Multiple sclerosis as a biological and clinical continuum: from risk factors to the early stages of disease

Multiple sclerosis (MS) has traditionally been diagnosed after the onset of clinical symptoms, supported by characteristic radiological findings. However, mounting evidence suggests that MS-related biological processes may precede the first overt neurological manifestations by several years. The disease appears to unfold along a biological continuum that includes genetic susceptibility, environmental exposures, and possible early manifestations characterized by subtle, nonspecific symptoms that precede detectable abnormalities such as MRI lesions or early biomarker changes. This review summarizes current knowledge about the temporal evolution of MS, from early risk factors through the radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS), to the onset of clinically definite MS. We discuss emerging biomarkers, advances in neuroimaging, and evolving insights into early immunopathological mechanisms. Conceptualizing MS as a continuum may facilitate improved risk stratification and the development of targeted monitoring strategies in individuals at higher risk. Nevertheless, this model remains limited by the absence of biomarkers with sufficient specificity to reliably characterize preclinical or prodromal biological disease activity, and of validated tools to translate such findings into clinical practice.