Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS) with a complex pathology that varies with respect to the extent and character of inflammation, demyelination, gliosis, axonal injury, and remyelination. These factors, in turn, depend on the stage of demyelinating activity in the lesion and the clinical phase of the disease. In early disease phases, MS is characterized by acute exacerbations of neurologic dysfunction owing to a combination of inflammation, edema, and focal demyelination resulting in conduction block. Resolution of the inflammation coupled with early remyelination typically leads to recovery. However, after an initial relapsing course, most patients enter a progressive disease phase characterized by continuous neurologic decline. During these later disease phases, most of the irreversible damage does not depend on the formation of new inflammatory demyelinating lesions. Axonal degeneration, cortical pathology, and diffuse alterations in the normal-appearing white matter (NAWM) likely contribute to disease progression. Although MS pathogenesis is often referred to as a biphasic disease with an inflammatory phase early that leads to a subsequent neurodegenerative phase late, this may inadvertently deemphasize the potential for chronic ongoing inflammatory processes contributing to disease evolution and progression. This review discusses the pathologic hallmarks of MS in relation to early and late disease. A better appreciation of these pathologic differences provides greater insight into the underlying mechanisms of disease initiation, evolution, and progression. Attempts to understand the relative contributions and complex sequence of events related to inflammation, demyelination, gliosis, axonal degeneration, and remyelination in MS will hopefully lead to more effective therapeutic strategies to target these diverse processes.
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