LINKING EVIDENCE AND PRACTICE. Exercise for Managing the Symptoms of Multiple Sclerosis Parminder K. Padgett, Susan L. Kasser

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1 Exercise for Managing the Symptoms of Multiple Sclerosis Parminder K. Padgett, Susan L. Kasser LEAP LINKING EVIDENCE AND PRACTICE <LEAP> highlights the findings and application of Cochrane reviews and other evidence pertinent to the practice of physical therapy. The Cochrane Library is a respected source of reliable evidence related to health care. Cochrane systematic reviews explore the evidence for and against the effectiveness and appropriateness of interventions medications, surgery, education, nutrition, exercise and the evidence for and against the use of diagnostic tests for specific conditions. Cochrane reviews are designed to facilitate the decisions of clinicians, patients, and others in health care by providing a careful review and interpretation of research studies published in the scientific literature. 1 Each article in this PTJ series summarizes a Cochrane review or other scientific evidence resource on a single topic and presents clinical scenarios based on real patients to illustrate how the results of the review can be used to directly inform clinical decisions. This article focuses on an ambulatory patient with multiple sclerosis and mild to moderate impairments. Can exercise improve the quality of life for individuals like this patient with multiple sclerosis? Find the <LEAP> case archive at collection/leap. Individuals with multiple sclerosis (MS) experience a range of symptoms that present significant challenges to daily functioning, mobility, and family and community participation. 2,3 In addition, the physical decline and mobility restrictions associated with the disease often lead to increased fall risk 4,5 and seriously reduced physical activity levels. 6 9 Cumulative evidence suggests that, for people with MS, activity limitations are associated with greater disability progression 10,11 and poorer health-related quality of life. 12 Although in the past many considered exercise to be contraindicated for individuals with MS, research to date offers evidence that it is well tolerated by people with the disease. 13,14 As such, exercise is now viewed as an important component of disease management, 15 both in terms of optimizing daily functioning and increasing participation across various life contexts. 3,16 18 Because deconditioning, osteoporosis, and falls are so common in this population, the National Multiple Sclerosis Society recommends that people with MS participate in individualized exercise programs to improve cardiovascular fitness, strength, and balance and to decrease fatigue and depression. 19 In view of the potential benefits of exercise for people with MS, evaluating the efficacy of specific exercise regimens remains important in understanding how to maximize functional gains and improve quality of life in this population. To assess the effectiveness of exercise on performance of activities of daily living (ADL) and health-related quality of life for individuals with MS, Rietberg and colleagues 20 published a systematic review of randomized controlled trials (RCTs) in the Cochrane Database of Systematic Reviews. To be included in the review, interventions needed to include participants with MS who were not experiencing any exacerbations and to have the exercise outcomes focus on 1 or more of the International Classification of Functioning, Disability and Health (ICF) codes. 21 The review included 9 RCTs: 6 comparing a group that performed an exercise regimen with a control exercise group or a no-exercise group and 3 evaluating 2 different exercise interventions where both interventions met the definition of exercise therapy. Outcomes reported included muscle power functions, mobility activities, mood, balance, fatigue, cognitive impairment, disability status, ADL, hand and arm use, and health-related quality of life. A summary of findings is presented in Table 1. Take-Home Message Given the diversity of outcome measures reported in the reviewed studies, it was not possible to pool data. As such, conclusions were based on a best-evidence qualitative synthesis of the 6 high-quality exercise versus no-exercise RCTs, with a total of 164 participants. The research synthesized by Rietberg et al 20 suggests benefits of exercise therapy for people with MS across a range of outcomes. Improvements in isometric strength were shown in 3 RCTs, and increases in mobility and balancerelated ADL such as standing balance and time to transfer were found in 3 RCTs. Positive findings related to mood also were evident in 1 of the RCTs. Although the objective of the review was to assess the effectiveness of exercise therapy on ADL and health-related quality of life, 3 RCTs also revealed benefits regarding aer- June 2013 Volume 93 Number 6 Physical Therapy f 723

