as in fetal myotubes. The cylinder of myo-
fibrils shows mature histochemical differentiation with adenosine tri-
phosphatase stains. The connective tissue of muscle spindles, blood
vessels, intramuscular nerves, and motor end plates is mature. Ultra-
structural features other than those that define the disease are also
mature. Electron microscopy shows disorganized triads and focal
loss of myofilaments. Vimentin and desmin show strong immunore-
activity in muscle fibers in congenital centronuclear myopathy and
no demonstrable activity in normal term neonatal muscle. The molec-
ular genetic marker in blood is available also for early prenatal
diagnosis if suspicion is strong because of family history. Table
A 608-4 distinguishes centronuclear myopathy from other congenital
myopathies.
GENETICS
At least 5 genes are involved in this disorder and account for approxi-
mately 80% of patients. These include mutations in myotubularin
(MTM1 gene) with X-linked severe manifestations; dynamin 2 (DNM2)
with autosomal dominant or sporadic occurrence; amphiphysin 2
(BIN1) and titin (TTN) mutations with autosomal recessive inheri-
tance and ryanodine receptor 1 (RYR1), with autosomal recessive or
sporadic occurrence.
X-linked recessive inheritance is the most common trait in this
disease affecting boys. The mothers of affected infants are clinically
asymptomatic, but their muscle biopsy specimens show minor altera-
tions. Genetic linkage on the X chromosome has been localized to the
Xq28 site, a locus different from the Xp21 gene of Duchenne and
B Becker muscular dystrophies. A deletion in the responsible MTM1
gene has been identified. It encodes a protein called myotubularin.
This gene belongs to a family of similar genes encoding enzymatically
active and inactive forms of phosphatidylinositol-3-phosphatases
that form dimers. MTM1, dynamin-2, and amphiphysin all are local-
ized to the T-tubule wall in triads. This crucial region is where the
action potential releases a signal to the ryanodine receptor to release
calcium. The pathogenesis is in the regulation of enzymatic activity and
binding to other proteins induced by dimer interactions. Although
only a single MTM1 gene is involved, 5 distinct point mutations and
many different alleles, as well as large duplications, can produce the
same clinical disease. Mutations in the dynamin-2 protein result in an
autosomal dominant form of centronuclear myopathy and may account
for up to half of all patients with centronuclear myopathy, but these
cases usually are mild and might not manifest clinically until adult
life as diffuse, slowly progressive weakness and generalized muscular
pseudohypertrophy.
Other rarer centronuclear myopathies also are known; some are
autosomal recessive and affect both sexes and others are sporadic and
C of unknown genetic origin. The recessive forms are sometimes divided
into an early-onset form with or without ophthalmoplegia and a late-
Figure 608-1 Cross section of muscle from a 14 wk old human fetus onset form without ophthalmoplegia.
(A), a normal full-term neonate (B), and a term neonate with X-linked
recessive myotubular myopathy (C). Myofibers have large central nuclei TREATMENT
in the fetus and in myotubular myopathy patient, and nuclei are at the
Only supportive and palliative treatment is presently available. Pro-
periphery of the muscle fiber in the term neonate as in the adult (hema-
toxylin and eosin, ×500). gressive scoliosis may be treated by long posterior fusion. Genetic and
neuropathologic studies of X-linked centronuclear (“myotubular”)
myopathy have led to effective gene therapy in mice and in dogs, so
that even after a single dose the animals are more ambulatory and have
much improved weakness. Gene replacement therapy in this disease is
electrocardiogram appears normal. Chest radiographs show no cardio- now being studied in humans.
megaly; the ribs may be thin.
PROGNOSIS
DIAGNOSIS Approximately 75% of severely affected neonates with the X-linked
If the diagnosis is strongly suspected from the clinical presentation, disease die within the 1st few wk or mo of life. Survivors do not experi-
especially if this diagnosis was confirmed in a sibling, genetic tests can ence a progressive course but have major physical handicaps, rarely
be performed in the neonatal period. In most cases the diagnosis is not walk, and remain severely hypotonic. Late-onset and especially auto-
so evident, but the muscle biopsy findings are diagnostic at birth, even somal dominant forms have a much better prognosis, often with mild
in premature infants. More than 90% of muscle fibers are small and static weakness.
have centrally placed, large vesicular nuclei in a single row. Spaces
between nuclei are filled with sarcoplasm containing mitochondria. Bibliography is available at Expert Consult.
Bibliography Lawlor MW, Armstrong D, Viola MG, et al: Enzyme replacement therapy rescues
Amburgey K, Lawlor MW, Del Gaudio D, et al: Large duplications in MTM1 weakness and improves muscle pathology in mice with X-linked myotubular
associated with myotubular myopathy, Neuromuscul Disord 23:214–218, 2013. myopathy, Hum Mol Genet 22:1525–1538, 2013.
Catteruccia M, Fattori F, Codemo V, et al: Centronuclear myopathy related to Pierson CR, Tomczak K, Agrawal P, et al: X-linked myotubular and centronuclear
dynamin-2 mutations: clinical, morphological, muscle imaging and genetic myopathies, J Neuropathol Exp Neurol 64:555–564, 2005.
features of an Italian cohort, Neuromuscul Disord 23:229–238, 2013. Romero NB: Centronuclear myopathies: a widening concept, Neuromuscul Disord
Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, et al: Recessive truncating titin gene, 20:229–237, 2010.
TTN mutations presenting as centronuclear myopathy, Neurology 81:1–10, 2013.
Dowling JJ, Vreede AP, Low SE, et al: Loss of myotubularin function results in
T-tubule disorganization in zebrafish and human myotubular myopathy, PLoS
Genet 5:e1000372, 2009.
Table 608-4 Specific Congenital Myopathies: Distinguishing Clinical Features

NEONATAL SEVERE FORM EXTRAOCULAR
HYPOTONIA WITH NEONATAL FACIAL MUSCULAR
MYOPATHY AND WEAKNESS DEATH WEAKNESS PTOSIS WEAKNESS
Central core disease + 0 ± 0 0
Nemaline myopathy + + + 0 0
Myotubular myopathy + + + + +
(centronuclear myopathy)
Congenital fiber-type + ± ± 0 +
disproportion
+, Often a prominent feature; ±, variably a prominent feature; 0, not a prominent feature.
From Volpe JJ: Neurology of the newborn, ed 5, Philadelphia, 2008, Elsevier Saunders, p. 820.
608.2 Congenital Muscle Fiber-Type DIAGNOSIS

CMFTD is diagnosed by muscle biopsy that shows disproportion in
Disproportion size and relative ratios of histochemical fiber types: Type I fibers are
Harvey B. Sarnat uniformly small, and type II fibers are hypertrophic; type I fibers are
more numerous than type II fibers. Degeneration of myofibers and
Congenital muscle fiber-type disproportion (CMFTD) occurs as an other primary myopathic features are absent. The biopsy is diagnostic
isolated congenital myopathy but also develops in association with at birth. Table 608-2 lists the features that distinguish CMFTD from
various unrelated disorders that include nemaline rod disease, Krabbe other congenital myopathies.
disease (globoid cell leukodystrophy) early in the course before expres-
sion of the neuropathy, cerebellar hypoplasia and certain other brain GENETICS
malformations, fetal alcohol syndrome, some glycogenoses, multiple Many cases of simple CMFTD are sporadic, although autosomal reces-
sulfatase deficiency, Lowe syndrome, rigid spine myopathy, and some sive inheritance is well documented in some families and an autosomal
infantile cases of myotonic muscular dystrophy. CMFTD should, dominant trait is suspected in others. The genetic basis is heteroge-
therefore, be regarded as a syndrome, unless a specific genetic mutation neous in hereditary forms; a mutation in the insulin receptor gene at
is confirmed. 19p13.2 is reported. Translocation t(10;17) was seen in 1 family.
X-linked transmission with linkage to Xp23.12-p11.4 and Xq13.1-q22.1
PATHOGENESIS also is described. In 3 unrelated families with CMFTD, a heterozygous
The association of CMFTD with cerebellar hypoplasia suggests that the missense mutation of the skeletal muscle α-actin gene (ACTA1) was
pathogenesis may be an abnormal suprasegmental influence on the demonstrated, but this genetic defect represents a minority; mutations
developing motor unit during the stage of histochemical differentiation in TPM3 are a more common genetic finding. As with X-linked myo-
of muscle between 20 and 28 wk of gestation. Muscle fiber types and tubular myopathy, large duplications in the TPM3 gene can cause
growth are determined by innervation and are mutable even in adults. CMFTD. In CMFTD associated with cerebellar hypoplasia, the genetic
Although CMFTD does not actually correspond with any normal stage effect is on cerebellar development and the muscular expression is
of development, it appears to be an embryologic disturbance of fiber secondary.
type differentiation and growth.
TREATMENT
CLINICAL MANIFESTATIONS No drug therapy is available. Physiotherapy may be helpful for some
As an isolated condition not associated with other diseases, CMFTD patients in strengthening muscles that do not receive sufficient exercise
is a nonprogressive disorder present at birth. Patients have generalized in daily activities. Mild congenital contractures often respond well to
hypotonia and weakness, but the weakness is usually not severe and gentle range-of-motion exercises and rarely require plaster casting or
respiratory distress and dysphagia are rare. Contractures are present at surgery.
birth in 25% of patients. Poor head control and developmental delay
for gross motor skills are common in infancy. Walking is usually Bibliography is available at Expert Consult.
delayed until 18-24 mo but is eventually achieved. Because of the hypo-
tonia, subluxation of the hips can occur. Muscle bulk is reduced. The
muscle wasting and hypotonia are proportionately greater than the
weakness, and the child may be stronger than expected during exami- 608.3 Nemaline Rod Myopathy
nation. Cardiomyopathy is a rare complication. Harvey B. Sarnat
The facies of children with CMFTD often raise suspicion, especially
if the child is referred for assessment of developmental delay and hypo- Nemaline rods (derived from the Greek nema, meaning “thread”) are
tonia. The head is dolichocephalic, and facial weakness is present. The rod-shaped, inclusion-like abnormal structures within muscle fibers.
palate is usually high arched. Thin muscles of the trunk and extremities They are difficult to demonstrate histologically with conventional
give a thin, wasted appearance. The phenotype is very similar to that hematoxylin-and-eosin stain, but are easily seen with special stains.
of nemaline myopathy that also includes CMFTD as part of the patho- They are not foreign inclusion bodies but rather consist of excessive
logic picture. Patients do not complain of myalgias. The clinical course Z-band material with a similar ultrastructure (Fig. 608-2). Chemically,
is nonprogressive. the rods are composed of actin, α-actinin, tropomyosin-3, and the
protein nebulin. Nemaline rod formation may be an unusual reaction
LABORATORY FINDINGS of muscle fibers to injury because these rod structures have rarely been
Serum CK, electrocardiogram, electromyography, and nerve conduc- found in other diseases. They are most abundant in the congenital
tion velocity results are normal in simple CMFTD. If other diseases are myopathy known as nemaline rod disease. Most rods are within the
associated, laboratory investigation of those conditions discloses the myofibrils, but intranuclear rods are occasionally demonstrated by
specific features. electron microscopy. Intranuclear rods occur mainly in neonates with
Bibliography Laing NC, Clarke NF, Dye DE, et al: Actin mutations are one cause of congenital
Amburgey K, Lawlor MW, Del Gaudio D, et al: Large duplications in MTM1 fibre type disproportion, Ann Neurol 56:689–694, 2004.
associated with type I myofiber hypotrophy in congenital fiber-type Lawlor MW, Dechene ET, Roumm E, et al: Mutations of tropomyosin 3 (TPM3)
disproportion, Hum Mutat 31:176–183, 2010. are common and associated with type 1 myofiber hypotrophy in congenital
Clarke NF, Kolski H, Dye D, et al: Mutations in TPM3 are a common cause of fiber type disproportion, Hum Mutat 31(2):176–183, 2010.
congenital fiber type disproportion, Ann Neurol 63:327–329, 2008. Sarnat HB: Congenital muscle fiber-type disproportion, San Diego, 2013, MedLink.
Clarke NF: Congenital fiber-type disproportion, Semin Pediatr Neurol 18:264–271, Schuelke M, Wagner KR, Stolz LE, et al: Myostatin mutation associated with gross
2011. muscle hypertrophy in a child, N Engl J Med 350:2682–2688, 2004.
nr
Figure 608-2 Electron micrograph of the muscle from a patient

shown in Figure 608-4. Nemaline rods (nr) are seen within many myo-
fibrils. They are identical in composition to the normal Z bands (z)
(×6,000).
Figure 608-4 Infantile form of nemaline rod disease in a 6 yr old

boy. Facial weakness and generalized muscle wasting are severe. The
head is dolichocephalic. The mouth is usually open because the mas-
seters are too weak to lift the mandible against gravity for more than
a few seconds.
The head is dolichocephalic, and the palate high arched or even

cleft. Muscles of the jaw may be too weak to hold it closed (Fig.
608-4). Decreased fetal movements are reported by the mother, and
neonates suffer from hypoxia and dysphagia; arthrogryposis may be
present. Infants with severe neonatal and infantile nemaline myopathy
have facies and phenotype that are nearly indistinguishable from
those of neonatal myotonic dystrophy, but their mothers have normal
facies. The juvenile form is the mildest and is not associated with
respiratory failure, but the phenotype, including facial involvement,
is similar.
LABORATORY FINDINGS
Serum CK level is normal or mildly elevated. The muscle biopsy is
diagnostic. In addition to the characteristic nemaline rods, it also
shows CMFTD or at least fiber type I predominance. In some patients,
uniform type I fibers are seen with few or no type II fibers. Focal
Figure 608-3 Back of a 13 yr old girl with the juvenile form of nema- myofibrillar degeneration and an increase in lysosomal enzymes have
line rod disease. The paraspinal muscles are very thin, and winging of been found in a few severe cases associated with progressive symptoms.
the scapulas is evident. The muscle mass of the extremities is also
greatly reduced proximally and distally.
Intranuclear nemaline rods, demonstrated by electron microscopy,
correlate with the most severe neonatal manifestations. Because nema-
line bodies can occur in other myopathies, their presence in the muscle
biopsy is not pathognomonic in the absence of the supportive clinical
severe weakness; they usually indicate ACTA1 mutations and may manifestations. Adult-onset cases may be associated with monoclonal
coexist with the more usual cytoplasmic rods. Nemaline myopathy gammopathy.
caused by ACTA1 mutation is one of a spectrum of “actinopathies.”
Mutations in tropomyosin-2 (TPM2) can cause a congenital myopa- GENETICS
thy related to nemaline rod myopathy, designated cap myopathy, in Autosomal dominant and autosomal recessive forms of nemaline
which accumulations of distorted myofilaments are focally present on rod disease occur, and an X-linked dominant form in girls also can
the periphery of fibers. They may coexist with myofibrillar nemaline occur. Nemaline myopathy can be caused by mutation in at least 7
rods. Somatic mosaicism is demonstrated in TPM2-related nemaline genes, including α-actin, α-tropomyosin, β-tropomyosin, troponin-T,
myopathy with cap structures. nebulin, cofilin-2, and Kelch-like family member (KLML40). The latter
causes severe neonatal autosomal recessive nemaline myopathy. The
CLINICAL MANIFESTATIONS proteins encoded for by all these genes are related to the thin filaments
Neonatal, infantile, and juvenile forms of the disease are known. of myofibrils. Dominant nemaline myopathy is most often caused by
The neonatal form is severe and usually fatal because of respiratory mutations in ACTA-1 or α-tropomyosin (TPM3 at the 1q21-q23 locus);
failure since birth. In the infantile form, generalized hypotonia and recessive mutations most frequently result from nebulin mutations
weakness, which can include bulbar-innervated and respiratory (2q21.2-q22 locus), which account for about half the cases of nemaline
muscles, and a very thin muscle mass are characteristic (Fig. 608-3). myopathy and are particularly prevalent in Ashkenazi Jews. Some
mutations in the α-actin gene give rise to a severe neonatal myopathy myofibers is now believed to be of little importance and they represent
with masses of exclusively thin filaments, with or without rods. Muta- the same basic disease process.
tions in tropomyosin-2 can cause a congenital myopathy with nonspe- The serum CK value is normal in central core disease except during
cific findings. In α-actin defects both autosomal dominant and crises of malignant hyperthermia, which can result in rhabdomyolysis
recessive varieties occur at the same 1q42.1 locus. The autosomal or extensive acute myofiber necrosis (see Chapter 611.2). Central core
dominantly inherited defect of β-tropomyosin at 9q13 and the disease is consistently associated with malignant hyperthermia, which
α-tropomyosin defects are rare and account for only 3% of patients can precede the diagnosis of central core disease. All patients should
with nemaline myopathy. An autosomal recessive troponin-T defect is have special precautions with pretreatment with dantrolene before an
at locus 19q13 and has been found only in the Amish population, in anesthetic agent is administered.
whom the incidence of nemaline myopathy is as high as 1 in 500,
whereas in Australia in non-Amish ethnic groups it is estimated at 1 Bibliography is available at Expert Consult.
in 500,000.
TREATMENT AND PROGNOSIS

Therapy is supportive. Survivors are confined to an electric wheelchair 608.5 Myofibrillar Myopathies
and are usually unable to overcome gravity. Both proximal and distal Harvey B. Sarnat
muscles are involved. Congenital arthrogryposis can occur and pre-
dicts a poor prognosis. Gastrostomy may be needed for chronic dys- Most myofibrillar myopathies are not symptomatic in childhood, but
phagia. In the juvenile form, patients are ambulatory and are able to occasionally older children and adolescents show early symptoms of
perform most tasks of daily living. Weakness is not usually progressive, nonspecific proximal and distal weakness. An infantile form also
but some patients have more difficulty over time or enter a phase of occurs and can cause mild neonatal hypotonia and weakness with
progressive weakness. Cardiomyopathy is an uncommon complica- disproportionately severe dysphagia and respiratory insufficiency, at
tion. Death usually results from respiratory insufficiency, with or times leading to early death. It is not progressive, however, and some
without superimposed pneumonia. patients show improvement in later infancy and early childhood,
acquiring the ability to swallow by 3 yr of age. Cardiomyopathy is a
Bibliography is available at Expert Consult. complication in a minority.
The diagnosis is by muscle biopsy: some sarcomeres of myofibers
have disorganization or dissolution of myofibrils adjacent to other
608.4 Central Core, Minicore, and areas of normal sarcomeres within the same fiber. These zones are
associated with streaming of the Z bands and focally increased desmin
Multicore Myopathies intermediate filaments, myotilin, and αB-crystallin. Immunocyto-
Harvey B. Sarnat chemical and ultrastructural study of the muscle biopsy tissue is
required. Mutation in the desmin gene is implicated as a contributory
Central core disease most often manifests itself in children with slow factor in the etiology of both adult-onset and childhood myofibrillar
motor development who are hypotonic and have mild weakness espe- myopathies, but the primary defect is a mutation in, not just an upregu-
cially in the hip girdle; congenital dislocation or dysplasia of the hips lation of, the αB-crystallin molecule. An associated secondary mito-
may be diagnosed in the neonatal period. In older children, central chondrial defect is detected in some patients.
core disease is an important differential diagnosis of progressive tho- A unique autosomal recessive myopathy in Cree native infants is
racolumbar scoliosis. Central core myopathies are transmitted as either characterized by severe generalized muscular hypertonia that is not
an autosomal dominant or recessive trait and are caused by the same relieved by neuromuscular blockade and hence is myopathic in origin.
abnormal gene at the 19q13.1 locus. This gene programs the ryanodine Most die in infancy of respiratory insufficiency as a result of diaphrag-
receptor (RYR1), a tetrameric receptor that contains a non–voltage- matic involvement. The muscle biopsy shows findings similar to many
gated calcium channel; it is prevalent in the sarcoplasmic reticulum other myofibrillar myopathies (Fig. 608-5); a novel αB-crystallin gene
and especially at the junction of the T-tubule with the cisternae of the mutation is the cause.
sarcoplasmic reticulum. It contains the channel by which calcium is
released among the myofilaments. Mutations in the RYR1 gene are also Bibliography is available at Expert Consult.
the cause of malignant hyperthermia.
Infantile hypotonia, proximal weakness, muscle wasting, and
involvement of facial muscles and neck flexors are the typical features
in both the dominant and recessive forms. Contractures of the knees,
hips, and other joints are common, and kyphoscoliosis and pes cavus
often develop, even without much axial or distal muscle weakness.
There is a high incidence of cardiac abnormalities. The course is not
progressive, except for the contractures. In one variant, external oph-
thalmoplegia also is present. Rare cases of minicore myopathy also
show hypertrophic cardiomyopathy associated with short-chain acyl-
coenzyme A dehydrogenase deficiency.
The disease is characterized pathologically by central cores within
muscle fibers in which only amorphous, granular cytoplasm is found
with an absence of myofibrils and organelles. Histochemical stains
show a lack of enzymatic activities of all types within these cores, as
well as absence of contractile proteins (actin and myosin) that form
the thin and thick myofilaments. Variants of central cores, called mini-
cores and multicores, are described in some families.
Minicores or multicores are small areas, usually multiple within Figure 608-5 Electron micrograph of quadriceps femoris muscle
muscle fibers, that lack mitochondria and show Z-disc streaming. They biopsy of a 1 mo old native girl with Cree myofibrillar myopathy.
can be caused by mutations in the gene (SEPN1) for the selenoprotein Within the same myofiber, some sarcomeres are well formed and
N, localized to triads, but RYR1 mutations also are reported. The others exhibit disarray of the thick and thin myofilaments and fragmen-
distinction previously made between single and multiple cores in tation of Z bands. Mitochondria appear normal (×21,400).
Bibliography Nowak KJ, Ravenscroft G, Laing NG: Skeletal muscle α-actin diseases
de Winter JM, Buck D, Hidalgo C, et al: Troponin activator augments muscle force (actinopathies): pathology and mechanisms, Acta Neuropathol 125:19–32, 2013.
in nemaline myopathy patients with nebulin mutations, J Med Genet Tasca G, Fattori F, Ricci E, et al: Somatic mosaicism in TPM2-related myopathy
50:383–392, 2013. with nemaline rods and cap structures, Acta Neuropathol 125:169–171, 2013.
Gatayama R, Ueno K, Nakamura H, et al: Nemaline myopathy with dilated Wallgren-Patterson C, Pelin K, Nowak KH, et al: Genotype-phenotype correlations
cardiomyopathy in childhood, Pediatrics 131:e1986–e1990, 2013. in nemaline myopathy caused by mutations in the genes for nebulin and
Malfatti E, Schaeffer U, Chapon F, et al: Combined cap disease and nemaline skeletal muscle α-actin, Neuromuscul Disord 14:461–470, 2004.
myopathy in the same patient caused by an autosomal dominant mutation in Wallgren-Pattersson C, Sewry CA, Nowak KJ, et al: Nemaline myopathies, Semin
the TPM3 gene, Neuromuscul Disord 23(12):992–997, 2013. Pediatr Neurol 18:230–238, 2011.
2974.e2 Chapter 608 ◆ Developmental Disorders of Muscle
Bibliography
Quinlivan RM, Muller CR, Davis M, et al: Central core disease: clinical,
pathological, and genetic features, Arch Dis Child 88:1051–1055, 2003.
Zhou H, Jungbluth H, Sewry CA, et al: Molecular mechanisms and phenotypic
variation in RYR1-related congenital myopathies, Brain 130:2024–2036, 2007.
Bibliography
Del Bigio M, Chudley AF, Sarnat H, et al: Infantile muscular dystrophy in
Canadian Aboriginals is an αB-crystallinopathy, Ann Neurol 69:866–871, 2011.
Selcen D, Bromberg MB, Chin SS, et al: Reducing bodies and myofibrillar features
in FHL1 muscular dystrophy, Neurology 77:1951–1959, 2011.
Selcen D, Engel AG: Myofibrillar myopathies, Handb Clin Neurol 101:143–154,
2011.
608.6 Brain Malformations and Muscle bones, and excessive growth of muscles without weakness. Severe sei-
zures, beginning in neonates, are uncommon. Histologically, the
Development muscle demonstrates a unique muscular dysgenesis. Abnormal zones
Harvey B. Sarnat are adjacent to zones of normal muscle formation and do not follow
anatomic boundaries.
Infants with cerebellar hypoplasia are hypotonic and developmentally
delayed, especially in gross motor skills. Muscle biopsy is sometimes Bibliography is available at Expert Consult.
performed to exclude a congenital myopathy. A biopsy specimen can
show delayed maturation of muscle, fiber-type predominance, or
CMFTD. Other malformations of the brain may also be associated with
abnormal histochemical patterns, but supratentorial lesions are less 608.9 Benign Congenital Hypotonia
likely than brainstem or cerebellar lesions to alter muscle development. Harvey B. Sarnat
Abnormal descending impulses along bulbospinal pathways probably
alter discharge patterns of lower motor neurons that determine the Benign congenital hypotonia is not a disease, but it is a descriptive term
histochemical differentiation of muscle at 20-28 wk of gestation. The for infants or children with nonprogressive hypotonia of unknown
corticospinal tract does not participate because it is not yet functional origin. The hypotonia is not usually associated with weakness or devel-
during this period of fetal life. opmental delay, although some children acquire gross motor skills
In several congenital muscular dystrophies (see Chapter 609.6), more slowly than normal. Tendon stretch reflexes are normal or hypo-
including the Walker-Warburg syndrome, Fukuyama disease, and active. There are no cranial nerve abnormalities, and intelligence is
muscle-eye-brain disease of Santavuori, major cerebral malformations, normal.
such as pachygyria and lissencephaly, are present. It is clear that in at The diagnosis is one of exclusion (see Table 607-2 in Chapter 607)
least some of these cases, the abnormal protein implicated in patho- after results of laboratory studies, including muscle biopsy and imaging
genesis of the syndrome is expressed in both muscle and brain and is of the brain with special attention to the cerebellum, are normal.
important for both stabilization of muscle and migration of central Muscle biopsy is deferred in some mild cases to follow the clinical
neurons. evolution over time, but the diagnosis in these infants is more provi-
sional. No known molecular genetic basis for this syndrome has been
Bibliography is available at Expert Consult. identified. Table 607-3 in Chapter 607 lists the differential diagnosis.
The prognosis is generally good; no specific therapy is required.
Contractures do not develop. Physical therapy might help achieve
motor milestones (walking) sooner than expected. Hypotonia persists
608.7 Amyoplasia into adult life. The disorder is not always as “benign” as its name
Harvey B. Sarnat implies because a common complication is recurrent dislocation of
joints, especially the shoulders. Excessive motility of the spine can
Congenital absence of individual muscles is common and is often result in stretch injury, compression, or vascular compromise of nerve
asymmetric. A common aplasia is the palmaris longus muscle of the roots or of the spinal cord. These are particular hazards for patients
ventral forearm, which is absent in 30% of normal subjects and is fully who perform gymnastics or who become circus performers because of
compensated for by other flexors of the wrist. Unilateral absence of a agility of joints without weakness or pain.
sternocleidomastoid muscle is one cause of congenital torticollis.
Absence of 1 pectoralis major muscle is part of the Poland anomalad. Bibliography is available at Expert Consult.
When innervation does not develop, as in the lower limbs in severe
cases of myelomeningocele, muscles can fail to develop. In sacral agen-
esis, the abnormal somites that fail to form bony vertebrae can also fail
to form muscles from the same defective mesodermal plate, a disorder 608.10 Arthrogryposis
of induction resulting in segmental amyoplasia. Skeletal muscles of the Harvey B. Sarnat
extremities fail to differentiate from embryonic myomeres if the long
bones do not form. Absence of 1 long bone, such as the radius, is Arthrogryposis multiplex congenita is not a disease but is a descrip-
associated with variable aplasia or hypoplasia of associated muscles, tive term that signifies multiple congenital contractures and is hetero-
such as the flexor carpi radialis. End-stage neurogenic atrophy of geneous in etiology (see Chapter 682).
muscle is sometimes called amyoplasia, but this use is semantically
incorrect. Bibliography is available at Expert Consult.
Generalized amyoplasia usually results in fetal death, and liveborn
neonates rarely survive. A mutation in 1 of the myogenic genes is the
suspected etiology because of genetic knockout studies in mice, but it
has not been proven in humans.
608.8 Muscular Dysgenesis (Proteus

Syndrome Myopathy)
Harvey B. Sarnat
Proteus syndrome is a disturbance of cellular growth involving ecto-

dermal and mesodermal tissues, representing a cellular mosaicism. The
genetic defect is a mutation in the AKT1 gene, of the same genetic
family as AKT3, which causes hemimegalencephaly; indeed many
cases of Proteus syndrome also have hemimegalencephaly. These genes
participate in the mammalian target of rapamycin pathway. Proteus
syndrome also manifests as asymmetric overgrowth of the extremities,
verrucous cutaneous lesions, angiomas of various types, thickening of
Bibliography
Sarnat HB: Cerebral dysgeneses and their influence on fetal muscle development,
Brain Dev 8:495–499, 1986.
Bibliography
Lindhurst MJ, Sapp JC, Teer JK, et al: A mosaic activating mutation in AKT1
associated with the Proteus syndrome, N Engl J Med 365:611–619, 2011.
Sarnat HB, Diadori P, Trevenen CL: Myopathy of the Proteus syndrome: hypothesis
of muscular dysgenesis, Neuromuscul Disord 3:293–301, 1993.
Bibliography
Laugel V, Cossee M, Matis J, et al: Diagnostic approach to neonatal hypotonia:
retrospective study on 144 neonates, Eur J Pediatr 167:517–523, 2008.
Mintz-Itkin R, Lerman-Sagie T, Zuk L, et al: Does physical therapy improve
outcome in infants with joint hypermobility and benign hypotonia? J Child
Neurol 24:714–719, 2009.
Bibliography
Haliloglu G, Topaloglu H: Arthrogryposis and fetal hypomobility syndrome,
Handb Clin Neurol 113:1311–1319, 2013.
Chapter 609 ◆ Muscular Dystrophies 2975
Chapter 609
Muscular Dystrophies
Harvey B. Sarnat
The term dystrophy means abnormal growth, derived from the Greek
trophe, meaning “nourishment.” A muscular dystrophy is distinguished
from all other neuromuscular diseases by 4 obligatory criteria: It is a
primary myopathy, it has a genetic basis, the course is progressive, and
degeneration and death of muscle fibers occur at some stage in the
disease. This definition excludes neurogenic diseases such as spinal pencil, and a computer keyboard. Respiratory muscle involvement is
muscular atrophy, nonhereditary myopathies such as dermatomyositis, expressed as a weak and ineffective cough, frequent pulmonary infec-
nonprogressive, and nonnecrotizing congenital myopathies such as tions, and decreasing respiratory reserve. Pharyngeal weakness can
congenital muscle fiber-type disproportion, and nonprogressive inher- lead to episodes of aspiration, nasal regurgitation of liquids, and an
ited metabolic myopathies. Some metabolic myopathies can fulfill the airy or nasal voice quality. The function of the extraocular muscles
definition of a progressive muscular dystrophy but are not traditionally remains well preserved. Incontinence due to anal and urethral sphinc-
classified as dystrophies (muscle carnitine deficiency). ter weakness is an uncommon and very late event.
All muscular dystrophies might eventually be reclassified as meta- Contractures most often involve the ankles, knees, hips, and elbows.
bolic myopathies once the biochemical defects are better defined. Mus- Scoliosis is common. The thoracic deformity further compromises
cular dystrophies are a group of unrelated diseases, each transmitted pulmonary capacity and compresses the heart. Scoliosis usually pro-
by a different genetic trait and each differing in its clinical course and gresses more rapidly after the child becomes nonambulatory and may
expression. Some are severe diseases at birth that lead to early death; be uncomfortable or painful. Enlargement of the calves (pseudohyper-
others follow very slow progressive courses over many decades, may trophy) and wasting of thigh muscles are classic features. The enlarge-
be compatible with normal longevity, and might not even become ment is caused by hypertrophy of some muscle fibers, infiltration of
symptomatic until late adult life. Some categories of dystrophies, such muscle by fat, and proliferation of collagen. After the calves, the next
as limb-girdle muscular dystrophy (LGMD), are not homogeneous most common site of muscular hypertrophy is the tongue, followed by
diseases but rather syndromes encompassing several distinct myopa- muscles of the forearm. Fasciculations of the tongue do not occur. The
thies. Relationships among the various muscular dystrophies are voluntary sphincter muscles rarely become involved.
resolved by molecular genetics rather than by similarities or differences Unless ankle contractures are severe, ankle deep tendon reflexes
in clinical and histopathologic features. remain well preserved until terminal stages. The knee deep tendon
reflexes may be present until about 6 yr of age but are less brisk than
the ankle jerks and are eventually lost. In the upper extremities, the
609.1 Duchenne and Becker Muscular brachioradialis reflex is usually stronger than the biceps or triceps
brachii reflexes.
Dystrophies Cardiomyopathy, including persistent tachycardia and myocardial
Harvey B. Sarnat failure, is seen in 50-80% of patients with this disease. The severity of
cardiac involvement does not necessarily correlate with the degree of
Duchenne muscular dystrophy (DMD) is the most common heredi- skeletal muscle weakness. Some patients die early of severe cardiomy-
tary neuromuscular disease affecting all races and ethnic groups. Its opathy while still ambulatory; others in terminal stages of the disease
characteristic clinical features are progressive weakness, intellectual have well-compensated cardiac function. Smooth muscle dysfunction,
impairment, hypertrophy of the calves, and proliferation of connective particularly of the gastrointestinal tract, is a minor, but often over-
tissue in muscle. The incidence is 1 in 3,600 liveborn infant boys. This looked, feature.
disease is inherited as an X-linked recessive trait. The abnormal gene Intellectual impairment occurs in all patients, although only
is at the Xp21 locus and is one of the largest genes. Becker muscular 20-30% have an IQ <70. The majority have learning disabilities that
dystrophy (BMD) is a disease that is fundamentally similar to DMD, still allow them to function in a regular classroom, particularly with
with a genetic defect at the same locus, but clinically it follows a milder remedial help. A few patients are profoundly intellectually impaired,
and more protracted course. but there is no correlation with the severity of the myopathy. Epilepsy
is slightly more common than in the general pediatric population.
CLINICAL MANIFESTATIONS Autism-like behavior may develop but is uncommon. Dystrophin is
Infant boys are rarely symptomatic at birth or in early infancy, although expressed in brain and retina, as well as in striated and cardiac muscle,
some are mildly hypotonic. Early gross motor skills, such as rolling though the level is lower in brain than in muscle. This distribution
over, sitting, and standing, are usually achieved at the appropriate ages might explain some of the central nervous system manifestations.
or may be mildly delayed. Poor head control in infancy may be the first Abnormalities in cortical architecture and of dendritic arborization
sign of weakness. Distinctive facies are not an early feature because may be detected neuropathologically; cerebral atrophy is demonstrated
facial muscle weakness is a late event; in later childhood, a “transverse” by MRI late in the clinical course. The degenerative changes and fibro-
or horizontal smile may be seen. Walking is often accomplished at the sis of muscle constitute a painless process. Myalgias and muscle spasms
normal age of approximately 12 mo, but hip girdle weakness may be do not occur. Calcinosis of muscle is rare.
seen in subtle form as early as the 2nd yr. Toddlers might assume a Death occurs usually at about 18-20 yr of age. The causes of death
lordotic posture when standing to compensate for gluteal weakness. are respiratory failure during sleep, intractable heart failure, pneumo-
An early Gowers sign is often evident by age 3 yr and is fully expressed nia, or, occasionally, aspiration and airway obstruction.
by age 5 or 6 yr (see Fig. 590-5 in Chapter 590). A Trendelenburg gait, In BMD, boys remain ambulatory until late adolescence or early
or hip waddle, appears at this time. Common presentations in toddlers adult life. Calf pseudohypertrophy, cardiomyopathy, and elevated
include delayed walking, falling, toe walking, and trouble running or serum levels of creatine kinase (CK) are similar to those of patients
walking upstairs, developmental delay, and, less often, malignant with DMD. Learning disabilities are less common. The onset of weak-
hyperthermia after anesthesia. ness is later in BMD than in DMD. Death often occurs in the mid to
The length of time a patient remains ambulatory varies greatly. Some late 20s; fewer than half of patients are still alive by age 40 yr; these
patients are confined to a wheelchair by 7 yr of age; most patients survivors are severely disabled.
continue to walk with increasing difficulty until age 10 yr without
orthopedic intervention. With orthotic bracing, physiotherapy, and LABORATORY FINDINGS
sometimes minor surgery (Achilles tendon lengthening), most are able The serum CK level is consistently greatly elevated in DMD, even in
to walk until age 12 yr. Ambulation is important not only for postpon- presymptomatic stages, including at birth. The usual serum concentra-
ing the psychologic depression that accompanies the loss of an aspect tion is 15,000-35,000 IU/L (normal <160 IU/L). A normal serum CK
of personal independence but also because scoliosis usually does not level is incompatible with the diagnosis of DMD, although in terminal
become a major complication as long as a patient remains ambulatory, stages of the disease, the serum CK value may be considerably lower
even for as little as 1 hr per day; scoliosis often becomes rapidly pro- than it was a few years earlier because there is less muscle to degener-
gressive after confinement to a wheelchair. ate. Other lysosomal enzymes present in muscle, such as aldolase and
The relentless progression of weakness continues into the 2nd aspartate aminotransferase, are also increased but are less specific.
decade. The function of distal muscles is usually relatively well enough Cardiac assessment by echocardiography, electrocardiography
preserved, allowing the child to continue to use eating utensils, a (ECG), and radiography of the chest is essential and should be repeated
periodically. After the diagnosis is established, patients should be allowing calcium to enter the site of breakdown of the sarcolemmal
referred to a pediatric cardiologist for long-term cardiac care. membrane and trigger a contraction of the whole length of the muscle
Electromyography (EMG) shows characteristic myopathic features fiber. Calcifications within myofibers are correlated with secondary
but is not specific for DMD. No evidence of denervation is found. β-dystroglycan deficiency.
Motor and sensory nerve conduction velocities are normal. The decision about whether muscle biopsy should be performed to
establish the diagnosis sometimes presents problems. If there is a
DIAGNOSIS family history of the disease, particularly in the case of an involved
Polymerase chain reaction (PCR) for the dystrophin gene mutation is brother whose diagnosis has been confirmed, a patient with typical
the primary test, if the clinical features and serum CK are consistent
with the diagnosis. If the blood PCR is diagnostic, muscle biopsy may
be deferred, but if it is normal and clinical suspicion is high, the more
specific dystrophin immunocytochemistry performed on muscle
biopsy sections detects the 30% of cases that do not show a PCR abnor-
mality. Immunohistochemical staining of frozen sections of muscle
biopsy tissue detects differences in the rod domain, the carboxyl- deg
terminus (that attaches to the sarcolemma), and the aminoterminus
(that attaches to the actin myofilaments) of the large dystrophin mol- c
ecule, and may be prognostic of the clinical course as Duchenne or
Becker disease. More-severe weakness occurs with truncation of the
dystrophin molecule at the carboxyl-terminus than at the aminotermi- c
nus. The diagnosis should be confirmed by blood PCR or muscle
biopsy in every case. Dystroglycans and other sarcolemmal regional
proteins, such as merosin and sarcoglycans, also can be measured
because they may be secondarily decreased.
The muscle biopsy is diagnostic and shows characteristic changes c
(Figs. 609-1 and 609-2). Myopathic changes include endomysial con-
nective tissue proliferation, scattered degenerating and regenerating
myofibers, foci of mononuclear inflammatory cell infiltrates as a reac- Figure 609-1 Muscle biopsy of a 4 yr old boy with Duchenne mus-
tion to muscle fiber necrosis, mild architectural changes in still- cular dystrophy. Both atrophic and hypertrophic muscle fibers are
functional muscle fibers, and many dense fibers. These hypercontracted seen, and some fibers are degenerating (deg). Connective tissue (c)
fibers probably result from segmental necrosis at another level, between muscle fibers is increased (hematoxylin and eosin, ×400).
A B
C D
Figure 609-2 Dystrophin is demonstrated by immunohistochemical reactivity in the muscle biopsies of a normal term male neonate (A), a 10 yr
old boy with limb-girdle muscular dystrophy (B), a 6 yr old boy with Duchenne muscular dystrophy (C), and a 10 yr old boy with Becker muscular
dystrophy (D). In the normal condition, and also in non–X-linked muscular dystrophies in which dystrophin is not affected, the sarcolemmal mem-
brane of every fiber is strongly stained, including atrophic and hypertrophic fibers. In Duchenne dystrophy, most myofibers express no detectable
dystrophin, but a few scattered fibers known as revertant fibers show near-normal immunoreactivity. In Becker muscular dystrophy, the abnormal
dystrophin molecule is thin, with pale staining of the sarcolemma, in which reactivity varies not only between myofibers but also along the circum-
ference of individual fibers (×250).
clinical features of DMD and high concentrations of serum CK prob- immunohistochemical methods using either fluorescence or light
ably does not need to undergo biopsy. The result of the PCR might also microscopy of antidystrophin antisera (see Fig. 609-2). In classic DMD,
influence whether to perform a muscle biopsy. A first case in a family, levels of <3% of normal are found; in BMD, the molecular weight of
even if the clinical features are typical, should have the diagnosis con- dystrophin is reduced to 20-90% of normal in 80% of patients, but in
firmed to ensure that another myopathy is not masquerading as DMD. 15% of patients the dystrophin is of normal size but reduced in quan-
The most common muscles sampled are the vastus lateralis (quadriceps tity, and 5% of patients have an abnormally large protein caused by
femoris) and the gastrocnemius. excessive duplications or repeats of codons. Selective immunoreactiv-
ity of different parts of the dystrophin molecule in sections of muscle
GENETIC ETIOLOGY AND PATHOGENESIS biopsy material distinguishes the Duchenne and Becker forms (Fig.
Despite the X-linked recessive inheritance in DMD, approximately 609-3). The demonstration of deletions and duplications also can be
30% of cases are new mutations, and the mother is not a carrier. The made from blood samples by the more rapid PCR, which identifies as
female carrier state usually shows no muscle weakness or any clinical many as 98% of deletions by amplifying 18 exons but cannot detect
expression of the disease, but affected girls are occasionally encoun- duplications. The diagnosis can thus be confirmed at the molecular
tered, usually having much milder weakness than boys. These symp- genetic level from either the muscle biopsy material or from peripheral
tomatic girls are explained by the Lyon hypothesis in which the normal blood, although as many as 30% of boys with DMD or BMD have a
X chromosome becomes inactivated and the one with the gene deletion false-normal blood PCR; all cases of dystrophinopathy are detected by
is active (see Chapter 80). The full clinical picture of DMD has occurred muscle biopsy.
in several girls with Turner syndrome in whom the single X chromo- The same methods of DNA analysis from blood samples may be
some must have had the Xp21 gene deletion. applied for carrier detection in female relatives at risk, such as sisters
The asymptomatic carrier state of DMD is associated with elevated and cousins, and to determine whether the mother is a carrier or
serum CK values in 80% of cases. The level of increase is usually in the whether a new mutation occurred in the embryo. Prenatal diagnosis
magnitude of hundreds or a few thousand but does not have the is possible as early as the 12th wk of gestation by sampling chorionic
extreme values noted in affected males. Prepubertal girls who are car- villi for DNA analysis by Southern blot or PCR and is confirmed in
riers of the dystrophy also have increased serum CK values, with aborted fetuses with DMD by immunohistochemistry for dystrophin
highest levels at 8-12 yr of age. Approximately 20% of carriers have in muscle.
normal serum CK values. If the mother of an affected boy has normal
CK levels, it is unlikely that her daughter can be identified as a carrier TREATMENT
by measuring CK. Muscle biopsy of suspected female carriers can There is no medical cure for this disease. Much can be done to treat
detect an additional 10% in whom serum CK is not elevated; a specific complications and to improve the quality of life of affected children.
genetic diagnosis using PCR on peripheral blood is definitive. Some Cardiac decompensation often responds initially well to digoxin. Pul-
female carriers suffer cardiomyopathy without weakness of striated monary infections should be promptly treated. Patients should avoid
muscles. contact with children who have obvious respiratory or other conta-
A 427-kDa cytoskeletal protein known as dystrophin is encoded by gious illnesses. Immunizations for influenza virus and other routine
the gene at the Xp21.2 locus. This gene contains 79 exons of coding vaccinations are indicated.
sequence and 2.5 Mb of DNA, 10 times larger than the next largest Preservation of a good nutritional state is important. DMD is
gene yet identified. This subsarcolemmal protein attaches to the sarco- not a vitamin-deficiency disease, and excessive doses of vitamins
lemmal membrane overlying the A and M bands of the myofibrils and should be avoided. Adequate calcium intake is important to minimize
consists of 4 distinct regions or domains: the aminoterminus contains osteoporosis in boys confined to a wheelchair, and fluoride supple-
250 amino acids and is related to the N-actin binding site of α-actinin; ments may also be given, particularly if the local drinking water is
the second domain is the largest, with 2,800 amino acids, and contains not fluoridated. Because sedentary children burn fewer calories than
many repeats, giving it a characteristic rod shape; a third, cysteine-rich active children and because depression is an additional factor, these
domain is related to the carboxyl-terminus of α-actinin; and the children tend to eat excessively and gain weight. Obesity makes a
final carboxyl-terminal domain of 400 amino acids is unique to dys- patient with myopathy even less functional because part of the limited
trophin and to a dystrophin-related protein encoded by chromosome reserve muscle strength is dissipated in lifting the weight of excess
6. “Dystrophin deficiency” at the sarcolemma disrupts the membrane subcutaneous adipose tissue. Dietary restrictions with supervision may
cytoskeleton and leads to loss secondarily of other components of the be needed.
cytoskeleton. Physiotherapy delays but does not always prevent contractures. At
The molecular defects in the dystrophinopathies vary and include times, contractures are actually useful in functional rehabilitation. If
intragenic deletions, duplications, or point mutations of nucleotides. contractures prevent extension of the elbow beyond 90 degrees and the
Approximately 65% of patients have deletions; approximately 10% muscles of the upper limb no longer are strong enough to overcome
exhibit duplications while approximately 10% have point mutations or gravity, the elbow contractures are functionally beneficial in fixing an
smaller rearrangements. The site or size of the intragenic abnormality otherwise flail arm and in allowing the patient to eat and write. Surgical
does not always correlate well with the phenotypic severity; in both correction of the elbow contracture may be technically feasible, but the
Duchenne and Becker forms the mutations are mainly near the middle result may be deleterious. Physiotherapy contributes little to muscle
of the gene, involving deletions of exons 46-51. Phenotypic or clinical strengthening because patients usually are already using their entire
variations are explained by the alteration of the translational reading reserve for daily function, and exercise cannot further strengthen
frame of messenger RNA (mRNA), which results in unstable, trun- involved muscles. Excessive exercise can actually accelerate the process
cated dystrophin molecules and severe, classic DMD; mutations that of muscle fiber degeneration.
preserve the reading frame still permit translation of coding sequences Special vigilance should be maintained in watching for progres-
further downstream on the gene and produce a semifunctional dystro- sive scoliosis, which should be treated early by orthopedists using
phin, expressed clinically as BMD. An even milder form of adult-onset external braces or corsets and occasionally by surgeons. Scoliosis
disease, formerly known as quadriceps myopathy, is also caused by often becomes rapidly progressive once the patient is confined to a
an abnormal dystrophin molecule. The clinical spectrum of the dys- wheelchair.
trophinopathies not only includes the classic Duchenne and Becker Another recommended treatment of patients with DMD involves
forms but also ranges from a severe neonatal muscular dystrophy to the use of prednisone, prednisolone, deflazacort, or other steroids.
asymptomatic children with persistent elevation of serum CK levels Glucocorticoids decrease the rate of apoptosis or programmed cell
>1,000 IU/L. death of myotubes during ontogenesis and can decelerate the myofiber
Analysis of the dystrophin protein requires a muscle biopsy and necrosis in muscular dystrophy. Strength usually improves initially, but
is demonstrated by Western blot analysis or in tissue sections by the long-term complications of chronic steroid therapy, including
A B
C D
E F
Figure 609-3 Quadriceps femoris muscle biopsy specimens from a 4 yr old boy with Becker muscular dystrophy. A, Myofibers vary greatly in
size, with both atrophic and hypertrophic forms; at the right is a zone of degeneration and necrosis infiltrated by macrophages, similar to Duchenne
muscular dystrophy (hematoxylin and eosin, ×250). Immunoreactivity using antibodies against the dystrophin molecule in the rod domain
(B), carboxyl-terminus (C), and aminoterminus (D) all show deficient but not totally absent dystrophin expression; most fibers of all sizes retain
some dystrophin in parts of the sarcolemma but not around the entire circumference in cross section. Alternatively, the prominence of dystrophin
is less, appearing weak, when compared with the simultaneously incubated normal control from another child of similar age (E). F, Merosin expres-
sion is normal in this patient with Becker dystrophy, in both large and small myofibers, and is lacking only in frankly necrotic fibers. Compare with
classic Duchenne muscular dystrophy illustrated in Figure 609-2C and with Figure 609-6.
considerable weight gain and osteoporosis, can offset this advantage or dystrophin protein. The shortened protein has been demonstrated to
even result in greater weakness than might have occurred in the natural appear in muscle biopsies after treatment with these agents.
course of the disease. Nevertheless, some patients with DMD treated
early with steroids appear to have an improved long-term prognosis in Bibliography is available at Expert Consult.
muscle and myocardial outcome, as well as short-term improvement
in muscle strength, and steroids can help keep patients ambulatory for
more years than expected without treatment. One protocol gives pred-
nisone (0.75 mg/kg/day) for the 1st 10 days of each month to avoid 609.2 Emery-Dreifuss Muscular Dystrophy
chronic complications. Deflazacort, administered as 0.9 mg/kg/day, Harvey B. Sarnat
may be more effective than prednisone. Fluorinated steroids, such as
dexamethasone or triamcinolone, should be avoided because they Emery-Dreifuss muscular dystrophy, also known as scapuloperoneal
induce myopathy by altering the myotube abundance of ceramide. The or scapulohumeral muscular dystrophy, is a rare X-linked recessive
American Academy of Neurology and the Child Neurology Society dystrophy. The usual locus of its associated genetic abnormality is on
recommend administering corticosteroids during the ambulatory stage the long arm within the large Xq28 region that includes other muta-
of the disease. tions that cause myotubular myopathy, neonatal adrenoleukodystro-
Another potential treatment still under investigation is intravenous phy, and the Bloch-Sulzberger type of incontinentia pigmenti; it is far
or subcutaneous injection of antisense oligonucleotide drugs that from the gene for DMD on the short arm of the X chromosome.
induce exon skipping during mRNA splicing in patients with suscep- Another, rarer form of Emery-Dreifuss dystrophy is transmitted as an
tible mutations (~15% of patients) to restore the open reading frame autosomal dominant trait and is localized at 1q. This form can manifest
in the DMD gene. Drisapersen and eteplirsen are exon 51 skipping quite late, in adolescence or early adult life, although the muscular and
antisense oligonucleotides that bind RNA and skip (bridge) over the cardiac symptoms and signs are similar, and sudden death from ven-
defective exon, thus producing a shorter but potentially functional tricular fibrillation is a risk.
Chapter 609 ◆ Muscular Dystrophies 2979.e1
Bibliography Escolar DM, Hache LP, Clemens PR, et al: Randomized, blinded trial of weekend
Barber BJ, Andrews JG, Lu Z, et al: Oral corticosteroids and onset of vs daily prednisone in Duchenne muscular dystrophy, Neurology 77:444–452,
cardiomyopathy in Duchenne muscular dystrophy, J Pediatr 163:1080–1084, 2011.
2013. Goemans NM, Tulinius M, van den Akker JT, et al: Systemic administration of
Beenakker EAC, Fock JM, Van Tol MJ, et al: Intermittent prednisone therapy in PRO051 in Duchenne’s muscular dystrophy, N Engl J Med 364:1513–1522, 2011.
Duchenne muscular dystrophy, Arch Neurol 62:128–132, 2005. Kley RA, Tarnopolsky MA, Vorgerd M: Creatine for treating muscle disorders,
Bushby K, Finkel R, Birnkrant DJ, et al: Diagnosis and management of Duchenne Cochrane Database Syst Rev (2):CD004760, 2011.
muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial Manzur AY, Kinali M, Muntoni F: Update on the management of Duchenne
management, Lancet 9:77–93, 2010. muscular dystrophy, Arch Dis Child 93:986–990, 2008.
Centers for Disease Control and Prevention (CDC): Prevalence of Duchenne/ Manzur AY, Kuntzer T, Pike M, et al: Glucocorticoid corticosteroids for Duchenne
Becker muscular dystrophy among males aged 5–24 years—four states, 2007, muscular dynstrophy, Cochrane Database Syst Rev (1):CD003725, 2008.
MMWR Morb Mortal Wkly Rep 58:1119–1122, 2009. Mendell JR, Campbell K, Rodino-Klapac L, et al: Dystrophin immunity in
Chelly J, Desguerre I: Progressive muscular dystrophies, Handb Clin Neurol Duchenne’s muscular dystrophy, N Engl J Med 363(15):1429–1436, 2010.
113:1343–1366, 2013. Mercuri E, Muntoni F: Muscular dystrophy: new challenges and review of the
Ciafaloni E, Fox DJ, Pandya S, et al: Delayed diagnosis in Duchenne muscular current clinical trials, Curr Opin Pediatr 25:701–7070, 2013.
dystrophy: data from the muscular dystrophy surveillance, tracking, and Nakamura A, Takeda S: Exon-skipping therapy for Duchenne muscular dystrophy,
research network (MD STARnet), J Pediatr 155:380–385, 2009. Lancet 378:546–547, 2011.
Cirak S, Arechavala-Gomeza V, Guglieri M, et al: Exon skipping and dystrophin Opar A: Exon-skipping drug pulls ahead in muscular dystrophy field, Nat Med
restoration in patients with Duchenne muscular dystrophy after systemic 18:1314, 2012.
phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2,
dose-escalation study, Lancet 378:595–604, 2011.
Clinical manifestations begin at between 5 and 15 yr of age,

but many patients survive to late adult life because of the slow pro- 609.3 Myotonic Muscular Dystrophy
gression of the disease’s course. A rarer severe infantile presentation Harvey B. Sarnat
also is documented. Muscles do not exhibit pseudohypertrophy. Con-
tractures of elbows and ankles develop early, and muscle becomes Myotonic dystrophy (Steinert disease) is the second most common
wasted in a scapulohumeroperoneal distribution. Facial weakness muscular dystrophy in North America, Europe, and Australia, having
does not occur; this disease is thus distinguished clinically from auto- an incidence varying from 1 in 100,000 to 1 in 300,000 in the general
somal dominant scapulohumeral and scapuloperoneal syndromes of population. It is inherited as an autosomal dominant trait. Classic
neurogenic origin. Myotonia is absent. Intellectual function is normal. myotonic dystrophy (type 1) (DM1) is caused by a CTG trinucleotide
Dilated cardiomyopathy is severe and is often the cause of death, more expansion on chromosome 19q13.3 in the 3′ untranslated region of
commonly from conduction defects such as atrial fibrillation/flutter DMPK, the gene that encodes a serine-threonine protein kinase. Type 2
and sudden ventricular fibrillation than from intractable myocardial (DM2) is associated with unstable CCTG tetranucleotide repeat expan-
failure. Stroke is another complication, secondary to the cardiac sion on chromosome 3q21 of an intron of the zinc finger 9 protein
arrhythmia. The serum CK value is only mildly to moderately ele- gene. A third, late form (DM3) is identified, at locus 15q21-q24.
vated, further distinguishing this disease from other X-linked reces- Myotonic dystrophy is an example of a genetic defect causing dys-
sive muscular dystrophies. function in multiple organ systems. Not only is striated muscle severely
Nonspecific myofiber necrosis and endomysial fibrosis are seen in affected, but smooth muscle of the alimentary tract and uterus is also
the muscle biopsy. Many centronuclear fibers and selective histochemi- involved, cardiac function is altered, and patients have multiple and
cal type I muscle fiber atrophy can cause confusion with myotonic variable endocrinopathies, immunologic deficiencies, cataracts, dys-
dystrophy. morphic facies, increased risk for malignancies, intellectual impair-
ment, and other neurologic abnormalities.
GENETICS
The defective gene in the X-linked form is called EMD or EDMD and CLINICAL MANIFESTATIONS
encodes a protein, emerin. Unlike other dystrophies in which the DM1 becomes symptomatic at any age, but DM2 is rarely expressed in
defective gene is expressed at the sarcolemmal membrane, emerin is infancy or early childhood. In the usual clinical course, excluding the
expressed at the inner nuclear membrane; this protein stabilizes the severe neonatal form, DM1 infants can appear almost normal at birth,
nuclear membrane against the mechanical stresses that occur during or facial wasting and hypotonia can already be early expressions of the
muscular contraction. It interacts with Nesprin-1 and Nesprin-2 genes, disease. The facial appearance is characteristic, consisting of an inverted
also critical for nuclear membrane integrity. Complete deletion of V-shaped upper lip, thin cheeks, and scalloped, concave temporalis
EDMD occurs in approximately 25% of cases and results from an inver- muscles (Fig. 609-4). The head may be narrow, and the palate is high
sion in the Xq28 region; total absence of emerin is demonstrated by and arched because the weak temporal and pterygoid muscles in late
both Western blotting and immunoreactivity in tissue sections. fetal life do not exert sufficient lateral forces on the developing head
Another gene, LMNA, at the 1q21 locus, is linked to the nuclear enve- and face.
lope and encodes lamins A and C, sometimes termed laminopathy. Weakness is mild in the 1st few yr. Progressive wasting of distal
This genetic mutation causes an identical clinical phenotype to EMD muscles becomes increasingly evident, particularly involving intrinsic
defects, except that both sexes are affected and it is transmitted as either muscles of the hands. The thenar and hypothenar eminences are flat-
an autosomal dominant or recessive trait. Most EDMD deletions are tened, and the atrophic dorsal interossei leave deep grooves between
null mutations, whereas most LMNA alterations are mainly missense the fingers. The dorsal forearm muscles and anterior compartment
mutations with a minority being nonsense or out-of-frame mutations. muscles of the lower legs also become wasted. The tongue is thin and
Desmin protein also may be mutated and seen to be abnormally atrophic. Wasting of the sternocleidomastoids gives the neck a long,
expressed in the muscle biopsy. Homozygous nonsense mutations in thin, cylindrical contour. Proximal muscles also eventually undergo
these lamin A/C genes are lethal owing to cardiomyopathy and conduc- atrophy, and scapular winging appears. Difficulty with climbing stairs
tion disturbances.
DIAGNOSIS AND INVESTIGATIONS

In suspected cases, emerin deficiency may be demonstrated not only
in the muscle biopsy by immunoreactivity and Western blotting tech-
niques but also in a variety of other tissues, including circulating lym-
phocytes in peripheral blood, exfoliative buccal mucosal cells, and skin
fibroblasts. Emerin is absent in varying proportions in female carriers.
Genetic testing of the specific genes also is available. Patients should
all have careful cardiac evaluation, including electrocardiogram and
echocardiogram. Serum CK should be measured because it may be
moderately elevated; though nonspecific, it provides a baseline for
comparison with future measurements. Muscle MRI of the glutei and
lower extremities may be helpful, particularly in LMNA mutations.
EMG is not definitively diagnostic, but it provides a serial means of
following the progression of the myopathy. Muscle biopsy is diagnostic
from the onset of symptoms. In the differential diagnosis, an Emery-
Dreifuss–like syndrome with joint contractures, mild weakness, and
later-onset cardiac symptoms is caused by FHL1 mutations of myofi-
brillar myopathy, but reducing bodies are absent.
Treatment should be supportive, with special attention to cardiac
conduction defects, and can require medications or a pacemaker.
Implantable cardioverter-defibrillators are now available and have pre-
vented sudden death in some patients with Emery-Dreifuss muscular
dystrophy. Figure 609-4 Facial weakness, inverted V–shaped upper lip, and loss
of muscle mass in the temporal fossae are characteristic of myotonic
Bibliography is available at Expert Consult. muscular dystrophy, even in infancy, as seen in this 8 mo old girl.
Bibliography Jiménez-Escrig A, Gobernado I, García-Villanueva M, et al: Autosomal recessive

Bonne G, Quijano-Roy S: Emery-Dreifuss muscular dystrophy, laminopathies, and Emery-Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the
other nuclear envelopathies, Handb Clin Neurol 113:1367–1376, 2013. lamin A/C gene identified by exome sequencing, Muscle Nerve 45:605–610,
Boriani G, Gallina M, Merlini L, et al: Clinical relevance of atrial fibrillation/flutter, 2012.
stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular Meune C, Van Berlo JH, Anselme F, et al: Primary prevention of sudden death in
dystrophy: a long-term longitudinal study, Stroke 34:901–908, 2003. patients with lamin A/C gene mutations, N Engl J Med 12:209–210, 2006.
Brodsky GL, Muntoni F, Miocic S, et al: Lamin A/C gene mutation associated with Mutoni F, Bonne G, Goldfarb LG, et al: Disease severity in dominant Emery
dilated cardiomyopathy and variable skeletal muscle involvement, Circulation Dreifuss is increased by mutations in both emery and desmin proteins, Brain
101:473–476, 2000. 129:1260–1268, 2006.
Gueneau L, Bertrand AT, Jais JP, et al: Mutations of the FHL1 gene cause Worman HJ, Fong LG, Muchir A, et al: Laminopathies and the long strange trip
Emery-Dreifuss muscular dystrophy, Hum Genet 85:338–353, 2009. from basic cell biology to therapy, J Clin Invest 119:1825–1836, 2009.
and Gowers sign are progressive. Tendon stretch reflexes are usually reevaluated annually. Hypothyroidism is common; hyperthyroidism
preserved. occurs rarely. Adrenocortical insufficiency can lead to an addisonian
The distal distribution of muscle wasting in myotonic dystrophy is crisis even in infancy. Diabetes mellitus is common in patients with
an exception to the general rule of myopathies having proximal and myotonic dystrophy; some children have a disorder of insulin release
neuropathies having distal distribution patterns. The muscular atrophy rather than defective insulin production. Onset of puberty may be
and weakness in myotonic dystrophy are slowly progressive through- precocious or, more often, delayed. Testicular atrophy and testosterone
out childhood and adolescence and continue into adulthood. It is rare deficiency are common in adults and are responsible for a high inci-
for patients with myotonic dystrophy to lose the ability to walk even dence of male infertility. Ovarian atrophy is rare. Frontal baldness is
in late adult life, although splints or bracing may be required to stabi- also characteristic in male patients and often begins in adolescence.
lize the ankles. Immunologic deficiencies are common in myotonic dystrophy. The
Myotonia, a characteristic feature shared by few other myopathies, plasma immunoglobulin G level is often low.
does not occur in infancy and is usually not clinically or even electro- Cataracts often occur in myotonic dystrophy. They may be congeni-
myographically evident until about age 5 yr. Exceptional patients tal, or they can begin at any time during childhood or adult life. Early
develop it as early as age 3 yr. Myotonia is a very slow relaxation of cataracts are detected only by slit-lamp examination; periodic exami-
muscle after contraction, regardless of whether that contraction was nation by an ophthalmologist is recommended. Visual evoked poten-
voluntary or was induced by a stretch reflex or electrical stimulation. tials are often abnormal in children with myotonic dystrophy and are
During physical examination, myotonia may be demonstrated by unrelated to cataracts. They are not usually accompanied by visual
asking the patient to make tight fists and then to quickly open the impairment.
hands (grip myotonia; Fig. 609-5). It may be induced by striking the About half of the patients with myotonic dystrophy are intellectu-
thenar eminence with a rubber percussion hammer (percussion myo- ally impaired, but severe intellectual impairment is unusual. The
tonia), and it may be detected by watching the involuntary drawing of remainder are of average or occasionally above-average intelligence.
the thumb across the palm. Myotonia can also be demonstrated in the Epilepsy is not common. Cognitive impairment might result from
tongue by pressing the edge of a wooden tongue blade against its dorsal accumulations of mutant DMPK mRNA and aberrant alternative splic-
surface and by observing a deep furrow that disappears slowly. The ing in cerebral cortical neurons. A higher than expected incidence of
severity of myotonia does not necessarily parallel the degree of weak- autism occurs in children with DM1.
ness, and the weakest muscles often have only minimal myotonia. A severe congenital form of myotonic dystrophy appears in a
Myotonia is not a painful muscle spasm. Myalgias do not occur in minority of involved infants born to mothers with symptomatic myo-
myotonic dystrophy. tonic dystrophy. All patients with this severe congenital disease to date
The speech of patients with myotonic dystrophy is often articulated have had the DM1 form. Clubfoot deformities alone or more extensive
poorly and is slurred because of the involvement of the muscles of the congenital contractures of many joints can involve all extremities
face, tongue, and pharynx. Difficulties with swallowing sometimes (arthrogryposis multiplex congenita) and even include the cervical
occur. Aspiration pneumonia is a risk in severely involved children. spine. Generalized hypotonia and weakness are present at birth. Facial
Incomplete external ophthalmoplegia sometimes results from extra- wasting is prominent. Infants can require gavage feeding or ventilator
ocular muscle weakness. support for respiratory muscle weakness or apnea. Those requiring
Smooth muscle involvement of the gastrointestinal tract results in ventilation for <30 days often survive, and those with prolonged ven-
slow gastric emptying, poor peristalsis, and constipation. Some patients tilation have an infant mortality of 25%. Children ventilated for <30
have encopresis associated with anal sphincter weakness. Women with days have better motor, language, and daily activity skills than those
myotonic dystrophy can have ineffective or abnormal uterine contrac- requiring prolonged ventilation. One or both leaves of the diaphragm
tions during labor and delivery. may be nonfunctional. The abdomen becomes distended with gas in
Cardiac involvement is usually manifested as heart block in the the stomach and intestine because of poor peristalsis from smooth
Purkinje conduction system and arrhythmias (and sudden death) muscle weakness. The distention further compromises respiration.
rather than as cardiomyopathy, unlike most other muscular dystro- Inability to empty the rectum can compound the problem.
phies. Atrial or ventricular tachyarrhythmias have also resulted in
sudden death in adults and older children. LABORATORY FINDINGS
Endocrine abnormalities involve many glands and appear at any The classic myotonic electromyogram is not found in infants but can
time during the course of the disease so that endocrine status must be appear in toddlers or children in the early school years. The levels of
serum CK and other serum enzymes from muscle may be normal or
only mildly elevated in the hundreds (never the thousands).
ECG should be performed annually in early childhood. Ultrasound
imaging of the abdomen may be indicated in affected infants to deter-
mine diaphragmatic function. Radiographs of the chest and abdomen
and contrast studies of gastrointestinal motility may be needed.
Endocrine assessment should be undertaken to determine thyroid
and adrenal cortical function and to verify carbohydrate metabolism
(glucose tolerance test). Immunoglobulins should be examined, and,
if needed, more extensive immunologic studies should be performed.
DIAGNOSIS
The primary diagnostic test is a DNA analysis of blood to demonstrate
the abnormal expansion of the CTG or CCTG repeat. Prenatal diag-
nosis also is feasible. The muscle biopsy specimen in older children
shows many muscle fibers with central nuclei and selective atrophy of
histochemical type I fibers, but degenerating fibers are usually few and
widely scattered, and there is little or no fibrosis of muscle. Intrafusal
Figure 609-5 The patient was asked to squeeze with both of his
hands for several seconds and then suddenly release his grasp, and
fibers of muscle spindles are also abnormal. In young children with the
several seconds passed before full relaxation was achieved, an exam common form of the disease, the biopsy specimen can even appear
finding known as grip myotonia. (From Hughes BN, Hogue JS, Hsieh normal or at least not show myofiber necroses, which is a striking
DT: Grip and percussion myotonia in myotonic dystrophy type 1, contrast with DMD. In the severe neonatal form of myotonic dystro-
J Pediatr 164:1234, 2014.) phy, the muscle biopsy reveals maturational arrest in various stages of
development in some and congenital muscle fiber-type disproportion Treatment

in others. It is likely that the sarcolemmal membrane of muscle fibers There is no specific medical treatment, but the cardiac, endocrine,
not only has abnormal properties of electrical polarization but is also gastrointestinal, and ocular complications can often be treated. Phys-
incapable of responding to trophic influences of the motor neuron. iotherapy and orthopedic treatment of contractures in the neonatal
Muscle biopsy is not usually required for diagnosis, which in typical form of the disease may be beneficial. Myotonia may improve with
cases can be based on the clinical manifestations, including family exercise (warm-up phenomenon). Cardiac pacemaker implantation
history. Neonatal myotonic dystrophy must be distinguished from might be considered for heart block and antiarrhythmic drugs might
amyoplasia, congenital muscular dystrophy with or without merosin be indicated but are needed only rarely in children.
expression, congenital myasthenia gravis, spinal muscular atrophy, and Myotonia may be diminished, and function may be restored by
arthrogryposis secondary to oligohydramnios. drugs that raise the depolarization threshold of muscle membranes,
such as mexiletine, phenytoin, carbamazepine, procainamide, and
GENETICS quinidine sulfate. These drugs also have cardiotropic effects; thus,
The genetic defect in myotonic muscular dystrophy is on chromosome cardiac evaluation is important before prescribing them. Phenytoin
19 at the 19q13 locus. It consists of an expansion of the DM gene that and carbamazepine are used in doses similar to their use as antiepilep-
encodes a serine-threonine kinase (DMPK), with numerous repeats of tics (see Chapter 593.6); serum concentrations of 10-20 µg/mL for
the CTG codon. Expansions range from 50 to >2,000, with the normal phenytoin and 5-12 µg/mL for carbamazepine should be maintained.
alleles of this gene ranging in size from 5-37; the larger the expansion, If a patient’s disability is caused mainly by weakness rather than by
the more severe the clinical expression, with the largest expansions myotonia, these drugs will be of no value.
seen in the severe neonatal form. Rarely, the disease is associated with
no detectable repeats, perhaps a spontaneous correction of a previous OTHER MYOTONIC SYNDROMES
expansion but a phenomenon still incompletely understood. Another Most patients with myotonia have myotonic dystrophy. However, myo-
myotonic dystrophy (proximal myotonic myopathy) is a clinical entity tonia is not specific for this disease and occurs in several rarer
linked to at least 2 different chromosomal loci than classic myotonic conditions.
dystrophy but to 1 locus that shares a common unique pathogenesis in Myotonic chondrodystrophy (Schwartz-Jampel disease) is a rare
being mediated by a mutant mRNA. Defects in RNA splicing explain congenital disease characterized by generalized muscle hypertrophy
the insulin resistance in myotonic dystrophies as well as the myotonia. and weakness. Dysmorphic phenotypical features and the radiographic
Clinical and genetic expression can vary between siblings or between appearance of long bones are reminiscent of Morquio disease (see
an affected parent and child. In the severe neonatal form of the disease, Chapter 88), but abnormal mucopolysaccharides are not found. Dwarf-
the mother is the transmitting parent in 94% of cases, a fact not ism, joint abnormalities, and blepharophimosis are present. Several
explained by increased male infertility alone. Several cases of paternal patients have been the products of consanguinity, suggesting autoso-
transmission have been reported. Genetic analysis reveals that symp- mal recessive inheritance. The muscle protein perlecan, encoded by the
tomatic neonates usually have many more repeats of the CTG codon SJS1 gene, a large heparan sulfate proteoglycan of basement mem-
than do patients with the more classic form of the disease, regardless branes and cartilage, is defective in some cases of Schwartz-Jampel
of which parent is affected. Myotonic dystrophy often exhibits a pattern disease and explains both the muscular hyperexcitability and the
of anticipation in which each successive generation has a tendency to chondrodysplasia.
be more severely involved than the previous generation. Prenatal EMG reveals continuous electrical activity in muscle fibers closely
genetic diagnosis of myotonic dystrophy is available. resembling or identical to myotonia. Muscle biopsy reveals nonspecific
Table 609-1 Channelopathies and Related Disorders

PATTERN OF CLINICAL
DISORDER FEATURES INHERITANCE CHROMOSOME GENE
CHLORIDE CHANNELOPATHIES
Myotonia Congenita
Thomsen disease Myotonia Autosomal dominant 7q35 CLC1
Becker disease Myotonia and weakness Autosomal recessive 7q35 CLC1
SODIUM CHANNELOPATHIES
Paramyotonia congenita Paramyotonia Autosomal dominant 17q13.1-13.3 SCNA4A
Hyperkalemic periodic paralysis Periodic paralysis with Autosomal dominant 17q13.1-13.3 CNA4A
myotonia and paramyotonia
Hypokalemic periodic paralysis Periodic paralysis Autosomal dominant 17q13.1-13.3 SCNA4A
POTASSIUM-AGGRAVATED MYOTONIAS
Myotonia fluctuans Myotonia Autosomal dominant 17q13.1-13.3 SCNA4A
Myotonia permanens Myotonia Autosomal dominant 17q13.1-13.3 SCNA4A
Acetazolamide-responsive myotonia Myotonia Autosomal dominant 17q13.1-13.3 SCNA4A
CALCIUM CHANNELOPATHIES
Hypokalemic periodic paralysis Periodic paralysis Autosomal dominant 1q31-32 Dihydropyridine
receptor
Schwartz-Jampel syndrome Myotonia; dysmorphic Autosomal recessive 1q34.1-36.1 Perlecan
(chondrodystrophic myotonia)
Rippling muscle disease Muscle mounding, stiffness Autosomal dominant 1q41 Caveolin-3
Anderson syndrome Periodic paralysis, cardiac Autosomal dominant 17q23 KCNJ2-Kir2.1
arrhythmia, distinctive facies
Brody disease Delayed relaxation, no Autosomal recessive 16p12 Calcium adenosine
electromyogram myotonia triphosphatase
Malignant hyperthermia Anesthetic-induced delayed Autosomal dominant 19q13.1 Ryanodine receptor
relaxation
From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, WB Saunders.
myopathic features, which are minimal in some cases and pronounced autosomal recessive trait, but neither term defines the genetic etiol-
in others. The sarcotubular system is dilated. ogy. LGMD2 is mainly a group of several sarcoglycanopathies, cal-
Myotonia congenita (Thomsen disease) is a channelopathy (Table painopathy resulting from a mutation in the calpain-3 gene (CAPN3),
609-1) and is characterized by weakness and generalized muscular or dysferlinopathies that include Miyoshi myopathy, which usually
hypertrophy so that affected children resemble bodybuilders. Myoto- does not become symptomatic until adult life.
nia is prominent and can develop at age 2-3 yr, earlier than in myotonic The initial clinical manifestations rarely appear before middle or
dystrophy. The disease is clinically stable and is apparently not progres- late childhood or may be delayed until early adult life. Low back pain
sive for many years. Muscle biopsy specimens show minimal patho- may be a presenting complaint because of the lordotic posture resulting
logic changes, and the EMG demonstrates myotonia. Various families from gluteal muscle weakness. Confinement to a wheelchair usually
are described as showing either autosomal dominant (Thomsen becomes obligatory at about 30 yr of age. The rate of progression varies
disease) or recessive (Becker disease, not to be confused with BMD or from one pedigree to another but is uniform within a kindred. Although
DMD) inheritance. Rarely, myotonic dystrophy and myotonia con- weakness of neck flexors and extensors is universal, facial, lingual, and
genita coexist in the same family. The autosomal dominant and auto- other bulbar-innervated muscles are rarely involved. As weakness and
somal recessive forms of myotonia congenita have been mapped to the muscle wasting progress, tendon stretch reflexes become diminished.
same 7q35 locus. This gene is important for the integrity of chloride Cardiac involvement is unusual. Intellectual function is generally
channels of the sarcolemmal and T-tubular membranes. normal. The clinical differential diagnosis of LGMD includes juvenile
Paramyotonia is a temperature-related myotonia that is aggravated spinal muscular atrophy (Kugelberg-Welander disease), myasthenia
by cold and alleviated by warm external temperatures. Patients have gravis, and metabolic myopathies.
difficulty when swimming in cold water or if they are dressed inade- The EMG and muscle biopsy show confirmatory evidence of mus-
quately in cold weather. Paramyotonia congenita (Eulenburg disease) cular dystrophy, but none of the findings is specific enough to make
is a defect in a gene at the 17q13.1-13.3 locus, the identical locus identi- the definitive diagnosis without additional clinical criteria. In some
fied in hyperkalemic periodic paralysis. By contrast with myotonia cases, α-sarcoglycan (formerly known as adhalin), a dystrophin-related
congenita, paramyotonia is a disorder of the voltage-gated sodium glycoprotein of the sarcolemma, is deficient; this specific defect may
channel caused by a mutation in the α subunit. Myotonic dystrophy be demonstrated in the muscle biopsy by immunocytochemistry, as
also is a sodium channelopathy (see Table 609-1). may deficiency of 3 other forms of sarcoglycan as well. Increased serum
In sodium channelopathies, exercise produces increasing myotonia, CK level is usual, but the magnitude of elevation varies among families.
whereas in chloride channelopathies, exercise reduces the myotonia. The ECG is usually unaltered.
This is easily tested during examination by asking patients to close the In one autosomal dominant form of LGMD, a genetic defect has
eyes forcefully and open them repeatedly; it becomes progressively been localized to the long arm of chromosome 5. In the autosomal
more difficult in sodium channel disorders and progressively easier in recessive disease, it is on the long arm of chromosome 15. A mutated
chloride channel disorders. dystrophin-associated protein in the sarcoglycan complex (sarcogly-
canopathy; LGMD types 2C, 2E, and 2F) is responsible for some cases
Bibliography is available at Expert Consult. of autosomal recessive LGMD. Most sarcoglycanopathies result from
a mutation in α-sarcoglycan; other LGMDs resulting from deficiencies
in β-, γ-, and δ-sarcoglycan also occur. In normal smooth muscle,
α-sarcoglycan is replaced by ε-sarcoglycan, and the others are the
609.4 Limb-Girdle Muscular Dystrophies same. A dystroglycan mutation also is implicated in some cases.
Harvey B. Sarnat Another group of LGMDs (type 2B) are caused by allelic mutations
of the dysferlin (DYSF) gene, another gene expressing a protein essen-
Limb-girdle muscular dystrophies (LGMDs) encompass a heteroge- tial to structural integrity of the sarcolemma, though not associated
neous group of progressive hereditary muscular dystrophies that with the dystrophin-glycoprotein complex. DYSF interacts with
mainly affect muscles of the hip and shoulder girdles (Table 609-2). caveolin-3 or calpain-3, and DYSF deficiency may be secondary to
Distal muscles also eventually become atrophic and weak. Hypertro- defects in these other gene products. Primary calpain-3 defect (type
phy of the calves and ankle contractures develop in some forms, 2A) is reported in Amish families and in families from French Reunion
causing potential confusion with BMD. Sixteen genetic forms of Island and from Brazil. Autosomal recessive (Miyoshi myopathy) and
LGMD are now described, each at a different chromosomal locus autosomal dominant traits are documented. Both are slowly progres-
and expressing different protein defects. Some include diseases clas- sive myopathies with onset in adolescence or young adult life and can
sified with other traditional groups, such as the lamin-A/C defects affect distal as well as proximal muscles. Cardiomyopathy is rare.
of the nuclear membrane (see Emery-Dreifuss muscular dystrophy, Chronically elevated serum CK in the thousands is found in dysfer-
above), and some forms of congenital muscular dystrophy. LGMD1 linopathies. Ultrastructure shows a thickened basal lamina over defects
denotes autosomal dominant inheritance and LGMD2 implies an in the sarcolemma and replacement of the sarcolemma by multiple
Table 609-2 Autosomal Recessive Limb-Girdle Muscular Dystrophies

TYPE LOCATION GENE PRODUCT CLINICAL FEATURES
LGMD2A 15q Calpain 3 Onset at 8-15 yr, progression variable
LGMD2B 2p13-16 Dysferlin Onset at adolescence, mild weakness; gene site is the same as
for Miyoshi myopathy
LGMD2C 13q12 Sarcoglycan Duchenne-like, severe childhood autosomal recessive muscular
dystrophy (SCARMD1)
LGMD2D 17q12 α-Sarcoglycan (adhalin) Duchenne-like, severe childhood autosomal recessive muscular
dystrophy (SCARMD2)
LGMD2E 4q12 β-Sarcoglycan Phenotype between Duchenne and Becker muscular dystrophies
LGMD2F 5q33-34 Sarcoglycan Slowly progressive, growth retardation
LGMD, limb-girdle muscular dystrophy.
From Fenichel GM: Clinical pediatric neurology: a signs and symptoms approach, ed 5, Philadelphia, 2005, Elsevier Saunders, p. 176, Table 7-5.
Bibliography Hilbert JE, Johnson NE, Moxley RT: New insights about the incidence,
Campbell C, Sherlock R, Jacob P, et al: Congenital myotonic dystrophy: assisted multisystem manifestations, and care of patients with congenital myotonic
ventilation duration and outcome, Pediatrics 113:811–816, 2004. dystrophy, J Pediatr 163:12–14, 2013.
Day JW, Richater K, Jacobsen JP, et al: Myotonic dystrophy type 2: molecular, Hughes BM, Houge JS, Hsieh DT: Grip and percussion myotonia in myotonic
diagnostic and clinical spectrum, Neurology 60:657–664, 2003. dystrophy type 1, J Pediatr 164:1234, 2014.
Echenne B, Bassez G: Congenital and infantile myotonic dystrophy, Handb Clin Machuca-Tzili L, Brook JD, Hilton-Jones D: Clinical and molecular aspects of the
Neurol 113:1387–1393, 2013. myotonic dystrophies: a review, Muscle Nerve 32:1–8, 2005.
Echenne B, Rideau A, Roubertie A, et al: Myotonic dystrophy type 1 in childhood. Modoni A, Silvestri G, Pomponi MG, et al: Characterization of the pattern of
Long-term evolution in patients surviving the neonatal period, Eur J Paediatr cognitive impairment in myotonic dystrophy type 1, Arch Neurol 61:1943–1947,
Neurol 12:210–223, 2008. 2004.
Ekström AB, Hakenäs-Plate L, Samuelsson L, et al: Autism spectrum conditions in Wahbi K, Meune C, Porcher R, et al: Electrophysiological study with prophylactic
myotonic dystrophy type 1: a study on 57 individuals with congenital and pacing and survival in adults with myotonic dystrophy and conduction system
childhood forms, Am J Med Genet B Neuropsychiatr Genet 147B:918–926, 2008. disease, JAMA 307:1292–1301, 2012.
Gadalla SM, Lund M, Pfeiffer RM, et al: Cancer risk among patients with myotonic
muscular dystrophy, JAMA 306:2480–2486, 2011.
layers of small vesicles. Regenerating myofibers outnumber degenerat- About 30% of affected patients are asymptomatic or show only mild
ing myofibers. These disorders were formerly called hyperCKemia and scapular winging and decreased tendon stretch reflexes, of which they
rippling muscle disease, the latter sometimes confused with myotonia. were unaware until formal neurologic examination was performed.
An autosomal recessive mutation in the calcium-activated chloride
channel anoctamin-5 can cause proximal LGMD2. LABORATORY FINDINGS
There is overlap of the group of LGMDs with the congenital mus- Serum levels of CK and other enzymes vary greatly, ranging from
cular dystrophies, such as Walker-Warburg syndrome with POMT, normal or near-normal to elevations of several thousand. An ECG
Fukuyama muscular dystrophy with FKRP genetic defects, and Ullrich should be performed, although the anticipated findings are usually
muscular dystrophy of collagen VI subunits. normal. EMG reveals nonspecific myopathic muscle potentials. Diag-
nostic molecular testing in individual cases and within families is indi-
Bibliography is available at Expert Consult. cated for prediction.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

609.5 Facioscapulohumeral Muscular Molecular genetic diagnosis is the most specific confirmation if clinical
suspicion is high, with or without a family history of the disease.
Dystrophy Muscle biopsy distinguishes more than one form of facioscapulo-
Harvey B. Sarnat humeral dystrophy, consistent with clinical evidence that several dis-
tinct diseases are embraced by the term facioscapulohumeral dystrophy.
Facioscapulohumeral muscular dystrophy, also known as Landouzy- Muscle biopsy and EMG also distinguish the primary myopathy from
Dejerine disease, is probably not a single disease entity but a group a neurogenic disease with a similar distribution of muscular involve-
of diseases with similar clinical manifestations. Autosomal dominant ment. The general histopathologic findings in the muscle biopsy mate-
inheritance is the rule; genetic anticipation is often found within rial are extensive proliferation of connective tissue between muscle
several generations of a family, the succeeding more severely involved fibers, extreme variation in fiber size with many hypertrophic as well
at an earlier age than the preceding. The frequency is 1 : 20,000 popula- as atrophic myofibers, and scattered degenerating and regenerating
tion. Though the clinical onset is generally in later childhood or adult fibers. An “inflammatory” type of facioscapulohumeral muscular dys-
life, early molecular defects arising during myogenesis are demon- trophy is also distinguished, characterized by extensive lymphocytic
strated in the human fetus. The genetic mechanism in autosomal domi- infiltrates within muscle fascicles. Despite the resemblance of this form
nant facioscapulohumeral dystrophy involves integral deletions of a to inflammatory myopathies, such as polymyositis, there is no evidence
3.3-kb tandem repeat (D4Z4) in the subtelomeric region at the 4q35 of autoimmune disease, and steroids and immunosuppressive drugs do
locus. Several other genes clustered at the 4q35 locus are upregulated not alter the clinical course. A precise histopathologic diagnosis has
in fetuses with facioscapulohumeral dystrophy. D4Z4 acts as a lamins- important therapeutic implications. Mononuclear cell “inflammation”
dependent insulator exhibiting both enhancer-blocking and barrier in a muscle biopsy sample of infants younger than 2 yr old is usually
activities and displaces the telomere toward the nuclear periphery. A facioscapulohumeral dystrophy or, less often, a congenital muscular
3.3-kb repeat array at the subtelomeric locus 10q26 is closely homolo- dystrophy.
gous, with chromosomal translocation or sequence conversion between
these 2 regions, possibly predisposing to the DNA rearrangement TREATMENT
causing facioscapulohumeral dystrophy. Approximately 10% of fami- Physiotherapy is of no value in regaining strength or in retarding pro-
lies with this phenotype do not map to the 4q35 locus. gressive weakness or muscle wasting. Footdrop and scoliosis may be
treated by orthopedic measures. In selected cases, surgical wiring of
CLINICAL MANIFESTATIONS the scapulas to the thoracic wall provides improved shoulder stability
Facioscapulohumeral dystrophy shows the earliest and most severe and abduction of the arm, but brachial plexopathy, frozen shoulder,
weakness in facial and shoulder girdle muscles. The facial weakness and scapular fractures are reported complications. Cosmetic improve-
differs from that of myotonic dystrophy; rather than an inverted V– ment of the facial muscles of expression may be achieved by recon-
shaped upper lip, the mouth in facioscapulohumeral dystrophy is structive surgery, which grafts a fascia lata to the zygomatic muscle and
rounded and appears puckered because the lips protrude. Inability to to the zygomatic head of the quadratus labii superioris muscle. Exercise
close the eyes completely in sleep is a common expression of upper of facial muscles can help minimize secondary disuse atrophy. No
facial weakness; some patients have extraocular muscle weakness, effective pharmacologic or genetic treatment is presently available.
although ophthalmoplegia is rarely complete. Facioscapulohumeral
dystrophy has been associated with Möbius syndrome on rare Bibliography is available at Expert Consult.
occasions. Pharyngeal and tongue weakness may be absent and is
never as severe as the facial involvement. Hearing loss, which may
be subclinical, and retinal vasculopathy (indistinguishable from 609.6 Congenital Muscular Dystrophies
Coats disease) are associated features, particularly in severe cases of Harvey B. Sarnat
facioscapulohumeral dystrophy with early-childhood onset.
Scapular winging is prominent, often even in infants. Flattening or The term congenital muscular dystrophy is misleading because all mus-
even concavity of the deltoid contour is seen, and the biceps and triceps cular dystrophies are genetically determined. It is used to encompass
brachii muscles are wasted and weak. Muscles of the hip girdle and several distinct diseases that have a common characteristic of severe
thighs also eventually lose strength and undergo atrophy, and Gowers involvement at birth but that, ironically, often follow a more benign
sign and a Trendelenburg gait appear. Contractures of the extremities clinical course than the early onset and the histopathological changes
are rare. Finger and wrist weakness occasionally is the first symptom. in the muscle biopsy would suggest. A distinguishing feature of the
Weakness of the anterior tibial and peroneal muscles can lead to foot- congenital dystrophies, by contrast with other muscular dystrophies,
drop; this complication usually occurs only in advanced cases with is a high association with brain malformations, particularly disorders
severe weakness. Lumbar lordosis and kyphoscoliosis are common of cortical development such as lissencephaly/pachygyria and polymi-
complications of axial muscle involvement. Calf pseudohypertrophy is crogyria, often complicated by severe epilepsy. Autosomal recessive
not a usual feature but is described rarely. inheritance is the rule.
Facioscapulohumeral muscular dystrophy can also be a mild disease
causing minimal disability. Clinical manifestations might not be CLINICAL MANIFESTATIONS
expressed in childhood and are delayed into middle adult life. Unlike In several distinct clinical and genetic diseases grouped under the
most other muscular dystrophies, asymmetry of weakness is common. umbrella term congenital muscular dystrophies, infants often have
Bibliography Chelly J, Desguerre I: Progressive muscular dystrophies (limb girdle muscular

Bolduc V, Marlow G, Boycott KM, et al: Recessive mutation in the putative dystrophy), Handb Clin Neurol 113:1343–1366, 2013.
calcium-activated chloride channel anoctamin-5 cause proximal LGMD2L and Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, et al: A dystroglycan mutation
distal MMD3 muscular dystrophies, Am J Hum Genet 86:213–221, 2010. associated with limb-girdle muscular dystrophy, N Engl J Med 364(10):939–946,
Bonne G, Muchir A, Helbling-Leclerc A, et al: Clinical and genetical heterogeneity 2011.
of laminopathies, Acta Myol 20:138–144, 2001.
Bushby KM, Beckmann JS: Pathogenesis in the non–sarcoglycan limb-girdle
muscular dystrophies, Neuromuscul Disord 13:80–90, 2003.
2984.e2 Chapter 609 ◆ Muscular Dystrophies
Bibliography
Broucqsault N, Morere J, Gaillard MC, et al: Dysregulation of 4q35- and
muscle-specific genes in fetuses with a short D4Z4 array linked to facio-
scapulo-humeral dystrophy, Hum Mol Genet 22:4206–4214, 2013.
Ottaviani A, Schluth-Bolard C, Gilson E, et al: D4Z4 as a prototype of CTCF and
lamins-dependent insulator in human cells, Nucleus 1:30–36, 2010.
contractures or arthrogryposis at birth and are diffusely hypotonic. The genetic defect in a sibling), specific genetic testing might avoid the
muscle mass is thin in the trunk and extremities. Head control is poor. muscle biopsy.
Facial muscles may be mildly involved, but ophthalmoplegia, pharyn-
geal weakness, and weak sucking are not common. A minority has DIAGNOSIS
severe dysphagia and requires gavage or gastrostomy. Tendon stretch Muscle biopsy is diagnostic in the neonatal period or thereafter. An
reflexes may be hypoactive or absent. Arthrogryposis is common in all extensive proliferation of endomysial collagen envelops individual
forms of congenital muscular dystrophy (see Chapter 608.10). Con- muscle fibers even at birth, also causing them to be rounded in cross-
genital contractures of the elbows have a high association with the sectional contour by acting as a rigid sleeve, especially during contrac-
Ullrich type of congenital muscular dystrophy owing to a defect in tion. The perimysial connective tissue and fat are also increased, and
1 or more of the 3 collagen VI genes, each at a different locus. the fascicular organization of the muscle may be disrupted by the
The congenital muscular dystrophies can be classified according to fibrosis. Tissue cultures of intramuscular fibroblasts exhibit increased
the type of protein altered by the specific genetic mutations. Diseases collagen synthesis, but the structure of the collagen is normal. Muscle
of extracellular matrix proteins include merosin deficiency (LAMA2 fibers vary in diameter, and many show central nuclei, myofibrillar
mutation at locus 6q22-q23) and Ullrich disease (COL6A1, -A2 and splitting, and other cytoarchitectural alterations. Scattered degenerat-
-A3 mutations at 21q22 and 2q37 loci). A protein of the endoplasmic ing and regenerating fibers are seen. No inflammation or abnormal
reticulum (SEPN1 mutation at 1p35) is the basis of rigid spine syn- inclusions are found.
drome. Abnormal glycosylation of α-dystroglycan causes Walker- Immunocytochemical reactivity for merosin (α2 chain of laminin)
Warburg syndrome (POMT1 mutation at 9q34), muscle-eye-brain at the sarcolemmal region is absent in approximately 40% of cases
disease of Santavuori (POMGnT1 mutation at 1p32), Fukuyama mus- and normally expressed in the others (Figs. 609-6 and 609-7).
cular dystrophy (FCMD mutation at 8q31-q33 and 9q31), and congeni-
tal muscular dystrophy with secondary merosin deficiency (FKRP
mutation at 19q13). Glycosylation defects (dystroglycanopathies)
result in defective neuroblast migration in the fetal brain and also can
cause dilated cardiomyopathy. The dystroglycan molecule interacts
with both proteins of the plasma (sarcolemmal) membrane and those
of the extracellular matrix and basal lamina not only in muscle but
also in brain, where defective dystroglycan and poor glycosylation
result in gaps in the pial limiting membrane, a discontinuous glia
limitans, causing cobblestone lissencephaly and glioneuronal hetero-
topia of overmigrated neural cells during formation of the cerebral
cortex.
The Fukuyama type of congenital muscular dystrophy is the second
most common muscular dystrophy in Japan (after DMD); it has also
A
been reported in children of Dutch, German, Scandinavian, and
Turkish ethnic backgrounds. In the Fukuyama variety, severe cardio-
myopathy and malformations of the brain usually accompany the skel-
etal muscle involvement. Signs and symptoms related to these organs
are prominent: cardiomegaly and heart failure, intellectual disability,
seizures, microcephaly, and failure to thrive.
Central neurologic disease can accompany forms of congenital
muscular dystrophy other than Fukuyama disease. Mental and neuro-
logic status is the most variable feature; an apparently normal brain
and normal intelligence do not preclude the diagnosis if other mani-
festations indicate this myopathy. The cerebral malformations that
occur are not consistently of one type and vary from severe dysplasias
(holoprosencephaly, lissencephaly) to milder conditions (agenesis of
the corpus callosum, focal heterotopia of the cerebral cortex and sub- B
cortical white matter, cerebellar hypoplasia). Seizures are a frequent
complication, as early as the neonatal period, and may include infantile
spasms and other severe infantile epilepsies.
Congenital muscular dystrophy is a constant association with cere-
bral dysgenesis in the Walker-Warburg syndrome and in muscle-eye-
brain disease of Santavuori. The neuropathologic findings are those
of neuroblast migratory abnormalities in the cerebral cortex, cerebel-
lum, and brainstem. Studies indicate considerably more genetic overlap
between Walker-Warburg, Fukuyama, and muscle-eye-brain forms of
congenital muscular dystrophy that explain mixed and transitional
phenotypes, so that, for example, a Fukutin-related (FKRP) gene
can cause a Walker-Warburg or muscle-eye-brain presentation, or
POMGnT1 also can produce phenotypes other than classic Walker- C
Warburg disease.
Figure 609-6 Quadriceps femoris muscle biopsy of a 6 mo old girl
LABORATORY FINDINGS with congenital muscular dystrophy associated with merosin (α2-
laminin) deficiency. A, Histologically, the muscle is infiltrated by a great
Serum CK level is usually moderately elevated from several hundred
proliferation of collagenous connective tissue; myofibers vary in diam-
to many thousand IU/L; only marginal increases are sometimes found. eter, but necrotic fibers are rare. B, Immunocytochemical reactivity
EMG shows nonspecific myopathic features. Investigation of all forms for merosin (α2-laminin) is absent in all fibers, including the intrafusal
of congenital muscular dystrophy should include cardiac assessment myofibers of a muscle spindle seen at bottom. C, Dystrophin expres-
and an imaging study of the brain. Muscle biopsy is essential for the sion (rod domain) is normal. Compare with Figures 609-2, 609-3, and
diagnosis, but if there is a high degree of suspicion (e.g., a confirmed 609-7.
A
B
Figure 609-7 Quadriceps femoris muscle biopsy specimen of a 2 yr
old girl with congenital muscular dystrophy. A, The fascicular architec-
ture of the muscle is severely disrupted, and muscle is replaced by fat
and connective tissue; the remaining small groups of myofibers of vari-
able size are seen, including a muscle spindle at top. B, Merosin
expression is normal in both extrafusal fibers of all sizes and in intrafusal
spindle fibers. The severity of the myopathy does not relate to the
presence or absence of merosin in congenital muscular dystrophy.
Compare with Figure 609-6.
Merosin is a protein that binds the sarcolemmal membrane of the

myofiber to the basal lamina or basement membrane. Merosin also
is expressed in brain and in Schwann cells. The presence or absence
of merosin does not always correlate with the severity of the myopa-
thy or predict its course, but cases with merosin deficiency tend to
have more severe cerebral involvement. Adhalin (α-dystroglycan)
may be secondarily reduced in some cases. Collagen VI is selectively
reduced or absent in Ullrich disease because of a mutation in the
COL6A gene. Mitochondrial dysfunction may be another secondary
defect.
TREATMENT
Only supportive therapy is available in general. Cyclosporine might
correct the mitochondrial dysfunction and muscular apoptosis in col-
lagen VI myopathy. Though no curative treatment is presently avail-
able for the congenital muscular dystrophies, a consensus statement
on the standard of supportive care was issued at a special workshop
in 2009 and published the following year. It covers aspects of various
organ systems that could be involved, including neurologic, pulmo-
nary, gastroenterologic, cardiac, orthopedic/rehabilitation, and pallia-
tive care.

