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Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability
Multiple Sclerosis and Related Disorders 26 (2018) 103–111
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Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability☆ Thomas Edwardsa, Robert W. Motlb, Emerson Sebastiãoc, Lara A. Piluttid,
T
⁎
a
School of Human Kinetics, University of Ottawa, 200 Lees Avenue, Ottawa, ON K1N 6N5, Canada Department of Physical Therapy, University of Alabama at Birmingham, 1705 University Blvd., Birmingham, AL 35233-1212, USA c Department of Kinesiology and Physical Education, Northern Illinois University, 1425 Lincoln Hwy, DeKalb, IL 60115 USA d Interdisciplinary School of Health Sciences, Brain and Mind Research Institute, University of Ottawa, 200 Lees Avenue E250G, Ottawa, ON K1N 6N5, Canada b
A R T I C LE I N FO
A B S T R A C T
Keywords: Multiple sclerosis Exercise training Functional electrical stimulation Adapted-exercise Mobility
Background: Exercise training has been shown to be beneficial for persons with multiple sclerosis (MS). Adapted exercise modalities are needed to accommodate those with severe mobility impairment (Expanded Disability Status Scale [EDSS] scores 5.5–6.5). Functional electrical stimulation (FES) cycling is one such exercise modality; however, few studies have examined the feasibility and potential benefits of FES cycling for people with MS with severe mobility impairment. Objective: Determine the feasibility of FES cycling exercise for people with MS with severe mobility impairment, and the efficacy of FES cycling exercise for improving mobility and physiological fitness. Methods: 11 participants with MS with mobility impairment (EDSS = 5.5–6.5) were randomly allocated to FES cycling exercise (n = 6) or passive leg cycling (PLC; n = 5). Feasibility metrics included participant recruitment, retention, adherence, safety, and satisfaction. The primary mobility outcome was walking speed assessed by the Timed 25-Foot Walk (T25FW) test. The primary physiological fitness outcome was peak oxygen consumption (VO2peak), assessed using a cardiopulmonary exercise test. Results: Eight participants completed the intervention (FES n = 4; PLC n = 4) with an adherence rate ≥80%. Three participants (FES n = 2, PLC n = 1) withdrew due to a lack of time. Six Grade 1 (i.e., mild) adverse events were experienced by participants in the FES group. Participants in the FES cycling condition demonstrated smallto-moderate improvements on T25FW performance (Cohen's d = 0.40; 22.9%) and VO2peak (Cohen's d = 0.34; 13.8%) compared to participants in the PLC condition. Conclusions: We provide evidence that FES cycling exercise is feasible for individuals with MS with severe mobility impairment, and might have positive effects on mobility and physiological decondition. These results will inform the design of future efficacy trials of FES cycling exercise for persons with MS with mobility disability.
1. Introduction Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system characterized by accumulation of progressive neurological impairment (Frohman et al., 2006). Such impairment is
commonly reflected as the loss of mobility, one of the most common and poorly-managed consequences of MS (Larocca, 2011). Mobility impairment increases with disease progression and has negative consequences for employment, participation in everyday activities, and overall quality of life (QOL) (Larocca, 2011). Furthermore, the
Abbreviations: 2MW, 2-minute walk; AE, adverse event; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; EDSS, expanded disability status scale; FES, functional electrical stimulation; FM, fat mass; FFM, fat-free mass; MSM, multiple sclerosis; MSWS-12, Multiple Sclerosis Walking Scale-12; PLC, passive leg cycling; RCT, randomized control trial; T25FW, Timed 25-Foot Walk; TUG, Timed Up-and-Go; VO2peak, peak oxygen consumption; QOL, quality of life; WR, work rate ☆ Disclosure statement: We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated and we certify that all financial and material support for this research and work are clearly identified in the title page of the manuscript. ⁎ Corresponding author. E-mail address: [email protected] (L.A. Pilutti). https://doi.org/10.1016/j.msard.2018.08.020 Received 4 April 2018; Received in revised form 17 August 2018; Accepted 22 August 2018 2211-0348/ © 2018 Elsevier B.V. All rights reserved.
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progression of mobility disability has been associated with substantial socioeconomic costs (Karampampa et al., 2012; Grima, 2000), highlighting the need for therapeutic strategies for managing mobility loss. Mobility disability in MS is further impacted by physiological deconditioning (i.e., reduced physiological fitness) (Sandroff et al., 2013; Sandroff et al., 2015). There is substantial evidence for physiological deconditioning among persons with MS, including reduced cardiorespiratory and muscular fitness, and these measures have been associated with mobility outcomes (Sandroff et al., 2013; Motl and Goldman, 2011; Pilutti et al., 2015). Physiological fitness declines with disease progression in MS, further exacerbating mobility impairment (Pilutti et al., 2015; Motl and Learmonth, 2014). Exercise training is an effective strategy for improving physiological fitness in persons with MS (Platta et al., 2016) and has been reported to improve mobility outcomes (Pearson et al., 2015). Unfortunately, this evidence has primarily been established in people with mild-to-moderate disability, rather than among those with severe mobility impairment, and the greatest need for exercise rehabilitation (Latimer-Cheung et al., 2013a; Edwards and Pilutti, 2017). Traditional exercise modalities have limited the study and application of exercise training for people with MS with mobility disability (Pilutti and Hicks, 2013). One advanced exercise-rehabilitation modality that was originally developed for individuals with spinal cord injury, and may also be beneficial for those with MS is functional electrical stimulation (FES) cycling (Baldi et al., 1998). FES cycling uses mild electrical stimulation delivered though surface electrodes to initiate involuntary muscle contraction. The addition of FES enhances the capacity for muscle recruitment during exercise, and consequently, the potential for physiological and functional adaptations to exercise training. There is support for the application of FES cycling in persons with MS (Ratchford et al., 2010; Reynolds et al., 2015; Backus et al., 2016; Szecsi et al., 2009), but none of the current evidence derives from a randomized controlled trial (RCT) design, potentially limiting the applicability of the findings. We conducted the first pilot, RCT of supervised FES cycling exercise compared with passive leg cycling (PLC) as a placebo-control condition in individuals with MS with severe mobility impairment. The objectives of this study were to: (1) assess the feasibility of 24-weeks of supervised FES cycling exercise based on metrics of participant recruitment, retention, adherence, compliance, safety, and satisfaction; and (2) examine the efficacy of FES cycling exercise for improving mobility and physiological fitness. This pilot trial will provide critical information to design and deliver future efficacy trials of FES cycling exercise in persons with MS with mobility impairment.
Table 1 The demographic and clinical characteristics of participant who completed the FES cycling exercise and PLC interventions. Values are reported as means (SD), unless specified otherwise. Characteristic
Overall (n = 8)
FES (n = 4)
PLC (n = 4)
p-value
Age, y Sex, n Female Male Height, cm Weight, kg BMI, kg/m2 EDSS (mdn, IQR) Disease duration, y MS type, n Relapsing MS Progressive MS
52.9 (7.9)
57.3 (6.0)
48.5 (7.7)
7 1 160.8 (9.1) 78.2 (33.7) 29.7 (10.7) 6.3 (0.5) 21.5 (6.6)
3 1 161.1 (10.4) 70.6 (19.5) 27.2 (7.4) 6.3 (0.5) 22.3 (5.3)
4 0 160.5 (9.2) 85.8 (46.0) 32.1 (13.9) 6.3 (0.9) 20.8(8.5)
4 4
2 2
2 2
0.12 0.29 – – 0.93 0.56 0.56 0.67 0.77 1.0 – –
Anthropometric, clinical, and demographic characteristics were collected for descriptive purposes. 2.2.2. Feasibility Feasibility included metrics of participant recruitment, retention, adherence, compliance, safety, and satisfaction with the intervention. Recruitment and retention were described as the number of participants during each phase of the trial. Adherence was characterized as participants’ attendance at the prescribed exercise sessions, and quantified as the percentage of completed sessions out of a possible 72. Compliance was characterized as participants’ completion of the prescribed exercise at a specified intensity and duration, and was quantified with training variables recorded at each session (i.e., pedaling distance, resistance, work rate, and heart rate). Safety was assessed as adverse events (AEs), which were defined as any unfavorable change in health that occurred during the trial period (Requirements, 2018). Each AE was characterized based on severity (Grade 1 [mild] through 5 [death]), expectedness (expected or unexpected), and potential relation to study participation (not related, possibly related, or study-related) using the National Institutes of Health Terminology and Classification scheme (Chen et al., 2012). Participant satisfaction was assessed using a 7-item feedback questionnaire quantifying the level of satisfaction with various characteristics of the leg-cycling programs (i.e., overall, trainers, equipment, training intensity, and likeliness to recommend to others or to use the cycle at home). Each item was rated on a 5-point scale that ranged from 1 (Not at all) to 5 (Extremely), with higher scores indicating greater satisfaction with the intervention. Feasibility metrics were selected based on recommendations for feasibility trials and previous studies examining the feasibility of exercise training interventions in people with MS (Adamson et al., 2016; Tickle-Degnen, 2013).
