Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. The clinical disease course is variable, usually starts with reversible episodes of neurological disability in the third or fourth decade of life, and transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. We review data that support neurodegeneration as the major cause of irreversible neurological disability in MS patients. We question whether inflammatory demyelination is primary or secondary in the disease process and discuss the challenges of elucidating the cause of MS and developing therapies that will delay or prevent the irreversible and progressive neurological decline that most MS patients endure.

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