Abstract
Objective: To test the hypothesis that lower extremity progressive resistance training (PRT) can improve muscle strength and functional capacity in patients with multiple sclerosis (MS) and to evaluate whether the improvements are maintained after the trial.
Methods: The present study was a 2-arm, 12-week, randomized controlled trial including a poststudy follow-up period of 12 weeks. Thirty-eight moderately impaired patients with MS were randomized to a PRT exercise group (n = 19) or a control group (n = 19). The exercise group completed a biweekly 12-week lower extremity PRT program and was afterward encouraged to continue training. After the trial, the control group completed the PRT intervention. Both groups were tested before and after 12 weeks of the trial and at 24 weeks (follow-up), where isometric muscle strength of the knee extensors (KE MVC) and functional capacity (FS; combined score of 4 tests) were evaluated.
Results: KE MVC and FS improved after 12 weeks of PRT in the exercise group (KE MVC: 15.7% [95% confidence interval 4.3–27.0], FS: 21.5% [95% confidence interval 17.0–26.1]; p < 0.05), and the improvements were better than in the control group (p < 0.05). The improvements of KE and FS in the exercise group persisted at follow-up after 24 weeks. Also, the exercise effects were reproduced in the control group during the 12-week posttrial PRT period.
Conclusions: Twelve weeks of intense progressive resistance training of the lower extremities leads to improvements of muscle strength and functional capacity in patients with multiple sclerosis, the effects persisting after 12 weeks of self-guided physical activity.
Level of evidence: The present study provides level III evidence supporting the hypothesis that lower extremity progressive resistance training can improve muscle strength and functional capacity in patients with multiple sclerosis.
Glossary
- 10MWT=
- 10-m walk test;
- 6MWT=
- 6-minute walk test;
- CI=
- confidence interval;
- CST=
- chair stand test;
- EDSS=
- Expanded Disability Status Score;
- FS=
- functional capacity score;
- KE MVC=
- maximum voluntary contraction of the knee extensors;
- KF MVC=
- maximum voluntary contraction of the knee flexors;
- MS=
- multiple sclerosis;
- NS=
- not significant;
- PRT=
- progressive resistance training;
- RCT=
- randomized controlled trial;
- RM=
- repetition maximum;
- SCT=
- stair-climbing test.
The disabling consequences of multiple sclerosis (MS) ask for development of physiologically based rehabilitation strategies. An efficient rehabilitation strategy is physical exercise, but its role in MS rehabilitation has been a controversial issue. For years, patients with MS were advised not to participate in physical exercise because it was reported to lead to worsening of symptoms or fatigue.1 During the past decades, however, studies on physical exercise in MS have shown promising effects.2,3
Various training modalities, such as resistance and endurance training, are known to target different areas of the physiologic profile. Previous studies on mild, nonsupervised progressive resistance training (PRT)4–7 have all, except one,8 reported an improvement in muscle strength after PRT. However, the effect of resistance training on functional capacity in MS remains unclear,4–8 and consequently, controlled studies of supervised and intense PRT of the lower extremities on muscle strength and functional capacity in MS are needed.
We conducted a randomized controlled trial (RCT) to test the hypothesis that PRT of the lower body can improve muscle strength and functional capacity in patients with MS, and that the improvements will be maintained for 12 weeks after the trial.
METHODS
Study design.
The present study is a 2-arm, 12-week RCT including a poststudy follow-up period of 12 weeks in an exercise group and a control group. The exercise group was afterward encouraged to continue training on their own without supervision or access to training facilities. The control group continued their previous daily activity level during the trial period. After the trial, the control group was offered the same 12-week PRT intervention as completed by the exercise group. Both groups were tested before (pre) and after 12 weeks of the trial (post) and at 24 weeks (follow-up). The primary outcome measures were changes of maximum voluntary contraction of the knee extensors (KE MVC) and functional capacity score (FS) after 12 weeks of PRT.
A neurologic examination and evaluation of isometric muscle strength and functional capacity were performed pretrial and posttrial and at follow-up. After blinded pretesting, concealed randomization was performed. Posttesting and testing at follow-up were blinded to previous test results. The principal investigator (U.D.) supervised the exercise program and performed testing and data analysis. At testing, standardized written instructions were applied. The Expanded Disability Status Score (EDSS)9 was performed by 2 experienced MS specialists blinded to the intervention.
Subjects.
