Skip to main content

Advertisement

SpringerLink
Log in

Exercise as Medicine in Multiple Sclerosis—Time for a Paradigm Shift: Preventive, Symptomatic, and Disease-Modifying Aspects and Perspectives

  • Demyelinating Disorders (J. Bernard & M. Cameron, Section Editors)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

For many years, exercise was controversial in multiple sclerosis (MS) and thought to exacerbate symptoms and fatigue. However, having been found to be safe and effective, exercise has become a cornerstone of MS rehabilitation and may have even more fundamental benefits in MS, with the potential to change clinical practice again. The aim of this review is to summarize the existing knowledge of the effects of exercise as primary, secondary, and tertiary prevention in MS.

Recent Findings

Initial studies established exercise as an effective symptomatic treatment (i.e., tertiary prevention), but recent studies have evaluated the disease-modifying effects (i.e., secondary prevention) of exercise as well as the impact on the risk of developing MS (i.e., primary prevention).

Summary

Based on recent evidence, a new paradigm shift is proposed, in which exercise at an early stage should be individually prescribed and tailored as “medicine” to persons with MS, alongside conventional medical treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17.

    CAS  PubMed  Google Scholar 

  2. Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, et al. Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology. 2014;83(11):1022–4. https://doi.org/10.1212/Wnl.0000000000000768.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pilz G, Wipfler P, Ladurner G, Kraus J. Modern multiple sclerosis treatment - what is approved, what is on the horizon. Drug Discov Today. 2008;13(23–24):1013–25.

    CAS  PubMed  Google Scholar 

  4. Liguori M, Marrosu MG, Pugliatti M, Giuliani F, De RF, Cocco E, et al. Age at onset in multiple sclerosis. Neurol Sci. 2000;21(4 Suppl 2):S825–S9.

    CAS  PubMed  Google Scholar 

  5. Scalfari A, Neuhaus A, Daumer M, Ebers GC, Muraro PA. Age and disability accumulation in multiple sclerosis. Neurology. 2011;77(13):1246–52. https://doi.org/10.1212/WNL.0b013e318230a17d.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lunde HMB, Assmus J, Myhr KM, Bo L, Grytten N. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. J Neurol Neurosurg Psychiatry. 2017;88(8):621–5. https://doi.org/10.1136/jnnp-2016-315238.

    Article  PubMed  Google Scholar 

  7. Koch-Henriksen N, Bronnum-Hansen H, Stenager E. Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish Multiple Sclerosis Registry. J Neurol Neurosurg Psychiatry. 1998;65(1):56–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kister I, Bacon TE, Chamot E, Salter AR, Cutter GR, Kalina JT, et al. Natural history of multiple sclerosis symptoms. International Journal of MS care. 2013;15(3):146–58. https://doi.org/10.7224/1537-2073.2012-053.

    PubMed  PubMed Central  Google Scholar 

  9. Gyllensten H, Kavaliunas A, Alexanderson K, Hillert J, Tinghog P, Friberg E. Costs and quality of life by disability among people with multiple sclerosis: a register-based study in Sweden. Multiple Sclerosis Journal - Experimental, Translational and Clinical. 2018;4(3):2055217318783352. https://doi.org/10.1177/2055217318783352.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kobelt G, Thompson A, Berg J, Gannedahl M, Eriksson J, Group MS, et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler. 2017;23(8):1123–36. https://doi.org/10.1177/1352458517694432.

    Article  PubMed  PubMed Central  Google Scholar 

  11. World Health Organization. Neurological disorders : public health challenges. Geneva: World Health Organization; 2006.

    Google Scholar 

  12. De Angelis F, John NA, Brownlee WJ. Disease-modifying therapies for multiple sclerosis. BMJ. 2018;363:k4674. https://doi.org/10.1136/bmj.k4674.

    Article  PubMed  Google Scholar 

  13. Cohen JA, Krishnan AV, Goodman AD, Potts J, Wang P, Havrdova E, et al. The clinical meaning of walking speed as measured by the timed 25-foot walk in patients with multiple sclerosis. JAMA Neurol. 2014;71(11):1386–93. https://doi.org/10.1001/jamaneurol.2014.1895.

    PubMed  Google Scholar 

  14. Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult Scler Int. 2014;2014:798285–12. https://doi.org/10.1155/2014/798285.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Amato MP, Langdon D, Montalban X, Benedict RH, DeLuca J, Krupp LB, et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol. 2013;260(6):1452–68. https://doi.org/10.1007/s00415-012-6678-0.

    Article  CAS  PubMed  Google Scholar 

  16. Li H, Hu F, Zhang Y, Li K. Comparative efficacy and acceptability of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis. J Neurol. 2019. https://doi.org/10.1007/s00415-019-09395-w.