2. Methods 2.1. Trial design and participants
2.2.3. Mobility The primary mobility outcome was walking speed, assessed using the Timed 25-Foot Walk (T25FW) test. An average of two walking trials in seconds was calculated and converted to a walking speed in m/s. Walking endurance and agility were assessed with the 2-Minute Walk (2MW)(m) and the Timed Up-and-Go (TUG) tests (sec), respectively. All mobility tests were performed according to standard protocols (Coleman et al., 2012; Goldman et al., 2008; Nilsagard et al., 2007). The 12-item MS Walking Scale (MSWS-12) was used to capture selfreported mobility impairment. The total MSWS-12 score ranges from 0 to 100, where higher scores indicate greater walking impairment (Hobart et al. 2003).
The detailed protocol for this trial has been previously published (Pilutti et al., 2016). The trial design involved a parallel group, assessor-blinded, pilot randomized placebo-controlled trial. Participants were randomly allocated to receive FES cycling exercise or PLC for 24 weeks, using an allocation ratio of 1:1. Reporting of the trial follows the CONSORT guidelines for pilot and feasibility trials (Eldridge et al., 2016). Inclusion criteria for participants have previously been reported (Pilutti et al., 2016). 2.2. Outcome measures 2.2.1. Demographic/clinical characteristics Height and weight were measured in the laboratory using a scale with a stadiometer (Detecto, Webb City, MO). Disability status was confirmed through a clinically-administered EDSS (Ratzker et al., 1997) examination by a Neurostatus-certified assessor. Clinical and demographic characteristics were collected using a self-report questionnaire.
2.2.4. Physiological fitness Physiological fitness was assessed as cardiorespiratory fitness (CRF), muscular strength, and body composition using previously reported protocols in persons with MS (Sandroff et al., 2013; Pilutti et al., 2015; 104
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Fig. 1. CONSORT diagram demonstrating recruitment, allocation, and retention of all participants during each phase of the trial.
Bouchard et al., 1994). CRF was the primary fitness outcome expressed as peak oxygen consumption (VO2peak) from a cardiopulmonary exercise test (CPET) performed on a recumbent stepper (Nustep Inc., Ann Arbor, MI). CRF was further expressed as peak power output (WRpeak). Muscular strength was measured bilaterally using a Biodex System 3 dynamometer (Biodex Medical Systems, Inc, Shirley, NY) and expressed as average peak torque (N m) of the quadriceps (knee extensors) and hamstrings (knee flexors) muscle groups for both limbs. Body
composition was assessed by dual-energy X-ray absorptiometry (DXA) using a Hologic QDR 4500A bone densitometer (Hologic, Bedford, MA). Regional leg fat-free mass (FFM), fat mass (FM), % fat, and bone mineral density (BMD) were measured and expressed as totals (FFM; FM) or averages (% fat, BMD) of both limbs.
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Fig. 2. Weekly training means for cycling: (A) distance; (B) resistance; (C) power output; and (D) heart rate for the FES cycling exercise and PLC conditions across the 24-week intervention.
Table 2 7-item participant-feedback questionnaire used to determine level of satisfaction with the interventions. Values are presented as mean (SD). Cohen's d represents the difference between groups over time. Item
FES
1. 2. 3. 4. 5. 6. 7.
5.0 5.0 4.8 3.5 4.8 4.8 4.3
Overall satisfaction with leg cycling program (range = 1–5) Satisfaction with program trainers (range = 1–5) Satisfaction with leg cycling equipment (range = 1–5) Level of challenge of leg cycling program (range = 1–5) Satisfaction with leg cycling program (compared to other exercise programs) (range = 1–5) Likeliness to recommend leg cycling program to others with MS (range = 1–5) Likeliness of using leg cycling equipment in own home (range = 1–5)
(0.0) (0.0) (0.5) (0.6) (0.5) (0.5) (1.5)
PLC
Cohen's d
4.0 4.6 4.0 2.2 3.6 4.6 4.2
1.08 0.86 1.08 1.12 2.32 0.18 0.13
(1.0) (0.5) (0.7) (1.1) (1.1) (0.5) (0.8)
3. Intervention
4. Protocol
The FES cycling exercise and PLC conditions were delivered using RT300 cycles (Restorative Therapies Inc, Baltimore, MD) and the specific training parameters have been reported (Pilutti et al., 2016). Cycling duration and cadence (∼50 rpm) were matched between groups. Participants in the FES cycling exercise group received mild electrical stimulation while actively pedaling with the goal of maintaining the prescribed cadence and intensity based on target HR (Pilutti et al., 2016). The training intensity and progression was based on guidelines from the American College of Sports Medicine and MS-specific Physical Activity guidelines (American College of Sports Medicine 2013; Latimer-Cheung et al., 2013b). The PLC condition (i.e., placebo-control) did not receive electrical stimulation and did not actively pedal during the sessions. The PLC condition was identical to the FES cycling condition, without the active agent of increased energy expenditure that would be expected to drive adaptations in mobility and physiological fitness.
All procedures were approved by the University Institutional Review Board at the University of Illinois (#15426), UrbanaChampaign, and participants provided written informed consent prior to data collection. Screening for inclusion was first conducted over the telephone (Bredin et al., 2013; Kurtzke, 1983). Verification of MS diagnosis and approval for participation was confirmed by the eligible participants’ physician. Eligible participants were invited to the laboratory to complete the informed consent process and baseline testing. Participants were then randomized into one of the trial conditions by RWM who was uninvolved with the collection of outcomes or delivery of the intervention. All participants were prescribed three weekly supervised sessions for 24-weeks. Training variables were recorded at each session including HR (Polar Electro Oy, Kempele, Finland), ratings of perceived exertion (RPE), (Borg, 1982) distance peddled, power output (WR), and cycling resistance. The same testing protocol as 106
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Fig. 3. Mean change in: (A) T25FW; (B) TUG; (C) 2MW; and (D) MSWS-12 scores for the FES cycling and PLC conditions from baseline to 24 weeks. Error bars denote standard error of the mean (SEM).
p > 0.05) between the groups on any demographic or clinical variables at baseline.
baseline was administered at 24 weeks by treatment-blinded assessors. 5. Data analysis
6.2. Feasibility Data analysis was performed using SPSS statistics Version 24.0 (IBM Corp., Armonk, NY). Descriptive statistics were used to summarize the demographic, clinical, and feasibility metrics. Baseline characteristics were compared between groups using independent samples t-tests and chi-square tests. Based on the sample size and goal of the pilot trial to inform future work, the efficacy of the intervention (i.e., the difference between the groups over time) was determined using effect sizes (ES) expressed as Cohen's d, with calculated 95% confidence intervals (Durlak, 2009; Lee, 2016). ESs were interpreted as small, moderate, and large based on criteria of 0.2, 0.5, and 0.8, respectively (Cohen, 1988). Mean absolute differences and mean percent changes between groups over time were also calculated for comparative purposes with previous research. Lastly, exploratory Spearman's rank-order correlations (ρ) were performed for examining the relationship between change in mobility and change in physiological fitness in response to the intervention. The statistical significance level was adjusted for multiple comparisons (p < 0.006). Correlation coefficients of 0.1, 0.3, and 0.5 were interpreted as small, moderate, and large, respectively (Cohen, 1988).
