Multiple sclerosis: plaques caused by 2-step demyelination?

Selected studies concerning events at the contour of a progressive plaque are reviewed and an explanation of the subtle changes in periplaque white matter which various investigators have observed on autopsy or biopsy is presented. Recurrent exposure to toxic small molecular weight substances carried by arterial blood and capable of diffusing through the walls of blood vessels cause modification of protein or glycoprotein in the myelin sheath. These then act as allergens (modified native tissue considered as 'nonself' tissue by the immune system) which induce antibody formation (termed allo-auto-allergy). Phagocytosis of altered myelin, debris removal and cellular action to maintain homeostasis in the fluid surrounding neurons characterize the premorbid phase of multiple sclerosis. We suggest that the accumulation in the perivascular space of macrophages with large lysosomes digesting myelin debris (visible in electron micrographs) causes bottlenecks in the lymphatic channels serving the extracellular space near nodes of Ranvier. This changes the chemical microclimate and leads to the second step of demyelination and degeneration of the oligodendrocytes, i.e. plaque formation. Reference is made to outstanding problems. Research into the diffusion of small molecular weight substances into the extracellular spaces of white matter would aid in evaluating the hypothesis.