  17. Motl RW, Sandroff BM, Kwakkel G, Dalgas U, Feinstein A, Heesen C, et al. Exercise in patients with multiple sclerosis. Lancet Neurol. 2017;16(10):848–56. https://doi.org/10.1016/S1474-4422(17)30281-8.

    PubMed  Google Scholar 

  18. Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25(Suppl 3):1–72. https://doi.org/10.1111/sms.12581.

    Article  PubMed  Google Scholar 

  19. KM Z. Exercise as medicine in multiple sclerosis - moving beyond compensatory benefits. US Neurology. 2017;13(1):2. https://doi.org/10.17925/USN.2017.13.02.70.

    Google Scholar 

  20. Tallner A, Maurer M, Pfeifer K. Multiple sclerosis and physical activity : an historical perspective. Nervenarzt. 2013;84(10):1238–44.

    CAS  PubMed  Google Scholar 

  21. •• Pilutti LA, Platta ME, Motl RW, Latimer-Cheung AE. The safety of exercise training in multiple sclerosis: a systematic review. J Neurol Sci. 2014;15(343 (1-2)):3–7 Comprehensive review showing that exercise is safe in MS and that exercise positively impact relapse rate.

  22. Smith RM, ey-Steel M, Fulcher G, Longley WA. Symptom change with exercise is a temporary phenomenon for people with multiple sclerosis. Arch Phys Med Rehabil. 2006;87(5):723–7.

    PubMed  Google Scholar 

  23. Heine M, Van dP I, Rietberg MB, van Wegen EE, Kwakkel G. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2015;9:CD009956.

    Google Scholar 

  24. • Kjolhede T, Siemonsen S, Wenzel D, Stellmann JP, Ringgaard S, Pedersen BG et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Multiple sclerosis (Houndmills, Basingstoke, England). 2018;24(10):1356-65. https://doi.org/10.1177/1352458517722645. First randomised controlled exercise study to include MRI outcomes in MS.

    PubMed  Google Scholar 

  25. •• Wesnes K, Myhr KM, Riise T, Cortese M, Pugliatti M, Bostrom I, et al. Physical activity is associated with a decreased multiple sclerosis risk: the EnvIMS study. Mult Scler. 2018;24(2):150–7. https://doi.org/10.1177/1352458517694088 Large study linking increased physical activity to a decreased MS risk.

    Article  PubMed  Google Scholar 

  26. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100(2):126–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Dalgas U. Rehabilitation and multiple sclerosis: hot topics in the preservation of physical functioning. J Neurol Sci. 2011;311(S1):S43–S7.

    PubMed  Google Scholar 

  28. American College of Sports Medicine position stand. Progression models in resistance training for healthy adults. Med Sci Sports Exerc. 2009;41(3):687–708.

    Google Scholar 

  29. Hughes JR. Psychological effects of habitual aerobic exercise: a critical review. Prev Med. 1984;13(1):66–78.

    CAS  PubMed  Google Scholar 

  30. Kjolhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training: a systematic review. Mult Scler. 2012;18(9):1215–28.

    CAS  PubMed  Google Scholar 

  31. Langeskov-Christensen M, Heine M, Kwakkel G, Dalgas U. Aerobic capacity in persons with multiple sclerosis: a systematic review and meta-analysis. Paper submitted. 2014.

  32. Cramer H, Lauche R, Azizi H, Dobos G, Langhorst J. Yoga for multiple sclerosis: a systematic review and meta-analysis. PLoS One. 2014;9(11):e112414. https://doi.org/10.1371/journal.pone.0112414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sanchez-Lastra MA, Martinez-Aldao D, Molina AJ, Ayan C. Pilates for people with multiple sclerosis: a systematic review and meta-analysis. Multiple Sclerosis and Related Disorders. 2019;28:199–212. https://doi.org/10.1016/j.msard.2019.01.006.

    Article  PubMed  Google Scholar 

  34. Gunn H, Markevics S, Haas B, Marsden J, Freeman J. Systematic review: the effectiveness of interventions to reduce falls and improve balance in adults with multiple sclerosis. Arch Phys Med Rehabil. 2015;96(10):1898–912. https://doi.org/10.1016/j.apmr.2015.05.018.

    Article  PubMed  Google Scholar 

  35. Stathopoulos E, Felson DJ. History and principles of exercise-based therapy: how they inform our current treatment. Semin Speech Lang. 2006;27(4):227–35. https://doi.org/10.1055/s-2006-955113.

    Article  PubMed  Google Scholar 

  36. Van Roie E, Delecluse C, Opdenacker J, De Bock K, Kennis E, Boen F. Effectiveness of a lifestyle physical activity versus a structured exercise intervention in older adults. J Aging Phys Act. 2010;18(3):335–52.

