People with multiple sclerosis (MS) are more likely to experience fatigue, sleep disorders, anemia and pain in the five years before they develop the first clinically recognized signs of the disorder, according to a new study published this week.

The study is a follow up to previous work done by Dr. Helen Tremlett (pictured, right) and her team including UBC graduate student Fardowsa Yusuf (pictured, left), looking at the MS prodrome, which refers to early symptoms that occur before classical onset of the disease. Prodromal periods are well established in other diseases such as Parkinson’s, where people experience symptoms such as constipation years before motor deficiencies—the hallmark of Parkinson’s—kick in.

Historically, MS wasn’t thought to have a prodromal phase, but Dr. Tremlett’s previous work debunked this theory. Her team found people who went on to develop MS were up to four times more likely to have been treated for nervous system disorders in the five years leading up to the first clinically recognized signs of MS.

“In our previous work there were so many different symptoms that it was really challenging to unpack them all in one paper,” says Dr. Tremlett, who holds the position of Canada Research Chain in Neuroepidemiology and Multiple Sclerosis. “We were approached by a very talented graduate student who, for this particular study, was able to focus on fatigue, sleep disorders, anemia and pain in this prodromal phase which we defined as the five years before MS symptom onset.”

The study published in Multiple Sclerosis Journal found that, overall, the most prevalent conditions among MS cases over the five-year period before classic symptom onset were pain, sleep disorder, anemia, and fatigue, in this order. The odds of having a sleep disorder were up to 161% higher in MS cases than controls, and the odds of experiencing pain were up to 115% higher.

The team studied health records from across British Columbia and separated them into two MS cohorts. The first was a health administrative cohort, where they identified individuals who had accessed hospitals, physicians, or made prescription claims all related to MS at least three times. The second was a cohort of people who had been diagnosed with MS at one of four clinics across the province. In total, the team reviewed records of nearly 8,000 people with MS and more than 35,000 controls.

Once these individuals were identified, Fardowsa Yusuf, Dr. Tremlett and her team looked at their health records spanning the five years prior to their MS symptom onset—in other words, they looked for any time these individuals had seen a physician or filled a prescription related to anemia, fatigue, sleep problems, and/or pain before they showed any classic MS symptoms.

“We decided to investigate these conditions because of their high prevalence and importance among people with MS,” says Fardowsa Yusuf.

The study is uniquely Canadian in the sense that it required access to health administrative data. Canadian medical records are organized based on personal health numbers, which allows researchers to identify individuals anonymously while still being able to track their movement through the health care system, something that wouldn’t be possible in other countries like the United States.

“This data had been prospectively collected so there is no recall bias in this study—we’re essentially watching people move through the health care system before MS symptom onset,” says Dr. Tremlett. “Of course, we won’t capture the things people managed at home, so this is picking up the more medically significant issues, the ones people actually sought medical attention for.”

Dr. Tremlett says this study adds to existing evidence of an MS prodrome and also gives researchers something to be cognizant about.

“If you want to study what causes MS you have to be really careful about looking in the years just before MS symptom onset,” says Dr. Tremlett. “We don’t want people falling into the trap of reverse causation and mistaking features of the prodrome, such as anemia, for something that might cause MS. Moving forward, we need to be really mindful of this prodrome.”

In the long-term, this study offers the possibility of detecting MS earlier on as a way to start interventions sooner.

“Of course, you cannot say that something as common as fatigue is a hallmark of developing MS as that would not be helpful,” says Dr. Tremlett. “What we’re really showing here is that the prodrome is very complicated and is likely a constellation of many factors. We’re uncovering something that people didn’t use to think existed and we’re just starting to unpack it.”

Funding for this project: This investigation was supported by a research grant from the National Multiple Sclerosis Society (RG 5063A4/1; PI: Tremlett) and Helen Tremlett is funded by the Canada Research Chair Program.

Key prior studies:

Wijnands JMA, Zhu F, Kingwell E, Zhao Y, Ekuma O, Lu X, Evans C, Fisk JD, Marrie RA, Tremlett H. Five years before multiple sclerosis onset: phenotyping the prodrome. Mult Scler. 2019 Jul;25(8):1092-1101. doi: 10.1177/1352458518783662. Epub 2018 Jul 6.

Wijnands JMA, Kingwell E, Zhu F, Zhao Y, Högg T, Stadnyk K, Ekuma O, Lu X, Evans C, Fisk JD, Marrie RA, Tremlett H. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 2017 Jun;16(6):445-451.