Inflammatory cortical demyelination in early multiple sclerosis

Abstract

Background: Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.

Methods: We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).

Results: Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.

Conclusions: In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).

Figure 1. Representative Types of Cortical Demyelinated Plaques in Early Multiple Sclerosis on Immunohistochemical Staining for Proteolipid Protein

Panel A shows leukocortical demyelination; Panel B subpial demyelination (arrows delineate an area of cortex with preserved myelin); Panel C intracortical demyelination (arrows), with neurons in the demyelinated lesion (inset); and Panel D subpial and leukocortical demyelination in the same tissue section.

Figure 2. Inflammatory Features of Cortical Plaques

Panel A shows the percentage of plaques with myelin-laden macrophages, according to plaque type, among 78 lesions (41 patients) with cortical demyelination. The percentage of myelin-laden macrophages in leukocortical plaques (LK) was significantly higher than the percentages in intracortical plaques (IC) (P = 0.02) and subpial plaques (SP) (P<0.001). The percentages did not differ significantly between IC plaques and SP plaques (P = 0.56). Panel B shows the percentage of plaques with mild T-cell inflammation and the percentage with moderate or severe T-cell inflammation among 71 lesions (38 patients) analyzed on the basis of CD3+ counts. The percentages of plaques that showed any inflammation did not differ significantly across plaque types (P = 0.09). I bars represent 95% confidence intervals based on logistic-regression models. Significance tests were also based on logistic-regression models.

Figure 3. Components of Parenchymal Inflammatory Infiltrates in Cortical Lesions

In Panel A, myelin-laden macrophages (arrow) indicate the presence of active cortical demyelination in early multiple sclerosis (immunohistochemical staining for proteolipid protein [PLP]). In Panel B, macrophages are present in the molecular layer of the cortex at the subpial rim (immunohistochemical staining for CD68). In Panel C, myelin-laden macrophages (arrow) are also present in the subarachnoid space (PLP staining), and the inset shows the myelin-laden macrophage (arrow) at a higher magnification (PLP staining). In Panel D, marked perivascular inflammation is present in cortical plaques (PLP staining). Components of the perivascular inflammatory infiltrates include CD3+ T cells in Panel E (immunohistochemical staining for CD3) and cytotoxic T cells in Panel F (immunohistochemical staining for CD8).

Figure 4. Components of Meningeal Inflammatory Infiltrates

Panel A shows moderate-to-marked, diffuse meningeal inflammation (hematoxylin and eosin). Panel B shows moderate-to-marked, diffuse meningeal inflammation topographically associated with a subpial plaque (immunohistochemical staining for PLP). Panel C shows marked perivascular meningeal inflammation topographically associated with a subpial plaque (PLP staining). Neuritic loss reflects the destructive nature of the subpial plaque in Panel D (immunohistochemical staining for neurofilament). Components of the perivascular meningeal inflammatory infiltrates include CD3+ T cells in Panel E (immunohistochemical staining for CD3) and B cells in Panel F (immunohistochemical staining for CD20).

Figure 5. Other Neuropathological Characteristics of Cortical Demyelinating Lesions in Early Multiple Sclerosis

Panel A shows normal oligodendrocyte density (arrows) in nondemyelinated cortex (immunohistochemical staining for 2′3′-cyclic-nucleotide 3′-phosphodiesterase [CNPase]). Panel B shows reduced oligodendrocyte density (arrows) in demyelinated cortex (CNPase staining). In Panel C, neuronal injury is evidenced by the presence of pyknotic neurons (arrowheads) scattered among healthy neurons (arrow) (hematoxylin and eosin). Microglia in Panel D (immunohistochemical staining for KiM1P) are close to neurons, and T cells in Panel E (immunohistochemical staining for CD3) are close to oligodendrocytes.