Classification of disease courses: Implications for treatments

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) have been considered important for diagnosis communication, for estimating prognosis, for the design of clinical trials, and for treatment decision. Descriptions published in 2014 were based on MS experts consensus leaded by the International Advisory Committee on Clinical Trials of MS. Phenotypes were entirely based on the clinical picture but imaging and biological correlates were missing. Disease courses were divided into Clinically isolated syndromes (CIS), relapsing remitting disease (RRMS) and progressive disease (PMS). Progressive MS merged progressive forms from onset (PPMS) and secondary progressive forms (SPMS) after an initial relapsing course. For RRMS and for PMS, modifiers incorporating disease activity and disease progression were included but it was acknowledge that no clear clinical, imaging, immunologic, or pathologic criteria were able to determine the transition point when RRMS converts to SPMS. In recent years, we have learned several important concepts: 1) that pathological mechanisms leading to progression are present from disease onset, with degree changing over time and differing between individuals 2) that clinical progression starts when compensatory mechanisms failed and we must differentiate the drivers of neurodegeneration from compensatory mechanisms; 3) that age is also a contributing and confounding factor to the clinical expression. Questions that arise include: When does progression begin?; What clinical measure(s) of progression apart from EDSS should we incorporate to detect early or silent progression?; What other tools are available to measure the processes that contribute to neurodegeneration? What are the implications for treatment selection?