“Prodrome” is a word used to describe signs and symptoms that a patient might experience before the defining characteristics of a disease present themselves. In multiple sclerosis, the most common prodromal symptoms are fatigue, headache, and low mood. 

Multiple sclerosis is one of only a handful of diseases with scientifically validated prodromes. The onset of prodromal symptoms is both a blessing and a curse—a blessing in that it allows patients to start preparing for the worst, and a curse in that it is an ominous warning that something worse is yet to come. 

Physicians and medical researchers determine the parameters of what constitutes a prodrome and look for ways to use this knowledge to benefit patients. That way, prodromal symptoms can become a signal to physicians to intensify preparations and take prophylactic action if necessary. 

Continue Reading

It was not too long ago that it was the medical consensus that prodromes do not exist for multiple sclerosis Researchers who have looked back suggest that recall bias, a small sample size, and a lack of education on what constitutes a prodrome may have played a role in this belief. 

“Historically, a prodromal period was not thought to occur in multiple sclerosis. Although the concept of latency—or an “incubation” period between exposure(s) and multiple sclerosis onset—was recognized, the possibility of a measurable prodromal period was largely overlooked or dismissed by opinion leaders in the field,” Tremlett and Marrie wrote in the Multiple Sclerosis Journal. 

Read more about multiple sclerosis etiology 

However, studies in the last 10 years or so have moved the needle considerably in the direction that prodromes in multiple sclerosis exist, and that the group of symptoms experienced by patients is by and large similar. 

In addition to the list of symptoms mentioned earlier, there are other prodromal signs that deserve consideration.

Considering Nonclassical Symptoms

Studies have suggested that nonclassical symptoms such as depression can occur in the years prior to the onset of multiple sclerosis. This hypothesis rests largely on a study conducted on 45 patients with multiple sclerosis, in which nearly half of the patients were diagnosed with major depression. Whether or not this can be strictly regarded as a prodromal episode is debatable; patients may have depression for a multitude of unrelated reasons. 

Read more about multiple sclerosis prognosis 

Another nonclassical prodromal symptom is low cognitive performance. A study found that cognitive performance was significantly lower in patients with multiple sclerosis 2 years prior to disease onset. In the same study, patients with primary progressive multiple sclerosis had lower cognitive performance up to 20 years before the onset of multiple sclerosis symptoms. 

The difficulty with these studies is, as indicated earlier, a relatively small sample size (ie, not population-based), and the risk of recall bias. It is entirely possible that patients may retrospectively recognize prodromal symptoms when the question is put to them, which may result in less-than-accurate answers.

Finding Clues in Clinical Data

While studies based on the entire population are not feasible, researchers can rely on medical records and other clinical data to estimate the frequency of reported prodromes among patients who are later diagnosed with multiple sclerosis. 

“Collectively, population-based studies relying on these types of data sources have already demonstrated that it is possible to objectively measure a symptomatic prodromal period in multiple sclerosis which may last 5-10 years or perhaps longer before our current, classical understanding of ‘multiple sclerosis symptom onset,’ ” Tremlett and Marrie wrote. 

Another way in which medical researchers can conclude that prodromal symptoms do occur in patients later diagnosed with multiple sclerosis is by observing the changes in their relationship with healthcare services in the years leading up to a diagnosis. Studies demonstrate that patients have higher healthcare utilization (visits to the clinic, pharmacy, hospital, etc) in the years preceding a diagnosis of multiple sclerosis. 

“In the year before the first clinical demyelinating event, hospitalizations and physician visits were 78% and 88% higher, respectively, for people with multiple sclerosis than for matched controls,” Makhani and Tremlett wrote in Nature Reviews Neuroscience. “Similarly, dispensed prescription medications were 49% higher among patients who went on to develop multiple sclerosis.” 

Future Research 

Now that we have rather conclusive evidence of the existence of a multiple sclerosis prodrome, scientists are beginning to focus on unearthing more information that can lead to a higher suspicion index regarding a diagnosis of multiple sclerosis. 

There are a few approaches to this: pinpointing the average duration of the prodrome, identifying nonclassical prodromal symptoms not yet characterized in literature, and determining possible biomarkers linked to multiple sclerosis. In addition, more work needs to be done to understand how early intervention impacts long-term outcomes. 

“The immediate implication of recent advances in the recognition of the prodromal phase is that it changes our understanding of the etiologically relevant time period for exposure and should influence the design of future studies of novel risk factors,” Makhani and Tremlett concluded. 


Makhani N, Tremlett H. The multiple sclerosis prodromeNat Rev Neurol. 2021;17(8):515-521. doi:10.1038/s41582-021-00519-3

Tremlett H, Marrie RA. The multiple sclerosis prodrome: emerging evidence, challenges, and opportunitiesMult Scler. 2021;27(1):6-12. doi:10.1177/1352458520914844