Cortical lesions move to the center of multiple sclerosis pathology
For years, cortical lesions in multiple sclerosis sat at the edge of clinical attention. That position is no longer tenable. The review places grey matter injury, especially cortical demyelination, at the center of MS pathophysiology and shows how this compartment helps explain disability, cognitive decline and progression beyond relapses.
The most consequential shift is conceptual. Cortical injury is not a late epiphenomenon layered onto white matter disease; it appears early, varies in form, and tracks with meningeal inflammation and neuroaxonal damage. The pathology is heterogeneous, but the signal is consistent: subpial lesions and inflammation at the brain–cerebrospinal fluid interface are linked to more severe outcomes and to an outside-in gradient of cortical destruction.
One sentence captures the clinical weight of the field’s evolution: cortical lesions are no longer a hidden pathology, but a measurable marker of disease biology.
Meningeal inflammation and the outside-in injury pattern
The review draws a direct line between meningeal inflammation and extensive subpial demyelination. That association matters because it offers a biological framework for cortical vulnerability that differs from classic white matter plaque formation. In this model, inflammatory activity in the meninges and at the brain–cerebrospinal fluid interface may fuel injury that spreads inward across the cortex, leaving a pattern of damage associated with severe clinical phenotypes.
This is more than descriptive neuropathology. The biology helps explain why cortical pathology has been tied to progression independent of relapse activity, or PIRA, in which disability advances even when overt relapses are absent. Once cortical and meningeal compartments are involved, the disease ceases to be fully captured by relapse counting or by routine white matter lesion burden alone.
Pathological studies established that cortical demyelination is frequent and heterogeneous, with subpial lesions receiving particular attention. The review links this heterogeneity to the broader clinical spectrum of MS, where lesion topography can shape symptom burden, prognosis and therapeutic response. The implication is straightforward: a patient can accrue disabling damage while conventional inflammatory surveillance appears deceptively quiet.
MRI now detects only part of the cortical burden
In vivo imaging has changed what can be seen, but not yet everything that exists. Advanced MRI sequences detect cortical lesions that conventional imaging often misses, revealing only the visible fraction of a much larger pathological process. Postmortem and histopathological comparisons have already shown that standard MRI markedly underestimates cortical lesion burden, and newer sequences have pushed detection into clinical territory.
Double inversion recovery imaging established that cortical inflammatory lesions are frequent and detectable in early disease. Later work using 7-T MRI and multicontrast approaches extended that observation, showing improved visualization of cortical grey matter lesions and helping standardize scoring across studies. The review emphasizes that these advances have practical value: cortical lesions have high MS specificity, appear early, and improve diagnostic accuracy when paired with other imaging markers.
This is where imaging becomes clinically consequential. A lesion visible on advanced MRI is not just a marker on a scan; it may represent the accessible edge of a deeper cortical process tied to disability progression, cognitive impairment and treatment response. The challenge is sensitivity. Current methods still leave much of the pathology unseen, especially when the biology is diffuse or subpial.
Prognosis now includes physical disability, cognition and PIRA
The review compiles evidence that cortical lesions detected by both low- and high-field MRI independently predict physical disability progression, conversion to secondary progressive MS, early PIRA, cognitive impairment and treatment response. Those associations shift cortical imaging from a niche research tool to a meaningful prognostic biomarker.
This prognostic role is especially important in early disease. If cortical lesions already signal a trajectory toward more aggressive or less reversible injury, then they may help distinguish patients whose inflammatory activity is only part of the story from those in whom grey matter pathology is already driving decline. Clinically, that distinction could influence how aggressively treatment is escalated and how closely patients are monitored for cognitive and functional change.
The review also connects cortical damage to disability accrual over time. New and chronic cortical lesions both contribute to worsening function, reinforcing the idea that ongoing cortical injury is not merely a bystander but part of the mechanism of progressive impairment.
Treatment effects, biomarkers and artificial intelligence will define the next phase
Current disease-modifying therapies affect cortical injury incompletely, and the review makes clear that the response of this compartmentalized pathology remains incompletely understood. Cortical damage appears to sit partly outside the reach of routine inflammatory control, which may help explain why some patients continue to worsen despite conventional treatment.
Future progress depends on measurement. Quantitative MRI, fluid biomarkers, single-cell RNA sequencing and spatial transcriptomics are positioned as complementary tools that could define biologically meaningful cortical endotypes. The goal is not simply better detection, but a more precise map of which inflammatory, glial and neuronal programs are active in a given patient.
Artificial intelligence could accelerate that work. Automated lesion detection, trajectory prediction and multimodal integration may eventually combine imaging with biological signatures to estimate demyelination, repair and likely treatment response at the individual level. If that happens, cortical pathology could become part of routine precision medicine in MS rather than an abstract concept discussed only in research settings.
The final obstacle is technical and biological at once. Imaging sensitivity remains limited, cortical pathology is still incompletely visible, and the field has not yet unified MRI findings with a full mechanistic account of repair failure, meningeal inflammation and progression. The review leaves the field with a clear research agenda: improve detection, define endotypes and determine how much of progressive MS can be intercepted once cortical injury is identified early.