Multiple sclerosis as an asynchronous neuroinflammatory system

Multiple sclerosis (MS) has traditionally been conceptualized through an event-based framework in which relapses, lesion accumulation, and disability progression evolve along a linear temporal axis. However, converging pathological, imaging, biomarker, and clinical trial evidence indicates that inflammatory activity, chronic lesion expansion, axonal degeneration, and network reorganization unfold with partially independent temporal dynamics. The 2024 revisions of the McDonald criteria formally incorporate markers of immune persistence and chronic inflammatory organization. Dissemination in space (DIS) remains the diagnostic entry point with a relaxation for the need of dissemination in time (DIT) yet prognosis cannot be reduced to event frequency alone. Disability accumulation reflects the interaction between Relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA), revealing a decomposable hazard structure that challenges relapse-centered modeling. Traditional endpoints such as annualized relapse rate (ARR) and confirmed disability progression (CDP) capture partial projections of a higher-dimensional disease process. MS should therefore be understood not as an event-driven disorder but as a dynamically evolving system. Biological onset occurs before clinical presentation, diagnosis occurs at a threshold; progression unfolds as a trajectory through a multidimensional state space (MSS). Recognizing this distinction has direct implications for prognostic inference, trial design, biomarker integration, and state-dependent therapeutic modeling.