    PubMed  Google Scholar 

  37. Ascherio A, Munger KL, Lunemann JD. The initiation and prevention of multiple sclerosis. Nat Rev Neurol. 2012;8(11):602–12. https://doi.org/10.1038/nrneurol.2012.198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017;13(1):25–36. https://doi.org/10.1038/nrneurol.2016.187.

    Article  CAS  PubMed  Google Scholar 

  39. Abdollahpour I, Nedjat S, Mansournia MA, Sahraian MA, van der Mei I. Lifestyle factors and multiple sclerosis: a population-based incident case-control study. Mult Scler Relat Disord. 2018;22:128–33. https://doi.org/10.1016/j.msard.2018.03.022.

    Article  PubMed  Google Scholar 

  40. Ponsonby AL, Lucas RM, Dear K, van der Mei I, Taylor B, Chapman C, et al. The physical anthropometry, lifestyle habits and blood pressure of people presenting with a first clinical demyelinating event compared to controls: the Ausimmune study. Mult Scler. 2013;19(13):1717–25. https://doi.org/10.1177/1352458513483887.

    PubMed  Google Scholar 

  41. Cortese M, Riise T, Bjornevik K, Myhr KM. Multiple Sclerosis Conscript Service Database Study G. Body size and physical exercise, and the risk of multiple sclerosis. Mult Scler. 2018;24(3):270–8. https://doi.org/10.1177/1352458517699289.

    Article  PubMed  Google Scholar 

  42. Dorans KS, Massa J, Chitnis T, Ascherio A, Munger KL. Physical activity and the incidence of multiple sclerosis. Neurology. 2016;87(17):1770–6. https://doi.org/10.1212/WNL.0000000000003260.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord. 2012;5(2):81–95. https://doi.org/10.1177/1756285611430719.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Motl RW. Physical activity and irreversible disability in multiple sclerosis. Exerc Sport Sci Rev. 2010;38(4):186–91. https://doi.org/10.1097/JES.0b013e3181f44fab.

    Article  PubMed  Google Scholar 

  45. White LJ, Castellano V. Exercise and brain health - implications for multiple sclerosis: part 1 - neuronal growth factors. Sports Med. 2008;38(2):91–100.

    PubMed  Google Scholar 

  46. White LJ, Castellano V. Exercise and brain health--implications for multiple sclerosis: part II--immune factors and stress hormones. Sports medicine (Auckland, NZ). 2008;38(3):179–86 doi:3831.

    Google Scholar 

  47. •• Souza PS, Goncalves ED, Pedroso GS, Farias HR, Junqueira SC, Marcon R, et al. Physical exercise attenuates experimental autoimmune encephalomyelitis by inhibiting peripheral immune response and blood-brain barrier disruption. Mol Neurobiol. 2017;54(6):4723–37. https://doi.org/10.1007/s12035-016-0014-0 Comprehensive analysis of mechanisms underlying the disease modifying effects of exercise observed in the animal model of MS.

    Article  CAS  PubMed  Google Scholar 

  48. Pryor WM, Freeman KG, Larson RD, Edwards GL, White LJ. Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis. J Neurosci Res. 2015;93(5):697–706. https://doi.org/10.1002/jnr.23528.

    Article  CAS  PubMed  Google Scholar 

  49. Mandolesi G, Bullitta S, Fresegna D, De Vito F, Rizzo FR, Musella A, et al. Voluntary running wheel attenuates motor deterioration and brain damage in cuprizone-induced demyelination. Neurobiol Dis. 2019;129:102–17. https://doi.org/10.1016/j.nbd.2019.05.010.

    Article  CAS  PubMed  Google Scholar 

  50. Xie Y, Li Z, Wang Y, Xue X, Ma W, Zhang Y, et al. Effects of moderate- versus high- intensity swimming training on inflammatory and CD4(+) T cell subset profiles in experimental autoimmune encephalomyelitis mice. J Neuroimmunol. 2019;328:60–7. https://doi.org/10.1016/j.jneuroim.2018.12.005.

    CAS  PubMed  Google Scholar 

  51. Bonfiglio T, Olivero G, Vergassola M, Di Cesare ML, Pacini A, Iannuzzi F, et al. Environmental training is beneficial to clinical symptoms and cortical presynaptic defects in mice suffering from experimental autoimmune encephalomyelitis. Neuropharmacology. 2019;145(Pt A):75–86. https://doi.org/10.1016/j.neuropharm.2018.01.026.

    Article  CAS  PubMed  Google Scholar 

  52. Burrows DJ, McGown A, Jain SA, De Felice M, Ramesh TM, Sharrack B, et al. Animal models of multiple sclerosis: from rodents to zebrafish. Mult Scler. 2019;25(3):306–24. https://doi.org/10.1177/1352458518805246.

