RABIES : CLINICAL ASPECTS
Rabies in humans usually results from a bite by a rabid animal or contamination of a wound by its saliva. It presents as an acute, fulminant, fatal encephalitis; human survivors have been reported only occasionally. After an average incubation period of 20 to 90 days the disease begins as a nonspecific illness marked by fever, headache, malaise, nausea, and vomiting. Abnormal sensations at or around the site of viral inoculation occur fre-quently and probably reflect local nerve involvement. The onset of encephalitis is marked by periods of excess motor activity and agitation. Hallucinations, combativeness, muscle spasms, signs of meningeal irritation, seizures, and focal paralysis occur. Periods of men-tal dysfunction are interspersed with completely lucid periods; however, as the disease progresses, the patient lapses into coma. Autonomic nervous system involvement often results in increased salivation. Brainstem and cranial nerve dysfunction is characteristic, with double vision, facial palsies, and difficulty in swallowing. The combination of ex-cess salivation and difficulty in swallowing produces the fearful picture of “foaming at the mouth.” Hydrophobia, the painful, violent involuntary contractions of the diaphragm and accessory respiratory, pharyngeal, and laryngeal muscles initiated by swallowing liquids, is seen in about 50% of cases. Involvement of the respiratory center produces res-piratory paralysis, the major cause of death. Occasionally rabies may appear as an as-cending paralysis resembling Guillain – Barré syndrome. The median survival after onset of symptoms is 4 days, with a maximum of 20 days unless artificial supportive measures are instituted. Recovery is rare and has only been seen in partially immunized individuals.
The CSF of a rabies patient shows minimal to no abnormalities with some patients exhibit-ing a lymphocytic pleocytosis (5 to 30 cells/mm3). The test of choice in a live patient is de-tection of rabies antigen by immunofluorescent stain of a nape of the neck biopsy. PCR of CSF or saliva may supplant the neck biopsy. Laboratory diagnosis of rabies in animals or deceased patients is accomplished by demonstration of virus in brain tissue. Viral antigen can be demonstrated rapidly by immunofluorescence procedures. Intracerebral inoculation of infected brain tissue or secretions into suckling mice results in death in 3 to 10 days. Histologic examination of their brain tissue shows Negri bodies in 80% of cases; electron microscopy may demonstrate both Negri bodies and rhabdovirus particles. Specific anti-bodies to rabies virus can be detected in serum but generally only late in the disease.
Prevention is the mainstay of controlling human rabies. Intensive supportive care has re-sulted in two or three long-term survivals; despite the best modern medical care, however, the mortality still exceeds 90%. In addition, because of the infrequency of the disease, many cases die without definitive diagnosis. Human hyperimmune antirabies globulin, in- terferon, and vaccine do not alter the disease once symptoms have developed.
In the late 1800s Pasteur, noting the long incubation period of rabies, suggested that a vaccine to induce an immune response before the development of disease might be useful in prevention. He apparently successfully vaccinated Joseph Meister, a boy severely bit-ten and exposed to rabies, with multiple injections of a crude vaccine made from dried spinal cord of rabies-infected rabbits. This treatment emerged as one of the best known and most noteworthy accomplishments in the annals of medicine. It is now believed that vaccination induces antibody that is either neutralizing or inhibits cell to cell spread of virus. Natural infection does not lead to an early immune response and limitation of viral migration, because the virus is replicating in muscle or neural tissue and lymphocytes do not access these sites. Cytotoxic T lymphocytes are also induced by vaccine and appear to be directed against an antigen of the virus.
Currently, the prevention of rabies is divided into preexposure and postexposure pro-phylaxis. Preexposure prophylaxis is recommended for individuals at high risk of contact with rabies virus, such as veterinarians, spelunkers, laboratory workers, and animal han-dlers. The vaccine currently used in the United States for preexposure prophylaxis em-ploys an attenuated rabies virus grown in human diploid cell culture and inactivated with -propiolactone. Preexposure prophylaxis consists of two subcutaneous injections of vac-cine given 1 month apart, followed by a booster dose several months later.
Postexposure prophylaxis requires careful evaluation and judgment. Every year more than one million Americans are bitten by animals, and in each instance a decision must be made whether to initiate postexposure rabies prophylaxis. The physician must consider (1) whether the individual came into physical contact with saliva or another substance likely to contain rabies virus; (2) whether there was significant wounding or abrasion; (3) whether rabies is known or suspected in the animal species and area associated with the exposure; (4) whether the bite was provoked or unprovoked (i.e., the circumstances sur-rounding the exposure); and (5) whether the animal is available for laboratory examina-tion. Any wild animal or ill, unvaccinated, or stray domestic animal involved in a possible rabies exposure, such as an unprovoked bite, should be captured and killed. The head should be sent immediately to an appropriate laboratory, usually at the state health depart-ment, for search for rabies antigen by immunofluorescence. If examination of the brain by this technique is negative for rabies virus, it can be assumed that the saliva contains no virus and that the exposed person requires no treatment. If the test is positive, the patient should be given postexposure prophylaxis. It should be noted that rodents and rabbits are not important vectors of rabies virus.
Postexposure prophylaxis is based on immediate, thorough washing of the wound with soap and water; passive immunization with hyperimmune globulin, of which at least half the dose should be instilled around the wound site; and active immunization with antirabies vaccine. With human diploid vaccine, five doses given on days 1, 3, 7, 14, and 28 are recommended. Physicians should always seek the advice of the local health depart-ment when the question of rabies prophylaxis arises.
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