Bibliography mapping of the DM3 locus to chromosome 15q21–24, Brain 127:1979–1992,

Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A, et al: Mutations in the 2004.
O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration Nadeau A, Kinali M, Main M, et al: Natural history of Ullrich congenital muscular
disorder Walker-Warburg syndrome, Am J Hum Genet 71(5):1033–1043, 2002. dystrophy, Neurology 73:25–31, 2009.
de Bernabe DB, van Bokhoven H, van Beusekom E, et al: A homozygous nonsense Peat RA, Smith JM, Compton AG, et al: Diagnosis and etiology of congenital
mutation in the fukutin gene causes a Walker-Warburg syndrome phenotype, muscular dystrophy, Neurology 71:312–321, 2008.
J Med Genet 40:845–848, 2003. Ruggieri V, Lubieniecki F, Meli F, et al: Merosin-positive congenital muscular
Jiménez-Mallebrera C, Maioli MA, Kim J, et al: A comparative analysis of collagen dystrophy with mental retardation, microcephaly and central nervous system
VI production in muscle, skin and fibroblasts from 14 Ullrich congenital abnormalities unlinked to the Fukuyama muscular dystrophy and muscular-
muscular dystrophy patients with dominant and recessive COL6A mutations, eye-brain loci: report of three siblings, Neuromuscul Disord 11:570–578, 2001.
Neuromuscul Disord 16:571–582, 2006. Wang CH, Bonnemann CG, Rutkowski A, et al: Consensus statement on standard
Kirschner J: Congenital muscular dystrophies, Handb Clin Neurol 113:1377–1385, of care for congenital muscular dystrophies, J Child Neurol 25:1559–1581, 2010.
2013.
Le Ber I, Martínez M, Campion D, et al: A non-DM1, non-DM2 multisystem
myotonic disorder with frontotemporal dementia: Phenotype and suggestive
Chapter 610
Endocrine and Toxic
Myopathies
Harvey B. Sarnat
THYROID MYOPATHIES
See also Chapters 563-568.
Thyrotoxicosis causes proximal weakness and wasting accompanied
by myopathic electromyographic changes. Thyroxine binds to myofi-
brils and, if in excess, impairs contractile function. Hyperthyroidism
can also induce myasthenia gravis and hypokalemic periodic paralysis,
the latter mainly affecting East Asian males who have a genetic predis-
position. Mutation in the gene KCNJ18 may be responsible for altering
the potassium channel Kir2.6 in up to one third of cases. Potassium
supplementation and propranolol are useful in treating thyrotoxic peri-
odic paralysis.
Hypothyroidism, whether congenital or acquired, consistently pro-
duces hypotonia and a proximal distribution of weakness. Although
muscle wasting is most characteristic, one form of cretinism, the
Kocher-Debré-Sémélaigne syndrome, is characterized by generalized
pseudohypertrophy of weak muscles. Infants can have a Herculean
appearance reminiscent of myotonia congenita. The serum creatine
kinase (CK) level is elevated in hypothyroid myopathy and returns to
normal after thyroid replacement therapy.
Results of muscle biopsy in hypothyroidism reveal acute myopathic
changes, including myofiber necrosis and sometimes central cores. In
hyperthyroidism, the muscle biopsy specimen shows only mild, non-
specific myopathic changes without necrosis of myofibers.
The clinical and pathologic features of hyperthyroid myopathy and
hypothyroid myopathy resolve after appropriate treatment of the
thyroid disorder. Many of the systemic symptoms of hyperthyroidism,
including myopathic weakness and ophthalmoparesis, improve with
the administration of β-blockers.
Most patients with primary hyperparathyroidism (see Chapter 573)
develop weakness, fatigability, fasciculations, and muscle wasting that
is reversible after removal of the parathyroid adenoma. The serum cre-
atine kinase and muscle biopsy remain normal, but the electromyogra-
phy can show nonspecific myopathic features. A minority of patients
develop myotonia that could be confused with myotonic dystrophy.
STEROID-INDUCED MYOPATHY
Natural Cushing disease and iatrogenic Cushing syndrome from
exogenous corticosteroid administration can cause painless, symmet-
ric, progressive proximal weakness, increased serum creatine kinase
levels, and a myopathic electromyogram and muscle biopsy specimen
(see Chapter 577). Myosin filaments may be selectively lost. The
9α-fluorinated steroids, such as dexamethasone, betamethasone, and
triamcinolone, are the most likely to produce steroid myopathy. Dexa-
methasone alters the abundance of ceramides in myotubes in develop-
ing muscle. In patients with dermatomyositis or other myopathies
treated with steroids, it is sometimes difficult to distinguish refractori-
ness of the disease from steroid-induced weakness, especially after
long-term steroid administration. Vitamin D is another factor altering
muscle metabolism and particularly its sensitivity to insulin; vitamin
D deficiency may be accentuated and contribute to steroid myopathy,
especially in type 2 diabetic patients and insulin resistance.
All patients who have been taking steroids for long periods develop
reversible type II myofiber atrophy; this is a steroid effect but is not
steroid myopathy unless it progresses to become a necrotizing myopa-
thy. At greatest risk in the pediatric age group are children requiring
long-term steroid therapy for asthma, rheumatoid arthritis, dermato-
myositis, lupus, and other autoimmune or inflammatory diseases
or who are being treated for leukemia or other hematologic diseases.
Table 610-1 Toxic Myopathies
INFLAMMATORY MALIGNANT HYPERTHERMIA
Cimetidine Halothane
D-Penicillamine Ethylene
Procainamide Diethyl ether
L-Tryptophan Methoxyflurane
L-DOPA Ethyl chloride
Trichloroethylene
NONINFLAMMATORY
Gallamine
NECROTIZING OR VACUOLAR
Succinylcholine
Cholesterol-lowering agents
Chloroquine MITOCHONDRIAL
Colchicine Zidovudine
Emetine
ε-Aminocaproic acid MYOTONIA
Labetalol 2,4-d-Chlorophenoxyacetic acid
Cyclosporine and tacrolimus Anthracene-9-carboxycyclic acid
Isoretinoic acid (vitamin A Cholesterol-lowering drugs
analog) Chloroquine
Vincristine Cyclosporine
Alcohol MYOSIN LOSS
RHABDOMYOLYSIS AND Nondepolarizing neuromuscular
MYOGLOBINURIA blocking agents
Cholesterol-lowering drugs Intravenous glucocorticoids
(especially statins)
Alcohol
Heroin
Amphetamine
Toluene
Cocaine
ε-Aminocaproic acid
Pentazocine
Phencyclidine
From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia,
2004, WB Saunders, p. 2399.
In addition to steroids, the drugs listed in Table 610-1 can cause acute
or chronic toxic myopathies. An incompletely understood entity
known as critical illness myopathy is a progressive weakness of patients
with extended illnesses who remain in the intensive care unit; it is
associated pathologically with selective loss of thick (myosin) myofila-
ments; immobility and excessive steroid treatment are believed to be
important factors. Various steroids are sometimes used chronically in
the treatment of Duchenne muscular dystrophy; they may actually
exaggerate the weakness because of steroid myopathy superimposed
on the dystrophic process (see Chapter 609).
Hyperaldosteronism (Conn syndrome) is accompanied by episodic
and reversible weakness similar to that of periodic paralysis. The proxi-
mal myopathy can become irreversible in chronic cases. Elevated cre-
atine kinase levels and even myoglobinuria sometimes occur during
acute attacks. Arterial hypertension is a frequent manifestation and, in
children, aldosterone-secreting adenomas should be considered in the
differential diagnosis of idiopathic hypertension. Hereditary primary
aldosteronism is due to a mutation in one of the potassium channel
genes KCNJ5 and GIRK4.
Chronic growth hormone excess (sometimes illicitly acquired by
adolescent athletes or seen in acromegaly) produces atrophy of some
myofibers and hypertrophy of others, and scattered myofiber degenera-
tion. Despite the augmented protein synthesis induced by growth
hormone, it impairs myofibrillar adenosine triphosphatase activity and
reduces sarcolemmal excitability, with resultant diminished, rather
than increased, strength corresponding to the larger muscle mass. It
has been used therapeutically in muscular dystrophy with both a posi-
tive effect and complications. Ghrelin is an intestinal hormone that
activates a growth hormone secretagog receptor and stimulates growth
hormone release. In addition to its effect as a “hunger hormone” that
involves food intake and fat deposition, it also prevents muscular
atrophy by inducing myodifferentiation and myoblast fusion.

Chapter 610 ◆ Endocrine and Toxic Myopathies 2987.e1
Bibliography Pradhan G, Samson SL, Sun Y: Gherlin: much more than a hunger hormone, Curr
Beuschlein F: Regulation of aldosterone secretion: from physiology to disease, Eur Opin Clin Nutr Metab Care 16:619–624, 2013.
J Endocrinol 168:R85–R93, 2013. Scholl UUI, Lifton RP: New insights into aldosterone-producing adenomas and
Falhammar H, Thorén M, Calissendorff J: Thyrotoxic periodic paralysis: clinical hereditary aldosteronism: mutations in the K+ channel KCNJ5, Curr Opin
and molecular aspects, Endocrine 43:274–284, 2013. Nephrol Hypertens 22:141–147, 2013.
Girgis CM, Clifton-Bligh RJ, Hamrick MW, et al: The roles of vitamin D in skeletal Shee CD: Risk factors for hydrocortisone myopathy in acute, severe asthma, Respir
muscle: form, function and metabolism, Endocr Rev 34:33–83, 2013. Med 84:229–233, 1990.
Latronico N, Tomelleri G, Filosto M: Critical illness myopathy, Curr Opin Zennaro MC, Rickard AJ, Boulkroun S: Genetics of mineralocorticoid excess: an
Rheumatol 24:616–622, 2012. update for clinicians, Eur J Endocrinol 169:R15–R25, 2013.
Mastaglia FL, Ojeda VJ, Sarnat HB, et al: Myopathies associated with
hypothyroidism, Aust N Z J Med 18:799–806, 1988.
Chapter 611 ◆ Metabolic Myopathies 2987
Chapter 611
Metabolic Myopathies
Harvey B. Sarnat
Table 611-1 describes the differential diagnosis of metabolic

myopathies.
611.1 Periodic Paralyses (Potassium-

Related) and Other Muscle
Channelopathies
Harvey B. Sarnat
Episodic, reversible weakness or paralysis, known as periodic paraly-

sis, is associated with transient alterations in serum potassium levels,
usually hypokalemia but occasionally hyperkalemia. All familial forms
of periodic paralysis are caused by mutations in genes encoding
voltage-gated ion channels in muscle: sodium, calcium, and potassium.
Mutations in the CACNA1S voltage-gated calcium (not potassium)
channel are the etiology of hypokalemic periodic paralysis. Nonhe-
reditary causes of periodic paralysis are caused by a diverse group
of disorders that affect potassium balance (Table 611-2). During
Table 611-1 Metabolic and Mitochondrial Myopathies

GLYCOGEN METABOLISM DEFICIENCIES
Type II: α-1,4-Glucosidase (acid maltase)
Type III: Debranching
Type IV: Branching
Type V: Phosphorylase (McArdle disease)*
Type VII: Phosphofructokinase (Tarui disease)*
Type VIII: Phosphorylase B kinase*
Type IX: Phosphoglycerate kinase*
Type X: Phosphoglycerate mutase*
Type XI: Lactate dehydrogenase*
LIPID METABOLISM DEFICIENCIES
Carnitine palmitoyltransferase*
Primary systemic/muscle carnitine deficiency
Secondary carnitine deficiency
β-Oxidation defects
Medications (valproic acid)
PURINE METABOLISM DEFICIENCIES
Myoadenylate deaminase deficiency
MITOCHONDRIAL MYOPATHIES
Alpers-Huttenlocher syndrome
Chronic progressive external ophthalmoplegia
Kearns-Sayre syndrome
Pearson syndrome
Mitochondrial encephalomyopathy with lactic acidosis and
stroke-like episodes (MELAS)
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
Myoclonic epilepsy with ragged red fibers (MERRF)
Leber hereditary optic neuropathy
Leigh syndrome
Infantile myopathy and lactic acidosis
*Deficiency can produce exercise intolerance and myoglobinuria.
From Chinnery PF: Muscle diseases. In Goldman L, Schafer AI, editors:
Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Elsevier, Table 429-7,
p. 2413.
may be filled with glycogen. Muscle biopsy is not essential to diagnose

Table 611-2 Secondary Causes of Periodic Paralysis periodic paralysis, however. Hypoglycemia does not occur. Loci for the
HYPOKALEMIC majority of periodic paralyses have been demonstrated and the genes
Thyrotoxic at least partially characterized, but many patients with the same clinical
Primary hyperaldosteronism (Conn syndrome) phenotype exhibit no mutations in the identified genes.
Renal tubular acidosis (e.g., Fanconi syndrome)
Juxtaglomerular apparatus hyperplasia (Bartter syndrome) TREATMENT
Gastrointestinal potassium wastage Paralytic attacks of hypokalemic periodic paralysis are best treated by
Villous adenoma the oral administration of potassium or even fruit juices that contain
Laxative abuse potassium. A low sodium intake and the administration of acetazol-
Pancreatic non–insulin-secreting tumors with diarrhea
amide, 125-250 mg bid or tid in school-age children, often is effective
Nontropical sprue
Barium intoxication in abolishing attacks or at least reducing their frequency and severity.
Potassium-depleting diuretics Spironolactone, in a dose of 100-200 mg/day PO in school-age chil-
Amphotericin B dren, may be beneficial as well.
Licorice
Corticosteroids OTHER MUSCLE CHANNELOPATHIES
Toluene toxicity Disorders of ion channels other than the well-documented potassium
p-Aminosalicylic acid channelopathies also are recognized. A rare, severe neonatal myotonia
Carbenoxolone is secondary to a mutation of the voltage-gated sodium-channel
HYPERKALEMIC SCN4A gene; it is unrelated to neonatal myotonic dystrophy, myotonia
Addison disease congenita, or infantile myofibrillar myopathies. This same gene also is
Hypoaldosteronism responsible for severe neonatal episodic laryngospasm. Mexiletine is
Excessive potassium supplementation effective treatment of the myotonia, but the long-term prognosis
Potassium-sparing diuretics remains poor, with death by 2 yr of age. Sodium channel blockers, such
Chronic renal failure
as carbamazepine, phenytoin, and procainamide, are alternatives.
From Chinnery PF: Muscle diseases. In Goldman L, Schafer AI, editors: Neuromyotonia, a continuous muscle activity of neurogenic origin,
Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Elsevier, Table 429-8, may be caused by mutations in genes encoding or antibodies against
p. 2415.
potassium channels, but is rare in childhood. Schwartz-Jampel
disease, resulting from, an autosomal recessive trait, involves severe
muscle stiffness, myotonia, blepharospasm, and chondroplasia. It
becomes symptomatic in the 1st yr of life and is slowly progressive until
attacks, myofibers are electrically unexcitable, although the contractile midadolescence, after which it is stable. It is no longer considered a
apparatus can respond normally to calcium. The genetic disorder is variant of myotonic dystrophy and is caused by mutation in the HSPG2
inherited as an autosomal dominant trait. It is precipitated in some gene that encodes perlecan, the major heparin sulphate proteoglycan
patients by a heavy carbohydrate meal, insulin, epinephrine including of basement membranes. Sodium channel blockers may be useful.
that induced by emotional stress, hyperaldosteronism or hyperthyroid-
ism, administration of amphotericin B, or ingestion of licorice. The Bibliography is available at Expert Consult.
defective genes are at the 17q13.1-13.3 locus in hyperkalemic periodic
paralysis, the same as in paramyotonia congenita, and at the 1q31-32
locus in hypokalemic periodic paralysis.
Attacks often begin in infancy, particularly in the hyperkalemic 611.2 Malignant Hyperthermia
form, and the disease is nearly always symptomatic by 10 yr of age, Harvey B. Sarnat
affecting both sexes equally. Late childhood or adolescence is the more
typical age of onset of the hypokalemic form, Andersen-Tawil syn- See also Chapters 61 and 608.4.
drome, and paramyotonia congenita. Periodic paralysis is an episodic This syndrome is usually inherited as an autosomal dominant trait.
event; patients are unable to move after awakening and gradually It occurs in all patients with central core disease but is not limited to
recover muscle strength during the next few minutes or hours. All 4 that particular myopathy. The gene is at the 19q13.1 locus in both
extremities are involved. Muscles that remain active in sleep, such as central core disease and malignant hyperthermia without this specific
the diaphragm, extraocular muscles (rapid eye movements), and myopathy. At least 15 separate mutations in this gene are associated
cardiac muscle, are not affected. Patients are normal between attacks, with malignant hyperthermia. The gene programs the ryanodine
but in adult life the attacks become more frequent, and the disorder receptor, a tetrameric calcium release channel in the sarcoplasmic
causes progressive myopathy with permanent weakness even between reticulum, in apposition to the voltage-gated calcium channel of the
attacks. The usual frequency of attacks in childhood is once a week. transverse tubule. It occurs rarely in Duchenne and other muscular
The differential diagnosis includes thyrotoxic periodic paralysis, myo- dystrophies, in various other myopathies, in some children with scolio-
tonia congenita, and paramyotonia congenita. A triad of periodic sis, and in an isolated syndrome not associated with other muscle
paralysis, potentially fatal cardiac ventricular ectopy (caused by a disease. Affected children sometimes have peculiar facies. All ages are
defect in Kir2.1 channels for terminal repolarization), and character- affected, including premature infants whose mothers underwent
istic physical features is known as Andersen-Tawil syndrome. general anesthesia for cesarean section.
Alterations in serum potassium levels occur only during acute epi- Acute episodes are precipitated by exposure to general anesthetics
sodes and are accompanied by T-wave changes in the electrocardio- and occasionally to local anesthetic drugs. Patients suddenly develop
gram. Hypokalemia may be caused by alterations in calcium gradients. extreme fever, rigidity of muscles, and metabolic and respiratory aci-
The creatine kinase (CK) level may be mildly elevated at those times. dosis; the serum CK level rises to as high as 35,000 IU/L. Myoglobin-
Plasma phosphate levels often decrease during symptomatic periods. uria can result in tubular necrosis and acute renal failure.
Muscle biopsy findings are often normal between attacks, but during The muscle biopsy specimen obtained during an episode of malig-
an attack a vacuolar myopathy is demonstrated. Pathologic changes in nant hyperthermia or shortly afterward is not indicated but shows
the periodic paralyses are similar, whether the disease is the result of widely scattered necrosis of muscle fibers known as rhabdomyolysis.
a sodium or a potassium channel defect, suggesting that the changes Between attacks, the muscle biopsy specimen is normal unless there is
might result from the recurrent paralytic state rather than the specific an underlying chronic myopathy.
channelopathy. The vacuoles are dilated sarcoplasmic reticulum and It is important to recognize patients at risk of malignant hyperther-
invaginations of the extracellular space into the cytoplasm, and they mia because the attacks may be prevented by administering dantrolene
Chapter 611 ◆ Metabolic Myopathies 2988.e1
Bibliography Nicole S, Davoine CS, Topaloglu H, et al: Perlecan, the major proteoglycan of
Fontaine B: Muscle channelopathies and related diseases, Handb Clin Neurol basement membranes, is altered in patients with Schwartz-Jampel syndrome
113:1433–1436, 2013. (chondrodystrophic myotonia), Nat Genet 26:480–483, 2000.
Gay S, Dupuis D, Faivre L, et al: Severe neonatal non-dystrophic myotonia Venance SL, Cannon SC, Fialho D, et al: The primary periodic paralyses: diagnosis,
secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) pathogenesis and treatment, Brain 129:8–17, 2006.
gene, Am J Med Genet A 146:380–383, 2008.
Kullmann DM: Neurological channelopathies, Annu Rev Neurosci 33:151–171,
2010.
Chapter 611 ◆ Metabolic Myopathies 2989
sodium before an anesthetic is given. Patients at risk, such as siblings, sive distal muscle wasting, hepatic cirrhosis, recurrent hypoglycemia,
are identified by the caffeine contracture test: a portion of fresh muscle and heart failure. This more serious chronic course is particularly seen
biopsy tissue in a saline bath is attached to a strain gauge and exposed in the Inuit population. Minor myopathic findings including vacuola-
to caffeine and other drugs; an abnormal spasm is diagnostic. The tion of muscle fibers are found in the muscle biopsy specimen.
syndrome-associated receptor also may be demonstrated by immuno- Glycogenosis IV (Andersen disease) is a deficiency of brancher
chemistry in frozen sections of the muscle biopsy. The gene defect of enzyme, resulting in the formation of an abnormal glycogen molecule,
the ryanodine receptor is present in 50% of patients; gene testing is amylopectin, in the liver, reticuloendothelial cells, and skeletal and
available only for this genetic group. This receptor also may be seen in cardiac muscle. Hypotonia, generalized weakness, muscle wasting, and
the muscle biopsy by immunoreactivity. Another candidate gene is at contractures are the usual signs of myopathic involvement. Most
the 1q31 locus. patients die before age 4 yr because of hepatic or cardiac failure. A few
Apart from the genetic disorder of malignant hyperthermia, some children without neuromuscular manifestations have been described.
drugs can induce acute rhabdomyolysis with myoglobinuria and poten- Glycogenosis V (McArdle disease) is caused by muscle glycogen
tial renal failure, but this usually occurs in patients who are predisposed phosphorylase deficiency inherited as an autosomal recessive trait at
by some other metabolic disease (mitochondrial myopathies). Valproic locus 11q13, encoded by the PMGM gene. Exercise intolerance is the
acid can induce this process in children with mitochondrial cytopathies cardinal clinical feature. Physical exertion results in cramps, weakness,
or with carnitine palmitoyltransferase deficiency. and myoglobinuria, but strength is normal between attacks. The serum
CK level is elevated only during exercise. A characteristic clinical
feature is lack of the normal rise in serum lactate levels during ischemic
exercise because of inability to convert pyruvate to lactate under anaer-
611.3 Glycogenoses obic conditions in vivo. Myophosphorylase deficiency may be demon-
Harvey B. Sarnat strated histochemically and biochemically in the muscle biopsy tissue.
Some patients have a defect in adenosine monophosphate–dependent
See also Chapter 87.1. muscle phosphorylase β-kinase, a phosphorylase enzyme activator.
Glycogenosis I (von Gierke disease) is not a true myopathy because Muscle phosphorylase deficiency was the first neuromuscular disease
the deficient liver enzyme glucose-6-phosphatase is not normally to be diagnosed by MR spectroscopy, which shows that the intramus-
present in muscle. Nevertheless, children with this disease are hypo- cular pH does not decrease with exercise and there is no depletion of
tonic and mildly weak for unknown reasons. adenosine triphosphatase but that the phosphocreatine concentration
Glycogenosis II (Pompe disease) is an autosomal recessively inher- falls excessively. This noninvasive technique may be useful in some
ited deficiency of the glycolytic lysosomal enzyme α-glucosidase (for- patients if the radiologist is experienced with the disease.
merly known as acid maltase) that cleaves the α-1,4 and α-1,6 glycosidic A rare neonatal form of myophosphorylase deficiency causes
linkages. Of the 12 known glycogenoses, type II is the only one with a feeding difficulties in early infancy, may be severe enough to result in
defective lysosomal enzyme. The defective gene is at locus 17q23, with neonatal death, or can follow a course of slowly progressive weakness
more than 200 distinct mutations identified. Two clinical forms are resembling a muscular dystrophy. The long-term prognosis is good.
described. The infantile form is a severe generalized myopathy and Patients must learn to moderate their physical activities, but they do not
cardiomyopathy. Patients have cardiomegaly and hepatomegaly and develop severe chronic myopathic handicaps or cardiac involvement.
are diffusely hypotonic and weak. The serum CK level is greatly ele- Glycogenosis VII (Tarui disease) is muscle phosphofructokinase
vated. A muscle biopsy specimen reveals a vacuolar myopathy with deficiency. Although this disease is rarer than glycogenosis V, the
abnormal lysosomal enzymatic activities such as acid and alkaline symptoms of exercise intolerance, clinical course, and inability to
phosphatases. Evidence of a secondary mitochondrial cytopathy is convert pyruvate to lactate are identical. The distinction is made by
often demonstrated; it includes electron microscopic demonstration of biochemical study of the muscle biopsy specimen. It is transmitted as
paracrystallin structures within muscle mitochondria and low concen- an autosomal recessive trait at the 1cenq32 locus and some mutations
trations of respiratory chain enzymes. Death in infancy or early child- are particularly prevalent in the Ashkenazi Jewish population.
hood is usual; however, enzyme replacement therapy has improved the
outcome. Bibliography is available at Expert Consult.
The late childhood or adult form is a much milder myopathy
without cardiac or hepatic enlargement. It might not become clinically
expressed until later childhood or early adult life but may be symptom-
atic as myopathic weakness and hypotonia even in early infancy. Even 611.4 Mitochondrial Myopathies
in late adult-onset acid maltase deficiency, >50% of the patients report Harvey B. Sarnat
difficulties with muscle strength dating from childhood. Ultrastruc-
tural evidence of secondary mitochondrial cytopathy also occurs, as See also Chapters 87.4 and 598.2.
with infantile Pompe disease. MRI of muscle may show distinctive Several diseases involving muscle, brain, and other organs are associ-
changes that differ from other myopathies. ated with structural and functional abnormalities of mitochondria,
The serum CK level is greatly elevated, and the muscle biopsy find- producing defects in aerobic cellular metabolism, the electron trans-
ings are diagnostic even in the presymptomatic stage. The diagnosis of port chain, and the Krebs cycle. Because mitochondria are found in all
glycogenosis II is confirmed by quantitative assay of acid maltase activ- cells, except mature erythrocytes, the term mitochondrial cytopathy
ity in muscle or liver biopsy specimens. A rare variant of the milder is used preferentially to emphasize the multisystemic nature of these
form of acid maltase deficiency can show muscle acid maltase activity diseases. The structural aberrations are best demonstrated by electron
in the low normal range with only intermittent decreases to subnormal microscopy of the muscle biopsy sample, revealing a proliferation of
values; the muscle biopsy findings are similar although milder. In abnormally shaped cristae, including stacked or whorled cristae and
another form, Danon disease, transmitted as an X-linked recessive paracrystallin structures that occupy the space between cristae and are
trait at the Xq24 locus, the primary deficiency is lysosomal membrane formed from CK. Muscle biopsies of neonates, infants, and toddlers
protein-2 (LAMP2) and results in hypertrophic cardiomyopathy, prox- show more severe involvement of endothelial cells of intramuscular
imal myopathy, and intellectual disability. capillaries than of myofibers, unlike the reverse in adults, but endothe-
Glycogenosis III (Cori-Forbes disease), a deficiency of debrancher lial paracrystallin structures are globular rather than brick shaped as in
enzyme (amylo-1,6-glucosidase), is more common than is usually myofibers. The endoplasmic reticulum becomes abnormally adherent
diagnosed, and it is generally the least severe. Hypotonia, weakness, to mitochondria. Similar endothelial mitochondrial alterations are seen
hepatomegaly, and fasting hypoglycemia in infancy are common, but in brain in Leigh and other infantile mitochondrial encephalopathies.
these features often resolve spontaneously, and patients become asymp- Histochemical study of the muscle biopsy specimen reveals abnormal
tomatic in childhood and adult life. Others experience slowly progres- clumping of oxidative enzymatic activity and scattered myofibers, with
Bibliography Hagemans MLC, Winkel LPF, Van Doorn PA, et al: Clinical manifestations and
Bembi B, Cerini E, Danesino C, et al: Diagnosis of glycogenosis type II; natural course of late-onset Pompe disease in 54 Dutch patients, Brain
management and treatment of glycogenosis type II, Neurology 71:S4–S11, 128:671–677, 2005.
S12–S36, 2008. Marín-García J, Goldenthal MJ, Sarnat HB: Probing striated muscle mitochondrial
Dlamini N, Jan W, Norwood F, et al: Muscle MRI findings in siblings with phenotype in neuromuscular disorders, Pediatr Neurol 29:26–33, 2003.
juvenile-onset acid maltase deficiency (Pompe disease), Neuromuscul Disord Zimakas PJ, Rodd CJ: Glycogen storage disease type III in Inuit children, CMAJ
18:408–409, 2008. 172:355–358, 2005.
loss of cytochrome-c oxidase activity and with increased neutral lipids genes are identified, mostly in later-onset forms; hence mitochondrial
within myofibers. Ragged red muscle fibers occur in some mitochon- depletion is a syndrome and not a single disease. Barth syndrome
drial myopathies, particularly those with a combination of respiratory is an X-linked recessive mitochondrial disorder characterized by
chain complexes I and IV deficiencies. Accumulations of this membra- cardiomyopathy, myopathy of striated muscle, growth retardation,
nous material beneath the muscle fiber membrane are best demon- neutropenia, and high serum and urinary concentrations of 3-methyl-
strated by special stains, such as modified Gomori trichrome. glutaconic acid.
These characteristic histochemical and ultrastructural changes are Many rare diseases with only a few case reports are suspected of
most consistently seen with point mutations in mitochondrial transfer being mitochondrial disorders. It is also now recognized that second-
RNA. The large mitochondrial DNA (mtDNA) deletions of 5 or 7.4 kb ary mitochondrial defects occur in a wide range of nonmitochondrial
(the single mitochondrial chromosome has 16.5 kb) are associated diseases, including inflammatory autoimmune myopathies, Pompe
with defects in mitochondrial respiratory oxidative enzyme complexes, disease, and some cerebral malformations, and also may be induced
if as few as 2% of the mitochondria are affected, but minimal or no by certain drugs and toxins, so that interpretation of mitochondrial
morphologic or histochemical changes may be noted in the muscle abnormalities as primary defects must be approached with caution.
biopsy specimen, even by electron microscopy; hence, quantitative mtDNA is distinct from the DNA of the cell nucleus and is inherited
biochemical studies of the muscle tissue are needed to confirm the exclusively from the mother; mitochondria are present in the cyto-
diagnosis. Because most of the subunits of the respiratory chain com- plasm of the ovum but not in the head of the sperm, the only part that
plexes are encoded by nuclear DNA (nDNA) rather than mtDNA, enters the ovum at fertilization. The rate of mutation of mtDNA is 10
mendelian autosomal inheritance is possible, rather than maternal times higher than that of nDNA. The mitochondrial respiratory enzyme
transmission as with pure mtDNA point mutations. Complex II (suc- complexes each have subunits encoded either in mtDNA or nDNA.
cinate dehydrogenase) is the only enzyme complex in which all of its Complex II (succinate dehydrogenase, a Krebs cycle enzyme) has 4
subunits are encoded by nDNA; hence it is histochemically reactive in subunits, all encoded in nDNA; complex III (ubiquinol or cytochrome-b
all mitochondrial diseases with mtDNA point mutations. Serum lactate oxidase) has 9 subunits, only 1 of which is encoded by mtDNA and 8
is elevated in some diseases, and cerebrospinal fluid lactate is more of which are programmed by nDNA; complex IV (cytochrome-c
consistently elevated, even if serum concentrations are normal. oxidase) has 13 subunits, only 3 of which are encoded by mtDNA. For
Several distinct mitochondrial diseases that primarily affect striated this reason, mitochondrial diseases of muscle may be transmitted as
muscle or muscle and brain are identified. These can be divided into autosomal recessive traits rather than by strict maternal transmission,
the ragged red fiber diseases and non–ragged fiber diseases. The ragged even though all mitochondria are inherited from the mother.
red fiber diseases include Kearns-Sayre, MELAS (mitochondrial In Kearns-Sayre syndrome, a single large mtDNA deletion has been
encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, identified, but other genetic variants are known; in MERRF and
MERRF (myoclonic epilepsy with ragged red fibers) syndrome, and MELAS syndromes of mitochondrial myopathy, point mutations occur
progressive external ophthalmoplegia syndromes, which are associated in transfer RNA.
with a combined defect in respiratory chain complexes I and IV. The
non–ragged fiber diseases include Leigh encephalopathy and Leber INVESTIGATIONS
hereditary optic atrophy; they involve complex I or IV alone or, in Investigation for mitochondrial cytopathies begins with serum lactate.
children, the common combination of defective complexes III and V. Lactic acid is not increased in all mitochondrial cytopathies, so that a
Kearns-Sayre syndrome is characterized by the triad of progressive normal result is not necessarily reassuring; cerebrospinal fluid lactate
external ophthalmoplegia, pigmentary degeneration of the retina, and is increased in some cases in which serum lactate is normal, particu-
onset before age 20 yr. Heart block, cerebellar deficits, and high cere- larly if there are clinical signs of encephalopathy. Serum 3-methyl-
brospinal fluid protein content are often associated. Visual evoked glutaconic acid often is increased in mitochondrial cytopathies in
potentials are abnormal. Patients usually do not experience weakness general, demonstrated in more than 50 different genetic mutations, and
of the trunk or extremities or dysphagia. Most cases are sporadic. hence is a good screening measurement; it rarely is increased in other
Chronic progressive external ophthalmoplegia may be isolated or metabolic diseases. This product also may be increased in urine.
accompanied by limb muscle weakness, dysphagia, and dysarthria. A Hepatic enzymes (transaminases) should be measured in blood.
few patients described as having ophthalmoplegia plus have additional Cardiac evaluation often is warranted. Molecular markers in blood for
central nervous system involvement. Autosomal dominant inheritance the common diseases with known mtDNA point mutations identify
is found in some pedigrees, but most cases are sporadic. many of the mitochondrial cytopathies presenting in adult life or ado-
MERRF and MELAS syndromes are other mitochondrial disorders lescence, but less frequently in children and least in young infants. MRI
affecting children. The latter is characterized by stunted growth, epi- of the brain may reveal hyperintense lesions of the basal ganglia and
sodic vomiting, seizures, and recurring cerebral insults causing hemi- MR spectroscopy can demonstrate an increased lactate peak. The
paresis, hemianopia, or even cortical blindness, and dementia. The muscle biopsy provides the best evidence of all mitochondrial myopa-
disease behaves as a degenerative disorder, and children die within a thies and should include histochemistry for oxidative enzymes, elec-
few years. tron microscopy, and quantitative biochemical assay of respiratory
Other “degenerative” diseases of the central nervous system that chain enzyme complexes and coenzyme-Q10; muscle tissue also can
also involve myopathy with mitochondrial abnormalities include be analyzed for mtDNA. Many mitochondrial disorders also can affect
Leigh subacute necrotizing encephalopathy (see Chapter 87.4) and the Schwann cells and axons of peripheral nerves and present clinically
cerebrohepatorenal (Zellweger) disease, primarily a peroxisomal with neuropathy; hence motor and sensory nerve conduction velocities
disease with secondary mitochondrial alterations (see Chapter 86.2). can be measured in selected patients; sural nerve biopsy is required
Another recognized mitochondrial myopathy is cytochrome-c oxidase only rarely if neuropathy is the predominant finding and the diagnosis
deficiency. Oculopharyngeal muscular dystrophy is also fundamen- is not evident from other studies.
tally a mitochondrial myopathy.
Mitochondrial depletion syndrome of early infancy is character- TREATMENT
ized by severely decreased oxidative enzymatic activities in most or all There is no effective treatment of mitochondrial cytopathies, but various
5 of the complexes; in addition to diffuse muscle weakness, neonates “cocktails” are often used empirically to try to overcome the meta-
and young infants can show multisystemic involvement and the syn- bolic deficits. These include oral carnitine supplements, riboflavin,
drome occurs in several forms: myopathic; encephalomyopathic; hepa- coenzyme-Q10, ascorbic acid (vitamin C), vitamin E, and other anti-
toencephalopathic; and intestinal encephalopathic. Cardiomyopathy oxidants. Although some anecdotal reports are encouraging, no con-
and sometimes bullous skin lesions or generalized edema also can trolled studies that prove efficacy have been published.
occur. Alpers syndrome is genetically homogeneous and is caused by
mtDNA depletion and mutations in the POLG1 gene. Several other Bibliography is available at Expert Consult.
Bibliography Khan A, Trevenen CL, Wei X-C, et al: Alpers syndrome: the natural history of a
Darin N, Oldfors A, Moslemi A-R, et al: Genotypes and clinical phenotypes in case highlighting neuroimaging, neuropathology, and fat metabolism, J Child
children with cytochrome-c-oxidase deficiency, Neuropediatrics 34:311–317, Neurol 27:636–640, 2012.
2003. Nishino I, Yamamoto A, Sugie K, et al: Danon disease and related disorders, Acta
Delonlay P, Rötig A, Sarnat HB: Respiratory chain deficiencies, Handb Clin Neurol Myol 20:120, 2001.
113:1651–1666, 2013. Sarnat HB, Flores-Sarnat L, Casey R, et al: Endothelial ultrastructural alterations of
DiMauro S, Hirano M, Schon EA: Mitochondrial medicine, Informa Oxfon 2006. intramuscular capillaries in infantile mitochondrial cytopathies, Neuropathology
DiMauro S, Schon EA: Mitochondrial disorders in the nervous system, Annu Rev 32:617–627, 2012.
Neurosci 31:91–123, 2008. Sarnat HB, Marín-García J: Pathology of mitochondrial encephalomyopathies, Can
Dykens JA, Will Y, editors: Drug-induced mitochondrial dysfunction, Hoboken, NJ, J Neurol Sci 32:152–166, 2005.
2008, Wiley. Stickler DE, Valenstein E, Neiberger RE, et al: Peripheral neuropathy in genetic
Elpeleg O, Mandel H, Saada A: Depletion of the other genome-mitochondrial mitochondrial diseases, Pediatr Neurol 34:127–131, 2006.
DNA depletion syndromes in humans, J Mol Med 80:389–396, 2002. Tesarova M, Mayr J, Wendlich L, et al: Mitochondrial DNA depletion in Alpers
Finsterer J, Ahting U: Mitochondrial depletion syndromes in children and adults, syndrome, Neuropediatrics 35:217–223, 2004.
Can J Neurol Sci 40:635–644, 2013. Wortmann SB, Kluijtmans LA, Rodenburg RJ, et al: 3-methylglutaconic aciduria:
Jeffries JL: Barth syndrome, Am J Med Genet C Semin Med Genet 163:198–205, lessons from 50 genes and 977 patients, J Inherit Metab Dis 36(6):913–921,
2013. 2013.
Treatment with l-carnitine improves the maintenance of blood
611.5 Lipid Myopathies glucose and serum carnitine levels but does not reverse the ketosis or
Harvey B. Sarnat acidosis or improve exercise capacity.
Muscle carnitine palmitoyltransferase (CPT) deficiency manifests
See Chapter 86.4. as episodes of rhabdomyolysis, coma, and elevated serum CK levels
Considered as metabolic organs, skeletal muscles are the most that may be indistinguishable from Reye syndrome. It is the most
important sites in the body for long-chain fatty acid metabolism common identified cause of recurrent myoglobinuria in adults, but
because of their large mass and their rich density of mitochondria myoglobinuria is not a constant feature in all. CPT transfers long-chain
where fatty acids are metabolized. They are the major source of fatty acid acyl-coenzyme A residues to carnitine on the outer mito-
energy for skeletal muscle during sustained exercise or fasting. chondrial membrane for transport into the mitochondria. Exercise
Hereditary disorders of lipid metabolism that cause progressive intolerance and myoglobinuria resemble glycogenoses V and VII. The
myopathy are an important, relatively common, and often treatable degree of exercise that triggers an attack varies among individuals,
group of muscle diseases. Increased lipid within myofibers is seen ranging from casual walking to strenuous exercise. Fasting hypoglyce-
in the muscle biopsy of some mitochondrial myopathies and is a mia can occur. Some patients present only in late adolescence or adult
constant, rather than an unpredictable, feature of specific diseases. life with myalgias. Genetic transmission is autosomal recessive and is
Among the ragged red fiber diseases, Kearns-Sayre syndrome always caused by a defect on chromosome 1 at the 1p32 locus. Administration
shows increased neutral lipid, whereas MERRF and MELAS syn- of valproic acid can precipitate acute rhabdomyolysis with myoglobin-
dromes do not, a useful diagnostic marker for the pathologist. Free uria in patients with CPT deficiency; it should be avoided in the treat-
fatty acids are converted to acyl-coenzyme A by fatty acyl-coenzyme ment of seizures or migraine if they occur. Very long-chain acyl-coenzyme
A synthetases; the resulting long-chain fatty acids bind to carnitine A dehydrogenase deficiency has a similar clinical presentation but
and are transported into mitochondria where β-oxidation is carried mainly with adult onset.
out. Disorders of lipid fuel utilization and lipid storage disorders
can be divided into defects of transport and oxidation of exogenous Bibliography is available at Expert Consult.
fatty acids within mitochondria and defects of endogenous triglyc-
eride catabolism.
Muscle carnitine deficiency is an autosomal recessive disease
caused by mutations in the SLC22A5 gene, involving deficient trans- 611.6 Vitamin E Deficiency Myopathy
port of dietary carnitine across the intestinal mucosa. Carnitine is Harvey B. Sarnat
acquired from dietary sources but is also synthesized in the liver and
kidneys from lysine and methionine; it is the obligatory carrier of long- In experimental animals, deficiency of vitamin E (α-tocopherol, an
and medium-chain fatty acids into muscle mitochondria. antioxidant also important in mitochondrial superoxide generation)
The clinical course may be one of sudden exacerbations of weakness produces a progressive myopathy closely resembling a muscular dys-
or can resemble a progressive muscular dystrophy with generalized trophy. Myopathy and neuropathy are recognized in humans who lack
proximal myopathy and sometimes facial, pharyngeal, and cardiac adequate intake of this antioxidant. Patients with chronic malabsorp-
involvement. Symptoms usually begin in late childhood or adolescence tion, those undergoing long-term dialysis, and premature infants who
or may be delayed until adult life. Progression is slow but can end in do not receive vitamin E supplements are particularly vulnerable.
death. Treatment with high doses of vitamin E can reverse the deficiency.
Serum CK level is mildly elevated. Muscle biopsy material shows Myopathy caused by chronic hypervitaminosis E also occurs.
vacuoles filled with lipid within muscle fibers in addition to nonspecific
changes suggestive of a muscular dystrophy. Mitochondria can appear Bibliography is available at Expert Consult.
normal or abnormal. Carnitine measured in muscle biopsy tissue is
reduced, but the serum carnitine level is normal.
Treatment stops the progression of the disease and can even restore
lost strength if the disease is not too advanced. It consists of special
diets low in long-chain fatty acids. Steroids can enhance fatty acid
transport. Specific therapy with l-carnitine taken orally in large doses
overcomes the intestinal barrier in some patients. Some patients also
improve when given supplementary riboflavin, and other patients
seem to improve with propranolol.
Systemic carnitine deficiency is a disease of impaired renal and
hepatic synthesis of carnitine rather than a primary myopathy. Patients
with this autosomal recessive disease experience progressive proximal
myopathy and show muscle biopsy changes similar to those of muscle
carnitine deficiency; however, the onset of weakness is earlier and may
be evident at birth. Endocardial fibroelastosis also can occur. Episodes
of acute hepatic encephalopathy resembling Reye syndrome can occur.
Hypoglycemia and metabolic acidosis complicate acute episodes. Car-
diomyopathy may be the predominating feature in some cases and
result in death.
Cerebral infarctions and myopathy occur in children, particularly
when accompanied by hypoglycemia. Mean age at presentation is
approximately 9 yr. Brain MRI shows distinctive changes related to
multiple infarcts of various sizes.
The concentration of carnitine is reduced in serum as well as in
muscle and liver. l-Carnitine deficiency can be corrected by oral
administration of carnitine on a daily basis.
A similar clinical syndrome may be a complication of renal Fanconi
syndrome because of excessive urinary loss of carnitine or loss during
chronic hemodialysis.
Bibliography Kottlors M, Jaksch M, Ketelsen U-P, et al: Valproic acid triggers acute
D’Amico A, Bertini E: Metabolic neuropathies and myopathies, Handb Clin Neurol rhabdomyolysis in a patient with carnitine palmitoyltransferase type II
113:1437–1455, 2013. deficiency, Neuromuscul Disord 11:757–759, 2001.
Deschauer M, Wieser T, Zierz S: Muscle carnitine palmitoyltransferase II Tein I: Disorders of fatty acid oxidation, Handb Clin Neurol 113:1675–1688, 2013.
deficiency. Clinical and molecular genetic features and diagnostic aspects, Arch Thompson JE, Smith M, Castillo M, et al: MR in children with l-carnitine
Neurol 62:37–41, 2005. deficiency, AJNR Am J Neuroradiol 17:1585–1588, 1996.
Gregersen N, Andersen BS, Pedersen CB, et al: Mitochondrial fatty acid oxidation
defects–remaining challenges, J Inherit Metab Dis 31:643, 2008.
Haack TB, Danhauser K, Haberberger B, et al: Exome sequencing identifies
ACAD9 mutations as a cause of complex I deficiency, Nat Genet 42:1131–1134,
2010.
2991.e2 Chapter 611 ◆ Metabolic Myopathies
Bibliography
Chow CK: Vitamin E regulation of mitochondrial superoxide generation, Biol
Signals Recept 10:112–124, 2001.
Chapter 612 ◆ Disorders of Neuromuscular Transmission and of Motor Neurons 2991
Chapter 612
Disorders of
Neuromuscular
Transmission and of
Motor Neurons
Harvey B. Sarnat
612.1 Myasthenia Gravis

Harvey B. Sarnat
AUTOIMMUNE MYASTHENIA GRAVIS

Myasthenia gravis is a chronic autoimmune disease of neuromuscular
blockade, characterized clinically by rapid fatigability of striated
muscle, particularly extraocular and palpebral muscles and those of
swallowing. It must be distinguished from congenital myasthenic
syndrome, a genetic disorder of receptors on the postsynaptic mem-

brane of the neuromuscular junction and toxin-induced myasthenia, Table 612-1 Classification of the Congenital
such as botulism (see below). The release of acetylcholine (ACh) into Myasthenic Syndromes
the synaptic cleft by the axonal terminal is normal, but the postsynaptic PRESYNAPTIC DEFECTS
muscle membrane (i.e., sarcolemma) or motor end plate is less respon- • Paucity of synaptic vesicles and decreased quantal release
sive than normal. A decreased number of available ACh receptors is as • Congenital myasthenic syndromes with episodic apnea (choline
a result of circulating receptor-binding antibodies in most cases of acetyltransferase deficiency)
autoimmune myasthenia. • Lambert-Eaton syndrome–like form
A rare familial myasthenia gravis is an autosomal recessive trait not SYNAPTIC DEFECTS
associated with increased plasma anti-ACh antibodies. One familial • End plate acetylcholinesterase deficiency
form is a deficiency of motor end plate acetylcholinesterase (AChE).
Most congenital (familial) forms are postsynaptic defects. Infants born POSTSYNAPTIC DEFECTS
to myasthenic mothers can have a transient neonatal myasthenic • Primary acetylcholine receptor deficiency
• Reduced receptor expression as a result of acetylcholine receptor
syndrome secondary to placentally transferred anti-ACh receptor mutations
antibodies, distinct from congenital myasthenic syndromes (Tables • Reduced receptor expression because of rapsyn mutations
612-1 and 612-2). • Reduced receptor expression with plectin deficiency
• Primary acetylcholine receptor kinetic abnormality with or without
Clinical Manifestations acetylcholine receptor deficiency
In juvenile autoimmune myasthenia gravis, unilateral or bilateral • Slow-channel syndrome
but usually asymmetrical ptosis and some degree of extraocular • Fast-channel syndrome
muscle weakness are the earliest and most constant signs. Extraocular • Sodium-channel mutations
weakness is not confined to muscles innervated by just 1 or 2 of • Dok7 mutations
the 3 corresponding brainstem nuclei and is progressive. Older chil- From Muppidi S, Wolfe GI, Barhon RJ: Diseases of the neuromuscular junction.
dren might complain of diplopia, and young children might hold In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s pediatric
open their eyes with their fingers or thumbs if the ptosis is severe neurology, ed 5, Philadelphia, 2012, Elsevier, Box 91-3.
Table 612-2 Distinctive Clinical and Electrodiagnostic Features of Congenital Myasthenic Syndromes
Presynaptic Synaptic Postsynaptic
CHOLINE PRIMARY SLOW- FAST-
ACETYLTRANSFERASE LEMS-LIKE AChE AChR CHANNEL CHANNEL DOK7
DEFICIENCY FORM DEFICIENCY DEFICIENCY CMS CMS MUTATIONS
Autosomal dominant X (most
inheritance mutations)
Episodic apnea triggered X
by stressors
Neonatal hypotonia and X X X (in severe X (in severe
respiratory insufficiency cases) cases)
Skeletal deformities X X X (in
severe
cases)
Delayed pupillary light X
responses
Prominent neck, wrist, and X
finger extensor weakness
Repetitive CMAPs after X X
single stimulus
Progressive decrement X X
with prolonged exercise
or repetitive stimulation
Marked increment (>200%) X
with high-frequency
repetitive stimulation
Decrement repairs with X X
AChE inhibitors
Clinical improvement with X
AChE inhibitors
Clinical worsening with X X X
AChE inhibitors
AChE, acetylcholinesterase; AChR, acetylcholine receptor; CMAPs, compound muscle action potentials; CMS, congenital myasthenic syndrome; LEMS, Lambert-Eaton
myasthenic syndrome.
From Muppidi S, Wolfe GI, Barhon RJ: Diseases of the neuromuscular junction. In Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors: Swaiman’s pediatric
neurology, ed 5, Philadelphia, 2012, Elsevier, Table 91-3.
enough to obstruct vision. Pupillary responses to light are preserved. should be reconsidered, unless the patient had taken an overdose that
Dysphagia and facial weakness also are common and, in early infancy, was not prescribed.
feeding difficulties are frequent as the cardinal sign of myasthenia; in Approximately 30% of affected adolescents show elevations, but
severe cases, aspiration and airway obstruction may occur. Poor head anti-AChR antibodies are only occasionally demonstrated in the
control because of weakness of the neck flexors may be prominent. plasma of prepubertal children. Some with negative titers of AChE
Involvement initially may appear to be limited to bulbar-innervated exhibit anti–muscle-specific tyrosine kinase (MuSK) circulating anti-
muscles, but the disease is systemic and progressive weakness eventu- bodies. MuSK is localized at the neuromuscular junction and appears
ally involves limb-girdle muscles and distal muscles of the hands in essential to fetal development of this junction. MuSK myasthenia
most cases. Fasciculations of muscle, myalgias, and sensory symptoms usually occurs in female infants and toddlers and severe bulbar involve-
do not occur. Tendon stretch reflexes may be diminished but rarely ment with dysphagia is frequent, but clinical features alone cannot
are lost. Ocular myasthenia gravis may prove to be transitory over distinguish between these 2 different antibody forms of the disease.
time, but in some patients weakness never progresses to involve axial Infants born to myasthenic mothers can have respiratory insuffi-
or appendicular muscles. This group accounts for approximately 25% ciency, inability to suck or swallow, and generalized hypotonia and
of all juvenile myasthenia gravis patients and is most frequent in weakness. They might show little spontaneous motor activity for
children of Chinese and southeastern Asian descent, suggesting an several days to weeks. Some require ventilatory support and feeding
ethnic genetic predisposition. by gavage during this period. After the abnormal antibodies disappear
Rapid fatigue of muscles is a characteristic feature of myasthenia from the blood and muscle tissue, these infants regain normal strength
gravis that distinguishes it from most other neuromuscular diseases. and are not at increased risk of developing myasthenia gravis in later
Ptosis increases progressively as patients are asked to sustain an upward childhood. A small minority develop fetal akinesia sequence with
gaze for 30-90 sec. Holding the head up from the surface of the exam- multiple joint contractures (arthrogryposis) that develop in utero
ining table while lying supine is very difficult, and gravity cannot be from lack of fetal movement. AChR antibodies can usually be demon-
overcome for more than a few seconds. Repetitive opening and closing strated in maternal blood, but at times maternal antibodies may not
of the fists produces rapid fatigue of hand muscles, and patients cannot be detected.
elevate their arms for more than 1-2 min because of fatigue of the
deltoids. Patients are more symptomatic late in the day or when tired. CONGENITAL MYASTHENIC SYNDROMES
Dysphagia can interfere with eating, and the muscles of the jaw soon A heterogeneous group of genetic diseases of neuromuscular transmis-
tire when an affected child chews. Reviewing activities of daily living sion is collectively called congenital myasthenic syndromes. The eti-
helps determine the severity of symptoms (Table 612-3). ology and pathogenesis of these syndromes are unrelated to either
Left untreated, myasthenia gravis is usually progressive and can transitory neonatal myasthenia caused by placental transfer of mater-
become life-threatening because of respiratory muscle involvement nal antibodies or to autoimmune myasthenia gravis, despite overlap of
and the risk of aspiration, particularly at times when the child is oth- clinical symptoms. Congenital myasthenic syndromes are nearly
erwise unwell, such as with an upper respiratory tract infection. Famil- always permanent static disorders without spontaneous remission (see
ial myasthenia gravis usually is not progressive. Tables 612-1 and 612-2). Several distinct genetic forms are recognized,
Myasthenic crisis is an acute or subacute severe increase in weak- all with onset at birth or in early infancy with hypotonia, external
ness in patients with myasthenia gravis, usually precipitated by an ophthalmoplegia, ptosis, dysphagia, weak cry, facial weakness, easy
intercurrent infection, surgery, or even emotional stress. It may muscle fatigue generally, and sometimes respiratory insufficiency or
require intravenous cholinesterase inhibitors, immunoglobulin, plasma failure, the last often precipitated by a minor respiratory infection.
exchange, gavage feeding, and even transitory ventilator support. It Cholinesterase inhibitors have a favorable effect in most, but in some
must be distinguished from cholinergic crisis secondary to overdosing forms the symptoms and signs are actually worsened. Most congenital
with anticholinesterase medications. The muscarinic effects include myasthenic syndromes are transmitted as autosomal recessive traits,
abdominal cramps, diarrhea, profuse sweating, salivation, bradycardia, but the slow channel syndrome is autosomal dominant.
increased weakness, and miosis. Cholinergic crisis requires only sup- Mutations responsible for congenital myasthenic syndromes have
portive care and withholding of further doses of cholinergic drugs, and been identified in 18 different genes. The genetic mutations are known
it passes within a few hours; the dose of medication to be restarted in less than half of children with congenital myasthenic syndromes. Of
Table 612-3 Myasthenia Gravis Activities of Daily Living Scale (MG-ADL)

GRADE 0 1 2 3
Talking Normal Intermittent slurring or Constant slurring or nasal, but Difficult to understand
nasal speech can be understood speech
Chewing Normal Fatigue with solid food Fatigue with soft food Gastric tube
Swallowing Normal Rare episode of choking Frequent choking, necessitating Gastric tube
changes in diet
Breathing Normal Shortness of breath with Shortness of breath at rest Ventilator dependence
exertion
Impairment of ability to None Extra effort, but no rest Rest periods needed Cannot do 1 of these
brush teeth or comb hair periods needed functions
Impairment of ability to None Mild, sometimes uses arms Moderate, always uses arms Severe, requires
arise from a chair assistance
Double vision None Occurs, but not daily Daily, but not constant Constant
Eyelid droop None Occurs, but not daily Daily, but not constant Constant
TOTAL MG-ADL SCORE
From Wolfe GI, Herbelin L, Nations SP, et al: Myasthenia gravis activities of daily living profile. Neurology 52:1487–1489, 1999.
known genetic defects, rapsyn and downstream-of-kinase-7 (DOK7) are synthesis of ACh is mutated. In others, there is a defect in the quantal
demonstrated in 85% of cases. Acetylcholine receptor deficiencies have release of vesicles containing ACh. The treatment of such patients with
more than 60 identified genetic mutations. Basal lamina–associated cholinesterase inhibitors is futile. Assays of anti-rapsyn, anti-Dok7,
synaptic defects from mutations of the COLQ gene that encodes the COLQ, and ChAT antibodies are available in a few specialized
collagen tail of AChR account for another 10% of cases. Another 5% laboratories.
of cases are presynaptic, attributed to mutations in ChAT, encoding Other serologic tests of autoimmune disease, such as antinuclear
choline acetyltransferase. Anti-AChR and anti-MuSK antibodies are antibodies and abnormal immune complexes, should also be sought.
usually, but not always, absent in serum, unlike in autoimmune forms If these are positive, more extensive autoimmune disease involving
of myasthenia gravis affecting older children and adults. vasculitis or tissues other than muscle is likely. A thyroid profile should
Three presynaptic congenital myasthenic syndromes are recog- always be examined. The serum creatine kinase level is normal in
nized, all as autosomal recessive traits; some of these have anti-MuSK myasthenia gravis.
antibodies. These children exhibit weakness of extraocular, pharyngeal, The heart is not involved, and electrocardiographic findings remain
and respiratory muscles and later show shoulder girdle weakness as normal. Radiographs of the chest often reveal an enlarged thymus,
well. Episodic apnea is a problem in congenital myasthenia gravis. but the hypertrophy is not a thymoma. It may be further defined
Another synaptic form is caused by congenital absence or marked by tomography or by CT or MRI of the anterior mediastinum if the
deficiency of motor end plate AChE in the synaptic basal lamina; this radiographic findings are uncertain, but these imaging modalities are
was the first form recognized as caused by an enzymatic deficiency at not recommended routinely because of radiation exposure and anes-
the neuromuscular junction. Postsynaptic forms of congenital myas- thetic risk, which is higher in myasthenic patients than in normal
thenia are caused by mutations in ACh receptor subunit genes that children.
alter the synaptic response to ACh. An abnormality of the ACh recep- The role of conventional muscle biopsy in myasthenia gravis is
tor channels appearing as high conductance and excessively fast closure limited. It is not required in most cases, but approximately 17% of
may be the result of a point mutation in a subunit of the receptor patients show inflammatory changes, sometimes called lymphorrhages,
affecting a single amino acid residue. Children with congenital myas- that are interpreted by some physicians as a mixed myasthenia-
thenia gravis do not experience myasthenic crises and rarely exhibit polymyositis immune disorder. Muscle biopsy tissue in myasthenia
elevations of anti-ACh antibodies in plasma. gravis shows nonspecific type II muscle fiber atrophy, similar to that
seen with disuse atrophy, steroid effects on muscle, polymyalgia rheu-
RARE OTHER CAUSES OF MYASTHENIA matica, and many other conditions. The ultrastructure of motor end
Myasthenia gravis is occasionally associated with hypothyroidism, plates shows simplification of the membrane folds; the ACh receptors
usually as caused by Hashimoto thyroiditis. Other collagen vascular are located in these postsynaptic folds, as shown by bungarotoxin
diseases may also be associated with myasthenia gravis. Thymomas, (snake venom), which binds specifically to the ACh receptors.
noted in some adults, rarely coexist with myasthenia gravis in children, A clinical test for myasthenia gravis is administration of a short-
nor do carcinomas of the lung occur, which produce a unique form acting cholinesterase inhibitor, usually edrophonium chloride. Ptosis
of myasthenia in adults called Eaton-Lambert syndrome. The and ophthalmoplegia improve within a few seconds, and fatigability of
Eaton-Lambert syndrome in children is rare but is reported with lym- other muscles decreases.
phoproliferative disorders and with neuroblastoma. Postinfectious
myasthenia gravis in children is transitory and usually follows a Recommendations on the Use of Cholinesterase
varicella-zoster infection by 2-5 wk as an immune response. Inhibitors as a Diagnostic Test for Myasthenia Gravis
in Infants and Children
Laboratory Findings and Diagnosis Children 2 Yr and Older
Myasthenia gravis is one of the few neuromuscular diseases in which ◆ The child should have a specific fatigable weakness that can
electromyography (EMG) is more specifically diagnostic than a muscle be measured, such as ptosis of the eyelids, dysphagia, or inability
biopsy. A decremental response is seen to repetitive nerve stimulation; of the cervical muscles to support the head. Nonspecific
the muscle potentials diminish rapidly in amplitude until the muscle generalized weakness without cranial nerve motor deficits is
becomes refractory to further stimulation. Motor nerve conduction not a criterion.
velocity remains normal. This unique EMG pattern is the electrophysi- ◆ An IV infusion should be started to enable the administration of
ologic correlate of the fatigable weakness observed clinically and is medications in the event of an adverse reaction.
reversed after a cholinesterase inhibitor is administered. A myasthenic ◆ Electrocardiographic monitoring is recommended during the test.
decrement may be absent or difficult to demonstrate in muscles that ◆ A dose of atropine sulfate (0.01 mg/kg) should be available in a
are not involved clinically. This feature may be confusing in early cases syringe, ready for IV administration at the bedside during the
or in patients showing only weakness of extraocular muscles. Micro- edrophonium test, to block acute muscarinic effects of the
electrode studies of end plate potentials and currents reveal whether cholinesterase inhibitor, mainly abdominal cramps and/or sudden
the transmission defect is presynaptic or postsynaptic. Special electro- diarrhea from increased peristalsis, profuse bronchotracheal
physiologic studies are required in the classification of congenital secretions that can obstruct the airway, or, rarely, cardiac
myasthenic syndromes and involve estimating the number of ACh arrhythmias. Some physicians pretreat all patients with atropine
receptors per end plate and in vitro study of end plate function. These before administering edrophonium, but this is not recommended
special studies and patch-clamp recordings of kinetic properties of unless there is a history of reaction to tests. Atropine can cause
channels are performed on special biopsy samples of intercostal muscle the pupils to be dilated and fixed for as long as 14 days after a
strips that include both origin and insertion of the muscle but are only single dose, and the pupillary effects of homatropine can last
performed in specialized centers. If myasthenia is limited to the extra- 4-7 days.
ocular, levator palpebrae, and pharyngeal muscles, evoked-potential ◆ Edrophonium chloride (Tensilon) is administered IV. Initially, a
EMG of the muscles of the extremities and spine, diagnostic in the test dose of 0.01 mg/kg is given to ensure that the patient does not
generalized disease, usually is normal. have an allergic reaction or is otherwise very sensitive to
Anti-AChR antibodies should be assayed in the plasma but are muscarinic side effects. In children weighing <30 kg, 0.1 mg/kg is
inconsistently demonstrated. Antibodies against the MuSK receptor the maximum total delivered dose; in children weighing >30 kg,
should be sought in children without circulating AChR antibodies, a the total delivered dose is 0.2 mg/kg. After the test dose,
diagnostic finding when elevated, which further delineates the etiology. intravenous injection of 0.01-0.02 mg is administered every
Many cases of congenital myasthenia gravis result from failure to syn- 30-45 sec, as long as dosing does not exceed the recommended
thesize or release ACh at the presynaptic membrane. In some cases, maximum dose. In adults, the average edrophonium dose to show
the gene that mediates the enzyme choline acetyltransferase for the positive responses is approximately 3.3 mg for ptosis and
approximately 2.6 mg for oculomotor symptoms. Side effects Because of the autoimmune basis of the disease, long-term steroid
include nausea and emesis; light-headedness from bradycardia treatment with prednisone may be effective. Thymectomy should be
(atropine is the antidote) and bronchospasm are less common side considered and might provide a cure. Thymectomy is most effective in
effects. These doses may be given IM or subcutaneously, but these patients who have high titers of anti-ACh receptor antibodies in the
routes are not recommended because the results are much more plasma and who have been symptomatic for <2 yr. Thymectomy is
variable owing to unpredictable absorption, and the test may be ineffective in congenital and familial forms of myasthenia gravis. Treat-
ambiguous or falsely negative. ment of hypothyroidism usually abolishes an associated myasthenia
◆ Effects should be seen within 10 sec and disappear within without the use of cholinesterase inhibitors or steroids.
120 sec. Weakness is measured as, for example, distance If the specific genetic mutation can be identified in a patient with
between upper and lower eyelids before and after administration, one of the congenital myasthenic syndromes, specific therapeutic
degree of external ophthalmoplegia, or ability to swallow a sip of approaches are available for some that differ from the treatments listed
water. above; these are well outlined by Eyemard et al (2013).
◆ Long-acting cholinesterase inhibitors, such as pyridostigmine Plasmapheresis is effective treatment in some children, particularly
(Mestinon), are generally not as useful for the acute assessment of those who do not respond to steroids, but plasma exchange therapy
myasthenic weakness. The Prostigmin test may be used (as provides only temporary remission. IV immunoglobulin is beneficial
outlined later) but might not be as definitively diagnostic as the and should be tried before plasmapheresis because it is less invasive.
edrophonium test. Plasmapheresis and IV immunoglobulin appear to be most effective in
For Children Younger Than 2 Yr patients with high circulating levels of anti-ACh receptor antibodies.
◆ Infants ideally should have a specific fatigable weakness that can Refractory patients might respond to rituximab, a monoclonal anti-
be measured, such as ptosis of the eyelids, dysphagia, and inability body to the B-cell CD20 antigen.
of cervical muscles to support the head. Nonspecific generalized Neonates with transient maternally transmitted myasthenia gravis
weakness without cranial nerve motor deficits makes it less easy to require cholinesterase inhibitors for only a few days or occasionally for
assess results but may be a criterion at times. a few weeks, especially to allow feeding. No other treatment is usually
◆ An IV infusion should be started as a rapid route for necessary. In non–maternally transmitted congenital myasthenia
medications in the event of an adverse effect of the test gravis, identification of the specific molecular defect is important for
medication. treatment; Table 612-4 summarizes specific therapies for each type.
◆ Electrocardiographic monitoring is recommended during
the test. Complications
◆ Pretreatment with atropine sulfate to block the muscarinic effects Children with myasthenia gravis do not tolerate neuromuscular-
of the test medication is not recommended, but atropine sulfate blocking drugs, such as succinylcholine and pancuronium, and may be
should be available at the bedside in a prepared syringe. If needed, paralyzed for weeks after a single dose. An anesthesiologist should
it should be administered IV in a dose of 0.01 mg/kg. carefully review myasthenic patients who require a surgical anesthetic
◆ Edrophonium is not recommended for use in infants; its effect is and such anesthetics should be administered only by an experienced
too brief for objective assessment and an increased incidence of physician/anesthesiologist. Also, certain antibiotics can potentiate
acute cardiac arrhythmias is reported in infants, especially myasthenia and should be avoided; these include the aminoglycosides
neonates, with this drug. (gentamicin and others).
◆ Prostigmin methylsulfate (neostigmine) is administered IM at a
dose of 0.04 mg/kg. If the result is negative or equivocal, another Prognosis
dose of 0.04 mg/kg may be administered 4 hr after the first dose (a Some patients with autoimmune myasthenia gravis experience spon-
typical dose is 0.5-1.5 mg). The peak effect is seen in 20-40 min. taneous remission after a period of months or years; others have a
IV Prostigmin is contraindicated because of the risk of cardiac permanent disease extending into adult life. Immunosuppression, thy-
arrhythmias, including fatal ventricular fibrillation, especially in mectomy, and treatment of associated hypothyroidism might provide
young infants. a cure. Genetically determined congenital myasthenic syndromes may
◆ Long-acting cholinesterase inhibitors administered orally, such as show initial worsening in infancy but then remain static throughout
pyridostigmine (Mestinon), are generally not as useful for the childhood and into adult life.
acute assessment of myasthenic weakness because onset and
duration are less predictable. Other Causes of Neuromuscular Blockade
The test should be performed in the emergency department, hos- Organophosphate chemicals, commonly used as insecticides, can
pital ward, or intensive care unit; the important issue is preparation for cause a myasthenia-like syndrome in children exposed to these toxins
potential complications such as cardiac arrhythmia or cholinergic (see Chapter 63).
crisis, as outlined. Botulism results from ingestion of food containing the toxin of
Clostridium botulinum, a Gram-positive, spore-bearing, anaerobic
Treatment bacillus (see Chapter 210). The mechanism is cleavage by the botuli-
Some patients with mild myasthenia gravis require no treatment. num toxin of several of the structural glycoproteins of the wall (i.e.,
Cholinesterase-inhibiting drugs are the primary therapeutic agents. membrane) of synaptic vesicles within axonal terminals. These glyco-
Neostigmine methylsulfate (0.04 mg/kg) may be given IM every proteins include synaptobrevin and synaptotagmin, but synaptophysin
4-6 hr, but most patients tolerate oral neostigmine bromide, 0.4 mg/ is resistant. Honey is a common source of contamination. The incuba-
kg every 4-6 hr. If dysphagia is a major problem, the drug should be tion period is short, only a few hours, and symptoms begin with
given approximately 30 min before meals to improve swallowing. nausea, vomiting, and diarrhea. Cranial nerve involvement soon
Pyridostigmine is an alternative; the dose required is approximately follows, with diplopia, dysphagia, weak suck, facial weakness, and
4 times greater than that of neostigmine, but it may be slightly longer absent gag reflex. Generalized hypotonia and weakness then develop
acting. Overdoses of cholinesterase inhibitors produce cholinergic and can progress to respiratory failure. Neuromuscular blockade is
crises; atropine blocks the muscarinic effects but does not block the documented by EMG with repetitive nerve stimulation. Respiratory
nicotinic effects that produce additional skeletal muscle weakness. In support may be required for days or weeks until the toxin is cleared
the rare familial myasthenia gravis caused by absence of end plate from the body. No specific antitoxin is available. Guanidine, 35 mg/
AChE, cholinesterase inhibitors are not helpful and often cause kg/24 hr, may be effective for extraocular and limb muscle weakness
increased weakness; these patients can be treated with ephedrine or but not for respiratory muscle involvement.
diaminopyridine, both of which increase ACh release from terminal Tick paralysis is a disorder of ACh release from axonal terminals
axons. due to a neurotoxin that blocks depolarization. It also affects large
Table 612-4 Potential Therapies in Congenital Myasthenic Syndromes

AChE Ephedrine 3 mg/kg/day in 3 divided doses; begin with 1 mg/kg; not obtainable in several countries
If ephedrine is not obtainable, 3,4-diaminopyridine 1 mg/kg/day in 4 divided doses, up to 60 mg/day in adults
Avoid AChE inhibitors
AChR deficiency AChE inhibitors: pyridostigmine bromide (Mestinon) 4-5 mg/kg/day in 4-6 divided doses
If necessary add 3,4-diaminopyridine 1 mg/kg/day in 4 divided doses, up to 60 mg/day in adults
AChR fast channel AChE inhibitors: pyridostigmine bromide (Mestinon) 4-5 mg/kg/day in 4-6 divided doses
AChR slow channel Quinidine sulfate
• Adults: Begin for 1 wk with 200 mg tid; gradual increase to maintain a serum level of 1-25 µg/mL
• Children: 15-60 mg/kg/day in 4-6 divided doses; not available in several countries
If quinidine sulfate is not available, fluoxetine 80-100 mg/day in adults
ChAT AChE inhibitors: pyridostigmine bromide (Mestinon) 4-5 mg/kg/day in 4-6 divided doses
Dok7 Ephedrine 3 mg/kg/day in 3 divided doses; begin with 1 mg/kg; not obtainable in several countries
If ephedrine is not obtainable, 3,4-diaminopyridine 1 mg/kg/day in 4 divided doses, up to 60 mg/day in adults
Laminin β2 Ephedrine 3 mg/kg/day in 3 divided doses; begin with 1 mg/kg; not obtainable in several countries
MuSK AChE inhibitors: pyridostigmine bromide (Mestinon) 4-5 mg/kg/day in 4-6 divided doses
3,4-Diaminopyridine 1 mg/kg/day in 4 divided doses, up to 60 mg/day in adults
Rapsyn AChE inhibitors: pyridostigmine bromide (Mestinon) 4-5 mg/kg/day in 4-6 divided doses
Modified from Eyemard B, Hantaï D, Estounet B: Congenital myasthenic syndromes, Handb Clin Neurol 113:1469-1480, 2013.
myelinated motor and sensory nerve fibers. This toxin is produced by of types are based upon age at onset, severity of weakness, and clinical
the wood tick or dog tick, insects common in the Appalachian and course; muscle biopsy does not distinguish types 1 and 2, though type
Rocky Mountains of North America. The tick embeds its head into 3 shows a more adult than perinatal pattern of denervation and rein-
the skin, usually the scalp, and neurotoxin production is maximal nervation. Type 0 can show biopsy features more similar to myotubular
about 5-6 days later. Motor symptoms include weakness, loss of coor- myopathy because of maturational arrest; scattered myotubes and
dination, and sometimes an ascending paralysis resembling Guillain- other immature fetal fibers also are demonstrated in the muscle biop-
Barré syndrome. Tendon reflexes are lost. Sensory symptoms of sies of patients with types 1 and 2, but they do not predominate.
tingling paresthesias can occur in the face and extremities. The diag- Approximately 25% of patients have type 1, 50% type 2, and 25%
nosis is confirmed by EMG and nerve conduction studies and by type 3; type 0 is rare and accounts for <1%. Some patients are transi-
identifying the tick. The tick must be removed completely and the tional between types 1 and 2 or between types 2 and 3 in terms
buried head not left beneath the skin. Patients then recover com- of clinical function. A variant of SMA, Fazio-Londe disease, is a
pletely within hours or days. progressive bulbar palsy resulting from motor neuron degeneration
more in the brainstem than the spinal cord, but cranial nerves of
Bibliography is available at Expert Consult. extraocular muscles also are spared in this form. Table 612-5 lists other
variants.
Autonomic motor neurons of both the sympathetic and parasympa-
thetic systems are not spared, but usually do not show clinical mani-
612.2 Spinal Muscular Atrophies festations until late stages. Autonomic deficits may involve the detrusor
Harvey B. Sarnat muscle of the urinary bladder or the smooth muscle urethral and anal
sphincters, in all 3 forms of SMA. In some patients with type 1 SMA
Spinal muscular atrophies (SMAs) are degenerative diseases of motor and respiratory distress there may be severe autonomic dysregulation
neurons that begin in fetal life and continue to be progressive in with dysautonomia and cardiovascular collapse leading to death or to
infancy and childhood. The progressive denervation of muscle is com- severe ischemic brain damage.
pensated for in part by reinnervation from an adjacent motor unit, but
giant motor units are thus created with subsequent atrophy of muscle ETIOLOGY
fibers when the reinnervating motor neuron eventually becomes The cause of SMA is genetic as an autosomal recessive mendelian trait.
involved. Motor neurons of cranial nerves III, IV, and VI to extraocular Neuropathologically it appears to be a pathologic continuation of a
muscles, as well as those of the sacral spinal cord innervating striated process of programmed cell death (apoptosis) that is normal in embry-
muscle of the urethral and anal sphincters, are selectively spared. onic life. A surplus of motor neuroblasts and other neurons is gener-
Upper motor neurons (layer 5 pyramidal neurons in the cerebral ated from primitive neuroectoderm, but only about half survive and
cortex) also remain normal. mature to become neurons; the excess cells have a limited life cycle and
SMA is classified clinically into a severe infantile form, also known degenerate. If the process that arrests physiologic cell death fails to
as Werdnig-Hoffmann disease or SMA type 1; a late infantile and intervene by a certain stage, neuronal death can continue in late fetal
more slowly progressive form, SMA type 2; and a more chronic or life and postnatally. The survivor motor neuron gene (SMN) arrests
juvenile form, also called Kugelberg-Welander disease, or SMA type apoptosis of motor neuroblasts. Unlike most genes that are highly
3. A severe fetal form that is usually fatal in the perinatal period has conserved in evolution, SMN is a uniquely mammalian gene. An addi-
been described as SMA type 0, with motor neuron degeneration dem- tional function of SMN, both centrally and peripherally, is to transport
onstrated in the spinal cord as early as midgestation. These distinctions RNA-binding proteins to the axonal growth cone to ensure an adequate
Chapter 612 ◆ Disorders of Neuromuscular Transmission and of Motor Neurons 2996.e1
Bibliography Scherer K, Bedlack RS, Simel DL: Does this patient have myasthenia gravis? JAMA
Eyemard B, Hantaï D, Estounet B: Congenital myasthenic syndromes, Handb Clin 293:1906–1914, 2005.
Neurol 113:1469–1480, 2013. Schmidt C, Abicht A, Krampfl K, et al: Congenital myasthenic syndrome due to a
Felice KJ, DiMario F, Conway SR: Postinfectious myasthenia gravis: report of 2 novel missense mutation in the gene encoding choline acetyltransferase,
cases, J Child Neurol 20:441–444, 2005. Neuromuscul Disord 13:245–251, 2003.
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literature review, J Child Neurol 24:584–590, 2009. myasthenia: a surveillance study, Pediatrics 132:e939–e943, 2013.
Harper CM: Congenital myasthenic syndromes, Semin Neurol 24:111–123, 2004. Vincent A, McConville J, Farrugia ME, et al: Seronegative myasthenia gravis,
Jayawant S, Parr J, Vincent A: Autoimmune myasthenia gravis, Handb Clin Neurol Semin Neurol 24:125–133, 2004.
113:1465–1468, 2013. Wargon I, Richard P, Kuntzer T, et al: Long-term follow-up of patients with
Liew WKN, Jang PB: Update on juvenile myasthenia gravis, Curr Opin Pediatr congenital myasthenic syndrome caused by COLQ mutations, Neuromuscul
25:694–700, 2013. Disord 22:318–324, 2012.
Maselli RA, Kong DZ, Bowe CM, et al: Presynaptic congenital myasthenic Wylam ME, Anderson PM, Kuntz NL, et al: Successful treatment of refractory
syndrome due to quantal release deficiency, Neurology 57:279–289, 2001. myasthenia gravis using rituximab: a pediatric case report, J Pediatr 143:674–
Meriggioli MN, Sanders DB: Autoimmune myasthenia gravis: emerging clinical 677, 2003.
and biological heterogeneity, Lancet Neurol 8:475–490, 2009. Zafeiriou DI, Pitt M, de Sousa C: Clinical and neurophysiological characteristics of
Milone M, Shen XM, Selcen D, et al: Myasthenic syndrome due to defects in congenital myasthenic syndromes presenting in early infancy, Brain Dev
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Muller JS, Herczegfalvi A, Vilchez JJ, et al: Phenotypical spectrum of DOK7 Zinman L, Ng E, Bril V: IV immunoglobulin in patients with myasthenia gravis,
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Palace J, Lashley D, Newsom-Davis J, et al: Clinical features in a series of fast
channel congenital myasthenia syndrome, Neuromuscul Disord 22:112–117,
2012.
A B
Figure 612-1 Type 1 spinal muscular atrophy (Werdnig-Hoffmann disease). Clinical manifestations of weakness of limb and axial musculature
in a 6 wk old infant with severe weakness and hypotonia from birth. Note the marked weakness of the limbs and trunk on ventral suspension (A)
and of neck on pull to sit (B). (From Volpe JJ: Neurology of the newborn, ed 4, Philadelphia, 2001, WB Saunders, p. 644.)
Table 612-5 Spinal Muscular Atrophy Variants: Progressive or Severe Neonatal Anterior Horn Cell Disease Not Linked to
SMN
VARIANT MAJOR FEATURES
SMA with respiratory distress type 1 Mild hypotonia, weak cry, distal contractures initially
(SMARD1) Respiratory distress from diaphragmatic paralysis 1-6 mo, progressive distal weakness
Autosomal recessive, locus 11q13.2, gene: immunoglobulin mu-binding protein 2 (IGHMBP2)
Pontocerebellar hypoplasia type 1 Arthrogryposis, hypotonia, weakness, bulbar deficits early; later, microcephaly, extraocular defects,
cognitive deficits: pontocerebellar hypoplasia
Molecular defect unknown
Likely autosomal recessive
X-linked infantile SMA with bone Arthrogryposis, hypotonia, weakness, congenital bone fractures, respiratory failure
fractures Lethal course as in severe type 1 SMA
Most cases X-linked (X9/11.3-q11.2), a few cases likely autosomal recessive
Congenital SMA with predominant Arthrogryposis, hypotonia, weakness, especially distal lower limbs early
lower limb involvement Nonprogressive but severe disability
Autosomal dominant or sporadic; locus 12q23-24
SMA, spinal muscular atrophy; SMN, survivor motor neuron gene.
From Volpe JJ: Neurology of the newborn, ed 5, Philadelphia, 2008, Saunders Elsevier, Table 18-7, p. 775.
amount of protein-encoding transcripts essential for growth cone muscles. Patients are ambulatory. Symptoms of bulbar muscle weak-
mobility both during fetal development and in postnatal synaptic ness are rare. Approximately 25% of patients with this form of SMA
remodeling. have muscular hypertrophy rather than atrophy, and it may easily be
confused with a muscular dystrophy. Longevity can extend well into
CLINICAL MANIFESTATIONS middle adult life. Fasciculations are a specific clinical sign of denerva-
The cardinal features of SMA type 1 are severe hypotonia (Fig. 612-1); tion of muscle. In thin children, they may be seen in the deltoid and
generalized weakness; thin muscle mass; absent tendon stretch reflexes; biceps brachii muscles and occasionally the quadriceps femoris
involvement of the tongue, face, and jaw muscles; and sparing of extra- muscles, but the continuous, involuntary, worm-like movements may
ocular muscles and sphincters. Diaphragmatic involvement is late. be masked by a thick pad of subcutaneous fat. Fasciculations are best
Infants who are symptomatic at birth can have respiratory distress and observed in the tongue, where almost no subcutaneous connective
are unable to feed. Congenital contractures, ranging from simple club- tissue separates the muscular layer from the epithelium. If the intrinsic
foot to generalized arthrogryposis, occur in approximately 10% of lingual muscles are contracted, such as in crying or when the tongue
severely involved neonates. Infants lie flaccid with little movement, protrudes, fasciculations are more difficult to see than when the tongue
unable to overcome gravity (see Fig. 607-1 in Chapter 607). They lack is relaxed. Cramps and myalgias of appendicular and axial muscles are
head control. More than 65% of children die by 2 yr of age, and many common, especially in later stages, and problems of micturition may
die early in infancy. present, though adolescent patients may be too embarrassed to state
In type 2 SMA, affected infants are usually able to suck and swallow, them unless the physician directly inquires.
and respiration is adequate in early infancy. These children show pro- The outstretched fingers of children with SMA often show a
gressive weakness, but many survive into the school years or beyond, characteristic tremor owing to fasciculations and weakness. It should
although confined to an electric wheelchair and severely handicapped. not be confused with a cerebellar tremor.
Nasal speech and problems with deglutition develop later. Scoliosis The heart is not involved in SMA. Intelligence is normal, and chil-
becomes a major complication in many patients with long survival. dren often appear brighter than their normal peers because the effort
Gastroesophageal reflux may lead to malnutrition or to aspiration with they cannot put into physical activities is redirected to intellectual
acute airway obstruction or pneumonia. development, and they are often exposed to adult speech more than to
Kugelberg-Welander disease is the mildest SMA (type 3), and juvenile language because of the social repercussions of the disease.
patients can appear normal in infancy. The progressive weakness Progressive deterioration of ambulation and the high risk of falling and
is proximal in distribution, particularly involving shoulder girdle fracturing long bones or the pelvis eventually require use of a
suspected cases and for prenatal diagnosis. Most cases are inherited
as an autosomal recessive trait. The incidence of SMA is 10-15 in
100,000 live births, affecting all ethnic groups; it is the second most
common neuromuscular disease, following Duchenne muscular dys-
trophy. The incidence of heterozygosity for autosomal recessive SMA
is 1 in 50.
The genetic locus for all 3 of the common forms of SMA is on chro-
mosome 5, a deletion at the 5q11-q13 locus, indicating that they are
variants of the same disease rather than different diseases. The affected
SMN1 gene has a molecular weight of 38 kDa and contains 8 exons
that span 20 kb and telomeric and centromeric exons that differ only
by 5bp and produce a transcript encoding 294 amino acids. SMN1 is
duplicated in a highly homologous gene called SMN2 and both genes
are transcribed. SMN2 remains present in all patients with SMA, but
cannot fully compensate the SMN1 defect. However, a molecular basis
for correlation between the SMN2 copy number and clinical severity
of the SMA is the capability of SMN2 to encode a small amount of an
Figure 612-2 Muscle biopsy of neonate with infantile spinal muscular identical SMN protein. The critical difference between SMN1 and
atrophy. Groups of giant type I (darkly stained) fibers are seen within SMN2 genes is a cytosine (C) to thymine (T) transition in exon 7 of
muscle fascicles of severely atrophic fibers of both histochemical types. SMN2. Another gene, the neuronal apoptosis inhibitory gene (NAIP), is
This is the characteristic pattern of perinatal denervation of muscle. located next to the SMN gene and in many cases there is an inverted
Myofibrillar adenosine triphosphatase, preincubated at pH 4.6 (×400). duplication with 2 copies, telomeric and centromeric, of both genes;
isolated mutations or deletions of NAIP do not produce clinical SMA
and generate a mostly nonfunctional isoform lacking the carboxy-
wheelchair; an electric wheelchair often is needed because weakness of terminus amino acids encoded by exon 7. Milder forms of SMA have
the upper extremities does not allow the patient to manually push the more than 2 copies of SMN2, and in late-onset patients with homozy-
wheels. Progressive scoliosis is another serious complication and may gous deletion of the SMN1 gene, there are 4 copies of SMN2. An
have a further adverse effect on respiration. additional gene mapped to 11q13-q21 in SMA may help explain early
respiratory failure in some patients. Nucleotide expansions account for
LABORATORY FINDINGS only 5-10% of cases of SMA, and deletions or splicing out of exons 7
The serum creatine kinase level may be normal but more commonly and 8 are the genetic mechanism in the great majority of cases. Another
is mildly elevated in the hundreds. A creatine kinase level of several pair of genes adjacent to the SMN1 and SMN2 genes, SERF1 and
thousand is rare. The chest x-ray in early-onset disease demonstrates SERF2, also may play a secondary role. The SMN gene product modu-
thin ribs. Results of motor nerve conduction studies are normal, except lates axonal growth and localization of β-actin messenger RNA in
for mild slowing in terminal stages of the disease, an important feature growth cones of motor neurons.
distinguishing SMA from peripheral neuropathy. EMG shows fibrilla- Infrequent families with autosomal dominant inheritance are
tion potentials and other signs of denervation of muscle. A secondary described, and a rare X-linked recessive form also occurs. Carrier
mitochondrial DNA depletion is sometimes demonstrated in the testing by dose analysis is available.
muscle biopsy of infants with SMA. The molecular genetic test of the
SMN gene provides definite confirmation of the diagnosis. TREATMENT
No medical treatment is able to delay the progression. Supportive
DIAGNOSIS therapy includes orthopedic care with particular attention to scoliosis
The simplest, most definitive diagnostic test is a molecular genetic and joint contractures, mild physiotherapy, and mechanical aids for
marker in blood for the SMN gene. Muscle biopsy used to be the diag- assisting the child to eat and to be as functionally independent as
nostic test before the genetic marker from blood samples became avail- possible. Most children learn to use a computer keyboard with great
able, and muscle biopsy now is used more selectively in patients skill but cannot use a pencil easily. Valproic acid is sometimes admin-
showing equivocal or negative genetic findings. The muscle biopsy in istered because it increases SMN2 protein, and gabapentin and oral
infancy reveals a characteristic pattern of perinatal denervation that is phenylbutyrate also may slow the progression, but these treatments
unlike that of mature muscle. Groups of giant type I fibers are mixed do not alter the course in all patients. A benefit of antioxidants is
with fascicles of severely atrophic fibers of both histochemical types unproved. Gene replacement and protein replacement therapies
(Fig. 612-2). Scattered immature myofibers resembling myotubes also remain theoretical and experimental. Potential therapeutic genetic
are demonstrated. In juvenile SMA, the pattern may be more similar strategies in SMA include upregulation of SMN2 gene expression,
to adult muscle that has undergone many cycles of denervation and preventing exon 7 skipping of SMN2 transcripts and improving the
reinnervation. Neurogenic changes in muscle also may be demon- stability of the protein lacking the amino acid sequence encoded
strated by EMG, but the results are less definitive than by muscle biopsy by exon 7.
in infancy. Sural nerve biopsy is now performed only occasionally, but
shows mild sensory neuropathic changes, and sensory nerve conduc- Bibliography is available at Expert Consult.
tion velocity may be slowed; hypertrophy of unmyelinated axons also
is seen. At autopsy, mild degenerative changes are seen in sensory
neurons of dorsal root ganglia and in somatosensory nuclei of the
thalamus, but these alterations are not perceived clinically as sensory 612.3 Other Motor Neuron Diseases
loss or paresthesias. The most pronounced neuropathologic lesions are Harvey B. Sarnat
the extensive neuronal degeneration and gliosis in the ventral horns of
the spinal cord and brainstem motor nuclei, especially the hypoglossal Motor neuron diseases other than SMA are rare in children. Poliomy-
nucleus. elitis used to be a major cause of chronic disability, but with the routine
use of polio vaccine, this viral infection is now rare (see Chapter 249).
GENETICS Other enteroviruses, such as coxsackievirus and echovirus, or the live
Molecular genetic diagnosis by DNA probes in blood samples or in polio vaccine virus can also cause an acute infection of motor neurons
muscle biopsy or chorionic villi tissues is available for diagnosis of with symptoms and signs similar to poliomyelitis, although usually
Chapter 612 ◆ Disorders of Neuromuscular Transmission and of Motor Neurons 2998.e1
Bibliography Roper H, Quinlivan R, on Behalf of Workshop Participants: Implementation of

Berger A, Mayr JA, Meierhofer D, et al: Severe depletion of mitochondrial DNA in “the consensus statement for the standard of care in spinal muscular atrophy”
spinal muscular atrophy, Acta Neuropathol 105:245–251, 2003. when applied to infants with severe type 1 SMA in the UK, Arch Dis Child
Chung BHY, Wong VCN, Ip P: Spinal muscular atrophy: survival pattern and 95:845–849, 2009.
functional status, Pediatrics 114:e548–e553, 2004. Rossoll W, Jablonka S, Andreassi C, et al: Smn, the spinal muscular atrophy-
Grizelj R, Vuković J: Tongue fasciculations in the newborn, J Pediatr 163:1526, determining gene product, modulates axon growth and localization of
2013. beta-actin mRNA in growth cones of motoneurons, J Cell Biol 163:801–812,
Grohmann K, Varon R, Stolz P, et al: Infantile spinal muscular atrophy with 2003.
respiratory distress type 1 (SMARD1), Ann Neurol 54:719–724, 2003. Sarnat HB, Trevenen CL: Motor neuron degeneration in a 20-week male fetus:
Hardart MKM, Truog RD: Spinal muscular atrophy-type 1, Arch Dis Child spinal muscular atrophy type 0, Can J Neurol Sci 34:215–220, 2007.
88:848–850, 2003. Souchon F, Simard LR, Lebrun S, et al: Clinical and genetic study of chronic (types
Kizilates SU, Talim B, Sel K, et al: Severe lethal spinal muscular atrophy variant II and III) childhood onset spinal muscular atrophy, Neuromuscul Disord
with arthrogryposis, Pediatr Neurol 32:201–204, 2005. 6:419–424, 1996.
Lunn MR, Wang CH: Spinal muscular atrophy, Lancet 371:2120–2132, 2008. Toshihiro N, Takenouchi T, Fukushima H, et al: Catastrophic autonomic crisis with
Mercuri E, Messina S, Kinali M, et al: Congenital form of spinal muscular atophy cardiovascular collapse in spinal muscular atrophy with respiratory distress type
predominantly affecting the lower limbs: a clinical and muscle MRI study, 1, J Child Neurol 28:949–951, 2013.
Neuromuscul Disord 14:125–129, 2004. Viollet L, Melki J: Spinal muscular atrophies, Handb Clin Neurol 113:1395–1411,
Nadeau A, Anjou GD, Debray FG, et al: A newborn with spinal muscular atrophy 2013.
type 0 presenting with a clinicopathological picture of centronuclear myopathy,
Can J Neurol Sci 32(Suppl 1):S45, 2005.
milder. Specific polymerase chain reaction tests and viral cultures of
cerebrospinal fluid are diagnostic. Motor neuron infection with the
West Nile virus also occurs.
A juvenile form of amyotrophic lateral sclerosis is rare. Upper and
lower motor neuron loss is evident clinically, unlike in SMA. The
course is progressive and ultimately fatal.
Pena-Shokeir and Marden-Walker syndromes are progressive
motor neuron degenerations associated with severe arthrogryposis and
congenital anomalies of many organ systems. Pontocerebellar hypo-
plasias are progressive degenerative diseases of the central nervous
system that begin in fetal life; type 1 also involves motor neuron degen-
eration resembling an SMA, but the SMN gene on chromosome 5 is
normal.
Motor neurons become involved in several metabolic diseases of the
nervous system, such as gangliosidosis (Tay-Sachs disease), ceroid
lipofuscinosis (Batten disease), and glycogenosis II (Pompe disease),
but the signs of denervation may be minor or obscured by the more
prominent involvement of other parts of the central nervous system or
of muscle.
Chapter 613 ◆ Hereditary Motor-Sensory Neuropathies 2999
Chapter 613
Hereditary Motor-Sensory
Neuropathies
Harvey B. Sarnat
The hereditary motor-sensory neuropathies (HMSNs) are a group of

progressive diseases of peripheral nerves (Table 613-1). Motor compo-
nents generally dominate the clinical picture, but sensory and auto-
nomic involvement is expressed later. Sural nerve biopsy used to be the
most definitive means of diagnosis, but with the expanded knowledge
Text continued on p. 3003
Table 613-1 Hereditary Peripheral Neuropathies

DISORDER (OMIM NO.) CLINICAL FEATURES NERVE CONDUCTION STUDIES GENE OR LOCUS
CMT1 (DEMYELINATING)
CMT1 A-F (HMSN type I) Autosomal dominant. Onset 1st-4th decade. Delayed motor and sensory
Predominant distal weakness, decreased conduction studies. Motor
DTRs, mild distal sensory loss, hypertrophy of studies typically <38 m/s
nerves common
1A (118220) Commonest form recognized, seen in all ages PMP22 duplication
(but more adults) or point
mutation
1B (118200) Approximately 5% of CMT1 group MPZ
1C (601098) Childhood onset, starts with abnormal gait, LITAF
then distal weakness and wasting, occasional
nerve hypertrophy. Rarely, early-onset hearing
loss
1D (607678) Possible cranial nerve involvement. Late onset EGR2
in childhood or early adulthood
1E (118300) Associated with deafness (29-45%) PMP22
1F (607734) NEFL
Hereditary neuropathy with Autosomal dominant. Recurrent Significant slowing of motor and PMP 22 deletion
liability to pressure palsies mononeuropathy simplex or multiplex sensory conduction velocities in
(tomaculous neuropathy) frequently related to trauma clinically affected nerves but
(162500) also in unaffected nerves
Slowed NCVs Often a miscellaneous group. Incidentally Moderately slowed conduction ARHGEF10
Asymptomatic detected with no clinical symptoms. velocities
Autosomal dominant
CMT2 (AXONAL)
CMT2 A-L (HMSN type II) Autosomal dominant (A, B, D, E, F, G, I) Nerve conduction velocities
Autosomal recessive (BI, B2, H, K) greater than HMSN type I
Clinically similar to CMT type 1, except for later (>38 m/s) but below normal
onset, absence of peripheral nerve range occasionally
enlargement, and less marked weakness
2A1 (118210) CMT2A: prominent distal weakness, proximal 2A1: KIF1B (one
2A2 (609260) weakness also present in 60%. Optic atrophy family)
and central involvement reported. Main form 2A2: MFN2
related to MFN2 mutations
2B (600882) CMT2B: severe sensory loss: often 2B: RAB7
2B1 (605588) complications with infections, arthropathy, 2B1: LMNA
amputations, foot ulcers, distal weakness
2B2 (605589) Average onset 34 yr (Costa Rican family) ?MED25
2C (606071) Vocal cord, diaphragm, and respiratory TRP4
involvement, decreased longevity. Allelic with 12q23–q24
congenital dSMA (600175) and TRP4
scapuloperoneal muscular atrophy (181405)
2D (601472) (allelic to Upper limb predominance GARS
dSMA)
2E (607684) (1F dominant is 30% associated with deafness, early childhood Intermediate/slow nerve NEFL
allelic to CMT2E) onset with gait abnormalities, occasional conduction studies
hyperkeratosis, increased sensory involvement
Continued
Table 613-1 Hereditary Peripheral Neuropathies—cont’d

2F (606595) Trophic changes feet and knees HSPB1 (HSP27)
2G (608591) Onset age 9-76 yr, average age 20 yr, large 12q12–q13
Spanish family. Also severe form with early
onset
2H (607731) Pyramidal involvement, vocal cord involvement Intermediate/slow nerve GDAP1
2H (allelic to CMT4A– conduction studies
CMT4C2 in original
publication)
2I (607677) CMT I and J: possible late onset, pupillary MPZ
anomalies, pain, hearing loss, dysphagia
2J (607736) Vocal cord paralysis, more severe early-onset MPZ
form
2K (607831) Occasional proximal leg weakness (like dHMN GDAP1
II), large Chinese family, with onset at age
15-33 yr. Scoliosis
2L (608673) HSPB8
12q24
HMSN II with onset in early Autosomal dominant or recessive. Weakness Axonal pattern with axonal- MFN2; GDAP1
childhood (EOHMSN) within 1st 5 yr, rapid progression of weakness, degenerative polyneuropathy. Heterogeneous
Severe early-onset axonal usually complete paralysis below elbows and Absent SNAPs, no response to
neuropathy (SEOAN) knees by teens, absent DTRs, moderate stimulation in cerebral palsy
sensory changes in most cases. Normal CSF nerve, upper limb nerves normal
protein. Occasional optic atrophy or spasticity or mildly slowed. EMG:
denervation
Spinal muscular atrophy with Autosomal recessive. Onset in infancy (3-6 mo), Absent conduction in most cases IGHMBP2
respiratory distress type 1 respiratory failure, progressive distal
(SMARD1)/severe infantile weakness, eventual plateau. No recovery
axonal neuropathy with
respiratory failure (SIANR)
Allelic to dHMN6 dSMA1
(604320)
Hereditary motor and Adult onset (after 30 yr). Autosomal dominant. Motor and sensory axonal 3q13
sensory neuropathy Slowly progressive proximal dominant area of neuropathy. SNAPs, CMAPs,
(HMSN-P) (Okinawa type) weakness. Fasciculations of extremities and MNCVs, and SNCVs reduced or
trunk. Raised creatine kinase, hyperlipidemia, absent
diabetes mellitus, eventual loss of ambulation, EMG: fasciculations, fibrillations,
absent DTRs, sensory disturbances. Most and neuromyotonic picture early
patients described from Japan on
CMT3* AND 4
CMT3 (Dejerine-Sottas Onset 1st 2 yr, overall disability ?less severe Motor conduction velocities PMP22, MPZ, PRX,
syndrome) (145900) than CMT4. Hypotonia, motor delay by 1st yr, usually <10 m/s. SAPs absent. EGR2, FIG4
poor coordination, ataxia, distal weakness EMG: chronic denervation
(max. lower limbs), short stature. By 2nd
decade, proximal weakness, hand and foot
deformities. Nerve hypertrophy. Moderate to
severe sensory loss. Scoliosis. Common
cranial nerve involvement, nystagmus,
deafness, and mild bifacial weakness. Raised
CSF protein
CMT4 (A-J) Clinical picture similar to or slightly more Moderate slowing of nerve
Autosomal recessive severe than in CMT1 form, increased ataxia, conduction studies
areflexia, scoliosis. Nerve hypertrophy rare
4A (214400) Onset <2 yr, Tunisian and Moroccan families. 25-35 m/s GDAP1
Severe progressive. Less-severe European
phenotypes
4B1 (601382) Ophthalmoplegia, vocal cord paralysis, facial, 9-20 m/s MTMR2, (MPZ)
bulbar weakness (all infrequent). Weakness
below 5 yr, proximal and distal weakness,
absent DTRs
4B2 (604563) Early onset: 1st decade; glaucoma and 15-30 m/s SBF2, MTMR13
deafness sometimes. Recorded in Tunisia,
Japan, and Turkey
4C (601596) Early-onset scoliosis, commoner in Algerians, 4-37 m/s SH3TC2
glaucoma and neutropenia. 1st and 2nd (KIAA1985)
decades
4D (601455) (HMSN-Lom) Closed gypsy pedigree; onset <10 yr. Deafness 10-20 m/s NDRG1
(by 2nd-3rd decade). Tongue atrophy
4E (605253) Congenital hypomyelinating neuropathy 5-20 m/s ERG2/KROX 20,
MPZ

