Multiple Sclerosis
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Lifestyle Measures in Multiple Sclerosis

Published Online: October 10th 2022 touchREVIEWS in Neurology. 2022;18(2):Online ahead of journal publication
Authors: Cristina Fernandez-Carbonell, Natasha Hameed, Asaff Harel
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Abstract:
Overview

Despite substantial breakthroughs in pharmacological therapies for multiple sclerosis (MS) over the past two decades, lifestyle modification remains an important strategy in managing symptoms and potentially preventing disability for people with MS. There is growing evidence that certain dietary factors may influence MS incidence, symptoms and disease course. Obesity, which is closely linked to diet, has been shown to be a risk factor for the development and increased severity of MS. Although the precise mechanisms by which the above factors exert their effects on MS are unknown, it is important for physicians to consider how these factors can influence the management of patients with MS. For example, sleep interventions and regular exercise may help with the common symptoms of MS, such as fatigue, cognitive dysfunction and mood disorders. Other important interventions include avoidance of tobacco smoke and adequate vitamin D intake. This review summarizes existing knowledge regarding the abovementioned factors with respect to MS incidence and severity.

Keywords

Diet, exercise, lifestyle, multiple sclerosis, multiple sclerosis fatigue, sleep

Article:

Although disease-modifying therapies have been the primary focus of multiple sclerosis (MS) treatment during the past two decades, there is increasing awareness of the importance of treating patients holistically, paying attention to functional comorbidities and addressing mood and cognition. In general, promoting healthy behaviours and encouraging physical activity is essential to enhancing quality of life (QoL) and a sense of wellbeing in patients living with MS. This review summarizes the up-to-date literature on the lifestyle factors that may impact MS disease burden, including diet and obesity, exercise, sleep and fatigue, vitamin D, smoking tobacco and stress.

Diet and obesity

While the precise relationship between diet and MS risk and severity is unclear, it is a topic that is frequently queried by patients with MS. Although many studies are limited by sample size or study design, it is becoming clear that dietary habits play a role in the severity, and potentially the incidence, of MS. Certain dietary factors may promote immune-regulation, potentially through producing effects on the gut microbiome,1 while others may be pro-inflammatory.2 An in-depth discussion of the effects of dietary factors on the gut microbiome is outside of the scope of this review, but more detailed information can be found elsewhere.3 Obesity and elevated body mass index (BMI) are well established risk factors for MS.4–6 A study by Brenton et al. demonstrated increased obesity in paediatric patients with early-onset MS compared with those with later disease onset.7 When compared with demographically matched healthy controls, children with MS had significantly higher BMIs beginning up to 11 years before MS onset and remaining significantly elevated every year up to diagnosis.8

A summary of notable dietary intervention studies in MS is presented in Table 1.9–12 Outcomes studied include relapse rates, metrics of mood, Expanded Disability Status Scale scores, fatigue metrics and QoL metrics. Much of the literature to date emphasizes low-fat diets, including Mediterranean and omega-3 polyunsaturated fatty acids (PUFA)-based diets, albeit with conflicting clinical results.

One notable multicentre prospective cohort study demonstrated that each 10% increase in energy intake from fat led to a 56% increase in the hazard of MS relapse, and each 10% increase in energy from saturated fats tripled this risk.13 In contrast, an increase of a one-cup equivalent of vegetables led to a 50% decrease in relapse risk.13 However, a diet low in saturated fat did not appear to improve Expanded Disability Status Scale score or magnetic resonance imaging (MRI) activity.11,14 It is unclear whether PUFA intake impacts MS severity, as clinical trials have produced conflicting results.14–17 High-fibre diets, such as those high in fruits and vegetables, have also been suggested to be beneficial in patients with MS, but studies are limited by a small sample size and lack of randomization.18–20

While diets such as the Wahls diet (a modified paleo diet)21 and the Swank diet (a very low-fat diet)22 have been popular amongst patients, the evidence for specific and highly restrictive diets such as these remains limited. A recent short-duration longitudinal study randomizing patients to either the Wahls or the Swank diet found that both diets reduced fatigue and improved QoL from baseline.23 However, this study was limited by the lack of a non-intervention control group, and it did not assess whether changes in fatigue/QoL were related to a decrease in BMI during the study. Given the differences between the two diets, weight loss could be postulated as a common contributor to the improvements in fatigue scores, as suggested by a prior placebo-controlled pilot studying the effects of a Mediterranean diet.24 However, given that both diets are high in fibre and focus on a high intake of fruits, vegetables and unsaturated fats, with a low intake of processed foods, it is likely that these common factors may be beneficial for MS-related fatigue.