2 Table 1. Exercise Therapy for Individuals With Multiple Sclerosis (MS): Cochrane Review Results 20,a Nine randomized controlled trials including a total of 260 participants with MS were included in the March 2004 review. EDSS scores of the participants ranged from 1 to 6.5 (with a score of 1 indicating no visible disability and a score of 6.5 indicating ability to ambulate with bilateral support from an assistive device). Changes of at least 1.0 point for EDSS scores 6.0 and 0.5 point for EDSS scores 6.0 are considered reliable or clinically meaningful. The mean ages of participants ranged from 34.8 to 54 years, and the mean duration of MS was 4.3 to 18.3 years. Studies were divided based on type of intervention: Exercise versus no exercise: Six RCTs involving a total of 164 participants were identified. Interventions included aerobic and strengthening programs for 30 to 60 minutes, 2 to 3 times per week. Comparison of 2 different interventions: Three RCTs with a total of 96 participants were identified. Interventions included gait training, supervised range-of-motion and strengthening exercises, and aerobic exercise and were completed 3 to 5 times per week, with 1 study having 2 sessions per day, 5 days per week. Key outcomes of interest included activity limitations and HRQoL: Activity limitations, such as mobility or limitations caused by balance and cognitive impairments, were measured using the Rivermead Mobility Index, timed transfer task, balance times, walking cadence, and Short Orientation-Memory Concentration Test. HRQoL was measured with the Multiple Sclerosis Impact Scale and the Functional Assessment of Multiple Sclerosis and Sickness Impact Scale. Other indirect measures of HRQol such as mood and fatigue were measured using the Hospital Anxiety and Depression Scale, Profile of Mood States, and Fatigue Severity Scale. The methodological quality was based on a maximum feasible score of 22: For the 6 exercise versus no-exercise RCTs, scores ranged from 50% to 73%. For the 3 RCTs comparing interventions, scores ranged from 64% to 82%. Results for exercise versus no exercise RCTs (all results reported based on statistical significance, effect size was not reported): Muscle power and exercise tolerance functions Mobility-related activities obic capacity or fitness outcomes for this population. Although the data from Rietberg et al were only current as of March 2004, more recently published literature reviews further support the benefit of exercise for those with MS. Three RCTs included in a review by Dalgas et al 22 and 7 RCTs in a review by Kjolhede et al 23 showed that resistance training is effective in improving muscle strength. Although not as consistent, the 2 reviews also identified RCTs that showed endurance training is effective for improving functional capacity, balance, and quality of life. As the articles included in these more recent reviews were not all RCTs and were not assessed for risk of bias, there Four of the 6 studies indicated increases in isometric strength as measured by maximal voluntary contraction, Quantitative Myometry Assessment, leg extensor power, Modified Graded Exercise Test, maximum oxygen consumption, Physiological Cost Index, or Borg Rating of Perceived Exertion. Four of the 6 studies measuring mobility-related activities showed improvement based on the Rivermead Mobility Index, timed transfer, balance time, and walking cadence. Mood Two of the 6 studies indicated improved mood with exercise assessed with the Hospital Anxiety and Depression Scale and the Profile of Mood States. Results for exercise therapy versus control exercise intervention: There was no significant evidence from the 3 RCTs to indicate 1 type of intervention is better than another in factors related to mobility, fatigue, HRQoL, or physical fitness. a EDSS Expanded Disability Status Scale, RCT randomized controlled trial, HRQoL health-related quality of life. was no attempt to pool the data, thus limiting the ability to draw definitive conclusions. Nonetheless, there has been continued interest in empirically examining the effects of exercise in individuals with MS. As the need to treat these patients is clear and the benefits from exercise important, further and more rigorous study on the topic is warranted. In sum, exercise was well tolerated by participants with MS, with no increase in exacerbations or deleterious effects. However, none of the studies attempted to quantify a specific dose of exercise necessary to effect significant changes in physiological or psychological functioning of participants, and no specific program was more successful in increasing activities and participation than any other. Additionally, the duration of exercise in these studies was 6 months or less, rendering it difficult to ascertain long-term effects of exercise on disability progression. Furthermore, data verifying a connection between improved performance-based measures and enhanced functional mobility, quality of life, or community participation were limited and not well supported by this review. Clearly, further research is needed not only to confirm the effects of exercise on MS-related symptoms, activity, and participation but also to determine the specific dosage required to realize exercise benefits for people with the disease. 724 f Physical Therapy Volume 93 Number 6 June 2013

