Physical therapy

A. Manca, PhD, PT, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

G. Martinez, BSc, PT, Department of Biomedical Sciences, University of Sassari.

E. Aiello, MD, Department of Medical, Surgical and Experimental Sciences, University of Sassari.

L. Ventura, MSc, PT, Department of Biomedical Sciences, University of Sassari.

F. Deriu, MD, PhD, Department of Biomedical Sciences, University of Sassari, Viale S. Pietro 43/b, 07100 Sassari, Italy. Address all correspondence to Dr Deriu at: [email protected].

[Manca A, Martinez G, Aiello E, Ventura L, Deriu F. Effect of eccentric strength training on elbow flexor spasticity and muscle weakness in people with multiple sclerosis: proof-of-concept single-system case series. Phys Ther. 2020;100:1142–1152.]

© 2020 American Physical Therapy Association

Published Ahead of Print: April 7, 2020

Accepted: December 20, 2019 Submitted: June 9, 2019

Post a comment for this article at: https://academic.oup.com/ptj

Original Research Effect of Eccentric Strength Training on Elbow Flexor Spasticity and Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Single-System Case Series Andrea Manca, Gianluca Martinez, Elena Aiello, Lucia Ventura, Franca Deriu

Objective. To date, no attention has been devoted to the employment of eccentric contractions to manage spasticity in multiple sclerosis. This single-system case series aimed to explore the effects of eccentric training on spasticity-related resistance to passive motion in people with multiple sclerosis with elbow flexor spasticity.

Methods. Six people with multiple sclerosis (median Expanded Disability Status Scale score = 4.8, range = 2.0–5.5; Modified Ashworth Scale [MAS] score ≤ 3) underwent a 6-week eccentric strength training of the spastic muscles. Before and after the intervention, the following outcomes were assessed: resistive peak torque (RPT), isometric strength, resting limb position, passive range of motion and active range of motion, severity of hypertonia by MAS, and numerical rating scale. At baseline, the primary outcome (RPT) was tested over 3 time points to ensure a stable measurement. The 2-SD method was used to test pre-post training effects at individual level. Group-level analyses were also performed.

Results. Following the intervention RPT decreased by at least 2 SDs in all participants but 1, with a significant reduction at group level of 41.6 (29.6)%. Four people with multiple sclerosis reported a reduction in perceived spasticity severity. No changes in MAS score were detected. Group-level analyses revealed that maximal strength increased significantly in the trained elbow flexors (+30.9 [9.1]%). Elbow flexion at rest was found to be significantly reduced (−35.5 [12.4]%), whereas passive range of motion (+4.6%) and active range of motion (+11.8%) significantly increased.

Conclusion. Eccentric training is feasible and safe to manage spasticity in people with multiple sclerosis. Preliminary data showed that this protocol can reduce resistance to passive motion, also improving strength, spasticity-free range of motion, and limb positioning.

Impact. Patients with multiple sclerosis–related spasticity and moderate-to-severe dis- ability can benefit from adding slow submaximal eccentric contractions to the conventional management of spasticity.

1142 Physical Therapy Volume 100 Number 7 2020

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

I t is estimated that 60% to 90% of people with multiplesclerosis experience spasticity,1 a debilitating symptomusually associated with weakness, spasms, and pain. Spasticity negatively impacts a person’s participation in family, work, and social life and, consequently, quality of life.2 Moreover, patients with spasticity display tissue alterations, including contractures and connective changes in muscles, tendons, and joints, which can further impair limb positioning, movement, and function.3

Beyond pharmacological treatments, for which only short-term effectiveness is established, several nonpharmacological interventions are also used, such as physical modalities and structured exercise programs. A Cochrane Database review found “low-level” evidence of beneficial effects for exercise-based approaches given alone or in conjunction with physical modalities.4 In regard to rehabilitation programs, to our knowledge, no attention has so far been devoted to the employment of eccentric contractions (ie, the motion of an active muscle while it is lengthening under load)5 to specifically manage spasticity in multiple sclerosis.

Compared with other training regimens, eccentric contractions have been extensively reported in healthy populations to induce the highest gains in maximal force generation and muscle capability to maintain force over the range of motion.6 ,7 Additionally, these effects are obtained at a reduced energy cost, which is of critical importance to people with multiple sclerosis, who exhibit muscle weakness and low reserves of energy and are exposed to early-onset fatigue.8 In addition, lengthening eccentric actions can lead to a better positioning of the affected limb and can reduce the spasticity-associated active and passive muscular insufficiencies in the spastic muscle and in its nonspastic agonist, respectively, which prevent multijoint muscles from achieving the optimal production of strength.9 Overall, these properties were shown to have therapeutic implications in orthopedic conditions, especially for tendon disorders,5 and in neurological conditions characterized by muscle weakness and spasticity-induced contractures. In particular, eccentric protocols were found to increase strength without exacerbating spasticity in children and adolescents with cerebral palsy10 and in stroke survivors.11

In people with multiple sclerosis, eccentric contractions have been previously employed to manage lower limb muscle weakness, with controversial findings ranging from significant increases in strength12 to no additional effect when eccentric training was added to standard concentric exercise.13 These studies, however, only employed lengthening contractions to manage muscle weakness and, to the best of our knowledge, no studies have so far investigated whether an eccentric training protocol can reduce spastic hypertonia.