Fig. 1 presents the flow of participants through the trial. Eleven participants were recruited (29% of eligible participants) and eight participants (FES n = 4; PLC n = 4) completed the trial (67% and 80% retention, respectively). Average adherence for the FES cycling exercise and PLC conditions were 84.2% and 83.7%, respectively. Training variables used to describe exercise compliance are presented in Fig. 2. Across 24 weeks, participants in the FES cycling group demonstrated a gradual increase in cycling distance (mean Δ = 8.7 km), resistance (mean Δ = 1.08 N m), and power output (mean Δ = 5.3 W). Participants in the PLC group also demonstrated a gradual increase in cycling distance (mean Δ = 9.8 km), but no change in resistance or power output. Regarding trial safety, seven (six Grade 1; one Grade 2) AEs were reported in the FES cycling group. The Grade 1 (i.e., mild) AEs reported included: skin irritation/redness (n = 3; expected; study-related); nondebilitating fatigue (n = 2; expected; possibly related); and increased muscle spasticity (n = 1; expected; possibly related). The Grade 2 (i.e., moderate) AE involved a fall that required stiches and occurred outside of the training setting (unexpected; not related). No adverse events were reported by participants in the PLC group. Participant satisfaction measured with the feedback survey is reported in Table 2. Participants in the FES cycling group reported greater levels of satisfaction with various aspects of the intervention compared to PLC (d’s = 0.86–2.32). Participants in the FES cycling group reported that this condition was more challenging than PLC (d = 1.12). Both groups indicated strong
6. Results 6.1. Demographics/clinical characteristics The clinical and demographic characteristics of all participants are presented in Table 1. There were no significant differences (all 107
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Fig. 4. Mean change in: (A) VO2peak; (B) WR; (C) knee extensor strength; and (D) knee flexor strength for the FES cycling and PLC conditions from baseline to 24 weeks. Error bars denote standard error of the mean (SEM).
compared to the PLC group. Both conditions demonstrated a decrease in knee flexor strength after the intervention, and there was no difference in the change between groups over time (3.6%; d = −0.07; 95% CI = −1.5, 1.3). There was no difference between groups in leg FFM, FM, or % fat after the intervention (5.2%; d = 0.18; 95% CI = −1.2, 1.6/ 0.7%; d = 0.00; 95% CI = −1.4, 1.4/4.4%; d = −0.16; 95% CI = −1.5, 1.2, respectively). When examining leg BMD, participants in the FES group demonstrated a moderate increase of 0.08 g/cm2 compared to participants in the PLC group (7.5%; d = 0.57; 95% CI = −0.8, 2.0).
endorsement of recommending this program to others, with no difference between condition (d = 0.18), and would use the leg cycling equipment in a home-based setting (d = 0.09). 6.3. Mobility Change in mobility for the FES cycling exercise and PLC conditions are presented in Fig. 3. When examining walking speed (T25FW), participants in the FES cycling group demonstrated a small improvement of 0.15 m/s (22.9%; d = 0.40; 95% CI = −1.0, 1.8) compared to those who completed PLC. With respect to agility (TUG), participants in the FES cycling group demonstrated a small improvement of 8.4 s (27.6%; d = −0.30; 95% CI = −1.7, 1.1) compared to PLC. Participants in the FES cycling group demonstrated a small improvement in walking endurance (2MW) of 27.0 m (11.7%; d = 0.20; 95% CI = −1.2, 1.6), compared to PLC. Additionally, participants in the FES group reported a moderate decrease of 13.5-points (i.e., improvement) in MSWS-12 scores (−15.8%; d = −0.68; 95% CI = −1.1, 1.7) compared to the PLC group.
6.5. Correlations between mobility and physiological fitness Exploratory correlations between changes in physiological fitness and mobility in response to the intervention for all participants are reported in Table 3. We focus on correlations between T25FW and fitness, as this was the primary mobility outcome. Large correlations were observed between change in T25FW and change in CRF (VO2peak, WRpeak; ρ = 0.62–0.69), and leg FM (ρ = −0.69). Moderate correlations were observed between change in T25FW and change in knee extensor strength (ρ = 0.31). None of these correlations were statistically significant.
6.4. Physiological fitness Change in physiological fitness for the FES cycling exercise and PLC groups are presented in Figs. 4 and 5. Participants in the FES cycling group demonstrated a small improvement of 2.20 ml/kg/min in VO2peak (13.8%; d = 0.34; 95% CI = −1.1, 1.7) compared to the PLC group after the intervention. Regarding WRpeak, participants in the FES cycling group demonstrated a moderate improvement of 8.8 W (15.3%; d = 0.65; 95% CI = −0.8, 2.1) compared to the PLC group. When examining knee extensor strength, the FES group demonstrated a moderate improvement of 21.0 N m (22.7%; d = 0.56; 95% CI = −0.9, 2.0)
7. Discussion We report the first rigorously designed, pilot RCT of FES cycling exercise in people with MS with severe mobility impairment. We determined that FES cycling exercise is a feasible modality that caused few, mild AEs in this population. Additionally, we provide preliminary data for the potential benefits of FES cycling exercise for maintaining or possibly improving mobility and physiological fitness. 108
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Fig. 5. Mean change in: (A) leg FM; (B) leg FFM; (C) percentage of leg fat; and (D) leg BMD for the FES cycling and PLC conditions from baseline to 24 weeks. Error bars denote standard error of the mean (SEM).
FES cycling trial of a similar duration, where participants experienced increased muscle spasticity and bowel incontinence (Ratchford et al., 2010). All Grade 1 AEs reported in the current trial were alleviated within days, and had no impact on participants’ daily routines. Importantly, all related AEs were experienced within the first 2 weeks of the intervention, which was likely a reaction to unfamiliar stimuli (excise and stimulation) (Pilutti et al., 2014). The feasibility metrics reported herein will be beneficial for informing future trials on expected responses to this FES cycling prescription and informing future participants about risks associated with FES cycling exercise.
Table 3 Exploratory Spearman's correlation coefficients between change in mobility and change physiological fitness outcomes in response to the intervention in the overall sample (n = 8). Variable
Δ T25FW (m/sc)
Δ 2MW Δ TUG Δ MSWS-12
Δ VO2peak (ml/kg/min) Δ WRpeak (W) Δ Knee extensor peak force (N m) Δ Knee flexor peak force (N m) Δ Leg FFM, kg Δ Leg FM, kg Δ Leg fat, % Δ Leg BMD, g/cm2
0.69 0.62 0.31 −0.26 0.05 −0.69 −0.36 0.05
(m) 0.21 0.46 0.67 −0.14 0.52 −0.26 −0.45 −0.05
(sec) −0.50 −0.46 −0.07 −0.26 −0.17 0.43 0.24 −0.43
−0.82 −0.50 −0.31 0.43 0.00 0.39 0.15 0.22
7.2. Treatment efficacy The T25FW has been described as the best characterized objective measure of mobility for individuals with MS, and performance on this test is strongly correlated with other functional outcomes (Motl et al., 2017). The generally accepted minimal clinically important difference (MCID) on the T25FW test is a 20% change (Coleman et al., 2012). Participants in the FES cycling group demonstrated a 22.9% improvement on the T25FW compared to the PLC group over time, suggesting that FES cycling exercise can result in clinically meaningful changes in walking. The FES cycling group demonstrated improvements on other objective and patient-reported measures of mobility (TUG, 2MW, and MSWS-12), suggesting a comprehensive mobility effects of FES cycling exercise. The FES cycling exercise group demonstrated a 13.8% improvement in VO2peak compared to the PLC group over time, exceeding the threshold value of a 10% change that has been described as clinically relevant (Langeskov-Christensen et al., 2014). Participants in the FES cycling group also demonstrated substantial improvements in WRpeak, further supporting improvements in CRF. This improvement in CRF is likely a result of habitual moderate-to-vigorous physical activity
7.1. Feasibility In the current trial, we report an overall dropout rate of ∼27%, which is comparable to other studies (13−33%) of FES cycling in individuals with MS with severe mobility impairment (Ratchford et al., 2010; Backus et al., 2016; Szecsi et al., 2009). Few studies have reported on adherence with specialized exercise modalities in this population. The overall adherence rate of ∼84% observed in this trial is comparable to another study (∼89%) involving recumbent stepper exercise and body-weight supported treadmill walking in persons with progressive MS with mobility disability (EDSS = 6.0–8.0) (Pilutti et al., 2016). The high adherence rate observed in this trial might reflect the high level of participant satisfaction, as reported on the feedback survey. Participants in the current study reported mild skin irritation, muscle spasticity, and fatigue with FES cycling exercise. The frequency and severity of these AEs are comparable to those reported in another 109
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for the feasibility of FES cycling for people with MS with severe mobility impairment, and provide direction as to which outcomes are most responsive to the FES cycling exercise protocol. These data should be used to inform future, large-scale RCTs with the purpose of establishing treatment efficacy of FES cycling exercise in persons with MS with severe mobility impairment.
