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Effect of Contralateral Strength Training on Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Case Series

Andrea Manca, Maria Paola Cabboi, Enzo Ortu, Francesca Ginatempo, Daniele Dragone, Ignazio Roberto Zarbo, Edoardo Rosario de Natale, Giovanni Mureddu, Guido Bua, Franca Deriu
DOI: 10.2522/ptj.20150299 Published 1 June 2016

Abstract

Background The contralateral strength training (CST) effect is a transfer of muscle performance to the untrained limb following training of the contralateral side.

Objective The aim of this study was to explore, in individuals with multiple sclerosis (MS) presenting marked lower limb strength asymmetry, the effectiveness of CST on management of muscle weakness of the more-affected limb following training of the less-affected limb.

Design A single-subject research design was used.

Methods Eight individuals with MS underwent 16 to 18 high-intensity training sessions of the less-affected ankle dorsiflexor muscles. The primary outcome measure of this single-system case series was maximal strength expressed as peak moment and maximal work. Secondary outcome measures were: Six-Minute-Walk Test, Timed “Up & Go” Test, 10-Meter Timed Walk Test, and Multiple Sclerosis Quality of Life–54 questionnaire.

Results After the 6-week intervention, the contralateral more affected (untrained) limb showed a 22% to 24% increase in maximal strength. From pretest-posttest measurements, participants also performed significantly better on the clinical and functional secondary outcome measures. At the 12-week follow-up, the strength levels of the weaker untrained limb remained significantly superior to baseline levels in the majority (5 out of 8) of the outcome parameters.

Limitations Considering the design used, the absence of a control group, and the sample size, these findings should be cautiously generalized and will need confirmation in a properly planned randomized controlled trial.

Conclusions The present proof-of-concept study shows, for the first time, the occurrence of the CST effect on muscle performance of ankle dorsiflexor muscles in people with MS. These preliminary findings reveal new potential implications for CST as a promising rehabilitation approach to those conditions where unilateral muscle weakness does not allow or makes difficult performing conventional strength training of the weaker limb.

Multiple sclerosis (MS) is a neurological condition characterized by reduced muscle strength during both dynamic and static muscle contractions.1 Compared with matched healthy people, people with MS present a decreased ability to fully activate motor units (47%–93% versus 94%–100%) in the lower limb muscles,2 with an overall reduction of force development ranging from 30% to 40%.3 Muscle weakness severely affects the lifestyle of participants with MS, reducing their ability to perform even relatively mild physical exercise,4 with a consequent decrease in the level of daily living activities.3

Evidence has shown that resistance training has a significant positive effect on activities of daily living in people with MS, resulting in increased quality of life (QoL).5 Despite the effects of resistance training on walking performance are still inconclusive,5 it has proved effective in significantly reducing muscle weakness,3 potentially improving balance6 and inducing a remarkable decrease in self-reported fatigue.7

In rehabilitation, when strength impairment is prominently lateralized to one limb, resistance training is conventionally addressed on the weaker side in order to balance the deficit. However, this standard approach may not always be applicable to a severely weakened limb that is too compromised to sustain it.8 For people with predominantly unilateral hyposthenia, in whom training the more-affected limb is not initially possible, contralateral strength training (CST) may represent a viable alternative to the conventional direct approach. The CST effect, also known as “cross-education,”9 refers to an interlimb phenomenon whereby exercise on one limb can induce a transfer of strength or skills to the contralateral untrained side.10 Extensively studied in healthy people10,11 and in people with orthopedic conditions,12,13 the CST effect is surprisingly almost unaddressed in people with neurological disorders. In this regard, only 2 studies tested CST in people with stroke hemiparesis, where significant strength increases were observed in the ankle dorsiflexors14 and wrist extensors,15 respectively, of the paretic untrained limb after training of the contralateral unaffected side. Another study successfully tested CST in a single case of peripheral nerve injury.16 No studies, to our knowledge, have investigated the potential of CST in people with MS.

