The word “prodrome” is used to describe a set of early signs and symptoms that precede the imminent onset of an illness. In medicine, it is a curiously underused word, and is most prominently found in migraine headache literature. Many migraine sufferers tend to be well-versed in the potential signs and symptoms that precede a migraine attack, giving them time to seek appropriate medical attention before the episode begins in earnest. 

For most other diseases, the term “signs and symptoms” is preferred over the word “prodrome.” In other words, there seems to be a consensus that for most diseases, there are no “early warnings” of an attack, in the sense of the kinds seen in a migraine, and that a disease announces itself immediately with the onset of signs and symptoms, seemingly out of the blue. 

A Change in Thinking

There is scientific debate about what constitutes a prodrome, such as the minimum period required and how significant the signs and symptoms need to be for one to be classified as such. In multiple sclerosis (MS), a prodromal period historically was not thought to occur, Tremlett and Marrie wrote. However, the word “prodrome” has popped up in recent medical literature as researchers test the waters on whether it can be used to clinically describe a set of early warning signs. 


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“Although the concept of latency — or an “incubation” period between exposure(s) and MS 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. “Yet even at this time, prodromal phases were starting to gain recognition and interest in other neurological and neurodegenerative conditions, such as Parkinson disease.” 

Read more about MS diagnosis 

Makhani and Temlett echoed these sentiments, writing, “Prodromal phases are well recognized in several neurological and inflammatory diseases, but the possibility of a prodrome in MS has received relatively little attention until the past few years.”

Beyond being more terminology to add to the body of MS medical literature, what clinical significance does this carry? Plenty.

“Early recognition of MS could lead to greater ability to prevent future disability progression, and prompt identification of ‘at-risk’ individuals may be key when trialing neuroprotective interventions,“ Tremlett and Marrie explained. “Understanding the prodromal period in MS, including its features and duration, may also advance our ability to prevent typical clinical disease onset.” 

“Identification of triggers for MS onset requires careful consideration of the prodromal phase to avoid attributing a ‘risk factor’ for MS to manifestations of early symptoms of disease,” they added. ”Whether early recognition of prodromal MS could prevent the disease from occurring at all remains an exciting possibility.” 

In other words, recognizing a prodromal period in MS may have a similar effect to recognizing a prodromal period in migraine headaches: it allows both patient and physician to spot early warning signs (which are often vague), connect the dots, and plan early (such as anticipating that a sick leave from work may be necessary).

Using Data to Detect an MS Prodrome 

We now turn our attention to the work of Zhao and colleagues in their attempt to explore and delineate more clearly the MS prodrome using high-dimensional data. In the introduction of their study, they too wrote about the mystery surrounding the MS prodrome: “Emerging evidence suggests that there is a prodromal period in MS that is measurable as an increase in healthcare use in the years preceding MS onset or diagnosis. The ‘MS prodrome’ appears to comprise a complex constellation of signs and symptoms, evidenced by increased physician encounters for a diverse range of diagnoses and increased prescription medication use.” 

What better way to solve this mystery than by using a data-driven, exploratory approach with supervised statistical learning? Zhao et al accessed hospital, physician, and prescription data for all residents in British Columbia, Canada. Their study design consisted of a matched cohort. They identified MS patients (using the gold standard clinical diagnosis) and performed statistical analyses. 

In total, they identified 4862 MS cases and 22,649 controls. The patients were overwhelmingly female (72%). In going through the signs and symptoms that these patients experience, it was important for the researchers to identify those that could be plausibly linked to a particular treatment regime. However, not everything lined up: they wrote, “Compared to general population controls of the same age, sex, and the same physician-generated diagnostic codes, MS cases had higher odds of filling a prescription for 6 of the 7 medication classes that we examined: antivertigo preparations (by 148%), ‘other’ anti-epileptics (134%), glucocorticoids (76%), urinary anti-spasmodics (72%), muscle relaxants (33%), and benzodiazepines (26%).” 

Their theory? “This overrepresentation in MS cases may represent a signature of the MS prodrome,” they wrote.

Read more about MS treatment 

Zhao and colleagues recognized that the time period between first recognized MS symptoms and later diagnosis requires further investigation to speed diagnosis and hence optimize treatment. They wrote, “A better understanding of these events could ultimately lead to more timely recognition, diagnosis, and treatment of MS.”

In summary, it appears that we have some idea of what constitutes a MS prodrome, but more research needs to be carried out.

“Many other questions remain. The duration of the prodrome is uncertain and we need a clearer understanding of the myriad of signs and symptoms that can occur in the years leading up to MS onset,“ Makhani and Tremlett concluded. “Ultimately, validated research criteria to identify individuals with prodromal MS will help to advance the goals of early recognition and treatment of MS.” 

References

Makhani N, Tremlett H. The multiple sclerosis prodrome. Nat 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 opportunities. Mult Scler. 2021;27(1):6-12. doi:10.1177/1352458520914844

Zhao Y, Wijnands JMA, Högg T, et al. Interrogation of the multiple sclerosis prodrome using high-dimensional health data. Neuroepidemiology. 2020;54(2):140-147. doi:10.1159/000505331