Decoding the Multiple Sclerosis Prodrome

Author: Patricia K. Coyle, MD
Professor of Neurology and Director of the MS Comprehensive Care Center
Stony Brook University, Stony Brook, New York

Date Published:
October 9, 2020

Prodrome refers to an early set of signs or symptoms that indicate an underlying disease or illness. Prodromes are well documented for neurodegenerative disorders such as Parkinson disease and Alzheimer disease.1 There are increasing data for a prodrome in multiple sclerosis (MS), before the clear neurologic presentation of clinically isolated syndrome (CIS) heralding relapsing MS, or the slow worsening syndrome of primary progressive MS (Table). This prodrome may span up to 5 to 10 years.

In a Canadian study, researchers used matched cohorts from linked health administrative and clinical databases from 4 provinces.2 They compared 14,428 individuals with MS to 72,059 matched controls.2 Annual health care use went up in the 5 years prior to the CIS presentation.2 Particularly in the year prior to a diagnosis of MS, hospitalizations were 78% higher, visits to physicians were 88% higher, and prescriptions were 49% higher than controls. In another very large Canadian analysis, investigators evaluated prodromal features.3 The future MS cohort had more encounters involving the nervous, sensory, musculoskeletal, and genitourinary systems compared with controls.3 They had more psychiatric and urology encounters, but fewer pregnancy encounters.3 The future MS cohort had higher rates of musculoskeletal, genitourinary, and hormonal prescriptions than controls.3

The same results were noted on large analyses from the United Kingdom, where primary care symptoms were evaluated in 10,204 patients with future MS compared with 39,448 controls.4 Primary care visits were examined at 0 to 2, 2 to 5, and 5 to 10 years pre-MS.4 The future MS group had increased autonomic (gastrointestinal, urinary, anorectal issues), psychiatric (anxiety, depression), cognitive/fatigue (insomnia), and pain (headache) issues compared with controls.4 MS risk increased with each additional symptom.4 In another analysis of 6932 subjects with MS and 65,526 controls, the initial MS diagnosis group showed significantly more (p<0.05) depression, eye/ear infections, urinary tract infections, serious infections, autoimmune disorders, peripheral vascular disease, Raynaud phenomenon, and macular edema.5 The pre-MS group showed increased use of antidepressants, antipsychotics, antiepileptics, antihypertensives, proton pump inhibitors, and antibiotics. A recent analysis of 29 studies reported anxiety, depression, migraine, and lower cognitive performance as prodromal features of MS.6

The cognitive issue is highlighted in a study from Norway.7 All Norwegian men undergo a conscription examination at age 18 or 19 years. In a nested case-control study of those undergoing examination from 1950 to 1995, cognitive scores were available in 924 future MS cases vs 19,530 controls. Cognition was significantly worse among those who developed relapsing MS within 2 years, or primary progressive MS within 20 years.7

Some studies suggest there may be prodrome differences between relapsing and primary progressive MS8, as well as differences based on sex and age.9 Such details need to be examined further in future research. With regard to potential biomarkers, studies have supported elevations in blood neurofilament light protein among individuals who went on to develop MS 4 to 10 years (a median of 6 years) before MS onset compared with controls10 as well as unique cerebrospinal fluid and blood immune signatures.11,12

Identification of an MS prodrome is exciting. It raises the possibility of much earlier identification and potential treatment, with a goal of preventing the formal clinical onset of MS. Expect to see many additional studies on this important topic.


  1. Tremlett H and Marrie RA. The multiple sclerosis prodrome: emerging evidence, challenges, and opportunities. Mult Scler J. Published online March 13, 2020. doi:10.1177/1352458520914844
  2. Wijnands JMA, Kingwell E, Zhu F, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 2017;16(6):445-451. doi:10.1016/S1474-4422(17)30076-5
  3. Wijnands JMA, Zhu F, Kingwell E, et al. Five years before multiple sclerosis onset: phenotyping the prodrome. Mult Scler J. 2019;25(8):1092-1101. doi:10.1177/1352458518783662
  4. Disanto G, Zecca C, MacLachlan S, et al. Prodromal symptoms of multiple sclerosis in primary care. Ann Neurol. 2018;83(6):1162-1173. doi:10.1002/ana.25247
  5. Persson R, Lee S, Yood MU, et al. Multi-database study of multiple sclerosis: identification, validation and description of MS patients in two countries. J Neurol. 2019 May;266(5):1095-1106. doi:10.1007/s00415-019-09238-8
  6.  Yusuf FLA, Ng BC, Wijnands JMA, et al. A systematic review of morbidities suggestive of the multiple sclerosis prodrome. Expert Rev Neurother. 2020;20(8):799-819.
  7. Cortese M, Riise T, Bjørnevik K, et al. Preclinical disease activity in multiple sclerosis: a prospective study of cognitive performance prior to first symptom. Ann Neurol. 2016;80(4):616-24. doi:10.1002/ana.24769
  8. Wijnands JMA, Zhu F, Kingwell E, et al. Prodrome in relapsing-remitting and primary progressive multiple sclerosis. Europ J Neurol. 2019;26(7):1032-1036. doi:10.1111/ene.13925
  9. Yusuf FLA, Wijnands JMA, Kingwell E, et al. Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome. Mult Scler J. Published online April 6, 2020. doi:10.1177/1352458520908163
    doi: 10.1177/1352458520908163
  10. Bjornevik K, Munger KL, Cortese M, et al. Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis. JAMA Neurol. 2020;77(1):58-64. doi:10.1001/jamaneurol.2019.3238
  11. Beltrán E, Gerdes LA, Hansen J, et al. Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis. J Clin Invest. 2019;129(11):4758-4768. doi:10.1172/JCI128475
  12. Gerdes LA, Janoschka C, Eveslage M, et al. Immune signatures of prodromal multiple sclerosis in monozygotic twins. PNAS. 2020;117(35):21546-21556. doi:10.1073/pnas.2003339117


  • Population at risk
  • Asymptomatic
    • Radiologically isolated syndrome
  • Symptomatic
    • Prodrome
    • Clinically isolated syndrome/relapsing MS
    • Progressive MS (primary progressive from onset; secondary progressive)