Strength and work parameters in people with multiple sclerosis and in healthy individuals: A responsiveness study of the ankle dorsiflexors

2.1 Subjects

This study is a continuation of a previously published single-system interventional case series of 8 PwMS [22], whose baseline assessments of isokinetic strength have been considered also for the current investigation. Twenty PwMS with predominantly unilateral muscle weakness of the dorsiflexors were recruited from those participating in a larger interventional trial taking place in the University Hospital facilities. Inclusion criteria were: diagnosis of relapsing-remittent MS according to 2010 revision of diagnostic criteria [28]; patient-reported evidence of strength asymmetry between dorsiflexor muscles; age ⩾ 18 years; independent walking with or without unilateral assistance; Expanded Disability Status Scale score ⩽ 6.5 with Pyramidal Functional System score ⩾ 3. Exclusion criteria consisted of any medical condition contra-indicating participation in strength testing exercises; occurrence of relapses, treatment with corticosteroid and/or botulinum toxin, variations in disease-modifying drugs or symptomatic treatment in the previous 6 months; severe ataxia and postural instability; major depression; clinically relevant cognitive deficits; participation in rehabilitative or training programs within 6 months prior to the study. Participants deemed eligible after clinical examination were asked to refrain from any other exercise activity during the study. Twenty healthy individuals of comparable age, gender and anthropometric characteristics served as control subjects. The study was approved by the institutional Bioethics Committee of the Local Health Authority and conducted in accordance with the Declaration of Helsinki. A written informed consent was obtained by all the participants before enrollment.

2.2 Measurements of ankle dorsiflexion muscles’ strength

Bilateral concentric assessment of ankle dorsiflexors was conducted by the same examiner at a consistent time of the day, using an isokinetic dynamometer (Biodex System 3, Biodex, Shirley, NY, USA). The test was conducted in the sitting position with the trunk inclined at 85 ∘ , the tested knee flexed at 30 ∘ and the ankle in full plantar flexion as starting position [1]. The dynamometer shaft was aligned with the lateral malleolus. As all participants in this study were able to move the foot from full plantarflexion through an arc of 45–50 ∘ the test range of motion was adjusted to 45 ∘ . Participants in both groups had no prior experience with isokinetic testing. In the 2 weeks preceding the test, all participants attended a first orientation session where all the testing procedures were explained. During this session, each participant was positioned onto the device and the chair settings were recorded. Additionally, participants were instructed to perform a single concentric ankle dorsiflexion followed by a passive return to plantarflexion and then required to perform 4 to 6 very light movements. Visual feedback was provided at this stage by showing the real-time force traces during the motor task to ensure it was clearly understood.

In the next formal familiarization session, which was aimed at controlling the potential learning effect of practice-based improvements [4], the position settings previously recorded were verified and the subject was required to perform 2 sets of 4 submaximal single concentric dorsiflexions, with the first set carried out at a comfortable, self-selected level of exertion, and the second set performed at a moderate effort. These procedures resembled those employed for the warm-up phase preceding the criterion strength test. As in the orientation session, participants were requested to monitor the force traces on the PC screen located in front of them. This session was aimed at controlling potential practice-based improvements [4].

Prior to the formal testing sessions, all subjects underwent a 5-minute warm-up by performing two sets of 2-to-4 concentric submaximal repetitions at 45 ∘ /s with a 3-minute rest in between. Following a 5-min rest, the criterion test consisted of 4 maximal attempts at 45 ∘ /s. Sixty seconds of recovery were allowed among the attempts. Verbal communications were kept to the minimum and only the standardized instruction to “pull the foot and ankle upwards as fast and as hard as possible” was consistently delivered before each attempt. In the cohort of PwMS the less-affected leg was tested first. A 6-min rest elapsed between the testing of the less-affected and the more-affected leg in PwMS, and between the dominant and non-dominant leg in the control group. The entire procedure was repeated in 3 different sessions: 1) criterion test; 2) 1-day retest and 3) 1-week retest. Neither visual feedbacks nor verbal encouragements were provided to the participant during the testing procedure.

