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  • Roadmap
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From the prodromal stage of multiple sclerosis to disease prevention

Nature Reviews Neurology volume 18, pages 559–572 (2022)Cite this article

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Abstract

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

Key points

  • Emerging evidence supports the existence of a prodromal stage in multiple sclerosis (MS) as established in other neurological and immune-mediated diseases.

  • Revision of the natural history of MS to include the prodromal stage enables the identification of opportunities for future intervention and facilitates the design of clinical trials.

  • Clear research directions are needed to develop standardized criteria for prodromal MS, which will enable the identification of individuals who are at high risk of developing classical MS and who might benefit from intervention.

  • The prodromal stage of MS needs to be fully characterized through prospective studies that focus on informative populations such as people with radiologically isolated syndrome or first-degree relatives with MS.

  • Identification and validation of clinical, genetic, imaging and fluid biomarkers of prodromal MS in diverse populations are needed.

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Fig. 1: Proposed framework for the stages of MS.

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Acknowledgements

The workshop from which this Roadmap was generated was supported by the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society. R.A.M. is supported by the Waugh Family Chair in Multiple Sclerosis and Research Manitoba. The authors thank Margarita Lin for assistance with the preparation of tables. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

    Ruth Ann Marrie

  2. Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

    Ruth Ann Marrie

  3. National Multiple Sclerosis Society, New York, NY, USA

    Mark Allegretta, Bruce Bebo, Walter Kostich, Douglas Landsman & Kathleen M. Zackowski

  4. Division of Epidemiology and Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California Berkeley, Berkeley, CA, USA

    Lisa F. Barcellos

  5. Kaiser Permanente Division of Research, Oakland, CA, USA

    Lisa F. Barcellos

  6. Johns Hopkins University School of Medicine, Departments of Neurology, Neuroscience and Ophthalmology, Baltimore, MD, USA

    Peter A. Calabresi

  7. Department of Neurology, Fleni, Buenos Aires, Argentina

    Jorge Correale

  8. Multiple Sclerosis Society of Canada, Toronto, Ontario, Canada

    Benjamin Davis, Pamela Kanellis & Pamela Valentine

  9. Multiple Sclerosis Center, Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA

    Philip L. De Jager

  10. Department of Neurology, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany

    Christiane Gasperi & Bernhard Hemmer

  11. Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, WA, USA

    Carla Greenbaum

  12. Multiple Sclerosis International Federation, London, UK

    Anne Helme

  13. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Bernhard Hemmer

  14. CHU de Nice Pasteur 2, CRCSEP, UR2CA-URRIS, Université Nice Cote d’Azur Nice, Nice, France

    Christine Lebrun-Frenay

  15. Departments of Pediatrics and Neurology, Yale School of Medicine, New Haven, CT, USA

    Naila Makhani

  16. Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA

    Kassandra L. Munger

  17. The University of Texas Southwestern Medical Center, Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, Dallas, TX, USA

    Darin T. Okuda

  18. Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA

    Daniel Ontaneda

  19. Department of Neurology, McGill University, Montreal, Quebec, Canada

    Ronald B. Postuma

  20. Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Jacqueline A. Quandt

  21. Patient representative, Vancouver, British Columbia, Canada

    Sharon Roman

  22. Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Shiv Saidha

  23. Department of Health Sciences, University of Genova, and IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Maria Pia Sormani

  24. RealTalk MS, Long Beach, CA, USA

    Jon Strum

  25. MS Society, London, UK

    Clare Walton

  26. Faculty of Medicine (Neurology), University of British Columbia, Vancouver, British Columbia, Canada

    Yinshan Zhao & Helen Tremlett

Authors
  1. Ruth Ann Marrie
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  2. Mark Allegretta
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  3. Lisa F. Barcellos
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  4. Bruce Bebo
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  5. Peter A. Calabresi
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  6. Jorge Correale
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  7. Benjamin Davis
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  8. Philip L. De Jager
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  9. Christiane Gasperi
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  10. Carla Greenbaum
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  11. Anne Helme
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  12. Bernhard Hemmer
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  13. Pamela Kanellis
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  14. Walter Kostich
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  15. Douglas Landsman
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  16. Christine Lebrun-Frenay
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  17. Naila Makhani
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  18. Kassandra L. Munger
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  19. Darin T. Okuda
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  20. Daniel Ontaneda
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  21. Ronald B. Postuma
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  22. Jacqueline A. Quandt
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  23. Sharon Roman
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  24. Shiv Saidha
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  25. Maria Pia Sormani
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  26. Jon Strum
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  27. Pamela Valentine
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  28. Clare Walton
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  29. Kathleen M. Zackowski
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  30. Yinshan Zhao
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  31. Helen Tremlett
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Contributions

R.A.M. and H.T. researched data for the article. R.A.M., L.F.B., C.Greenbaum., C.L.-F., D.T.O., R.B.P., J.A.Q., S.S. and H.T. contributed to the writing of the manuscript. R.A.M., M.A., L.F.B., B.B., P.A.C., J.C., P.L.D.J., C.Gasperi, C.Greenbaum, A.H., B.H., W.K., D.L., C.L.-F., N.M., K.L.M., D.T.O., D.O., R.B.P., J.A.Q., S.S., M.P.S., J.S., K.M.Z. and H.T. made substantial contributions to the discussion of content. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Ruth Ann Marrie.