    Article  PubMed  Google Scholar 

  53. Prakash RS, Snook EM, Erickson KI, Colcombe SJ, Voss MW, Motl RW, et al. Cardiorespiratory fitness: a predictor of cortical plasticity in multiple sclerosis. Neuroimage. 2007;34(3):1238–44. https://doi.org/10.1016/j.neuroimage.2006.10.003.

    Article  PubMed  Google Scholar 

  54. Prakash RS, Snook EM, Motl RW, Kramer AF. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res. 2010;1341:41–51. https://doi.org/10.1016/j.brainres.2009.06.063.

    Article  CAS  PubMed  Google Scholar 

  55. Motl RW, McAuley E. Association between change in physical activity and short-term disability progression in multiple sclerosis. J Rehabil Med. 2011;43(4):305–10. https://doi.org/10.2340/16501977-0782.

    Article  PubMed  Google Scholar 

  56. Motl RW, Pilutti LA, Hubbard EA, Wetter NC, Sosnoff JJ, Sutton BP. Cardiorespiratory fitness and its association with thalamic, hippocampal, and basal ganglia volumes in multiple sclerosis. NeuroImage Clinical. 2015;7:661–6. https://doi.org/10.1016/j.nicl.2015.02.017.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Leavitt VM, Cirnigliaro C, Cohen A, Farag A, Brooks M, Wecht JM, et al. Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings. Neurocase. 2014;20(6):695–7. https://doi.org/10.1080/13554794.2013.841951.

    PubMed  Google Scholar 

  58. Prosperini L, Fanelli F, Petsas N, Sbardella E, Tona F, Raz E, et al. Multiple sclerosis: changes in microarchitecture of white matter tracts after training with a video game balance board. Radiology. 2014;273(2):529–38. https://doi.org/10.1148/radiol.14140168.

    PubMed  Google Scholar 

  59. Tavazzi E, Bergsland N, Cattaneo D, Gervasoni E, Lagana MM, Dipasquale O, et al. Effects of motor rehabilitation on mobility and brain plasticity in multiple sclerosis: a structural and functional MRI study. J Neurol. 2018;265(6):1393–401. https://doi.org/10.1007/s00415-018-8859-y.

    Article  PubMed  Google Scholar 

  60. Sandroff BM, Johnson CL, Motl RW. Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: a novel application of magnetic resonance elastography. Neuroradiology. 2017;59(1):61–7. https://doi.org/10.1007/s00234-016-1767-x.

    Article  PubMed  Google Scholar 

  61. Pilutti LA, Platta ME, Motl RW, Latimer-Cheung AE. The safety of exercise training in multiple sclerosis: a systematic review. J Neurol Sci. 2014;343(1–2):3–7. https://doi.org/10.1016/j.jns.2014.05.016.

    Article  PubMed  Google Scholar 

  62. Tallner A, Waschbisch A, Wenny I, Schwab S, Hentschke C, Pfeifer K, et al. Multiple sclerosis relapses are not associated with exercise. Mult Scler. 2012;18(2):232–5. https://doi.org/10.1177/1352458511415143.

    PubMed  Google Scholar 

  63. Hempel S, Graham GD, Fu N, Estrada E, Chen AY, Miake-Lye I, et al. A systematic review of the effects of modifiable risk factor interventions on the progression of multiple sclerosis. Mult Scler. 2017;23(4):513–24. https://doi.org/10.1177/1352458517690271.

    PubMed  Google Scholar 

  64. Negaresh R, Motl RW, Zimmer P, Mokhtarzade M, Baker JS. Effects of exercise training on multiple sclerosis biomarkers of central nervous system and disease status: a systematic review of intervention studies. Eur J Neurol. 2019;26(5):711–21. https://doi.org/10.1111/ene.13929.

    Article  CAS  PubMed  Google Scholar 

  65. Grp PS, G UBCMA. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS (vol 55, pg 1628, 2001). Neurology. 2001;57(6):1146-.

  66. Fritz NE, Keller J, Calabresi PA, Zackowski KM. Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis. Neuroimage Clin. 2017;14:490–8. https://doi.org/10.1016/j.nicl.2017.02.006.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Zackowski KM, Smith SA, Reich DS, Gordon-Lipkin E, Chodkowski BA, Sambandan DR, et al. Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord. Brain. 2009;132(Pt 5):1200–9. https://doi.org/10.1093/brain/awp032.

    PubMed  PubMed Central  Google Scholar 

  68. Fimland MS, Helgerud J, Gruber M, Leivseth G, Hoff J. Enhanced neural drive after maximal strength training in multiple sclerosis patients. Eur J Appl Physiol. 2010;110(2):435–43. https://doi.org/10.1007/s00421-010-1519-2.