Fasting-type diets have also gained popularity, although the evidence supporting their benefits is conflicting. Recent open-label studies have demonstrated improvements in several clinical disability metrics, but the lack of a control group heavily limited the interpretation of the results.25,26 A pilot study of 17 patients randomized to either intermittent fasting or a control diet showed no effects on clinical measures between the groups after 2 weeks.27 However, a longer 8-week randomized pilot study of 36 patients who underwent either daily calorie restriction, intermittent (2 days/week) calorie restriction or a control diet demonstrated substantial weight loss and improved emotional wellbeing in both CR intervention arms.28 Finally, a recent pilot study with a small sample size demonstrated improved serum neurofilament light chain levels after 6 months of an adapted ketogenic diet compared with controls, providing preclinical evidence of a possible neuroprotective effect.29 Further work is necessary to fully understand the relationship between these dietary modifications and MS and whether fasting-type diets offer an MS-specific benefit beyond weight loss alone.

While there is enough literature to recommend a diet for cardiovascular benefit – low in saturated fats, high in fibre and high in fatty fish – it is not clear which diet, if any, provides the highest benefits in MS due to limited evidence and conflicting study results, pointing to the need for further research to compare diets.13,21–23,25,27 However, there is general agreement in the literature that a diet high in fibre, vegetables, whole grains and fatty fish and low in saturated fat, sugar and processed foods can be potentially beneficial for patients with MS.

Exercise

Regular exercise is of the utmost importance in managing symptoms, restoring function and promoting wellness and QOL in people with MS.30 However, despite the growing body of evidence of these benefits, people with MS tend to exercise less than their healthy counterparts.30–33 This relative lack of exercise may reflect limitations related to ambulatory disability, pain, fatigue, environmental barriers or to depression and other psychosocial factors (e.g. self-efficacy, goal setting and social support). A recent evaluation of physical activity in young people with MS demonstrated that, while people with MS have positive perceptions of the benefits of exercise, this population also exhibited a fear that exercising could worsen chronic MS symptoms and/or lead to relapses. Other deterrents to exercise included lack of social support and time for exercise, and it was deemed that better education regarding specific exercises would be beneficial.34

Exercise has beneficial effects on cardiorespiratory fitness, walking mobility and balance.30 Additionally, moderate weight-bearing exercise has been shown to improve bone mineral density, which could help reduce fracture risk in the MS population.35 Flexibility-directed exercises are important to limit spasticity in the early stages of MS,36 and pelvic floor exercises can improve incontinence and sexual dysfunction.37

Outside of the physical benefits of exercise, there is conflicting evidence regarding its beneficial impact on fatigue, cognitive dysfunction and depressed mood, symptoms that are frequently exhibited by individuals with MS. A systematic review examining the effects of exercise on cognition did not find definitive evidence that physical activity was associated with improved cognitive function in people with MS, but this may be related to limitations and variability of clinical trials.38 Small pilot studies have suggested possible beneficial effects of exercise on cognition in people with MS.39,40 Two meta-analyses and one Cochrane review examined the effects of exercise on fatigue outcomes in people with MS, suggesting modest improvement in fatigue after exercise training, but showed overall heterogeneous results.41–43 Some commonstudy limitations included lack of adequate power, the variety of exercise interventions studied, selective reporting of outcomes and the absence of pre-screening for severe baseline fatigue. Of note, physical activity does appear to mitigate sleep dysfunction and fatigue in children with paediatric-onset MS.44 Finally, several meta-analyses have reported the consistent benefits of exercise on symptoms of depression in people with MS.45–47

Based on the above data, exercise is likely to have profound physiological benefits in people with MS and is potentially beneficial for cognition, fatigue, mood and QOL in general. Additionally, exercise may help prevent the development of obesity, which is known to be associated with higher disease severity.4–6 The National MS Society recently recommended that patients with MS undergo at least 150 minutes of exercise each week; however, progress towards that goal should be gradual to avoid worsening underlying symptoms, such as fatigue.48

Sleep and fatigue

Sleep disorders and fatigue are common in patients with MS and can precede the disease diagnosis in its prodromal phase.49 Common sleep disorders in MS include restless leg syndrome, periodic limb movements and sleep apnoea.50 Fatigue is an extremely common symptom associated with disease duration and a common cause of the inability to work in patients with MS.51 Insomnia is often associated with fatigue in MS, but one study found that the variance in fatigue could not be explained by insomnia, daytime sleepiness, depression or level of exercise, suggesting other factors at play.52 While the aetiology of MS-related sleep disorders is poorly understood, patients with disrupted sleep patterns display decreased functional connectivity in thalamic circuits.53 If sleep disorders are intractable in initial therapy, the patient should be referred to a sleep centre for formal evaluation.

