Loss of Neurologic Reserve in Progressive Multiple Sclerosis: A Paradigm Shift?

Phenotypic variability in multiple sclerosis (MS) remains poorly understood. At disease onset, the majority of patients with MS exhibit a relapsing-remitting MS (RRMS) disease course, and despite the availability of effective anti-inflammatory disease-modifying therapies (DMTs), a substantial proportion of patients will eventually evolve into a secondary progressive MS (SPMS) phase. Apart from SPMS, about 15% of patients with MS show clinical progression from onset without clear remissions, i.e., primary progressive MS (PPMS). The Lublin panel revising the definitions of the clinical course of MS in 2013 acknowledged that some evidence supports PPMS representing a distinct, noninflammatory or at least less inflammatory form of MS. The panel emphasized that a spectrum of progressive MS phenotypes exists and that any differences between a secondary and primary progressive course are relative rather than absolute. There are data to suggest that in MS, the acute inflammatory phase is followed by a chronic state that may include a smoldering condition in which inflammation as well as myelin and axonal degeneration may coexist. The transition of RRMS into SPMS is characterized by gradual worsening of neurologic disability independently of the occurrence of superimposed relapses. Currently available therapeutic options in both SP and PPMS are only modestly effective, and the approved DMT mainly targets the inflammatory component of the disease.