    Article  PubMed  Google Scholar 

  69. Dalgas U, Stenager E, Lund C, Rasmussen C, Petersen T, Sorensen H, et al. Neural drive increases following resistance training in patients with multiple sclerosis. J Neurol. 2013;260(7):1822–32.

    PubMed  Google Scholar 

  70. Kjolhede T, Vissing K, de Place L, Pedersen BG, Ringgaard S, Stenager E et al. Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up. Multiple sclerosis (Houndmills, Basingstoke, England). 2014.

  71. Vollmer T, Signorovitch J, Huynh L, Galebach P, Kelley C, DiBernardo A, et al. The natural history of brain volume loss among patients with multiple sclerosis: a systematic literature review and meta-analysis. J Neurol Sci. 2015;357(1–2):8–18. https://doi.org/10.1016/j.jns.2015.07.014.

    PubMed  Google Scholar 

  72. Tsivgoulis G, Katsanos AH, Grigoriadis N, Hadjigeorgiou GM, Heliopoulos I, Kilidireas C, et al. The effect of disease modifying therapies on brain atrophy in patients with relapsing-remitting multiple sclerosis: a systematic review and meta-analysis. PLoS One. 2015;10(3):e0116511. https://doi.org/10.1371/journal.pone.0116511.

    PubMed  PubMed Central  Google Scholar 

  73. Favaretto A, Lazzarotto A, Margoni M, Poggiali D, Gallo P. Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis. Multiple Sclerosis and Demyelinating Disorders. 2018;3(1):1. https://doi.org/10.1186/s40893-017-0033-3.

    Article  Google Scholar 

  74. Hobart J, Freeman J, Thompson A. Kurtzke scales revisited: the application of psychometric methods to clinical intuition. Brain. 2000;123 (Pt 5)(Pt 5):1027–40.

    PubMed  Google Scholar 

  75. Vellinga MM, Geurts JJ, Rostrup E, Uitdehaag BM, Polman CH, Barkhof F, et al. Clinical correlations of brain lesion distribution in multiple sclerosis. Journal of Magnetic Resonance Imaging : JMRI. 2009;29(4):768–73. https://doi.org/10.1002/jmri.21679.

    Article  CAS  PubMed  Google Scholar 

  76. Stephens S, Shams S, Lee J, Grover SA, Longoni G, Berenbaum T, et al. Benefits of physical activity for depression and fatigue in multiple sclerosis: a longitudinal analysis. J Pediatr. 2019;209:226–32.e2. https://doi.org/10.1016/j.jpeds.2019.01.040.

    Article  PubMed  Google Scholar 

  77. Rooney S, Riemenschneider M, Dalgas U, Jorgensen MK, Michelsen AS, Brond JC, et al. Physical activity is associated with neuromuscular and physical function in patients with multiple sclerosis independent of disease severity. Disabil Rehabil. 2019:1–8. https://doi.org/10.1080/09638288.2019.1634768.

  78. Motl RW, McAuley E, Snook EM. Physical activity and multiple sclerosis: a meta-analysis. Mult Scler. 2005;11(4):459–63.

    PubMed  Google Scholar 

  79. Kinnett-Hopkins D, Adamson B, Rougeau K, Motl RW. People with MS are less physically active than healthy controls but as active as those with other chronic diseases: an updated meta-analysis. Multiple Sclerosis and Related Disorders. 2017;13:38–43. https://doi.org/10.1016/j.msard.2017.01.016.

    Article  CAS  PubMed  Google Scholar 

  80. de HA, de Ruiter CJ, van der Woude LH, Jongen PJ. Contractile properties and fatigue of quadriceps muscles in multiple sclerosis. Muscle Nerve 2000;23(10):1534–1541.

    CAS  Google Scholar 

  81. Green R, Cutter G, Friendly M, Kister I. Which symptoms contribute the most to patients’ perception of health in multiple sclerosis? Multiple sclerosis journal - experimental, translational and clinical. 2017;3(3):2055217317728301. https://doi.org/10.1177/2055217317728301.

    Google Scholar 

  82. • Heesen C, Haase R, Melzig S, Poettgen J, Berghoff M, Paul F, et al. Perceptions on the value of bodily functions in multiple sclerosis. Acta Neurol Scand. 2018;137(3):356–62. https://doi.org/10.1111/ane.12881. Study rating the importance of different bodily functions from a patient and physician perspective.

    PubMed  Google Scholar 

  83. Pilutti L, Greenlee T, Motl RW, Nickrent M, Petruzzello SJ. Effects of exercise training on fatigue in multiple sclerosis: a meta-analysis. Psychosom Med 2013;75(6):575–580.

    CAS  PubMed  Google Scholar 

  84. Andreasen AK, Stenager E, Dalgas U. The effect of exercise therapy on fatigue in multiple sclerosis. Mult Scler. 2011;17(9):1041–54.

