Case Report Rabies : Bono

Session I :
Mr Bono, a 36 year old man from Sidoarjo was rushed to regional hospital by his relatives with
signs of fever, agitation, confusion, photophobia, and hydrophobia since 5 days ago. Mr Bono also
complain tingling and numbness on the proximal third of the right leg. But he was able to carry on
with daily activities. He has dog bite history 2 weeks ago

Problem Prodromal Features :

Since 5 days ago he complained fever
Agitation
Confusion
Photophobia
Hydrophobia
Tingling
Numbness on the proximal third of the right leg
Dog bite history

Learning objective :
At The end on the first session , the student should be able to :
1. Identify the patient problem
2. Generate the list of hypothesis
3. Describe the anatomy of pheripheral and Central Nervous System
Guiding Question :
1. Identify the patient problems :
1. He has dog-bite history 2 weeks ago
2. Since 5 days ago he complained fever, agitation, confusion, photophobia, hydrophobia,
tingling, numbness on the proximal third of the right leg.

2. Generate the list of hypothesis ?

Differential diagnostic possibilities for patient :
1. Rabies
2.Tetanus
3. Meningitis

3. Anatomy of peripheral and Central Nervous System

Session II :
History :
While to drive away to release outside the market, Mr Bono was bitten by a dog on the posterior
part of proximal third of the right leg. He sustained a 3 cm deep laceration with some blood
present at the margins. It was cleansed with washing with soap and water. He admitted in an
isolation Intensive Care Unit (ICU).

On physical examination, he was confused, but answered questions appropriately and obeyed
commands. His blood pressure measured was 120/70 mmHg, temperature 38,4 oC, pulse 104 beats
per minute regularly, and respiratory rates were 14 breaths per minute. The cardiovascular and
gastrointestinal system were observed to be normal. Neurological examination revealed normal
cranial nerves, pupil equal and reacted briskly to light with muscle spasms in all limbs. Painful
spasm on the throat muscle while trying to drink and spasm may be also precipitated by air
blowing into the face in the isolation ICU.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 1

Blood glucose, serum electrolytes, liver function, and renal function test of the patient were
normal. However his full blood count showed high white blood cell count.

The dog was furious, and bitting not only people but objects, salivate excessively, and paw at is
mouth as if trying to dislodge a foreign body. The dog, those not wearing a collar with vaccination
tag, was dead after five days bitten him.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 2

Physical diagnosis findings :

What are Bonos problems from anamnese and the physical findings ?
The problems from anamneses :
1. Bono, male, 36 years old
2. He was bitten by a dog on the posterior part of proximal third of the right leg
3. The wound was approximately 3cm in length with some blood present at the margins
4. It was cleansed with washing and flushing with soap and water.
5. The dog was furious, and bitting not only people but objects, salivate excessively, and
paw at is mouth as if trying to dislodge a foreign body.
6. The dog, those not wearing a collar with vaccination tag, was dead after five days bitten
him.

The Problems from the physical examinations :

1. She was confused, but answered questions appropriately and obeyed commands.
2. Blood pressure 120/70 mmHg
3. Pulse of 104 beat perminute
4. Temperature of 38.4oC.
5. Painful spam of the throat muscle while trying to drink and spasm may be also
precipitated by air blowing onto the face in the isolation ward.

Objective :
At The End on the second session the student should be able to :
1. Describe the definition of Rabies
2. Describe the etiologic Agent of Rabies ( microbiology )
3. Describe the Epidemiology of Rabies
4. Describe the pathogenesis of Rabies
5. Describe the classical symptomps of Rabies virus infection
6. Describe others clinical manifestation of Rabies

1. Describe Definition of Rabies :

Rabies is an acute viral disease of the central nervous system (CNS) that is transmitted to
humans by infected animals. After a prodromal phase, rabies manifests most often as
encephalitis or less frequently as a paralytic from of the disease and then progresses to
coma and death.

2. Describe Etiology Agent of Rabies ( bagian mikrobiologi )

Untuk pertimbangan bagian mikrobiologi dari Harrison :
Rabies virus is a member of the genus Lyssavirus in the family Rhabdoviridae, which includes
vesicular stomatitis virus (VSV), a bovine pathogen of significant economic importance that can
infect humans (see "Other Rhabdoviruses," below). Rhabdos, meaning "rodlike," refers to the
distinctive elongated shape of these viruses. Their enveloped virions contain a single-strand,
nonsegmented, negative-sense RNA. The rabies virus genome consists of 11,932 nucleotides
and encodes five proteins: nucleocapsid, matrix, phosphoprotein, glycoprotein, and an RNA
polymerase. Each animal reservoir harbors one or more distinct rabies virus variants that can
be distinguished by the sequence of the nucleocapsid gene.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 3

3. Describe Epidemiology of Rabies ( Sejawat dari IKM)
Untuk bahan pertimbangan : JIACM 2006; 7(1) : 39-46
Epidemiology
Table I : Modes of transmission of Rabies
Animal to man
1. Bites of rabid animals
2. Scratches by rabid animals
3. Licks on abraded skin or mucous membranes
Aerosols
1. In caves harbouring rabies infested bats
2. In laboratories handling rabies infected neural tissue*.
Oral**
1. Dringking unboiled raw milk or rabies infected cow or goat
2. Eating meat of rabid animal can theoretically lead to rabies

Man to man
1. Corneal transplant from an infected person
2. Solid organ transplant (liver, kidney) from an infected person
3. Bite from a rabid human; theoretical risk but no confirmed cases reported as yet
4. Kissing an infected person; theoretical risk but no confirmed case reported as yet.
*Contact with body fluids other than saliva and neural tissue (i.e., blood, urine of faeces) is not considered an exposure.
**Rabies virus is inactivated by desiccation, UV radiation and healting or cooking at > 60 oC. thus, dry material from a rabid animal
can be considered non-infectious.
JIACM 2006; 7(1) : 39-46

4. Describe Pathogenesis of Rabies

The incubation period of rabies (defined as the interval between virus exposure and onset of
clinical disease) is usually 13 months but in rare cases is as short as 2 weeks or >1 year. During
most of the incubation period, rabies virus is thought to be present at or close to the site of
inoculation (Fig. 188-1), predominantly in muscle cells. Administration of rabies PEP during this
incubation period is critical; the benefit of PEP in preventing disease progression once rabies
virus has entered peripheral nerves is limited. Several receptors probably account for the
ability of rabies virus to infect both sensory and motor neurons. The virus is known to bind to
nicotinic acetylcholine receptors, and acetylcholine receptor blockade inhibits rabies virus
attachment. Experimental evidence also supports a role for the neural cell adhesion molecule
and the p75NTR neurotrophin receptor as receptors for rabies virus. After entering sensory and
motor neurons, rabies virus spreads centripetally at a rate of 100400 mm/d via fast axonal
transport to the spinal cord or brainstem. Once the virus enters the CNS, it spreads rapidly
throughout the gray matter via established neuroanatomic connections. There are
inflammatory changes, but there are few degenerative changes involving neurons and little
evidence of neuronal death. These observations have led to the concept that neuronal
dysfunctionrather than neuronal deathis responsible for clinical disease in rabies. The
basis for the behavioral changes, including aggression, is not well understood. After CNS
infection is established, there is centrifugal spread along peripheral nerves to other tissues,
including the salivary glands, liver, muscle, skin, adrenal glands, and heart. Rabies virus
replication in acinar cells of the salivary glands results in viral excretion in the saliva of rabid
animals.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 4

 5. Classical symptomps of Rabies virus infection
Agitation, confusion, photophobia, and hydrophobia (7)
6. Clinical Manifestations of Rabies
Rabies has the highest case-fatality rate of any infectious disease. Although the diagnosis of
rabies should be considered in any case of unexplained encephalitis or flaccid paralysis
accompanied by fever, efforts to prevent the disease are appropriately focused on early
identification of rabies exposure and administration of PEP. After an asymptomatic incubation
period, clinical rabies progresses through three general phases: a prodrome, an acute
neurologic phase, and coma/death (Table 188-1).

Table 188-1 Progression of Rabies Virus Infection

Phase Duration Signs/Symptoms
Incubation period 13 monthsa None
Prodrome 17 days Fever, malaise, headache, nausea, vomiting, agitation,
focal paresthesias, pain
Acute neurologic phase
Encephalitic (80%) 17 days Fever, confusion, hallucinations, hyperactivity,
pharyngeal spasms (hydrophobia/aerophobia),
seizures
Paralytic (20%) 210 days Ascending flaccid paralysis
Coma/death 114 days ...
a
Typical duration, with a possible range of 2 weeks to >1 year.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 5

Prodromal Features
Clinically apparent rabies infection begins with nonspecific prodromal symptoms, including
fever, malaise, headache, nausea, and vomiting. Anxiety or agitation may also occur.
Paresthesias, pain, or pruritus near the site of the exposure occurs in 5080% of patients and
suggests rabies. The wound has usually healed by this point, and these symptoms may reflect
infection of local dorsal root or cranial sensory ganglia.

Encephalitic Rabies ( Bagian Neurologi )

Untuk pertimbangan : dari Harrison
Two acute neurologic forms of rabies are seen in humans: encephalitic (furious) in 80% and
paralytic in 20%. Manifestations of encephalitic rabies may be seen in many other viral
encephalitides as well. These features include fever, confusion, hallucinations, combativeness,
muscle spasms, hyperactivity, and seizures. Autonomic dysfunction is common and may result
in hypersalivation, excessive perspiration, gooseflesh, pupillary dilation, and/or priapism. In
encephalitic rabies, episodes of hyperexcitability are typically followed by periods of complete
lucidity that become shorter as the disease progresses. Rabies encephalitis is most
distinguished by early brainstem involvement, which results in the classic symptoms of
hydrophobia and aerophobia: involuntary, painful contraction of the diaphragm and accessory
respiratory, laryngeal, and pharyngeal muscles in response to swallowing liquids (hydrophobia)
or a draft of air (aerophobia). These symptoms are probably due to dysfunction of infected
brainstem neurons that normally inhibit inspiratory neurons near the nucleus ambiguus,
resulting in exaggerated defense reflexes that protect the respiratory tract. The combination of
hypersalivation and pharyngeal dysfunction is also responsible for the classic appearance of
"foaming at the mouth" (Fig. 188-3). Brainstem dysfunction progresses rapidly, and coma
followed within days by death is the rule unless the course is prolonged by supportive
measures. With such measures, late complications can include disturbances of water balance
(syndrome of inappropriate antidiuretic hormone secretion or diabetes insipidus),
noncardiogenic pulmonary edema, and cardiac arrhythmias due to brainstem dysfunction
and/or myocarditis.

Paralytic Rabies ( Bagian Neurologi )

Untuk pertimbangan : dari Harrison
For unknown reasons, muscle weakness predominates and cardinal features of encephalitic
rabies (hydrophobia, aerophobia, fluctuating consciousness) are lacking in ~20% of rabies
cases. Paralytic rabies is characterized by early and prominent muscle weakness, often
beginning in the bitten extremity and spreading to produce quadriparesis and facial weakness.
Sphincter involvement is common, but sensory involvement is usually mild. Guillain-Barr
syndrome is a common misdiagnosis. Transplantation of corneal tissue from donors in whom
paralytic rabies was misdiagnosed as Guillain-Barr syndrome has resulted in clinical rabies
and death in recipients. Patients with paralytic rabies generally survive a few days longer than
is typical in encephalitic rabies, but multiple-organ failure ensues even with aggressive
supportive care.

Session III :
A presumptive diagnosis Rabies has made on the first day of admission. Rabies virus specific anti
bodies in the CSF and serum for anti rabies virus anti body, RT-PCR of saliva and nuchal biopsy for
the presence of rabies RNA were detected. The patients wound was cleaned and dressed on daily
basis. He was administered intra muscular injection of 250 IU of human immune tetanus
immunoglobulin and placed on broad spectrum antibiotic (Ceftriaxone) as well as intra venous
fluid.
Seven days after treatment the patient responded very well to treatment, and the patients
condition improved drastically. He became oriented in time, place, and person with no
dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 6
photophobia and hydrophobia. Treatment continued until 15 days when he was discharged home
as his condition became much better and he complained of only mild headache.

Objective :
At The End on the third session the student should be able to :
1. Explain about the laboratory finding of Rabies ( Pathologie Klinik)
2. Explain about the Pathological Biology finding of Rabies (Pathologi Anatomi)
3. Describe the Rabies treatment
4. Describe the Pharmalogical of Rabies Vaccines ( Farmakologi)
5. Describe the prognosis of rabies
6. How Prevention of rabies ?
- For Human
- For Animal

