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. Brain Pathol 2007;17:38-44. INTRODUCTIONMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, which leads to large confluent demyelinated plaques in the white matter (15). However, recent studies show that in addition to focal white matter plaques, there is also widespread damage in the gray matter and a diffuse and global injury in the normal appearing white matter (6,9,11). With the introduction of new and sensitive staining techniques for myelin, extensive cerebral cortical demyelination in MS brains recently became apparent (2,17). Cortical lesions are prominent in patients with primary and secondary progressive MS (PPMS and SPMS, respectively) (11), and the majority of cortical demyelination occurs in the form of widespread and band-like subpial lesions, which appear to be related to an inflammatory process within the meninges (3, 11). Cortical demyelination has so far only been investigated in the forebrain. Here we describe that cortical demyelination is even more prominent in the cerebellum. PATIENTS AND METHODSAutopsy material. The study was performed on autopsy material from 40 MS patients, eight neurologically normal patients without cerebellar pathology and 34 patients with focal or diffuse cerebellar hypoxia (Tables 1 and 2). The MS cohort consisted of patients with acute MS (AMS; Marburg's type, n = 5), relapsing/remitting MS (RRMS; n = 3), SPMS (n = 19), PPMS (n = 10) and progressive MS, where clinical records were insufficient to differentiate between SPMS and PPMS (UPMS; n = 3). Patient demographics are given in Table 1. Clinical courses were determined by retrospective chart reviews, performed by a neurologist (PSS, CFL, HR and MS) blinded to the outcome of the neuropathological analysis.Neuropathological evaluation. Autopsy material was fixed in buffered formalin. ...