We characterized demyelinating lesions in cortical-biopsy specimens from patients with early-stage multiple sclerosis, which were obtained in passing during diagnostic procedures targeting white-matter lesions (Fig. 4 in the Supplementary Appendix
). Nearly 40% of these patients had cortical demyelination. Indirect evidence that cortical demyelination is common in early-stage multiple sclerosis comes from MRI studies showing cortical lesions in approximately 30% of 119 patients with a clinically isolated syndrome.25
Others have reported cortical lesions and cortical atrophy on MRI in patients with early multiple sclerosis,26–29
although cortical lesions were not observed in a study of children with multiple sclerosis.30
The spatial separation of intracortical and subpial lesions (which together represented about 50% of the lesions detected) from the biopsy specimens of white-matter lesions suggests intrinsic cortical demyelinating disease. The prevalence of intrinsic cortical lesions was remarkably high, given the small tissue samples available for study (core diameter, 1 mm).
We do not believe that the presence of tumefactive white-matter lesions affects the biology of the cortical lesions, hence our interpretation of the presence and appearance of these cortical lesions. We believe that the patients in our study who underwent biopsy are typical of those with multiple sclerosis; among 77 patients for whom long-term clinical follow-up data were available, 58 (75%) had definite multiple sclerosis and 19 (25%) were categorized as having a clinically isolated syndrome at the last follow-up.
Understanding the neuropathophysiology of multiple sclerosis requires analysis of tissue, which carries potential biases. Despite atypical clinical and radiographic presentations, evidence suggests that the results of biopsy studies in multiple sclerosis can be cautiously extrapolated to prototypical multiple sclerosis. In a previous study, we compared our patients with a population-based cohort of 218 persons with definite multiple sclerosis who were matched for age, sex, and disease duration with 91 persons with inflammatory demyelinating disease of the central nervous system who underwent biopsy, with a median clinical follow-up of 4.4 years.31
Multiple sclerosis developed in 82 of the 91 patients who underwent biopsy, and the clinical course and extent of disability in these patients were indistinguishable from those of patients in the prevalence cohort, who did not undergo biopsy. In another report, multiple sclerosis had developed by the time of the last follow-up assessment (median, 3.9 years) in 70% of 168 patients with tumefactive inflammatory demyelinating disease who underwent biopsy.32
The relevance of cortical injury in the diagnosis and prognosis of multiple sclerosis is widely acknowledged.28,33
Cognitive impairment correlates positively with gray-matter atrophy,34
and reduced cortical thickness.35
Cortical-lesion volume is an independent predictor of disability progression at follow-up,35
and cortical lesions are less common in patients with benign multiple sclerosis, in which remission between relapses is almost complete, with little (if any) accumulation of disability 15 to 20 years after the diagnosis.36
Cortical lesions are more common in patients who have relapsing–remitting multiple sclerosis with seizures than in those who have relapsing–remitting multiple sclerosis without seizures. 37
Therefore, an understanding of the prevalence and extent of cortical demyelination in early multiple sclerosis may help inform assessment of the prognosis and treatment decisions.
We found that cortical demyelination is common early in multiple sclerosis, and our characterization of the lesion underscored its inflammatory character. Cortical demyelination that occurs close to the onset of multiple sclerosis differs substantially from that seen in chronic multiple sclerosis. These findings do not support a primary (noninflammatory) neurodegenerative process during early-stage multiple sclerosis. Differences between cortical demyelination in early multiple sclerosis and in long-standing, progressive multiple sclerosis, in which inflammatory cortical demyelination is typically not observed, may relate to efficient clearance of cortical inflammation.38,39
With respect to a potential mechanism of disease progression, we speculate that myelin-laden macrophages may leave the cortex, enter the cerebrospinal fluid (CSF), gain access to deep cervical lymph nodes to promote epitope spreading,40
and thus propagate the disease process (Fig. 5 in the Supplementary Appendix
). Antigen-presenting cells injected into the CSF of rodents were found in deep cervical lymph nodes,41
and macrophage-containing myelin debris has been observed in the cervical lymph nodes of patients with multiple sclerosis.42
Meningeal aggregates in the tissues of patients with multiple sclerosis may contribute to cortical demyelination and progression.6,11,43,44
During the prodrome in experimental autoimmune encephalomyelitis, pathogenic T cells enter the CSF,45,46
are restimulated by meningeal antigen-presenting cells,47
undergo clonal expansion, and produce cytokines, promoting T-cell infiltration across pial vessels,48
activation of deeper vasculature,49
parenchymal invasion, and the onset of disease. These mechanisms have been studied mainly in the white matter of the spinal cord in experimental autoimmune encephalomyelitis, adjacent to CSF flow pathways. Cortex is the only common CSF-adjacent tissue obtained on biopsy in the clinical setting, and our findings broadly correspond to observations made in experimental autoimmune encephalomyelitis (Fig. 5 in the Supplementary Appendix
). Subpial cortical demyelination showed a strong topographic relation to meningeal inflammation, suggesting that meningeal infiltrates may contribute to early cortical demyelination.
We observed concurrent subpial and leukocortical lesions in individual tissue sections, suggesting that superficial demyelinating disease may contribute to the generation of deeper lesions by means of cytokine diffusion.41
In support of this hypothesis, a recent analysis of autopsy specimens from patients with progressive multiple sclerosis showed antigen-experienced B-cell clones in meningeal aggregates that were identical to those found in parenchymal perivascular spaces near plaques, as indicated by variable-region sequence alignment.50
Our findings of microglial activation, neuritic injury, pyknotic neurons, and reduced oligodendrocyte density in patients with early multiple sclerosis are consonant with the findings in patients with progressive multiple sclerosis,4
underscoring the potential of cortical demyelination to cause irreversible injury, although inflammation may resolve rapidly. The relationship between early cortical demyelination and cognitive impairment, disease progression, and cortical atrophy awaits future research.