Ocrelizumab-Induced Brain Volume Dynamics in Relapsing-Remitting Multiple Sclerosis

Background and Objectives: Ocrelizumab significantly reduces inflammatory activity in relapsing-remitting multiple sclerosis (RRMS), but treatment-induced brain volume change and the specific contributions of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) compartments to global atrophy and pseudoatrophy remain unclear. We aim to characterize the longitudinal and infusion-related dynamics of brain compartments in ocrelizumab-treated RRMS patients and identify the clinical and time-dependent predictors of these changes. Methods: Fifty-one RRMS patients were enrolled in a four-year prospective study. Brain volumes, including WM, GM, peripheral GM (pGRAY), CSF, ventricular CSF (vCSF), total brain volume (TBV) and their respective fractions (WMF, GMF, BPF) were evaluated by absolute time points (baseline to 4 years) and infusion-based intervals (baseline to 8th infusion), before and after each ocrelizumab cycle. Correlations between brain volume measures and the Expanded Disability Status Scale (EDSS), as well as time-dependent variables such as age, age at onset and disease duration (DD) were examined. Results: Mean age was 41.62 ± 9.76 years, mean age at onset 28.17 ± 7.85, mean DD 12.89 ± 8.55 years and mean EDSS 3.26 ± 1.5, indicating moderate disability. During the study, vCSF and CSF significantly increased, whereas WM, WMF, TBV and BPF significantly decreased. Notably, these measures exhibited marked, non-linear, and transient changes during the first year of ocrelizumab treatment, consistent with pseudoatrophy, likely reflecting early resolution of inflammation rather than irreversible tissue loss. GM and pGRAY remained relatively stable, with minor early increases. Correlation analyses revealed that higher EDSS scores, older age, later age at onset and longer DD were associated with lower GM, pGRAY and TBV, emphasizing the interplay between disease progression and development of brain volumetric patterns. Conclusions: Ocrelizumab-induced pseudoatrophy is predominantly WM-driven and age-dependent, with WM shrinkage being the main contributor to parenchymal loss and secondary widening of CSF spaces. Age remains a powerful predictor of brain atrophy and neurological impairment. These findings provide mechanistic insights into the biological basis of this modulation in RRMS.