1. Describe Laboratory infestigations : Sejawat Bagian Pathologi Klinik

Untuk bahan pertimbangan dari Harrison

Laboratory Investigations
During the early clinical stages of rabies, laboratory findings are nonspecific. Complete blood
counts are usually normal. Examination of cerebrospinal fluid (CSF) often reveals mild
mononuclear cell pleocytosis with a mildly elevated protein level. Severe pleocytosis (>1000
cells/L) is unusual and should prompt a search for an alternative diagnosis. CT head scans are
usually normal in rabies. MRI brain scans sometimes show signal abnormalities in the
brainstem or other areas, but these findings are variable and nonspecific.
Electroencephalograms show only nonspecific abnormalities. The most important tests in
suspected cases of rabies are those that may identify an alternative, potentially treatable
diagnosis (see "Differential Diagnosis," below).
Once rabies is suspected, rabies-specific tests should be employed to confirm the diagnosis.
Diagnostically useful specimens include serum, CSF, fresh saliva, brain tissue (when available),
and skin biopsy samples from the neck. Because skin biopsy relies on the demonstration of
rabies virus in cutaneous nerves at the base of hair follicles, samples from the neck should
include at least 10 hair follicles. Multiple testing modalities are required to ensure a high
negative predictive value. For example, because rabies virus infects immunologically privileged
neuronal tissues, serum antibodies often do not develop until very late in the disease.

Rabies VirusSpecific Antibodies

In a previously unimmunized patient, serum neutralizing antibodies to rabies virus are
diagnostic. Antibodies may be detected within a few days after the onset of symptoms, but
some patients die without detectable antibodies. The presence of rabies virusspecific
antibodies in the CSF suggests rabies, regardless of immunization status.

Reverse Transcription Polymerase Chain Reaction (RT-PCR)

Detection of rabies virus RNA by RT-PCR is highly sensitive and specific. This technique can
detect virus in fresh saliva samples, CSF, and tissue. In addition, RT-PCR can distinguish
between rabies virus variants, permitting the investigator to infer the likely source of an
infection.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 7

Direct Fluorescent Antibody (DFA) Testing
DFA testing with rabies antibodies conjugated to fluorescent dyes is highly sensitive and
specific and can be applied to brain tissue or skin biopsies from the nape of the neck. In the
latter samples, rabies virus can be detected in cutaneous nerves at the base of hair follicles.

2.Describe Pathological Biologic Finding : Bagian Pathologi Anatomi

3. Describe The Rabies Treatment

There is no established treatment for rabies.
There have been several recent treatment failures of antiviral therapy, ketamine, and
therapeutic comameasures that were used in a healthy survivor who had rabies virus
antibodies present at the time of presentation. Expert opinion should be sought before any
course of experimental therapy is embarked upon. A palliative approach may be appropriate
for some patients.

4. Describe pharmacological of Rabies Vaccines ( bagian Farmakologi )

5. Describe Prognosis of Rabies

Rabies is an almost uniformly fatal disease but is almost always preventable with appropriate
postexposure therapy during the incubation period (see below). There are only six well-
documented cases of survival after symptomatic rabies infection. All but one of the patients
involved had received rabies vaccine before disease onset; these patients represented failures
of postexposure rabies prophylaxis. Most patients with rabies die within several days, even
with aggressive care in a critical care unit.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 8

7. Describe Prevention of Rabies for Human
Postexposure Prophylaxis
Since there is no effective therapy for rabies, it is extremely important to prevent the disease after
an animal exposure. Figure 188-4 shows the steps involved in making decisions about rabies PEP.

Figure 188-4

Algorithm for rabies postexposure prophylaxis. RIG, rabies immune globulin. [From L Corey, in Harrison's Principles of
Internal Medicine, 15th ed. E Braunwald et al (eds): New York, McGraw-Hill, 2001, adapted with permission.]

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 9

PEP includes local wound care and both active and passive immunization. Local wound care is
essential and may decrease the risk of rabies virus infection by as much as 90%. Wound care should
not be delayed, even if the initiation of immunization is postponed pending the results of the 10-
day observation period. All bite wounds and scratches should be washed thoroughly with soap and
water. Devitalized tissues should be debrided, tetanus prophylaxis given, and antibiotic treatment
initiated whenever indicated.

All previously unvaccinated persons should be passively immunized with rabies immune globulin
(RIG). If RIG is not immediately available, it should be administered no later than 7 days after the
first vaccine dose. After day 7, endogenous antibodies are being produced, and passive
immunization may actually be counterproductive. If anatomically feasible, the entire dose of RIG
(20 IU/kg) should be infused at the site of the bite; otherwise, any RIG remaining after infiltration
of the bite site should be administered IM at a distant site. With multiple or large wounds, the RIG
preparation may need to be diluted in order to obtain a sufficient volume for adequate infiltration
of all wound sites. If the exposure involves a mucous membrane, the entire dose should be
administered IM. Rabies vaccine and RIG should never be administered at the same site or with the
same syringe. Commercially available RIG in the United States is purified from the serum of
hyperimmunized human donors. These human RIG preparations are much better tolerated than
are the equine-derived preparations still in use in some countries (see "Global Considerations,"
below). Serious adverse effects of human RIG are uncommon. Local pain and low-grade fever may
occur.

