Multiple sclerosis: what have we learned and can we still learn from electron microscopy.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease marked by the formation of demyelinated lesions in the central nervous system. MS lesions can undergo remyelination, temporarily alleviating symptoms, but as the disease advances, remyelination becomes less effective. Beyond lesions, normal-appearing brain tissue exhibits subtle alterations, potentially indicating a broader, diffuse pathology and/or increased susceptibility to lesion formation. The pathology of MS varies between grey and white matter lesions and their normal-appearing regions, which most likely relates to their distinct cellular composition. Despite insights gained from MRI studies, serum and blood analyses, and post-mortem tissue examination, the molecular mechanisms driving MS lesion formation and persistent demyelination remain poorly understood. Exploring less conventional methods, such as electron microscopy (EM), may provide valuable new insights. EM offers detailed, nanometre-scale structural analysis that may enhance findings from immunohistochemistry and 'omics' approaches on MS brain tissue. Although earlier EM studies from before the 1990's provided some foundational data, advancements in EM technology now enable more comprehensive and detailed structural analysis. In this review we outline the pathogenesis of MS, summarize current knowledge of its ultrastructural features, and highlight how cutting-edge EM techniques could uncover new insights into pathological processes, including lesion formation, remyelination failure and diffuse pathology, which may aid therapeutic development.