In multiple sclerosis (MS), disease course is defined by a subclinical or clinical relapsing remitting phase, a progressive phase, and the overlapping phase in-between. Each phase can have intermittently active or inactive periods. Subclinical activity in radiologically isolated syndrome evolving to primary-progressive MS is mostly indistinguishable from relapsing-remitting MS evolving to secondary-progressive MS. The onset of progressive-phase MS is age-dependent but time and pre-progressive phase agnostic. Pathologic hallmarks of progressive MS onset also appear to be age-dependent but pre-progressive phase agnostic. Onset of progressive MS is characterized by a peak in smoldering plaques.