With these considerations in mind, we hypothesized that, in individuals with MS, CST of the ankle dorsiflexor muscles of the less-affected (trained) limb might induce a transfer of performance to the more-affected (untrained) homologous muscles. If confirmed, this study would have clinical implications in the rehabilitation of unilateral impairments induced by neurological conditions.14–16

The main purpose of this trial, therefore, was to investigate the occurrence and magnitude, as well as the meaningfulness, of the CST effect in selected participants with MS with predominantly unilateral hyposthenia. Toward this aim, peak moment (PM) and maximal work (MW) were set as the primary outcome measures. Clinical and functional outcomes also were investigated.

Materials and Method

Participants

Participants with predominantly unilateral strength impairment of the ankle dorsiflexor muscles were selected from those referring to the Multiple Sclerosis Centre of the University of Sassari for periodical clinical and neurophysiological evaluations. Written informed consent was obtained from all participants before enrollment.

The inclusion criteria were: diagnosis of MS (according to the 2010 revision of diagnostic criteria17); age 18 years or older; evidence of strength asymmetry between ankle dorsiflexor muscles (patient-reported and then verified at the baseline assessment by isokinetic dynamometry as a difference between sides ≥20%); independent ambulation with or without use of unilateral assistance; and Expanded Disability Status Scale (EDSS) score ≤6, with Pyramidal Functional System score ≥3.

The exclusion criteria were: any medical condition contraindicating participation in strength training exercises; disability and comorbidities caused by other medical conditions and not related to MS; occurrence of relapses; treatment with corticosteroid or botulinum toxin; variations in disease-modifying drugs or symptomatic treatment within 6 months prior to recruitment; severe ataxia and postural instability (assessed with the Berg Balance Scale, cutoff value for exclusion: ≤35); major depression (assessed with the Beck Depression Inventory [BDI], cutoff for exclusion: ≥28); clinically relevant cognitive deficits (assessed with Frontal Assessment Battery [FAB], cutoff for exclusion: ≥14, and with the Trail Making Test [TMT], Parts A and B, cutoffs for exclusion: ≥78 seconds for TMT, Part A, and ≥273 seconds for TMT, Part B); and participation in rehabilitative or training programs within 6 months prior to the study. A team of neurologists and neurophysiologists performed all of the clinical examinations and testing procedures (M.P.C., E.O., I.R.Z., E.R.N.). Two of them (M.P.C., I.R.Z.) were assigned to determine the eligibility of the participants and their eventual enrollment in the study.

Participants deemed eligible underwent clinical, functional, and dynamometric assessments within a 2-week period. They were asked to refrain from any other exercise activity for the entire duration of the study.

Design

The design of the study is illustrated in Figure 1. A series of 8 replicated single-system case studies was completed using a pretest-posttest design with a short-term follow-up, which is an implementation of the simple one-group pretest-posttest study.18 It is also known as an AB design with follow-up, where A represents the baseline assessment and B refers to the intervention phase. The outcome measure is recorded repeatedly over both phases. The time line of the study, which was articulated in 4 phases, is shown in Figure 1. The study design was implemented using multiple pretests to control for the familiarization or learning effect that is frequently associated with strength testing protocols.17

Figure 1.
Figure 1.

Time line of the study. A1=pretraining phase (baseline) with test-retest procedures consisting of 3 bilateral measurements (test, 1-day retest, and 1-week retest) of maximal strength (peak moment and maximal work at 10°/s and 45°/s of angular velocity) from the dorsiflexor muscles of both sides. B=intervention phase consisting of 6 weeks of training (3 sessions per week) of the less-affected ankle dorsiflexors (upper panel) while leaving the more-affected limb untrained (lower panel). According to the cross-education paradigm,11 during phase B, multiple measurements (one for each of the 18 scheduled sessions) of maximal strength were obtained only from the less-affected trained limb (upper panel), while performing only one single measurement (intermediate) in a separate session after completing 3 weeks of training in the middle of phase B from the untrained more-affected ankle dorsiflexors. A2=posttraining test-retest procedures where 2 measurements (test, 1-day retest) of maximal strength were performed in both limbs within 1 week from the end of phase B. Follow-up=12-week period of follow-up, with no intervention administered for both limbs. A3=2 assessments (follow-up) as in phase A2, carried out within 1 week after the follow-up period. Arrows with continuous line indicate each resistance training session administered to the less-affected ankle dorsiflexors. Arrows with dashed line indicate the number of assessments performed in both limbs in phases A1 (pretest), B (intermediate), A2 (posttest), and A3 (follow-up).