All participants were recruited among patients with MS scheduled at the outpatient MS Clinic, Aarhus University Hospital, during a 5-month period (May to October 2006). To study a well-defined disease entity, only patients with relapsing-remitting MS were included. Of 426 patients with MS, 106 patients fulfilled the study criteria: definite relapsing-remitting MS according to McDonald criteria,10 EDSS between 3.0 and 5.5 with a pyramid function score ≥2.0, ability to walk ≥100 m, no need for help with transportation to training facility, age >18 years, and acceptance of diagnosis and treatment. Patients were excluded if they had dementia, alcoholism, or pacemaker treatment, had any serious medical comorbidities, had experienced an MS attack within the past 8 weeks, were pregnant, or had done systematic resistance training within the last 3 months. During the study, participants were excluded if they had an attack influencing pyramidal functions or if they participated in less than 80% of the training sessions. During a 17-month period (November 2, 2006, to March 31, 2008), 38 patients with MS were included and randomly assigned with respect to gender to either the exercise group (n = 19) or the control group (n = 19). Eligible patients (n = 106) were contacted in a random order until the required number of patients was included. Of the 95 patients contacted, 36 did not respond to the invitation and 21 rejected participation (figure 1). The number of patients recruited was calculated based on power analysis, where muscle strength was the primary outcome (expected group difference = 16%11; SD = 16%11; p = 0.05; power = 0.8; expected dropout rate = 15%). The calculation was conducted in STATA (StataCorp LP, College Station, TX). One subject dropped out because training worsened lower back pain. All other dropouts were caused by circumstances unrelated to the intervention.
Figure 1 Flowchart showing patient inclusion
MS = multiple sclerosis.
Standard protocol approvals, registrations, and patient consents.
The study was approved by the local scientific ethics committee (Videnskabsetisk Komité, Aarhus Amt, journal no. 20060088) and performed in accordance with the Helsinki Declaration 2. Written informed consent was obtained from all patients participating in the study, registered at www.clinicaltrials.gov (NCT00381576). The present study provides level III evidence.
Progressive resistance training.
The PRT intervention consisted of 12 weeks of resistance training of the lower extremities performed twice weekly (Monday and Thursday). After a 5-minute warm-up on a stationary bicycle, patients performed 5 different exercises, namely leg press, knee extension, hip flexion, hamstring curl, and hip extension. The participants were instructed to perform all exercises at a fast concentric phase and a slow eccentric phase. In terms of sets, repetitions, and load, the progression model was as follows: weeks 1 and 2, 3 sets of 10 repetitions at a load of 15 repetitions maximum (RM); weeks 3 and 4, 3 sets of 12 repetitions at a load of 12RM; weeks 5 and 6, 4 sets of 12 repetitions at a load of 12RM; weeks 7 and 8, 4 sets of 10 repetitions at a load of 10RM; weeks 9 and 10, 4 sets of 8 repetitions at a load of 8RM; weeks 11 and 12, 3 sets of 8 repetitions at a load of 8RM. Between sets and exercises, a rest period of approximately 2 to 3 minutes was allowed. To ensure progression, all training sessions were supervised. Most of the training sessions were conducted in groups of 2 to 4 subjects. If a participant missed a training session, it was attempted to substitute the session on an alternate day.
Muscle strength.
Maximum isometric muscle strength.
MVC KE and maximum voluntary contraction of the knee flexors (MVC KF) were measured with a Biodex System 3 PRO dynamometer (Biodex Medical Systems, Shirley, NY). The dynamometer used for testing was not applied during the training sessions, minimizing the effects of learning. The best functioning lower leg was attached to the lever arm, aligned to the lateral malleolus, at a level 2 cm proximal to the medial malleolus. During kicking, both arms were crossed and the upper body was strapped to the chair. The individual settings of the dynamometer were registered and used in all 3 test sessions. Isometric muscle strength was tested at 70-degree knee flexion. At first, the participants attempted to maximally extend their knee for approximately 4 seconds followed by a 1-minute rest period. Then, participants flexed the knee for another 4 seconds followed by a 1-minute rest period. This sequence was repeated 3 times. Peak torque values were calculated by the Biodex System 3 PRO software package. The torque signal was sampled at 100 Hz, and peak torque was determined as the highest attained torque during the test. Measured KE MVC was normalized with respect to gender, age, height, and weight and compared with expected KE MVC calculated from normative data from our laboratory (n = 158; unpublished data).
Maximum leg press.
The first and last PRT sessions were initiated by a 1RM leg press test on the leg press machine used for exercise. After a 5-minute bicycle warm-up, the participants conducted 10 repetitions at approximately 50% of 1RM. Then, the load was increased to 85% of expected 1RM followed by a step-wise weight increase of 2.5% to 5% until lifting failed. Approximately 3 to 4 minutes of rest was allowed between attempts.
