DEFINITION

Rabies
acute viral disease of the CNS
affects all mammals
transmitted by infected secretions, usually saliva.
exposures are through:
 Bite of an infected animal (most common)
 Contact with a virus-containing aerosol (occasional)
 Ingestion or transplantation of infected tissues (may
initiate the disease process)
ETIOLOGY
 Nucleocapsid antigen

• induces a complement-fixing antibody as well

as T helper cell reactivity
• This is where antibodies to rabies virus (used
in diagnostic immunofluorescence assays) are
generally directed
EPIDEMIOLOGY
Human infection
• occurs through:
– contact with unimmunized domestic animals
– exposure to wild animals in locales where rabies is
enzootic or epizootic
Areas where the disease is especially
common
–Southeast Asia
–Philippines
–Africa
–Indian subcontinent
–Tropical South America
 The ff. made the recognition of clinical rabies and its prevention of
increasing importance

• Increased spread of terrestrial rabies (i.e.,

rabies in animals that walk on the ground
rather than rabies in animals that fly)
• Rodents and lagomorphs
- rarely infected with rabies virus.
• Corneal transplantation
- several cases of human-to-human
transmission of rabies have also been
documented
• Bite and nonbite exposures to infected humans
- could theoretically transmit rabies
 ANIMAL SUSCEPTIBILITY TO RABIES

Very High High Moderate Low

Foxes Hamsters Dogs Opossums
Coyotes Skunks Sheep
Jackals Raccoons Goats
Wolves Cats Horses
Cotton Bats Nonhuman
rats Rabbits primates
Cattle
PATHOGENESIS
FIRST EVENT
• introduction of live virus through the
epidermis or onto a mucous
membrane.
INITIAL VIRAL REPLICATION
• appears to occur within striated muscle cells at
the site of inoculation
Peripheral nervous system
• exposed at the neuromuscular and/or
neurotendinous spindles of unmyelinated
sensory nerve cell endings
CENTRIPETAL SPREAD
• manner which the virus goes up the nerve to
the CNS
• probably via peripheral nerve axoplasm, at a
rate of ~3 mm/h.
VIREMIA
• documented in experimental
conditions but is thought not to play a
role in naturally acquired disease
 Once in the CNS

replicates almost exclusively within the gray matter

passes centrifugally along autonomic nerves to other tissues:

salivary glands
adrenal medulla
kidneys
lungs
liver
skeletal muscles
skin, and
heart
 Passage of the virus into the salivary glands

viral replication in mucinogenic acinar cells

facilitate further transmission via infected saliva

INCUBATION PERIOD
• exceedingly variable
• ranging from 7 days to >1 year (mean, 1 to 2
months)
• apparently depending on the:
– amount of virus introduced
– amount of tissue involved
– host defense mechanisms
– actual distance that the virus has to travel
from the site of inoculation to the CNS
Rates of infection and mortality as to
site of inoculation are:
• Highest: from bites on the face
• Intermediate: from bites on the
hands and arms
• Lowest: from bites on the legs
 Cases of human rabies
with an extended
incubation period
(2 to 7 years) have been
reported, but they are
 CLINICAL
MANIFESTATIONS
The clinical manifestations of rabies can be
divided into four stages:
1. nonspecific prodrome
2. acute encephalitis similar to other viral
encephalitides
3. profound dysfunction of brainstem centers
that produces the classic features of rabies
encephalitis
4. death or, in rare cases, recovery
PRODROMAL PERIOD
 Prodromal period
– usually lasts 1 to 4 days and is marked by:
• fever
• headache
• malaise
• myalgias
• increased fatigability
• anorexia
• nausea and vomiting
• sore throat
• nonproductive cough
 Prodromal period
PRODROMAL SYMPTOM suggestive of rabies is the
complaint of the ff. at or around the site of inoculation
of virus:
 Paresthesia and/or

 Fasciculations

- these may be related to the multiplication of

virus in the dorsal root ganglion of the sensory
nerve supplying the area of the bite

- reported by 50 to 80% of patients.