Muscle Strength Testing

Muscle performance of the ankle dorsiflexors was unilaterally assessed on both legs with an isokinetic dynamometer (Biodex System 3, Biodex Medical Systems, Shirley, New York). Each participant was positioned on the isokinetic device with the knee flexed at 30 degrees and the ankle in full plantar flexion taken as starting position.19 The participant was firmly secured to the dynamometer with supplied straps. Before the baseline assessment, participants were familiarized with the isokinetic strength testing protocol to minimize the potential effects of learning associated with this procedure.8

All participants underwent a predefined 5-minute warm-up. Following a 5-minute rest, the criterion test took place, consisting of 4 repetitions at 45°/s and 2 repetitions at 10°/s. The less-affected leg was tested first. There was a 6-minute rest between tests of the less-affected and more-affected legs.

Clinical and Functional Assessment

Walking ability in activities of daily living was assessed using the Six-Minute Walk Test (6MWT), the 10-Meter Timed Walk Test (10MTW), and the Timed “Up & Go” Test (TUG), which have been shown to be highly reliable mobility tests in individuals with MS.20–22 Quality of life (estimated with the Multiple Sclerosis Quality of Life–54 [MSQoL-54]) also was assessed.

Intervention

Participants performed a strength training program consisting of 6 weeks of maximal-intensity isokinetic concentric resistance training of the less-affected ankle dorsiflexor muscles at a frequency of 3 sessions per week. Participants performed 3 sets of 4 maximum repetitions at 45°/s of angular velocity and 3 sets of 4 maximum repetitions at 10°/s, with a 3-minute rest given between sets. Each session lasted approximately 25 minutes. A maximal rather than a submaximal exercise protocol was chosen to optimize the training-induced neural adaptations,23,24 which are acknowledged as the main neurophysiological underpinnings of cross-education.8,10 When a session was missed, participants were allowed to recover it at the end of the cycle to ensure that at least 16 out of the scheduled 18 sessions were accomplished.

Data Analysis

Statistical analysis was performed using SPSS software for Windows, version 18.0 (SPSS Inc, Chicago, Illinois). Test-retest reproducibility was estimated by calculating 2 different numerical indexes: the intraclass correlation coefficient (ICC) and the coefficient of variation (CV). The ICC, which is generally accepted as the preferred method of quantifying relative reproducibility, was calculated using a 2-way random ICC (2,1) for single measures.25 The ICC analysis was applied over 3 time points (test, 1-day retest, and 1-week retest) for the primary outcome measures (PM and MW) and over 2 time points (test and 1-day retest) for 2 out of the 3 clinical and functional outcome measures (10MTW and TUG); reliability of the 6MWT was not assessed due to fatigue concerns. We considered an ICC <.4 to be an index of poor reliability, an ICC of .4 to .75 to be an index of fair to good reliability, and an ICC >.75 to be an index of excellent reliability. The CV, which is an index of absolute reproducibility and is used to interpret the consistency of measurements across time, was calculated as a percentage: CV%=(method error/mean) × 100, where method error=SDdiff/√2.26 Data were processed using a dual approach: group- and individual-level analyses.

Group-level analysis.

The primary outcomes measures (PM and MW) were analyzed with a repeated-measures analysis of variance (ANOVA) using time (pretest, intermediate, posttest, and follow-up assessments) and side (less-affected and more-affected) as factors. For the time factor, only the highest values in PM or MW at each time point was recorded and kept for the statistical analysis. When significant main effects and time × side interactions were detected, pair-wise comparisons with Bonferroni adjustment were used to locate the differences. Pair-wise mean differences were estimated by the linear contrasts of the repeated-measures ANOVA and their confidence intervals. To compare the differences, we used a separated model for each side. If significant main effects or interactions were detected, a simple main effects analysis followed, using one-way ANOVA or dependent t tests when appropriate. The 6MWT, 10MTW, and TUG scores were analyzed using a repeated-measures ANOVA with time as the one-way factor.

