The Sclera PDF
The Sclera PDF
The Sclera PDF
The Sclera
Second Edition
Maite Sainz de la Maza, MD, PhD Joseph Tauber, MD
Clinical Associate Professor Tauber Eye Center
of Ophthalmology 4400 Broadway, Suite 202
Clinical Institute of Ophthalmology Kansas City, MO 64111, USA
Hospital Clinic of Barcelona jt@TauberEye.com
Urgel 224, Barcelona 08036, Spain
msainz@clinic.ub.es
C. Stephen Foster, MD
Professor of Ophthalmology
Harvard Medical School
Massachusetts Eye Research
and Surgery Institution
Cambridge, MA 02142, USA
sfoster@mersi.com
Dr. Sainz de la Maza published the first edition of this text on the sclera over
18 years ago, as a consequence of Dr. Sainz de la Maza being unable to find
a copy of a monograph on the subject by Dr. Hazleman and Mr. Watson upon
her return to Spain after her fellowship in Boston with me in Ocular
Immunology and Uveitis. She had fallen in love with my copy of that book,
and was stunned and depressed when she discovered that it was out of print
and that none of the libraries in Barcelona possessed a copy of the book.
Cunning catalan that she is, she connived to obtain a Fulbright scholarship to
return to Boston for another year of fellowship with me, with the prime objec-
tive of exploiting my collection of patients with scleritis (and me) for the
production of a book on the sclera. The text turned out to be a huge success,
selling out, and hence the invitation from Springer Verlag was forthcoming
for us to produce a second edition of this work. It has been a pleasure to work
once more with Dr. Sainz de la Maza on this project, producing this updated
work on a subject which is widely neglected and for which, therefore, there is
need for such a work.
The sclera composes 80% of the geographic extent of the exterior confines
or wall of the eyeball, yet it receives relatively little attention in the ophthal-
mic literature. This is understandable, given the fact that disorders of the
sclera are not common and the fact that, when relatively minor problems of
the sclera do develop, healing without consequence is the usual outcome.
After all, a scar in the sclera is of little importance, because the sclera is an
opaque structure. Such a scar in the cornea, or an opacity in the lens or vitre-
ous, or a scar in the macula, of course, carries infinitely more visual signifi-
cance. But it is exactly this rarity of significant sclera problems, coupled with
the profound systemic implications that some inflammatory disorders of the
sclera carry, that makes studies of the sclera and its disorders important.
Indeed, a substantial proportion of individuals who develop serious sclera
inflammation are discovered to have an occult systemic disease; in The Sclera
and Systemic Disorders, Watson and Hazleman1 emphasized that 27% of
patients who develop necrotizing scleritis are dead within 5 years from a
systemic, vasculitic lesion. Watson and Hazleman also emphasized that
because of the comparative rarity of sclera disease, the diagnosis is often
1
Watson PG, Hazleman BL: The Sclera and Systemic Disorders, WB Saunders, Philadelphia,
1976.
vii
viii Preface
missed, and 40% of eyes reported in one series of enucleated eyes had had a
primary diagnosis of scleritis.
We began with all that we had learned from Watson and Hazleman and
built on that excellent foundation. The basis of our current experience springs
from the Massachusetts Eye Research and Surgery Institution (MERSI) in
Cambridge, Massachusetts, and from the Hospital Clinic of Barcelona, Spain,
dating from 2005, both devoted to the study and care of patients with any
inflammatory problem related to the eye, from the lids to the optic nerve. The
first Research Fellow joined the service of Dr. Foster in 1980, and the first
Clinical Fellow arrived in 1984. Between 1977 and 2011 approximately
150,000 patient visits have occurred, approximately 10,000 new patients have
been evaluated, and 110 Ocular Immunology Fellows have been trained in the
service. Dr. Sainz de la Maza was one of those Fellows, and in the course of
training she developed a special interest in and affinity for patients with
scleritis. It was her initiative that was at the heart of the genesis of this project,
and it is entirely through her efforts that this project has been successfully
completed.
Our hope is that this book will serve as a resource for residents in ophthal-
mology, for cornea and immunology fellows in training, and for those oph-
thalmologists in practice and on faculties who have an interest in patients
with diseases of the sclera. The majority of the book is devoted to sclera
inflammation because scleritis represents, by far, the most common sclera
disorder encountered in ophthalmic practice, and because of the profound
systemic implications of scleritis. The references at the end of each chapter,
although not exhaustive, are generous in number and should provide the
reader with more than enough original source material for further reading.
Finally, we would enthusiastically encourage you to read the book The Sclera
and Systemic Disorders, second edition2 as well as this one.
2
Watson PG, Hazleman BL, Pavesio CE, Green WR: The Sclera and Systemic Disorders,
Elsevier Limited, Philadelphia, 2004.
Contents
ix
x Contents
Fig. 1.1 Diagrams of longitudinal and transverse sec- neural tube at the level of the forebrain in the diencepha-
tions of the fourth-week embryo, showing the neuroecto- lon to form the optic vesicle
dermal evagination from the ventrolateral aspect of the
mesoblastic cells displace the hypoblastic cells The mesoderm in the head and neck areas (cra-
laterally, forming the layer known as the embry- nial mesoderm) also undergoes differentiation,
onic endoderm. Hence, the epiblast is the source but the segmentation results in contiguous loose
of embryonic ectoderm, embryonic mesoderm, condensations or somitomeres [1, 2]. These
and most, if not all, of embryonic endoderm. mesodermal condensations are located close to
A solid cord of cells grows cranially from the neural crest cell population forming a neural
primitive knot to the prochordal plate between crest–mesoderm interface [1, 2]. The neural crest
ectoderm and endoderm forming a midline cord and mesoderm form the mesenchyme, which is a
known as the notochord. The notochord induces population of loosely arrayed stellate or fibro-
the thickening of the overlying ectoderm between blast-shaped cells.
the prochordal plate and the primitive knot form-
ing the neural plate. Shortly after its appearance, 1.2.1.4 Fourth Week
the neural plate invaginates along the long axis of The eye develops early in the fourth week as an
the embryo to form the neural groove. The lateral evagination from the ventrolateral aspect of the
walls of the groove are called the neural folds and neural tube or neuroectoderm, at the level of
the edges of the folds form the neural crest. By the forebrain in the diencephalon (Fig. 1.1) [3].
the end of the third week, the inner neural folds The end of the evagination becomes slightly
begin to fuse, forming the neural tube which dilated to form the optic vesicle. Neural crest
gives rise to the central nervous system. The pro- cells cover the convex surface of the vesicles or
cess of fusion starts in the future embryonic neck neuroectoderm and partially isolate them from
and extends toward the cranial and caudal ends of the dorsal, cranial, lateral, and ventral surface
the embryo. The cranial end of the neural tube ectoderm, and from the caudomedial paraxial
forms the forebrain, midbrain, and hindbrain; the mesoderm. At the same time, a small area of sur-
remainder of the tube forms the spinal cord. face ectoderm, overlying each optic vesicle thick-
The mesoderm down the center of the embryo ens, forms the lens placode (Fig. 1.2), which
differentiates into the paraxial mesoderm, the invaginates to become the lens vesicle.
intermediate mesoderm, and the lateral meso-
derm; the paraxial mesoderm divides into dense 1.2.1.5 Fifth Week
condensations or somites, each of which differen- Each optic vesicle then invaginates to form the
tiates into sclerotome, dermatome, and myotome. double-layered optic cup of neuroectoderm
1.2 Development of the Sclera 3
Fig. 1.2 Diagrammatic representation of the formation Rapid, subsequent, sequential development of the lens
of the lens placode (left transverse section) during the vesicle, the optic stalk, and (as shown in greater detail in
fourth week of embryo development (development of Fig. 1.3) the double-layered optic cup of neuroectoderm
the optic vesicle during week 4 is shown in Fig. 1.1). is shown
which is surrounded by neural crest, mesecto- other connective tissues are of neural crest–
derm, or ectomesenchyme. The neuroectoderm mesodermal origin; they include cartilage, bones,
gives rise to the pigment layer and the neural ligaments, tendons, dermis, leptomeninges, and
layer of the retina, the fibers and glia of the optic perivascular smooth muscle; [5] this may explain,
nerve, and the smooth muscle of the iris (Fig. 1.3) at least in part, the frequent association of sclera
(Table 1.1). The surface ectoderm forms the cor- and joints in many systemic diseases.
neal and conjunctival epithelium, lens, lacrimal The differentiation of neural crest cells into
gland, tarsal glands, and epidermis of the eyelids. sclera and choroid is induced by the retinal pig-
The neural crest (or mesectoderm, or ectomesen- ment epithelium [5–7]. In developmental colobo-
chyme, also of ectodermal origin) forms the mas, the defective pigment epithelium fails to
choroid, iris, ciliary musculature, part of the vit- induce development of the sclera and the chor-
reous, corneal stroma, corneal endothelium, tra- oid; the sclera remains thin and may develop
becular meshwork, optic nerve meninges, and internal staphylomas. The sclera, as well as the
almost all of the sclera. The mesoderm contrib- pigment epithelium and the choroid, also
utes only to the striated extraocular muscles, the requires the presence of the developing lens for
vascular endothelia, and a small, temporal por- normal growth and change in shape, structure,
tion of the sclera [2, 4]. The sclera, therefore, is and function [2].
of dual origin, reflecting the location of the neural The sclera differentiates from anterior to
crest–mesodermal interface. Like the sclera, posterior and from inside to outside [8–10].
4 1 Structural Considerations of the Sclera
Fig. 1.3 Further development of the eye (week 5). The primative sclera. The surface ectoderm has formed corneal
neuroectoderm has now given rise to the pigment layer and and conjunctival epithelium, lens, lacrimal gland, and tarsal
to the neural layer of the retina, the fibers and glia of the glands, as well as the epidermis of the skin. The neural crest
optic nerve, and the smooth muscle of the iris. The lens mesectoderm has formed the choroid, the iris, the ciliary
vesicle has completely separated and is now a distinct, musculature, part of the vitreous, the corneal stroma and
unattached entity within the developing globe, and the corneal endothelium, the trabecular meshwork, the optic
hyaloid artery has developed further throughout the vitre- nerve meninges, and the sclera. The mesoderm contributes
ous and to the posterior aspect of the lens vesicle. The vas- only to the striated extraocular muscles and vascular
cular plexus of the choroid has now developed, as has the endothelium and to a small temporal portion of the sclera
1.2.1.6 Sixth Week nuclei, the number of glycogen granules, and the
The differentiation of periocular mesenchymal number of lipid vacuoles; the cells in the anterior
cells into fibroblasts has already started by week portion possess elongated nuclei and many gly-
6.4 [10]. At this stage, the late mesenchymal cogen granules and lipid vacuoles, whereas the
cells or very early fibroblasts do not show pro- cells of the posterior portion possess round-to-
nounced differences between the anterior and oval nuclei and few glycogen granules and lipid
posterior portions of the globe, except for the vacuoles. The late mesenchymal cells or very
1.2 Development of the Sclera 5
early fibroblasts contain many free ribosomes glycogen granules than they had in week 9.7. The
and polyribosomes, as well as immature rough- intercellular space has more collagen fibrils and
surfaced endoplasmic reticulum and Golgi com- elastin deposits in comparison with week 9.7. By
plex. The intercellular space is filled with patches this stage, the only difference between anterior
of immature collagen with an average diameter and posterior portions is that the posterior area
of 27–29 nm (range, 22–35 nm) without band- has fewer collagen fibrils than the anterior area.
ing. There are no elastin deposits.
1.2.1.10 Thirteenth Week
1.2.1.7 Seventh Week By week 13, the cells again exhibit more devel-
By week 7.2, the cells of the anterior portion oped rough-surfaced endoplasmic reticulum and
have more developed rough-surfaced endoplas- Golgi complex and fewer glycogen granules than
mic reticulum and Golgi complex and have fewer do cells in week 10.9. Because collagen and elas-
ribosomes and polyribosomes. The intercellular tin have increased in comparison with week 10.9,
space in the outer portion is wider than in the the volume ratio between cells and intercellular
inner portion; the number and average diameter material is about 1:1. The average diameter of
(30–40 nm; range, 24–46 nm) of collagen fibrils collagen fibrils in this stage is 62–74 nm (range,
have increased in both locations in comparison 50–84 nm).
with week 6.4. Immature elastin deposits con-
sisting of microfibrillar components can be rec- 1.2.1.11 Sixteenth Week
ognized for the first time. The cells of the By week 16, the diameter of the collagen fibrils
posterior portion have more ribosomes and has increased in comparison with week 13. Our
polyribosomes and less mature rough-surfaced own transmission electron microscopy studies on
endoplasmic reticulum and Golgi complex than human fetal and adult sclera showed that there
do the cells of the anterior portion. The intercel- are still differences between week 16 (Fig. 1.4a)
lular space in the posterior portion reveals fewer and adult sclera (Fig. 1.4b); fetal sclera did not
collagen fibrils than does the intercellular space show the packed and dense, intermingled arrange-
in the anterior portion. There are no elastin ments of collagen bundles with few fibroblasts of
deposits. the adult sclera. Other characteristics of this stage
are further enlargement of the rough-surfaced
1.2.1.8 Ninth Week endoplasmic reticulum, complete loss of glyco-
By week 9.7, the cells of the inner anterior por- gen granules, and more elastin deposits.
tion exhibit more glycogen granules and more
elastin deposits than do the cells of the outer 1.2.1.12 Twenty-Fourth Week
anterior portion. The number and average diam- By week 24, the sclera has the same ultrastruc-
eter (50–58 nm; range, 42–68 nm) of collagen tural characteristics as the adult sclera. The aver-
fibrils have increased in both locations in com- age diameter of the collagen fibrils is 94–102 nm
parison with week 7.2. The cells of the poste- (range, 84–102 nm), which is the average diam-
rior portion have more cytoplasmic processes eter of adult sclera. Mature elastin deposits exhib-
and rough-surfaced endoplasmic reticulum, and iting electron-translucent central cores also can
the intercellular spaces have more collagen be found.
fibrils and elastin deposits in comparison with Defects in synthesis of extracellular matrix
week 7.2. components during scleral development at any
of these stages may account for scleral abnor-
1.2.1.9 Tenth Week malities, including Marfan syndrome, osteogen-
By week 10.9, the cells of the anterior portion esis imperfecta, pseudoxanthoma elasticum,
have more developed rough-surfaced endoplas- Ehlers–Danlos syndrome, congenital myopia,
mic reticulum and Golgi complex and fewer and nanophthalmos.
Fig. 1.4 (a and b) Transmission electron microscopy pho- sclera (a) compared to the adult sclera (b) and the densely
tomicrographs (×4,000) of human fetal sclera, week 16 of packed, intermingled arrangement of collagen bundles in the
development. Note the highly cellular nature of the fetal adult sclera (b) compared to the 16-week fetal sclera (a)
1.2 Development of the Sclera 7
Fig. 1.5 Immunofluorescence microscopy (using anti- 13-week fetal specimen steadily decreased throughout
collagen type IV antibody) of week 13 fetal sclera. The fetal development and was nearly absent in adult sclera,
relatively abundant amount of collagen type IV seen in this with the exception of its presence in the vascular walls
Fig. 1.6 Immunofluorescence microscopy (using anti-fibronectin antibodies) of 13-week fetal sclera. Note the reticular
pattern of the large amount of fibronectin present in the sclera. Fibronectin is nearly absent in adult sclera
Studies on tissue distribution of collagen type and adult sclera showed only a subtle positivity.
XII at the corneoscleral angle of the embryonic Heparan sulfate was identified in human fetal and
avian eye showed positive staining around the adult sclera in small amounts.
scleral ossicles and the scleral cartilages [12].
1.2.2.3 Glycoproteins
1.2.2.2 Proteoglycans Fibronectin, vitronectin, and laminin were identi-
Proteoglycans are macromolecular core proteins fied in human fetal and adult scleral specimens.
covalently attached to at least one sulfated gly- Fibronectin staining changed from an intense
cosaminoglycan (GAG) side chain. The GAG reticular pattern at 13 weeks to a dramatic fibril-
chain consists of a hexosamine (d-galactosamine lar pattern at 16 weeks; staining then decreased at
or d-glucosamine) and galactose units (keratan 22 weeks and was subtle in adult sclera (Fig. 1.6).
sulfate) or a hexuronic acid (l-iduronic acid or These findings indicate that, as in other organs
d-glucuronic acid). Chondroitin sulfate and der- during embryogenesis, fibronectin changes may
matan sulfate are galactosaminoglycans and hep- play a major role in directing developmental
aran sulfate is a GAG. GAGs are not homogeneous events. Like fibronectin, vitronectin staining also
even within a given GAG because of the variabil- decreased from fetal to adult scleral tissue.
ity in sulfate substitutions and chain lengths. Laminin staining was subtle at 13 weeks and dis-
We analyzed the GAG dermatan sulfate, chon- appeared at 16 weeks and onward, except for its
droitin sulfate, hyaluronic acid, and heparan sul- dramatic presence in the blood vessels.
fate in human fetal and adult scleral specimens.
Dermatan sulfate was present in moderate
amounts through the different gestational peri- 1.2.3 Postnatal Development
ods, and chondroitin sulfate always stained and Age-Related Changes
intensely without much difference between
13-week and adult sclera. In contrast, staining of In infancy and childhood, scleral tissue is more
hyaluronic acid changed from moderate at 13 translucent than in an adult, and a bluish color is
weeks to mild at 22 weeks; this then subsided, evident, owing to visibility of the underlying
1.3 Anatomy 9
uveal tissue through translucent sclera. With age, scleral plaques and usually occur in individuals
translucency decreases and rigidity increases over 70 years of age [16].
[13]. This age-related change in rigidity explains
the observation that infantile or childhood glau-
coma can lead to buphthalmos while this does not 1.3 Anatomy
occur in adults.
In elderly individuals, scleral distensibility 1.3.1 Gross and Microscopic Anatomy
decreases, making stretching secondary to glau-
coma very unlikely. However, ectasias (localized The scleral shell forms part of a circle averaging
protrusions of thin sclera) or staphylomas (local- 22 mm in diameter [13]. Scleral thickness varies
ized protrusions lined by uveal tissue) may appear from 0.3 mm immediately behind the insertion of
in areas, where injury or inflammation has caused the rectus muscles to 1.0 mm near the optic nerve.
scleral thinning. Other age-related changes are a It measures 0.4–0.5 mm at the equator, 0.6 mm
decrease in water content, a decrease in the where the tendons of the rectus muscles attach,
amount of proteoglycans, and the subconjuncti- and 0.8 mm adjacent to the limbus [17]. Traumatic
val deposition of lipids. The lipids, composed of scleral rupture usually occurs at the insertion of
cholesterol esters, free fatty acids, triglycerides, rectus muscles, at the equator, or in an area parallel
and sphingomyelin, give the sclera a yellowish to the limbus opposite from the site of the impact.
color. Cholesterol esters and sphingomyelin show The outer surface of the sclera is smooth,
the greatest increase in volume with age [14, 15]. except where the tendons of the extraocular mus-
Calcium phosphate is deposited in small rectan- cles insert. The insertions of the rectus muscles
gular areas just anterior to the insertions of medial are progressively more posterior, following a pat-
and lateral rectus muscles. These areas, about tern described by Tillaux and hence called the
1 mm wide and 6 mm high, may become translu- spiral of Tillaux (Fig. 1.7). The medial rectus
cent, revealing the bluish or brownish color due inserts 5.5 mm posterior to the limbus, the infe-
to the underlying uvea; they are called senile rior rectus 6.5 mm, the lateral rectus 6.9 mm, and
Fig. 1.7 Diagrammatic representation of the relative positions of the insertions of the horizontal and vertical rectus
muscles, illustrating the spiral of Tillaux
10 1 Structural Considerations of the Sclera
Fig. 1.8 Diagrammatic representation of the insertions of the superior oblique and inferior oblique muscles
the superior rectus 7.7 mm. The insertions of the dural sheath posteriorly. Tenon’s capsule lies
superior oblique and inferior oblique muscles are anteriorly between two vascular layers: the con-
posterior to the equator (Fig. 1.8). The long ten- junctival plexus and the episcleral plexus, both of
don for the superior oblique muscle inserts supe- which nourish it.
riorly and slightly laterally; the line of insertion is
convex posteriorly and laterally. The inferior 1.3.1.1 Scleral Foramina
oblique muscle inserts posterolaterally. Because The sclera is an incomplete sphere that terminates
this muscle has no tendon, the muscular fibers anteriorly at the anterior scleral foramen sur-
attach directly; the line of insertion is convex rounding the cornea and posteriorly at the poste-
superiorly and laterally. The most posterior point rior scleral foramen surrounding the optic nerve
lies 5 mm temporal to the optic nerve, external to canal.
the macula.
Tenon’s capsule, the fascial sheath of the eye- Anterior Scleral Foramen
ball, is closely connected to the outer portion of The anterior scleral foramen has an elliptical
the sclera or episclera by delicate lamellae, par- appearance externally (horizontal diameter of
ticularly when it fuses with the muscle tendon 11.6 mm and vertical diameter of 10.6 mm) and a
insertions anteriorly and with the optic nerve circular appearance internally (diameter of
1.3 Anatomy 11
Fig. 1.9 Diagrammatic representation of the corneo- relationships between sclera, peripheral cornea, conjunc-
scleral junction in longitudinal section, illustrating the tiva, and Tenon’s capsule, the canal of Schlemm, and the
watch glass-like insertion of cornea into sclera, and the trabecular meshwork and iris
11.6 mm); it is not a discontinuity in the outer muscle, tension on the scleral spur by the muscle
coat of the eye but is an anatomical concept of the opens the trabecular meshwork [3, 18].
sclera without the cornea. The sclera meets and The corneoscleral junction can be best distin-
merges with the cornea at the anterior scleral guished in a gross specimen of an enucleated eye
foramen forming the corneoscleral junction, after refrigeration because the cornea thickens
where the irregular scleral fibers tend to bend and opacifies, whereas scleral thickness is not
with the regular corneal lamellae. The corneo- modified; however, it is indistinguishable in
scleral junction is an area measuring about microscopic sections because of the similar struc-
1.5–2 mm wide; the concave scleral side is ture of cornea and sclera.
formed by the external scleral sulcus in its outer
surface and by the internal scleral sulcus in its Posterior Scleral Foramen
inner surface (Fig. 1.9). The external layers of the The sclera allows the passage of the optic nerve
internal scleral sulcus merge with the stroma of through the posterior scleral foramen. The site of
the cornea. The internal layers of the internal this perforation is located 3 mm medial to the
scleral sulcus contain the trabecular meshwork midline and 1 mm below the horizontal meridian.
and the Schlemm’s canal anteriorly and the The outer two-thirds of the scleral fibers continue
scleral spur posteriorly; the trabecular meshwork backward, fusing with the dural and arachnoid
merges with the Descemet’s membrane. Because sheaths of the optic nerve (Fig. 1.10). The inner
the scleral spur attaches to the meridional ciliary third of the scleral fibers crosses the posterior
12 1 Structural Considerations of the Sclera
Fig. 1.10 Diagrammatic representation of the optic nerve as it passes through the posterior scleral foramen, and the
relationship of the ophthalmic artery and vein, as well as the short posterior ciliary arteries
episcleral vessels. The episclera becomes pro- fluorescein anterior segment angiography [33],
gressively thinner toward the back of the eye. low-dose fluorescein anterior segment videoan-
giography [34], and fluorescein anterior segment
Scleral Stroma videoangiography with a scanning angiographic
The scleral stroma consists of collagen bundles microscope [35] helped in the study of circula-
associated with a few elastic fibers. Between the tory dynamics of the anterior segment circula-
bundles are a few fibroblasts with occasional tion, such as flow direction and flow velocity.
melanocytes. Collagen bundles, larger in diame-
ter than those in the episclera, vary in thickness Vascular Distribution
and form whorls and loops. Although they usu- Results of studies using static anatomical tech-
ally run parallel with the surface, many crisscross niques show that the blood supply of the anterior
freely with each other, forming a feltlike struc- segment of the eye has distinctive characteristics.
ture. Because of the interlacing of the collagen Except for the perforating vessels, the sclera is a
bundles, the sclera presents a dull white color. relatively avascular structure. It has a low meta-
Near the cornea and the optic nerve canal, the bolic requirement because of the slow turnover
bundles tend to run in concentric circles. In other rate of its collagen. The episcleral blood supply is
portions, they form patterns of loops running derived mainly from the anterior ciliary arteries
mainly in a meridional direction. This arrange- anterior to the insertions of the rectus muscles
ment permits adjustment to the changes in and from the long and short posterior ciliary
intraocular pressure and to the stress produced by arteries posterior to these insertions. Scleral
the extraocular muscles. stroma contains capillary beds but is supplied by
the episcleral and, to a lesser degree, choroidal
Lamina Fusca vascular networks.
The lamina fusca is the portion of the sclera that The arteries, veins, and nerves traverse the
is adjacent to the uvea; collagen bundles become sclera through emissary canals [36]. These canals
smaller and the number of elastic fibers is or passageways are separated from the sclera by a
increased. A large number of melanocytes are thin layer of loose connective tissue. There are
present, giving to this portion a faintly brown more emissary canals superiorly at 12 o’clock
color. The lamina has grooves that provide a pas- and inferiorly at 6 o’clock than nasally and tem-
sage for the ciliary vessels and nerves. It is sepa- porally. The fewest occur in the temporal quad-
rated from the outer aspect of the choroid by a rant. Emissary canals provide a passageway for
potential space, the perichoroidal space, filled by extraocular extensions of intraocular tumors [37].
fine collagen fibers that provide a weak attach- On the surface of the eye, the muscular arter-
ment between both layers. ies, which arise from the ophthalmic artery, run
forward as the anterior ciliary arteries. The ante-
1.3.1.3 Blood Supply and Emissary rior ciliary arteries pass through the sclera just in
Canals front of the insertions of the rectus muscles in a
The elegant dissections performed by Leber in slightly oblique direction from posterior to ante-
1903 form the foundation of our current under- rior. Each rectus muscle has two anterior ciliary
standing on the ocular anterior segment circula- arteries, except the lateral rectus muscle, which
tion [20]. Anatomical techniques involving Indian has only one (Fig. 1.7). The seven anterior ciliary
ink injections [21] and vascular casting using arteries meet via their lateral branches 1–5 mm
neoprene and methyl methacrylate [22–24], com- behind the limbus and form the anterior episcleral
bined with scanning electron microscopy [25– arterial circle, which feeds the limbal, anterior
27], confirmed Leber’s findings and provided a conjunctival, and anterior episcleral tissues
unique static method for three-dimensional anal- (Fig. 1.11). The anterior episcleral arterial circle
ysis of the ocular microvasculature. Anterior seg- broadly resolves into limbal arcades, an anterior
ment fluorescein angiography [28–32], low-dose conjunctival plexus, a superficial episcleral
14 1 Structural Considerations of the Sclera
Fig. 1.11 Scanning electron micrograph of a vascular limbus and form the anterior episcleral arterial circle
cast, showing the formation of the major vascular plex- (EC), which feeds the limbal, anterior conjunctival, and
uses of the anterior segment. The anterior ciliary arteries anterior episcleral tissues (Courtesy of Van Buskirk EM)
(ACA) meet via their lateral branches 1–5 mm behind the
plexus, and a deep episcleral plexus (Fig. 1.12). not form a capillary bed in the sclera but rather
Limbal arcades and anterior conjunctival plexus provide nutrients to the uveal tract (Fig. 1.15).
usually share their origins and form the most The limbal venous circle collects blood from
superficial layer of vessels. The superficial epis- the anterior conjunctival veins and limbal arcades,
cleral plexus lies within the parietal layer of the and drains into radial episcleral-collecting veins.
episclera and anastomoses at the limbus with the The episcleral-collecting veins also receive blood
conjunctival plexus, branches of the same plexus, from anterior episcleral veins and perforating
and with the deep episcleral plexus (Fig. 1.13). scleral veins. Perforating scleral veins emerge
The deep episcleral plexus lies within the visceral from Schlemm’s canal, from which they receive
layer of the episclera and anastomoses with aqueous humor. They penetrate the sclera through
branches of the same plexus. In addition, exten- different emissary canals than do the arteries.
sions of the remaining anterior ciliary arterial These canals, over the ciliary body, often also carry
branches perforate the limbal sclera through the ciliary nerves. As the episcleral-collecting
emissary canals and meet the long posterior cili- veins run posteriorly across the sclera, they form
ary arteries in the ciliary muscle to form the major the anterior ciliary veins, which leave the anterior
arterial circle of the iris (Fig. 1.14). The anterior surface of the globe over the rectus muscles.
episcleral arterial circle and the major arterial The two long posterior ciliary arteries (medial
circle of the iris communicate by scleral perforat- and lateral), which also arise from the ophthalmic
ing anterior ciliary arterial branches, which do artery, enter the sclera 3.6 mm nasal to the optic
1.3 Anatomy 15
Fig. 1.13 Scanning electron micrograph (×24) of a vas- as the superficial episcleral (SE) and deep episcleral (DE)
cular cast. Iris vessels (white arrows) are seen posterior to plexuses and their interconnectors (Courtesy of
the anterior ciliary artery (ACA) and its branches, as well Fryczkowski AW)
16 1 Structural Considerations of the Sclera
Fig. 1.14 Diagrammatic illustration of the vascular supply to the globe, showing the relationships between the internal
carotid, ophthalmic, central retinal, long posterior ciliary, lacrimal, short posterior ciliary, and anterior ciliary arteries
Fig. 1.15 Scanning electron micrograph (×50) of a vascular cast of a scleral perforating anterior ciliary arterial branch
connecting the anterior episcleral arterial circle and the major arterial circle of the iris (Courtesy of Van Buskirk EM)
1.3 Anatomy 17
Fig. 1.16 Diagrammatic representation of the sites of perforation of the sclera by the long and short posterior ciliary
arteries, the short posterior ciliary veins, and the inferior and superior vortex veins
Posterior to the equator, the sclera is perfo- circulation. Some of the branches of the short
rated obliquely by the emissary canals for the posterior ciliary arteries around the optic disk
vortex veins (Fig. 1.17). Each eye usually con- form the incomplete vascular circle of Zinn-
tains from four to seven veins. Vortex veins drain Haller near the inner scleral rim. The emissary
the venous system of the choroid, ciliary body, canals for the short ciliary vessels, arteries, and
and iris. One or more veins are in each quadrant. veins may be perpendicular, oblique, or spiral.
The superior vortex veins exit 8 mm posterior
to the equator, close to the most posterior edge of Circulatory Dynamics
the insertion of the superior oblique muscle. The The classic, static anatomical techniques have
inferior vortex veins exit 6 mm posterior to the provided the foundation for our knowledge of the
equator. blood supply of the anterior segment of the eye
The short posterior ciliary arteries arise from (described in the preceding section). However,
the ophthalmic artery as it crosses the optic nerve. the direction of flow in these vessels studied by
After dividing into 10–20 branches, they perfo- circulatory dynamic techniques, such as anterior
rate the sclera around the entrance of the optic segment fluorescein angiography, has excited
nerve (Fig. 1.18) and supply the choroid as far as controversy. Some studies support the traditional
the equator of the eye. The vessels pass directly view [20] that the anterior ciliary artery flow is
to the choroid without forming a capillary bed in from the region of the rectus muscles toward the
the sclera. Some of the branches in the sclera run inside of the eye, providing major perforating
toward the equator and anastomose with the contributions to the intraocular circulation [35,
branches of the long posterior ciliary arteries to 38–40]. This centripetal distribution is supported
supply the posterior episclera. However, this pos- by corrosion plastic castings of the ocular vascu-
terior episcleral plexus is so thin that it gives a lature, in which perforating anterior ciliary arter-
poor supply to the underlying sclera in the equa- ies divide extensively within the anterior uvea
tor. Most of the nutrient requirements of the [24, 26, 41], and by the fact that anterior segment
sclera in this area are supplied by the choroidal ischemia may arise from surgery on the vertical
18 1 Structural Considerations of the Sclera
Fig. 1.17 Diagrammatic representation of the relationships between the lacrimal, vortex, short posterior ciliary, infe-
rior ophthalmic, central retinal, supraorbital, and superior ophthalmic veins
Fig. 1.18 Diagrammatic representation of a transverse posterior ciliary, and anterior ciliary arteries and the short
section of the globe, illustrating another view of the posterior ciliary, anterior ciliary, and vortex veins
relationships between the short posterior ciliary, long
1.3 Anatomy 19
1.3.2.2 Vessels
Our own transmission electron microscopy stud-
ies on human adult sclera showed that episcleral
vessels, as capillaries and postcapillary venules,
are continuous and had simple walls consisting of
Fig. 1.21 Transmission electron micrograph of adult
endothelial cells attached to an underlying
sclera (×26,000). Note the periodicity in the longitudinal
fibers and the variable fibril diameter in the transverse basement membrane secreted by them and a dis-
bundles continuous layer of pericytes (Figs. 1.23–1.25).
1.3 Anatomy 21
Fig. 1.22 Transmission electron micrograph of human Fig. 1.24 Transmission electron micrograph of human
adult sclera (×17,750). Note the flat, spindle-shaped cells adult sclera (×17,750), episcleral vessel. Note the continu-
with long nuclei containing marginated chromatin. These ous, thin vascular basement membrane and the lack of a
fibroblasts are in a state of relative metabolic quiescence vascular wall other than that formed by the endothelial
cell, basement membrane, and the pericyte
Fig. 1.23 Transmission electron micrograph of human Fig. 1.25 Transmission electron micrograph of human
adult episcleral tissue (×7,500). Episcleral vessel (trans- adult sclera (×7,500). Episcleral vessel, with red blood
verse section) with discontinuous pericyte support, and cells in the lumen, endothelial cells lining the vessel, and
typical microvascular endothelium, are visible. A red supporting pericyte cytoplasm are visible. Note the scleral
blood cell is seen in the lumen fibroblasts and collagen underlying the vessel
22 1 Structural Considerations of the Sclera
The endothelial cells, irregular in shape, had a Elastin content, estimated by desmosine and
cytoplasm with mitochondria, rough-surfaced isodesmosine analysis, forms less than 2% of the
endoplasmic reticulum, smooth-surfaced endo- dry weight of the sclera [59].
plasmic reticulum, Golgi apparatus, and pinocy- Proteoglycans, determined by uronic acid anal-
totic vesicles. Endothelial cells interconnect ysis, constitute 0.7–0.9% of the dry weight of the
through thin areas of more or less tortuous inter- sclera [55]. Proteoglycans are composed of GAG
endothelial clefts composed of adjacent cell chains linked to a protein core. The most abundant
membranes. The basement membrane, almost GAG in sclera is dermatan sulfate, followed by
parallel to the outer contour of the endothelial chondroitin sulfate and hyaluronic acid [60, 61].
cells, consists of one to several dense layers with Little heparan sulfate and no keratan sulfate is pres-
a less dense zone filling the space between them. ent. Regional analysis shows that the sclera around
Pericytes are attached to the basement membrane, the optic nerve is the area richest in dermatan sul-
often with one or more dense zones between them fate, the sclera around the equator is the richest in
and the endothelial cell; their cytoplasm contains hyaluronic acid, and the sclera around the fovea is
endoplasmic reticulum, mitochondria, Golgi the richest in chondroitin sulfate [61].
apparatus, pinocytotic vesicles, and fine filaments. Glycoproteins, such as fibronectin and vit-
No smooth muscle cells are present. Bundles of ronectin, also can be detected in sclera. Laminin
collagen fibrils adjacent to the vessel walls merge has not been found [58], except in vessels.
into the surrounding connective tissue. The water content of sclera ranges from 65 to
Episcleral and conjunctival vessels in mon- 75%. The sclera appears opaque if the water con-
keys have an identical morphology [53]. tent is maintained between 40 and 80% but
Episcleral and conjunctival vessels are permeable becomes transparent if it falls below 40% or rises
to tracer molecules, such as fluorescein-labeled above 80% [55].
dextrans of different molecular weight or horse-
radish peroxidase injected into the blood stream
or into the anterior chamber; [53, 54] tracers 1.5 Immunohistochemistry
escape from the vessel lumen by crossing the thin
interendothelial clefts. It can equally be expected We studied the immunolocalization of extracel-
that the aqueous humor that reaches the episcleral lular matrix components in human adult sclera
and conjunctival vessels through the Schlemm´s using monoclonal antibodies against the colla-
canal and collector channels can diffuse freely gens, proteoglycans, and glycoproteins.
into the episcleral loose connective tissues and Collagen types I, III, V, and VI stained
the subconjunctival spaces across the walls of intensely in extravascular sclera, whereas col-
these permeable vessels. lagen type II and VII were not identified.
Collagen type IV was almost absent, except for
its dramatic presence in blood vessels (see
1.4 Biochemistry Chap. 5). Studies on tissue distribution of col-
lagen type VIII in human sclera showed a lin-
Collagen forms 75% of the dry weight of the ear or fibrous pattern of intense staining in
sclera, as determined by quantitation of anterior and posterior human adult sclera [11].
4-hydroxyproline in acid hydrolysates of the total The most abundant GAGs in sclera were der-
tissue [55]. Collagen type I is the predominant matan sulfate and chondroitin sulfate; hyaluronic
type, whereas type III is found in smaller amounts acid and heparan sulfate also were present,
[56–58]. There is no difference in the collagen although in small amounts.
content or collagen type in sclera between ante- The glycoproteins, fibronectin and vitronectin,
rior and posterior segments of the eye [56]. were identified in scleral specimens. Laminin was
1.7 Molecular Structure 23
absent in extravascular sclera but was dramatically or fetal cornea, are highly distensible, whereas
represented in vessel walls. adult tissues become more rigid as their water-
Scleral blood vessels showed the presence of holding capacity decreases [66–69]. Posterior
collagen types IV, V, and VI, the GAGs heparan sclera is more distensible than anterior sclera,
sulfate and chondroitin sulfate, and the glycopro- and the choroid is more distensible than the
teins fibronectin and laminin in endothelial cell sclera; the latter helps explains why the choroid
basement membranes. forms redundant folds in orbital or choroidal
tumors, ocular hypotony, and subretinal
neovascularization.
1.6 Biomechanics
By virtue of its poor distensibility, the sclera pro- 1.7 Molecular Structure
vides a stable viscoelastic system for the globe.
This property appears to be dependent, at least in Scleral connective tissue consists of cells and
part, on the GAG water-binding properties: the extracellular matrix. The cells, or fibroblasts,
higher the water-holding capacity of the GAG, play a critical role in the synthesis and organiza-
the more distensible the sclera. The adult sclera tion of the matrix elements. The extracellular
exhibits a biphasic response to a sudden force: a matrix is composed of fibrillar proteins, such as
rapid lengthening is followed by a slow stretch- collagen and elastin, and of amorphous ground
ing [62–64]. However, like most viscoelastic sys- substance, such as proteoglycans and glycopro-
tems, the sclera stretches proportionately more teins. The specific turnover rate of the scleral
with small pressure changes. The sclera stretches matrix by fibroblasts and the degradative enzymes
with initial elevations of intraocular pressure; they secrete (collagenases, elastases, proteogly-
therefore, small increases in intraocular volume canases, and glycoproteinases) is unknown, but
at low pressure result in small increases in collagen fibrils have a slower turnover rate than
intraocular pressure. As the pressure increases, proteoglycans [70]. Healing of scleral wounds,
the resistance to further stretching also increases, based on a delicate balance of fibroblast matrix
and therefore small increases in intraocular vol- synthesis and enzyme matrix degradation, is a
ume at high pressures result in large increases in slow process, taking months or years, and the
intraocular pressure. Following severe transient area of the wound can always be identified histo-
stretching of the sclera, as in acute glaucoma, logically by the abrupt change in scleral collagen
scleral distensibility returns to the baseline levels fiber orientation and disorganization that persists
prior to the increase of intraocular pressure. throughout the life of the individual [71].
Scleral distensibility is an important consider-
ation when methods of intraocular pressure mea-
surement are studied. The indentation method 1.7.1 Collagen
results in a significant increase of intraocular vol-
ume; the applanation method does not. In some Collagen types I, III, IV, V, VI, and VIII have been
eyes with increased scleral distensibility (e.g., as identified in scleral tissue. Each collagen mole-
produced by inflammatory diseases, high myo- cule is composed of three polypeptide a chains
pia, or retinal detachment surgery), the indenta- containing triple-helical and globular domain [72,
tion measurement method results in a false low 73]. The triple-helical regions have a repeating
reading because the sclera stretches to accommo- triplet amino acid sequence, summarized as (Gly-
date the pressure of the tonometer. X-Y)n, where X and Y are often proline and
Scleral distensibility decreases with age [65]. hydroxyproline, respectively. The presence of
This property appears to depend, at least in part, glycine at every third residue, with the exception
on the degree of hydration of connective tissue; of short sequences at the ends of the chain,
highly hydrated tissues, such as embryonic skin contributes to the triple-helical conformation.
24 1 Structural Considerations of the Sclera
and chondroitin sulfate [60]. Proteoglycans main- possesses multiple functional sites that mediate
tain the proper anatomical structure of the colla- its interactions with cells, such as endothelial
gen fibrils and protect them from attack [70]. cells, and with other extracellular matrix compo-
Proteoglycans also function as modulators of nents, such as GAGs, nonintegrin proteins, and
growth factors, such as fibroblast growth factor integrins [99]. Cells and extracellular matrix
or transforming growth factor [82]. proteins interact with laminin via specific sur-
face receptors. Laminin participates in the pro-
motion of cell adhesion, growth, migration, and
1.7.4 Glycoproteins differentiation, as well as assembly of basement
membranes [100].
Although collagen, elastin, and proteoglycans The fact that laminin is the first extracellular
are technically glycosylated proteins, the term matrix protein to appear in development empha-
glycoprotein is primarily used for molecules com- sizes its importance in the intricate process of tis-
posed of oligosaccharide with a mannose core sue organization [98].
N-glycosidically linked to asparagine. The glyco-
protein fibronectin has been detected in sclera as
part of the amorphous ground substance [58]. 1.7.5 Matrix-Degrading Enzymes
Fibronectin is a high-molecular-weight mole-
cule synthesized by scleral fibroblasts. It consists Collagenase, elastase, proteoglycanase, and gly-
of two similar subunits joined near their COOH coproteinase are enzymes capable of degrading
termini by disulfide bonds [88]. Each subunit can the matrix components. Some of these enzymes
be divided into a number of globular domains are synthesized by the scleral fibroblasts them-
that have specific binding characteristics. There selves, whereas others are secreted by inflamma-
are binding sites for fibrin, heparin, bacteria, col- tory cells, such as neutrophils and macrophages.
lagen, DNA, cell membranes, and a variety of Collagenase degrades cross-linked type I and
other macromolecules. Fibronectin is thought to type II collagen fibrils by attacking the collagen
be important in the organization of the pericellu- molecule at one specific locus one-quarter of the
lar and intercellular matrix by its ability to bind distance from the COOH-terminal. Two frag-
to collagen, fibroblasts, and GAGs [89, 90]. ments, TCA and TCB, three-quarters and one-
Antibodies directed against the collagen-binding quarter of the collagen molecule, respectively,
domain of fibronectin have been shown to inhibit are generated. These fragments denature sponta-
collagen fibril deposition [91]. Fibronectin has neously at temperatures greater than 33°C, are
also been found to play a role in host defense, phagocytosed, and become susceptible of further
presumably by its ability to interact with C1q attack in the lysosomes by proteinases, such as
component of complement, fibrin, bacteria, and cathepsins B and N. Collagen degradation in
DNA [92–94]. Characterization of fibronectin normal and inflamed tissues depends on the bal-
cDNA clones indicates that only a single fibronec- ance between the collagenase and its inhibitors
tin gene exists; but multiple forms of cellular [101]. The protein core of the proteoglycans
fibronectin are generated by alternative splicing must be broken by proteoglycanases for the col-
of mRNA [95–97]. These alternatively spliced lagenase to come into contact with the underly-
forms appear to have differential functions in ing collagen [70].
embryogenesis, defense, wound healing, and Elastase is a powerful proteinase that, unlike
homeostatic cell maintenance. collagenase, lacks specificity. It degrades not
Laminin, a glycoprotein found in basement only elastin, but also other components of the
membranes, consists of three polypeptide extracellular matrix, such as collagen and proteo-
chains—A(440 kDa), and B1 and B2 (each glycans. The neutrophil and macrophage elastases
220 kDa)—linked via disulfide bonds to form may be important in degrading elastin in inflam-
an asymmetric cross-structure [98]. Laminin matory reactions [102].
26 1 Structural Considerations of the Sclera
The core protein and link proteins of proteo- to the posterior pole by the 12th week. There are
glycans are degraded by proteoglycanases. The no more differences between the inner and outer
fragments are further degraded in the pericellular portions of the sclera by the beginning of week
area by other proteinases, such as cathepsin B. 10.9, and between the anterior and posterior por-
GAG peptides are phagocytosed and further tions of the sclera by week 13. The fetal sclera
degraded in the lysosomes by proteinases, such has the same ultrastructural characteristics as the
as cathepsin D. Subsequent attacks by different adult sclera by week 24.
exoenzymes result in monosaccharide residues Human fetal and adult sclera is formed by the
and free sulfate [103]. Fibronectin can be collagen types I, III, IV, V, VI, and VIII, by the
degraded by a wide variety of glycoproteinases, GAGs dermatan sulfate, chondroitin sulfate,
including trypsin, chymotrypsin, pepsin, hyaluronic acid, and heparan sulfate, and by the
elastases, and cathepsin G and D [104]. glycoproteins fibronectin, vitronectin, and lami-
nin. Collagen types I and VI increase steadily
from fetus to adult, collagen type III shows little
1.7.6 Fibroblast Growth Regulation change through the gestational periods, and col-
lagen type IV decreases steadily through 16, 19,
Human fibroblasts require growth factors for and 22 weeks, revealing only subtle positivity in
DNA synthesis. Fibroblast growth factors can be adult sclera, except for its dramatic presence in
classified either as “competence” factors or “pro- the vessels; the staining pattern of collagen type
gression” factors [105]. The competence factors, V is diffuse in fetal sclera but is granular along
including platelet-derived growth factor (PDGF) the edges of the collagen bundles in adult sclera;
and fibroblast growth factor, render cells in Go or collagen type VIII staining is intense in posterior
G1 phase ready for DNA synthesis stimulation fetal and adult sclera and anterior adult sclera but
[105, 106]. The progression factors, including is negative in anterior fetal sclera. Dermatan sul-
somatomedins A and C and insulin growth factor, fate and chondroitin sulfate are present in moder-
stimulate DNA synthesis in competent cells ate and large amounts, respectively, through the
[105–107]. Other known fibroblast growth fac- different gestational periods; in contrast,
tors, including interleukin-1 (IL-1), and T-cell- hyaluronic acid changes from a moderate stain-
derived fibroblast growth factor cannot be ing at 13 weeks to a subtle positivity in adult
considered as either competence or progression sclera; heparan sulfate is present in human fetal
factors and remain unclassified [108–111]. and adult sclera in small amounts. Fibronectin,
Specific receptors on fibroblasts for PDGF and vitronectin, and laminin are present at 13 weeks
IL-1 have been identified [105, 106, 108, 109]. but steadily disappear onward, except for their
Recombinant interferon g may stimulate or sup- presence in the vessels. Fibronectin and laminin
press fibroblast growth, depending on culture may play a major role in directing developmental
conditions [112, 113]. events.
The postnatal sclera is relatively distensible,
thin, and somewhat translucent, allowing the blue
1.8 Summary color of the underlying uvea to show through.
The sclera thickens gradually, becoming opaque
Almost all of the sclera is of neural crest origin, and more rigid. In elderly individuals, the sclera
except a small temporal portion formed from shows a decrease in scleral distensibility, water
mesoderm. The developmental process of the content, and amount of proteoglycans, and an
sclera is directed from anterior to posterior and increase in the amount of lipids and calcium
from inside to outside. Scleral differentiation has phosphate.
already started in the region destined to become Gross anatomical studies show that the scleral
the limbus by the sixth week, and progresses shell is an incomplete sphere averaging 22 mm in
backward to the equator by the eighth week and diameter that terminates anteriorly at the anterior
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Immunologic Considerations
of the Sclera 2
to the cell surface. The combination of these trolled manner the result may be deleterious to
degraded fragments in close juxtaposition to class host tissues. As the name suggests, they contain a
II MHC glycoproteins forms the recognition unit multilobed nucleus and many granules.
for the helper TCRs specific for the epitope of the Polymorphonuclear leukocytes are classified as
antigen [24–26]. Antigen-presenting cells pro- neutrophils, basophils, or eosinophils, depending
duce a variety of soluble factors during the pre- on the differential staining of their granules.
sentation of the antigen to T-helper lymphocytes,
including IL-1, which promotes the differentia- Neutrophils
tion of both T and B lymphocytes. Neutrophils represent over 90% of the circulating
Langerhans’ cells are also important antigen- granulocytes. They possess surface receptors for
presenting cells [27], particularly for the eye. the Fc portion of IgG (CD16) and for comple-
They are derived from bone marrow macrophage ment components, including C5a (important in
precursors and, like macrophages, they also pos- chemotaxis), and CR1 (CD35) and CR3 (CD11b)
sess a high density of class II MHC glycoproteins (important in adhesion and phagocytosis). When
on their cell surfaces (HLA-DR), along with appropriately stimulating by chemotactic agents
receptors for complement component (CR1/ (complement components, fibrinolytic and kinin
CD35) and the Fc portion of immunoglobulin G system components, and products from other leu-
(CD16). Unlike macrophages, Langerhans’ cells kocytes, platelets, and certain bacteria), neutro-
have a racket-shaped cytoplasmic granule (the phils move from blood to tissues through
Birbeck granule), are not phagocytic, and have margination (adhesion through endothelial cells)
the characteristic surface molecule CD1. and diapedesis (movement through the capillary
Other cells that do not arise from the monocyte/ wall). Neutrophils release the contents of their
macrophage lineage may also be important in pro- primary (azurophilic) granules (lysosomes) and
cessing and presenting antigen; B lymphocytes, secondary (specific) granules (Table 2.3) into an
constitutively rich in class II MHC glycoproteins, endocytic vacuole, resulting in phagocytosis of a
are functionally important as antigen-presenting microorganism or in tissue injury (type III
cells, particularly when the B lymphocyte is spe- hypersensitivity reactions or immune complex-
cific for the antigen being presented. mediated diseases) [31, 32]. Secondary granules
Cells other than macrophages, Langerhans’ release collagenase, which participates in con-
cells, or B lymphocytes can acquire the ability to nective tissue degradation. Aside from the prod-
“present” antigens through the induction of class ucts secreted by the granules, neutrophils also
II MHC glycoproteins on their cell surface under release lipids, such as an arachidonic acid deriva-
the influence of cytokines (interferon g and tumor tives as well as reactive oxygen derivatives [32].
necrosis factor); these cells include connective
tissue fibroblasts, corneal endothelial cells, or Eosinophils
vascular endothelial cells [28, 29]. It has been Eosinophils represent 3–5% of the circulating
suggested that such induction of expression of granulocytes. They possess surface receptors for
“inappropriate” class II MHC glycoproteins the Fc portion of IgE (low affinity) and IgG
might contribute to the pathogenesis of a variety (CD16) and for complement components.
of autoimmune diseases [30]. Eosinophils play a specialized role in allergic and
parasitic conditions. Although less important,
2.1.1.3 Polymorphonuclear Granulocytes they also participate in type III hypersensitivity
Polymorphonuclear granulocytes are leukocytes reactions or immune complex-mediated diseases
that form part of the natural immune system. following attraction to the inflammatory area by
They play a central role in host defense through products from mast cells, basophils (eosinophil
phagocytosis, but if they accumulate in excessive chemotactic factor of anaphylaxis, ECF-A), and
numbers, persist, and are activated in an uncon- complement. Eosinophils release the contents of
38 2 Immunologic Considerations of the Sclera
their granules to the outside of the cell after fusion They also can participate in type III hypersensi-
of the intracellular granules with the plasma tivity or immune complex-mediated diseases.
membrane (degranulation). Table 2.4 shows the IgE antibody induced by the antigen binds to cir-
known secretory products of eosinophils [32]. culating basophils or to tissue mast cells, which
then release histamine, platelet-activating factor,
Basophils/Mast Cells and other biological molecules when antigen
Basophils represent less than 0.2% of the circu- binds to two adjacent IgE molecules on the mast
lating granulocytes. They possess surface recep- cell surface (Table 2.6) [33]. Histamine and other
tors for the Fc portion of IgE (high affinity) and vasoactive amines cause an increase in vascular
IgG (CD16) and for complement components, permeability, allowing the immune complexes to
including C5a, CR1 (CD35), and CR3 (CD11b). become trapped in the vessel wall.
The mast cell is often indistinguishable from the
basophil in a number of properties. There are at 2.1.1.4 Platelets
least two classes of mast cells, distinguished on Blood platelets, cells highly adapted for blood clot-
the basis of their neutral protease composition, T ting, also are involved in the immune response to
lymphocyte dependency, and ultrastructural injury, reflecting their evolutionary heritage as
characteristics (Table 2.5): [33–36] one consists myeloid (inflammatory) cells. They possess surface
of the mucosa-associated mast cells (MMCs), receptors for the Fc portion of IgG (CD16) and IgE
and the other includes connective tissue-associ- (low affinity), for class I histocompatibility glyco-
ated mast cells (CTMCs). Basophils and mast proteins (HLA-A, -B, or -C), and for factor VIII.
cells play a specialized role in allergic reactions. They also carry molecules, such as Gp11b/111a
2.1 General Immune Response Considerations 39
Table 2.4 Secretory products of eosinophilsa Table 2.6 Secretory products of mast cells and
basophilsa
Peptides and enzymes
Lysosomal hydrolases Histamine
Arylsulfatase Serotonin
b-Glucuronidase Rat mast-cell protease I and II
Acid phosphatase Heparin
Alkaline phosphatase
Chondroitin sulfate
b-Glycerophosphatase
Ribonuclease b-Hexosaminidase
Proteinases b-Glucuronidase
Collagenase b-d-Galactosidase
Cathepsin Arylsulfatase
Histaminase Eosinophil chemotactic factor of anaphylaxis (ECF-A)
Peroxisomes Slow-reactive substance of anaphylaxis (SRS-A)
Major basic protein High-molecular-weight neutrophil chemotactic factor
Eosinophil cationic protein Arachidonic acid derivatives
Eosinophil peroxidases Platelet-activating factor
Phospholipases a
Adapted from reference [33]
Lysophospholipases
Lipids
Reactive oxygen intermediates
a
Adapted from reference [32]
Table 2.5 Differences between mast cell subtypesa Alfa granules Dense granules
Fibronectin Serotonin
Mucosal mast Connective tissue Fibrinogen Adenosine
Property cell (MMC) mast cell (CTMC) Plasminogen diphosphate (ADP)
Staining (Alcian Blue Red–blue Thrombospondin
Others
blue/safranin) von Willebrand´s factor
Arachidonic acid
Protease type Tryptase Tryptase and a2-Plasmin inhibitor
derivatives
chymase Platelet-derived growth factor
T lymphocyte Yes No (PDGF)
dependency Platelet factor 4s (PF4)
Transforming growth factor
Migration Migratory Nonmigratory
(TGF) a and b
Life span Short Long b-Lysin
Half-life <40 days >6 months Permeability factor
Proteoglycan Chondroitin Heparin Factors D and H
sulfate Decay-accelerating factor
a a
Adapted from reference [33] Adapted from reference [37]
(CDw41), which binds fibrinogen, and Gp1b cells after antigen–IgE antibody complex
(CDw42), which binds von Willebrand’s factor. formation induces platelets to aggregate and
Following endothelial injury, platelets adhere release their vasoactive amines. These amines
to and aggregate at the endothelial surface, releas- separate endothelial cells and allow the immune
ing from their granules permeability-increasing complexes to enter the vessel wall. Once the
molecules (Table 2.7) [37]. Endothelial injury immune complexes are deposited, they initiate an
may be caused by type III hypersensitivity or inflammatory reaction through activation of
immune complex-mediated reactions. Platelet- complement components and polymorphonuclear
activating factor released by basophils/mast granulocyte lysosomal enzyme release.
40 2 Immunologic Considerations of the Sclera
immune complex deposition: (1) exogenous, 2. Antigen and antibody valences: Monovalent
such as bacteria, virus, parasites, fungi, or drugs and oligovalent antigens bind only one or a few
and (2) endogenous or “self” components, such antibody molecules and form small immune
as nuclear antigens, immunoglobulins, or tumor complexes, whereas multivalent antigens bind
antigens (resulting in autoimmunity; this is dis- and cross-link many antibody molecules and
cussed in Sect. 2.1.3.2). form large, lattice-like structures [47].
Immune complex-mediated disease may be 3. Reticuloendothelial system function: Because
generalized, if immune complexes are formed in the reticuloendothelial system normally
the circulation and are deposited in many organs, phagocytizes the circulating immune com-
or localized, if the complexes are formed and plexes, its dysfunction increases the persis-
deposited locally (local Arthus reaction) to par- tence of immune complexes in circulation and
ticular organs, such as the kidney (glomerulone- tissue deposition.
phritis), joints (arthritis), or the small blood 4. Local characteristics of vessels: The focal dis-
vessels of the skin (purpura). tribution of vasculitic lesions in animals and
humans can be explained partially by struc-
Systemic Immune Complex Disease tural and hemodynamic differences among
The classic condition ascribed to systemic various blood vessels and by the tendency of
immune complex disease is acute serum sickness. immune complexes to deposit at the branch
Rabbits given a single intravenous injection of points of the vessels [48, 49].
bovine serum albumin (BSA) developed necro- Local vasoactive factors increase vascular per-
tizing arteritis and glomerulonephritis, similar to meability, which allows immune complexes to
the lesions seen in humans with polyarteritis leave the circulation and deposit within or out-
nodosa (PAN) [44, 45]. These lesions appear at side the vessel wall [50, 51]. The increased vas-
10–14 days, the period when circulating immune cular permeability results from the action of
complexes are being formed in slight antigen vasoactive amines derived from platelets (platelet-
excess. activating factor) and IgE (serotonin and hista-
The process is initiated by the introduction of mine). These amines induce contraction of
antigen into the circulation and its interaction vascular endothelial cells, disrupting their close
with immunocompetent cells, resulting approxi- apposition and producing interendothelial gaps
mately 5 days later in the formation of antibod- through which immune complexes travel, becom-
ies. Antibodies react with the antigen still present ing trapped in the basement membrane or depos-
in the circulation to form antigen–antibody com- iting in the tissues.
plexes. Antigen–antibody complexes formed in Once immune complexes are deposited in or
the circulation are deposited in various tissues. outside the vessel wall, complement components
The factors that determine whether immune com- are activated, some of which (1) are chemotactic
plex formation will result in tissue deposition and factors for neutrophils and eosinophils and
disease are diverse, and include the following. mononuclear leukocytes (C3a, C5a, and C5b67),
1. Immune complex size: The size of an immune (2) increase vascular permeability and cause
complex is determined by the ratio of antigen contraction of smooth muscle (C3a and C5a), or
to antibody. Large immune complexes (great (3) cause cell membrane damage (membrane
antibody excess) are readily phagocytized by attack complex, C5 through C9). Antibodies
the reticuloendothelial system and small IgG1, IgG2, IgG3, and IgM all activate the classic
immune complexes (great antigen excess) are complement pathway efficiently, whereas IgG4,
too small to localize in tissues. The most IgA, and aggregates of IgE interact with the com-
pathogenic complexes are of intermediate plement system via the alternative pathway.
size (formed in slight antigen or antibody During the active phase of the disease, consump-
excess) because of their longevity in the cir- tion of complement components decreases the
culation [46]. serum levels.