Based on the above rationale, the primary hypothesis of this study was that the employment of a program of

eccentric training of the spastic elbow flexor muscles would: (1) prove feasible and safe in people with multiple sclerosis; (2) reduce resistance to passive motion; (3) increase the spasticity-free range of motion (ROM), and (4) improve muscle strength of the spastic elbow flexors. Therefore, this study proposed to explore in people with multiple sclerosis with focal limb spasticity the effects of eccentric training of the spastic muscle(s) on their objective and subjective resistance to passive motion as well as muscle weakness, active/passive ROM, and resting limb positioning.

Methods Participants A convenience sample of 6 people with multiple sclerosis with a moderate-to-severe degree of spasticity was selected within the framework of a larger randomized controlled trial (NCT02010398) for which a degree of spasticity equal to or greater than moderate was set as exclusion criterion. The study was conducted according to the Declaration of Helsinki and approved by the institutional Bioethics Committee of the Local Health Authority (ASL n.1-Sassari, Italy; Prot. number 2420/CE 2016). Participants were given an informative note regarding all the modalities and timing of the study and were required to sign an informed consent form before enrollment. All data are stored and protected at the Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

Inclusion criteria were: (1) definite diagnosis of multiple sclerosis according to 2017 revision of diagnostic criteria14; (2) Expanded Disability Status Scale (EDSS) score less than or equal to 6.5 with a Pyramidal Functional System score of 2 to 4; (3) unilateral spasticity of the upper limb shown by excessive flexor or extensor muscle tone score less than or equal to 3 as measured by the Modified Ashworth Scale (MAS); (4) compliance with the study instructions; and (5) age greater than 18 years.

Criteria for exclusion or discontinuation were: (1) any medical condition contraindicating participation in resistance training exercises; (2) disability and comorbidities caused by medical conditions other than multiple sclerosis; (3) fixed contracture or relevant atrophy in the affected limb; (4) previous or current treatment with any botulin toxin serotype, or phenol, or cannabinoids, or surgery in the previous 6 months; (5) current casting for spasticity of the limb of interest; (6) occurrence of relapses or variations in disease-modifying drugs or symptomatic treatment within 6 months prior to recruitment; (7) major depression (assessed with Beck Depression Inventory scale, cutoff for exclusion ≥ 28); (8) clinically relevant cognitive deficits (assessed with Frontal Assessment Battery scale, cutoff for exclusion ≥ 14; and with the Trail Making Test A and B, cutoffs for exclusion Trail Making Test A ≥ 78 seconds and Trail Making Test B

2020 Volume 100 Number 7 Physical Therapy 1143

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

Figure 1. Time line of the study. PRE: baseline assessments (phase A of the AB design) with test-retest procedures consisting of 3 bilateral measurements (test, 1-day and 1-week retests) of the resistance to passive mobilization (isokinetic resistive spastic moment, primary outcome) from the spastic and nonspastic limbs; in this phase, baseline measures of dynamometric and clinical-functional outcomes were also performed (secondary outcomes). Intervention: 6-week eccentric training of the spastic elbow flexors (phase B of the AB design). Each arrow indicates 1 training session (total sessions = 18). Post: posttraining test-retest of the primary outcome and posttraining test of secondary outcomes.

≥ 273 seconds); and (9) participation in rehabilitative or training programs in the previous 6 months.

Participants deemed eligible underwent clinical and dynamometric assessments within 1 week. Participants were asked to refrain from any other exercise activity for the entire duration of the study.

Design A single-system case series study was chosen because it is acknowledged as an appropriate methodology to observe changes in a participant’s performance over time, providing clinically relevant information about individuals.15 ,16 The study design was implemented by carrying out multiple pretests at baseline to control for the familiarization/learning effect, which is frequently associated with strength testing protocols,17 and to control for the high variability in muscle performance observed in people with multiple sclerosis.8 ,18 Multiple baseline assessments were also performed to establish the reliability of the measurements.

A series of 6 case studies was completed employing a pretest-posttest design.19 It is also known as AB design, where A represents the multiple baseline assessments, and B refers to the intervention phase followed by the postintervention assessment. The timeline of the study is detailed in Figure 1.

Baseline Assessments Dynamometric assessments. All dynamometric tests were performed using an isokinetic device (Kinetic Communicator; KinCom, Chattanooga, TN, USA). The test

was carried out in the affected limb first. The unaffected side was also assessed for intraparticipant comparisons. The participant was asked to sit on the dynamometer seat, positioned according to the joint and muscle group under test, and stabilized using custom straps and harnesses. The axis of rotation was aligned with the center of rotation of the elbow joint.

