Widespread demyelination in the cerebellar cortex in multiple sclerosis

Abstract

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band-like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS.

Figure 1

Cortical pathology in MS and hypoxia. A–C. Schematic drawing of demyelination in the cerebellar cortex (red) and white matter (green) in different MS courses. A. AMS with massive demyelination in the brain stem and cerebellar white matter, but only minor demyelination in the cortex mainly associated with white matter lesions. B. SPMS with massive cortical demyelination and moderate white matter demyelination; some of the cortical lesions are in continuity with large white matter plaques, while others show only a rim of white matter involvement adjacent to cortical demyelination; most of the cortical demyelination is not associated with white matter lesions. C. PPMS: massive cortical demyelination with only very small areas of white matter involvement. D. Low power view of cerebellar cortex in SPMS shows large areas of complete demyelination (DM) adjacent to areas of preserved myelin (N); the rectangle marks the area shown in Figure 1H–K ). Immunocytochemistry for PLP; ×15. E. Higher magnification of demyelinated cortical area, showing complete loss of myelin in the cortical layers, but preservation of myelin in the subcortical white matter. Immunocytochenistry for PLP; ×120. F. Adjacent nondemyelinated cortical areas of the same section with normal myelin in the lower parts of the molecular layer (M), the Purkinje cell layer (P) and the granular layer (G); WM: subcortical white matter. Immunocytochemistry for PLP; ×120. G. Small focal intracortical demyelinated plaque in a patient with SPMS; V: central vein. Immunocytochemistry for PLP; ×120. H,I. Neurons and axons in demyelinated plaques in the cerebellar cortex of SPMS; serial sections are stained by immunocytochemistry for PLP (H), neurofilament (I). Cerebellar cortex on the left side is demyelinated, while myelin is preserved in the cortex at the right side (H); staining for neurofilament shows no major differences between demyelinated and myelinated areas, although there is some reduction of Purkinje cells (I). In addition, few dystrophic axonal spheroids are present (I; insert); ×150. J,K. Synaptic immunoreactivity in normal (J) and demyelinated (K) area of the granular layer reveals no visible difference in synaptic density; immunocytochemistry for synaptophysin; ×900. L. Normal distribution of myelinated fibers in the cerebellar cortex of a normal control patient. Immunocytochemistry for PLP; ×300. M. Acute diffuse hypoxia of the cerebellar cortex with massive reduction of granule cell nuclear staining, but regular distribution of myelin sheaths. Immunocytochemistry for PLP; ×300. N. Chronic diffuse hypoxia of the cerebellar cortex shows loss of Purkinje cells and granule cells and reactive gliosis; myelin sheaths, however, are preserved. Immunocytochemistry for PLP; ×300. O. Acute cerebellar cortical infarct with loss of neurons and myelin sheaths in the infarct area (I). Immunocytochemistry for PLP; ×300. P. Chronic cystic infarct of the cerebellar cortex; the myelin sheaths in the adjacent granular layer are well preserved. Immunocytochemistry for PLP; ×300. Abbreviations: MS = multiple sclerosis; AMS = acute MS (Marburg’s type); SPMS = secondary progressive MS; PPMS = primary progressive MS; PLP = proteolipid protein.