2.1 General Immune Response Considerations 43
Neutrophils attracted by complement compo- tated in the vessel walls, usually capillaries and
nents cause vessel and surrounding tissue dam- postcapillary venules, can be seen by light
age through the release of the lysosomal enzymes, microscopy as neutrophilic infiltration of the ves-
reactive oxygen metabolites, and proinflamma- sel wall and by immunofluorescence microscopy
tory substances, such as platelet-activating factor, as deposits of immunoglobulin and complement.
leukotrienes, and prostaglandins. Platelets may
adhere to locally damaged endothelium and Type IV Hypersensitivity Reactions
aggregate, obstruct blood vessels, and release Type IV hypersensitivity reactions are also known
more inflammatory mediators, augmenting ves- as delayed hypersensitivity reactions because
sel and tissue necrosis. The reaction spirals into they require more than 12 h after the antigenic
an amplification cascade, causing damage to ves- challenge to develop. They are mediated by cells
sel walls and other surrounding tissues. The (T lymphocytes) and not by antibodies. After anti-
resultant pathological lesion is termed vasculitis gen presentation by the antigen-presenting cells,
if it occurs in blood vessels, glomerulonephritis if T lymphocytes proliferate and release lymphok-
it occurs in renal glomeruli, arthritis if it occurs in ines, which may cause direct cytotoxicity or stim-
joints, and so on. The immune complexes can be ulate neutrophils and macrophages to produce
seen by immunofluorescence microscopy as tissue damage [7]. Four kinds of type IV hyper-
deposits of immunoglobulin and complement. sensitivity can be distinguished: (1) Jones-Mote,
A chronic form of serum sickness or immune (2) contact, (3) tuberculin, and (4) granulomatous.
complex disease results from repeated or pro- The first three reactions develop between 24 and
longed exposure to an antigen. This occurs in 72 h after antigen challenge, whereas the fourth
systemic vasculitic diseases, such as rheumatoid type requires at least 14 days [7].
arthritis, systemic lupus erythematosus, and pol- Granulomatous hypersensitivity causes many
yarteritis nodosa. However, although immuno- of the pathological hallmarks of diseases, such as
globulins and complement as part of immune tuberculosis, schistosomiasis, or scleral inflam-
complexes can be seen by immunofluorescence mation. Persistence of microbiological agents
techniques, the inciting antigens are unknown. (M. tuberculosis, viruses, parasites, and fungi),
foreign body deposition (talc), or immune com-
Local Immune Complex Disease plexes provides the long-term stimulus for the
(Arthus Reaction) inflammatory response to produce granulomas
The classic condition ascribed to local immune [53]. Histologically, granulomas are composed of
complex disease is the Arthus reaction [52]. In macrophages and epithelioid cells (modified
this model, necrotizing vasculitis is seen at the macrophage) with variable numbers of neutro-
site of locally injected antigen in animals preim- phils, eosinophils, lymphocytes, and plasma
munized (having circulating antibodies) with the cells. Also seen in this type of reaction is the
same antigen. Vessel damage occurs because of multinucleated giant cell (Langhans’ giant cell),
the reaction of preformed antibody with locally which is derived from fusion of several epithe-
injected antigen in vessel walls. As the antigen lioid cells; this cell is believed to be an end stage
diffuses into the vascular wall, large immune of differentiation of the monocyte/macrophage
complexes are formed because of the excess of line [54].
antibodies, which precipitate locally and trigger
the inflammatory reaction discussed earlier. The 2.1.3.2 Autoimmunity
Arthus reaction develops over a few hours and Autoimmunity is an immune response directed
reaches a peak 4–10 h after injection; the area against endogenous structures of an organism
discloses edema, hemorrhage, and occasionally (autoantigens or self-antigens); the organism
ulceration as a result of inflammatory reaction, escapes from the normal state of tolerance to its
rupture of the vessel wall, or thrombosis of the own tissue antigens to the abnormal state of
vessel lumen. The immune complexes precipi- responding to self as nonself [55]. The immune
44 2 Immunologic Considerations of the Sclera
products, leading to polyclonal activation. nents and eventual scar formation. Lymphocyte-
Some of the nonspecific immunoglobulins derived chemotactic factor released from T
produced may react with self-molecules, lymphocytes, platelet-derived growth factor
resulting in autoantibody production. For released from platelets, and leukotriene B4
example, bacterial lipopolysaccharide may released from leukocytes have been shown to
induce mouse B lymphocytes to form autoan- provide chemotactic signals for fibroblasts
tibodies in vitro; some viruses (EBV) are non- [58–61]. The C5-derived fragment from serum
specific, polyclonal B-lymphocyte mitogens complement activation by the classic or alterna-
(human B lymphocytes have surface receptors tive pathways can also provide chemotactic sig-
for EBV) and may thus induce the production nals for fibroblasts [62]. Collagen, elastin, and
of autoantibodies. fibronectin, as well as some of their degradation
6. Idiotypic networks: Abnormalities in the products, can be chemoattractants for fibroblasts
immune response involving the idiotypic net- [63–65].
work may lead to the production of antibodies Fibroblast functions, such as collagen, col-
(idiotype) against self-molecules. Anti- lagenase, and hyaluronic acid production, can
idiotypic antibodies against the idiotype (e.g., be modulated by components of the immune
antithyroid-stimulating hormone [TSH]) response. Type I collagen production is stimu-
resemble the original antigen (e.g., TSH) and lated by a lymphokine, the collagen production
may react with the antigen receptor on spe- factor, and by a monokine, interleukin 1, but it
cialized cells (e.g., TSH receptors on thyroid is inhibited by another lymphokine, interferon
cells in Graves’ disease) [57]. g [66–70]. Collagenase and hyaluronic acid
7. Abnormalities of immunoregulatory T cells: productions are stimulated by interleukin 1
The normal immune system has the capacity [67, 68, 71].
to produce a small amount of autoantibodies Fibroblasts have been found to synthesize
without the production of autoimmune reac- several complement components [72–74]. C1q,
tions; T-suppressor lymphocytes normally the recognition unit of the classical pathway, and
control this autoantibody production (through collagen have structural similarities because the
preventing T lymphocyte’s help to B lympho- genes for each share part of their coding region
cytes). Loss of T-suppressor lymphocyte func- [75, 76]. Complement synthesis by fibroblasts
tion (e.g., following viral infection) may allow can be regulated by several components of the
the production of large amounts of autoanti- immune response, including interleukin 1, tumor
bodies, leading to autoimmunity. necrosis factor, and interferon g [77–79].
Fibroblasts have been shown to express class I
HLA glycoproteins constitutively [80–82], but
2.2 Connective Tissue and under certain inflammatory stimuli, including
the Immune Response that of interferon g, they can also express class II
HLA glycoproteins [83–85]. Class II HLA
2.2.1 Fibroblast Functions and expression may allow fibroblasts to be involved
the Immune Response in the initiation and perpetuation of an immune
inflammatory response.
When connective tissue sustains an inflamma- Following stimulation by interleukin 1, fibro-
tory (immunological, mechanical, or chemical) blasts may synthesize and secrete prostaglandins,
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repair the damage. Specific chemoattractants provides a regulatory signal in modulating the
have been identified that direct their migration intensity of the inflammation during the immune
for subsequent synthesis of new matrix compo- response.
46 2 Immunologic Considerations of the Sclera
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Diagnostic Approach of Episcleritis
and Scleritis 3
Scleral inflammation gives rise to a spectrum of Although the process of clinical reasoning in
conditions, ranging from a trivial self-limiting medicine is based on several subjective factors,
episode to a vision-threatening necrotizing pro- such as interpretation of evidence, deductive rea-
cess. Clinical differentiation of these conditions soning, experience, and intuition, attempts at spe-
is important because they follow different courses cific sequential analysis of the process can improve
and have different prognostic significance. the ways in which the problems of individual
Several classifications have been proposed on the patients are approached and solved. In a simplified
basis of clinical, clinicopathological, and etio- model, the specific approach in clinical problem
logic aspects. The most frequently used is based solving that can be applied to scleritis includes five
on the anatomical site of the inflammation and on phases (Table 3.3). The first phase includes investi-
the clinical appearance of the disease at presenta- gation of the illness through the interview and
tion (Table 3.1). This classification, proposed by physical examination of the patient. Constructing a
Watson and Hayreh [1], has proved to be satisfac- diagnostic hypothesis generates more questions
tory because it enables one to assign most patients and answers in order to determine which possibili-
to a particular category and subcategory at the ties best fit the illness. As the ophthalmologist
initial clinical examination, with almost no completes this phase, possible diagnoses come to
changes over the course of the disease. Two main mind. The second phase consists of selection of
groups can be differentiated: episcleritis and diagnostic tests, each with its own level of accuracy
scleritis (Figs. 3.1 and 3.2). Episcleritis is a and usefulness for investigating the possibilities
benign recurrent disease with little systemic dis- raised in the former phase. Because relatively few
ease association, whereas scleritis not only can tests can be used to effectively establish the diagno-
cause great pain, loss of vision, and in some cases sis of the underlying systemic disease associated
destruction of the eye, but also may portend an with episcleritis and scleritis, the ophthalmologist
underlying, potentially lethal systemic disease can be selective and parsimonious in the request for
(Table 3.2). There are distinct clinical patterns tests. The third phase includes the decision as to
that help to distinguish episcleritis from scleritis. whether a tissue biopsy should be performed.
There are also distinguishing features that may Biopsies can be costly, time consuming, and entail
help uncover the underlying systemic diseases. some discomfort; it is important, therefore, to con-
Early detection and characterization of the scleral sider whether or not the results are likely to add
and systemic disease lead to early treatment, useful information to the diagnosis solving process.
which can improve both ocular and systemic In the fourth phase, the clinical data must be inte-
prognoses. This chapter provides specific guide- grated with test and biopsy results to confirm or
lines for a diagnostic approach in patients with discard the preliminary diagnoses. In the fifth and
episcleritis and scleritis. final phase, the comparative risks and benefits of
Table 3.1 Clinical classification of episcleral and scleral Table 3.2 Diseases associated with episcleritis and
inflammation scleritis
Episcleritis Noninfectious
Simple Connective tissue diseases and other inflammatory
Nodular conditions
Scleritis Rheumatoid arthritis
Anterior scleritis Systemic lupus erythematosus
Diffuse scleritis Ankylosing spondylitis
Nodular scleritis Reactive arthritis
Necrotizing scleritis: Psoriatic arthritis
With inflammation Arthritis and inflammatory bowel disease
Without inflammation (scleromalacia perforans) Relapsing polychondritis
Posterior scleritis Vasculitic diseases
Adapted from reference [1] Polyarteritis nodosa
Allergic granulomatous angiitis (Churg–Strauss
syndrome)
Granulomatosis with polyangiitis (Wegener)
Behçet’s disease
Giant-cell arteritis
Cogan’s syndrome
Vasculitic diseases associated with connective tissue
diseases and other inflammatory conditions
Miscellaneous
Atopy
Rosacea
Gout
Foreign body granuloma
Chemical injury
Infectious
Bacterial
Fungal
Viral
Parasitical
Fig. 3.1 Episcleritis. Note the vascular dilatation of con-
junctival vessels, and superficial episcleral and deep epis-
cleral vascular plexuses. There is no underlying scleral
edema or loss of sclera, and the eye appears bright red therapeutic possibilities for the particular diagnosis
are presented to the patient and, after appropriate
discussion of the options, a therapeutic plan is initi-
ated and the response to therapy observed. Each
step in this simplified model of the clinical approach
to scleral disease can be analyzed individually.
Table 3.3 Phases of clinical approach to episcleritis and The main symptoms present in scleral diseases
scleritis are the following.
1. Investigation of the illness 1. Pain is the most common symptom for which
Interview patients with scleral disorders seek medical
Major complaint
History of present illness assistance, and is the best indicator of the pres-
Past history ence of active inflammation. Pain is due to both
Family history direct stimulation and stretching of the nerve
Past and present therapy history endings by the inflammation. Important issues to
Review of systems
Physical examination consider in pain evaluation are the patient’s age,
Systemic examination cultural background, environment, and psycho-
Head logical circumstances, such as depression, anxi-
Extremities
ety, and tension. Inquiry should be made
Ocular examination
Episclera and sclera concerning character, location, radiation, timing,
Other ocular structures and analgesic response. No pain, mild discom-
2. Diagnostic tests fort, or occasional trivial pain localized to the
Blood and urine tests eye is characteristic of episcleritis. “Real” pain,
Anterior chamber polymerase chain reaction (PCR)
Smears and cultures (if infection is suspected)
severe, penetrating pain that radiates to the fore-
Skin testing head, the brow, the jaw, or the sinuses, awakens
Imaging studies the patient during the night, is only temporarily
3. Tissue biopsy relieved by analgesics, is characteristic of scleri-
4. Integration of clinical findings with tests and biopsy tis. We place great emphasis on pain in
results
discriminating between episcleritis and scleritis.
5. Therapeutic plan
Assessment of different therapeutic possibilities Differential diagnosis of other painful eye
Discussion of risks and benefits with patient diseases, including corneal surface problems,
angle-closure glaucoma, and acute anterior
uveitis, are easily excluded by ocular examina-
tion. Differential diagnosis of other painful peri-
3.1.1 Major Complaint and History ocular diseases, including migraine, sinusitis,
of Present Illness herpes zoster ophthalmicus, and orbital tumors,
are excluded by careful ocular and periocular
The major complaint is the main problem that examination, and additional imaging studies.
motivated the patient to seek medical help. The 2. Redness, a sign rather than a symptom, can be
ophthalmologist must begin with an open-ended detected by the patient’s family or friends or by
question to allow the patient to freely describe the the patient looking in the mirror. Almost all
major complaint and the history of the present ill- patients with episcleritis and scleritis present to
ness. Even though this may result in a disjointed the physician with redness as a clinical manifes-
and incomplete story, inflections of voice, facial tation. Clinically obvious redness may be absent
expression, descriptive efforts with hands, and in scleromalacia perforans (necrotizing scleritis
attitude may betray important clues to the mean- without inflammation) and in posterior scleritis.
ing of what the patient has been experiencing. The 3. Tearing or photophobia without mucopurulent
ophthalmologist should actively guide the inter- discharge occurs in approximately one-fourth
view in order to develop organization and content, of patients with episcleral and scleral inflam-
to clarify terms the patient uses, and to evaluate mation, but it is usually mild or moderate.
symptoms as of little or considerable importance. 4. Tenderness to palpation may be described by
Severity of symptoms may be estimated by the the patient. In general, ocular tenderness is mild,
extent to which they interfere with sleep or work if any, and localized to the site of inflammation
patterns. The patient soon learns that events must in episcleritis or is moderate or severe and
be dated, sequences established, and onset and diffuse, with possible radiation to other parts of
characteristics of symptoms precisely described. the head in true scleritis.
60 3 Diagnostic Approach of Episcleritis and Scleritis
5. Decreased visual acuity is almost never a side effects, complications, concomitant treatments
symptom of episcleritis but is a possible find- for other conditions, and reasons for discontinua-
ing in scleritis. The extension of the scleral tion often provide insight about the nature of the
inflammation to the adjacent structures may illness and for future therapeutic decision making.
cause keratitis, uveitis, glaucoma, papillitis, Careful attention to detail may often reveal simple,
macular edema, annular ciliochoroidal detach- correctable mistakes, such as inadequate dosage;
ment, and serous retinal detachment; these poor compliance, too short a trial of a slow-acting
abnormalities may impair visual acuity. medication; medications given for other condi-
tions; or foods that interfere with medications pre-
scribed for the scleritis.
3.1.2 Past History There is a great variability in patient response
to nonsteroidal anti-inflammatory drugs.
The past medical and ocular history elicitation Sometimes, one nonsteroidal anti-inflammatory
serves primarily to discover already known sys- drug may be better than another for a particular
temic diseases that can cause scleritis (Table 3.2). patient; therefore, inadequate response to one
Past ocular surgical procedures, especially in the nonsteroidal anti-inflammatory drug does not
few months prior to the onset of scleritis, can have indicate probable unresponsiveness to other non-
potential diagnostic importance. Determination of steroidal anti-inflammatory drugs. Furthermore,
past medical history is also important for discover- at least 2–4 weeks are required for full evaluation
ing certain conditions, such as gastric ulceration, of a particular nonsteroidal anti-inflammatory
diabetes, liver or renal disease, or hypertension agent. Therefore, caution is indicated in drawing
that might eventually modify future therapy. conclusions from the therapeutic response to only
one type of nonsteroidal anti-inflammatory drug
3.1.3 Family History or from responses to nonsteroidal anti-inflamma-
tory drugs used for brief periods.
The family history can be important in several The most important features of the steroid
respects. The growing field of immunogenetics has therapy history include the length of therapy,
demonstrated that diseases frequently associated route of administration, maximal and average
with scleritis, such as rheumatoid arthritis, systemic doses, side effects, and whether periodic attempts
lupus erythematosus, ankylosing spondylitis, reac- to decrease the dose were made (and if so, the
tive arthritis (we moved from “Reiter´s disease” size of the decrements). This historical informa-
term because Reiter was a criminal as a conse- tion may be essential in deciding whether to initi-
quence of doing experimentations on prisoners in ate immunosuppressive therapy.
concentration camps during World War 2), Behcet’s The patient should be asked whether he or she
disease, atopy, and gout, have a genetic basis. This has ever used immunosuppressive drugs; type,
information may give clues for specific systemic dosage, response, and side effects are extremely
diagnoses that can be pursued with additional stud- important to future treatment planning.
ies. Also, psychological factors, such as attitudes
toward illness, fears, and expectations, can be
assessed from previous illnesses within the family. 3.1.5 Review of Systems
Table 3.4 Review of system questionnaire for episcleri- Table 3.4 (continued)
tis and scleritis
Gastrointestinal
Manifestations Associated systemic diseases Abdominal pain SLE, reactive A, IBD, PAN,
Skin, hair, and nails Ch-S, Behçet
Rash/vesicles/ulcers Connective tissue, vasculitic, Nausea, vomiting SLE, IBD, RP, PAN, Cogan
and infectious diseases, atopy, Difficulty swallowing RA, SLE
Ros, Lyme Blood in stool IBD, PAN, Ch-S, Behçet
Sunburn easily SLE Diarrhea SLE, reactive A, IBD, PAN
Hyper/depigmentation SLE, leprosy Constipation IBD
Loss of hair SLE, leprosy Anal lesions IBD
Painfully cold fingers RA, SLE, GCA Neurological
Scaling Reactive A, PA, atopy Headaches SLE, RP, GCA, mumps,
Nail lesions Reactive A, PA, vasculitic Lyme, PAN, Behçet
diseases Numbness/tingling Connective tissue, vasculitic,
Respiratory and infectious systemic
Constant coughing RA, SLE, AS, RP, Ch-S, GPA diseases
(Weg), TB, Lyme Paralysis Connective tissue, vasculitic,
Coughing blood RA, SLE, AS, GPA (Weg), and infectious systemic
TB diseases
Shortness of breath RA, SLE, AS, RP, Ch-S, GPA Seizures SLE, RP, PAN, Ch-S, mumps,
(Weg), atopy, TB Lyme
Asthma attacks Ch-S, atopy Psychiatric SLE, reactive A, Ch-S,
Pneumonia SLE, AS, RP, Ch-S, GPA Behçet, GCA, mumps, Lyme
(Weg), atopy, TB Neuralgia Leprosy, VZV
Cardiac Ear
Anginal chest pain RA, SLE, PAN, GCA Deafness RP, GPA (Weg), GCA, Cogan,
Genitourinary mumps, Syph
Blood in urine SLE, reactive A, RP, PAN, Swollen ear lobes RP
Ch-S, GPA (Weg), TB Ear infections RP, GPA (Weg)
Urinary discharge Reactive A Vertigo RP, Cogan
Pain during urination Reactive A Noises in ears RP, Cogan
Prostate trouble AS, reactive A, IBD, Ch-S, Nose/sinus
TB, Nasal mucosal ulcers SLE, GPA (Weg)
Testicular pain PAN, mumps, Lyme Rhinitis/nosebleeds GPA (Weg), atopy, leprosy,
Genital lesions Reactive A, Behçet, mumps, Syph
TB, Syph Swollen nasal bridge RP, leprosy, Syph
Kidney stones Gout, IBD Sinus trouble GPA (Weg)
Rheumatological Mouth/throat
Painful joints Connective tissue and Oral mucosal ulcers SLE, reactive A, IBD, Behçet
vasculitic diseases, gout, TB, Persistent hoarseness RA, SLE, RP, leprosy
Lyme
Jaw claudication GCA
Morning stiffness RA, SLE, AS
SLE systemic lupus erythematosus, RA rheumatoid arthri-
Muscle aches RA, SLE, AS, PAN, GCA,
tis, RP relapsing polychondritis, PAN polyarteritis nodosa,
Lyme
GPA (Weg) granulomatosis with polyangiitis (Wegener),
Back pain AS, reactive A, PA, IBD Ch-S allergic granulomatous angiitis (Churg–Strauss syn-
Heel pain AS, reactive A, gout drome), GCA giant-cell arteritis, Reactive A reactive
Big toe pain Gout, PA arthritis, PA psoriatic arthritis, AS ankylosing spondilitis,
IBD arthritis associated with inflammatory bowel disease,
(continued) VZV varicella zoster virus (herpes zoster), Syph syphilis,
TB tuberculosis, Ros rosacea, Lyme Lyme disease, Behçet
Behçet´s disease, Cogan Cogan’s syndrome
62 3 Diagnostic Approach of Episcleritis and Scleritis
and infectious diseases. Our review of system Table 3.5 General examination of the head and extremities
questionnaire for episcleritis and scleritis, with in episcleritis and scleritis
the corresponding associated systemic diseases, Clinical finding Associated systemic disease
is shown in Table 3.4. Saddle nose deformity RP, GPA (Weg), leprosy,
Constitutional symptoms, such as chills, fever, Syph
poor appetite, recent weight loss, and fatigue, may Auricular pinna deformity RP, leprosy
Nasal mucosal ulcers GPA (Weg)
suggest an occult systemic disorder. Skin lesions,
Oral/lip/tongue mucosal SLE, reactive A, IBD,
including rashes, vesicles, and ulcers, may be man- ulcers Behçet
ifestations of connective tissue, vasculitic, and Facial butterfly rash SLE
infectious diseases; they also may be present in Alopecia SLE, Syph
atopy and rosacea. Hair abnormalities, such as hair Facial telangiectasias SLE, Ros
loss, may be found in systemic lupus erythemato- Rhinophyma Ros
sus, and nail findings may be associated with reac- Temporal artery erythema GCA
tive arthritis, psoriatic arthritis, and vasculitic Parotid enlargement Mumps
diseases. Respiratory manifestations are most com- Teeth abnormalities Syph
monly present in allergic granulomatous angiitis Lymphadenopathy RA, SLE, infectious disease
(Churg–Strauss syndrome), granulomatosis with Skin hypopigmentation RP, leprosy
polyangiitis (Wegener), systemic lupus erythema- Skin rashes Connective tissue and
vasculitic disease, Syph,
tosus, atopy, and tuberculosis. Cardiac symptoms,
atopy
such as anginal chest pain, may be found in some Skin vesicles VZV
vasculitic diseases. Genitourinary lesions may sug- Skin ulcers Vasculitic disease
gest reactive arthritis, granulomatosis with poly- Skin scaling SLE, reactive A, PA, Syph
angiitis (Wegener), and polyarteritis nodosa. Ear/arms/legs tophi Gout
Rheumatological abnormalities may be present in Ulcers in fingertips Vasculitic disease
any connective tissue or vasculitic disease and in Nail lesions SLE, reactive A, PA
many of the infectious diseases that may cause Subcutaneous nodules RA, SLE, PAN, GPA
episcleritis or scleritis. Gastrointestinal symptoms (Weg), Ch-S, gout
are frequently found in systemic lupus erythemato- Arthritis Connective tissue, vasculitic
and infectious systemic
sus, polyarteritis nodosa, reactive arthritis, and diseases
inflammatory bowel disease. Neurologic manifes- Tendinitis AS, reactive A
tations may be associated with connective tissue, Erythema nodosum IBD, Behçet, TB, RP
vasculitic, and infectious diseases. Ear and nose SLE systemic lupus erythematosus, RA rheumatoid arthri-
abnormalities are commonly associated with tis, RP relapsing polychondritis, PAN polyarteritis nodosa,
relapsing polychondritis, granulomatosis with GPA (Weg) granulomatosis with polyangiitis (Wegener),
polyangiitis (Wegener), and Cogan’s syndrome. Ch-S allergic granulomatous angiitis (Churg–Strauss syn-
drome), GCA giant-cell arteritis, Ros rosacea, Reactive A
Mouth lesions, such as oral ulcers, are characteris- reactive arthritis, PA psoriatic arthritis, IBD arthritis asso-
tically present in Behçet’s disease. ciated with inflammatory bowel disease, VZV varicella
zoster virus (herpes zoster), Syph syphilis, TB tuberculo-
sis, Behçet Behçet´s disease, AS ankylosing spondylitis
3.1.6 Systemic Examination
Physical signs are the objective marks of the disease especially when the history has been inconsistent or
and represent indisputable facts. Their significance confusing and the review of systems meaningless.
is enhanced when they confirm a functional or Skill in physical diagnosis reflects a way of thinking
structural change already suggested by the patient’s more than a way of doing.
history or review of systems. Sometimes, the physi- In a patient with a scleral disease, the exami-
cal signs may be the only evidence of disease, nation of the head and extremities, including the
3.1 Investigation of the Illness 63
Fig. 3.3 Loss of cartilage in both the nose (saddle nose with or without the presence of rhinophyma can
deformity) and the ears (“floppy ears”) is an important establish the diagnosis of acne rosacea. The
clue for diagnosis of relapsing polychondritis
detection of a temporal artery tenderness obli-
gates one to consider giant-cell arteritis. The
nose, mouth, external ear, skin, and joints, may finding of parotid enlargement can lead to the
reveal significant signs either ignored by the diagnosis of mumps infection or sarcoidosis.
patient or considered as of little importance “Peg-top” teeth, deafness, and/or saddle nose
(Table 3.5). deformity can be signs of congenital syphilis.
Lymphadenopathy may be present in rheumatoid
3.1.6.1 Head arthritis, systemic lupus erythematosus, or any
The detection of a “saddle nose” deformity and/ infectious disease. The finding of hypopigmented
or auricular pinna deformity can be important for areas may lead to the consideration of relapsing
the diagnosis of relapsing polychondritis polychondritis or leprosy. A rash can be a mani-
(Fig. 3.3) or leprosy; a saddle nose deformity festation of any vasculitic disease (Fig. 3.5),
and/or nasal mucosal ulcers can be manifesta- atopy, or syphilis. Vesicles in periocular areas,
tions of granulomatosis with polyangiitis the forehead, or the tip of the nose may confirm a
(Wegener). Ulcers in the mouth, even if minimal, herpes zoster infection. Skin purpuric lesions or
may guide one to the suspicion of systemic lupus ulcers can be important clues for the diagnosis of
erythematosus, reactive arthritis, arthritis associ- any of the vasculitic diseases.
ated with inflammatory bowel disease, or Behçet’s
disease (Fig. 3.4). A “butterfly” rash extending 3.1.6.2 Extremities
across the bridge of the nose to the malar areas The finding of nail-bed thrombi (Fig. 3.6), small
and/or alopecia oblige one to consider systemic infarcts of the fingers, or purpuric lesions is sug-
lupus erythematosus. Alopecia also can be a sign gestive of vasculitic disease. Skin scaling may
of syphilis. Erythema, telangiectasias, papules, or lead to the consideration of systemic lupus ery-
pustules on the forehead, cheek, nose, and chin thematosus, reactive arthritis, psoriatic arthritis,
64 3 Diagnostic Approach of Episcleritis and Scleritis
Fig. 3.5 Rash on left lower lid and cheek suggested sys-
temic lupus erythematosus, which was confirmed by a
review of systems, blood tests, and biopsy
or syphilis. The presence of tophi in cartilage is compatible with any of the systemic noninfec-
an important clue for the diagnosis of gout. Nail tious or infectious diseases (Fig. 3.8). Erythema
abnormalities can be manifestations of reactive nodosum would make one consider inflammatory
arthritis or psoriatic arthritis. The detection of bowel disease, Behçet’s disease, or tuberculosis.
subcutaneous nodules oblige one consider rheu-
matoid arthritis, systemic lupus erythematosus,
polyarteritis nodosa, allergic granulomatous 3.1.7 Ocular Examination
angiitis (Churg–Strauss syndrome), granulomato-
sis with polyangiitis (Wegener), or gout (Fig. 3.7). The examination of the eye enables one to detect
The finding of articular abnormalities can be and characterize scleral disease. It is important
3.1 Investigation of the Illness 65
to distinguish the benign, self-limiting, and fre- 3.1.7.1 Episcleral and Scleral Examination
quently symptomless episcleritis from the much Three vascular networks can be distinguished in
more severe, destructive, and often painful the anterior segment of the eye: a conjunctival net-
scleritis, which can lead to loss of vision and work, a superficial episcleral network, and a deep
portend serious systemic disease. Early diagno- episcleral network (Fig. 3.9). In episcleritis, maxi-
sis may lead to early treatment of the ocular and mum congestion is in the superficial episcleral
general condition. Differentiation between the vascular network, with no changes in the deep
two entities and further characterization of each episcleral network. The edema is localized to the
can be accomplished if the eye is examined episcleral tissue; the superficial episcleral network
methodically and thoroughly, following a strict is displaced forward because of underlying epis-
routine of examination. cleral edema, and the deep episcleral network
66 3 Diagnostic Approach of Episcleritis and Scleritis
Fig. 3.15 Necrotizing scleritis in same patient shown in Fig. 3.17 Diffuse illumination from a slit-lamp can show
Fig. 3.14; 1 year later, scleral loss has increased, leaving the altered pattern of congested vessels in scleritis; new
the underlying uvea covered by a thin layer of vessel formation around the avascular areas may appear in
conjunctiva necrotizing scleritis
Table 3.6 Other ocular manifestations in episcleritis- and scleritis-associated systemic disease
Associated disease EOM E C K AU PU R ON
Rheumatoid arthritis − − − + − − − −
Systemic lupus erythematosus + + − + − − + +
Ankylosing spondylitis − − − − + − − −
Reactive arthritis − − + + + + − −
Psoriatic arthritis − + + + + − + −
Arthritis/inflammatory bowel disease − − + + + + + +
Relapsing polychondritis + + + + + + + +
Polyarteritis nodosa + + + + + − + +
Allergic granulomatous angiitis (Churg–Strauss syndrome) − − − + − − − −
Granulomatosis with polyangiitis (Wegener) + + + + − + + +
Cogan’s syndrome − − − + + + + +
Behçet’s disease − − − − + + + +
Giant-cell arteritis + + + + + − − +
Gout − − + + − − − −
Rosacea − + + + − − − −
Atopy − + + + − + + −
Tuberculosis + + + + + + + +
Leprosy + + + + + + − −
Syphilis + + + + + + + +
Herpes zoster + + + + + + + +
Herpes simplex + + + + + + + +
Mumps + + + + + + + +
Lyme disease + + + + + + + +
EOM extraocular muscle palsies, E eyelids, C conjunctiva, K cornea, AU anterior uveitis, PU posterior uveitis, R retina,
ON optic nerve
3.1.7.2 General Eye Examination for loss of vision and destruction of the eye, a
Episcleritis and scleritis can appear as isolated complete general eye examination must never
lesions or can be accompanied by other ocular be omitted.
manifestations. These manifestations can appear
as a complication of the inflammatory process Visual Acuity
itself or concomitantly with the scleral disease. Visual acuity may be reduced in patients with
Complications of episcleritis and scleritis scleritis, but almost never is in patients with epis-
include extraocular muscle involvement, kerati- cleritis. The whole object of early diagnosis is
tis, uveitis, cataract, glaucoma, disk edema, and early, appropriate treatment to prevent impaired
macular edema. Concomitant manifestations of vision. A further reduction in vision most fre-
episcleritis and scleritis include any other ocular quently is due to the extension of the scleral
abnormalities present as part of the same sys- inflammation to adjacent structures leading to
temic inflammatory disease that can also affect keratitis, anterior uveitis, cataract, posterior
the sclera. In fact, many of the episcleritis- and uveitis, retinal detachment, optic neuritis, or glau-
scleritis-associated systemic diseases may coma. The most common method of visual acuity
involve other ocular structures, such as the measurement is the Snellen eye chart. The Snellen
extraocular muscles, eyelids, conjunctiva, cor- eye chart tests the ability of the eye to resolve
nea, anterior and posterior uvea, retina, and high-contrast targets. The best corrected visual
optic nerve (Table 3.6). Because involvement of acuity, tested either by refraction or at least by pin-
some of these structures is an important reason hole, must be documented. Improvement or wors-
70 3 Diagnostic Approach of Episcleritis and Scleritis
ening of the patient’s vision without evidence of patients who develop scleritis. Corneal changes
other ocular complications can be critically useful are primarily peripheral and adjacent to areas of
in monitoring the effect of medical therapy. scleral inflammation; therefore, they are usually
more extensive in diffuse than in nodular scleri-
Pupils and Extraocular Muscles tis. Infiltrates (Fig. 3.21), thinning, edema, neo-
The standard measurements of the direct and vascularization, and ulceration (Fig. 3.22) may
consensual pupillary reaction to light, and the result from the spread of the adjacent scleral
swinging flashlight to detect a Marcus Gunn or inflammation. Several characteristic patterns of
reverse Marcus Gunn pupil can be helpful in keratitis-associated scleritis have been described,
assessing the status of the optic nerve. The optic ranging from a relatively benign thinning to a
nerve can be affected by sustained high intraocu- progressive, destructive, peripheral ulcerative
lar pressure, direct spread of posterior scleral keratitis that can lead to perforation and eventual
inflammation, long-standing posterior uveitis, or loss of the eye. Early detection of corneal involve-
the same systemic diseases that may affect the ment may lead to adequate treatment, which may
sclera. For example, detection of an Argyll improve the ocular prognosis.
Robertson pupil, that is, a pupil that does not Because many scleritis-associated systemic
react to light but does react to convergence, in the diseases may also involve the peripheral cornea,
presence of scleral inflammation, obligates one to scleral and corneal changes may be caused by the
consider syphilis. same immunological mechanisms.
Reduction of extraocular muscle function may Mild corneal changes occur in a small minor-
occur because of inflammatory infiltration or ity of patients with episcleritis, but they do not
edema of a muscle secondary to surrounding become permanent.
scleral inflammation or because of III, IV, or VI
cranial nerve palsies due to direct involvement of Anterior Uvea
the nerve supply in the orbit by some systemic Anterior chamber examination with the slit-lamp
diseases that may also affect sclera. beam may reveal an anterior uveitis character-
ized by a mild-to-moderate amount of flare and
Cornea cells in the aqueous and anterior vitreous with a
Careful slit-lamp examination of the cornea few small endothelial keratic precipitates. Mild
should always be performed because corneal anterior uveitis may be found in a small percent-
involvement may occur in almost one-third of the age of cases of episcleritis. Scleritis-associated
3.2 Diagnostic Tests 71
working with a complement test using sheep develop RA. RF positivity frequently precedes
erythrocytes (srbc) coated with anti-srbc rabbit the onset of RA [9, 10].
antibodies. Waaler noted that serum from rheu- The presence of RF does not establish the diag-
matoid arthritis (RA) patients contained a factor nosis of RA as the predictive value of the presence
that could agglutinate the antibody-coated eryth- of RF in determining that diagnosis of RA is poor.
rocytes, and the antibodies were necessary to Thus, fewer than one-third of unselected patients
obtain agglutination [3]. Later, in 1948, Rose with a positive RF are found to have RA. Therefore,
et al. [4]. also noted, while working with a com- RF test is not useful as a screening procedure.
plement test for Rickettsia, agglutination induced However, the presence of RF can be of prognostic
by the sera of RA patients. significance because patients with high titers tend
Approximately 80% of the patients with RA to have more severe and progressive disease (rapid
exhibit RF positivity (seropositive RA) [5]. radiographic deterioration of involved joints and
However, RF is not specific for RA. Rather, it is greater functional impairment), with extraarticular
found in the sera of a variable portion of patients manifestations (e.g., subcutaneous nodules, vascu-
with other rheumatic diseases and with nonrheu- litis, neuropathy, ulcers, Felty’s syndrome,
matic diseases (Table 3.8) [6–8]; many of these Sjögren’s syndrome) [5, 11–16]. In summary, RF
conditions are associated with the presence of test can be employed to confirm a diagnosis in
IgM RF. RF is also found in 5% of apparently individuals with a suggestive clinical presentation
normal individuals and in 10–20% of nonrheu- and, if present in high titer, to designate patients at
matic individuals over 65 years old who will not risk for severe systemic disease.
3.2 Diagnostic Tests 73
Table 3.8 Diseases commonly associated with rheuma- located in the IgG molecule. Furthermore, non-
toid factor RF IgG present as antigen bound to IgM RF can
Connective tissue disease contribute to false-positive results. Thus, most
Rheumatoid arthritis immunoassays for IgG RF require tubes or
Systemic lupus erythematosus
Scleroderma microtest wells coated with rabbit IgG and often
Sjögren’s syndrome incorporate procedures to remove or destroy IgM
Polymyositis–dermatomyositis RF [19, 20]. The specificity of the RF for RA
Acute viral infection increases when IgM RF, IgA RF, and IgG RF are
Rubella positive.
Cytomegalovirus
Hepatitis
Infectious mononucleosis 3.2.1.2 Anticyclic Citrullinated Peptide
Influenza Antibodies
Chronic bacterial infection Antibodies to cyclic citrullinated peptide (anti-
Tuberculosis
CCP) can also be used to evaluate patients with
Leprosy
Syphilis RA [21]. Although these antibodies are most
Brucellosis commonly found in RF-positive patients, on
Salmonellosis occasion they can be detected in the absence of
Subacute bacterial endocarditis
RF. In addition, the anti-CCP test has a similar
Parasitic infections
sensitivity and a better specificity for RA than
Malaria
Trypanosomiasis does RF, and, therefore, some have advocated its
Filariasis use to evaluate RA patients instead of RF. This is
Chronic inflammatory disease particularly the case in individuals with early RA,
Sarcoidosis in whom assessment of anti-CCP may be the
Chronic pulmonary disease
Chronic liver disease
most useful to confirm the diagnosis and estab-
Mixed cryoglobulinemia lish a likely prognosis. The presence of anti-CCP
Hypergammaglobulinemic purpura is most common in patients with aggressive dis-
ease, with a tendency for developing bone ero-
sions [22]. The development of anti-CCP is most
RF can be IgG, IgM, or IgA antibody class. frequent in individuals with an RA associated
Most procedures used to detect RF activity are HLA-b1 allele and in those who smoke ciga-
based on the agglutination of carrier particles rettes, and may occur before the development of
(polystyrene latex or red blood cells) passively clinical manifestations of RA. However, as with
coated with human or rabbit IgG preparations. RF, the presence of anti-CCP is not useful to pre-
These techniques are modifications of the origi- dict the future development of RA because it can
nally described sensitized sheep cell agglutina- be found in 1.5% of normal individuals, most of
tion test (Waaler–Rose) or latex fixation tests and whom will not develop RA, and occasionally in
detect primarily IgM RF. IgM RF is not specific patients with other rheumatic diseases. However,
of RA because it is found in a wide variety of it is a useful test to confirm a diagnosis of RA and
acute and chronic inflammatory diseases, and to estimate prognosis.
even in some normal individuals. Interest in
improving sensitivity, quantitative accuracy, and 3.2.1.3 Antinuclear Antibodies
detection of other isotypes of RF has led to the In 1948, Hardgraves and colleagues initiated the
development of specific radioimmunoassays study of antibodies to nuclei with the description
(RIAs) and enzyme-linked immunoabsorbant of the lupus erythematosus (LE) phenomenon
assays (ELISAs) capable of measuring nanogram [23], which demonstrates the ingestion of trau-
quantities of IgA and IgG RF [17, 18]. The detec- matized cells from systemic lupus erythematosus
tion of IgG RF presents special problems in that (SLE) patients by neutrophils [24]. The phenom-
both the RF activity and the antigenic sites are enon is now known to be caused by the reaction
74 3 Diagnostic Approach of Episcleritis and Scleritis
Table 3.9 Antibodies to nuclear or cytoplasmic antigens related syndromes (Table 3.9). Among the ANAs,
Antibody Disease Pattern antibodies to DNA–histone, double-stranded
Anti-DNA–histone SLE, RA H, P DNA (ds DNA), single-stranded DNA (ssDNA),
Anti-dsDNA SLE H, P RNA, histone, nuclear ribonucleo protein (nRNP),
Anti-ssDNA SLE, other diseases negative and Small RNP (Sm), all occur in SLE, whereas
Anti-histone SLE S antibodies to Ro/SSA and La/SSB/Ha occur in
Anti-nRNP SLE, MCTD S SLE and Sjögren’s syndrome; antibodies to
Anti-SM SLE S nRNP also can be detected in patients with mixed
Anti-Ro/SSA SLE, Sjögren negative connective tissue disease, an entity whose fea-
Anti-La/SSB/Ha SLE, Sjögren S tures overlap those of SLE, scleroderma, and
Anti-phospholipid SLE ? polymyositis; antibodies to PM-Scl, Mi1, Mi2,
Anti-neuronal SLE ?
Jo2, and Ku all are found in patients with poly-
Anti-ribosomal P SLE ?
myositis; antibodies to Scl70 and centromere
Anti-PM-Scl PM S
occur in patients with progressive systemic scle-
Anti-Mi1, Mi2 PM ?
Anti-Jo2 PM ?CYT
rosis, whereas antibodies to anti-DNA–histone
Anti-Ku PM ? occur in patients with rheumatoid arthritis [29].
Anti-Scl70 PSS S Some of these entities are not associated with
Anti-centromere PSS N episcleritis or scleritis; however, they are impor-
SLE systemic lupus erythematosus, MCTD mixed connec- tant in the differential diagnosis of other connec-
tive tissue disease, PM polymyositis, PSS progressive sys- tive tissue diseases that may be associated with
temic sclerosis, RA rheumatoid arthritis H homogeneous episcleritis and scleritis (Table 3.2). The pattern
P peripheral, S speckled, CYT cytoplasmic, Sjögren of immunofluorescence positivity revealed by an
Sjögren’s syndrome
ANA test is of considerable diagnostic signifi-
cance. Major fluorescence patterns include homo-
of antibodies against nucleoprotein (DNA– geneous, peripheral (rim), speckled, and
histone) with cell nuclei and the subsequent nucleolar. The ANA pattern is relatively valuable
phagocytosis of such “sensitized” nuclei. The LE but is much less important than the identification
test has been replaced by a more sensitive and of a specific ANA or anticytoplasmic antibody
specific test, the indirect immunofluorescent (ACA) (e.g., anti-nRNP, anti-La/SSB, and anti-
assay (IFA) for the detection of antinuclear anti- PM-Scl). The homogeneous pattern can be pro-
bodies (ANAs) [25–27]. duced by anti-DNA–histone and ds DNA
The finding of ANAs indicates, in the majority antibodies associated with the LE phenomenon;
of cases, an ongoing or latent inflammatory con- the peripheral pattern also can be caused by anti-
dition within the broad classification of connec- bodies to DNA–histone and dsDNA; the speck-
tive tissue diseases [28]. However, infections, led pattern correlates with anti-Sm, anti-nRNP,
such as chronic active hepatitis, infectious mono- anti-La/SSB, and anti-Scl70 antibodies; the nucle-
nucleosis, and lepromatous leprosy, and other olar pattern can be produced by anticentromere
autoimmune diseases, such as primary biliary cir- antibodies. Disease associations with typical
rhosis and chronic glomerulonephritis, also are staining patterns are shown in Table 3.9 [30–36].
characterized by this serologic abnormality [27]. The ANA test is an indirect fluorescence reac-
ANA may occasionally be found in normal sub- tion in which a droplet of patient serum is reacted
jects, although usually in low titers; the frequency with substrate cells fixed with acetone or methanol
increases with age. on a slide. As many as 20 or 30 different sera can
The normal titer of ANA is 1:40 or less. Higher be examined on the same slide. After a certain
titers are indicative of an autoimmune disease. reaction period has elapsed, all excess serum is
ANAs really actually compose a family of autoan- washed off to remove other serum components,
tibodies directed against components of the cell except bound ANA. In the next step, the prepara-
nucleus; they are important markers of SLE and tion is then covered with fluorescein-tagged
3.2 Diagnostic Tests 75
antihuman IgG. This anti-immunoglobulin probe Table 3.10 Antineutrophil cytoplasmic antibodies
binds to any human IgG ANA on the slide. The (ANCAs): specificities and diseases
slide is washed again to remove unbound anti- c-ANCA (%) p-ANCA (%)
immunoglobulin. Fluorescence of the nuclear Granulomatosis with 85–95 5–15
structures of the leukocytes indicates an adherence polyangiitis (Weg)
of patient antibodies to nuclear proteins [29]. Polyarteritis nodosa 5 15
Microscopic polyangiitis 40 50–80
ANA titers and patterns acquired from dif-
ferent laboratories vary greatly. The factors c-ANCA Cytoplasmic pattern, antigen specificity for pro-
teinase-3 (PR-3)
that lead to variable results include the use of p-ANCA Perinuclear pattern, antigen specificity for
different substrate cells (such as mouse liver, myeloperoxidase (MPO)
mouse kidney, monkey kidney [Vero cells]) or
human tissue culture lines (WIL-2, KB, or detected in patients with systemic vasculitis, such
Hep-2 cells), different fluoresceinated antibod- as granulomatosis with polyangiitis (Wegener),
ies, microscopes of different powers and sensi- microscopic polyarteritis nodosa, and segmental
tivities, and varying levels of technical skill. necrotizing glomerulonephritis [37–40]. Although
Within the active, untreated SLE patients, still a subject of debate, these diseases are thought
positive ANAs are detected in 95% of the tests to be part of the spectrum of one disease process.
performed with mouse liver or kidney cells and The presence of ANCAs is specific and sensi-
in 98% of the tests performed with human tis- tive for granulomatosis with polyangiitis
sue culture lines. The difference between the (Wegener), an entity often associated with episc-
two substrates is due, at least in part, to the leritis and scleritis; the specificity is 99% by indi-
relative absence of the Ro/SSA antigen in rect immunofluorescence techniques and 98% by
mouse liver or kidney cells and its presence in ELISA detection; the sensitivity is 96% for active
the tissue culture lines. We advocate ANA test- generalized disease, 67% for active regional dis-
ing on two cell lines: one on mouse liver, mouse ease, and 32% for disease in full remission after
kidney, or monkey kidney cells, and the other initial regional symptoms [38–40]. However, the
on WIL-2, KB, or Hep-2 cells. presence of ANCA should be adjunctive and,
Absence of a positive ANA in tissue culture with very rare exceptions, should not substitute
lines makes the diagnosis of SLE unlikely. A for a tissue diagnosis. False-positive ANCA titers
negative ANA in a patient with clinical evidence have been reported in certain infectious and neo-
for a specific connective tissue disease suggests plastic diseases.
that the test should be repeated for confirmation Two types of ANCAs were originally
because the result could be due to faulty testing; described. A granular cytoplasmic staining pat-
in case of confirmed negative ANA, sequential tern produced by c-ANCA is caused by antibody
testing is advocated. directed in at least 95% of cases against protei-
A positive ANA in a patient with clinical evi- nase-3 (PR-3), a neutral serine protease of human
dence for a specific connective tissue disease neutrophils [39, 40]. A perinuclear staining pat-
requires specific ANA testing. A positive ANA in tern produced by p-ANCA is caused by antibod-
a patient with limited or nonspecific clinical find- ies directed against a variety of different antigens
ings requires continued observation until disease (myeloperoxidase [MPO], elastase, and lactofer-
expression is more complete. rin) [41]. The specificity of a positive PR-3
ANCA (c-ANCA) for granulomatosis with poly-
3.2.1.4 Antineutrophil Cytoplasmic angiitis (Wegener) is very high, especially if
Antibodies active glomerulonephritis is present. A small per-
Autoantibodies (IgG) directed against a cytoplas- centage of patients with granulomatosis with
mic antigen of human neutrophils—the antineu- polyangiitis (Wegener) may have anti-MPO
trophil cytoplasmic antibodies (ANCAs; synonym, rather than anti-PR-3 antibodies. The specificity
anticytoplasmic antibodies or ACPAs)—can be of a positive anti-MPO ANCA (p-ANCA) for
76 3 Diagnostic Approach of Episcleritis and Scleritis
microscopic polyangiitis and focal necrotizing deposit in renal glomeruli, synovial tissue, or ves-
and crescentic glomerulonephritis is also high sel walls, participating in the development or per-
(Table 3.10). A third distinct ANCA, x-ANCA, sistence of major inflammatory lesions.
has also been described. It may be seen in many Although CICs’ detection is not essential for
disease processes, but it is most commonly found the diagnosis of any condition, their presence
in chronic inflammatory bowel disease. helps support a specific disorder under the fol-
The discovery of ANCAs provided an invalu- lowing conditions: (1) CICs may be detected in
able tool in the evaluation of patients with ocular early arthritis several months prior to the defini-
or orbital inflammation suggestive of systemic tive diagnosis of RA; [48] (2) CICs may help to
vasculitis [42–45]. Either type of ANCA can be distinguish seronegative RA from other arthropa-
found in patients with limited or generalized thies, such as ankylosing spondylitis or reactive
granulomatosis with polyangiitis (Wegener) with arthritis, because CICs are found in 70% of
ocular or orbital inflammation [44, 45]. patients with seronegative RA and they are found
Because of its high specificity, a positive only rarely in patients with ankylosing spondyli-
ANCA is very suggestive of granulomatosis with tis or reactive arthritis [49, 50]. CIC detection
polyangiitis (Wegener); however, because ANCA may also be useful to monitor disease activity;
is positive only in 67% of patients with active lim- [51, 52] patients with rheumatoid vasculitis have
ited disease and in 32% of patients in full remis- high levels of CICs [53, 54]. Significant decreases
sion after limited disease, one or even repeatedly in CIC level may be interpreted as a favorable
negative ANCA testing does not exclude the diag- response to therapy; conversely, significant
nosis, especially in patients with limited clinical increases of CIC level may signify the need for
features and characteristic histologic findings. more aggressive therapy.
Because of the enormous diversity of antigens
3.2.1.5 Circulating Immune Complexes involved in CICs, it is doubtful that antigen-spe-
The formation of circulating immune complexes cific assays will ever find widespread use in clini-
(CICs) by binding of antigens to their correspond- cal immunological studies. Therefore, the
ing antibodies is a physiologic process usually of techniques available for detection of CICs are
benefit to the host because it allows the neutraliza- antigen nonspecific. The sensitivity of each
tion or the elimination of exogenous antigens. method for detecting CIC varies according to the
CICs primarily involve antigens from exogenous nature of the CIC involved and the influence of
sources (food, drugs, or microbes) and endoge- various interfering factors. Only a limited num-
nous sources (autoantigens and tumor antigens). ber of procedures are suitable for routine labora-
Deposition of CICs seems to be dependent on a tory investigation. Some of the most widely used
variety of factors, including size of complex, methods are described in the following sections.
nature of antigen, immunoglobulin class, antibody
affinity, ability to fix complement, interaction Fluid-Phase Binding Assays
with RFs, and clearance capacity of the reticu- Fluid-phase binding assays are based on the fact
loendothelial system [46]. CICs usually are elimi- that precipitation of radiolabeled C1q receptor (a
nated efficiently by the mononuclear phagocytic subcomponent of the first component of comple-
system, particularly by Kupffer cells in the liver; ment that binds CIC) differs from precipitation of
[47] therefore, CICs can be detected for only a radiolabeled C1q receptor bound to CIC.
short period of time after a specific antigenic chal-
lenge. However, CICs may persist in the blood C1q-Binding Assay
circulation of patients with autoimmune disor- In the C1q-binding assay, CICs are allowed to
ders, such as polyarteritis nodosa, allergic granu- bind C1q in liquid phase. Radiolabeled C1q is
lomatous angiitis (Churg–Strauss syndrome), added to ethylenediaminetetraacetic acid (EDTA)-
granulomatosis with polyangiitis (Wegener), and treated serum in the presence of polyethylene gly-
some connective tissue diseases; CICs may col, which precipitates CICs bound to C1q [55].
3.2 Diagnostic Tests 77
After 1 h, free C1q is separated from the precipi- vated by microorganisms. Because the levels of
tated bound C1q by centrifugation. The percent- complement components in various body fluids
age of radioactivity precipitated corresponds to may be decreased during complement activation,
the C1q-binding activity of the sample and indi- their measurements can give a rough index of dis-
cates the level of CICs. This test is particularly ease activity under conditions in which comple-
sensitive for CICs containing IgM, therefore ment activation is prominent.
explaining the high level of positivity usually Any disease that gives rise to CICs may show
observed in rheumatoid arthritis. CICs containing a hypocomplementemia, provided the CICs con-
IgG4, IgA, IgD, and IgE are not detected. The tain IgG or IgM antibodies capable of activating
technique is reasonably reliable, but C1q needs to complement. Serial serum complement levels
be radiolabeled, a procedure that can inactivate may be depressed in rheumatoid arthritis with
the delicate complement molecule if harshly vasculitis; [54, 59, 60] they also may be depressed
executed. in SLE exacerbations, particularly when there is
renal involvement [61, 62]. Conversely, as the
Cell-Binding Assays disease activity declines, there may be a parallel
These assays try to quantify the binding of CICs return of the complement level toward normal.
to cells. There are primarily two types of clinical
assays for complement components: (1) tests that
Raji Cell-Binding Assay detect and quantify the presence of complement
The basis of the Raji cell-binding assay is the components (immunochemical assays) and (2)
binding of CICs to C3b and C3bi receptors on a tests that determine functional or total hemolytic
continuous lymphoblastoid cell line originally activity of the complete complement cascade
derived from a patient with Burkitt’s lymphoma (complement hemolytic 50% or CH50).
(Raji cells) [56]. Raji cells are characterized by a
lack of surface immunoglobulins, few or low- Quantitation Tests
affinity receptors for IgG Fc, and a large number The basis of immunochemical assays is the
of receptors for complement. CICs bound to cells reaction of complement proteins with specific
are quantitated with a labeled anti-IgG antibody. antibodies [63]. The most widely used immuno-
This test is particularly sensitive for CICs con- chemical assay is radial immunodiffusion. In
taining IgG. The technique is reasonably reliable, this technique, monospecific antibody directed
but Raji cell lines cultured in different laborato- against a complement protein is incorporated
ries are quite different and express different lev- into an agarose gel, holes are punched in the gel,
els of C3 receptors. Therefore, data from different and test samples or known standards are placed
sources cannot be compared directly; for the in the holes. As the antigenic complement pro-
same reason, longitudinal studies in a specific tein diffuses into the gel and encounters its spe-
laboratory can be done only if the line is continu- cific antibody, a precipitin ring forms, which is
ously subcloned. proportional to the concentration of comple-
ment placed in the hole. A standard curve is
3.2.1.6 Complement constructed from the size of the rings produced
The complement cascade consists of a group of by samples of known concentration, and the
serum proteins that participate in inflammation concentration of complement in the test sample is
through the actions of increased vascular perme- determined. A more rapid and slightly more
ability, chemotaxis, opsonization, and cell lysis sensitive technique is electroimmunodiffusion.
[57, 58]. Once the first component is activated, In this technique, the sample is unidirectionally
each component is activated by its predecessor. electrophoresed into an antibody-containing
C4 can be activated by the classical pathway, gel, yielding a set of “rockets” whose height is
which can be initiated by antigen–antibody reac- proportional to concentration. Quantification
tions. C3 can be activated by the classic pathway tests for complement components include mea-
and the alternative pathway, which can be acti- surements of C3 and C4 complement proteins.
78 3 Diagnostic Approach of Episcleritis and Scleritis
for virus does not indicate whether a viral infec- impact the interpretation and utility of the PPD.
tion took place recently or not. Direct comparative studies in routine practice
The ELISA test is the blood test most com- thus far suggest that the ELISpot has a lower rate
monly used for the diagnosis of toxoplasmosis of indeterminate results and probably a higher
and toxocariasis. The presence of a high IgM degree of diagnostic sensitivity than the whole-
anti-Toxoplasma and anti-Toxocara titers indi- blood ELISA. Further studies are under way to
cates a recent infection. assess the performance of these tests in contact
investigations and in persons with suspected
3.2.1.9 Interferon-Gamma Release tuberculosis disease, health care workers, HIV-
Assays (IGRAs) infected individuals, persons with iatrogenic
Recently, two in vitro assays that measure T-cell immunosuppression, and children. These tests
release of interferon-gamma (IFN-g) in response may be useful for antituberculous treatment deci-
to stimulation with the highly tuberculosis-spe- sion making in chronic ocular diseases [76–78].
cific antigens, ESAT-6 and CFP-10, have become
commercially available [74]. QuantiFERON-TB
Gold® (Cellestis Ltd., Carnegie, Australia) is a 3.2.2 Anterior Chamber Polymerase
whole-blood ELISA for measurement of IFN-g, Chain Reaction Testing
and T-SPOT.TB® (Oxford Immunotec, Oxford,
UK) is an enzyme-linked immunospot (ELISpot) Polymerase chain reaction (PCR) of aqueous
assay. IGRAs are more specific than the samples obtained by anterior chamber tap
intracutaneous tuberculin purified protein deriva- (approximately 100–200 ml volume) can be use-
tive (PPD) as a result of less cross-reactivity due ful in patients with sclerouveitis for detection of
to BCG vaccination and sensitization by nontu- DNA from herpes simplex virus, VZV, cytomeg-
berculous mycobacteria [75]. IGRAs also appear alovirus, and for the parasite Toxoplasma gondii.
to be at least as sensitive as the PPD for active This procedure can be performed conveniently in
tuberculosis (used as a surrogate for latent the outpatient setting and has been shown to be
Mycobacterium tuberculosis infection). Although safe in the hands of an experienced ophthalmolo-
diagnostic sensitivity for latent infection cannot gist dealing with uveitis [79].
be directly estimated because of the absence of a
gold standard, these tests have shown better cor-
relation than the PPD with exposure to M. tuber- 3.2.3 Smears and Cultures
culosis in contact investigations in low-incidence
settings. Scrapings for smears and cultures must be
Other potential advantages of IGRAs include obtained in cases of infectious suspect. Material
logistical convenience, need for fewer patient from vigorous scraping of the infected scleral or
visits to complete testing, avoidance of unreliable corneoscleral area with a surgical blade should be
and somewhat subjective measurements such as smeared onto glass slides for staining (Gram and
skin induration, and the ability to perform serial Giemsa) and onto agar plates or broths for bacte-
testing without inducing the boosting phenome- rial or fungal cultures (two blood agar prepara-
non (a spurious PPD conversion due to boosting tions: one kept at 35°C for blood agar, chocolate
of reactivity on subsequent PPDs among BCG- agar, Sabouraud dextrose agar, thioglycollate
vaccinated persons and those infected with other broth, and brain–heart infusion medium and the
mycobacteria). Because of the high specificity other kept at room temperature). In case of acan-
and other potential advantages, IGRAs are likely thamoeba suspect, staining with calcofluor white
to replace the PPD for latent infection diagnosis stain or Gomori methenamine silver and culture
in low-incidence, high-income settings, where in non-nutrient agar with Escherichia coli must
cross-reactivity due to BCG might adversely be performed.
80 3 Diagnostic Approach of Episcleritis and Scleritis
The PPD is a reliable method for recognizing All techniques of X-ray imaging rely on two
prior mycobacterial infection unless the patient basic properties of tissues to produce their
was vaccinated with BCG previously. The usual images: the ability to absorb X-ray photons and
tuberculin test is of intermediate-strength PPD the ability to scatter them.
(five tuberculin units) and is applied in the fore- 1. Chest X-rays are of diagnostic significance in
arm. Reactions should be read by measuring the tuberculosis, granulomatosis with polyangiitis
transverse diameter of induration as detected by (Wegener), allergic granulomatous angiitis
gentle palpation at 48–72 h [80]. Patients with (Churg–Strauss syndrome), and atopy.
tuberculosis have reactions with a mean of 2. Sinus films showing mucosal thickening and/
17 mm; patients infected but with no active dis- or destruction of bony walls can be helpful in
ease have similar reactions. Therefore, a positive the diagnosis of granulomatosis with poly-
test means a prior mycobacterial infection and angiitis (Wegener).
does not rule out other etiologic factors, as it may 3. Sacroiliac X-rays are of diagnostic signifi-
be a coincidental finding. Repeated skin testing cance in ankylosing spondylitis, reactive
with PPD does not lead to positive reactions in arthritis, psoriatic arthritis, and arthritis asso-
uninfected persons. ciated with inflammatory bowel disease.
Every individual is normally exposed and 4. Limb joint X-rays, such as hand, wrist, foot,
sensitized to many antigens. Modern prophylac- and knee joint X-rays, can show the arthritic
tic immunization results in the purposeful expo- changes characteristic of rheumatoid arthritis,
sure to antigens from microorganisms responsible juvenile rheumatoid arthritis, gout, psoriatic
for diphtheria, tetanus, mumps, influenza, and arthritis, and arthritis associated with inflam-
other virus infections. In addition, natural expo- matory bowel disease.
sure results in sensitization to antigens prepared
from streptococci, staphylococci, certain com-
mon fungi, and other ubiquitous antigens. Skin 3.2.6 Anterior Segment Fluorescein
tests elicit delayed cutaneous hypersensitivity Angiography
reactions to these antigens in most healthy sub-
jects. Impairment of delayed hypersensitivity The information that can be obtained from ante-
reaction to an antigen in an adequately exposed rior segment fluorescein angiography may be a
subject is called anergy. Anergy or hyporeactiv- valuable adjunct to the diagnosis of scleritis. For
ity to skin testing is typical, although not diag- example, although most forms of anterior scleral
nostic of lepromatous leprosy, herpes zoster, or disease can be diagnosed clinically, difficulties
sarcoidosis. Systemic steroid therapy may sometimes arise in distinguishing between severe
reverse anergy, whereas immunosuppressive episcleritis and diffuse anterior scleritis or
therapy, such as cyclosporin, may suppress a between the relatively benign diffuse or nodular
positive skin test. anterior scleritis and the early changes of the
Skin testing can also help detect allergies, more severe necrotizing scleritis. Early detection
such as pollen, animal dander, mold, dust, and of the most severe forms of scleritis is crucial if
many other environmental allergens. Direct one is to institute correct treatment before more
reproduction of an immediate allergic reaction by destructive changes occur. Because the adequate
introducing a small amount of extract of sus- therapy of scleritis depends on an accurate diag-
pected allergen into the skin is a good method nosis, it is important to find objective methods to
with which to diagnose atopy. Two procedures, evaluate the different clinical conditions. Anterior
the intradermal test and the prick test, are the segment fluorescein angiography has been found
most consistent and interpretable. to show characteristic patterns in the various
3.2 Diagnostic Tests 81
forms of episcleritis and scleritis, providing con- ment fluorescein angiography can sometimes be
siderable information in guiding subsequent ther- useful in deciding the extent of appropriate surgi-
apy [81, 82]. cal intervention [85].