(MVPA). Indeed, it has been reported that an acute session of FES cycling exercise elicits a cardiorespiratory response that is consistent with MVPA, and therefore, can be expected to improve CRF with training (Edwards et al., 2018). Importantly, CRF is considered an important indicator of health status and low CRF has been associated with increased risk for morbidity and mortality for both clinical and nonclinical populations (Wei et al., 1999). FES cycling exercise appears to be an efficacious method for maintaining and possibly improving CRF for individuals with MS with severe mobility impairment. This is particularly important given the low fitness levels reported in this population (Pilutti et al., 2015). The large increase in knee extensor strength observed in the FES cycling group may be attributed to the added stimulation delivered during FES cycling exercise. The supplemental stimulation allows greater motor-unit recruitment, muscle mass involvement, and force production (Fornusek and Hoang, 2014). This added stimulation theoretically increases active muscle mass during exercise and potential for adaptations. Indeed, it has been reported that individuals with MS have impaired muscular strength and motor-unit recruitment compared to healthy controls (Ng et al., 2004). Such impairments may be overcome with combined external neuromuscular stimulation and leg cycling exercise (Reynolds et al., 2015). Interestingly, both groups demonstrated a decline in knee flexor strength. This may be attributed to the biomechanics of leg cycling, which relies heavily on knee extensor engagement and less on knee flexor engagement (Bini and Diefenthaeler, 2010; Ambrosini et al., 2016). A different exercise stimulus might be required to target knee flexor strength in order to improve overall lower limb strength in persons with MS with severe mobility impairment. Lastly, higher leg BMD in the FES group likely reflects increased bone loading with external neuromuscular stimulation and contraction of lower extremity muscle groups involved in leg cycling. It is realistic to expect that improvements in physiological fitness might be responsible, in part, for observed improvements in mobility. Moderate-to-strong (although non-significant), associations were observed between changes in T25FW performance and changes in CRF and knee extensor strength, such that T25FW performance increased with increasing physiological fitness. Such relationships between physiological fitness and walking performance have been previously reported in individuals with MS (Sandroff et al., 2015). Indeed, the FES cycling exercise group demonstrated an improvement/maintenance of many fitness outcomes, which may have translated into improved mobility. In contrast, the PLC group demonstrated a decline in walking performance, potentially due to physiological deconditioning over this same period.
Acknowledgments This study was supported, in part, by the National Multiple Sclerosis Society [PR-1411-0209], the Consortium of Multiple Sclerosis Centers, and the Multiple Sclerosis Society of Canada [2665]. References Adamson, B.C., Learmonth, Y.C., Kinnett-Hopkins, D., Bohri, M., Motl, R.W., 2016. Feasibility study design and methods for project GEMS: guidelines for exercise in multiple sclerosis. Contemp. Clin. Trials 47, 32–39. https://doi.org/10.1016/j.cct. 2015.12.002. Ambrosini, E., De Marchis, C., Pedrocchi, A., et al., 2016. Neuro-mechanics of recumbent leg cycling in post-acute stroke patients. Ann. Biomed. Eng. 44 (11), 3238–3251. https://doi.org/10.1007/s10439-016-1660-0. American College of Sports Medicine, 2013. ACSM's Guidelines for Exercise Testing and Prescription, ninth ed. LWW, Philadelphia. Backus, D., Burdett, B., Hawkins, L., Manella, C., McCully, K.K., Sweatman, M., 2016. Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory. Int. J. MS Care 19 (3), 113–121. https:// doi.org/10.7224/1537-2073.2015-036. Baldi, J.C., Jackson, R.D., Moraille, R., Mysiw, W.J., 1998. Muscle atrophy is prevented in patients with acute spinal cord injury using functional electrical stimulation. Spinal Cord 36 (7), 463–469. Bini, R.R., Diefenthaeler, F., 2010. Kinetics and kinematics analysis of incremental cycling to exhaustion. Sports Biomech. 9 (4), 223–235. https://doi.org/10.1080/14763141. 2010.540672. Borg, G, 1982. Psychophysical bases of perceived exertion. - PubMed - NCBI. Med. Sci. Sports Exerc. 14 (5), 377–381. Bouchard, C., Shephard, R.J., Stephens, T., 1994. Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement xxiv Human Kinetics Publishers, Champaign, IL, England. Bredin, S.S.D., Gledhill, N., Jamnik, V.K., Warburton, D.E.R., 2013. PAR-Q+ and ePARmed-X+ New risk stratification and physical activity clearance strategy for physicians and patients alike. Can. Fam. Physician 59 (3), 273–277. Chen, A.P., Setser, A., Anadkat, M.J., et al., 2012. Grading dermatologic adverse events of cancer treatments: the common terminology criteria for adverse events version 4.0. J. Am. Acad. Dermatol. 67 (5), 1025–1039. https://doi.org/10.1016/j.jaad.2012.02. 010. Cohen, J., 1988. Statistical Power Analysis for the Behavioral Sciences, second ed. L. Erlbaum Associates, Hillsdale, NJ. Coleman, C.I., Sobieraj, D.M., Marinucci, L.N., 2012. Minimally important clinical difference of the timed 25-foot walk test: results from a randomized controlled trial in patients with multiple sclerosis. Curr. Med. Res. Opin. 28 (1), 49–56. https://doi.org/ 10.1185/03007995.2011.639752. Durlak, J.A., 2009. How to select, calculate, and interpret effect sizes. J. Pediatr. Psychol. 34 (9), 917–928. https://doi.org/10.1093/jpepsy/jsp004. Edwards, T., Motl, R.W., Pilutti, L.A., 2018. Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment. Appl. Physiol. Nutr. Metab. 43 (1), 71–76. https:// doi.org/10.1139/apnm-2017-0397. Edwards, T., Pilutti, L.A., 2017. The effect of exercise training in adults with multiple sclerosis with severe mobility disability: a systematic review and future research directions. Mult. Scler. Relat. Disord. 16, 31–39. https://doi.org/10.1016/j.msard. 2017.06.003. Eldridge, S.M., Chan, C.L., Campbell, M.J., et al., 2016. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2, 64. https:// doi.org/10.1186/s40814-016-0105-8. Fornusek, C., Hoang, P., 2014. Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis. J. Rehab. Med. 46 (7), 698–702. https:// doi.org/10.2340/16501977-1792. Frohman, E.M., Racke, M.K., Raine, C.S., 2006. Multiple sclerosis — the plaque and its pathogenesis. N. Engl. J. Med. 354 (9), 942–955. https://doi.org/10.1056/ NEJMra052130. Goldman, M.D., Marrie, R.A., Cohen, J.A., 2008. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult. Scler. 14 (3), 383–390. https:// doi.org/10.1177/1352458507082607. Grima, D.T., Torrance, G.W., Francis, G., Rice, G., Rosner, A.J., Lafortune, L., 2000. Cost and health related quality of life consequences of multiple sclerosis. Mult. Scler. J. 6 (2), 91–98. https://doi.org/10.1177/135245850000600207. Hobart, J.C., Riazi, A., Lamping, D.L., Fitzpatrick, R., Thompson, A.J., 2003. Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology 60 (1), 31–36. https://doi.org/10.1212/WNL.60.1.31. Karampampa, K., Gustavsson, A., Miltenburger, C., Kindundu, C.M., Selchen, D.H., 2012.
8. Limitations and future direction The primary limitation of this study is the small sample size, which may limit the generalizability of the findings. This study reported on a limited number of outcomes and may not have captured all aspects of feasibility. Future research would benefit from testing the lasting effects of this intervention, and the feasibility and efficacy of this training outside of a supervised exercise setting. This study also included a very specific population of individuals with MS (EDSS = 5.5–6.5); therefore, these results may be limited to MS samples with similar characteristics. Another aspect that should be investigated in future studies is the specific exercise prescription and FES cycling parameters, for optimizing the training response and maximizing the potential benefits. 9. Conclusions We report that FES cycling exercise is feasible for individuals with MS with severe impairment, and provide ESs for mobility and physiological fitness outcomes that can be used for informing future trials. These results build on previous research by providing further support 110
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Treatment experience, burden, and unmet needs (TRIBUNE) in multiple sclerosis: the costs and utilities of MS patients in Canada. J. Popul. Ther. Clin. Pharmacol. 19 (1), 11–25. Kurtzke, J.F., 1983. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33 (11), 1444–1452. Langeskov-Christensen, M., Langeskov-Christensen, D., Overgaard, K., Møller, A.B., Dalgas, U., 2014. Validity and reliability of VO2-max measurements in persons with multiple sclerosis. J. Neurol. Sci. 342 (1), 79–87. https://doi.org/10.1016/j.jns.2014. 04.028. Larocca, N.G., 2011. Impact of walking impairment in multiple sclerosis: perspectives of patients and care partners. Patient 4 (3), 189–201. https://doi.org/10.2165/ 11591150-000000000-00000. Latimer-Cheung, A.E., Pilutti, L.A., Hicks, A.L., et al., 2013a. Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Arch. Phys. Med. Rehab. 94 (9), 1800–1828. https://doi.org/10.1016/j.apmr.2013.04.020. e3. Latimer-Cheung, A.E., Martin Ginis, K.A., Hicks, A.L., et al., 2013b. Development of evidence-informed physical activity guidelines for adults with multiple sclerosis. Arch. Phys. Med. Rehabil 94 (9), 1829–1836. https://doi.org/10.1016/j.apmr.2013. 05.015. Lee, D.K., 2016. Alternatives to P value: confidence interval and effect size. Korean J. Anesthesiol. 69 (6), 555–562. https://doi.org/10.4097/kjae.2016.69.6.555. Motl, R.W., Cohen, J.A., Benedict, R., et al., 2017. Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. Mult. Scler. J. 23 (5), 704–710. https://doi.org/10.1177/1352458517690823. Motl, R.W., Goldman, M., 2011. Physical inactivity, neurological disability, and cardiorespiratory fitness in multiple sclerosis. Acta Neurol. Scand. 123 (2), 98–104. https://doi.org/10.1111/j.1600-0404.2010.01361.x. Motl, R.W., Learmonth, Y.C., 2014. Neurological disability and its association with walking impairment in multiple sclerosis: brief review. Neurodegener. Dis. Manag. 4 (6), 491–500. https://doi.org/10.2217/nmt.14.32. Ng, A.V., Miller, R.G., Gelinas, D., Kent-Braun, J.A., 2004. Functional relationships of central and peripheral muscle alterations in multiple sclerosis. Muscle Nerve 29 (6), 843–852. https://doi.org/10.1002/mus.20038. Nilsagard, Y., Lundholm, C., Gunnarsson, L.G., Dcnison, E., 2007. Clinical relevance using timed walk tests and “timed up and go” testing in persons with multiple sclerosis. Physiother. Res. Int. 12 (2), 105–114. Pearson, M., Dieberg, G., Smart, N., 2015. Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis. Arch. Phys. Med. Rehab. 96 (7), 1339–1348. https://doi.org/10.1016/j.apmr.2015.02.011. e7. Pilutti, L.A., Hicks, A.L., 2013. Rehabilitation of ambulatory limitations. Phys. Med. Rehab. Clin. N. Am. 24 (2), 277–290. https://doi.org/10.1016/j.pmr.2012.11.008. Pilutti, L.A., Motl, R.W., Edwards, T.A., Wilund, K.R., 2016. Rationale and design of a randomized controlled clinical trial of functional electrical stimulation cycling in persons with severe multiple sclerosis. Contemp. Clin. Trials Commun. 3, 147–152.
