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When does multiple sclerosis actually begin? To jumpstart research on this question, researchers in the fields of MS, type 1 diabetes, Parkinson’s disease, and other experts, including people affected by MS, attended a virtual workshop in June 2021 to strategize on approaches for detecting MS before typical symptoms of MS develop. The ultimate goal is to find ways to detect MS earlier to enable interventions that will improve outcomes and preserve quality of life.
 
Now the workshop organizers and presenters have summarized the landscape of the prodrome of MS and other disorders, and offer recommendations for prioritizing research opportunities to accelerate this important work in a paper published in Nature Reviews Neurology on July 15, 2022.
 
The workshop was convened by the MS Society of Canada and the National MS Society (USA) to identify knowledge gaps and to recommend priorities for research on the MS “prodrome” -- a period when vague or seemingly unconnected symptoms, signs, or health issues may indicate the beginning of MS before more typical symptoms occur.
 
Background and Details

• MS attacks the brain, spinal cord and optic nerves. Its symptoms can vary significantly between people, but commonly may include vision problems and eye pain, walking difficulties, fatigue, and numbness or tingling. Recent research suggests that some people who are eventually diagnosed with MS may experience health and psychiatric issues well before specific MS symptoms emerge.
  • For example, people who were eventually diagnosed with MS made more doctor visits up to 5 years before their diagnosis; children were more likely to have been hospitalized before being diagnosed with MS. Beyond symptoms, one study showed that blood levels of a biomarker for nerve degeneration (called neurofilament light chain) was elevated a median of 6 years before specific MS signs or symptoms arose.
• The paper reviews what is known about the MS prodrome and advances in early detection of diseases like Type 1 Diabetes and Parkinson’s Disease. Progress is being made in these disorders, where researchers have developed scoring systems for the prodromal phase that combine risk factors, age, sex, family history, and genetic factors to calculate an individual’s chances of eventually developing that disease, similar to what’s done for cardiovascular disease. Applying this idea to MS, if a person’s risk score reaches a pre-determined level, then their risk of developing the disease is high, so it increases the importance of considering early treatment as a possible prevention.

• The paper’s authors note that several clinical trials are underway in people with radiologically isolated syndrome, who have brain MRI scans with lesions suggestive of MS but who have no discernable signs or definite MS symptoms. A portion of individuals with this syndrome go on to develop MS. These trials focus on seeing whether MS disease-modifying therapies can slow or stop the development of definite MS, and on better defining the profiles of those who do progress to MS.

 
Proposed Stages of MS
To help advance this research and enable comparison of findings across studies in the future, the authors propose alignment to standard terminology for stages of MS as it advances before diagnosis. They note that these stages may overlap, may vary in length in individuals, or may be indistinct or absent, and may not be apparent in those with primary progressive MS:

• The susceptibility stage is a period when an individual may be exposed to multiple MS risk factors (such as Epstein-Barr virus infection, obesity, smoking, and low vitamin D) layered over a genetic profile that may itself confer risk for MS. This stage may kick-start the biological processes that lead to MS.
• The subclinical stage starts once the disease process begins, in the absence of any detectable signs or symptoms. This stage may or may not lead to a prodromal stage, or may skip directly to the onset of typical symptoms of MS. Although, by definition, there would be no signs or symptoms of MS, based on what’s known from other diseases, it’s possible that changes in immune function are at work and could be identified in future research.
• The prodromal stage is a time when vague, non-typical medical or mood issues may arise, but these would not be considered classical symptoms of MS. This stage ends when the first neurological symptom that lasts at least 24 hours occurs, which qualifies as clinically isolated syndrome (a precursor of definite MS). Once that occurs, this stage would be considered the classical MS symptom onset stage.

 
Research goals, approaches, and accelerators
The authors outline priority research areas to advance this work, with the goal of developing a better understanding and detection of the biological and clinical underpinnings of the MS prodrome to identify individuals at high risk for developing classical MS symptoms. Ultimately, the goal is to create a score that accounts for various indicators of MS risk, including expected local prevalence of MS, a risk factor profile, and demographics, clinical, imaging, and blood/other fluid markers that together may indicate an individual is at high risk for developing classical MS. The paper includes examples of how scores could be calculated (“likelihood ratios”) to determine an individual’s likelihood for developing MS. A calculation like this could be used to inform pre-emptive treatment decisions.
 
Research goals include:

• Refine global prevalence estimates to include age and gender
• Characterize the MS prodromal stage and identify risk factors that increase susceptibility to MS in diverse populations, beyond those of European ancestry, and better understand how exposures alter the expression/influence of genes and impact disease variability
• Define key signs and symptoms of the MS prodrome according to age, sex, geography, and other characteristics, and which may form identifiable patterns or markers likely to increase the probability of developing definite MS
• When more data are available, develop and validate criteria for the MS prodromal stage that would enable solid estimates of any individual’s likelihood of progressing to classical MS, which might provide a rationale for intervention or for clinical trial enrollment

 
Some recommended approaches and accelerators include:

• Focusing on populations that are more likely to be at risk for MS, such as:
  • individuals with radiologically isolated syndrome
  • individuals whose twin has MS but they do not
  • immediate family members of people diagnosed with MS
• Developing standardized questionnaires to capture individual’s non-specific symptoms
• Making standardized genetic testing more accessible and low cost to enable the development of genetic risk scores for individuals
• Improving accessibility of screening tools such as imaging to identify those at high risk of MS
• Identifying biomarkers that provide early indicators of immune abnormalities and central nervous system injury
• When more data and markers are available, determine the threshold when a combination of prodromal markers indicate a high probability that someone will progress to classic MS symptoms, making intervention ethical

 
The authors also outline considerations for future studies focusing on the MS prodrome, including the types of populations to study, the number of participants to include, study design, and markers to track.
 
“We are confident that the publication of this paper will raise awareness and open up new avenues and help prioritize research toward detecting MS at its earliest stages and preventing or slowing the nervous system damage with potential huge benefits for people at risk for MS,” said Bruce Bebo, PhD, Executive Vice President of Research at the National MS Society (USA), who was one of the workshop organizers.
 
Workshop co-chairs Ruth Ann Marrie, MD, PhD (University of Manitoba) and Helen Tremlett, PhD (University of British Columbia) were lead authors of “From the Prodromal Stage of Multiple Sclerosis to Disease Prevention,”  by Ruth Ann Marrie, Mark Allegretta, Lisa F. Barcellos, Bruce Bebo, Peter Calabresi, Jorge Correale, Benjamin Davis, Philip L. De Jager, Christiane Gasperi, Carla Greenbaum, Anne Helme, Bernhard Hemmer, Pamela Kanellis, Walter Kostich, Douglas Landsman, Christine Lebrun-Frenay, Naila Makhani, Kassandra L. Munger, Darin T. Okuda, Daniel Ontaneda, Ronald Postuma, Jacqueline A. Quandt, Sharon Roman, Shiv Saidha, Maria Pia Sormani, Jon Strum, Pamela Valentine, Clare Walton, Kathleen M. Zackowski, Yinshan Zhao, and Helen Tremlett. It was published online on date July 15, 2022 in Nature Reviews Neurology.