In our experience, corneal involvement can be
found in 13% of patients with scleritis. Although 3.2.6.1 Anterior Segment Fluorescein
most of the different forms of keratitis associated Angiography Techniques
with scleral disease can be diagnosed clinically, Conventional photographic fluorescein angiogra-
differentiation between the early changes of the phy [81, 87–93], low-dose photographic fluores-
relatively benign peripheral corneal opacifica- cein angiography [94], low-dose fluorescein
tion with or without neovascularization and the videoangiography [95], and scanning angio-
early changes of the more serious corneal thin- graphic microscopic fluorescein videoangiogra-
ning, either with limbal guttering or peripheral phy [96] are different techniques used to describe
corneal ulceration, can sometimes be difficult. the circulatory dynamics of the anterior segment
Early detection of the most severe forms of kera- of the eye, such as the direction of flow, distinc-
titis associated with scleritis is important if one tion between arteries and veins, and integrity of
is to institute adequate treatment before visual the circulation.
acuity becomes affected. Because the accurate Fluorescein angiography has been available
diagnosis of keratitis associated with scleritis for examining the retinal microcirculation since
can add valuable information to the choice of 1961 [97], when venous injection of low-molec-
therapy, it is important to find objective methods ular-weight sodium fluorescein was used to dem-
to evaluate early keratitis. Anterior segment fluo- onstrate abnormalities in the retinal capillaries,
rescein angiography can sometimes help in this retinal pigment epithelial cells, and Bruch’s
regard [83]. membrane. The tight apposition of contiguous
Adequate medical treatment for scleral inflam- retinal capillary endothelial cells may explain, at
mation with or without corneal involvement fre- least in part, why normal retinal vessels do not
quently results in halting the process, either leak fluorescein [88, 98]. Iris capillary endothe-
through new vessel formation to cover the defect lial cells also are joined by tight junctions, and
or through recanalization of existing vessels [84]. anterior segment fluorescein angiography was
Although most of the individual responses to introduced in 1968 [99, 100] with the primary
treatment can be easily monitored by clinical purpose of diagnosing iris lesions. Conventional
examination, difficulties sometimes arise in being anterior segment fluorescein angiography has
certain if the scleral disease with or without cor- not, however, been widely used for conjunctival
neal involvement is completely under control. and scleral abnormalities because normal con-
Anterior segment fluorescein angiography can junctival and episcleral vessels leak molecules
sometimes be of assistance in monitoring the smaller than serum albumin, such as fluorescein.
effect of medical therapy [85]. Low-molecular-weight molecules may escape
If in spite of intensive medical therapy no new from the conjunctival and episcleral vessel
vessels are formed or no preexisting vessels are lumens by crossing the interendothelial clefts,
recanalized, progressive thinning of the sclera endothelial cells through pinocytotic vesicles, or
and/or cornea with possible eventual perforation both [101]. Interestingly, the limbal vessels never
may occur. In these cases, tectonic surgery, such leak fluorescein, suggesting that their endothelial
as scleral, corneal, or sclerocorneal grafting, must cells are united by tight junctions [102]. Five mil-
be considered to maintain the integrity of the eye liliters of 10% sodium fluorescein via antecubital
[86]. Although the site and extent of the surgical vein injection rapidly extravasates from conjunc-
procedure can be frequently decided by clinical tival and episcleral vessels, restricting the diag-
examination, determination of the amount of nostic value of this technique to the demonstration
necrotic tissue to be removed and replaced surgi- of either early leakage or gross hypoperfusion
cally can sometimes be difficult. Anterior seg- [81]. If leakage is to be avoided, the fluorescein
82 3 Diagnostic Approach of Episcleritis and Scleritis
must be bound to large molecules. Fluorescein- [96]. Anterior segment fluorescein videoangiog-
labeled isothiocyanate (FITC)–dextran conju- raphy techniques with fluorescein-labeled dex-
gates are molecules of high molecular weight that trans may become the probes of choice for the
do not leak from anterior segment vessels. FITC– study of the anterior segment vasculature of the
dextrans have been shown to enhance the diag- human eye.
nostic value of the angiograms in retinal vessels
of rats, cats, and monkeys [103–105] and in epis- 3.2.6.2 Normal Anterior Segment
cleral vessels of rabbits [94]. Additionally, low- Fluorescein Angiography
dose fluorescein angiogram techniques have been Anterior segment fluorescein angiography occurs
shown to give better quality anterior segment in three phases: an arterial phase, a capillary
angiograms than does conventional-dose fluores- phase, and a venous phase [94]. Vessels that fill
cein [94]. Approximately 90% of injected fluo- early with high fluorescence and high tortuosity,
rescein is bound to serum albumin and 10% thick walls, and pulsatile flow are considered as
remains unbound [106]. It is known that the arteries. Vessels that fill after arteries, with lower
unbound fluorescein leaks from the vessels; [105] fluorescence, lower tortuosity, thinner walls, and
because the time for binding to serum albumin is no pulsatile flow are considered as veins.
directly proportional to the dose given, by reduc- Furthermore, arteries never show streaming of
ing the dose of injected fluorescein, leakage from blood and branch rarely, whereas veins often
the episcleral vessels can be minimized. show laminar flow and branch a good deal.
Intravenous injection of six-tenths of a milliliter However, because veins fill gradually and dif-
of 20% sodium fluorescein, followed by film fusely, subsequent to artery filling, the moment
photography, provides better dynamic studies in of their first perfusion is difficult to evaluate.
normal and diseased conjunctival and episcleral Despite excellent anatomical descriptions
vessels [94]. But although photographic low-dose [108–111] and modern videoangiographic tech-
anterior segment fluorescein angiography gives niques [95, 96], controversy still exists regarding
high spatial resolution, the slow recycling rate of the flow patterns within the vessels of the anterior
most flash units (one frame per second) restricts segment of the eye. Whereas some studies sup-
the temporal resolution of flow characteristics port the view that the anterior ciliary arterial flow
and direction. Low-dose anterior segment fluo- is from the region of the recti muscles toward the
rescein videoangiography with an image capture inside of the eye through perforating vessels, that
rate of 25 frames per second, associated with an is, centripetal [96, 112–116], others suggest that
image intensifier that enhances sensitivity in spite the anterior ciliary arterial flow is primarily sup-
of high luminescence, improves temporal resolu- plied by retrograde flow from the intraocular
tion and magnification for flow dynamic studies medial and lateral long posterior ciliary arteries,
in the anterior segment of the human eye [95]. that is, centrifugal [81, 88, 93, 95, 117]. Some
The use of a microcomputer program in conjunc- investigators who favor the centripetal distribu-
tion with low-dose anterior segment videoan- tion theory believe that other interpretations of
giography provides complete control of the the dynamic events result from deficiencies in
angiogram, allowing immediate access to any photographic and conventional video camera
frame, comparison between different frames, and techniques [96]. Resolution of this controversy
subtraction of any sequence of the study from the will require additional studies. Because the main
remaining ones [107]. Anterior segment fluores- applicability of anterior segment fluorescein
cein videoangiography with a scanning angio- angiography in scleral diseases is to detect areas
graphic microscope shows advantages over the of vascular closure in the episcleral or conjuncti-
photographic and video camera methods through val circulation, the issue of direction of flow is
longer depth of focus, larger field of view, lower not critical for patient management.
light levels, coaxial illumination, and real-time The different phases of the angiography pre-
traverse of conjunctival/episcleral vasculature sented below assume the conventional centripetal
3.2 Diagnostic Tests 83
Fig. 3.23 Anterior segment fluorescein angiogram: Fig. 3.24 Anterior segment fluorescein angiogram:
arterial phase. Note the extraordinary radiality of the ante- capillary phase. Note the rich abundance of the capillary
rior ciliary tributaries, culminating in the formation of vascular supply in the episclera. Note also the tiny capil-
loops and anastamoses at the corneoscleral limbus lary twigs extending into the far corneal periphery
Arterial Phase
The first vessels to fill in an angiography of the
bulbar conjunctiva and episclera are the anterior
ciliary arteries. These run radially within the
episclera toward the limbus, following variable
courses (Fig. 3.23). Between 2 and 5 mm poste-
rior to the limbus, the anterior ciliary arteries
divide into two branches, which run circumferen-
tially to meet other branches from adjacent ante-
rior ciliary arteries. These anastomoses form the Fig. 3.25 Anterior segment fluorescein angiogram:
anterior episcleral arterial circle, which broadly venous phase. Filling of venous collectors is shown. Note
resolves into five distinct vascular networks: (1) the scattered “bright spots” residual from the capillary
phase. Leakage from capillaries is normal
anterior conjunctival, (2) superficial episcleral,
(3) deep episcleral, (4) limbal, and (5) iris.
Because the anterior episcleral arterial circle is a arch, which is itself formed by terminal vessels
variable anatomical entity, it may take between derived from the ophthalmic artery. This explains
1.5 and 14 s to fill. the watershed zone between anterior and poste-
The arteries from the anterior episcleral circle rior conjunctival circulation, which can fill late.
run forward to the limbus, curve backward radi- Branches from the anterior episcleral arterial
ally, and divide to form the anterior conjunctival circle run posteriorly and divide to form the ante-
arteriolar plexus. The anterior conjunctival arteri- rior episcleral arteriolar plexus. Neither superfi-
oles fill approximately 1.5 s after the segment of cial nor deep vascular layers can be detected.
the anterior episcleral segment that supplies them. These vessels fill shortly after the anterior epis-
The anterior conjunctival circulation, supplied by cleral arterial circle.
the anterior ciliary arteries, fluoresces approxi- The limbal vessels often share their origins
mately 4 s before the posterior conjunctival cir- with the anterior conjunctival vessels. Unlike
culation, supplied by the peripheral palpebral conjunctival and episcleral vessels, they do not
84 3 Diagnostic Approach of Episcleritis and Scleritis
A-Scan Ultrasonography
The A scan technique shows one-dimensional
time–amplitude representations of echoes
received along the beam path. The echoes appear
as vertical deflections rising from a horizontal
zero line. In the axial A echogram of the normal
eye, high echoes are produced by the two corneal
surfaces, two lens surfaces, and vitreoretinal
interface. The vitreoretinal interface echo is fol-
Fig. 3.29 Computrized tomogram demonstrating opaci-
lowed by a complex of echoes representing ret- fication of the left maxillary sinus in this patient with
ina, choroid, sclera, and retrobulbar fat. Posterior Wegener’s granulomatosis
scleral thickening due to inflammation can be
detected by high-amplitude continuous spikes.
same vasculitic process. Immunosuppressive what probability this ratio favors a specific
therapy can be life and eye saving for this group strategy. The therapeutic plan should reflect an
of patients. In patients with suspected (no defini- agreement between a well-informed patient and
tive diagnosis) systemic vasculitic disease and an ophthalmologist who, by virtue of education
recurrent nodular or diffuse scleritis, the demon- and training, is an expert in the type of therapy
stration of inflammatory microangiopathy in con- selected and in the early recognition and man-
junctival and/or scleral tissue provides additional agement of drug-induced complications.
justification for the institution of immunosup-
pressive therapy.
3.6 Summary
3.3.2 Biopsy for Suspected Local The approach to the patient with scleritis should
or Systemic Infectious Disease include five phases. The first phase includes the
investigation of the illness through the interview
Detection of an infectious agent in conjunctival and physical examination of the patient. Because
and/or scleral tissues is essential in confirming a scleritis often portends an underlying, potentially
suspected infectious scleritis. Bacteria, fungi, lethal systemic disease, this phase cannot be
viruses, and parasites may be isolated from con- overemphasized. The interview consists of an
junctiva and/or scleral tissues of patients with analysis of the major complaint and history of the
diffuse, nodular, or necrotizing scleritis as a result present illness; episcleritis presents as an uncom-
of direct invasion either from local or systemic fortable watery red eye with the absence of severe
infections. Infectious agent isolation in conjunc- pain and scleral swelling, whereas scleritis pres-
tival and/or scleral tissue allows the institution of ents with deep, severe, periorbital pain radiating
specific local or systemic treatment that may to the head, temple, and jaw, often preventing the
improve the ocular and systemic prognoses. patient from sleep. The history continues with the
past and family history, the past and present ther-
apy history, and an exhaustive review of systems.
3.4 Data Integration: Diagnosis Within the latter, constitutional symptoms, such
as chills, fever, poor appetite, recent weight loss,
In the fourth phase of the clinical approach to and fatigue, may suggest a systemic process; skin
patients with scleritis, the clinical data are inte- and hair, respiratory, genitourinary, rheumato-
grated with test and biopsy results to confirm or logical, gastrointestinal, neurological, and ear,
discard the preliminary diagnosis. Although clin- nose, and throat manifestations should lead the
ical data, test results, and biopsy findings may not ophthalmologist to suspect certain types of sys-
be diagnostic when each is considered indepen- temic disorders, such as connective tissue dis-
dently, the combination of the three can lead to eases with or without vasculitis, infectious
better diagnostic predictions. diseases, gout, rosacea, or atopy. Physical exami-
nation includes not only the eye, but also the head
and extremities; scleral examination includes an
3.5 Therapeutic Plan external examination in daylight and a slit-lamp
examination with white and red-free light. As the
In the fifth and final phase, therapeutic possi- ophthalmologist completes this phase, possible
bilities for the particular diagnosis are discussed diagnoses should come to mind.
with the patient. Whether considering medical The second phase consists of the selection of
or surgical procedures, the proper role of the blood, urine, and imaging studies that are needed
doctor is to educate the patient, apprising him to investigate the possibilities raised in the first
or her of the relative risks and benefits of pos- phase. In the third phase, the decision is made as
sible strategies, and providing an opinion of to whether a tissue biopsy is likely to add useful
90 3 Diagnostic Approach of Episcleritis and Scleritis
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References 93
Because episcleritis and scleritis are entities pathologic findings, prognoses, and treatments
encountered infrequently in general ophthalmic are difficult to obtain. The excellent episcleritis
practice, the diagnosis and subsequent treatment and scleritis survey [2] and treatise [3], performed
may be missed or delayed because of the relative by Watson and coworkers at Moorfields Eye
lack of experience in their detection and manage- Hospital in London in 1976, has provided us with
ment. Fraunfelder and Watson [1] reported that in an exceptional perspective of the spectrum of
a series of 30 enucleated eyes (sent from hospi- episcleritis and scleritis. The Scleritis Clinic at
tals from all parts of Great Britain) with a pri- Moorfields Eye Hospital in London was estab-
mary histological diagnosis of scleritis, the lished in 1963 and since then has been receiving
clinical diagnosis of scleritis had been missed in highly selected patients with inflammatory con-
12 (40%) often because the scleritis was marked ditions of sclera or episclera. All the patients are
by multiple complications, such as uveitis, glau- referred because of difficulties in diagnosis, dif-
coma, and keratolysis. Many of these 12 eyes had ficulties in treatment, or both. Subsequent reports
not received anti-inflammatory treatment and by Watson and coworkers on different aspects of
many of the 18 eyes affected by clinical scleritis diagnosis and management have also been help-
had received insufficient anti-inflammatory treat- ful and have served as the foundation on which
ment. The main reason for enucleation was pain contemporary studies of smaller patient popula-
with loss of vision. Many of these patients had tions rest [4–13]. In an attempt to contribute to
had the ocular inflammation for up to 30 years the study of the intricacies of scleral disease, we
before the enucleation. have analyzed our experience with patients with
Inflammation of the wall of the eyeball ranges episcleritis and scleritis seen at two tertiary eye
from innocent and harmless self-limiting episc- care centers, the Massachusetts Eye Research
leritis, requiring little or no anti-inflammatory and Surgery Institution (MERSI) in Cambridge,
therapy, to very painful, sight-threatening, necro- MA, USA, during the 5-year period from April
tizing scleritis requiring intensive anti-inflamma- 2005 to April 2010, and the Institute Clinic of
tory and/or immunosuppressive therapy if the Ophthalmology at the Hospital Clinic of
globe is to be preserved; moreover, scleritis may Barcelona, Spain, during the 3-year period from
often be the presenting manifestation of many April 2007 to April 2010. This study group com-
potentially lethal systemic diseases. It is, there- prised 585 patients (825 eyes), 85 with episcleri-
fore, vital that the correct diagnosis is made and tis (119 eyes), and 500 with scleritis (706 eyes)
that subsequent adequate treatment is given as (Table 4.1). The mean follow-up period was
early as possible in the course of the disease. 1.77 years (range 1 month to 5 years) for patients
Because of the comparative rarity of scleritis, with scleritis and 1.43 years (range, 1 month to
general considerations on the symptoms, signs, 5 years) for patients with episcleritis. Our results
are inevitably biased to higher numbers of patients during a 5-year period (April 2005 to April 2010),
with scleritis compared with patients with episc- 8.7% had scleritis and 1.4% had episcleritis.
leritis, and to higher numbers of patients with Recognizing the bias of our two tertiary eye
episcleritis and scleritis with respect to the total care centers, the prevalence of the different types
number of new patient referrals. A significant of episcleritis and scleritis in our current series is
factor in this is underreporting of episcleral dis- shown in Table 4.1.
ease. Objective data on the prevalence of episc- This chapter focuses on the clinical consider-
leritis are very difficult to estimate because many ations of episcleritis and scleritis and their
patients with previously diagnosed episcleritis subcategories.
understand that recurrent episodes are unlikely to
cause damage to the eye, so either they do not
treat the condition or they self-medicate. The 4.1 Episcleritis
only ones who seek ophthalmological consulta-
tion (and usually not at a tertiary referral center) 4.1.1 Introduction
are those who are having their first attack or who
are overstressed. Objective data on the prevalence Episcleritis is a benign inflammatory disease that
of scleritis are also difficult to obtain because is characterized by edema and cellular infiltration
they can vary greatly depending on the type of of the episcleral tissue. Whether treated or not,
institution in which the studies are performed. the condition is self-limited after a few days, and
Data from tertiary referral centers are inevitably although it may recur over a period of many years
biased to higher numbers of patients with scleri- it rarely leaves any residual ocular damage. In
tis with respect to the total number of new patient two-thirds of the cases, the disease is considered
referrals. Examples of the prevalence variability idiopathic.
depending on the type of institution are the fol-
lowing: of 9,600 new patient referrals to the
Department of Ophthalmology of Southern 4.1.2 Patient Characteristics
General Hospital and Victoria Infirmary in
Glasgow during an 8-year period, 0.08% had Episcleritis occurs in young adults, usually
scleritis [14]. Of 6,600 new patient referrals to women, with a peak incidence in the fourth
the Immunology Service at the Massachusetts decade [3]. In our series of patients with episc-
Eye and Ear Infirmary Hospital in Boston during leritis (Table 4.2), the mean age of onset of the
an 11-year period (May 1980 to May 1991), 2.6% first episode was 47 years. Episcleritis was three
had scleritis, and 1.4% had episcleritis [15]. Data times as common in women as in men. Although
from our current experience show higher num- episcleritis may affect individuals of all races,
bers with respect to scleritis patients: of 4,909 there are no studies on the incidence and preva-
new patient referrals to the MERSI in Cambridge lence within racial groups. Some early reports
4.1 Episcleritis 97
suggested that the condition had a Mendelian described as a slight ache localized to the eye. On
dominant transmission; [15, 16] our experience rare occasions, severe pain radiating to the fore-
shows that episcleritis is not per se a hereditary head and tenderness to the touch may be present,
condition, although some of the episcleritis-asso- but these symptoms are more commonly charac-
ciated systemic diseases, such as rheumatoid teristic of scleritis; if marked pain and/or tender-
arthritis, systemic lupus erythematosus, ankylos- ness to touch exists in a patient who appears
ing spondylitis, reactive arthritis, Behcet’s dis- clinically to have episcleritis, the likelihood is
ease, gout, and atopy, have a genetic basis. considerable that in fact the patient has some
component of occult scleritis. Redness, best
examined in daylight, may range in intensity
4.1.3 Clinical Manifestations from a mild red flush to fiery red, but it is not
accompanied by the bluish tinge present in scleri-
Episcleritis is usually characterized by recur- tis. In a severe attack of episcleritis, lid swelling
rences involving different eyes at different times and associated spasm of the sphincter of the iris
and affecting one area after another. Sometimes, and ciliary muscle, resulting in miosis and tem-
however, the patient develops the inflammation porary myopia, may occur, but this is a rare
in both eyes at the same time. Over 60% of occurrence. Other symptoms include tearing
patients with episcleritis may have recurrences (never true discharge) and mild photophobia.
for 3–6 years after the onset of the disease, but Clinical examination with the slit lamp, par-
the episodes become less frequent after the first ticularly with red-free light, discloses that the
3–4 years, until the problem no longer recurs [2, 3]. inflammation is entirely localized within the epis-
In a series of patients with episcleritis, the dura- cleral tissue. The underlying sclera is never
tion ranged from 1 month to 38 years [15]. involved. The superficial edge of the narrow beam
Bilaterality was found in 40% of our patients of the slit lamp is displaced forward, showing the
(Table 4.2). The main symptom is mild discom- episcleral edema. The deep edge of the narrow
fort, which can be described as a feeling of heat, beam of the slit lamp remains flat against the
sharpness, or irritation, and the main sign is red- sclera, showing no displacement forward by
ness, which can be localized in one sector or can underlying scleral edema. The distribution of
involve the whole episclera. Pain, if any, is usually inflammation is more common in the interpalpebral
98 4 Clinical Considerations of Episcleritis and Scleritis
against the sclera in episcleritis and is displaced patients with episcleritis had had rheumatic fever
forward in scleritis. in the past; however, we did not consider the
conditions associated because they had not been
concomitant.
4.1.5 Associated Diseases
Once again, the field of neuroendocrine immu- Without treatment, the condition may be pro-
nology may potentially provide logical explana- gressively destructive, sometimes leading to loss
tions for such an association [39]. No clear of vision or loss of the eye. Furthermore, scleri-
association between the onset of episcleritis and tis may be the presenting manifestation of a
menstruation or ovulation was evident in any of potentially lethal systemic vasculitic disorder or
our female patients. may herald the onset of an occult systemic vas-
Exposure to airborne allergens, occupational culitis in a patient with an already diagnosed
(e.g., vapor of printing inks), seasonal (e.g., pol- systemic disease that is apparently in remission.
len), or perennial (e.g., house dust mite), has also Because medical intervention can halt the relent-
been found to trigger recurrent attacks, as in the less progression of both ocular and systemic
case of the patient who had active episcleritis destructive processes, early detection may not
after contact with printer’s inks [3, 18, 21]. only prevent devastating ocular complications,
Although several of our patients had positive skin but also may prolong survival and improve the
tests to multiple allergens, only one (1%) quality of life.
(Table 4.3) had a clear history of atopy with aller-
gic asthma, hay fever, perennial allergic rhinitis,
or atopic dermatitis (eczema). Skin testing was 4.2.2 Patient Characteristics
investigated by McGavin et al. [18] in 17 patients
with episcleritis. Of the eight patients who had a Scleritis is most common in the fourth to sixth
positive reaction to some allergen (three with decades of life, with a peak incidence in the fifth
mild reaction to one antigen, usually house dust decade [5, 13, 18], and affects women more fre-
or house dust mite), only three of them gave a quently than men (1.6:1) [5]. In our series of
clear history of either hay fever or asthma. Twelve patients (Table 4.4), the condition had a mean
percent of the patients with episcleritis in Watson age at the onset of the first episode of 54 years
and Hayreh’s series [2] had a history of asthma (range, 12–96 years) and it was 50% more com-
and hay fever. Allergy to food products has also mon among women than men. Our experience
been reported as a potential trigger of active epis- shows that scleritis may occur in patients of all
cleritis; recurrent attacks or stable periods have races, but there are no studies on its incidence
been described, depending on the ingestion or and prevalence within racial groups. Scleritis is
avoidance of the specific products in the diet not a familial condition, although some of the
[40–42]. None of our patients had a clear associa- scleritis-associated systemic diseases (rheuma-
tion between the onset of the disease and the toid arthritis, systemic lupus erythematosus,
ingestion of specific food products, but this area ankylosing spondylitis, reactive arthritis syn-
of dietary allergy has been an especially difficult drome, Behcet’s disease, gout, and atopy) have a
one to study, historically and experimentally, and genetic basis.
so we cannot exclude the possibility that sensitiv-
ity to one or another products consumed by some
of our patients might be a provocative factor for 4.2.3 Clinical Manifestations
recurrent episcleritis.
Scleritis, like episcleritis, is characterized by
recurrences involving the same or different eyes at
4.2 Scleritis different times, or both eyes at the same time.
Recurrences may appear for many years, espe-
4.2.1 Introduction cially if the initial attack has not been successfully
treated. More than 69% of patients may have
Unlike episcleritis, scleritis is a severe inflam- recurrences for 3–6 years after the onset of the dis-
matory condition that is characterized by edema ease; however, after this period, the episodes
and inflammatory cell infiltration of the sclera. become less frequent until the disease no longer
4.2 Scleritis 103
recurs [2, 3]. In our series of patients with scleritis, as a result of edema, inflammatory mediators, or
the duration of the disease ranged from 1 month to necrosis [3]. Pain is, therefore, a good indicator of
30 years. The condition was bilateral in 41% of the presence of active scleritis; it always vanishes
our patients (Table 4.4). The symptoms and signs with adequate medical treatment of the inflamma-
of scleritis, when present, are much more severe tory condition.
than in episcleritis. Pain is the main symptom of The primary sign of scleritis is redness, which
scleral disease, although it is sometimes almost is gradual in the onset, increasing over a period of
absent in some patients with posterior scleritis or several days. This redness has a bluish-red tinge
with scleromalacia perforans. It may be insidious in appearance, best seen when the examination is
in the onset, severe in intensity, penetrating in performed in natural light (Fig. 4.4). Redness is
character, and only temporarily relieved by anal- present in almost all eyes with scleritis. It may be
gesics. The pain is sometimes localized to the eye, localized to one sector, most frequently in the
but it more frequently radiates to the forehead, the interpalpebral area (followed by the superior
jaw, and the sinuses. In these cases, the patient quadrants) [18] or may involve the whole sclera.
may be erroneously diagnosed as having migraine, After recurrent attacks of scleral inflammation,
temporomandibular joint arthritis, sinusitis, her- the sclera becomes translucent due to postedema
pes zoster, or orbital tumor. Although the pain rearrangement of the collagen fibers; because the
may always be present, it can recrudesce with vio- underlying choroidal pigment becomes visible,
lent paroxysms, sometimes triggered by touching the translucent sclera shows a blue–gray color
the temple or the eye, preventing the patient from best seen when viewed in daylight (Fig. 4.5).
laying his/her head on the affected side. These These areas may be invisible by the slit-lamp
paroxysms may occur more frequently at night, examination.
causing anxiety, depression, and lack of sleep. The Other symptoms include tearing (which is
pain is probably caused either by distention or rarely severe and never accompanied by dis-
destruction of the sensory nerve fibers in the sclera charge), and mild-to-moderate photophobia. If
104 4 Clinical Considerations of Episcleritis and Scleritis
Fig. 4.4 Scleritis. Note the slightly violaceous character Fig. 4.6 Patient with necrotizing scleritis prior to instilla-
of the inflammation. The patient complains of pain, and tion of 10% phenylephrine
the globe is tender to palpation through the upper lid
Fig. 4.5 Same eye as in Fig. 4.4. Two years after the pho- Fig. 4.7 Same eye as in Fig. 4.6. Ten minutes after instil-
tograph in Fig. 4.4 was taken. The scleritis has been suc- lation of 10% phenylephrine drops. Note that the degree
cessfully treated and has been held in remission for 1 year. of clinical inflammatory signs is virtually unchanged,
Note, however, the areas of scleral loss with uveal “show” indicating that this patient’s inflammation, even in areas
through the remaining scleral fibers outside the focus of frank necrotizing scleritis, represents
true scleritis
the inflammatory process is severe, an associated congested than the superficial episcleral vessels,
spasm of the sphincter of the iris and ciliary mus- without coexisting congestion of the conjunctival
cle may appear, resulting in miosis and tempo- network. The use of a topical vasoconstrictor
rary myopia. (topical phenylephrine [10%] or epinephrine
Clinical examination with the slit lamp, par- [1:1,000]) makes the differentiation between epis-
ticularly with a red-free light, shows that the cleritis and scleritis easier because the drug con-
inflammation is localized within the scleral and stricts the congested superficial episcleral network
episcleral tissue. The deep edge of the narrow with minimal effect on the congested deep epis-
beam of the slit lamp is displaced forward, show- cleral network (Figs. 4.6 and 4.7).
ing the underlying scleral edema. The superficial Scleritis may cause decrease in vision through
edge of the narrow beam of the slit lamp also is the complications it produces. The main causes
displaced forward, showing the underlying epis- of decrease in vision in patients with scleritis are
cleral edema. The deep episcleral vessels are more keratitis, uveitis, glaucoma, cataract, exudative
4.2 Scleritis 105
4.2.4 Classification
Scleritis can be divided into anterior and posterior nodular anterior scleritis (51.9 years) was lower
forms. Even recognizing than posterior scleritis is than the mean age of patients with necrotizing
underdiagnosed, anterior scleritis is much more varieties (66.4 years for necrotizing and 61.1 years
frequent [2]. In a series of 30 enucleated eyes for scleromalacia perforans) and that the mean
with the primary histological diagnosis of scleri- age of patients with posterior scleritis was
tis, Fraunfelder and Watson [1] found that ante- 43.6 years. The sex distribution within each sub-
rior scleritis was present histologically in 100% category always maintained the female predomi-
of eyes; 43% of them also had posterior scleritis. nancy, and bilaterality was more frequently linked
None of these eyes in this series was found to be with diffuse anterior scleritis, necrotizing anterior
affected by posterior scleritis alone. In our own scleritis, and posterior scleritis. In our series,
series of patients, 93% of the patients had an ante- decrease in vision, anterior uveitis, PUK, and
rior scleritis (Table 4.1). Anterior scleritis may be associated disease were significantly more fre-
further classified, depending on clinical appear- quent in necrotizing scleritis.
ance, into diffuse, nodular, necrotizing with
inflammation (necrotizing), and necrotizing with- 4.2.4.1 Diffuse Anterior Scleritis
out inflammation (scleromalacia perforans) [2]. The inflammation of diffuse anterior scleritis is
This classification has been shown to be useful generalized, involving either some small area or
because only 8% of Tuft and Watson’s patients the whole anterior segment (Fig. 4.8). The onset
progressed from one subcategory to another dur- is insidious, gradually increasing in signs and
ing the course of their scleral inflammation [13]. symptoms for 5–10 days. Without treatment, it
In our series, diffuse anterior scleritis was the may last several months. It is a form that may be
most common subcategory, followed by nodu- misdiagnosed as simple episcleritis and therefore
lar anterior scleritis, posterior scleritis, necrotiz- sometimes is undertreated. In slit-lamp examina-
ing anterior scleritis, and scleromalacia perforans tion, the superficial and deep episcleral plexuses
anterior scleritis (Table 4.1) [2, 13, 43]. Although are not only congested, but also distorted and
any of these types can be associated with any dis- tortuous, losing the normal radial pattern of the
ease, they serve as an indicator of severity and, vessels. When the inflammation disappears, the
therefore, as a guide to therapy. In our series sclera may show a bluish color due to the rear-
(Table 4.4), the association between age and type rangement of the collagen fibers. This increased
of scleritis showed that the mean age of patients translucency is not accompanied by scleral thin-
with diffuse anterior scleritis (54.2 years) or ning or loss of tissue.
106 4 Clinical Considerations of Episcleritis and Scleritis
Fig. 4.13 Nodular scleritis evolving into necrotizing Fig. 4.14 Necrotizing scleritis. Note not only the loss of
scleritis. The area of scleral necrosis is clearly apparent at sclera, but also the pronounced vascularity in the area
the 10–11 o’clock position in the anterior sclera adjacent
to the corneoscleral limbus. This is an area of previous
nodular scleritis
Fig. 4.18 Necrotizing scleritis and peripheral ulcerative Fig. 4.19 Same patient as in Fig. 4.18, 4 weeks into ther-
keratitis in a patient with positive antineutrophil cytoplas- apy with systemic cyclophosphamide. The inflammatory
mic antibody staining and abnormal sinus X rays; process is beginning to resolve
Granulomatosis with polyangiitis (Weg)
may be low when the perforation occurs but rises through the pupil, but although the sclera is
rapidly to normal as soon as the iris incarcerates. thinned (from 0.6 to 0.3 mm) [78] the wall is
Paralimbic scleromalacia is a rare condition affect- resistant, with no tendency to perforation.
ing individuals of either sex between the ages of Histologically, it is considered as a degenerative
25 and 50 years, without evidence of systemic dis- lesion with a lack of cellular elements, replace-
ease or previous ocular inflammation. If there is ment of the superficial layers of the sclera by
association with rheumatoid arthritis, the condi- large masses of hyaline degeneration, and calcifi-
tion should probably be regarded as necrotizing cation. The collagen fibers in the area adjacent to
scleritis without inflammation or as scleromalacia the plaque are fragmented and swollen, making
perforans. Paralimbic scleromalacia has a good the sclera weak. The location of the plaque, there-
prognosis without treatment. fore, may be determined by the maximal stresses
of the muscles. Senile scleral plaque has a good
Senile Scleral Hyaline Plaques prognosis without treatment because there is no
Senile scleral hyaline plaques also can be mis- evidence of systemic disease or previous ocular
taken for scleromalacia perforans because both inflammation associated with this condition.
lesions involve loss of scleral substance, lack of
inflammatory reaction, and painless development 4.2.4.5 Posterior Scleritis
[58, 69, 70]. The scleral plaque, which occurs in Posterior scleritis accounts for the inflammation
individuals of either sex between the ages of 60 of the sclera posterior to the ora serrata, which
and 75 years, appears as a dark, oval, nonprogres- may spread to the posterior segment of the eye,
sive patch with a size ranging from 1 to 2 mm in involving choroid, retina, and optic nerve. Thus,
width and 2–6 mm in length [5, 21, 63, 72–79]. because a fundus mass, choroidal folds, retinal
The lesion, usually bilateral and symmetrical, is striae, choroidal or retinal detachments, and disk
localized to the interpalpebral region, between or macular edema may appear, posterior scleritis
the insertion of the lateral or medial rectus mus- may be confused with many other diseases, such
cles and the limbus (Chap. 3, Fig. 3.16). In slit- as primary or secondary choroidal tumors, uveal
lamp examination, the plaque appears as a effusion syndrome, rhegmatogenous retinal
translucent area through which the underlying detachments, Vogt–Koyanagi–Harada syndrome,
uvea can be seen, surrounded by a calcareous yel- central serous retinal detachments, and optic
lowish ring and covered by atrophic episclera and neuritis [4, 80–86]. Because posterior scleritis
normal conjunctiva. The central translucent area also may extend outward, involving extraocular
can be transilluminated by directing the light muscles and orbital tissues, it also may be
114 4 Clinical Considerations of Episcleritis and Scleritis
confused with orbital tumors or orbital inflam- decrease in vision and asthenopia, which can
matory diseases [84, 87, 88]. Furthermore, pos- be corrected with the addition of convex lenses.
terior scleritis is often associated with anterior In other cases, the reduction in vision is not
scleritis; but it also may occur alone, in which correctable because it is caused by severe com-
case the absence of anterior scleral involvement plications, such as choroidal or retinal detach-
makes the diagnosis difficult [1, 2, 7, 8, 84]. And ments, distortion of the macula by an area of
if the concomitant anterior scleritis is severe, scleral inflammation, cystoid macular edema,
posterior scleritis may be overlooked. Therefore, and optic neuritis [7, 8, 84–86, 91, 92]. These
posterior scleritis is a more common condition complications are frequently reversible, with a
than is realized, and the diagnosis is often missed good visual outcome if adequate treatment for
or delayed [1, 3–5, 7]. Recognition of the pro- posterior scleritis is initiated shortly after its
tean clinical manifestations and confirmation by onset. If diagnosis and treatment are delayed,
ancillary testing are important to reach a correct permanent damage may cause irreversible
diagnosis of posterior scleritis. Early diagnosis decrease in vision [7]. In our series, decrease
leads to early therapy and prevention of compli- in vision as the initial symptom was noted by
cations that could cause permanent decrease in 280 of the 31 patients (90%) with posterior
vision. scleritis.
Posterior scleritis may be a posterior exten- The pain varies from mild to severe and often
sion of either nodular or diffuse anterior scleritis. is referred to the brow, temple, face, or jaw. In our
In our series, anterior scleritis was present or had series, pain was present in all of the 311 patients
occurred in 21 of 31 patients (68%) with poste- (100%) with posterior scleritis; of these, 3 patients
rior scleritis. Posterior scleritis may present described pain as severe, 18 as moderate, and 10
alone, in which case anterior involvement may or as mild. The pain is often correlated with the
may not appear later [3]. Evidence of posterior severity of the anterior involvement, and there-
scleritis must, therefore, be searched for during fore patients with posterior scleritis alone have
the course of an anterior scleritis, although the either no pain or pain of a mild degree [7, 84].
absence of anterior scleritis does not exclude the Mild pain may result from stretching of Tenon’s
possibility of posterior scleritis. capsule by edema, stretching of scleral sensory
nerve endings by edema, optic nerve sheath
Symptoms and Signs swelling, or orbital or extraocular muscle swell-
Symptoms and signs at presentation are variable ing [85]. All 21 patients with posterior scleritis
because they depend on the degree and site of who described the pain as severe or moderate
inflammation. The most common presenting also had anterior involvement. Photopsia may
symptoms are decrease in vision and pain, occur secondary to retinal striae or retinal
although diplopia, flashes, and tenderness may detachment.
also be present [3, 7, 86]. The most common pre- The sclera and Tenon’s capsule are closely
senting sign is redness, related to anterior scleri- connected, especially around the optic nerve
tis; conjunctival chemosis, proptosis, lid swelling, and behind the limbus. Similarly, the connec-
lid retraction, and limitation of ocular movements tive tissue of the orbit and the connective tissue
may also be detected [3, 7, 86]. of the muscle sheaths form a direct continuation
Some decrease in vision is almost always of Tenon’s capsule. Extension of posterior
present and its severity depends on the site, scleral inflammation to the orbit explains the
type, and degree of the complications associ- signs of proptosis, chemosis, lid swelling, and
ated. The reduction in vision may reflect a lower lid retraction with upgaze. Extension of
transient hyperopia, which is caused by a posterior scleral inflammation to the extraocular
decrease in the axial length of the globe sec- muscles causes myositis which may lead to
ondary to posterior scleral thickening [85, 89, diplopia and ptosis due to ocular movement
90]. In these cases, patients complain of mild impairment [92].
4.2 Scleritis 115
Fundus Findings
The most common fundus findings in posterior
scleritis are choroidal folds, subretinal mass, disk
edema, and macular edema. Annular ciliochoroi-
dal detachment, serous retinal detachment,
intraretinal deposits, and retinal striae may also
appear. Because enucleation has been a conse-
quence of misdiagnosis, posterior scleritis must
be considered in the differential diagnosis of all
these entities [1, 93, 94].
Choroidal Folds
Choroidal folds are a series of alternating light
and dark lines confined to the posterior pole,
Fig. 4.22 Fundus photomicrograph of patient with pos-
often temporal, and rarely extending beyond the terior scleritis. Note the choroidal folds, as shown by the
equator (Fig. 4.22). Although they are usually alternating light and dark lines
arranged in a horizontal and parallel pattern, sur-
rounding a subretinal mass, they may be vertical,
oblique, or irregular. Increased scleral and chor- neuritis [93]. Disk edema may cause an afferent
oidal thickening, forcing Bruch’s membrane and pupillary defect or visual field changes, but the
retinal pigment epithelium into folds, has been visual acuity is usually preserved. Extension of
proposed as a possible mechanism [95–98]. the scleral and choroidal inflammation with or
Because choroidal folds result in reduction of the without uveitis may cause cystoid macular edema
anteroposterior diameter of the eye, they induce a [8]. Untreated disk edema or macular edema usu-
relative hyperopia. Prompt recognition and treat- ally results in permanent structural damage and
ment of the underlying cause restore visual acu- loss of vision. Prompt treatment of posterior
ity; however, prolonged choroidal folding may scleritis may prevent this.
cause mechanical distortion of the neurorecep-
tors of the retina, leading to permanent loss of Annular Ciliochoroidal Detachment
vision. Choroidal folds may be the only abnormal and Serous Retinal Detachment
fundus finding in a relatively moderate posterior Extension of the scleral inflammation into the
scleritis. choroid allows exudation of fluid, which may
account for an annular ciliochoroidal detachment,
Subretinal Mass multiple retinal pigment epithelial detachments
A subretinal mass caused by a circumscribed (Figs. 4.23 and 4.24), and/or a serous retinal
area of scleral thickening may be detected in detachment [93, 99]. Detachment of the periph-
posterior scleritis [7, 8, 84, 86, 94]. The scleral eral choroid and ciliary body may push the lens-
mass has the same orange color as the adjacent iris diaphragm forward and precipitate an acute
normal pigment epithelium, preserves the over- angle-closure glaucoma attack [100]. Subretinal
lying normal choroidal vascular pattern, and is fluid in serous retinal detachment originates from
frequently surrounded by choroidal folds or reti- choroid through multiple leaking spots in the reti-
nal striae [84, 86, 94]. In some cases, the surface nal pigment epithelium. Serous retinal detachment
of the mass may show scattered yellowish-white, may be confined to the posterior pole as a serous
circumscribed lesions. macular detachment or may extend or localize
more peripherally as a bullous retinal detachment
Disk Edema and Macular Edema with shifting subretinal fluid. In the latter, the fluid
Extension of the scleral and choroidal inflamma- pools inferiorly when the patient is upright and
tion to the optic nerve may account for an optic superiorly when the patient is positioned with
116 4 Clinical Considerations of Episcleritis and Scleritis
Associated Diseases
Disease association in posterior scleritis is less
common than in anterior scleritis [2, 7]. In our
series of 31 patients with posterior scleritis, 6
(19%) were found to have an associated systemic
disease (Table 4.4). This is in contrast to the 36%
disease association found in our patients with
anterior scleritis. Diagnoses included psoriatic
arthritis in two patients, HLA-B27+ (without
spondyloarthropathy)-associated scleritis in one
patient, arthritis and inflammatory bowel disease
Fig. 4.23 Posterior scleritis with annular retinochoroidal
and serous retinal detachment
in one patient, systemic lupus erythematosus in
one patient, and tubulointerstitial nephritis and
uveitis syndrome in one patient (Table 4.5).
Complications
Posterior uveitis is universally present in posterior
scleral inflammation because the choroid is
always involved by the adjacent posterior scleral
inflammation; [2, 6] anterior uveitis may also
appear, but it is often associated with concomitant
anterior scleritis. Glaucoma, particularly in com-
bination with uveitis, is considered to be an omi-
nous sign in the course of scleritis because its
presence indicates a more diffuse and severe pro-
cess [3]. Whether caused by anterior uveitis, cil-
iochoroidal detachment, angle neovascularization,
Fig. 4.24 Same eye as shown in Fig. 4.23. Fluorescein or chronic use of steroids, increased intraocular
angiogram, confirming the findings described in Fig. 4.23
pressure in posterior scleritis may result in the
development of irreversible optic nerve damage
[9, 100].
head down; despite a cloudy subretinal fluid, a
pale gray subretinal mass with a surrounding dark Ancillary Tests
gray line and an overlying normal choroidal vas- Ultrasonography
cular pattern may sometimes be visible through Ultrasonography is the most useful test in the
the poorly mobile bullous serous retinal detach- diagnosis of posterior scleritis because it shows
ment. The bullous serous retinal detachments do the flattening and thickening of the posterior coats
not have retinal holes or fixed retinal folds. The of the eye (choroid and sclera) associated with ret-
ciliochoroidal or retinal detachments usually robulbar edema [84, 86, 89, 101] (Fig. 4.25).
resolve completely with prompt and aggressive Occasionally, retinal and choroidal detachments
treatment of the scleritis. Although they may dis- may also be detected. B-scan ultrasonography
appear within hours, they are often absorbed shows multiple internal echoes in the area of the
slowly over a period of several weeks or months, scleral thickening and lack of echoes in the area of
leaving only a diffuse pigmentation in the affected retrobulbar edema; the multiple echoes remain
area; however, if the macular area has been after sound beam attenuation, indicating high
4.2 Scleritis 117
internal reflectivity of the scleral mass (Fig. 4.26). from orbital, choroidal, and retinal entities that
On the other hand, in choroidal thickening with- clinically may mimic it (Tables 4.7–4.9) [86].
out scleral thickening, the echoes do not remain
after sound beam attenuation (low internal reflec- Computerized Tomography (CT) Scanning
tivity) (Fig. 4.27). When retrobulbar edema sur- Computerized tomography also shows scleral
rounds the optic nerve, the “T” sign may appear, thickening, the image of which can be enhanced
which consists of a lack of echoes in the edema- by radiopaque medium injection [86, 102].
tous Tenon’s space and adjacent optic nerve Retrobulbar edema may also be seen. The ability
(Fig. 4.28). A-scan ultrasonography shows high- of computerized tomography to delineate extraoc-
amplitude internal spikes in the area of the scleral ular muscles, lacrimal glands, optic nerves,
thickening and low-amplitude internal spikes in scleral coats, orbital walls, and paranasal tissues
the area of retrobulbar edema. The combination of helps to detect extraocular muscle or lacrimal
both A scan and B scan techniques gives the most gland enlargement, optic nerve or scleral inflam-
useful results in distinguishing posterior scleritis mation, bone erosion, and sinus involvement,
118
Table 4.7 Differential diagnosis of posterior scleritis: proptosis, chemosis, lid swelling, and limitation of ocular movements
Acute diffuse idiopathic orbital
Parameter Posterior scleritis Orbital tumor inflammation Thyroid ophthalmopathy
Sex predilection Female – – Female
Age predilection Middle aged and elderly – – Middle aged and elderly
Laterality Unilateral Unilateral Unilateral Bilateral
Onset Gradual Gradual Acute Gradual
Pain Variable ± Variable −
Tenderness + − + −
Anterior scleritis + − − −
Visual loss + ± ± Variable
Fundus mass Variable ± ± −
Color of the mass Orange Orange Orange −
Proptosis ± + + +
Motility disturbance ± + + +
Conjunctival chemosis ± + + −
4
Lid edema ± + + −
Pigment epithelium Yellowish nodules Normal Normal Normal
Disk edema + ± ± ±
Uveitis + − ± −
Choroidal folds + ± ± ±
Serous retinal detachment + − ± −
Fluorescein angiography Multiple small leaks Normal Normal Normal
(other than choroidal folds)
Ultrasound Scleral and choroid thickening Orbital mass Orbital mass (low reflectivity) EOM enlargement
retrobulbar edema (high reflectivity) and/or EOM enlargement
CT scan Scleral and choroid thickening Orbital mass with sinus Orbital mass without sinus involvement EOM enlargement
involvement/bone erosion or bone erosion; EOM enlargement
Biopsy indication No biopsy Biopsy Biopsy No biopsy
Response to steroids Good Absent Very good Variable
EOM extraocular muscle
Clinical Considerations of Episcleritis and Scleritis
4.2 Scleritis
Table 4.9 Differential diagnosis of posterior scleritis: serous detachment of choroid, ciliary body, and retina
Idiopathic centralserous
Parameter Posterior scleritis Uveal effusion syndrome Vogt–Koyanagi–Harada syndrome chorio retinopathy
Sex predilection Female Male – Male
Age predilection Middle aged and elderly Middle aged Young and middle aged Middle aged
Race predilection – – Oriental and pigmented Caucasian
Laterality Unilateral Bilateral Bilateral Unilateral
Pain Variable − − (photophobia) −
Anterior scleritis + − − −
Uveitis + − + −
Disk edema + + + −
Pigment epithelium Yellowish nodules “Leopard spots” Depigmented or Serous detachments
hyperpigmented lines pigment epithelium
4
Fluorescein Angiography
Fig. 4.31 Fluorescein angiogram: posterior scleritis.
Fluorescein angiography may reveal retinal pig- Note the choroidal and retinal striae as well as the retinal
ment epithelial detachment (Figs. 4.29 and 4.30), pigment epithelial window defects
serous retinal detachment, disk edema, or cys-
toid macular edema. In cases with serous retinal
detachment, subretinal fluid shows diffuse chor- fluorescence, whereas the dark portion of the
oidal mottling in the early phases, numerous fold corresponds to the valley and does not trans-
pinpoint spots of hyperfluorescence in the mid- mit the choroidal fluorescence. Inclination and
dle phases, and intense staining of the subretinal subsequent thickness of the retinal pigment epi-
fluid in the late phases [84]. Choroidal folds are thelium in the valleys and atrophy of the retinal
seen as alternating hyperfluorescent and hypo- pigment epithelium in the crests may be a pos-
fluorescent streaks (Fig. 4.31) [108]. The fluo- sible explanation for the hypofluorescent and
rescein pattern confirms their presence in case of hyperfluorescent areas, respectively [95, 108,
clinical doubt. The folds are recognized by the 109]. Retinal striae are not seen on fluorescein
early passage of fluorescein through the choroid, angiography; this helps to differentiate them
persisting through the late venous phase without from choroidal folds [95]. Because all these
leakage. The light portion of the fold corre- findings may also be seen in many other choroi-
sponds to the crest and transmits the choroidal dal, retinal, and orbital conditions, fluorescein
122 4 Clinical Considerations of Episcleritis and Scleritis
Thyroid ophthalmopathy and posterior scleri- occasional overlying orange lipofuscin pigment
tis may also have similar symptoms and signs. In contrasts with the uniform normal color of the
both, ultrasonography and computerized tomog- retinal pigment epithelium over the scleral
raphy may show extraocular muscle enlargement mass [119, 121]. Furthermore, although a chor-
(Fig. 4.32); however, thyroid disease does not oidal melanoma may also be surrounded by
show scleral thickening with retrobulbar edema. choroidal folds, the finding is not frequent [95].
Aside from the symptoms of thyroid disease and Ultrasonography may show the choroidal mass
upper lid retraction and lid lag when looking with the characteristic findings of low internal
downward, the most definite differential point of reflectivity, acoustic quiet zone, choroidal
thyroid ophthalmopathy is the thyroid-releasing excavation, and orbital shadowing without ret-
hormone (TRH) infusion test; screening tests, robulbar edema (Fig. 4.33) [119, 122]. It is
including triiodothyronine (T3) and thyroxine important to stress that intraocular inflamma-
(T4) by radioimmunoassay, and T3 resin uptake tion does not exclude the possibility of choroi-
may be normal [102, 103, 117, 118]. dal melanoma. A small percentage of patients,
usually with a large, necrotic choroidal mela-
Subretinal Mass noma, can have intraocular inflammation as the
Aside from posterior scleritis, a subretinal mass presenting sign [123].
may be caused by several choroidal (Table 4.8) Metastatic uveal carcinoma from breast, lung,
and orbital entities (Table 4.7). kidney, gastrointestinal, or genitourinary tumors
Differential diagnosis from choroidal mela- may present as a unilateral subretinal mass with
noma is important because many cases of pos- or without overlying subretinal fluid, occasion-
terior scleritis have been enucleated as a ally surrounded by choroidal folds; but they are
consequence of this mistaken diagnosis [1, 80, usually amelanotic with hyperplastic pigmenta-
81, 93, 94, 106]. Choroidal melanoma and pos- tion (mottling) of the overlying retinal pigmented
terior scleritis may present with a unilateral epithelium [119, 124, 125]. Differential diagnosis
subretinal mass with or without serous retinal is important because metastatic uveal carcinoma
detachment [119, 120]. In both, fluorescein may be the first sign of a systemic malignancy in
angiography may show multiple point-sources as many as 50% of the cases [124]. Ultrasonography
leakages. However, hyperpigmentation or shows a solid choroidal tumor with medium-to-
hypopigmentation of the choroidal mass with high reflectivity without retrobulbar edema; there
124 4 Clinical Considerations of Episcleritis and Scleritis
is no acoustic quiet zone, choroidal excavation, pattern of the chorioretinal folds, the presence of
or orbital shadowing characteristic of choroidal drusen in Bruch’s membrane, and the detection
melanomas [119, 122]. of the neovascular membrane. Fluorescein
Choroidal hemangiomas may also present as a angiography shows a sea fan pattern of subretinal
unilateral subretinal mass with or without overly- vessels, a nonfluorescent halo around the area of
ing subretinal fluid. However, they are usually staining, and a serous detachment of the retinal
pinkish-orange in color, frequently associated pigment epithelium.
with Sturge–Weber syndrome, and not sur- Papilledema may also produce choroidal
rounded by choroidal folds [119, 126, 127]. folds. Increased intracranial pressure, most com-
Although fluorescein angiograhy may show mul- monly due to intracranial tumors, causes increased
tiple small leaks, as in the case of posterior scleri- cerebrospinal fluid pressure within the optic
tis, the early filling of the choroidal vessels in the nerve sheath. The distended sheath may act as a
area of the tumor prior to the filling of the retinal space-occupying lesion causing the formation of
vessels is typical of a choroidal hemangioma the choroidal folds [130, 131]. Although bilateral
[128]. Ultrasonography shows a solid tumor with papilledema and choroidal folds may be present
uniform high reflectivity without retrobulbar in posterior scleritis, the ultrasonographic find-
edema; there is no acoustic quiet zone, choroidal ings of scleral thickening and retrobulbar edema
excavation, or orbital shadowing typical of chor- make the differentiation straightforward.
oidal melanomas [119, 122]. Chorioretinal folds may appear as a result of
Orbital tumors and diffuse idiopathic orbital the redundancy of the choroid and the retina
inflammatory diseases may also present with a when the scleral wall shrinks or collapses inward
subretinal mass that has the same color as the during hypotony [132, 133]. The normal ultra-
adjacent normal retinal pigment epithelium, pre- sonography and the past ocular history of intraoc-
served choroidal vascular pattern, and surround- ular surgery or intraocular trauma as causes of
ing choroidal folds as in the case of posterior hypotony help to differentiate this entity from
scleritis. However, clinical findings and imaging posterior scleritis.
studies may help to differentiate the different Scleral buckle procedures for retinal detach-
entities (Table 4.7). ment, causing scleral shrinkage and secondary
choroidal folding, can be recognized and differ-
Choroidal Folds entiated from posterior scleritis [108].
Choroidal folds can be caused by multiple entities,
such as orbital tumors, idiopathic orbital inflam- Annular Ciliochoroidal Detachment
mation, thyroid ophthalmopathy (Table 4.7), and and/or Serous Retinal Detachment
primary or secondary choroidal tumors Aside from posterior scleritis, serous detach-
(Table 4.8); they may also be present in macular ments of the choroid, ciliary body, and retina may
degeneration with choroidal neovascularization, be caused by the uveal effusion syndrome, by
papilledema, hypotony, and following scleral intraocular surgery, and by rhegmatogenous reti-
buckling retinal detachment surgery [87, 95, 96, nal detachment with uveal detachment (Table 4.9).
108, 109]. Bullous serous detachment of the retina and, less
Choroidal neovascularization in senile macu- commonly, serous ciliochoroidal detachment
lar degeneration may produce chorioretinal folds. may also be seen in choroidal melanoma, meta-
Contraction of a subpigment epithelial fibrovas- static uveal carcinoma (Table 4.8), and Vogt–
cular membrane adherent to Bruch’s membrane Koyanagi–Harada syndrome [120, 134, 135].
may cause a series of chorioretinal folds radiat- Bullous serous retinal detachment or serous mac-
ing outward from the periphery of the contracted ular detachment without ciliochoroidal detach-
membrane [129]. Differential diagnosis is ment can be found in the idiopathic central serous
straightforward because of the typical radiating choroidopathy.
4.2 Scleritis 125
Uveal effusion syndrome and posterior scleritis and neurological (meningeal inflammation)
may both present with annular ciliochoroidal involvement. Patients with Vogt–Koyanagi–
detachments, bullous serous retinal detachments, Harada syndrome are often orientals or have
and/or serous macular detachments; [136, 137] dark skin pigmentation, and they have bilateral
however, in uveal effusion syndrome, there is involvement. As in posterior scleritis, ultraso-
minimal or no pain, there may be dilated epis- nography in Vogt–Koyanagi–Harada syndrome
cleral vessels but no scleritis, and there is usually shows choroidal thickening and serous retinal
bilaterality. Furthermore, there is minimal or no detachment; however, unlike in posterior scleri-
uveitis (some vitreous cells); there are hyperpig- tis, the choroidal thickening shows a low internal
mented spots in the retinal pigmented epithelium reflectivity, and there is no retrobulbar edema.
(“leopard spots”), and there is a clear subretinal Idiopathic central serous chorioretinopathy
fluid. Fluorescein angiography in uveal effusion and posterior scleritis may have serous macular
syndrome shows slow perfusion of the choroid detachments and/or bullous serous retinal detach-
and prolonged choroidal hyperfluorescence [138]. ments, but in the former there are neither the
Occasionally, there are some focal leaks in the ocular findings of uveitis, anterior scleritis, and
pigment epithelium, but this finding is much less disk edema, nor the ultrasonographic findings
common than in posterior scleritis [137]. of sclerochoroidal thickening and retrobulbar
Ultrasonography shows choroidal thickening and edema [137].
serous ciliochoroid and/or retinal detachments in
both entities; however, the detection in some Disk and Macular Edema
cases of an eye smaller than normal (nanophthal- Disk and macular edema may occur in posterior
mos) or the finding of retrobulbar edema may be scleritis, in many inflammatory conditions of the
helpful for establishing the diagnosis of uveal uveal tract, and after intraocular surgery [8]. Past
effusion syndrome or posterior scleritis, respec- and present history, review of systems, ocular
tively. Unlike posterior scleritis, the response to examination, laboratory tests, and imaging stud-
steroids in uveal effusion syndrome is poor. ies may be helpful in distinguishing these condi-
A history of recent intraocular surgery is help- tions from posterior scleritis.
ful in differentiating a postoperative serous cilio-
choroidal detachment from one appearing in
posterior scleritis. 4.2.5 Associated Diseases
The finding of a retinal break with folds in a
retinal detachment with serous ciliochoroidal Connective tissue diseases, vasculitic diseases,
detachment is characteristic of a rhegmatogenous herpes, tuberculosis, and rosacea are the diseases
retinal detachment. most commonly associated with scleritis [2, 5,
Vogt–Koyanagi–Harada syndrome should also 17]. In our series, an associated systemic disease
be considered in the differential diagnosis of pos- was found in 36% of the patients with scleritis
terior scleritis because both may present with (Table 4.4), including 25% with connective tis-
bullous serous retinal detachments, serous macu- sue or vasculitic diseases, 10% with infectious
lar detachments, and, although infrequently in the diseases, and 1% with miscellaneous diseases
former, serous ciliochoroidal detachments [139– (rosacea, foreign body) (Table 4.5). Within the
142]. In both, fluorescein angiography may show connective tissue diseases and vasculitic diseases,
multifocal subretinal leaks. Furthermore, in both, rheumatoid arthritis was the most common entity,
there may be anterior and/or posterior uveitis, followed by HLA-B27+ (without spondyloar-
disk edema, and cloudy subretinal fluid. However, thropathy)-associated scleritis, granulomatosis
Vogt–Koyanagi–Harada syndrome also presents with polyangiitis (Wegener), relapsing polychon-
with signs of integumentary (vitiligo, poliosis, dritis, arthritis and inflammatory bowel disease,
and alopecia), auditory (dysacusis and tinnitus), and systemic lupus erythematosus. Scleritis may
126 4 Clinical Considerations of Episcleritis and Scleritis
appearance of an eye wearing a hard contact lens narrow gutter (0.5 mm or less in width) nor adja-
(“contact lens” cornea) [149]. cent scleral inflammation [155, 156]. Unlike
The differential diagnosis of peripheral cor- peripheral corneal thinning associated with scleri-
neal thinning associated with scleritis includes tis, Terrien’s marginal degeneration, pellucid
Terrien’s marginal degeneration (Fig. 4.35), pel- marginal degeneration, and senile furrow degen-
lucid marginal degeneration, and senile furrow eration are not associated with any systemic
degeneration (Table 4.10). All of these are slowly disease.
progressive, bilateral, and painless peripheral Suppression of the scleral inflammation usu-
stromal thinning with intact epithelium. In all of ally allows regression, but in some patients the
these, there is rare loss of vision or central cornea defect remains. Lubrication or therapeutic soft
involvement. Furthermore, in peripheral corneal contact lens may prove effective in some patients.
thinning associated with scleritis and in Terrien’s In cases of astigmatic error, spectacles or rigid
marginal degeneration, the peripheral gutter may contact lens may be used, depending on the sever-
have lipid deposition and vascularization. ity. Progression to a thinned, ectatic cornea may
However, Terrien’s marginal degeneration usu- be treated by cyanoacrylate glue application with
ally occurs superiorly and, although an atypical or without conjunctival resection or by excising
pterygium may be present in 20% of the cases, it the ectatic tissue and replacing it with an annular
is not associated with true scleritis [150, 151]. lamellar keratoplasty or with a conjunctival flap.