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Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability☆ Thomas Edwardsa, Robert W. Motlb, Emerson Sebastiãoc, Lara A. Piluttid,
T
⁎
a
School of Human Kinetics, University of Ottawa, 200 Lees Avenue, Ottawa, ON K1N 6N5, Canada Department of Physical Therapy, University of Alabama at Birmingham, 1705 University Blvd., Birmingham, AL 35233-1212, USA c Department of Kinesiology and Physical Education, Northern Illinois University, 1425 Lincoln Hwy, DeKalb, IL 60115 USA d Interdisciplinary School of Health Sciences, Brain and Mind Research Institute, University of Ottawa, 200 Lees Avenue E250G, Ottawa, ON K1N 6N5, Canada b
A R T I C LE I N FO
A B S T R A C T
Keywords: Multiple sclerosis Exercise training Functional electrical stimulation Adapted-exercise Mobility
Background: Exercise training has been shown to be beneficial for persons with multiple sclerosis (MS). Adapted exercise modalities are needed to accommodate those with severe mobility impairment (Expanded Disability Status Scale [EDSS] scores 5.5–6.5). Functional electrical stimulation (FES) cycling is one such exercise modality; however, few studies have examined the feasibility and potential benefits of FES cycling for people with MS with severe mobility impairment. Objective: Determine the feasibility of FES cycling exercise for people with MS with severe mobility impairment, and the efficacy of FES cycling exercise for improving mobility and physiological fitness. Methods: 11 participants with MS with mobility impairment (EDSS = 5.5–6.5) were randomly allocated to FES cycling exercise (n = 6) or passive leg cycling (PLC; n = 5). Feasibility metrics included participant recruitment, retention, adherence, safety, and satisfaction. The primary mobility outcome was walking speed assessed by the Timed 25-Foot Walk (T25FW) test. The primary physiological fitness outcome was peak oxygen consumption (VO2peak), assessed using a cardiopulmonary exercise test. Results: Eight participants completed the intervention (FES n = 4; PLC n = 4) with an adherence rate ≥80%. Three participants (FES n = 2, PLC n = 1) withdrew due to a lack of time. Six Grade 1 (i.e., mild) adverse events were experienced by participants in the FES group. Participants in the FES cycling condition demonstrated smallto-moderate improvements on T25FW performance (Cohen's d = 0.40; 22.9%) and VO2peak (Cohen's d = 0.34; 13.8%) compared to participants in the PLC condition. Conclusions: We provide evidence that FES cycling exercise is feasible for individuals with MS with severe mobility impairment, and might have positive effects on mobility and physiological decondition. These results will inform the design of future efficacy trials of FES cycling exercise for persons with MS with mobility disability.
1. Introduction Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system characterized by accumulation of progressive neurological impairment (Frohman et al., 2006). Such impairment is
commonly reflected as the loss of mobility, one of the most common and poorly-managed consequences of MS (Larocca, 2011). Mobility impairment increases with disease progression and has negative consequences for employment, participation in everyday activities, and overall quality of life (QOL) (Larocca, 2011). Furthermore, the
Abbreviations: 2MW, 2-minute walk; AE, adverse event; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; EDSS, expanded disability status scale; FES, functional electrical stimulation; FM, fat mass; FFM, fat-free mass; MSM, multiple sclerosis; MSWS-12, Multiple Sclerosis Walking Scale-12; PLC, passive leg cycling; RCT, randomized control trial; T25FW, Timed 25-Foot Walk; TUG, Timed Up-and-Go; VO2peak, peak oxygen consumption; QOL, quality of life; WR, work rate ☆ Disclosure statement: We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated and we certify that all financial and material support for this research and work are clearly identified in the title page of the manuscript. ⁎ Corresponding author. E-mail address: [email protected] (L.A. Pilutti). https://doi.org/10.1016/j.msard.2018.08.020 Received 4 April 2018; Received in revised form 17 August 2018; Accepted 22 August 2018 2211-0348/ © 2018 Elsevier B.V. All rights reserved.
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progression of mobility disability has been associated with substantial socioeconomic costs (Karampampa et al., 2012; Grima, 2000), highlighting the need for therapeutic strategies for managing mobility loss. Mobility disability in MS is further impacted by physiological deconditioning (i.e., reduced physiological fitness) (Sandroff et al., 2013; Sandroff et al., 2015). There is substantial evidence for physiological deconditioning among persons with MS, including reduced cardiorespiratory and muscular fitness, and these measures have been associated with mobility outcomes (Sandroff et al., 2013; Motl and Goldman, 2011; Pilutti et al., 2015). Physiological fitness declines with disease progression in MS, further exacerbating mobility impairment (Pilutti et al., 2015; Motl and Learmonth, 2014). Exercise training is an effective strategy for improving physiological fitness in persons with MS (Platta et al., 2016) and has been reported to improve mobility outcomes (Pearson et al., 2015). Unfortunately, this evidence has primarily been established in people with mild-to-moderate disability, rather than among those with severe mobility impairment, and the greatest need for exercise rehabilitation (Latimer-Cheung et al., 2013a; Edwards and Pilutti, 2017). Traditional exercise modalities have limited the study and application of exercise training for people with MS with mobility disability (Pilutti and Hicks, 2013). One advanced exercise-rehabilitation modality that was originally developed for individuals with spinal cord injury, and may also be beneficial for those with MS is functional electrical stimulation (FES) cycling (Baldi et al., 1998). FES cycling uses mild electrical stimulation delivered though surface electrodes to initiate involuntary muscle contraction. The addition of FES enhances the capacity for muscle recruitment during exercise, and consequently, the potential for physiological and functional adaptations to exercise training. There is support for the application of FES cycling in persons with MS (Ratchford et al., 2010; Reynolds et al., 2015; Backus et al., 2016; Szecsi et al., 2009), but none of the current evidence derives from a randomized controlled trial (RCT) design, potentially limiting the applicability of the findings. We conducted the first pilot, RCT of supervised FES cycling exercise compared with passive leg cycling (PLC) as a placebo-control condition in individuals with MS with severe mobility impairment. The objectives of this study were to: (1) assess the feasibility of 24-weeks of supervised FES cycling exercise based on metrics of participant recruitment, retention, adherence, compliance, safety, and satisfaction; and (2) examine the efficacy of FES cycling exercise for improving mobility and physiological fitness. This pilot trial will provide critical information to design and deliver future efficacy trials of FES cycling exercise in persons with MS with mobility impairment.