3 Table 2. Preintervention and Postintervention Outcome Measures a Outcome Measure Properties of Measure Preintervention Postintervention Timed Up & Go Test Norm for elderly people who are healthy: 8.5 s 34 Faster time indicates decreased risk of falling Meaningful change for people with MS: 23% or 31% 35 Single-leg stance Balance Evaluation Systems Test (BESTest) Activities-specific Balance Confidence (ABC) Scale Although there has been a recent surge in research on exercise and MS since the Cochrane Review, many of the studies have not been large RCTs The additional RCTs completed to date may prove informative, thus signaling the need for further systematic review. In addition, a deeper understanding of the effects of exercise on disease progression and other MS-related factors such as neurocognitive functioning may further guide the development of exercise interventions aimed at promoting improved function and enhancing quality of life in this population. 32,33 Longer stance time indicates higher balance function MDC: 24.1 s in older adults, with SEM of 8.7 s, poor absolute reliability and sensitivity 36 Range: points Higher score indicates greater balance ability Preliminary fall risk cutoff in literature ranges from 66 to 87 points for people with MS 37 Range: points Higher score indicates greater balance confidence a MS multiple sclerosis, MDC minimum detectable change, SEM standard error of the mean. Case #15: Exercise for Multiple Sclerosis Can an exercise program help this patient? Mr White is a 61-year-old man diagnosed by a neurologist with relapsing-remitting MS at the age of 48 years. Mr White s neurologist provided a medical release for him to participate in a 12-week exercise program with no restrictions on intensity or type of activity. However, the neurologist did recommend supervision during exercise because of balance deficits noted on neurologic examination and a history of falls. On initial contact, Mr White indicated that he enjoys walking and playing golf with the use of a cart. Mr White s goals for participating in the exercise program were to improve his lower-extremity strength and balance. Prior to the exercise program, Mr White was independent with all basic and instrumental ADL, but he indicated that, at times, fatigue limited his ability to fully participate in desired social activities. Mr White reported 2 falls in the previous 3 months and problems with shortterm memory and clarity of speech. He ambulated without an assistive device and had no other musculoskeletal or cardiovascular comorbidities. Several outcome measures were completed upon initial assessment, including the Activities-specific Balance Confidence (ABC) Scale, the Timed Up & Go Test (TUG), singleleg stance time, and the Balance Evaluation Systems Test (BESTest). The results of Mr White s assessment are presented in Table 2. How did the clinician apply the results of the Cochrane review to Mr White? The physical therapist considered whether Mr White would be a good candidate for participation in a supervised exercise program. Using the PICO (Patient, Intervention, 9.22 s 9.83 s 5.12 s (right), 4.75 s (left) s (right), 4.27 s (left) Comparison, Outcome) format, the clinician asked the question: Will an independently ambulatory 61-yearold man with relapse-remitting MS benefit from a supervised exercise program (compared with no exercise program) for improving balance and strength? The clinician determined that the information provided in the systematic review by Rietberg et al 20 is relevant and applicable for this patient. Although Mr White is slightly older than the participants involved in the reviewed research studies, his diagnosis of relapsingremitting MS approximately 13 years earlier and his Expanded Disability Status Scale (EDSS) score of 4.5 are similar to the findings for the research participants. Based on these demographics, the medical referral, and Mr White s previous and routine participation in walking for exercise, the clinician deemed it would be appropriate and tolerable for him to engage in a supervised exercise program. From an appraisal of the systematic review, the clinician developed an exercise program commensurate with the outlined recommendations. The findings support a multifaceted intervention of exercise 2 to 3 times per week for 30 to 60 minutes per session, as well as the inclusion of June 2013 Volume 93 Number 6 Physical Therapy f 725

4 both aerobic and strengthening exercises with focused outcomes on balance and strength. As such, Mr White was enrolled in an exercise program consisting of 2 sessions per week for 60 minutes each for 12 weeks. Each session included 5 minutes of warm-up on a stationary recumbent bike, 10 minutes of specific stretching exercises, and the remaining time focused on balance activities and specific muscle group strengthening exercises. Strengthening included calf raises, lunges, wall squats, and core strengthening exercises, such as pelvic lifts. Mr White began with 1 set of 6 to 8 repetitions and progressed to 2 sets of 8 to 10 repetitions, depending on the specific exercise. His balance was challenged by standing with various bases of support, on and off different support surfaces (eg, foam), and with eyes open and eyes closed. In addition, dynamic balance exercises such as standing and reaching to various positions through the limits of stability were included in the intervention. All exercises, weights, and repetitions were monitored and recorded throughout the 12 weeks. How well do the outcomes of the intervention provided Mr White match those suggested by the systematic review? Mr White attended all but 1 session during the 12-week intervention. His exercise log revealed increased strength as noted by an increase in weight lifted and total repetitions completed during the strength portion of his exercise program. Postintervention results showed differential benefits (Tab. 2). None of the findings showed a clinically detectable change in Mr White s balance ability, but there also was no significant decline over the course of the 12-week intervention. 