Abstract

Aim:

This review aimed to provide evidence and highlight the importance of including physical activity (PA) and/or exercise training (ET) as part of the comprehensive multiple sclerosis (MS) care.

Methods:

Using the current literature on the subject, we provide a brief overview of MS incorporating its definition, common symptoms, prevalence, and potential disease consequences. We further succinctly describe MS as the first line of treatment, as well as the role of PA and ET in the disease. We end the commentary highlighting important recommendations from an international initiative to improve MS-related physical activity research that we believe will help not only improve the area of study but also best practices within this population.

Results:

There is compelling evidence for the beneficial effects of PA and/or ET on MS-related symptoms and consequently health and quality of life. There is preliminary evidence suggesting the potential for a disease-modifying effect.

Conclusion:

Fomenting this discussion is timely due to the increased prevalence of MS in different regions of the globe, and people with MS report low levels of PA participation and high amounts of sedentary time. The consequences of inactivity in this population can be drastic. The current body of evidence supports the notion that PA and ET are safe health behaviors that should be adopted as an adjuvant treatment option within the comprehensive and complex MS care due to its benefits on a variety of disease-related symptoms and its potential for improving health and quality of life in this population.

Keywords
health-related quality of life; neurodegenerative disease; patient care; motor activity; rehabilitation

Introduction

Multiple sclerosis (MS) is neurodegenerative, often disabling, unpredictable disease of the central nervous system (CNS) that disrupts the flow of information within the brain, and between the brain and the body¹1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-17.doi
doi... . The disease presents with a large array of symptoms that include, but are not limited to, muscle weakness, balance, mobility and cognitive impairment, depression, fatigue, pain and spasticity, vision, and sensory impairment¹1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-17.doi
doi... . It is estimated that 2.8 million people live with MS worldwide. In Brazil, the prevalence of MS ranges from 5 to 27 per 100,000 habitants²2. da Gama Pereira ABCN, Sampaio Lacativa MC, da Costa Pereira FFC, Papais-Alvarenga RM. Prevalence of multiple sclerosis in Brazil: a systematic review. Mult Scler Relat Disord. 2015;4:572-9. doi
doi... . These numbers are significantly lower compared with countries like the United States (309.2 per 100,000)³3. Wallin MT, Culpepper WJ, Campbell JD, Nelson LM, Langer-Gould A, Marrie RA, et al. The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019,92(10):e1029-e1040. doi
doi... and Canada (240 per 100,000)⁴4. Marrie RA, Yu N, Blanchard J, Leung S, Elliott L. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology. 2010;74(6):465-71. doi
doi... .

The lower MS prevalence in Brazil may be partially explained by the fact that Brazil is situated close to the equator, and this probably contributes toward higher vitamin D levels. Low levels of vitamin D have been described as a potential risk factor for MS⁵5. Tao C, Simpson S, van der Mei I, Blizzard L, Havrdova E, Horakova D, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(12):1343-9. doi
doi... . Nevertheless, MS can have devastating consequences, and therefore, should be a concern regardless of worldwide location. For example, there is evidence demonstrating that people with MS have a lower life expectancy compared with the life expectancy of the general population⁶6. Lunde HMB, Assmus J, Myhr KM, Bø 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. doi
doi... . In addition, MS is more prevalent in women than men (2-3:1 ratio) and its onset occurs in younger adults (i.e., labor force age)⁷7. Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: clinical aspects. Curr Opin Neurol. 2018;31(6):752-9. doi
doi... ; this increases the chance of unemployment due to disease-related disability^8,8. Souza A, Kelleher A, Cooper R, Cooper RA, Iezzoni LI, Collins DM. Multiple sclerosis and mobility-related assistive technology: systematic review of the literature. J Rehabil Res Dev. 2010;47(3):213-23. doi
doi... ⁹9. Gafari S, Khoshknab MF, Nourozi K, Mohamadi E. Informal caregivers’ experiences of caring of multiple sclerosis patients: a qualitative study. Iran J Nurs Midwifery Res. 2017;22(3):243-7. doi
doi... . One recent study conducted in Brazil with nearly 700 MS patients with mild levels of disability demonstrated that 95% of the participants were at working age and that roughly 50% were employed. In addition, 94% reported being affected by fatigue and approximately 64% reported cognitive difficulties¹⁰10. Kobelt G, Teich V, Cavalcanti M, Canzonieri AM. Burden, and cost of multiple sclerosis in Brazil. PLoS One. 2019;14(1):e0208837. doi
doi... .

Multiple sclerosis: first line of treatment

Currently, there is no cure for MS. The first line of treatment for the disease is the use of disease-modifying therapies (DMTs), and these are commonly prescribed following disease diagnosis. There are 17 approved DMTs for the treatment of relapsing forms of MS (i.e., CIS, RRMS, and SPMS), and one for the PPMS (Figure 1). These drugs focus on reducing both the number and severity of relapses (exacerbations) by targeting latent immune dysregulation of cytokines and lymphocytes and, therefore, slowing the progression of the disease^11,11. Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs. 2005;19(3):239-52. doi
doi... ¹²12. MS Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current vidence. A consensus paper by the Multiple Sclerosis Coalition; 2019. Available from: https://ms-coalition.org/the-use-of-disease-modifying-therapies-in-multiple-sclerosis-updated/.
https://ms-coalition.org/the-use-of-dise... . However, DMTs are not appropriate for treating the disease symptoms or curing MS. For instance, these medications seem to not positively affect common disease symptoms such as fatigue and cognition^13,13. Amato MP, Langdon D, Montalban X, Benedict RHB, DeLuca J, Krupp LB, et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol. 2013;260(6):1452-68. doi
doi... ¹⁴14. 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. doi
doi... . In addition, DMTs may cause significant side effects¹⁵15. 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. 2020;267(12):3489-98. doi
doi... ; which may compromise medication adherence. For symptoms management, people with MS are often prescribed numerous medications for alleviating the numerous symptoms and therefore improving their quality of life¹⁶16. Frahm N, Hecker M, Zettl UK. Polypharmacy among patients with multiple sclerosis: a qualitative systematic review. Expert Opin Drug Saf. 2020;19(2):139-45. doi
doi... . Consequently, polypharmacy may have serious side effects, such as the increased risk of adverse drug events, drug interactions, reduced functional capacity, and medication non-adherence^17,17. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57-65. doi
doi... ¹⁸18. Kołtuniuk A, Rosiaczuk J. Adherence to disease-modifying therapies in patients with multiple sclerosis. Patient. 2018; 2018(12):1557-66.. To this end, non-pharmacological therapies that engender minimal side-effects are of particular interest for the MS population. A non-pharmacological therapy with potential beneficial effects in a wide-array of MS symptoms with minimal to no almost no side-effects is physical activity (PA) or exercise training¹⁹19. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-97. doi
doi... 20. 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. doi
doi... ^-2121. Motl RW. Lifestyle physical activity in persons with multiple sclerosis: the new kid on the MS block. Mult Scler J. 2014;20(8):1025-9. doi
doi... . In fact, the idea of prescribing PA/exercise training as a potential treatment for disease symptoms and progression in people with MS corroborates the global exercise is medicine movement²²22. Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sport. 2015;25(Suppl 3):1-72. doi
doi... .

Multiple sclerosis: physical activity and exercise training as adjuvant therapy

Researchers and health professionals have agreed that wellness should be a priority for people with MS, and can be achieved through health behaviors including PA and exercise training^23,23. Motl RW, Mowry EM, Ehde DM, LaRocca NG, Smith KE, Costello K, et al. Wellness and multiple sclerosis: the national ms society establishes a wellness research working group and research priorities. Mult Scler J. 2018;24(3):262-7. doi
doi... ²⁴24. Hart DL, Memoli RI, Mason B, Werneke MW. Developing a wellness program for people with multiple sclerosis: description and initial results. Int J MS Care. 2011;13(4):154-62. doi
doi... . In fact, PA - particularly exercise training, represents an adjuvant therapy for managing symptoms of MS. In the past, partaking in exercise training was controversial for people with MS. It was believed that such practice would cause an exacerbation of the symptoms²⁵25. Sutherland G, Andersen MB. Exercise and multiple sclerosis: physiological, psychological, and quality of life issues. J Sports Med Phys Fitness. 2001;41(4):421-32.. However, studies conducted in the United States, Canada, and across European countries, where the prevalence of MS is high, have demonstrated that both PA and exercise training is safe and yield beneficial effects in this population, including improvements in fitness, fatigue, depression, balance, function, and walking performance, and those collectively improve quality of life^19,19. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-97. doi
doi... ^26,26. Kalb R, Brown TR, Coote S, Costello K, Dalgas U, Garmon E, et al. Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course. Mult Scler J. 2020;26(12):1459-69. doi
doi... ²⁷27. Sandroff BM, Jones CD, Baird JF, Motl RW. Systematic review on exercise training as a neuroplasticity-inducing behavior in multiple sclerosis. Neurorehabil Neural Repair. 2020;34(7):575-88. doi
doi... (Figure 1). Although isolated studies have observed improvements in cognition, results from a recent meta-analysis do not support the efficacy of exercise training on global or domain-specific (e.g., attention, processing speed) cognitive performance in people with MS²⁸28. Gharakhanlou R, Wesselmann L, Rademacher A, Lampit A, Negaresh R, Kaviani M, et al. Exercise training and cognitive performance in persons with multiple sclerosis: a systematic review and multilevel meta-analysis of clinical trials. Mult Scler J. 2020;27(13):1977-93. doi
doi... . There is further positive evidence of the benefits of PA/exercise training in “preventing” (i.e. risk reduction) MS, MS pathogenesis, relapses, central nervous system structures, and participation outcomes as well as risk for comorbidities^19,19. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-97. doi
doi... ^29,29. Kjølhede T, Siemonsen S, Wenzel D, Stellmann JP, Ringgaard S, Pedersen BG, et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler J. 2018;24(10):1356-65. doi
doi... ³⁰30. Dalgas U, Langeskov-Christensen M, Stenager E, Riemenschneider M, Hvid LG. Exercise as medicine in multiple sclerosis - time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives. Curr Neurol Neurosci Rep. 2019;19(11):88. doi
doi... . Collectively, the current body of knowledge in this area supports meaningful consequences of PA and exercise training in people with MS; which underscores its important role in both primary (i.e., prevent disease before it develops) and secondary (i.e., reduce the impact of the disease that has already developed) prevention.

The multitude of clinical trials in this area yielded a recent publication on recommendations for exercise training and lifestyle PA for people with MS across the disability spectrum²⁶26. Kalb R, Brown TR, Coote S, Costello K, Dalgas U, Garmon E, et al. Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course. Mult Scler J. 2020;26(12):1459-69. doi
doi... . This initiative led and sponsored by the National MS Society of the United States brought together renowned researchers from different parts of the globe and underscores the important role of PA and exercise training as a treatment for people with MS. Major points described in the referred manuscript are summarized in Table 1.

Nevertheless, those with MS engage in lower levels of PA than counterparts from the general population³¹31. Casey B, Coote S, Galvin R, Donnelly A. Objective physical activity levels in people with multiple sclerosis: meta-analysis. Scand J Med Sci Sport. 2018;28(9)1960-9. doi
doi... . This is a concern because inactivity can place people with MS in a vicious cycle whereby physical deconditioning due to inactivity worsens symptoms and accelerates disease progression, which in turn increases inactivity levels due to increased disability³²32. Sandroff BM, Klaren RE, Motl RW. Relationships among physical inactivity, deconditioning, and walking impairment in persons with multiple sclerosis. J Neurol Phys Ther. 2015;39(2):103-10. doi
doi... . The current body of evidence regarding the benefits of PA and/or exercise for people with MS supports the notion that PA and exercise training are safe health behaviors that should be adopted as an adjuvant treatment option within the comprehensive and complex MS care due to its benefits on a variety of disease-related symptoms. This is especially important in countries where the prevalence of MS is relatively low such as Brazil. For instance, in consensus guidelines for MS treatment in Brazil published by the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology, the only treatment discussed was pharmacological^33,33. Comini-Frota ER, Vasconcelos CCF, Mendes MF. Guideline for multiple sclerosis treatment in Brazil: consensus from the neuroimmunology scientific department of the Brazilian Academy of Neurology. Arq Neuropsiquiatr. 2017;75(1):57-65. doi
doi... ³⁴34. Marques VD, dos Passos GR, Mendes MF, Collegaro D, Lana-Peixoto MA, Comini-Frota ER, et al. Brazilian consensus for the treatment of multiple sclerosis: Brazilian Academy of Neurology and Brazilian Committee on treatment and research in multiple sclerosis. Arq Neuropsiquiatr. 2018;76(8):539-54. doi
doi... . The high-cost medications (MS drugs included) in Brazil are financed by the Universal Health System (SUS in Portuguese). According to Comini-Frota et al.³³33. Comini-Frota ER, Vasconcelos CCF, Mendes MF. Guideline for multiple sclerosis treatment in Brazil: consensus from the neuroimmunology scientific department of the Brazilian Academy of Neurology. Arq Neuropsiquiatr. 2017;75(1):57-65. doi
doi... , the distribution of MS-specific medications follows the protocol from the Ministry of Health, which is based upon “bureaucratic rules and pharmacoeconomics”, posing a challenge to a neurologist, as it is inflexible. Such a model does not consider the complexity and individual heterogeneity of the disease and its treatment. Thus, given the numerous benefits of PA and/or exercise training for people with MS, supporting and promoting such behavior along with standard treatment (i.e., DMT) seems to be paramount.

Figure 1
Overview of the multiple sclerosis treatment and the health benefits of physical activity and exercise training in this population.

Final considerations

There is solid evidence that PA and exercise training are important components in the management of MS due to its plethora of benefits for this population. The number of studies using exercise as a treatment effect in people with MS is increasing exponentially. However, a recent international initiative urged for the necessity for the development of consensus within the MS-related exercise research in several different aspects (i.e., definitions and terminologies, studies methodologies, reporting and outcomes, adherence and compliance to exercise, and mechanisms of action)³⁵35. Dalgas U, Hvid LG, Kwakkel G, Motl RW, Groot V, Feys P, et al. Moving exercise research in multiple sclerosis forward (the MoXFo initiative): developing consensus statements for research. Mult Scler J. 2020;26(11):1303-8. doi
doi... . According to this initiative, achieving consensus in the highlighted areas will better equip researchers to conduct large, international multicenter efforts that would target the most pressing research questions in this area, with a positive impact on those who need the most of best practices - the MS patients. Altogether, PA or exercise training are powerful tools in managing MS-related symptoms and are essential for general health and well-being. Of note, PA or exercise training does not have to be a high-intensity type of activity for benefits, and general activities that can normally be at home or in the community can result in positive physical and mental health outcomes²¹21. Motl RW. Lifestyle physical activity in persons with multiple sclerosis: the new kid on the MS block. Mult Scler J. 2014;20(8):1025-9. doi
doi... . PA and exercise training do not increase the number of relapses or exacerbate symptoms²⁵25. Sutherland G, Andersen MB. Exercise and multiple sclerosis: physiological, psychological, and quality of life issues. J Sports Med Phys Fitness. 2001;41(4):421-32., but rather improve quality of life and well-being, and promote participation³⁶36. 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. doi
doi... .

References

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