Ethics declarations

Competing interests

R.A.M. receives research funding from the Canadian Institutes of Health Research, Consortium of Multiple Sclerosis Centers, Crohn’s and Colitis Canada, Multiple Sclerosis Scientific Foundation, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Research Manitoba and the US Department of Defense, and is a co-investigator on studies that receive funding from Biogen Idec and Roche Canada. L.F.B. receives research funding from the National Institutes of Health/National Institute of Nursing Research and the National Multiple Sclerosis Society. P.A.C. is a principal investigator on grants to Johns Hopkins University from Genentech and Principia and has received consulting fees from Avidea, Biogen, Disarm and Nerveda. J.C. has received financial compensation for academic presentations, attended advisory boards, research programmes, and assistance for travel to congresses from Bayer, Biogen, Bristol Myers Squibb, Gador, Janssen, Merck, Novartis, Raffo, Roche and Sanofi-Genzyme. P.L.D.J. is on the advisory board for Biogen, Celgene, Genzyme and Roche, and has sponsored research agreements with Biogen and Roche. C. Gasperi receives research support from the German Federal Ministry of Education and Research (BMBF), the German Research Foundation (Deutsche Forschungsgesellschaft, DFG), the Hans and Klementia Langmatz Stiftung and the Hertie Foundation. C. Greenbaum has served on an advisory board for Merck, receives funding for investigator-initiated trials from Bristol Myers Squibb and Janssen, and serves as Principal Investigator on clinical trials sponsored by Intrexon, Pfizer and ProventionBio. A.H. is an employee of the Multiple Sclerosis International Federation, which receives income from a range of corporate sponsors, recently including Biogen, Bristol Myers Squibb, Janssen, Merck, Mylan, Novartis, Roche and Sanofi. B.H. has served on scientific advisory boards for Novartis and as Data Safety Monitoring Committee member for AllergyCare, Polpharma and TG Therapeutics. He and his institution have received speaker honoraria from Desitin. His institution has received research grants from Regeneron for multiple sclerosis research. He holds part of two patents: one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. C.L.-F. has participated in expert advisory boards for Genzyme, Novartis and Roche. Speaker honoraria are either declined or donated to the University Hospital Radiologically Isolated Syndrome Research Unit, University Cote d’Azur, Nice, France. N.M. is funded by NIH/NINDS (grant number K23NS101099) and the Charles H. Hood Foundation. K.L.M. has received personal compensation for serving on a scientific advisory board for Biogen. D.T.O. has received personal compensation for consulting and advisory services from Biogen, Celgene, EMD Serono, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica and Viela Bio, and has received research support from Biogen. D.T.O. also has issued and pending patents and has received royalties related to licensed intellectual property. D.O. receives research support from Genentech, Genzyme, National Institutes of Health, National Multiple Sclerosis Society, Novartis, Patient Centered Outcomes Research Institute, and Race to Erase MS Foundation. He has received consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Janssen, Merck and Novartis. R.B.P. has received grants and personal fees from Fonds de la Recherche en Sante and Roche; grants from the Canadian Institute of Health Research, the Michael J. Fox Foundation, the National Institute of Health, the Parkinson Society of Canada, the Webster Foundation and the Weston-Garfield Foundation; and personal fees from Abbvie, Biogen, Boehringer Ingelheim, GE HealthCare, Inception Sciences, Jansen, Jazz Pharmaceuticals, Otsuko, Paladin, Phytopharmics, Takeda, Teva Neurosciences, and Theranexus. J.A.Q. receives research funding from the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society. S.R. serves on the Patient Editorial Board for the Journal of Neurology, Neurosurgery and Psychiatry, and University of British Columbia BC Brain Wellness Program Participant Advisory Committee. S.S. has received consulting fees from Medical Logix for the development of Continuing Medical Education programmes in neurology and has served as a consultant for Biogen, Bristol Meyers Squibb, Genentech Novartis and TG Therapeutics. He is the Principal Investigator of investigator-initiated studies funded by Biogen and Genentech, was the site investigator of a trial sponsored by MedDay Pharmaceuticals, and has received support from the Race to Erase MS Foundation. He has received equity compensation for consulting from JuneBrain LLC. M.P.S. has received personal fees from Biogen, Celgene, Geneuro, GlaxoSmithKline, Immunic, Medday, Merck, Novartis, Roche and Sanofi. J.S. is the host of the RealTalk MS podcast. He has received sponsorship fees from Bristol Myers Squibb, EMD Serono, Janssen Pharmaceuticals and the National Multiple Sclerosis Society. He has received travel expenses from the Accelerated Cure Project, EMD Serono, the National Multiple Sclerosis Society and the International Progressive Multiple Sclerosis Alliance. He has received speaking honoraria from EMD Serono, the European Multiple Sclerosis Platform and Novartis. He has received consulting fees from Merck. He is currently co-Principal Investigator on research conducted through iConquer MS and underwritten by EMD Serono. H.T. is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. Current research support is received from the Canadian Institutes of Health Research, the Multiple Sclerosis Scientific Research Foundation, the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society. In addition, in the past 5 years, she has received research support from the UK Multiple Sclerosis Trust; travel expenses to present at Continuing Medical Education conferences from the Americas Committee for Treatment and Research in Multiple Sclerosis, the American Academy of Neurology, the Consortium of MS Centres (2018), the European Committee for Treatment and Research in Multiple Sclerosis and the National MS Society. Speaker honoraria are either declined or donated to a multiple sclerosis charity or to an unrestricted grant for use by H.T.’s research group. All other authors declare no competing interests.

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Marrie, R.A., Allegretta, M., Barcellos, L.F. et al. From the prodromal stage of multiple sclerosis to disease prevention. Nat Rev Neurol 18, 559–572 (2022). https://doi.org/10.1038/s41582-022-00686-x

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