first rabies vaccine of the 1880s was produced from desiccated infected rabbit spinal cord, and occasional cases of acute encephalomyelitis were seen following multiple injections of the vaccine. These were initially thought to result from inadequate attenuation or inactivation of the virus or the activation of some endogenous agent in the human brain. Because early attenuated or inactivated rabies vaccines were prepared in animal nervous system tissue, the question that the causal factor might be some factor within animal tissues was also raised (Hemachudha et al., 1987a,b). On rare occasions, a clinically and histologically similar encephalomyelitis also complicated injection of the vaccinia virus used for the prevention of smallpox, although this vaccine contained no animal neural tissue. ADEM also has been seen after natural infections with measles, varicella, mumps, rubella, and other viruses (Johnson et al., 1985).

Experimental Models

Thomas Rivers, the father of American virology, worked extensively with vaccinia virus and was intrigued by the similarity of the demyelinating complication of vaccination and the histopathologic changes seen after administration of rabies vaccines. With Schwenker, he carried out multiple inoculations of normal brain tissue into monkeys, and in 1935, they reported the induction of acute, experimental, allergic (autoimmune) encephalomyelitis (EAE) (Rivers and Schwenker, 1935). Subsequently, Kabat et al. (1947) found that EAE could consistently be induced by a single inoculation of brain tissue if it was mixed with adjuvant. Disease developed in 7 to 21 days in some species, and detailed studies of the pathogenesis of EAE were possible. Although multiple brain antigens have been implicated, myelin basic protein most readily induces the disease, and since EAE can be passively transferred with immune cells but not serum, cell-mediated immunity appears to be of primary pathogenetic importance. In drawing analogies to human diseases, it should be noted that different inbred strains of animals show different susceptibilities, and although myelin basic protein is similar between species, the encephalitogenic region of myelin basic protein differs between different species (Martin et al., 1992).

In Latin America, a rabies vaccine was prepared in unmyelinated neonatal mouse brains to avoid the use of central nervous system myelin. Multiple injections of these preparations into humans, however, were complicated in some cases by an acute polyneuritis similar to GBS (Held and Adaros, 1972). It was assumed that the induction of autoimmunity to a peripheral nerve antigen might be the mechanism. In 1955, Waksman and Adams reported that rabbits injected with peripheral nerve tissue in adjuvant developed an experimental allergic (autoimmune) neuritis (EAN) resembling GBS. The predominant protein related to EAN is a peripheral

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