High levels of perivascular inflammation and active demyelinating lesions at time of death associated with rapidly progressive multiple sclerosis disease course: a retrospective post-mortem cohort study

Objective: Analysis of post-mortem multiple sclerosis (MS) tissues combined with in-vivo disease milestones suggest that while perivascular white matter infiltrates associate with demyelinating activity in the initial stages; leptomeningeal immune cell infiltration, enriched in B cells and associated with cortical lesions, contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at post-mortem with clinical milestones. Methods: In 269 MS brains; 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22 a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. Results: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death associated with increased prevalence and higher levels of PVI (both p<0.0001). Shorter time from onset of progression to wheelchair use associated with higher prevalence of ALs (OR 0.921, 95% CI (0.858, 0.989), p=0.0230) and higher level of PVI (0.932, (0.886, 0.981), p=0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. Interpretation: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. This article is protected by copyright. All rights reserved.