MS Pathology

When the cerebral hemispheres are sectioned, the demyelinating lesions become obvious. These may be numerous or scanty and rounded (as illustrated), oval, or irregular. Recently acquired lesions are soft and pink, whereas lesions of long standing tend to be numerous, firm, and to have a grayish gelatinous appearance indicative of substantial gliosis. These lesions also tend to be scattered asymmetrically through the gray and white matter. Smaller lesions are spheric or oval. Larger lesions form by coalescence of smaller ones and by bouts of relapse-driven expansion at their edges. Large lesions usually have an irregular shape and a sharp outline, provided disease is inactive.

A favored site for plaque location is under the floor of the fourth ventricle, as illustrated, but plaques may occur in any location and spread from their origins at the pial and ependymal surfaces over a larger or smaller area. In the spinal cord, lesions are once again based on the pial surface and extend inward as hemispheric or conical areas. Histologically, plaques are most easily demonstrated in sections stained for myelin, where they appear as demyelinated areas.

HISTOPATHOLOGY OF MULTIPLE SCLEROSIS

Microscopic analysis demonstrates that many archetypical plaques have no relation to specific nerve tracts. Often the plaques have a perivenular and paraventricular distribution. Severe loss of oligodendrocytes within MS plaques is associated with the concomitant nonspecific finding of hypertrophic astrocytes. Pathologists classify MS plaques in numerous ways. Perhaps the simplest is to judge MS plaques as acute, chronic active, or chronic silent.

Acute plaques are likely to be responsible for a new exacerbation. They present as regions of active demyelination with ill-defined boundaries, extensive inflammation throughout, perivascular cuffs, and macrophages engaged in myelin stripping and removal. In addition, there are diffuse MHC class II–positive macrophages/microglia that release (1) IL-1β, TNF-α, and lymphotoxin (LT) among other cytokines, (2) nitric oxide and other free radicals, (3) proteolytic enzymes such as matrix metalloproteinases (MMPs), and (4) express surface-bound co-stimulatory molecules. Acute plaques contain myelin debris.

Chronic active plaques demonstrate recent disease at their periphery, or parts of it, but chronic changes within its center. Ongoing demyelination is restricted to the plaque edge, extending into the adjacent parenchyma in a centrifugal fashion, and there is a border of MHC class II positivity.

Chronic silent plaques demonstrate a marked down-regulation of MHC class II reactivity throughout, an absence of further demyelinating activity, and a sharp border. Astrocytes now take on a fibrillary morphology and express the sinuous processes of chronic gliosis. There may be clusters of demyelinated axons within a chronic silent plaque, but in addition, there is clear evidence of axonal loss that is maximal centrally. OGCs are absent.

Myelin loss from a nerve fiber is distinct and best defined by toluidine blue stains. Macrophage accumulation is a frequent accompaniment. Signs of leptomeningeal inflammation, not unlike that found in acute disseminated encephalomyelitis, may be evident. There is also a very significant component of axonal and neuronal damage in multiple sclerosis.

This is particularly relevant to the long-term outcome and eventual disability. One can find evidence of axonal injury early in the disease process. This is found both in areas of obvious demyelination as well as in areas of white and gray matter that appear normal to gross inspection. It is proposed that an antigen-specific destructive component related to both T cells and autoantibodies as well as nonspecific effects of activated macrophages and microglia can lead to very significant axonal damage, the latter particularly evident in SPMS. Mitochondrial function may also be impaired, perhaps by nitric oxide released by activated microglia, and further contribute to axonal loss.

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