4F (145900) Severely affected at birth or by 7 yr; <5 m/s PRX
arthrogryposis multiplex congenita common;
respiratory and feeding difficulties; often die
young
4G (605285) Type Russe. Onset 8-16 yr. Origin Bulgaria 30-35 m/s 10q22
4H (609311) Increased in Lebanese/Turkish. Onset infancy to <10 m/s or absent FDG4
childhood (1-2 yr). Delayed motor milestones.
Occasional scoliosis, increased distal
weakness, usually absent DTRs
4J (611228) Onset by 5 yr. Severe disorder. Similarities to 2-7 m/s; some cases higher FIG4
motor neuron disease
CCFDN (604168) Congenital cataract, microcornea, facial 19-33 m/s CTDP1
dysmorphism, mental retardation, distal motor
peripheral neuropathy
MIXED PATHOLOGY (AXONAL AND DEMYELINATING)
CMT X X-linked dominant. Onset 1st-2nd decade. Median nerve motor conduction GJB1
X-linked CMT Progressive wasting and weakness of distal studies <40 m/s (but faster than
X1 (302800) limb musculature, especially hands, more CMT1A). Intermediate slowing
marked in affected males than carrier females less uniform along nerves with
dispersion more pronounced
X2 (302801) X-linked recessive. Rare infantile onset, Mixed demyelinating/axonal Xp22.2
intellectual disability, females very mildly
affected
X3 (302802) X-linked recessive. ± Spasticity. Females Mixed demyelinating/axonal Xq26
unaffected
X4 (310490) X-linked (Cowchock syndrome). Severe Axonal neuropathy. Motor Xq24–26.1
neuropathy, females very mildly affected. conduction velocities: mild
Isolated case reports. Onset birth to early delay (33-56 m/s). Sensory very
childhood. Slowly progressive. Many develop abnormal. EMG: denervation,
deafness by 5 yr. Mental retardation large motor unit potential, and
commonly seen. Occasional optic atrophy fasciculation
X5 (311070) X-linked. Mild to moderate neuropathy, Axonal neuropathy–mild Xq21.32–q24
deafness, optic atrophy. Allelic with demyelinating changes PRPS1
Rosenberg-Chutorian (opticoacoustic
neuropathy) and Arts syndromes
Intermediate forms of CMT Patients have neurophysiologic results that fall “Intermediate values” 30-40 m/s–
between axonal and demyelinating ranges most accurate from median
motor nerves. Some forms have
normal nerve conduction
studies (DI-CMTB)
DI-CMTA Italian family 10q24.1–q25.1
DI-CMTB (606482) American family DNM2
DI-CMTC (608323) YARS
DI-CMTD (607791) Myelin protein zero MPZ
A–autosomal recessive form Overlap conditions: Overlap:
(608340) Recessive CMT with GADP1 mutations: (CMT2K GJB1
and 4A) Spanish and Tunisian family–severe NF-L
childhood forms reported. Also called GDAP1
DI-CMTA autosomal recessive form
CMT with NF-L: (CMT1F and 2E)
OTHER HMSN AND HMN SYNDROMES
HMSN V/spastic paraplegia Variable inheritance. Spasticity in lower limbs Small/absent SNAPs. Motor SPG3A, SPAST,
with HMSN type V/CMT5 causing difficulty walking and toe walking. studies axonal in type NIPA1, BSCL2,
(CMT with pyramidal signs) Autosomal recessive form associated with SPG4, SPG7,
(600631) mental retardation. Lower limb marked SPG20, SPG21,
spasticity with little weakness, increased DTRs, SPG30, PLP1
extensor plantars, pes cavus, often distal CMT with
amyotrophy. Expanding field with multiple pyramidal signs:
subforms, n = 37. Not all associated with MFN2
peripheral neuropathy
CMT with pyramidal signs: part of HMSN V but
described without spasticity
HMSN VI (allelic CMT2A) Visual impairment due to optic atrophy. No response or motor conduction MFN2
Dominant and recessive forms. Onset in 1st around 45 m/s. Sensory nerves
decade. Distal weakness, often proximal often cannot be stimulated
involvement too. Less sensory involvement.
Scoliosis
HMSN VII HMSN with retinitis pigmentosa. CSF protein
raised. Usually adult onset. Rare entity
described in a few families, mainly of adult
onset
Continued

DISTAL HEREDITARY MOTOR NEURONOPATHIES (DHMN)
dHMNI (182960) Autosomal dominant. Juvenile onset. Distal Normal nerve conduction studies, HSPB1
weakness and wasting occasional mild slowing. EMG 7q34–q36
neurogenic
dHMNII (608634) Autosomal dominant. Adult onset, distal HSPB8, HSPB3
weakness and wasting
dHMNIIjuv (158590) (Allelic CMT2F, CMT2L) HSPB1
dHMNIII Autosomal recessive. Infantile to adult onset. 11q13.3
Slow, progressive muscle wasting and
weakness, variable diaphragmatic paralysis
dHMNIV (607088) Autosomal recessive. Juvenile onset. Severe 11q13
Distal SMA type 3 muscle wasting and weakness and
diaphragmatic paralysis
dHMNV (600794) (Allelic CMT2D) GARS
Autosomal dominant. Upper limb
predominance, occasional pyramidal features
dHMN type V (Silver Autosomal dominant. Prominent hand muscle BSCL2
syndrome) (270685) weakness and wasting, mild to severe
spasticity of lower limbs
dHMNVI (604320) (Allelic SMARD1) IGHMBP2
Autosomal recessive. Severe infantile form with
respiratory distress
dHMNVIIA (158580) Autosomal dominant. Onset with vocal cord DCTN1
paralysis
dHMNVIIB (607641) Autosomal dominant. Onset with vocal cord 2q14
paralysis and facial weakness Xq13–q21
X-linked dHMN
dHMN/ALS4 (602433) X-linked recessive. Juvenile onset with distal SETX
wasting and weakness
dHMN-J (Jerash) Autosomal dominant. Early onset symptomatic 9p21.1–p12
in 2nd decade with pyramidal tract signs
Congenital distal SMA Autosomal recessive. Onset from 6-10 yr with 12q23–q24
(600175) pyramidal features in 1 Jordanian family
Autosomal dominant congenital nonprogressive
distal HMN with contractures
Peripheral neuropathy with Autosomal recessive. Increased in French EMG: denervation. Axonal SLC12A6 (KCC3)
agenesis of corpus Canadian populations. Progressive axonal neuropathy
callosum (Charlevoix neuropathy. CNS malformations—absence/
disease or Andermann hypoplasia of corpus callosum in most, early
syndrome) (218000) onset, developmental delay, areflexia,
dysmorphology. Later, increased motor
disability, hallucinatory psychosis. Death by
3rd decade
Hereditary neuralgic Autosomal dominant. Episodes of paralysis and Normal or mildly prolonged SEPT9
amyotrophy (brachial muscle weakness initiated by severe pain. MNCVs distal to affected
plexus neuropathy) Onset can be from birth or later childhood brachial plexus
(162100) but usually adult onset. Outcome usually
good but some left with residual dysfunction.
Episodes often triggered by infections,
immunizations, and stress. Some pedigrees
dysmorphic with hypotelorism
HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES
HSN (HSAN) 1 (162400) Type 1: Autosomal dominant. Onset 2nd–5th Normal to low-normal MNCVs, SPTLC1
decade. Predominant loss of pain and disturbance of sensory RAB7
temperature sensation, preservation of conduction of variable severity 3p24–p22
vibration sense, lancinating pain, variable Type 1B: Autosomal dominant.
distal motor involvement Predominantly sensory
neuropathy with cough and
gastroesophageal reflux, rarely
foot ulcers. More often adult
onset. Hearing often abnormal
HSN (HSAN) 2(A) (201300) Autosomal recessive. Onset in infancy/early Normal MNCVs; SNAPs are WNK1
childhood–1st 2 decades. Mutilating absent
acropathy. Often unrecognized fractures.
Marked sensory loss affecting all cutaneous
modalities, most marked distally in all limbs.
Autonomic dysfunction less marked. Absent
or decreased DTRs
HSN (HSAN) 2B (223900) Autosomal recessive. Impaired sensation, FAM134B
ulcers, and arthropathy develop in childhood

HSN (HSAN) 3 (Riley-Day Autosomal recessive. History of neurologic Motor conduction velocities IKBAP
syndrome, familial abnormality and of difficult feeding from usually slightly below control
dysautonomia) (223900) birth. Failure to produce tears regularly. values. Sensory conduction
Absent or reduced DTRs. Absent corneal normal or decreased
reflexes, postural hypotension, emotional
lability. Relative indifference to pain, absence
of fungiform papillae on tongue, absence of
flare with intradermal histamine. Normal
intelligence
HSN (HSAN) 4 (congenital Autosomal recessive. Onset from infancy, often Nerve conduction studies normal. NTRK1
insensitivity to pain with high fevers due to truncal anhidrosis during Sympathetic skin responses are
anhidrosis, CIPA) (256800) hot weather. Painless injuries of extremities absent (histamine test)
and oral structures, often self-mutilation. Lack
of pain sensation, both peripheral and
visceral, inability to distinguish hot and cold.
Preservation of DTRs. Mild mental retardation.
Hyperactivity and emotional lability common
HSN (HSAN) 5 (608654) Autosomal recessive. Onset in early life. Rare Normal motor and sensory nerve NGFβ
disorder. Painless injuries of the extremities. conduction studies
Lack of pain and thermal sensitivity in the
limbs but preservation of response to tactile
and mechanical stimuli. Preservation of
muscle strength and DTRs. Distal anhidrosis.
Bone and joint fractures; arthropathy. Normal
intelligence
*The term CMT3 should be reserved for hereditary neuropathies in which hypomyelination is the dominant feature. This would include congenital hypomyelinating
neuropathy, Dejerine-Sottas disease, and congenital amyelinating neuropathy.
CCFDN, congenital cataract, microcornea, facial dysmorphism, mental retardation, distal motor peripheral neuropathy; CIPA, congenital insensitivity to pain with
anhidrosis; CMAP, compound motor unit action potential; CMT, Charcot-Marie-Tooth disease; CP, common peroneal; CSF, cerebrospinal fluid; dHMN, distal
hereditary motor neuronopathy; DI, dominant intermediate; dSMA, distal spinal muscular atrophy; DTR, deep tendon reflex; EMG, electromyography;
EOHMSN, early-onset HMSN; HMN, hereditary motor neuropathy; HMSN, hereditary motor and sensory neuropathy; HSAN, hereditary sensory and autonomic
neuropathy; HSN, hereditary sensory neuropathy; MNCV, motor nerve conduction velocity; OMIM, Online Mendelian Inheritance in Man; SAP, sensory action
potential; SEOAN, severe early-onset axonal neuropathy; SMA, spinal muscular atrophy; SNAP, sensory nerve action potential.
From Wilmshurst JM, Ouvrier R: Hereditary peripheral neuropathies of childhood: an overview for clinicians, Neuromuscul Disord 21(11):763–775, 2011.
of the molecular genetics of this group of diseases, the diagnosis of CLINICAL MANIFESTATIONS
most can be confirmed by less invasive genetic testing. Electromyog- Most patients are asymptomatic until late childhood or early adoles-
raphy (EMG) remains a useful adjunct to clinical diagnosis and helps cence, but young children sometimes manifest gait disturbance as
distinguish between demyelinating or hypomyelinating and axonal early as the 2nd yr of life. The peroneal and tibial nerves are
forms. the earliest and most severely affected. Children with the disorder are
Classification of HMSNs is difficult because no simple unifying often described as being clumsy, falling easily, or tripping over their
scheme is capable of incorporating all the clinical presentations and own feet. Application of the Cumberland Ankle Instability Tool for
overlapping genetics (see Table 613-1). In some neuropathies, a diverse Youth is a means of objectively documenting and following this mani-
genotype of mutations of different genes at different chromosomal loci festation. The onset of symptoms may be delayed until after the 5th
may produce a similar phenotype. One classification identifies: I. decade.
Hereditary neuropathies secondary to general diseases; II. Primary Muscles of the anterior compartment of the lower legs become
neuropathies as: IIa. Hereditary motor sensory neuropathies; IIb. wasted, and the legs have a characteristic stork-like contour. The mus-
Distal hereditary motor neuropathies; IIc. Hereditary sensory ± auto- cular atrophy is accompanied by progressive weakness of dorsiflexion
nomic neuropathies; III. Syndromic neuropathies including congenital of the ankle and eventual footdrop. The process is bilateral but may be
hypomyelinating neuropathies; and IV. Hereditary sensory neuropathy slightly asymmetric. Pes cavus deformities invariably develop as a
(Refsum disease). result of denervation of intrinsic foot muscles, further destabilizing the
gait. Atrophy of muscles of the forearms and hands is usually not as
severe as that of the lower extremities, but in advanced cases contrac-
613.1 Peroneal Muscular Atrophy (Charcot- tures of the wrists and fingers produce a claw hand. Proximal muscle
Marie-Tooth Disease, Hereditary weakness is a late manifestation and is usually mild. Axial muscles are
not involved.
Motor-Sensory Neuropathy Type IIa) The disease is slowly progressive throughout life, but patients occa-
Harvey B. Sarnat sionally show accelerated deterioration of function over a few years.
Most patients remain ambulatory and have normal longevity, although
Charcot-Marie-Tooth disease is the most common genetically deter- orthotic appliances are required to stabilize the ankles.
mined neuropathy and has an overall prevalence of 3.8/100,000 popu- Sensory involvement mainly affects large myelinated nerve fibers
lation. It is transmitted as an autosomal dominant trait with 83% that convey proprioceptive information and vibratory sense, but the
expressivity; the 17p11.2 locus is the site of the abnormal gene. Auto- threshold for pain and temperature can also increase. Some children
somal recessive transmission also is described but is rarer. The gene complain of tingling or burning sensations of the feet, but pain is rare.
product is peripheral myelin protein 22 (PMP22). A much rarer Because the muscle mass is reduced, the nerves are more vulnerable to
X-linked HMSN type I results from a defect at the Xq13.l locus, causing trauma or compression. Autonomic manifestations may be expressed
mutations in the gap junction protein connexin-32. Other forms have as poor vasomotor control with blotching or pallor of the skin of the
been reported (see Table 613-1). feet and inappropriately cold feet.
Nerves often become palpably enlarged. Tendon stretch reflexes are HMSN type I but more severe. Symptoms develop in early infancy and
lost distally. Cranial nerves are not affected. Sphincter control remains are rapidly progressive, with hypotonia and breathing and feeding dif-
well preserved. Autonomic neuropathy does not affect the heart, gas- ficulties. Pupillary abnormalities, such as lack of reaction to light and
trointestinal tract, or bladder. Intelligence is normal. A unique point Argyll Robertson pupil, are common. Kyphoscoliosis and pes cavus
mutation in PMP22 causes progressive auditory nerve deafness in addi- deformities complicate approximately 35% of cases. Nerves become
tion, but this is usually later in onset than the peripheral neuropathy. palpably enlarged at an early age. Dejerine-Sottas disease is a more
Davidenkow syndrome is a variant of HMSN type I with a scapu- slowly progressive variant with onset usually before age 5 yr.
loperoneal distribution. An autosomal recessive form of congenital hypomyelinating neu-
ropathy also is known and may be caused by various genetic mutations,
LABORATORY FINDINGS AND DIAGNOSIS including MTMR2, PMP22, EGR2, and MPZ. Neonatal hypotonia and
Motor and sensory nerve conduction velocities are greatly reduced, developmental delay in infancy are hallmark clinical features. Many
sometimes as slow as 20% of normal conduction time. In new cases patients exhibit congenital insensitivity to pain. Cranial nerves are
without a family history, both parents should be examined, and nerve inconsistently involved, and respiratory distress and dysphagia are rare
conduction studies should be performed. complications. Tendon reflexes are absent. Arthrogryposis is present
EMG and muscle biopsy are not usually required for diagnosis, but at birth in at least half the cases.
they show evidence of many cycles of denervation and reinnervation. The onion bulb formations seen in the sural nerve biopsy specimen
Serum creatine kinase level is normal. Cerebrospinal fluid (CSF) are pronounced. Hypomyelination also occurs. In the recessive form,
protein may be elevated, but no cells appear in the CSF. hypomyelination may not be accompanied by interstitial hypertrophy
Sural nerve biopsy is diagnostic. Large- and medium-size myelin- in all cases.
ated fibers are reduced in number, collagen is increased, and charac- The genetic locus of 17p11.2 is identical to that of HMSN type I or
teristic onion bulb formations of proliferated Schwann cell cytoplasm Charcot-Marie-Tooth disease. Monoallelic mutations in MPZ (myelin
surround axons. This pathologic finding is called interstitial hypertro- protein zero), PMP22, or EGR2 (early grow response 2) are the most
phic neuropathy. Extensive segmental demyelination and remyelin- frequent genetic causes. The clinical and pathologic differences may be
ation also occur. phenotypical variants of the same disease, analogous to the situation
The definitive molecular genetic diagnosis may be made in blood. in Duchenne and Becker muscular dystrophies. An autosomal reces-
sive form of Dejerine-Sottas disease is incompletely documented.
TREATMENT
Stabilization of the ankles is a primary concern. In early stages, stiff
boots that extend to the midcalf often suffice, particularly when 613.4 Roussy-Lévy Syndrome
patients walk on uneven surfaces such as ice and snow or stones. As Harvey B. Sarnat
the dorsiflexors of the ankles weaken further, lightweight plastic splints
may be custom made to extend beneath the foot and around the back Roussy-Lévy syndrome is defined as a combination of HMSN type II
of the ankle. They are worn inside the socks and are not visible, reduc- and cerebellar deficit resembling Friedreich ataxia, but it does not have
ing self-consciousness. External short-leg braces may be required when cardiomyopathy.
footdrop becomes complete. Surgical fusion of the ankle may be con-
sidered in some cases.
The leg should be protected from traumatic injury. In advanced 613.5 Refsum Disease (Hereditary Sensory
cases, compression neuropathy during sleep may be prevented by Neuropathy Type IV) and Infantile
placing soft pillows beneath or between the lower legs. Burning pares-
thesias of the feet are not common but are often abolished by phe- Refsum Disease
nytoin, carbamazepine, or gabapentin. No medical treatment is Harvey B. Sarnat
available to arrest or slow the progression.
See Chapter 86.2.
Refsum disease is a rare autosomal recessive disease caused by an
613.2 Peroneal Muscular Atrophy enzymatic block in β-oxidation of phytanic acid to pristanic acid. Phy-
tanic acid is a branched-chain fatty acid that is derived mainly from
(Axonal Type) dietary sources: spinach, nuts, and coffee. Levels of phytanic acid are
Harvey B. Sarnat greatly elevated in plasma, CSF, and brain tissue. The CSF shows an
albuminocytologic dissociation, with a protein concentration of
Peroneal muscular atrophy is clinically similar to HMSN type I, but 100-600 mg/dL. Genetic linkage studies identify 2 distinct loci at
the rate of progression is slower and the disability is less. EMG shows 10p13 and 6q22-q24 with PHYH and PEX7 genetic mutations, respec-
denervation of muscle. Sural nerve biopsy reveals axonal degeneration tively. The infantile form also can be caused by PEX1, PEX2, or
rather than the demyelination and whorls of Schwann cell processes PEX26 genes, which produce both clinical and biochemical differences
typical in type I. The locus is on chromosome 1 at 1p35-p36; this is a from the classical form, and include minor facial dysmorphism, reti-
different disease than HMSN type I, although both diseases are trans- nitis pigmentosa, sensorineural hearing loss, hypercholesterolemia,
mitted as autosomal dominant traits. An autosomal recessive infantile hepatomegaly, and failure to thrive. Phytanic acid accumulation in
motor axonal neuropathy can closely mimic infantile spinal muscular infantile Refsum disease is secondary to a primary peroxisomal disor-
atrophy. der; hence autosomal recessive Refsum disease is really a different
disease.
Clinical onset of classical Refsum disease is usually between 4 and
613.3 Congenital Hypomyelinating 7 yr of age, with intermittent motor and sensory neuropathy. Ataxia,
Neuropathy and Dejerine-Sottas progressive neurosensory hearing loss, retinitis pigmentosa with loss
Disease (Hereditary Motor-Sensory of night vision, ichthyosis, and liver dysfunction also develop in various
degrees. Skeletal malformations from birth and cardiac findings of
Neuropathy Type III) conduction disturbances and cardiomyopathy appear in the majority.
Harvey B. Sarnat Motor and sensory nerve conduction velocities are delayed. Sural
nerve biopsy shows loss of myelinated axons. Treatment is by dietary
Congenital hypomyelinating neuropathy is an interstitial hypertrophic management and periodic plasma exchange. With careful manage-
neuropathy of autosomal dominant transmission, clinically similar to ment, life expectancy can be normal.
(carbamazepine, phenytoin, gabapentin, lamotrigine) are effective, as

613.6 Fabry Disease are narcotic and nonnarcotic analgesics. Enzyme replacement therapy
Harvey B. Sarnat has improved the short- and long-term prognosis of the clinical neu-
ropathy and also reverses the increased blood flow velocity in the brain.
See Chapter 86.4.
Fabry disease, a rare X-linked recessive trait, results in storage
of ceramide trihexose because of deficiency of the enzyme ceramide
trihexosidase, which cleaves the terminal galactose from ceramide 613.7 Giant Axonal Neuropathy
trihexose (ceramide-glucose-galactose-galactose), resulting in tissue Harvey B. Sarnat
accumulation of this trihexose lipid in central nervous system neurons,
Schwann cells and perineurial cells, ganglion cells of the myenteric Giant axonal neuropathy is a rare autosomal recessive disease with
plexus, skin, kidneys, blood vessel endothelial and smooth muscle onset in early childhood. It is a progressive mixed peripheral neuropa-
cells, heart, sweat glands, cornea, and bone marrow. It results from a thy and degeneration of central white matter, similar to the leukodys-
missense mutation disrupting the crystallographic structure of trophies. Ataxia and nystagmus are accompanied by signs of progressive
α-galactosidase A. peripheral neuropathy. A large majority of affected children have frizzy
hair, which microscopically shows variation in diameter of the shaft
CLINICAL MANIFESTATIONS and twisting, similar to that in Menkes disease; hence, microscopic
The presentation is in late childhood or adolescence, with recurrent examination of a few scalp hairs provides a simple screening tool in
episodes of burning pain and paresthesias of the feet and lower legs so suspected cases. Focal axonal enlargements are seen in both the
severe that patients are unable to walk. These episodes are often pre- peripheral nervous system and the central nervous system, but the
cipitated by fever or by physical activity. Objective sensory and motor myelin sheath is intact. The disease is a general proliferation of inter-
deficits are not demonstrated on neurologic examination, and reflexes mediate filaments, including neurofilaments in axons, glial filaments
are preserved. Characteristic skin lesions are seen in the perineal (i.e., Rosenthal fibers) in brain, cytokeratin in hair, and vimentin in
region, scrotum, buttocks, and periumbilical zone as flat or raised red- Schwann cells and fibroblasts.
black telangiectases known as angiokeratoma corporis diffusum. Nonsense and missense mutations or deletions occur in the GAN
Hypohidrosis may be present. Corneal opacities, cataracts, and necro- gene, with allelic heterogeneity, at 16q24. These mutations are respon-
sis of the femoral heads are inconstant features. Tortuosity of retinal sible for defective synthesis of the protein gigaxonin, a member of the
vessels and of the vertebral and basilar arteries can occur. The disease cytoskeletal BTB/kelch superfamily, crucial to linkage between inter-
is progressive. Hypertension and renal failure are usually delayed until mediate proteins and the cell membrane. MRI shows white matter
early adult life. Recurrent strokes result from vascular wall involve- lesions of the brain similar to leukodystrophies, and MR spectroscopy
ment. Death often occurs in the 5th decade owing to cerebral infarc- demonstrates increased ratios of choline : creatine and myoinosi-
tion or renal insufficiency, but a significant morbidity already occurs tol : creatine, with a normally preserved ratio of N-acetyl aspartate : cre-
in childhood despite the absence of major organ failure. Heterozygous atine, indicating demyelination and glial proliferation without axonal
female carriers may be asymptomatic or, rarely, are as affected as males; loss. Gigaxonin is expressed in a wide variety of neuronal cell types
corneal opacities involve 70-80%, though cataracts are rare. and is localized to the Golgi apparatus and endoplasmic reticulum.
The diagnosis is established by microscopy of scalp hair and by MRI
LABORATORY FINDINGS and MR spectroscopy of the brain; it is confirmed by sural nerve biopsy
Motor and sensory nerve conduction velocities are normal to only and/or by genetic studies, if available, of the GAN gene. A mutation of
mildly slow, showing preservation of large myelinated nerve fibers. CSF BAG3, one of several genes associated with myofibrillar myopathy (see
protein is normal. Proteinuria is present early in the course. Chapter 608.5), also can cause giant axonal neuropathy as another
Calcifications often are seen in pulvinar of the thalamus, as demon- genetic etiology not associated with the more frequent GAN gene.
strated by CT or MRI and are specific imaging findings, believed
caused by cerebral hyperperfusion. Positron tomography, by contrast,
shows reduced cerebral blood flow velocity and impaired autoregula- 613.8 Tomaculous (Hypermyelinating)
tion because of the glycosphingolipid storage in vascular endothelial Neuropathy; Hereditary Neuropathy
cells.
Pathologic features are usually first detected in skin or sural nerve with Liability to Pressure Palsies
biopsy specimens. Electron microscopy demonstrates crystalline Harvey B. Sarnat
glycosphingolipids, appearing as zebra bodies, in lysosomes of endo-
thelial cells, in smooth myocytes of arterioles, and in Schwann This hereditary neuropathy is characterized by redundant overproduc-
cells. Nerves show a selective loss of small myelinated fibers and tion of myelin around each axon in an irregular segmental fashion so
relative preservation of large and medium-sized axons, contrasting to that tomaculous (sausage-shaped) bulges occur in the individual
most axonal neuropathies in which large myelinated fibers are most myelinated nerve fibers. Other sections of the same nerve can show
involved. loss of myelin. Such nerves are particularly prone to pressure palsies,
Assay for the deficient enzyme, α-galactosidase-A, may be per- and patients, usually beginning in adolescence, present with recurrent
formed from skin fibroblasts, leukocytes, and other tissues. This test or intermittent mononeuropathies secondary to minor trauma or
permits detection of the female carrier state and provides a reliable entrapment neuropathies, such as carpal tunnel syndrome, peroneal
means of prenatal diagnosis. palsies, and even “writer’s cramp.” It is transmitted as an autosomal
dominant trait, with loci identified at 17p11.2 and 17p12, deletion
TREATMENT of exons in the PMP22 gene, in some patients only microdeletions.
See Chapter 86.4 for specific therapy of Fabry disease, including Duplication of the same 17p12 locus leads to Charcot-Marie-Tooth
enzyme replacement. disease type 1A, myelin protein zero (MPZ) gene mutation. Sural nerve
Medical therapy of painful neuropathies includes management of biopsy is diagnostic, but special teased fiber preparations should be
the initiating disease and therapy directed to the neuropathic pain made to demonstrate the myelin abnormalities most clearly. Skin or
independent of etiology. Pain may be burning or associated with par- conjunctival biopsies also may be diagnostic. Electrophysiologic nerve
esthesia, hyperalgesia (abnormal response to noxious stimuli), or allo- conduction studies are abnormal but nonspecific. Genetic studies are
dynia (induced by non–noxious stimuli; see Chapter 62). Neuropathic definitive.
pain is often successfully managed by tricyclic antidepressants; selec- Treatment is supportive and includes avoiding trauma and pro-
tive serotonin reuptake inhibitors are less effective. Anticonvulsants longed nerve compression, including postures when sitting or lying.
Surgical release of entrapped nerves is indicated at times, particularly
of the ulnar nerve.
613.9 Leukodystrophies
Harvey B. Sarnat
Several hereditary degenerative diseases of white matter of the central

nervous system also cause peripheral neuropathy. The most important
are Krabbe disease (globoid cell leukodystrophy), metachromatic leu-
kodystrophy, and adrenoleukodystrophy (see Chapters 86 and 599).

Chapter 613 ◆ Hereditary Motor-Sensory Neuropathies 3006.e1
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Boyer O, Nevo F, Plaisier E, et al: INF2 mutations in Charcot-Marie-Tooth disease patient with Charcot-Marine-Tooth neuropathy, N Engl J Med 362(13):1181–
with glomerulopathy, N Engl J Med 365:2377–2388, 2011. 1190, 2010.
Bruno C, Bertini E, Federico A, et al: Clinical and molecular findings in patients Mandarakas M, Hiller CE, Rose KJ, et al: Measuring ankle instability in paediatric
with giant axonal neuropathy (GAN), Neurology 62:13–16, 2004. Charcot-Marie-Tooth disease, J Child Neurol 28:1456–1462, 2013.
Chance PF: Inherited focal, episodic neuropathies: hereditary neuropathy with Mendell JR, Sahenk Z: Painful sensory neuropathy, N Engl J Med 348:1243–1255,
liability to pressure palsies and hereditary neuralgic amyotrophy, 2003.
Neuromolecular Med 8:159–174, 2006. Moore DF, Altarescu G, Ling GS, et al: Elevated cerebral blood flow velocities in
Dierick I, Baets J, Irobi J, et al: Relative contribution of mutations in genes for Fabry disease with reversal after enzyme replacement, Stroke 33:525–531, 2002.
autosomal dominant distal hereditary motor neuropathies: a genotype- Pleasure D: New treatments for denervating diseases, J Child Neurol 20:258–262,
phenotype correlation study, Brain 131:1217–1227, 2008. 2005.
Evgrafov OV, Mersiyanova I, Irobi J, et al: Mutant small heat-shock protein 27 Ries M, Gupta S, Moore DF, et al: Pediatric Fabry disease, Pediatrics 115:344–355,
causes axonal Charcot-Marie-Tooth disease and distal hereditary motor 2005.
neuropathy, Nat Genet 36:602–606, 2004. Seithi PK, Khandelwal D, Sethi NK, et al: Hereditary infantile motor axonal
Fellgiebel A, Keller I, Marin D, et al: Diagnostic utility of different MRI and MR neuropathy mimicking SMA: a case report, J Pediatr Neurol 7:175–179, 2009.
angiography measures in Fabry’s disease, Neurology 72:63–68, 2009. Smit LS, Roofthooft D, van Ruissen F, et al: Congenital hypomyelinating
Gordon N: Giant axonal neuropathy, Dev Med Child Neurol 46:717–719, 2004. neuropathy, a long-term follow-up study in an affected family, Neuromuscul
Houlden H, Reilly MM: Molecular genetics of autosomal-dominant demyelinating Disord 18:59–62, 2008.
Charcot-Marie-Tooth disease, Neuromolecular Med 8:43–62, 2006. Tachi N, Kozuka N, Ohya K, et al: Tomaculous neuropathy in Charcot-Marie-
Jaffer F, Murphy SM, Scoto M, et al: BAG3 mutations: another cause of giant Tooth disease with myelin protein zero gene mutation, J Neurol Sci 153:106–
axonal neuropathy, J Peripher Nerv Syst 17:210–216, 2012. 109, 1997.
Kim GH, Kim KM, Suh S, et al: Charcot-Marie-Tooth disease masquerading as Taggart TF, Allen TR: Surgical treatment of a tomaculous neuropathy, J R Coll Surg
acute demyelinating encephalomyelitis-like illness, Pediatrics 134:e270–e273, Edinb 46:240–241, 2001.
2014. Taioli F, Cabrini I, Cavallaro T, et al: Inherited demyelinating neuropathies with
Kovach MJ, Lin JP, Boyadjiev S, et al: A unique point mutation in the PMP22 gene micromutations of peripheral myelin protein 22 gene, Brain 134(Pt 2):608–617,
is associated with Charcot-Marie-Tooth disease and deafness, Am J Hum Genet 2011.
64:1580–1593, 1999. Yagerman SE, Cross MB, Green DW, et al: Pediatric orthopedic conditions in
Landouré G, Zdebik AA, Martinez TL, et al: Mutations in TRPV4 cause Charcot-Marie-Tooth disease: a literature review, Curr Opin Pediatr 24:50–56,
Charcot-Marie-Tooth disease type 2C, Nat Genet 42(2):170–174, 2010. 2012.
Landrieu P, Baets J, de Jonghe P: Hereditary motor-sensory, motor, and sensory
neuropathies in childhood, Handb Clin Neurol 113:1413–1432, 2013.
Table 614-1 Toxic and Metabolic Neuropathies
METALS Nitrofurantoin
Arsenic (insecticide, herbicide) Nitrous oxide
Lead (paint, batteries, pottery) Nucleosides (antiretroviral
Mercury (metallic, vapor) agents dideoxycytidine [ddC],
Thallium (rodenticides) didanosine [ddI], d4T, others)
Gold Penicillamine
Pentamidine
OCCUPATIONAL OR Phenytoin
INDUSTRIAL CHEMICALS Pyridoxine (excessive)
Acrylamide (grouting, Statins
flocculation) Stilbamidine
Carbon disulfide (solvent) Suramin
Cyanide Tacrolimus
Dichlorophenoxyacetate Taxanes (paclitaxel, docetaxel)
Dimethylaminopropionitrite Thalidomide
Ethylene oxide (gas sterilization) Tryptophan (eosinophilia-
Hexacarbons (glue, solvents) myalgia syndrome)
Organophosphates (insecticides, Vincristine
petroleum additive)
Chapter 614 Polychlorinated biphenyls
Tetrachlorbiphenyl
METABOLIC DISORDERS
Fabry disease
Toxic Neuropathies Trichloroethylene

DRUGS
Krabbe disease
Leukodystrophies
Porphyria
Amiodarone
Harvey B. Sarnat Chloramphenicol
Tangier disease
Tyrosinemia
Chloroquine Uremia
Cisplatin
Colchicine BIOLOGIC AND INFECTIOUS
Many chemicals (organophosphates), toxins, and drugs can cause Dapsone NEUROPATHIES
Ethambutol Diphtheria
peripheral neuropathy (Table 614-1). Heavy metals are well-known
Ethanol Herpesviruses
neurotoxins. Lead poisoning, especially if chronic, causes mainly a Fluoroquinolones HIV
motor neuropathy selectively involving large nerves, such as the Gold Leprosy
common peroneal, radial, and median nerves, a condition known as Hydralazine Lyme disease
mononeuritis multiplex (see Chapter 721). Arsenic produces painful Isoniazid Rabies
burning paresthesias and motor polyneuropathy. Exposure to indus- Metronidazole West Nile virus
trial and agricultural chemicals is a less-common cause of toxic neu-
ropathy in children than in adults, but insecticides are neurotoxins for
both insects and humans, and if they are used as sprays in closed spaces, is particularly prevalent in children in several African countries,
they may be inhaled and induce lethargy, vomiting, seizures, and neu- including those who immigrate to western countries as refugees. Tick
ropathy, particularly with recurrent or long-term exposure. Working paralysis, botulism, and paralytic shellfish poisoning cause neuromus-
adolescents and children in developing countries are also at risk. Puffer cular junction blockade rather than true neuropathy. Various
fish poisoning, which can be acquired even when fish contaminated inborn errors of metabolism are also associated with peripheral
with the venom has been cooked, produces a Guillain-Barré–like syn- neuropathy from metabolite toxicity or deficiencies (see Part XI
drome. Ethanol abuse can be neurotoxic and particularly affects the and Table 614-1).
optic nerves, but optic neuritis is not a true peripheral neuropathy.
The most frequent cause of toxic neuropathies in children is pre- Bibliography is available at Expert Consult.
scribed medications, though street drugs also can be neurotoxic. Anti-
metabolic and immunosuppressive drugs, such as vincristine, cisplatin,
and paclitaxel, produce polyneuropathies as complications of chemo-
therapy for neoplasms and immunologic disorders, such as juvenile
idiopathic arthritis. This “iatrogenic” cause is usually an axonal degen-
eration rather than primary demyelination, unlike primary autoim-
mune neuropathies. Excessive vitamin intake (“megavitamins”) can be
neurotoxic.
Chronic uremia is associated with toxic neuropathy and myopathy.
The neuropathy is caused by excessive levels of circulating parathyroid
hormone. Reduction in serum parathyroid hormone levels is accom-
panied by clinical improvement and a return to normal of nerve con-
duction velocity. Peripheral nerve axonal damage, particularly of small
fibers, can be secondary to mitochondrial loss or dysfunction in toxic
neuropathies. Abnormal toxic complex lipids, generated in Schwann
cells by deficient mitochondrial respiration, are capable of damaging
or destroying neighboring axons, a secondary mitochondrial toxic
neuropathy. Small heat-shock proteins can be provoked that also may
contribute to toxic neuropathy.
Biologic neurotoxins associated with diphtheria, Lyme disease, West
Nile virus disease, leprosy, herpesviruses (Bell palsy), and rabies also
produce peripheral nerve– or ventral horn cell–induced weakness or
paralysis. HIV infections also produce neuropathy and this infection
3006.e2 Chapter 614 ◆ Toxic Neuropathies
Bibliography taken by mouth or by injection, Posted 8–15, 2013. Available at: http://
De Weerdt A, Claeys KG, De Jonghe P, et al: Tacrolimus-related polyneuropathy: www.fda.gov/downloads/Drugs/DrugSafety/UCM365078.pdf.
case report and review of the literature, Clin Neurol Neurosurg 110:291–294, Grisold W, Cavaletti G, Windebank AJ: Peripheral neuropathies from
2008. chemotherapeutics and targeted agents: diagnosis, treatment, and prevention,
Diezi M, Buclin T, Kuntzer T: Toxic and drug-induced peripheral neuropathies: Neuro-Oncol 14(Suppl 4):iv45–iv54, 2012.
updates on causes, mechanisms and management, Curr Opin Neurol 26:481– Kushlaf HA: Emerging toxic neuropathies and myopathies, Psychiatr Clin North
488, 2013. Am 36:209–218, 2013.
Di Paolo G, Przedborski S: When Schwann cells conspire with mitochondria, Morrison B, Chaudhry V: Medication, toxic, and vitamin-related neuropathies,
neighboring axons are under attack by glia-derived neurotoxic lipids, Neuron Continuum (Minneap Minn) 18:139–160, 2012.
77:801–803, 2013. Sindic CJ: Infectious neuropathies, Curr Opin Neurol 26:510–515, 2013.
Federal Drug Administration: FDA requires label changes to warn of risk for
possibly permanent nerve damage from antibacterial fluoroquinolone drugs
Chapter 615
Autonomic Neuropathies
Harvey B. Sarnat
Involvement of small, lightly or unmyelinated autonomic nerve fibers

may be seen in many peripheral neuropathies; the autonomic manifes-
tations are usually mild or subclinical. Certain autonomic neuropathies
are more symptomatic and demonstrate varying degrees of involve-
ment of the autonomic nervous system regulation of the cardiovascu-
lar, gastrointestinal, genitourinary, thermoregulatory, sudomotor, and
pupillomotor systems. Figure 615-1 shows the classification of auto-
nomic disorders (dysautonomias).
The differential diagnosis is noted in Tables 613-1 (in Chapter
613) and 615-1; Table 615-2 compares the neonatal-infantile onset
Chapter 615 ◆ Autonomic Neuropathies 3007
Dysautonomia
Structural Functional
Peripheral Central
Postural Reflex
Afferent Efferent tachycardia syncope
Multiple system
atrophy
Shy-Drager
Pure Interstitial Irritable bowel
Baroreflex
autonomic cystitis syndrome
failure
failure
Parkinson or
Lewy body
Complex
disease Fibromyalgia
regional pain
HSAN III Small fiber
(familial neuropathy
dysautonomia) Myelopathy
Functional Cyclic vomiting
GI disorders syndrome
Central
Diabetes Immune autonomic Migraine
network stroke Raynaud
headache
Genetic Metabolic
Genetic: Chronic fatigue Syncopal

Inflammatory Mitochondrial Rett CCHS syndrome migraine
Figure 615-1 Classification of autonomic disorders or dysautonomias. The first conceptual division is between a structural and functional disorder.
The word “functional” is being used in its true meaning of a disturbance in autonomic function, without clear evidence of structural damage to
the autonomic nervous system, akin to the use of the word “functional” in functional gastrointestinal disorders, and without implication of a psy-
chiatric etiology. In the absence of any evidence of consistent structural abnormalities functional disorders clearly cannot be localized in the nervous
system. In contrast, structural disorders can be further divided into those localized in the central and peripheral nervous systems, with the division
point usually taken at the sympathetic ganglion. Finally, peripheral nervous system disorders can be further classified based on whether they
primarily involve afferent or efferent nerves. It should be emphasized that there is overlap between these groups, for example, diabetes will often
involve afferent nerve fibers, but this classification emphasizes the predominant fiber involvement. A dotted line links Parkinson disease to a
peripheral efferent group as Lewy bodies are present in the both parasympathetic and sympathetic ganglia, impairing peripheral autonomic func-
tion. See below for discussion of specific disorders. CCHS, Congenital central hypoventilation syndrome; HSAN, hereditary sensory autonomic
neuropathy. (From Chelimsky T, Robertson D, Chelimsky G: Disorders of the autonomic nervous system. In Daroff RB, Fenichel GM, Jankovic J,
Mazziotta JC, editors: Bradley’s neurology in clinical practice, ed 6, Philadelphia, 2012, WB Saunders, Fig. 77-1, p. 2018.)
Table 615-1 Autonomic Neuropathies

Guillain-Barré syndrome (see Chapter 608) Metabolic
Non–Guillain-Barré syndrome autoimmunity • Fabry disease
• Paraneoplastic (type I antineuronal nuclear antibody) • Diabetes mellitus
• Lambert-Eaton syndrome • Tangier disease
• Antibodies to neuronal nicotinic acetylcholine receptors • Porphyria
• Antibodies to P/Q-type calcium channels Infectious
• Other autoantibodies • HIV
• Systemic lupus erythematosus • Chagas disease
Hereditary sensory and autonomic neuropathies • Botulism
• Type I autosomal dominant • Leprosy
• Type II autosomal recessive (Morvan disease) • Diphtheria
• Type III autosomal recessive (Riley-Day) Other
• Type IV autosomal recessive (congenital insensitivity to pain with • Triple A (Allgrove) syndrome
anhidrosis) • Navajo Indian neuropathy
• Type V absence of pain • Multiple endocrine neoplasia type 2b
Toxins (see Table 614-1 in Chapter 614)
Table 615-2 Major Clinical Features of Hereditary Sensory-Autonomic Neuropathy Types II, III, and IV
CLINICAL FEATURES HSAN TYPE II HSAN TYPE III HSAN TYPE IV
Onset Birth Birth Birth
Initial symptoms (from birth to age Swallowing problems Swallowing problems Fevers
3 yr)
Self-mutilation (65%) Aspiration pneumonia Self-mutilation (88%)
Delayed development Breech presentation (37%)
Hypothermia
Delayed development
Unique features No axon flare No axon flare No axon flare
Lack of fungiform papilla Lack of fungiform papilla Anhidrosis
Hearing loss (30%) Alacrima Consanguinity 50%
Sensory dysfunction
Depressed deep tendon reflexes Frequent (71%) Almost consistent (99%) Infrequent (9%)
Pain perception Absent Mild to moderate decrease Absent
Temperature perception Severe decrease Mild to moderate decrease Absent
Vibration sense Normal Normal Normal to moderate decrease
Autonomic
Gastroesophageal reflux Frequent (71%) Frequent (67%) Uncommon (24%)
Postural hypotension Uncommon (25%) Almost consistent (99%) Uncommon (29%)
Episodic hypertension Rare Frequent Rare
Ectodermal features
Dry skin No No Consistent
Fractures 29% 40% 71%
Scoliosis 59% 85% 23%
Intelligence
IQ <65 Common (38%) Uncommon (10%) Common (33%)
Hyperactivity Common (41%) Uncommon Common (54%)
Frequency definitions: rare = <1%; infrequent = <10%; uncommon = <30%; common = 30-65%; frequent = >65%.
From Axelrod FB, Gold-von Simson G: Hereditary sensory and autonomic neuropathies: types II, III, and IV, Orphanet J Rare Dis 2:39, 2007, Table 2.
Table 615-3 Autonomic Function Testing Table 615-4 Management of Autonomic Neuropathies
Sympathetic and parasympathetic divisions of the autonomic PROBLEM TREATMENT
nervous system are involved in all tests of autonomic function
Orthostatic Volume and salt supplements
CARDIAC PARASYMPATHETIC NERVOUS SYSTEM FUNCTION hypotension Fluorohydrocortisone (mineralocorticoid)
Heart rate variability with deep respiration (respiratory sinus Midodrine (α agonist)
arrhythmia); time-domain and frequency-domain assessments
Heart rate response to Valsalva maneuver Gastroparesis Prokinetic agents (metoclopramide,
Heart rate response to standing domperidone, erythromycin)
SYMPATHETIC ADRENERGIC FUNCTION Hypomotility Fiber, laxatives

Blood pressure response to upright posture (standing or tilt table) Urinary dysfunction Timed voiding; bladder catheterization
Blood pressure response to Valsalva maneuver
Microneurography Hyperhidrosis Anticholinergic agents (glycopyrrolate,
propantheline)
SYMPATHETIC CHOLINERGIC FUNCTION Intracutaneous botulism toxin
Thermoregulatory sweat testing
Quantitative sudomotor-axon reflex test
Sweat imprint methods
Sympathetic skin response
From Freeman R: Autonomic peripheral neuropathy, Lancet 365:1259–1270,
2005. 615.1 Familial Dysautonomia
Harvey B. Sarnat
Familial dysautonomia (Riley-Day syndrome) is an autosomal reces-

hereditary sensory-autonomic neuropathies (HSANs). Table 615-3 sive disorder that is common in Eastern European Jews, among whom
lists autonomic nervous system functional tests. The general treatment the incidence is 1 in 10,000-20,000, and the carrier state is estimated
of acquired autonomic dysfunction includes treating the primary dis- to be 1%. It is rare in other ethnic groups but is the most common
order (systemic lupus erythematosus, diabetes) and long-term man- HSAN. The defective gene is at the 9q31-q33 locus. The familial dys-
agement of specific organ system manifestations (Table 615-4). Acute autonomia gene is identified as IKBKAP (IκB kinase–associated
fluctuations of autonomic symptoms may be seen in Guillain-Barré protein), with aberrant splicing and a truncated protein (see Table
syndrome. Rapid fluctuations of hypertension or tachycardia changing 615-2). This and other autonomic neuropathies are often regarded as
to hypotension or bradycardia should be managed carefully and with neurocristopathies because the abnormal target tissues are largely
very short-acting medications. derived from neural crest.
Chapter 615 ◆ Autonomic Neuropathies 3009
in the 1st 5 yr of life. Episodic arterial hypertension and hypotension

may be related to loss of baroreceptor modulation of muscle vasocon-
strictor drive, and an acute fall in blood pressure manifests as ortho-
static hypotension. Chronic and progressive renal disease may result
from renal hypoperfusion. Responses to hypoxia are reduced.
As affected children become older, insensitivity to pain becomes
evident and traumatic injuries are frequent. Pain and temperature sen-
sation is reduced but is not as severe as in other HSANs (see Table
615-2). Corneal ulcerations are common partly as a result of decreased
corneal reflexes and perhaps because of alacrima (absence of tears with
emotional crying), which is a universal finding. Newly erupting teeth
cause tongue ulcerations and, in older children, dental trauma and oral
soft tissue mutilation may be prominent. Walking is delayed or clumsy
or appears ataxic because of poor sensory feedback from muscle spin-
A
dles. The ataxia is probably related more to deficient muscle spindle
feedback and to vestibular nerve dysfunction than to cerebellar involve-
ment, but defective ocular saccades also may indicate cerebellar dys-
function and cerebellar atrophy. Tendon stretch reflexes are absent.
Scoliosis or kyphosis is a serious complication in the majority of
patients and usually is progressive. Overflow tearing with crying does
not normally develop until 2-3 mo of age but fails to develop after that
time or is severely reduced or absent in children with familial dysau-
tonomia. There is an increased incidence of urinary incontinence. Bra-
dycardia and other cardiac arrhythmias can occur, and some patients
require a cardiac pacemaker.
Approximately 40% of patients have generalized major motor sei-
zures; some of these are associated with acute hypoxia during breath-
holding and some with extreme fevers, but most do not have an
apparent precipitating event. Body temperature is poorly controlled;
B both hypothermia and extreme fevers occur. Impaired intellectual
Figure 615-2 A, Normal tongue with fungiform papillae present on function is not secondary to epilepsy. Emotional lability and learning
the tip. B, Dysautonomic tongue. Note the absence of the highly vas- disabilities are common in school-age children with the disorder.
cularized fungiform papillae from the tongue tip, which gives the Puberty is often delayed, especially in girls. Short stature can occur, but
appearance of a smooth tongue. (From Axelrod FB, Gold-von Simson growth velocity can be accelerated by treatment with growth hormone.
G: Hereditary sensory and autonomic neuropathies: types II, III, and IV, Speech is often slurred or nasal.
Orphanet J Rare Dis 2:39, 2007, Fig. 4.) After 3 yr of age, autonomic crises begin, usually with attacks of
cyclic vomiting lasting 24-72 hr or even several days. Retching and
vomiting occur every 15-20 min and are associated with hypertension,
profuse sweating, blotching of the skin, apprehension, and irritability.
Prominent gastric distention can occur, causing abdominal pain and
PATHOLOGY even respiratory distress. Hematemesis can complicate pernicious
This disease of the peripheral nervous system is characterized patho- vomiting. Activation of dopamine receptors may explain the cyclic
logically by a reduced number of small unmyelinated nerve fibers that vomiting and retching.
carry pain, temperature, and taste sensations and that mediate auto- Allgrove syndrome (triple A syndrome) is a clinical variant,
nomic functions including baroreceptors. Large myelinated afferent involving early-onset alacrima, feeding difficulties and achalasia, auto-
nerve fibers that relay impulses from muscle spindles and Golgi tendon nomic dysfunction with orthostatic hypotension, altered heart rate
organs also are deficient. The degree of demonstrable anatomic change variability, hyperreflexia, ataxia, muscle weakness, sensorimotor
in peripheral and especially autonomic nerves is variable. Optic neu- polyneuropathy, and adrenocorticotropic hormone–resistant adrenal
ropathy with predominant loss of papillomacular nerve fibers may insufficiency (develops in 1st decade). The gene AAAS (alacrima-
impair visual acuity. Fungiform papillae of the tongue (taste buds) are achalasia-adrenal insufficiency neurologic disorder) is located on
absent or reduced in number (Fig. 615-2). The number of parasympa- chromosome 12q13.
thetic ganglion cells in the myenteric plexuses is reduced. There is
terminal vessel hyperperfusion in tissues, despite an overall hypoperfu- LABORATORY FINDINGS
sion of organs and extremities. Electrocardiography discloses prolonged corrected QT intervals with
lack of appropriate shortening with exercise, a reflection of the aber-
CLINICAL MANIFESTATIONS ration in autonomic regulation of cardiac conduction. Chest radio-
Clinical manifestations are highly variable between individuals. The graphs show atelectasis and pulmonary changes resembling cystic
disease is expressed in infancy by poor sucking and swallowing. Aspi- fibrosis. Urinary vanillylmandelic acid level is decreased, and the
ration pneumonia can occur. Feeding difficulties with oral incoordina- homovanillic acid level is increased. Plasma level of dopamine
tion is a major symptom throughout childhood. Vomiting crises can β-hydroxylase (the enzyme that converts dopamine to epinephrine)
occur, and indeed nausea, retching, and hyperemesis (dysautonomic is diminished. Sural nerve biopsy shows a decreased number of
crisis) are the most disabling symptoms in some children. Apart from unmyelinated fibers. Electroencephalography is useful for evaluating
dysphagia, esophageal dysmotility can contribute to these symptoms. seizures.
Episodic somnolence can occur in infants, as does hypotonia. Exces-
sive sweating and blotchy erythema of the skin are common, especially DIAGNOSIS
at mealtime or when the child is excited. Infants are vulnerable to Slow IV infusion of norepinephrine produces an exaggerated pressor
heatstroke. Episodic hyperhidrosis is caused by chemical hypersensi- response. The hypotensive response to infusion of methacholine is
tivity of the remaining sudomotor axons rather than of the sweat gland increased. Intradermal injection of 1 : 1,000 histamine phosphate fails
secretory cells. Breathholding spells followed by syncope are common to produce a normal axon flare, and local pain is absent or diminished.
Because the skin of a normal infant reacts more intensely to histamine, Chapter 613.3). The sympathetic skin response as an electrophysiologic
a 1 : 10,000 dilution should be used. Instillation of 2.5% methacholine study is a reliable diagnostic test in cases associated with a mutation
into the conjunctival sac produces miosis in patients with familial in the TrKA receptor for nerve growth factor.
dysautonomia and no detectable effect on a normal pupil; this is a
nonspecific sign of parasympathetic denervation from any cause. REFLEX SYMPATHETIC DYSTROPHY
Methacholine is applied to only 1 eye in this test, with the other eye Reflex sympathetic dystrophy is a form of local causalgia, usually
serving as a control; the pupils are compared at 5 min intervals for involving a hand or foot but not corresponding to the anatomic distri-
20 min. The combination of alacrima, absent fungiform papillae, bution of a peripheral nerve (see Chapter 168.2). A continuous burning
decreased patellar reflexes, and an abnormal histamine test with Ash- pain and hyperesthesia are associated with vasomotor instability in the
kenazi Jewish lineage is diagnostic. Because of variable expression and affected zone, resulting in increased skin temperature, erythema, and
potential overlap with other HSANs, genetic testing should be used to edema caused by vasodilation and hyperhidrosis. In the chronic state,
confirm the diagnosis. atrophy of skin appendages, cool and clammy skin, and disuse atrophy
of underlying muscle and bone occur. More than 1 extremity is occa-
TREATMENT sionally involved. The pain is disabling and is exacerbated by the move-
Symptomatic treatment includes special attention to the respiratory ment of an associated joint, although no objective signs of arthritis are
and gastrointestinal systems to prevent aspiration and malnutrition, seen; immobilization provides some relief. The most common preced-
methylcellulose eyedrops or topical ocular lubricants to replace tears ing event is local trauma in the form of a contusion, laceration, sprain,
and prevent corneal ulceration, orthopedic management of scoliosis or fracture that occurred days or weeks earlier.
and joint problems, and appropriate anticonvulsants for epilepsy. Several theories of pathogenesis have been proposed to explain
Chlorpromazine is an effective antiemetic and may be given as rectal this phenomenon. The most widely accepted is reflexive overactivity
suppositories during autonomic crises; however, clonidine may be of autonomic nerves in response to injury, and regional sympathetic
more effective. It also reduces apprehension and lowers the blood pres- blockade often affords temporary relief. Physiotherapy also is helpful.
sure. Diazepam has also been effective in some cases. Dehydration and Some cases resolve spontaneously after weeks or months, but others
electrolyte disturbances should be anticipated. A more specific and continue to be symptomatic and require sympathectomy. A psy-
promising approach is the administration of carbidopa, an inhibitor of chogenic component is suspected in some cases but is difficult to
dopa-decarboxylase, particularly for the hyperemesis that is so promi- prove.
nent and disabling in many patients. Blockers of dopamine receptors
are alternative drugs for cyclic vomiting. It is also useful for enuresis, Bibliography is available at Expert Consult.
another common complication, and augments tear production.
Protection from injuries is important because of the lack of pain as a
protective mechanism. Scoliosis often requires surgical treatment.
Antiepileptic drugs may be required. A cardiac pacemaker may be
required by some children. Blood pressure monitoring may be impor-
tant in some cases. A promising genetic approach to treatment, which
corrects the splicing defect, is the use of oral kinetin to regulate the
expression of IKBKAP transcripts. Specific compounds identified from
stem cells obtained from dysautonomia patients provide a potential
therapy to rescue IKBKAP expression.
PROGNOSIS
Sixty percent of patients die in childhood before the age of 20 yr,
usually of chronic pulmonary failure or aspiration. Treatment in a
center familiar with the diverse complications greatly extends the life
expectancy; some have survived to age 40 yr. Prevention of aspiration
with fundoplication, gastrostomy, and tube feeding reduces the risk of
aspiration. Newer measures to better control vasomotor stability and
vomiting improve the quality of life, but whether they change longevity
is not yet known.
615.2 Other Autonomic Neuropathies

Harvey B. Sarnat
CONGENITAL INSENSITIVITY TO PAIN

AND ANHIDROSIS
Congenital insensitivity to pain and anhidrosis is an autosomal reces-
sive disorder HSAN type IV (see Table 615-2). Onset is in infancy.
Patients have episodes of extreme fevers related to warm environmen-
tal temperatures because they have absent or reduced sweating. Fre-
quent burns and traumatic injuries result from apparent lack of pain
perception. Poor healing of fractures occurs, as does osteomyelitis.
Neonatal hypotonia improves with growth but learning problems may
develop. Intelligence is normal. Nerve biopsy reveals an almost total
absence of unmyelinated nerve fibers that convey impulses of pain,
temperature, and autonomic functions. Some cases of hypomyelinating
neuropathy manifest clinically as congenital insensitivity to pain (see
Chapter 615 ◆ Autonomic Neuropathies 3010.e1
Bibliography Mendoza-Santiesteban CE, Hedges TR III, Norcliffe-Kaufmann L, et al: Clinical

Axelrod FB, Chelimsky GG, Weese-Meyer DE: Pediatric autonomic disorders, neuro-ophthalmic findings in familial dysautonomia, J Neuroophthalmol
Pediatrics 118:309–321, 2006. 32:23–26, 2012.
Axelrod FB, Gold-von Simson G: Hereditary sensory and autonomic neuropathies: Norcliffe-Kaufmann LJ, Axelrod FB, Kaufmann H: Cyclic vomiting associated with
types II, III, and IV, Orphanet J Rare Dis 2:39, 2007. excessive dopamine in Riley-Day syndrome, J Clin Gastroenterol 47:136–138,
Axelrod FB, Rolnitzky L, Gold-von Simson G, et al: A rating scale for the 2013.
functional assessment of patients with familial dysautonomia (Riley Day Norcliffe-Kaufmann LJ, Axelrod FB, Kaufmann H: Developmental abnormalities,
syndrome), J Pediatr 161:1160–1165, 2012. blood pressure variability and renal disease in Riley-Day syndrome, J Hum
Freeman R: Autonomic peripheral neuropathy, Lancet 365:1259–1270, 2005. Hypertens 27:51–55, 2013.
Gold-Von Simson G, Rutkowski M, Berlin D, et al: Pacemakers in patients with Norcliffe-Kaufmann LJ, Martínez J, Axelrod FB, et al: Hyperdopaminergic crises in
familial dysautonomia—a review of experience with 20 patients, Clin Auton Res familial dysautonomia: a randomized trial of carbidopa, Neurology 80:1611–
15:15–20, 2005. 1617, 2013.
Kamboj MK, Axelrod FG, David R, et al: Growth hormone treatment in children Rubin BY, Anderson SL: The molecular basis of familial dysautonomia: overview,
with familial dysautonomia, J Pediatr 144:63–67, 2004. new discoveries and implications for directed therapies, Neuromolecular Med
Lee G, Ramírez CN, Kim H, et al: Large-scale screening using familial 10:148–156, 2008.
dysautonomia-induced pluripotential stem cells identifies compounds that
rescue IKBKAP expression, Nat Biotechnol 30:1244–1248, 2012.
Macefield VG, Norcliffe-Kaufmann LJ, Axelrod FB, et al: Cardiac-locked bursts of
muscle sympathetic nerve activity are absent in familial dysautonomia, J Physiol
591(Pt 3):689–700, 2013.
3010.e2 Chapter 615 ◆ Autonomic Neuropathies
Bibliography Milenkovic T, Zdravkovic D, Savic N, et al: Triple A syndrome: 32 years experience

England JD, Gronseth GS, Franklin G, et al: Practice parameter: evaluation of of a single centre (1977-2008), Eur J Pediatr 169:1323–1328, 2010.
distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and Oaklander AL, Klein MM: Evidence of small-fiber polyneuropathy in unexplained
skin biopsy (an evidence-based review), Neurology 72:177–184, 2009. juvenile-onset, widespread pain syndromes, Pediatrics 131:e1091–e1100, 2013.
Gold-Von Simson G, Goldberg JD, Rolnitzky LM, et al: Kinetin in familial van den Bosch GE, Baartmans MGA, Vos P, et al: Pain insensitivity syndrome
dysautonomia carriers: implication for a new therapeutic strategy targeting misinterpreted as inflicted burns, Pediatrics 133:e1381–e1387, 2014.
mRNA splicing, Pediatr Res 65:341–346, 2009.
Chapter 616
Guillain-Barré Syndrome
Harvey B. Sarnat
Guillain-Barré syndrome is an autoimmune disorder often considered

a postinfectious polyneuropathy involving mainly motor but also
sensory and sometimes autonomic nerves. This syndrome affects
people of all ages and is not hereditary. Most patients in the United
States and Europe have a demyelinating neuropathy, but primarily
axonal degeneration is documented in some cases, mainly in China,
Mexico, Bangladesh, and Japan.
The paralysis usually follows a nonspecific gastrointestinal or respira-
tory infection by approximately 10 days. The original infection might
have caused only gastrointestinal (especially Campylobacter jejuni, but
also Helicobacter pylori) or respiratory tract (especially Mycoplasma
pneumoniae) symptoms. Consumption of undercooked poultry,
unpasteurized milk, and contaminated water are the main sources of
gastrointestinal infections. West Nile virus also can mimic Guillain-
Barré–like syndrome, but more often it causes motor neuron disease
similar to poliomyelitis. Guillain-Barré syndrome is reported follow-
ing administration of vaccines against rabies, influenza, and poliomy-
elitis (oral) and following administration of conjugated meningococcal
vaccine, particularly serogroup C. Additional infectious precursors
of Guillain-Barré syndrome include mononucleosis, Lyme disease,
cytomegalovirus, and Haemophilus influenzae (for the Miller-Fisher
syndrome).
Chapter 616 ◆ Guillain-Barré Syndrome 3011
Initial symptoms include numbness and paresthesia, followed by patients exhibit symptoms of viral meningitis or meningoencephalitis.
weakness. There may be associated neck, back, buttock, and leg pain. Extraocular muscle involvement is rare, but in an uncommon variant,
Weakness usually begins in the lower extremities and progressively oculomotor and other cranial neuropathies are severe early in the
involves the trunk, the upper limbs, and, finally, the bulbar muscles, course.
a pattern known as Landry ascending paralysis. Proximal and distal Miller-Fisher syndrome (MFS) consists of acute external and occa-
muscles are involved relatively symmetrically, but asymmetry is found sionally internal ophthalmoplegia, ataxia, and areflexia. The 6th cranial
in 9% of patients. The onset is gradual and progresses over days or nerve is most often involved in MFS. Papilledema may precede or
weeks; the process plateaus in 1-28 days. Particularly in cases with follow MFS and suggests a diagnosis of pseudotumor; optic neuritis
an abrupt onset, tenderness on palpation and pain in muscles are may also be noted. Although areflexia is seen in MFS, patients do not
common in the initial stages. Affected children are irritable. Weak- have significant lower extremity weakness compared with Guillain-
ness can progress to inability or refusal to walk and later to flaccid Barré syndrome. Distal paresthesias are noted in MFS. Urinary incon-
tetraplegia. Maximal severity of weakness is usually reached by 4 wk tinence or retention of urine is a complication in approximately 20%
after onset. The differential diagnosis of acute weakness is noted in of cases but is usually transient. MFS overlaps with Bickerstaff brain-
Table 607-3 (in Chapter 607) and of Guillain-Barré syndrome in stem encephalitis, which also shares many features with Guillain-Barré
Table 616-1. syndrome with lower motor neuron involvement.
Bulbar involvement occurs in about half of cases. Respiratory insuf- Tendon reflexes in Guillain-Barré syndrome are lost, usually early
ficiency can result. Dysphagia and facial weakness are often impending in the course, but are sometimes preserved until later; areflexia is
signs of respiratory failure. They interfere with eating and increase the common but hyporeflexia may be seen; 10% may have normal reflexes.
risk of aspiration. The facial nerves may be involved. Some young This variability can cause confusion when attempting early diagnosis.
The autonomic nervous system is also involved in some cases. Lability
of blood pressure and cardiac rate, postural hypotension, episodes of
profound bradycardia, or tachycardia and occasional asystole occur.
Cardiovascular monitoring is important. A few patients require inser-
tion of a temporary venous cardiac pacemaker.
Table 616-1 Differential Diagnosis of Childhood Subtypes of Guillain-Barré syndrome include an acute inflammatory
Guillain-Barré Syndrome demyelinating polyneuropathy and an acute motor axonal neuropathy;
these are distinguished by nerve conduction studies, geography, and
SPINAL CORD LESIONS the pattern of antiganglioside antibodies (Table 616-2). Localized
Acute transverse myelitis forms also occur and include a pattern of facial diplegia with paresthe-
Epidural abscess sias and a pattern of pharyngeal-cervical-brachial weakness.
Tumors Chronic inflammatory demyelinating polyradiculoneuropathies
Poliomyelitis (natural or live virus)
Enteroviruses
(CIDPs, sometimes called chronic inflammatory relapsing polyneuritis
Hopkins syndrome or chronic unremitting polyradiculoneuropathy) are chronic varieties of
Vascular malformations Guillain-Barré syndrome that recur intermittently, or do not improve,
Cord infarction or progress slowly and relentlessly for periods of months to years.
Fibrocartilaginous embolism Approximately 7% of children with Guillain-Barré syndrome suffer an
Cord compression from vertebral subluxation related to congenital acute relapse. Patients are usually severely weak and can have a flaccid
abnormalities or trauma tetraplegia with or without bulbar and respiratory muscle involvement.
Acute disseminated encephalomyelitis Hyporeflexia or areflexia is almost universal. Motor deficits occur in
Bickerstaff brainstem encephalitis for Miller-Fisher syndrome 94% of cases, sensory paresthesias in 64%, and cranial nerve involve-
PERIPHERAL NEUROPATHIES ment in less than a third of patients. Autonomic and micturitional
Toxic involvement is variable. Cerebrospinal fluid (CSF) shows no pleocyto-
• Vincristine sis and protein is variably normal or mildly elevated. Nerve conduction
• Glue sniffing
• Heavy metal: gold, arsenic, lead, thallium
• Organophosphate pesticides
• Fluoroquinolones
Infections
• HIV
• Diphtheria Table 616-2 Classification of Guillain-Barré Syndrome
• Lyme disease and Related Disorders and Typical
Inborn errors of metabolism Antiganglioside Antibodies By Pathology
• Leigh disease
• Tangier disease DISORDER ANTIBODIES
• Porphyria
Critical illness: polyneuropathy/myopathy Acute inflammatory demyelinating Unknown
Vasculitis syndromes polyradiculoneuropathy
Porphyria Acute motor and sensory axonal GM1, GM1b, GD1a
Mitochondrial neurogastrointestinal encephalomyopathy neuropathy
CD59 deficiency Acute motor axonal neuropathy GM1, GM1b, GD1a,
GalNac-GD1a
NEUROMUSCULAR JUNCTION DISORDERS Acute sensory neuronopathy GD1b
Tick paralysis
Myasthenia gravis ACUTE PANDYSAUTONOMIA
Botulism Regional Variants
Hypercalcemia Fisher syndrome GQ1b, GT1a
Myopathies Oropharyngeal GT1a
Periodic paralyses Overlap
Dermatomyositis Fisher/Guillain-Barré overlap GQ1b, GM1, GM1b, GD1a,
Critical illness myopathy/polyneuropathy syndrome GalNac-GD1a
From Agrawal S, Peake D, Whitehouse WP: Management of children with From Hughes RAC: Treatment of Guillain-Barré syndrome with corticosteroids:
Guillain Barré syndrome, Arch Dis Child Educ Pract Ed 92:161–168, 2007. lack of benefit? Lancet 363:181–182, 2004.
velocity studies and sural nerve biopsy are abnormal. Polymorphic Table 616-1. MRI findings include thickening of the cauda equina and
nucleotide repeats in the SH2D2A gene are associated with a predis- intrathecal nerve roots with gadolinium enhancement. These finds are
position to CIDP. fairly sensitive and are present in >90% of patients (Fig. 616-1). Imaging
Congenital Guillain-Barré syndrome is described rarely, manifest- in CIDP is similar but demonstrates greater enhancement of spinal
ing as generalized hypotonia, weakness, and areflexia in an affected nerve roots (Fig. 616-2).
neonate, fulfilling all electrophysiologic and CSF criteria and in the Motor nerve conduction velocities are greatly reduced, and sensory
absence of maternal neuromuscular disease. Treatment might not be nerve conduction time is often slow. Electromyography shows evi-
required, and there is gradual improvement over the 1st few mo and dence of acute denervation of muscle. Serum creatine kinase level may
no evidence of residual disease by 1 yr of age. In 1 case, the mother be mildly elevated or normal. Antiganglioside antibodies, mainly
had ulcerative colitis treated with prednisone and mesalamine from against GM1 and GD1, are sometimes elevated in the serum in Guillain-
the 7th mo of gestation until delivery at term. Barré syndrome, particularly in cases with primarily axonal rather than
demyelinating neuropathy, and suggest that they might play a role in
LABORATORY FINDINGS AND DIAGNOSIS disease propagation and/or recovery in some cases (see Table 616-1).
CSF studies are essential for diagnosis. The CSF protein is elevated to Muscle biopsy is not usually required for diagnosis; specimens appear
more than twice the upper limit of normal, the glucose level is normal, normal in early stages and show evidence of denervation atrophy in
and there is no pleocytosis. Fewer than 10 white blood cells/mm3 may chronic stages. Sural nerve biopsy tissue shows segmental demyelin-
be found. The results of bacterial cultures are negative, and viral cul- ation, focal inflammation, and wallerian degeneration but also is
tures rarely isolate specific viruses. The dissociation between high CSF usually not required for diagnosis.
protein and a lack of cellular response in a patient with an acute or Serologic testing for Campylobacter and Helicobacter infections
subacute polyneuropathy is diagnostic of Guillain-Barré syndrome. helps establish the cause if results are positive but does not alter the
MRI of the spinal cord may be indicated to rule out disorders listed in course of treatment. Results of stool cultures are rarely positive because
A B
C D
Figure 616-1 Guillain-Barré syndrome. Sagittal off-midline (A) and midline (B) postgadolinium T1-weighted fat-saturated images through the
lumbar spine of a patient who could not ambulate. C and D, Axial postcontrast T1-weighted images through the conus medullaris and proximal
lumbar nerve roots, respectively. The images show extensive contrast enhancement of nerve roots (arrows in A-D), in keeping with changes of
Guillain-Barré. (From Slovis TL, editor: Caffey’s pediatric diagnostic imaging, ed 11, Philadelphia, 2008, Mosby, Fig. 65-6.)
Chapter 616 ◆ Guillain-Barré Syndrome 3013
A B C
Figure 616-2 Chronic inflammatory demyelinating polyneuropathy (CIDP) in a 13 yr old boy with peripheral neuropathy and gait disturbance.
Sagittal fat-saturated T1-weighted images off the midline to the right (A), at the midline (B), and off the midline to the left (C). (From Slovis TL,
editor: Caffey’s pediatric diagnostic imaging, ed 11, Philadelphia, 2008, Mosby, Fig. 65-7.)
the infection is self-limited and only occurs for about 3 days, and the Even if C. jejuni infection is documented by stool culture or sero-
neuropathy follows the acute gastroenteritis. logic tests, treatment of the infection is not necessary because it is
self-limited, and the use of antibiotics does not alter the course of the
TREATMENT polyneuropathy.
Patients in early stages of this acute disease should be admitted to For the treatment of chronic neuropathic pain following Guillain-
the hospital for observation because the ascending paralysis can Barré syndrome, gabapentin is more effective than carbamazepine, and
rapidly involve respiratory muscles during the next 24 hr. Respiratory the requirement for fentanyl is reduced. But no pharmacologic treat-
effort (negative inspiratory force, spirometry) must be monitored to ments for neuropathic pain in this disease are wholly effective.
prevent respiratory failure and respiratory arrest. Patients with slow
progression might simply be observed for stabilization and spontane- PROGNOSIS
ous remission without treatment. Rapidly progressive ascending The clinical course is usually benign, and spontaneous recovery begins
paralysis is treated with intravenous immunoglobulin (IVIG), admin- within 2-3 wk. Most patients regain full muscular strength, although
istered for 2, 3, or 5 days. A commonly recommended protocol is some are left with residual weakness. The tendon reflexes are usually
IVIG 0.4 g/kg/day for 5 consecutive days, but some studies suggest the last function to recover. Improvement usually follows a gradient
that larger doses are more effective (1 g/kg/day for 2 consecutive days) opposite the direction of involvement: bulbar function recovering first,
and related to improved outcome. Plasmapheresis and/or immuno- and lower extremity weakness resolving last. Bulbar and respiratory
suppressive drugs are alternatives if IVIG is ineffective. Steroids are muscle involvement can lead to death if the syndrome is not recog-
not effective. Supportive care, such as respiratory support, prevention nized and treated. Although prognosis is generally good and the
of decubiti in children with flaccid tetraplegia, nutritional support, majority of children recover completely, 3 clinical features are predic-
pain management, prevention of deep vein thrombosis, and treatment tive of poor outcome with sequelae: cranial nerve involvement, intuba-
of secondary bacterial infections, is important. tion, and maximum disability at the time of presentation. The
CIDPs, whether relapsing-remitting or unremitting, also are electrophysiologic features of conduction block are predictive of good
treated with oral or pulsed steroids and IVIG. Subcutaneous immu- outcome. Long-term follow-up studies of patients who recover from
noglobulin infusion may be an alternative to the intravenous route. an attack of Guillain-Barré syndrome reveal that many do have some
Plasma exchange, sometimes requiring as many as 10 exchanges permanent axonal loss, with or without residual clinical signs of
daily, is an alternative. Remission in these cases may be sustained, chronic neuropathy. Easy fatigue is one of the most common chronic
but relapses can occur within days, weeks, or even after many months; symptoms, but it is not the rapid fatigability of muscles seen in myas-
relapses usually respond to another course of plasmapheresis. Steroid thenia gravis. Most patients with the axonal form of Guillain-Barré
and immunosuppressive drugs are another alternative, but their syndrome had a slow recovery over the 1st 6 mo and could eventually
effectiveness is less predictable. High-dose pulsed methylprednisolone walk, although some required years to recover. Electromyography and
given intravenously is successful in some cases. The prognosis in nerve conduction velocity electrophysiologic studies do not necessarily
chronic forms of the Guillain-Barré syndrome is more guarded than predict the long-term outcome.
in the acute form, and many patients are left with major residual
handicaps. Bibliography is available at Expert Consult.
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infection and acute inflammatory demyelinating polyradiculoneuropathy, Eur J methylprednisone when added to standard treatment with intravenous
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Chapter 617 The upper and lower portions of the face are paretic, and the corner of
the mouth droops. Patients are unable to close the eye on the involved
Bell Palsy side and can develop an exposure keratitis at night. Taste on the ante-
rior two thirds of the tongue is lost on the involved side in approxi-
mately 50% of cases; this finding helps to establish the anatomic limits
Harvey B. Sarnat of the lesion as being proximal or distal to the chorda tympani branch
of the facial nerve. Numbness and paresthesias do not usually occur,
but ipsilateral numbness of the face is reported in a few cases and
Bell palsy is an acute unilateral peripheral facial nerve palsy that is not probably is caused by viral (especially herpes) or postviral immuno-
associated with other cranial neuropathies or brainstem dysfunction. logic impairment of the trigeminal and the facial nerves. Pain behind
It is a common disorder at all ages from infancy through adolescence the ear may precede weakness. Acute hearing loss may occur in Bell
and usually develops abruptly about 2 wk after a systemic viral infec- palsy associated with Rickettsia infection. Several grading systems have
tion. The preceding infection is caused by the herpes simplex virus, been devised for Bell palsy, including the Sunnybrook, House-
varicella-zoster virus, Epstein-Barr virus, Lyme disease, mumps virus, Brackmann, and Yanagihara systems.
Toxocara, Rickettsia, Mycoplasma, or HIV infection (Table 617-1).
Ramsay Hunt syndrome (herpes zoster oticus) is associated with ves- IMAGING THE FACIAL NERVE AND
icles in the external auditory canal or auricle and an ipsilateral facial ITS BONY CANAL
palsy. Active or reactivation of herpes simplex or varicella-zoster virus Modern high-resolution MRI, particularly with multiplanar recon-
may be the most common cause of Bell palsy (Fig. 617-1). The disease struction, is able to visualize the facial nerve within its canal and
is occasionally a postinfectious allergic or immune demyelinating determine whether there are bony anomalies, compressive aneurysms,
facial neuritis. It also may be a focal toxic or inflammatory neuropathy vascular malformations, or nerve sheath or infiltrative tumors that
and has been associated with ribavirin and interferon-α therapy for might explain a palsy anatomically. The two sides can be compared
hepatitis C. Hereditary forms are rare, but it may be associated with and, in particular, the labyrinthine segment within the petrous bone,
other genetic polyneuropathies. Rarely, Bell palsy occurs in the context which is the narrowest site in the facial nerve canal, can be examined.
of hypertension or juvenile type 1 diabetes mellitus, most often associ- Ultrasound of the facial nerve also has been used, in part as a predictor
ated with concomitant viral infections. of functional outcome in Bell palsy. More recently, diffusion tensor
tractography enables a tridimensional display of facial nerve axons.
TREATMENT
Table 617-1 Etiologies of Acute Peripheral Facial Palsy Oral prednisone (1 mg/kg/day for 1 wk, followed by a 1 wk taper)
started within the 1st 3-5 days results in improved outcome and is a
COMMON OTHER LESS-COMMON traditional treatment, its efficacy confirmed in a recent long-term pro-
Idiopathic CONDITIONS spective study in the United Kingdom. Because of the recovery of
Herpes simplex virus type 1* Trauma herpes simplex virus in the neural fluid of the 7th nerve, some also
Varicella-zoster virus* Schwannoma of facial nerve recommend adding oral acyclovir or valacyclovir to the prednisone
Infiltrative tumor
LESS-COMMON INFECTIONS therapy. Alone, antiviral agents are not effective in reducing adverse
Aneurysm or vascular
Otitis media ± cholesteatoma malformation sequelae (synkinesis, autonomic dysfunction), but added to predni-
Lyme disease Anomalous narrowing of facial sone may be associated with an additional small benefit. If a specific
Epstein-Barr virus canal infection can be identified as a predisposing cause, specific antiviral or
Cytomegalovirus Hypertension antibacterial treatment is more justified. Surgical decompression of the
Mumps Sjögren syndrome facial canal, theoretically to provide more space for the swollen facial
Human herpesvirus 6
Intranasal influenza vaccine
Diabetes mellitus, type 1 nerve, is not of value unless imaging provides evidence of nerve com-
Guillain-Barré syndrome pression or an anatomic lesion. Both high- and low-level laser therapy
Mycoplasma Sarcoidosis
Toxocara has been used with good results in some cases as a form of physio-
Melkersson-Rosenthal syndrome† therapy. Traditional physiotherapy to the facial muscles is recom-
Rickettsia Ribavirin
AIDS/HIV Interferon
mended in some chronic cases with poor recovery, but the efficacy of
this treatment is uncertain. Protection of the cornea with methylcel-
*Implicated in idiopathic Bell palsy.
†
lulose eyedrops or an ocular lubricant is especially important at night.
Noncaseating granulomas with facial (lips, eyelids) edema, recurrent Botulinum toxin has been applied in adults to the contralateral normal
alternating facial paralysis, family history, migraines, or headaches.
facial muscles for cosmetic purposes to minimize the apparent asym-
metry or to treat chronic unilateral ptosis, but this has little application
in pediatric patients.
Bell palsy Ramsay PROGNOSIS

Hunt The prognosis for functional recovery is excellent. More than 85% of
Zoster syndrome patients recover spontaneously with no residual facial weakness.
without
vesicles Another 10% have mild facial weakness as a sequela, often perceived
only as a mild facial asymmetry, and only 5% are left with permanent
Herpes simplex virus Varicella-zoster virus
severe facial weakness. In patients who do not recover within a few
31-79% of Bell palsy 8-28% of weeks (chronic), electrophysiologic examination of the facial nerve
Bell
palsy helps to determine the degree of neuropathy and regeneration. In
chronic cases, other causes of facial neuropathy should be considered,
including facial nerve tumors such as schwannomas and neurofibro-
mas, infiltration of the facial nerve by leukemic cells or by a rhabdo-
Figure 617-1 Involvement of herpes simplex and varicella-zoster myosarcoma of the middle ear, brainstem infarcts or tumors, and
viruses in acute facial palsy. (Modified from Hato N, Murakami S, Gyo traumatic injury of the facial nerve.
K: Steroid and antiviral treatment for Bell’s palsy, Lancet 371:1818– Nerve regrowth may be misdirected and result in synkinesis, where
1820, 2008.) activation of one muscle group may produce activation of another
Chapter 617 ◆ Bell Palsy 3015
inappropriate muscle group; blinking may result in mouth twitching, cries, and is often associated with other congenital anomalies, especially
smiling may cause eye blinking, and lacrimation (crocodile tears) may of the heart. It is not a facial nerve lesion but is a cosmetic defect that
occur while eating. does not interfere with feeding. Infants with Möbius syndrome can
have bilateral or, less commonly, unilateral facial palsy; this syndrome
FACIAL PALSY AT BIRTH is usually caused by symmetric calcified infarcts in the tegmentum of
Facial palsy at birth is usually a compression neuropathy from forceps the pons and medulla oblongata during midgestation or late fetal life,
application during delivery and recovers spontaneously in a few days although it rarely is a developmental anomaly of the brainstem.
or weeks in most cases. Congenital absence of the depressor angularis
oris muscle causes facial asymmetry, especially when an affected infant Bibliography is available at Expert Consult.
Chapter 617 ◆ Bell Palsy 3015.e1
Bibliography Kim J: Contralateral botulinum toxin injection to improve facial asymmetry after
Alayat MS, Elsodany AM, El Fiky AA: Efficacy of high and low level laser therapy acute facial paralysis, Otol Neurotol 34:3190–3324, 2013.
in the treatment of Bell’s palsy: a randomized double blind placebo-controlled Loechelt BJ, Boulware D, Green M, et al: Epstein-Barr and other herpesvirus
trial, Lasers Med Sci 29(1):335–342, 2014. infections in patients with early onset type 1 diabetes treated with daclizumab
Berg T, Jonsson L: Peripheral neuropathies: corticosteroids and antivirals in Bell’s and mycophenolate mofetil, Clin Infect Dis 56:248–254, 2013.
palsy, Nat Rev Neurol 9:128–129, 2013. Madhok V, Falk G, Fahey T, Sullivan: Prescribe prednisolone alone for Bell’s palsy
Biebl A, Lechner E, Hrocek K, et al: Facial nerve paralysis in children: is it as diagnosed within 72 hours of symptom onset, BMJ 338:410–411, 2009.
benign as supposed? Pediatr Neurol 49:178–181, 2013. Morales DR, Donnan PT, Daly F, et al: Impact of clinical trial findings on Bell’s
De Almeida JR, Khabori MA, Guyatt GH, et al: Combined corticosteroid and palsy management in general practice in the U.K. 2001-2012: interrupted time
antiviral treatment for Bell palsy, JAMA 302:985–993, 2009. series regression analysis, BMJ Open 3(7):e003121, 2013.
De Ru JA, Van Benthem PP: Combination therapy of steroids and antivirals Murai A, Kariya S, Tamura K, et al: The facial nerve canal in patients with Bell’s
improves the recovery rate in patients with severe Bell’s palsy, Evid Based Med palsy: an investigation by high-resolution computed tomography with
19(1):15, 2014. multiplanar reconstruction, Eur Arch Otorhinolaryngol 270:2035–2038, 2013.
Eidlitz-Markus T, Gilai A, Mimouri M, et al: Recurrent facial nerve palsy in Nilsson K, Wallménius K, Hartwig S, et al: Bell’s palsy and sudden deafness
pediatric patients, Eur J Pediatr 160:659–663, 2001. associated with Rickettsia spp. infection in Sweden. A retrospective and
Furuta Y, Ohtani F, Aizawa H, et al: Varicella-zoster virus reactivation is an prospective serological survey including PCR findings, Eur J Neurol 21(2):206–
important cause of acute peripheral facial paralysis in children, Pediatr Infect 214, 2014.
Dis J 24:97–101, 2005. Steiner JF: Treatment of Bell palsy—translating uncertainty into practice, JAMA
Gupta S, Mends F, Hagiwara M, et al: Imaging the facial nerve: a contemporary 302:1003–1004, 2009.
review, Radiol Res Pract 2013:248039, 2013. Sullivan FM, Swan IR, Donnan PT, et al: Early treatment with prednisolone or
Hadlock TA, Malo JS, Cheney ML, et al: Advances in surgical treatment of facial acyclovir in Bell’s palsy, N Engl J Med 357:1598–1607, 2007.
nerve paralysis in children, JAMA 305:2106–2107, 2011. Toulgoat F, Sarrazin JL, Benoudiba F, et al: Facial nerve: from anatomy to
Hato N, Murakami S, Gyo K: Steroid and antiviral treatment for Bell’s palsy, Lancet pathology, Diagn Interv Imaging 94(10):1033–1042, 2013.
371:1818–1820, 2008.
Karadima G, Kokotis P, Kalfakis N, et al: Bell’s palsy and hereditary neuropathy
with liability to pressure palsy (HNPP): is there a common genetic background?
J Clin Neurosci 20:1042, 2013.
PART
Disorders of the Eye XXIX
Remnants of the primitive hyaloid vascular system may also be
seen as small tufts or wormlike structures projecting from the disc
Chapter 618 (Bergmeister papilla) or as a fine strand traversing the vitreous; in some
cases, only a small dot (Mittendorf dot) remains on the posterior aspect
Growth and Development of the lens capsule.
An infant’s eye is somewhat hyperopic (farsighted). The general
Scott E. Olitsky, Denise Hug, trend is for hyperopia to increase from birth until age 7 yr. Thereafter,
the level of hyperopia tends to decrease rapidly until age 14 yr. Elimi-
Laura S. Plummer, Erin D. Stahl, nation of the hyperopic state may occur during this time. If the process
Michelle M. Ariss, and continues, myopia (nearsightedness) develops. A slower continuation
Timothy P. Lindquist of the decrease in hyperopia, or increase in myopia, continues into the
3rd decade of life. The refractive state at any time in life depends on
the net effect of many factors: the size of the eye, the state of the lens,
and the curvature of the cornea.
The eye of a normal full-term infant at birth is approximately 65% of Newborn infants tend to keep their eyes closed much of the time,
adult size. Postnatal growth is maximal during the 1st yr, proceeds at but normal newborns can see, respond to changes in illumination, and
a rapid, but decelerating rate until the 3rd yr, and continues at a slower fixate points of contrast. The visual acuity in newborns is estimated to
rate thereafter until puberty, after which little change occurs. The ante- be approximately 20/400. This poor vision is a result of the immature,
rior structures of the eye are relatively large at birth but thereafter grow multilayered foveal anatomy. Retinal development continues postna-
proportionately less than the posterior structures. This results in a tally, maturing completely during the 1st few yr of life. One of the earli-
progressive change in the shape of the globe such that it becomes more est responses to a formed visual stimulus is an infant’s regard for the
spherical. mother’s face, evident especially during feeding. By 2 wk of age, an
In an infant, the sclera is thin and translucent, with a bluish tinge. infant shows more sustained interest in large objects, and by 8-10 wk
The cornea is relatively large in newborns (averaging 10 mm) and of age, a normal infant can follow an object through an arc of 180
attains adult size (nearly 12 mm) by the age of 2 yr or earlier. Its cur- degrees. The acuity improves rapidly and may reach 20/30-20/20 by
vature tends to flatten with age, resulting in a progressive change in the the age of 2-3 yr.
refractive properties of the eye. A normal cornea is perfectly clear. In Many normal infants may have imperfect coordination of the eye
infants born prematurely, however, the cornea may have a transient movements and alignment during the early days and weeks, but proper
opalescent haze. The anterior chamber in a newborn appears shallow, coordination should be achieved by 3-6 mo, usually sooner. Persistent
and the angle structures, important in the maintenance of normal deviation of an eye in an infant at 6 mo of age requires evaluation.
intraocular pressure, must undergo further differentiation after birth. Tears often are not present with crying until after 1-3 mo. Preterm
The iris, typically light blue or gray at birth in white individuals, under- infants have reduced reflex and basal tear secretion, which may allow
goes progressive change of color as the pigmentation of the stroma topically applied medications to become concentrated and lead to
increases in the 1st 6 mo of life. The pupils of a newborn infant tend rapid drying of their corneas.
to be small and are often difficult to dilate. This is the result of an
immature iris dilator muscle. Remnants of the pupillary membrane Bibliography is available at Expert Consult.
(anterior vascular capsule) are often evident on ophthalmoscopic
examination, appearing as cobweb-like lines crossing the pupillary
aperture, especially in preterm infants.
The lens of a newborn infant is more spherical than that of an adult;
its greater refractive power helps to compensate for the relative short-
ness of the young eye. The lens continues to grow throughout life; new
fibers added to the periphery continually push older fibers toward the
center of the lens. With age, the lens becomes progressively denser and
more resistant to change of shape during accommodation.
The fundus of a newborn’s eye is less pigmented than that of an
adult; the choroidal vascular pattern is highly visible, and the retinal
pigment pattern often has a fine peppery or mottled appearance. In
some darkly pigmented infants, the fundus has a gray or opalescent
sheen. In a newborn, the macular landmarks, particularly the foveal
light reflex, are less-well defined and may not be readily apparent. The
peripheral retina appears pale or grayish, and the peripheral retinal
vasculature is immature, especially in premature infants. The optic
nerve head color varies from pink to slightly pale, sometimes grayish.
Within 4-6 mo, the appearance of the fundus approximates that of the
mature eye.
Superficial retinal hemorrhages may be observed in many newborn
infants. These are usually absorbed promptly and rarely leave any per-
manent effect. The majority of birth-related retinal hemorrhages
resolve within 2 wk, with complete resolution of all such hemorrhages
within 4-6 wk of birth. Conjunctival hemorrhages also may occur at
birth and are resorbed spontaneously without consequence.
3016
Chapter 618 ◆ Growth and Development 3016.e1
Bibliography Krishnamohan VK, Wheeler MB, Testa MA, et al: Correlation of postnatal
Archer SM, Sondhi N, Helveston EM: Strabismus in infancy, Ophthalmology regression of the anterior vascular capsule of the lens to gestational age,
96:133–137, 1989. J Pediatr Ophthalmol Strabismus 19:28–32, 1982.
Emerson MV, Pieramici DJ, Stoessel KM, et al: Incidence and rate of disappearance Roarty JD, Keltner JL: Normal pupil size and anisocoria in newborn infants, Arch
of retinal hemorrhage in newborns, Ophthalmology 108:33–39, 2001. Ophthalmol 108:94–95, 1990.
Isenberg SJ, Apt L, McCarty J: Development of tearing in preterm and term Spieres A, Isenberg SJ, Inkelis SH: Characteristics of the iris in 100 neonates,
infants, Arch Ophthalmol 116:773–776, 1998. J Pediatr Ophthalmol Strabismus 26:28–30, 1989.
Khodadoust AA, Ziai M, Biggs SL: Optic disc in normal newborns, Am J
Ophthalmol 66:502–504, 1968.
Chapter 619
Examination of the Eye
Scott E. Olitsky, Denise Hug,
Laura S. Plummer, Erin D. Stahl,
Michelle M. Ariss, and
Timothy P. Lindquist
The eye exam is a routine part of the pediatric wellness evaluation,

which begins in the newborn period. The primary care physician
plays a critical role in the detection of both obvious and insidious,
asymptomatic eye diseases. School and community screening pro-
grams can also be effective in identifying problems at an early age. The
American Academy of Ophthalmology recommends preschool vision
screening as a means of reducing preventable visual loss (Table 619-1).
The screening process begins with the pediatrician during well child
visits. Referrals to an ophthalmologist should be made when a sig-
nificant ocular abnormality or visual acuity deficit is suspected. An
Chapter 619 ◆ Examination of the Eye 3017
Table 619-1 Vision Screening Guidelines

FUNCTION RECOMMENDED TESTS REFERRAL CRITERIA COMMENTS
AGES 3-5 YR
Distance visual acuity Snellen letters <4 of 6 correct on 20-ft line Tests are listed in decreasing order of
Snellen numbers with either eye tested at 10 ft cognitive difficulty; the highest test that
Tumbling E test monocularly (i.e., <10/20 or the child is capable of performing should
HOTV test 20/40), or be used; in general, the tumbling E or the
Two-line difference between HOTV test should be used for ages 3-5 yr
eyes, even within the passing and Snellen letters or numbers for ages
range (i.e., 10/12.5 and 10/20 6 yr and older.
or 20/25 and 20/40)
Picture tests Testing distance of 3 m (10 ft) is
recommended for all visual acuity tests.
-Allen figures
-Lea symbols A line of figures is preferred over a single
figure.
The nontested eye should be covered by an
occluder held by the examiner or by an
adhesive occluder patch applied to eye;
the examiner must ensure that it is not
possible to peek with the nontested eye.
Ocular alignment Cross cover test at 3 m (10 ft) Any eye movement
or
Random dot E stereo test at <4 of 6 correct
40 cm (630 sec of arc)
Simultaneous red reflex test Any asymmetry of pupil color, Direct ophthalmoscope used to view both
(Bruckner test) size, brightness red reflexes simultaneously in a darkened
room from 2-3 ft away; detects asymmetric
refractive errors as well.
Ocular media clarity Red reflex White pupil, dark spots, absent Direct ophthalmoscope, darkened room.
(cataracts, tumors, etc.) reflex View eyes separately at 12-18 inches; white
reflex indicates possible retinoblastoma.
AGES 6 YR AND OLDER
Distance visual acuity Snellen letters <4 of 6 correct on 4.5 m (15 ft) Tests are listed in decreasing order of
Snellen numbers line with either eye tested at cognitive difficulty; the highest test that
Tumbling E test 3 m (10 ft) monocularly (i.e., the child is capable of performing should
HOTV test <10/15 or 20/30) be used; in general, the tumbling E or the
HOTV test should be used for ages 3-5 yr
and Snellen letters or numbers for ages
6 yr and older.
Picture tests Two-line difference between Testing distance of 3 m (10 ft) is
eyes, even within the passing recommended for all visual acuity tests.
range (i.e., 10/10 and 10/15
or 20/20 and 20/30)
-Allen figures
-Lea symbols A line of figures is preferred over a single
figure.
The nontested eye should be covered by an
occluder held by the examiner or by an
adhesive occluder patch applied to the
eye; the examiner must ensure that it is not
possible to peek with the nontested eye.
Ocular alignment Cross cover test at 3 m (10 ft) Any eye movement
or
Random dot E stereo test at <4 of 6 correct
40 cm (630 sec of arc)
ophthalmologist should also examine high-risk children, such as those VISUAL ACUITY
with a family history of eye disease, or various systemic or genetic There are various means of assessing visual acuity in the pediatric
disorders, such as Down syndrome. population. A child’s age and ability to cooperate, as well as clinician
The basic eye exam, whether performed by a pediatrician or an preference, all factor in deciding which test to use. The most common
ophthalmologist, must include: visual acuity and visual field testing, visual acuity test in infants is an assessment of their ability to fixate and
assessment of pupils, ocular motility and alignment, a general external/ follow a target. If appropriate targets are used, this response can be
facial examination, and finally, examination of the media and fundus demonstrated by approximately 6 wk of age.
via ophthalmoscopy. When indicated, biomicroscopy (slit-lamp exam- The test begins by seating the child comfortably in the caretaker’s
ination), cycloplegic refraction, and tonometry are performed by an lap. The object of visual interest, usually a bright-colored toy, or target
ophthalmologist. Special diagnostic procedures, such as ultrasound, with lights, is slowly moved to the right and to the left. The examiner
fluorescein angiography, electroretinography, or visual evoked response observes whether the infant’s eyes turn toward the object and follow
testing, are also indicated for specific conditions. its movements. The examiner can use a thumb or palm of the hand to
3018 Part XXIX ◆ Disorders of the Eye
occlude one of the infant’s eyes, in order to test each eye separately. male patients but rare in females, as the gene is transmitted in an
Although a sound-producing object might compromise the purity of X-linked manner. Achromatopsia, which may be encountered occa-
the visual stimulus, in practice, toys that squeak or rattle heighten an sionally, is a condition of complete color blindness associated with
infant’s awareness and interest in the test. subnormal visual acuity, nystagmus, and photophobia.
The human face is a better target than test objects. The examiner can Color discrimination is a means of assessing the intensity of a hue,
exploit this by moving his or her face slowly in front of the infant’s face. typically red. Patients describe the intensity of red depicted from the
If the appropriate following movements are not elicited, the test should test object. A change in color discrimination (often referred to as color
be repeated with the caretaker’s face as the test stimulus. It should be “desaturation”) can be a sign of optic nerve or retinal disease.
remembered that even children with poor vision can follow a large
object without apparent difficulty, especially if only 1 eye is affected. PUPILLARY EXAMINATION
An objective measurement of visual acuity is usually possible when The pupil exam includes evaluations of both the direct and consensual
children reach the age of 2.5-3 yr. Children this age are tested using a responses to light, accommodation (a near target), and reduced illu-
schematic picture or other illiterate eye chart. Examples include Allen mination, noting the size and symmetry of the pupils under each
or Lea symbols and tumbling E. Each eye should be tested separately. testing condition. Special care must be taken to differentiate the reac-
It is essential to prevent peeking. The examiner should hold the tion to light from the reaction to near gaze. A child’s natural tendency
occluder in place and observe the child throughout the test. The child is to look directly at the approaching light, inducing the near gaze
should be reassured and encouraged throughout the test as many chil- reflex when one is attempting to test only the reaction to light; accord-
dren are intimidated by the process and fear a “bad grade” or punish- ingly, every effort must be made to control fixation on a distance target.
ment for errors. The swinging flashlight test is especially useful for detecting unilateral
The tumbling E test, in which the child indicates which direction or asymmetric prechiasmatic afferent defects in children (see “Marcus
the E is facing, is the most widely used visual acuity test for preschool Gunn Pupil” section in Chapter 622).
children. Right–left presentations are more confusing than up–down
presentations. With pretest practice, the test can be performed by most OCULAR MOTILITY
children ages 3-4 yr. Ocular motility testing assesses alignment and extraocular muscle
An adult-type Snellen acuity chart can be used at 5-6 yr of age if function. This is tested by having a child follow an object in various
the child knows letters. A visual acuity of 20/40 is generally accepted positions of gaze, known as the cardinal positions. The cardinal posi-
as normal for 3 yr old children. At 4 yr of age, 20/30 is acceptable. By tions are those in which one extraocular muscle predominantly func-
5 or 6 yr of age, most children attain 20/20 vision. tions and a deficit can be identified if present. Movements of each eye
Optokinetic nystagmus (the response to a sequence of moving individually (ductions) and of the 2 eyes together (versions, conjugate
targets; “railroad” nystagmus) can also be used to assess vision; this movements, and convergence) are assessed.
can be calibrated by targets of various sizes (stripes or dots) or by a Alignment can be assessed in 2 ways. The first is symmetry of the
rotating drum (known as an OKN drum) at specified distances. corneal light reflexes. The second method is to occlude each eye in an
The visual evoked response, an electrophysiologic method of evalu- alternating fashion and observe for a change in fixation of the viewing
ating the response to light and special visual stimuli, such as calibrated eye (see discussion on cover testing for strabismus in Chapter 623).
stripes or a checkerboard pattern, can also be used to study visual
function in selected cases. BINOCULAR VISION
Preferential looking tests are used for evaluating vision in infants Attaining binocular visual function is one of the primary goals of
and children who cannot respond verbally to standard acuity tests. This amblyopia therapy and ocular realignment surgery. Just as there are
is a behavioral technique based on the observation that, given a choice, multiple methods for assessing visual acuity, there are various means
an infant prefers to look at patterned rather than unpatterned stimuli. of testing the level of binocular vision. The Titmus test is probably the
Because these tests require the presence of a skilled examiner, their use most frequently used test; a series of three-dimensional images are
is often limited to research protocols involving preverbal children. shown to the child while he or she wears a set of polarized glasses. The
level of difficulty with which these images can be detected correlates
VISUAL FIELD ASSESSMENT with the degree of binocular vision present.
Like visual acuity testing, visual field assessment must be geared to a
child’s age and abilities. Formal visual field examination (perimetry EXTERNAL EXAMINATION
and scotometry) can often be accomplished in school-age children. In The external examination begins with general inspection, in good illu-
younger children and in the pediatrician’s office, the examiner must mination of the face, paying close attention to the orbits and lids,
often rely on confrontation techniques and finger counting in quad- noting the size, shape, and symmetry of the orbits; position and move-
rants of the visual field. In many such children, only testing by attrac- ment of the lids; and position and symmetry of the globes. Viewing
tion can be accomplished; the examiner observes a child’s response to the eyes and lids in such a manner aids in detecting orbital asymmetry,
familiar objects brought into each of the 4 quadrants of the visual field lid masses, proptosis (exophthalmos), and abnormal pulsations. Pal-
of each eye in turn. The child’s bottle, a favorite toy, and lollipops are pation is also important in detecting orbital and lid masses. Orbital
particularly effective attention-getting items. These gross methods can dermoids and capillary hemangiomas are frequently evaluated during
often detect diagnostically significant field changes such as the bitem- the external examination.
poral hemianopia of a chiasmal lesion or the homonymous hemiano- The lacrimal system is assessed by looking for evidence of tear defi-
pia of a cerebral lesion. ciency, overflow of tears (epiphora), erythema, and swelling in the
region of the tear sac or gland. The lacrimal gland is located in the
COLOR VISION TESTING superotemporal orbit, beneath the eyebrow. The tear drain system,
Color vision testing can be accomplished when a child is able to name which includes the lacrimal sac, is located within the medial wall of
or trace the test symbols, which include numbers, shapes, or other the orbit, where the eyelids meet the bridge of the nose. The sac is
symbols. The common color vision testing tools include Ishihara color massaged to check for reflux when obstruction is suspected. The pres-
plates or Hardy Rand Littler. Color vision testing is not frequently ence and position of the puncta are also checked.
necessary in young children; however, parents may request testing, The lids and conjunctivae are specifically examined for focal lesions,
particularly if their child seems to be slow in learning colors or if there foreign bodies, and inflammatory signs; loss and misdirection of lashes
is a family history of color vision deficiency. It is important to keep in should also be noted. When necessary, the lids can be everted in the
mind, and reassure parents that “color-deficient” children do not following manner: (1) instruct the patient to look down; (2) grasp the
misname colors, and that true “color blindness” is very rare and not lashes of the patient’s upper lid between the thumb and index finger of
compatible with normal vision. Defective color vision is common in 1 hand; (3) place a probe, a cotton-tipped applicator, or the thumb of
the other hand at the upper margin of the tarsal plate; and (4) pull the it may be performed with sedation or general anesthesia. A gross esti-
lid down and outward and evert it over the probe, using the instrument mate of pressure can be made by palpating the globe with the index
as a fulcrum. Foreign bodies commonly lodge in the concavity just fingers placed side by side on the upper lid above the tarsal plate.
above the lid margin and are exposed only by fully everting the lid.
The anterior segment of the eye is then evaluated with oblique focal Bibliography is available at Expert Consult.
illumination, noting the luster and clarity of the cornea, the depth and
clarity of the anterior chamber, and the features of the iris. Transillu-
mination of the anterior segment aids in detecting opacities and in
demonstrating atrophy or hypopigmentation of the iris; these latter
signs are important when ocular albinism is suspected. When neces-
sary, fluorescein dye can be used to aid in diagnosing abrasions, ulcer-
ations, and foreign bodies.
BIOMICROSCOPY (SLIT-LAMP EXAMINATION)