Individual-level analysis.

The 2–standard deviations (2-SD) band method was used to quantify the visual findings.18 The smallest real difference (SRD), which is a measure of responsiveness and is defined as the smallest change in score that exceeds the error of measurement and thus may be recognized as clinically meaningful at the level of the individual patient,27 also was calculated. The individual SRD (SRDi) was calculated according to the formula: SRDi=2.77 × rms (2) × rms (1 − ICC) and reported as SRDi%, calculated as 2.77 × (SRDi/grand mean) × 100, where “rms” is root mean square and the grand mean represents the mean of the 3 testing sessions. Difference scores were calculated as the difference between the PM or MW value recorded at the baseline assessment and the values recorded at the intermediate assessment (3-week difference score), the posttest assessment (6-week difference score), and the follow-up assessment (12-week difference score). Each difference score was calculated individually and compared with the absolute SRDi score and with the SRDi% score. The SRD analysis also was applied to evaluate any change in the clinical and functional outcomes (10MTW and TUG).

Role of the Funding Source

This work was supported by Fondazione Italiana Sclerosi Multipla (grant FISM 2013/R/11) and by Fondazione Banco di Sardegna (grant FBS 2014/0190). Upon request, the authors can provide any underlying research materials related to the article.

Results

All participants (mean age=39.5 years, SD=12.14) had a diagnosis of definite MS, with a mean disease duration of 11.37 years (SD=5.88. In our sample, neurological examination revealed 3 out of 8 participants (participants 6, 7, and 8) exhibiting a foot drop disorder of gait. On average, participants had moderate disability (median EDSS score=3.5), absence of depression (mean BDI score=11.3, SD=6.2), and normal cognitive functions, with special regard to the attentive domain (median TMT B−A=44.7 seconds) and the executive domain (mean FAB score=16.6, SD=1.5).

Demographic and clinical characteristics are reported for each participant in Table 1. No relapses or changes in medications occurred during the study. The results of the reproducibility and responsiveness analyses are detailed in Table 2. Overall, at both velocities, all ICCs for relative reliability were ≥.80, whereas the CV%, calculated for absolute reliability purposes, ranged from 1.0% to 14.7%, with a median value of 8.4%.

View this table:
Table 1.

Demographic and Clinical Features of the Participants at Study Entrya

View this table:
Table 2.

Reproducibility and Responsiveness of Maximal Strength Measurements From the LA and MA Ankle Dorsiflexor Muscles at Baseline Over 3 Time Points (Test, 1-Day Retest, 1-Week Retest)a

Group Results

Muscle strength.

Participants in this study exhibited lower levels of ankle dorsiflexor muscle performance compared with healthy people under isokinetic conditions (Fig. 2).11,28,29 In all participants, the more-affected limb was significantly weaker than the less-affected limb in terms of both PM and MW at 10°/s and 45°/s of angular velocity (all P values <.03). Participant 8 was excluded by group-level analysis because she underwent only isometric testing due to her inability to generate functional dorsiflexion with the more-affected limb under isokinetic conditions. Following training, a significant main effect of time was detected in both PM and MW at 10°/s (PM: F3,33=17.65, P<.0005; MW: F3,33=14.03, P<.0005) and at 45°/s (PM: F3,33=15.01, P<.0005; MW: F3,33=23.03, P<.0005). However, the trained and untrained limbs improved in such a similar manner over time that no significant time × side interaction was observed at 10°/s (PM: F3,33=1.078, P=.37; MW: F3,33=.923, P=.44) and 45°/s (PM: F3,33=0.375, P=.77; MW: F3,33=1.018, P=.40). Average PM and MW results at the different time points of the study are detailed by side and angular velocity in Table 3. Regarding the directly trained less-affected limb, significant pretest-posttest changes for all dynamometric variables at 45°/s and 10°/s (Tab. 3) were found. Significant pretest-posttest improvements also were detected in the more-affected limb, depicting a CST effect.