Peripheral corneal thinning associated with
scleritis may account for some cases considered Stromal Keratitis
to be “inflammatory Terrien’s marginal corneal Extension of the diffuse, nodular, or necrotizing
disease.” [152] Unlike peripheral corneal thin- scleral inflammation into the cornea may appear
ning associated with scleritis, pellucid marginal as isolated or multiple white or gray nummular
degeneration is a noninflammatory condition that midstromal opacities, which usually are in the
affects only the inferior cornea and is not accom- periphery, although they can involve the central
panied by lipid deposition or vascularization cornea. The opacities are usually in the same
[153, 154]. Finally, in senile furrow degeneration, quadrant as the scleral inflammation; therefore,
a peripheral corneal thinning of the clear interval the corneal involvement in the diffuse type of
between an arcus senilis and the limbus, there is scleritis is usually more extensive than in the nod-
neither vascularization and lipid infiltration in the ular type. If the treatment for the scleritis is
128 4 Clinical Considerations of Episcleritis and Scleritis
Table 4.10 Differential diagnosis of peripheral corneal thinning associated with scleritis
Peripheral corneal Terrien’s marginal Pellucid marginal Senile furrow
Parameter thinning scleritis degeneration degeneration degeneration
Age predilection Middle aged and elderly Young and Young and Old
middle aged middle aged
Sex predilection Female Male − −
Laterality Bilateral Bilateral Bilateral Bilateral
Pain − − − −
Visual loss ± ± ± −
Epithelial defect − − − −
Stromal thinning + + + +
Progression Slow Slow Slow Slow
Location Circumferential Superior Inferior Circumferential
Width (mm) 1–2 1–2 1–2 0.5 or less
Central edge Eventually lipids Gray–white line Protruding Arcus senilis (lipid)
Gutter lipids Eventually develop + − − (lucid interval)
Gutter vessels Eventually develop + − −
Scleral/conjunctival + (mild to moderate) ± (occasional − −
inflammation atypical pterygium)
Perforation ± ± ± −
Associated disease Systemic disease − − −
(rheumatoid arthritis)
Treatment Scleritis treatment Contact lenses Contact lenses −
Contact lenses Tectonic Tectonic
Tectonic keratoplasty keratoplasty keratoplasty
Conjunctival flap
Fig. 4.37 Peripheral ulcerative keratitis in a patient with Fig. 4.38 Peripheral ulcerative keratitis, which has pro-
rheumatoid arthritis. This slit-lamp photomicrograph gressed centrally and circumferentially in a patient with
illustrates the degree of peripheral corneal ulceration, anterior scleritis associated with rheumatoid arthritis. Like
nearly 80% in depth. The extent, circumferentially, is the ulcer shown in Fig. 4.37, this one has an overhanging
from 5 to 8 o’clock. The degree of corneal destruction is lip with undermining of the edge of the ulcer and destruc-
much greater than is clinically apparent: exploration of tion of stroma far in excess of what one would predict as a
the ulcer with a smooth-tipped tying forcep disclosed result of a simple slit-lamp examination. The digestive
undermining of this ulcer, leaving an overhanging lip, process has extended into the pupillary zone in this
with active digestion of the corneal stroma extending patient
approximately 5 mm into the cornea from the area of the
obvious active peripheral ulcer
membrane (Fig. 4.37). An intrastromal yellow– be painful and crescent shaped, may follow a
white blood cell infiltrate may easily be seen at circumferential and central progression, and may
the advancing edge of the ulcer, which progresses have an undermined central edge with stromal
circumferentially and occasionally centrally yellow–white infiltrates. However, in Mooren’s
(Fig. 4.38), in which case vision is lost. In some ulcer, there is neither adjacent scleritis nor sys-
cases, anterior uveitis may also be present. If no temic disease association [157].
treatment is instituted, spontaneous corneal per- Treatment for PUK includes cyanoacrylate
foration may easily occur. glue application following keratectomy and
Seven percent of our patients had PUK, and conjunctival resection while vigorous systemic
the majority of these were associated with necro- treatment is directed at controlling the scleral
tizing scleritis (Table 4.4). PUK with or without inflammation [158–160].
scleritis is frequently an ocular manifestation of a
systemic disease [154–156]. PUK was highly 4.2.6.2 Uveitis
associated with the presence of a potentially Uveitis is also caused by extension of the scleral
lethal, often occult, systemic disease in our inflammation. Fraunfelder and Watson [1] found
patients with scleritis. Most of these cases had that 68% of 30 enucleated eyes with a primary
the necrotizing variety of scleritis. These data histological diagnosis of scleritis had signs of hav-
show that the presence of PUK-accompanying ing had uveitis; scleritis with uveitis and glaucoma
scleritis should be considered a grave sign: it was the most common combination of complica-
indicates an extension of the inflammatory pro- tions leading to enucleation. Wilhelmus et al. [6],
cess that may cause perforation of the eye, and in another series of 100 enucleated eyes with a pri-
may signal the presence of a potentially lethal mary histological diagnosis of scleritis, found that
systemic disease. 63% had had anterior uveitis. These findings sug-
Differentiation from Mooren’s ulcer may be gest that scleritis with uveitis, particularly when
difficult because both peripheral ulcerations may associated with glaucoma, should be regarded as
130 4 Clinical Considerations of Episcleritis and Scleritis
extremely ominous. The uveitis associated with diagnosis of scleritis showed signs of having had
scleritis is more frequently anterior, mild to mod- glaucoma; scleritis with glaucoma and uveitis
erate in intensity, and appears during the late was the most common cause of enucleation.
course of the scleral inflammation [6]. Whilhelmus et al. [9], in another series of 92 enu-
In our series, 132 of the 500 patients (26%) cleated eyes with a primary histological diagnosis
with scleritis had had at least one episode of of scleritis, found that 49% of them had had glau-
anterior uveitis (Table 4.4). There was no differ- coma [9]. These data suggest that the presence of
ence in the sex and age distribution between the scleritis with glaucoma, particularly when associ-
patients with scleritis with and without uveitis. ated with uveitis, should be considered as an omi-
The presence of anterior uveitis was highly nous sign [1]. The reported incidence of increased
associated with the presence of necrotizing ante- intraocular pressure in patients with scleritis var-
rior scleritis (45%), diffuse anterior scleritis ies between 12% and 22% [2, 9, 18]. In our series
(28%), and posterior scleritis (26%); five of the of 500 patients with scleritis, 71 (14%) had
eight patients with posterior scleritis and ante- increased intraocular pressure (Table 4.4). Angle-
rior uveitis also had some degree of anterior closure glaucoma, open-angle glaucoma, and
scleritis. neovascular glaucoma are some of the possible
Posterior uveitis was present in all cases of mechanisms.
posterior scleritis. Because the presence of poste-
rior uveitis in association with anterior scleritis is Angle-Closure Glaucoma
rare, the detection of posterior uveitis in a patient A primary angle-closure attack can appear in
with anterior scleral inflammation obligates one scleral inflammation, particularly if the patient
to search for posterior scleritis [3]. has narrow angles. Swelling of the angle struc-
Decrease in vision in patients with scleritis tures combined with a mildly dilated pupil may
may be caused by complications, such as kerati- account for the closure of the angle. The therapy
tis, uveitis, cataract, glaucoma, or macular edema. includes the standard antiglaucomatous treat-
Long-standing uveitis may cause cataract, glau- ment, primarily with hyperosmotic agents, miot-
coma, or macular edema. The presence of ante- ics, beta blockers, and laser iridectomy, combined
rior uveitis with scleritis was highly associated with anti-inflammatory treatment for controlling
with the presence of ocular complications (includ- the scleral inflammation.
ing decrease in vision, peripheral keratitis, or Secondary angle closure in patients with
ocular hypertension) indicating that uveitis occurs scleritis may be caused by anterior synechiae, iri-
with scleritis cases undergoing complications dolenticular adhesions, or ciliary body edema
that may lead to visual loss. secondary to long-standing anterior uveitis [9]. In
The presence of uveitis-accompanying scleri- this case, relief of anterior adhesions (laser iri-
tis should be considered as a grave sign because dogonioplasty or filtering procedures) and/or
it indicates not only an extension of the inflam- pupillary block (laser iridectomy) and control of
matory process to the intraocular structures, but the sclerouveal inflammation may restore the
also the presence of complications that may cause intraocular pressure to normal.
progressive visual loss. The detection of uveitis- Secondary angle closure may occur in patients
accompanying scleritis requires early and aggres- with posterior scleritis when a ciliochoroidal effu-
sive therapy to control both the uveal and scleral sion displaces the iris-lens diaphragm forward,
inflammation. shallowing the anterior chamber and closing the
filtration angle [100]. In this case, treatment with
4.2.6.3 Glaucoma miotics may cause further shallowing of the ante-
Increased intraocular pressure is caused by the rior chamber, whereas treatment of the scleral
accompanying scleral edema and uveal inflamma- inflammation with anti-inflammatory drugs
tion. Fraunfelder and Watson [1] found that 46% resolves the inflammatory effusion and allows the
of 30 enucleated eyes with a primary histological angle to reopen.
4.2 Scleritis 131
between surgery and the onset of scleritis varied Unlike episcleritis, scleritis is a severe inflam-
from 2 weeks to 24 months. Four patients (57%) matory disease that can be progressively destruc-
were found to have an infectious process. In tive, sometimes leading to loss of vision or loss
another study performed by us [161], 91% of the of the eye. Furthermore, scleritis may be the
patients were found to have an underlying autoim- presenting manifestation of a potentially lethal
mune vasculitic systemic disease. Immune com- systemic vasculitic disease or may herald the
plex-mediated vasculitis and T-cell-mediated onset of an occult systemic vasculitis in a patient
immune responses can be triggered in patients with an already diagnosed systemic disease that
with underlying systemic autoimmune vasculitic is apparently in remission. Scleritis is most com-
or infectious diseases after ocular surgical trauma mon in the fourth to sixth decades of life, more
resulting in necrotizing scleritis. These findings often in women, with a peak incidence in the
emphasize the need for meticulous diagnostic fifth decade. Scleritis is also characterized by
pursuit of systemic autoimmune vasculitic or recurrences involving both eyes at the same time
infectious diseases in patients with necrotizing or different eyes at different times. It presents
scleritis following intraocular surgery. with deep severe pain, often radiating to the
forehead, the jaw, and the sinuses. Other symp-
toms include tearing and mild photophobia. The
4.3 Summary main sign is redness that, unlike episcleritis, has
a bluish tinge, best seen under natural light.
Episcleritis is a benign disease that occurs in Clinical examination with a slit lamp discloses
young adults, usually women, with a peak inci- that the inflammation is localized within the
dence in the fourth decade. Although the course episcleral and scleral tissue. Redness does not
is self-limiting, episcleritis is usually character- diminish after instillation of topical phenyleph-
ized by recurrences involving both eyes at the rine (10%) because this vasoconstrictor has
same time or different eyes at different times. It minimal effect on the deep episcleral vessels,
presents as an uncomfortable red eye, sometimes which are congested in scleritis. Scleritis may
with tearing and mild photophobia. Pain, if any, cause decrease in vision, corneal involvement,
is mild and localized to the eye. Clinical exami- uveitis, glaucoma, cataract, exudative retinal
nation with a slit lamp discloses that the inflam- detachment, and macular edema. Two types of
mation is entirely localized within the episcleral sclerits may be distinguished: anterior and
tissue, never involving the underlying sclera. posterior. Anterior scleritis may be further
Redness diminishes greatly after instillation of classified into diffuse, nodular, necrotizing with
topical phenylephrine (10%) since this vasocon- inflammation (necrotizing), and necrotizing
strictor has great effect on the superficial epis- without inflammation (scleromalacia perforans).
cleral vessels, which are congested in episcleritis. Necrotizing scleritis is the most severe and
Episcleritis rarely causes decrease in vision, cor- destructive form because it may lead to the loss
neal involvement, uveitis, or glaucoma. Two of the eye from multiple complications and
types of episcleritis may be distinguished: simple because it is highly associated with potentially
and nodular. In simple episcleritis, in which there lethal systemic vasculitic diseases. Approximately
is a diffuse vascular congestion, the course lasts 36% of the patients have an underlying associ-
between 5 and 10 days without treatment. In nod- ated disease, including 25% with connective tis-
ular episcleritis, in which one or more nodules sue or vasculitic diseases, 10% with infectious
form, the course lasts between 4 and 6 weeks diseases, and 1% with miscellaneous diseases
without treatment. Approximately 27% of (rosacea, foreign body). It is, therefore, extremely
patients have an underlying associated disease, important that the correct diagnosis is made and
including 15% with connective tissue diseases, that subsequent adequate treatment is given as
6% with infectious diseases, 5% with rosacea, early as possible during the course of the
and 1% with atopy. disease.
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Pathology in Scleritis
5
The histopathological aspects of scleral localize specific antigens (herpes simplex virus)
inflammation have been studied extensively in in inflamed tissue.
the past. Although certain inferences can be This chapter has, as its primary focus, a
drawn from these descriptions, terms such as description of the histopathologic, immunopatho-
“chronic nonspecific inflammation,” or even logic, and ultrastructural characteristics of sclera
“chronic granulomatous inflammation,” only affected by inflammation of diverse origins.
camouflaged our ignorance about the possible Although recognizing that a clear understanding
pathogenic roles that cells might play. Even of the etiology and pathogenesis of scleritis is not
sophisticated techniques, such as electron yet available, study of the pathology of scleritis
microscopy provided limited insights into the may contribute to insights into the mechanism of
delineation of the distinctive composition of the inflammation as well as into the search for most
cellular infiltrates as well as into the compo- appropriate forms of treatment.
nents of the matrix during inflammation. It was
not until the relatively recent development of
immunohistochemistry, particularly the exploi- 5.1 General Considerations
tation of monoclonal antibody technology, that of Connective Tissue
the etiology and pathogenesis of scleral diseases Inflammation
have become less obscure. Our ability to charac-
terize cells and determine extracellular matrix Inflammation, defined as the reaction of tissue to
changes during inflammatory reactions contrib- a noxious stimulus, is characterized by increased
utes to the understanding of mechanisms of vascular exudation of fluid, plasma proteins, and
lesion production and thereby to the develop- inflammatory cells. Histologically, connective
ment of treatment options most likely to suc- tissue diseases are characterized by the presence
ceed. Thus, it is possible to distinguish between of chronic inflammation. Chronic inflammation
T and B lymphocytes, to determine mononu- may arise as a result of a persistent inciting stim-
clear subsets (T-helper, T-cytotoxic/suppressor, ulus following acute inflammation or directly, as
natural killer, macrophages, and Langerhans’ a smoldering response. Two main forms of
cells), and to detect HLA-DR glycoproteins in chronic inflammation are recognized: nongranu-
scleral inflammation; it is now possible to iden- lomatous and granulomatous. Chronic granulo-
tify and further characterize different types of matous inflammation surrounds a central area of
components of extracellular matrix (collagen, extracellular matrix degradation known as fibrin-
glycosamynoglycans, and glycoproteins) during oid necrosis; in some instances, vasculitis may
inflammatory reactions; it is also possible to result in further necrosis.
5.1.1 Chronic Nongranulomatous cell. Their function is poorly understood, but the
Inflammation presence of numerous organelles, such as endo-
plasmic reticulum, Golgi apparatus, vesicles, and
The histological hallmarks of chronic nongranu- vacuoles suggests that they are particularly adapted
lomatous or nonspecific inflammation are infil- to secretion of the biologically active products
tration of mononuclear cells, including explained above, rather than phagocytosis, antigen
macrophages, lymphocytes, and plasma cells, processing, and antigen presentation [5, 6]. As the
proliferation of fibroblasts, and sometimes blood epithelioid cells coalesce and fuse, amitotic nuclear
vessels, and degeneration of the tissue affected division may occur, thus forming a multinucleated
by the inflammatory process. Macrophages are giant cell containing a row of nuclei arranged
important components of chronic inflammation along the periphery, the Langhans-type giant cell
because of the great number of biologically active [7]. Multinucleated giant cells have been shown
products they can produce [1, 2]. Some of these in vitro to secrete more collagenase than do cul-
products cause proliferation of fibroblasts and tures of unfused epithelioid cells. Their presence
vessels (interleukin 1 and growth-promoting fac- in tissues may be associated with accelerated rates
tors for fibroblasts and blood vessels), some are of matrix degradation. Giant cells, lymphocytes,
toxic to tissues (acid proteases, collagenase, plasma cells, fibroblasts, neutrophils, mast cells,
elastase, and reactive oxygen intermediates), eosinophils, as well as blood vessel proliferation,
some are chemotactic for other cell types (neu- and destruction of the tissue, can be seen in a gran-
trophils and lymphocytes), and some produce uloma, but the detection of epithelioid cells is the
coagulation and fibrin accumulation (factor V only requirement for the diagnosis of granuloma-
and thromboplastin). Lymphocytes participate in tous inflammation. Macrophages are chemotacti-
both antibody- and cell-mediated hypersensitiv- cally attracted into an area of inflammation in
ity reactions. After contact with antigen, they response to complement components (which may
produce lymphokines that are chemotactic for have been attracted by immune complexes) [2],
monocytes; lymphocytes also cause macrophage and through interleukin 1 production they activate
activation and differentiation (interferon g) [3, 4]. T lymphocytes. T cell activity then potentiates
Macrophages produce monokines that activate granuloma formation [2, 8] because lymphokines,
both T- and B-lymphocytes (interleukin 1). B such as interferon g and possibly interleukin 4,
lymphocytes produce plasma cells that partici- enhance the transformation of macrophages to epi-
pate in antibody formation. Neutrophils are usu- thelioid cells and multinucleated giant cells [9,
ally considered the hallmark of acute inflammation 10]. If macrophages are intensively stimulated,
but they also participate in many forms of chronic they secrete acid proteases (cathepsins), neutral
inflammation as well. Since fibroblasts and neu- proteases (collagenase and elastase), and reactive
trophils may release collagenase and other pro- (free radical) oxygen intermediates, thereby par-
teases, they play prominent roles in tissue ticipating in the production of a central area of
damage. Mast cells and eosinophils may also be extracellular matrix degeneration known as fibrin-
present but their precise functions in chronic oid necrosis.
inflammation are not well understood.
stages of degradation, granular debris, and cell delayed hypersensitivity response, results in
membranes. Accumulation of fibrin is probably granuloma formation.
the result of coagulation factors (factor V and Endothelial cells activated by chronic inflam-
thromboplastin) [2] released by macrophages as mation migrate through the openings of degraded
well as of impairment of the normal mechanism basement membranes and generate new capillary
for debris removal. The necrosis is probably the blood vessels through the complex proliferative
result of the enormous quantities of proteases process of angiogenesis [20]. Vascular inflamma-
produced by macrophages (including modified tion involves vessels usually present in the tissue
macrophages, such as epithelioid cells and multi- and new formed vessels produced as a result of
nucleated giant cells) and fibroblasts. Intracellular the inflammation.
digestion by lysosomal acid hydrolases, and
extracellular digestion by neutral proteases, is the
main mechanism of proteoglycan, collagen, and 5.2 Specific Considerations
glycoprotein degradation. Microinfarctions of Scleral Tissue Inflammation
resulting from thrombosis of terminal vessels
may also play a role, through ischemia, in the tis- The sclera, the dense connective tissue that cov-
sue destruction. ers about five-sixths of the eye, consists of fibro-
blasts, collagen, proteoglycans, glycoproteins,
and few blood vessels. These components are
5.1.4 Vascular Inflammation functionally and metabolically interdependent in
maintaining tissue homeostasis. In scleral inflam-
Connective tissue vessels may show an inflam- mation, normal sclera homeostasis breaks down,
matory infiltration that leads to endothelial dam- resulting in loss of scleral integrity. The destruc-
age and subsequent reparative proliferation tive events in the sclera are consequent to a com-
responses of the vascular endothelium. Circulating plex interaction of many cell types and their
immune complexes (CICs) may precipitate in a soluble products.
vessel wall and activate the complement system, Episcleral and scleral vasculature has not been
which is chemotactic for neutrophils and mac- extensively studied and clearly deserves more
rophages. Endothelial cell damage exposes the careful morphologic characterization. Unlike
subendothelium or basement membrane, which elastic arteries (large-sized vessels), muscular
is composed of collagen, proteoglycans, and gly- arteries (medium-sized vessels), and arterioles
coproteins; these components can be degraded by (small-sized vessels), these vessels in the epis-
proteolytic enzymes secreted by neutrophils, clera and sclera appear to be capillaries and post-
macrophages, and activated endothelial cells. capillary venules, which do not possess a tunica
Activated endothelial cells also enhance aggrega- media that consists chiefly of smooth muscle
tion of platelets (platelet-activating factor) [13], cells. Episcleral and perforating scleral vessels
fibrinogen accumulation (tissue factor and factor appear to possess a simple wall composed of con-
V) [14, 15], polymerization of fibrin, and fibrin tinuous endothelial cells and pericytes, without
deposition, which in turn promote thrombus for- smooth muscle cells (see Figs. 1.23–1.25).
mation and infarction of the tissues supplied by Classic vasculitis is a clinicopathological pro-
the vessel. Because activated endothelial cells cess characterized by inflammation and necrosis
also express HLA-DR glycoproteins, they par- of blood vessels; the classically described histo-
ticipate in the immune response through their pathological hallmarks as defined in vessels con-
interaction with T lymphocytes [16–19]. taining a tunica media include neutrophilic
Macrophages activate fibroblasts and together infiltration of the vessel wall and fibrinoid degen-
participate in extracellular matrix degradation eration leading to necrosis of the tunica media
through enzyme release. Further stimulation of (Figs. 5.1 and 5.2). Vasculitic syndromes com-
macrophages, probably through a T-cell-related prise a broad spectrum of disorders involving
140 5 Pathology in Scleritis
Table 5.3 Mononuclear cell subset antibody panel in and B lymphocytes (CD22) were present in
immunoperoxidase studies scleritis but their numbers were not significantly
Antibody Specificity increased when compared with normal tissue.
Anti-CD3 T lymphocytes HLA-DR glycoproteins (anti-HLA-DR), present
Anti-CD8 T suppressor/cytotoxic lymphocytes constitutively in macrophages, and after inflam-
Anti-CD4 T helper/inducer lymphocytes matory stimuli in scleral fibroblasts and endothe-
Anti-CD16 Neutrophils lial cells, were markedly increased. These
Anti-CD22 B lymphocytes
findings show the participation of macrophages
Anti-CD14 Macrophages
and T lymphocytes, particularly T helper lym-
Anti-HLA-DR HLA-DR (class II histocompatibility
antigen) phocytes, in scleritis, and support the idea that
Anti-CD1 Langerhans’ cells macrophages and fibroblasts activate T lympho-
cytes, which in turn may participate in granuloma
formation. Damaged endothelial cells also may
Table 5.4 Cell subsets in scleritisa play a role as antigen-presenting cells. The T
Scleral specimen helper/T suppressor imbalance may contribute to
Cell subset Normal (n = 4) Scleritis (n = 9) the perpetuation of the highly inflammatory
Macrophages (CD14) 0.00 ± 0.00b 43.50 ± 10.91b nature of the lesion. In addition to the predomi-
T lymphocytes (CD3) 0.17 ± 0.10 b
145.70 ± 59.46b nant macrophages and T helper lymphocytes,
b
T helper/inducer 0.10 ± 0.10 192.37 ± 41.24b neutrophils, B lymphocytes, and Langerhans
lymphocytes (CD4) cells may be present.
T cytotoxic/suppressor 0.19 ± 0.13b 89.96 ± 38.15b
lymphocytes (CD8)
Neutrophils (CD16) 0.00 ± 0.00 44.56 ± 34.86
Extracellular Matrix
B lymphocytes (CD22) 0.20 ± 0.12 58.56 ± 39.59 Collagen degradation may take place by two
HLA-DR glycoproteins 1.46 ± 0.22b 210.00 ± 59.46b mechanisms, one (intracellular) involving acid
(HLA-DR) proteases of macrophages, and the other (extra-
Langerhans’ cells 0.00 ± 0.00 6.96 ± 5.47 cellular) involving neutral proteases (collagenase
(CD1) and elastase) of fibroblasts and macrophages [34].
T helper/T suppressor 1.09 ± 0.06b 8.20 ± 4.47b
In intracellular digestion of collagen, the col-
ratio
a
lagen fibrils undergo phagocytosis into phago-
Mean cell count/mm,2 ± standard error of the mean
b
Significant values, using Student’s t test (P < 0.05) lysosomes (acid pH) of macrophages, where
lysosomal acid proteases lead to tissue break-
down. In extracellular digestion, the collagen
glycoproteins (anti-HLA-DR) (Becton Dickinson, fibrils appear swollen and unraveled in areas of
Inc., Mountain View, CA), and Langerhans’ cells scleral stroma (neutral pH) as a result of the
(CD1) (Ortho Pharmaceuticals Corp., Raritan, release of neutral proteases by fibroblasts and
NJ) (Table 5.3). Details of tissue processing and macrophages into the connective tissue matrix.
staining have been previously published [28]. A Both intracellular and extracellular mechanisms
comparison between nine scleral specimens from of collagen degradation may occur simultane-
patients with necrotizing scleritis and four scleral ously, distant from the granuloma, suggesting
specimens from normal eyes (New England Eye that collagen degradation may precede granu-
Bank, Boston, MA), revealed a predominance of loma formation in scleral inflammation [35].
macrophages (CD14) and T lymphocytes (CD3) Degradation of collagen may be almost total
in scleral tissue (Table 5.4). Although both T in the center of the granuloma. Fibril fragments
helper/inducer lymphocytes (CD4) and T sup- may be found in close apposition to the fibroblast
pressor/cytotoxic (CD8) lymphocytes were plasma membrane or enclosed in invaginations
increased, a high T helper/T suppressor ratio of the fibroblast plasma membrane or vacuole
revealed a predominance of the former. membranes within the cytoplasm (intracellular
Neutrophils (CD16), Langerhans cells (CD1), mechanism). Derangements of collagen fibril
5.2 Specific Considerations of Scleral Tissue Inflammation 145
structure, such as fibril swelling and unraveling, proteoglycans heparan sulfate, dermatan sulfate,
irregular contour, and increased interfibrillar dis- hyaluronic acid, and chondroitin sulfate, collagen
tance, may also be seen without close apposition types I, II, III, IV, V, VI, VII, IX, XII, XIII, XIV,
to active fibroblasts (extracellular mechanism) XVII, and the glycoproteins fibronectin, vitronec-
[35]. In areas distal to the inflammatory focus, tin, and laminin (Table 5.5).
collagen appears normal by light microscopy; 1. Proteoglycans. The most abundant proteogly-
however, intracellular or extracellular resorptive cans in normal sclera were dermatan sulfate
changes in the absence of inflammatory cells can and chondroitin sulfate; hyaluronic acid and
be seen by electron microscopy [35, 36]. heparan sulfate also were present, although in
Electron microscopy studies with cuprolinic small amounts. Dermatan sulfate in necrotiz-
blue staining show that proteoglycans are reduced ing scleritis was frankly decreased when com-
or absent in areas of active scleral inflammation pared to normal sclera. A negative background
before the collagen fibrils undergo resorptive with scattered areas of mild patchy positivity
changes; these results suggest that proteoglycan in diseased sclera contrasted with an intense
degradation precedes collagen degradation [37]. striped pattern in normal sclera. (Figs. 5.8
Our own studies on immunolocalization of extra- and 5.9). Chondroitin sulfate in necrotizing
cellular matrix components in two diseased scleritis also showed a marked reduction in
scleral specimens as compared with five normal amount of staining, unlike normal sclera,
scleral specimens show similar findings. An indi- which showed a generalized speckled pattern
rect immunofluorescence technique was per- of intense positivity (Figs. 5.10 and 5.11).
formed in anterior, equatorial, and posterior Because the presence of heparan sulfate and
areas, using monoclonal antibodies against the hyaluronic acid was detected in small amounts
146 5 Pathology in Scleritis
Fig. 5.8 Immunofluorescence microscopy: specimen is Fig. 5.10 Immunofluorescence microscopy: scleral
from a patient with scleritis. The antibody is antidermatan biopsy from a patient with scleritis. Note (particularly in
sulfate antibody. Note (in comparison to Fig. 5.9) the dra- relationship to Fig. 5.11) the relative lack of bright stain-
matic reduction in the presence of dermatan sulfate in the ing, except around the vessels, indicating a relative pau-
scleritis specimen city of chondroitin sulfate in this scleral specimen
(Magnification, ×40)
Fig. 5.9 Immunofluorescence microscopy: biopsy of Fig. 5.11 Immunofluroescence microscopy: normal
normal sclera. Antibody is antidermatan sulfate antibody. sclera. Antibody is anti-chondroitin sulfate antibody. Note
Note the large amount of bright apple-green fluorescence, the relative abundance of bright apple-green fibrils, indi-
indicating rather large amounts of dermatan sulfate in nor- cating a relatively large amount of chondroitin sulfate in
mal sclera (Magnification, ×100) normal sclera (Magnification, ×40)
in normal sclera, comparison of these proteo- intensity or pattern. Collagen types I and III
glycans between normal and diseased sclera showed intense homogeneous fibrillar staining;
did not show obvious differences. these two collagen types impart tensile
2. Collagens. The most abundant types of colla- strength (type I) and resilience (type III) to the
gen in normal extravascular sclera were col- scleral “skeleton” [38]. Collagen type V
lagens type I and III collagens; type V and showed mild, delicate, patchy, granular stain-
type VI also were present. Type II, VII, IX, ing, particularly associated with the edges of
XII, XIII, XIV, and XVII were not identified. the collagen bundles; this pattern leads us to
Collagen type IV also was absent except for suspect that collagen V forms a fine network
its dramatic presence in the vessels. that maintains the structural integrity of the
Comparison of staining of collagen types I, main fibril core (types I and III). Collagen
III, V, and VI between normal and necrotizing type VI showed an intense, fine, regional,
scleritis specimens did not show differences in granular staining; this pattern also leads us to
5.2 Specific Considerations of Scleral Tissue Inflammation 147
suggest that collagen type VI has a role similar Table 5.6 Antibody panel used in immunofluorescence
to that of type V in maintaining the structural studies of scleral specimens
integrity of the collagenous core. The fact that Antibody Working dilution
there were no differences in intensity or pat- Anti-Ig G (fluorescein conjugated) 1:30
tern of the collagen stainings between normal Anti-Ig A (fluorescein conjugated) 1:16
and necrotizing scleritis suggests that proteo- Anti-Ig M (rhodamine conjugated) 1:8
glycans are the first extracellular matrix com- Anti-Ig D (fluorescein conjugated) 1:8
Anti-Ig E (fluorescein conjugated) 1:8
ponents to be degraded in necrotizing scleritis.
Anti-C3 (rhodamine conjugated) 1:4
Proteoglycan degradation may enhance intra-
Anti-C4 (fluorescein conjugated) 1:4
cellular and extracellular mechanisms of
Anti-albumin (fluorescein 1:30
collagen fibril depletion. conjugated)
3. Glycoproteins. Fibronectin and vitronectin Anti-collagen IVa 1:100
showed subtle, granular, patchy positivity in a
Indirect immunofluorescence technique
normal and inflamed sclera. Laminin was absent
in extravascular sclera, normal or inflamed, but
was dramatically represented in vessel walls.
Vessels
The area of active scleral inflammation shows
old and new vessels, many of which display neu-
trophil and lymphocyte infiltration within and
around the vessels, with occasional thrombosis
[28, 30, 39, 40].
Our own studies on scleral vasculature in 26
scleral specimens from patients with noninfec-
tious necrotizing scleritis were accomplished by
use of histopathological and direct immunofluo-
Fig. 5.12 Inflammatory microangiopathy. Note the neu-
rescence techniques. Specimens examined by the trophil infiltration in and around the wall of the conjunctival
direct immunofluorescence technique were vessel
incubated with fluorescein- and rhodamine-
conjugated goat antibodies directed against
human immunoglobulins IgG, IgA, IgM, IgD,
and IgE, complement components C3 and C4, and
albumin [28] (as a negative control for vascular
positivity) (Organon Teknika-Cappel Scientific,
West Chester, PA) (Table 5.6). Goat anti-human
collagen IV (Biodesign International, Kenne-
bunkport, ME) was used as a positive control for
vessels. Fluorescence microscopy was performed
on a Zeiss (Thornwood, NY) Photomic III fluo-
rescence microscope. All scleral specimens but
one (96%) showed an inflammatory microan-
giopathy characterized by neutrophilic infiltra-
tion in and around the vessel wall, as visualized Fig. 5.13 Inflammatory microangiopathy, as visualized
by histopathological technique (Fig. 5.12), or by immunofluorescence microscopy. The antibody used
in this specimen is anti-IgG antibody, and the photomicro-
immunoreactant deposition on the vessel wall, as graph shows the presence of IgG in the vessel walls, with
visualized by the immunofluorescence technique the bright fluorescence in the area of the basement mem-
(Fig. 5.13). Inflammatory microangiopathy as brane of the vessel wall (Magnification, ×64)
148 5 Pathology in Scleritis
Fig. 5.16 Conjunctival biopsy, again demonstrating Fig. 5.17 Enucleation specimen from a patient who had
microangiopathy with inflammatory cells in the vessel posterior scleritis. Note the inflammatory cell infiltrate in
wall and surrounding dense inflammatory infiltration of the sclera, but also the granulomatous inflammation of the
the substantia propria choroid
Table 5.7 Vasculitic syndromes associated with scleritis vasculitis of small- and medium-sized muscular
Noninfectious diseases arteries, with a predilection for branching points
Primarily small- and medium-sized vessel vasculitic and bifurcations. PAN may affect any small- or
diseases medium-sized artery of any organ, although there
Primarily vasculitic (and/or granulomatous) diseases is less involvement of the pulmonary and splenic
Polyarteritis nodosa
Allergic granulomatous angiitis (Churg–Strauss
arteries [48, 50, 51]. Small- and medium-sized
syndrome) muscular arterial inflammation may extend to
Granulomatosis with polyangiitis (Wegener) arterioles and, sometimes, to contiguous venules
Behçet’s disease and veins. Skin, joints, peripheral nerves, gut,
Cogan’s syndrome
Schönlein–Henoch purpura and kidney are the tissues most commonly
Connective tissue diseases in which vasculitis may involved [52]. Episcleritis or scleritis may be
occur manifestations of ocular involvement [52, 53];
Adult rheumatoid arthritis the latter may range from mild diffuse scleritis to
Systemic lupus erythematosus severe necrotizing scleritis.
Relapsing polychondritis
Juvenile rheumatoid arthritis Histopathologically, systemic vascular lesions
Sjögren’s syndrome of affected organs are characterized by fibrinoid
Dermatomyositis necrosis and neutrophil infiltration, which may
Inflammatory conditions in which vasculitis may occur extend to involve the full thickness of the arterial
Arthritis and inflammatory bowel disease wall; less often, eosinophils and lymphocytes are
Psoriatic arthritis
present in and around the vessels. The arterial seg-
Primarily large-sized vessel vasculitic diseases
Inflammatory conditions in which vasculitis may occur ment often thromboses or bulges in an aneurysmal
Ankylosing spondylitis fashion. As the lesions heal, there is proliferation of
Reactive arthritis fibrous tissue and endothelial cells of the affected
Primarily vasculitic diseases arterial wall, which may lead to further occlusion
Giant cell arteritis
Takayasu’s arteritis of the vessel lumen. In any patient different arter-
Infectious diseases ies, or even separate branches of the same artery,
may be seen in acute, chronic, or healed stages of
arteritis [54]. Eosinophil tissue infiltration and
Clinicopathologic Correlates in Noninfectious granulomas are not characteristically found [48].
Scleritis: Association with Systemic The pathology of scleral involvement demon-
Vasculitic Diseases strates an inflammatory microangiopathy of
The clinical spectrum of systemic vasculitis- scleral vasculature that may lead to occlusion of
associated scleritis encompasses diseases thought some vessels. Choroidal vessels may also be
to be primary vasculitic syndromes (PAN), dis- involved [53, 55]. Unlike lesions elsewhere in
eases that are predominantly granulomatous the body, ocular involvement in PAN may show
(granulomatosis with polyangiitis [Wegener]), granulomatous changes in and around episcleral
and diseases associated with underlying condi- and choroidal vessels [9, 55–59].
tions, such as the acquired connective tissue In our past series [60], polyarteritis nodosa
disorders (rheumatoid arthritis) or other inflam- was diagnosed in two patients with scleritis, one
matory conditions [48, 49]. A classification of with diffuse scleritis and the other with necrotiz-
vasculitic syndromes that can be associated with ing scleritis; diagnosis confirmation was obtained
scleritis is shown in Table 5.7. In the following after muscle and cutaneous nodule biopsy respec-
sections, we review the pathology of some of tively. One of the cases is described as follows:
these conditions. A 56-year-old white woman developed inter-
mittent fever, chills, weight loss, fatigue, and low
Polyarteritis Nodosa back pain. Discharge diagnoses after hospitaliza-
The pathology of systemic PAN consists of tion at a community hospital were urinary tract
nongranulomatous focal panmural necrotizing infection and lumbar disk disease. Shortly
5.2 Specific Considerations of Scleral Tissue Inflammation 151
Fig. 5.18 Fifty-six-year-old woman with necrotizing Fig. 5.19 Subcutaneous nodule below the left elbow
scleritis and peripheral ulcerative keratitis. Note the (same patient as in Fig. 5.18)
intense scleritis and area of necrotizing scleritis, with a
loss of approximately 85% of scleral thickness
granulomas was termed “allergic angiitis and Granulomatosis with Polyangiitis (Wegener)
granulomatosis” by Churg and Strauss in 1951 Complete (classic) granulomatosis with poly-
[63]. The pathology of this disease consists of angiitis (Wegener) is characterized by necrotiz-
small, necrotizing granulomas and necrotizing ing granulomatous lesions of the upper and lower
vasculitis involving predominantly small arter- respiratory tract (nose, sinuses, and lung), gener-
ies, arterioles, venules, and veins rather than alized small-vessel vasculitis in the lung and
small- and medium-sized muscular arteries. other organs, and focal or diffuse necrotizing
Granulomas are composed of a central eosino- glomerulonephritis [71–76]. Less extensive or
philic core surrounded radially by macrophages limited forms of this condition also exist, in
and giant cells. Inflammatory cells, predomi- which case renal involvement is absent [77]. In
nantly eosinophils, are present; neutrophils and highly limited forms of granulomatosis with
lymphocytes also may be found in smaller num- polyangiitis (Wegener), ocular or orbital involve-
bers. Chronic lesions are characterized by mac- ment is present in the absence of systemic mani-
rophages and giant cells and lesser numbers of festations [78].
eosinophils. Necrotizing vasculitis is character- In the complete form of granulomatosis with
ized by segmental fibrinoid necrosis and leuko- polyangiitis (Wegener), ophthalmic involvement
cytic (predominantly eosinophil) infiltration, in may be present in up to 58% of the cases [53,
and around the vessels; variable numbers of 79–82]. In the limited form of granulomatosis
macrophages and giant cells also may be present with polyangiitis (Wegener), ocular manifesta-
around the necrotic areas. There may be throm- tions, including scleritis, may constitute the major
bosis or aneurysmal dilatation at the site of the signs and symptoms, or indeed may be the only
lesion. Healed areas show proliferation of manifestation of the disease [81–89]. In the
fibrous tissue and endothelial cells, which may highly limited form of granulomatosis with poly-
lead to further narrowing of the vessel lumen angiitis (Wegener), ocular or orbital involvement,
[64–66]. including scleritis, is the only objective finding of
Allergic granulomatous angiitis (Churg– the condition [78].
Strauss syndrome) may affect any organ in the Because granulomatosis with polyangiitis
body; however, unlike classic PAN, lung involve- (Wegener) is predominantly a granulomatous
ment is predominant, with gastrointestinal tract, disease rather than a form of primary vasculitis [90],
skin, heart, kidney, and peripheral nerves also necrotizing granulomas on involved organs are
commonly involved [67, 68]. Scleritis may also invariably present. Purely granulomatous disease
occur [69]. Scleral tissue from patients with the without vasculitis may represent an early mani-
Churg–Strauss syndrome and scleritis shows festation of granulomatosis with polyangiitis
numerous eosinophils, granulomatous prolifera- (Wegener) [91]. Granulomas contain a central
tion of epithelioid and giant cells, and vascular area of necrosis surrounded by a zone of fibro-
closure by inflammatory microangiopathy [69]. blastic proliferation with multinucleated giant
Demonstration of necrotizing small vasculitis cells, epithelioid cells, neutrophils, lymphocytes,
and eosinophilic necrotizing intra- and extravas- and plasma cells [74]. Eosinophils are often
cular granulomas on biopsy material of involved present [78]. Vasculitis is frequently found. The
extraocular tissues confirms the diagnosis of vascular changes are similar to those of PAN;
Churg–Strauss syndrome in a patient with com- acute lesions show fibrinoid necrosis with neu-
patible multisystem clinical findings and laboratory trophil and mononuclear cell infiltration within
tests [62–66, 69, 70]. Involved tissues more com- and often adjacent to the vessel wall, which may
monly biopsied for diagnosis are lung, skin, and lead to lumen narrowing and subsequent oblit-
peripheral nerves. Demonstration of eosinophilic eration; healed lesions show fibroblastic and
granulomas and inflammatory microangiopathy endothelial proliferation, which may contribute
in conjunctiva and/or scleral specimens further to further vessel narrowing. Whereas both types
strenghtens the diagnosis. of lesions are seen in some areas, only one type
5.2 Specific Considerations of Scleral Tissue Inflammation 153
of lesion is present in others [75]. Pathologically, without compatible clinical and histopathological
lesions of granulomatosis with polyangiitis findings. The sensitivity of ANCA testing is
(Wegener) differ from extraocular lesions of dependent on disease severity; whereas ANCA
PAN in that the former are characterized by testing is positive in 95% of patients with active
granulomas that may be in, around, or clearly complete (classic) granulomatosis with poly-
separated from the vessel walls. Pathosis in angiitis (Wegener), it is positive only in 67% of
granulomatosis with polyangiitis (Wegener) dif- patients with active limited disease and in 32% of
fers often from that of Churg–Strauss syndrome patients in full remission after limited disease
in that in the former, the disintegrating cells in [95]. Therefore, a negative ANCA test does not
the center of the granuloma are neutrophils, usu- exclude the diagnosis, especially in patients with
ally not eosinophils [92]. However, although limited clinical features and characteristic histo-
pathological findings are helpful in differentiat- logical findings.
ing different entities, a specific diagnosis can be Pathologic detection of necrotizing granulo-
confirmed only with the association of character- mas with or without vasculitis in involved
istic clinical findings [78]. extraocular tissues confirms the diagnosis of
Pathology of scleral lesions may demonstrate granulomatosis with polyangiitis (Wegener) in a
lesions similar to those found in other organs [9, patient with compatible systemic clinical find-
10, 44, 78, 84, 88, 93]. The constellation of histo- ings, such as chronic sinusitis, nasal ulceration,
pathological features on conjunctival and scleral chronic cough, or hematuria, with or without
tissues include (1) collagen necrosis, (2) nuclear positive ANCA testing [96, 97]. Pathologic detec-
dust, (3) granulomatous foci with multinucleated tion of necrotizing granulomas with or without
giant cells surrounded by epithelioid cells, neu- inflammatory microangiopathy in conjunctiva
trophils, lymphocytes, and plasma cells, and fre- and/or scleral specimens in association with com-
quently (4) inflammatory microangiopathy. plete and, especially, limited clinical features,
The diagnosis of granulomatosis with poly- confirms the diagnosis of granulomatosis with
angiitis (Wegener) is based on the interpretation polyangiitis (Wegener), even if ANCA testing is
of clinical features and histological findings. negative.
Anti-neutrophil cytoplasmic antibody (ANCA) Biopsy of involved nasal mucosal, sinus tis-
testing is an important adjunct in the diagnosis of sue, skin, or sclera offers the best opportunity for
granulomatosis with polyangiitis (Wegener) [94]. obtaining a histological diagnosis [74, 84, 92, 96,
ANCAs are antibodies directed against cytoplas- 97]. Involved lung tissue, preferably through
mic azurophilic granules of neutrophils and open biopsy, also may be obtained. Because renal
monocytes and may be divided into two classes involvement ranges from diffuse proliferative
based on the pattern of staining seen on immuno- glomerulonephritis and interstitial nephritis to
fluorescence. The cytoplasmic pattern, or hyalinization of glomeruli, results of renal biopsy
c-ANCA (antigen specificity for proteinase-3 are rarely distinctive enough from other condi-
[PR3]) is both sensitive and specific for granulo- tions to be definitive [49].
matosis with polyangiitis (Wegener). The peri- Pathologic detection of necrotizing granulo-
nuclear ANCA, or p-ANCA (antigen specificity mas with or without inflammatory microangiopa-
for myeloperoxidase [MPO]), is associated with thy in sclera confirms the diagnosis of the highly
PAN, microscopic polyangiitis, relapsing poly- limited form of granulomatosis with polyangiitis
chondritis, and renal vasculitis. Between 85 and (Wegener) in a patient with scleritis and positive
95% of all ANCA found in granulomatosis with ANCA testing [78]. In the absence of characteristic
polyangiitis (Wegener) is c-ANCA while 5–5% ocular histological findings, a positive ANCA test
is p-ANCA. Because of its high specificity, a is suggestive of highly limited granulomatosis with
positive ANCA test is suggestive of granulomatosis polyangiitis (Wegener), although not diagnostic.
with polyangiitis (Wegener), even in patients In the absence of a positive ANCA test, the
154 5 Pathology in Scleritis
Table 5.8 Scleral and conjunctival biopsies in patients with Wegener’s granulomatosis
Duration prior Biopsy
Patient no./ to diagnosis Systemic Abnormal
age/sex Severitya (months)b clinical findingsc X-rays Conjunctiva Sclera ANCA
1/41/M L 7 Epistaxis, skin lesions joint Sinus NSd G + Vd +
swelling, fever microscopic
hematuria
2/78/F HL 4 – – NS G +
3/65/F L 5 Epistaxis, tongue blisters, Sinus NS G+V +
microscopic hematuria,
Sinusitis
4/56/M HL 2 – – G G +
5/45/M L 25 Sinusitis abnormal LFT’sd, Sinus NA G +
arthralgias
6/66/M C 0 Epistaxis, hemoptysis, Chest/sinus G+V G+V NA
red blood cell casts,
hematuria
7/69/F L 24 Sinusitis, cough, hematuria Chest/sinus V G+V NA
8/45/M L 5 Skin ulcer NA NA G+V NA
9/69/M L 9 Epistaxis, microscopic Sinus G+V NA NA
hematuria
10/78/M L 24 Cough, arthralgias sinusitis Sinus G+V NA NA
microscopic hematuria
11/68/F L 5 Microscopic hematuria NA V G+V NA
12/81/M L 2 Polymialgia rheumatica NA NA G+V +
13/68/M L 36 Cough, arthralgias Chest G+V G+V NA
a
C complete, L limited, HL highly limited
b
Duration of scleritis prior to diagnosis (in cases in which scleritis was the first manifestation of the disease)
c
At the moment of diagnosis
d
LFTs liver function tests, NS nonspecific, NA not available, G granulomatous foci, V vasculitis (either by histopathol-
ogy or by immunofluorescence)
negative, <20). The patient was diagnosed with ficity for RA than does RF, and, therefore,
granulomatosis with polyangiitis (Wegener) and some have advocated its use to evaluate RA
treatment with cyclophosphamide was instituted. patients instead of RF. This is particularly the
Ocular and systemic manifestations were brought case in individuals with early RA, in whom
under control and the patient is alive and well assessment of anti-CCP may be the most use-
5 years after the initiation of cyclophosphamide ful to confirm the diagnosis and establish a
therapy. likely prognosis. The presence of anti-CCP is
most common in patients with aggressive dis-
Connective Tissue Diseases ease, with a tendency for developing bone
Scleritis may be an ocular manifestation of sev- erosions. The development of anti-CCP is
eral connective tissue diseases. Conjunctival and/ most frequent in individuals with an
or scleral histopathological findings range from RA-associated HLA-b1 allele and in those
nonspecific inflammation with neutrophils, lym- who smoke cigarettes, and may occur before
phocytes, and plasma cells to granulomatous the development of clinical manifestations of
reaction with a central area of necrosis rimmed RA. However, as with RF, the presence of
by a corona of epithelioid cells, in turn sur- anti-CCP is not useful to predict the future
rounded by giant cells, lymphocytes, and plasma development of RA because it can be found in
cells. An inflammatory microangiopathy also 1.5% of normal individuals, most of whom
may be found. Pathological detection of vascular will not develop RA, and occasionally in
inflammation in involved tissues, including con- patients with other rheumatic diseases.
junctiva and/or sclera, in connective tissue dis- However, it is a useful test to confirm a diag-
eases should be regarded as an ominous sign, nosis of RA and to estimate prognosis.
because it may indicate a more severe and wide- An example of proliferative granuloma in RA
spread destructive process that markedly worsens is the rheumatoid nodule, which is characterized
life prognosis. The two connective tissue diseases by a central area of necrosis rimmed by palisad-
in which vasculitis occurs most frequently are ing fibroblasts that are surrounded by chronic
rheumatoid arthritis and systemic lupus erythe- inflammatory cells with occasional distinct giant
matosus [48, 49]. cells. Although chronic changes are predomi-
1. Rheumatoid arthritis. Rheumatoid arthritis nantly granulomatous, small-vessel vasculitis
(RA) is a chronic, inflammatory disease char- occurs early in the development of the rheuma-
acterized by a polyarthropathy that ranges toid nodule [99]. Immunofluorescent staining of
from mild joint discomfort to severe, symmet- nodules shows small vessel walls containing
ric articular involvement. Although the diag- immunoglobulins [100]. Vessel endothelium,
nosis of RA is based on the basis of clinical histiocytes, fibroblasts, lymphocytes, and plasma
criteria, approximately 70% of patients are cells proliferate. Fibroblasts may release collage-
positive for RF, as opposed to 1–5% of the nase and proteoglycanase, resulting in a central
general population [98]. Patients with a posi- necrosis [101]. A similar histology can be found
tive RF have a higher incidence of extraarticu- in the sclera: a focus of scleral necrosis sur-
lar manifestations than do patients without a rounded by a wall of epithelioid cells, neutro-
positive RF. Extraarticular manifestations phils, lymphocytes, plasma cells, and occasional
may be related to proliferative granulomas or giant cells [102].
to vasculitis. Antibodies to cyclic citrullinated A superimposed systemic vasculitis may com-
peptide (anti-CCP) can also be used to evalu- plicate RA. The spectrum of rheumatoid vasculi-
ate patients with RA. Although these antibod- tis ranges from a hypersensitivity vasculitis
ies are most commonly found in RF-positive affecting small vessels to a severe, systemic
patients, on occasion they can be detected in necrotizing vasculitis syndrome similar to that
the absence of RF. In addition, the anti-CCP seen in classic polyarteritis nodosa [103]. It is
test has a similar sensitivity and a better speci- thought that the lesions are related to deposition
5.2 Specific Considerations of Scleral Tissue Inflammation 157
of circulating antigen–antibody–complement
complexes, because there are depressed serum
complement levels [104, 105], immunofluores-
cent staining of IgG, IgM, and C3 in the vessel
wall [106], and large amounts of serum cryoim-
munoglobulins [107]. Clinical vasculitis may
manifest as cutaneous ulceration, peripheral neu-
ropathy, pericarditis, or arteritis of the viscera
(heart, lungs, bowel, kidney, liver, spleen, pan-
creas, lymph nodes, and testis). Patients with Fig. 5.24 Periungual nailfold infarct in a patient with
rheumatoid arthritis complicated by systemic rheumatoid arthritis-associated vasculitis
vasculitis are more likely to have severe erosive
joint disease and rheumatoid subcutaneous nod- high (mean titer, 1:3,157; normal, <60), as were
ules than are patients with rheumatoid arthritis circulating immune complexes (mean titer by Raji
without vasculitis [108, 109]. Vasculitis may cell assay, 250; normal, 0–50). All ten patients
occur in rheumatoid arthritis patients who have required systemic immunosuppressive therapy to
had their disease for more than 10 years. Males halt the progression of scleral destruction; four of
are afflicted as commonly as females. Patients these also underwent scleral grafting to maintain
with rheumatoid arthritis-associated vasculitis the integrity of the globe because of the advanced
usually have higher titers of rheumatoid factor, extent of scleral necrosis [33]. Jayson and Jones
higher titers of circulating immune complexes, [121] found systemic vasculitis in 10 of 14 patients
and lower titers of complement than do patients with rheumatoid arthritis and necrotizing scleritis;
with rheumatoid arthritis without vasculitis [108– 6 of those patients died of vasculitic complications
118]. Patients with rheumatoid arthritis and wide- during the follow-up period. Foster et al. [122]
spread vasculitis have an alarmingly high reported that 7 of 20 patients with rheumatoid
mortality rate; frequent causes of death are related arthritis and necrotizing scleritis died of vascular-
to mesenteric, coronary, and cerebral artery related events within 8 years of the onset of the
inflammation [119, 120]. Ferguson and Slocumb scleritis; aggressive treatment with systemic
[114] reported that 8 of 19 (42%) rheumatoid immunosuppressive therapy may favorably alter
arthritis patients with vascular involvement, the ocular and the general outcome. These data
manifested by sensorimotor neuropathy in three suggest that inflammatory microangiopathy in
of four extremities, died of vasculitic events. scleral tissue in patients with connective tissue
Pathological detection of inflammatory diseases and scleritis indicates a more destructive
microangiopathy in conjunctiva and/or sclera in phase in the patient’s clinical systemic course,
patients with connective tissue diseases and necro- worsening not only the ocular prognosis, but also
tizing scleritis may also indicate a manifestation of the general prognosis as well. Early detection of
widespread vasculitis. In our past series [60], the these clinicopathological changes may lead to
ten patients (six females and four males) with RA, early aggressive treatment of both the ocular and
necrotizing scleritis, and inflammatory microan- the general conditions. One of our cases is
giopathy in scleral tissue had had the rheumatoid described as follows:
arthritis for more than 10 years. They had severe, A 55-year-old white woman with a 38-year
often incapacitating, articular lesions, and had history of rheumatoid arthritis developed pain
extraarticular manifestations, such as rheumatoid and redness in both eyes 7 months prior her
nodules, nailfold infarcts (Fig. 5.24), extremity first examination by us. She was diagnosed with
purpuric lesions, peripheral neuropathies, nerve bilateral nodular scleritis and treated with local
entrapment syndromes, cardiac conduction and systemic steroidal and nonsteroidal anti-
defects, cardiac valvulopathies, pneumonias, or inflammatory drugs. As the steroids were tapered,
pleural diseases. Rheumatoid factor titers were symptoms reappeared and she was sent to our
158 5 Pathology in Scleritis
Fig. 5.27 Forty-nine-year-old man with scleritis and Fig. 5.28 Same patient as in Fig. 5.27: different area and
associated keratitis. Note the feathery central advancing view. Note the intense scleritis
edge of the keratitis (arrow)
demonstration of HSV protein can make a from periphery to the center, and without
definitive diagnosis. Prolonged administration anterior chamber reaction (Fig. 5.27). Epis-
of acyclovir is required for effective therapy cleral and scleral diffuse edema and redness
[156]. We use indirect immunofluorescence were observed adjacent to the corneal stromal
techniques on ocular tissues, including conjunc- infiltration (Fig. 5.28). Infectious keratoscleri-
tiva and sclera, to identify viral antigen in cells tis was diagnosed and possible etiological
infected with HSV. The primary antibody used agents considered included fungus, virus
is mouse monoclonal antibody directed against (HSV type 1), spirochetes (T. pallidum),
HSV type 1 (1:20; Chemicon International). Acanthamoeba, and bacteria. Although
One of our cases is described as follows: unlikely, an autoimmune process was not dis-
A 49-year-old white male with a history of counted. A corneo-conjunctiva-scleral biopsy
right maxilla osteosarcoma underwent facial was performed and specimens were sent
bone surgical removal and replacement with for fungal, bacterial, and Acanthamoeba
right fibular bone grafting. Several days post- cultures (tissue homogenates) as well as for
operatively he developed right facial and right histopathology and for immunofluorescence
leg osteomyelitis which was treated with sys- (anti-immunoglobulin and anti-complement
temic antibiotics. Two months later, debride- antibodies, and anti-HSV type 1 antibodies)
ment of the previous right facial graft was studies. Conventional blood work included a
performed and replaced with left fibular bone fluorescent treponemal antibody absorption
grafting. A new focus of left fibula osteomy- test (FTA-ABS) which was negative. Gram
elitis prompted his doctors to place a continu- stain, calcofluor white stain, and appropriate
ous intravenous central line antibiotic pump cultures for fungus, bacteria, and Acan-
containing oxacillin and ceftazidime. During thamoeba were negative. Histopathology
this treatment, the patient noticed discomfort studies revealed a chronic nongranulomatous
and redness in his left eye. Keratitis was diag- inflammation, and direct immunofluorescent
nosed and treatment with tobramycin drops studies (anti-immunoglobulin and anticomple-
and gentamicin ointment was instituted. Two ment antibodies) were negative for detection
weeks later, the eye had deteriorated and the of vasculitis. Results of immunofluorescent
patient was sent to our institution for further studies, using monoclonal antibodies directed
studies. At the time of his first examination by against HSV type 1, were dramatic, revealing
us, visual acuity was 20/40 in the right eye and positive detection of the viral antigen in cor-
20/80 in the left eye. Slit-lamp examination nea, conjunctiva, and sclera, with the appro-
revealed blotchy white infiltrates in corneal priate negative controls (Figs. 5.29 and 5.30).
stroma, extending from 4 to 5 o’clock, 4–5 mm The patient was diagnosed with HSV type 1
5.2 Specific Considerations of Scleral Tissue Inflammation 161
Fig. 5.31 Right eye of a 67-year-old dairy farmer who Fig. 5.32 Scleral biopsy (same patient as in Fig. 5.20):
was struck in the eye by a cow’s tail. Note the intense Note the granulomatous inflammation with perivasculitis
scleritis, with scleral loss inferior to the area of obvious and collagen necrosis
intense inflammation
glycerin-preserved full-thickness human donor and outside the vessel wall, with subsequent
sclera is then cut to size, using this template. The activation of complement.
graft is secured with 10–0 nylon sutures to the Demonstration of necrotizing vasculitis with
edges of the resention site and the knots are bur- or without granulomas in biopsy material of
ied. Conjunctiva is pulled down over the graft involved extraocular tissues confirms the diagno-
whenever enough tissue is present and is sutured sis of systemic vasculitic diseases in patients with
with 8–0 Vicryl. compatible multisystem clinical findings.
Inflammatory microangiopathy in scleral or con-
junctival specimens from patients with scleritis
5.4 Summary further strengthens the concept of an underlying
vasculitic disease. Because noninfectious necro-
Histopathologically, most cases of episcleritis tizing scleritis is highly associated with the pres-
and diffuse or nodular scleritis show chronic, ence of inflammatory microangiopathy, scleral,
nongranulomatous inflammation with lympho- and/or conjunctival biopsy is not necessary to
cytes and plasma cells, vascular dilatation, and prove a vasculitic process. The presence of necro-
edema. By contrast, most cases of necrotizing tizing scleritis should be regarded as an ominous
scleritis show chronic granulomatous inflamma- sign because it indicates an ocular and probably a
tion with epithelioid cells, multinucleated giant systemic vasculitic process that should be treated
cells, lymphocytes, plasma cells, and less often with high dosage of corticosteroids or other
neutrophils, along with inflammatory microan- immunosuppressive drugs. Because noninfec-
giopathy. Mast cells and eosinophils can some- tious recurrent diffuse or nodular scleritis is less
times be seen in the granuloma and around highly associated with inflammatory microan-
vessels. T lymphocyte subset and surface glyco- giopathy, scleral biopsy may be helpful in detect-
protein studies in necrotizing scleritis show a ing a local and systemic vasculitic process that
predominance of macrophages and T lympho- should be treated with a high dosage of corticos-
cytes, with a high T helper/T suppressor ratio, teroids or other immunosuppressive drugs.
and a marked increase in HLA-DR glycoproteins. Pathological detection of granulomas with or
These findings suggest an underlying cell-medi- without inflammatory microangiopathy in scleral
ated reaction (type IV hypersensitivity reaction) and/or conjunctival specimens confirms the diag-
in which the tissue injury is the result of mac- nosis of granulomatosis with polyangiitis
rophage and lymphocyte immune interaction and (Wegener) in a patient with necrotizing, diffuse,
enzyme liberation with subsequent extracellular or nodular scleritis with complete and, especially,
matrix component degradation. limited clinical features, particularly if ANCA
Comparison of extracellular matrix compo- testing is borderline or low positive. Pathological
nents between normal and necrotizing scleritis detection of granulomas with or without inflam-
specimens shows a decrease in dermatan sulfate matory microangiopathy in sclera and/or con-
and chondroitin sulfate without obvious differ- junctival specimens confirms the diagnosis of
ences collagen types I, III, V, and VI; these find- the highly limited form of granulomatosis with
ings suggest that proteoglycans may be the first polyangiitis (Wegener) in a patient with necrotiz-
extracellular matrix components to be degraded ing, diffuse, or nodular scleritis and positive
in necrotizing scleritis. ANCA testing. In the absence of granulomas in
The presence of inflammatory microangiopa- sclera and/or conjunctival specimens, a positive
thy in many of the diffuse and nodular recurrent ANCA test in a patient with necrotizing, diffuse,
scleritis specimens and most of the necrotizing or nodular scleritis is suggestive of highly lim-
scleritis specimens suggests an underlying ited granulomatosis with polyangiitis (Wegener),
immune complex reaction (type III hypersensi- although not diagnostic. In the absence of posi-
tivity reaction), in which the vascular injury is tive ANCA testing, the presence of granulomas
the result of antigen–antibody conjugation within without systemic clinical features does not
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149. Witmer R, Iwamoto T. Electron microscope observa- leritis (a proved case of tubercular origin). Indian J
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Ophthalmol. 1968;79:331. 163. Swan KC. Some comtemporary concepts of scleral
150. Weller TH, Witton HM, Bell EJ. The etiologic agents disease. Arch Ophthalmol. 1951;45:630.
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Noninfectious Scleritis
6
The intrinsic nature of scleritis poses an ultimate (GPA) (Wegener), or PAN; scleritis is less
challenge to the skill of the managing ophthal- commonly found in association with vasculitic
mologist. The chronicity of the disease, its ten- diseases that affect predominantly large-sized
dency to exacerbate and remit, its relationship arteries, such as ankylosing spondylitis (AS), reac-
with many ocular and systemic diseases, and its tive arthritis (ReA), or giant-cell arteritis (GCA).
variable response to specific treatment combine In some cases, scleritis may antedate the onset of a
to complicate the management. potentially lethal systemic immune-mediated dis-
Scleritis may occur in association with a vari- ease. Early diagnosis and subsequent therapy of
ety of noninfectious and infectious local and sys- the underlying disease may improve the ocular
temic disorders. Within the noninfectious and life prognoses.
universe, several types of diseases—immune Dermatologic and metabolic conditions may
mediated, dermatologic, metabolic, foreign body secondarily cause scleritis. Foreign bodies
induced, and chemical substance induced—can embedded in the sclera may excite a granuloma-
cause scleritis (Table 6.1). tous inflammatory reaction, and scleral acid or
Systemic immune-mediated diseases, particu- alkali chemical injuries may lead to scleritis and
larly the vasculitides, are the most severe and subsequent collagen destruction.
destructive conditions that may involve sclera. The presence of scleritis, therefore, demands a
The presence, degree, and nature of scleritis may thorough systemic and ocular evaluation to define
correlate with the chronicity, severity, and activity any associated disease. A detailed past general
of the systemic immune-mediated associated dis- and ocular history, exhaustive review of systems,
ease. For example, diffuse or nodular scleritis may standard physical examination, meticulous slit-
progress to necrotizing scleritis in association with lamp examination, and appropriate ancillary tests
the development of a vasculitic process in colla- must be included as part of the diagnostic strat-
gen diseases, such as rheumatoid arthritis (RA) or egy for the patient with scleritis.
systemic lupus erythematosus (SLE); necrotizing Ophthalmologists are not only “eye doctors.”
scleritis may appear suddenly in association with They are physicians who must consider the systemic
primarily vasculitic diseases, such as polyarteritis manifestations of the patient and decide whether
nodosa (PAN). Scleritis also correlates with the or not there is any interconnection between sys-
type of vasculitic involvement of the associated temic and ocular findings. They must be competent
disease. For example, scleritis is frequently seen in enough to promptly diagnose and treat an under-
association with vasculitic diseases that affect pre- lying systemic disease that is associated with ocular
dominantly small- and medium-sized vessels, inflammation, such as scleritis. Ophthalmologists,
such as RA, SLE, arthritis and inflammatory bowel therefore, must remain current with the systemic
disease (IBD), granulomatosis with polyangiitis disorders that are associated with scleritis.
loss of full extension (Fig. 6.2). Ankle and foot and, less commonly, slowly progressive spastic
arthritis may cause deformities (hallux valgus quadriparesis, often with painless sensory loss of
and plantar subluxation of metatarsal heads) and the hands (Fig. 6.4). Other joints that may be
severe pain during ambulation (Fig. 6.3). Cervical affected are the temporomandibular, cri-
spine osteochondral destruction may lead to coarytenoid, ossicles of the ear, sternoclavicular,
atlantoaxial subluxation, which may cause par- and manubriosternal joints. Hip involvement is
esthesias in the shoulders or arms during neck uncommon. Thoracic and lumbar spine joint dis-
movement, pain radiating up into the occiput, ease cannot be ascribed to RA.
