Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that affects approximately one million people worldwide and is the most common cause of nontraumatic disability in young adults (1). The cardinal features of the MS lesion, namely focal demyelination with relative axonal sparing, inflammation, and gliosis, were described and illustrated over 160 years ago by Carswell (1838), Cruveilher (1841), and Charcot (1868, 1880).

Although there is considerable heterogeneity in the clinical characteristics of MS, the disease is classified principally on the features of the clinical course at onset into "relapsing-remitting" or "primary progressive'' (no attacks) (2). Relapses (exacerbations) are considered to represent the clinical correlate of recurrent episodes of inflammation and demyelination in the CNS, often accompanied by axonal injury. Recurrent attacks are commonly superseded by a phase of progressive disability thought to reflect a combination of ongoing demyelination, gliosis, and axo-nal loss. Remission of symptoms is likely due to remyelination and resolution of inflammation. A combination of both inflammatory and noninflammatory factors contribute to short- and long-term disability. The clinical predictors of natural history, however, are far from perfect, and there are no surrogate markers that accurately predict clinical course or outcome. Pathological features that clearly distinguish relapsing-remitting from progressive courses or favorable from poor prognoses in individual patients are not well defined. Furthermore, the biologic basis for the variable treatment response, often observed among MS patients, is not well understood and may reflect genetic, clinical, and/or pathologic heterogeneity. The advent of more sophisticated histological and molecular techniques to study MS pathology has provided new insights into the development and evolution of both focal and global tissue injury in MS. This chapter focuses on what we can learn about MS via detailed pathological analysis. The clinical and pathogenic relevance of these pathological studies is discussed.

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