1 |
P a g e
Rabies
is an acute viral disease of the central nervous system (CNS) is caused by a
rhabdovirus that is transmitted to humans by infected animals. After a prodromal phase,
rabies manifests most often as
encephalitis
—or less frequently as a
paralytic
form of the
disease—and then progresses to coma and death.
Epidemiology
Rabies is a zoonosis that is generally transmitted to humans
by the bite of a rabid animal
.
Rabies virus can infect most mammals and is worldwide in distribution. Historically,
dogs
were the primary reservoir and vector for rabies
, and they remain the major source of
transmission to humans in Asia and Africa.
Exposures to aerosols in the laboratory or in caves containing millions of bats have resulted
in human rabies.
Transplanted corneal tissue & recently from solid organ transplantation has been the source
of eight cases of human rabies, and strict guidelines for donor screening have been adopted
in an effort to eliminate this risk.
Pathogenesis
The incubation period of rabies (defined as the interval between virus exposure and onset of
clinical disease) is usually 1–3 months. During most of the incubation period, rabies virus is
thought to be present at or close to the site of inoculation, predominantly in muscle cells.
Several receptors probably account for the ability of rabies virus to infect both sensory and
motor neurons.
After entering sensory and motor neurons, rabies virus spreads centripetally at a rate of
100–400 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. 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.
The most characteristic pathologic finding in rabies is the Negri body. Negri bodies are
eosinophilic cytoplasmic inclusions in brain neurons and are composed of randomly oriented
rabies virus nucleocapsids embedded in an amorphous substance or matrix. These inclusions
occur in a minority of infected cells, are most commonly present in Purkinje cells of the
cerebellum and in pyramidal cells in the hippocampus, and are less frequently seen in
cortical neurons and in the brainstem.
2 |
P a g e
Clinical Manifestations
After an asymptomatic incubation period, clinical rabies progresses through three general
phases: a prodrome, an acute neurologic phase, and coma/death.
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 50–80% of patients and
suggests rabies.
Two acute neurologic forms of rabies are seen in humans: encephalitic (furious) in 80% and
paralytic in 20%.
Encephalitic Rabies
A prodromal period of 1-10 days, during which the patient is increasingly anxious, leads to
the characteristic 'hydrophobia'. Although the patient is thirsty, attempts at drinking
provoke violent contractions of the diaphragm and other inspiratory muscles. Delusions and
hallucinations may develop, accompanied by spitting, biting and mania, with lucid intervals
in which the patient is markedly anxious. Cranial nerve lesions develop and terminal
hyperpyrexia is common. Death ensues, usually within a week of the onset of symptoms.
Paralytic Rabies
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-Barré syndrome is a common misdiagnosis. 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.
Diagnosis
This diagnosis should be considered in patients presenting with acute encephalitis or with
unexplained ascending paralysis . A lack of animal-bite history or a lack of hydrophobia is
not unusual in rabies. Once rabies is suspected, rabies-specific tests should be employed to
confirm the diagnosis.
Rabies Virus–Specific 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.
3 |
P a g e
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.
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.
Treatment
There is no established treatment for rabies. Only a few patients with established rabies
have survived. All received some post-exposure prophylaxis, and needed intensive care
facilities to control cardiac and respiratory failure. Otherwise, only palliative treatment is
possible once symptoms have appeared. The patient should be heavily sedated with
diazepam 10 mg 4-6-hourly, supplemented by chlorpromazine 50-100 mg if necessary.
Nutrition and fluids should be given intravenously or through a gastrostomy.
Prognosis
Rabies is an almost uniformly fatal disease but is almost always preventable with
appropriate postexposure therapy during the incubation period. There are only six well-
documented cases of survival after symptomatic rabies infection. Most patients with rabies
die within several days, even with aggressive care in a critical care unit.
Postexposure Prophylaxis
The wounds should be thoroughly cleaned, preferably with a quaternary ammonium
detergent or soap; damaged tissues should be excised and the wound left unsutured. Rabies
can usually be prevented if treatment is started within a day or two of biting. Delayed
treatment may still be of value. For maximum protection, hyperimmune serum and vaccine
are required.
The safest antirabies antiserum is human rabies immune globulin; the dose is 20 U/kg body
weight. Half is infiltrated around the bite and half is given intramuscularly at a different site
from the vaccine. The dose of hyperimmune animal serum is 40 U/kg; hypersensitivity
reactions, including anaphylaxis, are common.
The safest vaccine, free of complications, is human diploid cell strain vaccine; 1.0 ml is given
intramuscularly on days 0, 3, 7, 14, 30 and 90. In developing countries, where human rabies
globulin may not be obtainable, 0.1 ml of vaccine should be given intradermally into eight
sites on day 1, with single boosters on days 7 and 28. Where human products are not
available and when risk of rabies is slight (licks on the skin, or minor bites of covered arms or
legs), it may be justifiable to delay starting treatment for up to 5 days while observing the
biting animal or awaiting examination of its brain.
4 |
P a g e
Pre-exposure prophylaxis
Pre-exposure prophylaxis is required by those who professionally handle potentially
infected animals, those who work with rabies virus in laboratories and those who live at
special risk in rabies-endemic areas. Protection is afforded by two intradermal injections of
0.1 ml human diploid cell strain vaccine, or two intramuscular injections of 1 ml, given 4
weeks apart, followed by yearly boosters.