MS Likely Unfolds Along a Continuum Years Before First Symptoms

Long before a first relapse brings a person with multiple sclerosis (MS) to a neurologist, the disease may already be underway, quietly reshaping the immune system and injuring nerve fibers for years.

A narrative review, published in Frontiers in Neurology, reframed MS not as a condition that begins at its first clinical attack but as a biological, clinical, and diagnostic continuum stretching from genetic and environmental susceptibility through a prodromal phase, radiologically isolated syndrome (RIS), and clinically isolated syndrome (CIS) to clinically definite disease.¹

Prodrome and RIS Framed as One Disease Continuum

The idea that MS begins before its first attack has gained independent support. A 2025 expert commentary described the MS prodrome and RIS as overlapping parts of a single disease continuum and noted that the 2024 revisions to the McDonald diagnostic criteria now allow an MS diagnosis in some people with RIS, sharpening interest in the earliest detectable manifestations.² That perspective established why mapping the preclinical course matters, since recognizing early activity could move diagnosis and monitoring earlier without yet justifying treatment before formal criteria are met.

Susceptibility began with a complex interplay of inherited and environmental factors.¹ Genome-wide studies identified more than 200 risk variants, 32 of them within the human leukocyte antigen (HLA) region, and carrying at least 1 copy of HLA-DRB1*15:01 roughly tripled MS risk. A consortium analysis of 47,429 people with MS and 68,374 controls placed MS heritability near 48%, with monozygotic twin concordance reported at 71% vs 46% for dizygotic twins. Epstein-Barr virus infection, smoking (with a population-attributable fraction near 18%), adolescent obesity, and low vitamin D emerged as the most consistently established modifiable exposures, several of which interacted with HLA risk variants.

Silent Disease Activity Years Before First Symptoms

A prodromal phase spanning roughly 5 to 10 years, and up to 20 years in primary progressive MS, preceded symptom onset in large population studies. People later diagnosed with MS showed higher health care use, more psychiatric consultations, and recurrent nonspecific symptoms such as fatigue, pain, and mood disturbance in the years before their first demyelinating event. Biomarker data added plausibility, with serum neurofilament light chain (sNfL) rising a median of about 6 years before clinical onset. RIS occupied an overlapping position, and roughly half of people with RIS experienced a first clinical event within 10 years. Two randomized trials, ARISE (NCT02739542) and TERIS (NCT03122652), showed that dimethyl fumarate and teriflunomide reduced the risk of a first clinical event by 82% and 72%, respectively.

Neurofilament and Imaging Markers Tracking Disease Activity

Only a handful of biomarkers have been validated for routine practice. MRI remains the gold standard, with thalamic atrophy emerging early, sometimes at the RIS or CIS stage, and central vein signs and paramagnetic rim lesions recognized as supportive features. Cerebrospinal fluid oligoclonal bands and the kappa free light chain index supported early recognition and risk stratification, while sNfL tracked inflammatory axonal injury, and glial fibrillary acidic protein appeared better suited to capturing progression independent of relapse activity. Among people with CIS and MRI lesions, historical cohorts reported that 50% to 75% converted to MS within 2 years untreated.

The review applied no formal systematic procedure, relying on expert judgment and conceptual relevance to select sources. Many prodromal features represented population-level statistical associations with limited predictive value for individuals, and much of the supporting evidence came from administrative databases susceptible to surveillance bias, diagnostic delay, and misclassification. The authors emphasized that no biomarker yet shows sufficient specificity to reliably characterize preclinical or prodromal disease activity.

The authors wrote that "by the time classical symptoms appear, significant neuroaxonal damage and lesion accumulation may already have occurred."

References

1. Caminero AB, Martínez Ginés ML, Gómez Gutiérrez M, García Castañón I. Multiple sclerosis as a biological and clinical continuum: from risk factors to the early stages of disease. Front Neurol. 2026;17:1812340. doi:10.3389/fneur.2026.1812340
2. Tremlett H. The multiple sclerosis prodrome: insights into how and when disease starts. Nat Rev Neurol. 2025;21(12):661-663. doi:10.1038/s41582-025-01144-0