The slit-lamp exam provides a highly magnified view of the various
structures of the eye and an optical section through the media of the
eye—the cornea, aqueous humor, lens, and vitreous. Lesions can be
identified and localized according to their depth within the eye; the
resolution is sufficient to detect individual inflammatory cells in the
aqueous and anterior vitreous. With the addition of special lenses and
prisms, the angle of the anterior chamber and components of the
fundus also can be examined with a slit lamp. Biomicroscopy is often
crucial in trauma and in examining for iritis. It is also helpful in diag-
nosing many metabolic and genetic diseases of childhood.
FUNDUS EXAMINATION
(OPHTHALMOSCOPY)
The ideal setting for ophthalmoscopy is with a well-dilated pupil,
unless there are neurologic or other contraindications. Tropicamide
(Mydriacyl) 0.5-1% and phenylephrine (Neo-Synephrine) 2.5% are
recommended as mydriatics of short duration. These are safe for most
children, but the possibility of adverse systemic effects must be recog-
nized. For very small infants, especially 6 mo or younger, more dilute
preparations may be advisable. Beginning with posterior landmarks,
the disc and the macula, the 4 quadrants are systematically examined
by following each of the major vessel groups to the periphery. Retinal
hemorrhages, vascular anomalies, and posterior uveitis are often appre-
ciated during this segment of the examination. Color, cup, and contour
of the optic nerve should be noted as well. Abnormalities are frequently
followed with further imaging studies such as a CT or MRI or diag-
nostic testing such as automated perimetry (see “Visual Field Assess-
ment” above). The midperipheral retina can be seen if a child is directed
to look up and down and to the right and left. Even with care, only a
limited fraction of the fundus can be seen with a direct or handheld
ophthalmoscope. For examination of the far periphery, an indirect
ophthalmoscope is used, and full dilation of the pupil is essential.
REFRACTION
Refraction determines the focusing power of the eye: the degree of
nearsightedness (hypermetropia), farsightedness (myopia), or astigma-
tism. Retinoscopy provides an objective determination of the amount
of correction needed and can be performed at any age, including the
newborn period. In young children, it is best done with cycloplegia
using cyclopentolate 1% eyedrops in an ophthalmologist’s office. Sub-
jective refinement of refraction involves asking patients for preferences
in the strength and axis of corrective lenses; it can be accomplished in
many school-age children. Refraction and determination of visual
acuity with appropriate corrective lenses in place are essential steps in
deciding whether a patient has a visual defect or amblyopia. Photo-
screening cameras aid ancillary medical personnel in screening for
refractive errors in preverbal children. The accuracy and practical use-
fulness of these devices are still being investigated.
TONOMETRY
Tonometry is the method of assessing intraocular pressure. It may be
performed with a portable, stand-alone instrument or by the applana-
tion method during slit-lamp examination. Alternative methods are
pneumatic, electronic, or rebound tonometry. When accurate mea-
surement of the pressure is necessary in a child who cannot cooperate,
Chapter 619 ◆ Examination of the Eye 3019.e1
Bibliography Fulton A: Screening preschool children to detect visual and ocular disorders, Arch
Committee on Practice and Ambulatory Medicine, Section on Ophthalmology. Ophthalmol 110:1553–1554, 1992.
American Association of Certified Orthoptists; American Association for Isenberg SJ: Clinical application of the pupil examination in neonates, J Pediatr
Pediatric Ophthalmology and Strabismus; American Academy of 118:650–652, 1991.
Ophthalmology: Eye examination in infants, children, and young adults by Salcido AA, Bradley J, Donahue SP: Predictive value of photoscreening and
pediatricians, Pediatrics 111:902–907, 2003. traditional screening of preschool children, J AAPOS 9:114–120, 2005.
Donahue SP, Johnson TM, Ottar W, et al: Sensitivity of photoscreening to detect
high-magnitude amblyogenic factors, J AAPOS 6:86–91, 2002.
Chapter 620 ◆ Abnormalities of Refraction and Accommodation 3019
Chapter 620
Abnormalities of
Refraction and
Accommodation
Emmetropia is the state in which parallel rays of light come to focus

on the retina with the eye at rest (nonaccommodating). Even though
such an ideal optical state is common, the opposite condition, ametro-
pia, often occurs. Three principal types of ametropia exist: hyperopia
(farsightedness), myopia (nearsightedness), and astigmatism (Fig.
620-1). The majority of children are physiologically hyperopic at birth.
Yet a significant number, especially those born prematurely, are myopic
and often have some degree of astigmatism. With growth the refractive
state tends to change and should be evaluated periodically.
Measurement of the refractive state of the eye (refraction) can be
accomplished both objectively and subjectively. The objective method
involves directing a beam of light from a retinoscope onto a patient’s
retina. Using loose lenses of various strengths held in front of the eye,
the retinal light reflex (viewed through the pupil) can be neutralized,
yielding a precise refraction. An objective refraction is obtainable at
any age because it requires no response from the patient. In infants and
children, it is generally more accurate to perform a refraction after
instillation of eyedrops that produce mydriasis (dilation of the pupil)
and cycloplegia (paralysis of accommodation); those used most com-
monly are tropicamide (Mydriacyl), cyclopentolate (Cyclogyl), and
atropine sulfate. A subjective refraction involves placing lenses in front
of the eye and having the patient report which lenses provide the clear-
est image of the letters on a chart. This method is dependent on a
patient’s ability to discriminate and communicate, but can be used for
some children and can be helpful in determining the best refractive
correction for children who are developmentally capable.
HYPEROPIA
If parallel rays of light come to focus posterior to the retina with the
eye in a neutral state, hyperopia or farsightedness exists. This may
result from a shorter anteroposterior diameter of the eye or a lower
refractive power of the cornea or lens.
In hyperopia, the additional refracting power needed to bring
objects into focus at distance and near is generated through the accom-
modative mechanism. If the accommodative effort required for focus
is within that child’s accommodative amplitude, the vision is clear. In
high degrees of hyperopia requiring greater accommodative effort,
vision may be blurred, and the child may complain of eyestrain, head-
aches, or fatigue. Squinting, eye rubbing, and lack of interest in reading
are frequent manifestations. If the induced discomfort is great enough,
a child may not make an effort to focus and may develop bilateral
amblyopia (ametropic amblyopia). Esotropia may also be associated
(see discussion on convergent strabismus, accommodative esotropia in
Chapter 623). Convex lenses (spectacles or contact lenses) of sufficient
Figure 620-1 Schematic optics of the eye. A, B, and C, Emmetropic

eyes. D, Hyperopic eyes. E, F, and G, Myopic eyes. A, In emmetropic
eyes, the parallel rays of a distant object are focused on the photore-
ceptors. B, When a closer object is viewed, the image is in focus behind
the photoreceptors. The image can be brought forward into focus on
the photoreceptors by the process of accommodation—increasing the
optical power of the lens (C). In hyperopic eyes (D), the eye is too short,
and the image of a distant object is focused behind the photorecep-
tors, and can be brought into focus by accommodation. Myopic eyes
A are eyes that have grown too long (E), and the image of a distant object
falls in front of the photoreceptors, and cannot be brought into focus
by accommodation. When closer objects are viewed, the image moves
back toward the photoreceptors, and at a certain distance (the far
point), which is related inverse to the severity of the myopia, it comes
into focus (F). Closer objects can then be brought into focus using
accommodation. Optical correction for myopia is achieved with
concave (diverging) lenses, which move the image into focus on the
photoreceptors (G). Contact lenses work in a similar way, whereas
B refractive surgery reduces the power of the cornea to bring the image
of distant objects into focus. For equal corneal power, myopic eyes
have longer axial lengths than emmetropic eyes, with deeper anterior
and vitreal chambers. Their lenses tend to be thinner and of lower
power than those of emmetropic eyes. (From Morgan IG, Ohno-Matusi
K, Saw SM: Myopia. Lancet 379:1739–1746, 2012, Fig. 1, p. 1740.)
C strength to provide clear vision and comfort are prescribed when indi-
cated. Even children who have high degrees of hyperopia but who have
good vision will happily wear glasses because they provide comfort by
eliminating the excessive accommodation required to see well. Prever-
bal children should also be given glasses for high levels of hyperopia
to prevent the development of esotropia or amblyopia. Children with
normal levels of hyperopia do not require correction in the majority
of cases.
MYOPIA
D In myopia, parallel rays of light come to focus anterior to the retina.
This is a result of either a long anteroposterior diameter of the eye or
a higher refractive power of the cornea or lens. The principal symptom
is blurred vision for distant objects. The far point of clear vision varies
inversely with the degree of myopia; as the myopia increases, the far
point of clear vision moves closer to the eye. With myopia of 1 diopter,
for example, the far point of clear focus is 1 m from the eye; with
myopia of 3 diopters, the far point of clear vision is only 1 3 m from the
eye. Thus, myopic children tend to hold objects and reading material
closer, prefer to be close to the blackboard, and may be uninterested
in distant activities. Squinting is common because the visual acuity is
E
improved when the lid aperture is reduced, also known as the pinhole
effect.
Myopia is infrequent in infants and preschool-age children. It is
more common in infants with a history of retinopathy of prematurity.
A hereditary tendency to myopia is also observed, and children of
myopic parents should be examined at an early age. The incidence of
myopia increases during the school years, especially during the preteen
and teen years. The degree of myopia also increases with age during
the growing years.
F
Concave lenses (spectacles or contact lenses) of appropriate strength
to provide clear vision and comfort are prescribed. Changes are usually
needed periodically, from every few months to every 1-2 yr. Excessive
accommodation during near work has been considered by some to lead
to progression of myopia. Based on this philosophy, some practitioners
advocate the use of cycloplegic agents, bifocals, intentional undercor-
rection of myopic refractive errors, or mandatory removal of myopic
glasses for near work in an effort to retard the progression of myopia.
G The value of such treatment has not been scientifically proven.
Excimer laser correction for myopia has been approved for adults
since 1995. The laser is applied to the corneal stroma to reshape the
cornea, changing its refractive power. LASIK (laser-assisted in situ
keratomileusis) uses either a microkeratome or a femtosecond laser to
produce an epithelial-stromal flap permitting the underlying corneal
tissue to be ablated. The flap is then reseated and assumes the altered Chapter 622). An apparent defect in accommodation may be psycho-
corneal shape. Photorefractive keratectomy (PRK) uses manual genic in origin; it is common for a child to feign inability to read when
removal of the epithelium following treatment with alcohol to expose it can be demonstrated that visual acuity and ability to focus are
the Bowman layer and stroma, which is then treated by the excimer normal.
laser. The epithelium regenerates to cover the defect over a period of
4-10 days. Visual improvement is usually significant and remains stable Bibliography is available at Expert Consult.
over time. Risks are greatest with high degrees of myopia (>10 diop-
ters) and include starbursts, halos, and distorted images or multiple
images (usually at night). Refractive surgery is not approved for pedi-
atric patients but is being used off-label to treat of some forms of
amblyopia and certain circumstances of myopia and astigmatism,
usually by PRK.
In most cases, myopia is not a result of pathologic alteration of the
eye and is referred to as simple or physiologic myopia. Some children
may have pathologic myopia, a rare condition caused by a pathologi-
cally abnormal axial length of the eye; this is usually associated with
thinning of the sclera, choroid, and retina and often with some degree
of uncorrectable visual impairment. Tears or breaks in the retina may
occur as it becomes increasingly thin, leading to the development of
retinal detachments. Myopia may also occur as a result of other ocular
abnormalities, such as keratoconus, ectopia lentis, congenital station-
ary night blindness, and glaucoma. Myopia is also a major feature of
Stickler syndrome, a genetic disorder of connective tissue involving
problems with vision, hearing, and facial and skeletal development.
ASTIGMATISM
In astigmatism, the refractive powers of the various meridians of the
eye differ. Most cases are caused by irregularity in the curvature of the
cornea, although some astigmatism results from changes in the lens.
Mild degrees of astigmatism are common and may produce no symp-
toms. With greater degrees, distortion of vision can occur. To achieve
a clearer image, a person with astigmatism uses accommodation or
squints to obtain a pinhole effect. Symptoms include eyestrain, head-
ache, and fatigue. Cylindrical or spherocylindrical lenses are used to
provide optical correction when indicated. Glasses may be needed
constantly or only part time, depending on the degree of astigmatism
and the severity of the attendant symptoms. In some cases, contact
lenses are used.
Infants and children with corneal irregularity resulting from injury,
ptosis, or hemangiomas of the periorbita or eyelid are at increased risk
of astigmatism and associated amblyopia.
ANISOMETROPIA
When the refractive state of one eye is significantly different from the
refractive state of the other eye, anisometropia exists. If uncorrected,
1 eye may always be out of focus, leading to the development of ambly-
opia. Early detection and correction are essential if normal visual
development in both eyes is to be achieved.
ACCOMMODATION
During accommodation, the ciliary muscle contracts, the suspensory
fibers of the lens relax, and the lens assumes a more rounded shape,
adding power to the lens. The amplitude of accommodation is greatest
during childhood and gradually diminishes with age. The physiologic
decrease in accommodative ability that occurs with age is called
presbyopia.
Disorders of accommodation in children are relatively rare. Prema-
ture presbyopia is occasionally encountered in young children. The
most common cause of paralysis of accommodation in children is
intentional or inadvertent use of cycloplegic substances, topically or
systemically; included are all the anticholinergic drugs and poisons, as
well as plants and plant substances having these effects. Neurogenic
causes of accommodative paralysis include lesions affecting the oculo-
motor nerve (3rd cranial nerve) in any part of its course. Differential
diagnoses include tumors, degenerative diseases, vascular lesions,
trauma, and infectious etiologies. Systemic disorders that may cause
impairment of accommodation include botulism, diphtheria, Wilson
disease, diabetes mellitus, and syphilis. Adie tonic pupil may also lead
to a deficiency of accommodation after some viral illnesses (see
Chapter 620 ◆ Abnormalities of Refraction and Accommodation 3021.e1
Bibliography Kuo A, Sinatra RB, Donahue SP: Distribution of refractive error in healthy infants,
Bastawrous A, Silvester A, Batterbury M: Laser refractive eye surgery, BMJ J AAPOS 7:174–177, 2003.
342:d2345, 2011. Larsson EK, Rydberg AC, Holmstrom GE: A population-based study of the
Brown NP, Koretz JF, Bron AJ: The development and maintenance of emmetropia, refractive outcome in 10-year-old preterm and full-term children, Arch
Eye (Lond) 13:83–92, 1999. Ophthalmol 121:1430–1436, 2003.
Ding X, Wang D, Huang Q, et al: Distribution and heritability of peripheral eye Mayer DL, Hansen RM, Moore BD, et al: Cycloplegic refractions in healthy
length in Chinese children and adolescents: the Guangzhou Twin Eye Study, children aged 1 through 48 months, Arch Ophthalmol 119:1625–1628, 2001.
Invest Ophthalmol Vis Sci 54:1048–1053, 2013. Morgan IG, Ohno-Matusi K, Saw SM: Mypoia, Lancet 379:1739–1746, 2012.
French AN, Morgan IG, Burlutsky G, et al: Prevalence and 5- to 6-year incidence Paysse EA, Coats DK, Hussein MA, et al: Long-term outcomes of photorefractive
and progression of myopia and hyperopia in Australian schoolchildren, keratectomy for anisometropic amblyopia in children, Ophthalmology
Ophthalmology 120(7):1482–1491, 2013. 113:169–176, 2006.
Kleinstein RN, Sinnott LT, Jones-Jordan LA, et al: New cases of myopia in Sakimoto T, Rosenblatt MI, Azar DT: Laser eye surgery for refractive errors, Lancet
children, Arch Ophthalmol 130:1274–1279, 2012. 369:1432–1447, 2006.
Klimek DL, Cruz OA, Scott WE, et al: Isoametropic amblyopia due to high Ton Y, Wysenbeek YS, Spierer A: Refractive error in premature infants, J AAPOS
hyperopia in children, J AAPOS 8:310–313, 2004. 8:534–538, 2004.
Chapter 621 ◆ Disorders of Vision 3021
Chapter 621
Disorders of Vision
Severe visual impairment (corrected vision poorer than 6/60) and

blindness in children have many etiologies and may be caused by
multiple defects affecting any structure or function along the visual
pathways (Table 621-1). The overall incidence is approximately 2.5 per
100,000 children; the incidence is higher in developing countries, in
low birthweight infants, and in the 1st yr of life. The most common
causes occur during the prenatal and perinatal time periods; the
cerebral-visual pathways, optic nerve, and retinal sites are most often
affected. Important prenatal causes include autosomal recessive (most
common), autosomal dominant, and X-linked genetic disorders as
well as hypoxia and chromosomal syndromes. Perinatal/neonatal
causes include retinopathy of prematurity, hypoxia–ischemia, and
infection. Severe visual impairment starting in older children may be
due to central nervous system or retinal tumors, infections, hypoxia–
ischemia, injuries, neurodegenerative disorders, or juvenile idiopathic
arthritis.
AMBLYOPIA
This is a decrease in visual acuity, unilateral or bilateral, that occurs in
visually immature children as a result of a lack of a clear image project-
ing onto the retina. The unformed retinal image may occur secondary
to a deviated eye (strabismic amblyopia), an unequal need for vision
correction between the eyes (anisometropic amblyopia), a high
refractive error in both eyes (ametropic amblyopia), or a media
opacity within the visual axis (deprivation amblyopia).
The development of visual acuity normally proceeds rapidly in
infancy and early childhood. Anything that interferes with the forma-
tion of a clear retinal image during this early developmental period can
produce amblyopia. Amblyopia occurs only during the critical period
of development before the cortex has become visually mature, within
the 1st decade of life. The younger the child, the more susceptible he
or she is to the development of amblyopia.
The diagnosis of amblyopia is confirmed when a complete ophthal-
mologic examination reveals reduced acuity that is unexplained by an
organic abnormality. If the history and ophthalmologic examination
do not support the diagnosis of amblyopia in a child with poor vision,
consideration must be given to other causes (neurologic, psychologic).
Amblyopia is usually asymptomatic and can avoid detection until
vision screening, which may delay diagnosis as screening programs
often target school-age children. This is problematic as amblyopia is
more resistant to treatment at an older age, being reversed more rapidly
in younger children whose visual system is less mature. Thus, one key
to the successful treatment of amblyopia is early detection and prompt
intervention.
Most often treatment first consists of removing any media opacity
or prescribing appropriate glasses, if needed, so that a well-focused
retinal image can be produced in each eye. The sound eye is then
Table 621-1 Causes of Childhood Severe Visual Impairment or Blindness

CONGENITAL Special types: Dawson disease, Leigh disease, the Bassen-Kornzweig
Optic nerve hypoplasia or aplasia syndrome, Refsum disease
Septooptic dysplasia Retinal degenerations: retinitis pigmentosa and its variants and Leber
Optic coloboma congenital type
Congenital hydrocephalus Optic atrophies: congenital autosomal recessive type, infantile and
Hydranencephaly congenital autosomal dominant types, Leber disease, and atrophies
Porencephaly associated with hereditary ataxias—the types of Behr, of Marie, and
Micrencephaly of Sanger-Brown
Encephalocele, particularly occipital INFECTIOUS/INFLAMMATORY PROCESSES
Morning glory disc Encephalitis, especially in the prenatal infection syndromes caused by
Aniridia Toxoplasma gondii, cytomegalovirus, rubella virus, Treponema
Microphthalmia/anophthalmia pallidum, herpes simplex virus
Peters anomaly Meningitis; arachnoiditis
Rieger anomaly Chorioretinitis
Persistent pupillary membrane Endophthalmitis
Glaucoma Trachoma
Cataracts Keratitis
Persistent hyperplastic primary vitreous Uveitis
PHAKOMATOSES HEMATOLOGIC DISORDERS
Tuberous sclerosis Leukemia with central nervous system involvement
Neurofibromatosis (special association with optic glioma)
Sturge-Weber syndrome VASCULAR AND CIRCULATORY DISORDERS
von Hippel-Lindau disease Collagen vascular diseases
Arteriovenous malformations—intracerebral hemorrhage,
TUMORS subarachnoid hemorrhage
Retinoblastoma Central retinal occlusion
Optic glioma
Perioptic meningioma TRAUMA
Craniopharyngioma Contusion or avulsion of optic nerves, chiasm, globe, cornea
Cerebral glioma Cerebral contusion or laceration
Astrocytoma Intracerebral, subarachnoid, or subdural hemorrhage
Posterior and intraventricular tumors when complicated by Retinal detachment
hydrocephalus Laser injury
Pseudotumor cerebri
DRUGS AND TOXINS
NEURODEGENERATIVE DISEASES Quinine
Cerebral storage disease Ethambutol
Gangliosidoses, particularly Tay-Sachs disease, Sandhoff variant, Methanol
generalized gangliosidosis Many others
Other lipidoses and ceroid lipofuscinoses, particularly the late-onset
OTHER
disorders such as those of Jansky-Bielschowsky and of Batten-
Retinopathy of prematurity
Mayou-Spielmeyer-Vogt
Sclerocornea
Mucopolysaccharidoses, particularly Hurler syndrome and Hunter
Conversion reaction
syndrome
Optic neuritis
Leukodystrophies (dysmyelination disorders), particularly
Osteopetrosis
metachromatic leukodystrophy and Canavan disease
Demyelinating sclerosis (myelinoclastic diseases), especially Schilder
disease and Devic neuromyelitis optica
Modified from Kliegman R: Practical strategies in pediatric diagnosis and therapy. Philadelphia, 1996, WB Saunders.
covered (occlusion therapy) or blurred with glasses (fogging) or drops DIPLOPIA

(penalization therapy) to stimulate proper visual development of the Diplopia, or double vision, is generally a result of a misalignment of
more severely affected eye. Occlusion therapy may provide a more the visual axes. Occluding either eye relieves the diplopia if it is bin-
rapid improvement in vision, but some children may better tolerate ocular in origin. Affected children commonly squint, cover 1 eye with
atropine penalization. The best treatment for any one patient should a hand, or assume an abnormal head posture (a face turn or head tilt)
be selected on an individual basis. The goals of treatment should be to alleviate the bothersome sensation. These behaviors, especially in
thoroughly understood, and the treatment carefully supervised. Close preverbal children, are important clues to diplopia. The onset of diplo-
monitoring of amblyopia therapy by an ophthalmologist is essential, pia in any child warrants prompt evaluation; it may signal the onset of
especially in the very young, to avoid deprivation amblyopia in the a serious problem such as increased intracranial pressure, a brain tumor,
good eye. Many families need reassurance and support throughout the infection (Lyme disease), migraine, Guillain-Barré syndrome, or an
trying course of treatment. Although full-time occlusion has histori- orbital mass.
cally been considered the best way to treat children with amblyopia, a Monocular diplopia results from dislocation of the lens, cataract, dry
series of prospective studies has shown that some children can achieve eyes, or some defect in the media or macula. With this type of diplopia,
similar results with part-time patching or through the use of atropine occluding the nondiplopic eye will not relieve the symptoms. Monocu-
drops. Historical thought was that older children would not respond lar diplopia may often have psychological causes.
to amblyopia therapy. Recent studies now suggest children deemed
visually mature who demonstrate amblyopia, particularly refractive or SUPPRESSION
anisometropic in etiology, can demonstrate improvement in vision In the presence of strabismus, diplopia occurs secondary to the same
with appropriate therapy. image falling on different regions of the retina in each eye. In a visually
immature child, a process may occur in the cortex that eliminates the PSYCHOGENIC DISTURBANCES
disability of seeing double. This is an active process and is termed sup- Vision problems of psychogenic origin are common in school-age
pression. It develops only in children. Although suppression eliminates children. Both conversion reactions and willful feigning are encoun-
the annoying symptom of diplopia, it is the potential awareness of a tered. The usual manifestation is a report of reduced visual acuity in 1
second image that tends to keep our eyes properly aligned. Once sup- or both eyes. Another common manifestation is constriction of the
pression develops, it may allow an intermittent strabismus to become visual field. In some cases, the symptom is diplopia or polyopia (see
constant or strabismus to redevelop later in life, even after successful Chapters 22 and 25).
treatment during childhood. Important clues to the diagnosis are inappropriate affect, excessive
grimacing, inconsistency in performance, and suggestibility. A thor-
AMAUROSIS ough ophthalmologic examination is essential to differentiate organic
Amaurosis is partial or total loss of vision; the term is usually reserved from functional visual disorders.
for profound impairment, blindness, or near blindness. When amaurosis Affected children usually fare well with reassurance and positive
exists from birth, primary consideration in the differential diagnosis suggestions. In some cases, psychiatric care is indicated. In all cases,
must be given to developmental malformations, damage consequent the approach must be supportive and nonpunitive.
to gestational or perinatal infection, anoxia or hypoxia, perinatal
trauma, and the genetically determined diseases that can affect the eye DYSLEXIA
itself or the visual pathways. Often, the reason for amaurosis can be This is the inability to develop the capability to read at an expected
readily determined by objective ophthalmic examination; examples are level despite an otherwise normal intellect. The terms reading disability
severe microphthalmia, corneal opacification, dense cataracts, chorio- and dyslexia are often used interchangeably. Most dyslexic individuals
retinal scars, macular defects, retinal dysplasia, and severe optic nerve also display poor writing ability. Dyslexia is a primary reading disorder
hypoplasia. In other cases, an intrinsic retinal disease may not be and should be differentiated from secondary reading difficulties caused
apparent on initial ophthalmoscopic examination or the defect may by intellectual disability, environmental or educational deprivation,
involve the brain and not the eye. Neuroradiologic (MRI or CT) and and systemic physical or other organic brain or eye diseases. Because
electrophysiologic (electroretinography) evaluation may be especially there is no one standard test for dyslexia, the diagnosis is usually made
helpful in these cases. by comparing reading ability with intelligence and standard reading
Amaurosis that develops in a child who once had useful vision has expectations. Dyslexia is a language-based disorder and is not caused
different implications. In the absence of obvious ocular disease (cata- by any defect in the eye or visual acuity per se, nor is it attributable to
ract, chorioretinitis, retinoblastoma, retinitis pigmentosa), consider- a defect in ocular motility or binocular alignment. Although ophthal-
ation must be given to many neurologic and systemic disorders that mologic evaluation of children with a reading problem is recom-
can affect the visual pathways. Amaurosis of rather rapid onset may mended to diagnose and correct any concurrent ocular problems such
indicate an encephalopathy (hypertension), infectious or parainfec- as a refractive error, amblyopia, or strabismus, treatment directed to
tious processes, vasculitis, migraine, leukemia, toxins, or trauma. It the eyes themselves cannot be expected to correct developmental dys-
may be caused by acute demyelinating disease affecting the optic lexia (see Chapter 34).
nerves, chiasm, or cerebrum. In some cases, precipitous loss of vision
is a result of increased intracranial pressure, rapidly progressive hydro- Bibliography is available at Expert Consult.
cephalus, or dysfunction of a shunt. More slowly progressive visual loss
suggests tumor or neurodegenerative disease. Gliomas of the optic
nerve and chiasm and craniopharyngiomas are primary diagnostic
considerations in children who show progressive loss of vision.
Clinical manifestations of impairment of vision vary with the age
and abilities of a child, the mode of onset, and the laterality and severity
of the deficit. The first clue to amaurosis in an infant may be nystagmus
or strabismus, with the vision deficit itself passing undetected for
some time. Timidity, clumsiness, or behavioral change may be the
initial clues in the very young. Deterioration in school progress and
indifference to school activities are common signs in an older child.
School-age children often try to hide their disability and, in the case
of very slowly progressive disorders, may not themselves realize the
severity of the problem; some detect and promptly report small changes
in their vision.
Any evidence of loss of vision requires prompt and thorough oph-
thalmic evaluation. Complete delineation of childhood amaurosis and
its cause may require extensive investigation involving neurologic
evaluation, electrophysiologic tests, neuroradiologic procedures, and
sometimes metabolic and genetic studies. Furthermore, attendant
special educational, social, and emotional needs must be met.
NYCTALOPIA
Nyctalopia, or night blindness, is vision that is defective in reduced
illumination. It generally implies impairment in function of the rods,
particularly in dark adaptation time and perceptual threshold. Station-
ary congenital night blindness may occur as an autosomal dominant,
autosomal recessive, or X-linked recessive condition. It may be associ-
ated with myopia and nystagmus. Children may have excessive prob-
lems going to sleep in a dark room, which may be mistaken for a
behavioral problem. Progressive night blindness usually indicates
primary or secondary retinal, choroidal, or vitreoretinal degeneration
(see Chapter 630); it occurs also in vitamin A deficiency or as a result
of retinotoxic drugs such as quinine.
Chapter 621 ◆ Disorders of Vision 3023.e1
Bibliography Pediatric Eye Disease Investigator Group: A randomized trial of patching regimens
Dutton G, Cleary M: Should we be screening for and treating amblyopia? Br Med J for treatment of moderate amblyopia in children, Arch Ophthalmol 121:603–
327:1242–1243, 2003. 611, 2003.
Friedman DI: Pearls: diplopia, Semin Neurol 30:54–65, 2010. Pediatric Eye Disease Investigator Group: Randomized trial of treatment of
Gunton KB: Advances in amblyopia: what have we learned from PEDIG trials? amblyopia in children aged 7 to 17 years, Arch Ophthalmol 123:437–447, 2005.
Pediatrics 131:540–547, 2013. Pediatric Eye Disease Investigator Group: Stability of visual acuity improvement
Habib M, Giraud K: Dyslexia, Handb Clin Neurol 111:229–235, 2013. following discontinuation of amblyopia treatment in children aged 7 to 12
Holmes JM, Clarke MP: Amblyopia, Lancet 367:1343–1351, 2006. years, Arch Ophthalmol 125:655–659, 2007.
Olitsky SE, Nelson LB: Reading disorders in children, Pediatr Clin North Am Rahl JS, Cable N: Severe visual impairment and blindness in children in the UK,
50:213–224, 2003. Lancet 362:1359–1364, 2003.
Pediatric Eye Disease Investigator Group: A randomized trial of atropine vs. Shaywitz SE, Shaywitz BA: The science of reading and dyslexia, J AAPOS
patching for treatment of moderate amblyopia in children, Arch Ophthalmol 7:158–166, 2003.
120:268–278, 2002. Simons K: Amblyopia characterization, treatment, and prophylaxis, Surv
Pediatric Eye Disease Investigator Group: A randomized trial of prescribed Ophthalmol 50:123–166, 2005.
patching regimens for treatment of severe amblyopia in children,
Ophthalmology 110:2075–2087, 2003.
Chapter 622 ◆ Abnormalities of Pupil and Iris 3023
Chapter 622
Abnormalities of Pupil
and Iris
ANIRIDIA
The term aniridia is a misnomer because iris tissue is usually present,
although it is hypoplastic (Fig. 622-1). Two thirds of the cases are
dominantly transmitted with a high degree of penetrance. The other
third of cases are sporadic and are considered to be new mutations.
The condition is bilateral in 98% of all patients, regardless of the means
of transmission, and is found in approximately 1/50,000 persons. PAX6
is the mutated gene at the chromosome 11p3 region.
Aniridia is a panocular disorder and should not be thought of as an
isolated iris defect. Macular and optic nerve hypoplasias are commonly
present and lead to decreased vision and sensory nystagmus. The visual
acuity is measured as 20/200 in most patients, although the vision may
occasionally be better. Other ocular deformities are common and may
involve the lens and cornea. The cornea may be small, and a cellular
infiltrate (pannus) occasionally develops in the superficial layers of
externally visible part of an extensive malclosure of the embryonic

fissure that also involves the fundus and optic nerve. When this occurs,
vision is likely to be severely affected. Therefore, all children with an
iris coloboma should undergo a full ophthalmologic examination.
MICROCORIA
Microcoria (congenital miosis) appears as a small pupil that does not
react to light or accommodation and that dilates poorly, if at all, with
medication. The condition may be unilateral or bilateral. In bilateral
cases, the degree of miosis may be different in each eye. The eye may
be otherwise normal or may demonstrate other abnormalities of the
anterior segment. Congenital microcoria is usually transmitted as an
autosomal dominant trait, although it may occur sporadically.
CONGENITAL MYDRIASIS
Figure 622-1 Partial aniridia in a member of an autosomal dominant In this disorder, the pupils appear dilated, do not constrict significantly
pedigree. (From Hoyt CS, Taylor D, editors: Pediatric ophthalmology to light or near gaze, and respond minimally to miotic agents. The
and strabismus, ed 4, Philadelphia, 2013, Elsevier Saunders, Fig. 32.22, iris is otherwise normal, and affected children are usually healthy.
p. 304.) Trauma, pharmacologic mydriasis, and neurologic disorders should be
considered. Many apparent cases of congenital mydriasis show abnor-
malities of the central iris structures and may be considered a form of
aniridia.
DYSCORIA AND CORECTOPIA

Dyscoria is abnormal shape of the pupil, and corectopia is abnormal
pupillary position. They may occur together or independently as con-
genital or acquired anomalies.
Congenital corectopia is usually bilateral and symmetric and rarely
occurs as an isolated anomaly; it is usually accompanied by dislocation
of the lens (ectopia lentis et pupillae), and the lens and pupil are com-
monly dislocated in opposite directions. Ectopia lentis et pupillae is
transmitted as an autosomal recessive disorder; consanguinity is
common. It is associated with mutations in ADAMTSL4, a secreted
glycoprotein widely distributed in the eye, which binds fibrillin-1
microfibrils and accelerates microfibril biogenesis.
Figure 622-2 Coloboma (“keyhole pupil”). (From Hoyt CS, Taylor D, When acquired, distortion and displacement of the pupil are fre-
editors: Pediatric ophthalmology and strabismus, ed 4, Philadelphia, quently a result of trauma or intraocular inflammation. Prolapse of the
2013, Elsevier Saunders, Fig. 38.11, p. 372.) iris after perforating injuries of the eye leads to peaking of the pupil in
the direction of the perforation. Posterior synechiae (adhesions of the
iris to the lens) are commonly seen when inflammation due to any
cause occurs in the anterior segment.
the peripheral cornea. Clinically, this appears as a gray opacification.
Lens abnormalities include cataract formation and partial or total lens ANISOCORIA
dislocation. Glaucoma develops in as many as 75% of individuals with This is inequality of the pupils. The difference in size may be a result
aniridia. of local or neurologic disorders. As a rule, if the inequality is more
One fifth of sporadic aniridic patients may develop Wilms tumor pronounced in the presence of bright focal illumination or on near
(see Chapter 499.1). gaze, there is a defect in pupillary constriction and the larger pupil
The gene for aniridia is very close to the Wilms tumor gene; dele- is abnormal. If the anisocoria is worse in reduced illumination, a
tions in this area cause the association. Of particular interest is the defect in dilation exists and the smaller pupil is abnormal. Neurologic
association of aniridia, genitourinary anomalies, mental retardation, causes of anisocoria (parasympathetic or sympathetic lesions) must
and a partial deletion of the short arm of chromosome 11. Among be differentiated from local causes such as synechiae (adhesions),
individuals thus affected, the appearance of Wilms tumor is more congenital iris defects (colobomas, aniridia), and pharmacologic
common. It is thought that only patients with sporadic aniridia are at effects. Horner syndrome is an important cause of anisocoria (see
risk for developing Wilms tumor, although Wilms tumor has occurred below). Simple central anisocoria may occur in otherwise healthy
in a patient with familial aniridia. Wilms tumor usually presents individuals.
before the 5th yr. Therefore, these children should be screened using
renal ultrasonography every 3-6 mo until approximately 5 yr of age if DILATED FIXED PUPIL
there is an 11p13 region deletion placing the child at risk for Wilms Differential diagnosis of a dilated unreactive pupil includes internal
tumor. ophthalmoplegia caused by a central or peripheral lesion, Hutchinson
pupil of transtentorial herniation, tonic pupil, pharmacologic block-
COLOBOMA OF THE IRIS ade, and iridoplegia secondary to ocular trauma.
This developmental defect may present as a defect in a sector of the The most common cause of a dilated unreactive pupil is purposeful
iris, a hole in the substance of the iris, or a notch in the pupillary or accidental instillation of a cycloplegic agent, particularly atropine
margin (Fig. 622-2). Simple colobomas are frequently transmitted as and related substances. Central nervous system lesions, such as a pine-
an autosomal dominant trait and may occur alone or in association aloma, may cause internal ophthalmoplegia in children. Because the
with other anomalies. A coloboma is formed when the embryonic external surface of the oculomotor nerve carries the fibers responsible
fissure fails to close completely. Because of the anatomic location of the for pupillary constriction, compression of the nerve along its intracra-
embryonic fissure, an iris coloboma is always located inferiorly, giving nial course may be associated with internal ophthalmoplegia, even
the iris a keyhole appearance. An iris coloboma may be the only before the development of ptosis or an ocular motility deficit. Although
Chapter 622 ◆ Abnormalities of Pupil and Iris 3025
ophthalmoplegic migraine is a common cause of a 3rd nerve palsy

with pupillary involvement in children, an intracranial aneurysm must
also be considered in the differential diagnosis. The blown pupil of
transtentorial herniation, occurring with increasing intracranial pres-
sure, is generally unilateral, and patients usually are obviously ill. The
pilocarpine test can help differentiate neurologic iridoplegia from
pharmacologic blockade. In the case of neurologic iridoplegia, the
dilated pupil constricts within minutes after instillation of 1 or 2 drops A
of 0.5–1% pilocarpine; if the pupil has been dilated with atropine,
pilocarpine has no effect. Because pilocarpine is a long-acting drug,
this test is not to be used in acute situations in which pupillary signs
must be carefully monitored. Because of the consensual pupil response
to light, even complete uniocular blindness does not cause a unilater-
ally dilated pupil.
TONIC PUPIL
This is typically a large pupil that reacts poorly to light (the reaction B
may be very slow or essentially nil), reacts poorly and slowly to accom-
modation, and redilates in a slow, tonic manner. The features of tonic Figure 622-3 Left congenital Horner syndrome showing upper- and
pupil are explained by cholinergic supersensitivity of the sphincter lower-lid ptosis and an iris heterochromia, with the lighter eye being
after peripheral (postganglionic) denervation and imperfect reinnerva- the affected eye. A, In bright light and (B) in the dark. (From Hoyt CS,
tion. A distinctive feature of a tonic pupil is its sensitivity to dilute Taylor D, editors: Pediatric ophthalmology and strabismus, ed 4,
Philadelphia, 2013, Elsevier Saunders, Fig. 63.9, p. 661.)
cholinergic agents. Instillation of 0.125% pilocarpine causes significant
constriction of the involved pupil and has little or no effect on the
unaffected side. The condition is usually unilateral.
Tonic pupil may develop after the acute stage of a partial or complete
iridoplegia. It can be seen after trauma to the eye or orbit and may ocular signs, particularly the anisocoria, may pass undetected for years.
occur in association with toxic or infectious conditions. For those in Horner syndrome is also seen in some children after thoracic surgery.
the pediatric age group, tonic pupil is uncommon. Infectious processes Congenital Horner syndrome may occur in association with vertebral
(primarily viral syndromes) and trauma are the primary causes. Fea- anomalies and with enterogenous cysts. In some infants and children,
tures of tonic pupil may also be seen in infants and children with Horner syndrome is the presenting sign of tumor in the mediastinal
familial dysautonomia (Riley-Day syndrome), although the signifi- or cervical region, particularly neuroblastoma. Rare causes of Horner
cance of these findings has been questioned. Tonic pupil has also been syndrome, such as vascular lesions, also occur in the pediatric age
reported in young children with Charcot-Marie-Tooth disease. The group. In many cases, no cause of congenital Horner syndrome can be
occurrence of tonic pupil in association with decreased deep tendon identified. Occasionally, the condition is familial.
reflexes in young women is referred to as Adie syndrome. When the cause of Horner syndrome is in question, investigative
procedures should be implemented and may include imaging of the
MARCUS GUNN PUPIL head, neck, and chest as well as 24-hr urinary catecholamine assay.
This relative afferent pupillary defect indicates an asymmetric, prechi- Examining old photographs and old records can sometimes be helpful
asmatic, afferent conduction defect. It is best demonstrated by the in establishing the age at onset of Horner syndrome.
swinging flashlight test, which allows comparison of the direct and The cocaine test is useful in diagnosing oculosympathetic paralysis;
consensual pupillary responses in both eyes. With patients fixing on a a normal pupil dilates within 20–45 min after instillation of 1 or 2
distant target (to control accommodation), a bright focal light is drops of 4% cocaine, whereas the miotic pupil of an oculosympathetic
directed alternately into each eye in turn. In the presence of an afferent paresis dilates poorly, if at all, with cocaine. In some cases, there is
lesion, both the direct response to light in the affected eye and the denervation supersensitivity to dilute phenylephrine; 1 or 2 drops of a
consensual response in the other eye are subnormal. Swinging the light 1% solution dilates the affected pupil but not the normal one. Further-
to the better or normal eye causes both pupils to react (constrict) more, instillation of 1% hydroxyamphetamine hydrobromide dilates
normally. Swinging the light back to the affected eye causes both pupils the pupil only if the postganglionic sympathetic neuron is intact.
to redilate to some degree, reflecting the defective conduction. This is
a very sensitive and useful test for detecting and confirming optic nerve PARADOXICAL PUPIL REACTION
and retinal disease. This test is only abnormal if there is a “relative” Some children exhibit paradoxical constriction of the pupils to
difference in the conduction properties of the optic nerves. Therefore, darkness. An initial brisk constriction of the pupils occurs when the
patients with bilateral and symmetrical optic nerve disease will not light is turned off, followed by slow redilation of the pupils. The
demonstrate an afferent pupillary defect. A subtle relative afferent response to direct light stimulation and the near response are normal.
defect may be found in some children with amblyopia. The mechanism is not clear, but paradoxical constriction of the pupils
in reduced light can be a sign of retinal or optic nerve abnormalities.
HORNER SYNDROME The phenomenon has been observed in children with congenital sta-
The principal signs of oculosympathetic paresis (Horner syndrome) tionary night blindness, albinism, retinitis pigmentosa, Leber congeni-
are homolateral miosis, mild ptosis, and apparent enophthalmos with tal retinal amaurosis, and Best disease. It has also been observed
slight elevation of the lower lid as a result of the slight ptosis. Patients in those with optic nerve anomalies, optic neuritis, optic atrophy,
may also have decreased facial sweating, increased amplitude of and possibly amblyopia. Thus, children with paradoxical pupillary
accommodation, and transient decrease in intraocular pressure. If constriction to darkness should have a thorough ophthalmologic
paralysis of the ocular sympathetic fibers occurs before the age of 2 yr, examination.
heterochromia iridis with hypopigmentation of the iris may occur on
the affected side (Fig. 622-3). PERSISTENT PUPILLARY MEMBRANE
Oculosympathetic paralysis may be caused by a lesion (tumor, Involution of the pupillary membrane and anterior vascular capsule of
trauma, infarction) in the midbrain, brainstem, upper spinal cord, the lens is usually completed during the 5th–6th mo of fetal develop-
neck, middle fossa, or orbit. Congenital oculosympathetic paresis, ment. It is common to see some remnants of the pupillary membrane
often as part of Klumpke brachial palsy, is common, although the in newborns, particularly in premature infants. These membranes are
nonpigmented strands of obliterated vessels that cross the pupil and retinal pseudotumor of Norrie disease, the so-called pseudoglioma of
may secondarily attach to the lens or cornea. The remnants tend to the Bloch-Sulzberger syndrome, retinal dysplasia, and the retinal
atrophy in time and usually present no problem. In some cases, lesions of the phakomatoses. A white reflex may also be seen with
however, significant remnants that remain obscure the pupil and inter- fundus coloboma, large atrophic chorioretinal scars, and ectopic med-
fere with vision. Rarely, there is patency of the vascular elements; ullation of retinal nerve fibers. Leukocoria is an indication for prompt
hyphema may result from rupture of persistent vessels. and thorough evaluation.
Intervention must be considered to minimize amblyopia in infants The diagnosis can often be made by direct examination of the eye
with extensive persistent pupillary membrane of sufficient degree to by ophthalmoscopy and biomicroscopy. Ultrasonographic and radio-
interfere with vision in the early months of life. In some cases, mydriat- logic examinations are often helpful. In some cases, the final diagnosis
ics and occlusion therapy may be effective, but in others, surgery may rests with a pathologist.
be needed to provide an adequate pupillary aperture.
HETEROCHROMIA
In heterochromia, the 2 irides are of different color (heterochromia
iridium) or a portion of an iris differs in color from the remainder
(heterochromia iridis). Simple heterochromia may occur as an autoso-
mal dominant characteristic. Congenital heterochromia is also a
feature of Waardenburg syndrome, an autosomal dominant condition
characterized principally by lateral displacement of the inner canthi
and puncta, pigmentary disturbances (usually a median white forelock
and patches of hypopigmentation of the skin), and defective hearing.
Change in the color of the iris may occur as a result of trauma, hemor-
rhage, intraocular inflammation (iridocyclitis, uveitis), intraocular
tumor (especially retinoblastoma), intraocular foreign body, glaucoma,
iris atrophy, oculosympathetic palsy (Horner syndrome), melanosis
oculi, previous intraocular surgery, and some glaucoma medications.
OTHER IRIS LESIONS

Discrete nodules of the iris, referred to as Lisch nodules, are commonly
seen in patients with neurofibromatosis (see Chapter 596.1). Lisch
nodules represent melanocytic hamartomas of the iris and vary from
slightly elevated pigmented areas to distinct ball-like excrescences. The
nodules cause no visual disturbance. Lisch nodules are found in
92-100% of individuals older than 5 yr of age who have neurofibro-
matosis. Slit-lamp identification of these nodules may help to fulfill
the criteria required to confirm the diagnosis of neurofibromatosis.
In leukemia (see Chapter 495), there may be infiltration of the iris,
sometimes with hypopyon, an accumulation of white blood cells in
the anterior chamber, which may herald relapse or involvement of the
central nervous system.
The lesion of juvenile xanthogranuloma (nevoxanthoendotheli-
oma; see Chapter 670) may occur in the eye as a yellowish fleshy mass
or plaque of the iris. Spontaneous hyphema (blood in the anterior
chamber), glaucoma, or a red eye with signs of uveitis may be associ-
ated. A search for the skin lesions of xanthogranuloma should be made
in any infant or young child with spontaneous hyphema. In many
cases, the ocular lesion responds to topical corticosteroid therapy.
LEUKOCORIA
This includes any white pupillary reflex, or so-called cat’s-eye reflex.
Primary diagnostic considerations in any child with leukocoria are
cataract, persistent hyperplastic primary vitreous, cicatricial retinopa-
thy of prematurity, retinal detachment and retinoschisis, larval granu-
lomatosis, and retinoblastoma (Fig. 622-4). Also to be considered are
endophthalmitis, organized vitreous hemorrhage, leukemic ophthal-
mopathy, exudative retinopathy (as in Coats disease), and less-common
conditions such as medulloepithelioma, massive retinal gliosis, the
Figure 622-4 Leukocoria. White pupillary reflex in a child with

retinoblastoma.
Chapter 622 ◆ Abnormalities of Pupil and Iris 3026.e1
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Chandra A, Aragon-Martin JA, Hughes K, et al: A genotype-phenotype 160:703–704, 2012.
comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis, Invest Maloney WF, Younge BR, Moyer NJ: Evaluation of the causes and accuracy of
Ophthalmol Vis Sci 53:4889–4896, 2012. pharmacologic localization in Horner syndrome, Am J Ophthalmol 90:394–402,
Cross HE: Ectopia lentis et pupillae, Am J Ophthalmol 88:381–384, 1979. 1980.
Frank JW, Kushner BJ, France TD: Paradoxic pupillary phenomenon: A review of Miller NR, Newman NJ, Biousse V, et al: Walsh and Hoyt’s Clinical Neuro-
patients with pupillary constriction to darkness, Arch Ophthalmol 106:1564– Ophthalmology: The Essentials. Philadelphia, 2008, Lippincott, Williams &
1566, 1988. Wilkins, pp 299–301.
Greenwald MJ, Folk ER: Afferent pupillary defects in amblyopia, J Pediatr Rennie IG: Don’t it make my blue eyes brown: heterochromia and other
Ophthalmol Strabismus 20:63–67, 1983. abnormalities of the iris, Eye (Lond) 26:29–50, 2012.
Jeffery AR, Ellis FJ, Repka MX, et al: Pediatric Horner syndrome, J AAPOS Thompson HS: Segmental palsy of the iris sphincter in Adie’s syndrome, Arch
2:159–167, 1998. Ophthalmol 96:1615–1620, 1978.
Loewenfeld IE: Simple, central” anisocoria: A common condition seldom
recognized, Trans Am Acad Ophthalmol Otolaryngol 83:832, 1977.
Chapter 623
Disorders of Eye
Movement and Alignment
STRABISMUS
Strabismus, or misalignment of the eyes, is one of the most common
eye problems encountered in children, affecting approximately 4% of
children younger than 6 yr of age. Strabismus can result in vision loss
(amblyopia) and can have significant psychological effects. Early detec-
tion and treatment of strabismus are essential to prevent permanent
visual impairment. Of children with strabismus, 30-50% develop
amblyopia. Restoration of proper alignment of the visual axis must
occur at an early stage of visual development to allow these children a
chance to develop normal binocular vision. The word strabismus
means “to squint or to look obliquely.” Many terms are used in discuss-
ing and characterizing strabismus.
Orthophoria is the ideal condition of exact ocular balance. It implies
that the oculomotor apparatus is in perfect equilibrium so that the eyes
remain coordinated and aligned in all positions of gaze and at all dis-
tances. Even when binocular vision is interrupted, as by occlusion of
one eye, truly orthophoric individuals maintain perfect alignment.
Orthophoria is seldom encountered because the majority of individu-
als have a small latent deviation (heterophoria).
Heterophoria is a latent tendency for the eyes to deviate. This latent
deviation is normally controlled by fusional mechanisms that provide
binocular vision or avoid diplopia (double vision). The eye deviates
only under certain conditions, such as fatigue, illness, or stress, or
during tests that interfere with maintenance of these normal fusional
abilities (such as covering one eye). If the amount of heterophoria is
large, it may give rise to bothersome symptoms, such as transient
diplopia (double vision), headaches, or asthenopia (eyestrain). Some
degree of heterophoria is found in normal individuals; it is usually
asymptomatic.
Heterotropia is a misalignment of the eyes that is constant. It occurs
because of an inability of the fusional mechanism to control the devia-
tion. Tropias can be alternating, involving both eyes, or unilateral. In
an alternating tropia, there is no preference for fixation of either eye,
and both eyes drift with equal frequency. Because each eye is used
periodically, vision usually develops normally. A unilateral tropia is a
more serious situation because only 1 eye is constantly misaligned. The
undeviated eye becomes the preferred eye, resulting in loss of vision
or amblyopia of the deviated eye.
Chapter 623 ◆ Disorders of Eye Movement and Alignment 3027
It is common in ocular misalignments to describe the type of devia- condition is characterized by the false appearance of strabismus when
tion. This helps to make decisions on the cause and treatment of the the visual axes are aligned accurately. This appearance may be caused
strabismus. The prefixes eso-, exo-, hyper-, and hypo- are added to the by a flat, broad nasal bridge, prominent epicanthal folds, or a narrow
terms phoria and tropia to further delineate the type of strabismus. interpupillary distance. The observer may see less white sclera nasally
Esophorias and esotropias are inward or convergent deviations of the than would be expected, and the impression is that the eye is turned
eyes, commonly known as crossed eyes. Exophorias and exotropias are in toward the nose, especially when the child gazes to either side.
divergent or outward-facing eye deviations, walleyed being the lay Parents frequently comment that when their child looks to the side,
term. Hyperdeviations and hypodeviations designate upward or down- the eye almost disappears from view. Pseudoesotropia can be differen-
ward, respectively, deviations of an eye. In cases of unilateral strabis- tiated from a true misalignment of the eyes when the corneal light
mus, the deviating eye is often part of the description of the reflex is centered in both eyes and when the cover–uncover test shows
misalignment (left esotropia). no refixation movement. Once pseudoesotropia has been confirmed,
parents can be reassured that the child will outgrow the appearance of
Diagnosis esotropia. As the child grows, the bridge of the nose becomes more
Many techniques are used to assess ocular alignment and movement prominent and displaces the epicanthal folds, and the medial sclera
of the eyes to aid in diagnosing strabismic disorders. In a child with becomes proportional to the amount visible on the lateral aspect. It is
strabismus or any other ocular disorder, assessment of visual acuity is the appearance of crossing that the child will outgrow. Some parents
mandatory. Decreased vision in 1 eye requires evaluation for a strabis- of children with pseudoesotropia erroneously believe that their child
mus or other ocular abnormalities, which may be difficult to discern has an actual esotropia that will resolve on its own. Because true eso-
on a brief screening evaluation. Even strabismic deviations of only a tropia can develop later in children with pseudoesotropia, parents and
few degrees in magnitude, too small to be evident by gross inspection, pediatricians should be cautioned that reassessment is required if the
may lead to amblyopia and significant vision loss. apparent deviation does not improve.
Corneal light reflex tests are perhaps the most rapid and easily per- Esodeviations are the most common type of ocular misalignment
formed diagnostic tests for strabismus. They are particularly useful in in children and represent >50% of all ocular deviations. Congenital
children who are uncooperative and in those who have poor ocular esotropia is a confusing term. Few children who are diagnosed with
fixation. To perform the Hirschberg corneal reflex test, the examiner this disorder are actually born with an esotropia. Most reports in the
projects a light source onto the cornea of both eyes simultaneously as literature have, therefore, considered infants with confirmed onset
a child looks directly at the light. Comparison should then be made of earlier than 6 mo as having the same condition, which some observers
the placement of the corneal light reflex in each eye. In straight eyes, have designated infantile esotropia.
the light reflection appears symmetric and, because of the relationship Between 2 and 4 mo of age, many infants have infantile esotropia
between the cornea and the macula, slightly nasal to the center of each (neonatal misalignments), which in most resolve spontaneously. Those
pupil. If strabismus is present, the reflected light is asymmetric and that resolve without treatment do so before 10-12 wk of age and had
appears displaced in one eye. The Krimsky method of the corneal reflex intermittent or variable deviations, while those who may benefit from
test uses prisms placed over one or both eyes to align the light reflec- active treatment have persistent esotropia (10 weeks–6 mo of age), a
tions. The amount of prism needed to align the reflections is used to constant esotropia (40 PD), a refractive error ≤ +3.00 D, and the
measure the degree of deviation. Although it is a useful screening test, absence of prematurity, developmental delay, meningitis, nystagmus,
corneal light reflex testing may not detect a small angle or an intermit- eye anomalies, and incomitant or paralytic strabismus. The evaluation
tent strabismus. is noted in Figure 623-1.
Cover tests for strabismus require a child’s attention and coopera- The characteristic angle of congenital esodeviations is large and
tion, good eye movement capability, and reasonably good vision in constant (Fig. 623-2). Because of the large deviation, cross-fixation is
each eye. If any of these are lacking, the results of these tests may not frequently encountered. This is a condition in which the child looks to
be valid. These tests consist of the cover–uncover test and the alternate the right with the left eye and to the left with the right eye. With cross-
cover test. In the cover–uncover test, a child looks at an object in the fixation, there is no need for the eye to turn away from the nose (abduc-
distance, preferably 6 m away. An eye chart is commonly used for fixation) as the adducting eye is used in side gaze; this condition simulates
tion in children older than 3 yr of age. For younger children, a noise- a 6th nerve palsy. Abduction can be demonstrated by the doll’s-head
making toy or movie helps hold their attention for the test. As the child maneuver or by patching 1 eye for a short time. Children with con-
looks at the distant object, the examiner covers 1 eye and watches for genital esotropia tend to have refractive errors similar to those of
movement of the uncovered eye. If no movement occurs, there is no normal children of the same age. This contrasts with the characteristic
apparent misalignment of that eye. After 1 eye is tested, the same pro- high level of farsightedness associated with accommodative esotropia.
cedure is repeated on the other eye. When performing the alternate Amblyopia is common in children with congenital esotropia.
cover test, the examiner rapidly covers and uncovers each eye, shifting The primary goal of treatment in congenital esotropia is to eliminate
back and forth from one eye to the other. If the child has an ocular or reduce the deviation as much as possible. Ideally, this results in
deviation, the eye rapidly moves as the cover is shifted to the other eye. normal sight in each eye, in straight-looking eyes, and in the develop-
Both the cover–uncover test and the alternate cover test should be ment of binocular vision. Early treatment is more likely to lead to the
performed at both distance and near fixation. The cover–uncover test development of binocular vision, which helps to maintain long-term
differentiates tropias, or manifest deviations, from latent deviations, ocular alignment. Once any associated amblyopia is treated, surgery is
called phorias. performed to align the eyes. Even with successful surgical alignment,
it is common for vertical deviations to develop in children with a
Clinical Manifestations and Treatment history of congenital esotropia. The 2 most common forms of vertical
The etiologic classification of strabismus is complex, and the causative deviations to develop are inferior oblique muscle overaction and dis-
types must be distinguished; there are comitant and noncomitant sociated vertical deviation. In inferior oblique muscle overaction, the
forms of strabismus. overactive inferior oblique muscle produces an upshoot of the eye
closest to the nose when the patient looks to the side (Fig. 623-3). In
Comitant Strabismus dissociated vertical deviation, 1 eye drifts up slowly with no movement
Comitant strabismus is the most common type of strabismus. The of the other eye. Surgery may be necessary to treat either or both of
individual extraocular muscles usually have no defect. The amount of these conditions.
deviation is constant, or relatively constant, in the various directions It is important that parents realize that early successful surgical
of gaze. alignment is only the beginning of the treatment process. Because
Pseudostrabismus (pseudoesotropia) is one of the most common many children may redevelop strabismus or amblyopia, they need to
reasons a pediatric ophthalmologist is asked to evaluate an infant. This be monitored closely during the visually immature period of life.
Infant with esotropia

> 4 mo of age
Light Abnormal motility Abnormal Cycloplegic With abducting Other Infantile esotropia
reflexes/cover test anterior/posterior refraction nystagmus Consider
segment early surgery
Exclude Ciancia syndrome Sensory esotropia Refractive error Ciancia syndrome Neurological
pseudoesotropia Type 1 ≥ +2.50 D Nystagmus association—
Duane syndrome Consider blockage CP, PVL
early-onset syndrome
Congenital cranial accommodative
dysinnervation esotropia
syndrome
Congenital 6th Systemic
nerve palsy association—
Infantile DS, albinism
myasthenia
gravis
Möbius
syndrome
Figure 623-1 Work-up of infant ≥4 mo of age with esotropia. CP, cerebral palsy; DS, Down syndrome; PVL, periventricular leukomalacia. (From
Hoyt CS, Taylor D, editors: Pediatric ophthalmology and strabismus, ed 4, Philadelphia, 2013, Elsevier Saunders, Fig. 74.4, p. 767.)
Figure 623-2 Congenital esotropia. Note the large angle of

crossing.
Accommodative esotropia is defined as a “convergent deviation of the

eyes associated with activation of the accommodative (focusing)
reflex.” It usually occurs in a child who is between 2 and 3 yr of age
and who has a history of acquired intermittent or constant crossing.
Amblyopia occurs in the majority of cases.
The mechanism of accommodative esotropia involves uncorrected
hyperopia, accommodation, and accommodative convergence. The
image entering a hyperopic (farsighted) eye is blurred. If the amount
of hyperopia is not significant, the blurred image can be sharpened by Figure 623-3 Inferior oblique muscle overaction.
accommodating (focusing of the lens of the eye). Accommodation
is closely linked with convergence (eyes turning inward). If a child’s
hyperopic refractive error is large or if the amount of convergence that
occurs in response to each unit of accommodative effort is great, eso-
tropia may develop.
The age at onset of intermittent exotropia varies but is often between

age 6 mo and 4 yr. The decision to perform eye muscle surgery is based
on the amount and frequency of the deviation. If the deviation is small
and infrequent, it is reasonable to observe the child. If the exotropia is
large or increasing in frequency, surgery is indicated to maintain
normal binocular vision.
Constant exotropia may rarely be congenital. Congenital exotropia
may be associated with neurologic disease or abnormalities of the bony
orbit, as in Crouzon syndrome. Exotropia that occurs later in life may
represent a deterioration of an intermittent exotropia that was present
in childhood. Surgery can restore binocular vision even in long-
standing cases.
Noncomitant Strabismus
When an eye muscle is paretic, palsied, or restricted, a muscle imbal-
ance occurs in which the deviation of the eye varies according to the
direction of gaze. Recent onset of a paretic muscle can be suggested by
the symptom of double vision that increases in one direction, the find-
ings of an ocular deviation that increases in the field of action of the
paretic muscle, and an increase in the deviation when the child fixates
with the paretic eye. It is important to differentiate a noncomitant
strabismus from a comitant deviation because noncomitant forms of
strabismus are often associated with trauma, systemic disorders, or
neurologic abnormalities.
Figure 623-4 Accommodative esotropia. Control of deviation with 3rd Nerve Palsy
corrective lenses. In the pediatric population, 3rd nerve palsies are usually congenital.
The congenital form is often associated with a developmental anomaly
or birth trauma. Acquired 3rd nerve palsies in children can be an
To treat accommodative esotropia, the full hyperopic (farsighted) ominous sign and may indicate a neurologic abnormality such as an
correction is initially prescribed. These glasses eliminate a child’s need intracranial neoplasm or an aneurysm. Other less-serious causes
to accommodate and therefore correct the esotropia (Fig. 623-4). include an inflammatory or infectious lesion, head trauma, postviral
Although many parents are initially concerned that their child will not syndromes, and migraines.
want to wear glasses, the benefits of binocular vision and the decrease A 3rd nerve palsy, whether congenital or acquired, usually results in
in the focusing effort required to see clearly provide a strong stimulus an exotropia and a hypotropia, or downward deviation of the affected
to wear glasses, and they are generally accepted well. The full hyperopic eye, as well as complete or partial ptosis of the upper lid. This charac-
correction sometimes straightens the eye position at distance fixation teristic strabismus results from the action of the normal, unopposed
but leaves a residual deviation at near fixation; this may be observed muscles, the lateral rectus muscle, and the superior oblique muscle.
or treated with bifocal lenses or surgery. If the internal branch of the 3rd nerve is involved, pupillary dilation
It is important to warn parents of children with accommodative may be noted as well. Eye movements are usually limited nasally in
esotropia that the esodeviation may appear to increase without glasses elevation and in depression. In addition, clinical findings and treat-
after the initial correction is worn. Parents frequently state that before ment may be complicated in congenital and traumatic cases of 3rd
wearing glasses, their child had a small esodeviation, whereas after nerve palsy owing to misdirection of regenerating nerve fibers, referred
removal of the glasses, the esodeviation becomes quite large. Parents to as aberrant regeneration. This results in anomalous and paradoxical
often blame the increased esodeviation on the glasses. This apparent eyelid, eye, and pupil movement such as elevation of the eyelid,
increase is a result of a child’s using the appropriate amount of accom- constriction of the pupil, or depression of the globe on attempted
modative effort after the glasses have been worn. When these children medial gaze.
remove their glasses, they continue to use an accommodative effort to
bring objects into proper focus and increase the esodeviation. 4th Nerve Palsy
Most children maintain straight eyes once initially treated. Because These palsies can be congenital or acquired. Because the 4th nerve has
hyperopia generally decreases with age, patients may outgrow the a long intracranial course, it is susceptible to damage resulting from
need to wear glasses to maintain alignment. In some patients, a resid- head trauma. In children, however, 4th nerve palsies are more fre-
ual esodeviation persists even when wearing their glasses. This condi- quently congenital than traumatic. A palsied 4th nerve results in weak-
tion commonly occurs when there is a delay between the onset of ness in the superior oblique muscle, which causes an upward deviation
accommodative esotropia and treatment. In others, the esotropia may of the eye, a hypertropia. Because the antagonist muscle, the inferior
initially be eliminated with glasses but crossing redevelops and is not oblique, is relatively unopposed, the affected eye demonstrates an
correctable with glasses. The crossing that is no longer correctable with upshoot when looking toward the nose. Children typically present with
glasses is the deteriorated or nonaccommodative portion. Surgery for a head tilt to the shoulder opposite the affected eye, their chin down,
this portion of the crossing may be indicated to restore binocular and their face turned away from the affected side. This head position
vision. places the eye away from the area of greatest action of the affected
Exodeviations are the second most common type of misalignment. muscle and therefore minimizes the deviation and the associated
The divergent deviation may be intermittent or constant. Intermittent double vision. Long-standing head tilts may lead to facial asymmetry.
exotropia is the most common exodeviation in childhood. It is char- Because the abnormal head posture maintains the child’s ocular align-
acterized by outward drifting of 1 eye, which usually occurs when a ment, amblyopia is uncommon. Because no abnormality exists in the
child is fixating at distance. The deviation is generally more frequent neck muscles, attempts to correct the head tilt by exercises and neck
with fatigue or illness. Exposure to bright light may cause reflex closure muscle surgery are ineffective. Recognition of a superior oblique
of the exotropic eye. Because the eyes initially can be kept straight most paresis can be difficult because deviation of the head and the eye may
of the time, visual acuity tends to be good in both eyes and binocular be minimal. Eye muscle surgery can be performed to improve the
vision is initially normal. ocular alignment and eliminate the abnormal head posture.
6th Nerve Palsy muscle, which results in cocontraction of the medial and lateral rectus
These palsies produce markedly crossed eyes with limited ability to muscles on attempted adduction of the affected eye. Within the spec-
move the afflicted eye laterally. Children frequently present with their trum of Duane syndrome, patients may exhibit impairment of abduc-
head turned toward the palsied muscle, a position that helps preserve tion, impairment of adduction, or upshoot or downshoot of the
binocular vision. The esotropia is largest when the eye is moved toward involved eye on adduction. They may have esotropia, exotropia, or
the affected muscle. relatively straight eyes. Many exhibit a compensatory head posture to
Congenital 6th nerve palsies are rare. Decreased lateral gaze in maintain single vision. Some develop amblyopia. Surgery to improve
infants is often associated with other disorders, such as congenital alignment or to reduce a noticeable face turn can be helpful in selected
esotropia or Duane retraction syndrome. In neonates, a transient 6th cases. Duane syndrome usually occurs sporadically. It is sometimes
nerve paresis can occur; it usually clears spontaneously by 6 wk. It is inherited as an autosomal dominant trait. It usually occurs as an iso-
believed that increased intracranial pressure associated with labor and lated condition but may occur in association with various other ocular
delivery is the contributing factor. and systemic anomalies.
Acquired 6th nerve palsies in childhood are often an ominous sign
because the 6th nerve is susceptible to increased intracranial pressure Möbius Syndrome
associated with hydrocephalous and intracranial tumors. Other causes The distinctive features of Möbius syndrome are congenital facial
of 6th nerve defects in children include trauma, vascular malforma- paresis and abduction weakness. The facial palsy is commonly bilateral,
tions, meningitis, and Gradenigo syndrome. A benign 6th nerve palsy, frequently asymmetric, and often incomplete, tending to spare the
which is painless and acquired, can be noted in infants and older chil- lower face and platysma. Ectropion, epiphora, and exposure keratopa-
dren. This is frequently preceded by a febrile illness or upper respira- thy may develop. The abduction defect may be unilateral or bilateral.
tory tract infection and may be recurrent. Complete resolution of the Esotropia is common. The cause is unknown. Whether the primary
palsy is usual. Although not uncommon, other causes of an acute 6th defect is maldevelopment of cranial nerve nuclei, hypoplasia of the
nerve palsy should be eliminated before this diagnosis is made. muscles, or a combination of central and peripheral factors is unclear.
Some familial cases have been reported. Associated developmental
Strabismus Syndromes defects may include ptosis, palatal and lingual palsy, hearing loss, pec-
Special types of strabismus have unusual clinical features. Most of these toral and lingual muscle defects, micrognathia, syndactyly, supernu-
disorders are caused by structural anomalies of the extraocular muscles merary digits, and the absence of hands, feet, fingers, or toes. Surgical
or adjacent tissues. Most strabismus syndromes produce noncomitant correction of the esotropia is indicated and any attendant amblyopia
misalignments. should be treated.
Monocular Elevation Deficiency Brown Syndrome

A monocular elevation deficit in both abduction and adduction is In this syndrome, elevation of the eye in the adducted position is
referred to as monocular elevation deficiency (previously called restricted (Fig. 623-6). An associated downward deviation of the
double-elevator palsy). It may represent a paresis of both elevators, the affected eye in adduction may also occur. A compensatory head
superior rectus and inferior oblique muscles, or a possible restriction posture may be evident. Brown syndrome occurs as a result of restric-
to elevation from a fibrotic inferior rectus muscle. When an affected tion of the superior oblique tendon as it moves through the trochlea.
child fixates with the nonparetic eye, the paretic eye is hypotropic and Cases may be congenital or acquired. Acquired Brown syndrome may
the ipsilateral upper eyelid may appear ptotic. Fixation with the paretic follow trauma to the orbit involving the region of the trochlea or sinus
eye causes a hypertropia of the nonparetic eye and a disappearance surgery. It may also occur with inflammatory processes, particularly
of the ptosis (Fig. 623-5). Because the apparent ptosis is actually sec- sinusitis and juvenile idiopathic arthritis.
ondary to the strabismus, correction of the hypotropia treats the Acquired inflammatory Brown syndrome may respond to treatment
pseudoptosis. with either nonsteroidal medications or corticosteroids. Surgery may
be helpful for selected cases of Brown syndrome.
Duane Syndrome
This congenital disorder of ocular motility is characterized by retrac- Parinaud Syndrome
tion of the globe on adduction. This is attributed to the absence of the This eponym designates a palsy of vertical gaze, isolated or associated
6th nerve nucleus and anomalous innervation of the lateral rectus with pupillary or nuclear oculomotor (3rd cranial nerve) paresis. It
indicates a lesion affecting the mesencephalic tegmentum. The oph-
thalmic signs of midbrain disease include vertical gaze palsy, dissocia-
tion of the pupillary responses to light and to near focus, general
pupillomotor paralysis, corectopia, dyscoria, accommodative distur-
bances, pathologic lid retraction, ptosis, extraocular muscle paresis,
and convergence paralysis. Some cases have associated spasms of con-
vergence, convergent retraction nystagmus, and vertical nystagmus,
particularly on attempted vertical gaze. Combinations of these signs
are referred to as the sylvian aqueduct syndrome.
B
Figure 623-5 Double-elevator palsy of the right eye. Note the disap-
pearance of the apparent ptosis when fixating with the involved eye. Figure 623-6 Brown syndrome of the right eye.
A principal cause of vertical gaze palsy and associated mesence- optic atrophy. In some instances, nystagmus occurs as a dominant or
phalic signs in children is tumor of the pineal gland or third ventricle. X-linked characteristic without obvious ocular abnormalities.
Differential diagnosis includes trauma and demyelinating disease. Congenital idiopathic motor nystagmus is characterized by hori-
In children with hydrocephalus, impairment of vertical gaze and zontal jerky oscillations with gaze preponderance; the nystagmus is
pathologic lid retraction are referred to as the setting-sun sign. A coarser in one direction of gaze than in the other, with the jerk toward
transient supranuclear disorder of gaze is sometimes seen in healthy the direction of gaze. There are no ocular anatomic defects that cause
neonates. the nystagmus, and the visual acuity is generally near normal. There
may be a null point in which the nystagmus lessens and the vision
CONGENITAL OCULAR MOTOR APRAXIA improves; a compensatory head posture will develop that places the
This congenital disorder of conjugate gaze is characterized by a defect eyes into the position of least nystagmus. The cause of congenital
in voluntary horizontal gaze, compensatory jerking movement of the idiopathic motor nystagmus is unknown; in some instances, it is
head, and retention of slow pursuit and reflexive eye movements. Addi- familial. Eye muscle surgery may be performed to eliminate an abnor-
tional features are absence of the fast (refixation) phase of optokinetic mal head posture by bringing the point of best vision into straight-
nystagmus and obligate contraversive deviation of the eyes on rotation ahead gaze.
of the body. Affected children typically are unable to look quickly to Acquired nystagmus requires prompt and thorough evaluation.
either side voluntarily in response to a command or in response to an Worrisome pathologic types are the gaze-paretic or gaze-evoked oscil-
eccentrically presented object but may be able to follow a slowly lations of cerebellar, brainstem, or cerebral disease.
moving target to either side. To compensate for the defect in purposive Nystagmus retractorius or convergent nystagmus is repetitive
lateral eye movements, children jerk their head to bring the eyes into jerking of the eyes into the orbit or toward each other. It is usually seen
the desired position and may also blink repetitively in an attempt to with vertical gaze palsy as a feature of Parinaud (sylvian aqueduct)
change fixation. The signs tend to become less conspicuous with age. syndrome. The causal condition may be neoplastic, vascular, or inflam-
The pathogenesis of congenital ocular motor apraxia is unknown. It matory. In children, nystagmus retractorius suggests particularly the
may be a result of delayed myelination of the ocular motor pathways. presence of pinealoma or hydrocephalus.
Structural abnormalities of the central nervous system have been A diagnostic approach to nystagmus is noted in Figures 623-7 and
found in a few patients, including agenesis of the corpus callosum and 623-8.
cerebellar vermis, porencephaly, hamartoma of the foramen of Monro, Spasmus nutans is a special type of acquired nystagmus in child-
and macrocephaly. Many children with congenital ocular motor hood (see also Chapter 597). In its complete form, it is characterized
apraxia show delayed motor and cognitive development. by the triad of pendular nystagmus, head nodding, and torticollis. The
nystagmus is characteristically very fine, very rapid, horizontal, and
NYSTAGMUS pendular; it is often asymmetric, sometimes unilateral. Signs usually
Nystagmus (rhythmic oscillations of 1 or both eyes) may be caused by develop within the 1st yr or 2 of life. Components of the triad may
an abnormality in any one of the 3 basic mechanisms that regulate develop at various times. In many cases, the condition is benign and
position and movement of the eyes: the fixation, conjugate gaze, or self-limited, usually lasting a few months, sometimes years. The cause
vestibular mechanism. In addition, physiologic nystagmus may be of this classic type of spasmus nutans, which usually resolves spontane-
elicited by appropriate stimuli (Table 623-1). ously, is unknown. Some children exhibiting signs resembling those of
Congenital sensory nystagmus is generally associated with ocular spasmus nutans have underlying brain tumors, particularly hypotha-
abnormalities that lead to decreased visual acuity; common disorders lamic and chiasmal optic gliomas. Appropriate neurologic and neuro-
that lead to early-onset nystagmus include albinism, aniridia, achroma- radiologic evaluation and careful monitoring of infants and children
topsia, congenital cataracts, congenital macular lesions, and congenital with nystagmus are therefore recommended.
Table 623-1 Specific Patterns of Nystagmus

PATTERN DESCRIPTION ASSOCIATED CONDITIONS
Latent nystagmus Conjugate jerk nystagmus toward viewing Congenital vision defects, occurs with occlusion of
eye eye
Manifest latent nystagmus Fast jerk to viewing eye Strabismus, congenital idiopathic nystagmus
Periodic alternating Cycles of horizontal or horizontal-rotary Caused by both visual and neurologic conditions
that change direction
Seesaw nystagmus One eye rises and intorts as other eye falls Usually associated with optic chiasm defects
and extorts
Nystagmus retractorius Eyes jerk back into orbit or toward each Caused by pressure on mesencephalic tegmentum
other (Parinaud syndrome)
Gaze-evoked nystagmus Jerk nystagmus in direction of gaze Caused by medications, brainstem lesion, or
labyrinthine dysfunction
Gaze-paretic nystagmus Eyes jerk back to maintain eccentric gaze Cerebellar disease
Downbeat nystagmus Fast phase beating downward Posterior fossa disease, drugs
Upbeat nystagmus Fast phase beating upward Brainstem and cerebellar disease; some visual
conditions
Vestibular nystagmus Horizontal-torsional or horizontal jerks Vestibular system dysfunction
Asymmetric or monocular nystagmus Pendular vertical nystagmus Disease of retina and visual pathways
Spasmus nutans Fine, rapid, pendular nystagmus Torticollis, head nodding; idiopathic or gliomas of
visual pathways
From Kliegman R: Practical strategies in pediatric diagnosis and therapy. Philadelphia, 1996, WB Saunders.
Work-up and treatment as per ocular Yes ? Obvious ocular

malformation, tumor, dysgenesis malformation, tumor
Aniridia Ocular coloboma No
Iridocorneal dysgenesis Cicatricial ROP
? Asymmetric, rapid, Yes Yes
Congenital cataracts Bilateral PHPV + MRI scan Neurologic disorder
Congenital glaucoma Bilateral retinal dysplasia pendular
No No
Retinoblastoma Macular coloboma
Toxoplasmosis Juvenile retinoschisis Spasmus nutans
? Searching Yes Yes

nystagmus ? ERG flat Leber
No No
Congenital motor Yes Yes Yes Yes
? Pendular ? Optic nerve Neurologic
efferent or ? Vision normal + MRI scan
nystagmus pale/small disorder
idiopathic nystagmus No No
Yes ? Foveal hypoplasia Idiopathic optic

Albinism iris transillumination nerve disorder
No
Yes ? Macular NFL schisis
X-linked No No
retinoschisis + ERG abnormality
No
Yes ? + Photophobia
Achromatopsia
? + Sloan test/ – Flicker ERG
No
Yes ? Myopia No Yes

CSNB ? – Rod dark adaptation ? Associated with strabismus Nystagmus blockage syndrome
+ ERG abnormality Manifest latent nystagmus
No
Congenital motor efferent

or idiopathic nystagmus
Figure 623-7 Algorithm for the work-up of an infant with nystagmus. ⊕, positive; ⊝, negative; CSNB, congenital stationary night blindness;
ERG, electroretinogram; NFL, nerve fiber layer; PHPV, persistent hyperplastic primary vitreous; ROP, retinopathy of prematurity. (From Nelson LB:
Harley’s pediatric ophthalmology, ed 4, Philadelphia, 1998, WB Saunders, p. 470.)
Nystagmus in Childhood
Idiopathic Chiasmal Associated with Neurologic Spasmus Manifest Latent

Misrouting Ocular Diseases Syndromes Nutans Nystagmus
(Fusional
Maldevelopment
Nystagmus Syndrome)
No other ocular Albinism
or neurologic Achiasma
abnormalities
Infantile squint
syndrome
Achromatopsia Down syndrome

Congenital stationary Noonan syndrome
night blindness Structural malformations
Ciliopathies Space-occupying lesions
Leber congenital Periventricular leukomalacia
amaurosis Developmental diseases
Aiström syndrome Leukodystrophies
Bardet-Biedl syndrome Chiari malformations
Joubert syndrome Metabolic diseases or
Senior Løken syndrome mitochondrial diseases
Retinopathy of prematurity Spinal cerebellar ataxias
Aniridia (PAX6 mutations) Episodic ataxias
Isolated foveal hypoplasia Vestibular diseases
Optic nerve hypoplasia
Optic nerve atrophy
Congenital cataracts
Media opacity
Figure 623-8 Classification of nystagmus based on associated diseases. (From Hoyt CS, Taylor D, editors: Pediatric ophthalmology and strabis-
mus, ed 4, Philadelphia, 2013, Elsevier Saunders, Fig. 89.2, p. 910.)
Table 623-2 Specific Patterns of Nonnystagmus Eye Movements
PATTERN DESCRIPTION ASSOCIATED CONDITIONS
Opsoclonus Multidirectional conjugate movements of varying rate Hydrocephalus, diseases of brainstem and cerebellum,
and amplitude neuroblastoma, paraneoplasia syndrome
Ocular dysmetria Overshoot of eyes on rapid fixation Cerebellar dysfunction
Ocular flutter Horizontal oscillations with forward gaze and Cerebellar disease, hydrocephalus, or central nervous
sometimes with blinking system neoplasm
Ocular bobbing Downward jerk from primary gaze, remains for a few Pontine disease
sec, then drifts back
Ocular myoclonus Rhythmic to-and-fro pendular oscillations of the eyes, Damage to red nucleus, inferior olivary nucleus, and
with synchronous nonocular muscle movement ipsilateral dentate nucleus
From Kliegman R: Practical strategies in pediatric diagnosis and therapy. Philadelphia, 1996, WB Saunders.
OTHER ABNORMAL EYE MOVEMENTS

To be differentiated from true nystagmus are certain special types of
abnormal eye movements, particularly opsoclonus, ocular dysmetria,
and flutter (Table 623-2).
Opsoclonus
Opsoclonus and ataxic conjugate movements are spontaneous, non-
rhythmic, multidirectional, chaotic movements of the eyes. The eyes
appear to be in agitation, with bursts of conjugate movement of
varying amplitude in varying directions. Opsoclonus is most often
associated with infectious or autoimmune encephalitis. It may be the
first sign of neuroblastoma or other tumors producing a paraneoplastic
syndrome.
Ocular Motor Dysmetria

This is analogous to dysmetria of the limbs. Affected individuals show
a lack of precision in performing movements of refixation, character-
ized by an overshoot (or undershoot) of the eyes with several corrective
to-and-fro oscillations on looking from one point to another. Ocular
motor dysmetria is a sign of cerebellar or cerebellar pathway disease.
Flutter-Like Oscillations
These intermittent to-and-fro horizontal oscillations of the eyes may
occur spontaneously or on change of fixation. They are characteristic
of cerebellar disease.

Chapter 623 ◆ Disorders of Eye Movement and Alignment 3033.e1
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Chapter 624 ◆ Abnormalities of the Lids 3033
muscle would normally insert below the skin surface. Because the
levator is replaced by fibrous tissue, the lid does not move downward
fully in downgaze (lid lag). If the ptosis is severe, affected children often
attempt to raise the lid by lifting their brow or adapting a chin-up head
posture to maintain binocular vision. Marcus Gunn jaw-winking
ptosis accounts for 5% of ptoses in children. In this syndrome, an
abnormal synkinesis exists between the 5th and 3rd cranial nerves; this
causes the eyelid to elevate with movement of the jaw. The wink is
produced by chewing or sucking and may be more noticeable than the
ptosis itself.
Although ptosis in children is often an isolated finding, it may occur
in association with other ocular or systemic disorders. Systemic disor-
ders include myasthenia gravis, muscular dystrophy, and botulism.
Ocular disorders include mechanical ptosis secondary to lid tumors,
blepharophimosis syndrome, congenital fibrosis syndrome, combined
levator/superior rectus maldevelopment, and congenital or acquired
3rd nerve palsy. A small degree of ptosis is seen in Horner syndrome
(see Chapter 622). A complete ophthalmic and systemic examination
is therefore important in the evaluation of a child with ptosis.
Amblyopia may occur in children with ptosis. The amblyopia may
be secondary to the lid’s covering the visual axis (deprivation) or
induced astigmatism (anisometropia). When amblyopia occurs, it
should generally be treated before treating the ptosis.
Treatment of ptosis in a child is indicated for elimination of an
abnormal head posture, improvement in the visual field, prevention of
amblyopia, and restoration of a normal eyelid appearance. The timing
of surgery depends on the degree of ptosis, its cosmetic and functional
severity, the presence or absence of compensatory posturing, the
wishes of the parents, and the discretion of the surgeon. Surgical treat-
ment is determined by the amount of levator function that is present.
A levator resection may be used in children with moderate to good
Chapter 624 function. In patients with poor or absent function, a frontalis suspen-
sion procedure may be necessary. This technique requires that a sus-
Abnormalities of the Lids pension material be placed between the frontalis muscle and the tarsus
of the eyelid. It allows patients to use their brow and frontalis muscle
more effectively to raise their eyelid. Amblyopia remains a concern
Scott E. Olitsky, Denise Hug, even after surgical correction and should be monitored closely.
Michelle M. Ariss, and EPICANTHAL FOLDS
These vertical or oblique folds of skin extend on either side of the
Timothy P. Lindquist bridge of the nose from the brow or lid area, covering the inner canthal
region. They are present to some degree in most young children and
become less apparent with age. The folds may be sufficiently broad to
PTOSIS cover the medial aspect of the eye, making the eyes appear crossed
In blepharoptosis, the upper eyelid droops below its normal level. (pseudoesotropia). Epicanthal folds are a common feature of many
Congenital ptosis is usually a result of a localized dystrophy of the syndromes, including chromosomal aberrations (trisomies) and disor-
levator muscle in which the striated muscle fibers are replaced with ders of single genes.
fibrous tissue. The condition may be unilateral or bilateral and can be
familial, transmitted as a dominant trait. LAGOPHTHALMOS
Parents often comment that the eye looks smaller because of the This is a condition in which complete closure of the lids over the globe
drooping eyelid. The lid crease is decreased or absent where the levator is difficult or impossible. It may be paralytic because of a facial palsy
involving the orbicularis muscle, or spastic, as in thyrotoxicosis. It may

be structural when retraction or shortening of the lids results from
scarring or atrophy consequent to injury (burns) or disease. For
example, children with various craniosynostosis syndromes can have
problematic lagophthalmos. Infants with collodion membrane may
have temporary lagophthalmos caused by the restrictive effect of the
membrane on the lids. Lagophthalmos may accompany proptosis or
buphthalmos (enlarged cornea because of elevated intraocular pres-
sure) when the lids, although normal, cannot effectively cover the
enlarged or protuberant eye. A degree of physiologic lagophthalmos
may occur normally during sleep, but functional lagophthalmos in an
unconscious or debilitated patient can be a problem.
In patients with lagophthalmos, exposure of the eye may lead to
drying, infection, corneal ulceration, or perforation of the cornea; the
result may be loss of vision, even loss of the eye. In lagophthalmos,
protection of the eye by artificial tear preparations, ophthalmic oint- Figure 624-1 Epiblepharon.
ment, or moisture chambers is essential. Gauze pads are to be avoided
because the gauze may abrade the cornea. In some cases, surgical
closure of the lids (tarsorrhaphy) may be necessary for long-term tion for pathologic causes, such as trichiasis, keratitis, conjunctivitis,
protection of the eye. or foreign body, is indicated. Local injection of botulinum toxin may
give relief, but frequently must be repeated.
LID RETRACTIONS
Pathologic retraction of the lid may be myogenic or neurogenic. Myo- BLEPHARITIS
genic retraction of the upper lid occurs in thyrotoxicosis, in which it This inflammation of the lid margins is characterized by erythema and
is associated with 3 classic signs: a staring appearance (Dalrymple crusting or scaling; the usual symptoms are irritation, burning, and
sign), infrequent blinking (Stellwag sign), and lag of the upper lid on itching. The condition is commonly bilateral and chronic or recurrent.
downward gaze (von Graefe sign). The 2 main types are staphylococcal and seborrheic. In staphylococcal
Neurogenic retraction of the lids may occur in conditions affecting blepharitis, ulceration of the lid margin is common, the lashes tend to
the anterior mesencephalon. Lid retraction is a feature of the syndrome fall out, and conjunctivitis and superficial keratitis are often associated.
of the sylvian aqueduct. In children, it is commonly a sign of hydro- In seborrheic blepharitis, the scales tend to be greasy, the lid margins
cephalus. It may occur with meningitis. Paradoxical retraction of the are less red, and ulceration usually does not occur. The blepharitis is
lid is seen in the Marcus Gunn jaw-winking syndrome. It may also be often of mixed type.
seen with attempted eye movement after recovery from a 3rd nerve Thorough daily cleansing of the lid margins with a cloth or moist-
palsy, if aberrant regeneration of the oculomotor nerve fibers has ened cotton applicator to remove scales and crusts is important in the
occurred. treatment of both forms. Staphylococcal blepharitis is treated with an
Simple staring and the physiologic or reflexive lid retraction antistaphylococcal antibiotic applied directly to the lid margins. When
(“eye popping”), in contrast to pathologic lid retractions, occur in a child also has seborrhea, concurrent treatment of the scalp is
infants in response to a sudden reduction in illumination or as a startle important.
reaction. Pediculosis of the eyelashes may produce a clinical picture of blepha-
ritis. The lice can be smothered with ophthalmic-grade petrolatum
ECTROPION, ENTROPION, AND ointment applied to the lid margin and lashes. Nits should be mechani-
EPIBLEPHARON cally removed from the lashes. It should be remembered that pedicu-
Ectropion is eversion of the lid margin; it may lead to overflow of tears losis can represent a sexually transmitted disease. Molluscum virus
(epiphora) and subsequent maceration of the skin of the lid, inflam- involvement of the lids can also cause blepharitis.
mation of exposed conjunctiva, or superficial exposure keratopathy.
Common causes are scarring consequent to inflammation, burns, or HORDEOLUM (STYE)
trauma and weakness of the orbicularis muscle as a result of facial Infection of the glands of the lid may be acute or subacute; tender focal
palsy; these forms may be corrected surgically. Protection of the cornea swelling and redness are noted. The usual agent is Staphylococcus
is essential. Ectropion is also seen in certain children who have faulty aureus. When the meibomian glands are involved, the lesion is referred
development of the lateral canthal ligament; this may occur in Down to as an internal hordeolum; the abscess tends to be large and may
syndrome. point through either the skin or the conjunctival surface. When the
Entropion is inversion of the lid margin, which may cause discom- infection involves the glands of Zeis or Moll, the abscess tends to be
fort and corneal damage because of the inward turning of the lashes smaller and more superficial and points at the lid margin; it is then
(trichiasis). A principal cause is scarring secondary to inflammation referred to as an external hordeolum or stye.
such as occurs in trachoma or as a sequela of Stevens-Johnson syn- Treatment is frequent warm compresses and, if necessary, surgical
drome. There is also a rare congenital form. Surgical correction is incision and drainage. In addition, topical antibiotic preparations are
effective in many cases. often used. Untreated, the infection may progress to cellulitis of the lid
Epiblepharon is commonly seen in childhood and may be confused or orbit, requiring the use of systemic antibiotics.
with entropion. In epiblepharon, a roll of skin beneath the lower eyelid
lashes causes the lashes to be directed vertically and to touch the CHALAZION
cornea (Fig. 624-1). Unlike entropion, the eyelid margin itself is not A chalazion is a granulomatous inflammation of a meibomian gland
rotated toward the cornea. Epiblepharon usually resolves spontane- characterized by a firm, nontender nodule in the upper or lower
ously. If corneal scarring begins to occur, surgical correction may be lid. This lesion tends to be chronic and differs from internal hor-
necessary. deolum in the absence of acute inflammatory signs. Although many
chalazia subside spontaneously, excision may be necessary if they
BLEPHAROSPASM become large enough to distort vision (by inducing astigmatism by
This spastic or repetitive closure of the lids may be caused by irritative exerting pressure on the globe) or to be a cosmetic blemish. Patients
disease of the cornea, conjunctiva, or facial nerve; fatigue or uncor- who experience frequent chalazia formation, or those who have
rected refractive error; or common tic. Thorough ophthalmic examina- significant corneal changes secondary to the underlying blepharitis,
may benefit from systemic, low-dose erythromycin or azithromycin some cases, there is also orbital involvement. The treatment is surgical
treatment. excision.
Plexiform neuromas of the lids occur in children with neurofibro-
COLOBOMA OF THE EYELID matosis, often with ptosis as the first sign. The lid may take on an
This cleft-like deformity may vary from a small indentation or notch S-shaped configuration. The lids may also be involved by other tumors,
of the free margin of the lid to a large defect involving almost the such as retinoblastoma, neuroblastoma, and rhabdomyosarcoma of the
entire lid. If the gap is extensive, ulceration and corneal opacities may orbit; these conditions are discussed elsewhere.
result from exposure. Early surgical correction of the lid defect is rec-
ommended. Other deformities frequently associated with lid colobo- Bibliography is available at Expert Consult.
mas include dermoid cysts or dermolipomas on the globe; they often
occur in a position corresponding to the site of the lid defect. Lid colo-
bomas may also be associated with extensive facial malformation,
as in mandibulofacial dysostosis (Franceschetti or Treacher Collins
syndrome).
TUMORS OF THE LID

A number of lid tumors arise from surface structures (the epithelium
and sebaceous glands). Nevi may appear in early childhood; most are
junctional. Compound nevi tend to develop in the prepubertal years
and dermal nevi at puberty. Malignant epithelial tumors (basal cell
carcinoma, squamous cell carcinoma) are rare in children, but the
basal cell nevus syndrome and the malignant lesions of xeroderma
pigmentosum and of Rothmund-Thomson syndrome may develop in
childhood.
Other lid tumors arise from deeper structures (the neural, vascular,
and connective tissues). Capillary hemangiomas are especially common
in children (Fig. 624-2). Many tend to regress spontaneously, although
they may show alarmingly rapid growth in infancy. In many cases, the
best management of such hemangiomas is patient observation, allow-
ing spontaneous regression to occur (see Chapter 650). In the case of
a rapidly expanding lesion, which may cause amblyopia by obstructing
the visual axis or inducing astigmatism, corticosteroid, interferon, or
surgical treatment should be considered. Systemic propranolol has
been shown to be an effective treatment without the risks associated
with corticosteroid use. Other treatment options include corticoste-
roids, systemically or by direct injection, and surgical excision. Nevus
flammeus (port-wine stain), a noninvoluting hemangioma, occurs as
an isolated lesion or in association with other signs of Sturge-Weber
syndrome. Affected patients should be monitored for the development
of glaucoma. Lymphangiomas of the lid appear as firm masses at or
soon after birth and tend to enlarge slowly during the growing years.
Associated conjunctival involvement, appearing as a clear, cystic,
sinuous conjunctival mass, may provide a clue to the diagnosis. In
Figure 624-2 Capillary hemangioma of the eyelid. (Courtesy of Amy

Nopper, MD, and Brandon Newell, MD.)
Chapter 624 ◆ Abnormalities of the Lids 3035.e1
Bibliography Parikh SR, Darrow DH, Grimmer JF, et al: Propranolol use for infantile
Dray JP, Leibovitch I: Congenital ptosis and amblyopia: A retrospective study of hemangiomas: American Society of Pediatric Otolaryngology Vascular
130 cases, J Pediatr Ophthalmol Strabismus 39:222–225, 2002. Anomalies Task Force practice patterns, JAMA Otolaryngol Head Neck Surg
Gusek-Schneider GC, Martus P: Stimulus deprivation amblyopia in human 139:153–156, 2013.
congenital ptosis: A study of 100 patients, Strabismus 8:261–270, 2000. Plager DA, Snyder SK: Resolution of astigmatism after surgical resection of
Meisler DM, Raizman MB, Traboulsi EI: Oral erythromycin treatment for capillary hemangiomas in infants, Ophthalmology 104:1102–1106, 1997.
childhood blepharokeratitis, J AAPOS 4:379–380, 2000.
Chapter 625 ◆ Disorders of the Lacrimal System 3035
Chapter 625
Disorders of the Lacrimal
System
THE TEAR FILM

This film, which bathes the eye, is actually a complex structure com-
posed of 3 layers. The innermost mucin layer is secreted by the goblet
and epithelial cells of the conjunctiva and the acinar cells of the lacri-
mal gland. It adds stability and provides an attachment for the tear film
to the conjunctiva and cornea. The middle aqueous layer constitutes
98% of the tear film and is produced by the main lacrimal gland and
accessory lacrimal glands. It contains various electrolytes and proteins
as well as antibodies. The outermost lipid layer is produced largely
from the sebaceous meibomian glands of the eyelid and retards evapo-
ration of the tear film. Tears drain medially into the punctal openings
of the lid margin and flow through the canaliculi into the lacrimal sac
and then through the nasolacrimal duct into the nose (Fig. 625-1).
Preterm infants have reduced tear secretion. This may mask the diag-
nosis of a nasolacrimal duct obstruction and concentrate topically
applied medications. Tear production reaches adult levels near term.
Superior lacrimal
canal
Lacrimal
gland
Excretory
lacrimal
duct
Inferior
Lacrimal
lacrimal
punctum
canal
Nasolacrimal duct
Inferior nasal concha
Nasal cavity
Figure 625-1 The lacrimal apparatus.