Table 1 The demographic and clinical characteristics of participant who completed the FES cycling exercise and PLC interventions. Values are reported as means (SD), unless specified otherwise. Characteristic
Overall (n = 8)
FES (n = 4)
PLC (n = 4)
p-value
Age, y Sex, n Female Male Height, cm Weight, kg BMI, kg/m2 EDSS (mdn, IQR) Disease duration, y MS type, n Relapsing MS Progressive MS
52.9 (7.9)
57.3 (6.0)
48.5 (7.7)
7 1 160.8 (9.1) 78.2 (33.7) 29.7 (10.7) 6.3 (0.5) 21.5 (6.6)
3 1 161.1 (10.4) 70.6 (19.5) 27.2 (7.4) 6.3 (0.5) 22.3 (5.3)
4 0 160.5 (9.2) 85.8 (46.0) 32.1 (13.9) 6.3 (0.9) 20.8(8.5)
4 4
2 2
2 2
0.12 0.29 – – 0.93 0.56 0.56 0.67 0.77 1.0 – –
Anthropometric, clinical, and demographic characteristics were collected for descriptive purposes. 2.2.2. Feasibility Feasibility included metrics of participant recruitment, retention, adherence, compliance, safety, and satisfaction with the intervention. Recruitment and retention were described as the number of participants during each phase of the trial. Adherence was characterized as participants’ attendance at the prescribed exercise sessions, and quantified as the percentage of completed sessions out of a possible 72. Compliance was characterized as participants’ completion of the prescribed exercise at a specified intensity and duration, and was quantified with training variables recorded at each session (i.e., pedaling distance, resistance, work rate, and heart rate). Safety was assessed as adverse events (AEs), which were defined as any unfavorable change in health that occurred during the trial period (Requirements, 2018). Each AE was characterized based on severity (Grade 1 [mild] through 5 [death]), expectedness (expected or unexpected), and potential relation to study participation (not related, possibly related, or study-related) using the National Institutes of Health Terminology and Classification scheme (Chen et al., 2012). Participant satisfaction was assessed using a 7-item feedback questionnaire quantifying the level of satisfaction with various characteristics of the leg-cycling programs (i.e., overall, trainers, equipment, training intensity, and likeliness to recommend to others or to use the cycle at home). Each item was rated on a 5-point scale that ranged from 1 (Not at all) to 5 (Extremely), with higher scores indicating greater satisfaction with the intervention. Feasibility metrics were selected based on recommendations for feasibility trials and previous studies examining the feasibility of exercise training interventions in people with MS (Adamson et al., 2016; Tickle-Degnen, 2013).
2. Methods 2.1. Trial design and participants
2.2.3. Mobility The primary mobility outcome was walking speed, assessed using the Timed 25-Foot Walk (T25FW) test. An average of two walking trials in seconds was calculated and converted to a walking speed in m/s. Walking endurance and agility were assessed with the 2-Minute Walk (2MW)(m) and the Timed Up-and-Go (TUG) tests (sec), respectively. All mobility tests were performed according to standard protocols (Coleman et al., 2012; Goldman et al., 2008; Nilsagard et al., 2007). The 12-item MS Walking Scale (MSWS-12) was used to capture selfreported mobility impairment. The total MSWS-12 score ranges from 0 to 100, where higher scores indicate greater walking impairment (Hobart et al. 2003).
The detailed protocol for this trial has been previously published (Pilutti et al., 2016). The trial design involved a parallel group, assessor-blinded, pilot randomized placebo-controlled trial. Participants were randomly allocated to receive FES cycling exercise or PLC for 24 weeks, using an allocation ratio of 1:1. Reporting of the trial follows the CONSORT guidelines for pilot and feasibility trials (Eldridge et al., 2016). Inclusion criteria for participants have previously been reported (Pilutti et al., 2016). 2.2. Outcome measures 2.2.1. Demographic/clinical characteristics Height and weight were measured in the laboratory using a scale with a stadiometer (Detecto, Webb City, MO). Disability status was confirmed through a clinically-administered EDSS (Ratzker et al., 1997) examination by a Neurostatus-certified assessor. Clinical and demographic characteristics were collected using a self-report questionnaire.
2.2.4. Physiological fitness Physiological fitness was assessed as cardiorespiratory fitness (CRF), muscular strength, and body composition using previously reported protocols in persons with MS (Sandroff et al., 2013; Pilutti et al., 2015; 104
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Fig. 1. CONSORT diagram demonstrating recruitment, allocation, and retention of all participants during each phase of the trial.
Bouchard et al., 1994). CRF was the primary fitness outcome expressed as peak oxygen consumption (VO2peak) from a cardiopulmonary exercise test (CPET) performed on a recumbent stepper (Nustep Inc., Ann Arbor, MI). CRF was further expressed as peak power output (WRpeak). Muscular strength was measured bilaterally using a Biodex System 3 dynamometer (Biodex Medical Systems, Inc, Shirley, NY) and expressed as average peak torque (N m) of the quadriceps (knee extensors) and hamstrings (knee flexors) muscle groups for both limbs. Body
composition was assessed by dual-energy X-ray absorptiometry (DXA) using a Hologic QDR 4500A bone densitometer (Hologic, Bedford, MA). Regional leg fat-free mass (FFM), fat mass (FM), % fat, and bone mineral density (BMD) were measured and expressed as totals (FFM; FM) or averages (% fat, BMD) of both limbs.
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Fig. 2. Weekly training means for cycling: (A) distance; (B) resistance; (C) power output; and (D) heart rate for the FES cycling exercise and PLC conditions across the 24-week intervention.
Table 2 7-item participant-feedback questionnaire used to determine level of satisfaction with the interventions. Values are presented as mean (SD). Cohen's d represents the difference between groups over time. Item
FES
1. 2. 3. 4. 5. 6. 7.
5.0 5.0 4.8 3.5 4.8 4.8 4.3
Overall satisfaction with leg cycling program (range = 1–5) Satisfaction with program trainers (range = 1–5) Satisfaction with leg cycling equipment (range = 1–5) Level of challenge of leg cycling program (range = 1–5) Satisfaction with leg cycling program (compared to other exercise programs) (range = 1–5) Likeliness to recommend leg cycling program to others with MS (range = 1–5) Likeliness of using leg cycling equipment in own home (range = 1–5)
(0.0) (0.0) (0.5) (0.6) (0.5) (0.5) (1.5)
PLC
Cohen's d
4.0 4.6 4.0 2.2 3.6 4.6 4.2
1.08 0.86 1.08 1.12 2.32 0.18 0.13
(1.0) (0.5) (0.7) (1.1) (1.1) (0.5) (0.8)
3. Intervention
4. Protocol
The FES cycling exercise and PLC conditions were delivered using RT300 cycles (Restorative Therapies Inc, Baltimore, MD) and the specific training parameters have been reported (Pilutti et al., 2016). Cycling duration and cadence (∼50 rpm) were matched between groups. Participants in the FES cycling exercise group received mild electrical stimulation while actively pedaling with the goal of maintaining the prescribed cadence and intensity based on target HR (Pilutti et al., 2016). The training intensity and progression was based on guidelines from the American College of Sports Medicine and MS-specific Physical Activity guidelines (American College of Sports Medicine 2013; Latimer-Cheung et al., 2013b). The PLC condition (i.e., placebo-control) did not receive electrical stimulation and did not actively pedal during the sessions. The PLC condition was identical to the FES cycling condition, without the active agent of increased energy expenditure that would be expected to drive adaptations in mobility and physiological fitness.
All procedures were approved by the University Institutional Review Board at the University of Illinois (#15426), UrbanaChampaign, and participants provided written informed consent prior to data collection. Screening for inclusion was first conducted over the telephone (Bredin et al., 2013; Kurtzke, 1983). Verification of MS diagnosis and approval for participation was confirmed by the eligible participants’ physician. Eligible participants were invited to the laboratory to complete the informed consent process and baseline testing. Participants were then randomized into one of the trial conditions by RWM who was uninvolved with the collection of outcomes or delivery of the intervention. All participants were prescribed three weekly supervised sessions for 24-weeks. Training variables were recorded at each session including HR (Polar Electro Oy, Kempele, Finland), ratings of perceived exertion (RPE), (Borg, 1982) distance peddled, power output (WR), and cycling resistance. The same testing protocol as 106
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Fig. 3. Mean change in: (A) T25FW; (B) TUG; (C) 2MW; and (D) MSWS-12 scores for the FES cycling and PLC conditions from baseline to 24 weeks. Error bars denote standard error of the mean (SEM).
p > 0.05) between the groups on any demographic or clinical variables at baseline.
baseline was administered at 24 weeks by treatment-blinded assessors. 5. Data analysis
6.2. Feasibility Data analysis was performed using SPSS statistics Version 24.0 (IBM Corp., Armonk, NY). Descriptive statistics were used to summarize the demographic, clinical, and feasibility metrics. Baseline characteristics were compared between groups using independent samples t-tests and chi-square tests. Based on the sample size and goal of the pilot trial to inform future work, the efficacy of the intervention (i.e., the difference between the groups over time) was determined using effect sizes (ES) expressed as Cohen's d, with calculated 95% confidence intervals (Durlak, 2009; Lee, 2016). ESs were interpreted as small, moderate, and large based on criteria of 0.2, 0.5, and 0.8, respectively (Cohen, 1988). Mean absolute differences and mean percent changes between groups over time were also calculated for comparative purposes with previous research. Lastly, exploratory Spearman's rank-order correlations (ρ) were performed for examining the relationship between change in mobility and change in physiological fitness in response to the intervention. The statistical significance level was adjusted for multiple comparisons (p < 0.006). Correlation coefficients of 0.1, 0.3, and 0.5 were interpreted as small, moderate, and large, respectively (Cohen, 1988).
