A. Organism

1. Rabdovirus Family
   1. Virions are bullet-shaped particles
   2. Virions contain ribonucleoprotein-nucleocapsid core surrounded by lipid bilayer envelope
   3. RNA genome
   4. Virus encodes five structural proteins
   5. Nucleoprotein, transcriptase and phosphoprotein associate with viral genomic RNA
   6. Matrix protein lines inner side of lipid-bilayer envelope
   7. The rabies glycoprotein projects from outer lipid envelope layer
   8. Neutralizing antibodies mainly against glycoprotein
2. Rabies Strains
   1. Five antigenically distinct strains of rabies in USA and Canada
   2. The N (nucleocapsid protein) shows greatest variation and defines the antigenic type
3. One of the most lethal of all organisms arising from animal bites
   1. Should be considered in all unprovoked attacks by animals
   2. Increased risk in wild animals
   3. Patient may not recall being bitten by an animal
   4. Most domestic animals are immunized

B. Transmission

1. Mainly through animal bite
2. Main animal reservoirs are carnivores and bats
   1. Rapid dogs biting humans were historically major
   2. <100 rapid dogs reported in USA in 2002
   3. Rabid cats now outnumber rabid dogs
   4. Raccoons, skunks, bats and foxes are most commonly reported currently
3. Rabies virions initially enter soft tissues
4. May replicate in skeletal muscle, or may directly enter peripheral neurons
5. Intra-axonal retrograde transport occurs at 8-20mm per day
   1. Retrograde transport to spinal cord
   2. Rapid transport from spinal cord up into brain
6. Initially affects dencephalon, hippocampus and brain stem
7. Bulbar muscles affected early on (pharyngeal and laryngeal spasms)

C. Presentation and Diagnosis

1. Must be considered in any patient with rapidly progressive encephalitis
2. Presentation
   1. Pain and paresthesias initially at bite site
   2. Paresthesias likely arise once virus reaches spinal cord
   3. "Hydrophobia" is not an actual symptom
   4. Pharyngeal and laryngeal (bulbar) spasms cause frothing (rather than fear of water)
   5. Motor problems progressing to paralysis
   6. Diffuse paresthesias
   7. Agitation and confusion
   8. Altered mental status, lethargy; may progress to delirium
   9. Autonomic instability - hypotension, hypersalivation, arrhythmias
   10. Death occurs in 2-7 days from initial presentation without intenstive life-support
3. Diagnosis
   1. Demonstration of virus specific material is required
   2. Polymerase chain reaction (PCR) detection of nucleic acid is most sensitive
   3. Skin biopsy specimen early in course of disease may be analyzed
   4. Serum and cerebrospinal fluid should be analyzed for antibodies to rabies
   5. Saliva may be positive for PCR detection
   6. Testing of animal responsible for bite should be carried out if possible
4. Differential Diagnosis
   1. Other forms of encephalitis (as above)
   2. Intoxications
   3. Guillain-Barre Syndrome

D. Treatment

1. When vaccination status of patient in doubt, immunize
2. Contact local health department and animal control agency
3. Rabies immune globulin must be administered in high doses to unvaccinated persons
4. Rabies immune globulin dose is 20IU/kg in unvaccinated persons on days 0, 3, 7, 14 and 28
5. Glucocorticoids and alpha-interferon have not been effective

E. Prophylaxis and Vaccination [3,4]

1. In USA, 15-40,000 persons receive prophylaxis annually
2. Vaccines and rabies immune globulin are used for prophylaxis
3. Post-Exposure Prophylaxis
   1. Wound care
   2. Infiltration of rabies immune globulin
   3. Vaccine administration
4. Wound Care
   1. Immediate and thorough washing of wounds with soap solution
   2. Use of tetanus toxid as appropriate
   3. Antibiotics for wounds are important
5. Human rabies Immune Globulin
   1. Important part of early post-exposure prophylaxis
   2. Administer immune globulin only once to persons who have not been vaccinated
   3. Dose is 20IU/kg: as much as possible is given into and around the wound
   4. Remainder of immune globulin is given intramuscularly in deltoid or quadracept
6. Vaccination [4]
   1. Human diploid cell vaccine should be avoided, as it has 6% incidence of serum sickness
   2. Vaccinating naive persons 1mL in deltoid on days 0, 3, 7, 14 and 28
   3. Pre-exposure rabies prophylaxis dosing for vaccine is 1mL on days 0, 7, 21 and 28
   4. For persons previously vaccinated, post-exposure vaccination is on days 0 and 3 only

References

1. Noah DL, Drenzek CL, Smith JS, et al. 1998. Ann Intern Med. 128(11):922
2. Basgoz N and Rrosch MP. 1998. NEJM. 339(2):105 (Case Record)
3. Rupprecht CE and Gibbons RV. 2004. NEJM. 351(25):2626
4. Rabies Vaccines. 1998. Med Let. 40(1029):64