DACRYOSTENOSIS hospitalization. In the aforementioned study, 65% of infants with dac-
Congenital nasolacrimal duct obstruction (CNLDO), or dacryosteno- ryocystocele developed dacryocystitis/cellulitis. Once the cellulitis has
sis, is the most common disorder of the lacrimal system, occurring in improved, the nasolacrimal system should be probed if spontaneous
up to 20% of newborn infants. It is usually caused by a failure of canali- resolution has not occurred.
zation of the epithelial cells that form the nasolacrimal duct as it enters Not all tearing in infants and children is caused by nasolacrimal
the nose (valve of Hasner). Signs of CNLDO may be present at the time obstruction. Tearing may also be a sign of glaucoma, intraocular
of birth, although the condition may not become evident until normal inflammation, or external irritation, such as that from a corneal abra-
tear production develops. Signs of CNLDO include an excessive tear sion or foreign body.
lake, overflow of tears onto the lid and cheek, and reflux of mucoid
material that is produced in the lacrimal sac. Erythema or maceration ALACRIMA AND “DRY EYE”
of the skin may result from irritation and rubbing produced by drip- Alacrima refers to a wide spectrum of disorders with reduced or
ping of tears and discharge. If the blockage is complete, these signs may absent tear secretion. Occasionally, normal basal tearing occurs with
be severe and continuous. If obstruction is only partial, the nasolacri- an absence of emotional tearing. Etiologies can be divided into syn-
mal duct may be capable of draining the basal tear film that is pro- dromes that have a pathologic association or are inherited. Associated
duced. However, under periods of increased tear production (exposure syndromes include familial dysautonomia (Riley-Day syndrome),
to cold, wind, sunlight) or increased closure of the distal end of the anhidrotic ectodermal dysplasia, and triple-A syndrome (Allgrove syn-
nasolacrimal duct (nasal mucosal edema), tear overflow may become drome). Examples of pathologic association include aplasia of cranial
evident or may increase. nerve nuclei and lacrimal gland aplasia/hypoplasia. Both autosomal
Infants at increased risk for CNLDO include those with trisomy recessive and autosomal dominant inheritance has been reported in
21, EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome, isolated congenital alacrima. In addition, medications with anticholin-
branchiooculofacial syndrome, craniometaphyseal or craniodiaphy- ergic side effects can decrease tear production. The patients with alac-
seal dysplasias, LADD (lacrimo-auriculo-dento-digital) syndrome, rima have variable presentation including no symptoms, photophobia,
CHARGE (coloboma, heart anomaly, choanal atresia, retardation, foreign body sensation, eye pain, and decreased vision. The symptoms,
genital and ear anomalies) syndrome, and Goldenhar syndrome. if present, often occur early in life. Because the dryness can be severe,
Infants with CNLDO may develop acute infection and inflammation damage to the cornea and subsequent loss of vision may occur. The
of the nasolacrimal sac (dacryocystitis), inflammation of the sur- goal of treatment is to minimize corneal irritation, corneal scarring,
rounding tissues (pericystitis), or, rarely, periorbital cellulitis. With and loss of vision. Aggressive ocular lubrication is used to prevent these
dacryocystitis, the sac area is swollen, red, and tender, and patients may sequelae.
have systemic signs of infection such as fever and irritability. An acquired abnormality of any layer of the tear film may produce
The primary treatment of uncomplicated nasolacrimal duct obstruc- a dry eye. Commonly acquired disorders that may lead to a decreased
tion is a regimen of nasolacrimal massage, usually 2-3 times daily, or unstable tear film include Sjögren syndrome, Stevens-Johnson syn-
accompanied by cleansing of the lids with warm water. Topical antibi- drome, toxic epidermal necrolysis, vitamin A deficiency, viral infec-
otics are used for control of mucopurulent drainage. A bland ophthal- tions of the lacrimal gland, ocular pemphigoid, trachoma, chemical
mic ointment may be used on eyelids if the skin is macerated. Most burns, irradiation, isotretinoin treatment of acne, graft-versus-host
cases of CNLDO resolve spontaneously; 96% before 1 yr of age. For disease, and meibomian gland dysfunction. Exposure as a consequence
cases that do not resolve by 1 yr, the nasolacrimal duct may be probed of poor lid closure or other pathologic states can quickly lead to patho-
in the office with topical anesthesia, with a cure rate of approximately logically dry eyes. Examples of conditions leading to such exposure
80%. Some ophthalmologists intubate the nasolacrimal system at the include ichthyosis, xeroderma pigmentosum, and certain craniosynos-
same time as this has been shown to improve the outcome of the toses syndromes such as Crouzon, Apert, or Pfeiffer. Any tear defi-
procedure. ciency can lead to corneal ulceration, scarring, or infection. Treatment
Acute dacryocystitis or cellulitis requires prompt treatment with includes correction of the underlying disorder when possible and fre-
systemic antibiotics. In such cases, some form of definitive surgical quent instillation of an ocular lubricant. In some cases, occlusion of
intervention is usually indicated. the lacrimal puncta is helpful. In severe cases, tarsorrhaphy may be
A dacryocystocele (mucocele) is an unusual presentation of a non- necessary to protect the cornea.
patent nasolacrimal sac that is obstructed both proximally and distally.
Dacryocystoceles can be seen at birth or shortly after birth as a bluish Bibliography is available at Expert Consult.
subcutaneous mass just below the medial canthal tendon (Fig. 625-2).
Initial treatment of dacryocystocele is usually conservative, involving
massage/digital decompression of the lacrimal sac. If resolution of the
dacryocystocele is not achieved with conservative management, the
surgical probing may be beneficial. At times, the intranasal portion of
the nasolacrimal duct becomes distended, causing respiratory compro-
mise. In a recent study, 9.5% of infants with dacryocystocele had
related respiratory compromise. These infants benefit from early
probing. Another associated complication of dacryocystocele is that of
dacryocystitis/cellulitis. This requires systemic antibiotics, often with
Figure 625-2 Dacryocystocele below inner canthus of the right eye.

Chapter 625 ◆ Disorders of the Lacrimal System 3036.e1
Bibliography Pediatric Eye Disease Investigator Group: Primary treatment of nasolacrimal duct
American Academy of Ophthalmology Basic and Clinical Science Course: Section obstruction with probing in children younger than 4 years, Ophthalmology
8: External Disease and Cornea 2011–2012. 65–75. 115(3):577–584, 2008.
Frick KD, Hariharan L, Repka MX, et al: Cost-effectiveness of 2 approaches to Pediatric Eye Disease Investigator Group: Primary treatment of nasolacrimal duct
managing nasolacrimal duct obstruction in infants, Arch Ophthalmol obstruction with nasolacrimal duct intubation in children younger than 4 years
129:603–609, 2011. of age, J AAPOS 12(5):445–450, 2008.
Hegab SM, al-Mutawa SA: Congenital hereditary autosomal recessive alacrima, Pediatric Eye Disease Investigator Group: A random trial comparing the
Ophthalmic Genet 17(1):35–38, 1996. cost-effectiveness of 2 approaches for treating unilateral nasolacrimal duct
Huebner A, Yoon SJ, Ozkinay F, et al: Triple A syndrome—clinical aspects and obstruction, Arch Ophthalmol 130:1525–1533, 2012.
molecular genetics, Endocr Res 26:751–759, 2000. Schnall BM, Christian CJ: Conservative treatment of congenital dacryocele,
Kushner BJ: Congenital nasolacrimal system obstruction, Arch Ophthalmol J Pediatr Ophthalmol Strabismus 33:219–222, 1996.
100:597–600, 1982. Wong RK, VanderVeen DK: Presentation and management of congenital
MacEwen CJ, Young JD: Epiphora during the first year of life, Eye (Lond) dacryocystocele, Pediatrics 122(5):1108–1112, 2008.
5:596–600, 1991.
Mondino BJ, Brow SI: Hereditary congenital alacrima, Arch Ophthal 94(9):1478–
1484, 1976.
Chapter 626
Disorders of the
Conjunctiva
CONJUNCTIVITIS
The conjunctiva reacts to a wide range of bacterial and viral agents,
allergens, irritants, toxins, and systemic diseases. Conjunctivitis is
common in childhood and may be infectious or noninfectious. The
differential diagnosis of a red-appearing eye includes conjunctival as
well as other ocular sites (Table 626-1).
Chapter 626 ◆ Disorders of the Conjunctiva 3037
Table 626-1 The Red Eye

CONDITION ETIOLOGY SIGNS AND SYMPTOMS TREATMENT
Bacterial Haemophilus influenzae, Mucopurulent unilateral or bilateral Topical antibiotics, parenteral
conjunctivitis Haemophilus aegyptius, discharge, normal vision, ceftriaxone for gonococcus,
Streptococcus pneumoniae, photophobia H. influenzae
Staphylococcus aureus, Moraxella
catarrhalis
Hyperacute bacterial Neisseria gonorrhoeae, Conjunctival injection and edema
conjunctivitis Neisseria meningitides (chemosis); gritty sensation
Viral conjunctivitis Adenovirus, ECHO virus, As above; may be hemorrhagic, Self-limited
coxsackievirus, herpes simplex unilateral
virus
Neonatal Chlamydia trachomatis, gonococcus, Palpebral conjunctival follicle or Ceftriaxone for gonococcus and
conjunctivitis chemical (silver nitrate), S. aureus papillae; as above erythromycin for C. trachomatis
Allergic conjunctivitis Seasonal pollens or allergen Itching, incidence of bilateral Antihistamines, topical mast cell
exposure chemosis (edema) greater than that stabilizers or prostaglandin
of erythema, tarsal papillae inhibitors, steroids
Keratitis Herpes simplex virus, adenovirus, Severe pain, corneal swelling, Specific antibiotics for bacterial/
S. pneumoniae, S. aureus, clouding, limbus erythema, fungal infections; keratoplasty,
Pseudomonas, Acanthamoeba, hypopyon, cataracts; contact lens acyclovir for herpes
chemicals history with amebic infection
Endophthalmitis S. aureus, S. pneumoniae, Candida Acute onset, pain, loss of vision, Antibiotics
albicans, associated surgery or swelling, chemosis, redness;
trauma hypopyon and vitreous haze
Anterior uveitis JIA, postinfectious with arthritis and Unilateral/bilateral; erythema, ciliary Topical steroids, plus therapy for
(iridocyclitis) rash, sarcoidosis, Behçet disease, flush, irregular pupil, iris adhesions; primary disease
Kawasaki disease, inflammatory pain, photophobia, small pupil, poor
bowel disease vision
Posterior uveitis Toxoplasmosis, histoplasmosis, No signs of erythema, decreased Specific therapy for pathogen
(choroiditis) Toxocara canis vision
Episcleritis/scleritis Idiopathic autoimmune disease Localized pain, intense erythema, Episcleritis is self-limiting; topical
(e.g., SLE, Henoch-Schönlein unilateral; blood vessels bigger than steroids for fast relief
purpura) in conjunctivitis; scleritis may cause
globe perforation
Foreign body Occupational exposure Unilateral, red, gritty feeling; visible or Irrigation, removal; check for
microscopic size ulceration
Blepharitis S. aureus, Staphylococcus Bilateral, irritation, itching, hyperemia, Topical antibiotics, warm
epidermidis, seborrheic, blocked crusting, affecting lid margins compresses, lid hygiene
lacrimal duct; rarely molluscum
contagiosum, Phthirus pubis,
Pediculus capitis
Dacryocystitis Obstructed lacrimal sac: S. aureus, Pain, tenderness, erythema, and Systemic, topical antibiotics;
H. influenzae, pneumococcus exudates in area of lacrimal sac surgical drainage
(inferomedial to inner canthus);
tearing (epiphora); possible orbital
cellulitis
Dacryoadenitis S. aureus, Streptococcus, CMV, Pain, tenderness, edema, erythema Systemic antibiotics; drainage of
measles, EBV, enteroviruses; over gland area (upper temporal lid); orbital abscesses
trauma, sarcoidosis, leukemia fever, leukocytosis
Orbital cellulitis Paranasal sinusitis: H. influenzae, Rhinorrhea, chemosis, vision loss, Systemic antibiotics, drainage of
(postseptal cellulitis) S. aureus, S. pneumoniae, painful extraocular motion, orbital abscesses
streptococci proptosis, ophthalmoplegia, fever,
Trauma: S. aureus lid edema, leukocytosis
Fungi: Aspergillus, Mucor spp.
if immunodeficient
Periorbital cellulitis Trauma: S. aureus, streptococci Cutaneous erythema, warmth, normal Systemic antibiotics
(preseptal cellulitis) Bacteremia: pneumococcus, vision, minimal involvement of orbit;
streptococci, H. influenzae, fever, leukocytosis, toxic appearance
S. aureus
CMV, cytomegalovirus; EBV, Epstein-Barr virus; JIA, juvenile idiopathic arthritis; SLE, systemic lupus erythematosus.
From Behrman R, Kliegman R: Nelson’s essentials of pediatrics, ed 3, Philadelphia, 1998, WB Saunders.
Ophthalmia Neonatorum Diagnosis

This form of conjunctivitis, occurring in infants younger than 4 wk of Conjunctivitis appearing after 48 hr should be evaluated for a possibly
age, is the most common eye disease of newborns. Its many different infectious cause. Gram stain of the purulent discharge should be per-
causal agents vary greatly in their virulence and outcome. Silver nitrate formed and the material cultured. If a viral cause is suspected, a swab
instillation may result in a mild self-limited chemical conjunctivitis, should be submitted in tissue culture media for virus isolation. In
whereas Neisseria gonorrhoeae and Pseudomonas are capable of causing chlamydial conjunctivitis, the diagnosis is made by examining Giemsa-
corneal perforation, blindness, and death. The risk of conjunctivitis in stained epithelial cells scraped from the tarsal conjunctivae for the
newborns depends on frequencies of maternal infections, prophylactic characteristic intracytoplasmic inclusions, by isolating the organisms
measures, circumstances during labor and delivery, and postdelivery from a conjunctival swab using special tissue culture techniques, by
exposure to microorganisms. immunofluorescent staining of conjunctival scrapings for chlamydial
inclusions, or by tests for chlamydial antigen or DNA. The differential
Epidemiology diagnosis of ophthalmia neonatorum includes dacryocystitis caused by
Conjunctivitis during the neonatal period is usually acquired during congenital nasolacrimal duct obstruction with lacrimal sac distention
vaginal delivery and reflects the sexually transmitted infections preva- (dacryocystocele; see Chapter 625).
lent in the community. In 1880, 10% of European children developed
gonococcal conjunctivitis at birth. Ophthalmia neonatorum was the Treatment
leading cause of blindness during that period. The epidemiology of this Treatment of infants in whom gonococcal ophthalmia is suspected and
condition changed dramatically in 1881, when Crede reported that 2% the Gram stain shows the characteristic intracellular Gram-negative
silver nitrate solution instilled in the eyes of newborns reduced the diplococci should be initiated immediately with ceftriaxone, 50 mg/
incidence of gonococcal ophthalmia from 10% to 0.3%. kg/24 hr for 1 dose, not to exceed 125 mg. The eye should also be
During the 20th century, the incidence of gonococcal ophthalmia irrigated initially with saline every 10-30 min, gradually increasing to
neonatorum decreased in industrialized countries secondary to wide- 2-hr intervals until the purulent discharge has cleared. An alternative
spread use of silver nitrate prophylaxis and prenatal screening and regimen includes cefotaxime (100 mg/kg/24 hr given IV or IM every
treatment of maternal gonorrhea. Gonococcal ophthalmia neonato- 12 hr for 7 days or 100 mg/kg as a single dose). Treatment is extended
rum has an incidence of 0.3/1,000 live births in the United States. In if sepsis or other extraocular sites are involved (meningitis, arthritis).
comparison, Chlamydia trachomatis is the most common organism Neonatal conjunctivitis secondary to chlamydial infections is treated
causing ophthalmia neonatorum in the United States, with an inci- with oral erythromycin (50 mg/kg/24 hr in 4 divided doses) for 2 wk.
dence of 8.2/1,000 births. This cures conjunctivitis and may prevent subsequent chlamydial
pneumonia. Pseudomonas neonatal conjunctivitis is treated with sys-
Clinical Manifestations temic antibiotics, including an aminoglycoside, plus local saline irriga-
The clinical manifestations of the various forms of ophthalmia neona- tion and gentamicin ophthalmic ointment. Staphylococcal conjunctivitis
torum are not specific enough to allow an accurate diagnosis. Although is treated with parenteral methicillin and local saline irrigation.
the timing and character of the signs are somewhat typical for each
cause of this condition, there is considerable overlap and physicians Prognosis and Prevention
should not rely solely on clinical findings. Regardless of its cause, Before the institution of topical ophthalmic prophylaxis at birth, gono-
ophthalmia neonatorum is characterized by redness and chemosis coccal ophthalmia was a common cause of blindness or permanent eye
(swelling) of the conjunctiva, edema of the eyelids, and discharge, damage. If properly applied, this form of prophylaxis is highly effective
which may be purulent. unless infection is present at birth. Drops of 0.5% erythromycin or 1%
Neonatal conjunctivitis is a potentially blinding condition. The silver nitrate are instilled directly into the open eyes at birth using wax
infection may also have associated systemic manifestations that require or plastic single-dose containers. Saline irrigation after silver nitrate
treatment. Therefore, any newborn infant who develops signs of con- application is unnecessary. Silver nitrate is ineffective against active
junctivitis needs a prompt and comprehensive systemic and ocular infection and may have limited use against Chlamydia. Povidone-
evaluation to determine the agent causing the infection and the appro- iodine (2% solution) may also be an effective prophylactic agent, espe-
priate treatment. cially in developing countries.
The onset of inflammation caused by silver nitrate drops usually Identification of maternal gonococcal infection and appropriate
occurs within 6-12 hr after birth, with clearing by 24-48 hr. The usual treatment has become a standard element of routine prenatal care. An
incubation period for conjunctivitis caused by N. gonorrhoeae is 2-5 infant born to a woman who has untreated gonococcal infection should
days, and for that caused by C. trachomatis, 5-14 days. Gonococcal receive a single dose of ceftriaxone, 50 mg/kg (maximum 125 mg) IV
infection may be present at birth or be delayed beyond 5 days of life or IM, in addition to topical prophylaxis. The dose should be reduced
owing to partial suppression by ocular prophylaxis. Gonococcal con- for premature infants. Penicillin (50,000 units) should be used if the
junctivitis may also begin in infancy after inoculation by the contami- mother’s gonococcal isolate is known to be penicillin sensitive.
nated fingers of adults. The time of onset of disease with other bacteria Neither topical prophylaxis nor topical treatment prevents the afe-
is highly variable. brile pneumonia that occurs in 10-20% of infants exposed to C. tra-
Gonococcal conjunctivitis begins with mild inflammation and a chomatis. Although chlamydial conjunctivitis is often a self-limiting
serosanguineous discharge. Within 24 hr, the discharge becomes thick disease, chlamydial pneumonia may have serious consequences. It is
and purulent, and tense edema of the eyelids with marked chemosis important that infants with chlamydial disease receive systemic treat-
occurs. If proper treatment is delayed, the infection may spread to ment. Treatment of colonized pregnant women with erythromycin
involve the deeper layers of the conjunctivae and the cornea. Complica- may prevent neonatal disease.
tions include corneal ulceration and perforation, iridocyclitis, anterior
synechiae, and rarely panophthalmitis. Conjunctivitis caused by C. Acute Purulent Conjunctivitis
trachomatis (inclusion blennorrhea) may vary from mild inflammation This is characterized by more or less generalized (bilateral in 50-75%)
to severe swelling of the eyelids with copious purulent discharge. The conjunctival hyperemia, edema, mucopurulent exudate, glued eyes
process involves mainly the tarsal conjunctivae; the corneas are rarely (lids stuck together after sleeping), and various degrees of ocular pain
affected. Conjunctivitis caused by Staphylococcus aureus or other organ- and discomfort. It is usually a result of bacterial infection. In addition,
isms is similar to that produced by C. trachomatis. Conjunctivitis there is usually little or no pruritus or periauricular lymph node
caused by Pseudomonas aeruginosa is uncommon, acquired in the enlargement; the peak season is between December and April. Bacte-
nursery, and a potentially serious process. It is characterized by the rial conjunctivitis is more common in young children (<5 yr), whereas
appearance on days 5-18 of edema, erythema of the lids, purulent dis- viral conjunctivitis is more common among adults. The most frequent
charge, pannus formation, endophthalmitis, sepsis, shock, and death. causes are nontypeable Haemophilus influenzae (60-80%) (associated
Chapter 626 ◆ Disorders of the Conjunctiva 3039
Table 626-2 Topical Antibiotics Used to Treat Bacterial Conjunctivitis: Adult Dosages
DRUG DOSAGE
Bacitracin (AK-Tracin, Bacticin) ointment Apply 0.5 inch in eye q3-4h
Ciprofloxacin (Ciloxan) 0.3% ophthalmic solution 1-2 gtt in eye q15min × 6h, then q30min × 18h, then q1h × 1 day, then
q4h × 12 days*
Gatifloxacin (Zymar) 0.3% ophthalmic solution 1 gt in eye q2h up to 8 × per day × 2 days, then 1 gt qid × 5 days
Gentamicin (Gentak, Gentasol) 0.3% ophthalmic solution Ointment: 0.5 inch applied to eye 2-3 × per day
or ointment Solution: 1-2 gtt in eye q4h
Levofloxacin (Quixin) 0.5% ophthalmic solution 1-2 gtt in eye q2h × 2 days while awake, then q4h × 5 days while awake
Moxifloxacin (Vigamox) 0.5% ophthalmic solution 1 gt in eye tid × 7 days
Neomycin/polymyxin B/gramicidin (Neosporin) ophthalmic solution 1-2 gtt in eye q4h × 7-10 days
Ofloxacin (Ocuflox) 0.3% ophthalmic solution 1-2 gtt in eye q2-4h × 2 days, then 1-2 gtt in eye qid × 5 days
Polymyxin B and trimethoprim (Polytrim) ophthalmic solution 1 gt in eye q3h × 7-10 days
Sulfacetamide (Isopto Cetamide, Ocusulf-10, Sodium Sulamyd, Ointment: 0.5-inch ribbon in eye q3-4h and qhs × 7 days
Sulf-10, AK-Sulf) 10% ophthalmic solution, ointment Solution: 1-2 gtt in eye q2-3h × 7-10 days
Tobramycin (AK-Tob, Tobrex) 0.3% ophthalmic solution 1-2 gtt in eye q4h
*Exceeds dosage recommended by the manufacturer.
From: Bope ET, Kellerman RD, editors: Conn’s current therapy, Philadelphia, 2014, Elsevier/Saunders, Table 2, p. 321.
with ipsilateral otitis media), pneumococci (20%), and staphylococci

(5-10%). Bacterial purulent conjunctivitis, especially that caused by
pneumococcus or H. influenzae, may occur in epidemics. Conjunctival
smear and culture are helpful in differentiating specific types. These
common forms of acute purulent conjunctivitis usually respond well
to warm compresses and topical instillation of antibiotic drops, which
shortens the duration of illness and hastens return to school. Topical
antibiotics include aminoglycosides (gentamicin, tobramycin), quino-
lones (ciprofloxacin, ofloxacin, moxifloxacin), and combinations of
antibiotics and chloramphenicol (Table 626-2). Brazilian purpuric
fever caused by Haemophilus aegyptius manifests as conjunctivitis and
sepsis. Hyperacute bacterial conjunctivitis is caused by gonococcal
or meningococcal infection and requires systemic, not topical, antimi-
crobial therapies. Concerning symptoms that should require an oph-
thalmology referral include vision loss, severe purulent discharge,
corneal involvement, conjunctival scarring, cutaneous-conjunctival
involvement (Stevens-Johnson syndrome), recurrent symptoms, severe
pain, herpes simplex virus infection, severe photophobia, and involve- Figure 626-1 Hemorrhagic conjunctivitis caused by enterovirus 70.
(From Kono R, Uchida Y. Acute haemorrhagic conjunctivitis. Ophthal-
ment with a contact (cosmetic or prescription) lens.
mol Dig 39:14, 1977.)
Viral Conjunctivitis reduce visual acuity. Corneal complications are less common in chil-
This is generally characterized by a watery discharge. Follicular changes dren than in adults. Children may have associated upper respiratory
(small aggregates of lymphocytes) are often found in the palpebral tract infection and pharyngitis. No specific medical therapy is available
conjunctiva. Involvement is often unilateral and associated with peri- to decrease the symptoms or shorten the course of the disease. Empha-
auricular nodes. Viral conjunctivitis occurs more often in the summer sis must be placed on prevention of spread of the disease. Replicating
and in older children (>5 yr). Conjunctivitis resulting from adenovirus virus is present in 95% of patients 10 days after the appearance of
infection is relatively common, sometimes with corneal involvement symptoms.
as well as pharyngitis or pneumonia. Outbreaks of conjunctivitis Pharyngoconjunctival fever presents with high fever, pharyngitis,
caused by enterovirus are also encountered; this type may be hemor- bilateral conjunctivitis, and periauricular lymphadenopathy. It is
rhagic (Fig. 626-1). Acute hemorrhagic conjunctivitis may be epidemic highly contagious.
because of enterovirus CA24 or 70 and is characterized by red, swollen,
and painful eyes with a hemorrhagic watery discharge. Conjunctivitis Membranous and Pseudomembranous
is commonly associated with such systemic viral infections as the Conjunctivitis
childhood exanthems, particularly measles. Viral conjunctivitis is These types of conjunctivitis can be encountered in a number of dis-
usually self-limited. eases. The classic membranous conjunctivitis is that of diphtheria,
accompanied by a fibrin-rich exudate that forms on the conjunctival
Epidemic Keratoconjunctivitis surface and permeates the epithelium; the membrane is removed with
This is caused by adenovirus type 8 and is transmitted by direct contact. difficulty and leaves raw bleeding areas. In pseudomembranous con-
It initially presents as a sensation of a foreign body beneath the lids, junctivitis, the layer of fibrin-rich exudate is superficial and can often
with itching and burning. Edema (chemosis) and photophobia develop be stripped easily, leaving the surface smooth. This type occurs with
rapidly, and large oval follicles appear within the conjunctiva. Preau- many bacterial and viral infections, including staphylococcal, pneumo-
ricular adenopathy and a pseudomembrane on the conjunctival surface coccal, streptococcal, or chlamydial conjunctivitis, and in epidemic
occur frequently. Subepithelial corneal infiltrates may develop and may keratoconjunctivitis. It is also found in vernal conjunctivitis and in
cause blurring of vision; these usually disappear but may permanently Stevens-Johnson disease.
Figure 626-2 Vernal conjunctivitis. Figure 626-3 Conjunctival granulomas in Parinaud oculoglandular
syndrome.
Allergic Conjunctivitis Other Conjunctival Disorders

This is usually accompanied by intense itching, clear watery discharge, Subconjunctival hemorrhage is manifested by bright or dark red
and conjunctival edema (chemosis). It is commonly seasonal (spring- patches in the bulbar conjunctiva and may result from injury or inflam-
summer). Cold compresses and topical antihistamine drops give symp- mation. It commonly occurs spontaneously. It may occasionally result
tomatic relief. Topical mast cell stabilizers or prostaglandin inhibitors from severe sneezing or coughing. Rarely, it may be a manifestation of
may also help. In selected cases, topical corticosteroids are used under a blood dyscrasia. Subconjunctival hemorrhages are self-limiting and
an ophthalmologist’s supervision but should not be used routinely or require no treatment.
for a long time. Pinguecula is a yellowish-white, slightly elevated mass on the bulbar
conjunctiva, usually in the interpalpebral region. It represents elastic
Vernal Conjunctivitis and hyaline degenerative changes of the conjunctiva. No treatment is
This usually begins in the prepubertal years and may recur for many required except for cosmetic reasons, in which case simple excision
years. Atopy appears to have a role in its origin, but the pathogenesis suffices.
is uncertain. Extreme itching and tearing are the usual complaints. Pterygium is a fleshy triangular conjunctival lesion that may
Large, flattened, cobblestone-like papillary lesions of the palpebral con- encroach on the cornea. It typically occurs in the nasal interpalpebral
junctivae are characteristic (Fig. 626-2). A stringy exudate and a milky region. The pathologic findings are similar to those of a pinguecula.
conjunctival pseudomembrane are frequently present. Small elevated The development of pterygia is related to exposure to ultraviolet light,
lesions of the bulbar conjunctiva adjacent to the limbus (limbal form) and it therefore is more commonly found among people who live near
may be found. Smear of the conjunctival exudate reveals many eosino- the equator. Removal is suggested when the lesion encroaches far onto
phils. Topical corticosteroid therapy and cold compresses afford some the cornea. Recurrence after removal is common.
relief. Topical mast cell stabilizers or prostaglandin inhibitors are useful Dermoid cyst and dermolipoma are benign lesions, clinically
when long-term control is needed. The long-term use of corticoste- similar in appearance. They are smooth, elevated, round to oval lesions
roids should be avoided. of various sizes. The color varies from yellowish white to fleshy pink.
The most frequent site is the upper outer quadrant of the globe; they
Parinaud Oculoglandular Syndrome also commonly occur near or straddling the limbus. Dermolipoma is
This represents a form of cat-scratch disease and is caused by Barton- composed of adipose and connective tissue. Dermoid cysts may also
ella henselae, which is transmitted from cat to cat by fleas (see Chapter contain glandular tissue, hair follicles, and hair shafts. Excision for
209). Kittens are more likely than adult cats to be infected. Humans cosmetic reasons is feasible. Dermolipomas are often connected to the
can become infected when they are scratched by a cat. In addition, extraocular muscles, making their complete removal impossible
bacteria may pass from a cat’s saliva to its fur during grooming. The without sacrificing ocular motility.
bacteria can then be deposited on the conjunctiva after rubbing one’s Conjunctival nevus is a small, slightly elevated lesion that may vary
eyes after handling the cat. Lymphadenopathy and conjunctivitis are in pigmentation from pale salmon to dark brown. It is usually benign,
hallmarks of the disease. Conjunctival granulomas may develop (Fig. but careful observation for progressive growth or changes suggestive
626-3). The course is generally self-limited, but antibiotics may be used of malignancy is advised.
in some cases. Symblepharon is a cicatricial adhesion between the conjunctiva
of the lid and the globe; the lower lid is usually affected. It follows
Chemical Conjunctivitis operation or injuries, especially burns from lye, acids, or molten
This can result when an irritating substance enters the conjunctival sac metals. It is a serious complication of Stevens-Johnson syndrome.
(as in the acute but benign conjunctivitis caused by silver nitrate in It may interfere with motion of the eyeball and may cause diplopia.
newborns). Other common offenders are household cleaning sub- The adhesions should be separated and the raw surfaces kept from
stances, sprays, smoke, smog, and industrial pollutants. Alkalis tend to uniting during healing. Grafts of oral mucous membrane may be
linger in the conjunctival tissues and continue to inflict damage for necessary.
hours or days. Acids precipitate the proteins in tissues and so produce
their effect immediately. In either case, prompt, thorough, and copious Bibliography is available at Expert Consult.
irrigation is crucial. Extensive tissue damage, even loss of the eye, can
result, especially if the offending agent is an alkali.
Chapter 626 ◆ Disorders of the Conjunctiva 3040.e1
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Atik B, Thanh TTK, Luong VQ, et al: Impact of annual targeted treatment of Opin Allergy Clin Immunol 13:543–549, 2013.
infectious trachoma and susceptibility to reinfection, JAMA 296:1488–1497, Rietveld RP, ter Riet G, Bindels PJE, et al: Predicting bacterial cause in infectious
2006. conjunctivitis: Cohort study on informativeness of combinations of signs and
Azari AA, Barney NP: Conjunctivitis: a systematic review of diagnosis and symptoms, BMJ 329:206–208, 2004.
treatment, JAMA 310:1721–1728, 2013. Sauer A, Bourcier T: French Study Group for Contact Lenses Related Keratitis,
Centers for Disease Control and Prevention: Outbreak of bacterial conjunctivitis at Acta Ophthalmol 89:e439–e442, 2011.
a college—New Hampshire, January–March, 2002, MMWR Morb Mortal Wkly Sheikh A, Hurwitz B, van Schayck CP, et al: Antibiotics versus placebo for acute
Rep 51:205–208, 2002. bacterial conjunctivitis (review), Cochrane Database Syst Rev (9):CD001211,
Centers for Disease Control and Prevention: Adenovirus-associated epidemic 2012.
keratoconjunctivitis outbreaks–four states, 2008-2010, MMWR Morb Mortal Shiuey Y, Ambati BK, Adamis AP, and the Viral Conjunctivitis Study Group: A
Wkly Rep 32:637–640, 2013. randomized, double-masked trial of topical ketorolac versus artificial tears for
Everitt HA, Little PS, Smith PWF: A randomised controlled trial of management treatment of viral conjunctivitis, Ophthalmology 107:1512–1517, 2000.
strategies for acute infective conjunctivitis in general practice, BMJ 333:321– Williams L, Malhotra Y, Murante B, et al: A single-blinded randomized clinical
324, 2006. trial comparing polymyxin B-trimethoprim and moxifloxacin for treatment of
Gower EW: Solving the trachoma elimination puzzle, one piece at a time, Lancet acute conjunctivitis in children, J Pediatr 162:857–861, 2013.
379:102–103, 2012.
Chapter 627 ◆ Abnormalities of the Cornea 3041
Chapter 627
Abnormalities of the
Cornea
MEGALOCORNEA
This is a nonprogressive symmetric condition characterized by an
enlarged cornea (>12 mm in diameter) and an anterior segment in Figure 627-1 Acute hydrops from keratoconus with significant
which there is no evidence of previous or concurrent ocular hyperten- corneal edema.
sion. High myopia is frequently present and may lead to reduced
vision. A frequent complication is the development of lens opacities in
adult life. All modes of inheritance have been described, although
X-linked recessive is the most common; therefore, this disorder more keratoconus. If the cornea vaults too severely for the vision to be cor-
commonly affects males. Systemic abnormalities that may be associ- rected with contact lenses then a corneal transplant must be performed
ated with megalocornea include Marfan syndrome, craniosynostosis, to restore vision.
and Alport syndrome. The cause of the enlargement of the cornea and
the anterior segment is unknown, but possible explanations include a NEONATAL CORNEAL OPACITIES
defect in the growth of the optic cup and an arrest of congenital glau- Loss of the normal transparency of the cornea in neonates may occur
coma. The region on the X chromosome responsible for this disorder secondary to either intrinsic hereditary or extrinsic environmental
has been identified. causes (Table 627-1).
Pathologic corneal enlargement caused by glaucoma is to be
differentiated from this anomaly. Any progressive increase in the SCLEROCORNEA
size of the cornea, especially when accompanied by photophobia, lac- In sclerocornea, the normally translucent cornea is replaced by sclera-
rimation, or haziness of the cornea, requires prompt ophthalmologic like tissue. Instead of a clearly demarcated cornea, white, feathery, often
evaluation. ill-defined and vascularized tissue develops in the peripheral cornea,
appearing to blend with and extend from the sclera. The central cornea
MICROCORNEA is usually clearer, but total replacement of the cornea with sclera may
Microcornea, or anterior microphthalmia, is an abnormally small occur. The curvature of the cornea is often flatter, similar to the sclera.
cornea in an otherwise relatively normal eye. It may be familial, Potentially coexisting abnormalities include a shallow anterior
with transmission being dominant more often than recessive. More chamber, iris abnormalities, and microphthalmos. This condition is
commonly, a small cornea is just one feature of an otherwise devel- usually bilateral. In approximately 50% of cases, a dominant or reces-
opmentally abnormal or microphthalmic eye; associated defects sive inheritance has been described. Sclerocornea has been reported in
include colobomas, microphakia, congenital cataract, glaucoma, and association with numerous systemic abnormalities including limb
aniridia. deformities, craniofacial defects, and genitourinary disorders. In gen-
eralized sclerocornea, especially if bilateral, early corneal transplanta-
KERATOCONUS tion should be considered in an effort to provide vision.
This is a disease of unclear pathogenesis characterized by progressive Sclerocornea is classified into one of the congenital corneal opacity
thinning and bulging of the central cornea, which becomes cone disorders with cornea plana if it involves peripheral scleralization or
shaped. Although familial cases are known, most cases are sporadic. It total sclerocornea disorders such as Peters anomaly.
is a common ocular condition with an incidence of 1 in 2,000 adults.
Eye rubbing and contact lens wear have been implicated as pathogenic, PETERS ANOMALY
but the evidence to support this is equivocal. The incidence is increased Peters anomaly is a central corneal opacity (leukoma) that is present
in individuals with atopy, Down syndrome, Marfan syndrome, and at birth (Fig. 627-2). It is often associated with iridocorneal adhesions
retinitis pigmentosa. that extend from the iris collarette to the border of the corneal opacity.
Most cases are bilateral, but involvement may be asymmetric. The Approximately 50% of patients have other ocular abnormalities, which
disorder usually presents and progresses rapidly during adolescence; may include cataracts, glaucoma, and microcornea. As many as 80%
progression slows and stabilizes when patients reach full growth. Des- of cases may be bilateral and 60% are associated with systemic malfor-
cemet membrane may occasionally be stretched beyond its elastic mations (Peters plus syndrome) that may include short stature, devel-
breaking point, causing an acute rupture in the membrane with resul- opmental delay, dysmorphic facial features, and cardiac, genitourinary,
tant sudden and marked corneal edema (acute hydrops, Fig. 627-1) and central nervous system malformations. Some investigators have
and decrease in vision. The corneal edema resolves as endothelial cells divided Peters anomaly into 2 types: a mesodermal or neuroectoder-
cover the defective area. Some degree of corneal scarring occurs, but mal form (type I), which does not show associated lens changes,
the visual acuity is often better than before the initial incident. Signs and a surface ectodermal form (type II), which does. Histologic
of keratoconus include Munson sign (bulging of the lower eyelid on findings include a focal absence of Descemet membrane and corneal
looking downward) and the presence of a Fleischer ring (a deposit of endothelium in the region of the opacity. Peters anomaly may be
iron in the epithelium at the base of the cone). Glasses and contact caused by incomplete migration and differentiation of the precursor
lenses are the first step in treating the visual distortion caused by kera- cells of the central corneal endothelium and Descemet membrane or
toconus. Emerging research now suggests that a corneal cross-linking a defective separation between the primitive lens and cornea during
procedure using riboflavin and UV light may arrest the progression of embryogenesis.
Table 627-1 STUMPED: Differential Diagnosis of Neonatal Corneal Opacities

OCULAR OTHER OCULAR NATURAL
DIAGNOSIS LATERALITY OPACITY PRESSURE ABNORMALITIES HISTORY INHERITANCE
S—Sclerocornea Unilateral or Vascularized, Normal (or Cornea plana Nonprogressive Sporadic
bilateral blends with elevated)
sclera, clearer
centrally
T—Tears in endothelium
and Descemet
membrane
Birth trauma Unilateral Diffuse edema Normal Possible hyphema, Spontaneous Sporadic
periorbital improvement in
ecchymoses 1 mo
Infantile glaucoma Bilateral Diffuse edema Elevated Megalocornea, Progressive unless Autosomal
photophobia treated recessive
and tearing,
abnormal angle
U—Ulcers
Herpes simplex keratitis Unilateral Diffuse with Normal None Progressive Sporadic
geographic
epithelial defect
Congenital rubella Bilateral Disciform or Normal or Microphthalmos, Stable, may clear Sporadic
diffuse edema, elevated cataract,
no frank pigment
ulceration epithelial
mottling
Neurotrophic exposure Unilateral or Central ulcer Normal Lid anomalies, Progressive Sporadic
bilateral congenital
sensory
neuropathy
M—Metabolic (rarely Bilateral Diffuse haze, Normal Few Progressive Autosomal
present at birth) denser dominant
(mucopolysaccharidoses peripherally
IH, IS; mucolipidosis
type IV)*
P—Posterior corneal Unilateral or Central, diffuse Normal or Anterior chamber Stable, sometimes Sporadic,
defect bilateral haze or elevated cleavage early clearing or autosomal
vascularized syndrome vascularization recessive
leukoma
E—Endothelial dystrophy
Congenital hereditary Bilateral Diffuse corneal Normal None Stable Autosomal
endothelial dystrophy edema, marked dominant or
corneal recessive
thickening
Posterior polymorphous Bilateral Diffuse haze, Normal Occasional Slowly progressive Autosomal
dystrophy normal corneal peripheral dominant
thickness anterior
synechiae
Congenital hereditary Bilateral Flaky, feathery Normal None Stable Autosomal
stromal dystrophy stromal dominant
opacities; normal
corneal thickness
D—Dermoid Unilateral or White vascularized Normal None Stable Sporadic
bilateral mass, hair, lipid
arc
*Mucopolysaccharidosis IH (Hurler syndrome); mucopolysaccharidosis IS (Scheie syndrome).
From Nelson LB, Calhoun JH, Harley RD: Pediatric ophthalmology, ed 3, Philadelphia, 1991, WB Saunders, p. 210.
CORNEAL DYSTROPHIES is in TGFB1, which is associated with the granular corneal dystrophy
These are rare inherited disorders that may present during childhood types 1 and 2, as well as lattice corneal dystrophy. Congenital heredi-
or early adulthood with bilateral involvement (although severity may tary endothelial dystrophy is both an autosomal recessive (SLC4A11)
be asymmetric) that progresses with time. In most, inheritance is auto- and dominant (unknown gene) disorder; the recessive form presents
somal dominant with variable expression; the most common mutation at birth and is more severe.
Chapter 627 ◆ Abnormalities of the Cornea 3043
may include mechanical debridement of the involved corneal epithe-

lium to remove the source of infection and eliminate an antigenic
stimulus to inflammation in the adjacent stroma. Medical treatment
involves the use of trifluridine, topical ganciclovir, or systemic acyclo-
vir. In addition, a cycloplegic agent is useful to relieve pain from spasm
of the ciliary muscle. Overly aggressive topical antiviral treatment itself
can be toxic to the cornea and should be avoided. Recurrent infection
and deep stromal involvement can lead to corneal scarring and loss of
vision.
Topical use of corticosteroids causes exacerbation of superficial her-
petic disease of the eye and may lead to corneal perforation; eyedrops
combining steroids and antibiotics are therefore to be avoided in treat-
ment of red eye unless there are clear-cut indications for their use and
close supervision during therapy.
Infants born to mothers infected with herpes simplex virus should
be examined carefully for signs of ocular involvement. Intravenous
acyclovir is required for treatment of ocular herpes in newborns.
CORNEAL ULCERS
The usual signs and symptoms are focal or diffuse corneal haze, hyper-
emia, lid edema, pain, photophobia, tearing, and blepharospasm.
Figure 627-2 Peters anomaly. Central opacity in a patient with Peters Hypopyon (pus in the anterior chamber) is common. Corneal ulcers
anomaly. require prompt treatment. They result most frequently from contact
lens wear and traumatic lesions that become secondarily infected.
Many organisms are capable of infecting the cornea. One of the most
serious is Pseudomonas aeruginosa; it can rapidly destroy stromal tissue
and lead to corneal perforation. Neisseria gonorrhoeae also is particu-
larly damaging to the cornea. Indolent ulcers may be caused by fungi,
often in association with the use of contact lenses. In each case, scrap-
ings of the cornea must be studied in an effort to identify the infectious
agent and to determine the best therapy. Although aggressive local
treatment is generally needed to save the eye, systemic treatment may
be necessary in some cases as well. Perforation or scarring resulting
from corneal ulceration is an important cause of blindness throughout
the world and is estimated to be responsible for 10% of blindness in
the United States.
Unexplained corneal ulcers in infants and young children should
raise the question of a sensory defect, as in Riley-Day or Goldenhar-
Figure 627-3 Limbal dermoid. Inferotemporal lesion in a patient with Gorlin syndrome, or of a metabolic disorder such as tyrosinemia (Fig.
Goldenhar syndrome. 627-4). Corneal ulceration can also occur as a consequence of severe
vitamin deficiencies, such as those seen with cystic fibrosis.
DERMOIDS PHLYCTENULES
Epibulbar dermoids are choristomas. They are often present at birth These are small, yellowish, slightly elevated lesions usually located at
and may increase in size with age. They occur most frequently in the the corneal limbus; they may encroach on the cornea and extend cen-
lower temporal quadrant. They most commonly straddle the limbus trally. A small corneal ulcer is often found at the head of the advancing
and extend into the peripheral cornea (Fig. 627-3). Rarely, they may lesion, with a fascicle of blood vessels behind the head of the lesion.
be confined entirely to the cornea or conjunctiva. Epibulbar (or limbal) Although once thought to represent a sign of systemic tuberculin infec-
dermoids may cause visual disturbance by encroaching on the visual tion, phlyctenular keratoconjunctivitis is now accepted as a morpho-
axis or by contributing to the development of astigmatism, which may logic expression of delayed hypersensitivity to diverse antigens. In
lead to amblyopia. children, it commonly occurs as a result of a hypersensitivity reaction
A dermoid usually appears as a well-circumscribed rounded or oval, to nonpathogenic staphylococcal strains at the eyelid margin. Treat-
gray or pinkish-yellow mass with a dry surface from which short hairs ment usually consists of eliminating the underlying disorder, usually
may protrude. It may affect only the superficial layers of the cornea, staphylococcal blepharitis or meibomianitis, and suppressing the
although full-thickness involvement is common. Associated ocular immune response with the use of topical corticosteroid therapy. A
anomalies include eyelid and iris colobomas, microphthalmos, and superficial stromal pannus and scarring sometimes remain after
retinal and choroidal defects. A total of 30% of dermoids are associated treatment.
with systemic abnormalities. Many of the associated anomalies involve
developmental defects of the first branchial arch (vertebral anomalies, INTERSTITIAL KERATITIS
dysostosis of the facial bones, ear anomalies and dental anomalies, and This denotes nonulcerative inflammation of the corneal stroma. There
Goldenhar syndrome). Epibulbar dermoids are found in 75% of cases is a diverse list of causes of interstitial keratitis (IK), including bacterial,
of Goldenhar syndrome. viral, parasitic, and inflammatory etiologies. In the United States,
herpesvirus infections and congenital syphilis account for the majority
DENDRITIC KERATITIS of cases of IK. Although the corneal findings may regress with time,
Infection of the cornea with the herpes simplex virus produces a char- “ghost vessels,” which represent the previous vascular changes, and
acteristic lesion of the corneal epithelium, referred to as a dendrite; it patchy corneal scarring remain and serve as permanent stigmata of the
has a branching tree-like pattern that can be demonstrated by fluores- disease.
cein staining. The acute episode is accompanied by pain, photophobia, Cogan syndrome is IK associated with hearing loss and vestibular
tearing, blepharospasm, and conjunctival injection. Specific treatment symptoms. Although its cause is unknown, a systemic vasculitis is
Figure 627-4 Riley-Day syndrome. This child had a combination of
anesthetic corneas and dry eyes that had been treated for several
months by topical wetting agents without success. He responded well
to a bilateral tarsorrhaphy and lubricant ointment. Later, punctal occlu-
sion allowed enough wetting of his eyes to allow the tarsorrhaphies to
be undone. (From Hoyt CS, Taylor D, editors: Pediatric ophthalmology
and strabismus, ed 4, Philadelphia, 2013, Elsevier Saunders, Fig. 33-9,
p. 315.)
suspected. Prompt treatment is required to avoid permanent hearing

loss. Both the corneal changes and the auditory involvement may
respond to the use of immunosuppressive agents.
CORNEAL MANIFESTATIONS OF SYSTEMIC

DISEASE
Several metabolic diseases produce distinctive corneal changes in
childhood. Refractile polychromatic crystals are deposited throughout
the cornea in cystinosis (see Chapter 85.4). Corneal deposits produc-
ing various degrees of corneal haze also occur in certain types of
mucopolysaccharidosis (MPS; see Chapter 88), particularly MPS IH
(Hurler), MPS IS (Scheie), MPS I H/S (Hurler-Scheie compound),
MPS IV (Morquio), MPS VI (Maroteaux-Lamy), and sometimes MPS
VII (Sly). Corneal deposits may develop in patients with GM1 (general-
ized) gangliosidosis (see Chapter 86.4). In Fabry disease, fine opacities
radiating in a whorl or fan-like pattern occur, and corneal changes can
be important in identifying the carrier state (see Chapter 86.4). A
spray-like pattern of corneal opacities may also be seen in the Bloch-
Sulzberger syndrome (incontinentia pigmenti; see Chapter 596.7). In
Wilson disease (see Chapter 357.2), the distinctive corneal sign is the
Kayser-Fleischer ring, a golden brown ring in the peripheral cornea
resulting from changes in Descemet’s membrane. Pigmented corneal
rings may develop in neonates with cholestatic liver disease. Corneal
changes may occur in autoimmune hypoparathyroidism and band
keratopathy in patients with hypercalcemia (see Chapter 570). Tran-
sient keratitis may occur with rubeola and sometimes with rubella (see
Chapter 247).

Chapter 627 ◆ Abnormalities of the Cornea 3044.e1
Bibliography Nischal KK: Congenital corneal opacities–a surgical approach to nomenclature and
Beauchamp GR, Gillette TE, Friendly DS: Phlyctenular keratoconjunctivitis, classification, Eye (Lond) 21:1326–1337, 2007.
J Pediatr Ophthalmol Strabismus 18:22–28, 1981. Nischal KK: A new approach to the classification of neonatal corneal opacities,
Comer RM, Daya SM, O’Keefe M: Penetrating keratoplasty in infants, J AAPOS Curr Opin Ophthalmol 23:344–354, 2012.
5:285–290, 2001. Reidy JJ: Congenital corneal opacities, Ophthalmol Clin North Am 2:199–213, 1996.
Dana MR, Moyes AL, Gomes JA, et al: The indications for and outcome in Traboulsi EI, Maumenee IH: Peters’ anomaly and associated congenital
pediatric keratoplasty. A multicenter study, Ophthalmology 102:1129–1138, malformations, Arch Ophthalmol 110:1739–1742, 1992.
1995. Yang LL, Lambert SR, Fernhoff PM, et al: Peters’ anomaly: Associated congenital
Mackey DA, Buttery RG, Wise GM, et al: Description of X-linked megalocornea malformations and etiology, Invest Ophthalmol Vis Sci 36:S41, 1995.
with identification of the gene locus, Arch Ophthalmol 109:829–833, 1991. Yang LL, Lambert SR, Lynn MJ, et al: Long-term results of corneal graft survival in
Mohandessan MM, Romano PE: Neuroparalytic keratitis in Goldenhar-Gorlin infants and children with Peters anomaly, Ophthalmology 106:833–848, 1999.
syndrome, Am J Ophthalmol 85:111–113, 1978.
Chapter 628
Abnormalities of the Lens
CATARACTS
A cataract is any opacity of the lens (Fig. 628-1). Some are clinically
unimportant; others significantly affect visual function. The incidence
of infantile cataracts is approximately 2-13/10,000 live births. An epi-
demiologic study of infantile cataracts published in 2003 suggests that
approximately 60% of cataracts are an isolated defect; 22% are part of
a syndrome; and the remainder are associated with other unrelated
major birth defects. Cataracts are more common in low birthweight
infants. Infants who weigh at or below 2,500 g have 3-4–fold increased
odds of developing infantile cataracts. Some cataracts are associated
with other ocular or systemic diseases.
Differential Diagnosis
The differential diagnosis of cataracts in infants and children includes
a wide range of developmental disorders, infectious and inflammatory
processes, metabolic diseases, and toxic and traumatic insults (Table
628-1). Cataracts may also develop secondary to intraocular processes,
such as retinopathy of prematurity, persistent hyperplastic primary
vitreous, retinal detachment, retinitis pigmentosa, and uveitis. Finally,
a fraction of cataracts in children are inherited (Fig. 628-2).
Developmental Variants
Early developmental processes may lead to various congenital lens
opacities. Discrete dots or white plaque-like opacities of the lens
capsule are common and sometimes involve the contiguous subcapsu-
lar region. Small opacities of the posterior capsule may be associated
with persistent remnants of the primitive hyaloid vascular system (the
common Mittendorf dot), whereas those of the anterior capsule may
be associated with persistent strands of the pupillary membrane or
vascular sheath of the lens. Congenital cataracts of this type are usually
stationary and rarely interfere with vision, but in some cases, progres-
sion occurs.
Prematurity
A special type of lens change seen in some preterm newborn infants
is the so-called cataract of prematurity. The appearance is of a cluster
of tiny vacuoles in the distribution of the Y sutures of the lens. They
Figure 628-1 Leukocoria secondary to cataract.

Chapter 628 ◆ Abnormalities of the Lens 3045
Table 628-1 Differential Diagnosis of Cataracts

DEVELOPMENTAL VARIANTS Inborn Errors of Metabolism
Prematurity (Y-suture vacuoles) with or without retinopathy of Abetalipoproteinemia (absent chylomicrons, retinal degeneration)
prematurity Fabry disease (α-galactosidase A deficiency)
Mittendorf dot (remnant of hyaloid artery) Galactokinase deficiency
Persistent pupillary membrane (remnant of embryonic lens Galactosemia (galactose-1-phosphate uridyltransferase deficiency)
vasculature) Homocystinemia (subluxation of lens, mental retardation)
Infantile neuronal ceroid lipofuscinosis
GENETIC DISORDERS
Mannosidosis (acid α-mannosidase deficiency)
Simple Mendelian Inheritance Niemann-Pick disease (sphingomyelinase deficiency)
Autosomal dominant (most common) Refsum disease (phytanic acid α-hydrolase deficiency)
Autosomal recessive Wilson disease (accumulation of copper leads to cirrhosis and
X-linked neurologic symptoms)
Major Chromosomal Defects Zellweger syndrome
Trisomy disorders (13, 18, 21)
Turner syndrome (45X) ENDOCRINOPATHIES
Deletion syndromes (11p13, 18p, 18q) Hypocalcemia (hypoparathyroidism)
Duplication syndromes (3q, 20p, 10q) Hypoglycemia
Multisystem Genetic Disorders Diabetes mellitus
Alport syndrome (hearing loss, renal disease) CONGENITAL INFECTIONS
Alström syndrome (nerve deafness, diabetes mellitus) Toxoplasmosis
Apert disease (craniosynostosis, syndactyly) Cytomegalovirus infection
Cerebrooculofacial syndrome Syphilis
Cockayne syndrome (premature senility, skin photosensitivity) Rubella
Conradi disease (chondrodysplasia punctata) Perinatal herpes simplex infection
Crouzon disease (dysostosis craniofacialis) Measles (rubeola)
Ectodermal dysplasia Poliomyelitis
Hallermann-Streiff syndrome (microphthalmia, small pinched nose, Influenza
skin atrophy, and hypotrichosis) Varicella-zoster
Hypohidrotic ectodermal dysplasia (anomalous dentition,
hypohidrosis, hypotrichosis) OCULAR ANOMALIES
Ichthyosis (keratinizing disorder with thick, scaly skin) Microphthalmia
Incontinentia pigmenti (dental anomalies, mental retardation, Coloboma
cutaneous lesions) Aniridia
Lowe syndrome (oculocerebrorenal syndrome: hypotonia, renal Mesodermal dysgenesis
disease) Persistent pupillary membrane
Marfan syndrome Posterior lenticonus
Meckel-Gruber syndrome (renal dysplasia, encephalocele) Persistent fetal vasculature
Myotonic dystrophy Primitive hyaloid vascular system
Nail–patella syndrome (renal dysfunction, dysplastic nails, hypoplastic Retinitis pigmentosa
patella)
MISCELLANEOUS DISORDERS
Marinesco-Sjögren syndrome (cerebellar ataxia, hypotonia)
Atopic dermatitis
Nevoid basal cell carcinoma syndrome (autosomal dominant, basal
Drugs (corticosteroids)
cell carcinoma erupts in childhood)
Radiation
Peters anomaly (corneal opacifications with iris-corneal dysgenesis)
Trauma
Progeria
Juvenile idiopathic arthritis
Rieger syndrome (iris dysplasia, myotonic dystrophy)
Retinopathy of prematurity
Rothmund-Thomson syndrome (poikiloderma: skin atrophy)
Rubinstein-Taybi syndrome (broad great toe, mental retardation) IDIOPATHIC
Smith-Lemli-Opitz syndrome (toe syndactyly, hypospadias, mental
retardation)
Sotos syndrome (cerebral gigantism)
Spondyloepiphyseal dysplasia (dwarfism, short trunk)
Werner syndrome (premature aging in 2nd decade of life)
can be visualized with an ophthalmoscope and are best seen with the syndromes (e.g., toxoplasmosis, cytomegalovirus, syphilis, rubella,
pupil well dilated. The pathogenesis is unclear. In most cases, the opaci- herpes simplex virus). Cataracts may also occur secondary to other
ties disappear spontaneously, often within a few weeks. perinatal infections, including measles, poliomyelitis, influenza,
varicella-zoster, and vaccinia.
Mendelian Inheritance
Many cataracts unassociated with other diseases are hereditary. The Metabolic Disorders
most common mode of inheritance is autosomal dominant. Pene- Cataracts are a prominent manifestation of many metabolic diseases,
trance and expressivity vary. Autosomal recessive inheritance occurs particularly certain disorders of carbohydrate, amino acid, calcium,
less frequently; it is sometimes found in populations with high rates of and copper metabolism. A primary consideration in any infant with
consanguinity. X-linked inheritance of cataracts unassociated with cataracts is the possibility of galactosemia (see Chapter 87.2). In classic
disease is relatively rare. infantile galactosemia, galactose-1-phosphate uridyl transferase defi-
ciency, the cataract is typically of the zonular type, with haziness or
Congenital Infection Syndrome opacification of 1 or more of the perinuclear layers of the lens. Haziness
Cataracts in infants and children can be a result of prenatal infection. or clouding of the nucleus also often occurs. In its early stages, the
Lens opacity may occur in any of the major congenital infection cataract generally has a distinctive oil droplet appearance and is best
Figure 628-3 Diffuse cataract related to blunt trauma.
occur in some cases. All children receiving long-term steroid treatment

should have periodic eye examinations.
Trauma to the eye is a major cause of cataracts in children (Fig.
628-3). Opacification of the lens may result from blunt or penetrating
injury. Cataracts can be an important manifestation of child abuse.
Figure 628-2 Central lamellar cataract. Cataract formation after exposure to radiation is dose and duration
dependent. Adult research shows 50% occurrence in lens dose of 15
detected with the pupil fully dilated. Progression to complete opacifica- Gy. Delayed onset is the rule.
tion of the lens may occur within weeks. With early treatment
(galactose-free diet), the lens changes may be reversible. Miscellaneous Disorders
In galactokinase deficiency, cataracts are the sole clinical manifes- The list of multisystem syndromes and diseases associated with lens
tation. The cataracts are usually zonular and may appear in the 1st few opacities and other eye anomalies is extensive (see Table 628-1).
mo of life, 1st few yr of life, or later in childhood.
In children with juvenile-onset diabetes mellitus, lens changes are Treatment
uncommon. Some develop snowflake-like white opacities and vacuoles The treatment of cataracts that significantly interfere with vision
of the lens. Others develop cataracts that may progress and mature includes the following: (1) surgical removal of lens material to provide
rapidly, sometimes in a matter of days, especially during adolescence. an optically clear visual axis; (2) correction of the resultant aphakic
An antecedent event may be the sudden development of myopia caused refractive error with spectacles, contact lenses, or intraocular lens
by changes in the optical density of the lens. Congenital lens opacities implantation; and (3) correction of any associated sensory deprivation
may be seen in children of diabetic and prediabetic mothers (see amblyopia. Because the use of spectacles may not be possible in chil-
Chapter 107.1). dren after cataract removal, the use of contact lenses for visual reha-
Hypoglycemia in neonates can also be associated with early develop- bilitation is sometimes a medical necessity. Intraocular lens implantation
ment of cataracts. Ketotic hypoglycemia is also associated with has become a mainstay for visual rehabilitation in children 2 yr or
cataracts. older. A multicenter trial is underway to try to determine visual out-
An association between cataracts and hypocalcemia is well estab- comes in very young children treated with a contact lens versus an
lished. Various lens opacities may be seen in patients with hypopara- intraocular lens implant. One yr after treatment, the children random-
thyroidism (see Chapter 570). ized into the intraocular lens implant group had more statistically
The oculocerebral renal syndrome of Lowe is associated with cata- significant intraoperative complications, adverse events, and need for
racts in infants. Affected male children frequently have dense bilateral additional intraocular surgery. Grating visual acuity at 1 yr was mea-
cataracts at birth, often in association with glaucoma and miotic pupils. sured and 86% of patients in the contact lens group and 77% in the
Punctate lens opacities are frequently present in heterozygous females. intraocular lens group had 20/200 vision or better. The median visual
The distinctive sunflower cataract of Wilson disease is not com- acuity between the groups was analyzed and although the median
monly seen in children. Various lens opacities may be seen in children acuity was better in the contact lens group, the difference did not reach
with certain of the sphingolipidoses, mucopolysaccharidoses, and statistical significance. Final outcome will be the comparison of visual
mucolipidoses, particularly Niemann-Pick disease, mucosulfatidosis, acuity at 4.5 yr of age. Treatment of the amblyopia may be the most
Fabry disease, and aspartylglycosaminuria (see Chapter 86). demanding and difficult step in the visual rehabilitation of infants or
children with cataracts. Not all cataracts require surgical intervention.
Chromosomal Defects Cataracts that are not visually significant should be monitored for
Lens opacities of various types may occur in association with chromo- change and the child should be monitored for development of
somal defects, including trisomies 13, 18, and 21; Turner syndrome; amblyopia.
and a number of deletion (11p13, 18p, 18q) and duplication (3q, 20p,
10q) syndromes. Prognosis
Prognosis depends on many factors, including the nature of the cata-
Drugs, Toxic Agents, and Trauma ract, the underlying disease, age at onset, age at intervention, duration
Of the various drugs and toxic agents that may produce cataracts, and severity of any attendant amblyopia, and presence of any associ-
corticosteroids are of major importance in the pediatric age group. ated ocular abnormalities (e.g., microphthalmia, retinal lesions, optic
Steroid-related cataracts characteristically are posterior subcapsular atrophy, glaucoma, nystagmus, and strabismus). Persistent amblyopia
lens opacities. The incidence and severity vary. The relative significance is the most common cause of poor visual recovery after cataract
of dose, mode of administration, duration of treatment, and individual surgery in children. Secondary conditions and complications may
susceptibility is controversial, and the pathogenesis of steroid-induced develop in children who have had cataract surgery, including inflam-
cataracts is unclear. The effect on vision depends on the extent and matory sequelae, secondary membranes, glaucoma, retinal detach-
density of the opacity. In many cases, the acuity is only minimally or ment, and changes in the axial length of the eye. All of these should be
moderately impaired. Reversibility of steroid-induced cataracts may considered in planning treatment.
Chapter 628 ◆ Abnormalities of the Lens 3047
(see Chapter 622). In this condition, both the lens and pupil are dis-
placed, usually in opposite directions. This condition is generally bilat-
eral, with 1 eye being almost a mirror image of the other. Ectopia lentis
et pupillae is an autosomal recessive condition, although variable
expression with some intermingling with simple ectopia lentis has been
reported.
Systemic disorders associated with displacement of the lens include
Marfan syndrome, homocystinuria, Weill-Marchesani syndrome, and
sulfite oxidase deficiency. Ectopia lentis occurs in approximately 80%
of patients with Marfan syndrome. In approximately 50% of patients
with Marfan syndrome, the ectopia is evident by 5 yr of age. In most
cases, the lens is displaced superiorly and temporally; it is almost
always bilateral and relatively symmetric. In homocystinuria, the lens
is usually displaced inferiorly and somewhat nasally. The subluxation
of the lens occurs early in life and is often evident by 5 yr of age. In
Figure 628-4 Complete dislocation of lens into the anterior chamber Weill-Marchesani syndrome, the displacement of the lens is often
seen in Weill-Marchesani syndrome. downward and forward, and the lens tends to be small and round.
Ectopia lentis is also associated occasionally with other conditions,
including Ehlers-Danlos, Sturge-Weber, Crouzon, and Klippel-Feil
syndromes; oxycephaly; and mandibulofacial dysostosis. A syndrome
of dominantly inherited blepharoptosis, high myopia, and ectopia
lentis has also been described.
Treatment and Prognosis

Displacement of the lens often results only in optical problems. In
some cases, however, more serious complications may develop, such
as glaucoma, uveitis, retinal detachment, or cataract. Management
must be individualized according to the type of displacement, its cause,
and the presence of any complicating ocular or systemic conditions.
For many patients, optical correction by spectacles or contact lenses
can be provided. Manipulation of the iris diaphragm with mydriatic or
miotic drops may sometimes help improve vision. In selected cases,
the best treatment is surgical removal of the lens. In many children,
treatment of any associated amblyopia must be instituted early. In
addition, for children with ectopia lentis, safety precautions should be
Figure 628-5 Marfan syndrome. Upward lens subluxation. (From taken to prevent injury to the eye.
Hoyt CS, Taylor D: Pediatric ophthalmology and strabismus, ed 4,
Philadelphia, 2013, Elsevier Saunders, Fig. 35.9A, p. 333.) Microspherophakia
The term microspherophakia refers to a small, round lens that may
Ectopia Lentis occur as an isolated anomaly (probably autosomal recessive) or in asso-
Normally, the lens is suspended in place behind the iris diaphragm by ciation with other ocular abnormalities, such as ectopia lentis, myopia,
the zonular fibers of the ciliary body. Abnormalities of the suspensory or retinal detachment (possibly autosomal dominant). Microsphero-
system resulting from a developmental defect, disease, or trauma may phakia may also occur in association with various systemic disorders,
result in instability or displacement of the lens. Displacement of the including Marfan syndrome, Weill-Marchesani syndrome, Alport syn-
lens is classified as luxation, which is complete displacement of the lens drome, mandibulofacial dysostosis, and Klinefelter syndrome.
(also known as dislocation) (Fig. 628-4), or as subluxation, which is a
partial displacement (Fig. 628-5). Symptoms include blurring of vision, Anterior Lenticonus
which is often the result of refractive changes such as myopia, astig- Anterior lenticonus is a rare bilateral condition in which the anterior
matism, or aphakic hyperopia. Some patients experience diplopia capsule of the lens thins, allowing the lens to bulge forward centrally.
(double vision). An important sign of displacement is iridodonesis, a It may be accompanied by lens opacities or other eye anomalies and is
tremulousness of the iris caused by the loss of its usual support. Also, a prominent feature of Alport syndrome. The increased curvature of
the anterior chamber may appear deeper than normal. Sometimes the the central area may cause high myopia. Spontaneous rupture of the
equatorial region (“edge”) of the displaced lens may be visible in the anterior capsule may occur, requiring prompt surgical intervention.
pupillary aperture. On ophthalmoscopy, this may appear as a black
crescent. Also, the difference between the phakic and aphakic portions Posterior Lenticonus
can be appreciated when focusing on the fundus. Posterior lenticonus, which occurs more commonly than anterior len-
ticonus, is characterized by a circumscribed round or oval bulge of the
Differential Diagnosis posterior lens capsule and cortex, involving the central region of the
A major cause of lens displacement is trauma. Displacement may also lens. In the early stages, by the red reflex test, this may look like an oil
occur as a result of ocular disease such as uveitis, intraocular tumor, droplet. It occurs in infants and young children and tends to increase
congenital glaucoma, high myopia, megalocornea, or aniridia or in with age. Usually the lens material within and surrounding the capsular
association with cataract. Ectopia lentis may also be inherited or asso- bulge eventually becomes opacified. Posterior lenticonus usually
ciated with systemic disease. occurs as an isolated ocular anomaly. It is generally unilateral but may
Displacement of the lens occurring as a heritable ocular condition be bilateral. It is believed to be sporadic, although autosomal dominant
unassociated with systemic abnormalities is referred to as simple and X-linked inheritance has been suggested in some cases. Infants or
ectopia lentis. Simple ectopia lentis is usually transmitted as an auto- children with posterior lenticonus may require optical correction,
somal dominant condition. The lens is generally displaced upward and amblyopia treatment, and surgery for progressive cataract.
temporally. The ectopia may be present at birth or may appear later in
life. Another form of heritable dislocation is ectopia lentis et pupillae Bibliography is available at Expert Consult.
Chapter 628 ◆ Abnormalities of the Lens 3047.e1
Bibliography Russell HC, McDougall V, Dutton GN: Congenital cataract, BMJ 342:d3075, 2011.
Anteby I, Isaac M, BenEzra D: Hereditary subluxated lenses: visual performances Russell-Eggit IM: Non-syndromic posterior lenticonus a cause of childhood
and long-term follow-up after surgery, Ophthalmology 110:1344–1348, 2003. cataract: evidence for x-linked inheritance, Eye (Lond) 14(Pt 6):861–863, 2000.
Bhatti TR, Dott M, Yoon PW, et al: Descriptive epidemiology of infantile cataracts SanGiovanni JP, Chew EY, Reed GF, et al: Infantile cataract in collaborative
in metropolitan Atlanta, GA, 1968–1998, Arch Pediatr Adolesc Med 157:341– perinatal project: prevalence and risk factors, Arch Ophthalmol 120(11):1559–
347, 2003. 1565, 2002.
Fallaha N, Lambert SR: Pediatric cataracts, Ophthalmol Clin North Am 14:479–492, Tesser RA, Hess DB, Buckley EG: Pediatric cataracts and lens anomalies. In Nelson
2001. LB, Olitsky SE, editors: Harley’s Pediatric Ophthalmology, ed 5, Philadelphia,
Peterseim MW, Wilson ME: Bilateral intraocular lens implantation in the pediatric 2005, Lippincott Williams & Wilkins, pp 255–284.
population, Ophthalmology 107:1261–1266, 2000. The Infant Aphakia Treatment Study Group: A randomized clinical trial comparing
Plager DA, Lynn MJ, Buckley EG, et al: Complications, adverse events and contact lens to intraocular lens correction of monocular aphakia during
additional intraocular surgery one year after cataract surgery in the Infant infancy: grating acuity and adverse events at age 1 year, Arch Ophthalmol
Aphakia Treatment Study, Ophthalmology 118(12):2330–2334, 2011. 128(7):810–818, 2010.
Plager DA, Yang S, Neely D, et al: Complications in the first year following cataract
surgery with and without IOL in infants and older children, J AAPOS 6:9–14,
2002.
Iritis may occur alone or in conjunction with inflammation of the

Chapter 629 ciliary body as iridocyclitis or in association with pars planitis. Pain,
photophobia, and lacrimation are the characteristic symptoms of acute
Disorders of the Uveal anterior uveitis, but the inflammation may develop insidiously without
disturbing symptoms. Signs of anterior uveitis include conjunctival
hyperemia, particularly in the perilimbal region (ciliary flush), and
Tract cells and protein (“flare”) in the aqueous humor (Fig. 629-1). Inflam-
matory deposits on the posterior surface of the cornea (keratic precipi-
Scott E. Olitsky, Denise Hug, tates) and congestion of the iris may also be seen. More chronic cases
may show degenerative changes of the cornea (band keratopathy),
Laura S. Plummer, Erin D. Stahl, lenticular opacities (cataract), development of glaucoma, and impair-
Michelle M. Ariss, and Timothy P. Lindquist ment of vision. The cause of anterior uveitis is often obscure; primary
considerations in children are rheumatoid disease, particularly pau-
ciarticular arthritis, Kawasaki disease, Reiter syndrome, and sarcoid-
UVEITIS (IRITIS, CYCLITIS, CHORIORETINITIS) osis. Iritis may be secondary to corneal disease, such as herpetic
The uveal tract (the inner vascular coat of the eye, consisting of the keratitis or a bacterial or fungal corneal ulcer, or to a corneal abrasion
iris, ciliary body, and choroid) is subject to inflammatory involvement or foreign body. Traumatic iritis and iridocyclitis are especially
in a number of systemic diseases, both infectious and noninfectious, common in children.
and in response to exogenous factors, including trauma and toxic Iridocyclitis that occurs in children with arthritis deserves special
agents (Table 629-1). Inflammation may affect any one portion of the mention. Unlike most forms of anterior uveitis, it rarely creates pain,
uveal tract preferentially or all parts together. photophobia, or conjunctival hyperemia. Loss of vision may not be
noticed until severe and irreversible damage has occurred. Because of
the lack of symptoms and the high incidence of uveitis in these chil-
Table 629-1 Uveitis in Childhood dren, routine periodic screening is necessary. Ophthalmic screening
guidelines are based on 3 factors that predispose children with arthritis
ANTERIOR UVEITIS to uveitis:
Juvenile idiopathic arthritis (pauciarticular) 1. Type of arthritis
Sarcoidosis 2. Age of onset of arthritis
Trauma
Tuberculosis
3. Antinuclear antibody (ANA) status
Kawasaki disease Table 629-2 has been developed by the American Academy of Pedi-
Ulcerative colitis atrics for children with juvenile idiopathic arthritis without known
Crohn syndrome iridocyclitis.
Postinfectious (enteric or genital) with arthritis and rash Choroiditis, inflammation of the posterior portion of the uveal
Spirochetal (syphilis, leptospiral) tract, invariably also involves the retina; when both are obviously
Brucellosis affected, the condition is termed chorioretinitis. The causes of posterior
Heterochromic iridocyclitis (Fuchs) uveitis are numerous; the more common are toxoplasmosis, histoplas-
Viral (herpes simplex, herpes zoster) mosis, cytomegalic inclusion disease, sarcoidosis, syphilis, tuberculo-
Ankylosing spondylitis
sis, and toxocariasis (Fig. 629-2). Depending on the etiology, the
Stevens-Johnson syndrome
Chronic infantile neurologic cutaneous arthritis syndrome (CINCA)
inflammatory signs may be diffuse or focal. Vitreous reaction often
Familial Mediterranean fever occurs as well. With many types, the result is atrophic chorioretinal
Hyperimmunoglobulin D syndrome scarring demarcated by pigmentation, often with visual impairment.
Tumor necrosis factor receptor–associated periodic syndrome Secondary complications include retinal detachment, glaucoma, and
Muckle-Wells syndrome phthisis.
Blau syndrome Panophthalmitis is inflammation involving all parts of the eye. It is
Psoriasis frequently suppurative, most often as a result of a perforating injury or
Multiple sclerosis of septicemia. It produces severe pain, marked congestion of the eye,
Cyclic neutropenia inflammation of the adjacent orbital tissues and eyelids, and loss of
Chronic granulomatous disease
vision. In many cases, the eye is lost despite intensive treatment of the
X-linked lymphoproliferative disease
Hypocomplementemic vasculitis infection and inflammation. Enucleation of the eye or evisceration of
Idiopathic the orbit may be necessary.
Drugs
POSTERIOR UVEITIS (CHOROIDITIS—MAY INVOLVE RETINA)
Toxoplasmosis
Toxocariasis
Parasites (toxocariasis)
Sarcoidosis
Cat-scratch disease
Tuberculosis
Viral (rubella, herpes simplex, HIV, cytomegalovirus, West Nile)
Subacute sclerosing panencephalitis
Tubulointestinal nephritis and uveitis syndrome
Idiopathic
ANTERIOR AND/OR POSTERIOR UVEITIS
Sympathetic ophthalmia (trauma to other eye)
Vogt-Koyanagi-Harada syndrome (uveootocutaneous syndrome:
poliosis, vitiligo, deafness, tinnitus, uveitis, aseptic meningitis,
retinitis)
Behçet syndrome
Lyme disease
Figure 629-1 Cell and flare in the anterior chamber. The flare rep-
resents protein leakage. (Courtesy of Peter Buch, CRA.)
development of glaucoma and cataracts. To reduce the need for topical
and systemic corticosteroids, systemic immunosuppression is often
used in patients requiring long-term treatment. Commonly used
immunosuppressive agents include methotrexate, cyclosporine, and
tumor necrosis factor inhibitors. Multiple agents may be needed in
recalcitrant cases. Cycloplegic agents, particularly atropine, are also
used to reduce inflammation and to prevent adhesion of the iris to the
lens (posterior synechiae), especially in anterior uveitis. Extensive pos-
terior synechiae formation can lead to acute angle closure glaucoma.
Surgery may be required for patients who develop glaucoma because
of the underlying disease process or the need for corticosteroid treat-
ment. Cataract surgery should be delayed until the inflammation has
been under control for a period of time. Cataract surgery in children
with a history of prolonged uveitis can carry significant risk. There is
no universal agreement concerning the use of intraocular lenses in
these patients.
Pars planitis is an uncommon idiopathic form of intermediate
uveitis characterized by anterior chamber involvement, anterior vitre-
ous cells and condensations, and peripheral retinal vasculitis. The
average age of onset is 9 yr. It is predominately bilateral and seen more
frequently in males. Painless decreased vision is the usual presenting
sign. The prognosis is good when adequate medical treatment is sought
Figure 629-2 Focal atrophic and pigmented scars of early in the course of the disease.
chorioretinitis. Masquerade syndromes can sometimes mimic intraocular inflam-
mation. Retinoblastoma, leukemia, retained intraocular foreign body,
juvenile xanthogranuloma, and peripheral retinal detachments may
produce signs similar to those seen in uveitis. These syndromes should
Table 629-2 Examination Schedule for Children with be kept in mind when evaluating a patient with suspected uveitis or
JIA Without Known Iridocyclitis if a patient does not respond as anticipated to antiinflammatory
AGE OF ONSET
treatment.
JIA SUBTYPE ≤6 yr >6 yr Bibliography is available at Expert Consult.

OLIGOARTHRITIS OR POLYARTHRITIS
Positive ANA
Less than 4 yr duration Every 3 mo Every 6 mo
4-7 yr duration Every 6 mo Annually
More than 7 yr duration Annually Annually
Negative ANA
Less than 4 yr duration Every 6 mo Annually
4-7 yr duration Annually Annually
More than 7 yr duration Annually Annually
Systemic Annually regardless Annually regardless
of duration of duration
ANA, antinuclear antibody; JIA, juvenile idiopathic arthritis; JRA, juvenile
rheumatoid arthritis.
Sympathetic ophthalmia is a rare type of inflammatory response

that affects the uninjured eye after a perforating injury. It may occur
weeks, months, or even years after the injury. A hypersensitivity phe-
nomenon is the most probable cause. Loss of vision in the uninjured
(sympathizing) eye may result. Removal of the injured eye prevents the
development of sympathetic ophthalmia but does not stop the progres-
sion of the disease once it has occurred. Therefore, early enucleation
should be considered if there is no hope of visual recovery after a severe
injury.
Treatment
The various forms of intraocular inflammation are treated according
to their underlying systemic causal factors. When infection is proved
or suspected, appropriate systemic antimicrobial or antiviral therapy is
used. In some cases, intravitreal injection is indicated.
Elimination of the intraocular inflammation is important to reduce
the risk of severe, and often permanent, vision loss. Untreated, the
inflammatory process may lead to the development of band keratopa-
thy (calcium deposition in the cornea), cataracts, glaucoma, and irre-
versible retinal damage. Anterior inflammation may respond well to
topical corticosteroid treatment. Posterior cases often require systemic
therapy. The use of topical and systemic corticosteroids can lead to the
Chapter 629 ◆ Disorders of the Uveal Tract 3049.e1
Bibliography Lowder C, Belfort R Jr, Lightman S, et al: Dexamethasone intravitreal implant for
BenEzra D, Cohen E: Cataract surgery in children with chronic uveitis, noninfectious intermediate or posterior uveitis, Arch Ophthalmol 129:545–553,
Ophthalmology 107:1255–1260, 2000. 2011.
Ferrini W, Aubert V, Balmer A, et al: Anterior uveitis and cataract after rubella McCluskey P, Powell RJ: The eye in systemic inflammatory diseases, Lancet
vaccination: a case report of a 12-month-old girl, Pediatrics 132:e1035–e1037, 364:2125–2133, 2004.
2013. Oren B, Sehgal A, Simon JW, et al: The prevalence of uveitis in juvenile
Holland GN, Stiehm ER: Special considerations in the evaluation and management rheumatoid arthritis, J AAPOS 5:2–4, 2001.
of uveitis in children, Am J Ophthalmol 135:867–878, 2003. Patel H, Goldstein D: Pediatric uveitis, Pediatr Clin North Am 50:125–136, 2003.
Kadayifcilar S, Eldem B, Tumer B: Uveitis in childhood, J Pediatr Ophthalmol Rosenberg KD, Feuer WJ, Davis JL: Ocular complications of pediatric uveitis,
Strabismus 40:335–340, 2003. Ophthalmology 111:2299–2306, 2004.
Chapter 630 ◆ Disorders of the Retina and Vitreous 3049
Chapter 630
Disorders of the Retina
and Vitreous
RETINOPATHY OF PREMATURITY
Retinopathy of prematurity (ROP) is a complex disease of the develop-
ing retinal vasculature in premature infants. It may be acute (early
stages) or chronic (late stages). Clinical manifestations range from
mild, usually transient changes of the peripheral retina to severe pro-
gressive vasoproliferation, scarring, and potentially blinding retinal
detachment. ROP includes all stages of the disease and its sequelae.
Retrolental fibroplasia, the previous name for this disease, described
only the cicatricial stages.
Pathogenesis
Beginning at 16 wk of gestation, retinal angiogenesis normally pro-
ceeds from the optic disc to the periphery, reaching the outer rim of
the retina (ora serrata) nasally at about 36 wk and extending tempo-
rally by approximately 40 wk. Injury to this process results in various
pathologic and clinical changes. The first observation in the acute
phase is cessation of vasculogenesis. Rather than a gradual transition
from vascularized to avascular retina, there is an abrupt termination the retina and appears relatively flat and white. Often noted is abnor-
of the vessels, marked by a line in the retina. The line may then grow mal branching or arcading of the retinal vessels that lead into the line.
into a ridge composed of mesenchymal and endothelial cells. Cell divi- Stage 2 is characterized by a ridge; the demarcation line has grown,
sion and differentiation may later resume, and vascularization of the acquiring height, width, and volume and extending up and out of
retina may proceed. Alternatively, there may be progression to an the plane of the retina. Stage 3 is characterized by the presence of
abnormal proliferation of vessels out of the plane of the retina, into the a ridge and by the development of extraretinal fibrovascular tissue
vitreous, and over the surface of the retina. Cicatrization and traction (Fig. 630-2A). Stage 4 is characterized by subtotal retinal detachment
on the retina may follow, leading to retinal detachment. caused by traction from the proliferating tissue in the vitreous or on
The risk factors associated with ROP are not fully known, but pre- the retina. Stage 4 is subdivided into 2 phases: (a) subtotal retinal
maturity and the associated retinal immaturity at birth represent the detachment not involving the macula and (b) subtotal retinal detach-
major factors. Oxygenation, respiratory distress, apnea, bradycardia, ment involving the macula. Stage 5 is total retinal detachment.
heart disease, infection, hypercarbia, acidosis, anemia, and the need When signs of posterior retinal vascular changes accompany the
for transfusion are thought by some to be contributory factors. Gener- active stages of ROP, the term plus disease is used (see Fig. 630-2B and
ally, the lower the gestational age, the lower the birthweight, and the C). Patients reaching the point of dilation and tortuosity of the retinal
sicker the infant are, the greater the risk is for ROP. vessels also frequently demonstrate the associated findings of engorge-
The basic pathogenesis of ROP is still unknown. Exposure to the ment of the iris, pupillary rigidity, and vitreous haze.
extrauterine environment, including the necessarily high inspired
oxygen concentrations, produces cellular damage, perhaps mediated Clinical Manifestations and Prognosis
by free radicals. Later in the course of the disease, peripheral hypoxia In more than 90% of at-risk infants, the course is one of spontaneous
develops and vascular endothelial growth factors (VEGFs) are pro- arrest and regression, with little or no residual effects or visual dis-
duced in the nonvascularized retina. These growth factors stimulate ability. Fewer than 10% of infants have progression toward severe
abnormal vasculogenesis, and neovascularization may occur. Because disease, with significant extraretinal vasoproliferation, cicatrization,
of poor pulmonary function, a state of relative retinal hypoxia occurs. detachment of the retina, and impairment of vision.
This causes upregulation of VEGF, which, in susceptible infants, can Some children with arrested or regressed ROP are left with demarca-
cause abnormal fibrovascular growth. This neovascularization may tion lines, undervascularization of the peripheral retina, or abnormal
then lead to scarring and vision loss. branching, tortuosity, or straightening of the retinal vessels. Some are
left with retinal pigmentary changes, dragging of the retina (so-called
Classification dragged disc), ectopia of the macula, retinal folds, or retinal breaks.
The currently used international classification of ROP describes the Others proceed to total retinal detachment, which commonly assumes
location, extent, and severity of the disease. To delineate location, the a funnel-like configuration. The clinical picture is often that of a ret-
retina is divided into 3 concentric zones, centered on the optic disc rolental membrane, producing leukokoria (a white reflex in the pupil).
(Fig. 630-1). Zone I, the posterior or inner zone, extends twice the Some patients develop cataract, glaucoma, and signs of inflammation.
disc-macular distance, or 30 degrees in all directions from the optic The end stage is often a painful blind eye or a degenerated phthisical
disc. Zone II, the middle zone, extends from the outer edge of zone I eye. The spectrum of ROP also includes myopia, which is often pro-
to the ora serrata nasally and to the anatomic equator temporally. Zone gressive and of significant degree in infancy. The incidence of aniso-
III, the outer zone, is the residual crescent that extends from the outer metropia, strabismus, amblyopia, and nystagmus may also be increased.
border of zone II to the ora serrata temporally. The extent of involve-
ment is described by the number of circumferential clock hours Diagnosis
involved. Systematic serial screening ophthalmologic examinations of infants
The phases and severity of the disease process are classified into 5 at risk are recommended. Infants with a birthweight of less than
stages. Stage 1 is characterized by a demarcation line that separates 1,500 g or gestational age of 32 wk or less, and selected infants with a
vascularized from avascular retina. This line lies within the plane of birthweight between 1,500 and 2,000 g or gestational age of more than
A B
Figure 630-1 The retina is divided into 3 zones (A, diagram shows right eye) and the extent or severity of retinopathy in these zones is classified
as stages (B). Stage 1 is characterized by a thin demarcation line between vascularized and nonvascularized retina, stage 2 by a ridge, stage 3 by
extraretinal fibrovascular proliferation, stage 4 by partial retinal detachment, and stage 5 by total retinal detachment. In stage 3, extraretinal neo-
vascularization can become severe enough to cause retinal detachment (stages 4-5), which usually leads to blindness. (B courtesy Lisa Hård. From
Hellström A, Smith LEH, Dammann O: Retinopathy of prematurity. Lancet 382:1445-1454, 2013, Fig. 3, p. 1450.)
A B C
Figure 630-2 Retinopathy of prematurity (ROP). A, In stage 3, there is a ridge and extraretinal vascular tissue. B, Retinal vessels are dilated and
tortuous in active zone 1 ROP with plus disease. C, Zone 1 ROP with plus disease.
the treatment modality of choice. Peripheral retinal ablation should

Table 630-1 Timing of First Eye Examination Based on be considered for any eye with type 1 ROP. Serial examinations are
Gestational Age at Birth indicated for any eye with type 2 ROP; treatment is considered if type
AGE AT INITIAL EXAMINATION 2 progresses to type 1 or if threshold ROP develops.
IN WEEKS Clinical trials using systemic propranolol or intravitreal VEGF
GESTATIONAL antagonists are ongoing and being evaluated for efficacy and risk.
AGE AT BIRTH POSTMENSTRUAL CHRONOLOGIC
22 31 9 Prevention
Prevention of ROP ultimately depends on prevention of premature
23 31 8
birth and its attendant problems (see Chapters 95 and 97.2). However,
24 31 7 a number of other potential factors have been studied in order to
25 31 6 decrease the occurrence of ROP in these premature infants. Ambient
light had been considered by some to be a potential agent that could
26 31 5 hopefully be manipulated. The LIGHT-ROP study definitively found
27 31 4 that ambient light reduction had no impact on ROP. The association
between ROP and oxygen saturation has been studied for decades.
28 32 4
Recent research has focused on maintaining oxygen saturation levels
29 33 4 for severely premature infants at levels sufficiently low to minimize the
30 34 4 risk of ROP and sufficiently high to optimize survival.
31 35 4 PERSISTENT FETAL VASCULATURE
32 36 4 Persistent fetal vasculature (PFV; formerly called persistent hyperplas-
tic primary vitreous) includes a spectrum of manifestations caused by
the persistence of various portions of the fetal hyaloid vascular system
and associated fibrovascular tissue.
32 wk with an unstable clinical course, including those requiring car-
diorespiratory support and who are believed by their attending pedia- Pathogenesis
trician or neonatologist to be at high risk, should have retinal screening During development of the eye, the hyaloid artery extends from the
examinations. The timing of the initial screening exam is based on the optic disc to the posterior aspect of the lens; it sends branches into the
infant’s age. Table 630-1 was developed from an evidence-based analy- vitreous and ramifies to form the posterior portion of the vascular
sis of the Multicenter Trial of Cryotherapy for ROP. The examination capsule of the lens. The posterior portion of the hyaloid system nor-
can be stressful to fragile preterm infants, and the dilating drops can mally regresses by the 7th fetal mo and the anterior portion by the 8th
have untoward side effects. Infants must be carefully monitored during fetal mo. Small remnants of the system, such as a tuft of tissue at the
and after the examination. Some neonatologists and ophthalmologists disc (Bergmeister papilla) or a tag of tissue on the posterior capsule of
advocate the use of topical tetracaine and/or oral sucrose to reduce the the lens (Mittendorf dot), are common findings in healthy persons.
discomfort and stress to the infant. Follow-up is based on the initial More extensive remnants and associated complications constitute PFV.
findings and risk factors but is usually 2 wk or less. Two major forms are described, anterior PFV and posterior PFV. Vari-
ability is great, and mixed or intermediate forms occur.
Treatment
In selected cases, cryotherapy or laser photocoagulation of the avascu- Clinical Manifestations
lar retina reduces the more severe complications of progressive ROP. The usual clinical feature of anterior PFV is the presence of a vascular-
Advances in vitreoretinal surgical techniques have led to limited ized plaque of tissue on the back surface of the lens in an eye that is
success in reattaching the retina in infants with total retinal detach- microphthalmic or slightly smaller than normal. The condition is
ment (stage 5 ROP), but the visual results are often disappointing. The usually unilateral and may occur in infants with no other abnormalities
Early Treatment for Retinopathy of Prematurity Cooperative study did and no history of prematurity. The fibrovascular tissue tends to undergo
find improved structural and visual outcomes with the redefined gradual contracture. The ciliary processes become elongated, and the
threshold for treatment. It demonstrated the importance of plus disease anterior chamber may become shallow. The lens usually is smaller than
and the presence of posterior retinal involvement in the determination normal and may be clear but often becomes cataractous and may swell
of when to treat ROP. This study also supported the fact that laser is or absorb fluid. Large or anomalous vessels of the iris may be present.
The anterior chamber angle may have abnormalities. In time, the 1/15,000 live births; 250-300 new cases are diagnosed in the United
cornea may become cloudy. States annually. Hereditary and nonhereditary patterns of transmission
Anterior PFV is usually noted in the 1st wk or mo of life. The most occur; there is no gender or race predilection. The hereditary form
frequent presenting signs are leukocoria (white pupillary reflex), stra- occurs earlier and is usually bilateral and multifocal, whereas the non-
bismus, and nystagmus. The course is usually progressive and the hereditary form is generally unilateral and unifocal. Fifteen percent of
outcome poor. Major complications are spontaneous intraocular hem- unilateral cases are hereditary. Bilateral cases often present earlier than
orrhage, swelling of the lens caused by rupture of the posterior capsule, unilateral cases. Unilateral tumors are often large by the time they are
and glaucoma. The eye may eventually deteriorate. The spectrum of discovered. The average age at diagnosis is 15 mo for bilateral cases,
posterior PFV includes fibroglial veils around the disc and macula, compared with 27 mo for unilateral cases. It is unusual for a child to
vitreous membranes and stalks containing hyaloid artery remnants present with a retinoblastoma after 3 yr of age. Rarely, the tumor is
projecting from the disc, and meridional retinal folds. Traction detach- discovered at birth, during adolescence, or even in early adulthood.
ment of the retina may occur. Vision may be impaired, but the eye is
usually retained. Clinical Manifestations
The clinical manifestations of retinoblastoma vary, depending on the
Treatment stage at which the tumor is detected. The initial sign in the majority of
Surgery is performed in an effort to prevent complications, to preserve patients is a white pupillary reflex (leukocoria). Leukocoria results
the eye and a reasonably good cosmetic appearance, and, in some because of the reflection of light off the white tumor. The second most
cases, to salvage vision. Surgical treatment usually involves aspirating frequent initial sign of retinoblastoma is strabismus. Less-frequent pre-
the lens and excising the abnormal tissue. If useful vision is to be senting signs include pseudohypopyon (tumor cells layered inferiorly
attained, refractive correction and aggressive amblyopia therapy are in front of the iris) caused by tumor seeding in the anterior chamber
required. In some cases, the affected eye is enucleated because distin- of the eye, hyphema (blood layered in front of the iris) secondary to
guishing between this white mass and retinoblastoma can be difficult. iris neovascularization, vitreous hemorrhage, and signs of orbital cel-
Ultrasonography and CT are valuable diagnostic aids. lulitis. On examination, the tumor appears as a white mass, sometimes
small and relatively flat, sometimes large and protuberant. It may
RETINOBLASTOMA appear nodular. Vitreous haze or tumor seeding may be evident.
Also see Chapter 502. The retinoblastoma gene is a recessive suppressor gene located on
Retinoblastoma (Fig. 630-3) is the most common primary malig- chromosome 13 at the 13q14 region. Because of the hereditary nature
nant intraocular tumor of childhood. It occurs in approximately of retinoblastoma, family members of affected children should undergo
B
Figure 630-3 Progression of retinoblastoma from small intraretinal tumors to massive orbital retinoblastoma probably extending into the brain.
Progression of retinoblastoma (A) from small intraretinal tumors that can be cured by laser treatment and cryotherapy (TNM T1a, IIRC A) to massive
orbital retinoblastoma probably extending into the brain (TNM T4a-b). A difference in age at diagnosis recorded between Canada and Kenya
could be the difference between possible cure and certain death (B). The Canadian child with leukocoria was diagnosed because of the left-hand
image, which was taken by his sister with his mother’s mobile phone. IIRC, International Intraocular Retinoblastoma Classification; TNM, Tumor
Node Metastasis Cancer Staging. (From Dimaras H, Kimani K, Dimba EAO, et al: Retinoblastoma. Lancet 379:1436-1444, 2012, Fig. 1, p. 1438.)
a complete ophthalmologic examination and genetic counseling.

Newborn siblings and children of affected patients should be referred
to an ophthalmologist shortly after birth, when the peripheral retina
can be evaluated without the need for an examination under
anesthesia.
Diagnosis
This is made by direct observation by an experienced ophthalmologist.
Ancillary testing such as CT or ultrasonography may help to confirm
the diagnosis and demonstrate calcification within the mass. MRI may
better detect the presence of an associated pineoblastoma (trilateral
retinoblastoma). A definitive diagnosis occasionally cannot be made,
and removal of the eye must be considered to avoid the possibility of
lethal metastasis of the tumor. Because a biopsy can lead to spread of
the tumor, histologic confirmation before enucleation is not possible
in most cases. Therefore, removal of a blind eye in which the diagnosis
of retinoblastoma is likely may be appropriate.
Treatment
Therapy varies, depending on the size and location of the tumor as well
as whether it is unilateral or bilateral. Advanced tumors may be treated
by enucleation. Other treatment modalities include the use of external
beam irradiation, radiation plaque therapy, laser or cryotherapy, and Figure 630-4 Retinitis pigmentosa.
chemotherapy. During the last decade there has been a dramatic shift
in the treatment of retinoblastomas. Chemoreduction (systemic che- (subretinal injection) presently shows early promise for people affected
motherapy) followed by local therapies (i.e., laser therapy, cryotherapy, with Leber congenital retinal amaurosis.
and brachytherapy) has markedly reduced the use of external beam Usher syndrome, an autosomal recessive disorder, is the most
radiation and is a more vision-sparing technique. Those children who common cause of retinitis pigmentosa and sensorineural deafness
are irradiated during their 1st yr of life are 2-8 times more likely to (incidence 1 : 25,000). Type 1 Usher syndrome presents at birth with
develop second cancers as those irradiated after 1 yr of age. Patients profound hearing loss and poor balance; visional loss progresses more
treated with radiation tend to develop brain tumors and sarcomas of the slowly and begins during adolescence. Patients with type 3 disease have
head and neck. Secondary cataracts can also develop from radiation. normal hearing at birth but develop hearing loss and night blindness
Nonocular secondary tumors are common in patients with germinal around puberty. To date, 11 genetic loci have been located (5 for type
mutations estimated to occur with an incidence of 1% per yr of life. 1; 3 for type 2; 1 for type 3).
The most common secondary tumor is osteogenic sarcoma of the skull Clinically similar, secondary pigmentary retinal degenerations
and long bones; the risk is higher in patients treated with radiation. that need to be differentiated from retinitis pigmentosa occur in a
Other malignancies include lung, brain, soft tissue, and skin. wide variety of metabolic diseases, neurodegenerative processes, and
The prognosis for children with retinoblastoma depends on the size multifaceted syndromes. Examples include the progressive retinal
and extension of the tumor. When confined to the eye, most tumors changes of the mucopolysaccharidoses (particularly Hurler, Hunter,
can be cured. The prognosis for long-term survival is poor when the Scheie, and Sanfilippo syndromes; see Chapter 88) and certain of
tumor has extended into the orbit or along the optic nerve. the late-onset gangliosidoses (Batten-Mayou, Spielmeyer-Vogt, and
Jansky-Bielschowsky diseases; see Chapters 86.4 and 599.2), the pro-
RETINITIS PIGMENTOSA gressive retinal degeneration that is associated with progressive exter-
This progressive retinal degeneration is characterized by pigmentary nal ophthalmoplegia (Kearns-Sayre syndrome; see Chapter 598.2), and
changes, arteriolar attenuation, usually some degree of optic atrophy, the retinitis pigmentosa–like changes in the Laurence-Moon and
and progressive impairment of visual function. Dispersion and aggre- Bardet-Biedl syndromes. The retinal manifestations of abetalipopro-
gation of the retinal pigment produce various ophthalmoscopically teinemia (Bassen-Kornzweig syndrome; see Chapter 86) and Refsum
visible changes, ranging from granularity or mottling of the retinal disease (see Chapter 86.2) are also similar to those found in retinitis
pigment pattern to distinctive focal pigment aggregates with the con- pigmentosa. The diagnosis of these latter two disorders in a patient
figuration of bone spicules (Fig. 630-4). Other ocular findings include with presumed retinitis pigmentosa is important because treatment is
subcapsular cataract, glaucoma, and keratoconus. possible. There is also an association of retinitis pigmentosa and con-
Impairment of night vision or dark adaptation is often the first clini- genital hearing loss, as in Usher syndrome.
cal manifestation. Progressive loss of peripheral vision, often in the
form of an expanding ring scotoma or concentric contraction of the STARGARDT DISEASE (FUNDUS
field, is usual. There may be loss of central vision. Retinal function, as FLAVIMACULATUS)
measured by electroretinography (ERG), is characteristically reduced. This autosomal recessive retinal disorder is characterized by slowly
The disorder may be autosomal recessive, autosomal dominant, or X progressive bilateral macular degeneration and vision impairment. It
linked. Children with autosomal recessive retinitis pigmentosa are usually appears at 8-14 yr of age, and affected children are often initially
more likely to become symptomatic at an earlier age (median age misdiagnosed as having functional visual loss. The foveal reflex becomes
10.7 yr). Those with autosomal dominant retinitis pigmentosa are more obtunded or appears grayish, pigment spots develop in the macular
likely to present in their 20s. Only supportive treatment is available. area, and macular depigmentation and chorioretinal atrophy eventually
A special form of retinitis pigmentosa is Leber congenital retinal occur. Macular hemorrhages also may develop. Some patients also have
amaurosis, in which the retinal changes tend to be pleomorphic, with white or yellow spots beyond the macula or pigmentary changes in the
various degrees of pigment disorder, arteriolar attenuation, and optic periphery; the term fundus flavimaculatus is commonly used for this
atrophy. The retina may appear normal during infancy. Vision impair- condition. It is now recognized that Stargardt disease and fundus fla-
ment, nystagmus, and poor pupillary reaction are usually evident soon vimaculatus represent different entities on the spectrum of the same
after birth, and the ERG findings are abnormal early and confirm the disease. Central visual acuity is reduced, often to 20/200, but total
diagnosis. Retinal pigment epithelium–specific 65-kDa deficiency is loss of vision does not occur. ERG findings vary. The condition is not
the cause of autosomal recessive disease. Gene replacement therapy associated with central nervous system abnormalities and is to be
Figure 630-5 Cherry-red spot seen in a case of Tay-Sachs disease.