 ENCEPHALITIC/
NEUROLOGIC PHASE
Encephalitic phase

Usually ushered in by periods of:

»excessive motor activity
»excitation
»agitation
THE FF. SOON APPEAR:
• Confusion
• Hallucinations
• Combativeness
• Bizarre aberrations of thought
• Muscle spasms
• Meningismus
• Opisthotonic posturing( the position of the body
in which the head, neck, and spine are arched
backwards)
• Seizures
• Focal paralysis
Periods of mental aberration
– Characteristically, are interspersed with completely lucid
periods, but as the disease progresses the lucid periods
get shorter until the patient lapses into coma.
Hyperesthesia, with excessive sensitivity to bright
light, loud noise, touch, and even gentle breezes
– very common
 PHYSICAL EXAMINATION
• temperature: may be found to be as high as 40.6°C
(105°F).
• Abnormalities of the autonomic nervous system include:
– dilated irregular pupils
– increased lacrimation
– increased salivation, and
– increased perspiration
– postural hypotension.
• Upper motor neuron paralysis, with weakness, increased
deep tendon reflexes, and extensor plantar responses
• Paralysis of the vocal cords
– common
• Presenting signs and symptoms of rabies
– indistinguishable from those of other viral and
neurologic diseases
delays in diagnosis
Hydrophobia or aerophobia
– seen in about two-thirds of recent cases
– presence increases the likelihood of antemortem
diagnosis
PHASE OF BRAIN STEM
DYSFUNCTION
 PHASE OF BRAIN STEM
DYSFUNCTION
• manifestations begin shortly after the onset of
the encephalitic phase
Cranial nerve involvement causes:
– diplopia
– facial palsies
– optic neuritis
– difficulty with deglutition
• Difficulty in swallowing
• Excessive salivation
–combination of produces the
traditional picture of "foaming at
the mouth."
• Hydrophobia
• painful, violent, involuntary contraction of the
diaphragmatic, accessory respiratory,
pharyngeal, and laryngeal muscles initiated by
swallowing liquids
- seen in ~50% of cases
• Amygdaloid nucleus
• involvement of the may result in:
- priapism
- spontaneous ejaculation

• Review of Basics:  Excitation of other portion of

amygdala can cause sexual activities that include
erection, copulatory movements, ejaculation, ovulation,
uterine activity, and premature labor. (Source: Guyton)

• Hypersexuality (has intense sex drives toward

inappropriate animals or even inanimate objects, and
loses all fear- and thus develops tameless as well) have
been noted as a prominent feature in some
experimental studies in lesions of amygdaloid complex,
may occur only when the lesions concomitantly involve
pyriform cortex. (Source: Carpenter)
 Patient lapses into coma
+
Involvement of the respiratory center

Produces an apneic death.

• Early brainstem dysfunction
- Prominence distinguishes rabies from

other viral encephalitides and

accounts for the rapid downhill course
• Survival after the onset of symptoms
- median period of 4 days
- maximum of 20 days, unless artificial
supportive measures are instituted
• Intensive respiratory support
- used
- number of late complications may appear,
includes:
• inappropriate secretion of antidiuretic hormone
• diabetes insipidus
• cardiac arrhythmias
• vascular instability
• adult respiratory distress syndrome
• gastrointestinal bleeding
• Thrombocytopenia
• paralytic ileus
RECOVERY PHASE
RECOVERY

• very rare
• when it occurs, it is gradual
ASCENDING PARALYSIS
• may also be a presentation of rabies resembling the
Landry/Guillain-Barre syndrome (dumb rabies, rage
tranquille)
• Initially, this clinical pattern was reported most
frequently among persons given postexposure rabies
prophylaxis after being bitten by vampire bats.
• The difficulty of diagnosing rabies associated with this
is illustrated by cases of person-to-person transmission
of the virus by tissue transplantation.
PARALYTIC RABIES
• also occurs in Southeast Asia among persons with
canine exposures
CORNEAL TRANSPLANTS
• if from donors who died of presumed
Landry/Guillain-Barre syndrome produced clinical
rabies in and caused the deaths of the recipients.
LABORATORY FINDINGS
Hemoglobin values and routine blood chemistry
• early in the disease, are normal
• abnormalities develop as hypothalamic
dysfunction, gastrointestinal bleeding, and other
complications ensue
Peripheral white blood cell count
• usually slightly elevated (12,000 to 17,000/uL)
• may be normal or as high as 30,000/uL.
The specific diagnosis of rabies depends on:
• the isolation of virus from infected secretions
[saliva or, rarely, cerebrospinal fluid (CSF)] or
tissue (brain)
• the serologic demonstration of acute infection
• detection of viral antigen in infected tissue (e.g.,
corneal impression smears, skin biopsies, or
brain), or
• detection of viral nucleic acid (RNA) by
polymerase chain reaction (PCR).
Reference laboratory evaluating antemortem
samples
• can confirm rabies with high sensitivity and
specificity
Most sensitive are:
• Isolation of virus from saliva
• Demonstration of viral nucleic acid in saliva, or
• Detection of viral antigen in a nuchal skin biopsy
specimen
• Examination of corneal epithelium specimens
– appears less sensitive