Figure 2.
Figure 2.

Changes in maximal strength following 6-week high-intensity resistance training of the less-affected (LA) ankle dorsiflexor muscles in patients with multiple sclerosis. Changes in peak moment (PM) and maximal work (MW) are reported by angular velocity at 10°/s (A and C, respectively) and 45°/s (B and D, respectively) for the LA trained limb (continuous line) and for the more-affected (MA) untrained limb (broken line). Pretest=assessment at baseline, intermediate=assessment after 3 weeks of resistance training, posttest=assessment at the end of 6-week intervention period, follow-up=assessment after 12 weeks from the end of intervention.

View this table:
Table 3.

Group-Level Assessments (N=7) of Dynamometric Outcomes at Baseline (Pretest), After a 3-Week Intervention, at the End of the 6-Week Intervention Period, and After 12 Weeks From the End of the Interventiona

At the follow-up, a pattern of detraining was evidenced in the 2 limbs by the significant deterioration of muscle performance compared with posttest measurements. However, strength levels remained significantly superior to baseline values in the majority of the outcome parameters (5 out of 8), revealing a consistent retention of muscle performance after 12 weeks from the training completion (Tab. 3).

Clinical and functional outcomes.

Test-retest reliability for the mobility measures proved excellent for both the 10MTW (ICC=.99) and TUG (ICC=.98). Due to the high degree of fatigue that the 6MWT induced in most of the participants at the baseline assessment, the retest for reliability purposes was not carried out in order to avoid potential fatigue-induced interferences that would have affected the planned training schedule.

The repeated-measures ANOVA revealed a main effect of time for the 10MTW (F2,14=5.165, P=.02) and the TUG (F2,14=6.405, P=.01). No significant effect of time was detected for the 6MWT (F2,14=0.568, P=.50). Pair-wise comparisons revealed significant pretest-posttest improvements in the 10MTW (−9.7%, P=.03) and the TUG (−11.3%, P=.04), whereas only a trend toward improvement was observed in the 6MWT, which failed to achieve statistical significance (+8%, P=.09) (eTab. 1). The observed improvements were not maintained at the 12-week follow-up. The analysis of the SRD that could be applied only to the 10MTW and TUG revealed for both outcome measures training-induced changes greater than the SRD values, which served as cutoffs for clinically meaningful changes (eTab. 1).

No change in the overall QoL, as measured with the MSQoL–54 physical health summary score (pretest: X̅=56.8, SD=20.3; posttest: X̅=60.0, SD=18.7; P=.12) and with the MSQoL-54 mental health summary score (pretest: X̅=67.9, SD=21.2; posttest: X̅=67.7, SD=24.2; P=.96), was detected. Unlike the rest of the sample, 3 participants with a foot drop disorder of gait (participants 6, 7, and 8) exhibited an increase in the physical health score following intervention (pretest: X̅=60.2, SD=8.8, 95% confidence interval [CI]=38.3, 82.1; posttest: X̅=67.9, SD=8.3, 95% CI=47.3, 88.5).

Individual Results

Individual-level results are reported for muscle strength, which was the only variable suited to be repeatedly assessed throughout the entire duration of the study. To adhere to the cross-education paradigm,10 during the training period (phase B of the study), strength measurements were carried out in each training session only in the less-affected limb, whereas only a single intermediate assessment was performed in the more-affected limb in the middle of the intervention period (Fig. 1).

Muscle performance of the ankle dorsiflexors of both sides is reported for participants 1 through 8 in terms of PM (Fig. 3) and for participants 1 through 7 in terms of MW (eFigure) because MW calculations were not possible for participant 8 (see above). Figure 3 and the eFigure show the individual responses to the intervention throughout the entire duration of the study. The visual analysis of trend, level, and slope of the curves revealed visible pretest-posttest improvements in the majority of the sample.

Figure 3.
Figure 3.

