Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The multiple sclerosis prodrome

Nature Reviews Neurology volume 17, pages 515–521 (2021)Cite this article

Subjects

Abstract

A prodrome is an early set of signs, symptoms or other findings that occur before the onset of typical symptoms of a disease. Prodromal phases are well recognized in several neurological and inflammatory diseases, but the possibility of a prodrome in multiple sclerosis (MS) has received relatively little attention until the past few years. In this Perspective, we summarize what is currently known about the MS prodrome, including its possible duration, clinical features and potential biomarkers. We also consider what insights and lessons can be learned from knowledge of and research into the prodromal phases of other diseases. A better understanding of the MS prodrome could have profound clinical implications as it could enable earlier recognition of MS and earlier initiation of treatments that reduce relapse rates and long-term disability. Knowledge of the MS prodrome could also affect research into the causes of MS, and putative risk factors must be re-evaluated in light of the MS prodrome. We conclude by outlining the major knowledge gaps and propose future initiatives.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Thompson, A. J. et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 17, 162–173 (2018).

    Article  PubMed  Google Scholar 

  2. Wolfson, C. & Wolfson, D. B. The latent period of multiple sclerosis: a critical review. Epidemiology 4, 464–470 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Giovannoni, G. The neurodegenerative prodrome in multiple sclerosis. Lancet Neurol. 16, 413–414 (2017).

    Article  PubMed  Google Scholar 

  4. Hogg, T. et al. Mining healthcare data for markers of the multiple sclerosis prodrome. Mult. Scler. Relat. Disord. 25, 232–240 (2018).

    Article  PubMed  Google Scholar 

  5. Tremlett, H. & Marrie, R. A. The multiple sclerosis prodrome: emerging evidence, challenges, and opportunities. Mult. Scler. 27, 6–12 (2020).

    Article  PubMed  Google Scholar 

  6. Wijnands, J. M. A. et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 16, 445–451 (2017).

    Article  PubMed  Google Scholar 

  7. Marrie, R. A. Mounting evidence for a multiple sclerosis prodrome. Nat. Rev. Neurol. 15, 689–690 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. The Multiple Sclerosis International Federation. Atlas of MS 3rd Edition https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf (2020).

  9. Wijnands, J. M. et al. Five years before multiple sclerosis onset: phenotyping the prodrome. Mult. Scler. 25, 1092–1101 (2019).

    Article  PubMed  Google Scholar 

  10. Wijnands, J. M. A. et al. Prodrome in relapsing-remitting and primary progressive multiple sclerosis. Eur. J. Neurol. 26, 1032–1036 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Yusuf, F. et al. Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome. Mult. Scler. 27, 290–302 (2020).

    Article  PubMed  CAS  Google Scholar 

  12. Zhao, Y. et al. Interrogation of the multiple sclerosis prodrome using high-dimensional health data. Neuroepidemiology 54, 140–147 (2020).

    Article  PubMed  Google Scholar 

  13. Yusuf, F. L. A. et al. A systematic review of morbidities suggestive of the multiple sclerosis prodrome. Expert Rev. Neurother. 20, 799–819 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Poser, C. M. et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13, 227–231 (1983).

    Article  CAS  PubMed  Google Scholar 

  15. Matthews, W. B. McAlpine’s Multiple Sclerosis 2nd edn (Churchill Livingstone, 1991).

  16. Byatt, N., Rothschild, A. J., Riskind, P., Ionete, C. & Hunt, A. T. Relationships between multiple sclerosis and depression. J. Neuropsychiatry Clin. Neurosci. 23, 198–200 (2011).

    Article  PubMed  Google Scholar 

  17. Gout, O. et al. Prior suggestive symptoms in one-third of patients consulting for a “first” demyelinating event. J. Neurol. Neurosurg. Psychiatry 82, 323–325 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Sinay, V., Perez Akly, M., Zanga, G., Ciardi, C. & Racosta, J. M. School performance as a marker of cognitive decline prior to diagnosis of multiple sclerosis. Mult. Scler. 21, 945–952 (2015).

    Article  PubMed  Google Scholar 

  19. Disanto, G. et al. Prodromal symptoms of multiple sclerosis in primary care. Ann. Neurol. 83, 1162–1173 (2018).

    Article  PubMed  Google Scholar 

  20. Cortese, M. et al. Preclinical disease activity in multiple sclerosis: a prospective study of cognitive performance prior to first symptom. Ann. Neurol. 80, 616–624 (2016).

    Article  PubMed  Google Scholar 

  21. Marrie, R. A. et al. Increased mental health care use by mothers of children with multiple sclerosis. Neurology 94, e1040–e1050 (2020).

    Article  PubMed  Google Scholar 

  22. Marrie, R. A. et al. High rates of health care utilization in pediatric multiple sclerosis: a Canadian population-based study. PLoS ONE 14, e0218215 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marrie, R. A. et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol. Psychiatr. Sci. 28, 333–342 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Ponsonby, A. L. et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology 78, 867–874 (2012).