176 6 Noninfectious Scleritis
Vessels
Rheumatoid vasculitis presents classically as (1)
digital arteritis, a noninflammatory obliterative
endarteritis ranging from splinter infarcts in the
nailbeds to gangrene of the fingertips (Fig. 6.6)
[26]; (2) cutaneous ulceration, an inflammatory
infiltration with fibrinoid necrosis of the cutane-
ous venule walls on the lower legs, which clini-
cally appears as palpable purpura or urticaria
Fig. 6.7 Typical butterfly rash in a patient with systemic
(Fig. 6.7); (3) peripheral neuropathy, a mild distal
lupus erythematosus
sensory neuropathy or a severe sensorimotor neu-
ropathy (mononeuritis multiplex), the latter char-
acterized by severe arterial damage on nerve lymph nodes, and testis [28, 29]; the kidney is
biopsy specimens [27]; or (4) organ infarction, an rarely involved by vasculitis but often is compro-
arteritis with marked inflammatory infiltration, mised by amyloidosis or toxicity from therapy.
fibrinoid necrosis, and thrombosis of both small- An inflammatory microangiopathy is also the
and medium-sized arteries of different organs, cause of some ocular diseases, such as scleritis
such as lungs, heart, bowel, spleen, liver, pancreas, (Fig. 6.8) and peripheral ulcerative keratitis
178 6 Noninfectious Scleritis
symptoms include dyspnea, chest pain, cough, reticulonodular honeycomb-type pattern [41–43]
and sometimes fever. The fluid is an exudate con- and respiratory function tests demonstrate a
taining leukocytes, predominantly lymphocytes, restrictive defect with abnormal diffusing capac-
elevated lactate dehydrogenase levels, rheuma- ity [44]. Although pulmonary insufficiency and
toid factor titers equal to or greater than those in even death may occur, diffuse pulmonary fibrosis
serum, low complement levels, and low glucose ascribed to RA is usually slowly progressive and
concentrations. The latter, due to impaired trans- has a better prognosis than idiopathic diffuse pul-
port of glucose into the pleural cavity [37], helps monary fibrosis. The treatment of choice is effec-
to differentiate this effusion from other nonpuru- tive control of the rheumatoid synovitis.
lent effusions because the only other condition Rheumatoid pneumoconiosis was initially
that usually has low glucose concentrations in described by Caplan as a nodular lung disease
pleural fluid is sepsis, particularly tuberculosis. among coal miners with RA [45], but it can also
Tuberculosis may be excluded after a needle appear in chalk, asbestos, gold, and silica work-
biopsy. Pleural disease usually improves sponta- ers [46, 47]. RA and pneumoconiosis are syner-
neously within a few months, although in some gistic and may produce a violent fibroblastic
patients persistent effusion may lead to pleural reaction to the dust, leading to multiple periph-
thickening or empyema. eral nodules greater than 1 cm in diameter, often
Parenchymal pulmonary rheumatoid nodules with cavitation. Nodular lung disease appears in
may occur at any time after the onset of arthritis a small number of patients with RA and pneumo-
and occasionally may antedate or appear simulta- coniosis, usually after the onset of arthritis; the
neous with joint involvement [38]. Patients with nodules rarely may antedate the articular disease
intrapulmonary nodules have more subcutaneous [3]. The prognosis depends on the severity of the
nodules and other extraarticular manifestations, pneumoconiosis. Removal from exposure to
particularly cardiac lesions. Whether single or in inhalants and control of the arthritis are the treat-
clusters, they are usually asymptomatic. Differ- ments of choice.
ential diagnosis with malignancy, tuberculosis, Pulmonary infections, including bronchiecta-
and fungal infection may require needle biopsy. sis, acute bronchitis, chronic bronchitis, and
Nodules may cavitate, leading to a bronchopleu- pneumonia, are more common in patients with
ral fistula [39]. Effective therapy of RA may clear RA [48]. Interestingly, most of the pulmonary
or diminish the nodules. infections usually antedate the onset of arthritis
Diffuse interstitial fibrosis may follow (70%), by many years.
precede (11%), or occur simultaneously (18%) Pulmonary arteritis, although rare, may cause
with the onset of arthritis [40]. Although patients pulmonary hypertension. It is occasionally asso-
with diffuse interstitial fibrosis have a high inci- ciated with digital arteritis.
dence of associated subcutaneous nodules, the
arthritis does not seem to be more severe. The Heart
most common symptoms are dyspnea and cough, Postmortem studies show that 30–50% of patients
but chest pain, fever, and hemoptysis occur occa- with classic RA have cardiac manifestations [49–
sionally. Ten percent of patients are asymptom- 53]. Cardiac involvement can be classified as fol-
atic at the time of diagnosis. The most common lows: (1) pericarditis, (2) myocarditis, (3)
signs are basal crepitations, finger clubbing, and, endocarditis (valvular), and (4) coronary arteritis.
in severe cases, cyanosis. Differential diagnosis Pericarditis is the most common cardiac mani-
includes Hamman–Rich syndrome, hypersensi- festation of RA. Although necropsy studies show
tivity pneumonitis, and sarcoidosis. The finding that 40% of patients with RA have evidence of
of intrapulmonary nodules or low glucose pericarditis, clinical disease is diagnosed only in
levels in pleural effusions helps to diagnose this 10% [54]. However, if echocardiographic studies
fibrosis as being part of RA. Radiographic are performed, the incidence of clinical pericarditis
changes show a bilateral reticular or (15–40%) closely approximates the incidence of
180 6 Noninfectious Scleritis
pericarditis in necropsy studies [55, 56]. Patients of the leaflet, leaving a small rim of uninvolved
with pericarditis in RA usually show a high inci- tissue in the periphery. The nodules can spread to
dence of subcutaneous nodules (up to 47%), ane- involve the base of the aorta in severe cases [68].
mia, and high sedimentation rates [57, 58]. The These nodules, seen in 5–15% of cases, are histo-
presence of pericarditis does not correlate with logically identical to subcutaneous nodules [69].
the duration of the arthritis; in fact, it can precede Coronary arteritis is found in 15–20% of
the onset of arthritis [58]. Pericardial rheumatoid patients with RA at autopsy [27]. It is usually
nodules are rarely found. The majority of patients clinically silent, but anginal chest pain or myo-
are asymptomatic, but pain and congestive heart cardial infarction may occasionally occur, par-
failure may occur. Signs consist of pericardial fric- ticularly in patients with severe systemic
tion or paradoxical pulse. Pericardial fluid is an vasculitis or in young patients without athero-
exudate containing leukocytes, rheumatoid factor sclerotic coronary artery disease [70–72].
titers equal to or greater than those in serum, high
lactate dehydrogenase, low complement, low glu- Nervous System
cose, immune complexes, lymphokines (migra- Although both the central and peripheral nervous
tion inhibition factor), and cholesterol crystals. system can be damaged in RA, peripheral neuro-
Symptomatic patients usually respond to salicy- logic involvement is much more common. The
lates or nonsteroidal anti-inflammatory drugs, but major causes of peripheral neuropathy in RA
if pain is refractory or systemic vasculitis is present include (1) compression neuropathy (carpal tun-
steroids should be used. In case of severe systemic nel syndrome) and (2) angiopathic neuropathy
vasculitis, cytotoxic agents are recommended. (distal sensory neuropathy and distal sensorimo-
Myocarditis in RA can be interstitial or granu- tor neuropathy).
lomatous. Interstitial myocarditis, occurring in Compression neuropathy, specifically a carpal
4–30% of RA patients at autopsy, is usually a focal tunnel syndrome, may be the presenting feature
inflammation of the myocardium, although occa- of RA or may occur at any time during the clini-
sionally a diffuse necrotizing process may occur cal course. The proliferative synovitis compresses
[49, 50, 59–61]. It is characterized microscopi- the nerve within a bony canal. The diagnosis is
cally by focal or diffuse inflammatory infiltration suggested by the characteristic symptoms, such
of plasma cells, lymphocytes, and histiocytes. as paresthesias in the area of the median nerve
Focal interstitial myocarditis is clinically silent, distribution and nocturnal pain in the arm or
but diffuse intertitial myocarditis may show con- hand, and is confirmed by nerve conduction stud-
gestive heart failure, conduction abnormalities, ies. However, electrodiagnostic abnormalities
and pulmonic and systemic embolizations. showing compression of the median nerve are
Granulomatous myocarditis, occurring in 5% relatively common in asymptomatic patients with
of RA patients at autopsy, is characterized by the RA. Ulnar, radial, sciatic, or posterior tibial (tar-
presence of grayish yellow nodules that histo- sal tunnel syndrome) nerve entrapments also may
logically resemble subcutaneous rheumatoid occur in RA. Although entrapment neuropathies
nodules [50, 62]. Patients are usually asymptom- usually are related to the severity of arthritis, they
atic unless the nodules are located in critical do not correlate with the duration of RA, rheuma-
areas, such as the conduction system, where they toid factor, sex, acute-phase reactant levels, or
can cause conduction abnormalities [63]. other extraarticular features.
Endocarditis (valvular) is found in 30–40% of Angiopathic neuropathy is the result of axonal
RA patients at autopsy [64–66]. The mitral, aor- degeneration of nerve fibers caused by occlusion
tic, tricuspid, and pulmonic valves are affected, of vasa nervorum and resultant ischemia of the
in decreasing order of frequency [67]. The entire peripheral nerve. The milder form is distal sen-
valve may be involved by a nonspecific inflam- sory neuropathy, which may precede the onset of
mation, resulting in either stenosis or insuffi- arthritis, although it more often appears many
ciency. In a specific granulomatous inflammation, years after the joint disease [73]. The clinical pic-
inflammatory nodules involve the central core ture is characterized by symmetrical burning,
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 181
numbness, or tingling of lower limbs with distal synovitis [77–79]. The nodes most commonly
loss of vibration sense and proprioception; involved are axillary, epitrochlear, and inguinal,
occasionally, the upper limbs are involved in a and their presence does not correlate with eryth-
stocking-glove distribution [74, 75]. There is rocyte sedimentation rate (ESR), C-reactive pro-
usually a concomitant motor deficit that can be tein (CRP), anemia, or disease severity. Effective
detected by electromyogram, but this is often not treatment of proliferative synovitis may improve
clinically demonstrable, particularly in patients or correct lymphadenopathy. Development of
with joint pain or deformity [76]. Muscle wast- lymphoma occurs with greater frequency in RA
ing, weakness, and loss of tendon reflexes are patients who also have Sjögren’s syndrome [80],
frequently present. Distal sensory neuropathy is a a disorder associated with increased risk for this
manifestation seen in vasculitis that may occur neoplasm [81].
alone, without widespread vascular involvement.
The prognosis is good with effective treatment of Larynx
RA, although in a small number of cases the dis- Laryngeal manifestations in RA include (1) cri-
order progresses to the more ominous sensorimo- coarytenoid joint involvement, (2) vocal cord
tor neuropathy. paralysis, and (3) vocal cord nodules.
Less common but more severe is distal senso- Cricoarytenoid joint involvement may be
rimotor neuropathy, which may present as an found in nearly 50% of RA cases at autopsy and
abrupt painful asymmetric multiple mononeurop- approximately 25% of living patients with RA.
athy (mononeuritis multiplex) characterized ini- Signs and symptoms may be subtle and include
tially by severe pain and paresthesias of individual tenderness on palpation, hoarseness, tightness of
peripheral nerves followed hours to days later by the throat, difficulty in swallowing, and mild dys-
a wristdrop, a footdrop, or motor weakness in pnea. Laryngoscopy may show, in severe cases,
another involved peripheral nerve. Asymmetric edema of the cricoarytenoid joint and the vocal
multiple mononeuropathy may progress to sym- cords.
metric polyneuropathy. Electromyogram abnor- Vocal cord paralysis in patients with RA is
malities corroborate the clinical findings, and in secondary to neuropathy affecting intrinsic laryn-
questionable cases biopsy of an involved sural geal muscles.
nerve confirms the diagnosis. This type of Vocal cord nodules may also appear in patients
neuropathy is seen in patients with long-standing with RA. Signs and symptoms may resemble
RA (average duration, 10 years), severe joint those of a tumor.
deformities, rheumatoid nodules, anemia,
anorexia, fever, high titers of rheumatoid factor, Felty’s Syndrome
and low serum complement levels. Males are Felty’s syndrome consists of RA, splenomegaly,
afflicted as commonly as females, unlike uncom- and leukopenia [82]. It is most common in the
plicated RA, in which there is a female prepon- fourth through the sixth decades of life and usu-
derance. Patients with sensorimotor neuropathy ally occurs after 10 years of arthritis. Patients
frequently have skin vasculitic lesions, such as with Felty’s syndrome have more erosive and
nailfold infarcts, leg ulcers, and digital gangrene, deforming articular disease, a more elevated ESR,
and widespread underlying vasculitis that may higher rheumatoid factor titers, and more extraar-
extend to involve mesenteric, coronary, or cerebral ticular manifestations than do other patients with
arteries. Prognosis is poor, with a 42% mortality RA [83, 84].
rate for patients with a sensorimotor neuropathy Extraarticular manifestations include subcuta-
involving three or four extremities [35]. Treatment neous nodules, leg ulcers, lymphadenopathy,
must include systemic immunosuppression. pleuritis, and neuropathy. Patients with Felty’s
syndrome are more susceptible to infection than
Lymph Nodes are other patients with RA [85–88]. Splenectomy
Asymptomatic enlarged, firm, and mobile lymph and effective control of RA are the treatments of
nodes are often found in patients with active choice [89, 90].
182 6 Noninfectious Scleritis
its incidence in the general rheumatoid popula- Rheumatoid scleritis is most common in the sixth
tion [114]. Use of artificial tear substitutes and decade of life, affects women more frequently
punctal occlusion, initially with punctal plugs and than men, and is often bilateral [114, 123–126].
then permanently with cautery, may be necessary Diffuse anterior scleritis is the most frequent type
adjunctive measures. Lid scrubs and hot com- of scleritis in patients with RA [114, 123]; how-
presses with or without systemic tetracyclines are ever, cases of scleromalacia perforans anterior
indicated if there is meibomian gland dysfunction scleritis in which a systemic diagnosis can be
or blepharitis associated. The use of slow-release ascribed, are almost exclusively due to RA [122].
artificial tear inserts without preservatives may Although posterior rheumatoid scleritis is uncom-
provide continuous lubrication in the presence of mon, it is usually accompanied by diffuse anterior
some moisture. Topical cyclosporine (CsA) is the scleritis [114]. In our own series of 500 patients
first US Food and Drug Administration (FDA)- with scleritis, 32 patients had RA (6.4%). The
approved drug therapy for dry eye. The effect of mean age of our patients was 59 years (range,
this drug on inflammatory disease is due to its 19–80 years) and the scleritis was more common
ability to inhibit T-cell-mediated inflammation by in women than in men (23 females and nine
preventing the activation of CD 4-positive helper/ males). Twelve patients (37%) had bilateral scleri-
inducer T lymphocytes. Eyes treated with topical tis. Diffuse anterior scleritis (81%) was the type
CsA have shown fewer apoptotic epithelial cells, most frequently encountered.
decreased levels of the proapoptotic markers, and Although scleritis may be the initial sign of
increased expression of the antiapoptotic factors. rheumatoid disease [125, 126], it usually presents
CsA significantly improved corneal fluorescein in patients with long-standing RA, usually 13 or
staining, Schirmer scores, blurred vision, and 14 years after the onset of arthritis [114, 127].
dryness, and significantly increased conjunctival Patients with rheumatoid scleritis have more
goblet cell density [115–120]. Occasionally, par- advanced joint disease and more extraarticular
tial tarsorraphy may be required to decrease manifestations than do rheumatoid patients with-
evaporation. out scleritis [114, 121, 125, 127, 128]. Many of the
extraarticular manifestations reflect an underlying
Scleritis rheumatoid vasculitis [129]. Although subcutane-
Rheumatoid arthritis is by far the most common ous nodules appear in 20–30% of patients with
systemic condition associated with scleritis. The classic RA, their presence increases to 50% in
reported incidence of RA in patients with scleritis patients with rheumatoid scleritis [114]. Pulmonary
ranges from 10 to 33% (Table 6.3) [114, 121–125]. disorders, such as pleural effusion, rheumatoid
Conversely, the reported incidence of scleritis in nodules of lung, and pneumonia, are more com-
patients with RA ranges from 0.15 to 6.3% [114]. monly present in patients with rheumatoid scleritis
184 6 Noninfectious Scleritis
than in rheumatoid patients without scleritis [114]. patients with rheumatoid scleritis will be dead
Cardiac manifestations, such as pericarditis [114, within 3 years of the onset of scleritis unless
129, 130], valvular disease [114, 125, 126], con- immunosuppressive or biologic response modifier
duction abnormalities [114], and myocardial therapy is used. This compares to an 18% 3-year
infarction [114, 129], have been described in asso- mortality in patients with RA without scleritis
ciation with rheumatoid scleritis. Myocardial isch- [114, 127]. Most causes of death are due to
emia is also more frequent in rheumatoid patients extraarticular RA vasculitic manifestations [122,
with scleritis [114]. Peripheral neuropathies, skin 129]. Necrotizing scleritis is the type of scleritis
ulcers, and amyloidosis also have been described most predictive of these deaths [122, 129].
in rheumatoid patients with scleritis [114, 129]. Because the presence of necrotizing scleritis
Exacerbation of scleritis often occurs at times in RA may indicate an underlying potentially
of increased activity of RA [121, 125, 127, 131, lethal systemic vasculitis, it is essential to detect
132], and a progression from diffuse or nodular both the ocular and systemic conditions as early
scleritis to necrotizing scleritis may indicate the as possible so that vigorous treatment can favor-
onset of rheumatoid vasculitis elsewhere in the ably alter not only the ocular, but also the life
body [122]. Necrotizing scleritis also may appear prognosis in these patients.
after surgical trauma to the sclera. The mean time Scleral inflammation in RA may extend to the
of presentation of scleritis in our series of 32 adjacent structures and may cause keratitis, ante-
patients with rheumatoid scleritis was 16 years rior uveitis, glaucoma, cataract, retinal, choroi-
after the onset of arthritis. In two cases, scleritis dal, optic nerve changes, and motility disturbances.
was the initial manifestation whose study led Some of these complications may affect visual
to the diagnosis of RA. Many patients with rheu- acuity. In our series of 32 patients with rheuma-
matoid scleritis had deforming joint disease toid scleritis, a decrease in visual acuity (loss of
and extraarticular RA manifestations. The most vision equal or greater to two Snellen lines at the
frequent extraarticular manifestations were sub- end of the follow-up period or vision equal to or
cutaneous nodules and skin vasculitic lesions. worse than 20/80 at the first examination)
Other extraarticular manifestations included (1) occurred in five patients (16%).
pulmonary disorders, such as pleural effusion,
pneumonia, and rheumatoid nodules of the lung; Keratitis
(2) cardiac abnormalities, such as conduction Corneal involvement associated with scleritis in
defects, mitral valvular disease, myocardial patients with RA can be classified depending on
infarction, and pericarditis; (3) neurologic whether or not thinning, infiltration, or ulceration
involvement, such as carpal tunnel syndrome, of the cornea occurs. Peripheral corneal thinning,
sensory neuropathy, and sensorimotor neuropa- acute or sclerosing stromal keratitis, and PUK are
thy; (4) lymphadenopathy and non-Hodgkin’s the most common corneal abnormalities associ-
lymphoma; (5) amyloidosis; (6) mild elevation of ated with rheumatoid scleritis (Fig. 6.6).
liver function tests; (7) gastrointestinal disorders, The reported incidence of keratitis associated
such as gastroduodenal ulcers in patients who with rheumatoid scleritis ranges from 36 to 43.5%
had received long-term steroidal or nonsteroidal [114, 127, 128]. In our series of 32 patients with
therapy; (8) kidney involvement secondary to rheumatoid scleritis, seven patients had keratitis
gold treatment; and (9) bone abnormalities, such (50%); of those, one patient had corneal thinning,
as osteoporosis in patients who had received two patients had acute stromal keratitis, and four
long-term steroidal therapy. Necrotizing scleritis patients had PUK. Keratitis in RA also may occur
appeared an average of 16 weeks after ocular sur- in the absence of adjacent scleritis [122, 133–139].
gery in four patients with RA.
The prognosis for life is poorer in patients Anterior Uveitis
with RA complicated by scleritis when compared Anterior uveitis in RA is almost always caused
with RA patients without scleritis [114, 122, by extension of scleral inflammation, but anterior
125, 127–129]. Thirty-six to forty-five percent of uveitis in the absence of scleritis has no higher
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 185
with episcleritis, three patients had RA (3.5%), lesser proportion of patients with other rheumatic
all of them females. The mean age of patients diseases (SLE, scleroderma, and Sjögren’s syn-
with rheumatoid episcleritis was 51 years (range drome), viral, bacterial, and parasitic infections,
42–63 years); there were two cases with nodular chronic inflammatory diseases, and neoplasms
episcleritis and one case with simple episcleritis; after chemotherapy or radiotherapy (see Table
all of them were unilateral. 3.8). Positive RF is also observed in healthy indi-
Although only about 10% of patients with viduals during the course of secondary immune
episcleritis have an underlying connective tissue responses [159] and in 10–20% of nonrheumatic
or vasculitic disease, RA is the most common individuals over 65 years old who will not
diagnosis [121–123]. In our series of 85 patients develop RA. The presence of rheumatoid factor
with episcleritis, 15% had an underlying connec- does not establish the diagnosis of RA; the pre-
tive tissue disease or vasculitic disease; RA, AS, dictive value of the presence of rheumatoid fac-
and arthritis associated with IBD were the most tor in determining a diagnosis of RA is poor.
common diagnoses. Thus, fewer than one-third of unselected patients
Bilateral episcleral nodules may occur in with a positive test for rheumatoid factor is found
patients with concomitant active joint manifesta- to have RA. Therefore, the rheumatoid factor test
tions of RA (rheumatoid nodules) [149–152]; is not useful as a screening procedure. However,
however, they also may appear in patients with the presence of rheumatoid factor can be of prog-
inactive RA (rheumatoid nodulosis) [153] or in nostic significance because patients with high
patients without any underlying disease (pseu- titers tend to have more severe and progressive
dorheumatoid nodules) [154–156]. disease with extraarticular manifestations [7, 10,
Although keratitis, such as peripheral thin- 21, 160–165]. Rheumatoid factor is uniformly
ning, acute stromal keratitis, and sclerosing kera- found in patients with nodules or vasculitis. In
titis, may occur more frequently in rheumatoid summary, a test for the presence of rheumatoid
episcleritis than in nonrheumatoid episcleritis, it factor can be employed to confirm a diagnosis in
is never severe [114]. Mild anterior uveitis occurs individuals with a suggestive clinical presenta-
in a small minority of patients with rheumatoid tion and, if present in high titer, to designate
episcleritis [114]. None of our three patients had patients at risk for severe systemic disease.
either keratitis or anterior uveitis and none had Patients with rheumatoid scleritis usually
changes in visual acuity. have positive RF; RF titers are high in some of
them [114].
6.1.1.4 Laboratory Findings
Although no laboratory tests are specific for diag- Antibodies to Cyclic Citrullinated
nosing RA, some of them are valuable in progno- Polypeptides
sis and management. Antibodies to cyclic citrullinated polypeptides
(Anti-CCPs) can also be used to evaluate patients
Rheumatoid Factor with RA. Although these antibodies are most
The association of positive-serum rheumatoid commonly found in rheumatoid factor-positive
factor with RA, initially described by Waaler, patients, on occasion they can be detected in the
Rose, and others, is well-known [157, 158]. absence of rheumatoid factor. In addition, the
Rheumatoid factor is generally defined as an anti-CCP test has a similar sensitivity and a better
autoantibody (generally IgM, but also IgG and specificity for RA than does rheumatoid factor,
IgA) that reacts with certain epitopes in the Fc and, therefore, some have advocated its use to
fragment of the IgG molecule. Approximately evaluate RA patients instead of rheumatoid fac-
70–90% of patients with definite or classic RA tor. This is particularly the case in individuals
have positive-serum RF (seropositive RA). with early RA, in whom assessment of anti-CCP
Rheumatoid factor is also positive in the sera of a may be the most useful to confirm the diagnosis
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 187
and establish a likely prognosis. The presence of Patients with rheumatoid scleritis have higher
anti-CCP is most common in persons with aggres- ESR values than do RA patients without
sive disease, with a tendency for developing bone scleritis [114].
erosions. The development of anti-CCP is most
frequent in individuals with an RA-associated Synovial Fluid Analysis
HLA-b1 allele and in those who smoke ciga- The synovial fluid in RA is usually turbid, with
rettes, and may occur before the development of reduced viscosity, poor mucin clot formation,
clinical manifestations of RA. However, as with slightly decreased glucose concentration, and
rheumatoid factor, the presence of anti-CCP is increased protein content. White cell count varies
not useful to predict the future development of between 2,000 and 75,000; 50% or more of the
RA because it can be found in ~1.5% of normal cells are neutrophils. Total hemolytic comple-
individuals, most of whom will not develop RA, ment (C3 and C4) in synovial fluid is less than
and occasionally in persons with other rheumatic 30% of the usually normal serum complement,
diseases. However, it is a useful test to confirm a reflecting activation of the classic complement
diagnosis of RA and to estimate prognosis. pathway by locally produced immune complexes
[175]. Synovial histopathology may also be help-
Complete Blood Count ful in RA diagnosis.
Patients with RA often have anemia, thrombocyto-
sis, and eosinophilia. Suppression of proliferative Circulating Immune Complexes
synovitis may reduce or eliminate hematologic Although the presence of CICs is not specific to
abnormalities. any particular disease, their detection may have
Rheumatoid arthritis patients usually have nor- some diagnostic and prognostic significance in
mocytic hypochromic anemia that tends to follow RA. In early arthritis, CICs may be detected sev-
the ESR, CRP levels, and activity of synovitis eral months prior to the definite diagnosis of RA
[166, 167]. The pathogenesis of the anemia seems [176]. The presence of CICs may help to distin-
to be related to ineffective erythropoiesis [167]. guish seronegative RA from other arthropathies
Mild thrombocytosis is often associated with because CICs are found in 70% of patients with
RA. It also correlates with the ESR, CRP levels, seronegative RA [177]. CIC levels may correlate
activity of synovitis, and the presence of extraar- with disease activity, although not as well as the
ticular manifestations [168]. The mechanism of ESR, CRP, or IgG RF [178]. Patients with rheu-
thrombocytosis is unknown. matoid vasculitis have high levels of CICs [31].
Eosinophilia (5% of total white blood cell In our series of patients with rheumatoid scleritis,
count or greater) appears frequently in RA CICs were detected in all but two patients in
patients with severe deforming articular disease which the test was done (16 patients). The mean
[169], pleuritic nodules, low complement levels, titer of the CICs by Raji cell assay was 236 U/ml
and high prevalence of vasculitis [170]. (normal, 0–50).
Table 6.4 American Rheumatism Association criteria for the diagnosis of rheumatoid arthritisa,b
1. Morning stiffness
2. Pain on motion or tenderness in at least one jointa
3. Swelling of one joint (soft tissue or fluid, not bony overgrowth alone)a
4. Swelling of at least one other jointa with an interval free of symptoms no longer than 3 months
5. Symmetrical joint swellinga with simultaneous involvement of the same joint, right and left. Terminal phalangeal
joint involvement is rare in RA and therefore does not satisfy this criterion
6. Subcutaneous nodulesa over bony prominences, extensor surfaces, or in juxtaarticular regions
7. Typical roentgenographic changes that must include at least bony decalcification localized to or greatest around
the involved joints; degenerative changes do not exclude diagnosis of RA
8. Positive test for rheumatoid factor in serum (1:64 or greater)
9. Synovial fluid; a poor mucin precipitate on adding synovial fluid to dilute acetic acid
10. Synovial histopathology consistent with RA (marked villous hypertrophy, proliferation of synovial cells,
lymphocyte/plasma cell infiltration in subsynovium, fibrin deposition within or upon microvilli, foci of cell
necrosis)
11. Characteristic histopathology of rheumatoid nodules biopsied from any site (granulomatous foci with central
zones of cell necrosis, surrounded by proliferated fixed cells, and peripheral fibrosis and chronic inflammatory cell
infiltration, predominantly perivascular)
To meet criteria 1–5, symptoms or signs must be present for at least 6 weeks
a
Observed by a physician
b
Classic RA, seven criteria needed; definite RA, five criteria needed; probable RA, three criteria needed; possible RA,
two criteria (1, 2, 3, or 6), elevated erythrocyte sedimentation rate (ESR) or C-reactive protein, or iritis
antibodies include Sm, nRNP, anti-La, Scl70, and erosion produced by the disease, particularly
other unidentified antigens. Rheumatoid vasc- when one is attempting to estimate the aggressive
ulitis may occur in patients with high levels of nature of the disease, monitoring the impact of
ANAs [31]. therapy with disease-modifying drugs, or deter-
mining the need for surgical intervention. Other
Complement means of imaging bones and joints, including
99m
Reduced serum complement occurs in seroposi- Tc bisphosphonate bone scanning and MRI,
tive RA in which CICs are present [1]. Rheumatoid may be capable of detecting early inflammatory
vasculitis may occur in patients with depressed changes that are not apparent from standard radi-
complement levels [31–33]. ography but are rarely necessary in the routine
evaluation of patients with RA.
Cryoglobulins
Serum cryoglobulins in patients with RA contain Diagnosis
immune complex materials. Elevated cryoglobu- The diagnosis of RA is essentially clinical,
lin levels occur most frequently in seropositive although the presence of RF, inflammatory syn-
RA patients with rheumatoid vasculitis and with ovial fluid, characteristic histologic changes in
Felty’s syndrome [1]. Serum cryoglobulin levels synovial membrane or nodules, and radiographic
correlate inversely with serum complement findings of periarticular osteoporosis and ero-
levels. sions of the affected joints support the diagnosis.
The American Rheumatism Association devel-
Radiographic Evaluation oped a set of diagnostic criteria for the diagnosis
Radiologic findings range from periarticular tis- of RA (Table 6.4). A diagnosis of classic RA may
sue swelling early in the disease to juxtaarticular be made in the presence of seven of these criteria,
osteopenia, loss of articular cartilage, bone ero- whereas definite RA is diagnosed in the presence
sions, and joint deformities in advanced disease. of five, and probable RA in the presence of three.
The primary value of radiography is to deter- Exclusions are based on the presence of criteria
mine the extent of cartilage destruction and bone for other diseases. These include heel pain,
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 189
conjunctivitis, and urethritis in ReA, spondylitis Table 6.5 Common systemic manifestations of systemic
in AS, tophi in gout, butterfly rash in SLE, and lupus erythematosus
so on. Articular: arthralgias and arthritis
Cutaneous: rash, alopecia, ulcers, and photosensitivity
Renal: glomerulonephritis
6.1.2 Systemic Lupus Erythematosus Cardiovascular: pericarditis, Raynaud’s phenomenon,
and thrombophlebitis
Gastrointestinal: nausea, vomiting, and abdominal pain
Systemic lupus erythematosus is an autoimmune
Neurologic: behavioral disturbance, seizures, and
disease in which organs and cells undergo dam- mononeuritis
age mediated by tissue-binding autoantibodies Pulmonary: pleural effusions, pleurisy, and pneumonitis
and immune complexes. The clinical course of Miscellaneous: splenomegaly, lymphadenopathy, and
SLE may be mild or severe and recurrent or con- parotid swelling
tinuous with a wide range of inflammatory mani- Ocular: keratitis, episcleritis, scleritis, and retinopathy
festations in almost any organ of the body.
the disease, preceding the multisystem involve- Organ infarction, such as cerebral thrombosis
ment by weeks or months. The rash may be con- and hemorrhages, myocardial infarction, diffuse
tinuous or intermittent and is exacerbated by proliferative lupus nephritis, or bowel perfora-
ultraviolet exposure, alcohol ingestion, or nervous- tion, may be caused by an arteritis of both small-
ness. The second most common rash is a maculo- and medium-sized arteries. Widespread
papular eruption, frequently pruritic and located at necrotizing arteritis mimicking PAN has been
any place on the body. described in a few patients with SLE.
Alopecia occurs in 25–40% of the patients
with SLE. Because in many patients recurrent Kidney
diffuse alopecia may be the first manifestation of Although only 40–50% of patients have clinical
an impending SLE flare-up, its presence should evidence of renal disease (proteinuria or hematu-
be viewed as evidence of disease activity. ria, nephrotic syndrome, or renal failure), nearly
Periungual erythema, atrophic blanche lesions, all show changes on renal biopsy. The spectrum
hives or angioneurotic edema, urticaria, bullous of kidney involvement includes (1) focal prolif-
lesions, and nail deformities have also been erative lupus nephritis (mild), (2) diffuse prolif-
described. erative lupus nephritis (severe), (3) membranous
lupus nephritis (moderate), and (4) mesangial
Vessels lupus nephritis (minimal) [191]. Hypertension is
Aside from RA, the connective tissue disease in commonly associated. The extent and severity of
which vasculitis occurs most frequently is SLE. the renal lesions correlate with the severity of the
Skin vasculitic lesions, noted in about 20% of disease, and end-stage renal disease is the most
patients with SLE, are most commonly located common cause of death in patients with SLE.
on the extensor surface of the forearm and on the
fingertips, but they also may be on the palms, Hearth
soles of the feet, and lower legs near the malleoli. The most frequent cardiac manifestation in SLE
These lesions may ulcerate, particularly during is pericarditis, which occurs in about 25% of
the periods of disease exacerbation. Livedo retic- patients, often during acute exacerbations.
ularis, purpura, and splinter hemorrhages may Although a pericardial rub is easily detected,
also be noted in severe active disease. Mucosal echocardiography is most helpful in detecting
vasculitic lesions, such as mucous membrane pericardial thickening [192]. Myocardial involve-
ulcers (nasal septum, palate, larynx, pharynx, and ment may present as tachycardia, cardiac enlarge-
vagina), may be the first manifestation of an ment, congestive heart disease, arrhythmias,
impending SLE flare-up. conduction defects, or even cardiac failure.
Raynaud’s phenomenon may occur in about Deaths caused by myocardial infarction from
20% of SLE patients (Fig. 6.8). It is usually pres- coronary arteritis have been reported early in the
ent with other manifestations at the time of diag- course of the disease in young patients [189, 193,
nosis but occasionally may precede the onset of 194]. Atypical verrucous endocarditis, termed
multisystem disease [189]. Raynaud’s phenome- Libman–Sacks endocarditis, is usually of little
non may gradually disappear as the disease goes clinical significance and is not easily diagnosed
into remission, although in active SLE may result in life. The pathological findings at necropsy
in digital gangrene with amputation of the finger- reveal ovoid vegetations, from 1 to 4 mm of
tips. Deep vein thrombosis also may occur and diameter, made up of degenerating valve tissue
may be migratory and recurrent [189]. with fibrin and platelet thrombi. Although the
Peripheral neuropathy and cranial nerve original descriptions by Libman and Sacks [195]
involvement are characterized by arterial damage were observed on the tricuspid valve, more recent
in nerve biopsy specimens. Psychosis, seizures, series show a higher incidence of lesions on the
hemiparesis, and chorea may be the result of vas- mitral valve [196]. Subacute bacterial endocardi-
culitic cerebral involvement [189, 190]. tis may occur when microorganisms become
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 191
implanted on the leaflets previously deformed by Acute pneumonitis may present with dyspnea
Libman–Sacks endocarditis. and, less often, cough or hemoptysis as symp-
toms, and diffuse acinar infiltrates, especially in
Nervous System the lung bases, as chest X-ray findings; lung func-
Central nervous system involvement is the sec- tion studies may reveal hypoxemia. Diffuse inter-
ond most frequent SLE-related cause of death stitial pneumonitis diagnosis is based on the
(after renal involvement) [197]. The most com- symptom of dyspnea on exertion, physical find-
mon neurological manifestation is psychiatric ill- ings of poor diaphragmatic movement and
ness (organic brain syndrome) characterized by decreased resonance to percussion over the bases,
impairment of orientation, perception, memory, and radiographic evidence of persistent, diffuse
and intellectual function [198]. The second most interstitial infiltrates; lung function studies reveal
common is seizures, especially grand mal sei- a restrictive pattern. Pulmonary involvement may
zure; petit mal, psychomotor epilepsy, temporal occur in SLE patients with no dyspnea and no
lobe epilepsy, and Jacksonian seizures may also radiographic abnormalities; the only disturbance
appear. Seizures may be present at the time of in these patients is an impairment in the diffusion
diagnosis or later in the course of the disease, but capacity.
in most cases they occur along with clinical and
laboratory evidence of severe systemic disease. Miscellaneous
SLE patients with central nervous system disease Gastrointestinal symptoms, such as anorexia,
(organic brain syndrome or seizures) are more nausea, vomiting, dysphagia, or abdominal pain,
likely to have evidence of vasculitis of other sys- may occur in SLE patients and may mimic an
tems than those without central nervous system acute surgical abdomen. Acute pancreatitis may
findings [197]. Chorea, recurrent headaches, result from active SLE or glucocorticoid therapy.
hemiparesis, and cerebellar signs may occur Elevated serum levels of liver enzymes are com-
along with other manifestations of the disease mon in active SLE, but they return to normal with
during an exacerbation. Cranial nerves, such as response of the disease to therapy [201]. Slight-
the ophthalmic, trochlear, abducens, and less to-moderate splenomegaly may occur in 20% of
commonly the trigeminal and facial, may be SLE patients; lack of splenic activity is uncom-
involved in episodes of active systemic disease mon [202]. Lymph nodes are enlarged in 50% of
when evidence of vasculitis is present in other SLE patients at the time of clinical disease activ-
systems [198]. Peripheral neuropathy occurs in ity. The parotid gland may also be enlarged dur-
about 14% of patients. The most common abnor- ing periods of active SLE [189].
mality is sensory, although occasionally a senso-
rimotor disturbance may be seen [197]. 6.1.2.3 Ocular Involvement
Psychological abnormalities, such as depression The ocular manifestations in SLE are important
and less often anxiety, are reactions to the disease because they may be the initial manifestation of
and to the disfigurement caused by both the dis- the disease or may serve as a barometer of the
ease and the corticosteroid therapy [198]. severity and prognosis of the systemic involve-
ment. Unlike other collagen diseases, which have
Lung a frank predilection for either anterior or poste-
Pleuropulmonary manifestations, which occur in rior segment involvement, SLE may affect every
50–75% of SLE patients, include pleurisy with or structure of the eye [203]. Any patient who devel-
without effusion, acute pneumonitis, and diffuse ops retinal vasculitis and scleritis must be care-
interstitial pneumonitis [199, 200]. Pleural effu- fully studied for SLE.
sions in SLE are exudates with more than 3.0 g of
protein per 100 ml, more than 55 mg/100 ml of Scleritis
glucose, and occasional lupus erythematosus The reported incidence of SLE in patients with
(LE) cells; pleuritic pain is the usual complaint. scleritis is about 1% [122, 123]. The presence of
192 6 Noninfectious Scleritis
scleritis is a reasonably accurate guide to the sys- episcleritis, there were no patients with SLE.
temic activity in a patient with SLE; the scleritis Conversely, three studies reported the incidence
attacks become more severe and recurrent as the of episcleritis in patients with SLE as 0.5, 1.9,
systemic disease deteriorates. Occasionally, and 1.1% (1 of 200 SLE patients, 2 of 105 SLE
scleritis may be the initial manifestation of SLE patients, and 1 of 94 patients, respectively) [123,
[123]. SLE scleritis generally takes the form of 207, 208]. Occasionally, episcleritis may be the
diffuse anterior scleritis or nodular anterior scleri- first manifestation of SLE [209]. In our own
tis, but necrotizing anterior scleritis may also series of 85 patients with episcleritis, no patients
occur, especially when systemic vasculitic lesions had SLE.
become significant [123, 204]. Posterior scleritis,
although uncommon, may also be an SLE mani- Other Ocular Findings
festation [205]. Any patient who presents with Aside from scleritis and episcleritis, anterior seg-
any type of scleritis should be screened for SLE; ment involvement in SLE may include conjuncti-
scleritis resolves with adequate control of sys- vitis, keratitis, and anterior uveitis. Conjunctivitis
temic disease. Scleral inflammation in SLE may may affect bulbar, fornix, and tarsal regions and
extent to the adjacent structures and may cause may eventually leave subepithelial fibrosis with
keratitis and anterior uveitis. Although anterior shrinkage of the conjunctiva. Although superfi-
uveitis is an unusual isolated finding in SLE cial punctate keratitis is the most common cor-
(reported incidence of uveitis in patients with neal problem, stromal infiltration, peripheral
SLE ranges from 0.5 to 1.6%) [206], its incidence ulceration, and vascularization may also occur
increases with the presence of SLE scleritis. [210–213]. KCS may be associated with SLE
In our own series of 500 patients with scleritis, (Sjögren’s syndrome), but its incidence is low
ten patients had SLE (2%); of those, four patients [214–217]. Anterior uveitis may rarely occur in
(40%) had bilateral scleritis. All patients were the absence of other ocular lesions [204, 206].
women with a mean age of 45.8 years (range, Although anterior uveitis may cause secondary
24–69 years). Eight patients had diffuse anterior glaucoma, it is never severe and responds well to
scleritis, one patient had nodular anterior scleri- adequate therapy. Posterior segment involvement
tis, and one patient had posterior scleritis. The is more common and serves as a better barometer
mean time of presentation of scleritis was of the severity of the disease than do anterior seg-
6 months after the SLE diagnosis. In most cases, ment manifestations. The most frequent posterior
scleritis appeared at the time of exacerbation of segment manifestations include cotton–wool
the systemic disease. In two cases, scleritis (pos- spots, retinal hemorrhages, retinal edema, and
terior and diffuse) was the initial manifestation optic disk edema; other reported fundus changes
whose study led to the diagnosis of SLE. Three of include retinal hard exudates, retinal vasculitis,
ten patients (30%) with SLE scleritis had had at central retinal vein occlusion, arteriolar narrow-
least one episode of anterior uveitis; all three had ing, arteriovenous crossing changes, macular
diffuse anterior scleritis. Two patients had keratitis- pigmentary mottling, and retinal scarring [206].
associated scleritis: one had peripheral corneal Although some of these manifestations may be a
thinning and another had PUK. A decrease in reflection of a hypertensive retinopathy, they may
visual acuity (equal to or greater than two Snellen appear as independent signs as well; in cases of
lines at the end of the follow-up period or vision associated hypertension, the decision as to
equal to or worse than 20/80 at the first examina- whether the retinal lesions are secondary to high
tion) occurred in 10% of the patients. blood pressure or to SLE immunological abnor-
malities may be difficult; the presence of anterior
Episcleritis segment manifestations, such as scleritis or epis-
Although episcleritis may occur in patients cleritis, may be helpful in this regard because
with SLE, the incidence is low. In the Watson they are reflections of the disease process. Several
and Hayreh [122] series of 159 patients with authors have emphasized that the presence of
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 193
retinal lesions correlates with the systemic course nephritis or vasculitis. Antibodies to Sm are also
of the disease [218–221]; Rothfield [221] found specific for SLE and assist in diagnosis; anti-Sm
an association between the presence of hard exu- antibodies do not usually correlate with disease
dates and central nervous system disease activity activity or clinical manifestations. Antiphospholipid
(seizures and organic brain disease). Regan and (aPL) antibodies are not specific for SLE, but their
Foster [222], however, think that localized mani- presence fulfills one classification criterion and
festations of the disease (eye, skin, and kidney) they identify patients at increased risk for venous
may sometimes occur, and therefore that retinal or arterial clotting, thrombocytopenia, and fetal
vasculitis also may appear without exacerbation loss. There are two widely accepted tests that mea-
of SLE [222]. Whichever the case is, if a patient sure different antibodies (anticardiolipin and lupus
with SLE develops retinopathy, a thorough search anticoagulant): (1) ELISA for anticardiolipin (inter-
for systemic evidence of disease activity must be nationally standardized with good reproducibility)
performed promptly and, if positive, aggressive and (2) a sensitive phospholipid-based activated
therapy must be instituted to control both sys- prothrombin time, such as the dilute Russell venom
temic and ocular abnormalities. Central nervous viper test. Some centers also recommend measure-
system SLE vasculitis may produce ocular abnor- ment of antibodies to b2 glycoprotein 1, a serum
malities, such as internuclear ophthalmoplegia, protein cofactor that is the target of most antibodies
nystagmus, cranial nerve palsies (second, third, to cardiolipin and some lupus anticoagulants. High
fifth, sixth, or seventh nerve palsies), homony- titers of IgG anticardiolipin (>50 IU) indicate high
mous hemianopia, and papilledema [198, 223]. risk for a clinical episode of clotting. Quantities of
aPL may vary markedly over time; repeated testing
6.1.2.4 Laboratory Findings is justified if clinical manifestations of the aPL anti-
Laboratory tests serve (1) to establish or rule out body syndrome (APS) appear. Making a diagnosis
the diagnosis; (2) to follow the course of disease, of APS, with or without SLE, requires the presence
particularly to suggest that a flare is occurring or of clotting and/or repeated fetal losses plus at least
organ damage is developing; and (3) to identify two positive tests for aPL, at least 12 weeks apart.
adverse effects of therapies. An additional autoantibody test with predictive
Diagnostically, the most important autoantibod- value (not used for diagnosis) detects anti-Ro,
ies to detect are ANA since the test is positive in which indicates increased risk for neonatal lupus,
>95% of patients, usually at the onset of symptoms sicca syndrome, and SCLE. Women with child-
[224]. A few patients develop ANA within 1 year of bearing potential and SLE should be screened for
symptom onset; repeated testing may, thus, be use- aPL and anti-Ro.
ful. ANA-negative lupus exists, but is very rare in Antibodies to coagulation factors VIII, IX, XI,
adults and is usually associated with other autoan- or XII, to platelets, or to immunoglobulins (rheu-
tibodies (anti-Ro or anti-DNA). High-titer IgG matoid factor) also may occur in SLE patients;
antibodies to double-stranded DNA (dsDNA) (but these abnormalities also may be seen in other
not to single-stranded DNA) are specific for SLE diseases.
(Table 3.9). There is no international standardized The presence of low serum complement [C3
test for ANA; variability between different service and C4, or CH50 (total hemolytic complement)]
laboratories is high. Enzyme-linked immunosor- levels coupled with the presence of anti-DNA
bent assays (ELISA) and immunofluorescent reac- antibodies is highly specific for SLE [225]. Low
tions of sera with the dsDNA in the flagellate serum complement levels, serum cryoglobulins,
Crithidia luciliae have ~60% sensitivity for SLE; or serum immune complexes may correlate with
identification of high-avidity anti-dsDNA in the exacerbation of the disease.
Farr assay is not as sensitive but may correlate bet- Urinalysis in active nephritis may show pro-
ter with risk for nephritis. Titers of anti-dsDNA teinuria, microscopic hematuria, and cellular
vary over time. In some patients, increases in quan- casts; this test and the serum creatinine test should
tities of anti-dsDNA herald a flare, particularly of be done periodically in patients with SLE.
194 6 Noninfectious Scleritis
Normochromic and normocytic anemia (due the criteria for the diagnosis of SLE may fall
to retarded erythropoiesis), neutropenia, lympho- short of satisfying the criteria for many years
cytopenia, and thrombocytopenia are frequent while experiencing their recurrent ocular inflam-
findings. A hemolytic anemia with reticulocyto- matory problem. Two or three of the established
sis and low hematocrit, with or without positive SLE diagnostic criteria may be present (most
Coombs’ test, may antedate other manifestations often ANA positivity, episodic mouth sores, pho-
of the disease by many years. Elevation of the tosensitivity, anemia, or arthritis) coincident with
ESR is common in active SLE [189]. or prior to the onset of the ocular inflammation.
It is useful to follow tests that indicate the sta- Over the ensuing years, other SLE manifesta-
tus of organ involvement known to be present tions, such as typical rash, glomerulonephritis, or
during SLE flares. These might include hemoglo- CNS vasculitis, appear, allowing definitive estab-
bin levels, platelet counts, urinalysis, and serum lishment of the diagnosis. We believe that ocular
levels of creatinine or albumin. There is great inflammation (scleritis, episcleritis, anterior
interest in identification of additional biomarkers uveitis, or retinal vasculitis) should be added to
of disease activity. Candidates include levels of the SLE diagnostic criteria list. We do not know
anti-DNA antibodies, several components of whether or not earlier definitive diagnosis estab-
complement (C3 is most widely available), acti- lishment with earlier systemic therapy would
vated complement products (including those that favorably alter the prognosis for SLE patients;
bind to the C4d receptor on erythrocytes), IFN- that possibility can be answered only by a large,
inducible genes, soluble IL-2, and urinary adi- prospective controlled clinical trial.
ponectin or monocyte chemotactic protein 1.
None is uniformly agreed upon as a reliable indi-
cator of flare or of response to therapeutic inter- 6.1.3 Ankylosing Spondylitis
ventions. The physician should determine for each
patient whether certain laboratory test changes Ankylosing spondylitis (Bekhterev’s disease,
predict flare. If so, altering therapy in response to Marie–Strümpell disease, rheumatoid spondyli-
these changes has been shown to prevent flares. tis) is a chronic inflammatory systemic disease of
unknown cause that primarily involves the joints
6.1.2.5 Diagnosis of the spine, sacroiliac joints, and periarticular
There is no clinical or laboratory abnormality soft tissues. The disease is the prototype of a
that is pathognomonic for SLE. Because SLE group of disorders referred to as spondyloar-
patients show marked variability in their clinical thropathies, and characterized by common fea-
manifestations and laboratory findings, a group tures that differentiate them from RA. These
of several criteria has been developed in an features include (1) radiographic sacroiliitis with
attempt to include SLE patients and to exclude or without accompanying spondylitis, with a
patients with other disorders and thereby estab- marked tendency toward calcification and ossifi-
lish a diagnosis of SLE. The American cation of ligaments (ankylosis); (2) inflammatory
Rheumatism Association developed in 1971 and peripheral arthritis, often asymmetric, with lack
revised in 1982 a set of 11 diagnostic criteria for of rheumatoid nodules; (3) no association with
the diagnosis of SLE (Table 6.6). A diagnosis of rheumatoid factor or ANA; (4) strong association
SLE may be made in the presence of four or more with HLA-B27; (5) tendency for ocular inflam-
of these criteria, serially or simultaneously, dur- mation (especially anterior uveitis and conjuncti-
ing any interval of observation. Our experience, vitis); (6) variable mucocutaneous lesions; and
extending over the past 20 years, with a large (7) occasional cardiac abnormalities. The spon-
number of patients with scleritis, episcleritis, dyloarthropaties include AS, ReA, psoriatic
anterior uveitis, and retinal vasculitis, shows arthritis (PA), and enteropathic (IBD) arthritis
unequivocally that patients who eventually fulfil (Table 6.7) [226].
Table 6.6 American Rheumatism Association revised criteria for the diagnosis of systemic lupus erythematosus (1982)
Four or more of the following:
1. Malar rash: fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rash: frythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic
scarring may occur in older lesions
3. Photosensitivity: skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis: nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling,
or efusion
6. Serositis
(a) Pleuritis: convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion
OR
(b) Pericarditis: documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder
(a) Persistent proteinuria greater than 0.5 g/day or greater than 3+ if quantitation not performed
OR
(b) Cellular casts: may be red, hemoglobulin, granular, tubular, or mixed
8. Neurological disorder
(a) Seizures: in the absence of offending drugs or known metabolic derangements: e.g., uremia, ketoacidosis, or
electrolyte imbalance
OR
(b) Psychosis: in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or
electrolyte imbalance
9. Hematological disorder
(a) Hemolytic anemia: with reticylocytosis
OR
(b) Leukopenia: less than 4,000/mm total on two or more occasions
(c) Lymphopenia: less than 1,500/mm on two or more occasions
OR
(d) Thrombocytopenia: less than 100,000/mm in the absence of offending drugs
10. Immunological disorder
(a) Positive LE cell preparation
(b) Anti-DNA antibody to native DNA in abnormal titer
(c) Anti-Sm: presence of antibody to Sm nuclear antigen
OR
(d) False-positive serological test for syphilis known to be positive for at least 6 months and confirmed by
Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear antibody: an abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at
any point in time and in the absence of drugs known to be associated with “drug-induced lupus syndrome”
6.1.3.1 Epidemiology
Ankylosing spondylitis has a prevalence of about
1% in the general population. It is seen mainly in
Caucasians and is exceptionally rare in Japanese
and black Africans. Onset is more frequent
between 15 and 40 years of age, and clinical evi-
dence of AS is 3–4 times more frequent in men
than in women. However, if radioisotope studies
that detect subclinical sacroiliitis are taken into
account, AS occurs almost as frequently in
females as in males (although with milder and
more peripheral disease) [227]. There is a defini-
tive correlation between the prevalence of the dis-
ease and the presence of the histocompatibility
antigen HLA-B27 [228]. More than 90% of AS
Caucasian patients and 52% of their first-degree
relatives are HLA-B27 positive, compared with
only 6% of a control population [229]. Between 1
and 10% of the HLA-B27-positive adults in the
general population and 20–30% of the HLA-B27-
positive first-degree relatives of spondylitis
patients are likely to suffer from AS [230].
with a large number of patients with uveitis, is precede the articular involvement of AS, it
that AS HLA-B27 patients may develop a violent, usually occurs after years of active AS disease,
explosive onset of anterior uveitis with hypopyon. especially in patients with marked articular and
The posterior segment is usually spared, although extraarticular manifestations. Any patient who
cystoid macular edema and, in our experience, develops diffuse anterior scleritis after previous
retinal vasculitis may occasionally occur. episodes of recurrent anterior uveitis should be
Individual attacks of uveitis usually subside with- examined for AS.
out residual visual impairment in 4–8 weeks, but
they may recur over a period of years and become Episcleritis
bilateral. Immediate ocular application of topical Episcleritis is rare in AS. In our own series of 85
steroids and mydriatics by the patient as soon as patients with episcleritis, there were three patients
the first symptoms appear may abort the attack, with AS: two female and one male. Two patients
provided he/she is soon seen by an ophthalmolo- had simple episcleritis and one had nodular epis-
gist who can manage the attack and detect the cleritis. Episcleritis appeared an average of
ocular complications either of the treatment or 6 years after the onset of the disease and responded
disease (e.g., glaucoma, cataract, and macular well to oral nonsteroidal anti-inflammatory ther-
edema). AS must always be considered in the dif- apy. There were no corneal lesions, cataract,
ferential diagnosis of anterior uveitis. macular edema, or decrease in visual acuity.
Fig. 6.11 Lumbosacral spine film of patient with reactive arthritis, including ankylosing spondylitis. Note the com-
plete obliteration of the right sacroiliac joint, with pronounced reactive sclerosis of the left sacroiliac joint due to
bony ankylosis
In mild cases, years may elapse before with certainty, the finding of HLA-B27 positivity
unequivocal sacroiliac abnormalities are evident increases the probability that the presumptive
on plain radiographs. Computed tomography and diagnosis is correct; however, it does not estab-
magnetic resonance imaging (MRI) can detect lish the diagnosis.
abnormalities reliably at an earlier stage than The widely used modified New York Criteria
plain radiography. Dynamic MRI with fat satura- (1984) are classification rather than diagnostic
tion, either short tau inversion recovery (STIR) criteria, and they are insensitive in early or mild
sequence or T1-weighted images with contrast cases. These consist of the following: (1) a his-
enhancement, is highly sensitive and specific for tory of inflammatory back pain, (2) limitation of
identifying early intraarticular inflammation, car- motion of the lumbar spine in both the sagittal
tilage changes, and underlying bone marrow and frontal planes, (3) limited chest expansion,
edema in sacroiliitis. These techniques are also and (4) definite radiographic sacroiliitis. Criterion
highly sensitive for evaluation of acute and 4 plus any one of the other three criteria are suf-
chronic spinal changes. ficient for a diagnosis of definite AS. Dynamic
MRI is definitely more sensitive than plain radi-
6.1.3.5 Diagnosis ography. Although its exact sensitivity and speci-
The diagnosis of AS depends on suspicion, his- ficity remain to be defined, it is recommended in
tory, clinical evaluation, and radiological confir- suspected cases in which plain radiography either
mation. HLA-B27 typing cannot be used as a fails to show definite changes or is undesirable
screening test because a majority of HLA-B27 (e.g., in young women or children).
individuals in the general population remains
unaffected, and AS may occasionally occur in
HLA-B27-negative individuals. Furthermore, 6.1.4 Reactive Arthritis (Reiter)
most patients with AS can be readily diagnosed
on the basis of clinical and radiological findings, Reactive arthritis follows certain enteric or geni-
and therefore do not need the HLA-B27 test. In tourinary infections in genetically susceptible
cases of clinical suspicion of AS but with radio- individuals. ReA may follow Shigella, Salmonella,
logic findings of sacroiliitis difficult to recognize Yersinia, or Campylobacter enteric infections
200 6 Noninfectious Scleritis
subtype, shows a severe destructive and deform- legs and scalp. Unilateral simple episcleritis
ing polyarthritis with ankylosing of joints, “tele- appeared 5 years after the onset of the psoriasis
scoping” of digits, and possible ankylosis of the and recurred many times. There were no other
spine. Apart from this deforming group, PA is not ocular findings or decrease in visual acuity.
a severe disease; the pain and disability are much
less than those produced by RA [265]. 6.1.5.4 Laboratory and Radiographic
Findings
6.1.5.3 Ocular Manifestations Tests for rheumatoid factor and ANAs are usually
Eye lesions of psoriasis consist of conjunctivitis negative. The ESR is frequently elevated and
and anterior uveitis and occasionally scleritis and mild anemia may appear. Hyperuricemia may be
episcleritis [266]. Anterior uveitis is usually mild associated in patients with severe skin involve-
with fine endothelial keratic precipitates. PA must ment and gout has been reported on several occa-
always be considered in the differential diagnosis sions [267]. HLA-B27 is found in 50–70% of
of anterior uveitis. patients with axial disease, but in less than
15–20% in patients with only peripheral joint
Scleritis involvement.