Effects of a 6-week unilateral resistance training program on the peak moment (PM) recorded from both the less-affected (LA) trained and more-affected (MA) untrained ankle dorsiflexors. The graphs report individual results obtained in all phases of the study (A1=pretest, B=intermediate, A2=posttest, A3=follow-up) for PM at 45°/s (continuous line) and at 10°/s (dashed line). To adhere to the cross-education paradigm,11 during phase B, the PM was assessed in each of the scheduled training sessions in the trained limb (left panel), and a single intermediate measurement was performed, in the middle of the intervention period, in the untrained limb (right panel). As the PM values of each participant were quite different at baseline, the ordinates in each graph are enhanced to emphasize as much as possible the variations of PM throughout the entire duration of the study. Missing points during phase B indicate that participants 1 and 4 missed the last training session. Missing points during phase A3 indicate that participant 5 missed the follow-up assessment due to dropout.

The results of the 2-SD band analysis, which was applied to the less-affected side only, are detailed in eTable 2 and displayed in Figure 3 and the eFigure (left panels). Data showed that all dynamometric parameters significantly improved in 3 of 7 participants (42.8%; participants 1, 2, and 4). Two of 7 participants (28.6%; participants 6 and 7) exhibited a significant improvement of at least 3 of 4 parameters. In 2 of 7 participants (28.6%; participants 3 and 5), all parameters improved without reaching statistical significance.

Visual inspection of data obtained from the more-affected ankle dorsiflexor muscles (Fig. 3 and eFigure right panels) showed the occurrence of the CST effect in all participants except participant 3. With specific regard to participant 8, the isometric PM showed consistent improvements in both limbs. The visual inspection analysis and the 2-SD band method were complemented by the appraisal of the minimum detectable change, expressed as the SRDi to discriminate relevant from irrelevant changes following an intervention.

Notably, only from pretest to posttest assessment, all outcomes, regardless of the limb and the angular velocity, exhibited increases that exceeded the SRDi cutoff values for meaningful change. The comparison between the SRDi cutoff value calculated for each outcome measure at baseline and the average changes that occurred at each assessment during and after the 6-week CST intervention is detailed in eTable 3. The number of participants able to exceed the SRDi cutoff values for meaningful change after 3 and 6 weeks of CST and at the 12-week follow-up is detailed in eTable 4.

Discussion

This proof-of-concept study explored, in participants with MS and predominantly unilateral hyposthenia of the lower limbs, the effects of a resistance training of the less-affected ankle dorsiflexors on muscle performance of the more-affected limb. This aim was achieved by using a dual statistical approach: group- and individual-level analyses.

Group-Level Analysis

Compared with recent randomized trials and with the current normative values of maximal strength obtained under isokinetic conditions from the ankle dorsiflexor muscles,11,28,29 participants in this study exhibited lower levels of muscle performance. In particular, Harbo et al28 isokinetically tested 161 healthy volunteers and recorded a sex-pooled 27.1 N·m peak of strength, which is superior to our 22.1 and 17.9 N·m from the less-affected and more-affected limbs, respectively.

In individuals with MS, a 6-week isokinetic resistance training proved effective in inducing significant increases in muscle performance of the directly trained less-affected limb, both in terms of PM and MW. These findings are in agreement with a previous study that investigated, in healthy participants, the effects of a similar isokinetic training regimen on the same variables,11 and with several reports portraying strength training as effective in significantly reducing muscle weakness in people with MS.3,6,7,30 The training of the less-affected ankle dorsiflexor muscles induced a significant transfer of maximal strength to the more-affected limb, depicting a CST effect, which, to our knowledge, is reported here for the first time in individuals with MS.

The magnitude and temporal development of the direct and indirect gains in strength exhibited, respectively, by the less-affected and more-affected limbs were quite similar. This finding may explain the lack of any time × side interaction. Such results are surprising because it is generally accepted that the gain of strength in the untrained limb is 25% to 50% of that in the trained limb.9,10 However, the results are consistent with previous studies performed in healthy individuals where high-intensity training was used in the same muscle group11 or in upper limbs.13 Interestingly, the crossed transfer of muscle performance was here evidenced not only in terms of PM but also in terms of MW, which is the average measure of the torque output throughout the entire range of motion and is highly correlated with activities of daily living,31 which are considered a better indicator of muscle function than PM.31,32 In this perspective, our findings may prove of particular interest in rehabilitative settings.