    Article  PubMed  Google Scholar 

  25. Okuda, D. T. et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 72, 800–805 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Makhani, N. et al. Radiologically isolated syndrome in children: clinical and radiologic outcomes. Neurol. Neuroimmunol. Neuroinflamm 4, e395 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Granberg, T., Martola, J., Kristoffersen-Wiberg, M., Aspelin, P. & Fredrikson, S. Radiologically isolated syndrome — incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult. Scler. 19, 271–280 (2013).

    Article  PubMed  Google Scholar 

  28. Morris, Z. et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 339, b3016 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kuhle, J. et al. Conversion from clinically isolated syndrome to multiple sclerosis: a large multicentre study. Mult. Scler. 21, 1013–1024 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Filippi, M. et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 17, 133–142 (2018).

    Article  PubMed  Google Scholar 

  31. Tintore, M. et al. Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain 138, 1863–1874 (2015).

    Article  PubMed  Google Scholar 

  32. Tintore, M. et al. Contribution of the symptomatic lesion in establishing MS diagnosis and prognosis. Neurology 87, 1368–1374 (2016).

    Article  PubMed  Google Scholar 

  33. Lebrun-Frenay, C. et al. Radiologically isolated syndrome: 10-year risk estimate of a clinical event. Ann. Neurol. 88, 407–417 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Kantarci, O. H. et al. Primary progressive multiple sclerosis evolving from radiologically isolated syndrome. Ann. Neurol. 79, 288–294 (2016).

    Article  PubMed  Google Scholar 

  35. Okuda, D. T. et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS ONE 9, e90509 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Lebrun, C., Blanc, F., Brassat, D., Zephir, H. & de Seze, J. Cognitive function in radiologically isolated syndrome. Mult. Scler. 16, 919–925 (2010).

    Article  PubMed  Google Scholar 

  37. Amato, M. P. et al. Association of MRI metrics and cognitive impairment in radiologically isolated syndromes. Neurology 78, 309–314 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Menascu, S. et al. Assessing cognitive performance in radiologically isolated syndrome. Mult. Scler. Relat. Disord. 32, 70–73 (2019).

    Article  PubMed  Google Scholar 

  39. Azevedo, C. J. et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol. Neuroimmunol. Neuroinflamm. 2, e102 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  40. George, I. C. et al. Cerebellar volume loss in radiologically isolated syndrome. Mult. Scler. 27, 130–133 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Alcaide-Leon, P. et al. Quantitative spinal cord MRI in radiologically isolated syndrome. Neurol. Neuroimmunol. Neuroinflamm. 5, e436 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Giorgio, A. et al. Cortical lesions in radiologically isolated syndrome. Neurology 77, 1896–1899 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Giorgio, A. et al. Appraisal of brain connectivity in radiologically isolated syndrome by modeling imaging measures. J. Neurosci. 35, 550–558 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stromillo, M. L. et al. Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. Neurology 80, 2090–2094 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Bjornevik, K. et al. Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis. JAMA Neurol. 77, 58–64 (2020).

    Article  PubMed  Google Scholar 

  46. Matute-Blanch, C. et al. Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome. Brain 141, 1085–1093 (2018).

    Article  PubMed  Google Scholar 

  47. Makhani, N. et al. Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome. Mult. Scler. J. Exp. Transl Clin. 5, 2055217319836664 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. Schafflick, D. et al. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat. Commun. 11, 247 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Beltrán, E. et al. Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis. J. Clin. Invest. 129, 4758–4768 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Simone, I. L. et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 59, 1922–1928 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Chitnis, T., Glanz, B., Jaffin, S. & Healy, B. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult. Scler. 15, 627–631 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Jansen, P. R. et al. Incidental findings on brain imaging in the general pediatric population. N. Engl. J. Med. 377, 1593–1595 (2017).

    Article  PubMed  Google Scholar 

  53. Polman, C. H. et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292–302 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Xia, Z. et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 74, 293–300 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. De Stefano, N. et al. Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis. Ann. Neurol. 59, 634–639 (2006).

    Article  PubMed  Google Scholar 

  56. Gabelic, T. et al. Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of patients with multiple sclerosis. AJNR Am. J. Neuroradiol. 35, 106–112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Berg, D. et al. MDS research criteria for prodromal Parkinson’s disease. Mov. Disord. 30, 1600–1611 (2015).

    Article  PubMed  Google Scholar 

  58. Heinzel, S. et al. Update of the MDS research criteria for prodromal Parkinson’s disease. Mov. Disord. 34, 1464–1470 (2019).