The reported incidence of PA in patients with Radiographic findings depend on the type of
scleritis is 1.44% [122]. Conversely, the articular involvement. Distal interphalangeal
reported incidence of scleritis in patients with PA joints may show erosions with widening of the
is 1.8% [266]. Scleritis in PA usually appears joint space and expansion of base of terminal
after many years of active disease and, although phalanx. Dissolution of bones, especially the
diffuse anterior scleritis is often seen [204], it metatarsal, may be seen in “arthritis mutilans”
may take almost any form of scleritis. resulting in a “pencil in cup” appearance or “fish
In our own series of 500 patients with scleritis, tail” deformity. Characteristics of axial PsA
five patients had PA (1%). They were three include asymmetric sacroiliitis; compared with
females and two males with a mean age of idiopathic AS, less zygoapophyseal joint arthritis
54 years. Three patients had diffuse scleritis and and fewer and less symmetric and delicate syn-
two patients had posterior scleritis with choroidal desmophytes; fluffy hyperperiostosis on anterior
folds, subretinal mass, choroidal detachment, and vertebral bodies; severe cervical spine involve-
diffuse anterior scleritis. All patients had had PA ment, with a tendency to atlantoaxial subluxation
for many years. One patient had anterior uveitis- but relative sparing of the thoracolumbar spine;
associated scleritis (sclerouveitis) and two patients and paravertebral ossification [261]. Ultrasound
had previous episodes of recurrent anterior uveitis. and MRI both readily demonstrate enthesitis and
There was no conjunctivitis, glaucoma, cataract, tendon sheath effusions that can be difficult to
or macular edema, and final visual acuity was not assess in physical examination.
decreased. Any patient who develops scleritis
should be questioned and examined for skin and 6.1.5.5 Diagnosis
nail lesions. Any patient who develops scleritis Psoriatic arthritis is diagnosed in the presence of
after previous episodes of recurrent anterior skin psoriatic lesions and the presence of one or
uveitis should be examined for PA, ReA, or AS. more swollen joints for at least 3 months (elbows,
wrists, knees, ankles, metacarpophalangeal,
Episcleritis proximal interphalangeal, and distal interphalan-
Episcleritis is also uncommon in PA and usually geal joints of the hands and feet, sacroiliacs, lum-
occurs after years of active disease. In our own bar or cervical spine), with radiologic changes
series of 85 patients with episcleritis, one patient compatible with PA, including erosions in periph-
had PA (1.2%). The patient was a 48-year-old eral joints or definite spinal changes. As in AS or
female with chronic seronegative asymmetric oli- ReA, the finding of HLA-B27 positivity increases
goarthritis and skin psoriatic lesions, especially in the probability that the presumptive diagnosis is
206 6 Noninfectious Scleritis
correct but does not establish the diagnosis. involved. Sacroiliitis with or without spondylitis
Diagnosis can be challenging when the arthritis appears in 10% of patients with CD or UC and
precedes psoriasis, the psoriasis is undiagnosed affects men more commonly than women. This
or obscure, or the joint involvement closely form of arthritis is strongly associated with HLA-
resembles another form of arthritis. A high index B27, which is present in 50–70% of the patients.
of suspicion is needed in any patient with an
undiagnosed inflammatory arthropathy. The his- 6.1.6.2 Systemic Manifestations
tory should include inquiry about psoriasis in the Gastrointestinal and articular manifestations are
patient and family members. Axial symptoms or the hallmarks of IBD. Other systemic manifesta-
signs, dactylitis, enthesitis, ankylosis, pattern of tions include anemia, hepatobiliary disorders,
joint involvement, and characteristic radiographic thrombophlebitis, ureteral obstruction, nephro-
changes can be helpful clues. A history of trauma lithiasis, prostatitis, oral ulcerations, erythema
to an affected joint preceding the onset of arthri- nodosum, and pyoderma gangrenosum. Some of
tis is said to occur more frequently in PsA than in these manifestations, particularly the skin lesions,
other types of arthritis, perhaps reflecting the are due to small-sized vessel vasculitis.
Koebner phenomenon in which psoriatic skin
lesions can arise at sites of the skin trauma. Gastrointestinal and Articular
Manifestations
Gastrointestinal symptoms in CD include right
6.1.6 Inflammatory Bowel Disease- lower quadrant colicky pain associated with
Associated Arthritis cramps and constipation, diarrhea, nausea, vom-
iting, fever, anorexia, and weight loss. Fistulae to
Crohn’s disease (CD) and ulcerative colitis (UC) the skin or other organs are common. Patients
are IBDs that may have articular manifestations, with UC present with left lower quadrant cramp-
such as peripheral arthritis or spondyloarthropa- ing pain, relapsing bloody mucoid diarrhea lead-
thy. Crohn´s disease is a chronic focal granu- ing to dehydration and electrolyte imbalance,
lomatous disease characterized by transmural fever, anorexia, and weight loss.
inflammation of the gastrointestinal tract, pre- Peripheral arthritis in both diseases usually
dominantly the terminal ileum and cecum. UC is occurs 6 months to several years after the onset
a chronic inflammatory disease that affects the of intestinal manifestations, although occasion-
colonic mucosa and submucosa, predominantly ally it may appear at the same time, or preceding
the rectosigmoid area [268]. colitis. The spectrum of peripheral arthritis
includes acute self-limited attacks of oligoarthri-
6.1.6.1 Epidemiology tis, primarily knees and ankles, that often coin-
Crohn´s disease occurs in 2–3 of 100,000 indi- cide with relapses of IBD and usually resolves
viduals and men are affected more often than within a few weeks without sequelae; other joints
women. UC occurs in 2–7 of 100,000 individuals that may be involved are the proximal interpha-
and females are more commonly affected than langeal, elbow, shoulder, and wrists. It also
men. Both diseases have a first peak of incidence includes a more chronic and symmetric polyar-
between the ages of 12 and 30 years, with a sec- ticular arthritis that runs a course independent of
ondary peak at the age 50. In comparison with the IBD. The patterns of joint involvement are simi-
general population, Jews have a higher risk of lar in UC and CD. Arthritis is more common in
developing the diseases. patients with extensive or severe bowel disease.
Peripheral arthritis appears in 20% of patients Joint involvement in UC is more frequent in
with CD and in 10% of patients with UC, usually patients with colon disease than in patients with
those with other extraintestinal manifestations. It isolated rectal involvement. In CD, articular
most commonly begins between the ages of 25 manifestations are more common in patients with
and 45 years, and women and men are equally colon disease than in patients with small bowel
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 207
involvement. Patients with UC or CD with other spondylitis [270, 271, 274]. IBD must always be
manifestations, such as skin lesions (erythema considered in the differential diagnosis of anterior
nodosum and pyoderma gangrenosum), finger uveitis.
clubbing, mouth ulceration, or uveitis, are more
likely to develop arthritis. Proctocolectomy may Scleritis
lead to remission of arthritis in many patients The reported incidence of IBD in patients with
with UC but in only a small number of patients scleritis ranges from 2.06 to 9.67% [121, 123,
with CD [268]. 124]. It is more common in patients with arthritis,
Sacroiliitis with or without spondylitis, indis- anemia, skin manifestations, oral ulcers, or liver
tinguishable from AS, usually precedes the intes- disease than in patients without extraintestinal
tinal involvement and progresses independently manifestations [271, 274]. Although scleritis may
of the bowel disease or proctocolectomy [268]. precede bowel disease, it usually occurs some
years after the onset of gut symptoms, particu-
6.1.6.3 Ocular Manifestations larly during active episodes [272, 274, 276].
The reported incidence of ocular manifestations Scleritis associated with IBD is recurrent and
in patients with IBD ranges from 1.9 to 11.8% may take the form of almost any type of scleritis,
[269–272]. The most common eye findings in including necrotizing anterior scleritis [204, 274,
IBD patients include episcleritis, anterior uveitis, 277]. Treatment of the bowel manifestations may
keratitis, and scleritis; conjunctivitis, macular control the ocular condition. Knox et al. [271]
edema, serous retinal detachment, choroidal infil- reported that the presence of scleritis or episcleri-
trates, orbital pseudotumor, extraocular muscle tis in a patient with IBD is useful in differentiat-
paresis, retrobulbar neuritis, papillitis, orbital cel- ing CD and UC because, in their experience,
lulitis, and myositis are seen less frequently [273, these ocular lesions are not associated with UC.
274]. Ocular involvement in CD or UC patients is In our own series of 500 patients with scleritis,
more common in those with arthritis [269, 270, 11 patients had IBD (2.2%), nine had CD, and
274]; other extraintestinal manifestations, such as two had UC. The patients were eight women and
anemia, skin lesions, liver disease, and oral three men with a mean age of 47 years (range,
ulcers, also are frequently associated with ocular 33–67 years). All nine patients with CD had
disease. Ocular involvement in CD patients is arthritis. Other extraintestinal manifestations
more likely in those with colitis or ileocolitis than included anemia, sclerosing colangitis, and oral
in patients with small bowel involvement alone ulcers. In two patients, scleritis was the initial
[274]. Although eye lesions may precede the manifestation whose study led to the diagnosis of
bowel disease, they often occur with exacerba- CD. Six patients had diffuse scleritis, one patient
tion of colitis [269, 272–275]. After proctocolec- had nodular scleritis, one patient had necrotizing
tomy, the ocular prognosis is variable [269]. scleritis, and one patient had posterior scleritis.
Because effective treatment of the bowel disease The scleritis was persistent or recurrent, and often
may improve the ocular and systemic prognoses, related to episodes of active bowel disease. There
patients with ocular manifestations and gastroin- were anterior uveitis in two patients, peripheral
testinal symptoms must be studied to define the keratitis in three patients, and glaucoma in one
nature of their gut involvement. The ophthalmol- patient, but final visual acuity was not affected.
ogist may be the first to diagnose an IBD. Scleritis occurred after several episodes of ante-
rior uveitis in two patients. Any patient who
Anterior Uveitis develops scleritis after recurrent anterior uveitis
Anterior uveitis is usually nongranulomatous and should be examined for CD. Crohn’s disease
recurrent, with fine white keratic precipitates, mod- must always be included in the differential diag-
erate cells, and flare. It may occur before, during, nosis of a patient with scleritis.
or after the initial bowel attack, and often is associ- The two patients with UC had diffuse scleritis
ated with the presence of arthritis, particularly with anterior uveitis. There were no corneal
208 6 Noninfectious Scleritis
lesions, glaucoma, and loss of vision. There was occult IBD. Radiographic changes in the axial
no previous uveitis. Scleritis was the initial mani- skeleton are the same as in uncomplicated AS,
festation whose study led to the diagnosis of UC that is, minimal destructive signs, such as cystic
in both patients. changes, narrowing of the joint space, and ero-
sions. Erosions are uncommon in peripheral
Episcleritis arthritis but may occur, particularly in the meta-
Episcleritis is common in IBD [271, 274]. Knox tarsophalangeal joints.
et al. [271] reported that the presence of episc-
leritis in UC is a good indicator to consider 6.1.6.5 Diagnosis
changing the diagnosis to CD because, in their Diarrhea and arthritis are both common condi-
experience, episcleritis is associated only with tions that can coexist for a variety of reasons. ReA
CD. Although episcleritis may appear prior to the and IBD-associated arthritis are the most com-
onset of gut manifestations [276], it usually mon causes. Rare causes include celiac disease,
occurs after some years of bowel disease, espe- blind loop syndromes, and Whipple’s disease.
cially during periods of disease exacerbation Diagnosis of CD is made on the basis of clini-
[274]. Episcleritis is more frequently seen in cal signs and symptoms combined with charac-
patients with arthritis and other extraintestinal teristic X-ray findings, including deep (collar
manifestations [269, 271, 274]. button) ulcerations, long strictured segments
In our own series of 85 patients with episcleri- (string sign), and skip areas. Colonoscopy may
tis, two patients had IBD (2.35%); one patient be helpful when there is colonic involvement,
had CD and one patient had UC. All were female, and biopsies may show granuloma formation
with a mean age of 55 years, who developed with transmural inflammation [279].
recurrent simple and nodular episcleritis, respec- Diagnosis of UC is based on clinical presenta-
tively, an average of 6 years (range, 5–7 years) tions along with the exclusion of infectious, para-
after the diagnosis of CD and UC. There were no sitic, and neoplastic etiologies. Proctoscopy may
corneal lesions, anterior uveitis, glaucoma, or reveal friability, edema, ulcerations, and mucopu-
decrease in visual acuity. rulent exudate. Characteristic X-ray findings
include lack of haustral markings, fine serrations,
Keratitis large ulcerations, and pseudopolyps. Biopsies
Keratitis in IBD, specifically in CD, consists of show microabcesses of the crypts of Lieberkühn
either peripheral small round subepithelial gray and macroscopic ulcerations; the inflammatory
infiltrates, probably due to acute inflammation, or response is limited to the mucosa.
peripheral nebulous subepithelial infiltrates,
probably due to scarring [278].
6.1.7 Relapsing Polychondritis
6.1.6.4 Laboratory and Joint Radiologic
Findings Relapsing polychondritis (RP) is an uncommon
Inflammatory bowel disease may account for multisystem disease of unknown cause. Cartilage
anemia, leukocytosis, elevated sedimentation and other tissues with a high concentration of
rate, and evidence of malabsorption or protein glycosaminoglycans are the main target of dam-
loss. Rheumatoid factor and ANA tests are nega- age. These include the pinnae of the ears, nasal
tive. Joint fluid is usually at least mildly inflam- cartilage, eustachian tubes, larynx, trachea, bron-
matory. Of patients with AS and IBD, 30–70% chi, joints, vessels, and sclera [280].
carry the HLA-B27 gene, compared with >90%
of patients with AS alone and 50–70% of those 6.1.7.1 Epidemiology
with AS and psoriasis. Hence, definite or proba- Relapsing polychondritis is most frequent in the
ble AS in an HLA-B27-negative individual in the fourth decade of life, occurs predominantly in
absence of psoriasis should prompt a search for Whites, and does not have sexual predilection.
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 209
edema, cotton-wool spots, irregular caliber of one woman, with a mean age of 58 years. One
retinal vessels, and retinal vascular occlusion patient had unilateral diffuse scleritis and the
[300, 304, 305]. Sometimes, retinopathy may be other patient had unilateral necrotizing scleritis
secondary to concomitant hypertension. with PUK. PAN had already been diagnosed
Papilledema or papillitis due to optic nerve vasc- 1 year before the onset of nodular scleritis in the
ulitis may occur and inflammation of orbital ves- first patient. Necrotizing scleritis with PUK was
sels may lead to exophthalmos [300, 301, the first manifestation whose study led to the
306–308]. Vasculitic involvement of the central diagnosis of PAN in the second patient; biopsy of
and peripheral nervous system may produce third, an elbow nodule compatible with PAN and sac-
fifth, sixth, and seventh nerve palsies, homony- cular aneurysms in the superior mesenteric artery
mous hemianopia, nystagmus, amaurosis fugax, in the setting of systemic clinical findings, such
and Horner’s syndrome [306]. Anterior uveal as constitutional symptoms, dizziness, profound
vascular inflammation is occasionally seen as quadriceps muscle weakness, tinnitus, skin
anterior uveitis with leakage of protein into the lesions, and grand mal seizure, confirmed the
anterior chamber [304, 309]. Conjunctival infarc- diagnosis of PAN. Prompt and aggressive therapy
tion may produce pale yellow, raised and friable improved the ocular and systemic prognoses. The
conjunctival lesions, chemosis, and subconjuncti- ophthalmologist may play an important role in
val hemorrhages [309]. Vascular inflammation of the diagnosis and management of a patient with
episcleral, scleral, and limbal vessels may lead to this potentially lethal vasculitic disease.
episcleritis, scleritis, and sclerokeratitis [303,
304, 310–312]. Ocular involvement may be the Episcleritis
first manifestation of PAN [203, 311, 313]. Although histological involvement of episcleral
vessels is frequently seen, episcleritis is less often
Scleritis detected clinically [298, 303]. It may be simple
The reported incidence of PAN in patients with or diffuse, and recurrent [204]. Episcleritis in
scleritis ranges from 0.68 to 6.45% [121–124]. patients with PAN is less common than scleritis
Necrotizing anterior scleritis, often associated [122]. There were no patients with PAN in our
with PUK, is the most frequent type of scleritis in series of patients with episcleritis.
patients with PAN [310–312]. Scleritis becomes
extremely painful and is highly destructive unless 6.1.8.4 Laboratory and Angiographic
correct diagnosis and control of the underlying Findings
systemic disease are achieved. Corneal ulceration There are no laboratory tests that can confirm the
is progressive, both circumferentially and cen- diagnosis of PAN. Leukocytosis, anemia, and an
trally, with undermining of the central edge of the elevated ESR may be seen. Eosinophilia is seen
ulcer, resulting in overhanging lip of the cornea. only rarely and, when present at high levels, sug-
Scleral involvement helps to distinguish classic gests the diagnosis of Churg–Strauss syndrome.
Mooren’s ulcer from sclerokeratitis associated Hypergammaglobulinemia may be present, and
with vasculitic diseases, such as RA, GPA up to 30% of patients have a positive test for hep-
(Wegener), or PAN. In most cases, sclerokeratitis atitis B surface antigen. Antibodies against
present after PAN diagnosis, but occasionally myeloperoxidase or proteinase-3 (PR-3) (ANCA)
may be the presenting manifestation of the dis- are rarely found in patients with PAN.
ease [203, 311, 313]. The ophthalmologist may In cases with urinary sediment red cells, red
play an important role in the diagnosis and man- cell casts, or proteinuria, renal disease must be
agement of a patient with this potentially lethal suspected. The angiographic finding of small,
vasculitic disease. In our series of 500 patients aneurysmal dilatations in renal, hepatic, and gas-
with scleritis, there were no patients with PAN. trointestinal vessels may be helpful in establish-
However, in our prior series [123], PAN was ing the diagnosis, although they may also be found
diagnosed in two patients (1.16%): one man and in SLE [314] and fibromuscular dysplasia [315].
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 213
Table 6.9 Classic diagnostic triad for granulomatosis with polyangiitis (Wegener)a
1. Necrotizing granuloma of the upper and/or lower respiratory tract:
There is typically mucosal inflammation and ulceration in the respiratory tract. Mucosal inflammation is
characterized by foci of epithelioid cells, multinucleated giant cells, and fibrillar organization with secondary
necrosis of fibrillar tissue. Tissue eosinophilia is common
2. Vasculitis:
The vasculitis involves both arteries and veins and is of a focal necrotizing variety. The vasculitis is granuloma-
tous in nature, featuring multinucleated giant cells. This vasculitis is typically seen in lung tissue, and is variable
present elsewhere
3. Nephritis:
The nephritis is a focal necrotizing glomerulitis with fibrinoid necrosis and thrombosis of capillary loops,
sometimes extending beyond Bowman’s capsule. Neutrophils are usually present; granulomatous inflammation
with giant cells is only occasionally seen
a
Based on the pathological findings described by Godman and Churg [329]
with Churg–Strauss syndrome have circulating kidneys are spared; chronic hemorrhagic rhinitis,
ANCA that is usually antimyeloperoxidase. sinusitis, otitis, ulcerations in the oral cavity,
nasolacrimal duct obstruction, orbitopathy, con-
6.1.9.5 Diagnosis junctivitis, keratitis, scleritis, or uveitis also may
Diagnosis of Churg–Strauss syndrome is based occur [331–337]. Pathologically, involved tissues
on both pathological and clinical findings. reveal necrotizing granulomatous inflammation
Demonstration of necrotizing small-vessel vasc- and vasculitis. A highly limited form of GPA has
ulitis and eosinophilic necrotizing intra- and been described by our group [338] in patients
extravascular granulomas on biopsy material with only ocular or orbital disease on the basis of
confirms the diagnosis of Churg–Strauss syn- a constellation of histopathological findings and
drome in a patient with compatible multisystem a positive laboratory test (ANCAs).
clinical findings and laboratory tests (most impor- Untreated GPA is rapidly fatal, particularly
tantly asthma and peripheral blood eosinophilia) once there is functional renal impairment; onset
[318, 319, 322–327]. Involved tissues more com- of renal disease is associated with a mean sur-
monly biopsied for diagnosis are lung, skin, and vival of 5 months, with a 1-year mortality rate of
peripheral nerves. 82% of patients and a 2-year mortality rate of
90% [330]. Therapy with systemic corticoster-
oids and immunosuppressive agents may induce
6.1.10 Granulomatosis with remission in 93% of patients [337]. It is impera-
Polyangiitis (Wegener) tive, therefore, to establish the diagnosis and ini-
tiate appropriate treatment as early as possible in
Granulomatosis with polyangiitis (Wegener) is a the course of the disease.
systemic disease of unknown etiology character-
ized, as it was originally described, by granu- 6.1.10.1 Epidemiology
lomatous inflammation of the upper and lower GPA (Wegener) is a rare disease that typically
respiratory tract, necrotizing vasculitis, and occurs in patients between 40 and 60 years of
nephritis [327–329]. A description of classic age, although presentation at ages ranging from
pathological findings is shown in Table 6.9. Aside 7 to 75 has been reported [337, 339]. The dis-
from this fulminant, active, generalized, or dis- ease occurs slightly more frequently in men
seminated form of the disease, an indolent form than in women, with a ratio up to 1.5:1 [330,
called limited, initial, or locoregional GPA also 337, 340]. GPA (Wegener) may affect blacks
may occur [330–334]. In the limited form of and Hispanics, but is most commonly seen in
GPA, the respiratory tract is involved and the Whites [337].
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 215
symptoms and may be the initial manifestation of abnormalities found in patients with GPA.
a systemic disease exacerbation [342, 351]. Thrombocytosis may be seen as an acute-phase
Necrotizing scleritis may appear after surgical reactant. It was in 1985 that the presence of
trauma of the sclera. ANCA in serum was found to be specific for WG
In our series of 500 patients with scleritis, 14 and to correlate with disease activity [352].
patients had GPA (2.8%). Two patients had com- Subsequent studies confirmed that ANCA is
plete GPA, ten patients had limited GPA, and two indeed specific for GPA [340, 353, 354], with
patients had highly limited GPA. The mean age of specificity as high as 99% by indirect immuno-
our patients was 55 years (range, 31–86 years) and fluorescence techniques and 98% by ELISA
the scleritis was more common in females than in detection [340]. The sensitivity of ANCA depends
males (nine females and five males). In seven on disease activity and extent: sensitivity is 32%
patients, the presence of scleritis was the first for GPA patients in full remission after limited
manifestation whose study led to the diagnosis of disease, 67% for GPA patients with active limited
GPA; the mean time between the onset of scleritis disease, and 96% for GPA patients with active
and diagnosis of GPA was 8.5 months. The scleri- generalized disease. These findings indicate that
tis attacks were persistent or recurrent, and often a negative ANCA test does not rule out a diagno-
related to episodes of active disease. Necrotizing sis of GPA. “False-positive” ANCA titers have
anterior scleritis was present in three patients and been found in only 0.6% of patients, all of whom
diffuse anterior scleritis was present in 11 patients. have glomerulonephritis, pulmonary–renal syn-
PUK was present in 5 of 14 patients (36%) with drome, or vasculitis [340]. Although still pending
scleritis; three patients had necrotizing anterior confirmation, relapses of GPA seem to be pre-
scleritis and two patients had diffuse anterior ceded by elevation of ANCA titers.
scleritis. Anterior uveitis was present in 3 of 14 At least two types of ANCA staining of neu-
patients (21.4%) with scleritis. Keratitis, uveitis, trophils may occur. The classic granular cyto-
glaucoma, cataract, and disk edema caused by plasmic staining pattern (C-ANCA) is specific
scleral inflammation may affect visual acuity. A for myeloblastin, a neutrophil serine protease
decrease in visual acuity (equal to or greater than referred to as PR-3 [355, 356]. C-ANCA is highly
two Snellen lines at the end of the follow-up period specific for GPA [338, 339], but not all patients
or vision equal to or worse than 20/80 at the first positive for C-ANCA fullfil the classic criteria
examination) occurred in 36% of the patients. for GPA [357]. A perinuclear staining pattern
(P-ANCA) is specific for various lysosomal
Episcleritis enzymes, such as myeloperoxidase, cathepsin G,
Episcleritis may occur in GPA but is less frequent human leukocyte elastase, or lactoferrin. P-ANCA
than scleritis [342, 344]. It may be simple or nod- is a specific marker of idiopathic necrotizing and
ular and often is recurrent. Episcleritis in GPA crescentic glomerulonephritis, a disease fre-
may be the first manifestation that prompts the quently associated with microscopic polyarteritis
patient to seek medical advice [342]. In our series and occasionally with GPA [355]. The absence of
of 85 patients with episcleritis, there was one granulomata helps to distinguish microscopic
patient with GPA (1.18%). The patient was a polyarteritis from GPA, athough the clinical pic-
50-year-old man with complete GPA who devel- ture is similar. It would seem that GPA, micro-
oped recurrent simple episcleritis soon after the scopic polyarteritis, and idiopathic necrotizing
diagnosis of GPA. and crescentic glomerulonephritis are part of the
spectrum of one disease process. Although
6.1.10.4 Laboratory Findings C-ANCA is typically the ANCA associated with
Normochromic normocytic anemia, leukocyto- GPA [357, 358], there are cases that fullfil the
sis, thrombocytosis, an elevated ESR, mild classic criteria for GPA and show the P-ANCA
hypergammaglobulinemia (particularly of the pattern of staining [359].
IgA class), mildly elevated rheumatoid factor, The ANCA test must be included in the diag-
elevated CRP, and CICs are common nonspecific nostic evaluation of patients with ophthalmic
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 217
manifestations suggestive of systemic vasculitis all the typical features are not present at once, it
[351, 360]. In a study performed by us on the needs to be differentiated from the other vascu-
diagnostic value of ANCA testing in patients with litides, Goodpasture’s syndrome, relapsing
scleritis associated with GPA, ANCA titers were polychondritis, tumors of the upper airway or
highly specific and sensitive for GPA in patients lung, and infectious diseases, such as histoplas-
with scleritis [361]: of 23 patients with scleritis in mosis, mucocutaneous leishmaniasis, and rhino-
which ANCA titers were obtained, all seven scleroma, as well as noninfectious granulomatous
patients with positive titers had limited or gener- diseases. ANCA testing is an important adjunct
alized GPA and none of the 16 patients with neg- in the diagnosis of GPA because it has been
ative ANCA titers had GPA. found to be 99% specific and 96% sensitive for
Positive ANCA testing confirms the diagnosis the active generalized condition [340]. Because
of the highly limited forms of GPA in a patient of its high specificity, a positive test is sugges-
with scleritis and pathological detection of necro- tive of GPA, even in patients without compatible
tizing granulomas with or without inflammatory clinical and histopathological findings. However,
microangiopathy [338]. because ANCA is positive only in 67% of
Either type of ANCA (C- or P-ANCA) can be patients with active limited disease and in 32%
found in patients with generalized, limited, or of patients in full remission after limited disease
highly limited forms of GPA with ophthalmic [340], a negative ANCA test does not exclude
involvement [338, 360, 361]. the diagnosis, especially in patients with limited
The discovery of ANCA as a specific and sen- clinical features and characteristic histological
sitive index of generalized disease in GPA is findings.
likely to improve the prognosis for patients with Pathologic detection of necrotizing granulo-
this disease by facilitating earlier diagnosis and mas with or without vasculitis in involved
detection of relapse. However, a single positive extraocular tissues (nasal mucosal, sinus tissue,
ANCA test should be interpreted with caution. skin, and lung) confirms the diagnosis of GPA in
a patient with compatible systemic clinical find-
6.1.10.5 Diagnosis ings with or without positive ANCA testing.
The diagnosis of GPA is generally made on the Pathological detection of necrotizing granulomas
basis of the clinicopathological findings of necro- with or without inflammatory microangiopathy
tizing granulomatous lesions of the upper and in conjunctiva and/or scleral specimens in asso-
lower respiratory tract, glomerulonephritis, and ciation with complete and, especially, limited
frequent vasculitis involving other organ systems. clinical features confirms the diagnosis of GPA
The American College of Rheumatology estab- even if the ANCA testing is negative.
lished criteria for the diagnosis of GPA [362]. The In the absence of characteristic ocular histo-
presence of two or more of the following four cri- logical findings, a positive ANCA test is sugges-
teria was associated with a sensitivity of 88.2% tive of highly limited GPA, although not
and a specificity of 92% for GPA: (1) abnormal diagnostic. In the absence of positive ANCA test,
urinary sediment (red cell casts or five blood cells the presence of characteristic ocular histological
per high power field); (2) abnormal findings on findings without systemic clinical features does
chest radiograph (nodules, cavities, or fixed infil- not support the diagnosis of GPA.
trates); (3) oral ulcers or nasal discharge; and (4)
granulomatous inflammation (in the vessel wall,
perivascular, or extravascular). 6.1.11 Adamantiades–Behçet’s Disease
Cultures and special stains must be done to
rule out infectious causes of granulomatous Adamantiades–Behçet’s disease (ABD) is a
inflammation, such as acid-fast bacilli and fungi. chronic relapsing systemic vasculitis of unknown
In its typical presentation, the clinicopatho- etiology characterized by oral ulceration, genital
logic complex of GPA usually provides ready ulceration, and ocular inflammation. Although
differentiation from other disorders. However, if Hippocrates had already noted the association
218 6 Noninfectious Scleritis
between ocular inflammation and oral and genital Mucosal ulcers of the vulva and vagina in females
ulcers [363], it was Benedictos Adamantiades, a and of the scrotum and penis in males are similar
Greek ophthalmologist, who first recognized the to the oral ulcers, but tend to be deeper and often
disease as a distinct entity in 1931 [364]. Hulusi scar. Genital ulcerations recur less frequently
Behçet [365], a Turkish professor of dermatol- than oral ulcerations. Nonmucosal genital ulcers
ogy, publishing in the German dermatologic lit- are nodular with central ulceration.
erature, which was very widely read at the time The skin lesions typical of ABD include ery-
(1937), also published on a series of patients with thema nodosum, pustules, and papules, all con-
this syndrome, naming it for himself, giving the sidered to be manifestations of cutaneous
name its most common eponymic name. vasculitis. However, because cutaneous vasculi-
tis is common in other systemic diseases, skin
6.1.11.1 Epidemiology lesions are nonspecific. Erythema nodosum is an
The prevalence of ABD has a peculiar distribu- eruption of tender, raised, red nodules, usually
tion as most cases have been reported from Japan confined to the lower extremities, that usually
and the eastern Mediterranean countries, espe- resolves without ulceration in a matter of weeks.
cially along ancient silk trade routes. The highest Pustular vasculitis or papulopustular eruption
reported prevalence is in Japan, with 7–8.5 cases also may occur in ABD. A nonspecific skin sensi-
per 100,000 population [366]. However, the dis- tivity to simple trauma or pathergy test has been
ease may occur worldwide. Our series of cases reported in patients with ABD; the presence of
with ocular ABD have been reported from the marked redness, swelling, and/or a pustular lesion
USA with a higher than expected proportion of 24–48 h after a sterile skin prick, or after intrad-
Hispanic patients [367]. ermal injection of air or saline, is interpreted as a
Although the number of male patients exceeds positive result. However, because this test has a
females in Turkish [368], Israeli [369], and lower positivity rate in British and North
Japanese clinic populations [370], reports from American patients with ABD, it is not helpful for
the US clinic populations have equal numbers of diagnosis in these clinical populations [376].
male and female patients [367, 371]. Male sex Nonmigrating, recurrent, seronegative, non-
and early age of the onset of ABD are associated deforming arthritis, affecting knees, ankles, and
with greater severity [369]. wrist, may occur in up to 60% of patients with
There is no association between HLA antigens ABD [377]. Cardiovascular involvement includes
and ABD in Northern European and American venous and arterial occlusion and aneurysms,
populations [372, 373]. By contrast, in Japanese with venous involvement being twice as common
and Mediterranean populations, ABD is associ- as arterial involvement. Venous involvement
ated with the histocompatibility B5 antigen, and includes deep vein occlusion (superior vena cava,
particularly the B51 subgroup [374, 375]. inferior vena cava, femoral and subclavian veins,
or common iliac and hepatic vein) and superficial
6.1.11.2 Systemic Manifestations thrombophlebitis. Arterial involvement includes
Systemic manifestations of ABD include oral and stenosis or occlusion of subclavian, renal, carotid,
genital mucosal ulcers. In addition to that, there or femoral arteries. Cardiovascular involvement
may be involvement of the skin, joints, major in ABD carries a poor prognosis [377].
vessels, gastrointestinal tract, and central nervous Gastrointestinal ulcerations may occur, particu-
system. larly in the lower ileum and right side of colon;
Mucosal oral ulcers, ranging from 2 to 10 mm they may perforate and require hemicolectomy
in diameter, are typically round or oval, with a and distal ileal resection. Central nervous system
central yellow base, and surrounded by a red manifestations of ABD can cause sensory, motor,
halo. They are exceedingly painful and can or neuropsychiatric symptoms. Meningoenceph-
appear on the buccal mucosa, lips, tongue, and alitis can cause headache, fever, stiff neck, cere-
pharynx. These ulcers heal in 3–30 days usually brospinal pleocytosis, and focal neurologic
without scarring, and typically are recurrent. deficits.
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 219
6.1.11.3 Ocular Manifestations In our series of 500 patients with scleritis, two
Ocular involvement may be the presenting mani- patients had ABD (0.4%). They were two females
festation of ABD. It also may correlate with sys- with a mean age of 46 years (range, 38–54 years)
temic exacerbations of the disease, particularly with unilateral diffuse anterior scleritis. One of the
with central nervous system complications [366]. two patients had mild anterior uveitis-associated
Ocular disease usually begins in one eye but scleritis. There were no posterior pole abnor-
eventually involves both; inflammation is more malities, keratitis, or glaucoma, and visual acuity
severe in one eye when it is bilateral. Sterile was not decreased. Review of systems disclosed
hypopyon, occurring in one-third of cases, is the oral ulcers, genital ulcers, erythema nodosum, and
classic ocular finding described by both arthritis.
Adamantiadess and Behçet. It may be a late sign
and tends to disappear quickly. Sterile hypopyon Episcleritis
in ABD can be distinguished from an infectious Episcleritis is also rare in ABD and often appears
hypopyon in that it does not coagulate; it moves after other ocular manifestations, such as retinal
with gravity, changing with position. Anterior vasculitis or disk edema. ABD must be strongly
uveitis and vasculitic involvement of the retina considered in a young patient with recurrent,
and optic nerve are much more common than bilateral retinal vasculitis associated with episc-
hypopyon in ABD. Anterior uveitis may lead to leritis. Mucosal and skin examination may be
cataract as well as synechia formation and subse- helpful in determining the diagnosis of BD. Like
quent glaucoma. Retinal vasculitis can involve other ocular abnormalities in ABD, episcleritis
small vessels of both the arterial and venous sys- may appear during episodes of active disease.
tems and can produce vascular “sheathing” with Only one patient of our 85 patients with episcleri-
intraretinal hemorrhages, edema, and exudates, tis had BD (1.18%). The patient was a 47-year-
branch and central retinal vein occlusion, arterio- old White female who had nodular episcleritis as
lar attenuation, and venous dilatation and tortuos- well as retinal vasculitis and disk edema in the
ity. Serous retinal detachment is sometimes seen. left eye. Vision in the left eye was reduced to the
Optic nerve vasculitis leads to disk hyperemia or level of counting fingers. The patient had already
edema and eventual optic atrophy [369]. Retinal been diagnosed with ABD because of oral ulcers,
or optic nerve vasculitis may lead to blindness. genital ulcers, papulopustular eruptions in skin,
Although much less common, involvement of arthritis, gastrointestinal complaints, retinal vas-
the anterior segment of the eye may lead to con- culitis, and optic neuritis.
junctivitis, keratitis, scleritis, and episcleritis.
6.1.11.4 Laboratory Findings
Scleritis Numerous immunological abnormalities in
Scleritis is rare in ABD [366]. ABD is also rare in patients with BD have been detected, but none is
patients with scleritis; the reported incidence of diagnostic. These abnormalities include elevated
ABD in patients with scleritis is about 0.68% CICs and decreased complement components,
[123, 124]. Occasionally, however, it may be the leukocytosis, cryoglobulins, elevated interferon g,
presenting symptom that prompts the patient to increased chemotactic activity of neutrophils, and
seek medical advice and whose study leads to the elevation of serum immunoglobulins A, G, and
ABD diagnosis. Scleritis may appear as an iso- M. Furthermore, T-cell subsets CD4+ (helper) and
lated ocular finding or may be part of a complex CD8+ (suppressor), which are normally in serum
ocular involvement with retinal vasculitis and in a 2:1 ratio, change to a 1:1 ratio in ABD.
papillitis. ABD must be strongly considered in a
young patient with recurrent, bilateral retinal vas- 6.1.11.5 Diagnosis
culitis associated with scleritis. A careful review The diagnosis of ABD is based on a constellation
of systems and dermatologic examination are of clinical findings that may occur simultane-
essential in establishing the diagnosis. Scleritis ously or sequentially [365, 378]. The International
may correlate with systemic disease activity. Study Group (ISG) for ABD [379] established in
220 6 Noninfectious Scleritis
1990 new internationally agreed-on diagnostic The HLA antigens, HLA-B8 [386] and
criteria for ABD. These criteria include recurrent HLA-DR4 [387], may be associated with GCA
oral ulceration plus two of the following: (1) gen- more commonly than expected by chance alone;
ital ulceration, (2) typical defined eye lesions, (3) however, these associations have not been defini-
typical defined skin lesions, and (4) a positive tively established [388, 389].
pathergy test.
The diagnosis of ABD should be considered in 6.1.12.2 Systemic Manifestations
any young patient with bilateral and recurrent Headache, occurring in more than two-thirds of
retinal vasculitis or vascular occlusion that may patients, is the most common systemic manifes-
be associated with anterior uveitis, scleritis, or tation of GCA [390]. Bilateral or unilateral, it
episcleritis. Fluorescein angiography may be use- usually begins early in the course and is often the
ful in determining the extent of retinal and disk initial symptom. The pain is throbbing or shoot-
involvement. Meticulous review of systems and ing in quality, sometimes severe enough to pre-
mucosal and skin examination are essential in vent sleep [391]. It is commonly localized to the
establishing the diagnosis. temporal or occipital areas. Other cranial symp-
toms, such as temporal artery or scalp tenderness
and jaw claudication, are present in the majority
6.1.12 Giant-Cell Arteritis of patients. Constitutional symptoms, including
fatigue, fever, anorexia, and weight loss, may be
Giant-cell arteritis, also called temporal arteritis, present in about half of patients, and may be an
cranial arteritis, or granulomatous arteritis, is a initial finding of the disease [392]. Because head-
systemic vasculitis of unknown etiology that ache, fever, fatigue, and anorexia are nonspecific
involves the medium-sized extracranial arteries manifestations, many patients do not seek medi-
of the carotid circulation (superficial temporal, cal attention until more specific symptoms, such
vertebral, and ophthalmic), and sometimes the as scalp tenderness or jaw claudication, appear or
aorta and its primary branches [380, 381]. catastrophic vision loss occurs.
Complications of this vasculitis can lead to blind- Although medium-sized extracranial arteries
ness, stroke, and death. Certain clinical features, of the carotid circulation are the arteries most
laboratory tests, and histopathological findings commonly affected in GCA, the aorta and its
are helpful in distinguishing GCA from other branches to the upper extremities and neck also
vasculitides: the age at onset, temporal headache can be involved, leading to cardiovascular and
or tenderness, reduced temporal artery pulsation, cerebrovascular disease [386, 389]. Upper
transient or irreversible visual loss, polymyalgia extremity claudication, bruits over the carotid,
rheumatica (PMR), an elevated ESR, and mono- subclavian, and axillary arteries, and decreased
nuclear or multinucleated giant cells in the inter- or absent pulses in the neck or arms are some of
nal elasticum of the artery wall [382]. the findings. Angina pectoris, congestive heart
failure, and myocardial infarction secondary to
6.1.12.1 Epidemiology coronary arteritis may occasionally occur.
Giant-cell arteritis appears to be relatively com- Neurological manifestations, such as peripheral
mon in Europe and in the USA, although the neuropathy, hemiparesis, acute hearing loss, con-
incidence varies with the location of the fusion, depression, psychosis, and brainstem
population studied. It ranges from 17 cases per strokes, are not uncommon, occurring in one-
100,000 population (age 50 years or older) in third of cases of biopsy-proven temporal arteritis
Scandinavia to 0.49 cases per 100,000 in Israel [393, 394].
[383, 384]. GCA occurs in patients over 60 years Forty to 60 % of patients with GCA have
of age, women are affected about three times as PMR, a disorder characterized by pain and stiff-
often as men, and is most commonly seen in ness involving the neck, and the shoulder and hip
Caucasians [385]. girdles [395, 396]. In the majority of patients, the
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 221
shoulder girdle is the first to become symptomatic; Diplopia is also a common complaint in GCA
in the remainder, hips and neck are involved at [391] and may be the presenting symptom of
the onset. Morning stiffness and “gelling” after GCA. Diplopia is due to sixth nerve palsy in half
inactivity are common. PMR may be the initial of the patients; third nerve palsy accounts for the
symptom of GCA in 20–40% of patients. other half. However, ocular motility disturbances
Conversely, 15% of patients with PMR may have in GCA may be the result of muscle ischemia
GCA [397]. PMR is not associated with blind- rather than nerve ischemia.
ness, stroke, and death per se [395], but may be Typically, there is no conjunctival, corneal,
indirectly associated because of its relationship scleral, episcleral, uveal, or retinal vasculitis in
with GCA [398]. If patients with PMR, even GCA because the arteritic process usually
those who are “adequately treated,” [396] develop involves only the medium- and large-sized arter-
complaints suggestive of vasculitic involvement, ies, sparing the ocular tissues. Occasionally,
an ESR should be obtained as soon as possible however, small vessels, such as the anterior cili-
and, if elevated, treatment with high-dose oral ary and long posterior ciliary vessels, may be
steroids should be started immediately. involved, leading to ocular manifestations, such
as scleritis [403].
6.1.12.3 Ocular Manifestations
Ocular involvement usually occurs several weeks Scleritis
after the onset of systemic manifestations. The Scleritis is rare in GCA with or without PMR
most frequent ocular symptom is vision loss. [132]. However, the diagnosis of GCA must be
Rates of vision loss as high as 35–50% have been considered in an elderly patient with a high ESR,
reported in early reports [399–401], but more particularly in cases of diplopia or vision loss as
recent series present a lower rate of vision loss symptoms and AION, central retinal artery occlu-
(7–8%), probably reflecting earlier recognition sion, or branch retinal artery occlusion as signs.
and treatment [383, 393]. Vision loss in GCA The reported incidence of GCA with PMR in
occurs as a result of arteritic anterior ischemic patients with scleritis ranges from 0.58 to 0.68%
optic neuropathy (AION) or central or branch [123, 124]. Scleritis may correlate with the activ-
retinal artery occlusion. Arteritic AION in GCA ity of the systemic disease [204]. In our series of
is due to occlusion of the two main posterior cili- 500 patients with scleritis, one patient had GCA
ary arteries that supply the optic nerve and chor- associated with PMR (0.2%). The patient was an
oid. Arteritic AION in GCA is characterized by 85-year-old female diagnosed with GCA and
transient monocular visual loss or amaurosis PMR, with diffuse scleritis and anterior uveitis
fugax, sometimes alternating between the two after choroidal folds and retinal deposits. There
eyes, persisting for 2–3 min, and rarely lasting were no signs of disk edema. The ESR was
more than 5–30 min. Amaurosis fugax is one of 88 mm/h. Increased doses of steroids controlled
the most important warning symptoms of impend- the scleral inflammatory process as well as the
ing blindness. If the diagnosis and treatment of ESR. There were no patients with GCA in our
GCA are missed, sudden profound vision loss, series of patients with episcleritis.
usually to less than 20/200, may occur in 40–50%
of patients. It is often bilateral, either simultane- 6.1.12.4 Laboratory Findings
ously or sequentially. Other manifestations are An elevated ESR is characteristic of most cases
color vision deficit, relative afferent pupillary with GCA, although 5–10% of patients have a
defect (Marcus Gunn pupil), and severe disk normal sedimentation rate [391, 404]. Because a
edema. Fundus examination may help to distin- normal sedimentation rate does not exclude the
guish arteritic AION from nonarteritic AION by diagnosis, elevations of other acute-phase reac-
revealing the chalky appearance of an edematous tants, such as CRP, fibrinogen, and haptoglobin,
disk, a cilioretinal artery occlusion, or cotton- may be helpful in making the diagnosis [405, 406].
wool spots [402]. Leukocytosis and anemia are variably present.
222 6 Noninfectious Scleritis
Increased serum alkaline phosphatase, glutamic– should be done within 1 week of initiation of
oxaloacetic transaminase, glutamyl transferase steroid therapy because the rate of positive biopsy
may also be found in GCA [390, 407], as well falls from 82% in patients who had received no
as prolonged prothrombin time and decreased steroid to 60% in patients who had received up to
peripheral blood CD8+ (suppressor/cytotoxic) 1 week of steroid therapy [411]. The false-nega-
lymphocytes [408]. Increased levels of IgG, tive rate has been reported as 5 [412] and 9%
complement, and enzymes indicative of muscle [413]; these data may be explained, at least in
damage (serum creatine kinase) have been part, by the inclination of some clinicians to
reported. biopsy with minimal evidence of the disease.
6.1.12.5 Diagnosis
The diagnosis of GCA should be considered in 6.1.13 Cogan’s Syndrome
any patient over the age of 60 years who has a
new onset of headache, transient or irreversible Cogan’s syndrome is a systemic disease of
visual loss, PMR, unexplained prolonged fever unknown etiology that is typically manifested as
or anemia, and elevated ESR. Temporal artery nonsyphilitic interstitial keratitis associated with
biopsy, or less commonly facial or occipital artery vertigo, tinnitus, and profound deafness. Young
biopsy, is necessary to confirm the diagnosis adults are most likely to be affected. Atypical
[409]. Because the arterial involvement may be forms with ocular manifestations other than kera-
focal, a symptomatic or clinically suspicious titis may occur. It is probable that most cases of
arterial segment several centimeters long this syndrome are caused by a small-sized vessel
(1–5 cm) should be biopsed and carefully sec- vasculitis of the inner ear and eye.
tioned serially for histopathological examination
at several points along its length. The pathologi- 6.1.13.1 Clinical Manifestations
cal diagnosis is based on the presence of non- There are typical and atypical forms of Cogan’s
granulomatous inflammation with mononuclear syndrome. The typical form, as it was first
cells or granulomatous inflammation with epithe- described by Cogan in 1945 [414], is character-
lioid cells with or without Langhans’ (foreign ized by an abrupt onset of pain and redness in the
body type) multinucleated giant cells in the arte- eyes, reduced vision, vertigo, nausea, vomiting,
rial wall. Although characteristic of GCA, giant noises in the ears, and progressive hearing loss
cells need not be present to make the diagnosis [414, 415]. The ocular signs consist of patchy
pathologically. Because skip areas have been midstromal corneal infiltrates that tend to fluctu-
described along the length of affected arteries ate in intensity and distribution, are usually
[410], patients with GCA and elevated sedimen- located in the periphery, and are associated with
tation rates may have a negative temporal artery deep corneal vascularization in the later stages of
biopsy. However, a patient with clinical features the disease [414]. As the inflammation subsides,
suggestive of GCA and an elevated sedimenta- deep stromal infiltrates remain; they are inter-
tion rate should have a temporal artery biopsy. rupted by clear intervals around the now empty
The opposite temporal artery may be biopsed if old vessels. It has been suggested that nummular
the first biopsy is negative and clinical suspicion anterior stromal keratitis may be an early mani-
of the diagnosis is high. Ultrasonography of the festation of interstitial keratitis; progression to
temporal artery has been reported to be helpful in interstitial keratitis may be halted by suppression
diagnosis. of nummular anterior stromal keratitis with topi-
High-dose oral steroid therapy should be cal steroid treatment [416]. Either the ocular or
started immediately in a patient with ocular or the vestibuloauditory symptoms may be affected
systemic symptomatology suggestive of GCA first, but the time between both types of manifes-
and an elevated sedimentation rate, even before tations never exceeds a few months [417]. A small
performing the biopsy. However, the biopsy population of patients (10%) develops a systemic
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 223
necrotizing vasculitis affecting large arteries, Prednisone therapy seemed to halt both recurrent
which is manifested by proximal aortitis, aortic scleritis and hearing loss.
insufficiency, and infarction of other organ sys-
tems [418–424]. Other abnormalities include Episcleritis
myalgias, arthralgias, and arthritis. Whereas Episcleritis with or without keratitis may also
severe hearing loss occurs in 60% of patients occur in association with vestibuloauditory
without treatment, prednisone therapy preserves symptoms as part of atypical Cogan’s syndrome
hearing in 80% of patients [425]. Cogan’s syn- [426, 429]. There were no patients with Cogan´s
drome has been described in patients diagnosed syndrome in our series of patients with episcleri-
with other systemic diseases, such as RA or PAN tis. However, in our prior series of 94 patients
[422, 423, 426]. with episcleritis [123], one patient had Cogan’s
An atypical form of Cogan’s syndrome, syndrome (1.06%). The patient was a 39-year-old
accounting for about 30% of the cases, consists woman who developed recurrent simple episc-
of vestibuloauditory dysfunction associated with leritis in her left eye one month after the onset of
ocular manifestations other than keratitis (scleri- progressive sensorineural hearing loss. Systemic
tis, episcleritis, anterior uveitis, posterior uveitis, evaluation did not show evidence of aortic
optic neuritis, and orbital pseudotumor) [426– involvement or systemic vasculitis. Tests for
431]. Atypical forms of Cogan’s syndrome often ANAs, rheumatoid factor, ANCAs, and cryo-
overlap with other systemic diseases, such as globulins were negative; ESR and CICs were
GPA (Wegener), PAN, rheumatoid vasculitis, sar- elevated and complement levels were decreased.
coidosis, or Vogt–Koyanagi–Harada syndrome. Prednisone controlled recurrences of episcleritis
Patients with the atypical form of Cogan’s syn- and progression of hearing loss.
drome are more likely to develop a systemic
necrotizing vasculitis (21%) [421]. 6.1.13.2 Laboratory Findings
There are no specific diagnostic tests for Cogan’s
Scleritis syndrome. ESR and CICs are typically elevated.
The atypical form of Cogan’s syndrome may Leukocytosis and, occasionally, eosinophilia may
become manifest with vestibuloauditory dysfunc- occur. No evidence of syphilis infection is found.
tion and scleritis [426–428, 431]. Keratitis may
or may not be present. Vestibuloauditory symp-
toms may be present before or after the scleritis, 6.1.14 Systemic Immune-Mediated
but usually both events are not separated by more Diseases Associated with
than a few months. Although nodular anterior Scleritis: Atopy
scleritis is a frequent type of scleritis in Cogan’s
disease, other varieties, such as diffuse anterior Atopy (a means “without,” topos means “place”)
scleritis and necrotizing anterior scleritis, may is a term coined by Coca and Cooke [432] in
occur [204, 428]. 1923, which refers to “strange reactivity” or
In our series of 500 patients with scleritis, one “hypersensitivity” to environmental antigens in
patient had Cogan’s syndrome (0.2%). The patients with hereditary backgrounds of allergic
patient was a 69-year-old male who had recurrent disease. The major atopies are seasonal rhinitis
diffuse anterior scleritis in his right eye 1 month (hay fever), perennial rhinitis, bronchial asthma,
before developing bilateral progressive hearing and atopic dermatitis (eczema). The minor atopies
loss. There was no keratitis, anterior uveitis, include food allergy, urticaria, and nonhereditary
glaucoma, or loss of vision. Review of systems angioedema.
revealed arthritis, and laboratory tests disclosed Although conjunctivitis or keratoconjunctivitis
an elevated sedimentation rate and positive CICs (allergic, giant papillary, vernal, and atopic) is the
detected by Raji cell assay. Tests for rheumatoid most characteristic ocular manifestation in atopy,
factor, ANAs, and ANCAs were negative. scleritis, and particularly episcleritis, also may
224 6 Noninfectious Scleritis
occur. Exposure to airborne allergens, occasional group [436]. Patients with polyarticular onset of
(e.g., vapor of printing inks), seasonal (e.g., pol- JIA follow a clinical course similar to that of adults
len), or perennial (e.g., house dust mite), may trig- with RA. Ocular involvement in JIA occurs most
ger recurrent attacks of episcleritis [114, 122, 204, commonly in the pauciarticular onset group of
433]. Skin testing was investigated by McGavin JIA; it is characterized by anterior uveitis, which
et al. [114] in 23 patients (17 patients with episc- may lead to band keratopathy, cataracts, or sec-
leritis and six patients with scleritis). Of the eight ondary glaucoma [437]. However, ocular involve-
patients with episcleritis and one patient with ment also may occur in the polyarticular onset
scleritis who had a positive reaction to some aller- group of JIA [438]; it is characterized by scleritis,
gen, only three gave a clear history of either hay usually of the diffuse or nodular variety, and epis-
fever or asthma. In the Watson and Hayreh series cleritis [121, 204]. JIA patients with episcleritis or
[122], 12% of patients with episcleritis and 0.96% scleritis are usually girls who are seropositive for
of patients with scleritis had a history of asthma or rheumatoid factor. Patients with the systemic onset
hay fever. Although several of our patients with of JIA (Still’s disease) do not develop ocular mani-
episcleritis and scleritis had positive skin tests festations. Patients with the pauciarticular onset of
result to multiple allergens, only seven patients JIA do not develop scleritis or episcleritis [242]. In
with episcleritis (7.44%) and one patient with our series of 500 patients with scleritis, one patient
scleritis (0.58%) had a clear history of major had JIA (0.2%). The patient was a 17-year-old
atopies with bronchial asthma (four patients), hay female with polyarticular JIA for 10 years. She
fever (four patients), eczema (two patients), and had had previous episodes of anterior uveitis. She
perennial rhinitis (two patients). In two patients, developed unilateral diffuse scleritis with anterior
episcleritis was associated with a past history of uveitis without other complications, including
perennial keratoconjunctivitis and giant papillary keratitis, glaucoma, or loss of vision.
conjunctivitis. Episcleritis was recurrent, almost Occasionally, scleritis has been associated
always bilateral, and simple or nodular. Scleritis with dermatomyositis [439], Sjögren’s syndrome
was recurrent, bilateral, and diffuse. There were [439], Takayasus’ arteritis [121], and thyroid dis-
no corneal lesions, cataract, or glaucoma, and the eases, including Hashimoto’s thyroiditis or thyro-
visual acuity was not affected. toxicosis [204]. Simple episcleritis may, although
The incidence of atopy in patients with episc- rarely, accompany the onset of Schönlein–Henoch
leritis or scleritis in these studies is not higher purpura, a small-sized vessel vasculitis, which
than that expected in patients without episcleritis commonly affects young children, especially
or scleritis (10–20% of the general population) boys [204].
[434, 435], indicating that there is no significant Ocular manifestations of sarcoidosis include
relationship between atopy and episcleritis or conjunctival granulomas, infiltration of the lacri-
scleritis. mal gland, KCS, anterior, intermediate, or poste-
rior uveitis, retinal vasculitis, and optic nerve
involvement. Scleral and episcleral nodules occur
6.1.15 Other Systemic Immune- rarely; these may recur when the systemic condi-
Mediated Diseases That Rarely tion exacerbates [123, 132, 440–444]. Anterior
May Be Associated with Scleritis staphyloma has occasionally been found to be the
and Episcleritis first ocular manifestation of sarcoidosis [445].
Because Vogt–Koyanagi–Harada syndrome is
Juvenile idiopathic arthritis (JIA) is diagnosed in caused by an autoimmune attack directed against
patients under 16 years of age who have had arthri- organs containing melanocytes, ocular involve-
tis for 3 months or more. JIA may be classified ment is usually characterized by bilateral pro-
into three groups, depending on the number of gressive panuveitis affecting the choroid, ciliary
involved joints at the onset: systemic onset group, body, and iris. The sclera may contain some mel-
polyarticular onset group, and pauciarticular onset anocytes, especially at the site of emergence of
6.1 Systemic Immune-Mediated Disease-Associated Scleritis: Vasculitides 225
long ciliary nerves anterior to the insertion of the diseases, such as RA, GPA (Wegener), or IBD
recti muscles. Although uncommon, focal necro- [449, 450]. Surgical trauma may favor CICs
tizing scleritis in Vogt–Koyanagi–Harada syn- becoming entrapped in episcleral vessels and
drome may occur and may lead to uveal show perforating scleral vessels. Inflammatory
and anterior staphyloma [446]. Scleritis also may microangiopathy may lead to scleral destruction
be caused by an extension of an orbital granu- [451, 452]. Subcutaneous nodules in RA usually
lomatous process or a uveal granulomatous pro- appear in areas subjected to mechanical trauma,
cess, such as sympathetic ophthalmia [439]. such as the olecranon, the buttock, or the finger-
Tubulointerstitial nephritis and uveitis (TINU) tip pads. Pathological studies show vasculitis and
is an uncommon syndrome involving the kidney fibroblast proliferation; vessel thrombosis and
and the eye. It occurs mainly in children and collagenase production result in tissue destruc-
young adults, and females are affected more often tion [453–455]. Cutaneous vascular lesions, such
than males. Patients usually present with sys- as purpura, pustules, vesicles, and ulcers, most
temic symptoms, including fatigue, malaise, often appear in areas of repeated low-grade
anorexia, abdominal pain, fever, and anemia. The trauma. Pathological studies show cutaneous
neprhitis usually precedes the uveitis, although necrotizing venulitis [456, 457].
simultaneous onset in both organs has been In our prior series of scleritis [123], 10 of 11
described. The nephropathy typically resolves patients (90.9%) who developed necrotizing
spontaneously or responds favorably to systemic scleritis up to 6 months after ocular surgery (inter-
steroid therapy, but the uveitis may become val range, 2–4 weeks) had an underlying systemic
chronic and treatment resistant. Laboratory find- autoimmune vasculitic disease; these diseases
ings of high ESR, normochromic normocytic included RA, GPA (Wegener), and IBD.
anemia, elevated serum creatinine and BUN lev- Appropriate studies led to the discovery and sub-
els, and abnormal urinalysis findings (glycosuria, sequent treatment of the systemic diseases in five
proteinuria, aminoaciduria, microhematuria, b2 patients; the other five had been previously diag-
microglobulinuria) support the diagnosis, nosed. These results emphasize the need for
although definitive diagnosis is established by meticulous diagnostic pursuit of systemic auto-
kidney biopsy [447]. immune vasculitic diseases in patients with necro-
Although uncommonly, scleritis may occur tizing scleritis following intraocular surgery.
with TINU syndrome [448]. In our series of 500 Sclerokeratitis may appear following kerato-
patients with scleritis, two patients had TINU plasty in patients with severe atopy. Lyons et al.
(0.4%). They were two females, with a mean age [458] reported a series of five severe atopic
of 30 years. One patient had diffuse anterior and patients in whom sclerokeratitis developed
posterior scleritis with anterior uveitis, posterior 1–4 weeks after keratoplasty. Serum IgE levels
uveitis, and optic neuritis. The other patient had were elevated in all these patients. The scleritis
diffuse anterior scleritis with anterior uveitis. was of the diffuse type and the keratitis was char-
Any patient who develops scleritis with elevated acterized by host stromal inflammation, which,
serum creatinine and BUN levels should be through loosening of the graft sutures, caused pro-
examined for TINU syndrome. trusion of the graft or incompetence of the graft–
host interface. The authors proposed that IgE
binding on the surface of mast cells in the con-
6.1.16 Systemic Immune-Mediated junctiva with subsequent degranulation could be
Disease-Associated Scleritis involved in the pathogenesis of the sclerokeratitis.
After Ocular Surgery These results emphasize that severe atopic patients
undergoing keratoplasty require prophylactic
Scleritis, particularly necrotizing anterior scleri- measures for stabilization of the atopic ocular dis-
tis, may appear following surgical trauma of ease (seasonal timing of the operation, cromolyn
the sclera in patients with autoimmune vasculitic sodium, and, if necessary, topical steroids), use of
226 6 Noninfectious Scleritis
interrupted sutures, and frequent postoperative occasionally may occur [132, 463]. Rosacea
follow-up for detection of sclerokeratitis. High- episcleritis and scleritis are accompanied by mei-
dose oral steroids at the onset of the condition may bomianitis (solidified plugs, dilated glands, pout-
adequately suppress the ocular inflammation. ing orifices, distorted orifices, hordeolum, and
Suture-related episcleritis may occur after chalazion), blepharitis (crusting, decreased cilia,
transscleral fixation of a posterior chamber margin thickening or irregularity, and scaling),
intraocular lens in a patient with the absence of telangiectasia of lid margins, conjunctivitis
capsular and zonular support [459]. (bulbar injection, tarsal papillary hypertrophy,
and symblepharon), or keratitis (superficial
punctate keratopathy, corneal vascularization,
6.2 Dermatological Disease- PUK, and corneal perforation). Mechanical and
Associated Scleritis hygienic maneuvers with or without doxycycline
is the treatment of choice for rosacea episcleritis
6.2.1 Rosacea and scleritis.
The diagnosis of ocular rosacea is made on the
Acne rosacea is a chronic disease characterized basis of skin clinical findings, although in 20% of
by skin manifestations, which include persistent cases the ocular manifestations appear first.
erythema, telangiectasias, papules, and pustules Meibomian gland dysfunction is a nonspecific
in the flush areas of the face and neck. The classic ocular finding but, when is seen in combination
rhinophyma, caused by sebaceous gland hyper- with characteristic skin manifestations, it allows
trophy, also is a typical feature of the advanced a firm diagnosis of ocular rosacea. Any patient
stage of the disease. Ocular rosacea occurs in who develops episcleritis or scleritis and meibo-
3–58% of the cases with acne rosacea, depending mian gland dysfunction should be examined for
on the series, and consists primarily of meibo- skin manifestations.
mian gland (modified sebaceous gland) dysfunc-
tion associated with the cutaneous disease [460].
Abnormalities in meibomian gland secretions 6.3 Metabolic Disease-Associated
(alteration in melting points of waxes and choles- Scleritis
terol esters, excessive free fatty acids, or bio-
chemical abnormalities) [461] may secondarily 6.3.1 Gout
inflame the external surface of the eye, causing
conjunctivitis, keratitis, and less frequently epis- Gout is a defect of purine metabolism that is
cleritis and scleritis [460, 462–464]. A type IV manifest by (1) an increase in the serum urate
hypersensitivity reaction may play a significant concentration, (2) recurrent attacks of acute
role in the pathogenesis of the disease [464]. arthritis with deposits of monosodium urate
Burning, tearing, eyelid swelling, irritation, pho- monohydrate (tophi) in and around the joints of
tophobia, blurred vision, dryness, and mild itch- the extremities (often the big toe), (3) renal dis-
ing are the usual symptoms. ease, and (4) uric acid urolithiasis.
