Active and progressive: a new duality of MS classification.

In this issue of Neurology®, Lublin and over 30 multiple sclerosis (MS) specialists from around the world propose a new consensus framework for MS classification. The increasing importance of MRI in clinical management and treatment trials, together with expanding treatment options and improved understanding of the pathophysiology of MS, motivated the present re-examination of MS phenotypic classifications and clinical course descriptions. The new schema supplants the one proposed by Lublin and Reingold in 1996 depicting 4 courses of MS that has been widely embraced in research and in clinical practice. The original 4 clinical subtypes were based on an international survey of MS clinicians, and utilized clinical information alone to describe relapsingremitting, primary progressive, secondary progressive, and progressive-relapsing phenotypes. However, distinctions among the original 4 subtypes are imprecise and do not reflect current capabilities to target MS treatments based on integrated assessment of clinical and MRI data. Ten disease-modifying therapies (DMTs) for relapsing MS are approved in the United States, with an 11th, alemtuzumab, approved elsewhere in North America and in Europe. Although effective against the inflammatory pathology of MS, as measured by reduction of clinical relapses and accrual of new MRI lesions, currently approved therapies do not effectively abrogate the neurodegenerative processes that appear to underlie the primary and secondary progressive forms of MS. However, new types of therapies directed at arresting progressive MS or reversing damage via remyelination or neural regeneration, including 2 potential remyelinating agents that lack anti-inflammatory properties, anti-LINGO-1 and rhIgM22, are being evaluated in clinical trials. Improved patient classification is essential to ensure that imprecision in enrollment criteria does not lead to misleading findings or confusing differences in the outcomes of similarly conducted controlled trials. The new classification scheme retains core concepts of relapsing and progressive disease and adds clinically isolated syndrome (CIS) as a distinct MS phenotype (although CIS without an accompanying MRI that reveals gadolinium-enhancing and nonenhancing lesions does not meet current MS diagnostic criteria). The group stops short of including radiologically isolated syndrome, which is the detection of MRI lesions consistent with MS in the absence of clinical symptoms and signs, and recommends that such patients be monitored prospectively. Two modifiers of the core phenotypes based on activity and worsening are proposed. Within a 1-year time frame, the occurrence of clinical relapses or MRI-detected CNS lesions (gadolinium-enhancing T1 lesions or new or clearly enlarging T2 lesions) are used to distinguish patients who have active MS from those with inactive disease. At least yearly brain MRI is strongly recommended to assess activity in relapsing MS, but no consensus was reached on the frequency of MRI scans for progressive MS. The proposed activity modifier renders the progressive relapsing phenotype from the 1996 schema obsolete; such patients would now be described as having primary progressive MS with disease activity. The group suggests implementing the term worsening to describe patients with MS whose impairment is increasing due to relapses, reserving the term progression for those patients with established progressive MS whose function is deteriorating independent of relapse activity. Therefore, patients may be described as having (1) relapsing MS that is active or inactive, with or without worsening; or (2) primary or secondary progressive disease that is active or inactive, with or without progression. The panel proposes to use the term confirmed worsening over a specified time period, eschewing the oftenused term sustained because sustained implies a permanence that often is not borne out. The panel acknowledges the need for further data and offers a research agenda. Whether benign and malignant MS are useful terms has long been debated. The panel recommends retaining these terms with the traditional caveat that these terms be used with caution and only retrospectively. A quantitative definition based on the rate of disability increase over time is favored, with