    CAS  PubMed  Google Scholar 

  85. Demaneuf T, Aitken Z, Karahalios A, Leong TI, De Livera AM, Jelinek GA, et al. Effectiveness of exercise interventions for pain reduction in people with multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. Arch Phys Med Rehabil. 2019;100(1):128–39. https://doi.org/10.1016/j.apmr.2018.08.178.

    Article  PubMed  Google Scholar 

  86. Dalgas U, Stenager E, Sloth M, Stenager E. The effect of exercise on depressive symptoms in multiple sclerosis based on a meta-analysis and critical review of the literature. Eur J Neurol. 2015;22(3):443–e34.

    CAS  PubMed  Google Scholar 

  87. Ensari I, Motl RW, Pilutti LA. Exercise training improves depressive symptoms in people with multiple sclerosis: results of a meta-analysis. J Psychosom Res. 2014;76(6):465–71.

    PubMed  Google Scholar 

  88. Pearson M, Dieberg G, Smart N. Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis. Arch Phys Med Rehabil. 2015;96:1339–1348.e7.

    PubMed  Google Scholar 

  89. Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair. 2008;23(108):116.

    Google Scholar 

  90. Charron S, McKay KA, Tremlett H. Physical activity and disability outcomes in multiple sclerosis: a systematic review (2011-2016). Multiple sclerosis and related disorders. 2018;20:169–77. https://doi.org/10.1016/j.msard.2018.01.021.

    Article  PubMed  Google Scholar 

  91. Kjølhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training - a systematic review. Mult Scler. 2012;18(9):1215–28.

    PubMed  Google Scholar 

  92. Manago MM, Glick S, Hebert JR, Coote S, Schenkman M. Strength training to improve gait in people with multiple sclerosis: a critical review of exercise parameters and intervention approaches. Int J MS Care. 2019;21(2):47–56. https://doi.org/10.7224/1537-2073.2017-079.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Paltamaa J, Sjogren T, Peurala SH, Heinonen A. Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012;44(10):811–23. https://doi.org/10.2340/16501977-1047.

    Article  PubMed  Google Scholar 

  94. Kalron A, Zeilig G. Efficacy of exercise intervention programs on cognition in people suffering from multiple sclerosis, stroke and Parkinson’s disease: a systematic review and meta-analysis of current evidence. NeuroRehabilitation. 2015;37:273–89.

    PubMed  Google Scholar 

  95. Sandroff BM, Motl RW, Scudder MR, DeLuca J. Systematic, evidence-based review of exercise, physical activity, and physical fitness effects on cognition in persons with multiple sclerosis. Neuropsychol Rev. 2016;26(3):271-294. doi:https://doi.org/10.1007/s11065-016-9324-2.

    PubMed  Google Scholar 

  96. Platta ME, Ensari I, Motl RW, Pilutti LA. Effect of exercise training on fitness in multiple sclerosis: a meta-analysis. Arch Phys Med Rehabil. 2016;97(9):1564–72.

    PubMed  Google Scholar 

  97. Campbell E, Coulter EH, Paul L. High intensity interval training for people with multiple sclerosis: a systematic review. Multiple sclerosis and related disorders. 2018;24:55–63. https://doi.org/10.1016/j.msard.2018.06.005.

    Article  PubMed  Google Scholar 

  98. Jorgensen M, Dalgas U, Wens I, Hvid LG. Muscle strength and power in persons with multiple sclerosis - a systematic review and meta-analysis. J Neurol Sci. 2017;376:225–41. https://doi.org/10.1016/j.jns.2017.03.022.

    Article  PubMed  Google Scholar 

  99. Motl RW, Gosney JL. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Mult Scler. 2008;14(1):129–35.

    CAS  PubMed  Google Scholar 

  100. Sanchez-Lastra MA, Martinez-Aldao D, Molina AJ, Ayan C. Corrigendum to ‘Pilates for people with multiple sclerosis: a systematic review and meta-analysis’ Multiple Sclerosis and Related Disorders 28 (2019)199-212. Multiple Sclerosis and related Disorders. 2019;32:139–40. https://doi.org/10.1016/j.msard.2019.04.027.

    Article  PubMed  Google Scholar 

  101. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014;10(4):225–38. https://doi.org/10.1038/nrneurol.2014.37.

    Article  CAS  PubMed  Google Scholar 

  102. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464–72. https://doi.org/10.1016/j.tins.2007.06.011.

    Article  CAS  PubMed  Google Scholar 

  103. Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013;3(3):1337–62. https://doi.org/10.1002/cphy.c120033.