The reported incidence of rosacea in patients Deposits of monosodium urate monohydrate
with episcleritis is 1.88% [122]. In our series of may also precipitate in the eye, leading to con-
85 patients with episcleritis, four patients had junctivitis, episcleritis, or (less commonly) scleri-
rosacea (0.8%). Rosacea episcleritis may be sim- tis [114, 122, 465]. They also may precipitate in
ple or nodular, and is usually bilateral. The the corneal epithelium or Bowman’s membrane,
reported incidence of rosacea in patients with and in the iris. The reported incidence of high-
scleritis ranges from 0.34 to 0.96% [122–124]. In serum uric acid values in patients with episcleri-
our series of 500 patients with scleritis, five tis is 11%, and that of clinical gout is 7% [122].
patients had rosacea (1%). Rosacea scleritis is The onset of episcleritis in gout is sudden and
usually diffuse or nodular, but scleral perforation may be triggered by cold, heat, or indiscretions of
6.5 Chemical Injury-Associated Scleritis 227
diet. Episcleritis is simple or nodular, recurrent, mineral matters, such as pieces of stone, talc, and
and is often accompanied by conjunctivitis. silk or catgut surgical sutures, may cause scleral
Occasionally, fine crystals may be seen in the granulomas. The foreign body may occasionally
episclera or conjunctiva close to the vessels be seen in the scleral nodule or in the adjacent
[439]. Although these crystals have never been cornea (caterpillar hairs) after meticulous slit-
biopsied, their presence suggests that a serum lamp examination, particularly if the episcleral
uric acid analysis should be performed. Gouty congestion has been cleared with topical phe-
tophi in conjunctiva or episclera have been nylephrine (10%). Removal of the noxious mate-
reported but are extremely unusual [466–468]. rial, sometimes through excision of the scleral
The attacks usually last approximately 10 days, nodule with or without scleral homografting,
in spite of the medication; if the patient recog- should be performed. Some foreign bodies, espe-
nizes that an episcleritis attack is imminent and cially the vegetal ones, may secondarily compli-
initiates the treatment before episcleral inflam- cate with infection, often mycotic, and produce a
mation develops, the attack may be aborted. scleral abcess.
Episcleritis may be accompanied by keratitis In our series of 500 patients with scleritis, two
(crystals in epithelium and Bowman’s membrane) patients had scleritis due to a foreign body granu-
or anterior uveitis. Corneal scrapings reveal ura- lomatous reaction (0.40%). One patient was a
tes that can be demonstrated by colorimetry and 62-year-old female who developed unilateral dif-
spectrophotometry [469]. Episcleritis may be the fuse scleritis due to a retained sponge following a
first or the only clinical manifestation of the trabeculectomy with mitomycin. The other
disease. patient was a 26-year-old female who developed
Scleritis in gout is less frequent than episcleri- nodular scleritis following a scleral buckling pro-
tis [114, 122]. The reported incidence of gout in cedure for retinal detachment. Scleral buckle
patients with scleritis ranges from 0.34 to 2.41% removal halted the scleral inflammation.
[122, 123]. Scleritis is more painful than episc-
leritis and may be accompanied by keratitis or
anterior uveitis. Therapy for gout may control the 6.5 Chemical Injury-Associated
systemic and ocular manifestations. There were Scleritis
no patients with gout in our series of patients with
episcleritis and scleritis. In most cases, alkali or acid chemical injuries to
the eye are relatively minor and heal without
sequelae. Occasionally, strong alkali or acid
6.4 Foreign Body Granuloma- chemicals may cause severe ocular damage and, if
Associated Scleritis they come into direct contact with the sclera, may
cause scleritis and scleral destruction. Alkaline
A sterile foreign body in the sclera or episclera substances produce scleral damage through
may produce a granulomatous inflammatory changes in pH produced by the hydroxyl ion. At
reaction without scleral or episcleral abscess. A high pH, cations bind to scleral collagen and gly-
history of accidental or surgical injury can usu- cosaminoglycans by reacting with carboxyl
ally be elicited. Because the granuloma is con- groups, leaving the collagen more susceptible to
fined to the affected area, scleritis secondary to a enzymatic degradation; collagenolitic enzymes
foreign body is usually nodular and unresponsive are synthesized by inflammatory cells that are
to anti-inflammatory therapy. Sometimes, the attracted to the region of tissue damage. Acid sub-
nodular process can progress to necrotizing stances produce scleral damage through changes
scleritis; scleral thinning may threaten the integ- in pH produced by hydrogen ion and coagulation
rity of the globe. Vegetable matter, such as plant and precipitation of tissue proteins caused by
hairs or needles, animal matter, such as mite interaction with the ionic portion of the acid.
mouth parts [442] and caterpillar hairs [439], and Scleral tissue excision and scleral homografting
228 6 Noninfectious Scleritis
may be performed in severely damaged scleras to 3. Hull S, Mathews JA. Pulmonary necrobiotic nodules
retain sufficient integrity after collagen break- as a presenting feature of rheumatoid arthritis. Ann
Rheum Dis. 1982;41:21.
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in our series of patients with episcleritis and festations. Br Med J. 1969;3:131.
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diseases that affect predominantly small- and arthritis in young adults: comparison of patients with
medium-sized vessels, such as RA, GPA and without rheumatoid factor positivity at entry and
(Wegener), relapsing polychondritis, arthritis and identification of variables correlating with outcome.
Semin Arthritis Rheum. 1976;5:299.
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Infectious Scleritis
7
Although systemic immune-mediated diseases are There are no specific clinical signs that confirm
the main possibilities in the differential diagnosis scleral infection. When the diagnosis is sus-
of scleritis, other unusual etiologies, such as infec- pected, laboratory studies are required to estab-
tious diseases, must also be considered. Infectious lish the causative agent. Appropriate therapy is
scleritis, either endogenous or exogenous, may be initiated on the basis of clinical suspicion, the
caused either by a direct invasion of organisms results of initial laboratory studies, and knowl-
that cause the systemic and local signs, or by an edge of the most likely responsible organisms
immune response induced by the infectious agent. responsible. The plan may be modified later,
All classes of microbial organisms can infect depending on the clinical response and labora-
the sclera, including bacteria, fungi, viruses, and tory results. With advanced infection or with a
parasites (Table 7.1). As the scleritis caused by severe host inflammatory response, devastating
these conditions may be identical to that caused complications can occur, resulting in structural
by immune-mediated diseases, the challenge for alterations, such as thinning, perforation, or
the ophthalmologist is to distinguish infectious extension to adjacent structures.
scleritis from other inflammatory conditions of In theory, any infectious agent that induces an
the sclera. The differential diagnosis between immune response can cause vasculitis. Bacteria,
both groups of diseases is important because such as Pseudomonas, Streptococcus, Staphy-
infectious etiologies are usually treatable with lococcus, or viruses such as herpes simplex virus
specific therapy, and because corticosteroid ther- (HSV) or Varicella-zoster virus (VZV) may be
apy or immunosuppressive therapy, often used in associated with small-sized vessel vasculitis.
scleritis associated with immune-mediated dis- Syphilis and tuberculosis may cause large-sized
eases, is contraindicated in active infection; if vessel vasculitis (aortitis). Vascular damage is
topical or systemic corticosteroids are started commonly incurred by direct invasion or the ves-
because it is thought the scleritis has an immuno- sel by the organism, or by embolization, both of
logic basis, scleral destruction, and extension of which result in an inflammatory response and
the microbial process may progress. immune complex formation and deposition.
In evaluating a patient with scleritis, it is This chapter focuses on the infectious diseases
important to take a history not only for evidence that may be associated with scleritis.
of underlying systemic diseases, but also for Recommendations for an approach to the man-
trauma, contact lens effects, past ocular condi- agement and therapy of infectious scleritis are
tions, topical therapy, and surgical procedures. presented.
Table 7.1 Classification of organisms scleritis with or without keratitis may occur, in
causing infectious scleritis which case they may follow accidental or surgical
1. Bacteria injury, or a severe endophthalmitis [1, 7–18].
Gram-positive cocci Surgical injuries include pterygium excision fol-
Gram-negative rods lowed by ß irradiation or topical thiotepa, retinal
Mycobacteria
Atypical mycobacteria detachment repair with buckling procedures and/
Mycobacterium tuberculosis or diathermy, or strabismus surgery.
Mycobacterium leprae Scleritis also may be the result of immune-
Spirochetes mediated scleral or episcleral vascular damage
Treponema pallidum
Borrelia burgdorferi caused by infectious agents. Bacteria, such as
Chlamydiae Pseudomonas, Streptococcus, or Staphylococcus,
Actinomycetes may cause an inflammatory microangiopathy in
Nocardia asteroides sclera by inducing immune-mediated responses
2. Fungi
in the vessel wall, such as formation and deposi-
Filamentous fungi
Dimorphic fungi tion of immune complexes containing bacterial
3. Viruses products. The scleritis then becomes autoim-
Herpes zoster mune, and thereafter, independent of the presence
Herpes simplex type I of the initiating organism.
Mumps
4. Parasites
Protozoa 7.1.1.2 Organisms
Acanthamoeba Certain bacterial groups are most fre-
Toxoplasma gondii quently encountered in scleral infections. These
Helminths include the Pseudomonadaceae (Pseudomonas),
Toxocara canis
Streptococcaceae (Streptococcus), Micrococca-
ceae (Staphylococcus), and Enterobacteriaceae
(Proteus).
Pseudomonas aeruginosa is the most common
7.1 Bacterial Scleritis cause of exogenous scleral infection. It is usually
associated with primary corneal infection and
7.1.1 Gram-Positive Coccus subsequent scleral extension in a compromised
and Gram-Negative Rod Scleritis host [1–4, 6]. It also may appear after pterygium
excision followed by either ß irradiation or topi-
7.1.1.1 Pathogenesis cal thiotepa (reported range, 6 weeks to 10 years)
Bacteria are capable of establishing a focus of [1, 7, 9–11]; persistent bare sclera due to failure
infection in the sclera if normal host barriers or of conjunctival regrowth contributes to chronic
defense mechanisms are compromised. The pres- scleral exposure and subsequent infection [11].
ence of exogenous bacteria in scleral tissue leads Streptococcus pneumoniae scleritis also has
to an inflammatory response. Bacterial scleritis is been described as an extension of corneal infec-
usually the result of scleral extension of primary tion [1] or after pterigium removal followed by ß
corneal infections [1–6]. Risk factors in these radiation [7]. Staphylococcus aureus [1, 19],
cases include contact lens wear, recent ocular Staphylococcus epidermidis [1], Proteus [14],
surgery or suture removal, use of topical medica- and Stenotrophomonas malthophilia [15, 17] also
tions (corticosteroids, beta blockers), neovascu- have been reported.
lar or phacomorphic glaucomas, adnexal disease,
corneal tissue devitalization (recurrent attacks of 7.1.1.3 Management
herpes simplex or herpes zoster keratitis, corneal Bacterial scleritis should be suspected in cases of
exposure), and debilitating systemic diseases indolent progressive scleral necrosis with suppu-
(AIDS, diabetes). However, primary bacterial ration, especially if there is a history of accidental
7.1 Bacterial Scleritis 243
Table 7.2 Selection of initial antibiotic for infectious scleritis or keratoscleritis on the basis of smear morphology
Smear morphology Topicala Subconjunctivalb Systemicc
Gram-positive cocci Cefuroxime 5% or vancomycin Vancomycin 25 mg Fluoroquinolone, PO
5% (levofloxacin, gatifloxacin,
or moxifloxacin)
Gram-negative rods Gentamicin 1.4% or fluoroqui- Tobramycin 40 mg Fluoroquinolone, PO
nolone 0.3% or ceftazidime 5% (ciprofloxacin, ofloxacin)
Acid-fast bacilli Amikacin 2% Amikacin 25–50 mg Amikacin, IV
Nocardia Amikacin 2% or trimethoprim Amikacin 25–50 mg Trimethoprim
1.6% + sulfamethoxazole 8% sulfamethoxazole, PO
No microorganisms Cefuroxime 5% and gentamicin Vacomycin 40 mg, Fluoroquinolone, PO
but infectious suspect 1.4% or fluoroquinolone 0.3% tobramycin 25 mg (levofloxacin, gatifloxacin,
or moxifloxacin)
Hyphal fragments Natamycin 5% or econazol 1% Itraconazol 20 mg Itraconazol or voriconazol, PO
or voriconazol 1%
Yeast or pseudohyphae Amphotericin-B 0.15% or Fluconazol 20 mg Itraconazol or voriconazol, PO
econazol 1% or voriconazol 1%
Cysts or trophozoites Clorhexidine 0.02% or PHMBd Itraconazol, PO
0.02% + propamidine isethionate
0.1%
a
Topical solutions should be used hourly; cefuroxime, vancomycin, gentamicin, fluoroquinolone, ceftazidime, and
amikacin are tapered over 1–2 weeks to four times a day for 2 more weeks. Natamycin, econazol, voriconazol,
and amphotericin are tapered over several weeks, depending on clinical response
b
Vacomycin, tobramycin, and amikacin subconjunctival therapy should be used every 24 h and fluconazol every 48 h.
Although two or three doses are commonly given, length of therapy depends on process severity
c
Length of therapy depends on process severity
d
PHMB: polyhexamethylene biguanide
trauma, debilitating ocular or systemic disease, acid-Schiff [PAS], Gomori methenamine silver,
chronic topical medication use (including corti- acid-fast, calcofluor white) for identification of
costeroids), or surgical procedures. Scrapings for infectious agents.
smears (Gram, Giemsa) and cultures (blood agar,
chocolate agar, Sabouraud dextrose agar, thiogly- 7.1.1.4 Therapy
collate broth) must be obtained and fortified anti- A classification of bacteria based on Gram’s stain
bacterial therapy, depending on smear results, findings from scleral or corneoscleral smears per-
must be initiated as soon as possible. Infection mits organization of therapy (Table 7.2).
around implants used in retinal detachment sur- Aggressive and prolonged topical, subconjuncti-
gery or around stitches in any type of scleral sur- val, and systemic antibiotics must be instituted,
gery, mandate removal of the foreign body. If particularly if keratoscleritis occurs. As soon as
bacterial infection is the primary clinical suspi- the bacteria are isolated by culture, therapy may
cion, but smears and cultures (at 48 h) are nega- be refined with antibiotic sensitivity results. The
tive, and the patient is not improving on the initial avascular nature and the tightly bound collagen
broad-spectrum antibacterial therapy chosen, structure of the sclera and the cornea make these
scleral or corneoscleral biopsy is recommended. tissues relatively impermeable to topical and
Biopsied tissue is then bisected and half is trans- systemic antibiotics. Therefore, if the patient is
ported immediately to the microbiology labora- not improving on the topical fortified, subcon-
tory for homogenization and culture in the usual junctival, and systemic antibacterial therapy,
medium or PCR. The remaining half is placed in subpalpebral lavage with continuous irrigation of
formalin and transported to the pathology laboratory antibiotics can improve scleral penetration [3].
for histopathology with special stains (periodic Topical corticosteroids should not be included in
244 7 Infectious Scleritis
the initial therapy of bacterial keratoscleritis or complicating pterygium excision with adjunctive
scleritis, but may be of benefit after several days b irradiation. The remaining eye, which retained
of aggressive antibiotic therapy if the infection is useful vision, was associated with little delay in
coming under control, or if the histopathologial the institution of aggressive anti-Pseudomonas
study reveals an inflammatory microangiopathy. therapy. Alfonso and coworkers [2], reviewing
An exception to this includes Pseudomonas their series of 3 patients and another series of 9
infection because steroid therapy has almost patients, noted that in 7 of 12 patients with
always been associated with persistence and pro- Pseudomonas keratoscleritis who had predispos-
gression of infection. Corticosteroids act as mod- ing conditions, the involved eye was enucleated.
ulators of the inflammatory response associated Those eyes receiving early, appropriate, and
with the infection which also may be destructive prolonged anti-Pseudomonas therapy, retained
to the sclera. Patients with prolonged corticoster- useful vision. Farrell and Smith [7] showed the
oid therapy must be carefully monitored, particu- devastating visual outcome (no light perception)
larly if antibiotics are discontinued, because they of a case with S. pneumoniae keratoscleritis and
may have recurrences of the infection [20]. endophthalmitis that appeared 2 weeks after
Strong consideration should be given to surgi- pterygium excision with b irradiation. They also
cal management if the patient is not improving reported on a patient with Pseudomonas kerato-
within the first few days of antibacterial therapy. scleritis that appeared 6 weeks after pterygium
Surgical procedures include conjunctival resec- excision and topical thiotepa therapy; the final
tion and cryotherapy to the immediate underlying visual acuity light perception only. Both patients
sclera [1]. Some of the possible mechanisms for waited several days after symptoms began before
efficacy of cryotherapy include mechanical seeking medical care. Reynolds and Alfonso [1]
destruction of microorganisms, osmotic changes, noted that whereas 9 of their 17 cases (52%) of
or disruption of DNA. Cryotherapy may enhance bacterial keratoscleritis were either enucleated or
antibiotic penetration through bacterial cell walls eviscerated, none of the 8 cases of bacterial
or into the sclera as well [5, 21]. Surgical inter- scleritis required enucleation. These findings
vention also may include definitive excisional suggest that isolated bacterial scleritis has a bet-
biopsy for therapeutic and isolation purposes. ter prognosis than bacterial keratoscleritis, and
Definitive excisional biopsy includes deep scleral that early, aggressive, and prolonged appropriate
dissection with subsequent scleral graft and/or antibacterial therapy may improve final visual
lamellar or penetrating keratoplasty. If bacteria acuity. Early diagnosis, therefore, is essential in
are not isolated and histopathological study order to institute early treatment to halt the pro-
reveals an inflammatory microangiopathy, gression of the corneal and/or scleral bacterial
immune-mediated responses associated with pre- infection.
vious bacterial infection or with systemic auto-
immune vasculitic diseases must be suspected 7.1.1.6 Our Experience
and therapy with corticosteroids or immunosup- In our prior series of 172 patients with scleritis
pressive agents must be considered; continued [13], two patients had primary bacterial scleritis
antibiotic coverage is recommended. (1.16%). One of these was a 70-year-old white
male with Grave’s ophthalmopathy, diabetes
7.1.1.5 Prognosis mellitus, hypertension, anemia, and atheroscle-
Bacterial scleritis is generally associated with a rotic heart disease, who developed a suppurative
poor prognosis. Poor penetration of antibiotics necrotizing anterior scleritis and posterior scleri-
into the tightly bound collagen fibers of the scleral tis in his left eye 2 weeks after strabismus surgery
coat may account, at least partially, for that. Tarr [14]. Visual acuity at that time was 20/70. Biopsy
and Constable [10, 11] reported one eye with of the sclera showed perivascular neutrophilic
light perception and two eyes enucleated in their and lymphocytic infiltration; Gram’s stain showed
series of four patients with Pseudomonas scleritis gram-negative rods, and periodic acid-Schiff
7.1 Bacterial Scleritis 245
Tuberculous scleritis may be the result either of a pyridoxine), depending on antibiotic sensitivities.
direct M. tuberculosis scleral invasion or of an Streptomycin may be applied topically and sub-
immune-mediated reaction to circulating tubercu- conjunctivally [42]. Systemic or topical steroids
loproteins. Early diagnosis may minimize ocular may worsen the active infection [38]. Recently,
and systemic complications. interferon-gamma release assays (IGRAS) have
Direct M. tuberculosis scleral invasion is usu- become commercially available. There are two
ally due to hematogenous miliary spread of pul- in vitro assays that measure T cell release of
monary tuberculosis; [36, 39–42] occasionally, interferon gamma (IFN-g) in response to stimula-
scleritis may occur from local infection caused tion with the highly tuberculosis-specific anti-
by direct injury [43] or by extension of lesions in gens ESAT-6 and CFP-10. QuantiFERON-TB
adjacent tissues, such as cornea, conjunctiva, or Gold® (Cellestis Ltd., Carnegie, Australia) is a
iris [44, 45]. Direct M. tuberculosis scleral inva- whole-blood ELISA for the measurement of
sion may appear as nodular scleritis that, IFN-g, and T-SPOT.TB® (Oxford Immunotec,
untreated, may progress to necrotizing scleritis Oxford, UK) is an enzyme-linked immunospot
[42, 43, 46, 47]. Tuberculous posterior scleritis (ELISpot) assay. IGRAs are more specific than
has also been described [48]. The marginal cor- the intracutaneous tuberculin-purified protein
nea may be secondarily involved with infiltrates derivative (PPD) as a result of less cross-reactiv-
and neovascularization, and there may be ity due to BCG vaccination and sensitization by
mucopurulent discharge. Occasionally, M. tuber- nontuberculous mycobacteria. IGRAs also appear
culosis may involve episclera, causing simple or to be at least as sensitive as the PPD for active
nodular episcleritis [37, 49]. Tuberculosis may be tuberculosis (used as a surrogate for latent M.
diagnosed from sputum, urine, ocular tissue, or tuberculosis infection). Although diagnostic sen-
other body fluids by demonstrating acid-fast sitivity for latent infection cannot be directly esti-
bacilli on Ziehl-Neelsen stain and by identifica- mated because of the absence of a gold standard,
tion of M. tuberculosis on Löwenstein–Jensen these tests have shown better correlation than the
culture media at a temperature optimum of 37°C. PPD with exposure to M. tuberculosis in contact
Intradermal skin testing (PPD) and chest X-rays investigations in low-incidence settings. Other
may aid in the diagnosis. Diagnosis of tubercu- potential advantages of IGRAs include logistical
lous scleritis requires scleral biopsy; scleral spec- convenience, the need for fewer patient visits to
imens show caseating granulomas with complete testing, the avoidance of unreliable and
multinucleated giant cells and characteristic acid- somewhat subjective measurements, such as skin
fast bacilli. Because cultures may become posi- induration, and the ability to perform serial test-
tive after several weeks, detection of acid-fast ing without inducing the boosting phenomenon
bacilli in scleral tissue and in sputum enables the (a spurious PPD conversion due to boosting of
presumptive diagnosis of systemic tuberculosis, reactivity on subsequent PPDs among BCG-
allowing institution of adequate therapy with vaccinated persons and those infected with other
ethambutol (400 mg orally twice a day), isoni- mycobacteria). Because of the high specificity
azid (300 mg orally once a day), rifampin (600 mg and other potential advantages, IGRAs are likely
orally once a day), and pyridoxine (50 mg orally to replace the PPD for latent infection diagnosis
once a day) for 6–12 months [18]. Detection of in low-incidence, high-income settings where
acid-fast bacilli in scleral tissue but not in sputum cross-reactivity due to BCG might adversely
or other body fluid is regarded as characteristic of impact the interpretation and utility of the PPD.
localized mycobacterial disease, allowing institu- Direct comparative studies in routine practice
tion of amikacin before definitive mycobacterial thus far suggest that the ELISpot has a lower rate
identification by culture (Table 7.2). If M. tuber- of indeterminate results and probably a higher
culosis is identified, therapy should include con- degree of diagnostic sensitivity than the whole-
comitant use of two or more systemic drugs blood ELISA. Further studies are under way to
(isoniazid, rifampin, ethambutol, streptomycin, assess the performance of these tests in contact
248 7 Infectious Scleritis
investigations and in persons with suspected 55-year-old black Haitian female with a 4-year
tuberculosis disease, health care workers, HIV- history of intermittent redness without pain and
infected individuals, persons with iatrogenic gradual decrease in vision in her right eye. Past
immunosuppression, and children. family history disclosed a member with tubercu-
Immune-mediated tuberculous scleritis, usu- losis and review of systems revealed constitu-
ally with interstitial or phlyctenular keratitis or tional symptoms and productive cough. At the
phlyctenular keratoconjunctivitis, is considered moment of her first visit with us, the visual acuity
to be a host immune response to cell wall compo- was hand motions in the right eye and 20/50 in
nents of M. tuberculosis proteins. Occasionally, the left eye. Slit-lamp examination showed dif-
episcleritis may occur [37]. The pathogenesis fuse scleritis associated with adjacent interstitial
appears to be related to a cell-mediated type IV keratitis in the right eye. A PPD intradermal skin
hypersensitivity reaction to these antigens. test was reactive and the chest X-ray showed
Although there is no mycobacterial invasion of extensive left lower and middle lobe infiltrates.
sclera, immune-mediated tuberculous scleritis Her sputum contained acid-fast bacilli and M.
often occurs in conjunction with active systemic tuberculosis grew when cultured. Systemic tuber-
disease. Histologically, scleral specimens show a culosis was diagnosed and systemic tuberculo-
granulomatous reaction without acid-fast bacilli. static agents were instituted. Sclerokeratitis was
Interstitial keratitis associated with scleritis tends believed to be due to tuberculosis, probably sec-
to be peripheral and sectorial. Unlike luetic inter- ondary to an immune-mediated reaction, and
stitial keratitis, in which the deep stroma is topical steroids were begun. Ocular inflammation
involved, tuberculosis interstitial keratitis affects subsided 2 months after the initiation of systemic
the superficial and midstromal layers. There are and topical treatment. Visual acuity was at the
often nodular infiltrates with superficial stromal level of counting fingers at 4 ft, due to corneal
vascularization. The clinical course is prolonged, scarring. Tapering and discontinuation of topical
with residual corneal scarring. Phlyctenular kera- steroids was followed by a recurrence of the scle-
toconjunctivitis develops as a small vesicle in rokeratitis; reinstitution of topical steroids with a
peripheral cornea, bulbar conjunctiva, or tarsal slow taper halted the process without further
conjunctiva. The vesicle progresses to a nodule, recurrences.
which degenerates and heals. Resolution of cor- In our current series of 500 patients with
neal phlyctenules involves scarring and neovas- scleritis, five patients had scleritis associated with
cularization; resolution of conjunctival tuberculosis (1%). They were three males and
phlyctenules does not involve scarring. Corneal two females with a mean age of 53 years (range
phlyctenules may spread centrally, leaving a 35–72 years). Three patients had recurrent nodu-
characteristic leash of vessels from the central lar scleritis, one patient had recurrent diffuse
lesions to the healed peripheral areas marking its scleritis, and one patient had recurrent necrotiz-
path. The diagnosis of tuberculosis as the cause ing scleritis. Past family history of a member
of immune-mediated scleritis with or without with tuberculosis was found in two patients and
keratitis is in most cases difficult or impossible to review of systems revealed constitutional symp-
confirm. It depends on the associated ocular find- toms and productive cough in all patients. PPD
ings and evidence of previous or present systemic intradermal skin test and QuantiFERON-TB
tuberculosis demonstrated by a positive PPD test, Gold® were positive in all patients. T-SPOT.TB®
chest X-ray compatible findings, and positive was also positive in the three tested patients.
sputum culture. Treatment must include topical Chest X-ray revealed compatible findings in all
corticosteroids with meticulous tapering and sys- patients and positive sputum smears and cultures
temic tuberculostatic drugs if there is evidence of contained acid-fast bacilli and M. tuberculosis in
active disease [50, 51]. three patients. Systemic tuberculostatics agents
In our prior series of 172 patients with scleritis were instituted associated with topical steroids.
[13], one patient had scleritis associated with Scleral inflammation subsided without further
systemic tuberculosis (0.57%). The patient was a recurrences.
7.1 Bacterial Scleritis 249
bacilli on scleral biopsy specimen. Therapy consists the genital area, with regional lymphadenopathy.
of a combination of oral dapsone, clofazimine, One month to 3 years later, hematogenous spread
and rifampin. This is supplemented by prolonged of T. pallidum leads to secondary syphilis charac-
treatment with local steroids, which must be care- terized by skin and mucous membrane lesions, as
fully monitored and slowly tapered. well as generalized lymphadenopathy. The
humoral and cellular immune responses can sup-
press the treponemes in an immunocompetent
7.1.3 Spirochetal Scleritis individual, resulting in a latent stage. In one third
of affected individuals, often after latent periods
The spirochetes that most frequently cause scleri- of 1–30 years, tertiary syphilis develops. Tertiary
tis or episcleritis are Treponema pallidum and syphilis consists of an immune-mediated response
Borrelia burgdorferi, etiological agents of syphilis to T. pallidum and its metabolic products, leading
and Lyme disease, respectively. Because syphilis to the formation of gummas. Although gummas
and Lyme disease have increasingly been detected may appear in any organ, they usually cause car-
for the past decade in the USA and Europe, both diovascular lesions (aortic aneurysms) and cen-
entities must be included in the differential diag- tral nervous system involvement (paralysis).
nosis of patients with scleritis and episcleritis. Past Treponemes may be found in the gummas.
history, review of systems and laboratory testing T. pallidum dissemination through transpla-
are important contributors to the diagnosis of cental passage from an infected mother, followed
spirochetal scleritis or episcleritis. by hypersensitivity reactions, causes congenital
syphilis. Interstitial keratitis, peg top teeth, and
7.1.3.1 Syphilis deafness, considered the cardinal signs, are late
Scleritis and episcleritis may be ocular manifes- manifestations of the disease. Other, less com-
tations of syphilis, a sexually transmitted disease mon manifestations are saddle nose deformity,
caused by the spirochete T. pallidum. skull abnormalities, and arched palate.
characteristically localized at the limbus. Limbal azathioprine and to local steroid therapy. At the
swelling may overlap the corneal margin. moment of her first examination by us, visual
3. Tertiary Syphilis: Scleritis and episcleritis dur- acuity was 20/25 in the right eye and 20/20 in the
ing tertiary syphilis are not clinically different left and slit-lamp examination revealed nodular
from that caused by any other disease. Scleritis scleritis and mild anterior uveitis. Past history
in this stage has an insidious onset, may be of review did not reveal any prior disease or specific
the diffuse anterior, nodular anterior, necrotiz- treatment, and review of systems did not disclose
ing anterior, or posterior type, and is often teeth, hearing, skull, or nose abnormalities.
recurrent [78–80]. Immune-mediated mecha- Serological tests were unremarkable and scleral
nisms lead to scleral granulomatous inflam- biopsy disclosed only subacute inflammation. No
mation and inflammatory microangiopathy silver stains or immunostains were performed on
[81]. Occasionally, scleritis is associated with the specimen. Prednisone was slowly tapered and
interstitial keratitis. Interstitial keratitis often oxyphenbutazone was begun. The inflammation
is unilateral, localizes in the superior sector, resolved but the patient returned again 3 months
and appears as tiny stromal opacities, mild later with a nodular scleritis in her left eye. This
endothelial edema, and keratic precipitates new episode prompted repeat laboratory studies,
5 months to 10 years following primary infec- including tests for syphilis. The fluorescent
tion. Stromal opacities may coalesce, affect- treponemal antibody absorption (FTA-ABS) test
ing either a localized area or the entire cornea, was positive. Retrospective indirect immunofluo-
giving a ground-glass appearance. Later, ves- rescence testing in an attempt to demonstrate T.
sels arrive and invade the deep stroma. Once pallidum in the prior scleral biopsy (rabbit anti-
the inflammation subsides, vascular flow treponemal antibody and fluorescein-labeled
diminishes, leaving behind the empty ghost sheep anti-rabbit antibody) was negative. The
vessels. Anterior uveitis may occasionally patient was advised to begin therapy for syphilis
occur. Episcleritis in this stage may be simple but she did not return until 7 months later, when
or nodular [78]. The presence of ocular she had a nodular scleritis recurrence in her left
involvement in tertiary syphilis may be asso- eye. She refused spinal tap. The patient was hos-
ciated with other systemic lesions characteris- pitalized and treated with intravenous penicillin
tic of this stage, such as neurosyphilis [65] or (24 million units of aqueous penicillin G daily for
cardiovascular involvement. 10 days), topical prednisolone acetate (1%, four
4. Congenital Syphilis: Scleritis in congenital times daily), and scopolamine (0.25%, twice
syphilis develops many years after the cardi- daily). Therapy was continued on an outpatient
nal characteristics appear and is usually of basis with penicillin (2.4 million units of penicil-
long duration, mild severity, and resistant to lin G benzathine, intramuscular, once a week for
treatment. Scleritis is usually of the diffuse 3 weeks); topical steroid was tapered and discon-
anterior or posterior type [80]. Interstitial ker- tinued after 8 weeks. The scleritis resolved within
atitis in congenital syphilis usually begins 2 weeks after the onset of therapy. The patient did
between the ages of 5 and 20 years and may not have recurrences of her scleritis during the
reappear at the same time as the onset of following 2 years. The presence of scleritis in this
scleritis. It is eventually bilateral and is more patient was the first manifestation whose study
severe and diffuse than the interstitial keratitis led to the diagnosis and treatment of syphilis.
seen in tertiary syphilis [82]. Anterior uveitis
is often associated. Diagnosis
In our prior series of 172 patients with scleritis Because treponemes may be scant in sclera, par-
[13], one patient had syphilis (0.58%). The patient ticularly in tertiary or congenital syphilis, their
was a 63-year-old black female with a 1-year his- identification with silver stains (Levaditi’s stain
tory of nodular scleritis in her right eye, which or Warthin–Starry stain) or by immunological
was unresponsive to systemic prednisone and methods (direct or indirect immunofluorescence
252 7 Infectious Scleritis
intramuscular therapy inadequate [67]. Therefore, last two stages. They include neuroophthalmic
a patient with primary, secondary, tertiary, or findings, such as involvement of third, sixth, and
congenital syphilis and concurrent HIV infection seventh cranial nerves, optic nerve (optic neuritis
needs intravenous antibiotic therapy. and perineuritis, papilledema, ischemic optic
neuropathy, optic nerve atrophy), and retina (reti-
7.1.3.2 Lyme Disease nal hemorrhages, exudative retinal detachments,
Scleritis and episcleritis may be ocular manifes- cystoid macular edema) [96, 114, 119–123].
tations of Lyme disease, a tick-borne illness Other ocular findings are anterior and posterior
caused by B. burgdorferi, a larger spirochete than uveitis, endophalmitis, keratitis, conjunctivitis,
T. pallidum. blepharitis, scleritis, and episcleritis [124–133].
Keratitis may manifest as stromal opacities,
Epidemiology punctate superficial keratitis, or peripheral ulcer-
Lyme disease was first described in 1977 by Steere ative keratitis. Ocular manifestations also may
et al. [93], in three Connecticut communities. indicate recrudescence of the Lyme disease after
Since then it has been increasingly recognized in inadequate treatment of the infection [130, 132].
the USA, particularly in the northeast, upper mid-
west, and California, as well as in certain areas of Scleritis and Episcleritis
the Pacific Northwest and midwest [94, 95]. Lyme Scleritis and episcleritis may occur in Lyme dis-
disease has also been detected in Europe [96]. ease. Their pathogenesis may be related either
with direct invasion of the Borrelia species or to
Pathogenesis and Clinical Features an immune-mediated response to Borrelia or its
Lyme disease is acquired by the bite of Ixodes metabolic products. Scleritis has not been previ-
dammini, a well-recognized tick vector for the ously reported in Lyme disease.
spirochete B. burgdorferi [97, 98]. However, In our prior series of 172 patients with scleritis
only approximately 30% of persons recall being [13], one patient had Lyme disease (0.58%). The
bitten [99]. Lyme disease has three defined clinical patient was a 57-year-old female who had been
stages [100–102]. Stage 1 appears within 1 month living in New England for the past 5 years. She
of an infected tick bite, usually in the summer, and had had recurrent episodes of diffuse scleritis in
is characterized by a skin macular rash of varying her left eye along with mild anterior uveitis, disk
severity, often with a clear center at the area of the edema, and cystoid macular edema. The patient
bite, known as erythema chronicum migrans. There did not recall being bitten and no systemic clini-
may be associated stiff neck, fever, headache, mal- cal abnormalities were found. Laboratory tests
aise, fatigue, myalgias, and/or arthralgias [99]. revealed a Lyme titer of 1:640 by enzyme-linked
Stage 2 begins several weeks to months after immunosorbent assay (ELISA) and elevated cir-
the tick bite and is characterized by neurological culating immune complexes by Raji cell assay;
(meningitis, radiculoneuropathies, severe head- an FTA-ABS test was negative. No scleral biopsy
ache) and cardiac (atrioventricular block, myo- for silver stains or immunostains was performed.
pericarditis) manifestations [103–109]. Therapy with intravenous ceftriaxone (2 mg a
Stage 3 occurs up to 2 years after the tick bite day for 14 days) and topical steroids controlled
and is characterized by a migratory oligoarthritis the scleritis without further recurrences.
[103, 110–112]. Neurological manifestations Lyme disease must always be considered in
(encephalopathy, seizure, dementia, myelitis, the differential diagnosis of scleritis associated
spastic paraparesis, psychiatric disturbances, with neuroophthalmological findings.
ataxia) also may occur in this stage [113–118]. Episcleritis also may appear in Lyme disease
Other manifestations include fatigue, lymphade- [132, 133], usually after other ocular manifesta-
nopathy, splenomegaly, sore throat, dry cough, tions, such as follicular conjunctivitis or stromal
nephritis, hepatitis, or testicular swelling. keratitis. Episcleritis may indicate a recurrence of
Ocular manifestations of Lyme disease may the infection after inadequate treatment for Lyme
appear at any stage but are more common in the disease [132].
254 7 Infectious Scleritis
7.2.1.5 Our Experience Fig. 7.3 Inferior sclera of the same patient as in Fig. 7.2
In our prior series of 172 patients with scleritis
[13], one patient had fungal scleritis (0.58%) (see
section on “Local Infections” in Chap. 5). The
patient developed a necrotizing scleritis in his
right eye a few days after being struck by a cow’s
tail. Initial cultures were negative but specimens
from scleral biopsy stained with Giemsa and
Gomori methenamine silver (Fig. 5.33) revealed
the presence of fungal forms with septate hyphae
forming acute angles, a morphology consistent
with Aspergillus. Aspergillus fumigatus was later
recovered in culture. Prolonged systemic and
topical therapy cured the infection without fur-
Fig. 7.4 Same patient as in Figs. 7.2 and 7.3, showing the
ther further recurrence (Figs. 7.2–7.7). extensive involvement of the scleritic process, with necro-
In our current series of 500 patients with scleri- tizing lesions nasally as well as inferiorally and
tis, one patient had fungal scleritis (0.2%). The supratemporally
patient was a 63-year-old male without any prior
systemic disease with recurrent superior temporal including hematoxylin and eosin, Gram, acid-fast,
nodular scleritis in his left eye. Other ocular find- and Gomori methenamine silver staining did not
ings were unremarkable. A biopsy was taken from show any microorganisms, only inflammatory cells.
superior scleral nodule; pathohistologic studies, Rheumatologic evaluations, including complete
258 7 Infectious Scleritis
deteriorating vision, severe pain, or even (occa- or zoster. Herpes zoster most commonly involves
sionally) perforation of the globe. Scleritis during the thoracic nerves; however, the trigeminal
the acute episode of herpes zoster ophthalmicus nerve is involved in 9–16% of patients [163–166].
is easily associated with VZV infection. However, Of the three divisions of the trigeminal nerve
because scleritis often occurs months after the (ophthalmic, maxillary, and mandibular), the first
onset of the VZV infection, herpes zoster scleritis or ophthalmic is the most frequently affected.
is sometimes difficult to diagnose. A careful past The ophthalmic division of the trigeminal
history review and meticulous facial and ocular nerve has three branches, the frontal, the lacri-
examination are essential for early diagnosis of mal, and the nasociliary. The frontal branch, sup-
herpes zoster scleritis. Subsequent aggressive plying the upper lid, forehead, and superior
and prolonged treatment may halt the progres- conjunctiva, is the most commonly involved. The
sion of the scleral destruction. lacrimal branch supplies the lacrimal gland, the
conjunctiva, and the skin of the temporal angle of
the eye. The nasociliary branch is the sensory
Epidemiology nerve that supplies the eyeball. This branch
Herpes zoster may occur in any age group, but is divides into the infratrochlear and the nasal
most common in individuals over age 60. That nerves. The infratrochlear nerve goes to the lacri-
the aging process enhances the risk of developing mal sac, conjunctiva, skin of both lids, and root
herpes zoster infection can be judged from the of the nose. The nasal nerve goes to the most
fact that herpes zoster has an incidence of three critical structures: the sclera, cornea, uveal tract,
cases per 1,000 population per year for ages and the tip of the nose. Because VZV most com-
20–49 years, and of ten cases per 1,000 population monly affects all three branches of the ophthal-
per year for ages 80–89 years [158]. Immuno- mic division, ocular involvement in herpes zoster
suppressed patients, such as patients with
may lead to devastating ocular pathology.
acquired immune deficiency syndrome, organ
Skin papules, pustules, or vesicles, conjuncti-
transplantation, neoplasia, or blood dyscrasia, are
val or episcleral vesicles, and corneal dendritic
also at great risk for developing herpes zoster
ulcers are caused by direct invasion of the virus.
infection [159].
Scleritis, sometimes episcleritis, keratitis, trabe-
culitis, and anterior uveitis are most commonly
Pathogenesis caused by immune-mediated reactions triggered
Varicella (chickenpox) and herpes zoster are dif- by the virus; [167] recurrences are independent
ferent clinical conditions caused by the same of the presence of the virus.
virus. Primary infection with VZV results in
chickenpox. In the USA, over 90% of adults have Clinical Features
serologic evidence of previous infection by VZV Herpes zoster is a disease characterized by an
and most of them have VZV in a latent state [160]. intense painful, vesicular eruption involving the
About 20% of these adults may have a reactiva- skin or mucous membrane in the distribution of a
tion of VZV occurring as herpes zoster [161]. single sensory nerve. Although the incubation
Ocular herpes zoster is thought to represent a period after reactivation of endogenous virus is
reactivation of latent VZV left in the trigeminal not known, the incubation period after contact
ganglion following a previous attack of chicken- with exogenous virus ranges from a few days to
pox; [162] this involves a partial immune response 2 weeks [168]. Headache, malaise, fever, and
after first exposure to the virus: the immune sys- chills may precede the skin eruption by 4 or
tem is not capable of effectively eliminating the 5 days; neuralgia may precede the skin eruption
virus but is capable of producing immunopathol- by 2 or 3 days. The skin eruptions begin as pap-
ogy. There is no convincing evidence that herpes ules, which rapidly become vesicles and pustules;
zoster can occur after contact with exogenous vesicles subside within 2 weeks, often leaving
VZV from a patient suffering active chickenpox permanent scars, variable degrees of hypoesthe-
260 7 Infectious Scleritis
sia, or severe post-zoster neuralgia [169]. Eye to sclerosing keratitis or even to peripheral ulcer-
lesions occur in about 50% of these cases [170]. ative keratitis. It also may be associated with
Rarely, the ocular manifestations may appear anterior uveitis, which may cause a sectorial iris
without the skin eruption; a careful search for atrophy and/or trabeculitis, which in turn may
subtle papules, pustules, or vesicles in scalp or cause glaucoma. Decreased corneal sensation in
serial VZV blood titers may contribute greatly to the affected area and sectorial iris atrophy are
the diagnosis. helpful indicators for the diagnosis of herpes
Ocular involvement in VZV infection often zoster ophthalmicus.
includes conjunctivitis, episcleritis, scleritis, ker- In our prior series of 172 patients with scleritis
atitis, uveitis, and glaucoma; scarred lid retrac- [13], two patients had scleritis secondary to herpes
tion, paralytic ptosis, retinitis, acute retinal zoster infection (1.16%). The first patient was an
necrosis, disk edema, pupil abnormalities, and 85-year-old white female who developed necrotiz-
extraocular nerve palsies also may occur [170, ing scleritis and sclerosing keratitis near the supe-
171]. Hypopyon, hemorrhage into the anterior rior limbus in her right eye. Visual acuity at
chamber and phthisis bulbi may result from her- presentation was at the count fingers level in the
pes zoster vasculitis and ischemia (anterior seg- right eye and corneal sensation was markedly
ment necrosis). decreased. Six months prior to the onset of scleritis
Postherpetic neuralgia may be defined as pain she had had an episode of herpes zoster ophthal-
in the involved dermatome persisting for more micus with skin lesions and dendritic keratitis,
than 2 months following the onset of zoster der- which was treated with oral acyclovir and oral ste-
matitis. It is more common in patients over roids. She had also had an uncomplicated extraoc-
60 years of age (about 50% of these). It may be ular cataract extraction with implantation of an
the result of herpes zoster vasculitis and neuritis. intraocular lens 9 months prior to the onset of
scleritis. An extensive laboratory investigation
Scleritis revealed only circulating immune complexes. A
The reported incidence of scleritis in herpes diagnosis of herpes zoster necrotizing scleritis with
zoster ophthalmicus ranges from 0.68 to 8% [7, marked scleral destruction and uveal show associ-
13, 80, 172–174]. Although scleritis may occur ated with peripheral ulcerative keratitis was made
during the acute disease (about 10–15 days after (Fig. 7.8), treatment with oral prednisone was initi-
the onset of skin lesions), it most commonly ated, and scleral debridement and homografting
appears months or years after an episode of were performed (Fig. 7.9). Pathological examina-
herpes zoster ophthalmicus [175], sometimes tion of the sclera showed chronic granulomatous
triggered by ocular surgery. Zoster scleritis is of inflammation with multinucleated giant cells and
immune etiology and, although it may be diffuse epithelioid cells, and inflammatory microangiopa-
or nodular, it often is necrotizing, with painful, thy. Immunohistochemical studies with anti-VZV
persistent, circumscribed nodules with translu- antibodies did not detect VZV antigen. The patient
cent centers, and risk of perforation or staphy- could not tolerate oral prednisone and oral acyclo-
loma formation [176–179]. It requires aggressive vir, and she developed progressive melting of the
and prolonged therapy or even adjunctive proce- scleral graft and peripheral ulcerative keratitis
dures, such as scleral homografting to maintain (Fig. 7.10). Institution of oral methotrexate initially
the integrity of the globe. Scleritis may take reduced scleral and corneal inflammation but, after
months to resolve and often leaves extensive 3 weeks, progressively destructive inflammatory
scleral thinning. Recurrences, sometimes occur- activity again increased. Extensive scleral and cor-
ring not at the same site as the previous attack of neal melting, and hemorrhage into the anterior
scleritis, may be frequent, even after many years. chamber with a profound fibrin-type reaction, indi-
Zoster scleritis may be accompanied by stromal cated anterior segment necrosis. Enucleation was
keratitis, either immune disciform or white performed by her local ophthalmologist and we did
necrotic interstitial keratitis, which may progress not obtain the pathology report. VZV infection in
7.3 Viral Scleritis 261
The role of systemic steroids in preventing of direct viral invasion during the active HSV
postherpetic neuralgia is controversial [195–197]; infection. Scleritis may occur during the active
however, they reduce the incidence and severity HSV infection as a result of direct viral invasion,
of ocular complications, such as scleritis, kerati- or months after the initial viral encounter as a
tis, anterior uveitis, or glaucoma [169, 197], result of an immune-mediated reaction induced
Systemic steroids may be reserved for immuno- by the virus.
competent adults over age 60 years because they
are at greatest risk for severe or permanent pain. Epidemiology
The suggested dosage is 40–60 mg/day for HSV is ubiquitous and primary infection usually
5–7 days, 30–40 mg/day for 5–7 days, and 20 mg occurs between 6 months and 5 years of age.
for 5–7 days. More than 70% of individuals have been infected
Capsaicin (a 0.025% topical skin cream with HSV by age 15–25 years and, therefore,
applied 3–6 times daily in the involved der- have HSV antibodies; this percentage progres-
matome after the skin has healed) relieves pain in sively increases with age to about 97% of indi-
75% of patients (after 2–6 weeks of treatment) viduals 60 years of age being infected [204].
through depletion of substance P from the sen- Because only about 1–6% of patients with pri-
sory peripheral neurons [198, 199]. Tricyclic mary HSV infection experience some form of
antidepressants, especially amitriptyline hydro- clinical disease [205], most primary HSV infec-
chloride, may also relieve postherpetic neuralgia tions are subclinical and, therefore, more than
[200–203]. 95% of HSV-related clinical manifestations are
Systemic nonsteroidal anti-inflammatory the result of recurrences that develop long after a
drugs may be helpful in patients with immune- primary infection [206].
mediated ophthalmic complications, such as
scleritis (diffuse or nodular) with or without Pathogenesis
keratitis or anterior uveitis. If systemic non- Viral transmission in primary HSV seems to be
steroidal anti-inflammatory agents are not effec- by direct contact from infected individuals. The
tive in diffuse or nodular scleritis, systemic virus infects a peripheral end organ and travels to
steroids may be used. Oral acyclovir, famciclo- the ganglia, where it becomes latent. The virus
vir, or valaciclovir should be added for preven- may be reactivated by different stimuli, such as
tion of acute VZV infection or if the diagnosis is fever, sunlight, trauma, or stress, presumably
not completely clear in terms of differentiating through cyclic nucleotide concentration changes
herpes zoster from herpes simplex. Topical [207]; it travels to the peripheral end organ via the
steroid therapy has little effect on scleral inflam- neuronal network and produces recurrent HSV
mation. Immunosuppressive agents (alone or in disease. Immunosuppressed individuals, such as
combination with systemic steroids) are indi- patients with leukemia, malignancies, or trans-
cated if there is a necrotizing scleritis, if the planted organs, are at high risk for reactivation of
scleritis is steroid unresponsive, or if the scleri- latent HSV [208, 209].
tis is steroid responsive but requires prolonged Clinical disease and frequency of recurrences
toxic doses of systemic steroids. Addition of seem to depend on the type of virus strain (viral
oral acyclovir, famciclovir, or valaciclovir is genome) of the primary HSV infection [210,
recommended for prevention of recurrent VZV 211]: although most people are colonized by a
infection or if the diagnosis is not completely “good” virus incapable of producing disease
clear in terms of differentiating herpes zoster except under extreme conditions (leukemia,
from herpes simplex. malignancies, etc.), some patients are colonized
by a more virulent virus that causes clinical man-
7.3.1.2 Herpes Simplex Scleritis ifestations with varying frequencies of recurrence
HSV may occasionally cause episcleritis and [206]. Viral genome and neuronal stimuli, there-
scleritis. Episcleritis most often occurs as a result fore, are important factors in the development of
264 7 Infectious Scleritis
viral reactivation and subsequent clinical recur- HSV infection (1.16%). One patient was a
rent disease. 49-year-old white male with a maxilla osteosar-
coma that required bone removal and multiple
Clinical Features debridement and bone grafts because of second-
Primary ocular HSV usually occurs as an acute ary osteomyelitis (see section on “Systemic
follicular conjunctivitis with preauricular adenop- Infections” in Chap. 5). While receiving antibiot-
athy, with or without vesicular ulcerative blepharitis ics via a continuous intravenous central line anti-
or periocular cutaneous involvement, and punctate biotic pump, the patient developed blotchy white
or branching epithelial keratitis. The virus estab- infiltrates in the corneal stroma and diffuse scleri-
lishes a latent infection, which may recur under tis adjacent to the corneal infiltration.
different types of neuronal stimuli. Immunofluorescence studies of the corneo-con-
Recurrent ocular HSV is mainly characterized junctiva-scleral biopsy, using anti-HSV type 1
by keratitis, including epithelial keratitis (den- antibodies, revealed positive detection of HSV
dritic ulcers, geographic ulcers, and metaherpetic type 1 antigens in cornea, conjunctiva, and sclera.
ulcers), stromal keratitis (necrotizing, interstitial, Treatment with acyclovir and steroids resolved
or disciform keratitis, immune rings, and limbal the process.
vasculitis), and endotheliitis. Dendritic or geo- The second patient was a 77-year-old white
graphic ulcers are caused by direct viral invasion; male with multiple recurrences of HSV dendritic
necrotizing stromal keratitis is caused by direct keratitis who developed necrotizing scleritis and
viral invasion and by immune complex hypersen- peripheral ulcerative keratitis in his right eye
sitivity immune disease [206, 212]; interstitial 1 month after the last active infectious episode.
stromal keratitis, immune rings, limbal vasculi- An extensive systemic review of systems was
tis, and peripheral ulcerative keratitis are caused negative. Histopathologic examination of the
by immune complex hypersensitivity immune conjunctiva and scleral biopsies revealed granu-
disease; disciform keratitis is caused by delayed lomatous inflammation with epithelioid and
hypersensitivity immune disease; endotheliitis multinucleated giant cells, and inflammatory
may be caused by active viral invasion or by microangiopathy in both tissues; immunofluores-
immune disease; metaherpetic ulcers are caused cence studies with anti-immunoglobulins and
by trophic factors. anti-complement antibodies revealed immune
Uveitis and retinitis also may occur in recurrent complex deposition in the vessel walls in both tis-
HSV. Episcleritis and scleritis are uncommon. sues; immunofluorescence studies with anti-HSV
type 1 antibodies were negative in both tissues.
Scleritis Superficial keratectomy and conjunctival-scleral
Direct HSV invasion (often with epithelial infec- debridement followed by cornescleral grafting
tious ulceration or necrotizing stromal disease) or stopped the progression of the process.
the host immune reaction to the virus (often with Keratoscleritis in this patient seemed to have
necrotizing or interstitial stromal keratitis, been caused by an autoimmune mechanism
immune rings, limbal vasculitis, disciform kerati- induced by HSV type 1.
tis, or peripheral ulcerative keratitis) may cause
scleritis. Active infectious scleritis is usually of Episcleritis
the diffuse or nodular type [37]; immune-medi- Episcleritis may rarely occur in HSV infection
ated scleritis is most often of the necrotizing type. [17, 213–215]. It may be simple or nodular and is
Corneal-conjunctival-scleral biopsy, using anti- often accompanied by areas of lymphocytic infil-
HSV type 1 antibodies may reveal positive detec- tration manifested as yellow spots in conjunctiva
tion of HSV type 1 antigens in cornea, conjunctiva, and episclera, or by dendrites in cornea [17].
and sclera [206]. Episcleritis is usually the result of direct viral
In our prior series of 172 patients with scleritis invasion and resolves in a few weeks without
[13], two patients had scleritis associated with sequelae. Recurrences are not unusual.
7.3 Viral Scleritis 265
In our prior series of 94 patients with episc- available to substantiate HSV as the responsible
leritis [13], one patient had episcleritis associated agent of the immune damage.
with HSV infection (1.06%). The patient was a
64-year-old white female who developed a folli- Therapy
cular conjunctivitis; there were also vesicles in Active HSV infection, including epithelial kerati-
bulbar conjunctiva and episclera with surround- tis, scleritis, or episcleritis, may be treated with
ing redness and edema in the absence of keratitis. topical antiviral agents, such as idoxuridine, vid-
Treatment with trifluridine resolved the inflam- arabine, trifluridine, or acyclovir [206]. Trifluridine
mation completely in 1 week. Visual acuity was (1% drops, one drop nine times a day for
not affected. Unfortunately, scrapings for cytology, 14–21 days) and acyclovir (3% ophthalmic oint-
antigen detection, or cultures were not taken. ment, one application five times a day), are the
most effective agents in clinical trials [216, 217],
Diagnosis although acyclovir ointment is available only on a
Although often clinically characteristic, diagno- compassionate plea basis in the USA. Idoxuridine
sis of either primary or recurrent active ocular and vidarabine remain effective agents and can be
HSV infection can be assisted with laboratory used in the absence of a history of drug failure or
techniques. Giemsa or Papanicolaou staining intolerance. Long-term oral acyclovir (200 mg,
may show eosinophilic intranuclear inclusions, five times a day) significantly reduces recurrences
ballooning degeneration, multinucleated giant of HSV epithelial keratitis (Pavan Langston D:
cells, and monocytic infiltration (indistinguish- Systemic acyclovir in herpes simplex keratitis.
able from VZV) from corneal dendrite or skin Personal communication, New England Ophthal-
vesicle scrapings; conjunctival swabbing is not mological Society Meeting, Sept 13, 1991); we
usually helpful, unless there is follicular con- may assume that long-term oral acyclovir may also
junctivitis with or without episcleritis. HSV-1 decrease recurrences of episcleritis or scleritis due
antigen may be detected by immunofluorescence to active viral invasion. Long-term oral acyclovir
assays performed on scrapings (corneal dendrite, has been shown to reduce recurrences of HSV
upper palpebral conjunctiva, and skin vesicle) or keratitis following penetrating keratoplasty [218].
tissue biopsies (skin, cornea, conjunctiva, epis- Therapeutically, the same rules apply to the
clera, and sclera) [206]. HSV causes a cytopathic treatment of immune-mediated scleritis second-
effect in ordinary tissue cultures (HeLa cells, ary to HSV as to immune-mediated scleritis sec-
human amnion cells, or Vero cells). Herpes virus ondary to VZV (see Sect. 7.3.1.1). If systemic or
also may be detected by electron microscopy topical steroids are used, concomitant prophylactic
studies, but HSV and VZV are indistinguishable. antiviral agents, such as topical trifluridine drops
Serology may differentiate primary HSV infec- (four times a day) or oral acyclovir (200 mg, five
tion from recurrent HSV infection because only times a day), should be used.
primary infection shows an increase in HSV type
1 antibody titer: negligible titers are found dur- Our Experience
ing the acute phase and considerably higher titers In our current series of 500 patients with scleritis,
are found 4–6 weeks later. Because most adults 35 patients had herpetic scleritis (7%). The most
have developed an anti-HSV antibody titer indi- common type of scleritis was diffuse in 80% of the
cating prior, usually asymptomatic or subclini- patients, followed by nodular (11.4%), and necro-
cal, primary infection, absence of antibody can tizing in 8.6%. The scleritis was most often unilat-
help to exclude HSV as a cause of atypical eral (80%) and associated with keratitis and/or
keratitis. anterior uveitis with subsequent loss of vision.
HSV immune-mediated keratitis and/or scleri- Herpes virus infection was confirmed by anti-HSV
tis diagnosis is suggested by clinical findings in a and anti-HZV immunofluorescent analysis of scleral
patient with a prior history of herpetic epithelial specimens in 16 patients. Diagnosis was presump-
keratitis. There is no current laboratory method tive by unequivoval findings of dendritic or stromal
266 7 Infectious Scleritis
keratitis at some point of follow-up in four patients, brackish water, swimming pools, water baths,
by anti-HSV and/or anti-HZV serologic titers in the and sea water), contact lenses (hard and soft
setting of typical herpetic infection exam in five lenses), and solutions used to rinse contact lenses
patients, and by a dramatic response and resolution (tap water, saliva, well water, homemade non-
of symptoms following antiviral therapy in the set- sterile saline) [224]. Scleritis is believed to be
ting of clinical findings of chronic herpetic infection unrelated to direct invasion of Acanthamoeba
(corneal hypoesthesia) in ten patients. We strongly and attributable to an immune-mediated response,
suggest to biopsy and analyze scleral tissue by anti- of uncertain etiology, triggered by the corneal
HSV and anti-HZV immunofluorescence to estab- infection [225].
lish a definite diagnosis, especially in cases where Acanthamoeba keratitis with or without
clinical findings are nonspecific. scleritis is a potentially devastating infection
[226, 227]. Patients with keratoscleritis due to
Acanthamoeba are usually young, healthy,
7.3.2 Mumps Scleritis immunocompetent individuals, with at least one
of the following risk factors: (1) history of
Mumps may affect the eye, leading to catarrhal minor corneal trauma, (2) direct exposure to
conjunctivitis, punctate epithelial keratitis, or soil or contaminated fluids, or (3) contact lens
severe stromal keratitis. Occasionally, scleritis, wear [227–229]. Scleritis is usually diffuse or
episcleritis, uveitis, optic neuritis, glaucoma, retin- nodular, although it may progress to necrotiz-
itis, and extraocular muscle palsies may occur ing, and lead to scleral ectasia [225], and is
[219–223]. Diagnosis is usually made by the pres- accompanied by a ring-shaped infiltrative
ence of systemic manifestations of mumps, stromal keratitis [230], sometimes with persis-
although isolation of virus and rising antibody tent or recurrent pseudodendritic or punctate
titers confirm the disease. Mumps ocular manifes- epithelial erosions; anterior uveitis rarely with
tations usually resolve spontaneously without hypopyon also may be present. Herpes simplex
recurrences. No specific therapy is recommended. keratitis is the initial diagnosis in about 65% of
the patients. Standard cultures are usually nega-
tive for bacteria, fungi, and viruses and the
7.4 Parasitic Scleritis course is chronic and progressive in spite of
treatment with antimicrobial agents. Many
Parasites are generally seen by doctors as exotic patients present with intense ocular pain, usu-
organisms that infect individuals from underde- ally out of proportion to the stromal keratitis;
veloped countries. However, the increased the pain is probably due to predilection of the
interchange of people from different parts of the amoeba for neural tissue [231].
world through international travel, and the The diagnosis of keratoscleritis due to
improved diagnostic skills of doctors, have con- Acanthamoeba is usually missed because the
tributed to an increased recognition of these infection is uncommon; herpes simplex kerato-
microorganisms as the cause of parasitic infections scleritis is the most frequent misdiagnosis.
of the ocular structures, including the sclera. However, even if the infection is considered ini-
tially, diagnosis of Acanthamoeba may still be
difficult to confirm. A provisional diagnosis can
7.4.1 Protozoal Scleritis be made using the clinical features and confocal
microscopy, although a definitive diagnosis
7.4.1.1 Acanthamoeba requires culture, histology, or identification of
Acanthamoeba is a small amoeba that may be Acanthamoeba deoxyribonucleic acid by poly-
found in soil, contaminated water (distilled merase chain reaction. Routine use of tissue
water, tap water, well water, hot tube water, diagnosis is recommended, particularly for
7.4 Parasitic Scleritis 267
7.4.1.2 Toxoplasmosis
Although the most frequent ocular manifestation
in toxoplasmosis is retinochoroiditis, scleritis,
and episcleritis occasionally may occur [237–
239]. Scleritis in toxoplasmosis, usually associ-
ated with retinochoroiditis, is probably the result
of scleral extension of severe toxoplasmic retini-
tis and choroiditis [240]. Either nongranuloma- Fig. 7.15 Same patient as in Figs. 7.11 through 7.14:
Progressive necrotizing scleritis in spite of aggressive
tous or granulomatous inflammation of the sclera topical and systemic therapy for Acanthamoeba. The eye
has been found [240]. Toxoplasmosis is a disease was eventually enucleated because of an unsightly phthi-
caused by the protozoan Toxoplasma gondii; sical eye
7.4 Parasitic Scleritis 269
ocular damage may occur either from direct includes corticosteroids, either systemic or tran-
invasion of the protozoan or from immunologi- septal; thiabendazole also may be added.
cal reactions against protozoan products. Scleritis has not previously been described
Toxoplasmosis is almost always congenital but as a presenting manifestation of ocular toxo-
may be acquired through inhalation of oocytes in cariasis [18, 241]. In our prior series of 172
cat feces or ingestion of contaminated pork or patients with scleritis [13], one patient had
lamb meat. In both forms, an acute focal chori- toxocariasis (0.58%). The patient was a 70-year-
oretinitis lesion develops between ages 10 and old white female who developed recurrent nod-
40 years. The lesions are usually single, poste- ular scleritis, anterior uveitis, dense cataract,
rior to the equator, and are often about one disk and 360o posterior synechiae in her left eye.
diameter in size; they commonly occur next to an Visual acuity in the left eye was at the level of
area of scar. hand motions only. Because adequate examina-
Although a definitive diagnosis of ocular tox- tion of the posterior segment of the eye could
oplasmosis can be made only by identifying the not be done, ultrasonography was performed;
protozoa histologically, a supportive diagnosis is this showed a temporal mass and vitreous mem-
made on the basis of the clinical picture and sero- branes in the left eye. Review of systems dis-
logical tests. The serological tests most com- closed a history of cervical cancer. Given the
monly used are the ELISA and the IFA test. The patient’s age, history of cervical cancer, and the
presence of high IgM anti-toxoplasma titers indi- presence of an intraocular mass, a metastatic
cates a recent infection. lesion versus a primary ocular melanoma was
Treatment of toxoplasmosis retinochoroiditis considered. Extracapsular cataract extraction,
with or without scleritis includes oral corticoster- sphincterotomy, and pars plana vitrectomy were
oids and antitoxoplasmic agents, such as sulfadi- performed to improve visualization of the pos-
azine, pyrimethamine, and clindamycin; folinic terior segment. A granuloma temporal to the
acid should be added to avoid toxic depression of disk, subretinal exudates, and a tractional
the bone marrow by pyrimethamine. detachment of the retina were found. Biopsy of
Any patient with scleritis and retinochoroidi- the scleral nodule and fine needle biopsy of the
tis should be examined for toxoplasmosis. intraocular mass were performed; nongranu-
lomatous inflammation of the scleral specimen
and granulomatous inflammation of the intraoc-
7.4.2 Helminthic Scleritis ular mass specimen were found with the absence
of tumor cells from either lesion. An ELISA test
7.4.2.1 Toxocariasis for Toxocara was positive (titer, 1:64) and ocu-
Toxocariasis is a common parasitic disease in the lar toxocariasis was diagnosed. The patient was
USA; humans are infected after ingestion of the subsequently treated with topical and systemic
helminth Toxocara canis. The natural host for corticosteroids; ocular inflammation, including
this parasite is the dog; droppings from which scleritis was controlled, but the visual acuity did
can contaminate sand and earth, which is later not improve.
inadvertently ingested, primarily by children at Results of serology, and clinical and histologi-
play. Ocular manifestations, usually affecting cal granuloma in the posterior segment of the
individuals 6–40 years of age, include posterior eye, supported the diagnosis of toxocariasis in
pole and retinal periphery granulomas and spite of the organism not being isolated, and the
chronic endophthalmitis [241]. Although a defin- patient was beyond the age group normally asso-
itive diagnosis of ocular toxocariasis can be made ciated with ocular toxocariasis.
only by identifying the larva histologically, sup- Any patient who develops scleritis and poste-
portive diagnosis is made on the basis of the rior pole or peripheral retinal granuloma should
clinical picture and ELISA blood tests. Treatment be examined for toxocariasis.