Overall, sleep disorders adversely affect the QOL of people with MS by worsening fatigue and depressive symptoms.50,54–56 As the treatment of sleep dysfunction has been shown to improve MS fatigue,57 which is tied to QOL,50 the treatment of sleep disorders may improve overall QOL. Patients with MS and sleep disorders frequently report a decline in self-perceived cognitive function;58 however, one study failed to show differences in objective cognitive scores between those with associated sleep disorders and those without them.59

With regards to treating MS-related fatigue specifically, recent evidence suggests that pharmacologic interventions may not be superior to placebo.60 In fact, several studies have demonstrated that multimodal non-pharmacologic interventions, such as cognitive behavioural therapy and rehabilitation, can effectively improve fatigue, sleep disorders and depression in patients with MS.61,62

It is important to differentiate between primary fatigue (a direct result of MS) and secondary fatigue (caused by comorbid conditions) in MS. There are various potential drivers of secondary fatigue in MS, such as sleep disorders, pain, spasticity, bladder disorders, mood disorders and medication effects. Therefore, potentially contributory comorbid conditions and medications should be ruled out before behavioural interventions and therapeutic trials can be considered.63 A careful analysis of the factors contributing to sleep disturbance and/or fatigue is of utmost importance before considering lifestyle or pharmaceutical interventions.

Vitamin D

There are several genetic and environmental factors that can contribute to the risk of developing MS: one of particular interest is vitamin D.64 Vitamin D is prohormone derived from sun exposure, diet and supplementation.65 It has anti-inflammatory effects on both the innate and adaptive immune system.66 Vitamin D deficiency not only influences the risk of developing MS67–69 but has also been associated with MS disease activity,70–75 progression74–76 and the conversion from a clinically isolated syndrome to clinically definite MS.77 Furthermore, vitamin D deficiency in mothers during early pregnancy has been linked to a two-fold increased risk of their offspring developing MS in the future.68

Several studies have evaluated the impact of vitamin D supplementation on MS development and disease course.67–78 A large observational study examining vitamin D intake in relation to the risk of developing MS found that women who supplemented with vitamin D had a 40% reduced risk of developing MS over a 20-year follow-up period compared with those who had no supplemental vitamin D intake.67 However, the two largest studies to date – the SOLAR (Supplementation of VigantOL® oil versus placebo as add-on in patients with relapsing remitting multiple sclerosis receiving Rebif® treatment [SOLAR]; ClinicalTrials.gov identifier: NCT01285401)75 and CHOLINE (A multicentre study of the efficacy and safety of supplementary treatment With cholecalciferol in patients with relapsing multiple sclerosis treated with subcutaneous interferon beta-1a 44 µg 3 times weekly [CHOLINE]; ClinicalTrials.gov identifier: NCT01198132)78 studies – evaluating the effects vitamin D supplementation as add-on therapy to interferon beta-1a failed to show an effect on clinical parameters such as relapse rate and disability worsening.

Despite the inconsistent results regarding supplementation, there remains evidence to support the role of vitamin D in reducing MS severity. Prospective and retrospective studies have shown a reduction in relapse risk in individuals with higher serum vitamin D levels, with the risk further declining with every 10 ng/mL (25 nmol/L) increase in serum level.70–72 Higher vitamin D levels have also been associated with a reduction in disease activity on brain MRI, showing a protective effect on the development of new T2 lesions and contrast-enhancing lesions.73–75

The current evidence suggests that vitamin D is a modifiable risk factor and highlights the importance of preventing vitamin D deficiency in MS. While the correction of vitamin D deficiency in people with MS is recommended, the optimal level of vitamin D is currently unknown. We recommend regular monitoring of vitamin D levels in patients with MS, with the avoidance of both deficiency and over-replacement.

