Multiple Sclerosis

Helen Tremlett, PhD, on Prodromal Multiple Sclerosis

Fatigue, sleep disorders, anemia, and pain appear to be elevated prior to a multiple sclerosis (MS) diagnosis, providing further evidence of a prodromal phase in MS, according to new findings published in the Multiple Sclerosis Journal.

The researchers arrived at their conclusion after performing a population-based matched cohort study. Data were obtained from linked administrative and clinical databases in British Columbia, Canada. Among MS cases, the likelihood of experiencing fatigue, sleep disorders, pain, and anemia in the 5 years prior to the first demyelinating claim or onset of MS symptoms, as well as the frequency of physician visits for any of these conditions, were compared with that of controls from the general population. The researchers took modifying effects of age and sex into account.

A total of 6863 MS cases and 31,865 controls were evaluated prior to the first demyelinating event, and 966 MS cases and 4534 controls were evaluated prior to MS symptom onset. The results of the study indicated that, in the 5 years prior to the first demyelinating event, fatigue (adjusted odds ratio [aOR] 3.37), sleep disorders (aOR 2.61), anemia (aOR: 1.53) and pain (aOR 2.15) occurred more frequently among MS cases compared with controls. Physician visits also increased among MS cases compared with controls during this time period.

Prior to onset of MS symptoms, sleep disorders (aOR 1.72) and pain (aOR 1.53) appeared to be more prevalent among MS cases compared with controls. The researchers noted that the association between MS and anemia was most pronounced among men, and that the association between MS and pain was most pronounced among older patients.

Neurology Consultant discussed these findings further with corresponding study author Helen Tremlett, PhD, professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis in the Department of Medicine at the University of British Columbia in Canada.

NEURO CON: Could you overview the increasing evidence of prodromal MS?

Dr Tremlett: One thing I find interesting is that the idea of an MS prodrome was actually dismissed for a long time, despite other fields of study, including Parkinson disease and Alzheimer disease, seriously examining this paradigm at the same time. Some of the leading medical textbooks for MS, such as McAlpine’s Multiple Sclerosis, categorically stated that a prodromal period did not exist in MS. This textbook was in print until the early 2000s.

As time progressed, scientific data supporting the MS prodrome, as well as anecdotal information from clinical experiences, increasingly emerged. If one asks a patient, “did you experience any fuzzy or strange symptoms that, in hindsight, you think may have been part of your MS?”, that patient will likely have a story to tell. This prompted my colleagues and me to conduct our first study, which was published in The Lancet Neurology in 2017. In that study, which included 14,428 MS cases and 72,059 controls in the general population matched for age, sex, and calendar year, we found that in the 5 years leading up to MS symptom onset or first demyelinating event, patients were more likely to be hospitalized, more likely to visit a physician, and more likely to fill a prescription compared with controls.

Our next question was, “what are the reasons for these increases in health service use among MS cases?” Our data indicated that patients with MS made 50% more visits to their physician for mental health disorders and 50% more visits to psychiatrists in that 5-year period before MS symptom onset or the first demyelinating event compared with controls. When we delved even deeper into our data, we found an increase in factors including sleep disturbances, more visits to the urologist, headaches and migraine pain, fibromyalgia, irritable bowel syndrome, etc, among people with MS.

Our present analysis, which was published in the Multiple Sclerosis Journal, really honed in on a specific group of symptoms–fatigue, sleep disorders, anemia, and pain–that we had not had an opportunity to examine in detail in the past. These symptoms are related and very prevalent in people who receive a diagnosis of MS, but to our knowledge, no other study has really examined the prevalence of these symptoms as a group in the 5 years leading up to MS symptom onset or a first demyelinating event.

NEURO CON: In your study, you found that fatigue, sleep disorders, anemia, and pain were more common among MS cases compared with controls in the 5 years prior to the first demyelinating event, and that age and sex played a significant role in fatigue and pain. Could you elaborate on the role of age and sex in your findings?

Dr Tremlett: In the present analysis, we had the opportunity to break all of our findings down by age and sex. My colleagues and I unexpectedly found that the relative immediate burden of anemia was higher in men with MS than in women with MS (relative to matched men and women in the general population) in the 5 years before MS symptom onset or the first demyelinating event. We also found that pain seems to be more evident in older adults during this prodromal phase.

The exact mechanisms behind these findings remain unclear, but we have hypothesized potential factors that may play a role. In regard to the anemia piece, the literature has suggested that the inflammatory processes of MS may lead to a reduction in iron levels called anemia of inflammation, which is seen in other inflammatory diseases such as rheumatoid arthritis. That may not elucidate why there is a sex difference when it comes to anemia in MS, but I find this difference incredibly intriguing because, in the general population, anemia is more common among women than men.

NEURO CON: What key takeaways do you hope to leave with neurologists on this topic?

Dr Tremlett: There are 2 things I really want to highlight. First, our study and other studies indicate that it may be possible to identify MS, diagnose it, and manage it earlier than we do currently, but that is a lofty goal, and we are not there yet. We do not yet know enough about the prodrome to package it in a way that is clinically meaningful and does not result in overdiagnosis or overmedicalization of a population.

However, other fields, such as Parkinson disease, have been studying this prodromal phase for much longer and have now created validated criteria that include symptoms of the prodrome, along with other metrics. These have been very powerful and have enabled researchers in Parkinson disease to enroll people with prodromal Parkinson disease into clinical trials, in which researchers are attempting to treat them with neuroprotective drug therapies to prevent long-term disability.

The second key takeaway has to do with what can be done with this information right now. I think this is fundamentally important because if we want to know what causes MS, we must really be mindful about this prodromal phase, and we must be really careful when figuring out whether certain symptoms are causing or triggering MS vs just being a feature of the prodrome, where the patient is already destined to develop MS and manifests with these very early symptoms. When we design studies to determine what causes MS, we may need to look back even further than the 5 years before MS symptom onset so that we do not confuse the prodromal phase with a factor that actually triggers the onset of MS.

NEURO CON: What are the next steps in terms of future research in this area?

Dr Tremlett: I think we need to look back very carefully now at our studies that have examined risk factors for MS onset and figure out how much of the previous literature still stands today, given that we now know that there is a prodromal phase in MS. I suspect that some of the risk factors that we think may cause MS may actually just be part of the prodromal phase. This is quite an interesting concept, and we need to figure out how to package these prodromal features in a way that is clinically useful so that we can start to recognize and potentially diagnose and treat people with MS earlier if and when we have a drug or intervention that is neuroprotective. We are not there yet, but that is where the field needs to go.

—Christina Vogt

Yusuf FLA, Wijnands JMA, Kingwell E, et al. Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome. Multiple Sclerosis J. Published online April 6, 2020. doi: