Based on the topographical distribution of the macrophages and their immunoreac-tivity for minor and major myelin protein degradation products, several active MS plaque types can be distinguished (Fig. 2). The acute active plaque is characterized by the synchronous destruction of myelin, with all the macrophages containing early and late myelin degradation products distributed evenly throughout the lesion. The chronic active plaque consists of numerous macrophages clustered at the radially expanding plaque edge immunoreactive for both minor and major myelin degradation products, which diminish in number toward the inactive plaque center. The
Acute active and chronic active plaques most likely represent the pathologic substrate of acute neurological dysfunction due to a combination of inflammation, edema, conduction-blocking demyelination, and variable axonal damage. They are mainly found in early-phase MS patients or in secondary progressive (SPMS) patients with ongoing clinical relapses. With increased disease duration and progression, as in SPMS and primary progressive MS, inactive plaques predominate, and acute and chronic active plaques are uncommon. Occasionally, smoldering plaques appear, and these may contribute to disease progression in SPMS .
Destructive plaques are characterized by demyelination associated with a pronounced destruction of other tissue elements including axons, oligodendrocytes and astrocytes. These lesions are often necrotic and cystic, resulting in encephalomalacia associated with prominent gray and white matter atrophy . Destructive plaques are a hallmark of Marburg's acute MS, typically characterized by a rapidly progressive course leading to death within 1 year of onset . Destructive plaques are also frequently found in patients with neuromyelitis optica (NMO), an inflammatory, typically relapsing demyelinating disorder affecting the optic nerves and spinal cord .
Shadow plaques are sharply demarcated plaques in a typical MS distribution, with only a moderate reduction of axonal density and a uniform presence of nerve fibers with disproportionately thin myelin sheaths. Shadow plaques typically contain few macrophages and are associatedwith pronounced fibrillary gliosis. Immunocytochemical and ultrastructural data suggest shadow plaques represent complete remyelination of previously demyelinated plaques [53, 79] and are characterized by reduced staining of myelin (myelin pallor) due to a decreased ratio between myelin thickness and axonal diameter. However, reduced myelin density may also present within active plaques or in areas of secondary Wallerian degeneration. Areas of active demyelina-tion, however, are clearly defined by macrophages containing myelin degradation products, whereas areas of Wallerian degeneration have ill-defined borders and preserved nerve fibers in the lesions and show a broad range of thick to thin myelin sheaths. Shadow plaques may become targets of new demyelinating attacks .
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