    Article  PubMed  Google Scholar 

  59. Postuma, R. B. Prodromal Parkinson disease: do we miss the signs? Nat. Rev. Neurol. 15, 437–438 (2019).

    Article  PubMed  Google Scholar 

  60. Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Mankia, K. & Emery, P. Preclinical rheumatoid arthritis: progress toward prevention. Arthritis Rheumatol. 68, 779–788 (2016).

    Article  PubMed  Google Scholar 

  62. Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).

    Article  PubMed  Google Scholar 

  63. van de Stadt, L. A., Witte, B. I., Bos, W. H. & van Schaardenburg, D. A prediction rule for the development of arthritis in seropositive arthralgia patients. Ann. Rheum. Dis. 72, 1920–1926 (2013).

    Article  PubMed  Google Scholar 

  64. Greenblatt, H. K., Kim, H. A., Bettner, L. F. & Deane, K. D. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr. Opin. Rheumatol. 32, 289–296 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  65. van der Helm-van Mil, A. & Landewé, R. B. M. The earlier, the better or the worse? Towards accurate management of patients with arthralgia at risk for RA. Ann. Rheum. Dis. 79, 312–315 (2020).

    Article  PubMed  Google Scholar 

  66. Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Eriksson, C. et al. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden. Arthritis Res. Ther. 13, R30 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Melinder, C. et al. Physical fitness in adolescence and subsequent inflammatory bowel disease risk. Clin. Transl. Gastroenterol. 6, e121 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Turpin, W. et al. Increased intestinal permeability is associated with later development of Crohn’s disease. Gastroenterology 159, 2092–2100 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Porter, C. K., Cash, B. D., Pimentel, M., Akinseye, A. & Riddle, M. S. Risk of inflammatory bowel disease following a diagnosis of irritable bowel syndrome. BMC Gastroenterol. 12, 55 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Runmarker, B. & Andersen, O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 118, 253–261 (1995).

    Article  PubMed  Google Scholar 

  72. McKay, K. A., Jahanfar, S., Duggan, T., Tkachuk, S. & Tremlett, H. Factors associated with onset, relapses or progression in multiple sclerosis: a systematic review. Neurotoxicology 61, 189–212 (2017).

    Article  PubMed  Google Scholar 

  73. Yong, H. Y., McKay, K. A., Daley, C. G. J. & Tremlett, H. Drug exposure and the risk of multiple sclerosis: a systematic review. Pharmacoepidemiol. Drug Saf. 27, 133–139 (2018).

    Article  CAS  PubMed  Google Scholar 

  74. Wijnands, J. M. A. & Tremlett, H. Concussion may not cause multiple sclerosis. Ann. Neurol. 82, 651–652 (2017).

    Article  PubMed  Google Scholar 

  75. Montgomery, S. et al. Reply to “concussion may not cause multiple sclerosis”. Ann. Neurol. 82, 652–653 (2017).

    Article  PubMed  Google Scholar 

  76. Montgomery, S. et al. Concussion in adolescence and risk of multiple sclerosis. Ann. Neurol. 82, 554–561 (2017).

    Article  PubMed  Google Scholar 

  77. Smith, K. A. et al. Hospital diagnosed pneumonia before age 20 years and multiple sclerosis risk. BMJ Neurol. Open 2, e000044 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lucas, A. & Wolf, M. Vitamin D and health outcomes: then came the randomized clinical trials. JAMA 322, 1866–1868 (2019).

    Article  PubMed  Google Scholar 

  79. Yung, A. R. & Nelson, B. The ultra-high risk concept-a review. Can. J. Psychiatry 58, 5–12 (2013).

    Article  PubMed  Google Scholar 

  80. Liu, S.-Y., Chan, P. & Stoessl, A. J. The underlying mechanism of prodromal PD: insights from the parasympathetic nervous system and the olfactory system. Transl Neurodegener. 6, 4 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Naila Makhani

  2. Faculty of Medicine (Neurology), The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada

    Helen Tremlett

Authors
  1. Naila Makhani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helen Tremlett
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed to all aspects of the manuscript.

Corresponding author

Correspondence to Helen Tremlett.

Ethics declarations

Competing interests

N.M. is funded by NIH/NINDS (grant number K23NS101099) and the Charles H. Hood Foundation. H.T. is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. Current research support has been received from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation. In the past 5 years, she has received research support from the UK MS Trust and travel expenses to present at CME conferences from the Consortium of MS Centres (2018), the National MS Society (2016, 2018), ECTRIMS and ACTRIMS (2015, 2016, 2017, 2018, 2019, 2020), and the American Academy of Neurology (2015, 2016, 2019). Speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by H.T.’s research group.

Additional information

Peer review information

Nature Reviews Neurology thanks M. Amato, T. Chitnis, G. Disanto and R. Dobson for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Makhani, N., Tremlett, H. The multiple sclerosis prodrome. Nat Rev Neurol 17, 515–521 (2021). https://doi.org/10.1038/s41582-021-00519-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-021-00519-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research