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The multiple sclerosis prodrome

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.

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References

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

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  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).

    PubMed  Article  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).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  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).

    PubMed  Article  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).

    CAS  PubMed  Article  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).

    PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  Article  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).

    PubMed  Article  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).

    CAS  PubMed  PubMed Central  Article  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).

    CAS  PubMed  Article  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).

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  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).

    PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  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).

    CAS  PubMed  Article  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).

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  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).

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  Article  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).

    CAS  PubMed  PubMed Central  Article  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).

    PubMed  PubMed Central  Article  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).

    CAS  PubMed  Article  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).

    CAS  PubMed  Article  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).

    PubMed  Article  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).

    PubMed  PubMed Central  Article  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).

    PubMed  PubMed Central  Article  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).

    PubMed  Article  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  Article  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).

    PubMed  Article  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).

    PubMed  PubMed Central  Article  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).

    PubMed  Article  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).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  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).

    CAS  PubMed  PubMed Central  Article  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).

    PubMed  Article  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).

    PubMed  Article  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).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    PubMed  Article  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).

    PubMed  PubMed Central  Article  Google Scholar 

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Both authors contributed to all aspects of the manuscript.

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Correspondence to Helen Tremlett.

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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.

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

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

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