Increasing interest in characterizing the MS prodrome

BY FRIEDA WILEY


The concept of prodromes has largely been recognized across the spectrum of neurodegenerative diseases, including the potential of early detection in improving outcomes. Yet, only in the last decade has the concept of a multiple sclerosis (MS) prodrome garnered increasing attention, owing much to its role in the pathogenesis and predictive outcomes for the disease state.

Helen Tremlett, PhD, a professor and Canada Research Chair in neuroepidemiology and MS at the University of British Columbia, Vancouver, stressed the importance of the new attention devoted to the MS prodrome. After all, erroneously diagnosing prodromal symptoms as MS can have disastrous effects on symptom management and overall MS outcomes.

"If you want to know what causes MS, you need to be very careful not to measure something during the prodromal phase, thinking it causes MS when the person already has the condition," she said in an interview. "Now editorials and articles on missed opportunities for the diagnosis will highlight the difficult journey people undertake when getting diagnosed with MS."


Dr. Helen Tremlett

In response to the heightened interest in MS prodrome research, the U.S. National MS Society launched a competition regarding the concept of the prodrome. Dr. Tremlett and associates were one of the awardees.

In patients who have MS, the prodromal onset occurs for many months or years before their condition begins to manifest as a disease state.

By definition, a prodrome is a group of signs or symptoms that suggest the presence of a disease. However, prodromic manifestations appear in advance of the signs and symptoms normally considered characteristic of the disease and confirming the diagnosis. When in place, the comprehensive nature of electronic health records facilitates researchers' ability to conduct population-based studies by allowing trend analysis and other research that reviews large data sets.

"If you want to know what causes MS, you need to be very careful not to measure something during the prodromal phase, thinking it causes MS when the person already has the condition," she said in an interview. "Now editorials and articles on missed opportunities for the diagnosis will highlight the difficult journey people undertake when getting diagnosed with MS."
Dr. Tremlett and colleagues identified several manifestations of MS prodrome in an article published in 2018. These include declining health occurring prior to an MS diagnosis. As their overall health deteriorates, patients with prodromic onset tend to utilize the health care system more.

Poor cognition before the typical MS symptoms is another factor. In addition, researchers acknowledge race and age as "features of the MS prodrome" also included in the prodrome. However, data on demographic information such as race and gender remain largely understudied.

Furthermore, patients in the prodromic state are also more likely to visit the dermatologist for skin complaints than those patients already experiencing the primary progressive disease in the 5-year period before typical MS symptoms occur.

Beyond that, MRI offers researchers and clinicians another clue. MRI studies reveal that certain biomarkers commonly found in people with symptomatic MS often appear in patients who have no symptoms. This is known as radiologically isolated syndrome (RIS). Dr. Tremlett and colleagues pointed out that RIS could be classified as an MS prodrome marker. However, like many areas concerning prodromic onset, additional investigation is necessary.

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In the same article, Dr. Tremlett and colleagues offered a set of criteria to help researchers establish criteria to facilitate the designs of future studies on prodromal MS. They include the following:
  • A need to establish what the authors refer to as a consensus terminology for the phases of MS from the risk factor phase through the prodromal phase to clinical MS.
  • The creation of predictive models that would incorporate data such as neuroimaging studies and clinical prodromal symptoms.
  • Development of massive networks consisting of multicenter facilities.
Despite the impact of the prodrome in MS only catching fire in recent years, Dr. Tremlett believes the historical omission in MS did not occur intentionally.

"I’m guessing the reason why it was dismissed or largely overlooked earlier is that there was no evidence to show whether not the prodrome existed,” Dr. Tremlett conjectured.

Looking forward, Dr. Tremlett felt the MS world stands much to gain from research in the prodromic space. “If it can help us reduce risk of MS in the future generations, that would be great for us,” she said.

Future research, she added, should focus on determining the duration of the prodrome and whether it varies across individuals. Also needed is a better understanding of all its potential features, including identification of relevant biomarkers that may support accurate identification of individuals at high risk of a future diagnosis of MS.

Suggested Reading

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