270 7 Infectious Scleritis
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276 7 Infectious Scleritis
Noninflammatory diseases of the sclera are to pursue the appropriate course of action should
encountered infrequently in ophthalmic practice. such abnormalities be discovered.
Their detection is easily overlooked by the oph-
thalmologist because of this and because of the
absence of inflammation. Furthermore, major 8.1 Scleral Deposits
textbooks of ophthalmology usually do not
include discussions of the differential diagnosis Scleral depositions of abnormal substances are
of noninflammatory diseases of the sclera, and so due to either systemic inherited or acquired meta-
ophthalmologists are generally unaware that dis- bolic abnormalities, or ocular degenerative pro-
tinguishing features, such as deposits, thinning, cesses. For organizational purposes, these
thickening, and masses of the sclera can be diag- disorders are discussed in groups based on the
nostically valuable (Table 8.1). biochemical substance accumulated (Table 8.1).
Like scleritis and episcleritis, noninflamma- Scleral changes characteristics of the different
tory diseases of the sclera cannot be properly metabolic diseases are shown in Table 8.2.
understood as isolated entities but must be seen
in relation to the larger picture of a patient’s gen-
eral health. Noninflammatory diseases of the 8.1.1 Scleral Protein Deposition
sclera may be signs of systemic diseases, such
as metabolic disorders, connective tissue 8.1.1.1 Porphyria
abnormalities, or hematologic disturbances. The porphyrias are characterized by the exces-
Noninflammatory diseases of the sclera also may sive excretion of one or more fluorescent pig-
be signs of ocular diseases, such as inherited or ments known as porphyrins. The porphyrias are
congenital connective tissue abnormalities, inherited disorders which can be divided into two
degenerations, or tumors. In many instances, the major types: erythropoietic, in which porphyrins
attributes of the scleral abnormalities are suffi- accumulate in red blood cells, and hepatic por-
ciently distinctive that the diagnosis of the asso- phyria, in which porphyrins accumulate in the
ciated illness is first suspected by the ocular liver. The former may be subdivided into erythro-
presentation. poietic uroporphyria (congenital porphyria) and
This chapter reviews the clinical features and erythropoietic protoporphyria; the latter may be
pathophysiology of the diseases associated with subdivided into acute intermittent porphyria, por-
noninflammatory diseases of the sclera. The aim phyria cutanea tarda, porphyria variegata, and
is to stimulate the readers to search for them and hereditary coproporphyria. Exposure to sunlight,
The presence of episcleral or scleral polychro- eral cornea [30, 31]. Conjunctiva and lid
matic crystals associated with the characteristic pigmentation also may be seen.
corneal involvement is very suggestive of cysti- Any patient who develops scleral or episcleral
nosis. The diagnosis of cystinosis can be con- pigmentation should be questioned and examined
firmed by conjunctival biopsy and analysis of for urine and cartilage abnormalities.
cystine by column chromatography [22]. Long-
term oral administration of cysteamine is effec- 8.1.1.4 Amyloidosis
tive in improving renal function and growth in Amyloid is an eosinophylic hyaline extracellular
young patients [23], but it does not prevent cor- material made up of sheets of fibrous protein that
neal crystal deposition. Frequent instillation of may be deposited in various tissues of the body,
topical cysteamine (0.1%) may reverse the depo- including the sclera [32]. Although foreign-body
sition of crystals in the central cornea [24, 25]. cell reactions occasionally may be seen, amyloid
does not produce any inflammatory response by
8.1.1.3 Alkaptonuria its presence in tissues. Several classifications of
Alkaptonuria (ochronosis) is a rare autosomal the amyloidoses by various criteria have been
recessive disorder characterized by the absence only partially successful because of the overlap-
of the enzyme homogentisic acid oxidase, nor- ping of the different categories. One of the clas-
mally present in liver and kidney [26, 27]. As a sifications differentiates amyloidosis into primary
result of this error of metabolism, homogentisic and secondary amyloidosis, depending on the
acid, a normal intermediary in the metabolism of absence or the presence of a preexisting disease,
phenylalanine and tyrosine, accumulates in tis- respectively. Both categories are further classi-
sues, including the episclera and sclera, and is fied into familial and nonfamilial types. Primary
excreted in the urine. amyloidosis, particularly the familial type, is the
Alkaptonuria is usually diagnosed on the basis form most commonly associated with deposition
of the urine containing homogentisic acid that of amyloid in the lid, cornea (lattice corneal dys-
darkens slowly if left to stand, or rapidly with the trophy), conjunctiva, iris, choroid, retina, vitre-
addition of strong alkali (alkapton), pigmentation ous, ciliary nerves, extraocular muscles, orbit,
of cartilage of the ear, trachea, nose, tendons, and sclera [33–36]. Scleral amyloidosis is asymp-
heart valves, and prostate (ochronosis), and, in tomatic and does not show any specific lesion.
later years, arthritis. In the infant, a first sign of Amyloidosis is suspected clinically, and con-
alkaptonuria may be the presence of dark urine in firmed by biopsy of appropriate tissues.
a wet diaper. Ocular findings are helpful in sus- Although there are no detectable clinical
pecting the diagnosis of alkaptonuria. They changes, histologic studies show that amyloid
include scleral pigmentation, seen as triangular deposition in sclera occurs more often as age
patches in the interpalpebral area at the insertion increases [37]. Amyloid deposition in sclera also
of the horizontal recti muscles (areas exposed to may occur following severe scleral inflammation
light), and episcleral pigmentation, seen as at any age [38, 39].
pinguecular-like masses between the limbus and Amyloid stains brown with Congo red and
the insertion of horizontal recti muscles [28–31]. exhibits dichroism and birefringence with
Occasionally, pigmentation may involve the polarized light. It also shows metachromasia
whole sclera. The pigment is gray or bluish black with crystal violet, fluorescence with thiofla-
(although microscopically it appears ochre), and vine T, and positive staining with hematoxylin-
it increases with age. More diffuse pigmentation, eosin, periodic acid Schiff (PAS), iodine, and
seen as oil drop-like globules when examined by Sirius red.
retroillumination, may be found in the subepithe-
lium and in Bowman’s membrane of the periph-
8.1 Scleral Deposits 281
8.1.4.1 Hyperparathyroidism
8.1.3 Scleral Carbohydrate Deposition Calcium deposition in cornea, conjunctiva, and
sclera may occur as a result of the calcium and
8.1.3.1 Mucopolysaccharidosis phosphorous imbalance seen either in primary
Histopathologic scleral involvement may occa- causes of hyperparathyroidism, such as benign
sionally occur as a result of mucopolysaccharide adenoma or hyperplasia of the parathyroid glands
deposition. [49–54], or in secondary causes of hyperparathy-
Mucopolysaccharide deposition between the roidism, such as chronic renal disease [52, 54,
collagen fibers of the posterior sclera may occur 55]. The calcium is deposited in the form of
in mucopolysaccharidosis type VI or Maroteaux– hydroxyapatite crystals in the nucleus and cyto-
Lamy syndrome [43]. Mucopolysaccharidosis plasm of the stromal cells of the sclera [53].
282 8 Noninflammatory Diseases of the Sclera
blood rises above 1.5 mg/100 ml; bilirubin binds Although the exact biochemical defect is not
strongly to the elastin fibers of the sclera. known, the disorder is thought to be caused by a
Unilateral yellow discoloration of the sclera basic anomaly of connective tissue.
may appear after choroidal hemorrhage follow- The most conspicuous physical features of a
ing surgery for retinal detachment; [76] the yel- patient with Marfan’s syndrome are the musculo-
low staining is due to accumulation of skeletal defects. There is a generalized over-
unconjugated bilirubin derived from the break- growth of long bones; patients are tall and have
down of hemoglobin from the hemorrhage; bili- long slender fingers and toes (aracnodactylia).
rubin binds weakly to the elastin and to the Prognathism, high arched palate, kyphoscoliosis,
collagen fibers of the sclera. pectus excavatum, muscular hypoplasia, and
hypotony also are characteristic. Cardiovascular
anomalies include degeneration of the tunica
8.2 Scleral Thinning (Blue Sclerae) media of the aortic valve and ascending aorta
which may cause dissecting aneurysms.
Bluish sclera, although considered normal in pre- Other ocular manifestations aside from sub-
mature infants and in white newborns, is patho- luxated lenses include myopia, ptosis, megalo-
logic if it persists beyond the first month of cornea, strabismus, hypoplasia of the iris dilator
infancy. Several inherited or congenital disorders muscle, spherophakia, glaucoma, peripheral
may be associated with blue sclerae. The blue retinal degeneration, and blue sclerae. Since the
color is due to translucency of the sclera as a anomalous scleral connective tissue is unable to
result of scleral thinning, allowing the uveal pig- resist elevated intraocular pressure, it allows the
ment to show through. intraocular contents of the globe to bulge, pro-
Other causes of blue sclerae are acquired dis- ducing a staphyloma. Cataract formation, lens
orders, the most common being iron-deficiency dislocation, and glaucoma may necessitate ocu-
anemia [77–82]. Iron is an important cofactor in lar surgery, but surgical complications, such as
the hydroxylation of proline and lysine residues vitreous loss and incarceration in the wound,
in collagen synthesis. Fibroblasts in culture do not iris prolapse, hyphema, persistent anterior
synthesize collagen in the presence of iron-chelat- uveitis, and corneal edema are seen more often
ing agents [80]. Iron deficiency in vivo may lead in these patients than in the general population
to impaired collagen synthesis and a thin sclera [86, 87].
through which the choroid can be seen, making The diagnosis is clinical; approximately 50%
the sclerae appear blue. Blue sclerae also may be of patients with Marfan’s syndrome are diag-
seen associated with myasthenia gravis [83]. nosed by the ophthalmologist, usually because of
myopia not adequately corrected by lenses. The
differential diagnosis is principally from homo-
8.2.1 Scleral Thinning in Inherited cystinuria, an inborn error of amino acid metabo-
or Congenital Diseases lism which is also characterized by subluxated
lenses, myopia, strabismus, spherophakia, glau-
8.2.1.1 Marfan’s Syndrome coma, peripheral retinal degeneration, long slen-
Marfan’s syndrome, as it was described in 1896, der extremities, kyphoscoliosis, and pectus
is a congenital mesodermal dystrophy classically excavatum; however, scleral connective tissue in
characterized by the triad of subluxated lenses, homocystinuria is thicker and more resistant to
skeletal abnormalities, and cardiovascular dis- high intraocular pressure than in Marfan’s syn-
ease. Marfan’s syndrome also may involve lungs, drome. The diagnosis in homocystinuria is estab-
muscles, genitourinary system, skin, and nearly lished by amino acid electrophoresis and
every structure of the eye, including the sclera chromatography of urine and plasma [88].
[84, 85]. This autosomal-dominant condition Any patient with congenital blue sclerae
affects both sexes equally and is seen in all races. should be questioned and examined for skeletal
284 8 Noninflammatory Diseases of the Sclera
anomalies and cardiovascular disease. The Blue sclerae, the most characteristic ocular
immediate family also should be evaluated. manifestation in all types of osteogenesis imper-
fecta [93, 95], are due to increased thinness of the
8.2.1.2 Osteogenesis Imperfecta scleral wall allowing the visualization of the
Osteogenesis imperfecta (van der Hoeve’s syn- underlying uveal layer. Ocular histopathologic
drome) is a genetically determined defect in the examination reveals a 50–75% thinning of the
synthesis of extracellular matrix leading to abnor- sclera. Osteogenesis imperfecta patients with
malities in connective tissue, primarily collagen, blue sclerae have significantly lower ocular rigid-
and proteoglycans. Partially described in 1896 by ity measurements than do patients without the
Spurway [89] and in 1900 by Eddowes [90], and disease [98]. The Saturn ring, a white ring in the
completely described in 1918 by van der Hoeve paralimbal sclera, is a common finding; the lack
[91], osteogenesis imperfecta is characterized by of uvea behind the sclera in the paralimbal area
the triad of blue sclerae, brittle bones, and deaf- gives a comparative whitening aspect. The cor-
ness (otosclerosis) [92]. It may be inherited as neas also are thin and vulnerable to perforation
either an autosomal dominant or autosomal reces- from minor trauma. Sclera and cornea can usually
sive condition; the autosomal recessive form is withstand the normal intraocular pressure, but
associated with more severe skeletal abnormali- elevated pressures will produce a staphyloma.
ties. Osteogenesis imperfecta has an incidence of Ultrastructurally, the scleral and corneal fibers
1 in 20,000 births, affects both sexes equally, and in eyes of patients with osteogenesis imperfecta
is seen in all races [93]. The disorder is caused by appear immature. There have been some reports
anomalies at the level of the type I collagen genes showing either a decreased number [99, 100], or
which result in the failure of type I collagen fibers a reduced diameter [101–106] of collagen fibers
to mature to their normal diameters. Individual in both the sclera and the cornea. An ultrastruc-
variants result from a structural or regulatory tural study revealed vacuoles in the endoplasmic
abnormality of the alpha1 or alpha2 chains of type reticulum of scleral fibrocytes and in keratocytes,
I collagen. as well as deposits (possibly chondroitin sulfate)
Two classifications have been proposed for between the scleral lamellae, suggesting a distur-
osteogenesis imperfecta. The oldest one classi- bance of the fibroblasts [107]. In addition to
fies the disease into the congenital form, which is abnormalities of collagen, biochemical quantita-
manifest at birth, leading to early death, and the tive and qualitative defects of glycosaminogly-
tarda form, which is manifest early in childhood cans also have been reported [108]. Keratoconus,
and has a relatively benign course [94, 95]. In the megalocornea, hypermetropia, posterior embryo-
congenital form, musculoskeletal defects, includ- toxon, zonular cataracts, retrobulbar neuritis,
ing extremity deformities, rib fractures, and mus- optic atrophy, and glaucoma may develop.
cular hypotony, may be detectable at birth. In the The diagnosis of osteogenesis imperfecta is
tarda form, fractures may occur at 2–4 years of clinical. Any patient with congenital blue sclerae
age, and skeletal deformities, such as scoliosis should be examined for skeletal and ear abnor-
may become manifest early in life. Some patients malities. The immediate family also should be
with osteogenesis imperfecta tarda do not have evaluated.
gross bony abnormalities and go through life
without a fracture; the disease is limited to mini- 8.2.1.3 Pseudoxanthoma Elasticum
mal radiologic defects associated with ear mani- Pseudoxanthoma elasticum is an autosomal
festations and blue sclerae. Deafness occurs in recessive disorder characterized by skin elastic-
30% of these patients. Other ear abnormalities ity; small yellow papules and plaques eventually
may include tinnitus and vertigo [96, 97]. form redundant folds typically located on the
Osteogenesis imperfecta also may be classi- neck, antecubital and popliteal fossae, abdomen,
fied into types I, II, III, and IV, on the basis of perineum, thighs, axillas, and groin areas [108].
inheritance, clinical features, and severity [93]. Angioid streaks of the retina, gastrointestinal
8.2 Scleral Thinning (Blue Sclerae) 285
bleeding and cardiovascular abnormalities also blue sclerae may lead to spontaneous perfora-
develop [109–111]. Thin blue sclerae may appear tion of the sclera [125]. Surgery should be
in pseudoxanthoma elasticum patients and in avoided, if possible, because of the high inci-
their relatives [81]. Pseudoxanthoma elasticum dence of complications secondary to fragility
usually begins by age 30, although it may appear of tissues [126, 127]. The ocular-scoliotic form
at a younger or older age, and is more common in of Ehlers–Danlos syndrome has been associ-
women than in men (2:1). Although the exact ated with a primary deficiency of the enzyme
biochemical defect is not known, the disorder is lysyl hydroxylase [94, 128, 129]. Lysyl hydrox-
thought to be caused by abnormal formation of ylase converts lysine to hydroxylysine; alde-
the elastic fibers of connective tissue [112]. hydes which cross-link spontaneously are
Angioid streaks of the retina, occurring in 85% of formed. A deficiency in lysyl hydroxylase
the patients, consist of cracks in an abnormal results in a lack of collagen cross-linking and,
Bruch’s membrane which may interfere with subsequently, in a weakened connective tissue;
visual acuity if they involve the macular area however, normal enzyme levels have been
[108, 109, 113, 114]. Angioid streaks may not be described, suggesting that the ocular form of
visible on fundus examination, but they can be Ehlers–Danlos syndrome has some degree of
clearly seen on fluorescein angiography. genetic heterogeneity [130].
The diagnosis of pseudoxanthoma elasticum The diagnosis of Ehlers–Danlos syndrome is
is based on clinical findings. Any patient with based on clinical findings. Any patient with con-
congenital blue sclerae should be examined for genital blue sclerae should be examined for skin
skin and retinal abnormalities. The immediate and joint abnormalities, marked epicanthal folds,
family also should be evaluated. and retinal findings. The immediate family should
also be evaluated.
8.2.1.4 Ehlers–Danlos Syndrome
Ehlers–Danlos syndrome is a multisystem genetic 8.2.1.5 Keratoconus
disorder characterized by hyperelasticity and fra- Blue sclerae or scleral thinning may occur in
gility of the skin; bleeding, atrophic scars, and association with keratoconus [124]. Keratoconus
even hemangiomatous pseudotumors often occur or ectatic corneal dystrophy is a disorder charac-
after minor trauma around joints or pressure terized by corneal thinning of the central cornea;
points [115]. Other findings include hyperexten- conical ectasia or protrusion may occur leading
sibility of the joints, particularly those of the fin- to a painless, progressive loss of vision due to a
gers, toes, and knees, blood vessel fragility, with progressive irregular myopic astigmatism.
varicose veins or aneurysms and arterial ruptures, Heredity plays a significant role in at least some
and ocular abnormalities, such as marked epican- keratoconus patients [131–135], although the
thal folds, angioid streaks, strabismus, keratoco- majority of cases show no definitive inheritance
nus, keratoglobus, microcorneas, subluxated pattern. In the early form, distortion of kerato-
lenses, retinal detachment, severe myopia, or metric mires or retinoscopic reflex occurs. In the
blue sclerae [116–124]. Ehlers–Danlos is usually advanced form, Vogt’s striae or a Fleisher ring
an autosomal-dominant condition, although it may be seen. Vogt’s striae are fine vertical folds
may be recessive in some families. in the deep stroma and Descemet’s membrane
At least nine types of Ehlers–Danlos syn- that parallel the steep axis of the cone. A Fleisher
drome have been described depending on inher- ring is a yellow brownish corneal epithelial pig-
itance, clinical features, severity, ultrastructural ment ring localized around the base of the cone;
abnormalities, and biochemical defects. In type the color is due to deposition of ferritin in the
VI or ocular-scoliotic form of Ehlers–Danlos, subepithelium. Breaks in Bowman’s layer,
ocular features are prominent; it is also charac- enlarged corneal nerves, increased intensity of
terized by severe scoliosis and joint and skin the corneal endothelial reflex, and fine subepithe-
disturbances. Within the ocular features, thin lial fibrillary lines also may occur.
286 8 Noninflammatory Diseases of the Sclera
Aside from blue sclerae, other ocular anoma- progresses steadily throughout life; this form of
lies which may occur associated with keratoco- myopia is usually severe and is associated
nus are subluxated lenses, cataract, aniridia, with significant chorioretinal complications.
retinitis pigmentosa, and optic atrophy. Degenerative myopia is associated with an
Keratoconus has been described in association enlargement of the axial length of the posterior
with various systemic connective tissue disor- segment of the globe. The heredity and certain
ders, such as Marfan’s syndrome [136, 137], developmental abnormalities play an important
osteogenesis imperfecta [94, 132], and Ehlers– role in myopia. Some investigators observed that
Danlos syndrome; [124, 130, 138, 139]. chickens raised with translucent occluders over
their eyes developed eyes with long axial lengths
8.2.1.6 Buphthalmos [143]. Monkeys raised with unilateral lid suture
The high intraocular pressure of congenital glau- or after unilateral opacification of the cornea with
coma produces enlargement and stretching of polystyrene beads also developed eyes with
scleral and corneal collagen fibers before matu- abnormal axial lengths; [144, 145] this effect
ration. This leads to a very large eye or buphthal- could only be demonstrated when the monkeys
mos with a corneal diameter greater than were raised in light as opposed to dark. The
10.5 mm at birth or greater than 12 mm at age 1 investigators suggested that visual stimulation is
year [140, 141]. The sclera, usually thin in pre- necessary for the development of the alterations.
mature infants and in white newborns, is even However, small periods of normal vision (2 h)
thinner at birth and persists like this beyond the can prevent the development of axial elongation
first month of infancy; light transmitted through [146]. There appears to be an age window of sus-
the thinned sclera strikes the uvea and is reflected ceptibility during which abnormal axial length
outward, producing a bluish tinge. After surgical can be induced since adult monkeys cannot be
relief of congenital glaucoma, there is no further made myopic with lid occlusion [144] and mon-
stretching of scleral fibers; however, the scleral keys at age 12 months can only be made less
fibers which have become stretched never return myopic [147].
to normal. In degenerative myopia, the sclera is thin, par-
ticularly in the posterior segment of the globe;
[148, 149] posterior scleral thinning may cause
8.2.1.7 Coloboma posterior pole and equatorial staphylomas as a
Cystic outpouching of the posteroinferior sclera result of stretching of the fibers. However, rather
or scleral ectasia may occur in association with a than a purely mechanical stretch, the increase in
peripapillary coloboma of the choroid [55, 142]. axial length in myopic eyes seems also to be due to
The normal vessels of the disc pass over bare increased scleral growth during which both the
ectatic sclera or atrophic choroid and then into fibrocytes and the extracellular matrix overgrow;
normal retina. there are more DNA, collagen, protein, and proteo-
Occasionally, intrauterine fetal infection, such glycan synthesis in the myopic sclera [150–152].
as toxoplasmosis may secondarily cause focal
areas of scleral thinning and ectasia at the sites of
intense retinal and choroidal inflammation [55]. 8.2.2 Scleral Thinning in Acquired
Diseases
8.2.1.8 Myopia
Simple or stationary myopia develops during 8.2.2.1 Iron-Deficiency Anemia
youth and stops after completion of body growth; Iron-deficiency anemia is the most frequent cause
this form of myopia is usually of low to moderate of acquired blue sclerae. There are no data on the
severity and is not associated with significant body depletion of iron stores needed before blue
chorioretinal complications. Degenerative or sclerae develop, but the presence of blue sclerae
pathologic myopia develops during youth but is a useful guide to iron-deficiency anemia in
8.3 Scleral Thickening 287
patients with low dietary iron or chronic blood cell cultures of nanophthalmic scleral cells; [159]
loss associated with duodenal ulcers, ulcerative the decreased level of glycosaminoglycans may
colitis, and gluten enteropathy [78]. result either from a reduced synthesis, or an
Blue sclerae occasionally has been reported increased degradation, or a combination of both.
associated with myasthenia gravis [83]. These in vitro findings conflict with the in vivo
findings of Trelstad and coworkers who reported
8.2.2.2 Paralimbal Scleromalacia increased quantities of Alcian blue staining mate-
Paralimbic scleromalacia or spontaneous interca- rial that they thought to be glycosaminoglycan in
lary scleral perforation is a scleral degenerative the sclera of two nanophthalmic patients [160].
process which appears in either one or both eyes Whichever the case is, the abnormalities in gly-
of young individuals of either sex; it is character- cosaminoglycan metabolism may lead to the
ized by a noninflammatory, painless scleral thin- abnormal collagen fiber formation and packing
ning of the corneoscleral limbus (between the of collagen bundles [161], which may in turn
ciliary body and the limbus) which leads to a contribute to the thickening of sclera and the for-
small, nonprogressive, well-defined hole with iris mation of nanophthalmos. In a later study, Yue
prolapse [38, 65, 66, 74, 75, 153–155]. Sometimes, and coworkers found that the levels of fibronectin
the pupil may be drawn up into the hole. A small were increased [162].
perforating scleral vessel may run through the The diagnosis of nanophthalmos is based on
defect to anastomose with the posterior ciliary clinical findings. Resolution of effusions may be
circulation [38]. Differential diagnosis of paral- achieved with surgical decompression of the
imbic scleromalacia should include scleromala- vortex veins [157].
cia perforans, since both conditions have loss of
scleral substance, lack of inflammatory reaction,
and painless development. Unlike scleromalacia 8.3.2 Scleropachynsis
perforans, paralimbic scleromalacia affects indi-
viduals between 25 and 50 years of age without Bilateral localized thickening of the inner two
evidence of rheumatoid arthritis, and it has a thirds of the posterior temporal sclera has
good prognosis without treatment (Table 4.11). been reported in one case as the cause of choroi-
dal compression and maculopathy [44].
Ultrastructurally, the collagen fibers in the inner
8.3 Scleral Thickening two thirds of the sclera in the submacular region
were enlarged in diameter; mucopolysaccharide
8.3.1 Nanophthalmos deposition was detected between the bundles of
collagen.
The characteristics of the nanophthalmic eye
include a thickened sclera (up to 2 mm), small
cornea, high hyperopia (up to 20 diopters), shal- 8.3.3 Phthisis Bulbi
low anterior chamber, and a tendency for the
development of uveal effusion. Nanophthalmos The term phthisis bulbi is applied to those eyes
is usually bilateral and may be inherited follow- which show not only diffuse degeneration or
ing either a dominant or a recessive pattern [156, atrophy, but also shrinkage and disorganization
157]. The thickening of the sclera may cause vor- of the ocular contents after severe injury or
tex vein compression which results in impaired inflammation. The sclera becomes markedly
venous drainage; this may lead to uveal effusion thickened and irregular due to scarring. The
and serous retinal detachment [158–160]. The intraocular structures also are replaced by scarred
ultrastructure of nanophthalmic sclera has tissue. It is not known whether internal fibrosis
been described with conflicting results [161, leads to the loss of intraocular pressure or the
162]. Yue and coworkers found that the levels of lack of ocular tension results in intraocular
glycosaminoglycans were markedly reduced in scarring.
288 8 Noninflammatory Diseases of the Sclera
and human immunodeficiency virus seropositiv- episclera and, although it usually remains
ity [167, 170]. Necrotizing scleritis may occa- localized, metastasis may occur. Excisional
sionally be the initial manifestation of the invasive biopsy is essential for diagnosis and therapy.
tumor [169]. Histologically, there may be interweaving fasci-
cles of fibroblasts (storiform pattern) and stellate
deposits of dense collagen with fibroblasts inter-
8.4.3 Dense Connective Tissue Tumors mingling with lipid-laden histiocytes [55].
Recurrences may occur after excision.
8.4.3.1 Nodular Fasciitis
Nodular fasciitis is a benign nodular reactive pro- 8.4.3.4 Sarcomas
liferation of fibroblasts and vascular tissue within Although primary sarcomas of the episclera and
the fascias of the trunk, upper extremities, scalp, sclera are exceptionally rare [38, 175], secondary
neck, and face, including the ones in the eye [171]. invasion from adjacent ocular structures occa-
The lesion appears as a tender, isolated, vascular- sionally may occur [176]. Rhabdomyosarcoma in
ized, round or oval nodule with a size ranging a child has been reported to manifest as nodular
from 0.5 to 1.5 cm in diameter; sometimes, the episcleritis [38].
rapid growth suggest a malignant tumor, particu-
larly a lymphoma or sarcoma, but excisional
biopsy reveals proliferating fibroblasts varying in 8.4.4 Vascular Tumors
configuration from spindle to stellate. In the eye,
the nodule may involve Tenon’s capsule, eyelid, 8.4.4.1 Hemangiomas
periorbital tissue, and the ligaments of the extraoc- Episcleral capillary hemangioma occurs early in
ular muscles [172–174]. Episcleral nodules usu- life, may grow rapidly, and often regresses before
ally occur at the limbus or under the bulbar the child is 5 years old. Sometimes, however, the
conjunctiva anterior to the insertion of the recti small and circumscribed tumor may be present
muscles. Episcleral tissue heals well after exci- for many years without any further growing, in
sion of the nodule and there are no recurrences. which case it can be mistaken for nodular episc-
leritis; in the episcleral capillary hemangioma,
8.4.3.2 Fibroma the new vessels appear to radiate from the mass
Fibroma of the episclera may occur anywhere but rather than skirt it, as in the inflammatory condi-
usually arises adjacent to the limbus. They are tions [38]. Episcleral capillary hemangioma may
vascularized, firm, of variable size, and not adher- be the only external manifestation of Sturge–
ent to the sclera. Histologically, fibroma is a Weber syndrome, which usually presents with
tumor composed by packed fibroblasts intermin- facial (port-wine stain, nevus flammeus) and lep-
gled with inflammatory cells. If extracellular tomeningeal angiomas. Because of its small size,
matrix components outnumber the fibroblasts, it usually does not require to be removed.
the tumor may be termed a myxoma. If extracel- Episcleral cavernous hemangiomas are often a
lular matrix components and fibroblasts are pres- peripheral manifestation of an orbital cavernous
ent in similar amounts, the tumor may be termed hemangioma. They present as a mass of vessels
a myxofibroma [118]. associated with an overlying conjunctival over-
growth which may bleed spontaneously and
8.4.3.3 Fibrous Histiocytoma severely. Both episclera and conjunctiva are read-
Fibrous histiocytoma is a tumor composed of ily moveable over the underlying sclera. They are
fibroblasts and histiocytes which arises from present at birth, grow rapidly, and often regress
primitive mesenchymal cells with capacity to dif- before the child is 5 years old. Conservative ther-
ferentiate into either or both cell lines. The orbit apy is advised unless it is cosmetically intolera-
is one of the most common locations of the tumor. ble, in which case, surgical removal is the proper
Rarely, fibrous histiocytoma may originate in the treatment.
290 8 Noninflammatory Diseases of the Sclera
positive for both neurilemmomas and neurofibro- A branch of the long posterior ciliary nerve
mas; however, neurilemmomas show a more gen- (intrascleral nerve loop of Axenfeld) may loop
eralized and stronger staining pattern than out through the sclera in the region between the
neurofibromas, since S-100 stain does not stain limbus and the insertions of the recti muscles,
fibroblasts. Under electron microscopy examina- forming a nodule which is often darkened with
tion, the Lüse bodies are seen in neurilemmomas melanocytes. The nerve loop, may be mistaken
and not in neurofibromas; Lüse bodies are aggre- clinically for a melanotic tumor or for a foreign
gates of long-spaced or broad-banded collagen body [188], and histologically for a neurofibroma,
with an axial periodicity of 130 nm [186]. They especially when the nerve is associated with
were considered in the past as pathognomonic of neurilemmal or connective tissue proliferation.
neurilemmomas, but it is now known that they
occur in other tumors, such as basal and squamous 8.4.7.1 Nevus
carcinomas and nevoid tumors. This lesion is present at birth but may not be
Since surgical removal of neurilemmoma may noticed until middle childhood. Approximately
lead to rupture, the possibility of donor sclera 33% of conjunctival–episcleral nevi are not pig-
homografting must always be kept in mind [186]. mented. Both pigmented or nonpigmented nevi
are diffuse and flat lesions localized close to the
limbus and sometimes they may look like nodu-
8.4.7 Pigmented Tumors lar episcleritis. More than 50% of conjunctival–
episcleral nevi have epithelial cysts which can be
Pigmented tumors of the episclera are common. clinically evident [189]. Increased melanogenesis
The differential diagnosis must include congeni- in nevi can result from pituitary stimulation
tal episcleral melanosis, acquired episcleral mel- (puberty, pregnancy, adrenal insufficiency),
anosis, and nerve loops of Axenfeld. Melanocytes physical irritation (sun exposition, trauma,
are normally present in the episclera and in sclera inflammation), and coexisting malignant mela-
lamellae adjacent to and along the course of vas- noma. Malignant transformation of nevi to mela-
cular and neuronal transcleral channels. An nomas is rare; a great increase in vascularity
increased number of melanocytes may exist in without obvious growing and increase in pig-
these locations in association with these congeni- mentation may be the first signs before extension
tal and acquired benign pigmentations. in the conjunctiva–episclera and to the sclera
Ocular melanocytosis (melanosis oculi) is a occurs. The episcleral vessels radiate from the
congenital unilateral pigmentation of episclera, mass rather than skirt it, as in inflammatory con-
sclera, and uveal tract. There is an increased inci- ditions, such as necrotizing scleritis [38]. Biopsy
dence of uveal melanomas in the involved eye. should be performed before therapy is planned.
Oculodermal melanocytosis (nevus de Ota) is Management of nevi requires photography at
ocular melanocytosis associated with ipsilateral regular intervals to look for the possibility of
pigmentation of the periocular tissues. It occurs malignant transformation. Therapy is conserva-
more often in the nonwhite races. Malignant tive unless it is cosmetically intolerable, in which
transformation is not common. case surgical removal is the proper treatment.
Acquired melanosis is a flat, diffuse, and Surgical removal also eliminates the remote
slowly growing melanotic lesion which may chance of malignant change.
appear either in the skin or in the conjunctiva-
episclera. Biopsy should be performed before 8.4.7.2 Melanocytoma
therapy is planned. Management is conservative Melanocytoma of the conjunctiva–episclera may
unless there is malignant transformation. In the arise from nevi, from acquired melanosis, or
conjunctiva-episclera, 17% of the melanosis may without preexisting lesion. They also may result
progress to melanoma; mortality in patients with from extension of melanoma arising in ciliary
these melanomas is up to 40% [187]. body, or the skin or mucous membranes anywhere
292 8 Noninflammatory Diseases of the Sclera
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Treatment of Episcleritis
and Scleritis 9
9.1 Treatment of Episcleritis way in which the patient with scleritis is initially
treated, that is, with systemic nonsteroidal anti-
Episcleritis may or may not require treatment; inflammatory drug (NSAID) therapy. A substan-
scleritis always does. Although simple, diffuse tial proportion of those individuals with nodular
episcleritis may produce low-grade aggravation episcleritis will require treatment, and the sys-
and temporary cosmetic consequences for the temic NSAIDs are typically effective. Table 9.1
patient, it does not absolutely require therapy, lists the currently available NSAIDs, along with
because untreated it will eventually resolve leav- suggested initial dosage. As usual, package insert
ing no sequelae. Regrettably, topical steroid ther- directions should be followed from the standpoint
apy appears to be the reflex treatment prescribed of frequency of hematological monitoring, and so
by many physicians in developed countries. This on. We advise uninterrupted therapy for a mini-
is regrettable not simply because of the potential mum of 6 months, followed by subsequent
side effects of such treatment, but because expe- attempts to taper and discontinue the medicine
rience suggests that such treatment actually pro- while observing for recurrence.
longs the overall duration of the patient’s problem: Episcleritis associated with some specific dis-
the number of recurrences following discontinua- ease may, of course, require systemic NSAID
tion of each episode of steroid therapy appears to therapy, but also typically requires addressing the
be greater, and the so-called rebound effect, in specific etiology of the episcleritis. Atopic indi-
which the episcleritis intensifies with each recur- viduals require appropriate environmental con-
rent episode after discontinuation of steroid ther- trols and systemic antihistamine therapy, and
apy, has been observed. Our philosophy, and that may even require systemic calcineurin inhibitor
of Watson [1], is to leave simple episcleritis therapy (e.g., cyclosporine). Patients with gout
untreated except for comfort and supportive ther- require allopurinol. Patients with rosacea require
apy, such as cold compresses and iced artificial one of the systemic tetracyclines. Patients with a
tears. It appears that, on the basis of the results of specific connective tissue disease who have epis-
randomized double-masked placebo-controlled cleritis may or may not require systemic therapy
clinical trial, topical nonsteroidal anti-inflammatory with medications other than NSAIDs. Plaquenil
therapy is not effective [2]. (hydroxychloroquine; 200 mg twice daily by
If the patient demands treatment, or if the mouth), is often effective in treating the dermato-
patient’s occupation is such that withholding logical and superficial ocular (e.g., episcleritis)
treatment would produce a vocational disability consequences of systemic lupus erythematosus
(actor, television personality, etc.), we suggest (SLE). Patients with nodular episcleritis associ-
treating the patient with episcleritis in the same ated with rheumatoid arthritis usually respond to
Table 9.1 Nonsteroidal anti-inflammatory drugs avail- The patient with atopy was treated successfully
able for treatment of episcleritis and scleritis with appropriate environmental controls and sys-
Trade name Generic name Dosage temic antihistamine therapy. The four patients
Dolobid Diflunisal 500 mg bid with rosacea responded to oral doxycycline
Naproxyn Naproxen 250–500 mg bid (100–200 mg/day). The five patients with infec-
Motrin Ibuprofen 800 mg tid tions were treated with appropriate antivirals or
Nalfon Fenoprofen 600 mg tid antibiotics. Twenty patients with idiopathic epis-
Orudis Ketoprofen 100 mg tid cleritis required therapy. Each had suffered from
Ansaid Flurbiprofen 100 mg tid
recurrent episcleritis for prolonged periods
Indocin Indomethacin 75 mg SR bida
(6–24 months) and each had been treated with
Voltaren Diclofenac 75 mg SR bida
topical steroids, with the predictable result: recur-
Feldene Piroxicam 20 mg qd
Mobic Meloxicam 7.5–15 mg qd
rence of episcleritis more severe than prior to ste-
Meclomen Meclofenamate 100 mg qid roid therapy after steroids were discontinued.
a
Each of these patients responded well to oral
SR sustained-release preparation
NSAID therapy, with no recurrence of episcleri-
tis after drug withdrawal.
one systemic NSAID or another; however, one
may have to experiment sequentially with two or
more NSAIDs before finding the one to which 9.2 Treatment of Scleritis
the patient responds. The efficacy of topical
cyclosporine A is unclear, and appropriate stud- 9.2.1 Medical Treatment
ies to test this agent as applied topically will be
required to answer the question of efficacy. Patients with diffuse or even nodular scleritis
Three of our 85 patients with episcleritis had rarely require cytotoxic drug therapy for success-
rheumatoid arthritis, 3 had ankylosing spondyli- ful control of their inflammation. Systemic
tis, 1 had psoriatic arthritis, 2 had arthritis and NSAID therapy is almost invariably effective,
inflammatory bowel disease, 1 had sarcoidosis, 1 although as mentioned above, sequential trials of
had Adamantiades–Behçet’s disease, 1 had juve- several NSAIDs may be required before one that
nile idiopathic arthritis, 1 had granulomatosis is completely effective is found. We habitually
with polyangiitis (Wegener), 1 had atopy, 4 had treat our scleritis patients who have responded to
rosacea, 5 had infections, and 62 had idiopathic an NSAID for a minimum of 1 year before
episcleritis. The three patients with rheumatoid attempting to taper and discontinue the medicine.
arthritis, one with simple episcleritis and two Patients with an associated disease, such as rosa-
with nodular episcleritis, did not respond to oral cea, gout, or atopy, will require specific treatment
NSAIDs; low-dose methrotrexate once a week for those diseases as described above. One hun-
was required for the ocular and joint activity. Two dred and forty-one (48%) of our 291 patients with
of the patients subsequently required the addition idiopathic diffuse and nodular scleritis responded
of adalimumab. The three patients with ankylos- to oral NSAID therapy. Twenty-eight (10%)
ing spondylitis required oral NSAIDs with the patients required the addition of systemic predni-
addition of low-dose methotrexate weekly in one sone, 94 (32%) required the addition of an immu-
of them. The patients with psoriatic arthritis, nosuppressive medication, and 28 (10%) required
arthritis, and inflammatory bowel disease, the addition of a biologic.
Adamantiades–Behçet’s disease, and juvenile The treatment of patients with scleritis associ-
idiopathic arthritis responded well to adali- ated with connective tissue or collagen vascular
mumab. The patient with sarcoidosis required diseases requires slightly more consideration in
systemic steroids. The patient with granulomato- that control of their scleral inflammation often
sis with polyangiitis (Wegener) responded well to needs more potent therapy, and vigilance for
systemic steroids and mycophenolate mofetil. extraocular, “silent” inflammatory foci requires
9.2 Treatment of Scleritis 301
extra effort. For example, we were once consulted 9.2.1.1 Rheumatoid Arthritis
about a patient with limited granulomatosis with We suggest treating rheumatoid arthritis patients
polyangiitis (Wegener) scleritis, sinus involve- who develop diffuse scleritis with an oral NSAID,
ment, and a positive antineutrophil cytoplasmic with or without the concomitant use of topical
antibody (ANCA) test whose scleritis responded corticosteroids. If the scleritis does not respond,
to systemic NSAID therapy, prompting the or if it recurs with attempted discontinuation of
patient’s ophthalmologist and rheumatologist to the topical corticosteroid, we generally switch to
settle for this treatment and to become less vigi- a different NSAID, treat once again with topical
lant for a transformation of the patient’s limited corticosteroids, taper the steroids and observe for
form of granulomatosis with polyangiitis recurrence. We go through these steps as many as
(Wegener) into the lethal generalized form, three times, that is, with three different NSAIDs,
despite our advice to treat the patient with cyclo- before concluding that additional systemic medi-
phosphamide. The patient died of renal compli- cation is required. Our next step, if additional
cations of granulomatosis with polyangiitis systemic medication is deemed necessary, is to
(Wegener) 2 years later. treat the patient with a short course of systemic
We believe, quite strongly, that NSAID ther- prednisone. We typically start with 1 mg/kg per
apy alone is unacceptable in the care of an indi- day, taper when the scleritis has resolved totally
vidual with scleritis in whom the diagnosis of (usually within 7–14 days), and then switch to
granulomatosis with polyangiitis (Wegener) or alternate-day therapy once the dose of the predni-
polyarteritis nodosa has been made. It is our frank sone is down to 20 mg/day. If the patient has had
view that such therapy represents negligence. no recurrence of the scleritis with topical steroid
The published evidence on this point of appropri- discontinuation and tapering of the systemic ste-
ate therapy for these two lethal diseases is too roid to 20 mg/day, our next therapeutic step is to
abundant and the conclusions are unarguable. switch the systemic prednisone to 40 mg every
Regardless of other therapy these patients might other day. This dose is continued for 2 weeks,
be receiving, the 5-year death rate of patients after which it is further tapered to 30 mg ever-
with polyarteritis nodosa who are not receiving other-day for the following 2 weeks. If there is
cytotoxic chemotherapy is 87% [3], and the still no relapse of the scleritis, the drug is tapered
5-year mortality rate of patients with granuloma- to 20 mg every other day for an additional
tosis with polyangiitis (Wegener) who are not 2 weeks, with further tapering on an ever-other-
receiving cytotoxic chemotherapy is 95% [4]. week basis to 15 mg every other day, 10 mg every
Furthermore, we would extend this therapeutic other day, 7.5 mg every other day, and 5 mg every
attitude to patients with necrotizing scleritis asso- other day, after which the drug is discontinued.
ciated with rheumatoid arthritis or with relapsing This is the usual withdrawal program we use for
polychondritis. Multiple studies have now shown systemic prednisone. It is the rare rheumatoid
that, in the rheumatoid arthritis patient who arthritis patient with diffuse scleritis who does
develops necrotizing scleritis and who is not not respond to this program and who then requires
treated with an immunosuppressive agent, the low-dose methotrexate once a week.
5-year mortality rate from extraocular vasculitic Although the vast majority of rheumatoid
lesions is approximately 50% [5–7]. Patients with arthritis patients with nodular scleritis respond
relapsing polychondritis who develop necrotiz- well to the systemic prednisone program
ing scleritis may also die, either from the tracheal described above for diffuse scleritis, some require
complications of this disease or from the eventual once-a-week methotrexate therapy. We always
emergence of renal pathology. Therefore, our go through these steps first with our nodular
recommendations for the treatment of patients scleritis patients, but in a small number of cases
with the various collagen vascular diseases who we have discovered that the scleritis does not
develop scleritis are as follow. respond completely or that it continues to recur
302 9 Treatment of Episcleritis and Scleritis
with steroid tapering. We treat these patients risk of serious infections that appears to be similar
with methotrexate, generally beginning with to that with TNF inhibitors.
15 mg given once a week (10 mg once a week Cyclophosphamide is considered, in patients
for an individual weighing less than 50 kg); the with severe or rapidly progressive necrotizing
drug dosage is generally advanced, every scleritis, unilateral or bilateral. The dosage
6 weeks, if the scleritis does not resolve com- employed at MERSI is administered intrave-
pletely, with a maximum dose in our practice of nously on alternate weeks, beginning with 1 g per
35 mg/week. square meter body area and then choosing subse-
Patients with necrotizing scleritis, we believe, quent doses based upon the total and absolute
must be treated with a systemic immunosuppres- neutrophil white blood cell counts and platelet
sant. Systemic prednisone is generally appropri- count, striving to keep the total white blood cell
ate as well, concomitant with the nonsteroidal count in the range of 3,000–4,500, the absolute
immunosuppressive medication. If the necrotiz- neutrophil count to 1,000 or above, and the plate-
ing scleritis is unilateral, is not severe, and is not let count to 70,000 or above. If one must employ
rapidly progressive, our first-choice therapy once oral cyclophosphamide, the initial dose is 2 mg/
again is once-a-week methotrexate, with the kg per day, restricted to morning and noontime,
usual caveats vis-à-vis liver bone marrow, and with high fluid intake in afternoons and evenings.
appropriate monitoring [8, 9]. The dose used is Hematological, urological, and systemic moni-
the same as stated above for nodular scleritis. If toring is as previously described, with the usual
the disease is bilateral, severe, or rapidly progres- caveats. The target cell count goals are the same
sive, or if the patient has not responded to the as those described above for intravenous therapy
methotrexate, we generally use azathioprine at a (see Sect. 9.2.3) [8, 9].
starting dose of 2 mg/kg per day, with dosage
adjusted on the basis of clinical response and sys- 9.2.1.2 Systemic Lupus Erythematosus
temic tolerance. Systemic mycophenolate with or Patients with SLE who have diffuse scleritis are
without cyclosporine A is an alternative medica- treated by us with an oral NSAID as described
tion under this circumstance, as is the addition of above for diffuse scleritis associated with rheu-
a TNFa inhibitor, such as infliximab or adali- matoid arthritis. We typically add hydroxychlo-
mumab. Recently, three new biological agents, roquine (plaquenil; 200–400 mg once daily) if
rituximab, abatacept, and tocilizumab, have the response to the oral NSAID is not complete.
become available for the treatment of rheumatoid Systemic prednisone is added if these first two
arthritis in patients with active disease, including steps are inadequate to bring about a complete
scleritis, who have not responded to TNF block- resolution of the scleritis. The strategy for the use
ade. Rituximab is an anti-CD20 monoclonal anti- of the systemic steroid is the same as that
body, abatacept modulates T-cell activation, and described above for the care of patients with dif-
tocilizumab is an interleukin-6 receptor antago- fuse or nodular scleritis associated with rheuma-
nist. Clinical studies with these agents have dem- toid arthritis, with the exception that SLE patients
onstrated that they are effective in rheumatoid often respond better to split dosage corticosteroid
arthritis patients with active disease who have not than to once daily dosing. Our strategy for treat-
responded to treatment with at least one TNF ing patients with SLE who have nodular scleritis
inhibitor. Thus far, there is no convincing evi- is the same as for treating those with diffuse
dence to show that one of these three new drugs scleritis, with the additional recommendation that
has a superior efficacy over the others. However, low-dose methotrexate be given once a week for
the benefit for any of these new biological agents those rare patients that do not adequately respond
appears to outweigh the risk for a rheumatoid to oral NSAID, plaquenil, and/or systemic corti-
arthritis patient with active disease. Adverse costeroids. Mycophenolate mofetil may also be
events, including (usually mild) infusion reac- used and seems to be especially effective in
tions, are common. There is a small increased patients with SLE. In the extremely rare event
9.2 Treatment of Scleritis 303
Fig. 9.4 Diagrammatic illustration of the fitting of a cor- sutures (Fig. 9.5). The knots are rotated into the
neoscleral graft to the surgical bed previously prepared
(see Fig. 9.3)
tissue (buried) and, if possible, conjunctiva sur-
rounding the surgical site is undermined and
advanced over the graft and secured with 7–0
which the choroid is exposed or in which the only Vicryl sutures (Fig. 9.6). In instances in which
tissue overlying the choroid is the necrotic sclera uveal ectasia is pronounced, securing the graft
to be removed (lest it remain a stimulant for non- into the graft bed can be facilitated by first per-
specific inflammation) the scleral dissection forming an anterior chamber paracentesis to par-
requires great care, patience, and often a great tially decompress the globe.
deal of time. In instances in which peripheral ulcerative
Once the limits of the surgical bed to be rein- keratitis is not part of the destructive lesion
forced with donor material have been defined, we either frozen sclera, a frozen globe or glycerin-
create a template, using a piece of plastic surgical preserved sclera can serve as a source for the
drape, of the surgical bed; this template is then graft material. Glycerine-preserved sclera must
used to outline the size of the graft to be excised be thoroughly washed and allowed to rehydrate
from the donor eye. The outlined graft material is in balanced salt solution for approximately
excised, trimmed of nonscleral material, trimmed 10 min prior to grafting.
to fit the surgical recipient bed (Fig. 9.4), and Vascularization of the graft and repopulation
secured with interrupted 10–0 and/or 9–0 nylon of it by recipient fibroblasts may take many
References 307
months. We tend not to use topical steroids recurrent inflammation is high. Surgical treat-
postoperatively, in order not to inhibit this process. ment through tectonic scleral and peripheral cor-
neal grafting is rarely, although sometimes,
indicated. It is to be emphasized, however, that
9.3 Summary such treatment alone will virtually never solve the
patient’s problem; the essential ingredient for
The treatment of episcleritis can usually be strictly success is control or cure of the underlying immu-
supportive, although in some instances systemic noregulatory dysfunction that has created the
NSAID therapy is indicated. Such treatment can destruction in the first place.
usually be tapered and discontinued after 6 months
of freedom from an attack of episcleritis. Diffuse
and nodular scleritis can usually be effectively References
treated in the same way, that is, with NSAIDs,
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also always indicated (e.g., tetracycline in patients 2. Lyons CJ, Hakin KN, Watson PG. Topical flurbipro-
fen: and effective treatment for episcleritis? Eye.
with rosacea, allopurinol in patients with gout,
1990;4:521.
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mation, a limited course of systemic corticoster- patients with periarteritis nodosa. Am J Med. 1967;
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4. Fauci AS. Vasculitis. In: Parker CW, editor. Clinical
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60:192.
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6. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J
(without recurrence of the scleritis) for several Ophthalmol. 1976;60:163.
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pressive therapy should be considered. The same editors. Clinical ophthalmic pharmacology. Boston:
applies for patients who develop serious steroid- Little Brown; 1987. p. 173–92.
induced side effects. Patients with an established, 9. Hemady R, Tauber J, Foster CS. Immunosuppressive
drugs in immune and inflammatory ocular disease.
potentially lethal systemic vasculitis as the cause
Surv Ophthalmol. 1991;35:369.
of scleritis (e.g., polyarteritis nodosa or granulo- 10. McCune WJ, Golbus J, Zeldes W, et al. Clinical and
matosis with polyangiitis (Wegener)), and patients immunologic effects of monthly administration of
with necrotizing scleritis, always require treat- intravenous cyclophosphamide in severe lupus erythe-
matosus. N Engl J Med. 1988;318:1423.
ment with an immunosuppressive chemothera-
11. Raizman MB, Sainz de la Maza M, Foster CS.
peutic drug. The cure rate in such instances Tectonic keratoplasty for peripheral ulcerative keratitis.
following 1 year of freedom from any evidence of Cornea. 1991;10:312.
Index
A ocular manifestations
ABD. See Adamantiades–Behçet’s disease (ABD) anterior uveitis, 197–198
Acanthamoeba, 266–268 episcleritis, 198
Actinomycetic scleritis, 254–255 scleritis, 198
Acute pneumonitis, 191 spondyloarthropaties, 194, 195
Adamantiades–Behçet’s disease (ABD) systemic manifestations
diagnosis, 219–220 articular involvement, 196–197
epidemiology, 218 extraarticular systemic manifestations, 197
laboratory findings, 219 Annular ciliochoroidal detachment, 115, 124–125
medical treatment, 304 Anterior chamber polymerase chain reaction testing, 79
ocular manifestations Anterior ischemic optic neuropathy (AION), 221
episcleritis, 219 Anterior scleral foramen, 10–11
scleritis, 219 Anterior scleritis, 105
systemic manifestations, 218 Anterior segment fluorescein angiography, 80–84.
Adaptive immune response See also Normal anterior segment fluorescein
components, 32 angiography
afferent arc, 32 Anterior segment indocyanine green
central processing, 32 angiography, 84–85
efferent arc, 32 Anterior uveitis, 184–185
lymphocytes, 34–36 Antibodies to cyclic citrullinated polypeptides
monocytes/macrophages, 36–37 (Anti-CCPs), 186–187
platelets, 38–39 Antibody-dependent cell-mediated cytotoxicity
polymorphonuclear granulocytes, 37–38 (ADCC), 35–36
ADCC. See Antibody-dependent cell-mediated cytotox- Antibody titers against infectious organisms, 78
icity (ADCC) Anti-CCPs. See Antibodies to cyclic citrullinated
Afferent arc, adaptive immune response, 32 polypeptides (Anti-CCPs)
AION. See Anterior ischemic optic neuropathy (AION) Anticyclic citrullinated peptide antibodies, 73
Alfonso, M.E., 244 Antigen
Alkaptonuria, 280 and antibody valences, 42
Allergic granulomatous angiitis. See Churg–Strauss blocking mechanism, 40
syndrome mimicry, 44
American Rheumatism Association, 188, 194, 195 Antigen-presenting cells, 36–37
Amyloidosis, 182, 280 Anti-neutrophil cytoplasmic antibodies
ANAs. See Antinuclear antibodies (ANAs) (ANCAs), 75–76, 153, 154, 165
ANCAs. See Anti-neutrophil cytoplasmic antibodies Antinuclear antibodies (ANAs), 73–75, 187, 188
(ANCAs) Antiphospholipid (aPL), 193
Ancillary therapy, 304 Aortitis, 209
Anergy, 80 Arthus reaction, 43
Angiopathic neuropathy, 180 AS. See Ankylosing spondylitis (AS)
Angle-closure glaucoma, 130 A-scan ultrasonography, 85
Ankylosing spondylitis (AS) Aspergillus fumigatus, 163
diagnosis, 199 Asymmetric multiple mononeuropathy, 181
epidemiology, 196 Atopy, 223–224
laboratory findings and radiologic evaluation, 198–199 Autoimmunity, 43–45
R cataract, 185
RA. See Rheumatoid arthritis (RA) episcleritis, 185–186
Radioactive phosphorus (32P) uptake, 121 glaucoma, 185
Radioimmunoassay (RIAs), 72–73 incidence, 183
Raji cell-binding assay, 77 keratitis, 184
Reactive arthritis (ReA) keratoconjunctivitis sicca, 182, 183
diagnosis, 203 motility disturbances, 185
epidemiology, 200 retinal, choroidal and optic nerve changes, 185
laboratory and radiographic findings, 202, 203 scleral inflammation, 184
ocular manifestations systemic manifestations
anterior uveitis, 202 amyloidosis, 182
conjunctivitis, 202 bone involvement, 182
episcleritis, 202 Felty’s syndrome, 181
keratitis, 202 gastrointestinal involvement, 182
scleritis, 202 heart, 179–180
systemic manifestations kidney involvement, 182
articular involvement, 200 larynx, 181
circinate balanitis, 201 lung, 178–179
genitourinary involvement, 200 lymph nodes, 181
keratoderma blennorrhagicum, 201 nervous system, 180–181
mucocutaneous lesions, 200 polyarthritis, 176
subungual hyperkeratosis, 201 tegument, 176–177
Receptor crosslinking mechanism, 40–41 vessels, 177–178
Red-free illumination, 68 Rheumatoid factor (RF), 71–73, 186
Regan, C.D.J., 193 RIAs. See Radioimmunoassay (RIAs)
Reiter, H., 200 Rosacea, 226
Reiter’s syndrome, 199, 201 Rose, H.M., 71, 186
Relapsing polychondritis (RP) Rothfield, N., 193
diagnosis, 210–211 RP. See Relapsing polychondritis (RP)
epidemiology, 208
laboratory findings, 210
medical treatment, 303 S
ocular manifestations Sacks, B., 190
episcleritis, 210 Sacroiliac X-rays, 80
scleritis, 209–210 Sainz de la Maza, M., 183
systemic manifestations, 209 Sarcomas, 289
Reticuloendothelial system function, 42 Scleral foramina
Reynolds, M.G., 244 anterior scleral foramen, 10–11
RF. See Rheumatoid factor (RF) posterior scleral foramen, 11–12
Rheumatoid arthritis (RA), 71, 72 Scleral stroma, 13
anti-CCP, 156 Scleritis, 57, 102
epidemiology ancillary therapy, 304
extraarticular clinical features, 176 associated diseases, 125–126
HLA-Dw4, 176 biopsy, 87
signs and symptoms, 174–175 for suspected local/systemic infectious disease, 88
laboratory findings for suspected systemic vasculitic disease, 88
acute-phase reactants, 187 classification, 96, 105–125
anti-CCPs, 186–187 diffuse anterior scleritis, 103, 105–108
antinuclear antibodies, 187, 188 necrotizing scleritis, 109–111
circulating immune complexes, 187 nodular anterior scleritis, 106, 108–109
complement, 188 posterior scleritis, 113–125
complete blood count, 187 scleromalacia perforans, 111–113
cryoglobulins, 188 clinical classification, 58
diagnosis, 188–189 clinical manifestations, 102–105
radiographic evaluation, 188 complications
rheumatoid factor, 186 cataract, 131–132
synovial fluid analysis, 187 glaucoma, 130–131
medical treatment, 301–302 keratopathy, 126–129
ocular manifestations uveitis, 129–130
anterior uveitis, 184–185 demographic and clinical characteristics, 103
318 Index