Pathogenesis of multiple sclerosis. A critical reappraisal.

The pathogenesis of multiple sclerosis remains a dilemma despite many years of study. Evidence for an infective agent is lacking: much doubt remains regarding the pathogenetic significance, if any, of the many reported alterations of the immune system. On the other hand, the well-documented facts that multiple sclerosis plaques are invariably located around blood vessels and that alterations of the blood-brain barrier permeability are always present in the plaque suggest that these old observations should be reconsidered. There is strong evidence to support the idea that the alteration of the blood-brain barrier is an obligatory step in the development of the plaque. It may result from a variety of environmental factors among which must be mentioned trauma to the nervous system, as well as the immunological changes resulting from viral infections and vaccinations. The available data lead to the following hypothesis: multiple sclerosis is a disease which requires the following factors for the production of demyelinating lesions of the central nervous system: a genetically determined susceptibility, an environmental, probably viral, probably immune-mediated initiatory event producing a symptomless systemic illness, a subsequent alteration of the blood-brain barrier resulting from diverse mechanisms including trauma or a second, immune-mediated event, a myelinoclastic plaque-forming mechanism which is operative only in the central nervous system.