Because the parafoveal area has many retinal ganglion cells and the
fovea has none, the fovea retains its orange-red color but is surrounded
by retina that is whitish. This produces the cherry-red spot in the Figure 630-6 Retinal phakoma of tuberous sclerosis.
macula. (From Cheng KP, Biglan AW: Ophthalmology. In Zitelli BJ,
McIntire S, Nowalk AJ (eds): Zitelli and Davis’ atlas of pediatric physical
diagnosis, ed 6, Philadelphia: Saunders, 2012. Fig. 19-102.) a refractile, yellowish, multinodular cystic lesion arising from the disc
or retina; the appearance of this typical lesion is often compared with
differentiated from the macular changes of many progressive metabolic that of an unripe mulberry (Fig. 630-6). Equally characteristic and
neurodegenerative diseases. The genetic mutation responsible for Star- more common in tuberous sclerosis are flatter, yellow to whitish retinal
gardt macular dystrophy has been identified. lesions, varying in size from minute dots to large lesions approaching
the size of the disc. These lesions are benign astrocytic proliferations.
BEST VITELLIFORM DEGENERATION Rarely, similar retinal phakomas occur in von Recklinghausen disease
This macular dystrophy is characterized by a distinctive yellow or (neurofibromatosis). In von Hippel-Lindau disease (angiomatosis of
orange discoid subretinal lesion in the macula, resembling the intact the retina and cerebellum), the distinctive fundus lesion is a heman-
yolk of a fried egg. Diagnosis is usually made at 3-15 yr of age with a gioblastoma; this vascular lesion usually appears as a reddish globular
mean age of presentation of 6 yr. Vision is usually normal at this stage. mass with large paired arteries and veins passing to and from the
The condition may be progressive; the yolk-like lesion may eventually lesion. In Sturge-Weber syndrome (encephalofacial angiomatosis), the
degenerate (“scramble”) and result in pigmentation, chorioretinal fundus abnormality is a choroidal hemangioma; the hemangioma may
atrophy, and vision impairment. The condition is usually bilateral. impart a dark color to the affected area of the fundus, but the lesion is
There is no association with systemic abnormalities. Inheritance is best seen with fluorescein angiography.
usually autosomal dominant. The vitelliform macular dystrophy gene
(VMD2) has been identified and DNA testing is available. In vitelliform RETINOSCHISIS
macular degeneration, the ERG response is normal. Electrooculo- Congenital hereditary retinoschisis, also referred to as juvenile X-linked
graphic findings are abnormal in affected patients and carriers, and this retinoschisis, is a bilateral vitreoretinal dystrophy that has a bimodal
test is useful in diagnosis and in genetic counseling. age of presentation. The first group presents with strabismus and nys-
tagmus at a mean age of 1.5-2 yr and is the most severely affected
CHERRY-RED SPOT group. The second group presents at 6-7 yr with poor vision. It is
Because of the special histologic features of the macula, certain patho- characterized by splitting of the retina into inner and outer layers. The
logic processes affecting the retina produce an ophthalmoscopically usual ophthalmoscopic finding in affected males is an elevation of the
visible sign referred to as a cherry-red spot, a bright to dull red spot at inner layer of the retina, most commonly in the inferotemporal quad-
the center of the macula surrounded and accentuated by a grayish- rant of the fundus, often with round or oval holes visible in the inner
white or yellowish halo (Fig. 630-5). The halo is a result of a loss of layer. Schisis of the fovea is virtually pathognomonic and is found in
transparency of the retinal ganglion cell layer secondary to edema or almost 100% of patients. Ophthalmoscopically, this appears in early
lipid accumulation, or both. Because ganglion cells are not present in stages as small, fine striae in the internal limiting membrane. These
the fovea, the retina surrounding the fovea is opacified but the fovea striae radiate outward in a petaloid or spoke wheel configuration. In
transmits the normal underlying choroidal color (red), accounting for some cases, frank retinal detachment or vitreous hemorrhage occurs.
the presence of the cherry-red spot. A cherry-red spot typically occurs Vision impairment varies from mild to severe; visual acuity may
in certain sphingolipidoses, principally in Tay-Sachs disease (GM2 type worsen with age, but good vision is often retained. Carrier females
1), in the Sandhoff variant (GM2 type 2), and in generalized ganglio- are asymptomatic, but linkage studies may be useful to help detect
sidosis (GM1 type 1). Similar but less distinctive macular changes occur carriers.
in some cases of metachromatic leukodystrophy (sulfatide lipidosis),
in some forms of neuronopathic Niemann-Pick disease, galactosiali- RETINAL DETACHMENT
dosis, and in certain mucolipidoses. The cherry-red spot that charac- A retinal detachment is a separation of the outer layers of the retina
teristically occurs as a result of retinal ischemia secondary to vasospasm, from the underlying retinal pigment epithelium (RPE). During
ocular contusion, or occlusion of the central retinal artery must be embryogenesis, the retina and RPE are initially separated. During
differentiated from the cherry-red spot of neurodegenerative disease ocular development, they join together and are held in apposition to
(see Chapters 86.4 and 599). each other by various physiologic mechanisms. Pathologic events
leading to a retinal detachment return the retina–RPE to its former
PHAKOMAS separated state. The detachment can occur as a congenital anomaly but
See also Chapter 596. more commonly arises secondary to other ocular abnormalities or
These are the herald lesions of the hamartomatous disorders. In trauma. Three types of detachment are described; each may occur in
Bourneville disease (tuberous sclerosis), the distinctive ocular lesion is children. Rhegmatogenous detachments result from a break in the
Figure 630-7 Coats disease with massive retinal exudation.
Figure 630-8 Hypertensive retinopathy.

retina that allows fluid to enter the subretinal space. In children, these
are usually a result of trauma (such as child abuse) but may occur condition with incomplete penetrance. Asymptomatic family members
secondary to myopia or ROP or after congenital cataract surgery. Trac- often display a zone of avascular peripheral retina.
tional retinal detachments result when vitreoretinal membranes pull The findings in FEVR may resemble those of ROP in the cicatricial
on the retina. They can occur in diabetes, sickle cell disease, and ROP. stages, but unlike ROP, the neovascularization of FEVR seems to
Exudative retinal detachments result when exudation exceeds absorp- develop years after birth and most patients with FEVR have no history
tion. This can be seen in Coats disease, retinoblastoma, and ocular of prematurity, oxygen therapy, prenatal or postnatal injury or infec-
inflammation. tion, or developmental abnormalities. FEVR is also to be differentiated
The presenting sign of retinal detachment in an infant or child may from Coats disease, angiomatosis of the retina, peripheral uveitis, and
be loss of vision, secondary strabismus or nystagmus, or leukocoria other disorders of the posterior segment.
(white pupillary reflex). In addition to direct examination of the eye,
special diagnostic studies such as ultrasonography and neuroimaging HYPERTENSIVE RETINOPATHY
(CT, MRI) may be necessary to establish the cause of the detachment In the early stages of hypertension, no retinal changes may be observ-
and the appropriate treatment. Prompt treatment is essential if vision able. Generalized constriction and irregular narrowing of the arterioles
is to be salvaged. are usually the first signs in the fundus. Other alterations include
retinal edema, flame-shaped hemorrhages, cotton-wool spots (retinal
COATS DISEASE nerve fiber layer infarcts), and papilledema (Fig. 630-8). These changes
This exudative retinopathy of unknown cause is characterized by tel- are reversible if the hypertension can be controlled in the early stages,
angiectasia of retinal vessels with leakage of plasma to form intraretinal but in long-standing hypertension, irreversible changes may occur.
and subretinal exudates and by retinal hemorrhages and detachment Thickening of the vessel wall may produce a silver- or copper-wire
(Fig. 630-7). The condition is usually unilateral. It predominantly appearance. Hypertensive retinal changes in a child should alert the
affects boys, usually appearing in the 1st decade. The condition is physician to renal disease, pheochromocytoma, collagen disease, and
nonfamilial and for the most part occurs in otherwise healthy children. cardiovascular disorders, particularly coarctation of the aorta.
The most frequent presenting signs are blurring of vision, leukocoria,
and strabismus. Rubeosis of the iris, glaucoma, and cataract may DIABETIC RETINOPATHY
develop. Treatment with photocoagulation or cryotherapy may be The retinal changes of diabetes mellitus are classified as nonprolifera-
helpful. tive or proliferative. Nonproliferative diabetic retinopathy is character-
ized by retinal microaneurysms, venous dilation, retinal hemorrhages,
FAMILIAL EXUDATIVE VITREORETINOPATHY and exudates. The microaneurysms appear as tiny red dots. The hem-
This progressive retinal vascular disorder is of unknown cause, but orrhages may be of both the dot and blot type, representing deep
clinical and angiographic findings suggest an aberration of vascular intraretinal bleeding, and the splinter or flame-shaped type, involving
development. Avascularity of the peripheral temporal retina is a sig- the superficial nerve fiber layer. The exudates tend to be deep and to
nificant finding in most cases, with abrupt cessation of the retinal appear waxy. There may also be superficial nerve fiber infarcts called
capillary network in the region of the equator. The avascular zone often cytoid bodies or cotton-wool spots, as well as retinal edema. These
has a wedge- or V-shaped pattern in the temporal meridian. Glial signs may wax and wane. They are seen primarily in the posterior pole,
proliferation or well-marked retinochoroidal atrophy may be found in around the disc and macula, well within the range of direct ophthal-
the avascular zone. Excessive branching of retinal arteries and veins, moscopy. Involvement of the macula may lead to decreased vision.
dilation of the capillaries, arteriovenous shunt formation, neovascular- Proliferative retinopathy, the more serious form, is characterized by
ization, and leakage from retinal vessels of the farthest vascularized neovascularization and proliferation of fibrovascular tissue on the
retina occur. Vitreoretinal adhesions are usually present at the periph- retina, extending into the vitreous. Neovascularization may occur on
eral margin of the vascularized retina. Traction, retinal dragging and the optic disc, elsewhere on the retina, or on the iris and in the anterior
temporal displacement of the macula, falciform retinal folds, and chamber angle (or rubeosis irides) (Fig. 630-9). Traction on these new
retinal detachment are common. Intraretinal or subretinal exudation, vessels leads to hemorrhage and, eventually, scarring. The vision-
retinal hemorrhage, and recurrent vitreous hemorrhages may develop. threatening complications of proliferative diabetic retinopathy are
Patients may also develop cataracts and glaucoma. Vision impairment retinal and vitreous hemorrhages, cicatrization, traction, and retinal
of varying severity occurs. The condition is usually bilateral. Familial detachment. Neovascularization of the iris may lead to secondary glau-
exudative vitreoretinopathy (FEVR) is usually an autosomal dominant coma if not treated promptly.
Figure 630-10 Shaken baby syndrome (inflicted neurotrauma).

Retinal hemorrhages in multiple layers too numerous to count into far
Figure 630-9 Proliferative diabetic retinopathy with neovasculariza- periphery.
tion of the disc.
Diabetic retinopathy involves the alteration and nonperfusion of spots), papilledema, and, rarely, embolic occlusion of the central retinal
retinal capillaries, retinal ischemia, and neovascularization, but its artery.
pathogenesis is not yet completely understood, either in terms of loca-
tion of the primary pathogenetic mechanism (retinal vessels vs sur- BLOOD DISORDERS
rounding neuronal or glial tissue) or the specific biochemical factors In primary and secondary anemias, retinopathy in the form of hemor-
involved. The better the degree of long-term metabolic control, the rhages and cotton-wool patches may occur. Vision can be affected if
lower the risk of diabetic retinopathy. hemorrhage occurs in the macular area. The hemorrhages may be light
Clinically, the prevalence and course of retinopathy relate to a and feathery or dense and preretinal. In polycythemia vera, the retinal
patient’s age and to disease duration. Detectable microvascular changes veins are dark, dilated, and tortuous. Retinal hemorrhages, retinal
are rare in prepubertal children, with the prevalence of retinopathy edema, and papilledema may be observed. In leukemia, the veins are
increasing significantly after puberty, especially after the age of 15 yr. characteristically dilated, with sausage-shaped constrictions; hemor-
The incidence of retinopathy is low during the 1st 5 yr of disease and rhages, particularly white-centered hemorrhages and exudates, are
increases progressively thereafter, with the incidence of proliferative common during the acute stage. In the sickling disorders, fundus
retinopathy becoming substantial after 10 yr and with increased risk changes include vascular tortuosity, arterial and venous occlusions,
of visual impairment after 15 yr or more. “salmon patches,” refractile deposits, pigmented lesions, arteriolar-
Ophthalmic examination guidelines have been proposed by the venous anastomoses, and neovascularization (with “sea-fan” forma-
American Academy of Pediatrics. An initial exam is recommended at tions), sometimes leading to vitreous hemorrhage and retinal
age 9 yr if the diabetes is poorly controlled. If the diabetes is well con- detachment. Individuals with sickle cell hemoglobin C and sickle cell
trolled, an initial exam 3 yr after puberty with annual follow-up is hemoglobin β-thalassemia hemoglobinopathies are at a higher risk of
recommended. the development of retinopathy than are those with homozygous
In addition to retinopathy, patients with juvenile-onset diabetes may hemoglobin S disease. It is thought that the more anemic state of those
develop optic neuropathy, characterized by swelling of the disc and patients with homozygous hemoglobin S disease offers protection from
blurring of vision. Patients with diabetes may also develop cataracts, vascular occlusions in the retina.
even at an early age, sometimes with rapid progression.
TRAUMA-RELATED RETINOPATHY
Treatment Retinal changes may occur in patients who suffer trauma to other parts
Macular edema is the leading cause of visual loss in diabetic persons. of the body. The occurrence of retinal hemorrhages in infants who have
Photocoagulation may be used to decrease the risk of continued vision been physically abused is well documented (Fig. 630-10; see Chapter
loss in patients with macular edema. 40). Retinal, subretinal, subhyaloid, and vitreous hemorrhages have
Proliferative retinopathy causes the most severe vision loss and been described in infants and young children with inflicted neu-
can lead to total loss of vision and even loss of the eye. Patients rotrauma. Often there are no signs of direct trauma to the eye, periocu-
who have proliferative disease and who display certain high-risk char- lar region, or head. Such cases may result from violent shaking of an
acteristics should undergo panretinal photocoagulation to preserve infant, and permanent retinal damage may result.
their central vision. Neovascularization of the iris is also treated with In patients with severe head or chest compressive trauma, a trau-
panretinal photocoagulation to stop the development of neovascular matic retinal angiopathy known as Purtscher retinopathy may occur.
glaucoma. This is characterized by retinal hemorrhage, cotton-wool spots, possible
Vitrectomy and other intraocular surgery may be necessary in disc swelling, and decreased vision. The pathogenesis is unclear, but
patients with nonresolving vitreous hemorrhage or traction retinal there is evidence of arteriolar obstruction in this condition. A Purtscher-
detachment. The value of technologic advances, such as insulin infu- like fundus picture may also occur in several nontraumatic settings,
sion pumps and pancreatic transplants, in preventing ocular complica- such as acute pancreatitis, lupus erythematosus, and childbirth.
tions is under investigation (see Chapter 589).
MYELINATED NERVE FIBERS
SUBACUTE BACTERIAL ENDOCARDITIS Myelination of the optic nerve fibers normally terminates at the level
At some time during the course of the disease, retinopathy is present of the disc, but in some individuals, ectopic myelination extends to
in approximately 40% of cases of subacute bacterial endocarditis. The nerve fibers of the retina. The condition is most commonly seen adja-
lesions include hemorrhages, hemorrhages with white centers (Roth cent to the disc, although more peripheral areas of the retina may be
involved. The characteristic ophthalmoscopic picture is a focal white
patch with a feathered edge or brushstroke appearance. Because the
macula is generally unaffected, the visual prognosis is good. A relative
or absolute visual field defect corresponding to areas of ectopic myelin-
ation is usually the only associated ocular abnormality. Extensive uni-
lateral involvement, however, is associated with ipsilateral myopia,
amblyopia, and strabismus. If unilateral high myopia and amblyopia
are present, appropriate optical correction and occlusion therapy
should be instituted. For unknown reasons, the disorder is more com-
monly encountered in patients with craniofacial dysostosis, oxyceph-
aly, neurofibromatosis, and Down syndrome.
COLOBOMA OF THE FUNDUS

The term coloboma describes a defect such as a gap, notch, fissure, or
hole. The typical fundus coloboma is a result of malclosure of the
embryonic fissure, which leaves a gap in the retina, RPE, and choroid,
thus baring the underlying sclera. The defect may be extensive, involv-
ing the optic nerve, ciliary body, and iris and even the lens, or it may
be localized to 1 or more portions of the fissure. The usual appearance
is of a well-circumscribed, wedge-shaped white area extending infero-
nasally below the disc, sometimes involving or engulfing the disc. In
some cases, there is ectasia or cyst formation in the area of the defect.
Less-extensive colobomatous defects may appear as only single or mul-
tiple focal punched-out chorioretinal defects or anomalous pigmenta-
tion of the fundus in the line of the embryonic fissure. Colobomas may
occur in 1 or both eyes. A visual field defect usually corresponds to the
chorioretinal defect. Visual acuity may be impaired, particularly if the
defect involves the disc or macula.
Fundus colobomas may occur in isolation as sporadic defects or as
an inherited condition. Isolated colobomatous anomalies are com-
monly inherited in an autosomal dominant manner with highly vari-
able penetrance and expressivity. Family members of affected patients
should receive appropriate genetic counseling. Colobomas may also be
associated with such abnormalities as microphthalmia, glioneuroma of
the eye, cyclopia, or encephalocele. They occur in children with various
chromosomal disorders, including trisomies 13 and 18, triploidy, cat’s-
eye syndrome, and 4p−. Ocular colobomas also occur in many multi-
system disorders, including the CHARGE (C, coloboma; H, heart
disease; A, atresia choanae; R, retarded growth and development and/
or central nervous system anomalies; G, genetic anomalies and/or
hypogonadism; E, ear anomalies and/or deafness) association; Joubert,
Aicardi, Meckel, Warburg, and Rubinstein-Taybi syndromes; linear
sebaceous nevus; Goldenhar and Lenz microphthalmia syndromes;
and Goltz focal dermal hypoplasia.

Chapter 630 ◆ Disorders of the Retina and Vitreous 3057.e1
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following threshold retinopathy of prematurity, Arch Ophthalmol 123:311–318, improves retinal function in infants at risk of retinopathy of prematurity,
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Chapter 631 ◆ Abnormalities of the Optic Nerve 3057
OPTIC NERVE HYPOPLASIA

Hypoplasia of the optic nerve is a nonprogressive condition character-
ized by a subnormal number of optic nerve axons with normal meso-
dermal elements and glial supporting tissue. In typical cases, the nerve
head is small and pale, with a pale or pigmented peripapillary halo or
double-ring sign.
This anomaly is associated with defects of vision and of visual fields
of varying severity, ranging from blindness to normal or near-normal
vision. It may be associated with systemic anomalies that most com-
monly involve the central nervous system (CNS). Protean CNS defects
such as hydranencephaly or anencephaly or more focal lesions compat-
ible with continued development of a patient may accompany optic
nerve hypoplasia, but unilateral or bilateral optic nerve hypoplasia may
be found without any concomitant defects.
Optic nerve hypoplasia is a principal feature of septooptic dysplasia
of de Morsier, a developmental disorder characterized by the associa-
tion of anomalies of the midline structures of the brain with hypoplasia
of the optic nerves, optic chiasm, and optic tracts; typically noted are
agenesis of the septum pellucidum, partial or complete agenesis of the
corpus callosum, and malformation of the fornix, with a large chias-
matic cistern. Patients may have hypothalamic abnormalities and
endocrine defects, ranging from panhypopituitarism to isolated defi-
ciency of growth hormone, hypothyroidism, or diabetes insipidus.
Neonatal hypoglycemia and seizures are important presenting signs in
affected infants.
MRI is preferred for evaluating CNS abnormalities in patients with
optic nerve hypoplasia. During MRI, special attention should be
directed to the pituitary infundibulum, where ectopia of the posterior
pituitary may be found. Posterior pituitary ectopia appears on MRI as
an absence of the pituitary infundibulum with an abnormal bright spot
at the upper infundibulum area. This abnormality is present in approx-
imately 15% of patients and suggests posterior pituitary hormone defi-
ciency, requiring further endocrinologic work-up. Endocrine function
should be watched closely in patients with optic nerve hypoplasia. The
cause of optic nerve hypoplasia remains unclear.
Children with periventricular leukomalacia display an unusual
form of optic nerve hypoplasia. The optic nerves demonstrate a large
cup within a normal-size optic disc. This form of optic nerve hypopla-
sia occurs secondary to transsynaptic degeneration of optic axons
caused by the primary bilateral lesion in the optic radiation (periven-
tricular leukomalacia).
OPTIC NERVE COLOBOMA

Optic nerve colobomas can be unilateral or bilateral. The visual acuity
can range from normal to complete blindness. The coloboma develops
secondary to incomplete closure of the embryonic fissure. The defect
may produce a partial or total excavation of the optic disc (Fig. 631-1).
Chapter 631
Abnormalities of the
Optic Nerve
OPTIC NERVE APLASIA

This rare congenital anomaly is typically unilateral. The optic nerve,
retinal ganglion cells, and retinal blood vessels are absent. A vestigial
dural sheath usually connects with the sclera in a normal position, but
no neural tissue is present within this sheath. Optic nerve aplasia typi-
cally occurs sporadically in an otherwise healthy person. Figure 631-1 Optic nerve coloboma.
Chorioretinal and iris colobomas may also occur. Optic nerve colobo- pulsation, nerve fiber layer hemorrhages around the disc, and peripap-
mas may be seen in a multitude of ocular and systemic abnormalities illary exudates (see Fig. 590-1 in Chapter 590). In some cases, edema
including the CHARGE (C, coloboma; H, heart disease; A, atresia extending into the macula may produce a fan- or star-shaped figure.
choanae; R, retarded growth and development and/or CNS anomalies; In addition, concentric peripapillary retinal wrinkling (Paton lines)
G, genetic anomalies and/or hypogonadism; E, ear anomalies and/or may be noted. Transient obscuration of vision may occur, lasting
deafness) association. seconds and associated with postural changes. Vision, however, is
usually normal in acute papilledema. Normally, when the ICP is
MORNING GLORY DISC ANOMALY relieved, the papilledema resolves and the disc returns to a normal or
This term describes a congenital malformation of the optic nerve char- nearly normal appearance within 6-8 wk. Sustained chronic papill-
acterized by an enlarged, excavated, funnel-shaped disc with an ele- edema or long-standing unrelieved increased ICP may, however, lead
vated rim, resembling a morning glory flower. White glial tissue is to permanent nerve fiber damage, atrophic changes of the disc, macular
present in the central part of the disc. The retinal vessels are abnormal scarring, and impairment of vision.
and appear at the peripheral disc and course over the elevated pink rim The pathophysiology of papilledema is probably as follows: elevation
in a radial fashion. Pigmentary mottling of the peripapillary region is of intracranial subarachnoid cerebrospinal fluid (CSF) pressure, eleva-
usually seen. Most cases are unilateral. Females are affected twice as tion of CSF pressure in the sheath of the optic nerve, elevation of tissue
often as males. Visual acuity is usually severely reduced. Morning glory pressure in the optic nerve, stasis of axoplasmic flow and swelling of
disc anomaly has been associated with basal encephalocele in patients the nerve fibers in the optic nerve head, and secondary vascular
with midfacial anomalies. Abnormalities of the carotid circulation can changes and the characteristic ophthalmoscopic signs of venous stasis.
also be seen in patients with morning glory anomaly. Moyamoya Associated neuroophthalmic signs of increased ICP in infants and
disease is a well-described associated finding. children include 6th cranial nerve palsy and attendant esotropia, lid
retraction, paresis of upward gaze, tonic downward deviation of the
TILTED DISC eyes, and convergent nystagmus.
In this congenital anomaly, the vertical axis of the optic disc is directed The common etiologies of papilledema in childhood are intracra-
obliquely, so that the upper temporal portion of the nerve head is more nial tumors and obstructive hydrocephalus, intracranial hemorrhage,
prominent and anterior to the lower nasal portion of the disc. The the cerebral edema of trauma, meningoencephalitis, toxic encepha-
retinal vessels emerge from the upper temporal portion of the disc lopathy, and certain metabolic diseases. Whatever the cause, the
rather than from the nasal side. Often noted is a peripapillary crescent optic disc signs of increased ICP in early childhood may occasionally
or conus. Associated visual field defects and myopic astigmatism may be modified by the distensibility of the young skull. In the absence
be found. Clinical recognition of the tilted disc syndrome is important of conditions associated with early closure of sutures and early
to avoid confusion of its disc and visual field signs with those of pap- obliteration of the fontanel (craniosynostosis, Crouzon disease, and
illedema and intracranial tumor. Apert syndrome), infants with increased ICP may not develop
papilledema.
DRUSEN OF THE OPTIC NERVE The differential diagnosis of papilledema includes structural
These globular, acellular bodies are thought to arise from axoplasmic changes of the disc (pseudopapilledema, pseudoneuritis, drusen, and
derivatives of disintegrating nerve fibers. Drusen may be buried within myelinated nerve fibers), with which it may be confused, and the disc
the optic nerve, producing elevation of the optic nerve head (which swelling of papillitis associated with optic neuritis in addition to the
can be confused with papilledema), or they may be partially or com- disc changes of hypertension and diabetes mellitus. Unless retinal
pletely exposed, appearing as refractile bodies at the surface of the disc. hemorrhage or edema involves the macular area, the preservation of
Visual field defects and spontaneous peripapillary nerve fiber layer good central vision and the absence of an afferent pupillary defect
hemorrhages may occur in association with drusen. Drusen may occur (Marcus Gunn pupil) help to differentiate acute papilledema from the
as an autosomal dominant condition. B scan ultrasonography can edema of the optic nerve head found in acute optic neuritis.
help positively identify drusen suspected on clinical ophthalmic exam Papilledema is a neurologic emergency. It can be accompanied by
(Fig. 631-2). other signs of increased ICP, including headaches, nausea, and vomit-
ing. Neuroimaging should be performed; if no intracranial masses are
PAPILLEDEMA detected, a lumbar puncture and determination of CSF pressure should
The term papilledema is reserved to describe swelling of the nerve head follow.
secondary to increased intracranial pressure (ICP). Clinical manifesta-
tions of papilledema include edematous blurring of the disc margins, OPTIC NEURITIS
fullness or elevation of the nerve head, partial or complete obliteration This is any inflammation or demyelinization of the optic nerve with
of the disc cup, capillary congestion and hyperemia of the nerve head, attendant impairment of function. The process is usually acute, with
generalized engorgement of the veins, loss of spontaneous venous rapidly progressive loss of vision. It may be unilateral or bilateral.
Pain on movement of the globe or pain on palpation of the globe
may precede or accompany the onset of visual symptoms. There is
decreased visual activity, decreased color vision and contrast sensitiv-
ity, a relative afferent pupillary defect, and a normal macula and
peripheral retina.
When the retrobulbar portion of the nerve is affected without oph-
thalmoscopically visible signs of inflammation at the disc, the term
retrobulbar optic neuritis is applied. When there is ophthalmoscopically
visible evidence of inflammation of the nerve head, the term papillitis
or intraocular optic neuritis is used. When there is involvement of both
the retina and the papilla, the term optic neuroretinitis is used.
In childhood, optic neuritis may occur as an isolated condition or
as a manifestation of a neurologic or systemic disease. Optic neuritis
may be secondary to inflammatory diseases (systemic lupus erythe-
matosus, sarcoidosis, Behçet disease, autoimmune optic neuritis);
infections (tuberculosis, syphilis, Lyme disease, meningitis, viral
encephalitis, HIV, or postinfectious disease); and toxic or nutritional
Figure 631-2 Optic nerve drusen seen on B scan ultrasonography. disorders (methanol, ethambutol, vitamin B12 deficiency). It may
Chapter 631 ◆ Abnormalities of the Optic Nerve 3059
signify one of the many demyelinating diseases of childhood (see of the disc and loss of substance of the nerve head, sometimes with
Chapter 600). Although a significant percentage of adults who experi- enlargement of the disc cup. The associated vision defect varies with
ence an episode of optic neuritis eventually develop other symptoms the nature and site of the primary disease or lesion.
associated with multiple sclerosis (MS), young children with optic Optic atrophy is the common expression of a wide variety of con-
neuritis are seemingly at less risk (risk of MS is 19% within 20 yr). genital or acquired pathologic processes. The cause may be traumatic,
High-risk features suggestive of MS include visual acuity better than inflammatory, degenerative, neoplastic, or vascular; intracranial
no light perception, periocular pain, acutely normal-appearing optic tumors and hydrocephalus are principal causes of optic atrophy
nerve, no retinal abnormalities, and abnormal MRI suggesting a demy- in children. In some cases, progressive optic atrophy is hereditary.
elinating disease. Bilateral optic neuritis in children may be associated Dominantly inherited infantile optic atrophy is a relatively mild
with acute disseminated encephalomyelitis or neuromyelitis optica heredodegenerative type that tends to progress through childhood
(NMO or Devic disease). NMO is characterized by rapid and severe and adolescence. Autosomal recessively inherited congenital optic
bilateral visual loss accompanied by transverse myelitis and paraplegia. atrophy is a rare condition that is evident at birth or develops at a very
Brainstem and occasionally involvement of the cortex may be seen on early age; the visual defect is usually profound. Behr optic atrophy is
MRI. NMO-specific immunoglobulin G (directed to the aquaporin 4 a hereditary type associated with hypertonia of the extremities,
water channel) is the diagnostic test of choice for Devic syndrome. increased deep tendon reflexes, mild cerebellar ataxia, some degree of
Optic neuritis may also be secondary to an exogenous toxin or drug, mental deficiency, and possibly external ophthalmoplegia. This disor-
such as with lead poisoning or as a complication of long-term high- der afflicts principally boys age 3-11 yr. Some forms of heredodegen-
dose treatment with chloramphenicol or vincristine. Extensive pediat- erative optic atrophy are associated with sensorineural hearing loss, as
ric neurologic and ophthalmic investigation, including MRI and may occur in some children with juvenile-onset (insulin-dependent)
lumbar puncture, is usually required. Idiopathic NMO is associated diabetes mellitus. In the absence of an obvious cause, optic atrophy in
with antiaquaporin 4 antibodies, otherwise known as NMO an infant or child warrants extensive etiologic investigation.
antibodies.
In most cases of acute optic neuritis, some improvement in vision OPTIC NERVE GLIOMA
begins within 1-4 wk after onset, and vision may improve to normal Optic nerve glioma, more properly referred to as juvenile pilocytic
or near normal within weeks or months. The course varies with cause. astrocytoma, is the most frequent tumor of the optic nerve in child-
Although central vision may fully recover, it is common to find hood. This neuroglial tumor may develop in the intraorbital, intra-
permanent defects in other areas of visual function (contrast sensitiv- canalicular, or intracranial portion of the nerve; the chiasm is often
ity, color, brightness sense, and motion perception). Recurrences involved.
may occur especially, but not universally, in patients who go on to The tumor is a cytologic benign hamartoma that is generally station-
develop MS. ary or only slowly progressive. The principal clinical manifestations
A treatment trial demonstrated that high-dose intravenous methyl- when the tumor occurs in the intraorbital portion of the nerve are
prednisolone may help to speed the visual recovery in young adults, unilateral loss of vision, proptosis, and deviation of the eye; optic
and it may prevent the development of MS in those at risk. Orally atrophy or congestion of the optic nerve head may occur. Chiasmal
administered corticosteroids should not be used because they are asso- involvement may be attended by defects of vision and visual fields
ciated with a significant increase in the recurrence rate of optic neuri- (often bitemporal hemianopia), increased ICP, papilledema or optic
tis. It is unknown to what degree the results of the aforementioned trial atrophy, hypothalamic dysfunction, pituitary dysfunction, and some-
may be extrapolated to optic neuritis in childhood. Eculizumab, an times nystagmus or strabismus. Juvenile pilocytic astrocytomas occur
inhibitor of complement C5, has had some success in reducing relapses with increased frequency in patients with neurofibromatosis.
in patients with NMO. Treatment of optic pathway gliomas is controversial. The best
management is usually periodic observation with serial radiography
LEBER OPTIC NEUROPATHY (preferably MRI). Only symptomatic and radiographically progressing
This entity is characterized by sudden loss of central vision occurring optic nerve gliomas require strong consideration for treatment. Surgi-
in the 2nd and 3rd decades of life, and primarily affects young males. cal removal may be appropriate when the tumor is confined to the
A characteristic peripapillary telangiectatic microangiopathy occurs intraorbital, intracanalicular, or prechiasmal portion of the nerve if a
not only in the presymptomatic phase of involved eyes but also in a patient has unsightly proptosis with complete or nearly complete loss
high number of asymptomatic offspring in the female line. Disc hyper- of vision of the affected eye. When the chiasm is involved, resection
emia and edema mark the acute phase of visual loss. One eye is usually is not usually indicated and radiation and chemotherapy may be
affected before the other. Visual field loss and impaired color vision are necessary.
also present. In time, progressive optic atrophy and vision loss usually
ensue. The tortuous angiopathy becomes less obvious. Although visual TRAUMATIC OPTIC NEUROPATHIES
function after the initial loss generally remains stable, a significant and Injury to the optic nerve may result from both direct and indirect
sometimes complete recovery may occur in as many as 30% of affected trauma. Direct trauma to the optic nerve is a result of a penetrat-
individuals. This recovery may take place years or decades after the ing injury to the orbit with transection or contusion of the nerve.
initial episode of acute vision loss. The peripapillary angiopathy, the Blunt trauma to the orbit may also lead to severe visual loss if the
lack of short-term remission, and the degree of symmetry serve to traumatic force is transmitted to the optic canal and causes disrup-
distinguish most cases of Leber disease from the optic neuritis of MS. tion of the blood supply to the intracanalicular portion of the nerve.
Leber optic neuropathy is maternally inherited and is caused by Treatment with high-dose corticosteroids has not been proven to
defective cytoplasmic mitochondrial DNA. Multiple point mutations be effective, and similar regimens have shown there is an increased
in the mitochondrial DNA that lead to the development of the disorder relative risk of death when such regimens are given to patients
have been found. Because of the mitochondrial nature of the disorder, after significant head injury.
skeletal and cardiac muscle disorders, including electrocardiographic
abnormalities, may also be encountered in affected individuals. Bibliography is available at Expert Consult.
OPTIC ATROPHY
This term denotes degeneration of optic nerve axons, with attendant
loss of function. The ophthalmoscopic signs of optic atrophy are pallor
Chapter 631 ◆ Abnormalities of the Optic Nerve 3059.e1
Bibliography Hickman SJ, Dalton CM, Miller DH, et al: Management of acute optic neuritis,
Atkins EJ, Biousse V, Newman NJ: Optic neuritis, Semin Neurol 27:211–220, 2007. Lancet 360:1953–1962, 2002.
Auw-Haedrich C, Staubach F, Witschel H: Optic disk drusen, Surv Ophthalmol Massaro M, Thorarensen O, Liu GT, et al: Morning glory disc anomaly and
47:515–532, 2002. moyamoya vessels, Arch Ophthalmol 116:253–254, 1998.
Balcer LJ: Optic neuritis, N Engl J Med 354:1273–1280, 2006. Optic Neuritis Study Group: Visual function 5 years after optic neuritis.
Benavente E, Paira S: Neuromyelitis Optica-AQP4: an update, Curr Rheumatol Rep Experience of the optic neuritis treatment trial, Arch Ophthalmol 115:1545–
13:496–505, 2011. 1552, 1997.
Birkebaek NH, Patel L, Wright NB, et al: Endocrine status in patients with optic Repka MX, Miller NR: Optic atrophy in children, Am J Ophthalmol 106:191–193,
nerve hypoplasia: Relationship to midline central nervous system abnormalities 1988.
and appearance of the hypothalamic-pituitary axis on magnetic resonance Rostasy K, Mader S, Schanda K, et al: Anti-myelin oligodendrocyte glycoprotein
imaging, J Clin Endocrinol Metab 88:5281–5286, 2003. antibodies in pediatric patients with optic neuritis, Arch Neurol 69:752–756,
El-Dairi MA, Ghasia F, Bhatti MT: Pediatric optic neuritis, Int Ophthalmol Clin 2012.
52:29–48, 2012. Skarf B, Hoyt CS: Optic nerve hypoplasia in children: Association with anomalies
Garcia-Filion P, Fink C, Geffner ME, et al: Optic nerve hypoplasia in North of the endocrine and CNS, Arch Ophthalmol 102:62–67, 1984.
America: a re-appraisal of perinatal risk factors, Acta Ophthalmol 88(5):527– Weiss AH, Beck RW: Neuroretinitis in childhood, J Pediatr Ophthalmol Strabismus
534, 2010. 26:198–203, 1989.
infantile (congenital); that which begins between the ages of 3 and

30 yr is called juvenile.
Chapter 632 Primary glaucoma indicates that the cause is an isolated anomaly of
the drainage apparatus of the eye (trabecular meshwork). More than
Childhood Glaucoma 50% of infantile cases are primary glaucoma. In secondary glaucoma,
other ocular or systemic abnormalities are associated, even if a similar
Scott E. Olitsky, Denise Hug, developmental defect of the trabecular meshwork is also present.
Laura S. Plummer, Erin D. Stahl, Primary infantile glaucoma occurs with an incidence of 0.03%
(Table 632-1).
Timothy P. Lindquist CLINICAL MANIFESTATIONS
The symptoms of infantile glaucoma include the classic triad of epiph-
ora (tearing), photophobia (sensitivity to light), and blepharospasm
Glaucoma is a general term used to indicate damage to the optic nerve (eyelid squeezing; Fig. 632-1). Each can be attributed to corneal irrita-
with visual field loss that is caused by or related to elevated pressure tion. Only approximately 30% of affected infants demonstrate the
within the eye. It is classified according to the age of the affected indi- classic symptom complex. Signs of glaucoma include corneal edema,
vidual at presentation and the association of other ocular or systemic corneal and ocular enlargement, and conjunctival injection (Fig.
conditions. Glaucoma that begins within the 1st 3 yr of life is called 632-2).
Table 632-1 Primary and Secondary Childhood Glaucomas

I. PRIMARY GLAUCOMAS II. SECONDARY GLAUCOMAS
A. Congenital open-angle glaucoma A. Traumatic glaucoma
1. Congenital 1. Acute glaucoma
2. Infantile a. Angle concussion
3. Late recognized b. Hyphema
B. Autosomal dominant juvenile glaucoma c. Ghost cell glaucoma
C. Primary angle-closure glaucoma 2. Late-onset glaucoma with angle recession
D. Associated with systemic abnormalities 3. Arteriovenous fistula
1. Sturge-Weber syndrome B. Secondary to intraocular neoplasm
2. Neurofibromatosis type 1 (NF-1) 1. Retinoblastoma
3. Stickler syndrome 2. Juvenile xanthogranuloma
4. Oculocerebrorenal (Lowe) syndrome 3. Leukemia
5. Rieger syndrome 4. Melanoma
6. Hepatocerebrorenal syndrome 5. Melanocytoma
7. Marfan syndrome 6. Iris rhabdomyosarcoma
8. Rubinstein-Taybi syndrome 7. Aggressive nevi of the iris
9. Infantile glaucoma associated with mental retardation and C. Secondary to uveitis
paralysis 1. Open-angle glaucoma
10. Oculodentodigital dysplasia 2. Angle-blockage glaucoma
11. Open-angle glaucoma associated with microcornea and a. Synechial angle closure
absence of frontal sinuses b. Iris bombé with pupillary block
12. Mucopolysaccharidosis D. Lens-induced glaucoma
13. Trisomy 13 1. Subluxation–dislocation and pupillary block
14. Cutis marmorata telangiectasia congenita a. Marfan syndrome
15. Warburg syndrome b. Homocystinuria
16. Kniest syndrome (skeletal dysplasia) 2. Spherophakia and pupillary block
17. Michel syndrome 3. Phacolytic glaucoma
18. Nonprogressive hemiatrophy E. Secondary to surgery for congenital cataract
E. Associated with ocular abnormalities 1. Lens material blockage of the trabecular meshwork (acute or
1. Congenital glaucoma with iris and pupillary abnormalities subacute)
2. Aniridia 2. Pupillary block
a. Congenital glaucoma 3. Chronic open-angle glaucoma associated with angle defects
b. Acquired glaucoma F. Steroid-induced glaucoma
3. Congenital ocular melanosis G. Secondary to rubeosis
4. Sclerocornea 1. Retinoblastoma
5. Iridotrabecular dysgenesis 2. Coats disease
6. Peters syndrome 3. Medulloepithelioma
7. Iridotrabecular dysgenesis and ectropion uveae 4. Familial exudative vitreoretinopathy
8. Posterior polymorphous dystrophy H. Secondary angle-closure glaucoma
9. Idiopathic or familial elevated episcleral venous pressure 1. Retinopathy of prematurity
10. Anterior corneal staphyloma 2. Microphthalmos
11. Congenital microcornea with myopia 3. Nanophthalmos
12. Congenital hereditary endothelial dystrophy 4. Retinoblastoma
13. Congenital hereditary iris stromal hypoplasia 5. Persistent hyperplastic primary vitreous
6. Congenital pupillary iris–lens membrane
I. Glaucoma associated with increased venous pressure
1. Carotid or dural-venous fistula
2. Orbital disease
J. Secondary to maternal rubella
K. Secondary to intraocular infection
1. Acute recurrent toxoplasmosis
2. Acute herpetic iritis
From Nelson LB: Harley’s pediatric ophthalmology, ed 4, Philadelphia, 1998, WB Saunders, p. 294.
Some infants and children with early-onset glaucoma have more
extensive maldevelopment of the anterior segment of the eye. The
neurocristopathies comprise a spectrum of conditions relating to
abnormal embryologic development of the anterior segment. They are
usually bilateral and may include abnormalities of the iris, cornea, and
lens. Other ocular anomalies that may be associated with glaucoma in
infants and children are aniridia, cataract, spherophakia, and ectopia
lentis. Glaucoma may also develop secondary to persistent hyperplastic
primary vitreous or retinopathy of prematurity.
Trauma, intraocular hemorrhage, ocular inflammatory disease, and
intraocular tumor are also important causes of glaucoma in the pedi-
atric population. Systemic disorders associated with glaucoma in
infants and children are Sturge-Weber syndrome (see Chapter 596.3),
neurofibromatosis (see Chapter 596.1), Lowe syndrome, Marfan syn-
drome (see Chapter 702), congenital rubella (see Chapters 109.6 and
247), and a number of chromosomal syndromes (see Chapter 81).
Glaucoma occurs frequently in children with a history of congenital
cataracts. Glaucoma may develop in up to 25% of children who have
undergone cataract surgery early in life. The cause of aphakic glaucoma
is not known but is thought to be the result of a coexistent anterior
chamber deformity. Children treated for cataracts need to be moni-
tored closely for this complication that may threaten vision.
DIAGNOSIS AND TREATMENT

The diagnosis of infantile glaucoma is made on recognition of the signs
and symptoms. Once the diagnosis is established, treatment is started
promptly. Unlike adult glaucoma, in which medication is often the first
line of therapy, for infantile glaucoma, the treatment is primarily surgi-
Figure 632-1 Tearing of the right eye caused by glaucoma. Note the cal. Procedures used to treat glaucoma in children include surgery to
increased corneal diameter of the right eye. (From Nelson LB: Harley’s establish a more normal anterior chamber angle (goniotomy and tra-
pediatric ophthalmology, ed 4, Philadelphia, 1998, WB Saunders, beculotomy), to create a site for aqueous fluid to exit the eye (trabecu-
p. 285.)
lectomy and seton surgery), or to reduce aqueous fluid production
(cyclocryotherapy and cyclophotocoagulation). Many children fre-
quently require several operations to lower and maintain their IOP
adequately, and long-term medical therapy may be necessary as well.
Patients with multiple ocular abnormalities and those with aphakic
glaucoma generally require more surgeries to achieve and maintain
adequate IOP control. Although vision may be reduced secondary to
glaucomatous optic nerve damage or corneal scarring, amblyopia is the
most common cause of loss of vision in these children.
Figure 632-2 Infantile glaucoma. The left cornea is enlarged and

edematous.
The sclera and cornea are more elastic in early childhood than later
in life. An increase in intraocular pressure (IOP), therefore, leads to an
expansion of the globe, including the cornea, and the development of
buphthalmos (“ox eye”). If the cornea continues to enlarge, breaks
occur in the endothelial basement membrane (Descemet membrane)
and may lead to permanent corneal scarring. These breaks in Descemet
membrane (Haab striae) are visible as horizontal edematous lines that
cross or curve around the central cornea. They rarely occur beyond
3 yr of age or in corneas <12 mm in diameter. The cornea also becomes
edematous and cloudy, with increased IOP. The corneal edema leads
to tearing and photophobia. Glaucoma should be considered in a child
suspected of having a nasolacrimal duct obstruction if any of these
other signs or symptoms are present.
Children with unilateral glaucoma generally present early because
the difference in the corneal size between the eyes can be noticed.
When the disease is bilateral, parents may not recognize the increased
corneal size. Many parents view the large eyes as attractive and do not
seek help until other symptoms develop.
Cupping of the optic nerve head is detected by ocular examination.
The optic nerve of an infant is easily distended by excessive pressure.
Deep, central cupping readily occurs and may regress with normaliza-
tion of pressure.
Chapter 632 ◆ Childhood Glaucoma 3061.e1
Bibliography Neely DE, Plager DA: Endocyclophotocoagulation for management of difficult

Beck AD, Freedman S, Kammer J, et al: Aqueous shunt devices compared with pediatric glaucomas, J AAPOS 5:221–229, 2001.
trabeculectomy with mitomycin-C for children in the first two years of life, Sidoti PA, Belmonte SJ, Liebmann JM, et al: Trabeculectomy with mitomycin-C in
Am J Ophthalmol 136:994–1000, 2003. the treatment of pediatric glaucomas, Ophthalmology 107:422–429, 2000.
Chen TC, Walton DS, Bhatia LS: Aphakic glaucoma after congenital cataract Simon JW, Mehta N, Simmons ST, et al: Glaucoma after pediatric lensectomy/
surgery, Arch Ophthalmol 122:1819–1825, 2004. vitrectomy, Ophthalmology 98:670–674, 1991.
Morad Y, Donaldson CE, Kim YM, et al: The Ahmed drainage implant in the Yonekawa Y, VanderVeen DK, Shah AS: Congenital glaucoma, J Pediatr 163:301,
treatment of pediatric glaucoma, Am J Ophthalmol 135:821–829, 2003. 2013.
Chapter 633 ◆ Orbital Abnormalities 3061
Chapter 633
Orbital Abnormalities
HYPERTELORISM AND HYPOTELORISM

Hypertelorism is wide separation of the eyes or an increased interor-
bital distance, which may occur as a morphogenetic variant, a primary
deformity, or a secondary phenomenon in association with develop-
mental abnormalities, such as frontal meningocele or encephalocele or
the persistence of a facial cleft. Often associated are strabismus, gener-
ally exotropia, and sometimes optic atrophy.
Hypotelorism refers to narrowness of the interorbital distance,
which may occur as a morphogenetic variant alone or in association
with other anomalies, such as epicanthus or holoprosencephaly, or
secondary to a cranial dystrophy, such as scaphocephaly.
EXOPHTHALMOS AND ENOPHTHALMOS
Protrusion of the eye is referred to as exophthalmos or proptosis and
is a common indicator of orbital disease. It may be caused by shallow-
ness of the orbits, as in many craniofacial malformations, or by
increased tissue mass within the orbit, as with neoplastic, vascular, and
inflammatory disorders. Ocular complications include exposure kera-
topathy, ocular motor disturbances, and optic atrophy with loss of A
vision.
Posterior displacement or sinking of the eye back into the orbit is
referred to as enophthalmos. This may occur with orbital fracture or
with atrophy of orbital tissue.
ORBITAL INFLAMMATION
Inflammatory disease involving the orbit may be primary or secondary
to systemic disease. Idiopathic orbital inflammation (orbital pseudo-
tumor) represents a wide spectrum of clinical entities. Symptoms at
the time of presentation may include pain, eyelid swelling, proptosis,
a red eye, and fever. The inflammation may involve a single extraocular
muscle (myositis) or the entire orbit. Orbital apex syndrome is a
serious condition that may also involve the cavernous sinus and may
compress or displace the optic nerve. Confusion with orbital cellulitis
is common but can be differentiated by the lack of associated sinus
disease, its appearance on CT scan, and lack of improvement with
systemic antibiotics. Orbital pseudotumor is associated with systemic B
lupus erythematosus, Crohn disease, myasthenia gravis, and lym-
phoma. Treatment includes the use of high-dose systemic corticoste- Figure 633-1 Orbital hemangioma. A, Note the proptosis. B, CT
scan. (Courtesy of Amy Nopper, MD, and Brandon Newell, MD.)
roids. Often, the symptoms improve dramatically shortly after
treatment is initiated. Bilateral involvement, associated uveitis, disc
edema, and recurrence of inflammation are not uncommon in the signs of a mass lesion. In selected cases, an incisional or excisional
pediatric population. Immunotherapy or radiation treatment may be biopsy of the lesion may be warranted.
necessary for resistant or recurrent cases.
Thyroid-related ophthalmopathy (see also Chapter 563) is believed Bibliography is available at Expert Consult.
to be secondary to an immune mechanism, leading to inflammation
and deposition of mucopolysaccharides and collagen in the extraocu-
lar muscles and orbital fat. Involvement of the extraocular muscles may
lead to a restrictive strabismus. Lid retraction and exophthalmos may
cause corneal exposure and infection or perforation. Involvement of
the posterior orbit can compress the optic nerve. Treatment of thyroid-
related ophthalmopathy may include the use of systemic corticoste-
roids, radiation of the orbit, eyelid surgery, strabismus surgery, or
orbital decompression to eliminate symptoms and protect vision. The
degree of orbital involvement is often independent of the status of the
systemic disease.
Other systemic disorders that may cause inflammatory disease
within the orbit include lymphoma (see Chapter 496), sarcoidosis (see
Chapter 165), amyloidosis (see Chapter 164), polyarteritis nodosa (see
Chapter 167.3), systemic lupus erythematosus (see Chapter 158), der-
matomyositis (see Chapter 159), Wegener granulomatosis (see Chapter
167), and juvenile xanthogranuloma (see Chapter 507).
TUMORS OF THE ORBIT

Various tumors occur in and about the orbit in childhood. Among
benign tumors, the most common are vascular lesions (principally
hemangiomas) (Fig. 633-1) and dermoids. Among malignant neo-
plasms, rhabdomyosarcoma, lymphosarcoma, and metastatic neuro-
blastoma are the most frequent. Optic nerve gliomas (see Chapter 631)
are most commonly seen in patients with neurofibromatosis and may
present with poor vision or proptosis. Retinoblastoma (see Chapter
502) may extend into the orbit if it is discovered late or goes untreated.
Teratomas are rare tumors that typically grow rapidly after birth and
exhibit explosive proptosis.
The effects of orbital tumors vary with their locations and growth
patterns. The principal signs are proptosis, resistance to retroplacement
of the eye, and impairment of eye movement. A palpable mass may be
found. Other significant signs are ptosis, optic nerve head congestion,
optic atrophy, and loss of vision. Bruit and visible pulsation of the globe
are important clues to vascular lesions.
Evaluation of orbital tumors includes ultrasonography, MRI, and
CT. Pseudotumor of the orbit also must be considered in children with
Chapter 633 ◆ Orbital Abnormalities 3062.e1
Bibliography Shields JA, Shields CL, Scartozzi R: Survey of 1264 patients with orbital tumors
Gorospe L, Royo A, Berrocal T, et al: Imaging of orbital disorders in pediatric and simulating lesions: The 2002 Montgomery Lecture, part 1, Ophthalmology
patients, Eur Radiol 13:2012–2026, 2003. 111:997–1008, 2004.
Ohtsuka K, Hashimoto M, Suzuki Y: A review of 244 orbital tumors in Japanese Yuen SJA, Rubin PAD: Idiopathic orbital inflammation, Arch Ophthalmol
patients during a 21-year period: Origins and locations, Jpn J Ophthalmol 121:491–499, 2003.
49:49–55, 2005.
Chapter 634
Orbital Infections
Orbital infections are common in children. It is important to be

able to distinguish the different forms of infection that occur in the
orbital region to allow rapid diagnosis and treatment to prevent loss of
vision or spread of the infection to the nearby intracranial structures
(Table 634-1).
DACRYOADENITIS
Dacryoadenitis, or inflammation of the lacrimal gland, is uncommon
in childhood. It may occur with mumps (in which case it is usually
acute and bilateral, subsiding in a few days or weeks) or with infectious
mononucleosis. Staphylococcus aureus may produce a suppurative dac-
ryoadenitis. Chronic dacryoadenitis is associated with certain systemic
diseases, particularly sarcoidosis, tuberculosis, and syphilis. Some sys-
temic diseases may produce enlargement of the lacrimal and salivary
glands (Mikulicz syndrome).
DACRYOCYSTITIS
Dacryocystitis is an infection of the lacrimal sac. Dacryocystitis gener-
ally requires obstruction of the nasolacrimal system to allow its devel-
opment. Acute dacryocystitis presents with redness and swelling over
the region of the lacrimal sac (Fig. 634-1). It is treated with warm
compresses and systemic antibiotics. This helps to control the
Chapter 634 ◆ Orbital Infections 3063
Figure 634-1 Dacrycystitis in a child previously treated for nasolac-

rimal duct obstruction.
Figure 634-2 CT scan of a patient with preseptal cellulitis.
Table 634-1 Chandler Classification of Orbital

Complications of Sinusitis, a Clinical caused by bacteremia, sinusitis, trauma, an infected wound, or an
Description abscess of the lid or periorbital region (pyoderma, hordeolum, con-
junctivitis, dacryocystitis, insect bite). Patients present with eyelid
CHANDLER CLINICAL DESCRIPTION swelling; the edema may be so intense as to make it difficult to evaluate
CLASS STAGE AND DEFINITION the globe. Prior to the Haemophilus influenzae type B vaccine, the most
I Inflammatory Eyelid edema and erythema common cause of pediatric preseptal (facial) cellulitis was bacteremia
edema Normal extraocular movement caused by H. influenzae type B. Group A streptococcus, S. aureus, and
Normal visual acuity pneumococcus are common etiologic agents. Clinical examination will
II Orbital Diffuse edema of orbital show lack of proptosis, normal ocular movement, and normal pupil
cellulitis contents without discrete function. CT examination will demonstrate edema of the lids and
abscess formation subcutaneous tissues anterior to the orbital septum (Fig. 634-2). Anti-
biotic therapy and careful monitoring for signs of sepsis and local
III Subperiosteal Collection of purulent exudate*
progression are essential.
abscess beneath periosteum of
lamina papyracea
Displacement of globe ORBITAL CELLULITIS
downward/laterally This is a condition involving inflammation of the tissues of the orbit,
with proptosis, limitation of movement of the eye, edema of the con-
IV Orbital Purulent collection within orbit*
junctiva (chemosis), and inflammation and swelling of the eyelids with
abscess Proptosis
Chemosis
potentially decreased visual acuity (see Table 634-1). The mean age is
Ophthalmoplegia approximately 7 yr but the range is 10 mo–18 yr. Patients often feel ill
Decreased vision with general symptoms of toxicity, fever, and leukocytosis (also see
Chapter 194).
V Cavernous Bilateral eye findings Orbital cellulitis may follow direct infection of the orbit from a
sinus Prostration
thrombosis
wound, metastatic deposition of organisms during bacteremia, or
Meningismus
more often direct extension or venous spread of infection from con-
*The radiographic correlation of a subperiosteal or orbital abscess seen with CT tiguous sites such as the lids, conjunctiva, globe, lacrimal gland, or
is a contrast-enhancing mass in the extraconal or intraconal space, possibly with nasolacrimal sac or, more commonly, from the paranasal (ethmoid)
areas of cavitation, because purulence cannot be determined with CT scanning.
From Rudloe TF, Harper M, Prabhu SP, et al: Acute periorbital infections: who sinuses. In some cases, primary or metastatic tumor in the orbit can
needs emergent imaging? Pediatrics 125:e719–e726, 2010. produce the clinical picture of orbital cellulitis. The most common
cause of orbital cellulitis in children is paranasal sinusitis. The spread
of infection to the orbit from the sinuses is more prevalent in children
infection, but the obstruction usually requires definitive treatment to because of their thinner bony septa and sinus wall, greater porosity of
reduce the risk of recurrence. bones, open suture lines, and larger vascular foramina. The spread of
Dacryocystitis may occur in newborns as a complication of a con- infection is also facilitated by the venous and lymphatic communica-
genital dacryocystocele (see Chapter 625). If present, systemic antibiot- tion between the sinuses and surrounding structures, which allow flow
ics and digital pressure for decompression are recommended. The in either direction, facilitating retrograde thrombophlebitis. Frequent
obstruction of the nasolacrimal system may resolve once the infection pathogenic organisms include S. aureus, including methicillin-resistant
clears. If spontaneous resolution does not occur, probing should be S. aureus, streptococcus species (Streptococcus anginosus), and Hae-
considered within a short time frame. An intranasal cyst may be mophilus species.
present in conjunction with the dacryocystocele. If this occurs, mar- The potential for complications is great. Visual loss can occur sec-
supialization of the cyst may be needed at the time of the probing. ondary to an increase in orbital pressure that causes retinal artery
occlusion or optic neuritis. This is more likely to occur in the presence
PRESEPTAL CELLULITIS of an orbital abscess. Extension of infection from the orbit into the
Inflammation of the lids and periorbital tissues without signs of true cranial cavity may lead to cavernous sinus thrombosis or meningitis,
orbital involvement (such as proptosis or limitation of eye movement) epidural or subdural empyema, or brain abscesses. Additional compli-
is generally referred to as periorbital or preseptal cellulitis and is a form cations include optic atrophy, exposure keratitis, and retinal or choroi-
of facial cellulitis. This is common in young children and may be dal ischemia. The differential diagnosis includes idiopathic orbital
inflammation, myositis, sarcoidosis, granulomatous vasculitis, leuke- pupillary abnormalities, decreased vision, or failure to improve, the
mia, lymphoma, histiocytic disorders, rhabdomyosarcoma, ruptured subperiosteal abscess should be drained. Many recommend routine
dermoid cyst, orbital trauma, and orbital foreign body. drainage for a subperiosteal abscess in children >9 yr of age. If there is
Orbital cellulitis must be recognized promptly and treated aggres- an orbital abscess with an abnormal physical exam, the recommenda-
sively. Hospitalization and systemic antibiotic therapy are usually indi- tion is that drainage be performed and antibiotics given at the time of
cated. All patients require CT imaging of the orbit, including the diagnosis. The use of adjunctive corticosteroids and anticoagulation for
surrounding central nervous system, preferably with intravenous con- cavernous venous thrombosis and or superior ophthalmic vein throm-
trast to detect a subperiosteal abscess, orbital abscess, or intracranial bosis is controversial.
extension. Parenteral antibiotics must be started immediately. Antimi-
crobial agents should begin with vancomycin and cefotaxime (or cef- Bibliography is available at Expert Consult.
triaxone); some include metronidazole. If there is no evidence of
improvement or if there are signs of progression, sinus drainage may
be required. The presence of an orbital or subperiosteal abscess (Figs.
634-3 and 634-4) may require urgent drainage of the orbit. The clinical
presentation and course of each individual patient should dictate the
need and timing of abscess drainage.
Children <9 yr of age with a medial subperiosteal abscess can
initially be managed with a trial of intravenous antibiotics, which
usually is sufficient for resolution of the abscess. They must be exam-
ined frequently (every 6 hr until improvement) for signs of visual
deterioration or pupillary abnormalities. Most will become afebrile
within 48 hr and have exam improvement by 72 hr. If there are
Figure 634-3 CT scan demonstrating a subperiosteal abscess along

the medial wall of the orbit.
Figure 634-4 An orbital subperiosteal abscess in a 9 yr old girl. A

coronal contrast-enhanced computed tomography image shows a
small, low-attenuation, rim-enhancing fluid collection consistent with
an abscess (arrows) in the medial aspect of the orbit with mass effect
on the medial rectus muscle (arrowhead), which is thickened. Bilateral
ethmoid sinus disease with infiltration of the right retroorbital fat is
demonstrated. (From Coley BD, editor: Caffey’s Pediatric diagnostic
imaging, ed 12, Vol 1, Philadelphia, 2013, Elsevier Saunders, Fig. 8-17,
p. 80.)
Chapter 634 ◆ Orbital Infections 3064.e1
Bibliography Greenberg MF, Pollard ZF: Medical treatment of pediatric subperiosteal orbital
Ambati BK, Ambati J, Azar N, et al: Periorbital and orbital cellulitis before and abscess secondary to sinusitis, J AAPOS 2:351–355, 1998.
after the advent of Haemophilus influenzae type B vaccination, Ophthalmology Nageswaran S, Woods CR, Benjamin DK Jr, et al: Orbital cellulitis in children,
107:1450–1453, 2000. Pediatr Infect Dis J 25:695–699, 2006.
Brook I: Microbiology and antimicrobial treatment of orbit and intracranial Peña MT, Preciado D, Orestes M, et al: Orbital complications of acute sinusitis,
complications of sinusitis in children and their management, Int J Pediatr JAMA Otolaryngol Head Neck Surg 139:223–227, 2013.
Otorhinolaryngol 73:1183–1186, 2009.
Garcia GH, Harris GJ: Criteria for nonsurgical management of subperiosteal
abscess of the orbit: Analysis of outcomes 1988–1998, Ophthalmology
107:1454–1456, 2000.
Chapter 635
Injuries to the Eye
Approximately 30% of all blindness in children results from trauma.

Children and adolescents account for a disproportionate number of
episodes of ocular trauma. Boys ages 11-15 yr are the most vulnerable;
their injuries outnumber those in girls by a ratio of about 4 : 1. The
majority of injuries are related to sports, sticks, stones, fireworks, paint
balls, air-powered BB guns, and other projectiles. High-velocity pro-
jectiles and fireworks cause particularly devastating ocular and orbital
injuries. Much of the trauma is avoidable (see Chapter 5.1). Any part
of the orbit or globe may be affected (Fig. 635-1).
ECCHYMOSIS AND SWELLING OF THE

EYELIDS
Ecchymosis and edema of the eyelids are common after blunt trauma
(Fig. 635-2). These disorders are self-limiting, absorb spontaneously,
and can be treated with iced compresses and analgesics. Periorbital
ecchymosis should prompt careful examination of the eye and sur-
rounding structures for more serious injuries such as orbital bone
fracture, intraocular hemorrhage, or rupture of the globe.
Abnormal eye movements: Foreign Distorted pupil:

always refer body beware penetrating injury
Deep laceration orbit:
Basal tear of iris: beware intraorbital
always refer penetration and
retinal foreign body
Hyphema:
Marginal laceration:
always refer
always refer
Subconjunctival
Epithelial loss: may hemorrhage: if it tracks
be missed without posteriorly beware of
fluorescein fracture
Figure 635-1 The injured eye. (From Khaw PT, Shah P, Elkington AR:
Injury to the eye. BMJ 2004;328:36–38.)
Chapter 635 ◆ Injuries to the Eye 3065
Figure 635-2 Eyelid ecchymosis and subconjunctival hemorrhage.
Figure 635-4 Corneal abrasion with fluorescein staining.
Figure 635-3 Eyelid margin laceration.
LACERATIONS OF THE EYELIDS

Eyelid lacerations may vary from simple to complex. When evaluating
an eyelid laceration, key findings include depth of the laceration, its
location, and whether there is involvement of the canaliculus. Most
superficial eyelid lacerations may be closed by the primary caregiver,
but if a laceration is deep, involves the lid margin, or involves the Figure 635-5 Vertically oriented linear corneal abrasions secondary
canaliculus, it should be evaluated by an ophthalmologist. The levator to a foreign body underneath the upper eyelid.
muscle is responsible for elevation of the upper eyelid and runs deep
to the skin and orbicularis oculi muscle. If the levator muscle is com-
promised and not recognized at initial repair, ptosis will occur. There- (Fig. 635-4). A slit lamp is ideal for this examination, but a direct
fore, if orbital fat is visible in the laceration, the laceration has ophthalmoscope with blue filter or a handheld Wood lamp is adequate
compromised the skin, orbicularis oculi and levator muscles, and for young children.
orbital septum and must be meticulously repaired to avoid ptosis. Treatment of a corneal abrasion is directed at promoting healing
Eyelid margin involvement (Fig. 635-3) also requires careful repair to and relieving pain. Abrasions are treated with frequent applications of
avoid lid malposition and notch formation. These can lead to ocular a topical antibiotic ointment until the epithelium is completely healed.
surface problems in the future, resulting in corneal scarring and loss The use of a semipressure patch does not improve healing time or
of vision. Lacerations involving the canaliculus require intubation of decrease pain. An improperly applied patch may itself abrade the
the nasolacrimal system in addition to repair of the laceration of the cornea. A topical cycloplegic agent (cyclopentolate hydrochloride 1%)
eyelid to avoid future tearing problems. Proper primary repair of eyelid can relieve the pain from ciliary spasm in patients with large abrasions.
lacerations often achieves a superior outcome to secondary repair at a Topical anesthetics should not be given at home because they retard
later date. As with any eyelid injury, careful examination of the eye and epithelial healing and inhibit the natural blinking reflex.
surrounding tissue is required.
FOREIGN BODY INVOLVING THE OCULAR
SUPERFICIAL ABRASIONS OF THE CORNEA SURFACE
When the corneal epithelium is scratched, abraded, or denuded, it This usually produces acute discomfort, tearing, and inflammation.
exposes the underlying epithelial basement layer and superficial Most foreign bodies can be detected by examination in good light with
corneal nerves. This is accompanied by pain, tearing, photophobia, the aid of magnification (Fig. 635-5) or a direct ophthalmoscope set
and decreased vision. Corneal abrasions are detected by instilling on a high plus lens (+10 or +12). In many cases, slit-lamp examination
fluorescein dye and inspecting the cornea using a blue-filtered light is necessary, especially if the particle is deep or metallic. Some
B
Figure 635-6 Superficial corneal foreign body.
Figure 635-7 A, External photograph of an open globe injury with a
peaked pupil because of iris prolapse through the sclera, a shallow
anterior chamber, and a traumatic cataract. B, CT imaging demonstrat-
conjunctival foreign bodies tend to lodge under the upper eyelid, ing a shallow left anterior chamber when compared with the right, but
causing the sensation of corneal foreign body as they come into contact without evidence of an intraocular foreign body. (From Hwang RY,
with the globe on eyelid movement; they may also produce vertically Schoenberger SD: Imaging a peaked pupil in a traumatic open globe
oriented linear corneal abrasions (Fig. 635-6). Finding these abrasions injury. J Pediatr 163:1517, 2013, Figs. A and B, p. 1517.)
should lead to a suspicion of such a foreign body, and eversion of the
lid may be necessary (see Chapter 619). If a foreign body is suspected
but not found, further examination is indicated. If the history suggests OPEN GLOBE
injury with a high-velocity particle, radiologic examination of the eye A penetrating, perforating, or blunt injury resulting in compromise of
may be needed to explore the possibility of an intraocular foreign body. the cornea or sclera of the eye is one of the most sight-threatening
Removal of a foreign body can be facilitated by instillation of a drop injuries that can be sustained (Fig. 635-7). This is known as an open
of topical anesthetic. Many foreign bodies can be removed by irrigation globe. An open globe is a true ophthalmologic emergency that requires
or by gently wiping them away with a moistened cotton-tipped applica- prompt, careful evaluation and immediate repair to minimize vision
tor. Embedded foreign bodies or foreign bodies in the central cornea loss. Permanent vision loss can result from corneal scarring, loss of
should be treated by an ophthalmologist. Removal of corneal foreign intraocular contents, or infection. Evaluation involves careful history
bodies may leave epithelial defects, which are treated as corneal abra- including time and mechanism of the injury, as well as visual acuity
sions. Metallic foreign bodies may cause rust to form in the corneal and inspection of the eye. A full-thickness corneal wound will often
tissues; examination by an ophthalmologist 1 or 2 days after removal present with prolapsed iris tissue through the wound. If this is not
of a foreign body is recommended because a rust ring might require immediately evident, a peaked or irregular pupil may be a sign of full-
further treatment. thickness laceration. Scleral compromise may be more difficult to iden-
tify because of overlying structures. The thinnest part of the sclera is
HYPHEMA at the corneoscleral junction (the limbus) and just posterior to the
This is the presence of blood in the anterior chamber of the eye. It may insertion of the rectus muscles. When an open globe is caused by blunt
occur with either a blunt or perforating injury and represents a situa- force injury, these are the 2 areas most likely involved. The overlying
tion that may threaten vision. Hyphema appears as a bright or dark red conjunctiva may not be compromised but a subconjunctival hemor-
fluid level between the cornea and iris or as a diffuse murkiness of the rhage may be present, obscuring the view. In these cases, look for a
aqueous humor. Children with hyphema present with acute loss of shallow anterior chamber, low intraocular pressure, or pigment within
vision, with or without pain. The treatment of hyphema involves efforts the involved area. If the patient has been diagnosed with an open globe,
to minimize the vision-threatening sequelae such as rebleeding, glau- the examination should be stopped, an eye shield placed immediately,
coma, and corneal blood staining. Bedrest is necessary, with elevation and the ophthalmologist contacted to minimize further ocular
of the head of the bed to 30 degrees. A shield (without underlying compromise.
patch) is placed on the affected eye, and a cycloplegic agent is used to
immobilize the iris. Additionally, topical or systemic steroids are used OPTIC NERVE TRAUMA
to minimize intraocular inflammation. Antiemetics should be consid- The optic nerve may be injured in both penetrating and blunt trauma.
ered if the patient is experiencing nausea. All nonsteroidal anti- The injury may occur at any point between the globe and the chiasm.
inflammatories and aspirin must be avoided. Rarely, hospitalization Traumatic injury to the optic nerve, regardless of cause or location,
and sedation may be necessary to ensure compliance in some children. results in reduced vision and a pupillary defect. Direct trauma to the
If the intraocular pressure is elevated, topical and systemic pressure- intraorbital optic nerve may cause transection, partial transection, or
lowering medications are used. If the pressure is not controllable by optic sheath hemorrhage. Fractures involving the skull base may cause
such measures, then surgical evacuation of the clot may be required to injury to the intracranial portions of the optic nerve. Treatment deci-
minimize the risk of permanent vision loss. Patients with sickle cell sions are difficult because there are no universally accepted guidelines,
disease or trait are at higher risk of acute loss of vision secondary to and the prognosis for good visual outcome is often poor. Medical
elevated intraocular pressure or optic nerve infarction and may require management involves observation and the use of high-dose corticoste-
more aggressive intervention. Individuals with a history of traumatic roids, although the use of corticosteroids has not been proven to
hyphema have an increased incidence of glaucoma later in life and improve visual outcomes and has been shown to increase the risk of
should be monitored on a regular basis throughout their lives. death in patients with significant head injury. Surgical intervention
Chapter 635 ◆ Injuries to the Eye 3067
involves optic nerve sheath decompression for nerve sheath hemor- primary gaze or downgaze that persists for 2 wk, enophthalmos, or
rhages. If compression of the optic nerve is secondary to orbital hemor- fracture of the orbital floor involving more than half of the floor. Extra-
rhage, prompt lateral canthotomy and cantholysis should be performed ocular muscle entrapment often requires prompt surgical repair
to relieve intraorbital pressure. Decompression of the optic canal may because affected patients have significant pain, nausea, and vomiting
be performed if there is compression of the optic nerve by a bone frag- that are difficult to control. Rarely, extraocular muscle entrapment can
ment. Optic canal decompression is controversial in the absence of cause activation of the oculocardiac reflex, requiring urgent fracture
direct bone compression. repair.
CHEMICAL INJURIES PENETRATING WOUNDS OF THE ORBIT

Chemical burns of the cornea and adnexal tissue are among the most These demand careful evaluation for possible damage to the eye, optic
urgent of ocular emergencies. Alkali burns are usually more destruc- nerve, orbital contents, or brain. Examination should include investi-
tive than acid burns because they react with fats to form soaps, which gation for a retained foreign body. Orbital hemorrhage and infection
damage cell membranes, allowing further penetration of the alkali into are common with penetrating wounds of the orbit; such injuries must
the eye. Acids generally cause less severe, more localized tissue damage. be treated as emergencies.
The corneal epithelium offers moderate protection against weak acids,
and little damage occurs unless the pH is 2.5 or less. Most stronger CHILD ABUSE
acids precipitate tissue proteins, creating a physical barrier against their See Chapter 40.
further penetration. This is a major cause of injuries to the eye and orbital region. The
Mild acid or alkali burns are characterized by conjunctival injection possibility of nonaccidental trauma must be considered in any child
and swelling and mild corneal epithelial erosions. The corneal stroma with ecchymosis or laceration of the lids, hemorrhage in or about the
may be mildly edematous, and the anterior chamber may have mild to eye, cataract or dislocated lens, retinal detachment, or fracture of the
moderate cell and flare reactions. With strong acids, the cornea and orbit. Inflicted childhood neurotrauma (shaken baby syndrome)
conjunctiva rapidly become white and opaque. The corneal epithelium occurs secondary to violent, nonaccidental, repetitive, unrestrained
may slough, leaving a relatively clear stroma; this appearance may acceleration-deceleration head and neck movements, with or without
initially mask the severity of the burn. Severe alkali burns are charac- blunt head trauma in children typically younger than 3 yr of age.
terized by corneal opacification. Inflicted childhood neurotrauma accounts for approximately 10% of
Emergency treatment of a chemical burn begins with immediate, all cases of child abuse and carries a mortality rate of up to 25%. Detec-
copious irrigation with water or saline. Local debridement and removal tion of abuse is not only important in order to treat the pathology that
of foreign particles should be performed as irrigation continues. If the is discovered but also to prevent further abuse or even death. The
nature of the chemical injury is unknown, the use of pH test paper is ocular manifestations are numerous and may have a prominent role in
helpful in determining whether the agent was basic or acidic. Irrigation recognition of this syndrome. Retinal hemorrhage is the most common
should continue for at least 30 min or until 2 L of irrigant has been ophthalmic finding and occurs at all levels of the retina. The pattern
instilled in mild cases and for 2-4 hr or until 10 L of irrigant has been of hemorrhage helps to distinguish this disorder from other causes of
instilled in severe cases. At the end of irrigation, the pH should be retinal hemorrhage or from accidental injuries (Fig. 635-8). Retinal
within a normal range (7.3-7.7). The pH should be checked again hemorrhages can occur without associated intracranial pathology.
approximately 30 min after irrigation to ensure that it has not changed.
The goal of treatment is to minimize sequelae that may threaten vision, FIREWORKS-RELATED INJURIES
such as conjunctival scarring, corneal scarring/opacification, glau- Injuries related to the use of fireworks can be the most devastating of
coma, cataract, and phthisis. all ocular traumas that occur in children. At least 20% of emergency
department visits for fireworks-related injuries are for ocular trauma.
ORBITAL FRACTURES In the United States, a majority of these injuries take place around
The orbit is the bony structure surrounding the eye. Any of these bones Independence Day, and most occur despite adult supervision.
may fracture in a traumatic incident. Superior and lateral wall fractures
are the least common of the fracture sites, but superior orbital fracture SPORTS-RELATED OCULAR INJURIES
is the most significant because of the potential of intracranial injury. AND THEIR PREVENTION
The medial wall of the orbit is very susceptible to fracture because of Although sports injuries occur in all age groups, far more children
the thin nature of the lamina papyracea. Perhaps the most common and adolescents participate in high-risk sports than do adults. The
site of fracture from blunt trauma is the orbital floor. This is often
referred to as blowout fracture. At times, the fracture may act as a
trapdoor, entrapping orbital contents within the fracture site.
The patient often presents with a recent history of periorbital trauma
and pain. Diplopia, eyelid swelling, eye movement restriction, or hyp-
esthesia may or may not be present. Eye symptoms may be associated
with nausea and bradycardia if the inferior rectus is entrapped in the
fracture site. A complete ophthalmic examination, including, visual
acuity, examination of the pupil for ocular alignment, ocular motility,
anterior segment and fundus status, as well as the history of the injury,
is required because there are often accompanying ocular injuries. The
diagnosis of fracture is suspected if eye misalignment, eye movement
restriction, or enophthalmos (sunken eye) is present. The diagnosis is
verified by orbital CT scan.
Medical management includes iced compresses to the orbit and
elevation for the head of the bed for the 1st 24-48 hr. Broad-spectrum
antibiotics are sometimes recommended for 14 days because of the
exposure of the orbital contents to the sinus cavity. In medial wall
fractures, instructions not to blow one’s nose should be given to the
patient to avoid orbital emphysema and subsequent optic nerve com-
pression. Consider neurosurgical consultation in orbital roof fractures.
Indications for surgical repair of orbital fractures are diplopia in Figure 635-8 Retinal hemorrhages in an abused child.
B C
Figure 635-9 Laser damage to the left eye. A, Color photo of the fundus of the left eye showing a macular hole. Note the changes at the retinal
pigment epithelium. B, Infrared photo of the left fundus. C, Optical coherence tomography (OCT) of the left eye showing the macular hole. (From
Petrou P, Patwary S, Banerjee PJ, et al: Bilateral macular hole from a handheld laser pointer, Lancet 383:1780, 2014.)
greater number of participating children, their athletic immaturity, are suggested. For hockey, football, lacrosse, and baseball (batter), spe-
and the increased likelihood of their using inadequate or improper eye cific helmets with polycarbonate face shields and guards are available.
protection account for their disproportionate share of sports-related Children should also wear sports goggles under the helmets. For base-
eye injuries (see Chapters 688 and 693). ball, goggles and helmets should be worn for batting, catching, and
The sports with the highest risk of eye injury are those in which no base running; goggles alone are usually sufficient for other positions.
eye protection can be worn, including boxing, wrestling, and martial
arts. Other high-risk sports include those that use a rapidly moving HANDHELD LASER RETINAL INJURY
ball or puck, bat, stick, racquet, or arrow (baseball, hockey, lacrosse, Handheld laser pointers, often purchased to light cigarettes or for other
racquet sports, and archery) or involve aggressive body contact (foot- purposes, may produce significant retinal damage if the power output
ball and basketball). Related to both risk and frequency of participa- is ≥150 mW. If a person looks directly at the light, direct foveal injury
tion, the highest percentage of eye injuries are in basketball and may occur before he or she has time to blink. Central (foveal) blurring
baseball. and decreased visual activity are the chief complaints. Retinal injuries
Protective eyewear, designed for a specific activity, is available for include retinal disruption, subretinal edema, and macular holes (Fig.
most sports. For basketball, racquet sports, and other recreational 635-9), which usually require surgical repair.
activities that do not require a helmet or face mask, molded polycar-
bonate sports goggles that are secured to the head by an elastic strap Bibliography is available at Expert Consult.
Chapter 635 ◆ Injuries to the Eye 3068.e1
Bibliography Hwang RY, Schoenberger SD: Imaging a peaked pupil in a traumatic open globe
American Academy of Pediatrics Committee on Sports Medicine and Fitness, injury, J Pediatr 163:1517, 2013.
American Academy of Ophthalmology Committee on Eye Safety and Sports Khaw PT, Shah P, Elkington AR: Injury to the eye, BMJ 328:36–38, 2004.
Ophthalmology: Protective eyewear for young athletes, Pediatrics 98:311–313, Kivlin JD, Simons KB, Lazoritz S, et al: Shaken baby syndrome, Ophthalmology
1996. 107:1246–1254, 2000.
Buys YM, Levin AV, Enzenauer RW, et al: Retinal findings after head trauma in Lane K, Penne RB, Bilyk JR: Evaluation and management of pediatric orbital
infants and young children, Ophthalmology 99:1718–1723, 1992. fractures in primary care setting, Orbit 26(3):183–191, 2007.
Centers for Disease Control and Prevention: Serious eye injuries associated with Michael JG, Hug D, Dowd MD: Management of corneal abrasion in children:
fireworks—United States, 1990–1994, MMWR Morb Mortal Wkly Rep A randomized clinical trial, Ann Emerg Med 40:67–72, 2002.
44:449–452, 1995. Morad Y, Avni I, Benton SA, et al: Normal computerized tomography of brain in
Crouch ER Jr, Crouch ER: Management of traumatic hyphema: therapeutic children with shaken baby syndrome, J AAPOS 8:445–450, 2004.
options, J Pediatr Ophthalmol Strabismus 36:238–250, 1999. Petrou P, Patwary S, Banerjee PJ, et al: Bilateral macular hole from a handheld
Dhoot DS, Xu D, Srivastave S: High-powered laser pointer injury resulting in laser pointer, Lancet 383:1780–1781, 2014.
macular hole formation, J Pediatr 164:668, 2014. Smith GA, Knapp JF, Barnett TM, et al: The rocket’s red glare, the bombs bursting
Egbert JE, May K, Kersten RC, et al: Pediatric orbital floor fracture: Direct in air: Fireworks-related injuries to children, Pediatrics 98:1–9, 1996.
extraocular muscle involvement, Ophthalmology 107:1875–1879, 2000.
Forbes BJ, Christian CW, Judkins AR, et al: Inflicted childhood neurotrauma
(shaken baby syndrome): Ophthalmic findings, J Pediatr Ophthalmol Strabismus
41:80–88, 2004.
The Ear XXX
PART
FACIAL PARALYSIS
The facial nerve may be dehiscent in its course through the middle ear
Chapter 636 in as many as 50% of patients. Infection with local inflammation, most
commonly in acute OM, can lead to a temporary paralysis of the facial
General Considerations nerve. It also can result from Lyme disease, cholesteatoma, Bell palsy,
Ramsay Hunt syndrome (herpes zoster oticus), fracture, neoplasm, or
infection of the temporal bone. Congenital facial paralysis can result
and Evaluation from birth trauma or congenital abnormality of the 7th nerve or from
a syndrome such as Möbius or CHARGE (coloboma, heart defects,
Joseph Haddad Jr. and Sarah Keesecker atresia choanae, retarded growth, genital hypoplasia, and ear anoma-
lies), or it may be associated with other cranial nerve abnormalities
and craniofacial anomalies.
PHYSICAL EXAMINATION
CLINICAL MANIFESTATIONS Complete examination with special attention to the head and neck can
Diseases of the ear and temporal bone typically manifest with 1 or reveal a condition that can predispose to or be associated with ear
more of 8 clinical signs and symptoms. disease in children. The facial appearance and the character of speech
Otalgia usually is associated with inflammation of the external or can give clues to an abnormality of the ear or hearing. Many craniofa-
middle ear, but it can represent pain referred from involvement of the cial anomalies, such as cleft palate, mandibulofacial dysostosis
teeth, temporomandibular joint, or pharynx. In young infants, pulling (Treacher Collins syndrome), and trisomy 21 (Down syndrome), are
or rubbing the ear along with general irritability or poor sleep, espe- associated with disorders of the ear and eustachian tube. Mouth
cially when associated with fever, may be the only signs of ear pain. breathing and hyponasality can indicate intranasal or postnasal
Ear pulling alone is not diagnostic of ear pathology. obstruction. Hypernasality is a sign of velopharyngeal insufficiency.
Purulent otorrhea is a sign of otitis externa, otitis media with Examining the oropharyngeal cavity might uncover an overt cleft
perforation of the tympanic membrane (TM), drainage from the palate or a submucous cleft (usually associated with a bifid uvula), both
middle ear through a patent tympanostomy tube, or, rarely, drainage of which predispose to OM with effusion. A nasopharyngeal tumor
from a first branchial cleft sinus. Bloody drainage may be associated with nasal and eustachian tube blockage may be associated with OM.
with acute or chronic inflammation (often with granulation tissue and/ The position of the patient for examination of the ear, nose, and
or an ear tube), trauma, neoplasm, foreign body, or blood dyscrasia. throat depends on the patient’s age and ability to cooperate, the clinical
Clear drainage suggests a perforation of the TM with a serous middle- setting, and the examiner’s preference. The child can be examined on
ear effusion or, rarely, a cerebrospinal fluid leak draining through an examination table or in the parent’s lap. The presence of a parent or
defects (congenital or traumatic) in the external auditory canal or from assistant usually is necessary to minimize movement and provide
the middle ear. better examination results (Fig. 636-1). An examining table may be
Hearing loss results either from disease of the external or middle desirable for uncooperative older infants or when a procedure, such as
ear (conductive hearing loss) or from pathology in the inner ear, ret- microscopic evaluation or tympanocentesis, is performed. Wrapping
rocochlear structures, or central auditory pathways (sensorineural the child in a sheet or using a papoose board can help to minimize
hearing loss). The most common cause of hearing loss in children is movement. Lap examination is adequate and preferable in most infants
otitis media (OM). and young children; the parent may assist in restraining the child by
Swelling around the ear most commonly is a result of inflammation folding the child’s wrists and arms over the child’s own abdomen with
(e.g., external otitis, perichondritis, mastoiditis), trauma (e.g., hema- one hand and holding the child’s head against the parent’s chest with
toma), benign cystic masses, or neoplasm. the other hand. If necessary, the child’s legs can be held between the
Vertigo is a specific type of dizziness that is defined as any illusion parent’s knees. To avoid ear trauma with movement, the examiner
or sensation of motion. Dizziness is less specific than vertigo and refers should hold the otoscope with the hand placed firmly against the
to a sensation of altered orientation in space. Vertigo is an uncommon child’s head or face, so that the otoscope moves with the head. Pulling
complaint in children; the child or parent might not volunteer infor- up and out on the pinna straightens the ear canal and allows better
mation about balance unless asked specifically. The most common exposure of the TM.
cause of dizziness in young children is eustachian tube–middle-ear When examining the ear, inspecting the auricle and external audi-
disease, but true vertigo also may be caused by labyrinthitis, perilym- tory meatus for infection can aid in evaluating complications of OM.
phatic fistula between the inner and middle ear as a result of trauma External otitis can result from acute OM with discharge, or inflamma-
or a congenital inner ear defect, cholesteatoma in the mastoid or tion of the posterior auricular area can indicate a periostitis or sub-
middle ear, vestibular neuronitis, benign paroxysmal vertigo, Ménière periosteal abscess extending from the mastoid air cells. The presence
disease, or disease of the central nervous system. Older children might of preauricular pits or skin tags also should be noted because affected
describe a feeling of the room spinning or turning; younger children children have a slightly higher incidence of sensorineural hearing loss;
might express the dysequilibrium only by falling, stumbling, or ear pits can develop chronic infection.
clumsiness. Cerumen is a protective, waxy, water-repellent coating in the ear
Nystagmus may be unidirectional, horizontal, or jerk nystagmus. It canal that can interfere with examination. Cerumen usually is removed
is vestibular in origin and usually is associated with vertigo. using the surgical head of the otoscope, which allows passage of a wire
Tinnitus rarely is described spontaneously by children, but it is loop or a blunt curette under direct visualization. Other methods
common, especially in patients with eustachian tube–middle-ear include gentle irrigation of the ear canal with warm water, which
disease or sensorineural hearing loss (SNHL). Children can describe should be performed only if the TM is intact, or instillation of a solu-
tinnitus if asked directly about it, including laterality and the quality tion such as diluted hydrogen peroxide in the ear canal (with intact
of the sound. TM only) for a few minutes to soften the wax for suction removal or
3069
3070 Part XXX ◆ The Ear
irrigation. Some commercial preparations such as trolamine polypep- middle-ear disease with fixation of the ossicles, ossicular ligaments, or
tide oleate–condensate (Cerumenex) can cause dermatitis of the exter- TM. When retraction is present, the bony malleus appears more prom-
nal canal with chronic use and should be used only under a physician’s inent, and the incus may be more visible posterior to the malleus.
supervision. The normal TM has a silvery-gray, “waxed paper” appearance (Fig.
Inflammation of the ear canal with associated pain often indicates 636-2). A white or yellow TM can indicate a middle-ear effusion. A
external otitis. Abnormalities of the external auditory canal include red TM alone might not indicate pathology, because the blood vessels
stenosis (common in children with trisomy 21), bony exostoses, otor- of the membrane may be engorged as a result of crying, sneezing, or
rhea, and the presence of foreign bodies. Cholesteatoma of the middle nose blowing. A normal TM is translucent, allowing the observer to
ear can manifest in the canal as intermittent foul-smelling drainage, visualize the middle-ear landmarks: incus, promontory, round window
sometimes associated with white debris; cholesteatoma of the external niche, and, often, the chorda tympani nerve. If a middle-ear effusion
canal can appear as a white, pearl-like mass in the canal skin. White is present, an air–fluid level or bubbles may be visible (Fig. 636-2).
or gray debris of the canal suggests fungal external otitis. Newborn ear Inability to visualize the middle-ear structures indicates opacification
canals are filled with vernix caseosa, which is soft and pale yellow and of the drum, usually caused by thickening of the TM or a middle-ear
should disappear shortly after birth. effusion, or both. Assessment of the light reflex often is not helpful,
The TM and its mobility are best assessed with a pneumatic oto- because a middle ear with effusion reflects light as well as a normal ear.
scope. The normal TM is in a neutral position; a bulging TM may be TM mobility is helpful in assessing middle-ear pressures and the
caused by increased middle-ear air pressure, with or without pus or presence or absence of fluid (see Fig. 636-2). To best perform pneu-
effusion in the middle ear; a bulging drum can obscure visualization matic otoscopy, a speculum of adequate size is used to obtain a good
of the malleus and annulus. Retraction of the TM usually indicates seal and allow air movement in the canal. A rubber ring around the
negative middle-ear pressure, but it also can result from previous tip of the speculum can help to obtain a better canal seal. Normal
middle-ear pressure is characterized by a neutral TM position and
brisk TM movement to both positive and negative pressures.
Eardrum retraction is most common when negative middle-ear
Restraint
pressure is present; with even moderate negative middle-ear pressure
there is no visible inward movement with applied positive pressure in
the ear canal (see Fig. 636-1). However, negative canal pressure, which
is produced by releasing the rubber bulb of the pneumatic otoscope,
can cause the TM to bounce out toward the neutral position. The TM
can retract in both the presence and absence of middle-ear fluid, and
if the middle-ear fluid is mixed with air, the TM might still have some
mobility. Outward eardrum movement is less likely in the presence of
Papoose Board severe negative middle-ear pressure or middle-ear effusion.
The TM that exhibits fullness (bulging) moves to applied positive
pressure but not to applied negative pressure if the pressure within the
middle ear is positive. A full TM and positive middle-ear pressure
without an effusion may be seen in young infants who are crying
during the otoscopic examination, in older infants and children with
Figure 636-1 Methods of restraining an infant for examination and nasal obstruction, and in the early stage of acute OM. When the
for procedures such as tympanocentesis or myringotomy. (From middle-ear–mastoid air cell system is filled with an effusion and little
Bluestone CD, Klein JO: Otitis media in infants and children, ed 2, or no air is present, the mobility of the TM is severely decreased or
Philadelphia, 1995, WB Saunders, p. 91.) absent in response to both applied positive and negative pressures.
NORMAL FLUID LEVEL

Position—neutral Position—retracted
Color—normal Color—yellow or amber
Translucency—translucent Translucency—translucent
Mobility—moves briskly with Mobility—same as with high
slight positive and negative negative pressure, but fluid
pressure level and bubbles change with
applied pressure
A D
NEGATIVE MIDDLE-EAR OTITIS MEDIA WITH
PRESSURE EFFUSION
Position—retracted Position—usually retracted
Color—normal Color—white (or yellow or blue)
Translucency—translucent Translucency—opaque (may be
Mobility—moves only with translucent)
applied negative pressure Mobility—poor when both
positive and negative
B E pressures are applied
ACUTE OTITIS MEDIA PERFORATION (OR PATENT

Position—full to bulging TYMPANOSTOMY TUBE)
Color—red (can be pink, Position—neutral or retracted
white, or yellow) Color—white, pink, red, or
Translucency—opaque normal
Mobility—poor when both Translucency—translucent or
positive and negative opaque
pressures are applied Mobility—none
C F
Figure 636-2 A-F, Common conditions of the middle ear, as assessed with the otoscope. (From Bluestone CD, Klein JO: Otitis media in infants
and children, ed 3, Philadelphia, 2001, WB Saunders, p. 131.)
Trap
Suction
Figure 636-3 Tympanocentesis can be performed with a needle

attached to a tuberculin syringe (left) or by using an Alden-Senturia
collection trap (Storz Instrument Co, St. Louis). (From Bluestone CD,
Klein JO: Otitis media in infants and children, ed 2, Philadelphia, 1995,
WB Saunders, p. 127.)
Tympanocentesis, or aspiration of the middle ear, is the definitive

method of verifying the presence and type of a middle-ear effusion and
is performed by inserting, through the inferior portion of the TM, an
18-gauge spinal needle attached to a syringe or a collection trap (Fig.
636-3). Culturing of the ear canal and alcohol cleansing should precede
tympanocentesis and culture of the middle-ear aspirate; a canal culture
is taken first to help determine whether organisms cultured from the
middle ear are contaminants from the external canal or true middle-
ear pathogens.
Further diagnostic studies of the ear and hearing include audiomet-
ric evaluation, impedance audiometry (tympanometry), acoustic
reflectometry, and specialized eustachian tube function studies. Diag-
nostic imaging studies, including CT and MRI, often provide further
information about anatomic abnormalities and the extent of inflam-
matory processes or neoplasms. Specialized assessment of labyrinthine
function should be considered in the evaluation of a child with a sus-
pected vestibular disorder (see Chapter 641).

