RABIES

RABIES

Dr Sujith Chadala ,Resident in Internal Medicine ,Osmania General Hospital.

EpidemiologyAcute rapid progressive & highly fatal viral disease of CNS caused by Lyssavirus type 1.Zoonotic disease of warm blooded animals (dogs, cats , bats, racoons, skunks, foxes )Transmitted to man by bite of rabid animal.Non-bite exposures : aerosols; generated in labs , caves with bats , corneal transplantation.Human to human transmission extremely rare. Worldwide endemic canine rabies : 55,000 deaths annually ( India alone 20,000 )Louis Pasteur and Emile Roux first developed rabies vaccine in 1885.

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Causative agentRabies virus belongs to family Rhabdoviridae , genus Lyssavirus & serotype 1.Bullet shaped neurotropic single stranded RNA non-segmented antisense genome consists of 11,932 nucleotides and encodes 5 proteins.Six other non-rabies virus species in Lyssavirus genus have been reported to cause a clinical picture similar to rabies.

PathogenesisIncubation period : 20-90 days.STAGES:Virus inoculated by bite.Replication in muscles: virus binds to nicotinic acetylcholine receptors on post synaptic membranes at NMJ.Retrograde axonal transport :Spreads centripetally along peripheral nerves towards CNS( ~ 250 mm/day) through local dorsal root ganglion, spinal cord. CNS dissemination Centrifugal spread along sensory & autonomic nerves

Most characteristic pathologic finding Negri bodyEosinophilic cytoplasmic inclusion in neurons composed of rabies virus proteins & viral RNA.Not observed in all cases of rabies.Commonly seen in hippocampus & cerebellum.

Basis for behavioural changes including aggressive behaviour is not well understood.Lack of prominent degenerative neuronal changes has led to concept that neuronal dysfunction (rather than neuronal death) responsible for clinical disease in rabies.

Negri bodies in cytoplasm of a cerebellar purkinje cell

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Clinical ManifestationsProdromal features :-FeverMalaiseHeadacheVomitingAnxietyAgitationPain / paresthesias at the site of exposure ( in 50-80% cases ).

Encephalitic RabiesEncephalitic ( 80%) :-FeverConfusionHallucinationCombativenessSeizuresAutonomic dysfunction (Hypersalivation , gooseflesh , cardiac arrythmias , priapism)HydrophobiaAerophobiaLate complications ( cardiac failure , respiratory failure , multi organ failure )

Hydrophobia :-Involuntary painful contractions of diaphragm , accessory respiratory , laryngeal muscles in response to swallowing fluids.Dysfunction of infected brainstem neurons that normally inhibit inspiratory neurons near Nucleus Ambiguus resulting in exaggerated defense reflexes that protect respiratory tract.Pathognomic of rabies and absent in animals.Aerophobia :-Same features caused by stimulation from a draft of air.

Presents as atypical encephalitis with relative preservation of consciousness.Episodes of hyper excitability followed by complete lucidity ( as disease progress interval between them shortens )Progress rapidly and coma followed within a day by death is rule unless course prolonged by supportive measures.Difficult to recognise late in clinical course when progression to coma has occured.

B. Paralytic Rabies (20%) :-Muscle weakness predominates.Early & prominent flaccid muscle weakness often in bitten extremity & spreading to produce quadriparesis & facial weakness.Sphincter involvement common.Sensory involvement mildLacks cardinal features ( hyperexcitability , hydrophobia , aerophobia )

Investigations CSF analysis :-Mild mononuclear cell pleocytosis with mildly elevated proteinSevere pleocytosis >1000 WBC/mcl unusual & search alternate diagnosis.Rabies virus specific antibodies in CSF suggest rabies encephalitis regardless of immunisation status.

RT PCR amplification :-Highly sensitive & specific in rabies virus detection in fresh saliva , skin , CSF & brain tissues. Direct Fluorescent Antibody testing :-Highly sensitive & specific in testing rabies virus antibodies conjugated to fluorescent dyes.Quickly performed & applied to skin biopsies and brain.

Skin biopsy :- Obtained from nape of neck.Demonstration of virus in cutaneous nerves at base of hair follicles.Corneal impressive smears low diagnostic yield.MRI brain variable & non-specific.EEG non-specific abnormalities.

Differential DiagnoisGuillian Barre Syndrome :- Paralytic rabies mimic GBSFever , bladder dysfunction , CSF pleocytosis favour rabies.

Rabies Hysteria :- Characterised by shorter incubation period , inability to communicate , aggressive behaviour , long course with recovery.

Allergic Encephalomyelitis :-History of rabies vaccine.

