“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of , delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.