Chapter 636 ◆ General Considerations and Evaluation 3071.e1
Bibliography Neilan RE, Roland PS: Otalgia, Med Clin North Am 94:961–971, 2010.
Johnson KC: Audiologic assessment of children with suspected hearing loss, Rothman R, Owens T, Simel DL: Does this child have acute otitis media? JAMA
Otolaryngol Clin North Am 35:711–732, 2002. 290:1633–1640, 2003.
McDivitt K: The pediatric tympanic membrane: see it, describe it, treat it, ORL Shaikh N, Hoberman A, Kaleida PH, et al: Videos in clinical medicine. Diagnosing
Head Neck Nurs 21:14–17, 2003. otitis media–otoscopy and cerumen removal, N Engl J Med 362:e62, 2010.
Chapter 637 ◆ Hearing Loss 3071
The onset of hearing loss among children can occur at any time in
childhood. When less-severe hearing loss or the transient hearing loss
that commonly accompanies middle-ear disease in young children is
considered, the number of affected children increases substantially.
TYPES OF HEARING LOSS

Hearing loss can be peripheral or central in origin. Peripheral hearing
loss can be conductive, sensorineural, or mixed. Conductive hearing
loss (CHL) commonly is caused by dysfunction in the transmission of
sound through the external or middle ear or by abnormal transduction
of sound energy into neural activity in the inner ear and the 8th nerve.
CHL is the most common type of hearing loss in children and occurs
when sound transmission is physically impeded in the external and/or
middle ear. Common causes of CHL in the ear canal include atresia or
stenosis, impacted cerumen, or foreign bodies. In the middle ear, per-
foration of the tympanic membrane (TM), discontinuity or fixation of
the ossicular chain, otitis media (OM) with effusion, otosclerosis, and
cholesteatoma can cause CHL.
Damage to or maldevelopment of structures in the inner ear can
cause sensorineural hearing loss (SNHL). Causes include hair cell
destruction from noise, disease, or ototoxic agents; cochlear malforma-
tion; perilymphatic fistula of the round or oval window membrane; and
lesions of the acoustic division of the 8th nerve. A combination of CHL
and SNHL is considered a mixed hearing loss.
An auditory deficit originating along the central auditory nervous
system pathways from the proximal 8th nerve to the cerebral cortex
usually is considered central (or retrocochlear) hearing loss. Tumors
or demyelinating disease of the 8th nerve and cerebellopontine angle
can cause hearing deficits but spare the outer, middle, and inner ear.
These causes of hearing loss are rare in children. Other forms of central
auditory deficits, known as central auditory processing disorders,
include those that make it difficult even for children with normal
hearing to listen selectively in the presence of noise, to combine infor-
mation from the 2 ears properly, to process speech when it is slightly
degraded, and to integrate auditory information when it is delivered
faster although they can process it when delivered at a slow rate. These
deficits can manifest as poor attention or as academic or behavior
problems in school. Strategies for coping with such disorders are avail-
able for older children, and identification and documentation of the
central auditory processing disorder often is valuable so that parents
and teachers can make appropriate accommodations to enhance
learning.
ETIOLOGY
Most CHL is acquired, with middle-ear fluid the most common cause.
Congenital causes include anomalies of the pinna, external ear canal,
TM, and ossicles. Rarely, congenital cholesteatoma or other masses in
the middle ear manifest as CHL. TM perforation (e.g., trauma, OM),
ossicular discontinuity (e.g., infection, cholesteatoma, trauma), tympa-
Chapter 637 nosclerosis, acquired cholesteatoma, or masses in the ear canal or
middle ear (Langerhans cell histiocytosis, salivary gland tumors,
Hearing Loss glomus tumors, rhabdomyosarcoma) also can manifest as CHL.
Uncommon diseases that affect the middle ear and temporal bone and
can manifest with CHL include otosclerosis, osteopetrosis, fibrous dys-
Joseph Haddad Jr. and Sarah Keesecker plasia, and osteogenesis imperfecta.
SNHL may be congenital or acquired. Acquired SNHL may be
caused by genetic, infectious, autoimmune, anatomic, traumatic, oto-
INCIDENCE AND PREVALENCE toxic, and idiopathic factors (Tables 637-1, 637-2, 637-3, and 637-4).
Bilateral neural hearing loss is categorized as mild (20-30 dB), moder- The recognized risk factors account for approximately 50% of cases of
ate (30-50 dB), severe (50-70 dB), or profound (>70 dB). The World moderate to profound SNHL.
Health Organization estimates that approximately 360 million people Sudden SNHL in a previously healthy child is uncommon but may
(5% of the world’s population, including 32 million children) have be from OM or other middle-ear pathologies such as autoimmunity.
disabling hearing loss. An additional 364 million people have mild Usually these causes are obvious from the history and physical exami-
hearing loss. Half of these cases could have been prevented. In the nation. Sudden loss of hearing in the absence of obvious causes often
United States, the average incidence of neonatal hearing loss is 1.1 in is the result of a vascular event affecting the cochlear apparatus or
1,000 infants; the rate by state varies from 0.22-3.61 in 1,000. Among nerve, such as embolism or thrombosis (secondary to prothrombotic
children and adolescents, the rate of mild or greater hearing loss is conditions), or an autoimmune process. Additional causes include
3.1% and is higher among Latin Americans, African-Americans, and perilymph fistula, drugs, trauma, and the first episode of Ménière
persons from lower-income families. syndrome. In adults, sudden SNHL is often idiopathic and unilateral;
Table 637-1 Indicators Associated with Hearing Loss

INDICATORS ASSOCIATED WITH SENSORINEURAL AND/OR CONDUCTIVE HEARING LOSS
Neonates (Birth-28 Days) When Universal Screening Is Not Available
Family history of hereditary childhood sensorineural hearing loss
In utero infection, such as cytomegalovirus, rubella, syphilis, herpes simplex, or toxoplasmosis
Craniofacial anomalies, including those with morphologic abnormalities of the pinna, ear canal, ear tags, ear pits, and temporal bone
anomalies
Birthweight <1500 g (3.3 lb)
Hyperbilirubinemia at a serum level requiring exchange transfusion
Ototoxic medications, including but not limited to the aminoglycosides, used in multiple courses or in combination with loop diuretics
Bacterial meningitis
Apgar scores of 0-4 at 1 min or 0-6 at 5 min
Mechanical ventilation lasting ≥5 days; extracorporeal membrane oxygenation
Stigmata or other findings associated with a syndrome known to include a sensorineural and/or conductive hearing loss; white forelock
Infants and Toddlers (Age 29 Days-2 Yr) When Certain Health Conditions Develop That Require Rescreening
Parent or caregiver concern regarding hearing, speech, language, and/or developmental delay
Bacterial meningitis and other infections associated with sensorineural hearing loss
Head trauma associated with loss of consciousness or skull fracture
Stigmata or other findings associated with a syndrome known to include a sensorineural and/or conductive hearing loss; neurofibromatosis,
osteopetrosis, and Usher Hunter, Waardenburg, Alport, Pendred, or Jervell and Lange-Nielsen syndrome
Ototoxic medications, including but not limited to chemotherapeutic agents or aminoglycosides used in multiple courses or in combination
with loop diuretics
Recurrent or persistent otitis media with effusion for 3 mo or longer
Skeletal dysplasia
Infants and Toddlers (Age 29 Days-3 Yr) Who Require Periodic Monitoring of Hearing
Some newborns and infants pass initial hearing screening but require periodic monitoring of hearing to detect delayed-onset sensorineural
and/or conductive hearing loss. Infants with these indicators require hearing evaluation at least every 6 mo until age 3 yr, and at appropriate
intervals thereafter
INDICATORS ASSOCIATED WITH DELAYED-ONSET SENSORINEURAL HEARING LOSS
Family history of hereditary childhood hearing loss
In utero infection, such as cytomegalovirus, rubella, syphilis, herpes simplex, or toxoplasmosis
Neurofibromatosis type 2 and neurodegenerative disorders
Cogan syndrome (vasculitis: keratitis, uveitis, vertigo, arthritis, dermatitis)
INDICATORS ASSOCIATED WITH CONDUCTIVE HEARING LOSS
Recurrent or persistent otitis media with effusion
Anatomic deformities and other disorders that affect eustachian tube function
Neurodegenerative disorders
Note: At all ages, parents’ concern about hearing loss must be taken seriously even in the absence of risk factors.
Adapted from American Academy of Pediatrics, Joint Committee on Infant Hearing: Joint Committee on Infant Hearing 1994 position statement, Pediatrics 95:152,
1995.
Table 637-2 Common Types of Early-Onset Hereditary Nonsyndromic Sensorineural Hearing Loss
LOCUS GENE AUDIO PHENOTYPE
DFN3 POU3F4 Conductive hearing loss as a result of stapes fixation mimicking otosclerosis; superimposed progressive
SNHL
DFNA1 DIAPH1 Low-frequency loss beginning in the 1st decade and progressing to all frequencies to produce a flat
audio profile with profound losses throughout the auditory range
DFNA2 KCNQ4 Symmetric high-frequency sensorineural loss beginning in the 1st decade and progressing over all
frequencies
GJB3 Symmetric high-frequency sensorineural loss beginning in the 3rd decade
DFNA3 GJB2 Childhood-onset, progressive, moderate-to-severe high-frequency sensorineural hearing impairment
GJB6 Childhood-onset, progressive, moderate-to-severe high-frequency sensorineural hearing impairment
DFNA6, 14, WFS1 Early-onset low-frequency sensorineural loss; approximately 75% of families dominantly segregating this
and 38 audio profile carry missense mutations in the C-terminal domain of wolframin
DFNA8, and 12 TECTA Early-onset stable bilateral hearing loss, affecting mainly mid to high frequencies
DFNA10 EYA4 Progressive loss beginning in the 2nd decade as a flat to gently sloping audio profile that becomes
steeply sloping with age
DFNA11 MYO7A Ascending audiogram affecting low and middle frequencies at young ages and then affecting all
frequencies with increasing age
DFNA13 COL11A2 Congenital midfrequency sensorineural loss that shows age-related progression across the auditory range
DFNA15 POU4F3 Bilateral progressive sensorineural loss beginning in the 2nd decade
Table 637-2 Common Types of Early-Onset Hereditary Nonsyndromic Sensorineural Hearing Loss—cont’d
LOCUS GENE AUDIO PHENOTYPE
DFNA20, and ACTG1 Bilateral progressive sensorineural loss beginning in the 2nd decade; with age, the loss increases with
26 threshold shifts in all frequencies, although a sloping configuration is maintained in most cases
DFNA22 MYO6 Postlingual, slowly progressive, moderate to severe hearing loss
DFNB1 GJB2, Hearing loss varies from mild to profound. The most common genotype, 35delG/35delG, is associated
GJB6 with severe to profound SNHL in about 90% of affected children; severe to profound deafness is
observed in only 60% of children who are compound heterozygotes carrying 1 35delG allele and any
other GJB2 SNHL-causing allele variant; in children carrying 2 GJB2 SNHL-causing missense mutations,
severe to profound deafness is not observed
DFNB3 MYO7A Severe to profound sensorineural hearing loss
DFNB4 SLC26A4 DFNB4 and Pendred syndrome (see Table 637-3) are allelic. DFNB4 hearing loss is associated with
dilation of the vestibular aqueduct and can be unilateral or bilateral. In the high frequencies, the loss is
severe to profound; in the low frequencies, the degree of loss varies widely. Onset can be congenital
(prelingual), but progressive postlingual loss also is common
DFNB7, and 11 TMC1 Severe-to-profound prelingual hearing impairment
DFNB9 OTOF OTOF-related deafness is characterized by 2 phenotypes: prelingual nonsyndromic hearing loss and, less
frequently, temperature-sensitive nonsyndromic auditory neuropathy. The nonsyndromic hearing loss is
bilateral severe-to-profound congenital deafness
DFNB12 CDH23 Depending on the type of mutation, recessive mutations of CDH23 can cause nonsyndromic deafness or
type 1 Usher syndrome (USH1), which is characterized by deafness, vestibular areflexia, and vision loss as
a result of retinitis pigmentosa
DFNB16 STRC Early-onset nonsyndromic autosomal recessive sensorineural hearing loss
mtDNA 12S rRNA Degree of hearing loss varies from mild to profound but usually is symmetric; high frequencies are
1555A > G preferentially affected; precipitous loss in hearing can occur after aminoglycoside therapy
SNHL, sensorineural hearing loss.
Adapted from Smith RJH, Bale JF Jr, White KR: Sensorineural hearing loss in children, Lancet 365:879–890, 2005.
Table 637-3 Common Types of Syndromic Sensorineural Hearing Loss

SYNDROME GENE PHENOTYPE
DOMINANT
Waardenburg (WS1) PAX3 Major diagnostic criteria include dystopia canthorum, congenital hearing loss,
heterochromic irises, white forelock, and an affected 1st-degree relative. Approximately
60% of affected children have congenital hearing loss; in 90%, the loss is bilateral.
Waardenburg (WS2) MITF, others Major diagnostic criteria are as for WS1 but without dystopia canthorum. Approximately
80% of affected children have congenital hearing loss; in 90%, the loss is bilateral.
Branchiootorenal EYA1 Diagnostic criteria include hearing loss (98%), preauricular pits (85%), and branchial
(70%), renal (40%), and external-ear (30%) abnormalities. The hearing loss can be
conductive, sensorineural, or mixed, and mild to profound in degree.
CHARGE syndrome CHD7 Choanal atresia, colobomas, heart defect, retardation, genital hypoplasia, ear anomalies,
deafness. Can lead to sensorineural or mixed hearing loss. Can be autosomal
dominant or isolated cases.
Goldenhar Unknown Part of the hemifacial microsomia spectrum. Facial hypoplasia, ear anomalies,
syndrome hemivertebrae, parotid gland dysfunction. Can cause conductive or mixed hearing loss.
Can be autosomal dominant or sporadic.
RECESSIVE
Pendred syndrome SLC26A4 Diagnostic criteria include sensorineural hearing loss that is congenital, nonprogressive,
and severe to profound in many cases, but can be late-onset and progressive; bilateral
dilation of the vestibular aqueduct with or without cochlear hypoplasia; and an
abnormal perchlorate discharge test or goiter.
Alport syndrome COL4A3, COL4A4, and Nephritis, deafness, lens defects, retinitis. Can lead to bilateral sensorineural hearing
COL4A5 loss in the 2,000-8,000 Hz range. The hearing loss develops gradually and is not
generally present in early infancy.
Usher syndrome USH1A, MYO7A, USH1C, Diagnostic criteria include congenital, bilateral, and profound hearing loss, vestibular
type 1 (USH1) CDH23, USH1E, areflexia, and retinitis pigmentosa (commonly not diagnosed until tunnel vision and
PCDH15, USH1G nyctalopia become severe enough to be noticeable).
Usher syndrome USH2A, USH2B, USH2C, Diagnostic criteria include mild to severe, congenital, bilateral hearing loss and retinitis
type 2 (USH2) others pigmentosa; hearing loss may be perceived as progressing over time because speech
perception decreases as diminishing vision interferes with subconscious lip reading.
Usher syndrome USH3 Diagnostic criteria include postlingual, progressive sensorineural hearing loss, late-onset
type 3 (USH3) retinitis pigmentosa, and variable impairment of vestibular function.
Adapted from Smith RJH, Bale JF Jr, White KR: Sensorineural hearing loss in children, Lancet 365:879–890, 2005.
branchiootorenal syndromes represent 2 of the most common autoso-

Table 637-4 Infectious Pathogens Implicated in mal dominant syndromic types of SNHL. Types of SNHL are coded
Sensorineural Hearing Loss in Children with a 4 letter code and a number, as follows: DFN = deafness, A =
CONGENITAL INFECTIONS dominant, B = recessive, and number = order of discovery, for example,
Cytomegalovirus DFNA 13. Autosomal dominant conditions in addition to those just
Lymphocytic choriomeningitis virus discussed include DFNA 1-18, 20-25, 30, 36, 38, and mutations in the
Rubella virus crystallin gene (CRYM).
Toxoplasma gondii Autosomal recessive genetic SNHL, both syndromic and nonsyn-
Treponema pallidum dromic, accounts for approximately 80% of all childhood cases of
ACQUIRED INFECTIONS SNHL. Usher syndrome (types 1, 2, and 3: all associated with blindness,
Borrelia burgdorferi retinitis pigmentosa), Pendred syndrome, and the Jervell and Lange-
Epstein-Barr virus Nielsen syndrome (one form of the long Q-T syndrome) are 3 of the
Haemophilus influenzae most common syndromic recessive types of SNHL. Other autosomal
Lassa virus recessive conditions include Alström syndrome, type 4 Bartter syn-
Measles virus drome, biotinidase deficiency, and DFNB 1-18, 20-23, 26-27, 29-33,
Mumps virus 35-40, 42, 44, 46, 48, 49, 53, and 55.
Neisseria meningitidis
Unlike children with an easily identified syndrome or with anoma-
Nonpolio enteroviruses
Plasmodium falciparum lies of the outer ear, who may be identified as being at risk for hearing
Streptococcus pneumoniae loss and consequently monitored adequately, children with nonsyn-
Varicella-zoster virus dromic hearing loss present greater diagnostic difficulty. Mutations of
the connexin-26 and -30 genes have been identified in autosomal
From Smith RJH, Bale JF Jr, White KR: Sensorineural hearing loss in children,
Lancet 365:879–890, 2005.
recessive (DNFB 1) and autosomal dominant (DNFA 3) SNHL and in
sporadic patients with nonsyndromic SNHL; up to 50% of nonsyn-
dromic SNHLs may be related to a mutation of connexin-26. Muta-
tions of the GJB2 gene colocalize with DFNA 3 and DFNB 1 loci on
it may be associated with tinnitus and vertigo. Identifiable causes of chromosome 13, are associated with autosomal nonsyndromic suscep-
sudden SNHL include infections (Epstein-Barr virus, varicella-zoster tibility to deafness, and are associated with as many as 30% of cases of
virus, herpes simplex virus), vascular injury to the cochlea, endolym- sporadic severe to profound congenital deafness and 50% of cases of
phatic hydrops, and autoimmune inflammatory diseases. In most autosomal recessive nonsyndromic deafness. In addition, mutations in
patients with sudden SNHL, no etiology is discovered, and it is termed GJB6 are associated with approximately 5% of recessive nonsyndromic
idiopathic sudden SNHL. deafness. Sex-linked disorders associated with SNHL, thought to
account for 1-2% of SNHLs, include Norrie disease, the otopalatal
Infectious Causes digital syndrome, Nance deafness, and Alport syndrome. Chromo-
The most common infectious cause of congenital SNHL is cytomega- somal abnormalities such as trisomy 13-15, trisomy 18, and trisomy
lovirus (CMV), which infects 1 in 100 newborns in the United States 21 also can be accompanied by hearing impairment. Patients with
(see Chapters 255 and 638). Of these, 6,000-8,000 infants each yr Turner syndrome have monosomy for all or part of 1 X chromosome
have clinical manifestations, including approximately 75% with SNHL. and can have CHL, SNHL, or mixed hearing loss. The hearing loss may
Congenital CMV warrants special attention because it is associated be progressive. Mitochondrial genetic abnormalities also can result in
with hearing loss in its symptomatic and asymptomatic forms, and the SNHL (see Table 637-2).
hearing loss may be progressive. Some children with congenital CMV Many genetically determined causes of hearing impairment, both
have suddenly lost residual hearing at 4-5 yr of age. Much less common syndromic and nonsyndromic, do not express themselves until some-
congenital infectious causes of SNHL include toxoplasmosis and syphi- time after birth. Alport, Alström, Down, and Hunter-Hurler syn-
lis. Congenital CMV, toxoplasmosis, and syphilis also can manifest dromes and von Recklinghausen disease are genetic diseases that can
with delayed onset of SNHL months to years after birth. Rubella, once have SNHL as a late manifestation.
the most common viral cause of congenital SNHL, is very uncommon
because of effective vaccination programs. In utero infection with Physical Causes
herpes simplex virus is rare, and hearing loss is not an isolated Agenesis or malformation of cochlear structures, including the Scheibe,
manifestation. Mondini (Fig. 637-1), Alexander, and Michel anomalies, enlarged ves-
Other postnatal infectious causes of SNHL include neonatal group tibular aqueducts (which may be associated with Pendred syndrome),
B streptococcal sepsis and bacterial meningitis at any age. Streptococcus and semicircular canal anomalies, may be genetic. These anomalies
pneumoniae is the most common cause of bacterial meningitis that probably occur before the 8th wk of gestation and result from arrest in
results in SNHL after the neonatal period and has become less common normal development or aberrant development, or both. Many of these
with the routine administration of pneumococcal conjugate vaccine. anomalies also have been described in association with other congeni-
Haemophilus influenzae type b, once the most common cause of mental conditions such as intrauterine CMV and rubella infections. These
ingitis resulting in SNHL, is rare owing to the H. influenzae type b abnormalities are quite common; in as many as 20% of children with
conjugate vaccine. Uncommon infectious causes of SNHL include SNHL, obvious or subtle temporal bone abnormalities are seen on
Lyme disease, parvovirus B19, and varicella. Mumps, rubella, and high-resolution CT scanning or MRI.
rubeola, all once common causes of SNHL in children, are rare owing Conditions, diseases, or syndromes that include craniofacial abnor-
to vaccination programs. malities may be associated with CHL and possibly with SNHL. Pierre
Robin, Treacher Collins, Klippel-Feil, Crouzon, and branchiootorenal
Genetic Causes syndromes and osteogenesis imperfecta often are associated with
Genetic causes of SNHL probably are responsible for as many as 50% hearing loss. Congenital anomalies causing CHL include malforma-
of SNHL cases (see Tables 637-2 and 637-3). These disorders may be tions of the ossicles and middle-ear structures and atresia of the exter-
associated with other abnormalities, may be part of a named syndrome, nal auditory canal.
or can exist in isolation. SNHL often occurs with abnormalities of the SNHL also can occur secondary to exposure to toxins, chemicals,
ear and eye and with disorders of the metabolic, musculoskeletal, and antimicrobials. Early in pregnancy, the embryo is particularly vul-
integumentary, renal, and nervous systems. nerable to the effects of toxic substances. Ototoxic drugs, including
Autosomal dominant hearing losses account for approximately aminoglycosides, loop diuretics, and chemotherapeutic agents (cispla-
10% of all cases of childhood SNHL. Waardenburg (types I and II) and tin) also can cause SNHL. Congenital SNHL can occur secondary to
classes or schools for children with special needs. The auditory man-
agement and choices regarding modes of communication and educa-
tion for children with hearing handicaps must be individualized,
Cochlear because these children are not a homogeneous group. A team approach
dysplasia to individual case management is essential, because each child and
family unit has unique needs and abilities.
Mondini HEARING SCREENING

* dysplasia Hearing impairment can have a major impact on a child’s development,
and because early identification improves prognosis, screening pro-
Dilated
grams have been widely and strongly advocated. The National Center
vestibular for Hearing Assessment and Management estimates that the detection
aqueduct and treatment at birth of hearing loss saves $400,000 per child in
special education costs; screening costs approximately $8-50/child.
Data from the Colorado newborn screening program suggest that if
hearing-impaired infants are identified and treated by age 6 mo, these
children (with the exception of those with bilateral profound impair-
ment) should develop the same level of language as their age-matched
Figure 637-1 Mondini dysplasia shown by CT of the temporal bone peers who are not hearing impaired. This is compelling support for the
in a child with Pendred syndrome. Both dilation of the vestibular aque- establishment of mandated newborn hearing screening programs for
duct and cochlear dysplasia are present in this section. In the larger of all children. The American Academy of Pediatrics endorses the goal of
the 2 inset images of a normal temporal bone, the vestibular aqueduct
universal detection of hearing loss in infants before 3 mo of age, with
is visible but much smaller (arrow). The cochlea appears normal, and
in the smaller inset image of a more inferior axial section, the expected appropriate intervention no later than 6 mo of age. Newborn screening
number of cochlear turns can be clearly counted. *Internal auditory rates in the United States have increased significantly; the Centers for
canal. (From Smith RJH, Bale JF Jr, White KR: Sensorineural hearing Disease Control and Prevention estimates that of the approximately 4
loss in children, Lancet 365:879–890, 2005.) million infants born in the United States in 2009, 97% were screened
for hearing loss.
Until mandated screening programs are established universally,
exposure to these drugs as well as to thalidomide and retinoids. Certain many hospitals will continue to use other criteria to screen for hearing
chemicals, such as quinine, lead, and arsenic, can cause hearing loss loss. Some use the high-risk criteria (see Table 637-1) to decide which
both prenatally and postnatally. infants to screen; some screen all infants who require intensive care;
Trauma, including temporal bone fractures, inner ear concussion, and some do both. The problem with using high-risk criteria to screen
head trauma, iatrogenic trauma (e.g., surgery, extracorporeal mem- is that 50% of cases of hearing impairment will be missed, either
brane oxygenation), radiation exposure, and noise, also can cause because the infants are hearing impaired but do not meet any of the
SNHL. Other uncommon causes of SNHL in children include immune high-risk criteria or because they develop hearing loss after the neona-
disease (systemic or limited to the inner ear), metabolic abnormalities, tal period.
and neoplasms of the temporal bone. The recommended hearing screening techniques are either oto-
acoustic emissions (OAE) testing or auditory brainstem evoked
EFFECTS OF HEARING IMPAIRMENT responses (ABRs). The ABR test, an auditory evoked electrophysiologic
The effects of hearing impairment depend on the nature and degree of response that correlates highly with hearing, has been used successfully
the hearing loss and on the individual characteristics of the child. and cost-effectively to screen newborns and to identify further the
Hearing loss may be unilateral or bilateral, conductive, sensorineural, degree and type of hearing loss. OAE tests, used successfully in most
or mixed; mild, moderate, severe, or profound; of sudden or gradual universal newborn screening programs, are quick, easy to administer,
onset; stable, progressive, or fluctuating; and affecting a part or all and inexpensive, and they provide a sensitive indication of the presence
of the audible spectrum. Other factors, such as intelligence, medical of hearing loss. Results are relatively easy to interpret. OAE tests elicit
or physical condition (including accompanying syndromes), family no response if hearing is worse than 30-40 dB, no matter what the
support, age at onset, age at time of identification, and promptness of cause; children who fail OAE tests undergo an ABR for a more defini-
intervention, also affect the impact of hearing loss on a child. tive evaluation. Screening methods such as observing behavioral
Most hearing-impaired children have some usable hearing. Only 6% responses to uncalibrated noisemakers or using automated systems
of those in the hearing-impaired population have bilateral profound such as the Crib-o-gram (Canon) or the auditory response cradle (in
hearing loss. Hearing loss very early in life can affect the development which movement of the infant in response to sound is recorded by
of speech and language, social and emotional development, behavior, motion sensors) are not recommended.
attention, and academic achievement. Some cases of hearing impair- Many children become hearing impaired after the neonatal period
ment are misdiagnosed because affected children have sufficient and therefore are not identified by newborn screening programs.
hearing to respond to environmental sounds and can learn some Often it is not until children are in preschool or kindergarten that
speech and language but when challenged in the classroom cannot further hearing screening takes place. Primary care physicians and
perform to full potential. pediatricians should be alert to the signs and symptoms of childhood
Even mild or unilateral hearing loss can have a detrimental effect on hearing impairment, so that children with hearing impairment
the development of a young child and on school performance. Chil- who have not been screened formally can be identified as early as
dren with such hearing impairments have greater difficulty when lis- possible. Figure 637-2 identifies recommendations for postneonatal
tening conditions are unfavorable (e.g., background noise and poor screening.
acoustics), as can occur in a classroom. The fact that schools are
auditory-verbal environments is unappreciated by those who minimize IDENTIFICATION OF HEARING IMPAIRMENT
the impact of hearing impairment on learning. Hearing loss should The impact of hearing impairment is greatest on an infant who has yet
be considered in any child with speech and language difficulties to develop language; consequently, identification, diagnosis, descrip-
or below-par performance, poor behavior, or inattention in school tion, and treatment should begin as soon as possible. In general, infants
(Table 637-5). with a prenatal or perinatal history that puts them at risk (see Table
Children with moderate, severe, or profound hearing impairment 637-2) or those who have failed a formal hearing screening should be
and those with other handicapping conditions often are educated in monitored closely by an experienced clinical audiologist until a reliable
assessment of auditory function has been obtained. Pediatricians Hearing-impaired infants, who are born at risk or are screened for
should encourage families to cooperate with the follow-up plan. Infants hearing loss in a neonatal hearing screening program, account for only
who are born at risk but who were not screened as neonates (often a portion of hearing-impaired children. Children who are congenitally
because of transfer from one hospital to another) should have a hearing deaf because of autosomal recessive inheritance or subclinical congeni-
screening by age 3 mo. tal infection often are not identified until 1-3 yr of age. Usually, those
Table 637-5 Hearing Handicap as a Function of Average Hearing Threshold Level of the Better Ear
AVERAGE
THRESHOLD DEGREE OF
LEVEL (dB) AT WHAT CAN BE HANDICAP (IF NOT
500-2,000 Hz HEARD WITHOUT TREATED IN 1ST YR
(ANSI) DESCRIPTION COMMON CAUSES AMPLIFICATION OF LIFE) PROBABLE NEEDS
0-15 Normal range Conductive hearing loss All speech sounds None None
16-25 Slight hearing Otitis media, TM Vowel sounds heard Mild auditory Consideration of need
loss perforation, clearly, may miss dysfunction in for hearing aid,
tympanosclerosis; unvoiced language learning speech reading,
eustachian tube consonant sounds Difficulty in perceiving auditory training,
dysfunction; some some speech sounds speech therapy,
SNHL appropriate surgery,
preferential seating
26-30 Mild Otitis media, TM Hears only some Auditory learning Hearing aid
perforation, speech sounds, the dysfunction Lip reading
tympanosclerosis, louder voiced Mild language Auditory training
severe eustachian sounds retardation Speech therapy
dysfunction, SNHL Mild speech problems Appropriate surgery
Inattention
31-50 Moderate Chronic otitis, ear Misses most speech Speech problems All of the above, plus
hearing loss canal/middle ear sounds at normal Language retardation consideration of
anomaly, SNHL conversational level Learning dysfunction special classroom
Inattention situation
51-70 Severe hearing SNHL or mixed loss Hears no speech Severe speech problems All of the above;
loss due to a combination sound of normal Language retardation probable assignment
of middle-ear disease conversations Learning dysfunction to special classes
and sensorineural Inattention
involvement
71+ Profound SNHL or mixed Hears no speech or Severe speech problems All of the above;
hearing loss other sounds Language retardation probable assignment
Learning dysfunction to special classes or
Inattention schools
ANSI, American National Standards Institute; SNHL, sensorineural hearing loss; TM, tympanic membrane.
Modified from Northern JL, Downs MP: Hearing in children, ed 4, Baltimore, 1991, Williams & Wilkins.
Objective screens scheduled at:

Newborn and 4, 5, 6, 8,
10, 12, 15, and 18 yr
Office visit
Visit with
Yes Abnormal Referral to
scheduled Objective Screen
audiology and
objective screen results?
speech evaluation
screen?
No Normal
Otolaryngology,
Risk Ongoing risk
genetics, ENT,
assessment (e.g., CMV or Evaluation Abnormal
speech referral
Risk other high-risk results?
for diagnostic
Table 629-1 present diagnoses)
testing
No risk No Yes Normal
Schedule early
Stop return
(~6 mo)
Figure 637-2 Hearing-assessment algorithm within an office visit. CMV, cytomegalovirus; ENT, ear, nose, and throat. (From Harlor AD Jr, Bower
C: Clinical report—hearing assessment in infants and children: recommendations beyond neonatal screening, Pediatrics 124:1252–1263, 2009,
Fig. 1, p. 1254.)
PURE-TONE AUDIOGRAM
Table 637-6 Criteria for Referral for Audiologic Frequency (cycles/sec)
Assessment
125 250 500 1000 2000 4000 8000
REFERRAL GUIDELINES FOR CHILDREN
AGE (mo) WITH “SPEECH” DELAY 10
12 No differentiated babbling or vocal imitation 0

18 No use of single words 10
24 Single-word vocabulary of ≤10 words
20
30 <100 words; no evidence of 2 word combinations;
unintelligible 30
36 <200 words; no use of telegraphic sentences; clarity 40

<50%
50
48 <600 words; no use of simple sentences; clarity ≤80%
From Matkin ND: Early recognition and referral of hearing-impaired children, 60
Pediatr Rev 6:151–156, 1984. Reproduced by permission of Pediatrics.
70
80
Table 637-7 Guidelines for Referral of Children with 90

Suspected Hearing Loss
100
AGE (mo) NORMAL DEVELOPMENT
110
0-4 Should startle to loud sounds, quiet to mother’s
voice, momentarily cease activity when sound is AUDIOGRAM KEY
presented at a conversational level Air Bone
5-6 Should correctly localize to sound presented in a Right
horizontal plane, begin to imitate sounds in own Left
speech repertoire or at least reciprocally vocalize
with an adult Figure 637-3 Audiogram showing bilateral conductive hearing loss.
7-12 Should correctly localize to sound presented in any
plane
Should respond to name, even when spoken quietly Therapy for hearing-impaired children includes considering and often
13-15 Should point toward an unexpected sound or to fitting an amplification device, using a frequency modulation system
familiar objects or persons when asked in the classroom, monitoring hearing and auditory skills, counseling
parents and families, advising teachers, and dealing with public
16-18 Should follow simple directions without gestural or agencies.
other visual cues; can be trained to reach toward
an interesting toy at midline when a sound is
presented Audiometry
The technique of the audiologic evaluation varies as a function of the
19-24 Should point to body parts when asked; by age or developmental level of the child, the reason for the evaluation,
21-24 mo, can be trained to perform play and the child’s otologic condition or history. An audiogram provides
audiometry
the fundamental description of hearing sensitivity (Fig. 637-3). Hearing
From Matkin ND: Early recognition and referral of hearing-impaired children, thresholds are assessed as a function of frequency using pure tones
Pediatr Rev 6:151–156, 1984. (sine waves) at octave intervals from 250-8,000 Hz. Earphones typi-
cally are used when age-appropriate, and hearing is assessed indepen-
dently for each ear. Air-conducted signals are presented through
with more-severe hearing loss are identified at an earlier age, but iden- earphones (or loudspeakers) and are used to provide information
tification often occurs later than the age at which intervention can about the sensitivity of the auditory system. These same test sounds
provide an optimal outcome. Children who hear normally develop an can be delivered to the ear through an oscillator that is placed on the
extensive language by 3-4 yr of age (Table 637-6) and exhibit behavior head, usually on the mastoid. Such signals are considered bone-
reflecting normal auditory function (Table 637-7). Failure to fulfill conducted because the bones of the skull transmit vibrations as sound
these criteria should be the reason for an audiologic evaluation. Parents’ energy directly to the inner ear, essentially bypassing the outer and
concern about hearing and any delayed development of speech and middle ears. In a normal ear, and also in children with SNHL, the air-
language should alert the pediatrician, because parents’ concern and bone-conduction thresholds are the same. In those with CHL, the
usually precedes formal identification and diagnosis of hearing impair- air- and bone-conduction thresholds differ. This is called the air–bone
ment by 6 mo to 1 yr of age. gap, which indicates the amount of hearing loss attributable to dys-
function in the outer and/or middle ear. With mixed hearing loss, both
CLINICAL AUDIOLOGIC EVALUATION the bone- and air-conduction thresholds are abnormal, and there is an
Even the youngest infants can be evaluated for auditory function. air–bone gap.
When hearing impairment is suspected in a young child, reliable and
valid estimates of auditory function can be obtained. Successful treat- Speech-Recognition Threshold
ment strategies for hearing-impaired children rely on prompt identifi- Another measure useful for describing auditory function is the speech-
cation and ongoing assessment to define the dimensions of auditory recognition threshold (SRT), which is the lowest intensity level at
function. Cooperation among the pediatrician and specialists in areas which a score of approximately 50% correct is obtained on a task of
such as audiology, speech and language pathology, education, and child recognizing spondee words. Spondee words are 2 syllable words or
development is necessary to optimize auditory-verbal development. phrases that have equal stress on each syllable, such as baseball, hotdog,
and pancake. Listeners must be familiar with all the words for a valid A probe is inserted into the entrance of the external ear canal so that
test result to be obtained. The SRT should correspond to the average an airtight seal is obtained. The probe varies air pressure, presents a
of pure-tone thresholds at 500, 1,000, and 2,000 Hz, the pure-tone tone, and measures sound pressure level in the ear canal through the
average. The SRT is relevant as an indicator of a child’s potential for probe assembly. The sound pressure measured in the ear canal relative
development and use of speech and language; it also serves as a check to the known intensity of the probe signal is used to estimate the
of the validity of a test because children with nonorganic hearing loss acoustic admittance of the ear canal and middle-ear system. Admit-
(malingerers) might show a discrepancy between the pure-tone average tance can be expressed in a unit called a millimho (mmho) or as a
and SRT. volume of air (mL) with equivalent acoustic admittance. The test is
The basic battery of hearing tests concludes with an assessment of a performed so that an estimate can be made of the volume of air
child’s ability to understand monosyllabic words when presented at a enclosed between the probe tip and TM. The acoustic admittance of
comfortable listening level. Performance on such word intelligibility this volume of air is deducted from the overall admittance measure to
tests assists in the differential diagnosis of hearing impairment and obtain a measure of the admittance of the middle-ear system alone.
provides a measure of how well a child performs when speech is pre- Estimating ear canal volume also has a diagnostic benefit, because an
sented at loudness levels similar to those encountered in the abnormally large value is consistent with the presence of an opening
environment. in the TM (perforation or tube).
Once the admittance of the air mass in the external auditory canal
Play Audiometry has been eliminated, it is assumed that the remaining admittance
Hearing testing is age dependent. For children at or above the devel- measure accurately reflects the admittance of the entire middle-ear
opmental level of a 5-6 yr old, conventional test methods can be used. system. Its value is controlled largely by the dynamics of the TM.
For children 30 mo to 5 yr of age, play audiometry can be used. Abnormalities of the TM can dictate the shape of tympanograms, thus
Responses in play audiometry usually are conditioned motor activities obscuring abnormalities medial to the TM. In addition, the frequency
associated with a game, such as dropping blocks in a bucket, placing of the probe tone, the speed and direction of the air pressure change,
rings on a peg, or completing a puzzle. The technique can be used to and the air pressure at which the tympanogram is initiated can all
obtain a reliable audiogram for a preschool child. For those who will influence the outcome.
not or cannot repeat words clearly for the SRT and word intelligibility When air pressure in the ear canal is equal to that in the middle
tasks, pictures can be used with a pointing response. ear, the middle-ear system is functioning optimally. Therefore, the ear
canal pressure at which there is the greatest flow of energy (admit-
Visual Reinforcement Audiometry tance) should be a reasonable estimate of the air pressure in the
For children between the ages of about 6 mo and 30 mo, visual rein- middle-ear space. This pressure is determined by finding the
forcement audiometry (VRA) commonly is used. In this technique, maximum or peak admittance on the tympanogram and obtaining
the child is observed for a head-turning response on activation of an its value on the x-axis. The value on the y-axis at the tympanogram
animated (mechanical) toy reinforcer. If infants are properly condi- peak is an estimate of peak admittance based on admittance tympa-
tioned, by giving sounds associated with the visual toy cue, VRA can nometry (Table 637-8). This peak measure sometimes is referred to
provide reliable estimates of hearing sensitivity for tones and speech as static acoustic admittance, even though it is estimated from a
sounds. In most applications of VRA, sounds are presented by loud- dynamic measure.
speakers in a sound field, so no ear-specific information is obtained.
Assessment of an infant often is designed to rule out hearing loss that Tympanometry in Otitis Media with Effusion
would affect the development of speech and language. Normal sound- Children who have OM with effusion often have reduced peak admit-
field response levels of infants indicate sufficient hearing for this tance or high negative tympanometric peak pressures (see Fig. 640-5C
purpose despite the possibility of different hearing levels in the 2 ears. in Chapter 640). However, in the diagnosis of effusion, the tympano-
metric measure with the greatest sensitivity and specificity is the shape
Behavioral Observation Audiometry of the tympanogram rather than its peak pressure or admittance. This
Used as a screening device for infants <5 mo of age, behavioral obser- shape sometimes is referred to as the tympanometric gradient or
vation audiometry is limited to unconditioned, reflexive responses to width; it measures the degree of roundness or peakedness of the tym-
complex (not frequency-specific) test sounds such as noise, speech, or panogram. The more rounded the peak (or, in an absent peak, a flat
music presented using calibrated signals from a loudspeaker or uncali-
brated noisemakers. Response levels can vary widely within and among
infants and usually do not provide a reliable estimate of sensitivity.
Assessment of a child with suspected hearing loss is not complete
until pure-tone hearing thresholds and SRTs (a reliable audiogram) Table 637-8 Norms for Peak (Static) Admittance Using
have been obtained in each ear. Behavioral observation audiometry a 226-Hz Probe Tone for Children and
and VRA in sound-field testing give estimates of hearing responsivity Adults
in the better-hearing ear.
Speed of Air Pressure Sweep
AGE ADMITTANCE
Acoustic Immittance Testing GROUP (mL) ≤50 daPa/sec* 200 daPa/sec†
Acoustic immittance testing is a standard part of the clinical audiologic
test battery and includes tympanometry. It is a useful objective assess- Children Lower limit 0.30 0.36
ment technique that provides information about the status of the (3-5 yr) Median 0.55 0.61
middle ear. Tympanometry can be performed in a physician’s office and Upper limit 0.90 1.06
is helpful in the diagnosis and management of OM with effusion, a Adults Lower limit 0.56 0.27
common cause of mild to moderate hearing loss in young children. Median 0.85 0.72
Upper limit 1.36 1.38
Tympanometry *Ear canal volume measurement based on admittance at lowest tail of
Tympanometry provides a graph of the middle ear’s ability to transmit tympanogram.
sound energy (admittance, or compliance) or impede sound energy †
Ear canal measurement based on admittance at lowest tail of tympanogram
(impedance) as a function of air pressure in the external ear canal. for children and at +200 daPa for adults.
daPa, decaPascals.
Because most immittance test instruments measure acoustic admit- Adapted from Margolis RH, Shanks JE: Tympanometry: basic principles of
tance, the term admittance is used here. The principles apply to what- clinical application. In Rintelman WS, editor: Hearing assessment, ed 2, Austin,
ever units of measurement are used. 1991, PRODED, pp. 179–245.
tympanogram), the higher is the probability that an effusion is present The ABR test does not assess “hearing.” It reflects auditory neuronal
(see Fig. 640-5B in Chapter 640). It is important to know which instru- electrical responses that can be correlated to behavioral hearing thresh-
ment is used, because some compute gradient automatically but others olds, but a normal ABR result only suggests that the auditory system,
do not. up to the level of the midbrain, is responsive to the stimulus used.
Conversely, a failure to elicit an ABR indicates an impairment of the
Acoustic Reflex Test system’s synchronous response but does not necessarily mean that
The acoustic reflex test also is part of the immittance test battery. With there is no “hearing.” The behavioral response to sound sometimes
a properly functioning middle-ear system, admittance at the TM is normal when no ABR can be elicited, such as in neurologic demy-
changes on activation of the stapedius and tensor tympani muscles. In elinating disease. The ABR test may be used to infer whether and at
healthy ears, the stapedial reflex occurs after exposure to loud sounds. what level of the auditory system impairment exists.
Admittance instruments are designed to present reflex activating Hearing losses that are sudden, progressive, or unilateral are indica-
signals (pure tones of various frequencies or noise), either to the same tions for ABR testing. Although it is believed that the different waves
ear or the contralateral ear, while monitoring admittance. Very small of the ABR reflect activity in increasingly rostral levels of the auditory
admittance changes that are time locked to presentations of the signal system, the neural generators of the response have not been precisely
are considered to be a result of middle-ear muscle reflexes. Admittance determined. Each ABR wave beyond the earliest waves probably is the
changes may be absent when the hearing loss is sufficient to prevent result of neural firing at many levels of the system, and each level of
the signal from reaching the loudness level necessary to elicit the reflex the system probably contributes to several ABR waves. High-intensity
or when a middle-ear condition affects the ear’s ability to monitor a click stimuli are used for the neurologic application. The morphology
small admittance change. Reflexes usually are absent in patients with of the response and wave and interwave latencies are examined in
CHL because of the presence of an abnormal transfer system; thus, the respect to age-appropriate forms. Delayed or missing waves in the ABR
acoustic reflex test is useful in the differential diagnosis of hearing result often have diagnostic significance.
impairment. The acoustic reflex test also is used in the assessment of The ABR and other electrical responses are extremely complex and
SNHL and the integrity of the neurologic components of the reflex arc, difficult to interpret. A number of factors, including instrumentation
including cranial nerves VII and VIII. design and settings, environment, degree and configuration of hearing
loss, and patients’ characteristics, can influence the quality of the
Auditory Brainstem Response recording. Therefore, testing and interpretation of electrophysiologic
The auditory brainstem response (ABR) test is used to screen newborn activity as it possibly relates to hearing should be carried out by trained
hearing, confirm hearing loss in young children, obtain ear-specific audiologists to avoid the risk that unreliable or erroneous conclusions
information in young children, and test children who cannot, for what- will affect a patient’s care.
ever reason, cooperate with behavioral test methods. It also is impor-
tant in the diagnosis of auditory dysfunction and of disorders of the Otoacoustic Emissions
auditory nervous system. The ABR test is a far-field recording of During normal hearing, OAEs originate from the hair cells in the
minute electrical discharges from numerous neurons. The stimulus, cochlea and are detected by sensitive amplifying processes. They travel
therefore, must be able to cause simultaneous discharge of the large from the cochlea through the middle ear to the external auditory canal,
numbers of neurons involved. Stimuli with very rapid onset, such as where they can be detected using miniature microphones. Transient
clicks or tone bursts, must be used. Unfortunately, the rapid onset evoked OAEs (TEOAEs) may be used to check the integrity of the
required to create a measurable ABR also causes energy to be spread cochlea. In the neonatal period, detection of OAEs can be accom-
in the frequency domain, reducing the frequency-specificity of the plished during natural sleep, and TEOAEs can be used as screening
response. tests in infants and children for hearing at the 30 dB level of hearing
The ABR result is not affected by sedation or general anesthesia. loss. They are less time consuming and elaborate than ABRs and are
Infants and children from about 4 mo to 4 yr of age routinely are more sensitive than behavioral tests in young children. TEOAEs are
sedated to minimize electrical interference caused by muscle activity reduced or absent owing to various dysfunctions in the middle and
during testing. The ABR also can be performed in the operating room inner ears. They are absent in patients with >30 dB of hearing loss and
when a child is anesthetized for another procedure. Children younger are not used to determine the hearing threshold; rather, they provide
than 4 mo of age might sleep for a long enough period of time after a screen for whether hearing is present at >30-40 dB. Diseases such as
feeding to allow an ABR to be done. OM or congenitally abnormal middle-ear structures reduce the trans-
The ABR is recorded as 5-7 waves. Waves I, III, and V can be fer of TEOAEs and may incorrectly indicate a cochlear hearing disor-
obtained consistently in all age groups; waves II and IV appear less der. If a hearing loss is suspected based on the absence of OAEs, the
consistently. The latency of each wave (time of occurrence of the wave ears should be examined for evidence of pathology, and then ABR
peak after stimulus onset) increases, and the amplitude decreases with testing should be used for confirmation and identification of the type,
reductions in stimulus intensity or loudness; latency also decreases degree, and laterality of hearing loss.
with increasing age, with the earliest waves reaching mature latency
values earlier in life than the later waves. Acoustic Reflectometry
The ABR test has 2 major uses in a pediatric setting. As an audio- In acoustic reflectometry, a handheld instrument is placed next to
metric test, it provides information on the ability of the peripheral the opening of a child’s ear canal and an 80 dB sound is delivered
auditory system to transmit information to the auditory nerve and that varies in frequency from 2,000-4,500 Hz in a 100 msec period.
beyond. It also is used in the differential diagnosis or monitoring of The instrument measures the total level of reflected and transmitted
central nervous system pathology. For audiometry, the goal is to find sound. Some physicians have found this device useful to help gauge
the minimum stimulus intensity that yields an observable ABR. Plot- the presence or absence of middle-ear fluid, and a commercial
ting latency vs intensity for various waves also aids in the differential version is marketed to parents as a way to monitor ear fluid. The
diagnosis of hearing impairment. A major advantage of auditory instrument does not provide any information about hearing; if the
assessment using the ABR test is that ear-specific threshold estimates presence of chronic fluid is suggested, audiometric evaluation should
can be obtained on infants or patients who are difficult to test. ABR be obtained.
thresholds using click stimuli correlate best with behavioral hearing
thresholds in the higher frequencies (1,000-4,000 Hz); responsivity in TREATMENT
the low frequencies requires different stimuli (tone bursts or filtered With the use of universal hearing screening in the majority of states
clicks) or the use of masking, neither of which isolates the low- within the United States, the early diagnosis and treatment of children
frequency region of the cochlea in all cases, and this can affect with hearing loss is common. Testing for hearing loss is possible even
interpretation. in very young children, and it should be done if parents suspect a
Table 637-9 Recommended Pneumococcal Vaccination Schedule for Persons with Cochlear Implants
AGE AT FIRST PCV13 DOSE (mo)* PCV12 PRIMARY SERIES PCV13 ADDITIONAL DOSE PPV23 DOSE
2-6 3 doses, 2 mo apart† 1 dose at 12-15 mo of age‡ Indicated at ≥24 mo of age§
7-11 2 doses, 2 mo apart† 1 dose at 12-15 mo of age‡ Indicated at ≥24 mo of age§
12-23 2 doses, 2 mo apart ¶
Not indicated Indicated at ≥24 mo of age§
24-59 2 doses, 2 mo apart¶ Not indicated Indicated§
≥60 Not indicated |
Not indicated |
Indicated
*A schedule with a reduced number of total 13-valent pneumococcal conjugate vaccine (PCV13) doses is indicated if children start late or are incompletely
vaccinated. Children with a lapse in vaccination should be vaccinated according to the catch-up schedule (see Chapter 182).
†
For children vaccinated at younger than age 1 yr, minimum interval between doses is 4 wk.
‡
The additional dose should be administered 8 wk or more after the primary series has been completed.
§
Children younger than age 5 yr should complete the PCV13 series first; 23-valent pneumococcal polysaccharide vaccine (PPV23) should be administered to children
24 mo of age or older 8 wk or more after the last dose of PCV13 (see Chapter 182). (Centers for Disease Control and Prevention Advisory Committee on
Immunization Practices: Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization
Practices [ACIP], MMWR Recomm Rep 49[RR-9]:1–35, 2000, and Licensure of a 13-valent pneumococcal conjugate vaccine [PCV13] and recommendations for use
among children—Advisory Committee on Immunization Practices [ACIP], 2010, MMWR Morb Mortal Wkly Rep 59(9);258–261, 2010.)
¶
Minimum interval between doses is 8 wk.
|
PCV13 is not recommended generally for children age 5 yr or older.
PCV, pneumococcal conjugate vaccine; PPV, pneumococcal polysaccharide vaccine.
From Centers for Disease Control and Prevention Advisory Committee on Immunization Practices: Pneumococcal vaccination for cochlear implant candidates and
recipients: Updated recommendations of the Advisory Committee on Immunization Practices, MMWR Morb Mortal Wkly Rep 52(31):739–740, 2003.
problem. Any child with a known risk factor for hearing loss should
be evaluated in the 1st 6 mo of life.
Once a hearing loss is identified, a full developmental and speech
and language evaluation is needed. Counseling and involvement of
parents are required in all stages of the evaluation and treatment or
rehabilitation. A CHL often can be corrected through treatment of a
middle-ear effusion (i.e., ear tube placement) or surgical correction of
the abnormal sound-conducting mechanism. Children with SNHL
should be evaluated for possible hearing aid use by a pediatric audiolo-
gist. Hearing aids may be fitted for children as young as 2 mo of age.
Compelling evidence from the hearing screening program in Colorado
shows that identification and amplification before age 6 mo makes a
very significant difference in the speech and language abilities of
affected children, compared with cases identified and amplified after
the age of 6 mo. In these children, repeat audiologic testing is needed
to reliably identify the degree of hearing loss and to fine-tune the use
of hearing aids.
Infants and young children with profound congenital or prelingual
onset of deafness have benefited from multichannel cochlear implants
(Fig. 637-4). These implants bypass injury to the organ of Corti and
provide neural stimulation by way of an external microphone and a
Figure 637-4 All cochlear implants share key components, including
signal processor that digitizes auditory stimuli into digital radiofre- a microphone, speech processor, and transmitter coil, shown in a
quency impulses. Cochlear implantation before age 2 yr (and even behind-the-ear position in this diagram. The microphone and speech
1 yr) improves hearing and speech, enabling more than 90% of chil- processor pick up environmental sounds and digitize them into coded
dren to be in mainstream education. Most develop age-appropriate signals. The signals are sent to the transmitter coil and relayed through
auditory perception and oral language skills. the skin to the internal device imbedded in the skull. The internal device
A serious complication of cochlear implants is an excessively high converts the code to electronic signals, which are transmitted to the
incidence of pneumococcal meningitis. All children receiving a electrode array wrapping around the cochlea. The inset shows the
cochlear implant must be vaccinated with the pneumococcal polyva- radiographic appearance of the stimulating electrode array. (Repro-
duced with permission from MED-EL Corporation, Innsbruck, Austria.
lent vaccine PCV13 (Table 637-9).
From Smith RJH, Bale JF Jr, White KR: Sensorineural hearing loss in
The best approach to the education of children with significant children, Lancet 365:879–890, 2005.)
hearing loss is a subject of ongoing controversy. Because we live in a
predominantly speaking world, some have advocated a pure auditory
and oral approach to hearing therapy. However, because affected chil-
dren often are slow to develop communication skills, many advocate a GENETIC COUNSELING
total communication approach; depending on the individual child’s Families of children with the diagnosis of SNHL or a syndrome associ-
needs, this technique uses a mixture of sign language, lip reading, ated with SNHL and/or CHL should consider genetic counseling,
hearing aids, and speech. The appropriate program for each child which will allow a discussion of the likelihood of similar diagnoses in
depends on the patient, family, and available resources. future pregnancies. The geneticist also can help in the evaluation and
Management of idiopathic sudden SNHL is controversial and has further testing of the patient with hearing loss to establish a
included oral prednisone, intratympanic (also called transtympanic) diagnosis.
dexamethasone perfusion, or a combination of both; the latter combi-
nation may be the most useful, although the data are not conclusive. Bibliography is available at Expert Consult.
Chapter 637 ◆ Hearing Loss 3080.e1
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Pediatrics 121:1119–1126, 2008. loss in US adolescents, JAMA 304:772–778, 2010.
Fellinger J, Holzinger D, Pollard R: Mental health of deaf people, Lancet Sharma A, Ruscetta MN, Chi DH: Ophthalmologic findings in children with
379:1037–1044, 2012. sensorineural hearing loss, Arch Otolaryngol Head Neck Surg 135:119–123, 2009.
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Gates GA, Miyamoto RT: Cochlear implants, N Engl J Med 349:421–423, 2003. measuring tumor necrosis factor in the peripheral circulation of patients with
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as a cause of Björnstad syndrome, N Engl J Med 356:809–819, 2007. J Otolaryngol 33:189–192, 2004.
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Head Neck Surg 133:65–68, 2007. dysplasia, Arch Otolaryngol Head Neck Surg 137:1236–1239, 2011.
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Chapter 638 ◆ Congenital Malformations 3081
considered for both cosmetic and functional reasons; children who

have some pinna can wear regular glasses, a hearing aid, and earrings
Chapter 638 and feel more normal in appearance. If the microtia is severe, some
patients may opt for creation and attachment of a prosthetic ear, which
Congenital Malformations cosmetically closely resembles a real ear. Surgery to correct severe
microtia may involve a multistage procedure, including carving and
transplantation of autogenous cartilage rib grafts and local soft tissue
Joseph Haddad Jr. and Sarah Keesecker flaps. Cosmetic reconstruction of the auricle usually is performed
between 5-7 yr of age and is performed before canal atresia repair in
children deemed appropriate for this surgery.
CONGENITAL STENOSIS OR ATRESIA

The external and middle ears, derived from the first and second bran- OF THE EXTERNAL AUDITORY CANAL
chial arches and grooves, grow throughout puberty, but the inner ear, Stenosis or atresia of the ear canal often occurs in association with
which develops from the otocyst, reaches adult size and shape by malformation of the auricle and middle ear. Malformations can occur
midfetal development. The ossicles are derived from the first and in isolation or as part of a genetic syndrome. For example, the ear
second arches (malleus and incus), and the stapes arises from the canal is narrow in trisomy 21 and external canal stenosis or atresia is
second arch and the otic capsule. The malleus and incus achieve adult common in branchiooculofacial syndrome, leading to CHL. Audio-
size and shape by the 15th wk of gestation, and the stapes achieves metric evaluation of these children should be undertaken as early in
adult size and shape by the 18th wk of gestation. Although the pinna, life as possible. Most children with significant CHL secondary to bilat-
ear canal, and tympanic membrane (TM) continue to grow after birth, eral atresia wear bone conduction hearing aids for the 1st several yr of
congenital abnormalities of these structures develop during the first life. Diagnosis, evaluation, and surgical planning often are aided by CT,
half of gestation. Malformed external and middle ears may be associ- and sometimes MRI, of the temporal bone. Mild cases of ear canal
ated with serious renal anomalies, mandibulofacial dysostosis, hemi- stenosis do not require surgical enlargement unless the patient devel-
facial microsomia, and other craniofacial malformations. Facial nerve ops chronic external otitis or severe cerumen impaction that affects
abnormalities may be associated with any of the congenital abnor- hearing.
malities of the ear and temporal bone. Malformations of the external Reconstructive ear canal and middle-ear surgery for atresia usually
and middle ears also may be associated with abnormalities of the is considered for children older than 5 yr of age who have bilateral
inner ear and both conductive (CHL) and sensorineural hearing deformities resulting in a significant CHL. The aim of reconstructive
loss (SNHL). surgery is to improve hearing to a point where the child may not need
Congenital ear problems may be minor and mainly cosmetic, or a hearing aid or to provide an ear canal and pinna so that the child can
major, affecting both appearance and function. Any child born with an derive improved benefit from an air-conduction hearing aid. Hearing
abnormality of the pinna, external auditory canal, or TM should have results for atresiaplasty range from fair to excellent. CT evidence of
a complete audiologic evaluation in the neonatal period. Imaging an adequate middle-ear cleft, ossicles, and mastoid is required to
studies are necessary for evaluation and treatment; in the patient with perform the surgery; the position of the facial nerve, which often is in
other craniofacial abnormalities a team approach with other specialists an abnormal location in these children, also must be considered (Fig.
can assist in guiding therapy. 638-1). The use of bone-anchored hearing aids is a safe, reliable, and
low-risk alternative to atresiaplasty and hearing results are generally
PINNA MALFORMATIONS excellent. Bone-anchored hearing aids may also be useful for rehabili-
Severe malformations of the external ear are rare, but minor deformi- tation of nonoptimal atresiaplasty hearing results. These devices are
ties are common. Isolated abnormalities of the external ear occur in approved by the U.S. Food and Drug Administration for surgical place-
approximately 1% of children. A pit-like depression just in front of the ment in children age 5 yr and older; prior to age 5 yr, they can be worn
helix and above the tragus may represent a cyst or an epidermis-lined with a soft band around the head. Disadvantages include the fact that
fistulous tract. These are common, with an incidence of approximately cosmesis is not very good (a bone-anchored hearing aid has a visible
8 in 1,000 children, and may be unilateral or bilateral and familial. The titanium abutment and snap-on hearing aid) and frequent wound care
pits require surgical removal only if there is recurrent infection. Acces- is required.
sory skin tags, with an incidence of 1-2/1,000 live births, can be
removed for cosmetic reasons by simple ligation if they are attached CONGENITAL MIDDLE-EAR MALFORMATIONS
by a narrow pedicle. If the pedicle is broad based or contains cartilage, Children may have congenital abnormalities of the middle ear as an
the defect should be corrected surgically. An unusually prominent or isolated defect or in association with other abnormalities of the tem-
“lop” ear results from lack of bending of the cartilage that creates the poral bone, especially the ear canal and pinna, or as part of a syndrome.
antihelix. It may be improved cosmetically in the neonatal period by Affected children usually have CHL but may have mixed CHL and
applying a firm framework (sometimes soldering wire is used) attached SNHL. Most malformations involve the ossicles, with the incus most
by Steri-Strips to the pinna and worn continuously for weeks to commonly affected. Other less-common abnormalities of the middle
months. Otoplasty for cosmetic correction can be considered in chil- ear include persistent stapedial artery, high-riding jugular bulb, and
dren older than 5 yr of age, when the pinna has reached approximately abnormalities of the shape and volume of the aerated portion of the
80% of its adult size. middle ear and mastoid; all present problems for a surgeon. Depending
The term microtia may indicate subtle abnormalities of the size, on the type of abnormality and the presence of other anomalies,
shape, and location of the pinna and ear canal, or major abnormalities surgery may be considered to improve hearing.
with only small nubbins of skin and cartilage and the absence of the
ear canal opening; anotia indicates complete absence of the pinna and CONGENITAL INNER EAR MALFORMATIONS
ear canal. Microtia can have a genetic or environmental predisposition. Congenital inner ear malformations have been identified and classified
Several hereditary forms of microtia have been identified that exhibit as a result of improvements in imaging modalities, especially CT and
either autosomal dominant or recessive mendelian inheritance. In MRI. As many as 20% of children with SNHL may have anatomic
addition, some forms due to chromosomal aberrations have been abnormalities identified on CT or MRI. Congenital malformations of
reported. Most of the responsible genes that have been identified are the inner ear usually are associated with SNHL of various degrees, from
homeobox genes. Microtic ears often are more anterior and inferior mild to profound. These malformations may occur as isolated anoma-
in placement than normal auricles, and the location and function of lies or in association with other syndromes, genetic abnormalities, or
the facial nerve may be abnormal. Surgery to correct microtia is structural abnormalities of the head and neck. Enlarged vestibular
A B
C D
Figure 638-1 External auditory canal atresia on CT scans. A, Coronal scan of right ear shows absent external auditory canal with thick bony
atresia plate (white arrows). Malleus neck is rotated and fused to superior portion of atresia plate (black arrow). B, Axial scan through attic shows
fused ossicular mass (arrow). C, Coronal scan more posterior to A shows mastoid segment of facial nerve canal positioned more anteriorly than
normal (arrows). D, Axial scan more inferior to B shows anterior-posterior mastoid segment of the facial nerve en face (arrow). Note abnormally
close relationship to mandibular condoyle. (From Faerber EN, Booth TN, Swartz JD. Temporal bone and ear. In Slovis TL, editor: Caffey’s pediatric
diagnostic imaging, ed 11, Philadelphia, 2008, Mosby, Fig. 44-7, p. 584.)
aqueducts have been identified on imaging studies in association with mal implants between the first and second branchial arch remnants,
SNHL; although no therapy exists for this condition, it may be associ- and residual amniotic fluid squamous debris. Congenital or acquired
ated with progressive SNHL in some children, and, therefore, diagnosis cholesteatoma should be suspected when deep retraction pockets,
may have some prognostic value. keratin debris, chronic drainage, aural granulation tissue, or a mass
Congenital perilymphatic fistula of the oval or round window behind or involving the TM is present. Besides acting as a benign
membrane may present as a rapid-onset, fluctuating, or progressive tumor causing local bone destruction, the keratinaceous debris of a
SNHL with or without vertigo and often is associated with congenital cholesteatoma is a good culture medium and may become a focus of
inner ear abnormalities. Middle-ear exploration may be required to infection for chronic otitis media. Complications include ossicular
confirm this diagnosis, because no reliable nonoperative diagnostic test erosion with hearing loss, bone erosion into the inner ear with dizzi-
exists. It may be necessary to repair a perilymphatic fistula to prevent ness, or exposure of the dura, with consequent meningitis or a brain
possible spread of infection from the middle ear to the labyrinth, to abscess. Cholesteatoma should be removed surgically after CT scan
stabilize hearing loss, and to improve vertigo when present. (Fig. 638-2) and hearing evaluation, and appropriate antibiotic therapy.
A second-look procedure 6-9 mo after primary surgery is often rec-
CONGENITAL CHOLESTEATOMA ommended to prevent further recurrence. Higher initial stage of
A congenital cholesteatoma (approximately 2% of all cholesteatomas) disease, erosion of ossicles, cholesteatoma abutting or enveloping the
is a nonneoplastic, destructive, cystic lesion that usually appears as a incus or stapes, and need for removal of the ossicles are associated
white, round, cyst-like structure medial to an intact TM. Cysts are with increased likelihood of residual cholesteatoma. In addition, more
seen most commonly in the anterior-superior portion of the middle extensive disease at initial surgery is associated with poorer hearing
ear, although they can present in other locations and within the TM outcomes. Recurrence rates vary and are related to the extent of
or in the skin of the ear canal. Affected children often have no prior involvement at the time of surgery. In a large case series, recurrence
history of otitis media. One theory for the pathogenesis is that the cyst rates were found to be as follows: 14% when disease was confined to 1
derives from a congenital rest of epithelial tissue that persists beyond quadrant, 33% when more than 1 quadrant was involved but the ossi-
33 wk of gestation, when it ordinarily would disappear. Other theories cles and mastoids were not, 41% with ossicular involvement, and 67%
include squamous metaplasia of the middle ear, entrance of squamous with mastoid involvement. Overall recurrence may be as high as 57%.
epithelium through a nonintact eardrum into the middle ear, ectoder- Congenital cholesteatoma is an aggressive disease, and early surgical
Figure 638-2 Congenital cholesteatoma. Axial CT of left ear shows
soft tissue mass (arrow) in the middle ear. This mass was noted oto-
scopically behind an intact membrane. (From Faerber EN, Booth TN,
Swartz JD. Temporal bone and ear. In Slovis TL, editor: Caffey’s pedi-
atric diagnostic imaging, ed 11, Philadelphia, 2008, Mosby, Fig. 44-31,
p. 598.)
removal and close monitoring will help prevent permanent damage to

the middle and inner ear.

Chapter 638 ◆ Congenital Malformations 3083.e1
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Carter MT, et al: Middle and inner ear malformations in mutation-proven radiologic findings with review of the literature, AJNR Am J Neuroradiol
branchio-oculo-facial (BOF) syndrome: Case series and review of the literature, 30:774–780, 2009.
Am J Med Genet A 158A:1977–1981, 2012. Potsic WP, Korman SB, Samadi DS, et al: Congenital cholesteatoma: 20 years’
Davids T, Gordon KA, Clutton D, et al: Bone-anchored hearing aids in infants and experience at The Children’s Hospital of Philadelphia, Otolaryngol Head Neck
children younger than 5 years, Arch Otolaryngol Head Neck Surg 133:51–55, Surg 126:409, 2002.
2007. van Wijk MP, Breugem CC, Kon M: Non-surgical correction of congenital
El-Bergermy MA, et al: Congenital auditory meatal atresia: a numerical review, Eur deformities of the auricle: a systematic review of the literature, J Plast Reconstr
Arch Otorhinolaryngol 266:501–506, 2009. Aesthet Surg 62:727–736, 2009.
Mylanus EA, Rotteveel LJ, Leeuw RL: Congenital malformation of the inner ear Yellon RF: Atresiaplasty versus BAHA for congenital aural atresia, Laryngoscope
and pediatric cochlear implantation, Otol Neurotol 25:308–317, 2004. 121:2–3, 2011.
Nevoux J, et al: Childhood cholesteatoma, Eur Ann Otorhinolaryngol Head Neck
Dis 127:143–150, 2010.
Chapter 639 ◆ External Otitis (Otitis Externa) 3083
skin of the canal vulnerable to infection by the normal flora or exog-

enous bacteria.
ETIOLOGY
External otitis (swimmer’s ear, although it can occur without swim-
ming) is caused most commonly by P. aeruginosa, but S. aureus, Entero-
bacter aerogenes, Proteus mirabilis, Klebsiella pneumoniae, streptococci,
coagulase-negative staphylococci, diphtheroids, and fungi such as
Candida and Aspergillus also may be isolated. External otitis results
from chronic irritation and maceration from excessive moisture in the
canal. The loss of protective cerumen may play a role, as may trauma,
but cerumen impaction with trapping of water also can cause infection.
Inflammation of the ear canal due to herpesvirus, varicella-zoster virus,
other skin exanthems, and eczema also may predispose to external
otitis.
The predominant symptom is acute rapid onset of ear pain (otalgia),
often severe, accentuated by manipulation of the pinna or by pressure
on the tragus and by jaw motion. The severity of the pain and tender-
ness (tragus or pinna, or both) may be disproportionate to the degree
of inflammation, because the skin of the external ear canal is tightly
adhered to the underlying perichondrium and periosteum. Itching
often is a precursor of pain and usually is characteristic of chronic
inflammation of the canal or resolving acute otitis externa. Conductive
hearing loss (CHL) may result from edema of the skin and tympanic
membrane (TM), serous or purulent secretions, or the canal skin thick-
ening associated with chronic external otitis.
Edema of the ear canal, erythema, and thick, clumpy otorrhea are
prominent signs of the acute disease. The cerumen usually is white and
soft in consistency, as opposed to its usual yellow color and firmer
consistency. The canal often is so tender and swollen that the entire ear
canal and TM cannot be adequately visualized, and complete otoscopic
examination may be delayed until the acute swelling subsides. If the
TM can be visualized, it may appear either normal or opaque. TM
mobility may be normal or, if the TM is thickened, mobility may be
Chapter 639 reduced in response to positive and negative pressure.
Other physical findings may include palpable and tender lymph
External Otitis (Otitis nodes in the periauricular region, and erythema and swelling of the
pinna and periauricular skin. Rarely, facial paralysis, other cranial
Externa) nerve abnormalities, vertigo, and/or sensorineural hearing loss are

present. If these occur, necrotizing (malignant) otitis externa is prob-
able. This invasive infection of the temporal bone and skull base
Joseph Haddad Jr. and Sarah Keesecker requires immediate culture, intravenous antibiotics, and imaging
studies to evaluate the extent of the disease. Surgical intervention to
obtain cultures or debride devitalized tissue may be necessary. P. aeru-
In an infant, the outer two thirds of the ear canal is cartilaginous and ginosa (see Chapter 205.1) is the most common causative organism of
the inner one third is bony. In an older child and adult the outer one necrotizing otitis externa. Fortunately, this disease is rare in children
third is cartilaginous and the inner two thirds is bony. The epithelium and is seen only in association with immunocompromise or severe
is thinner in the bony portion than in the cartilaginous portion, there malnourishment. In adults, it is associated with diabetes mellitus.
is no subcutaneous tissue, and epithelium is tightly applied to the
underlying periosteum; hair follicles, sebaceous glands, and apocrine DIAGNOSIS
glands are scarce or absent. The skin in the cartilaginous area has well- Diffuse external otitis may be confused with furunculosis, otitis
developed dermis and subcutaneous tissue and contains hair follicles, media (OM), and mastoiditis. Furuncles occur in the lateral hair-
sebaceous glands, and apocrine glands. The highly viscid secretions of bearing part of the ear canal; furunculosis usually causes a localized
the sebaceous glands and the watery, pigmented secretions of the apo- swelling of the canal limited to 1 quadrant, whereas external otitis is
crine glands in the outer portion of the canal combine with exfoliated associated with concentric swelling and involves the entire ear canal.
surface cells of the skin to form cerumen, a protective, waxy, water- In OM, the TM may be perforated, severely retracted, or bulging and
repellent coating. immobile; hearing usually is impaired. If the middle ear is draining
The normal flora of the external canal consists mainly of aerobic through a perforated TM or tympanostomy tube, secondary external
bacteria and includes coagulase-negative staphylococci (see Chapter otitis may occur; if the TM is not visible owing to drainage or ear canal
181.3), Corynebacterium (diphtheroids) (see Chapter 187), Micrococ- swelling, it may be difficult to distinguish acute OM with drainage from
cus, and, occasionally, Staphylococcus aureus (see Chapter 181.1), viri- an acute external otitis. Pain on manipulation of the auricle and sig-
dans streptococci (see Chapter 185), and Pseudomonas aeruginosa (see nificant lymphadenitis are not common features of OM, and these
Chapter 205.1). Excessive wetness (swimming, bathing, increased findings assist in the differential diagnosis. In some patients with exter-
environmental humidity), dryness (dry canal skin and lack of nal otitis, the periauricular edema is so extensive that the auricle is
cerumen), the presence of other skin pathologic conditions (previous pushed forward, creating a condition that may be confused with acute
infection, eczema, or other forms of dermatitis), and trauma (due to mastoiditis and a subperiosteal abscess. In mastoiditis, the postauricu-
digital or foreign body, use of cotton-tip applicators [Q-tips]) make the lar fold is obliterated, whereas in external otitis, the fold is usually
better preserved. In acute mastoiditis, a history of OM and hearing loss As the inflammatory process subsides, cleaning the canal with a
is usual; tenderness is noted over the mastoid and not on movement suction or cotton-tipped applicator to remove the debris enhances the
of the auricle; and otoscopic examination may show sagging of the effectiveness of the topical medications. In subacute and chronic infec-
posterior canal wall. tions, periodic cleansing of the canal is essential. In severe, acute exter-
Referred otalgia may come from disease in the paranasal sinuses, nal otitis associated with fever and lymphadenitis, oral or parenteral
teeth, pharynx, parotid gland, neck and thyroid, and cranial nerves antibiotics may be indicated; an ear canal culture should be done, and
(trigeminal neuralgia) (herpes simplex virus, varicella-zoster virus). empirical antibiotic treatment can then be modified if necessary, based
on susceptibility of the organism cultured. A fungal infection of the
TREATMENT external auditory canal, or otomycosis, is characterized by fluffy white
Topical otic preparations containing acetic acid with or without hydro- debris, sometimes with black spores seen; treatment includes cleaning
cortisone, or neomycin (active against Gram-positive organisms and and application of antifungal solutions such as clotrimazole or nystatin;
some Gram-negative organisms, notably Proteus spp.), polymyxin other antifungal agents include m-cresyl acetate 25%, gentian violet
(active against Gram-negative bacilli, notably Pseudomonas spp.), and 2%, and thimerosal 1 : 1,000.
hydrocortisone are highly effective in treating most forms of acute
external otitis. Other preparations of eardrops (e.g., ofloxacin, cipro- PREVENTION
floxacin with hydrocortisone or dexamethasone) are preferable and do Preventing external otitis may be necessary for individuals susceptible
not contain potentially ototoxic antibiotics. If canal edema is marked, to recurrences, especially children who swim. The most effective pro-
the patient may need referral to a specialist for cleaning and possible phylaxis is instillation of dilute alcohol or acetic acid (2%) immediately
wick placement. An otic antibiotic and corticosteroid eardrop is often after swimming or bathing. During an acute episode of otitis externa,
recommended. A wick can be inserted into the ear canal and topical patients should not swim and the ears should be protected from exces-
antibiotics applied to the wick 3 times a day for 24-48 hr. The wick can sive water during bathing. A hair dryer may be used to clear moisture
be removed after 2-3 days, at which time the edema of the ear canal from the ear after swimming as a method of prevention.
usually is markedly improved, and the ear canal and TM are better
seen. Topical antibiotics are then continued by direct instillation. OTHER DISEASES OF THE EXTERNAL EAR
When the pain is severe, oral analgesics (e.g., ibuprofen, codeine) may Furunculosis
be necessary for a few days. Careful evaluation for underlying condi- Furunculosis is caused by S. aureus and affects only the hair-containing
tions should be undertaken in patients with severe or recurrent otitis outer third of the ear canal. Mild forms are treated with oral antibiotics
externa. Figure 639-1 outlines an approach to managing acute external active against S. aureus. If an abscess develops, incision and drainage
otitis. may be necessary.
Patient age 2 yr or older

with diffuse AOE
Prescribe analgesics based on pain severity
Extension outside Prescribe systemic antimicrobial active

Yes against Pseudomonas aeruginosa and Go to
ear canal or host
Staphylococcus aureus, with or without A
factors* requiring
topical therapy, plus other management below
systemic therapy?
based on underlying condition
No *Factors requiring systemic therapy include
diabetes, immune deficiency, or inability to
effectively deliver topical therapy despite aural toilet
Perforated tympanic
membrane (known or Yes
suspected) or
tympanostomy tube?
No
Prescribe topical therapy based on Prescribe topical therapy with a
benefits, cost, compliance, preference nonototoxic preparation
Yes Perform aural toilet to remove

Obstructed ear canal obstructing debris; place wick if
edema prevents drug delivery
No
Educate patient or caregiver on how
to administer topical drops
Clinically improved No Reassess Illness other Yes Figure 639-1 Flow chart for managing acute
A
in 48-72 hr? patient than AOE? otitis externa (AOE). (From Rosenfeld RM, Brown L,
Cannon CR, et al: Clinical practice guideline: acute
Yes otitis externa, Otolaryngol Head Neck Surg 134:S4–
Assess drug delivery, No Treat
Complete course of therapy adherence to therapy, other S23, 2006. Copyright 2006 American Academy of
need to change therapy illness Otolaryngology-Head and Neck Surgery Founda-
tion, Inc.)
Acute Cellulitis Bullous Myringitis
Acute cellulitis of the auricle and external auditory canal usually is Commonly associated with an acute upper respiratory tract infection,
caused by group A streptococcus and occasionally by S. aureus. The bullous myringitis presents as an ear infection with more severe pain
skin is red, hot, and indurated, without a sharply defined border. Fever than usual. On examination, hemorrhagic or serous blisters (bullae)
may be present with little or no exudate in the canal. Parenteral admin- may be seen on the TM. The disease sometimes is difficult to differenti-
istration of penicillin G or a penicillinase-resistant penicillin is the ate from acute OM, because a large bulla may be confused with a
therapy of choice. bulging TM. The organisms involved are the same as those that cause
acute OM, including both bacteria and viruses. Treatment consists of
Perichondritis and Chondritis empiric antibiotic therapy and pain medications. In addition to ibu-
Perichondritis is an infection involving the skin and perichondrium of profen or codeine for severe pain, a topical anesthetic eardrop may also
the auricular cartilage; extension of infection to the cartilage is termed provide some relief. Incision of the bullae, although not necessary,
chondritis. The ear canal, especially the lateral aspect, also may be promptly relieves the pain.
involved. Early perichondritis may be difficult to differentiate from
cellulitis because both are characterized by skin that is red, edematous, Exostoses and Osteomas
and tender. The main cause of perichondritis/chondritis and cellulitis Exostoses represent benign hyperplasia of the perichondrium and
is trauma (accidental or iatrogenic, laceration or contusion), including underlying bone. Those involving the auditory canal tend to be found
ear piercing, especially when done through the cartilage. The most in people who swim often in cold water. Exostoses are broad based,
commonly isolated organism in perichondritis and chondritis is P. often multiple, and bilateral. Osteomas are benign bony growths in the
aeruginosa, although other Gram-negative and, occasionally, Gram- ear canal of uncertain cause (see Chapter 501.2). They usually are soli-
positive organisms may be found. Treatment involves systemic, often tary and attached by a narrow pedicle to the tympanosquamous or
parenteral, antibiotics; surgery to drain an abscess or remove nonviable tympanomastoid suture line. Both are more common in males; exos-
skin or cartilage may also be needed. Removal of all ear jewelry is toses are more common than osteomas. Surgical treatment is recom-
mandatory in the presence of infection. mended when large masses cause cerumen impaction, ear canal
obstruction, or hearing loss.
Dermatoses
Various dermatoses (seborrheic, contact, infectious eczematoid, or Bibliography is available at Expert Consult.
neurodermatoid) are common causes of inflammation of the external
canal; scratching and the introduction of infecting organisms cause
acute external otitis in these conditions.
Seborrheic dermatitis is characterized by greasy scales that flake
and crumble as they are detached from the epidermis; associated
changes in the scalp, forehead, cheeks, brow, postauricular areas, and
concha are usual.
Contact dermatitis of the auricle or canal may be caused by earrings
or by topical otic medications such as neomycin, which may produce
erythema, vesiculation, edema, and weeping. Poison ivy, oak, and
sumac also may produce contact dermatitis. Hair care products have
been implicated in sensitive individuals.
Infectious eczematoid dermatitis is caused by a purulent infection
of the external canal, middle ear, or mastoid; the purulent drainage
infects the skin of the canal or auricle, or both. The lesion is weeping,
erythematous, or crusted.
Atopic dermatitis occurs in children with a familial or personal
history of allergy; the auricle, particularly the postauricular fold,
becomes thickened, scaly, and excoriated.
Neurodermatitis is recognized by intense itching and erythema-
tous, thickened epidermis localized to the concha and orifice of the
meatus.
Treatment of these dermatoses depends on the type but should
include application of an appropriate topical medication, elimination
of the source of infection or contact when identified, and management
of any underlying dermatologic problem. In addition to topical antibi-
otics (or antifungals), topical steroids are helpful if contact dermatitis,
atopic dermatitis, or eczematoid dermatitis is suspected.
Herpes Simplex Virus

See Chapter 252.
Herpes simplex virus may appear as vesicles on the auricle and lips.
The lesions eventually become encrusted and dry and may be con-
fused with impetigo. Topical application of a 10% solution of carb-
amide peroxide in anhydrous glycerol is symptomatically helpful. The
Ramsay Hunt syndrome (herpes zoster oticus with facial paralysis)
may present with herpes vesicles in the ear canal and on the pinna
and with facial paralysis and pain. Other cranial nerves may be
affected as well, especially the 8th nerve. The current recommended
treatment of herpes zoster oticus includes systemic antiviral agents,
such as acyclovir, and corticosteroids. As many as 50% of patients
with Ramsay Hunt syndrome do not completely recover their facial
nerve function.
Chapter 639 ◆ External Otitis (Otitis Externa) 3085.e1
Bibliography Roland PS, Stroman DW: Microbiology of acute otitis externa, Laryngoscope
Alter SJ, et al: Common childhood bacterial infections, Curr Probl Pediatr Adolesc 112:1166–1177, 2002.
Health Care 41:256–283, 2011. Rosenfeld RM, Brown L, Cannon CR, et al: Clinical practice guideline: acute otitis
Haddad J Jr: Care of the draining ear in children, Emerg Pediatr 8:75, 1995. externa, Otolaryngol Head Neck Surg 134:S4–S23, 2006.
Majumdar S, Wu K, Bateman ND, et al: Diagnosis and management of otalgia in Rosenfeld RM, Schwartz SR, Cannon CR, et al: Clinical practice guideline: acute
children, Arch Dis Child Educ Pract Ed 94:33–36, 2009. otitis externa executive summary, Otolaryngol Head Neck Surg 150:161–168,
Nussinovitch M, Rimon A, Volovitz B, et al: Cotton-tip applicators as a leading 2014.
cause of otitis externa, Int J Pediatr Otorhinolaryngol 68:433–435, 2004. Siddiq MA, Samra MJ: Otalgia, BMJ 336:276–277, 2008.
Pankhanis M, Judd O, Ward A: Otorrhoea, BMJ 342:d2299, 2011. Van Balen FAM, Smit WM, Zuithoff PA, et al: Clinical efficacy of three common
Roland PS, Belcher BP, Bettis R, et al; Cipro HC Study Group: A single topical treatments in acute otitis externa in primary care: randomized controlled trial,
agent is clinically equivalent to the combination of topical and oral antibiotic BMJ 327:1201–1203, 2003.
treatment for otitis externa, Am J Otolaryngol 29(4):255–261, 2008. Wall GM, Stroman DW, Roland PS, et al: Ciprofloxacin 0.3%/dexamethasone 0.1%
Roland PS, Eaton DA, Gross RD, et al: Randomized, placebo-controlled evaluation sterile otic suspension for the topical treatment of ear infections, Pediatr Infect
of Cerumenex and Murine earwax removal products, Arch Otolaryngol Head Dis J 28:141–144, 2009.
Neck Surg 130:1175–1177, 2004.
Chapter 640 ◆ Otitis Media 3085
Chapter 640
Otitis Media
Joseph E. Kerschner and Diego Preciado
The term otitis media (OM) has 2 main categories: acute infection,
which is termed suppurative or acute otitis media (AOM), and inflam-
mation accompanied by middle-ear effusion (MEE), termed nonsup-
purative or secretory OM, or otitis media with effusion (OME). These
2 main types of OM are interrelated: acute infection usually is suc-
ceeded by residual inflammation and effusion that, in turn, predispose
children to recurrent infection. MEE is a feature of both AOM and of
OME and is an expression of the underlying middle-ear mucosal
inflammation. MEE results in the conductive hearing loss (CHL)
associated with OM, ranging from none to as much as 50 dB of
hearing loss.
The peak incidence and prevalence of OM is during the 1st 2 yr of
life. More than 80% of children will have experienced at least 1 episode
of OM by the age of 3 yr. OM is a leading reason for physician visits
and for use of antibiotics and figures importantly in the differential
diagnosis of fever. OM often serves as the sole or the main basis for
undertaking the most frequently performed operations in infants and
young children: myringotomy with insertion of tympanostomy tubes
and adenoidectomy. OM is also the most common cause of hearing
loss in children. OM has a propensity to become chronic and recur.
The earlier in life a child experiences the first episode, the greater the
degree of subsequent difficulty the child is likely to experience in terms
of frequency of recurrence, severity, and persistence of middle-ear
effusion.
Accurate diagnosis of AOM in infants and young children may be
difficult (Table 640-1). Symptoms may not be apparent, especially in
early infancy and in chronic stages of the disease. Accurate visualiza-
tion of the tympanic membrane and middle-ear space may be difficult
because of anatomy, patient cooperation, or blockage by cerumen,
removal of which may be arduous and time consuming. Abnormalities
of the eardrum may be subtle and difficult to appreciate. In the face of
these difficulties, both underdiagnosis and overdiagnosis occur.
Table 640-1 Treatments for Otalgia in Acute Otitis Media

TREATMENT MODALITY COMMENTS
Acetaminophen, ibuprofen Effective analgesia for mild to moderate pain. Readily available. Mainstay of pain
management for AOM
Home remedies (no controlled studies that directly address May have limited effectiveness
effectiveness)
Distraction
External application of heat or cold
Oil drops in external auditory canal
Benzocaine, procaine, lidocaine (topical) Additional, but brief, benefit over acetaminophen in patients older than 5 yr
Naturopathic agents Comparable to amethocaine/phenazone drops in patients older than 6 yr
Homeopathic agents No controlled studies that directly address pain
Narcotic analgesia with codeine or analogs Effective for moderate or severe pain. Requires prescription; risk of respiratory
depression, altered mental status, gastrointestinal tract upset, and constipation
Tympanostomy/myringotomy Requires skill and entails potential risk
From Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics 131:e964-e999, 2013, Table 3.
EPIDEMIOLOGY to this relationship include crowding, limited hygienic facilities, sub-

Several factors have been demonstrated to affect the occurrence of optimal nutritional status, limited access to medical care, and limited
OM, including age, gender, race, genetic background, socioeconomic resources for complying with prescribed medical regimens.
status, breast milk feeding, degree of exposure to tobacco smoke,
degree of exposure to other children, presence or absence of respira- Breast Milk Compared to Formula Feeding
tory allergy, season of the yr, and vaccination status. Children with Most studies have found a protective effect of breast milk feeding
certain types of congenital craniofacial anomalies are particularly against OM. This protective effect may be greater in socioeconomically
prone to OM. disadvantaged than in more advantaged children. The protective effect
is attributable to the milk itself rather than to the mechanics of
Age breastfeeding.
The age of onset of OM is an important predictor of the development
of recurrent and chronic OM, with earlier age of onset having an Exposure to Tobacco Smoke
increased risk for exhibiting these difficulties later in life. The develop- Exposure to tobacco smoke is thought to be an important preventable
ment of at least 1 episode of OM has been reported as 63-85% by 12 mo risk factor in the development of OM. Studies that have used objective
and 66-99% by 24 mo of age. The percentage of days with MEE has measures to determine infant exposure to second-hand tobacco smoke,
been reported as 5-27% during the 1st yr of life and 6-18% during the such as cotinine levels, have more consistently identified a significant
2nd yr of life. Across groups, rates were highest at 6-20 mo of age. After linkage between tobacco smoke and OM.
the age of 2 yr, the incidence and prevalence of OM decline progres-
sively, although the disease remains relatively common into the early Exposure to Other Children
school-age years. The most likely reasons for the higher rates in infants Many studies have established that a strong, positive relationship exists
and younger children include less-well–developed immunologic between the occurrence of OM and the extent of repeated exposure to
defenses and less-favorable eustachian tubal factors involving both the other children—measured mainly by the number of other children
structure and function of the tube. involved—whether at home or in out-of-home group daycare. Together,
but independently, family socioeconomic status and the extent of expo-
Gender sure to other children appear to constitute 2 of the most important
Epidemiologic data suggest an incidence of OM greater in boys than identifiable risk factors for developing OM.
in girls, although some studies have found no gender-related differ-
ences in the occurrence of OM. Season
In keeping with the pattern of occurrence of upper respiratory tract
Race infections in general, highest rates of occurrence of OM are observed
OM is especially prevalent and severe among Native American, Inuit, during cold weather months and lowest rates during warm weather
and indigenous Australian children. Studies comparing the occurrence months. In OM, it is likely that these findings strongly depend on the
of OM in white children and black children have given conflicting significant association of OM with viral respiratory illnesses.
results.
Congenital Anomalies
Genetic Background OM is universal among infants with unrepaired palatal clefts, and is
That middle-ear disease tends to run in families is a commonplace also highly prevalent among children with submucous cleft palate,
observation, suggesting that OM has a heritable component. The other craniofacial anomalies, and Down syndrome (see Chapter 81.2).
degree of concordance for the occurrence of OM is much greater The common feature in these congenital anomalies is a deficiency in
among monozygotic than among dizygotic twins. the functioning of the eustachian tubes, which predisposes these chil-
dren to middle-ear disease.
Socioeconomic Status
Poverty has long been considered an important contributing factor to Vaccination Status
both the development and the severity of OM. Elements contributing See “Immunoprophylaxis” below.
Other Factors or through exposure to tobacco smoke may tip the balance of patho-
Pacifier use is linked with an increased incidence of OM and recur- genesis in less-virulent OM pathogens in their favor, especially in chil-
rence of OM, although the effect is small. Neither maternal age nor dren with a unique host predisposition.
birthweight nor season of birth appears to influence the occurrence of
OM once other demographic factors are taken into account. Very Anatomic Factors
limited data are available regarding the association of OM with bottle Patients with significant craniofacial abnormalities affecting the eusta-
feeding in the recumbent position. chian tube function have an increased incidence of OM. During the
pathogenesis of OM the eustachian tube demonstrates decreased effec-
ETIOLOGY tiveness in ventilating the middle-ear space.
Acute Otitis Media Under usual circumstances the eustachian tube is passively closed
Pathogenic bacteria can be isolated by standard culture techniques and is opened by contraction of the tensor veli palatini muscle. In rela-
from middle-ear fluid in a majority of well-documented AOM cases. tion to the middle ear, the tube has 3 main functions: ventilation,
Three pathogens predominate in AOM: Streptococcus pneumoniae (see protection, and clearance. The middle-ear mucosa depends on a con-
Chapter 182), nontypeable Haemophilus influenzae (see Chapter 194), tinuing supply of air from the nasopharynx delivered by way of the
and Moraxella catarrhalis (see Chapter 196). The overall incidence of eustachian tube. Interruption of this ventilatory process by tubal
these organisms has changed with the use of the conjugate pneumo- obstruction initiates an inflammatory response that includes secretory
coccal vaccine. In countries where this vaccine is employed, nontype- metaplasia, compromise of the mucociliary transport system, and effu-
able H. influenzae initially overtook S. pneumoniae as the most common sion of liquid into the tympanic cavity. Measurements of eustachian
pathogen, being found in 40-50% of cases. However, over time, tube function have demonstrated that the tubal function is suboptimal
S. pneumoniae serotypes not covered in the conjugate vaccine have during the events of OM with increased opening pressures.
emerged, with S. pneumoniae again overtaking nontypeable H. influ- Eustachian tube obstruction may result from extraluminal blockage
enzae as the most common pathogen in many studies. M. catarrhalis via hypertrophied nasopharyngeal adenoid tissue or tumor, or may
represents the majority of the remaining cases. Other pathogens result from intraluminal obstruction via inflammatory edema of the
include group A streptococcus (see Chapter 183), Staphylococcus tubal mucosa, most commonly as a consequence of a viral upper respi-
aureus (see Chapter 181), and Gram-negative organisms. S. aureus and ratory tract infection. Progressive reduction in tubal wall compliance
Gram-negative organisms are found most commonly in neonates and with increasing age may explain the progressive decline in the occur-
very young infants who are hospitalized; in outpatient settings, the rence of OM as children grow older. The protection and clearance
distribution of pathogens in these young infants is similar to that in functions of the eustachian tube may also be involved in the pathogen-
older infants. Molecular techniques to identify nonculturable bacterial esis of OM. Thus, if the eustachian tube is patulous or excessively
pathogens have suggested the importance of other bacterial species compliant, it may fail to protect the middle ear from reflux of infective
such as Alloiococcus otitidis. nasopharyngeal secretions, whereas impairment of the mucociliary
Evidence of respiratory viruses also may be found in middle-ear clearance function of the tube might contribute to both the establish-
exudates of children with AOM, either alone or, more commonly, in ment and persistence of infection. The shorter and more horizontal
association with pathogenic bacteria. Of these viruses, rhinovirus and orientation of the tube in infants and young children may increase the
respiratory syncytial virus are found most often. AOM is a known likelihood of reflux from the nasopharynx and impair passive gravita-
complication of bronchiolitis; middle-ear aspirates in children with tional drainage through the eustachian tube.
bronchiolitis regularly contain bacterial pathogens, suggesting that In special patient populations with craniofacial abnormalities there
respiratory syncytial virus is rarely, if ever, the sole cause of their AOM. exists an increased incidence of OM that has been associated with the
Using more precise measures of viable bacteria than standard culture abnormal eustachian tube function. In children with cleft palate, where
techniques, such as polymerase chain reaction assays, a much higher OM is a universal finding, a main factor underlying the chronic
rate of bacterial pathogens can be demonstrated. It remains uncertain middle-ear inflammation appears to be impairment of the opening
whether viruses alone can cause AOM, or whether their role is limited mechanism of the eustachian tube. Possible factors include muscular
to setting the stage for bacterial invasion, and perhaps also to amplify- changes, tubal compliance factors, and defective velopharyngeal
ing the inflammatory process and interfering with resolution of the valving, which may result in disturbed aerodynamic and hydrody-
bacterial infection. Viral pathogens have a negative impact on eusta- namic relationships in the nasopharynx and proximal portions of the
chian tube function, can impair local immune function, and increase eustachian tubes. In children with other craniofacial anomalies and
bacterial adherence, and can change the pharmacokinetic dynamics, with Down syndrome, the high prevalence of OM has also been attrib-
reducing the efficacy of antimicrobial medications. uted to structural and/or functional eustachian tubal abnormalities.
Otitis Media with Effusion Host Factors

Using standard culture techniques, the pathogens typically found in The effectiveness of a child’s immune system in response to the bacte-
AOM are recoverable in only 30% of children with OME. However, in rial and viral insults of the upper airway and middle ear during early
studies of children with OME using polymerase chain reaction assays, childhood probably is the most important factor in determining which
middle-ear effusions have been found to contain evidence of bacterial children are otitis prone. The maturation of this immune system during
DNA and viral RNA in much larger proportions of these children. early childhood is most likely the primary event leading to the decrease
These studies suggest that these patients do not have sterile effusions in incidence of OM as children move through childhood. Immuno-
as previously thought. Biofilms of pathogenic bacteria have been dem- globulin (Ig) A deficiency is found in some children with recurrent
onstrated to be present on the middle-ear mucosa and adenoid pad in AOM, but the significance is questionable, inasmuch as IgA deficiency
a majority of children with chronic OM. Biofilms consist of aggregated is also found not infrequently in children without recurrent AOM.
and adherent bacteria, embedded in an extracellular matrix, allowing Selective IgG subclass deficiencies (despite normal total serum IgG)
for protection against antimicrobials, and their presence may contrib- may be found in children with recurrent AOM in association with
ute to the persistence of pathogens and the recalcitrance of chronic OM recurrent sinopulmonary infection, and these deficiencies probably
to antibiotic treatment (see Chapter 171). underlie the susceptibility to infection. Children with HIV infection
have recurrent and difficult to treat episodes of AOM in the 1st and
PATHOGENESIS 2nd yr of life. Children with recurrent OM that is not associated with
A multifactorial disease process, risk profile, and host–pathogen inter- recurrent infection at other sites rarely have a readily identifiable
actions have become recognized as playing important roles in the immunologic deficiency. Evidence that subtle immune deficits play a
pathogenesis of OM. Such events as alterations in mucociliary clear- role in the pathogenesis of recurrent AOM is provided by studies
ance through repeated viral exposure experienced in daycare settings involving antibody responses to various types of infection and
immunization; by the observation that breast milk feeding, as opposed difficulties or disequilibrium can also be associated with OME and
to formula feeding, confers some protection against the occurrence of older children may complain of mild discomfort or a sense of fullness
OM in infants with cleft palate; and by studies in which young children in the ear (see Chapter 636).
with recurrent AOM achieved a measure of protection from intramus-
cularly administered bacterial polysaccharide immune globulin or EXAMINATION OF THE
intravenously administered polyclonal immunoglobulin. This evi- TYMPANIC MEMBRANE
dence, along with the documented decrease in incidence of upper Otoscopy
respiratory tract infections and OM as children’s immune systems Two types of otoscope heads are available: surgical or operating, and
develop and mature, is indicative of the importance of a child’s innate diagnostic or pneumatic. The surgical head embodies a lens that can
immune system in the pathogenesis of OM (see Chapter 124). swivel over a wide arc and an unenclosed light source, thus providing
ready access of the examiner’s instruments to the external auditory
Viral Pathogens canal and tympanic membrane. Use of the surgical head is optimal for
Although OM may develop and certainly may persist in the absence removing cerumen or debris from the canal under direct observation,
of apparent respiratory tract infection, many, if not most, episodes are and is necessary for satisfactorily performing tympanocentesis or myr-
initiated by viral or bacterial upper respiratory tract infection. In chil- ingotomy. The diagnostic head incorporates a larger lens, an enclosed
dren in group daycare, AOM was observed in approximately 30-40% light source, and a nipple for the attachment of a rubber bulb and
of children with respiratory illness caused by respiratory syncytial virus tubing. When an attached speculum is fitted snugly into the external
(see Chapter 260), influenzaviruses (see Chapter 258), or adenoviruses auditory canal, an airtight chamber is created comprising the vault of
(see Chapter 262), and in approximately 10-15% of children with respi- the otoscope head, the bulb and tubing, the speculum, and the proxi-
ratory illness caused by parainfluenza viruses (see Chapter 259), rhi- mal portion of the external canal. Although examination of the ear in
noviruses (see Chapter 263), or enteroviruses (see Chapter 250). Viral young children is a relatively invasive procedure that is often met with
infection of the upper respiratory tract results in release of cytokines lack of cooperation by the patient, this task can be enhanced if done
and inflammatory mediators, some of which may cause eustachian with as little pain as possible. The outer portion of the ear canal con-
tube dysfunction. tains hair-bearing skin and subcutaneous fat and cartilage that allow a
Respiratory viruses also may enhance nasopharyngeal bacterial speculum to be placed with relatively little discomfort. Closer to the
colonization and adherence and impair host immune defenses against tympanic membrane the ear canal is made of bone and is lined only
bacterial infection. with skin and no adnexal structures or subcutaneous fat; a speculum
pushed too far forward and placed in this area often causes skin abra-
Allergy sion and pain. Using a rubber-tipped speculum or adding a small
Evidence that respiratory allergy is a primary etiologic agent in OM is sleeve of rubber tubing to the tip of the plastic speculum may serve to
not convincing; however, in children with both conditions it is possible minimize patient discomfort and enhance the ability to achieve a
that the otitis is aggravated by the allergy. proper fit and an airtight seal, facilitating pneumatic otoscopy.
Learning to perform pneumatic otoscopy is a critical skill in being
CLINICAL MANIFESTATIONS able to assess a child’s ear and in making an accurate diagnosis of AOM.
Symptoms of AOM are variable, especially in infants and young chil- By observing as the bulb is alternately squeezed gently and released,
dren. In young children, evidence of ear pain may be manifested by the degree of tympanic membrane mobility in response to both positive
irritability or a change in sleeping or eating habits and occasionally, and negative pressure can be estimated, providing a critical assessment
holding or tugging at the ear. Pulling at the ear alone has a low sensitiv- of middle-ear fluid, which is a hallmark sign of both AOM and OME
ity and specificity. Fever may also be present and may occasionally be (Fig. 640-1). With both types of otoscope heads, bright illumination is
the only sign. Rupture of the tympanic membrane with purulent otor- also critical for adequate visualization of the tympanic membrane.
rhea is uncommon. Systemic symptoms and symptoms associated with
upper respiratory tract infections also occur; occasionally there may Clearing the External Auditory Canal
be no symptoms, the disease having been discovered at a routine health Many children’s ears are “self-cleaning” because of squamous migration
examination. OME often is not accompanied by overt complaints of of ear canal skin. Parental cleaning of cerumen with cotton swabs often
the child but can be accompanied by hearing loss. This hearing loss complicates cerumen impaction by pushing cerumen deeper into the
may manifest as changes in speech patterns but often goes undetected canal compacting it. If the tympanic membrane is obscured by cerumen,
if unilateral or mild in nature, especially in younger children. Balance the cerumen should be removed. This can be accomplished through
At least two of: Bubbles or air–fluid interfaces Acute purulent otorrhea

1. Abnormal TM color: Or behind the TM not due to otitis externa
white, yellow, amber, or blue
2. Opacification not due to scarring
3. Decreased or absent mobility
Yes Yes
Middle-ear effusion Yes

(MEE)
No acute Acute
inflammation inflammation
At least one of:

1. Substantial ear pain, including
unaccustomed tugging or
rubbing of the ear
2. Marked redness of the TM
3. Distinct fullness or bulging of the TM
Yes
Figure 640-1 Algorithm for distinguishing