Handgrip strength.
Handgrip strength was measured using a handheld Jamar dynamometer (Sammons Preston Inc., Bolingbrook, IL). Participants were instructed to flex the elbow at 90° and to hold the elbow close to the body while performing 2 attempts with each hand.
Functional capacity.
To ensure a variety of lower extremity functions, capacity was assessed with 4 tests challenging the lower extremity in various ways conducted in the following order: chair stand test (CST),12 ascending stair-climbing test (SCT),13 10-m walk test (10MWT),14 and 6-minute walk test (6MWT).15–17 In the CST, participants performed 5 repetitions with folded arms; in the SCT, 20 stairs (height 15.5 cm) were climbed with a 180-degree separating swing halfway; a 10MWT was conducted in a wide corridor; and walking endurance was evaluated with a 6MWT. For all tests, time was measured with a handheld stopwatch.
Statistical analysis.
The primary outcome measures were changes of KE MVC and FS in the exercise group vs the control group during the 12 weeks of the trial. All other data were secondary outcome measures. Data from all functional tests were converted into velocities to rectify the effects of the tests. Subsequently, FS was calculated as a fraction of the pretrial value, expressed as a percentage and weighed equally.
Secondary study outcome measures were changes in KE MVC and FS after 12 weeks of self-guided physical activity as compared with the effect of PRT [(Exercisefollow-up − Exercisepost) vs (Exercisepost − Exercisepre)] as well as changes of KE MVC and FS in the control group after 12 weeks of PRT as compared with the previous period of normal daily activity [(Controlfollow-up − Controlpost) vs (Controlpost − Controlpre)].
A multivariate analysis of variance was used to evaluate possible time and group interactions during the intervention within each group. In case of group-time interaction, a post hoc multilevel mixed-effects linear regression test was performed. Time effects within groups for FS were evaluated with a paired t test. Pretrial to posttrial changes between groups were compared with an unpaired t test, whereas changes between pretrial and posttrial and between posttrial and follow-up within groups were compared with paired t tests. Categorical data (EDSS score) were compared by a Wilcoxon signed rank test. Relative changes during the intervention were calculated as the mean of the individual percentages. The correlation analyses were performed on collapsed data from both groups and from all study arms. Primary and secondary outcome measures were tested statistically using a 5% limit of significance. Data are presented as mean (95% confidence interval [CI]) in tables and mean ± SE in figures. All statistical analyses were performed using STATA version 9.0.
RESULTS
Baseline.
Table 1 shows demographic data and information about severity, duration, and treatment of MS in the control and exercise groups. No differences were seen between the 2 groups. Table 2 shows that KE MVC, KF MVC, and the various tests of functional capacity were similar in the control group and in the exercise group at the pretrial test. Also, it seems that KE MVC, after adjustments for differences of gender, age, height, and weight, was 10% to 12% lower than expected compared with our pool of normal controls.
Table 1 Demographic data at baseline
Table 2 Weight, EDSS, muscle strength, and functional capacity pretrial and posttrial and at follow-up
Effects of PRT during the 12 weeks of RCT.
EDSS, body weight, and handgrip strength remained unchanged during the trial in both groups of patients with MS. Participants in the exercise group completed a total of 23.9 (95% CI 23.7–24) sessions out of the planned 24 PRT sessions.
Muscle strength.
During resistance training, KE MVC increased in the exercise group, whereas it remained unchanged in the control group (table 2). After resistance training, KE MVC no longer differed from the normal value (98.1% [95% CI 90.1–106.2]). In figure 2, the relative changes of KE MVC are shown for the exercise group and the control group. In the exercise group, KE MVC improved by 15.7% (95% CI 4.3–27.0) vs 1.3% (95% CI −7.3 to 10.0) in the control group (p < 0.05). Also, KF MVC improved in the exercise group as compared with the control group (p < 0.05). One-RM leg press improved by 37.1% (95% CI 26.6–47.6) in the exercise group. The number needed to treat, defined as a strength improvement of ≥10% KE MVC, was 3.8.
Figure 2 Effects of progressive resistance training on muscle strength and functional capacity
Effects of 12 weeks of resistance training on changes in maximum voluntary contraction of the knee extensors (KE MVC) and functional capacity score (FS) during the trial in the exercise group (white bar) and during the poststudy exercise period in the control group (gray bar) compared with the change in the control group during the trial (black bar). *p < 0.05.
Functional capacity.
