Rabies - Summary (Park's Style)

Compiled from Tintinalli's Emergency Medicine, Jawetz Medical Microbiology 28e, Bradley & Daroff's Neurology, and Goldman-Cecil Medicine

1. Definition

Rabies is an acute, almost universally fatal viral encephalitis caused by the rabies virus (genus Lyssavirus, family Rhabdoviridae). It is primarily a zoonotic disease transmitted to humans through the saliva of infected animals.

2. Virus Characteristics

Morphology: Bullet-shaped rhabdovirus, 75 x 180 nm, enveloped with glycoprotein spikes (peplomers)
Genome: Single-stranded, negative-sense RNA (~12 kb)
Contains an RNA-dependent RNA polymerase
Receptor: Glycoprotein binds to the nicotinic acetylcholine receptor on host cells
Proteins: Five virion proteins - nucleocapsid (N), polymerase (L, P), matrix (M), glycoprotein (G)
Stability: Survives at 4°C for weeks, -70°C for years; inactivated by UV radiation, heat (50°C/1 hr), lipid solvents, detergents, extremes of pH

3. Epidemiology

Parameter	Details
Global burden	~60,000 deaths/year; >3 billion people at risk in >100 countries
Highest burden	India accounts for ~1/3 of global cases
WHO estimate	>15 million postexposure regimens administered annually
USA	>5,500 rabid animals reported per year; 40,000-50,000 persons receive postexposure prophylaxis/year; rabies prevention costs >$300 million/year

Major Vectors by Region:

Vector	Region
Dogs	Asia, Latin America, Africa (>99% of global human deaths)
Foxes	Europe, Arctic, North America
Skunks	Midwest USA, Western Canada
Bats	North America, Latin America, Europe (most common in USA)
Mongoose	Asia, Africa, Caribbean
Rabies-free	Hawaii, UK, Australasia, Antarctica

Host susceptibility: All warm-blooded animals. Very high susceptibility in foxes, coyotes, wolves; low in opossums.

4. Transmission

Primary route: Bite of a rabid animal (contaminated saliva inoculated into wound)
Other routes (less common):
- Mucous membrane contamination (eyes, nose, mouth)
- Aerosol (bat-inhabited caves, laboratory accidents)
- Organ/tissue transplantation (cornea, kidney, liver, vascular graft)
Bat bites may go unnoticed - US cases without known exposure are most often attributed to bats

5. Pathophysiology

Virus deposited in muscle/subcutaneous tissue at bite site
Remains near inoculation site during most of the long incubation period
Binds to nicotinic acetylcholine receptor at neuromuscular junction
Spreads via retrograde axoplasmic transport through peripheral nerves → dorsal root ganglia → spinal cord → CNS (gray matter)
Following CNS replication, spreads centrifugally to virtually all organs (salivary glands, cornea, skin)

Histopathology:

Encephalitis with lymphocyte, PMN, and plasma cell infiltration
Focal hemorrhage and demyelination in gray matter, basal ganglia, spinal cord
Negri bodies - eosinophilic intraneuronal inclusion bodies, pathognomonic for rabies; found in ~75% of animal rabies; maximally in hippocampus and cerebellum; 2-10 µm, basophilic granules in eosinophilic matrix

6. Clinical Features

Incubation Period: 1 week to several years; typically 20-90 days (1-3 months); longer for bites on lower extremities, shorter for head/face bites

Three Phases:

Phase 1 - Prodromal (2-10 days)

Fever, headache, malaise
Pain, paresthesias, itching at bite site (highly characteristic)

Phase 2 - Acute Neurological Phase

Furious (Encephalitic) Rabies (~70%):

Hydrophobia (fear of water) - pharyngeal muscle spasms triggered by swallowing attempts
Aerophobia (fear of drafts/air)
Spasms lasting 1-5 minutes triggered by tactile, auditory, visual, olfactory stimuli
Agitation, hallucinations, autonomic hyperactivity, seizures
High fever (105-107°F)
Abnormal cranial nerve and motor/sensory examination

Paralytic ("Dumb") Rabies (~30%):

Ascending flaccid paralysis
Slower disease course (some survive up to 30 days)
More common with bat-acquired rabies

Phase 3 - Coma and Death

Cardiorespiratory arrest (major cause of death)
Survival is extremely rare

Key Point: Rabies should be considered in any encephalitis/myelitis of unknown cause, especially with travel history or no known exposure.

