How premorbid structural reserve affects disability accrual in multiple sclerosis

Objective: To explore whether proxies of premorbid structural reserve—intracranial volume (ICV) and spinal cervical canal area (SCCA)—influence long-term disability accumulation in multiple sclerosis (MS), specifically through progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW). Methods: We included 253 patients with relapsing-onset MS, ⩾5-year follow-up from first demyelinating event (FDE), and available 3D T1-weighted magnetic resonance imaging (MRI) scan enabling estimation of ICV and SCCA. To account for PIRA and RAW co-occurrence in the same individuals, we used negative binomial regression to estimate adjusted event rate ratios (adj.-ERRs) and competing risk models to derive subdistribution hazard ratios (SHRs) for PIRA and RAW events. Results: Over a median 17-year follow-up, higher SCCA was associated with fewer PIRA events (adj.-ERR = 0.74, p = 0.014) and delayed PIRA onset (SHR = 0.50, p = 0.05), while larger ICV was associated with fewer RAW events (adj.-ERR = 0.70, p = 0.033) and both later occurrence (SHR = 0.41, p = 0.02) and older age at RAW (SHR = 0.30, p = 0.002). Patients with high combined reserve (both larger ICV and SCCA) reached EDSS ⩾ 6.0 later (hazard ratio (HR) = 0.33, p = 0.025) and at older age (HR = 0.37, p = 0.045) than those with low reserve. Conclusion: Pre-morbid structural reserve mitigates the MS-related disability accrual, supporting the integration of ICV and SCCA into prognostic models as markers of neuroanatomical resilience.