Phases and phenotypes of multiple sclerosis

PURPOSE OF REVIEW This article describes the dynamic evolution of multiple sclerosis (MS) through its phases and the impact of this understanding on treatment decisions. RECENT FINDINGS MS consists of three phases: (1) the high-risk phase, (2) the relapsing-remitting phase, and (3) the progressive phase. Increasingly, subclinical disease activity is becoming an integral part of our definition of disease course in MS. In many patients, the relapsing-remitting phase starts as subclinical activity, likely long before they present with a clinically isolated syndrome. Differentiating progressive MS subgroups is also becoming less relevant. This is illustrated by comparing progressive MS that evolves from an asymptomatic state in individuals with radiologically isolated syndrome (primary progressive MS) and symptomatic individuals with relapsing-remitting MS (secondary progressive MS). In each case, the background disease activity and pathology can be indistinguishable. These phases evolve on a continuum and largely follow the aging process with little influence by the preceding clinical activity level. Recently, it also became evident that one or a few poorly recovered relapses at the beginning of clinical manifestations of MS predict much earlier progressive MS onset. SUMMARY These findings suggest that interventions to prevent progressive MS, when they become available for clinical practice, may need to be considered as early as when the asymptomatic radiologically isolated syndrome is detected. This early treatment approach is being evaluated with ongoing trials with available disease-modifying therapies. In contrast, continuing the use of disease-modifying therapy beyond a certain age may have little benefit. However, being in the progressive phase of MS is not, in itself, an argument against disease-modifying therapy use in active disease in younger patients.