Smoking tobacco

Several studies have demonstrated that smoking tobacco is associated with a higher risk of developing MS and a higher disease burden following a diagnosis. In 2001, the Nurses’ Health Study demonstrated not only that smokers exhibited a higher risk of developing MS than non-smokers but that the number of cigarettes and duration of exposure were also predictive factors.79 Another large meta-analysis demonstrated similar findings, showing a higher odds ratio of developing MS related to increased cigarette exposure, a risk that appeared to persist even in ex-smokers.80 Interestingly, passive smoke exposure (i.e. second-hand smoke exposure) has also been reported as an independent risk factor for MS development.81 Finally, with an established MS diagnosis, smoking has been associated with faster disease progression and accumulation of disability compared with non-smoking,82 and smoking cessation has been associated with improved outcomes.83

The relationship between smoking and the development and severity of MS is incompletely understood. It is thought that it is likely resultant of pro-inflammatory and autoimmune effects and potentially arises from changes in the translational processing of immunological proteins.84 Furthermore, studies have demonstrated that certain components of cigarette smoke are toxic to oligodendrocytes and neurons,85 while nicotine itself may have protective properties.86 Given the definitive deleterious relationship between smoking tobacco and MS, special efforts should be made to counsel active smokers with MS and highly recommend cessation. Information on smoking cessation support resources can be found on the Centers for Disease Control and Prevention website.87

Stress

Stressful life events, conflicts and disruptions of routine have been associated with disease activity in MS.88,89 Hence, it is recommended that patients with MS take steps to limit stress. A randomized study that implemented a stress-management programme in patients with MS found that the programme significantly decreased perceived stress and depression compared with no stress-management intervention.90 In another randomized trial, stress management led to decreased rates of brain lesion formation.91 A systematic review of three randomized controlled trials found that mindfulness-based interventions led to improvements in QOL, mental health and fatigue.92 This suggests that stress-mitigation strategies could be a valuable tool in the treatment armamentarium for MS-related symptoms.

Conclusions

The treatment landscape in MS has been transformed in the past two decades with a myriad of effective pharmacologic therapies that have reduced the incidence of relapses and resultant disability. However, people with MS still often live with disabling symptoms. Despite the emphasis on pharmaceuticals, there is growing evidence that lifestyle measures are immensely important not only in mitigating the symptoms of MS but also perhaps in delaying or preventing disability.

A healthful diet low in saturated fats, processed foods and sugar, and high in fibre, vegetables and fatty fish is recommended; however, further research is necessary to determine whether certain specific diets provide more benefit than others. Avoidance of obesity, regular cardiovascular exercise exceeding 150 minutes per week, adequate sleep, adequate vitamin D level and avoidance of tobacco smoke are all important lifestyle factors that clinicians should regularly address with patients. Additionally, stress reduction techniques, such as mindfulness, may also be beneficial in mitigating symptoms. Given the need for comprehensive care, a multidisciplinary approach to MS is recommended. Neurologists can receive help from dieticians, physical therapists and physiatrists, psychologists, and primary care physicians to fully address lifestyle measures. Future research will serve to better elucidate the mechanisms by which these factors exert their effects on MS.

Article Information:
Disclosure

Asaff Harel has received personal funds from Biogen, Alexion, Banner Life Sciences and Horizon pharmaceuticals. He has received research funds from Biogen, Roche/Genentech, the National Multiple Sclerosis Society and the Consortium for Multiple Sclerosis Centers. Cristina Fernandez-Carbonell and Natasha Hameed have no financial or non-financial relationships or activities to declare in relation to this article.

Compliance With Ethics

This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.

Review Process

Double-blind peer review.

Authorship

The named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Correspondence

Asaff Harel, 130 East 77th Street, 8 Black Hall, NY 10075, USA. E: aharel@northwell.edu

Support

No funding was received in the publication of this article.

Access

This article is freely accessible at touchNEUROLOGY.com. © Touch Medical Media 2022

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this article.

