PURPOSE OF REVIEW: Knowledge of the early pathological changes observed in multiple sclerosis (MS) has advanced by implementation of many improved pathological, biochemical and imaging techniques. This review highlights the accumulating evidence for early pathological changes we term 'preactive lesions', characterized by clusters of activated microglia in otherwise normal-appearing white matter. RECENT FINDINGS: Compelling evidence is accumulating for pathological changes in normal-appearing white matter of MS patients, which occur before the actual development of the active demyelinating lesion. Focal disorder has been documented in normal-appearing white matter of MS months to years before the appearance of gadolinium-enhancing lesions. In these foci, clusters of activated microglia are found in the absence of demyelination and clear leukocyte infiltration, distinguishing them from the traditional demyelinating active and chronic active lesions. Although the events that give rise to preactive lesions are still to be identified, oligodendrocyte abnormalities appear to be crucially involved. Importantly, preactive lesions do not always develop into demyelinating lesions but often appear to resolve without subsequent disorder. SUMMARY: Preactive lesions in MS represent early stages in the formation of destructive MS lesions. As many of them spontaneously resolve, they are expected to hold important clues to stop the inflammatory process in MS.
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