Multiple sclerosis. Animal model: Theiler's virus infection in mice

Theiler's encephalomyelitis viruses (TMEV) are naturally occurring murine picornaviruses that are a prevalent cause of asymptomatic enteric infection in young adult mice. A biphasic disease of the CNS occurs in mice following infection. The early phase of infection is characterized by virus growth, pathologic involvement of gray matter, and flaccid paralysis (early disease). Surviving mice develop persistent infection of the CNS with demyelination occurring at the same time as a striking gait disorder (late disease). Infectious virus at low levels is readily detectable in the CNS of most mice for as long as 1 yr. During the chronic stage the lesions are strictly demyelinating, with primary affection of the spinal cord. Large patchy areas of meningeal and white matter mononuclear cell infiltrates with demyelination are present by the 3rd wk, reach maximum severity by about 3 mth, and are still observed as late as 1 yr. Remyelination and gliosis are most conspicuous at later times. Ultrastructurally, stripping of myelin lamellae by invading mononuclear cell processes and vesicular disruption of myelin are the main findings. Normal oligodendrocytes are present in the vicinty of demyelinating lesions, but degenerating oligodendrocytes have not been observed. Virus particles have not been found, but this is not unexpected considering the relatively low virus titers and small size of picornavirus virions. Immunosuppression (cyclophosphamide, rabbit antiserum to mouse thymocytes) eliminates the mononuclear cell infiltrates in the spinal cord white matter and prevents the occurrence of demyelination. In multiple sclerosis, it has been suggested that demyelination may result from an immune-mediated response triggered by a virus infection of the CNS. TMEV infection in mice seems a close analog of multiple sclerosis, because demyelination is the sole structural change during the chronic phase of infection and neurologic disease in the mouse can be directly attributed to this lesion; some mice only develop late disease (the demyelinating stage of this infection) which occurs only after several months; and because myelin breakdown appears to be immune-mediated. It should be pointed out that the mice have severe meningitis and the demyelination is essentially limited to the spinal cord. Both DA and Yale strains of TMEV produce demyelinating disease in mice; other TO (Theiler's original) strains probably will produce similar disease. The Yale strain can be purchased commercially and the DA strain can be obtained from the author's laboratory. Inbred SJL/J mice appear to be the optimal host, and they can be purchased commercially (addresses are given).