Multiple Sclerosis Phenotypes as a Continuum: The Role of Neurological Reserve

ABSTRACT Purpose of review This review presents the hypothesis that loss of neurological reserve explains onset of progressive multiple sclerosis (PrMS). Recent findings Evidence supporting the separate classification of PrMS and relapsing multiple sclerosis (RMS) is limited and does not explain PrMS or the response of these patients to therapy. Summary We argue that MS progresses along a continuum from RMS to PrMS, with differing levels of neurological reserve accounting for phenotypic differences. In early MS, inflammation causes brain atrophy with symptoms buffered by neurological reserve. As brain loss from normal aging and MS continues, reserve is depleted and effects of subclinical MS disease activity and aging are unmasked, manifesting as PrMS. Most therapies show limited benefit in PrMS; patients are older, have fewer inflammatory events and the effects of aging cause continued loss of neurological function, even if inflammation is terminated. Loss of neurological reserve means patients with PrMS cannot recover function, unlike patients with RMS. TAKE-HOME MESSAGES • There are no confirmed genetic or immunological differences between relapsing and progressive forms of MS. • The reported pathological and radiographic differences between these apparent MS subtypes represent quantitative differences on a pathological spectrum, influenced by patients with progressive disease generally being older, with longer disease duration rather than being pathognomonic to relapsing or progressive MS. • We propose that loss of neurological reserve owing to MS-related inflammation explains the onset of PrMS, and the level of neurological reserve may explain why some patients with MS develop progressive disease earlier than others. • We propose that reducing comorbidities, through strategies such as a healthy diet or active lifestyle, may help to protect neurological reserve, and could therefore prove beneficial in the care of patients with MS.