Stages of Demyelinating Activity

Although criteria for the pathological staging of MS lesions are controversial, in order to draw conclusions regarding the earliest events in the development of the MS lesion, it is critical that a precise definition for demyelinating activity be used. Some investigators rely on markers of inflammation to stage lesions based on the extent of perivascular or parenchymal inflammatory cell infiltration (5), the increased expression of histocompatibility antigens (6), or adhesion molecules (7,8), and the activation state of lymphocytes and macrophages within lesions (9,10). However this definition does not distinguish demyelinating activity from inflammatory activity, which may be present even in the absence of ongoing active demyelination.

Active plaques have also been defined by the presence of cholesterol esters and neutral lipids in macrophages that stain positively for lipophilic dyes, such as oil red O or sudan II (sudanophilic stage of myelin degradation). The sudanophilic stage of myelin degradation, however, may persist for several months after the actual destruction of myelin sheaths (3), and therefore does not necessarily reflect the earliest events in lesion formation.

Magnetic resonance imaging (MRI) studies rely on evidence for blood-brain barrier leakage, defined by the presence of gadolinium; as an indicator of an active lesion (11,12). This may not reliably differentiate active from inactive MS plaques because both can be associated with variable degrees of blood-brain barrier leakage. MRI sensitivity may not be sufficient to detect potentially small quantitative differences in blood-brain barrier dysfunction that distinguish active from inactive plaques.

Gay et al. (13) developed a multifactorial cluster analysis method to stage lesion activity based on inflammation and microglial activation, immunoglobulin and complement deposition, demyelination, and parameters of the clinical history. Although this approach may help to identify stages of MS lesions that precede demyelination, reliable clinical details are not always available in a given case, and there often is a poor correlation between the clinical symptoms and the distribution of plaques because most conspicuous lesions occur in relatively silent areas of the brain.

A stringent definition of demyelinating activity within a plaque can be obtained by studying the structural profile and chemical composition of myelin degradation products within macrophages (10). Whenever myelin sheaths are destroyed, their remnants are taken up by macrophages or microglia cells. Minor myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG) or myelin associated glycoprotein (MAG), are rapidly degraded within macrophages, within one to two days after phagocytosis. In contrast, major myelin proteins (MMP), such as myelin basic protein (MBP) and proteolipid protein (PLP), may persist in macrophages for 6 to 10 days. In later stages, the macrophages contain sudanophilic and periodic acid schif (PAS)-positive ''granular lipids'' that may persist in the lesion up to several months.

Stages of demyelinating activity can be defined as early or late active, inactive, or early and late remyelinating. ''Early active lesions'' are characterized by MOG+, PLP+, and luxol fast blue+ (LFB+) degradation products within the macrophage, as well as the expression of the acute-stage inflammatory macrophage markers, MRP14 and 27E10 (Figure 3). ''Inactive lesions'' are characterized by hypocellularity, complete myelin loss, fibrillary gliosis, and variable reduction in axons. Inflammation may still be present with macrophages containing either empty vacuoles or PAS+ degradation products; ''Early remyelinating lesions'' contain small clusters of axons surrounded by thin myelin sheaths, and no myelin degradation products within

Figure 3 (See color insert.) Early active demyelination. The early active lesion is characterized by the presence of LFB+ blue granules (A, arrow) and early myelin degradation products (B, arrows, MOG) within macrophage cytoplasm. Macrophages also stain positively for acute stage inflammatory macrophage markers (C, arrows; MRP14). Abbreviations: LFB, luxol fast blue; MOG, myelin oligodendrocyte glycoprotein.

Figure 3 (See color insert.) Early active demyelination. The early active lesion is characterized by the presence of LFB+ blue granules (A, arrow) and early myelin degradation products (B, arrows, MOG) within macrophage cytoplasm. Macrophages also stain positively for acute stage inflammatory macrophage markers (C, arrows; MRP14). Abbreviations: LFB, luxol fast blue; MOG, myelin oligodendrocyte glycoprotein.

macrophages; variable inflammation and the presence of reactive astrocytes. Early remyelination may coexist with ongoing active demyelination. "Late remyelinating" (shadow plaques) represent focal areas of gliosis and reduced myelin density. In any MS brain, a variety of lesions at different stages of demyelinating activity may be present. When these stringent criteria are used, the incidence of active lesions in MS brains is low, especially in classical cases sampled during the chronic phase of the disease.

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