It should be noted that the participants in the present study exhibited differences in level of performance at baseline, in terms of both PM and MW. However, in single-system designs, each participant acts as her or his own control. Regardless of whether the initial level of strength of each participant was high or low, the majority of our participants performed significantly better following the intervention.

The observed strength increases also were associated with significant improvements in the 10MTW and TUG mobility and walking performance outcomes, suggesting that the intervention had a positive impact on the functional walking measurements collected in this study. This finding is in line with the current opinion that resistance training leads to improvement of not only muscular strength but also functional outcomes.30,33 The finding of only a trend toward improvement in the 6MWT secondary outcome needs to be appraised considering the nature of this test, which is generally considered a cardiovascular fitness test and, therefore, may prove unresponsive to an intervention such as resistance training, which is not aimed at improving aerobic endurance. The training-induced improvements in maximal strength also were found to be significantly retained in the majority of the dynamometric outcomes considered by the directly trained less-affected limb and by the more-affected limb after 12 weeks from the end of the intervention period, suggesting that bilateral changes in muscle performance induced by unilateral training proved to be stable and persistent. However, no further improvements were made after the completion of the intervention, and, as expected with training protocols, a significant pattern of strength deterioration was observed from posttest to follow-up, suggesting a causal relationship between the observed effects and the intervention administered. The consistent deterioration of muscle performance that occurred at the cessation of the training might indicate the need for the prolongation of training in order to truly retain the achieved gains.

Individual-Level Analysis

Causality between the unilateral intervention and the observed bilateral effects was verified at the individual level by the visual inspection of every response to training exhibited by both limbs of each participant. A clear pattern toward improvement in the levels of maximal strength was visually detectable in the less-affected limb of all participants and statistically confirmed by the 2-SD band method in 6 of them (75%). The visual inspection of data obtained from the more-affected limb revealed an indirect increase in strength, depicting a CST effect, in 7 of 8 participants (87%). One participant (participant 3) did not show either direct or indirect responses to training. This lack of effects was attributed to poor collaboration observed during the intervention, likely due to a certain degree of mood alteration (BDI score=22), which may have affected her involvement in the study.

Visual inspection was complemented by the calculation and analysis of the SRDi, which is a measure of responsiveness and serves as a cutoff value to discriminate relevant changes from irrelevant changes.27 Although none of the changes exceeded the cutoffs in both limbs after 3 weeks of CST, the observed increases in strength at the end of the intervention were superior to the cutoff values of SRDi for clinically meaningful changes in both the trained and untrained ankle dorsiflexor muscles. Judging by the stringent standards of SRDi cutoff scores (both absolute and relative), at least 70% of the participants demonstrated an improvement following the 6-week intervention that exceeded the cutoff value in the directly trained ankle dorsiflexor muscles and in the untrained nondominant side. Moreover, at the 12-week follow-up, more than 50% of the sample showed levels of strength in both sides that were superior to baseline levels. These findings of good responsiveness, which indicate clinically important changes and corroborate the significance of the adaptations due to training, may have practical dose-response and cost-effectiveness implications when defining the training amount to be prescribed to achieve meaningful improvements in muscle performance and how much change needs to be achieved to induce a meaningful cross-education effect.

Strengths and Limitations of the Study

The single-system research design chosen for this study is routinely used to document patterns of clinical change and is considered an appropriate method to observe changes in a person's performance over time, providing clinically relevant information about individual patients.34 It is of particular value in evaluating clinical practice or preliminarily exploring the effects of specific treatments for specific problems.35 However, findings of single-system design studies should be cautiously generalized, as they are considered relatively weak in differentiating coincidence from causality,36 particularly because they do not include a control group, which is essential to discriminate causality from random and familiarization or learning effects. Therefore, further properly planned controlled trials are needed to test the clinical relevance and effectiveness of CST.