Fig. 1 presents the flow of participants through the trial. Eleven participants were recruited (29% of eligible participants) and eight participants (FES n = 4; PLC n = 4) completed the trial (67% and 80% retention, respectively). Average adherence for the FES cycling exercise and PLC conditions were 84.2% and 83.7%, respectively. Training variables used to describe exercise compliance are presented in Fig. 2. Across 24 weeks, participants in the FES cycling group demonstrated a gradual increase in cycling distance (mean Δ = 8.7 km), resistance (mean Δ = 1.08 N m), and power output (mean Δ = 5.3 W). Participants in the PLC group also demonstrated a gradual increase in cycling distance (mean Δ = 9.8 km), but no change in resistance or power output. Regarding trial safety, seven (six Grade 1; one Grade 2) AEs were reported in the FES cycling group. The Grade 1 (i.e., mild) AEs reported included: skin irritation/redness (n = 3; expected; study-related); nondebilitating fatigue (n = 2; expected; possibly related); and increased muscle spasticity (n = 1; expected; possibly related). The Grade 2 (i.e., moderate) AE involved a fall that required stiches and occurred outside of the training setting (unexpected; not related). No adverse events were reported by participants in the PLC group. Participant satisfaction measured with the feedback survey is reported in Table 2. Participants in the FES cycling group reported greater levels of satisfaction with various aspects of the intervention compared to PLC (d’s = 0.86–2.32). Participants in the FES cycling group reported that this condition was more challenging than PLC (d = 1.12). Both groups indicated strong
6. Results 6.1. Demographics/clinical characteristics The clinical and demographic characteristics of all participants are presented in Table 1. There were no significant differences (all 107
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Fig. 4. Mean change in: (A) VO2peak; (B) WR; (C) knee extensor strength; and (D) knee flexor strength for the FES cycling and PLC conditions from baseline to 24 weeks. Error bars denote standard error of the mean (SEM).
compared to the PLC group. Both conditions demonstrated a decrease in knee flexor strength after the intervention, and there was no difference in the change between groups over time (3.6%; d = −0.07; 95% CI = −1.5, 1.3). There was no difference between groups in leg FFM, FM, or % fat after the intervention (5.2%; d = 0.18; 95% CI = −1.2, 1.6/ 0.7%; d = 0.00; 95% CI = −1.4, 1.4/4.4%; d = −0.16; 95% CI = −1.5, 1.2, respectively). When examining leg BMD, participants in the FES group demonstrated a moderate increase of 0.08 g/cm2 compared to participants in the PLC group (7.5%; d = 0.57; 95% CI = −0.8, 2.0).
endorsement of recommending this program to others, with no difference between condition (d = 0.18), and would use the leg cycling equipment in a home-based setting (d = 0.09). 6.3. Mobility Change in mobility for the FES cycling exercise and PLC conditions are presented in Fig. 3. When examining walking speed (T25FW), participants in the FES cycling group demonstrated a small improvement of 0.15 m/s (22.9%; d = 0.40; 95% CI = −1.0, 1.8) compared to those who completed PLC. With respect to agility (TUG), participants in the FES cycling group demonstrated a small improvement of 8.4 s (27.6%; d = −0.30; 95% CI = −1.7, 1.1) compared to PLC. Participants in the FES cycling group demonstrated a small improvement in walking endurance (2MW) of 27.0 m (11.7%; d = 0.20; 95% CI = −1.2, 1.6), compared to PLC. Additionally, participants in the FES group reported a moderate decrease of 13.5-points (i.e., improvement) in MSWS-12 scores (−15.8%; d = −0.68; 95% CI = −1.1, 1.7) compared to the PLC group.
6.5. Correlations between mobility and physiological fitness Exploratory correlations between changes in physiological fitness and mobility in response to the intervention for all participants are reported in Table 3. We focus on correlations between T25FW and fitness, as this was the primary mobility outcome. Large correlations were observed between change in T25FW and change in CRF (VO2peak, WRpeak; ρ = 0.62–0.69), and leg FM (ρ = −0.69). Moderate correlations were observed between change in T25FW and change in knee extensor strength (ρ = 0.31). None of these correlations were statistically significant.
6.4. Physiological fitness Change in physiological fitness for the FES cycling exercise and PLC groups are presented in Figs. 4 and 5. Participants in the FES cycling group demonstrated a small improvement of 2.20 ml/kg/min in VO2peak (13.8%; d = 0.34; 95% CI = −1.1, 1.7) compared to the PLC group after the intervention. Regarding WRpeak, participants in the FES cycling group demonstrated a moderate improvement of 8.8 W (15.3%; d = 0.65; 95% CI = −0.8, 2.1) compared to the PLC group. When examining knee extensor strength, the FES group demonstrated a moderate improvement of 21.0 N m (22.7%; d = 0.56; 95% CI = −0.9, 2.0)
7. Discussion We report the first rigorously designed, pilot RCT of FES cycling exercise in people with MS with severe mobility impairment. We determined that FES cycling exercise is a feasible modality that caused few, mild AEs in this population. Additionally, we provide preliminary data for the potential benefits of FES cycling exercise for maintaining or possibly improving mobility and physiological fitness. 108
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Fig. 5. Mean change in: (A) leg FM; (B) leg FFM; (C) percentage of leg fat; and (D) leg BMD for the FES cycling and PLC conditions from baseline to 24 weeks. Error bars denote standard error of the mean (SEM).
FES cycling trial of a similar duration, where participants experienced increased muscle spasticity and bowel incontinence (Ratchford et al., 2010). All Grade 1 AEs reported in the current trial were alleviated within days, and had no impact on participants’ daily routines. Importantly, all related AEs were experienced within the first 2 weeks of the intervention, which was likely a reaction to unfamiliar stimuli (excise and stimulation) (Pilutti et al., 2014). The feasibility metrics reported herein will be beneficial for informing future trials on expected responses to this FES cycling prescription and informing future participants about risks associated with FES cycling exercise.
Table 3 Exploratory Spearman's correlation coefficients between change in mobility and change physiological fitness outcomes in response to the intervention in the overall sample (n = 8). Variable
Δ T25FW (m/sc)
Δ 2MW Δ TUG Δ MSWS-12
Δ VO2peak (ml/kg/min) Δ WRpeak (W) Δ Knee extensor peak force (N m) Δ Knee flexor peak force (N m) Δ Leg FFM, kg Δ Leg FM, kg Δ Leg fat, % Δ Leg BMD, g/cm2
0.69 0.62 0.31 −0.26 0.05 −0.69 −0.36 0.05
(m) 0.21 0.46 0.67 −0.14 0.52 −0.26 −0.45 −0.05
(sec) −0.50 −0.46 −0.07 −0.26 −0.17 0.43 0.24 −0.43
−0.82 −0.50 −0.31 0.43 0.00 0.39 0.15 0.22
7.2. Treatment efficacy The T25FW has been described as the best characterized objective measure of mobility for individuals with MS, and performance on this test is strongly correlated with other functional outcomes (Motl et al., 2017). The generally accepted minimal clinically important difference (MCID) on the T25FW test is a 20% change (Coleman et al., 2012). Participants in the FES cycling group demonstrated a 22.9% improvement on the T25FW compared to the PLC group over time, suggesting that FES cycling exercise can result in clinically meaningful changes in walking. The FES cycling group demonstrated improvements on other objective and patient-reported measures of mobility (TUG, 2MW, and MSWS-12), suggesting a comprehensive mobility effects of FES cycling exercise. The FES cycling exercise group demonstrated a 13.8% improvement in VO2peak compared to the PLC group over time, exceeding the threshold value of a 10% change that has been described as clinically relevant (Langeskov-Christensen et al., 2014). Participants in the FES cycling group also demonstrated substantial improvements in WRpeak, further supporting improvements in CRF. This improvement in CRF is likely a result of habitual moderate-to-vigorous physical activity
7.1. Feasibility In the current trial, we report an overall dropout rate of ∼27%, which is comparable to other studies (13−33%) of FES cycling in individuals with MS with severe mobility impairment (Ratchford et al., 2010; Backus et al., 2016; Szecsi et al., 2009). Few studies have reported on adherence with specialized exercise modalities in this population. The overall adherence rate of ∼84% observed in this trial is comparable to another study (∼89%) involving recumbent stepper exercise and body-weight supported treadmill walking in persons with progressive MS with mobility disability (EDSS = 6.0–8.0) (Pilutti et al., 2016). The high adherence rate observed in this trial might reflect the high level of participant satisfaction, as reported on the feedback survey. Participants in the current study reported mild skin irritation, muscle spasticity, and fatigue with FES cycling exercise. The frequency and severity of these AEs are comparable to those reported in another 109
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for the feasibility of FES cycling for people with MS with severe mobility impairment, and provide direction as to which outcomes are most responsive to the FES cycling exercise protocol. These data should be used to inform future, large-scale RCTs with the purpose of establishing treatment efficacy of FES cycling exercise in persons with MS with severe mobility impairment.
