Cortical lesions in multiple sclerosis: 25 years of progress, remaining challenges and future directions

Cortical lesions have evolved from a largely overlooked pathological feature to a central component of multiple sclerosis pathophysiology, yet their biology, clinical relevance and response to treatment remain incompletely understood. In this Review, we trace how pathological studies established the frequency and heterogeneity of cortical demyelination, with particular attention to subpial lesions and inflammation at the brain-cerebrospinal fluid interface. We examine the neuropathological and imaging evidence linking cortical pathology to meningeal inflammation, neuroaxonal injury and progression independent of relapse activity, and assess how emerging magnetic resonance imaging approaches for detecting and monitoring cortical lesions contribute to diagnosis and prognosis across the multiple sclerosis spectrum. Last, we discuss the sensitivity limits of imaging, the effects of disease-modifying therapies on this compartmentalized damage, and how quantitative magnetic resonance imaging, fluid biomarkers and artificial intelligence could help define biologically meaningful cortical endotypes and guide future therapeutic development.