Tetanus :-Presence of hydrophobia , aerophobia favours rabies.

Poliomyelitis :-Acute onset of flaccid paralysis in one or more limbs with decreased / absent tendon reflexes & without sensory or cognitive loss.

TreatmentNo established treatment.Isolation in quiet room ( as bright light , noise , cold draughts precipitates spasms / convulsions )Sedatives to relieve anxiety.Hydration.Intensive respiratory & cardiac support

PreventionHealth personnel should wear face masks , gloves , goggles , & aprons (saliva , vomits , tears , urine or other body fluids of rabies patient contain virus )Persons having bruises , cut or open wounds not entrusted to look after patient.Pre-exposure prophylaxis.Post exposure prophylaxis.

Post Exposure ProphylaxisLocal wound care ( all bite wounds/scratches washed with soap and water ) reduces chances up to 80%.Devitalised tissues debrided.Tetanus prophylaxis given.Suturing delayed( if necessary done after 24-48 hours later )Antibiotic treatment whenever indicated.Active immunisation by Rabies vaccine.Passive immunisation by Human Rabies Immuno Globulins (HRIG )

Recommended Post Exposure Prophylaxis :- Administration of single dose of anti-rabies serum with course of vaccine together with local treatment of wound is best specific prophylactic treatment after exposure of man to rabies.

Stop treatment if dog remains healthy or proven to be negative for rabies by reliable lab using diagnostic techniques.

Indication of AntiRabies TreatmentIf animal shows signs of rabies / dies within 10 days of observation.If biting animal cannot be traced / identified.Unprovoked bite.All bites by wild animals.Lab tests ( Flourescent Rabies antibody test , Test for Negri bodies in brain of biting animal ) positive for rabies.

Types of Rabies Vaccine Nervous Tissue Vaccine Suckling Mouse Brain Vaccine Duck Embryo Vaccine Purified Duck Embryo VaccineHuman Diploid Cell Vaccine 2nd Gen. Tissue culture Vaccine a. Purified Chick Embryo Cell Vaccine b. Purified Vero Cell VaccineIn Govt. Of India stopped producing Neural Tissue Vaccine since 2004.Purified Duck Embryo Vaccine & Purified Chick Embryo Vaccine available in India.

Cell Culture Vaccine

Intra Muscular Regimen ( 0-3-7-14-28)Standard WHO Intra Muscular Regimen ( Essen Schedule ) :- i) 1ml doses given IM deltoid ( children antero-lateral aspect of thigh ) ii) Five doses of vaccine should be given on day 0 , 3 , 7 , 14 , 28.

Intra Dermal Schedule (0-3-7-28-90)Two site Intra Dermal Vaccination has been used in India , endorsed by WHO Expert Committee on rabies.0.2ml doses given at each two sites on day 0 , 3 , 7 & one site on days 28 , 90.Intradermal dose is 1/5 th of intramuscular dose.

Rabies VaccineIn previously unvaccinated , five IM doses day 0 , 3 , 7 , 14 , 28.In previously immunised , two booster doses day 0 , 3 given.In pregnancy , not a contraindication for immunisation.Glucocorticoids / Immunosuppressant , should not be administered during PEP unless essential.

Local reactions :- pain , erythema , edema , pruritus , mild systemic reactions (fever , myalgias , headache , nausea )Anti-inflammatory & anti-pyretics may be used.Immunisation should not be discontinued.Systemic allergic reactions uncommon but anaphylaxis rarely occur ( treated with epinephrine and antihistamines )Risk of rabies development should be completely considered before decision is made to discontinue vaccine because of adverse reaction.

HRIGHuman RIG is purified from serum of hyperimmunised human donors.Single administration at site of bite (virus present at bite site during most of the incubation period)Given in < 7 days after 1st vaccine dose.(After day 7 , endogenous antibodies produced & passive immunisation may be counterproductive)Human RIG much tolerated than Equine derived.Doesnt require prior sensitivity testing.Local pain & low grade fever may occur.Severe adverse effects are uncommon.

i) Previously unvaccinated :-HRIG 20 I/U (40 I/U purified Equine RIG after test dose if human RIG not available ) should be infiltrated at site of bite.Remaining given IM ( at distant site from bite )If mucous membrane involved entire dose should be given IM.If multiple & large wounds RIG should diluted to obtain sufficient volume for adequate infiltration.ii) Previously immunised :-RIG should not be given.

Pre Exposure ProphylaxisFor people with occupational / recreational risk of rabies including travellers to rabies endemic areas have primary schedule consists of three doses 0 , 7 , 21/28 day.After one month if virus neutralising titre