During PRT, all functional scores improved in the exercise group, whereas no changes occurred in the control group (table 2; p < 0.05). In the exercise group, the FS improved by 21.5% (95% CI 17.0–26.1) vs −3.3% (95% CI −8.1 to 1.5) in the control group (figure 2; p < 0.05). Changes of normalized KE MVC were related to FS (r = 0.44, p = 0.0004) as well as to each of the individual function tests (r = 0.26–0.43, p = 0.0005–0.04).
Effects of 12 weeks of self-guided physical exercise after RCT in the exercise group.
It appears from figure 3 that the improvements attained during the trial in KE MVC and FS were maintained at follow-up in the exercise group. Table 2 shows that KE MVC decreased by −2.3% (95% CI −6.3 to 1.7; not significant [NS]), whereas the FS decreased by only −0.3% (95% CI −3.3 to 2.7; NS).
Figure 3 Muscle strength and functional capacity during follow-up
Paired individual values of maximum voluntary contraction of the knee extensors (KE MVC) and functional capacity score (FS) in the exercise group posttrial and at follow-up. Bars are means.
Effects of 12 weeks of PRT in the control group after RCT.
After the trial, participants in the control group completed an average of 22.6 (95% CI 21.5–23.7) PRT sessions out of 24 planned sessions during the 12-week exercise period. Table 2 and figure 2 shows that the effect of PRT in the control group after the RCT trial was similar to what was obtained in the exercise group during the trial. KE MVC improved by 10.0% (95% CI 5.3–14.7) as compared with 1.3% (95% CI −7.3 to 10.0) during the previous control period (p > 0.05). Similarly, FS improved by 12.8% (95% CI 9.0–16.6) as compared with −3.3% (95% CI −8.1 to 1.5) during the previous control period (p > 0.05).
DISCUSSION
The present RCT demonstrated that supervised and intense resistance training of the lower extremity can improve both muscle strength and functional capacity in moderately impaired subjects with relapsing-remitting MS. Also, the improvements obtained in the exercise group persisted after 12 weeks of self-guided physical activity. The observation that resistance training in MS improves muscle strength and functional capacity was confirmed by reproduction of a similar beneficial effect of resistance training for 12 weeks in the control group after the trial. Improvements of muscle strength and improvements of functional capacity were related, indicating a mutual relationship between physical strength and physical function. These findings are of interest because interventions counteracting weakness of the lower extremity18 as well as impairment of functional capacity19 are coveted in MS rehabilitation.
Muscle strength of knee extensors and flexors improved after the intervention. In fact, strength of knee extension was normalized. A review of all published studies evaluating the effects of resistance training on muscle strength in patients with MS reported that all studies except one8 showed improvements.4–6 However, only one study5 contains comparable isometric strength measurements showing a 7.4% increase of knee extensors after 8 weeks of biweekly resistance training without any significant increase of knee flexors.5 In the present study, the intervention period lasted 12 weeks, indicating that the effects obtained in these 2 studies are comparable. Despite the fact that only 3 of the 15 subjects in the exercise group reported that they had continued systematic resistance training after the RCT, isometric muscle strength was well preserved at follow-up. This observation indicates that the beneficial effect of PRT can be maintained for some time. Although speculative, it is likely that the effect is maintained partly due to a more active lifestyle in the exercise group after the period of PRT.
A significant increase in FS was found in the exercise group as compared with the control group. In fact, all individual functional tests showed significant improvements. Except for the 6MWT, these findings were replicated in the control group after the trial. Interestingly, the improvements of FS attained during intervention persisted after 12 weeks of self-guided physical activity. The nonambiguity of our findings contrasts with the heterogeneity reported in the literature regarding the effects of resistance training on functional capacity in MS.4–6,8 Furthermore, improvements of measures of functional capacity during resistance training were related to increase of knee extensor muscle strength.
One study found no changes during a-2 minute walk test after 10 weeks of resistance training, possibly explained by small sample size and a short intervention period.6 Data on 6MWT from a mixed group of healthy subjects aged 55–75 years showed walking distances of 659 m.20 The walking capacity of patients with MS in the present study was 495 m (95% CI 401–590) after training, indicating that abnormalities other than weakness play a role in capacity, also.
