Pathogenesis and Etiology

In considering how the geographic, epidemiological, genetic, and pathological data might fit together, it must be stressed that there is no wholly satisfactory framework within which to incorporate all the data.


Much evidence has accumulated suggesting an immunologic basis for the disorder in patients with multiple sclerosis. There is abnormal synthesis of antibodies, both inside and outside the brain; there are changes in the number and functional activity of peripheral blood lymphocyte subsets in active disease; and there are immune-competent cells around the venules in the lesions and in the brain itself. The occurrence of such changes in the retina (where there is no myelin) is evidence that the vascular events are not secondary to myelin breakdown produced in some other way. This, combined with the results of recent functional vascular studies and other evidence, suggests that a vascular change is a critical early event in development of the new lesion.


These processes provide a plausible though incomplete explanation for the development of the lesions in established multiple sclerosis. What of its initiation? There is good evidence from family studies and epidemiology that an environmental trigger, probably infective, is required in the genetically susceptible individual. The most likely infective agent would be a virus, though interest in spirochetes has been revived recently on rather slender grounds.

Two possible mechanisms for demyelination following viral infection are now known that occur only in genetically susceptible hosts. With visna, a retrovirus infection of certain strains of sheep, there are recurring episodes of demyelination of the central nervous system dependent on a direct attack of the virus; the remissions are due to the formation of neutralizing antibodies, whereas the exacerbations are due to mutations that lead to the loss of antibody control and renewed multiplication of the virus

(Johnson 1982). There are, however, a number of important clinical and pathological differences between visna and multiple sclerosis, including the consistent failure to isolate, reproducibly from the latter, a virus or fragments of one.

The second plausible mechanism involves the development of an autoimmune form of demyelination (after complete elimination of the virus) in mice inoculated intracerebrally with corona virus (Watanabe, Wege, and Ter Meulen 1983). The limitations of this model are that it is not known whether the process occurs after a natural route of infection, and whether in appropriate strains of animals a spontaneously relapsing and remitting disease can develop.

In conclusion, a solution to the problem of the nature and cause of multiple sclerosis would seem to be within sight. When we understand the reasons for the peculiar distribution of the disease, we are also likely to understand its etiology and pathogenesis.

W. I. McDonald

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