Structural Features of Cortical Lesions in MS

The structural features of cortical lesions differ in several aspects from those of white matter plaques. Although, as in white matter plaques (Trebst et al., 2001), microglia activation is always associated with active demyelination in the cortex, the density of perivascular and diffuse inflammation by T-lymphocytes and B-cells is very low (Bo et al., 2003). Thus classical perivascular inflammatory infiltrates are rare, and the diffuse infiltration of T- and B-cells is sparse and not significantly different from that in the adjacent normal cortex. This difference in the degree of inflammation between gray and white matter lesions can be directly seen in active leukocortical plaques, where the cortico-subcortical border sharply demarcates the profound inflammation in the white matter compared to the minimal inflammation in the gray matter (Fig. 5). This is also reflected in the sparse or absent blood-brain barrier leakage in cortical plaques (Fig. 5). Furthermore, microglia cells in the cortex generally main-

Figure 4 Distribution of demyelinating lesions in the brain of a patient with secondary progressive multiple sclerosis. Large lesions are present in the white matter, in particular in periventricular location (green lesions); in addition there is massive demyelination in the cerebral cortex (orange lesions); most of the cortical lesions are bandlike areas of demyelination, which affect the outermost layers of the cortex; furthermore, lesions can also be found in the deep gray matter, such as for instance the basal ganglia (blue lesions).

Figure 4 Distribution of demyelinating lesions in the brain of a patient with secondary progressive multiple sclerosis. Large lesions are present in the white matter, in particular in periventricular location (green lesions); in addition there is massive demyelination in the cerebral cortex (orange lesions); most of the cortical lesions are bandlike areas of demyelination, which affect the outermost layers of the cortex; furthermore, lesions can also be found in the deep gray matter, such as for instance the basal ganglia (blue lesions).

tain the ramified phenotype (Bo et al., 2003), while in white matter plaques, they are rapidly transformed into a macrophage phenotype (Trebst et al., 2001). The low intensity of the inflammatory reaction within active cortical plaques may explain why they are not detected as enhancing lesions in MRI.

A second feature that distinguishes cortical plaques from those in the white matter is the degree of selectivity of the pathological process. As mentioned previously, demyelination in the white matter is associated with quite extensive axonal loss. This results in a massive increase in the volume of the extracellular space, which renders the plaques easily detectable in conventional MRI sequences. Demyelination in the cortex is also associated with some acute axonal injury and some neuronal degeneration or alterations of dendrites (Peterson et al., 2001). Overall, however, this neuronal and axonal degeneration is minor compared to that occurring in the white matter, and the loss of cells does not lead to a major expansion of the cortical extracellular space (Fig. 5). Considering further the

Figure 5 Demyelinated plaques in the cerebral cortex in a patient with secondary progressive multiple sclerosis. (A) Staining for myelin shows widespread demyelination, affecting all cortical areas and extending into the subcortical white matter; the meninges in the center of the lesion show massive inflammation (x2) (B) Immunocytochemistry for HLA-D (activated microglia and macrophages) shows massive expression in the white matter areas of the plaques, but very little in the gray matter areas (x 2). (C) A similar distribution is also found by immunocytochemistry for immunoglobulins, which shows massive blood-brain barrier leakage in the white matter areas, but very little in the cortical areas (x 2). (D) Inactive demyelinated plaque affecting the white as well as the gray matter (cortex); immunocytochemistry for HLA-D shows profound residual macrophage infiltration in the white matter areas (WM), but very little in the gray matter (CORTEX) (x 80). (E) Actively demyelinating lesion in the cortex and subcortical white matter; in the white matter most HLA-D-positive cells show a macrophage phenotype, while in the cortex, most HLA-D-positive cells are activated microglia cells (x 80). (F, G) Actively demyelinating lesions in the cortex express inducible nitric oxide synthase (i-NOS) in activated microglia cells (x 300). (H) Demyelinated cortical lesions show profound expression of glia fibrillary acidic protein (GFAP) in reactive astrocytes (x 300).

Figure 5 Demyelinated plaques in the cerebral cortex in a patient with secondary progressive multiple sclerosis. (A) Staining for myelin shows widespread demyelination, affecting all cortical areas and extending into the subcortical white matter; the meninges in the center of the lesion show massive inflammation (x2) (B) Immunocytochemistry for HLA-D (activated microglia and macrophages) shows massive expression in the white matter areas of the plaques, but very little in the gray matter areas (x 2). (C) A similar distribution is also found by immunocytochemistry for immunoglobulins, which shows massive blood-brain barrier leakage in the white matter areas, but very little in the cortical areas (x 2). (D) Inactive demyelinated plaque affecting the white as well as the gray matter (cortex); immunocytochemistry for HLA-D shows profound residual macrophage infiltration in the white matter areas (WM), but very little in the gray matter (CORTEX) (x 80). (E) Actively demyelinating lesion in the cortex and subcortical white matter; in the white matter most HLA-D-positive cells show a macrophage phenotype, while in the cortex, most HLA-D-positive cells are activated microglia cells (x 80). (F, G) Actively demyelinating lesions in the cortex express inducible nitric oxide synthase (i-NOS) in activated microglia cells (x 300). (H) Demyelinated cortical lesions show profound expression of glia fibrillary acidic protein (GFAP) in reactive astrocytes (x 300).

fact that myelin sheaths occupy only a small fraction of the total cortical volume, it is not surprising that most cortical plaques escape detection by conventional MRI.

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