CHARLOTTE, N.C. — There was a time when experts doubted the existence of a multiple sclerosis (MS) prodrome. But over the past decade, it has become a widely recognized and increasingly studied phenomenon that may precede the onset of clinically apparent disease by 5-15 years.

Now, some researchers believe it could be a target for early intervention that could stop MS before symptoms appear.

Before the introduction of the revised McDonald criteria 2 years ago, therapy was not considered appropriate until patients became symptomatic, even though radiologically isolated syndrome (RIS) can reveal evidence of MS years before symptom onset.

But by that point, the opportunity for prevention has been lost, Mitchell Wallin, MD, MPH, director of the Veterans Affairs MS Center of Excellence in Washington, DC, said during a press briefing at the Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting.

“We want to slow the train before it is out of the station,” said Wallin, one of several speakers at a CMSC symposium on the MS prodrome held on May 27.

History of the MS Prodrome

Early references to a potential MS prodrome begin about 2010. In a study published that year, a higher rate of major depressive disorder among individuals who subsequently developed MS was identified as a potential prodrome.

A few years later, the concept began to take hold when researchers examined the medical records of patients who subsequently developed MS and identified symptoms that were present years before clinical diagnosis, said Dalia L. Rotstein, MD, associate professor in the Division of Neurology of the University of Toronto, Toronto, Ontario, Canada, who also spoke during the symposium.

These studies took place in Scandinavia and in Canada, but Rotstein referred specifically to a 2017 study led by Helen Tremlett, PhD, at the University of British Columbia in Vancouver, British Columbia, Canada. In this study, she and her co-investigators found that healthcare claims among patients who later developed MS began increasing at least 5 years before their first demyelinating event.

In a 2022 review article on the topic, Tremlett noted that while the evidence at the time was “nascent,” she had already come to the conclusion that this work might lead not only to earlier treatment but also to disease prevention.

Since that time, further studies have indicated that MS biomarkers are elevated during the prodrome, Rotstein said. Specifically, Epstein-Barr virus nuclear antigen-1 and neurofilament light chain (NfL) can be detected 10 or more years before clinical or radiologic symptoms.

Although it remains unclear whether these biomarkers can be therapeutically targeted, the first evidence that earlier intervention could alter the course of MS came from the 2023 ARISE and TERIS trials. Both studies showed major reductions in the time to the first clinical demyelinating event in asymptomatic patients with RIS treated with a disease-modifying therapy.

A Theory…for Now

These studies added to evidence that MS is a slowly progressive pathophysiologic process for which earlier treatment may result in less neurologic damage, Rotstein said. She acknowledged that they do not prove that MS can be prevented, but they do raise the possibility that sufficiently early intervention could alter the disease course.

“Rather than starting therapy in reaction to symptoms or brain lesions, we are looking at the prodrome for prevention,” Rotstein said.

Symptoms of the MS prodrome, including headache, anxiety, fatigue, pain, and various forms of autonomic dysfunction, are nonspecific. But Wallin predicts that biomarkers and risk factors will be combined to single out suspected prodromal MS driven by a probable neurodegenerative process.

In using the MS prodrome to identify patients for treatment, Rotstein said the first step will be an effective risk stratification. That goal is becoming more attainable with the growing number of fluid biomarkers, including NfL, glial fibrillary acidic protein, oligoclonal bands, and kappa free light chains.

“There is no risk calculator yet, but this might be coming,” she said.

Both investigators emphasized that at this point, the ability to identify and target the prodrome remains largely theoretical, but there are many reasons to believe these puzzle pieces will fit together.

“I think we are working toward strategies to target high-risk patients for primary prevention,” said Wallin.

Rotstein reported having financial relationships with Alexion, Amgen, Biogen, EMD Serono, Novartis, Roche, Sanofi Aventis, and touchIME. Wallin reported having a financial relationship with Sanofi, and Shah reported having financial relationships with Novartis and TG Therapeutics.