Reflections on the pathogenesis of optic (retrobulbar) neuritis in multiple sclerosis.

The conditions which lead to a plaque of demyelination in the retrobulbar optic nerve are discussed. Growth of the plaque occurs along venules as small fingerlike sleeves which develop outwards from the contour of the plaque. This occurs slowly and at intervals; the very gradually expanding lesion remain for a long time clinically silent. It is here postulated that the change to clinical disease is induced if cells digesting myelin debris settle in a more distal part of the perivascular space of a vein, than during the subclinical phase. In sufficient numbers these cells will impede the movement of molecules from extra-cellular fluid surrounding nodes of Ranvier into cerebrospinal fluid. A restriction in this vital drainage pathway results in oedema causing disturbed signal transmission in neurons passing through the veins drainage territory. Depending on intensity this can induce the characteristics symptom of blurred vision. These concepts have been used to speculate on sequential changes in neurons and to relate them to various phases of the disease. This seems to be justified as the pattern evolved corresponds well with the clinical symptomatology.

Chronic methanol poisoning with the clinical and pathologic-anatomical features of multiple sclerosis.

The details of two cases of chronic methanol poisoning are presented. Both patients initially developed clinical symptoms of multiple sclerosis: visual disturbances, intention tremor, reduced abdominal reflexes, impaired coordination and difficulties with walking. After the exposure to methanol had ceased the multiple sclerosis symptoms persisted in patient 1 but disappeared gradually in patient 2 (patient 2 had a history of excessive alcohol consumption, which is a critical fact in this discussion). Ultimately autopsies confirmed this picture: histological examination of patient 1 revealed plaques in the spinal cord, in the stem and in the proximity of the lower horn of one lateral ventricle, whereas no localized demyelination could be found in patient 2. The results are discussed in connection with the theory ("Methanol Hypothesis") that under certain circumstances multiple sclerosis itself is induced by formaldehyde stemming from the metabolism of methanol.

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.