7. Diagnosis

No tests available before symptom onset in humans.

Method	Details
Direct Fluorescent Antibody (DFA)	Gold standard; identifies rabies antigen in brain tissue; also used on skin biopsy (nape of neck at hairline)
Negri bodies	Pathognomonic on histology; present in brain/spinal cord; rarely found in bats
RT-PCR	Detects viral genome from saliva, CSF, brain tissue; allows strain identification
Serology	Antibodies develop slowly during illness; antibodies in CSF are diagnostic (not seen with vaccination alone)
Viral isolation	Intracerebral inoculation of suckling mice
MRI	T2/FLAIR hyperintensity in gray matter - basal ganglia, thalamus, midbrain, pontine nuclei
CSF	Mononuclear pleocytosis in >50% during first week, >87% after first week

8. Treatment

No proven effective treatment once symptoms develop
Supportive intensive care (sedation, analgesia, anticonvulsants, respiratory support)
Milwaukee Protocol (intensive care with therapeutic coma) - used in rare survivors but not widely validated
Prevention is the most effective intervention

9. Pre-Exposure Prophylaxis (PrEP)

Recommended for high-risk groups:

Risk Category	Population	Booster
Continuous	Rabies lab workers, biologics producers	Serology every 6 months; booster if titer low
Frequent	Rabies diagnostics staff, cavers, veterinarians	Serology every 2 years
Infrequent	Travelers to endemic areas, wildlife officers	No routine booster unless exposure
Rare	General public in rabies-endemic areas	Not recommended

Note: Pre-exposure vaccination does NOT eliminate the need for post-exposure prophylaxis (PEP), but simplifies it by eliminating HRIG and reducing vaccine doses.

10. Post-Exposure Prophylaxis (PEP)

Step 1 - Wound Care:

Immediate and thorough washing with soap and water (most important single step)
Flush with water for 15+ minutes
Apply virucidal agent (povidone-iodine, alcohol)
Do NOT suture wound primarily if possible

Step 2 - Risk Assessment:

Type of exposure (bite > scratch > mucous membrane contact)
Species and vaccination status of animal
Geographic epidemiology
Ability to observe or test the animal

Step 3 - Immunoprophylaxis:

Scenario	Regimen
Not previously vaccinated	HRIG (20 IU/kg, as much as possible into wound) + Rabies vaccine on days 0, 3, 7, 14
Previously vaccinated	Rabies vaccine only on days 0 and 3 (NO HRIG needed)

HRIG (Human Rabies Immunoglobulin): passive immunization; provides immediate protection
HRIG and vaccine should not be administered at the same anatomical site
PEP is essentially 100% effective when administered promptly and correctly

11. Control and Prevention

Animal vaccination - mass dog vaccination programs (most impactful globally)
Oral baiting of wildlife in endemic areas
Surveillance of animal rabies
Education on avoiding animal bites, reporting exposures
PrEP for high-risk occupational groups
Quarantine/observation of biting animals for 10 days (domestic dogs/cats)

12. Key Points for Exams

Rabies is caused by Lyssavirus (Rhabdoviridae), negative-sense ssRNA
Worldwide, dogs cause >99% of human deaths; in USA, bats are the leading cause
Incubation: typically 20-90 days (range: 1 week - years)
Hydrophobia and aerophobia are hallmark features
Negri bodies = pathognomonic intraneuronal inclusions
DFA of brain tissue = gold standard diagnosis
Wound washing with soap & water is the single most important immediate step
HRIG is given only to non-previously vaccinated individuals
Rabies is almost universally fatal once symptomatic; prevention is the only effective strategy
Areas free of rabies: Hawaii, UK, Australasia, Antarctica

Sources: Tintinalli's Emergency Medicine (Ch. 158), Jawetz Medical Microbiology 28e (Ch. 42), Bradley & Daroff's Neurology in Clinical Practice (Ch. 78), Goldman-Cecil Medicine

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