Figure 1.

Clinically silent, prodromal and clinically manifest ALS. The natural history of ALS, as a biological entity, includes a clinically silent (also known as pre-manifest) stage that is typically not observable except when disease-related biomarker abnormalities are detected. These biomarker abnormalities, if present, serve as the first (and only) indication that the disease process has begun. The clinically silent stage is followed by a prodromal stage characterized by mild motor, cognitive or behavioural impairment (MMI, MCI or MBI, respectively); the prodromal stage is more likely to be observed in slower progressing disease. As motor deficits accumulate, the prodromal stage gives way to clinically manifest ALS. The term phenotransition describes the transition from the clinically silent to the prodromal stage, and the term phenoconversion describes the transition to clinically manifest ALS.⁷ The shaded gradient indicates that these periods exist along a continuum. (Note that the figure is not drawn to scale, as the relative duration of each period is largely unknown and may vary between individuals.)