Two purified inactivated rabies vaccines are available for rabies PEP in the United States. They are
highly immunogenic and remarkably safe compared with earlier vaccines. Five 1-mL doses of rabies
vaccine should be given IM in the deltoid area. (The anterolateral aspect of the thigh is also
acceptable in children.) Gluteal injections, which may not always reach muscle, should not be given
and have been associated with rare vaccine failures. Ideally, the first dose should be given as soon
as possible after exposure; failing that, it should be given without further delay. The four additional
doses should be given on days 3, 7, 14, and 28. Pregnancy is not a contraindication for
immunization. Glucocorticoids and other immunosuppressive medications may interfere with the
development of active immunity and should not be administered during PEP unless they are
essential. In several studies, all persons vaccinated with the above schedule developed a serologic
response within 24 weeks. Routine measurement of serum neutralizing antibody titers is not
required, but titers should be measured 24 weeks after immunization in immunocompromised
persons. Local reactions (pain, erythema, edema, and pruritus) and mild systemic reactions (fever,
myalgias, headache, and nausea) are common; anti-inflammatory and antipyretic medications may
be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon,
but anaphylaxis does occur rarely and can be treated with epinephrine and antihistamines. The risk
of rabies development should be carefully considered before the decision is made to discontinue
vaccination because of an adverse reaction. Advice and assistance from state health officials or the
Centers for Disease Control and Prevention may be helpful in managing adverse reactions to
vaccine.

Preexposure Rabies Vaccination

Preexposure rabies prophylaxis should be considered for people with an occupational or
recreational risk of rabies exposures, including certain travelers to rabies-endemic areas. This
primary schedule consists of three doses of rabies vaccine given on days 0, 7, and 21 or 28. Serum
neutralizing antibody tests help determine the need for subsequent booster doses. When a
previously immunized individual is exposed to rabies, two booster doses of vaccine should be
administered on days 0 and 3. Wound care remains critical. RIG should not be administered to
previously vaccinated persons.

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 10

Table : Dosage of rabies vaccine (Shariq Haider MD)
Purpose Vaccine dosage
Pre-exposure prophylaxis 1.0 mL intramuscularly on days 0, 7 and 21
Postexposure prophylaxis
People previously vaccinated against 1.0 mL intramuscularly on days 0 and 3 no
rabies within 2 years and who have human rabies immune globulin
evidence of immunity
People not previously vaccinated 1.0 mL intramuscularly on days 0, 3, 7, 14 and 28,
against rabies plus human rabies immune globulin (20 iu/kg)
within 7 days of first vaccine dose.
In the absence of documented immunity, the full schedule of postexposure prophylaxis is indicated.
Deltoid muscle or anterolateral thigh in infants.
Source : Canadian Immunization Guide, 7th edition

Deterrence and Prevention (Untuk pertimbangan Sejawat dari IKM )

In the community, the public should be advised to do the following :
http://emedicine.medscape.com/article/220967-overviewe

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 11

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 12
 DAFTAR
PUSTAKA

1. Nath. A, Berger JR. Rabies, Goldman : Cecil Medicine, 23rd ed. Chapter 441, 2007
2. Rabies in Harrisons Internal Medicine, Chapter 188, e-book, McGraw Hills, Acces Medicine
3. Grompf, SG. Rabies, http://emedicine.medscape.com/article/220967-overview
4. Recovery of a patient from clinical rabies California, 2011,
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6104a1.html
5. Recovery of a patient from clinical rabies Wisconsin, 2004
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5350a1.html
6. Haider S, Rabies : Old Disease, New Chalengges, Division of Infectious Disease, Department of
Medicine, McMaster University, Hamilton, Ont.
7. A Presumptive Case of Human Rabies: A Rare Survived Case in Rural Ghana
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104963/

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 13

CASE RABIES PATHWAY

1) Anatomy CNS & PNS Anatomy

2) Rabies Definisi
Etiology : Rabies virus Mikrobiologi
Epidemiologi IKM
Pathogenesis & Pathophysiology
Sign & Symptoms
Diagnosis anamnesa
pemeriksaan fisik
penunjang laboratory
histo PA
Treatment
Complication
Preventive vaccination anjing IKM
manusia
Prognosis

3) Community medicine : penanganan kasus rabies

dr. M. Noer Abdoellah, Sp.PD, FINASIM./ 14