Based on previous work by Dr. Helen Tremlett, there is emerging evidence that a prodromal stage exists in multiple sclerosis (MS), which raises the possibility of intervention at this early stage to delay or prevent the development of classical MS. In a new article published in Nature Reviews Neurology today, Dr. Tremlett and her team propose a disease framework for MS that includes the prodromal stage and outline key steps in identifying early disease markers and developing standardized criteria for diagnosis.

The following is a summary written by Sharon Roman, a patient-partner working with Dr. Tremlett and also a patient editor with the BMJ group of journals.


“Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease in which genetic and environmental factors contribute to disease development.” While the cause of MS has been studied for many years, a growing body of compelling evidence has recently emerged to validate a set of signs and symptoms that indicates the onset of disease before more typical signs and symptoms present to fulfill a diagnosis of MS.

On June 24, 2021, a group of international researchers, patient advocates and stakeholders led by Professors Helen Tremlett (University of British Columbia) and Ruth Ann Marrie (University of Manitoba) convened virtually for a workshop to identify key gaps in knowledge, opportunities, and research priorities regarding the prodromal stage of MS. The group developed a new framework for MS that includes the stage of early signs and symptoms of MS – and outlined a roadmap to guide future research, with the “goal of preventing the progression to onset of typical symptoms of MS in those who present during the prodromal stage of MS.” A prodrome is “an early, often nonspecific, set of signs and/or symptoms indicating onset of a disease.” These have been shown to occur five to ten years before more typical signs and symptoms of disease appear in people subsequently diagnosed with MS.

The group revised the natural history of MS, drawing on progress already made in other neurodegenerative and autoimmune diseases, such as Parkinson disease and Type 1 diabetes mellitus. If high risk individuals in the early stages of MS can be identified with a high degree of certainty, there is an opportunity to intervene and minimize the risk of progressing to typical MS symptoms and a diagnosis of MS. The ability to identify the stages of MS more clearly and those most likely to benefit from intervention with a high degree of certainty can guide prevention efforts.

With this in mind, the group then drew a roadmap for future research priorities to further improve the understanding and definition of early MS so that standardized criteria can be developed and validated, and interventions tested. Several steps are needed to develop validated criteria that enable better identification of those in the early stage of disease with a high degree of certainty and those with a high probability of progressing to definite disease. The relative strengths of disease markers need to be established to determine their predictive value as indicators of risk and progression to disease. The steps needed to develop these formal criteria were mapped out.

The need for strong early markers of disease and intervention opportunities – a research roadmap

Four major goals are outlined in the proposed roadmap for researchers:

  1. Gather population-based, age and sex-specific estimates for MS prevalence worldwide to act as prior (pre-existing) probabilities for MS. The prior probability is the probability that an individual will in time develop MS before clinical assessment.
  2. Further identify the early signs and symptoms and identify new disease markers for MS with a focus on potentially informative populations such as first-degree relatives of a person with MS.
  3. Measure the association between early disease markers and the probability of typical MS using tools like standardized questionnaires and genetic risk scores. Identify and validate markers with a high predictive value.
  4. Develop and validate criteria for the early signs and symptoms stage of MS for research purposes and determine a meaningful point where intervention is warranted.

The need for sustained long-term commitments to multiple studies and clinical trials is crucial to developing standardized criteria and potential treatments. These studies, clinical trials and follow-up periods need to be much longer than the standard two to three years, with a concerted goal of developing criteria with a high degree of certainty. Specifically, there is a need to establish strong markers of the signs and symptoms of early disease activity, and those at high risk of typical MS symptom onset. The timing and duration of interventional therapy will also need to be established.

For the goal of standardized criteria to become a reality, long-term efforts of all parties, from industry and regulators to persons with MS, advocacy groups and organizations who develop clinical care guidelines are needed. Achieving these milestones and establishing a framework for the early stages of MS will enable us to better recognize, better diagnose and better treat MS.