• Demonstration of rabies antibodies in serum or

CSF
– in the unvaccinated person, may be useful, although such
antibodies may not appear until late in the course of disease.
• Samples of brain obtained at postmortem
examination or brain biopsy should be
subjected to
» mouse inoculation studies for virus isolation
» fluorescent antibody (FA) staining for viral antigen, and
» histologic and/or electron microscopic examination for
Negri bodies or
» reverse transcription PCR for rabies virus RNA.
• Postexposure rabies prophylaxis
» rarely elicits CSF neutralizing antibody to rabies
virus
• CSF neutralizing antibody to rabies virus
» If present after prophylaxis, it is usually found at a
low titer (<1:64), whereas CSF titers in human
rabies may vary from 1:200 to 1:160,000.
TREATMENT
 RABIES POSTEXPOSURE PROPHYLAXIS GUIDE

The following recommendations are only a guide.

In applying them, take into account the animal
species involved, the circumstances of the bite or
other exposure, the vaccination status of the animal,
and the presence of rabies in the region.
Note: Local or state public health officials should be
consulted if questions arise about the need for rabies
prophylaxes.
Animal type Evaluation of Animal Treatment of Exposed person1

Domestic Healthy and available for None, unless animal develops

Dogs, cats, and ferrets 10 days of observation symptoms of rabies

Rabid or suspected rabid Vaccine immediately

Unknown (escaped) Consult public health officials
Wild Regard as rabid unless Consider immediate vaccination
Skunks, raccoons, bats, animal is proved
foxes, coyotes, and negative by laboratory
other carnivores tests

Other Consider individually. Local and state public health officials

Livestock, rodents, should be consulted about the need for rabies prophylaxis.
andlagomorphs (rabbits Bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks,
and hares) rats, mice, other rodents, rabbits, and hares almost never
antirabies prophylaxis

1
All bites and wounds should immediately be thoroughly cleansed with
soap and water
 Postexposure Prophylaxis

The decision to initiate postexposure

prophylaxis should include the following
considerations:
• whether the individual came into physical contact with saliva or
another substance likely to contain rabies virus
• whether rabies is known or suspected in the species and area
associated with the exposure (e.g., all persons within the
continental United States bitten by a bat that escapes should
receive postexposure prophylaxis), and
• the circumstances surrounding the exposure (e.g., whether the
bite was provoked or unprovoked).
• Rabies is known or suspected to be present
in the animal species
– animal should be captured if possible.
• The ff. should be humanely killed:
• Any wild animal involved in a rabies exposure
• any ill, unvaccinated, or stray domestic animal involved
in a rabies exposure
• any animal inflicting an unprovoked bite, exhibiting
abnormal behavior, or suspected of being rabid.
• Animal's head
– should be sent immediately to an appropriate laboratory for
rabies FA examination.

• Brain FA yields negative result

– it can be assumed that:
» the saliva contains no virus
» exposed person need not be treated
• Persons exposed to wild animals that
subsequently escape, that are capable of
carrying rabies and that inhabit an area where
rabies is known or suspected to be present
- should undergo both passive and active
immunization against rabies as soon as possible after
exposure
• Area in which feline or canine rabies is not
prevalent
- healthy biting dog, cat, or ferret can be
confined and observed for 10 days
- Persons should not begin a course of
prophylaxis unless the animal develops clinical
signs of rabies
• Animal becomes ill or behaves abnormally during
the observation period
- should be killed for FA examination
Animals that remain healthy for 10 days after a
bite
• experimental and epidemiologic evidence
suggests that it will not have transmitted rabies
virus at the time of the bite

Areas of high endemicity for canine rabies

• immediate examination of the animal's brain,
especially in the case of a severe bite, may be
warranted
Bites of rodents, rabbits, and hares
• almost never require antirabies postexposure
prophylaxis
Postexposure Prophylaxis
• should be considered after direct contact
between a human and a bat unless the exposed
person can rule out a bite, scratch, or mucous
membrane exposure
• includes:
– rigorous cleansing
– treatment of the wound
– administration of rabies vaccine together with
antirabies immunoglobulin
POSTEXPOSURE PROPHYLAXIS

