Multiple sclerosis: role of meningeal lymphoid aggregates in progression independent of relapse activity

The emphasis on mechanisms driving multiple sclerosis (MS) symptomatic worsening suggests that we move beyond categorical clinical classifiers such as relapsing-remitting MS (RR-MS) and progressive MS (P-MS). Here, we focus on the clinical phenomenon progression independent of relapse activity (PIRA), which begins early in the disease course. PIRA occurs throughout MS, becoming more phenotypically evident as patients age. The underlying mechanisms for PIRA include chronic-active demyelinating lesions (CALs), subpial cortical demyelination, and nerve fiber injury following demyelination. We propose that much of the tissue injury associated with PIRA is driven by autonomous meningeal lymphoid aggregates, present before disease onset and unresponsive to current therapeutics. Recently, specialized magnetic resonance imaging (MRI) has identified and characterized CALs as paramagnetic rim lesions in humans, enabling novel radiographic-biomarker-clinical correlations to further understand and treat PIRA.