    Article  PubMed  Google Scholar 

  104. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab. 2013;18(5):649–59. https://doi.org/10.1016/j.cmet.2013.09.008.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Einstein O, Fainstein N, Touloumi O, Lagoudaki R, Hanya E, Grigoriadis N et al. Exercise training attenuates experimental autoimmune encephalomyelitis by peripheral immunomodulation rather than direct neuroprotection. Exp Neurol. 2018;299(Pt A):56–64. doi:https://doi.org/10.1016/j.expneurol.2017.10.008.

    PubMed  Google Scholar 

  106. Thoenen H. Neurotrophins and neuronal plasticity. Science. 1995;270(5236):593–8. https://doi.org/10.1126/science.270.5236.593.

    Article  CAS  PubMed  Google Scholar 

  107. Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol. 2019;15(7):383–92. https://doi.org/10.1038/s41574-019-0174-x.

    Article  PubMed  Google Scholar 

  108. Negaresh R, Motl RW, Mokhtarzade M, Dalgas U, Patel D, Shamsi MM, et al. Effects of exercise training on cytokines and adipokines in multiple sclerosis: a systematic review. Multiple Sclerosis and Related Disorders. 2018;24:91–100. https://doi.org/10.1016/j.msard.2018.06.008.

    PubMed  Google Scholar 

  109. Damasceno A, Damasceno BP, Cendes F, Damasceno A, Moraes AS, Farias A, et al. Serum BDNF levels are not reliable correlates of neurodegeneration in MS patients. Multiple Sclerosis and Related Disorders. 2015;4(1):65–6. https://doi.org/10.1016/j.msard.2014.11.003.

    PubMed  Google Scholar 

  110. Jorgensen MLK, Kjolhede T, Dalgas U, Hvid LG. Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-a randomized controlled trial. Multiple Sclerosis and Related Disorders. 2019;31:106–11. https://doi.org/10.1016/j.msard.2019.03.029.

    Article  CAS  PubMed  Google Scholar 

  111. Gejl AK, Enevold C, Bugge A, Andersen MS, Nielsen CH, Andersen LB. Associations between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy. Sci Rep. 2019;9(1):9655. https://doi.org/10.1038/s41598-019-45976-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Polacchini A, Metelli G, Francavilla R, Baj G, Florean M, Mascaretti LG, et al. A method for reproducible measurements of serum BDNF: comparison of the performance of six commercial assays. Sci Rep. 2015;5:17989. https://doi.org/10.1038/srep17989.

  113. Spencer JI, Bell JS, DeLuca GC. Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry. 2018;89(1):42–52. https://doi.org/10.1136/jnnp-2017-316011.

    Article  PubMed  Google Scholar 

  114. Martinez Sosa S, Smith KJ. Understanding a role for hypoxia in lesion formation and location in the deep and periventricular white matter in small vessel disease and multiple sclerosis. Clin Sci (Lond). 2017;131(20):2503–24. https://doi.org/10.1042/CS20170981.

    Article  CAS  Google Scholar 

  115. Malkiewicz MA, Szarmach A, Sabisz A, Cubala WJ, Szurowska E, Winklewski PJ. Blood-brain barrier permeability and physical exercise. J Neuroinflammation. 2019;16(1):15. https://doi.org/10.1186/s12974-019-1403-x.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Boraxbekk CJ, Salami A, Wahlin A, Nyberg L. Physical activity over a decade modifies age-related decline in perfusion, gray matter volume, and functional connectivity of the posterior default-mode network-a multimodal approach. NeuroImage. 2016;131:133–41. https://doi.org/10.1016/j.neuroimage.2015.12.010.

    Article  PubMed  Google Scholar 

  117. Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, Flores-Alvarado LJ, Mireles-Ramirez MA, Gonzalez-Renovato ED, et al. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res. 2014;45(8):687–97. https://doi.org/10.1016/j.arcmed.2014.11.013.

    Article  CAS  PubMed  Google Scholar 

  118. Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab. 2016;36(9):1481–507. https://doi.org/10.1177/0271678X16655551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta. 2011;1812(2):252–64. https://doi.org/10.1016/j.bbadis.2010.06.017.

    Article  CAS  PubMed  Google Scholar 

  120. D’Haeseleer M, Hostenbach S, Peeters I, Sankari SE, Nagels G, De Keyser J, et al. Cerebral hypoperfusion: a new pathophysiologic concept in multiple sclerosis? J Cereb Blood Flow Metab. 2015;35(9):1406–10. https://doi.org/10.1038/jcbfm.2015.131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wuerfel J, Paul F, Zipp F. Cerebral blood perfusion changes in multiple sclerosis. J Neurol Sci. 2007;259(1–2):16–20. https://doi.org/10.1016/j.jns.2007.02.011.

    Article  PubMed  Google Scholar 

  122. Kermode AG, Thompson AJ, Tofts P, MacManus DG, Kendall BE, Kingsley DP, et al. Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain J Neurol. 1990;113(Pt 5):1477–89. https://doi.org/10.1093/brain/113.5.1477.