Otitis media with effusion Acute otitis media between acute otitis media and otitis media with
(OME) (AOM)
effusion. TM, tympanic membrane.
direct visualization using a headlight or through the surgical head of

the otoscope by using an ear curette or gentle suction with a No. 5 or
7 French ear suction tube. During this procedure it may be most
advantageous to restrain the infant or young child in the prone position,
turning the child’s head to the left or right as each ear is cleared. In
children old enough to cooperate, usually beginning at about 5 yr of
age, clearing of the external canal may be achieved more easily and less
traumatically by lavage than by mechanical removal, provided one can
be certain that a tympanic membrane perforation is not present.
A B
Tympanic Membrane Findings
Important characteristics of the tympanic membrane (TM) consist of
contour, color, translucence, structural changes if any, and mobility.
The TM is anatomically divided into the pars tensa and pars flaccida.
The pars tensa comprises the lower two thirds of the drum inferior to
the lateral process of the malleus. Its contour is normally slightly
concave; abnormalities consist of fullness or bulging or, conversely,
extreme retraction. The normal color of the pars tensa is pearly gray,
with the pars flaccida being slightly more vascular in nature. Erythema
may be a sign of inflammation or infection, but unless intense, ery- C D
thema alone may result from crying or vascular flushing. Abnormal
whiteness of the membrane may result from either scarring or the Figure 640-2 Examples of normal tympanic membrane (A) and of
presence of effusion in the middle-ear cavity; this effusion also may mild bulging (B), moderate bulging (C), and severe bulging (D) of the
impart an amber, pale yellow, or, rarely, bluish color. Rarely a persistent tympanic membrane from middle-ear effusion. (Courtesy of Alejandro
focal white area may be indicative of a congenital cholesteatoma in the Hoberman, MD.)
middle-ear space. Normally, the membrane is translucent, although
some degree of opacity may be normal in the 1st few mo of life; later,
opacification denotes either scarring or, more commonly, underlying
effusion. Structural changes include scars, perforations, and retraction
pockets. Retractions or perforations, especially in the posterior-
superior quadrant, or pars flaccida, of the TM may be a sign of cho-
lesteatoma formation. Of all the visible characteristics of the TM,
mobility is the most sensitive and specific in determining the presence
or absence of MEE. Mobility is generally not an all-or-none phenom-
enon. A total absence of mobility does exist with a TM perforation that
can develop following a substantial increase in middle-ear pressure
associated with effusion. When a perforation is not present, substantial
impairment of mobility is the more common finding with MEE.
Bulging of the TM is the most specific finding of AOM (97%) but has
lower specificity (51%) (Fig. 640-2).
Diagnosis
The 2013 guidelines from the American Academy of Pediatrics for
diagnosis of AOM are more restrictive than were the earlier (2004)
guidelines. The 2004 guidelines employed a 3-part definition: (1) acute
onset of symptoms; (2) presence of an MEE; and (3) signs of acute
middle-ear inflammation. This definition was thought by the 2013 Figure 640-3 Tympanic membrane in acute otitis media.
American Academy of Pediatrics to lack sufficient precision and
thereby liable to include cases of OME and/or enable the diagnosis of bubbles outlined by small amounts of fluid may be visible behind the
AOM to be made without visualizing the TM. TM, a condition often indicative of impending resolution (Fig. 640-3).
A diagnosis of AOM according to the 2013 guideline should be To support a diagnosis of AOM instead of OME in a child with MEE,
made in children who present with: distinct fullness or bulging of the TM may be present, with or without
◆ moderate to severe bulging of the TM or new-onset otorrhea not accompanying erythema, or, at a minimum, MEE should be accompa-
caused by otitis externa nied by ear pain that appears clinically important. Unless intense,
◆ mild bulging of the TM and recent (<48 hr) onset of ear pain or erythema alone is insufficient because erythema, without other abnor-
intense TM erythema malities, may result from crying or vascular flushing. In AOM, the
A diagnosis of AOM should not be made in children without MEE. malleus may be obscured and the TM may resemble a bagel without a
AOM and OME may evolve into the other without any clearly dif- hole but with a central depression (see Fig. 640-3). Rarely, the TM may
ferentiating physical findings; any schema for distinguishing between be obscured by surface bullae or may have a cobblestone appearance.
them is to some extent arbitrary. In an era of increasing bacterial resis- Bullous myringitis is a physical manifestation of AOM and not an etio-
tance, distinguishing between AOM and OME is important in deter- logically discrete entity. Within days after onset, fullness of the mem-
mining treatment, because OME in the absence of acute infection does brane may diminish, even though infection may still be present.
not require antimicrobial therapy. Purulent otorrhea of recent onset is In OME, bulging of the TM is absent or slight or the membrane may
indicative of AOM; thus, difficulty in distinguishing clinically between be retracted (Fig. 640-4); erythema also is absent or slight, but may
AOM and OME is limited to circumstances in which purulent otorrhea increase with crying or with superficial trauma to the external auditory
is not present. Both AOM without otorrhea and OME are accompanied canal incurred in clearing the canal of cerumen.
by physical signs of MEE, namely, the presence of at least 2 of 3 TM Both before and after episodes of OM and also in the absence of
abnormalities: white, yellow, amber, or (rarely) blue discoloration; OM, the TM may be retracted as a consequence of negative middle-ear
opacification other than that caused by scarring; and decreased or air pressure. The presumed cause is diffusion of air from the middle-ear
absent mobility. Alternatively in OME, either air–fluid levels or air cavity more rapidly than it is replaced via the eustachian tube. Mild
retraction is generally self-limited, although in some children it is be thought of as roughly equivalent to TM mobility as perceived visu-
accompanied by mild conductive hearing loss. More extreme retrac- ally during pneumatic otoscopy. The absorption of sound by the TM
tion is of concern, as discussed later in the section on sequelae of OM. varies inversely with its stiffness. The stiffness of the membrane is
least, and accordingly its compliance is greatest, when the air pres-
Conjunctivitis-Associated Otitis Media sures impinging on each of its surfaces—middle-ear air pressure and
Simultaneous appearance of purulent and erythematous conjunctivitis external canal air pressure—are equal. In simple terms, anything
with an ipsilateral OM is a well-recognized presentation, caused by tending to stiffen the TM, such as TM scarring or middle-ear fluid,
nontypeable H. influenzae in most children. reduces the TM compliance, which is recorded as a flattening of the
The disease often is present in multiple family members and affects curve of the tympanogram. An ear filled with middle-ear fluid gener-
young children and infants. Topical ocular antibiotics are ineffective. ally has a very noncompliant TM and, therefore, a flattened tympano-
In an era of resistant organisms, this clinical association can be impor- gram tracing.
tant in antibiotic selection, with oral antibiotics (see later) effective Tympanograms may be grouped into 1 of 3 categories (Fig. 640-5).
against resistant forms of nontypeable H. influenzae. Tracings characterized by a relatively steep gradient, sharp-angled
peak, and middle-ear air pressure (location of the peak in terms of air
Asymptomatic Purulent Otitis Media pressure) that approximates atmospheric pressure (Fig. 640-5A) (type
Rarely, a child will present during a routine exam without fever, irrita- A curve) are assumed to indicate normal middle-ear status. Tracings
bility, or other overt signs of infection, but on exam, the patient will characterized by a shallow peak or no peak are often termed “flat” or
demonstrate an obvious purulent MEE and bulging TM. Although an type B (Fig. 640-5B), and usually are assumed to indicate the presence
uncommon presentation of “acute” OM, the bulging nature of the TM of a middle-ear abnormality that is causing decreased TM compliance.
and the obvious purulence of the effusion do warrant antimicrobial The most common such abnormality in infants and children is MEE.
therapy. Tracings characterized by intermediate findings—somewhat shallow
peak, often in association with a gradual gradient (obtuse-angled peak)
Tympanometry or negative middle-ear air pressure peak (often termed type “C”), or
Tympanometry, or acoustic immittance testing, is a simple, rapid, combinations of these features (Fig. 640-5C)—may or may not be
atraumatic test that, when performed correctly, offers objective evi- associated with MEE, and must be considered nondiagnostic or equiv-
dence of the presence or absence of MEE. The tympanogram provides ocal with respect to OM. However, type C tympanograms do suggest
information about TM compliance in electroacoustic terms that can eustachian tube dysfunction and some ongoing pathology in the
middle ear and warrant follow-up.
When reading a tympanogram it is important to look at the volume
measurement. The type B tympanometric response has to be analyzed
within the context of the recorded volume. A flat, “low”-volume
(≤1 mL) tracing typically reflects the volume of the ear canal only,
representing MEE, which impedes the movement of an intact ear
drum. A flat, high-volume (>1 mL) tracing typically reflects the volume
of the ear canal and middle-ear space, representing a perforation (or
patent tympanostomy tube) in the TM. In a child with a tympanostomy
tube present, a flat tympanogram with a volume <1 mL would suggest
a plugged or nonfunctioning tube and middle-ear fluid, whereas a flat
tympanogram with a volume >1 mL would suggest a patent tympanos-
tomy tube.
Although tympanometry is quite sensitive in detecting MEE, it
can be limited by patient cooperation, the skill of the individual admin-
istering the test, and the age of the child, with less-reliable results in
very young children. Use of tympanometry may be helpful in office
screening, may supplement the examination of difficult to examine
patients, and may help identify patients who require further attention
because their tympanograms are abnormal. Tympanometry also may
be used to help confirm, refine, or clarify questionable otoscopic find-
ings; to objectify the follow-up evaluation of patients with known
Figure 640-4 Tympanic membrane in otitis media with effusion. middle-ear disease; and to validate otoscopic diagnoses of MEE. Even
A B C
Figure 640-5 Tympanograms obtained with a Grason-Stadler GSI 33 Middle Ear Analyzer, exhibiting (A) high admittance, steep gradient (i.e.,
sharp-angled peak), and middle-ear air pressure approximating atmospheric pressure (0 decaPascals [daPa]); (B) low admittance and indeterminate
middle-ear air pressure; and (C) somewhat low admittance, gradual gradient, and markedly negative middle-ear air pressure.
though tympanometry can predict the probability of MEE, it cannot Second, symptomatic improvement and resolution of infection occur
distinguish the effusion of OME from that of AOM. more promptly and more consistently with antimicrobial treatment
than without, even though most untreated cases eventually resolve.
PREVENTION Third, prompt and adequate antimicrobial treatment may prevent the
General measures to prevent OM that have been supported by a development of suppurative complications. The sharp decline in such
number of investigations include avoiding exposure to individuals complications during the last half-century seems likely attributable,
with respiratory infection; appropriate vaccination strategies against at least in part, to the widespread routine use of antimicrobials for
pneumococci and influenzae; avoiding environmental tobacco smoke; AOM. In the Netherlands, where initial antibiotic treatment is rou-
and breast milk feeding. tinely withheld from most children older than 6 mo of age, and where
only approximately 30% of children with AOM receive antibiotics at
IMMUNOPROPHYLAXIS all, the incidence of acute mastoiditis, although low (in children
Heptavalent pneumococcal conjugate vaccine (PCV7) reduced the younger than age 14 yr, 3.8 per 100,000 person-years), appears slightly
overall number of episodes of AOM by only 6-8% but with a 57% higher than rates in other countries with higher antibiotic prescription
reduction in serotype-specific episodes. Reductions of 9-23% are seen rates by about 1-2 episodes per 100,000 person-years. Groups in
in children with histories of frequent episodes, and a 20% reduction is other countries where initial conservative management of AOM is
seen in the number of children undergoing tympanostomy tube inser- the standard in children older than 6 mo, such as Denmark, report
tion. A 13-valent pneumococcal polysaccharide-protein conjugate acute mastoiditis rates similar to those of the Netherlands (4.8 per
vaccine (PCV13) was licensed by the FDA in 2010. PCV13 contains 100,000 person-years).
the 7 serotypes included in PCV7 (serotypes 4, 6B, 9V, 14, 18C, 19F, Given that most episodes of OM will spontaneously resolve, consen-
and 23F) and 6 additional serotypes (serotypes 1, 3, 5, 6A, 7F, and 19A). sus guidelines have been published by the American Academy of Pedi-
The effects of PCV13 on AOM incidence reduce pneumococcal naso- atrics to assist clinicians who wish to consider a period of “watchful
pharyngeal carriage, including serotypes 19A, 7F, and 6C, in young waiting” or observation prior to treating AOM with antibiotics (see
children (younger than age 2 yr) with AOM. Given that 19A is a par- Tables 640-2 and 640-3; Fig. 640-6). The most important aspect of
ticularly invasive pneumococcal serotype, the effect of PCV13 on these guidelines is that close follow-up of the patient must be ensured
reducing complicated AOM will hopefully be of significance. Early to assess for lack of spontaneous resolution or worsening of symptoms
data indicate a significant reduction in the number of invasive pneu- and that patients should be provided with adequate analgesic medica-
mococcal mastoiditis cases since the introduction of PCV13. With the tions (acetaminophen, ibuprofen) during the period of observation.
widespread use of PCV13, continued surveillance will be necessary to When pursuing the practice of watchful waiting in patients with AOM,
detect other emerging serotypes, which are also demonstrating increas- the certainty of the diagnosis, the patient’s age, and the severity of the
ing resistance. Although the influenza vaccine also provides a measure disease should be considered. For younger patients, <2 yr of age, it is
of protection against OM, the relatively limited time during which recommended to treat all confirmed diagnoses of AOM. In very young
individuals and even communities are exposed to influenzaviruses patients, <6 mo of age, even presumed episodes of AOM should be
limits the vaccine’s effectiveness in broadly reducing the incidence of treated because of the increased potential of significant morbidity from
OM. Limitation of OM disease is only a portion of the benefit realized infectious complications. In children between 6 and 24 mo of age who
from the vaccinations for pneumococci and influenza viruses. Support have a questionable diagnosis of OM but severe disease, defined as
for these vaccination programs requires an understanding of the pre- temperature of >39°C (102°F), significant otalgia, or toxic appearance,
ventive benefit for OM in concert with the other benefits. antibiotic therapy is also recommended. Children in this age group
with a questionable diagnosis and nonsevere disease can be observed
TREATMENT for a period of 2-3 days with close follow-up. In children older than
Management of Acute Otitis Media 2 yr of age, observation might be considered in all episodes of nonse-
AOM can be very painful. Whether or not antibiotics are employed for vere OM or episodes of questionable diagnosis, while antibiotic therapy
treatment, pain should be assessed and if present, treated (see Table is reserved for confirmed, severe episodes of AOM. Information from
640-1). Finland suggests that the “watchful waiting” or delayed treatment
Individual episodes of AOM have traditionally been treated with approach does not worsen the recovery from AOM, or increase the
antimicrobial drugs. Concern about increasing bacterial resistance has complication rates. However, watchful waiting may be associated with
prompted some clinicians to recommend withholding antimicrobial transient worsening of the child’s condition and longer overall duration
treatment in some or most cases unless symptoms persist for 2 or 3 of symptoms.
days, or worsen (Table 640-2). Three factors argue in favor of routinely Accurate diagnosis is the most crucial aspect of the treatment of
prescribing antimicrobial therapy for children who have documented OM. In studies utilizing stringent criteria for diagnosis of AOM the
AOM using the diagnostic criteria outlined previously (see “Diagno- benefit of antimicrobial treatment is enhanced. Additionally, subpopu-
sis” above). First, pathogenic bacteria cause a large majority of cases. lations of patients clearly receive more benefit from oral antimicrobial
Table 640-2 Recommendations for Initial Management for Uncomplicated Acute Otitis Media*
UNILATERAL OR
OTORRHEA BILATERAL AOM* WITH BILATERAL AOM* UNILATERAL AOM*
AGE WITH AOM* SEVERE SYMPTOMS† WITHOUT OTORRHEA WITHOUT OTORRHEA
6 mo to 2 yr Antibiotic therapy Antibiotic therapy Antibiotic therapy Antibiotic therapy or
additional observation
≥2 yr Antibiotic therapy Antibiotic therapy Antibiotic therapy or Antibiotic therapy or
additional observation additional observation‡
*Applies only to children with well-documented AOM with high certainty of diagnosis.
†
A toxic-appearing child, persistent otalgia more than 48 hr, temperature ≥39°C (102.2°F) in the past 48 hr, or if there is uncertain access to follow-up after the visit.
‡
This plan of initial management provides an opportunity for shared decision making with the child’s family for those categories appropriate for additional
observation. If observation is offered, a mechanism must be in place to ensure follow-up and begin antibiotics if the child worsens or fails to improve within 48-72 hr
of AOM onset.
NOTE: For infants younger than age 6 mo, a suspicion of AOM should result in antibiotic therapy.
From Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics 131:e964–e999, 2013, Table 4.
Table 640-3 Recommended Antibiotics for (Initial or Delayed) Treatment and for Patients Who Have Failed Initial
Antibiotic Treatment
Antibiotic Treatment After 48-72 hr of Failure of Initial
Initial Immediate or Delayed Antibiotic Treatment Antibiotic Treatment
ALTERNATIVE RECOMMENDED
RECOMMENDED TREATMENT FIRST-LINE
FIRST-LINE TREATMENT (IF PENICILLIN ALLERGY) TREATMENT ALTERNATIVE TREATMENT
‡
Amoxicillin (80-90 mg/kg/day in 2 Cefdinir (14 mg/kg/day in Amoxicillin-clavulanate* Ceftriaxone (50 mg IM or IV for 3
divided doses) 1 or 2 doses) (90 mg/kg/day of days, every other day until clinical
amoxicillin, with improvement; max 3 doses)
6.4 mg/kg/day of Clindamycin (30-40 mg/kg/day in 3
clavulanate in 2 divided doses), with or without
divided doses) third-generation cephalosporin
or Cefuroxime‡ (30 mg/kg/day or Failure of second antibiotic
in 2 divided doses)
Amoxicillin-clavulanate* (90 mg/kg/day Cefpodoxime‡ Ceftriaxone (50 mg IM Clindamycin (30-40 mg/kg/day in 3
of amoxicillin, with 6.4 mg/kg/day of (10 mg/kg/day in 2 or IV for 3 days, every divided doses) with or without
clavulanate [amoxicillin : clavulanate divided doses) other day until clinical third-generation cephalosporin
ratio, 14 : 1] in 2 divided doses) or Ceftriaxone‡ (50 mg IM or improvement or for a Tympanocentesis†
Ceftriaxone (50 mg IM or IV for 3 IV per day for 1 or 3 maximum of 3 doses) Consult specialist†
days, every other day until days)
improvement; max 3 doses)
IM, intramuscular; IV, intravenous.
*May be considered in patients who have received amoxicillin in the previous 30 days or who have the otitis–conjunctivitis syndrome.
†
Perform tympanocentesis/drainage if skilled in the procedure, or seek a consultation from an otolaryngologist for tympanocentesis/drainage. If the
tympanocentesis reveals multidrug-resistant bacteria, seek an infectious disease specialist consultation.
‡
Cefdinir, cefuroxime, cefpodoxime, and ceftriaxone are highly unlikely to be associated with cross reactivity with penicillin allergy on the basis of their distinct
chemical structures.
From Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics 131:e964–e999, 2013, Table 5.
therapy than others. Younger children, children with otorrhea, and chil- β-lactam antibiotics at the site of infection can be achieved for a suf-
dren with bilateral AOM have a significantly enhanced benefit from ficient time interval. Many penicillin-resistant strains of S. pneumoniae
antimicrobial therapy in comparison to older children, children without are also resistant to other antimicrobial drugs, including sulfonamides,
otorrhea, or children with unilateral AOM. macrolides, and cephalosporins. In general, as penicillin resistance
increases, so also does resistance to other antimicrobial classes. Resis-
Bacterial Resistance tance to macrolides, including azithromycin and clarithromycin, by S.
Persons at greatest risk of harboring resistant bacteria are those who pneumoniae has increased rapidly, rendering these antimicrobials far
are younger than 2 yr of age, who are in regular contact with large less effective in treating AOM. One mechanism of resistance to mac-
groups of other children, especially in daycare settings, or who recently rolides also results in resistance to clindamycin, which otherwise is
have received antimicrobial treatment. Bacterial resistance is a particu- generally effective against resistant strains of S. pneumoniae. Unlike
lar problem in relation to OM. The development of resistant bacterial resistance to β-lactam antibiotics, macrolide resistance cannot be over-
strains and their rapid spread have been fostered and facilitated by come by increasing the dose.
selective pressure resulting from extensive use of antimicrobial drugs,
the most common target of which, in children, is OM. Many strains of First-Line Antimicrobial Treatment
each of the pathogenic bacteria that commonly cause AOM are resis- Amoxicillin remains the drug of first choice for uncomplicated AOM
tant to commonly used antimicrobial drugs. under many circumstances because of its excellent record of safety,
Although antimicrobial resistance rates vary between countries, in relative efficacy, palatability, and low cost. In particular, amoxicillin is
the United States approximately 40% of strains of nontypeable H. influ- the most efficacious of available oral antimicrobial drugs against both
enzae and almost all strains of M. catarrhalis are resistant to aminope- penicillin-susceptible and penicillin-nonsusceptible strains of S. pneu-
nicillins (e.g., ampicillin and amoxicillin). In most cases, the resistance moniae. Increasing the dose from the traditional 40-45 mg/kg/24 hr to
is attributable to production of β-lactamase and can be overcome by 80-90 mg/kg/24 hr will generally provide efficacy against penicillin-
combining amoxicillin with a β-lactamase inhibitor (clavulanate) or intermediate and some penicillin-resistant strains. This higher dose
by using a β-lactamase–stable antibiotic. Occasional strains of non- should be used particularly in children younger than 2 yr of age, in
typeable H. influenzae that do not produce β-lactamase are resistant to children who have recently received treatment with β-lactam drugs,
aminopenicillins and other β-lactam antibiotics by virtue of alterations and in children who are exposed to large numbers of other children
in their penicillin-binding proteins. It is worth noting that bacterial because of their increased likelihood of an infection with a nonsuscep-
resistance rates in northern European countries where antibiotic usage tible strain of S. pneumoniae. A limitation of amoxicillin is that it may
is less are comparatively exceedingly lower (β-lactamase resistance in be inactivated by the β-lactamases produced by many strains of non-
6-10% of isolates) than in the United States. typeable H. influenzae and most strains of M. catarrhalis. Episodes of
In the United States, approximately 50% of strains of S. pneumoniae AOM caused by these pathogens often resolve spontaneously. Allergies
are penicillin-nonsusceptible, divided approximately equally between to penicillin antibiotics should be categorized into type I hypersensitiv-
penicillin-intermediate and, even more difficult to treat, penicillin- ity, consisting of urticaria or anaphylaxis, and those that fall short of
resistant strains. A much higher incidence of resistance is seen in type I reactions, such as rash formation. For children with a non–type
children attending daycare. Resistance by S. pneumoniae to the penicil- I reaction in which cross reactivity with cephalosporins is less of a
lins and other β-lactam antibiotics is mediated not by β-lactamase concern, first-line therapy with cefdinir would be an appropriate
production but by alterations in penicillin-binding proteins. This choice. In children with a type I reaction or known sensitivity to
mechanism of resistance can be overcome if higher concentrations of cephalosporin antibiotics there are far fewer choices. Resistance to
1
Child aged 2 mo through 12 A diagnosis of acute otitis media requires:
yr with uncomplicated AOM
presents to office 1) History of acute onset of signs and symptoms
2 2) The presence of middle-ear effusion
The clinician 3) Signs and symptoms of middle-ear inflammation

assesses pain.
a) moderate to severe bulging of the TM or new
3 onset of otorrhea not due to otitis externa
4
Is pain No b) mild bulging of the TM and recent (48 hr)
present? Go to Box 6.
onset of ear pain or intense TM erythema
Yes A diagnosis of AOM should not be made in

5
children without MEE.
Clinician recommends
treatment to reduce
pain.
6 9 10
Is observation an Does the child Amoxicillin at a dose of

No have fever No 80-90 mg/kg/day is the
appropriate initial
treatment option?* 39C and/or moderate initial antibacterial of
or severe otalgia? choice for most children.
Yes
7
Yes 11
Child is observed for 48 to 12
72 hr with assurance of Go to Box 14.
appropriate follow-up. Child managed with
appropriate
antibacterial therapy. Criteria for antibacterial treatment or observation
8
in children with nonsevere illness:*
Go to Box 14.
13 1) 6 mo: antibacterial treatment
Go to Box 14. 2) 6 mo to 2 yr antibacterial treatment with cer-
tain diagnosis or severe illness or observation with
uncertain diagnosis and nonsevere illness
3) 2 yr and older: antibacterial treatment if severe

illness or observe with nonsevere illness with certain
diagnosis; observation for uncertain diagnosis
*Caregiver is informed and agrees to the option of

observation.
Caregiver is able to monitor child and return should
condition worsen.
Systems are in place for ready communication with
the clinician, reevaluation, and obtaining medication
if necessary.
14
16
Did patient respond
to initial treatment Clinician reassesses
intervention (either No
and confirms
antibacterial diagnosis of AOM.
treatment or
observation)? 18
17
Assess for other causes
15 Yes Is diagnosis No
of AOM of illness and manage
Patient follow-up confirmed? appropriately.
as appropriate.
Yes
19
Clinician should initiate
antibacterial treatment for children Antibacterial choice
initially managed with observation should be based on the
or change antibacterial treatment likely pathogen(s)
for patients initially managed with present and on clinical
antibacterial therapy. experience.
Figure 640-6 Management of acute otitis media. (From Subcommittee on Management of Acute Otitis Media: Diagnosis and management of
acute otitis media, Pediatrics 113:1451–1465, 2004.)
trimethoprim-sulfamethoxazole by many strains of both nontypeable the FDA for use in children, many clinicians have employed quino-
H. influenzae and S. pneumoniae and a reported high clinical failure lones in this patient population. Early alternative management in
rate in children with AOM treated initially with this antimicrobial these allergic patients with tympanostomy tubes can allow for lessen-
argue against its use. Similarly, increasing rates of macrolide resistance ing of the severity of their disease and the utilization of topical
argue against the efficacy of azithromycin. Although not approved by antimicrobials.
Duration of Treatment available 7 : 1 formulation. Diarrhea, especially in infants and young

The duration of treatment of AOM has historically been set at 10 days children, is a common adverse effect, but may be ameliorated in some
and most efficacy studies examining antimicrobial treatment in AOM cases by feeding active culture yogurt, and usually is not severe enough
have utilized this duration as a benchmark. Studies comparing shorter to require cessation of treatment. Cefdinir has demonstrated broad
with longer durations of treatment suggest that short-course treatment efficacy in treatment, is generally well tolerated with respect to taste,
will often prove inadequate in children younger than 6 yr of age and and can be given as a once-daily regimen. The ability to also utilize
particularly in children younger than 2 yr of age. Thus, for most epi- cefdinir in most children with mild type 1 hypersensitivity reactions
sodes in most children, treatment that provides tissue concentrations has further added to its favorable selection as a second-line agent.
of an antimicrobial for at least 10 days is advisable. Treatment for Both cefuroxime axetil and intramuscular ceftriaxone have important
longer than 10 days may be required for children who are very young limitations for use in young children. The currently available suspen-
or are having severe episodes or whose previous experience with OM sion of cefuroxime axetil is not palatable and its acceptance is low.
has been problematic. Ceftriaxone treatment entails both the pain of intramuscular injection
and substantial cost, and the injection may need to be repeated once
Follow-Up or twice at 2 day intervals to achieve the desired degree of effective-
The principal goals of follow-up are to assess the outcome of treatment ness. Nonetheless, use of ceftriaxone is appropriate in severe cases of
and to differentiate between inadequate response to treatment and AOM when oral treatment is not feasible, or in highly selected cases
early recurrence. The appropriate interval for follow-up should be indi- after treatment failure using orally administered second-line antimi-
vidualized. Follow-up within days is advisable in the young infant with crobials (i.e., amoxicillin-clavulanate or cefuroxime axetil), or when
a severe episode or in a child of any age with continuing pain. Follow-up highly resistant S. pneumoniae is found in aspirates obtained from
within 2 wk is appropriate for the infant or young child who has been diagnostic tympanocentesis.
having frequent recurrences. At that point, the TM is not likely to have Clarithromycin and azithromycin have only limited activity against
returned to normal, but substantial improvement in its appearance nonsusceptible strains of S. pneumoniae and against β-lactamase–
should be evident. In the child with only a sporadic episode of AOM producing strains of nontypeable H. influenzae. Macrolide use also
and prompt symptomatic improvement, follow-up 1 mo after initial appears to be a major factor in causing increases in rates of resistance
examination is early enough, or in older children, no follow-up may to macrolides by group A streptococcus and S. pneumoniae. Clinda-
be necessary. The continuing presence of MEE alone following an mycin is active against most strains of S. pneumoniae, including resis-
episode of AOM is not an indication for additional or second-line tant strains, but is not active against nontypeable H. influenzae or M.
antimicrobial treatment. However, persisting MEE does warrant addi- catarrhalis.
tional follow-up to ensure that this resolves and does not lead to per- Other antimicrobial agents that have been traditionally utilized in
sisting hearing loss or other complications. the management of AOM have such significant lack of effectiveness
against resistant organisms that employment seldom outweighs the
Unsatisfactory Response to potential side effects or complications possible from the medications.
First-Line Treatment This includes cefprozil, cefaclor, loracarbef, cefixime, trimethoprim-
AOM is essentially a closed-space infection and its resolution depends sulfamethoxazole, and erythromycin-sulfisoxazole. Cefpodoxime has
both on eradication of the offending organism and restoration of demonstrated reasonable effectiveness in some investigations but is
middle-ear ventilation. Factors contributing to unsatisfactory response generally poorly tolerated because of its taste.
to first-line treatment, in addition to inadequate antimicrobial efficacy,
include poor compliance with treatment regimens; concurrent or ANTIMICROBIAL PROPHYLAXIS
intercurrent viral infection; persistent eustachian tube dysfunction and In children who have developed frequent episodes of AOM, antimi-
middle-ear underaeration; reinfection from other sites or from incom- crobial prophylaxis with subtherapeutic doses of an aminopenicillin or
pletely eradicated middle-ear pathogens; and immature or impaired a sulfonamide has been utilized in the past to provide protection
host defenses. The identification of biofilm formation in the middle ear against recurrences of AOM (although not of OME). However, because
of children with chronic OM also indicates that, in some children, of the increased incidence of resistant organisms and the contribution
eradication with standard antimicrobial therapy is likely to be unsuc- of antimicrobial usage to bacterial resistance, the risks of sustained
cessful. Despite these many potential factors, switching to an alterna- antimicrobial prophylaxis clearly outweigh potential benefits.
tive or second-line drug is reasonable when there has been inadequate
improvement in symptoms or in middle-ear status as reflected in the Myringotomy and Tympanocentesis
appearance of the TM, or when the persistence of purulent nasal dis- Myringotomy is a long-standing treatment for AOM but is not com-
charge suggests that the antimicrobial drug being used has less-than- monly needed in children receiving antimicrobials. Indications for
optimal efficacy. Second-line drugs may also appropriately be used myringotomy in children with AOM include severe, refractory pain;
when AOM develops in a child already receiving antimicrobial therapy, hyperpyrexia; complications of AOM such as facial paralysis, mastoid-
or in an immunocompromised child, or in a child with severe symp- itis, labyrinthitis, or central nervous system infection; and immuno-
toms whose previous experience with OM has been problematic. logic compromise from any source. Myringotomy should be considered
as third-line therapy in patients that have failed 2 courses of antibiotics
Second-Line Treatment for an episode of AOM. In children with AOM in whom clinical
When treatment of AOM with a first-line antimicrobial drug has response to vigorous, second-line treatment has been unsatisfactory,
proven inadequate, a number of second-line alternatives are available either diagnostic tympanocentesis or myringotomy is indicated to
(see Table 640-3). Drugs chosen for second-line treatment should be enable identification of the offending organism and its sensitivity
effective against β-lactamase–producing strains of nontypeable H. profile. Either procedure may be helpful in effecting relief of pain.
influenzae and M. catarrhalis and against susceptible and most non- Tympanocentesis with culture of the middle-ear aspirate may also be
susceptible strains of S. pneumoniae. Only 4 antimicrobial agents meet indicated as part of the sepsis work-up in very young infants with
these requirements: amoxicillin-clavulanate, cefdinir, cefuroxime AOM who show systemic signs of illness such as fever, vomiting, or
axetil, and intramuscular ceftriaxone. Because high-dose amoxicillin lethargy, and whose illness accordingly cannot be presumed to be
(80-90 mg/kg/24 hr) is effective against most strains of S. pneumoniae limited to infection of the middle ear. Performing tympanocentesis can
and because the addition of clavulanate extends the effective antibacte- be facilitated by use of a specially designed tympanocentesis aspirator.
rial spectrum of amoxicillin to include β-lactamase–producing bac- Studies reporting the usage of strict, individualized criteria for the
teria, high-dose amoxicillin-clavulanate is particularly well-suited as diagnosis of AOM that include office tympanocentesis with bacterial
a second-line drug for treating AOM. The 14 : 1 amoxicillin-clavulanate culture followed by culture-guided antimicrobial therapy demonstrate
formulation contains twice as much amoxicillin as the previously significant reduction in the frequency of recurrent AOM episodes and
tympanostomy tube surgery. However, many primary care physicians for culture and the possibility of the development of fungal otitis,
do not feel comfortable performing this procedure, there is the poten- which has shown an increase with the utilization of broad-spectrum
tial for complications, and parents may view this procedure as trau- quinolone ototopicals, patients that fail topical therapy should also
matic. Often children requiring this intervention have a strong enough have culture performed to rule out the development of fungal otitis.
history of recurrent OM to warrant the consideration of tympanos- Other otic preparations are available; although these either have some
tomy tube placement, so that the procedure can be performed under risk of ototoxicity or have not received approval for use in the middle
general anesthesia. ear, many of these preparations were widely used prior to the develop-
ment of the current quinolone drops and were generally considered
Early Recurrence After Treatment reasonably safe and effective. In all cases of tube otorrhea, attention to
Recurrence of AOM after apparent resolution may be caused by either aural toilet (e.g., cleansing the external auditory canal of secretions,
incomplete eradication of infection in the middle ear or upper respira- and avoidance of external ear water contamination) is important. In
tory tract reinfection by the same or a different bacteria or bacterial some cases with very thick, tenacious discharge, topical therapy may
strain. Recent antibiotic therapy predisposes patients to an increased be inhibited due to lack of delivery of the medication to the site of
incidence of resistant organisms, which should also be considered in infection. Suctioning and removal of the secretions, often done through
choosing therapy, and, generally, initiating therapy with a second-line referral to an otolaryngologist, may be quite helpful. When children
agent is advisable (see Table 640-3). with tube otorrhea fail to improve satisfactorily with conventional
outpatient management, they may require tube removal, or hospital-
Myringotomy and Insertion ization to receive parenteral antibiotic treatment, or both.
of Tympanostomy Tubes
When AOM is recurrent, despite appropriate medical therapy, consid- MANAGEMENT OF OTITIS MEDIA
eration of surgical management of AOM with tympanostomy tube WITH EFFUSION
insertion is warranted. This procedure is effective in reducing the rate Management of OME depends on an understanding of its natural
of AOM in patients with recurrent OM and in significantly improving history and its possible complications and sequelae. Most cases of
the quality of life in patients with recurrent AOM. Individual patient OME resolve without treatment within 3 mo. To distinguish between
factors, including the risk profile, severity of AOM episodes, child’s persistence and recurrence, examination should be conducted monthly
development and age, presence of a history of adverse drug reactions, until resolution; hearing should be assessed if effusion has been present
concurrent medical problems, and parental wishes, will affect the for longer than 3 mo. When MEE persists for longer than 3 mo, con-
timing of a decision to consider referral for this procedure. When a sideration of referral to an otolaryngologist may be appropriate. For
patient experiences 3 episodes of AOM in a 6 mo period or 4 episodes young children, this referral is warranted for the assessment of hearing
in a 12 mo period with 1 episode in the preceding 6 mo, potential levels. In older children (generally older than age 4 yr), and depending
surgical management of the child’s AOM should be discussed with the upon the expertise in the primary care physician’s office, hearing
parents. Additionally, often patients with recurrent AOM may have screening may be achieved by the primary care physician. For any child
persisting MEE between episodes with accompanying hearing loss, who fails a hearing screening in the primary care physician’s office,
which may add to the indication for tympanostomy tube placement. referral to an otolaryngologist is warranted. In considering the decision
to refer the patient for consultation, the clinician should attempt to
Tube Otorrhea determine the impact of the OME on the child. Although hearing loss
Although tympanostomy tubes often reduce the incidence of AOM in may be of primary concern, OME causes a number of other difficulties
most children, patients with tympanostomy tubes may still develop in children that should also be considered. These include predisposi-
AOM. One advantage of tympanostomy tubes in children with recur- tion to recurring AOM, pain, disturbance of balance, and tinnitus. In
rent AOM is that if patients do develop an episode of AOM with a addition, long-term sequelae that have been demonstrated to be associ-
functioning tube in place, these patients will manifest purulent drain- ated with OME include pathologic middle-ear changes; atelectasis of
age from the tube. By definition, children with functioning tympanos- the TM and retraction pocket formation; adhesive OM; cholesteatoma
tomy tubes without otorrhea do not have bacterial AOM as a cause for formation and ossicular discontinuity; and conductive and sensorineu-
a presentation of fever or behavioral changes and should not be treated ral hearing loss. Long-term adverse effects on speech, language, cogni-
with oral antibiotics. If tympanostomy tube otorrhea develops, ototopi- tive, and psychosocial development have also been demonstrated. This
cal treatment should be considered as first-line therapy. With a func- impact is related to the duration of effusion present, whether the effu-
tioning tube in place, the infection is able to drain, there is usually sion is unilateral or bilateral, the degree of underlying hearing loss, and
negligible pain associated with the infection, and the possibility of other developmental and social factors affecting the child. In consider-
developing a serious complication from an episode of AOM is extremely ing the impact of OME on development, it is especially important to
remote. The current quinolone otic drops approved by the U.S. Food take into consideration the overall presentation of the child. Although
and Drug Administration for use in the middle-ear space in children it is unlikely that OME causing unilateral hearing loss in the mild range
are formulated with ciprofloxacin/dexamethasone (Ciprodex) and will have long-term negative effects on an otherwise healthy and devel-
ofloxacin (Floxin). The topical delivery of these otic drops allows them opmentally normal child, even a mild hearing loss in a child with other
to utilize a higher antibiotic concentration than can be tolerated by developmental or speech delays certainly has the potential to com-
administering oral antibiotics and they have excellent coverage of even pound this child’s difficulties (Table 640-4). At a minimum, children
the most resistant strains of common middle-ear pathogens as well as with OME persisting longer than 3 mo deserve close monitoring of
coverage of S. aureus and Pseudomonas aeruginosa. The high rate of their hearing levels with skilled audiologic evaluation; frequent assess-
success of these topical preparations, their broad coverage, the lower ment of developmental milestones, including speech and language
likelihood of their contributing to the development of resistant organ- assessment; and attention paid to their rate of recurrent AOM.
isms, the relative ease of administration, the lack of significant side
effects, and the lack of ototoxicity makes them the first choice for tube Variables Influencing Otitis Media with Effusion
otorrhea. Oral antibiotic therapy should generally be reserved for cases Management Decisions
of tube otorrhea that have other associated systemic symptoms, patients Patient-related variables that affect decisions on how to manage OME
who have difficulty in tolerating the use of topical preparations, or, include the child’s age; the frequency and severity of previous episodes
possibly, patients who have failed an attempt at topical otic drops. of AOM and the interval since the last episode; the child’s current
Despite these advantages of ototopical therapy, survey data have indi- speech and language development; the presence of a history of adverse
cated that, compared to otolaryngologists, primary care practitioners drug reactions, concurrent medical problems, or risk factors such as
are less likely to prescribe ototopicals as first-line therapy in tympanos- daycare attendance; and the parental wishes. In considering surgical
tomy tube otorrhea. As a result of the relative ease in obtaining fluid management of OME with tympanostomy tubes, particular benefit is
appropriate. Myringotomy alone, without tympanostomy tube inser-

Table 640-4 Sensory, Physical, Cognitive, or Behavioral tion, permits evacuation of middle-ear effusion and may sometimes be
Factors That Place Children Who Have effective, but often the incision heals before the middle-ear mucosa
Otitis Media with Effusion at an Increased returns to normal and the effusion soon reaccumulates. Inserting a
Risk for Developmental Difficulties (Delay tympanostomy tube offers the likelihood that middle-ear ventilation
or Disorder) will be sustained for at least as long as the tube remains in place and
Permanent hearing loss independent of otitis media with effusion functional. Tympanostomy tubes have a variable duration of efficacy
Suspected or diagnosed speech and language delay or disorder based on design. Tubes that are designed for a shorter duration,
Autism-spectrum disorder and other pervasive developmental 6-12 mo, have a lesser impact on disease-free middle-ear spaces in
disorders children. Some studies comparing the efficacy of tympanostomy tube
Syndromes (e.g., Down) or craniofacial disorders that include types, including shorter-acting tubes, with watchful waiting provide a
cognitive, speech, and language delays less helpful assessment of the differences between these approaches.
Blindness or uncorrectable visual impairment Tubes that are somewhat longer acting, effective for 12-18 mo, are
Cleft palate with or without associated syndrome generally more appropriate for most children undergoing tube place-
Developmental delay
ment. Regardless of type, tympanostomy tube placement nearly uni-
From American Academy of Family Physicians; American Academy of formly reverses the conductive hearing loss associated with OME.
Otolaryngology-Head and Neck Surgery; American Academy of Pediatrics Occasional episodes of obstruction of the tube lumen and premature
Subcommittee on Otitis Media with Effusion: Otitis media with effusion,
Pediatrics 113(5):1412–1429, 2004, Table 3, p. 1416.
tube extrusion may limit the effectiveness of tympanostomy tubes, and
tubes can also be associated with otorrhea. However, placement of
tympanostomy tubes is generally quite effective in providing resolution
of OME in children. Tympanostomy tubes generally extrude on their
seen in patients with persisting OME punctuated by episodes of AOM, own but rarely require surgical removal after several years in place.
as the tubes generally provide resolution of both conditions. Disease- Sequelae following tube extrusion include residual perforation of the
related variables that most otolaryngologists consider in the treatment eardrum, tympanosclerosis, localized or diffuse atrophic scarring of
of OME include whether the effusion is unilateral or bilateral; the the eardrum that may predispose to the development of atelectasis or
apparent quantity of effusion; the duration, if known; the degree of a retraction pocket, or both, residual conductive hearing loss, and
hearing impairment; the presence or absence of other possibly related cholesteatoma. The more serious of these sequelae are quite infrequent.
symptoms, such as tinnitus, vertigo, or disturbance of balance; and the Recurrence of middle-ear effusion following the extrusion of tubes
presence or absence of mucopurulent or purulent rhinorrhea, which, does develop, especially in younger children; most children without
if sustained for longer than 2 wk, would suggest that concurrent naso- underlying craniofacial abnormalities only require 1 set of tympanos-
pharyngeal or paranasal sinus infection is contributing to continuing tomy tubes, with developmental changes providing improved middle-
compromise of middle-ear ventilation. ear health and resolution of chronic OME by the time of tube extrusion.
Because even previously persistent OME often clears spontaneously
Medical Treatment during the summer mo, watchful waiting through the summer season
In some studies, antimicrobials have demonstrated some efficacy in is also advisable in most children with OME who are otherwise well.
resolving OME, presumably because they help eradicate nasopharyn- In considering surgical management of OME in children, primarily in
geal infection or unapparent middle-ear infection, or both. The most those with bilateral disease and hearing loss, it has been demonstrated
significant effects of antibiotics for OME have been shown with treat- that placement of tympanostomy tubes results in a significant improve-
ment durations of 4 wk and 3 mo. However, in the current era of bacte- ment in their quality of life.
rial antimicrobial resistance, the small potential benefit of antimicrobial
therapy is outweighed by the negative potential of treatment and is not Adenoidectomy
recommended. Instead, treatment should be limited to cases in which Adenoidectomy is efficacious to some extent in reducing the risk of
there is evidence of associated bacterial upper respiratory tract infec- subsequent recurrences of both AOM and OME in children who have
tion or untreated middle-ear infection. For this purpose, the most undergone tube insertion and in whom, after extrusion of tubes, OM
broadly effective drug available should be used as recommended for continues to be a problem. Efficacy appears to be independent of
AOM. adenoid size and probably derives from removal of the focus of infec-
The efficacy of corticosteroids in the treatment of OME is probably tion in the nasopharynx as a site of biofilm formation, chronic inflam-
short term. The risk: benefit ratio for steroids would argue against their mation impacting eustachian tube function, and recurrent seeding of
use. Antihistamine-decongestant combinations are not effective in the middle ear via the eustachian tube. In younger children with recur-
treating children with OME. Antihistamines alone, decongestants rent AOM who have not previously undergone tube insertion, ade-
alone, and mucolytic agents are unlikely to be effective. The risk profile noidectomy is usually not recommended along with tube insertion,
for decongestants and antihistamines in children suggests that they are unless significant nasal airway obstruction or recurrent rhinosinusitis
not indicated in the treatment of OME. Allergic management, includ- is associated, in which case, performing adenoidectomy might be
ing antihistamine therapy, might prove helpful in children with prob- considered.
lematic OME who also have evidence of environmental allergies,
although supporting data specifically analyzing this patient population Complications of Acute Otitis Media
are not conclusive. Recent randomized controlled trials do not support Most complications of AOM consist of the spread of infection to
the usage of topical intranasal steroid sprays to treat the manifestations adjoining or nearby structures or the development of chronicity, or
of eustachian tube dysfunction. Inflation of the eustachian tube by the both. Suppurative complications are relatively uncommon in children
Valsalva maneuver or other means has not demonstrated long-term in developed countries but occur not infrequently in disadvantaged
efficacy but is unlikely to lead to significant harm. Other “alternative” children whose medical care is limited. The complications of AOM
therapies, including spinal manipulation, currently have no demon- may be classified as either intratemporal or intracranial.
strated efficacy or role in children with OME.
Intratemporal Complications
Myringotomy and Insertion Direct but limited extension of AOM leads to complications within the
of Tympanostomy Tubes local region of the ear and temporal bone. These complications include
When OME persists despite an ample period of watchful waiting, dermatitis, TM perforation, chronic suppurative OM (CSOM), mas-
generally 3-6 mo or perhaps longer in children with unilateral effusion, toiditis, hearing loss, facial nerve paralysis, cholesteatoma formation,
consideration of surgical intervention with tympanostomy tubes is and labyrinthitis.
Infectious Dermatitis Fever

This is an infection of the skin of the external auditory canal resulting Lethargy/malaise/irritability
from contamination by purulent discharge from the middle ear. The Otalgia
skin is often erythematous, edematous, and tender. Management con- Bulging or erythematous TM
sists of proper hygiene combined with systemic antimicrobials and
ototopical drops as appropriate for treating AOM and tube otorrhea.
Proptotic ear?
Tympanic Membrane Perforation Postauricular edema or fluctuant mass?
Rupture of the TM can occur with episodes of either AOM or OME. EAC or neck mass or edema?
Although damage to the TM from these episodes generally heals spon- Facial nerve weakness?
taneously, chronic perforations can develop in a small number of cases Vestibular signs and symptoms?
and require further surgical intervention in the future. Neurologic signs and symptoms?
Chronic Suppurative Otitis Media

CSOM consists of persistent middle-ear infection with discharge Yes No
through a TM perforation. The disease is initiated by an episode of
AOM with rupture of the membrane. The mastoid air cells are invari-
ably involved. The most common etiologic organisms are P. aeruginosa CT scan with contrast Postauricular signs or symptoms?
and S. aureus; however, the typical AOM bacterial pathogens may also Otolaryngology consult (pain, erythema, or tenderness)
be the cause, especially in younger children or in the winter months. ± Neurosurgery consult
Treatment is guided by the results of microbiologic investigation. If an
associated cholesteatoma is not present, parenteral antimicrobial treat-
ment combined with assiduous aural cleansing is likely to be successful Yes No
in clearing the infection, but in refractory cases, tympanomastoidec-
tomy can be required.
CT scan with contrast Treat as acute
Acute Mastoiditis otitis media
Technically, all cases of AOM are accompanied by mastoiditis by virtue
of the associated contiguous inflammation of the mastoid air cells. Postauricular abscess?
However, early in the course of the disease, no signs or symptoms of Mastoid cortical bony erosion?
mastoid infection are present, and the inflammatory process usually is Coalescence of mastoid air cells?
readily reversible, along with the AOM, in response to antimicrobial
treatment. Spread of the infection to the overlying periosteum, but
without involvement of bone, constitutes acute mastoiditis with peri-
Yes No
osteitis. In such cases, signs of mastoiditis are usually present, includ-
ing redness and swelling in the postauricular area, often with protrusion
and displacement of the pinna inferiorly and anteriorly (Fig. 640-7 and
Table 640-5). Treatment with myringotomy and parenteral antibiotics, Otolaryngology Admit for
if instituted promptly, usually provides satisfactory resolution. consult IV antibiotic therapy
In acute mastoid osteitis, or coalescent mastoiditis, infection has
progressed further to cause destruction of the bony trabeculae of the
mastoid. Frank signs and symptoms of mastoiditis are usually, but not Clinical improvement
always, present. In acute petrositis, infection has extended further to in 24 hr?
involve the petrous portion of the temporal bone. Eye pain, a result of
irritation of the ophthalmic branch of cranial nerve V, is a prominent
symptom. Cranial nerve VI palsy is a later finding, suggesting further Yes No
extension of the infectious process along the cranial base. Gradenigo
syndrome is the triad of suppurative OM, paralysis of the external
rectus muscle, and pain in the ipsilateral orbit. Rarely, mastoid infec-
Transition to oral antibiotics Otolaryngology
tion spreads external to the temporal bone into the neck musculature and discharge home consult
that attaches to the mastoid tip, resulting in an abscess in the neck, with close PCP follow-up
termed a Bezold abscess.
When mastoiditis is suspected or diagnosed clinically, CT scanning Figure 640-7 Diagnosis and treatment algorithm for cases of sus-
of the temporal bones can be considered to further clarify the nature pected acute mastoiditis. (From Lin HW, Shargorodsky J, Gopen Q.
and extent of the disease. Bony destruction of the mastoid must be Clinical strategies for the management of acute mastoiditis in the
differentiated from the simple clouding of mastoid air cells that is pediatric population. Clin Pediatr (Phila) 49(2):110–115, 2010, Fig. 5.)
found often in uncomplicated cases of OM. The most common caus-
ative organisms in all variants of acute mastoiditis are S. pneumoniae, respond to the conservative regimen recommended for that condition.
group A streptococcus, and nontypeable H. influenzae. P. aeruginosa In most cases, mastoidectomy also is required.
is also a causative agent, primarily in patients with CSOM. Children
with acute mastoid osteitis generally require intravenous antimicrobial Facial Paralysis
treatment and mastoidectomy, with the extent of the surgery depen- The facial nerve, as it traverses the middle ear and mastoid bone, may
dent on the extent of the disease process. Early cases of mastoid osteitis be affected by adjacent infection. Facial paralysis occurring as a com-
may respond to myringotomy and parenteral antibiotics. Insofar as plication of AOM is uncommon, and often resolves after myringotomy
possible, choice of the antimicrobial regimen should be guided by the and parenteral antibiotic treatment. Facial paralysis in the presence of
findings of microbiologic examination from cultures. AOM requires urgent attention as prolonged infection can result in the
Each of the variants of mastoiditis may also occur in subacute or development of permanent facial paralysis, which can have a devastat-
chronic form. Symptoms are correspondingly less prominent. Chronic ing effect on a child. Facial paralysis in an infant or child requires
mastoiditis is always accompanied by CSOM, and occasionally will complete and unequivocal examination of the TM and middle-ear
Table 640-5 Differential Diagnosis of Postauricular Involvement of Acute Mastoiditis with Periosteitis/Abscess
Postauricular Signs and Symptoms
EXTERNAL CANAL MIDDLE-EAR
DISEASE CREASE* ERYTHEMA MASS TENDERNESS INFECTION EFFUSION
Acute mastoiditis with May be Yes No Usually No Usually
periosteitis absent
Acute mastoiditis with Absent Maybe Yes Yes No Usually
subperiosteal abscess
Periosteitis of pinna with Intact Yes No Usually No No
postauricular extension
External otitis with Intact Yes No Usually Yes No
postauricular extension
Postauricular Intact No Yes (circumscribed) Maybe No No
lymphadenitis
*Postauricular crease (fold) between pinna and postauricular area.
From Bluestone CD, Klein JO, editors: Otitis media in infants and children, ed 3, Philadelphia, 2001, WB Saunders, p. 333.
presents as a chronically draining ear in a patient with a history of

previous ear disease. Cholesteatoma should be suspected if otoscopy
demonstrates an area of TM retraction or perforation with white,
caseous debris persistently overlying this area. Along with otorrhea
from this area, granulation tissue or polyp formation identified in
conjunction with this history and presentation should prompt suspi-
cion of cholesteatoma. The most common location for cholesteatoma
development is in the superior portion of the TM (pars flaccida). Most
patients also present with conductive hearing loss on audiologic evalu-
ation. When cholesteatoma is suspected, otolaryngology consultation
S
should be sought immediately. Delay in recognition and treatment can
have significant long-term consequences, including the need for more
extensive surgical treatment, permanent hearing loss, facial nerve
injury, labyrinthine damage with loss of balance function, and intra-
cranial extension. The required treatment for cholesteatoma is tympa-
nomastoid surgery.
Congenital cholesteatoma is an uncommon condition generally
identified in younger patients (Fig. 640-9). The etiology of congenital
cholesteatoma is thought to be a result of epithelial implantation in the
middle-ear space during otologic development in utero. Congenital
cholesteatoma most commonly presents in the anterior-superior quad-
rant of the TM but can be found elsewhere. Congenital cholesteatoma
appears as a discrete, white opacity in the middle-ear space on otos-
Figure 640-8 A retraction pocket cholesteatoma of the posterosu- copy. Unlike patients with acquired cholesteatoma, there is generally
perior quadrant. The incus long process is eroded, which leaves the not a strong history of OM or chronic ear disease, history of otorrhea,
drum adherent to the stapes head (S). An effusion is present in the
middle ear, and squamous debris emanates from the attic. (From Isaa-
or changes in the TM anatomy such as perforation or retraction.
cson G: Diagnosis of pediatric cholesteatoma, Pediatrics 120:603–608, Similar to acquired cholesteatoma many patients do have some degree
2007, Fig. 9, p. 607.) of abnormal findings on audiologic evaluation, unless identified very
early. Congenital cholesteatoma also requires surgical resection.
space. Any difficulty in examination requires urgent consultation with Labyrinthitis

an otolaryngologist. Any examination that demonstrates an ear abnor- This occurs uncommonly as a result of the spread of infection from the
mality also requires urgent referral to an otolaryngologist. If facial middle ear and/or mastoid to the inner ear (see Chapter 641). Choles-
paralysis develops in a child with mastoid osteitis or with chronic sup- teatoma or CSOM is the usual source. Symptoms and signs include
purative OM, mastoidectomy should be undertaken urgently. vertigo, tinnitus, nausea, vomiting, hearing loss, nystagmus, and clum-
siness. Treatment is directed at the underlying condition and must be
Cholesteatoma undertaken promptly to preserve inner-ear function and prevent the
Cholesteatoma is a cyst-like growth originating in the middle ear, lined spread of infection.
by keratinized, stratified squamous epithelium and containing desqua-
mated epithelium and/or keratin (see Chapter 638; Fig. 640-8). INTRACRANIAL COMPLICATIONS
Acquired cholesteatoma develops most often as a complication of Meningitis, epidural abscess, subdural abscess, focal encephalitis, brain
long-standing chronic OM. The condition also may develop from a abscess (see Chapters 603 and 604), sigmoid sinus thrombosis (also
deep retraction pocket of the TM or as a consequence of epithelial called lateral sinus thrombosis), and otitic hydrocephalus each may
implantation in the middle-ear cavity from traumatic perforation of develop as a complication of acute or chronic middle-ear or mastoid
the TM or insertion of a tympanostomy tube. Cholesteatomas tend infection, through direct extension, hematogenous spread, or throm-
to expand progressively, causing bony resorption, often extend into bophlebitis. Bony destruction adjacent to the dura is often involved,
the mastoid cavity, and may extend intracranially with potentially and a cholesteatoma may be present. In a child with middle-ear or
life-threatening consequences. Acquired cholesteatoma commonly mastoid infection, the presence of any systemic symptom, such as high
A B C
Figure 640-9 A, Congenital cholesteatoma of the anterosuperior quadrant. B, The eardrum is reflected downward to reveal a white spherical
lesion. C, Removal of the lesion. (From Isaacson G: Diagnosis of pediatric cholesteatoma, Pediatrics 120:603–608, 2007, Fig. 3, p. 605.)
spiking fevers, headache, or lethargy of extreme degree, or a finding of chronic infection, but some may also result from the noninfective
meningismus or of any central nervous system sign on physical exami- inflammation of long-standing OME. The various sequelae may occur
nation should prompt suspicion of an intracranial complication. singly, or interrelatedly in various combinations.
When an intracranial complication is suspected, lumbar puncture Tympanosclerosis consists of whitish plaques in the TM and
should be performed only after imaging studies establish that there is nodular deposits in the submucosal layers of the middle ear. The
no evidence of mass effect or hydrocephalus. In addition to examina- changes involve hyalinization with deposition of calcium and phos-
tion of the cerebrospinal fluid, culture of middle-ear exudate obtained phate crystals. Uncommonly, there may be associated conductive
via tympanocentesis may identify the causative organism, thereby hearing loss. In developed countries, probably the most common cause
helping guide the choice of antimicrobial medications. Myringotomy of tympanosclerosis is tympanostomy tube insertion.
should be performed to permit middle-ear drainage. Concurrent tym- Atelectasis of the TM is a descriptive term applied to either severe
panostomy tube placement is preferable to allow for continued decom- retraction of the TM caused by high negative middle-ear pressure or
pression of the “infection under pressure” that is the causative event loss of stiffness and medial prolapse of the membrane as a consequence
leading to intracranial spread of the infection. of long-standing retraction or severe or chronic inflammation. A
Treatment of intracranial complications of OM requires urgent, retraction pocket is a localized area of atelectasis. Atelectasis is often
otolaryngologic, and, often, neurosurgical consultation, intravenous transient and usually unaccompanied by symptoms, but a deep retrac-
antibiotic therapy, drainage of any abscess formation, and tympano- tion pocket may lead to erosion of the ossicles and adhesive otitis, and
mastoidectomy in patients with coalescent mastoiditis. may serve as the nidus of a cholesteatoma. For a deep retraction pocket,
Sigmoid sinus thrombosis may be complicated by dissemination of and for the unusual instance in which atelectasis is accompanied by
infected thrombi with resultant development of septic infarcts in symptoms such as otalgia, tinnitus, or conductive hearing loss, the
various organs. With prompt recognition and wide availability of MRI, required treatment is tympanostomy tube insertion and, at times, tym-
which facilitates diagnosis, this complication is exceedingly rare. Mas- panoplasty. Patients with persisting atelectasis and retraction pockets
toidectomy may be required even in the absence of osteitis or coales- should have referral to an otolaryngologist.
cent mastoiditis, especially in the case of propagation or embolization Adhesive OM consists of proliferation of fibrous tissue in the
of infected thrombi. In the absence of coalescent mastoiditis, sinus middle-ear mucosa, which may, in turn, result in severe TM retraction,
thrombosis can often be treated with tympanostomy tube placement conductive hearing loss, impaired movement of the ossicles, ossicular
and intravenous antibiotics. Anticoagulation therapy may also be con- discontinuity, and cholesteatoma. The hearing loss may be amenable
sidered in the treatment of sigmoid sinus thrombosis; however, otolar- to surgical correction.
yngology consultation should be obtained before initiating this therapy Cholesterol granuloma is an uncommon condition in which the
to coordinate the possible need for surgical intervention prior to TM may appear to be dark blue secondary to middle-ear fluid of this
anticoagulation. color. Cholesterol granulomas are rare, benign cysts that occur in the
Otitic hydrocephalus, a form of pseudotumor cerebri (see Chapter temporal bone. They are expanding masses that contain fluids, lipids,
605), is an uncommon condition that consists of increased intracranial and cholesterol crystals surrounded by a fibrous lining and generally
pressure without dilation of the cerebral ventricles, occurring in asso- require surgical removal. Tympanostomy tube placement will not
ciation with acute or chronic OM or mastoiditis. The condition is provide satisfactory relief. This lesion requires differentiation from
commonly also associated with lateral sinus thrombosis, and the bluish middle-ear fluid, which can also rarely develop in patients with
pathophysiology is thought to involve obstruction by thrombus of the more common OME.
intracranial venous drainage into the neck, producing a rise in cerebral Chronic perforation may rarely develop after spontaneous rupture
venous pressure and a consequent increase in cerebrospinal fluid pres- of the TM during an episode of AOM or from acute trauma, but more
sure. Symptoms are those of increased intracranial pressure. Signs may commonly results as a sequelae of CSOM or as a result of failure of
include, in addition to evidence of OM, paralysis of 1 or both lateral closure of the TM following extrusion of a tympanostomy tube.
rectus muscles and papilledema with or without visual acuity loss. MRI Chronic perforations are generally accompanied by conductive hearing
can confirm the diagnosis. Treatment measures include the use of loss. Surgical repair of a TM perforation is recommended to restore
antimicrobials and medications such as acetazolamide or furosemide hearing, prevent infection from water contamination in the middle-ear
to reduce intracranial pressure, mastoidectomy, repeated lumbar punc- space, and prevent cholesteatoma formation. Chronic perforations are
ture, lumboperitoneal shunt, and ventriculoperitoneal shunt. If left almost always amenable to surgical repair, usually after the child has
untreated, otitic hydrocephalus may result in loss of vision secondary been free of OM for an extended period.
to optic atrophy. Permanent conductive hearing loss (see Chapter 637) may result
from any of the conditions just described. Rarely, permanent sensori-
PHYSICAL SEQUELAE neural hearing loss may occur in association with acute or chronic OM,
The physical sequelae of OM consist of structural middle-ear abnor- secondary to spread of infection or products of inflammation through
malities resulting from long-standing middle-ear inflammation. In the round window membrane, or as a consequence of suppurative
most instances, these sequelae are consequences of severe and/or labyrinthitis.
POSSIBLE DEVELOPMENTAL SEQUELAE
Permanent hearing loss in children has a significant negative impact
on development, particularly in speech and language. The degree to
which OM impacts long-term development in children is difficult to
assess and there have been conflicting studies examining this question.
Developmental impact is most likely to be significant in children that
have greater levels of hearing loss, hearing loss that is sustained for
longer periods of time, or hearing loss that is bilateral and in those
children that have other developmental difficulties or risk factors for
developmental delay (see Table 640-4).

Chapter 640 ◆ Otitis Media 3100.e1
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Alpert HR, Behm I, Connolly GN, et al: Smoke-free households with children and 2011.
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32:436–440, 2013. Laine MK, Tähtinen PA, Ruuskanen O, et al: Symptoms or symptom-based scores
Asher E, Dagan R, Greenberg D, et al: Persistence of pathogens despite clinical cannot predict acute otitis media at otitis-prone age, Pediatrics 125:e1154–
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and bacteriologic relapse, Pediatr Infect Dis J 27:296–300, 2008. Le Monnier A, Jamet A, Carbonnelle E, et al: Fusobacterium necrophorum middle
Bakhos D, Trijolet JP, Moriniére S, et al: Conservative management of acute ear infections in children and related complications, Pediatr Infect Dis J
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Bales CD, Sobol S, Wetmore R, et al: Lateral sinus thrombosis as a complication of Leibovitz E, Asher E, Piglansky L, et al: Is bilateral acute otitis media clinically
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Barkai G, Leibovitz E, Givon-Lavi N, et al: Potential contribution by nontypable Leibovitz E, Serebro M, Givon-Levi N, et al: Epidemiologic and microbiologic
Haemophilus influenzae in protracted and recurrent acute otitis media, Pediatr characteristics of culture-positive spontaneous otorrhea in children with acute
Infect Dis J 28:466–470, 2009. otitis media, Pediatr Infect Dis J 28:381–384, 2009.
Berkun Y, Nir-Paz R, Ami AB, et al: Acute otitis media in the first two months of Lieberthal AS, Carroll AE, Chonmaitree T, et al: The diagnosis and management of
life: characteristics and diagnostic difficulties, Arch Dis Child 93:690–694, 2008. acute otitis media, Pediatrics 131:e964–e999, 2013.
Bolt P, Barnett P, Babl FE, et al: Topical lignocaine for pain relief in acute otitis Noel GJ, Blumer JL, Pichichero ME, et al: A randomized comparative study of
media: results of a double-blind placebo-controlled randomized trial, Arch Dis levofloxacin versus amoxicillin/clavulanate for treatment of infants and young
Child 93:40–44, 2008. children with recurrent or persistent acute otitis media, Pediatr Infect Dis J
Brook I, Gober AE: Bacteriology of spontaneously draining acute otitis media in 27:483–489, 2008.
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Infect Dis J 28:640–642, 2009. Prevention of pneumococcal disease among infants and children-use of
Casey JR, Adlowitz DG, Pichichero ME: New patterns in the otopathogens causing 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal
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conjugate vaccine, Pediatr Infect Dis J 29:304–309, 2010. Immunization Practices (ACIP), MMWR Recomm Rep 59(RR–11):1–18, 2010.
Casey JR, Block SL, Hedrick J, et al: Comparison of amoxicillin/clavulanic acid Ongkasuwan J, Valdez TA, Hulten KG, et al: Pneumococcal mastoiditis in children
high dose with cefdinir in the treatment of acute otitis media, Drugs and the emergence of multidrug-resistant serotype 19A isolates, Pediatrics
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Clegg AJ, Loveman E, Gospodarevskaya E, et al: The safety and effectiveness of Paradise JL, Hoberman A, Rockette HE, et al: Treating acute otitis media in young
different methods of earwax removal: a systematic review and economic children, Pediatr Infect Dis J 32:745–747, 2013.
evaluation, Health Technol Assess 14(28):1–192, 2010. Pichichero ME, Casey JR, Almudevar A: Reducing the frequency of acute otitis
Coker TR, Chan LS, Newberry SJ, et al: Diagnosis, microbial epidemiology, and media by individualized care, Pediatr Infect Dis J 32(5):473–478, 2013.
antibiotic treatment of acute otitis media in children, JAMA 304(19):2161–2168, Poetker DM, Lindstrom DR, Patel NJ, et al: Ofloxacin otic drops vs neomycin-
2010. polymyxin B otic drops as prophylaxis against early postoperative
Dagan R, Schneider S, Givon-Lavi N, et al: Failure to achieve early bacterial tympanostomy tube otorrhea, Arch Otolaryngol Head Neck Surg 132(12):1294–
eradication increases clinical failure rate in acute otitis media in young children, 1298, 2006.
Pediatr Infect Dis J 27:200–206, 2008. Porat N, Amit U, Givon-Lavi N, et al: Increasing importance of multidrug-resistant
Farbound A, Skinner R, Pratap R: Otitis media with effusion (“glue ear”), BMJ serotype 6A Streptococcus pneumoniae clones in acute otitis media in southern
342:d3770, 2011. Israel, Pediatr Infect Dis J 29:126–130, 2010.
Gluth MB, McDonald DR, Weaver AL, et al: Management of eustachian tube Purzycki A, Thompson E, Argenta L, et al: Incidence of otitis media in children
dysfunction with nasal steroid spray: a prospective, randomized, placebo- with deformational plagiocephaly, J Craniofac Surg 20:1407–1411, 2009.
controlled trial, Arch Otolaryngol Head Neck Surg 137(5):449–455, 2011. Roland PS, Smith TL, Schwartz SR, et al: Clinical practice guideline: cerumen
Grossman Z, Silverman BG, Porter B, et al: Implementing the delayed antibiotic impaction, Otolaryngol Head Neck Surg 139:S1–S21, 2008.
therapy approach significantly reduced antibiotics consumption in Israeli Rosenfeld RM, Schwartz SR, Pynnonen MA, et al: Clinical practice guideline:
children with first documented acute otitis media, Pediatr Infect Dis J tympanostomy tubes in children–executive summary, Otolaryngol Head Neck
29:595–599, 2010. Surg 149:8–16, 2013.
Haggard M: Ventilation (tympanostomy) tubes for otitis media with effusion, BMJ Siegel RM: Acute otitis media guidelines, antibiotic use, and shared medical
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Hammaren-Malmi S, Saxen H, Tarkkanen J, et al: Adenoidectomy does not Simpson SA, Lewis R, van der Voort J, et al: Oral or topical nasal steroids for
significantly reduce the incidence of otitis media in conjunction with the hearing loss associated with otitis media with effusion in children, Cochrane
insertion of tympanostomy tubes in children who are younger than 4 years: a Database Syst Rev (5):CD001935, 2011.
randomized trial, Pediatrics 116:185–189, 2005. Smith N, Greinwald J Jr: To tube or not to tube: indications for myringotomy with
Hoberman A, Paradise JL, Rockette HE, et al: Treatment of acute otitis media in tube placement, Curr Opin Otolaryngol Head Neck Surg 19(5):363–366, 2011.
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Isaacson G: Diagnosis of pediatric cholesteatoma, Pediatrics 120:603–608, 2007. Sridhara SK, Brietzke SE: The “spoke sign”: an otoscopic diagnostic aid for
Jensen RG, Koch A, Homøe P: Long-term tympanic membrane pathology detecting otitis media with effusion, Arch Otolaryngol Head Neck Surg
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Infect Dis J 31(2):139–144, 2012. Stockmann C, Ampofo K, Hersh AL, et al: Seasonality of acute otitis media and
Kadhim AL, Spilsbury K, Semmens JB, et al: Adenoidectomy for middle ear the role of respiratory viral activity in children, Pediatr Infect Dis J 32:314–319,
effusion: a study of 50,000 children over 24 years, Laryngoscope 117:427–433, 2013.
2007. Tahtinen PA, Laine MK, Huovinen P, et al: A placebo-controlled trial of
Kalu SU, Ataya RS, McCormick DP, et al: Clinical spectrum of acute otitis media antimicrobial treatment for acute otitis media, N Engl J Med 364(2):116–126,
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30(2):95–99, 2011. Tähtinen PA, Laine MK, Ruuskanen O, et al: Delayed versus immediate
Kaur R, Adlowitz DG, Casey JR, et al: Simultaneous assay for four bacterial species antimicrobial treatment for acute otitis media, Pediatr Infect Dis J 31(12):1227–
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negative acute otitis media, Pediatr Infect Dis J 29(8):741–745, 2010. Tapiainen T, Kujala T, Renko M, et al: Effect of antimicrobial treatment of acute
Kaur R, Casey J, Pichichero M: Relationship with original pathogen in recurrence otitis media on the daily disappearance of middle ear effusion a placebo-
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relapse or new pathogen, Pediatr Infect Dis J 32:1159–1162, 2013. Thanaviratananich S, Laopaiboon M, Vatanasapt P: Once or twice daily versus
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3100.e2 Chapter 640 ◆ Otitis Media
Uitti JM, Laine MK, Tähtinen PA, et al: Symptoms and otoscopic signs in bilateral van Zon A, van der Heijden GJ, van Dongen TM, et al: Antibiotics for otitis
and unilateral acute otitis media, Pediatrics 131(2):e398–e405, 2013. media with effusion in children, Cochrane Database Syst Rev (9):CD009163,
Van Dongen TMA, van der Heijden GJMG, Venekamp RP, et al: A trial of 2012.
treatment for acute otorrhea in children with tympanostomy tubes, N Engl J Wallace IF, Berkman ND, Lohr KN, et al: Surgical treatments for otitis media with
Med 370:723–733, 2014. effusion: a systematic review, Pediatrics 133:296–311, 2014.
infection. Acyclovir and other antiviral agents can help the hearing loss
and other central nervous system manifestations (see Chapter 245).
TOXOPLASMOSIS
See Chapter 290.
Toxoplasma gondii is a protozoan that can cause congenital SNHL.
In an estimated 1-10 per 10,000 live births in the United States, 1 per
3,000 live births in France, and 1 per 770 live births in southeast Brazil,
infants are born each year with congenital toxoplasmosis; approxi-
mately 25% of untreated patients have SNHL. If maternal infection is
documented during the fetal period, medical therapy may be able to
prevent some of the clinical manifestations, including SNHL of the
offspring.
BACTERIAL MENINGITIS
Since the Haemophilus influenzae type b vaccine was introduced, Strep-
Chapter 641 tococcus pneumoniae (see Chapter 182) and Neisseria meningitidis (see
Chapter 191) have become the leading causes of bacterial meningitis
The Inner Ear and in children in the United States. Hearing loss occurs more commonly
with S. pneumoniae, with an estimated incidence of 15-20%. Approxi-
Diseases of the Bony mately 60% of the associated hearing loss is bilateral, although it often
is asymmetric. If hearing loss is present at the time of presentation with
Labyrinth meningitis, and especially if it is severe to profound, the likelihood of

significant improvement is low. However, if the hearing loss develops
after admission for treatment and is not severe, stabilization or
Joseph Haddad Jr. and Sarah Keesecker improvement is possible. Late progression of SNHL also has been
noted in some children years after meningitis. In the United States and
many other developed countries, bacterial meningitis is one of the
Genetic factors can impact the anatomy and function of the inner ear. major causes of profound deafness leading to cochlear implantation in
Infectious agents, including viruses, bacteria, and protozoa, also can children. Gadolinium-enhanced MRI could be utilized to detect men-
cause abnormal function, most commonly as sequelae of congenital ingitic labyrinthitis and therefore to predict which patients are at high
infection or bacterial meningitis. Other acquired diseases of the laby- risk for postmeningitic hearing loss. Gadolinium-enhanced MRI was
rinthine capsule include otosclerosis, osteopetrosis, Langerhans cell found to be 87% sensitive and 100% specific for predicting which ears
histiocytosis, fibrous dysplasia, and other types of bony dysplasia. All would develop permanent SNHL. The introduction of pneumococcal
of these can cause both conductive hearing loss (CHL) and sensori- conjugate vaccine is expected to lead to a reduction in SNHL caused
neural hearing loss (SNHL) as well as vestibular dysfunction. Use of by pneumococcal meningitis, although pneumococcal strains not sen-
currently available vaccines reduces the risk for bacterial meningitis sitive to the vaccine appear to be associated with rates of deafness
and the associated sensorineural hearing loss. equivalent to those that are sensitive.
Studies have shown favorable trends in the course and outcome after
VIRUSES administration of dexamethasone for hearing loss and other neuro-
The most common cause of childhood sensorineural hearing loss logic deficits associated with bacterial meningitis (see Chapter 603.1),
(SNHL) is congenital cytomegalovirus (CMV) infection (see Chapter although its effectiveness, especially for S. pneumoniae and N. menin-
255). Although the pathogenesis of hearing loss has not been eluci- gitidis meningitis, generally has not reached statistical significance
dated, there is histologic evidence of infection in the cells of both the because of the small number of cases in the trials. A metaanalysis of
cochlear and vestibular endolabyrinth. The strongest predictor of 2,029 patients from randomized, double-blinded, placebo-controlled
delayed hearing loss appears to be the presence of symptoms at birth; trials of dexamethasone for bacterial meningitis found that adjunctive
prolonged viral shedding may also be a risk factor. In one large study, dexamethasone does not seem to significantly reduce death or neuro-
children who passed initial audiologic examinations but who had logic disability but does reduce hearing loss among survivors. Dexa-
CMV-related symptoms at birth were approximately 6 times more methasone has been shown to reduce severe hearing loss associated
likely to develop hearing loss than those who were asymptomatic. with H. influenzae type b meningitis regardless of the timing of admin-
Stabilization (or even reversal) of the hearing loss may be possible by istration of dexamethasone (before or with antibiotics vs later) or of
using ganciclovir in very young infants with congenital CMV infection. the antibiotic used. For pneumococcal meningitis, dexamethasone
Administering ganciclovir for 6 wk improved hearing outcomes in might confer benefit only when given early and only for protection
neonates with symptomatic congenital CMV infections involving the against severe hearing loss.
central nervous system.
Other viral causes of SNHL include congenital rubella as well as SYPHILIS
acquired mumps (see Chapter 248), rubella (see Chapter 247), rubeola See Chapter 218.
(measles; see Chapter 246), and fifth disease, caused by parvovirus B19 Congenital syphilis, caused by Treponema pallidum, causes SNHL in
(see Chapter 251). Many other viruses also occasionally are associated 3-38% of affected children. The exact incidence is difficult to ascertain,
with SNHL. In as many as 50% of cases, hearing loss, which usually is because the hearing loss might not develop until adolescence or even
bilateral and often is asymmetric, progresses and worsens over weeks adulthood. When the condition is identified, treatment with antibiotics
to years. and corticosteroids can improve the hearing loss.
Before an effective vaccine was introduced, rubella was responsible
for as many as 60% of cases of childhood SNHL. Vaccination in devel- OTHER DISEASES OF THE INNER EAR
oped countries has reduced the rate of rubella by >97%. Similarly, Labyrinthitis (also called vestibular neuritis) may be a complication
measles and mumps are now uncommon causes of SNHL in the United of direct spread of infection from acute or chronic otitis media or
States because of successful vaccination programs. mastoiditis and also can complicate bacterial meningitis as a result of
Herpes simplex encephalitis can also be associated with SNHL, organisms entering the labyrinth through the internal auditory meatus,
which is more common in children with congenital herpesvirus endolymphatic duct, perilymphatic duct, vascular channels, or
hematogenous spread. Clinical manifestations of vestibular neuritis patients with lower bone mineral density are more susceptible to
can include a sudden onset of rotatory vertigo, dysequilibrium, pos- microfractures, which may lead to the conductive hearing loss compo-
tural imbalance (furniture walking) with falls to the affected side, deep- nent. If the hearing loss is severe enough, a hearing aid may be a prefer-
seated ear pain, nausea, vomiting, and spontaneous horizontal able alternative to surgical correction of the fixed stapes, because
(occasionally rotary) nystagmus. stapedectomy in children with osteogenesis imperfecta can be techni-
The dizziness may last a few days, but balance issues, particularly cally very difficult, and the disease and the hearing loss may be
following rapid head movements toward the affected ear, may last for progressive.
mo. Vestibular neuritis is usually unilateral and is not associated with Osteopetrosis, a very uncommon skeletal dysplasia, can involve the
other neurologic defects; subjective hearing loss is unusual in vestibu- temporal bone, including the middle ear and ossicles, resulting in a
lar neuritis. If hearing loss is present, idiopathic SNHL should be moderate to severe, usually conductive hearing loss. Recurrent facial
considered, as well as classical labyrinthitis (vestibular and cochlear nerve paralysis also can occur as a result of excess bone deposition;
nerves). Treatment of vestibular neuritis may include prednisone and with each recurrence, less facial function might return (see Chapter
vestibular rehabilitative exercises. Recurrent episodes should suggest 699).
another diagnosis such as vestibular migraine or benign paroxysmal
positional vertigo. Bibliography is available at Expert Consult.
In children, viral labyrinthitis is often associated with hearing loss.
Acute suppurative labyrinthitis, characterized by abrupt, severe onset
of these symptoms, requires intensive antimicrobial therapy. Vestibular
suppressants (dimenhydrinate 1-2 mg/kg) can also be used in the acute
stage but should not be given for more than 3 days. If it is secondary
to otitis media, otologic surgery may be required to remove underlying
cholesteatoma or drain the middle ear and mastoid, in addition to
antibiotics. Acute serous labyrinthitis, with milder symptoms of vertigo
and hearing loss, can develop secondary to middle-ear infection as
well. It usually responds well to antibiotics and corticosteroids, with
improvement in both vertigo and hearing. Chronic labyrinthitis, most
commonly associated with cholesteatoma, manifests with SNHL and
vestibular dysfunction that develops over time; surgery is required to
remove the cholesteatoma. Chronic labyrinthitis also occurs uncom-
monly secondary to long-standing otitis media, with the slow develop-
ment of SNHL, usually starting in the higher frequencies, and possibly
with vestibular dysfunction. Additionally, and more commonly, chil-
dren with chronic middle-ear fluid often are unsteady or off balance,
a situation that improves immediately when the fluid resolves.
Vertigo and dizziness are common among older children and ado-
lescents. Benign paroxysmal vertigo is common and is characterized
by short periods of vertigo or dizziness lasting seconds to a few min
and is associated with imbalance and nystagmus; tinnitus or hearing
loss is unusual. Basilar/vestibular migraine is a common cause of
episodic vertigo or dizziness and is associated with headache (50-70%
of patients), rotary or to and fro nystagmus, and sensitivity to noise
and bright light (see Chapter 595.1). Benign paroxysmal positional
vertigo is less common in young children and more common with
increasing age into adulthood. Particles form in the semicircular canals
(canalolithiasis), most often the posterior canal; symptoms occur with
position changes of the head and may last sec to min. Vertigo and
nystagmus may be demonstrated by changing position (sitting to lying
down on the right or left). Treatment involves canalith repositioning
maneuvers to shift the debris from the canals into the utricle.
Otosclerosis, an autosomal dominant disease that affects only the
temporal bones, causes abnormal bone growth that can result in fixa-
tion of the stapes in the oval window, leading to progressive hearing
loss. In one series in North America, otosclerosis was found in 0.6%
of temporal bones of children younger than 5 yr of age and 4% of those
ages 5-18 yr. The hearing loss is usually conductive at first, but SNHL
can develop. White girls and women are affected most commonly, with
onset of otosclerosis in teenagers or young adults, often associated with
pregnancy. Corrective surgery to replace the stapes with a mobile pros-
thesis often is successful.
Osteogenesis imperfecta is a systemic disease that can involve both
the middle and inner ears (see Chapter 701). Hearing loss occurs in
approximately 20% of young children and as many as 90% of adults
with this disease. The hearing loss most commonly is conductive
because of abnormalities of the ossicles, but SNHL can occur if other
areas of the otic capsule become affected. Hearing loss may be the
result of clinical or cochlear otosclerosis, fracture or atrophy of the
ossicles, and/or cochlear degeneration due to an unidentified mecha-
nism. An association between bone mineral density and hearing loss
in osteogenesis imperfecta has been demonstrated, suggesting that
Chapter 641 ◆ The Inner Ear and Diseases of the Bony Labyrinth 3101.e1
Bibliography Rajasingham CR, Bonsu BK, Chapman JI, et al: Serious neurologic sequelae in
Brown ED, Chau JK, Atashband S, et al: A systematic review of neonatal cases of meningitis arising from infection by conjugate vaccine-related and
toxoplasmosis exposure and sensorineural hearing loss, Int J Pediatr nonvaccine-related serogroups of Streptococcus pneumoniae, Pediatr Infect Dis J
Otorhinolaryngol 73(5):707–711, 2009. 27(9):771–775, 2008.
Chau J, Atashband S, Chang E, et al: A systematic review of pediatric sensorineural Rosenthal LS, Fowler KB, Boppana SB, et al: Cytomegalovirus shedding and
hearing loss in congenital syphilis, Int J Pediatr Otorhinolaryngol 73(6):787–792, delayed sensorineural hearing loss: results from longitudinal follow-up of
2009. children with congenital infection, Pediatr Infect Dis J 28(6):515–520, 2009.
Goudakos JK, Markou KD, Psillas G, et al: Corticosteroids and vestibular exercises Salomone R, Riskalla PE, Vicente Ade O, et al: Pediatric otosclerosis: case report
in vestibular neuritis single-blind randomized clinical trial, JAMA Otolaryngol and literature review, Braz J Otorhinolaryngol 74(2):303–306, 2008.
Head Neck Surg 140:434–440, 2014. Santos F, McCall AA, Chien W, et al: Otopathology in osteogenesis imperfecta,
Jahn K, et al: Vertigo and dizziness in childhood–update on diagnosis and Otol Neurotol 33:1562–1566, 2012.
management, Neuropediatrics 42:129–134, 2011. Strupp M, Zingler VC, Arbusow V, et al: Methylprednisolone, valacyclovir, or the
Kaski D, Bronstein AM: Making a diagnosis in patients who present with vertigo, combination for vestibular neuritis, N Engl J Med 351:354–360, 2004.
BMJ 345:e5809, 2012. Swinnen FK, De Leenheer EM, Goemaere S, et al: Association between bone
Kim JS, Oh SY, Lee SH, et al: Randomized clinical trial for geotropic horizontal mineral density and hearing loss in osteogenesis imperfecta, Laryngoscope
canal benign paroxysmal positional vertigo, Neurology 79:700–707, 2012. 122:401–408, 2012.
Kim JS, Zee DS: Benign paroxysmal positional vertigo, N Engl J Med 370:1138– van de Beek D, et al: Adjunctive dexamethasone in bacterial meningitis: a
1146, 2014. meta-analysis of individual patient data, Lancet Neurol 9:254–263, 2010.
Kimberlin DW, Lin CY, Sanchez PJ, et al: Effect of ganciclovir therapy on hearing von Brevern M, Seelig T, Radtke A, et al: Short-term efficacy of Epley’s manoeuvre:
in symptomatic congenital cytomegalovirus disease involving the central a double-blind randomized trial, J Neurol Neurosurg Psychiatry 77:980–982,
nervous system: a randomized, controlled trial, J Pediatr 143:16–25, 2003. 2006.
Kopelovich JC, Germiller JA, Laury AM, et al: Early prediction of postmeningitic Whitley RJ: The use of antiviral drugs during the neonatal period, Clin Perinatol
hearing loss in children using magnetic resonance imaging, Arch Otolaryngol 39:69–81, 2012.
Head Neck Surg 137:441–447, 2011.
Chapter 642 ◆ Traumatic Injuries of the Ear and Temporal Bone 3101
Chapter 642
Traumatic Injuries of the
Ear and Temporal Bone
Joseph Haddad Jr. and Sarah Keesecker
AURICLE AND EXTERNAL AUDITORY CANAL

Auricle trauma is common in certain sports. Hematoma, with accu-
mulation of blood between the perichondrium and the cartilage, can
follow trauma to the pinna and is especially common in teenagers
related to wrestling or boxing. Prompt drainage of a hematoma can
prevent irreversible damage. Immediate needle aspiration or, when the
hematoma is extensive or recurrent, incision and drainage and a pres-
sure dressing are necessary to prevent perichondritis, which can result
in cartilage loss and a “cauliflower ear deformity.” Sports helmets
should be worn when appropriate during activities when head trauma
is possible.
Frostbite of the auricle should be managed by rapidly rewarming
the exposed pinna with warm irrigation or warm compresses.
Foreign bodies in the external canal are common in childhood.
Often these can be removed in the office setting without general anes-
thesia if the child is mature enough to understand and cooperate and
is properly restrained; if an adequate headlight, surgical head otoscope,
or otomicroscope is used for visualizing the object; and if appropriate
instruments such as alligator forceps, wire loops or a blunt cerumen
curette, or suction are used, depending on the shape of the object.
Gentle irrigation of the ear canal with body temperature water or saline
may be used to remove very small objects, but only if the tympanic
membrane (TM) is intact. Attempts to remove an object from a strug-
gling child or with poor visualization and inadequate tools result in a
terrified child with a swollen and bleeding ear canal and can then
mandate general anesthesia to remove the object. Difficult foreign
bodies, especially those that are large, deeply embedded, or associated
with canal swelling, are best removed by an otolaryngologist and/or
under general anesthesia. Disk batteries are removed emergently
because they leach a basic fluid that can cause severe tissue destruction.
Insects in the canal are first killed with mineral oil or lidocaine and are
then removed under otomicroscopic examination.
After a foreign body is removed from the external canal, the TM
should be inspected carefully for possible traumatic perforation or for
a preexisting middle-ear effusion. If a foreign body has resulted in
acute inflammation of the canal, ear drop treatment as described for
acute external otitis should be instituted (see Chapter 639).
Figure 642-1 Intraoperative view of traumatic oval window perilym-

phatic fistula. (From Kim SH, Kazahaya K, Handler SD. Traumatic peri-
lymphatic fistulas in children: etiology, diagnosis and management. Int
J Pediatr Otorhinolaryngol 60(2):147–153, 2001, Fig. 2.)
TYMPANIC MEMBRANE AND MIDDLE EAR

Traumatic perforation of the TM usually occurs as a result of a sudden
external compression, such as a slap, or penetration by a foreign object
such as a stick or cotton-tipped applicator. The perforation may be
linear or stellate. It is most commonly in the anterior portion of the Figure 642-2 High-resolution axial CT of uncomplicated longitudinal
pars tensa when it is caused by compression, and it may be in any fracture (arrows). A hematoma is present. The course of the fracture
has been touched. (From Schubiger O, Valavanis A, Stuckman G, et al:
quadrant of the TM when caused by a foreign object. Systemic antibiot-
Temporal bone fractures and their complications: examination with
ics and topical otic medications are not required unless suppurative high resolution CT. Neuroradiology 28:93–99, 1986.)
otorrhea is present. Traumatic TM perforations often heal spontane-
ously, but it is important to evaluate and monitor the patient’s hearing
to ensure that spontaneous healing occurs. If the TM does not heal
within several mo, surgical graft repair should be considered. As long commonly manifested by bleeding from a laceration of the external
as the perforation is present, otorrhea can occur from water entering canal or TM; postauricular ecchymosis (Battle sign); hemotympanum
the middle ear from the ear canal, which can occur during swimming (blood behind an intact TM); conductive hearing loss resulting from
or bathing; appropriate precautions should be taken. Perforations TM perforation, hemotympanum, or ossicular injury; delayed onset of
resulting from penetrating foreign bodies are less likely to heal than facial paralysis (which usually improves spontaneously); and tempo-
those caused by compression. Audiometric examination reveals a con- rary CSF otorrhea or rhinorrhea (from CSF running down the eusta-
ductive hearing loss, with larger air–bone gaps seen in larger perfora- chian tube). Transverse fractures of the temporal bone have a graver
tions. Immediate surgical exploration may be indicated if the injury is prognosis than longitudinal fractures and are often associated with
accompanied by 1 or more of the following: vertigo, nystagmus, severe immediate facial paralysis. Facial paralysis might improve if caused by
tinnitus, moderate to severe hearing loss, or cerebrospinal fluid (CSF) edema, but surgical decompression of the nerve is often recommended
otorrhea. At the time of exploration, it is necessary to inspect the if there is no evidence of clinical recovery and facial nerve studies are
ossicles, especially the stapes, for possible dislocation or fracture and unfavorable. If the facial nerve has been transected, surgical decom-
to clear sharp objects that might have penetrated the oval or round pression and anastomosis offer the possibility of some functional
windows. SNHL results if the stapes subluxates or dislocates into the recovery. Transverse fractures are also associated with severe SNHL,
oval window or if either the oval or round window is penetrated. Chil- vertigo, nystagmus, tinnitus, nausea, and vomiting associated with loss
dren should not be given access to cotton-tipped applicators, because of cochlear and vestibular function; hemotympanum; rarely, external
the applicators commonly cause ear trauma. Contact with small objects canal bleeding; and CSF otorrhea, either in the external auditory canal
should be limited to times of parental supervision. or behind the TM, which can exit the nose via the eustachian tube.
Perilymphatic fistula can occur after barotrauma or an increase in If temporal bone fracture is suspected or seen on radiographs, gentle
CSF pressure. It should be suspected in a child who develops a sudden examination of the pinna and ear canal is indicated; lacerations or
SNHL or vertigo after physical exertion, deep water diving, air travel, avulsion of soft tissue is common with temporal bone fractures. Vigor-
playing a wind instrument, or significant head trauma. The leak char- ous removal of external auditory canal blood clots or tympanocentesis
acteristically is at the oval (Fig. 642-1) or the round window and may is not indicated, because removing the clot can further dislodge the
be associated with congenital abnormalities of these structures or an ossicles or reopen CSF leaks. The effectiveness of prophylactic antibiot-
anatomic abnormality of the cochlea or semicircular canals. Perilym- ics to prevent meningitis in patients with basilar skull fractures and
phatic fistulas occasionally close spontaneously, but immediate surgical CSF otorrhea or rhinorrhea cannot be determined because studies to
repair of the fistula is recommended to control vertigo and to stop any date are flawed by biases. If a patient is afebrile and the drainage is not
progression of the SNHL; even timely surgery does not usually restore cloudy, watchful waiting without antibiotics is indicated. Surgical
the SNHL. No reliable test is known for perilymphatic fistula, so intervention is reserved for children who require repair of a nonheal-
middle-ear exploration is required for diagnosis and treatment. ing TM perforation, who have suffered dislocation of the ossicular
chain, or who need decompression of the facial nerve. SNHL can also
TEMPORAL BONE FRACTURES follow a blow to the head without an obvious fracture of the temporal
Children are particularly prone to basilar skull fractures, which usually bone (labyrinthine concussion).
involve the temporal bone. Temporal bone trauma should be consid-
ered in head injuries, and the status of the ear and hearing should be ACOUSTIC TRAUMA
evaluated. Temporal bone fractures are divided into longitudinal (70- Acoustic trauma results from exposure to high-intensity sound
80%), transverse, and mixed. Longitudinal fractures (Fig. 642-2) are (fireworks, gunfire, loud music, heavy machinery) and is initially
manifested by a temporary decrease in the hearing threshold, most
commonly at 4,000 Hz on an audiometric examination, and tinnitus.
If the sound is between 85 and 140 dB, the loss is usually temporary
(after a rock concert), but both the hearing loss and the tinnitus can
become permanent with chronic noise exposure; the frequencies from
3,000-6,000 Hz are most often involved. Sudden, extremely loud
(>140 dB), short-duration noises with loud peak components (gunfire,
bombs) can cause permanent hearing loss after a single exposure.
Noise-induced hearing loss results from interactions between genes
and the environment. Ear protection and avoidance of chronic expo-
sure to loud noise are preventive measures. Hearing loss from chronic
noise exposure should be entirely preventable. Parents should be made
aware of the dangers of acoustic trauma, from the environment and
from the use of headphones, and should take measures to minimize
exposure. Treatment with high-dose steroids for 1-2 wk should be
considered to treat acute hearing loss related to noise trauma.

Chapter 642 ◆ Traumatic Injuries of the Ear and Temporal Bone 3103.e1
Bibliography Osman EZ, Swift A: Management of foreign bodies in the ears and upper
Fasunla AJ, Ogunleye OO, Ijaduola TG: Healthcare givers’ skill and foreign bodies aerodigestive tract, Br J Hosp Med (Lond) 68(11):M189–M191, 2007.
in the ears of children in the tropics, Int J Pediatr Otorhinolaryngol 71:191–195, Pawelczyk M, Van Laer L, Fransen E, et al: Analysis of gene polymorphisms
2007. associated with K ion circulation in the inner ear of patients susceptible and
Hough JVD, Stuart WD: Middle ear injuries in skull trauma, Laryngoscope resistant to noise-induced hearing loss, Ann Hum Genet 73(Pt 4):411–421, 2009.
78:899–937, 1968. Saraiya PV, Aygun N: Temporal bone fractures, Emerg Radiol 16:255–265, 2009.
Matsuda Y, Kurita T, Ueda Y, et al: Effect of tympanic membrane perforation on
middle-ear sound transmission, J Laryngol Otol 123(Suppl 31):81–89, 2009.
Chapter 643 ◆ Tumors of the Ear and Temporal Bone 3103
branchial cysts, dermoid cysts, and lipomas, may be confused with

primary mastoid tumors; imaging can help with the diagnosis and
treatment plan.
Eosinophilic granuloma, which can occur in isolation or as part of
the systemic Langerhans cell histiocytosis (see Chapter 507), should be
suspected in patients with otalgia, otorrhea (sometimes bloody),
hearing loss, abnormal tissue within the middle ear or ear canal, and
roentgenographic findings of a sharply delineated destructive lesion of
the temporal bone. Definitive diagnosis is made by biopsy. Treatment
depends on the site of the lesion and histology. Depending on the site,
it may be treated by surgical excision, curettage, or local radiation. If
the lesion is part of a systemic presentation of Langerhans cell histio-
cytosis, chemotherapy in addition to local therapy (surgery with or
without radiation) is indicated. Long-term follow-up is necessary
whether the temporal bone lesion is a single isolated lesion or part of
a multisystem disease.
Symptoms and signs of rhabdomyosarcoma (see Chapter 500) origi-
nating in the middle ear or ear canal include a mass or polyp in the
middle ear or ear canal, bleeding from the ear, otorrhea, otalgia, facial
paralysis, and hearing loss. Other cranial nerves also may be involved.
Diagnosis is based on biopsy, but the extent of disease is determined
by both CT and MRI of the temporal and facial bones, skull base, and
brain (Fig. 643-1). Management usually involves a combination of
Chapter 643 chemotherapy, radiation, and surgery.
Non-Hodgkin lymphoma (see Chapter 496.2) and leukemia (see
Tumors of the Ear and Chapter 495) also occur rarely in the temporal bone. Although primary
neoplasms of the middle ear are very uncommon in children, they
Temporal Bone include adenoid cystic carcinoma, adenocarcinoma, and squamous cell
carcinoma. Benign tumors of the temporal bone include glomus
tumors. The initial signs and symptoms of the more common nasopha-
Joseph Haddad Jr. and Sarah Keesecker ryngeal neoplasms (angiofibroma, rhabdomyosarcoma, epidermoid
carcinoma) may be associated with insidious onset of chronic otitis
media with effusion (often unilateral). A high index of suspicion is
Benign tumors of the external canal include osteomas and monostotic needed for diagnosing these tumors early.
and polyostotic fibrous dysplasia. Osteomas manifest as bony masses
in the canal and require removal only if hearing is impaired or external Bibliography is available at Expert Consult.
otitis results; osteomas may be confused clinically with exostoses (see
Chapter 501.2). Masses occurring over the mastoid bone, such as first
A B
Figure 643-1 Rhabdomyosarcoma in a 2 yr old child presenting with a large mass in the nose. A, CT scan of the head shows destruction of
the nose and lamina papyracea; a large soft tissue mass is present. B, MRI shows enhancement of the mass. (From Slovis T, editor: Caffey’s pedi-
atric diagnostic imaging, ed 11, Philadelphia, 2008, Mosby, p. 560.)
3103.e2 Chapter 643 ◆ Tumors of the Ear and Temporal Bone
Bibliography
Abbas A, Awan S: Rhabdomyosarcoma of the middle ear and mastoid: a case
report and review of the literature, Ear Nose Throat J 84:780–784, 2005.
Gibson SE, Prayson RA: Primary skull lesions in the pediatric population: a
25-year experience, Arch Pathol Lab Med 131:761–766, 2007.
Viswanatha B: Characteristics of osteoma of the temporal bone in young
adolescents, Ear Nose Throat J 90(2):72–79, 2011.

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Bonita F. Stanton, MD Nina F. Schor, MD, PhD

NELSON TEXTBOOK OF PEDIATRICS, TWENTIETH EDITION ISBN: 978-1-4557-7566-8

Copyright © 2016 by Elsevier, Inc.

International Standard Book Number: 978-1-4557-7566-8

Content Strategy Director: Mary Gatsch

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Table 590-1 Screening Scheme for Developmental Delay: Upper Range

unusual posture, or an abnormality of motor function manifested by a

Table 590-2 Timing of Selected Primitive Reflexes

Table 590-3 Preferred Imaging Procedures in Neurologic Diseases

INTRAPARENCHYMAL HEMORRHAGE EPILEPSY

ARTERIOVENOUS MALFORMATION BRAIN TUMOR

CEREBRAL ANEURYSM MULTIPLE SCLEROSIS

Bibliography is available at Expert Consult.

Bibliography Chiappa KH: Evoked potentials in clinical medicine, ed 3, Philadelphia, 1997,

paced our understanding of the epigenetic and environmental mecha-

Bibliography is available at Expert Consult.

591.1 Neural Tube Defects

Table 591-1 Cutaneous Lesions Associated with Occult

a role in the pathogenesis of meningomyelocele. These enzymes include

Bibliography is available at Expert Consult.

An anencephalic infant presents a distinctive appearance with a large

Table 591-2 Disorders Associated with Agenesis of the Corpus Callosum*

Bibliography Kerjan G, Gleeson JG: Genetic mechanisms underlying abnormal neuronal

innervation by the oculomotor nerve of the lateral rectus muscle.

BRAINSTEM AND CEREBELLAR DISORDERS

Table 591-3 Causes of Microcephaly

Bibliography Romani M, Micalizzi A, Valente EM: Joubert syndrome: congenital cerebellar

malformations such as lissencephaly, holoprosencephaly, polymicro-

branching or forking. In a small percentage of cases, aqueductal steno-

MEGALENCEPHALY The cause of hydranencephaly is unknown, but bilateral occlusion of

Bibliography is available at Expert Consult.

Craniosynostosis is defined as premature closure of the cranial sutures

DEVELOPMENT AND ETIOLOGY CLINICAL MANIFESTATIONS

Table 591-6 Epidemiology and Clinical Characteristics of the Common Craniosynostoses

Bibliography is available at Expert Consult.

Deformational plagiocephaly (DP), also known as positional plagio-

EPIDEMIOLOGY AND ETIOLOGY

Table 592-1 Factors That Increase Risk for

Causes rule out craniosynostosis as a primary cause for cranial asymmetry in

Positional molding Unilateral lambdoid synostosis

Figure 592-1 Differentiating physical find-

Figure 592-2 Cranial measurements. (Modified from

A seizure is a transient occurrence of signs and/or symptoms resulting

Table 593-1 Types of Epileptic Seizures

Table 593-3 Identified Genes for Epilepsy Syndromes*†

Table 593-4 Identified Genes for Syndromic Epilepsy Syndromes*

Table 593-5 Childhood Epileptic Syndromes with Generally Good Prognosis

Bibliography Kossoff EH: Infantile spasms, Neurologist 16:69–75, 2010.

Did the child have a seizure?

Benign paroxysmal Initial Seizure Recurrent Seizures

Abnormal Normal Normal (except EEG)

Figure 593-4 Approach to the child with a suspected convulsive disorder.

mortality (2 or more times the standardized mortality rates of the

Table 593-11 Comparison of Recommendations for the Treatment of Pediatric Epilepsy

Table 593-12 Teratogenesis and Perinatal Outcomes of Antiepileptic Drugs

Table 593-13 Dosages of Selected Antiepileptic Drugs