To adhere to the cross-education paradigm, repeated multiple assessments were not performed in the more-affected limb during the intervention period. Thus, it was not possible to use the 2-SD band method to statistically confirm the visual findings from the more-affected limb.

Following training, most of the participants exhibited direct improvements in the trained ankle dorsiflexor muscles and indirect “crossed” improvements in the untrained homologous muscles. These improvements, however, did not translate into changes in QoL. These findings were expected, as the participants showed at baseline a mild-to-moderate degree of disability, they were fully ambulant and independent, and their impaired dorsiflexion did not substantially affect gait or, in general, QoL. It also should be considered that participants underwent the training of the ankle dorsiflexors, which is a small muscle group possibly playing a minor role in the overall QoL in our sample of patients with a self-reported acceptable QoL at the time of enrollment. Although a slight improvement in the physical health score was observed in the 3 patients presenting foot drop, the possibility that strength changes were not functionally significant to the participants cannot be ruled out. Previous data on the effectiveness of CST in the management of foot drop secondary to stroke14 and peripheral nerve injury16 encourage future studies focusing on the use of CST in people with MS in whom foot drop (or weak dorsiflexor muscles) is reported as a factor limiting QoL.

A strength of this study may reside in the comprehensive assessment of maximal strength not only in terms of PM, as conventionally achieved, but also of MW, which, being a better indicator of muscle function than PM, may help to unveil the full potential of a CST approach as a rehabilitative strategy in the treatment of muscle weakness in selected individuals with MS presenting unilateral muscle weakness.

In conclusion, the novel finding of this study is the occurrence of the CST effect in MS that took place in terms of significant and persistent crossed transfer to the more-affected ankle dorsiflexor muscles of maximal strength, which also translated into consistent improvements of mobility and walking performance. The present findings contribute to the accumulating evidence portraying CST as a novel and viable approach with potential practical implications in the rehabilitation of unilateral impairments induced by neurological conditions.14–16 In this perspective, the enhanced muscle performance initially induced by CST in a highly compromised limb may be further implemented and consolidated by extending the duration of the same training protocol or, if possible, by switching to direct and more conventional training of the weaker side.

Footnotes

  • Dr Manca, Dr Deriu, and Dr Dragone conceptualized and designed the study. Dr Cabboi, Dr Ortu, Dr Ginatempo, Dr Zarbo, Dr de Natale, and Dr Mureddu collected the data. Dr Manca, Dr Deriu, Dr Bua, and Dr Dragone interpreted the data. Dr Manca, Dr Deriu, and Dr Dragone drafted the manuscript. All authors provided critical review of the manuscript.

  • The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Bioethics Committee of the Local Health Authority (ASL n.1-Sassari, Italy; Prot. number 1160/L/2013).

  • This work was supported by Fondazione Italiana Sclerosi Multipla (grant FISM 2013/R/11) and by Fondazione Banco di Sardegna (grant FBS 2014/0190). Upon request, the authors can provide any underlying research materials related to the article.

  • ClinicalTrials.gov identifier: NCT02010398.

  • Received May 20, 2015.
  • Accepted November 22, 2015.

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Vol 96 Issue 6 Table of Contents
Physical Therapy: 96 (6)

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Effect of Contralateral Strength Training on Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Case Series
Andrea Manca, Maria Paola Cabboi, Enzo Ortu, Francesca Ginatempo, Daniele Dragone, Ignazio Roberto Zarbo, Edoardo Rosario de Natale, Giovanni Mureddu, Guido Bua, Franca Deriu
Physical Therapy Jun 2016, 96 (6) 828-838; DOI: 10.2522/ptj.20150299

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Effect of Contralateral Strength Training on Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Case Series
Andrea Manca, Maria Paola Cabboi, Enzo Ortu, Francesca Ginatempo, Daniele Dragone, Ignazio Roberto Zarbo, Edoardo Rosario de Natale, Giovanni Mureddu, Guido Bua, Franca Deriu
Physical Therapy Jun 2016, 96 (6) 828-838; DOI: 10.2522/ptj.20150299
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