(MVPA). Indeed, it has been reported that an acute session of FES cycling exercise elicits a cardiorespiratory response that is consistent with MVPA, and therefore, can be expected to improve CRF with training (Edwards et al., 2018). Importantly, CRF is considered an important indicator of health status and low CRF has been associated with increased risk for morbidity and mortality for both clinical and nonclinical populations (Wei et al., 1999). FES cycling exercise appears to be an efficacious method for maintaining and possibly improving CRF for individuals with MS with severe mobility impairment. This is particularly important given the low fitness levels reported in this population (Pilutti et al., 2015). The large increase in knee extensor strength observed in the FES cycling group may be attributed to the added stimulation delivered during FES cycling exercise. The supplemental stimulation allows greater motor-unit recruitment, muscle mass involvement, and force production (Fornusek and Hoang, 2014). This added stimulation theoretically increases active muscle mass during exercise and potential for adaptations. Indeed, it has been reported that individuals with MS have impaired muscular strength and motor-unit recruitment compared to healthy controls (Ng et al., 2004). Such impairments may be overcome with combined external neuromuscular stimulation and leg cycling exercise (Reynolds et al., 2015). Interestingly, both groups demonstrated a decline in knee flexor strength. This may be attributed to the biomechanics of leg cycling, which relies heavily on knee extensor engagement and less on knee flexor engagement (Bini and Diefenthaeler, 2010; Ambrosini et al., 2016). A different exercise stimulus might be required to target knee flexor strength in order to improve overall lower limb strength in persons with MS with severe mobility impairment. Lastly, higher leg BMD in the FES group likely reflects increased bone loading with external neuromuscular stimulation and contraction of lower extremity muscle groups involved in leg cycling. It is realistic to expect that improvements in physiological fitness might be responsible, in part, for observed improvements in mobility. Moderate-to-strong (although non-significant), associations were observed between changes in T25FW performance and changes in CRF and knee extensor strength, such that T25FW performance increased with increasing physiological fitness. Such relationships between physiological fitness and walking performance have been previously reported in individuals with MS (Sandroff et al., 2015). Indeed, the FES cycling exercise group demonstrated an improvement/maintenance of many fitness outcomes, which may have translated into improved mobility. In contrast, the PLC group demonstrated a decline in walking performance, potentially due to physiological deconditioning over this same period.
Acknowledgments This study was supported, in part, by the National Multiple Sclerosis Society [PR-1411-0209], the Consortium of Multiple Sclerosis Centers, and the Multiple Sclerosis Society of Canada [2665]. References Adamson, B.C., Learmonth, Y.C., Kinnett-Hopkins, D., Bohri, M., Motl, R.W., 2016. Feasibility study design and methods for project GEMS: guidelines for exercise in multiple sclerosis. Contemp. Clin. Trials 47, 32–39. https://doi.org/10.1016/j.cct. 2015.12.002. Ambrosini, E., De Marchis, C., Pedrocchi, A., et al., 2016. Neuro-mechanics of recumbent leg cycling in post-acute stroke patients. Ann. Biomed. Eng. 44 (11), 3238–3251. https://doi.org/10.1007/s10439-016-1660-0. American College of Sports Medicine, 2013. ACSM's Guidelines for Exercise Testing and Prescription, ninth ed. LWW, Philadelphia. Backus, D., Burdett, B., Hawkins, L., Manella, C., McCully, K.K., Sweatman, M., 2016. Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory. Int. J. MS Care 19 (3), 113–121. https:// doi.org/10.7224/1537-2073.2015-036. Baldi, J.C., Jackson, R.D., Moraille, R., Mysiw, W.J., 1998. Muscle atrophy is prevented in patients with acute spinal cord injury using functional electrical stimulation. Spinal Cord 36 (7), 463–469. Bini, R.R., Diefenthaeler, F., 2010. Kinetics and kinematics analysis of incremental cycling to exhaustion. Sports Biomech. 9 (4), 223–235. https://doi.org/10.1080/14763141. 2010.540672. Borg, G, 1982. Psychophysical bases of perceived exertion. - PubMed - NCBI. Med. Sci. Sports Exerc. 14 (5), 377–381. Bouchard, C., Shephard, R.J., Stephens, T., 1994. Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement xxiv Human Kinetics Publishers, Champaign, IL, England. Bredin, S.S.D., Gledhill, N., Jamnik, V.K., Warburton, D.E.R., 2013. PAR-Q+ and ePARmed-X+ New risk stratification and physical activity clearance strategy for physicians and patients alike. Can. Fam. Physician 59 (3), 273–277. Chen, A.P., Setser, A., Anadkat, M.J., et al., 2012. Grading dermatologic adverse events of cancer treatments: the common terminology criteria for adverse events version 4.0. J. Am. Acad. Dermatol. 67 (5), 1025–1039. https://doi.org/10.1016/j.jaad.2012.02. 010. Cohen, J., 1988. Statistical Power Analysis for the Behavioral Sciences, second ed. L. Erlbaum Associates, Hillsdale, NJ. Coleman, C.I., Sobieraj, D.M., Marinucci, L.N., 2012. Minimally important clinical difference of the timed 25-foot walk test: results from a randomized controlled trial in patients with multiple sclerosis. Curr. Med. Res. Opin. 28 (1), 49–56. https://doi.org/ 10.1185/03007995.2011.639752. Durlak, J.A., 2009. How to select, calculate, and interpret effect sizes. J. Pediatr. Psychol. 34 (9), 917–928. https://doi.org/10.1093/jpepsy/jsp004. Edwards, T., Motl, R.W., Pilutti, L.A., 2018. Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment. Appl. Physiol. Nutr. Metab. 43 (1), 71–76. https:// doi.org/10.1139/apnm-2017-0397. Edwards, T., Pilutti, L.A., 2017. The effect of exercise training in adults with multiple sclerosis with severe mobility disability: a systematic review and future research directions. Mult. Scler. Relat. Disord. 16, 31–39. https://doi.org/10.1016/j.msard. 2017.06.003. Eldridge, S.M., Chan, C.L., Campbell, M.J., et al., 2016. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2, 64. https:// doi.org/10.1186/s40814-016-0105-8. Fornusek, C., Hoang, P., 2014. Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis. J. Rehab. Med. 46 (7), 698–702. https:// doi.org/10.2340/16501977-1792. Frohman, E.M., Racke, M.K., Raine, C.S., 2006. Multiple sclerosis — the plaque and its pathogenesis. N. Engl. J. Med. 354 (9), 942–955. https://doi.org/10.1056/ NEJMra052130. Goldman, M.D., Marrie, R.A., Cohen, J.A., 2008. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult. Scler. 14 (3), 383–390. https:// doi.org/10.1177/1352458507082607. Grima, D.T., Torrance, G.W., Francis, G., Rice, G., Rosner, A.J., Lafortune, L., 2000. Cost and health related quality of life consequences of multiple sclerosis. Mult. Scler. J. 6 (2), 91–98. https://doi.org/10.1177/135245850000600207. Hobart, J.C., Riazi, A., Lamping, D.L., Fitzpatrick, R., Thompson, A.J., 2003. Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology 60 (1), 31–36. https://doi.org/10.1212/WNL.60.1.31. Karampampa, K., Gustavsson, A., Miltenburger, C., Kindundu, C.M., Selchen, D.H., 2012.
8. Limitations and future direction The primary limitation of this study is the small sample size, which may limit the generalizability of the findings. This study reported on a limited number of outcomes and may not have captured all aspects of feasibility. Future research would benefit from testing the lasting effects of this intervention, and the feasibility and efficacy of this training outside of a supervised exercise setting. This study also included a very specific population of individuals with MS (EDSS = 5.5–6.5); therefore, these results may be limited to MS samples with similar characteristics. Another aspect that should be investigated in future studies is the specific exercise prescription and FES cycling parameters, for optimizing the training response and maximizing the potential benefits. 9. Conclusions We report that FES cycling exercise is feasible for individuals with MS with severe impairment, and provide ESs for mobility and physiological fitness outcomes that can be used for informing future trials. These results build on previous research by providing further support 110
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