- should be initiated as soon as possible

after exposure
As the incubation period of rabies is quite
variable, postexposure prophylaxis should be
begun as long as clinical signs of rabies are not
present.
1. WOUND CLEANSING AND TREATMENT
• Thorough cleansing and treatment of the bite
wound constitute an important component of
rabies prevention
• The wound should be scrubbed with soap and
then flushed with water.
• Both mechanical cleansing and chemical
cleansing are important
• Quaternary ammonium compounds such as 1 to
4% benzalkonium chloride, 1% cetrimonium
bromide, or povidone-iodine solutions should
be utilized
• Tetanus toxoid and antibiotic prophylaxis should
be administered as needed.
2. PASSIVE IMMUNIZATION WITH ANTIRABIES
ANTISERUM OF EITHER EQUINE OR HUMAN ORIGIN
• Postexposure antirabies vaccination should include the
administration of both passive antibody and vaccine,
except when the individual has previously received
preexposure prophylaxis
• Human rabies immune globulin (RIG) is preferred
because equine antiserum may cause serum sickness
• RIG is administered only once, at the beginning of the
postexposure prophylaxis regimen
• The recommended dose of RIG is 20 IU/kg
• The dose of equine antiserum is 40 units/kg.
• the full dose should be thoroughly infiltrated into the
area around the wound and into the wound itself
• Any remaining portion of the dose is injected
intramuscularly at a site distant from the vaccine.
3. ACTIVE IMMUNIZATION WITH ANTIRABIES VACCINE
• Three rabies vaccines are available in the United
States:
a. human diploid cell vaccine (HDCV), which can be given
either intramuscularly or intradermally
b. rabies vaccine absorbed (RVA)
c. purified chick embryo cell vaccine
• The latter two vaccines are administered intramuscularly
• Each vaccine is derived from a different strain of rabies virus and
prepared in a slightly different formulation
• The three vaccines are considered equally efficacious and safe, and
any of the three can be administered in conjunction with RIG
• Five 1-mL doses of HDCV are given intramuscularly, preferably in the
deltoid or anterolateral thigh area: the gluteal area should not be
utilized
• The five doses of HDCV should be administered within 28 days on
the following schedule:
 days 0, 3, 7, 14, and 28
• Combination of RIG and HDCV
» elicits high titers of neutralizing antibodies in
almost all recipients
» Only rarely has this regimen proved unsuccessful
in preventing the development of rabies
• Administration of vaccine alone
- appears to be associated with a higher failure rate than use
of the combination, especially in severe bite exposures
• Postexposure prophylaxis consisting of
intradermal injections of rabies vaccine
- because of cost, is being used increasingly in
the developing world
• Combination of RIG plus 0.1-mL intradermal
doses of HDCV
• given at:
– eight sites on day 0
– four sites on day 7
– one site on days 28 and 91
• produces good antibody responses
• has had excellent clinical results
• World Health Organization has approved
alternatively the ff:
1. regimen of two 0.1-mL doses at two
intradermal sites
- given at:
* days 0, 3, and 7
2. 0.1-mL intradermal injection at a single site
- Given at:
* days 21 and 90
PREEXPOSURE PROPHYLAXIS
 given at individuals at high risk of contact with
rabies virus, including:
» cave explorers
» veterinarians
» laboratory workers, and
» animal handlers
 Three 1-mL intramuscular or three 0.1-mL
intradermal injections of HDCV on days 0, 7, and
21 or 28
 Concomitant chloroquine administration
interferes with the antibody response to rabies
vaccine
Exposure Type of exposure Treatment
category
Contact with a rabid or suspected Contact with an inoculated animal carcass
rabid* wild or domestic animal
I -Touching/feeding animals, but clearly -Touching inoculated carcass; skin intact -No treatment necessary. In cases
no contact with their saliva; patient’s of uncertainty, immunization to be
skin undamaged prior to and during administered
contact
II -animal has nibbled or licked exposed -Touching inoculated carcass; skin damaged Immediate treatment as specified
skin of the patient in Schedule B. In cases of
-Contact with saliva uncertainty, simultaneous
Superficial, nonbleeding scratches administration of vaccine and
made by the animal, on the head, immunoglobulin (Active and
neck, shoulder region, arms and hands passive immunization) should be
(see exposure grade III) administered as specified in
schedule C.
If the animal proves to be healthy
after examination, it is advisable
to continue treatment as in
schedule A. Check patient’s
immunity against tetanus
III -All bites -Contact of inoculated carcass with mucous Initiate immediate simultaneous
-Bleeding scratches membrane or fresh skin wound administration of vaccine and
-All scratches on the head, neck, immunoglobulin (active and
shoulder region, arms, and hands passive immunization) as
-Contact of patient’s mucous specified in schedule C.
membrane with animal saliva (e.g., If the animal proves to be healthy
licking, spray) after examination, it is advisable
to continue treatment as in
schedule A. Check patient’s
immunity against tetanus
THANK YOU!!!