Statistical analysis was performed using the SPSS software (version 18) for Windows (SPSS Inc, Chicago, IL, USA). The highest PM value (in Nm) and MW value (in J) were recorded and used in the analysis. The MW/PM ratio was also calculated (in J/Nm). One-way ANOVA was employed to compare age, weight and the strength levels in the two groups. The Chi-square test was used to compare groups by gender. Means, standard deviations (SD) and 95% confidence intervals (CI) were calculated by side for PM and MW across the 3 testing sessions. Each OP was determined as the maximum value recorded among the tests. The equality of variances was assessed by the Levene’s test. A repeated-measures analysis of variance (ANOVA) was conducted to compare measurements among the sessions in the 2 groups to verify the repeatability of maximal isokinetic strength measurements in PwMS in comparison with healthy subjects. To control for any bias deriving from gender pooling, the strength levels were compared by two-way ANOVA between the groups with and without the male subjects. Significance was set at 0.05. When significance was detected, Bonferroni-adjusted pairwise comparisons were performed to locate the difference. Cohen’s d effect size magnitudes (small ⩽ 0.5; moderate 0.51–0.79; large ⩾ 0.8) were also used to estimate the clinical relevance of the inter-session differences and of the inter-group differences [6]. Linear correlation coefficients (Pearson’s r ) were used to evaluate the degree of linear relationship between PM and MW. Test-retest reproducibility and responsiveness were estimated in both groups by calculating the following indices: 1) 2-way random ICC (ICC 2 , 1 ) for single measures [13, 33]; 2) SRD at the individual level (SRDi) = 2.77*SEM where SEM (standard error of measurement) is equal to SD × √ (1-ICC 2 , 1 ) while SEM% = (SEM/mean) × 100 [21].

Descriptive statistics for the isokinetic findings of dorsiflexors’ strength are presented in Table 2.

The repeated-measures ANOVA, which was run separately for each group, revealed a main effect of the testing session in the PwMS group in both PM and MW. Bonferroni-adjusted pairwise comparisons detected significant reductions in both OP from the less-affected limb between sessions 1 and 2 (PM: - 2.5%; MW: - 4.2%) and sessions 1 and 3 (PM: - 8.4%; MW: - 14.9%) whilst in the more-affected limb significant reductions were found only in PM between sessions 1 and 2 (PM: - 6.1%; MW: - 5.3%) and between sessions 1 and 3 (PM: - 7.7%; MW: - 12.9%). Overall, the effect sizes of such differences between sessions were small for both PM and MW (Cohen’s d ranging 0.1 to 0.3).

A main effect of the testing session was detected also in the control group. Pairwise comparisons revealed significant increases (8.4%) only in the non-dominant limb in PM between sessions 1 and 3 and in MW between sessions 1 and 2 and sessions 1 and 3, at small effect sizes (Cohen’s d values 0.3).

The significant Session*Group interactions revealed that the temporal pattern of the changes over the 3 testing sessions was statistically different between the more-affected limb of PwMS and the non-dominant limb of controls (PM: F = 7.837; p = 0.001; MW: F = 7.715; p = 0.002) as well as between the less-affected limb of PwMS and the dominant limb of controls (PM: F = 6.987; p = 0.003; MW: F = 7.818; p = 0.001).

3.2 Reproducibility and responsiveness

The values of the ICC (reproducibility) and responsiveness (SRDi and SRDi%) of the PW and MW measurements are detailed by group, limb and type of comparison in Table 3. Relative reproducibility analyses performed separately for females and males within each group revealed that the scores calculated for females only were very similar to the pooled data reported in Table 3. In detail, in female PwMS ( n = 16/20) ICC was 0.93–0.94 in the less-affected limb and 0.91–0.94 in the more-affected limb. In the female controls ( n = 14/20) the coefficients ranged 0.82–0.95 in the dominant limb and 0.91–0.95 in the non-dominant limb.

The SRDi values relating to the PM of both legs in PwMS were appreciably lower than their MW-related counterparts: 11.4 vs 13% and 19.4 vs 19.8%, respectively and even lower than the parallel scores calculated for the controls (13.8 vs 14.4%).

4.1 General aspects

As expected, PwMS proved significantly weaker than controls, strongly supporting previous findings pointing to some 30–70% reduction in strength [26, 30, 32, 37]. On the other hand, the extent of asymmetry between the stronger and the weaker limb was differently portrayed by MW (significant inter-limb deficit of 20–24%) than by PM (non-significant inter-limb deficit of 12–14%). Linear correlation analysis showed that only 36–64% of the variability in one of these OPs is directly influenced by the other, suggesting that PM and MW relate differently to muscle function, echoing recent studies of the ankle dorsiflexors in healthy subjects both at baseline and after training [23, 24]. In particular, since MW represents the dissipated muscular output over the entire range of joint motion [25], adding it to the PM may complement the assessment of muscle performance in PwMS, who experience difficulties in maintaining the strength levels over distance and over time [30].