Received

2022-04-27

References

  1. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.
  2. Riccio P. The molecular basis of nutritional intervention in multiple sclerosis: A narrative review. Complement Ther Med. 2011;19:228–37.
  3. Valburg C, Sonti A, Stern JN, et al. Dietary factors in experimental autoimmune encephalomyelitis and multiple sclerosis: A comprehensive review. Mult Scler.2021;27:494–502.
  4. Hedström AK, Lima Bomfim I, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology. 2014;82:865–72.
  5. Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: A long-term cohort study. Mult Scler. 2013;19:1323–9.
  6. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73:1543–50.
  7. Brenton JN, Koenig S, Goldman MD. Vitamin D status and age of onset of demyelinating disease. Mult Scler Relat Disord.2014;3:684–8.
  8. Brenton JN, Woolbright E, Briscoe-Abath C, et al. Body mass index trajectories in pediatric multiple sclerosis. Dev Med Child Neurol.2019;61:1289–94.
  9. Weinstock-Guttman B, Baier M, Park Y, et al. Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids.2005;73:397–404.
  10. Riccio P, Rossano R, Larocca M, et al. Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study.Exp Biol Med (Maywood). 2016;241:620–35.
  11. Yadav V, Marracci G, Kim E, et al. Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial.Mult Scler Relat Disord. 2016;9:80–90.
  12. Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms.Cell Rep. 2016;15:2136–46.
  13. Azary S, Schreiner T, Graves J, et al. Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry. 2018;89:28–33.
  14. Hoare S, Lithander F, van der Mei I, et al. Higher intake of omega-3 polyunsaturated fatty acids is associated with a decreased risk of a first clinical diagnosis of central nervous system demyelination: Results from the Ausimmune Study. Mult Scler.2016;22:884–92.
  15. Bjornevik K, Chitnis T, Ascherio A, Munger KL. Polyunsaturated fatty acids and the risk of multiple sclerosis. Mult Scler.2017;23:1830–8.
  16. Torkildsen O, Wergeland S, Bakke S, et al. ù-3 fatty acid treatment in multiple sclerosis (OFAMS Study): A randomized, double-blind, placebo-controlled trial. Arch Neurol. 2012;69:1044–51.
  17. Dworkin RH, Bates D, Millar JH, Paty DW. Linoleic acid and multiple sclerosis: A reanalysis of three double-blind trials. Neurology. 1984;34:1441–5.
  18. Saresella M, Mendozzi L, Rossi V, et al. Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: A pilot study. Front Immunol.2017;8:1391.
  19. Fitzgerald KC, Tyry T, Salter A, et al. Diet quality is associated with disability and symptom severity in multiple sclerosis. Neurology. 2018;90:e1–11.
  20. Hadgkiss EJ, Jelinek GA, Weiland TJ, et al. The association of diet with quality of life, disability, and relapse rate in an international sample of people with multiple sclerosis. Nutr Neurosci. 2015;18:125–36.
  21. Irish AK, Erickson CM, Wahls TL. Randomized control trial evaluation of a modified Paleolithic dietary intervention in the treatment of relapsing-remitting multiple sclerosis: A pilot study. Degener Neurol Neuromuscul Dis.2017;7:1–18.
  22. Swank RL, Goodwin J. Review of MS patient survival on a Swank low saturated fat diet. Nutrition. 2003;19:161–2.
  23. Wahls TL, Titcomb TJ, Bisht B, et al. Impact of the Swank and Wahls elimination dietary interventions on fatigue and quality of life in relapsing-remitting multiple sclerosis: The WAVES randomized parallel-arm clinical trial. Mult Scler J Exp Transl Clin.2021;7:20552173211035399.
  24. Katz Sand I, Benn EKT, Fabian M, et al. Randomized-controlled trial of a modified Mediterranean dietary program for multiple sclerosis: A pilot study. Mult Scler Relat Disord. 2019;36:101403.
  25. Brenton JN, Banwell B, Bergqvist AGC, et al. Pilot study of a ketogenic diet in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2019;6:e565.
  26. Brenton JN. Ketogenic diet as a strategy for improved wellness and reduced disability in relapsing multiple sclerosis. Presented at: American Academy of Neurology meeting, Seattle, WA, USA, April 2022. Abstr S40.007.
  27. Cignarella, F, Cantoni, C, Ghezzi, L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab. 2018;27:1222–35.
  28. Fitzgerald, KC, Vizthum, D, Henry-Barron, B, et al. Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult Scler Relat Disord. 2018;23:33–9.
  29. Bock M, Steffen F, Zipp F, Bittner S. Impact of dietary intervention on serum neurofilament light chain in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;9:e1102.
