The Neuropathology of Progressive Multiple Sclerosis

The neuropathological findings in progressive MS support the hypothesis that neuroaxonal loss is the major substrate of progressive disability. Neuroaxonal injury appears to be initiated within focal regions of inflammatory demyelination. However, it is possible that at a certain stage, other factors ensue, which result in neurodegeneration persisting in the absence of ongoing demyelination. Such factors might include compartmentalized low-grade inflammation, loss of trophic support provided by myelin, oligodendrocytes, and astrocytes, and an energy-deficient state induced by sodium channel redistribution and mitochondrial depletion. Axonal degeneration may be paralleled by a declining capacity for repair, failure to remyelinate, and ongoing gliosis. Ultimately, a shift in the balance between injury and repair is likely to result in the numbers of functioning axons falling below a required threshold, causing permanent disability.