Furthermore, inspection of the morphology of the dynamometric curves and the calculation of the MW/ PM ratio revealed a significant difference between healthy subjects and PwMS. In the former, the MW obtained during a maximal dorsiflexion effort was 58% of the PM, while in the latter it was only 38%. These findings indicate that in PwMS the capacity of the dorsiflexors to sustain muscle tension over a given ankle range of motion is likely to be more affected than the ability to exert an instantaneous PM. It is worth noting that the analysis was based on the use of a relatively low angular velocity (45 ∘ /s) in view of the difficulties experienced by neurological patients in reaching high angular speeds [36]. Whether these results are generalizable to other muscles, velocities and contraction type, requires further exploration. However, we argue that both the MW and the MW/PM ratio may be considered an adjunct to the PM in the interpretation of findings pertaining to isokinetic muscle performance in PwMS, both at baseline and after rehabilitation.

4.2 Reproducibility over sessions

Reproducibility of PM and MW measurements, as assessed by ICC, proved excellent in PwMS and healthy subjects, regardless of gender. This general finding supports previous research relating to the ability of isokinetic dynamometry to yield clinically acceptable consistency of strength measurements in healthy subjects [12] as well as in PwMS under dynamic [17] and isometric conditions [3, 27, 32]. However, despite the high ICCs, significant inter-session differences were observed within each group, indicating that both PwMS and healthy controls performed differently depending on the time point of assessment. Despite the dedicated familiarization procedures, the two groups showed a different pattern of change across sessions, with strength increasing from session 1 to 2 in controls, while declining from session 1 to 3 in PwMS, in line with a recent single-system case series [22]. Even though a certain amount of practice-based improvement ( + 8.1%) may have occurred in the control group from session 1 to session 2, the decline in performance (from - 2.5% to - 14.9%) exhibited by PwMS raises questions regarding the temporal stability of maximal isokinetic strength measurements in this population. This is a crucial issue in the context of intervention since an unreliable baseline would not allow tracking of changes induced by training [2]. The onset of fatigue, which could account for the high day-to-day variability in performance exhibited by PwMS [18], may have played a role. However, it is worth noting that in the present protocol, changes occurred between sessions 1 and 2, which were separated by only 1 day, whereas significant changes were detected from sessions 1–3 and 2–3, when at least a 6-day rest period was allowed. Therefore, it is likely that, besides fatigue, other factors contributed to the instability of measurements. We argue that these are to be sought within the pathophysiology and clinical features of MS. In particular, in PwMS the level of muscle performance is affected by the impaired recruitment of motor units, which may result in reduced muscle strength, power and rate of force development leading to the physical deconditioning commonly observed in this population [15, 17, 32]. This feature has been linked to a decreased muscle cross-sectional area, reduced aerobic-oxidative energy supply [16], increased muscular fatigue [19], decreased motoneuron firing rates [30] and reduced cortico-spinal neural drive [10].

From a statistical standpoint, the results provided by the repeated-measures ANOVA and ICC analyses seem to be contradictory. Weir [38] suggests that an ICC can be large (indicating good reliability) while the ANOVA shows a significant trials effect. Indeed, as long as they are consistent across all the subjects (as indicated by all ICCs $>$ 0.9) even small differences among testing sessions may result in a statistically significant effect for trials. The finding of excellent reliability along with significant differences in the mean may raise some concerns regarding the exclusive employment of ICC without consideration of the trials effect. However, the analysis of the effect sizes revealed low scores (Cohen’s d 0.1–0.3) indicating that, although significant, the inter-session differences were not clinically relevant. Supporting this position is the observation that in the current cohort of PwMS even the largest change in PM, although flagged as statistically significant, was equal to less than 2 Nm.

Taken as a whole, the findings seem to confirm that, despite the employment of methodological procedures to optimize the consistency of the measurements, the assessment of maximal strength in PwMS is particularly challenging. Our cohort of PwMS achieved their peak performances in the first session, thus suggesting that one test may be sufficient to obtain valid findings. However, implementing 3 testing sessions revealed a trend of declining strength across sessions, which otherwise would have not been captured by a single test. Although the present study remains inconclusive as to how many tests are advisable for assessing PwMS, defining such variability across at least 3 sessions is a valuable information to adequately characterize the dynamometric profile of this population.

4.3 Responsiveness

Based on the results of the present study, any change in muscle performance falling below the individual cut-off value, expressed by SRDi, should be discarded even if statistically significant since it can be attributed to the measurement noise. This concept is particularly meaningful in terms of an intervention, since not every observed difference is clinically meaningful. Indeed, clinically meaningful improvements are at best no less than 10% and typically around 20–30% in orthopedic conditions [7], 26–55% in stroke survivors [20] and 11–39% in individuals with post-polio syndrome [10]. Importantly, the PM-based SRDi scores ranged 11.4–13% in PwMS and 13.8–14.4% in the controls, with the value for the more affected side in PwMS (13%) lower than the corresponding values for both the dominant and non-dominant sides in the controls. Noteworthy, in PwMS the PM-based SRDi scores were 40–50% lower than their MW counterparts, indicating that for these patients, a meaningful improvement in isokinetic strength could be detected relatively earlier by using the PM rather than the MW as the OP of choice. That said, the SRDi for MW for the ankle dorsiflexors in PwMS is coincident with what has been indicated as a clinically meaningful margin for real improvement in muscle function [8]. The findings thus indicate that in spite of inter-session differences in isokinetic strength and work capacity, the responsiveness of these measures is very well within clinically acceptable limits and may therefore serve for determination of clinically meaningful improvement or deterioration of these isokinetic markers, due to intervention or naturally occurring variations. Using the specific SRDi figures obtained in the ankle dorsiflexors of PwMS with same characteristics and measured isokinetically at relatively low velocities may practically translate into proclaiming that a change of slightly over 13% in the PM should be interpreted as clinically meaningful, thus informing a decision relating to the nature of the intervention.

In conclusion, measurements of maximal isokinetic concentric dorsiflexion strength obtained from PwMS proved to be highly reproducible, temporally unstable albeit in a clinically irrelevant manner but significantly well responsive to change. If the findings of this study are to be generalized to other muscle groups, contraction types and angular velocities, appropriate procedures should be instituted in PwMS when assessing physical capacities and/or the occurrence of meaningful changes that may be induced by rehabilitative interventions. These procedures should include methodological steps such as the inclusion of a proper familiarization protocol. Moreover, a comprehensive statistical approach should be employed in order to establish reproducibility and responsiveness of the measurements. Finally, the employment of the ANOVA for checking measurements’ stability over time and of the effect size for clinical relevance analyses may help to optimize the quantification and interpretation of test-retest results, which is particularly challenging in “unstable” individuals such as PwMS.

4.4 Study limitations

This study focused only on concentric testing. Eccentric measurements would have provided important information as lengthening contractions have a functional role in gait as well as in other functional activities. However, they were not included in order to keep the patients as mechanically unloaded as possible.

Another limitation was the employment of a single test velocity. However, the addition of more test velocities would not have necessarily changed the tenor of the main findings, as revealed by a study of orthopedic patients [41]. Admittedly, the efficiency of multiple velocity testing in MS requires further exploration, although the difficulty that these patients exhibit when exercising at high angular velocities should be taken into proper account [36].

In terms of sample size, although the present study is in line with the recommendation that reliability studies should enroll at least 15–20 patients [11], the present results need to be confirmed over a larger sample.

Finally, and as a precaution, the present findings should, at this point, not be generalized to muscle groups other than the ankle dorsiflexors considering their neurophysiological and biomechanical peculiarities [34].

4.5 Practical applications

In general, the massive increase of the literature dealing with new strategies to characterize muscle strength in PwMS is a decisive proof for the growing interest in new competencies and methodologies which are derived from exercise physiology and sports sciences. This interest has recently stimulated a translational process mandating the inclusion of exercise and strength conditioning experts in the multidisciplinary clinical team of neurologists, physiatrists and physiotherapists.

From the more focused viewpoint, strength and conditioning professionals involved in testing and rehabilitation of muscle strength in PwMS should be aware of the unique importance of the concept of responsiveness when adjusting or designing an intervention program. They should also take note of the additive value of using the MW when assessing the performance of people afflicted with this disease.