    Article  Google Scholar 

  123. Deckx N, Wens I, Nuyts AH, Hens N, De Winter BY, Koppen G, et al. 12 weeks of combined endurance and resistance training reduces innate markers of inflammation in a randomized controlled clinical trial in patients with multiple sclerosis. Mediat Inflamm. 2016;2016:6789276–13. https://doi.org/10.1155/2016/6789276.

    Article  CAS  Google Scholar 

  124. Zimmer P, Bloch W, Schenk A, Oberste M, Riedel S, Kool J, et al. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: a randomized controlled trial. Mult Scler. 2018;24(12):1635–44. https://doi.org/10.1177/1352458517728342.

    PubMed  Google Scholar 

  125. Mokhtarzade M, Motl R, Negaresh R, Zimmer P, Khodadoost M, Baker JS, et al. Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis. Neuropeptides. 2018;70:93–100. https://doi.org/10.1016/j.npep.2018.05.010.

    CAS  PubMed  Google Scholar 

  126. Alfini AJ, Weiss LR, Nielson KA, Verber MD, Smith JC. Resting cerebral blood flow after exercise training in mild cognitive impairment. J Alzheimers Dis. 2019;67(2):671–84. https://doi.org/10.3233/JAD-180728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Riemenschneider M, Hvid LG, Stenager E, Dalgas U. Is there an overlooked “window of opportunity” in MS exercise therapy? Perspectives for early MS rehabilitation. Mult Scler. 2018;24(7):886–94. https://doi.org/10.1177/1352458518777377.

    Article  PubMed  Google Scholar 

  128. Latimer-Cheung AE, Pilutti LA, Hicks AL, Martin Ginis KA, Fenuta A, Mackibbon KA, et al. The effects of exercise training on fitness, mobility, fatigue, and health related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Arch Phys Med Rehabil. 2013;94(9):1800–28.

    PubMed  Google Scholar 

  129. Giovannoni G, Butzkueven H, Dhib-Jalbut S, Hobart J, Kobelt G, Pepper G, et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016;9(Suppl 1):S5–S48. https://doi.org/10.1016/j.msard.2016.07.003.

    PubMed  Google Scholar 

  130. Ziemssen T, Derfuss T, de Stefano N, Giovannoni G, Palavra F, Tomic D, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016;263(6):1053–65. https://doi.org/10.1007/s00415-015-7986-y.

    PubMed  PubMed Central  Google Scholar 

  131. Elovaara I. Early treatment in multiple sclerosis. J Neurol Sci. 2011;311(Suppl 1):S24–8. https://doi.org/10.1016/S0022-510X(11)70005-3.

    Article  PubMed  Google Scholar 

  132. Heesen C, Bruce J, Gearing R, Moss-Morris R, Weinmann J, Hamalainen P, et al. Adherence to behavioural interventions in multiple sclerosis: follow-up meeting report (AD@MS-2). Mult Scler J Exp Transl Clin. 2015;1:2055217315585333. https://doi.org/10.1177/2055217315585333.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Public Health, Section for Sport Science, Aarhus University, Aarhus, Denmark

    Ulrik Dalgas, Martin Langeskov-Christensen, Morten Riemenschneider & Lars G. Hvid

  2. Department of Neurology, Hospital of Southern Jutland, Sønderborg, Denmark

    Egon Stenager

  3. Department of Regional Health Research, University of Southern Denmark, Odense, Denmark

    Egon Stenager

  4. MS Clinics of Southern Jutland (Sønderborg, Esbjerg, Kolding), Hospital of Southern Jutland, Sønderborg, Denmark

    Egon Stenager

Authors
  1. Ulrik Dalgas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Langeskov-Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Egon Stenager
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morten Riemenschneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lars G. Hvid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrik Dalgas.

Ethics declarations

Conflict of Interest

Ulrik Dalgas has received research support, travel grants, and/or teaching honoraria from Biogen Idec, Merck Serono, Novartis, Bayer Schering, and Sanofi Aventis, as well as honoraria from serving on the scientific advisory boards of Biogen Idec and Genzyme. Martin Langeskov-Christensen has received teaching honoraria from Novartis. Lars G. Hvid has received research support, travel grants, and/or teaching honoraria from Biogen and Sanofi Genzyme. Egon Stenager andMorten Riemenschneider each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

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

Topical Collection on Demyelinating Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dalgas, U., Langeskov-Christensen, M., Stenager, E. et al. Exercise as Medicine in Multiple Sclerosis—Time for a Paradigm Shift: Preventive, Symptomatic, and Disease-Modifying Aspects and Perspectives. Curr Neurol Neurosci Rep 19, 88 (2019). https://doi.org/10.1007/s11910-019-1002-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-019-1002-3

Keywords

Search

Navigation