The exercise group improved its 10MWT by 12.4% (95% CI −16.8 to −7.9). Some studies found improvements of maximum gait velocity after resistance training,6,7 whereas other studies could not confirm such an effect.5,8 Our findings correspond to the 10MWT improvements reported in a small study6 showing a 6% effect after 10 weeks of biweekly resistance training. Furthermore, our findings are in accord with a recent meta-analysis showing that exercise in general (effect size 0.19) and resistance training in particular (effect size 0.34) improve gait in patients with MS.21 In Denmark, most pelican crossings are programmed to require a gait velocity of 1.5 m/second to reach the opposite side at a green light. Interestingly, the exercise group increased its maximal gait speed from 1.6 m/second (95% CI 1.2–2.0) to 1.8 m/second (95% CI 1.4–2.2), improving the performances required by pedestrians. This improvement, therefore, might be clinically meaningful. To normalize maximal gait velocity, however, the exercise group needs to perform at 2.23 m/second,22 indicating the potential for further improvements.
Five-time CST performance has been examined in a mixed group of healthy elderly subjects aged 70 years, who, compared with our participants, performed the 5-time CST faster (8.9 seconds).23 After resistance training, the exercise group improved its chair stand time to 9.3 s (95% CI 7.7–11.1).
Stair-climbing improved in the exercise group by 12.3% (95% CI −17.7 to −6.9; p < 0.05). In comparison, no effects were found after 10 weeks of biweekly PRT.6 However, a larger effect would be expected in our study as a result of the slightly longer (12 vs 10 weeks), more intense (75%–90% vs 60%–80% of 1RM), and more extensive (5 leg exercises vs 3 exercises for whole body) intervention.
This study has several limitations that should be kept in mind when interpreting the results. First, the participants represent a selected group of patients with relapsing-remitting MS, and findings are not necessarily transferrable to more disabled patients or other types of MS. Second, the participants and the supervising investigators were not blinded to the intervention. However, it is difficult to blind participants (and trainers) to an exercise intervention, because a placebo exercise intervention will be revealed by participants. Third, we chose a design where social interaction could influence the effects of resistance training. Nonetheless, we conclude that supervised PRT performed in small groups of patients with relapsing-remitting MS is effective in improving muscle strength and functional capacity.
ACKNOWLEDGMENT
The authors thank Vivi Brandt, from The MS Clinic at Aarhus University Hospital, for skilful help with recruitment and handling of patients as well as handling of logistical matters and Associate Professor Bo Martin Bibby, from the Department of Biostatistics, Institute of Public Health, for statistical counseling. Further, the authors thank Henning Andersen, MD PhD, Department of Neurology, Aarhus University Hospital, for lending data on muscle strength from a healthy population.
AUTHOR CONTRIBUTIONS
Statistical analyses were conducted by U.D. with advice from K.O. and J.J.
DISCLOSURE
Dr. Dalgas has received funding for travel from Merck Serono, Sanofi-aventis, and Bayer Schering Pharma; and receives research support from the National Multiple Sclerosis Society, the Research Foundation of the MS Clinic of Southern Denmark, the Werner Richter and Wife's Foundation, the Augustinus Foundation, the Engineer Bent Boegh and Wife Inge Boegh Foundation, the Vilhelm Bangs Foundation, the Manufacturer Mads Clausen Foundation, the Toyota Foundation, the Mrs. Benthine Lund Foundation, and the AP Moeller Foundation. Dr. Stenager has received funding for travel from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi-aventis; and received research support from Biogen Idec, Merck Serono, and Bayer Schering Pharma. Dr. Jakobsen has received funding for travel from Baxter International Inc.; receives royalties from publishing Diabetes (Munksgaard, 2006); and receives research support from the Danish Multiple Sclerosis Society. Dr. Petersen has received funding for travel from Biogen Idec and Merck Serono; and has received research support from Biogen Idec, Merck Serono, and the Danish Multiple Sclerosis Society. Dr. Hansen has received funding for travel from Merck Serono and Sanofi-aventis. Dr. Knudsen reports no disclosures. Dr. Overgaard has received research support from the Carlsberg Foundation, the Danish Ministry of Culture's Committee of Sports Science, and the AP Moller Foundation. Dr. Ingemann-Hansen reports no disclosures.
Footnotes
-
Supported by the National Multiple Sclerosis Society, The Research Foundation of the MS Clinic of Southern Denmark (Vejle, Esbjerg, and Soenderborg), Director Werner Richter and Wife's Grant, The Augustinus-Foundation, Engineer Bent Boegh and Wife Inge Boeghs Foundation, Vilhelm Bangs Foundation, Manufacturer Mads Clausen's Foundation, The Toyota Foundation, Mrs. Benthine Lund's Foundation, and AP Moeller's Foundation.
Disclosure: Author disclosures are provided at the end of the article.
Received February 11, 2009. Accepted in final form July 21, 2009.
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