36,38 Mr White s ABC Scale score increased from 77.5 to 88 out of 100. This increase indicates a noticeable increase in his balance confidence, which has been shown to lower fall risk. 4,39 Mr White did not report a fall during the 12 weeks of the intervention. Although the intervention program did not specifically address aerobic training, Mr White increased his walking to 2 miles (3.2 km) per day and continued playing golf, although this activity may not have been of sufficient intensity to affect physiological changes in cardiovascular health. Given these results, Mr White met his goals of increased strength; however, he did not meet his goal to improve balance, as measured by the standardized assessments. These findings are not surprising given the short duration of the intervention and the multidimensional and complex nature of balance impairment. Subsequent to the intervention, Mr White joined an on-going individualized exercise program for people with MS. Thus, we were able to track his progress for another 1.5 years after the specific intervention reported here. Although there was no formal evaluation of Mr White s balance or mobility after 1.5 years of regular participation, he selfreported walking 2 or more miles each morning and playing golf regularly. He indicated that this selfselected distance was a strategy to proactively manage disease-related fatigue and ensure that he could meet the functional demands and energy requirements of the remainder of his day. His EDSS score has remained stable. These results, as well as Mr White s anecdotal reports of increased mood, lifestyle change to include willingness to participate in activity, and continued balance confidence, are significant when taken in the context of the variable and progressive nature of MS. Can you apply the results of the systematic review to your patients? The findings of the Cochrane Review by Rietberg et al 20 apply to patients with all types of MS with EDSS scores of 1 to 6.5 who are not experiencing an exacerbation of symptoms. Given that details about the study participants individual disease progression were unknown and the systematic review did not cite any deleterious effects of exercise, patients with medical clearance to exercise should be able to participate in an exercise program. What can be advised based on the results of this systematic review? Patients with MS who are ambulatory and have mild to moderate disability can tolerate exercise and are likely to benefit from a supervised exercise program that includes aerobic, balance, and strengthening exercises applied in an individual or group setting. Exercise has the potential to increase strength, mobility-related ADL, and mood in people with MS if offered for 30 to 60 minutes, 2 to 3 times per week, for a duration of 8 to 12 weeks. The systematic review did not provide any evidence indicating that regular exercise decreases fatigue or perception of disability in people with MS. The conclusions offered by the systematic review are limited by the small number of high-quality RCTs and their low sample sizes. Additionally, the authors acknowledged the great variety of outcome measures used across the studies and emphasized the need for consensus regarding a uniform, core set of outcome measures that examine exercise dose and magnitude of effect to determine optimal benefit from different exercise regimens with this population. However, for patients like Mr White, the existing evidence supports the 726 f Physical Therapy Volume 93 Number 6 June 2013

5 benefit of regular exercise to improve strength, mobility, and mood. Based on the ICF model of disability, the dynamic interplay of body function and structure with activity and participation determine a person s health-related quality of life. Through continued strengthening and balance training after the intervention program, Mr White continued participation in community, social, and recreational activities, such as golf, and maintained his quality of life beyond the 12-week program. P.K. Padgett, PT, DPT, Department of Physical Therapy and Athletic Training, College of Health and Rehabilitation Sciences: Sargent College, Boston University, 635 Commonwealth Ave, Boston, MA 02215(USA). Address all correspondence to Dr Padgett at: parmpadgett@gmail.com. S.L. Kasser, PhD, Department of Rehabilitation and Movement Science, University of Vermont, Burlington, Vermont. [Padgett PK, Kasser SL. Exercise for managing the symptoms of multiple sclerosis. 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6 36 Goldberg A, Casby A, Wasielewski M. Minimum detectable change for single-legstance-time in older adults. Gait Posture. 2011;33: Padgett PK, Jacobs JV, Kasser SL. Is the BESTest at its best? A suggested brief version based on interrater reliability, validity, internal consistency, and theoretical construct. Phys Ther. 2012;92: Learmonth YC, Paul L, McFadyen AK, et al. Reliability and clinical signficance of mobility and balance assessments in multiple sclerosis. Int J Rehabil Res. 2012;35: Schepens S, Goldberg A, Wallace M. The short version of the Activities-specific Balance Confidence (ABC) scale: its validity, reliability, and relationship to balance impairment and falls in older adults. Arch Gerontol Geriatr. 2010;51: f Physical Therapy Volume 93 Number 6 June 2013