  30. Motl RW, Sandroff BM, Kwakkel G, et al. Exercise in patients with multiple sclerosis.Lancet Neurol. 2017;16:848–56.
  31. 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.Mult Scler Relat Disord. 2017;13:38–43.
  32. Grover SA, Aubert-Broche B, Fetco D, et al. Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis. Neurology. 2015;85:1663–9.
  33. Grover SA, Sawicki CP, Kinnett-Hopkins D, et al. Physical activity and its correlates in youth with multiple sclerosis.J Pediatr. 2016;179:197–203.
  34. EM, Richardson EV, Motl RW. A qualitative study of exercise and physical activity in adolescents with pediatric-onset multiple sclerosis.Int J MS Care. 2019;21:81–91.
  35. Ozgocmen S, Bulut S, Ilhan N, et al. Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: Effect of ambulatory status and functional capacity. J Bone Miner Metab. 2005;23:309–13.
  36. Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: Recommendations for the application of resistance-, endurance- and combined training. Mult Scler. 2008;14:35–53.
  37. Altunan B, Gundogdu AA, Ozcaglayan TIK, et al. The effect of pelvic floor exercise program on incontinence and sexual dysfunction in multiple sclerosis patients. Int Urol Nephrol. 2021;53:1059–65.
  38. 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;26:271–94.
  39. Sandroff BM, Balto JM, Klaren RE, et al. Systematically developed pilot randomized controlled trial of exercise and cognition in persons with multiple sclerosis. Neurocase. 2016;22:443–50.
  40. Briken S, Gold SM, Patra S, et al. Effects of exercise on fitness and cognition in progressive MS: A randomized, controlled pilot trial. Mult Scler. 2014;20:382–90.
  41. Pilutti LA, Greenlee TA, Motl RW, et al. Effects of exercise training on fatigue in multiple sclerosis: A meta-analysis. Psychosom Med.2013;75:575–80.
  42. Asano M, Berg E, Johnson K, et al. A scoping review of rehabilitation interventions that reduce fatigue among adults with multiple sclerosis. Disabil Rehabil. 2015;37:729–38.
  43. Heine M, van de Port I, Rietberg MB, et al. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2015;(9):CD009956.
  44. Rocca MA, Filippi M, Deiva K. Promoting physical activity to control multiple sclerosis from childhood. Neurology. 2015;85:1644–5.
  45. Adamson BC, Ensari I, Motl RW. Effect of exercise on depressive symptoms in adults with neurologic disorders: A systematic review and meta-analysis. Arch Phys Med Rehabil. 2015;96:1329–38.
  46. 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;76:465–71.
  47. 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;22:443–e34.
  48. Kalb R, Brown TR, Coote S, et al. Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course. Mult Scler. 2020;26:1459–69.
  49. Yusuf F, Wijnands JM, Kingwell E, et al. Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome. Mult Scler.2021;27:290–302.
  50. Veauthier C, Gaede G, Radbruch H, et al. Sleep disorders reduce health-related quality of life in multiple sclerosis (Nottingham health profile data in patients with multiple sclerosis). Int J Mol Sci. 2015;16:16514–28.
  51. Oliva Ramirez A, Keenan A, Kalau O, et al. Prevalence and burden of multiple sclerosis-related fatigue: A systematic literature review. BMC Neurol.2021;21:468.
  52. Johansson K, Wasling P, Axelsson M. Fatigue, insomnia and daytime sleepiness in multiple sclerosis versus narcolepsy. Acta Neurol Scand.2021;144:566–75.
  53. van Geest Q, Westerik B, van der Werf YD, et al. The role of sleep on cognition and functional connectivity in patients with multiple sclerosis. J Neurol. 2017;264:72–80.
  54. Sarraf P, Azizi S, Moghaddasi AN, et al. Relationship between sleep quality and quality of life in patients with multiple sclerosis. Int J Prev Med. 2014;5:1582–6.
  55. Ghajarzadeh M, Sahraian MA, Fateh R, Daneshmand A. Fatigue, depression and sleep disturbances in Iranian patients with multiple sclerosis. Acta Med Iran. 2012;50:244–9.
  56. Storm Van’s Gravesande K, Blaschek A, Calabrese P, et al. Fatigue and depression predict health-related quality of life in patients with pediatric-onset multiple sclerosis. Mult Scler Relat Disord. 2019;36:101368.
  57. Veauthier C, Gaede G, Radbruch H, et al. Treatment of sleep disorders may improve fatigue in multiple sclerosis. Clin Neurol Neurosurg. 2013;115:1826–30.
  58. Hughes AJ, Turner AP, Alschuler KN, et al. Association between sleep problems and perceived cognitive dysfunction over 12 months in individuals with multiple sclerosis. Behav Sleep Med. 2018;16:79–91.
