Many diseases, such as Parkinson’s disease, type 1 diabetes, and schizophrenia, have early and subtle signs that give clues the disease is coming. Multiple sclerosis (MS) has them too. This phase is called prodrome.
You may not recognize a prodrome as a sign of disease because the symptoms don’t typically look the same as the full condition.
Better understanding the prodrome phase in demyelinating diseases such as MS is the goal of many researchers, including Dalia Rotstein, MD, MPH, assistant professor of medicine at the University of Toronto. Rotstein’s research is focused on ways to identify a prodrome phase in MS and other neurological diseases earlier.
Some MS prodrome symptoms include:
- Anemia
- Fatigue
- Mood disorders
- Pain
- Sleep disorders
Rotstein presented her team’s ongoing research at the 2025 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum in late February.
“We do have good treatments today for multiple sclerosis, but accumulating evidence has suggested the earlier we intervene, the better people do long term,” says Rotstein. “We still don't have effective therapy for the neurodegenerative or progressive aspect of multiple sclerosis.”
Part of the reason for this, she says, is that by the time doctors start therapy, when people with MS are going to the doctor with typical symptoms of the disease, the underlying disease process may have been going on for 10 to 15 years, or more.
“So if we can identify people in the prodromal phase, we may be able to intervene earlier to prevent accumulating damage and hopefully be more successful in our treatment of these neurologic diseases,” says Rotstein.
Epstein-Barr Virus (EBV) and MS
Rotstein is interested in the role the Epstein-Barr virus (EBV) plays in triggering MS and whether that can provide clues to prodrome identification. EBV is the most common cause of the infectious disease mononucleosis (mono). Experts long ago linked symptomatic mono to a higher risk of getting MS, but Rotstein says the connection may be even more meaningful.
“In 2022, more compelling evidence emerged to suggest that Epstein-Barr virus infection is actually a necessary event predating the development of MS,” says Rotstein.
In these studies, researchers test blood samples in people with MS from before their disease onset to see if they were positive for the Epstein-Barr virus. They found that almost everyone had an EBV-positive status before they developed MS.
Rostein’s research has looked to see if the prodrome goes back to the time of infectious mono and has found that they start around the same time. This adds to the evidence that EBV infection is a key step toward getting MS.
“In the future, we can explore the possibility that an Epstein-Barr virus vaccine might help to prevent MS,” says Rotstein. “You could also consider screening people after infectious mononucleosis to see if they develop early signs of MS.”
The Role of Biomarkers in Prodrome Identification
One way to do this is by using biomarkers. They could help identify people at risk for MS before symptoms appear. In MS, one of the most important biomarkers is lesions doctors see on MRI. This is proof they use to diagnose MS.
“The first step is to study people in this early phase and see if we find these positive biomarkers and then monitor them over time to see if they evolve in the direction of multiple sclerosis,” says Rotstein.
The next step would be to conduct a clinical trial with therapy to see if that therapy could help to prevent MS completely or delay its onset.
Rotstein’s group is doing further studies of both the MS prodrome and the prodrome of neuromyelitis optica spectrum disorder, a rare autoimmune disorder that affects the central nervous system.
“We're looking at large population-level data from Ontario to see if we can find cases of people who developed MS while they were still negative for EBV. If there are no such cases, then it would increase confidence that EBV is a critical event,” says Rotstein.
EBV vaccine trials are underway, but she says the endpoint for those trials will be prevention of infectious mononucleosis.
“We're going to have to find ways to monitor people in the early years after the trial to see if their risk of multiple sclerosis, and possibly other autoimmune diseases, decreases,” says Rotstein.
“But that certainly would be very powerful if we could find evidence that this could be a way to prevent multiple sclerosis.”
Show Sources
Photo Credit: iStock/Getty Images
SOURCES:
Dalia Rotstein, MD, MPH, assistant professor of medicine, University of Toronto.
National Multiple Sclerosis Society: "The MS Prodrome,"
ODC: “About Epstein-Barr Virus."