  59. Cote I, Trojan DA, Kaminska M, et al. Impact of sleep disorder treatment on fatigue in multiple sclerosis. Mult Scler. 2013;19:480–9.
  60. Nourbakhsh B, Revirajan N, Morris B, et al. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: A randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2021;20:38–48.
  61. van Kessel K, Moss-Morris R, Willoughby E, et al. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008;70:205–13.
  62. Mohr DC, Hart SL, Goldberg A. Effects of treatment for depression on fatigue in multiple sclerosis. Psychosom Med. 2003;65:542–7.
  63. Veauthier C, Hasselmann H, Gold SM, Paul F. The Berlin Treatment Algorithm: Recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue. EPMA J. 2016;7:25
  64. Nourbakhsh B, Mowry EM. Multiple sclerosis risk factors and pathogenesis. Continuum (Minneap Minn). 2019;25:596–610.
  65. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol.2010;9:599–612.
  66. Colotta F, Jansson B, Bonelli F. Modulation of inflammatory and immune responses by vitamin D. J Autoimmun. 2017;85:78–97.
  67. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62:60–5.
  68. Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol.2016;73:515–9.
  69. Rhead B, Bäärnhielm M, Gianfrancesco M, et al. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet. 2016;2:e97.
  70. Runia TF, Hop WC, de Rijke YB, et al. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis.2012;79:261–6.
  71. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol.2010;67:618–24.
  72. Simpson S Jr, Taylor B, Blizzard L, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;68:193–203.
  73. Ascherio A, Munger KL, White R, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol.2014;71:306–14.
  74. Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol.2012;72:234–40.
  75. Hupperts R, Smolders J, Vieth R, et al. Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon â-1a. Neurology. 2019;93:e1906–16.
  76. Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol.2016;23:327–32.
  77. Martinelli V, Dalla Costa G, Colombo B, et al. Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes.Mult Scler. 2014;20:147–55.
  78. Camu W, Lehert P, Pierrot-Deseilligny C, et al. Cholecalciferol in relapsing-remitting MS: a randomized clinical trial (CHOLINE). Neurol Neuroimmunol Neuroinflamm. 2019;7:e648.
  79. Hernán MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol. 2001;154:69–74.
  80. Poorolajal J, Bahrami M, Karami M, Hooshmand E. Effect of smoking on multiple sclerosis: A meta-analysis. J Public Health (Oxf).2017;39:312–20.
  81. Mikaelof Y, Caridade G, Tardieu M, et al. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007;130:2589–95.
  82. Manouchehrinia A, Tench CR, Maxted J, et al. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain. 2013;136:2298–304.
  83. Ramanujam R, Hedstrom AK, Manouchehrinia A, et al. Effect of smoking cessation on multiple sclerosis prognosis. JAMA Neurol.2015;72:1117–23.
  84. Makrygiannakis D, Hermansson M, Ulfgren AK, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67:1488–92.
  85. O’Gorman C, Lucas R, Taylor B. Environmental risk factors for multiple sclerosis: A review with a focus on molecular mechanisms.Int J Mol Sci. 2012;13:11718–52.
  86. Hedström AK, Hillert J, Olsson T, Alfredsson L. Nicotine might have a protective effect in the etiology of multiple sclerosis. Mult Scler.2013;19:1009–13.
  87. Centers for Disease Control and Prevention. Quitlines and other cessation support resources. 2021. Available at: www.cdc.gov/tobacco/patient-care/quitlines-other/index.html (accessed 26 May 2022).
  88. Mohr DC, Hart SL, Julian L, et al. Association between stressful life events and exacerbation in multiple sclerosis: A meta-analysis. BMJ. 2004;328:731.
  89. Mohr DC, Goodkin DE, Bacchetti P, et al. Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology. 2000;55:55–61.
  90. Artemiadis AK, Vervainioti AA, Alexopoulos EC, et al. Stress management and multiple sclerosis: A randomized controlled trial. Arch Clin Neuropsychol. 2012;27:406–16.
  91. Mohr DC, Lovera J, Brown T, et al. A randomized trial of stress management for the prevention of new brain lesions in MS. Neurology. 2012;79:412–9.
  92. Simpson R, Booth J, Lawrence M, et al. Mindfulness based interventions in multiple sclerosis – A systematic review. BMC Neurol. 2014;14:15.

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