Resistance to motor-driven passive mobilization. The isokinetic resistive peak torque (RPT) was set as the primary outcome of the study because it allows quantification of the amount of resistance opposed by the spastic muscle group to passive movement.20 ,21 In the affected side, RPTs were measured during passive elbow extensions to quantify passive resistance to limb movement opposed by the flexor muscles. The participant’s elbow joint was mobilized at increasing angular velocities (from 5 to 240◦/s), according to the participant’s comfort and tolerability. In particular, for angular speeds greater than 180◦/s the flexibility, rigidity, and self-reported perception of discomfort were carefully checked for each participant. During the procedure to measure the RPTs, participants were instructed to relax while the dynamometer was moving the limb throughout the predefined comfortable ROM, which was kept constant from baseline to postintervention assessments to ensure consistency and comparability. Passive torques obtained throughout the full ROM at the angular speed of 5◦/s were used to correct for the effects of gravity and limb weight and to detect the amount of stiffness from the soft tissues, which detracts from the actual torque produced by the flexor muscles.22 ,23 The lowest angular velocity found to elicit the spastic reflex was used for pre-post comparisons in RPT.

1144 Physical Therapy Volume 100 Number 7 2020

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

Given the high variability in neuromuscular performance observed in people with multiple sclerosis,8 the RPT was measured over 3 time points by means of test-retest procedures (test; 1-day retest; 1-week retest) for reliability purposes, to obtain a stable baseline, avoid potential effects of residual fatigue or muscle soreness, and minimize the presence of ongoing performance-based gains, which can reduce the ability to track the real changes from baseline following the intervention. Of the RPTs recorded over the 3 sessions, the highest was retained for analysis as the baseline value. Offline data analyses were then conducted to establish the RPT for each participant, which was obtained as the difference between the torque recorded from the unaffected and from the spastic elbow flexors.

Maximal strength. Maximal voluntary isometric contractions from the affected and unaffected elbow flexor muscles were measured at the optimal muscle length (intermediate ROM). Three trials, each lasting approximately 5 seconds, were collected. Each trial was followed by a 1-minute rest period.

Electrogoniometric assessments. The resting limb position and passive and active ROM were measured by electrogoniometry (DataLog Twin Axis, Biometrics Ltd, Newport, United Kingdom).

Clinical assessments. These included: (1) the severity of spastic hypertonia, as assessed by the clinician-reported MAS24; and (2) the variations in patient-reported perception of spasticity burden in the trained muscles, as assessed by the numerical rating scale (NRS), with a score from 0 (“no interference of spasticity”) to 10 (“unable to move the spastic joint”).

Intervention In general, throughout the training period special attention was devoted to the monitoring of the delayed onset of muscular soreness, which has been associated with eccentric contractions, although levels of soreness diminish with repeated bouts of eccentric exercise because muscle remodeling increases the muscle length.25

Participant-reported delayed muscular soreness relating to a training session was estimated via NRS at the beginning of the following session. The eccentric intervention was performed on the same isokinetic device employed for the dynamometric assessments. People with multiple sclerosis underwent a 6-week eccentric training program targeting the spastic elbow flexors. Each participant was provided with an individually adapted eccentric training regimen tailored according to the strength level recorded at baseline. Participants were required to actively resist (ie, “brake”) with the spastic muscles the forced elbow extension driven by the isokinetic device, which was preset to move at a slow angular velocity (30◦/s). The workload was adjusted to match 70% of the maximum

level of strength recorded at baseline. The training schedule consisted of 3 training sessions per week, each session consisting of 6 to 8 sets of 6 to 10 repetitions (increased on a weekly basis), with a complete recovery of 3 minutes between sets. The training schedule was planned and developed by 1 of the authors, a clinical exercise physiologist and physical therapist with a specific background in testing and training procedures for populations with neurological conditions. Each session was supervised in a 1:1 ratio by a physical therapist with a 5-year expertise with people with multiple sclerosis.

Postintervention Assessments Postintervention assessments of the primary and secondary outcomes were performed within 1 week from the end of the training (Fig. 1).

Statistical Analysis Data analysis was performed using the SPSS software for Windows, version 18.0 (SPSS Inc, Chicago, IL, USA). The assessment of measurements’ consistency was performed to determine the reliability of the primary outcome, the RPT, which has been previously reported as highly variable.21 ,23 According to Lexell and Downham,26

test-retest reproducibility was estimated by calculating the consistency of the RPT measurements at baseline. The intraclass correlation coefficient (ICC) was calculated over 3 time points using a 2-way random ICC2,1 for average measures. The ICC coefficients were calculated taking a value of less than 0.4 as an index of poor reliability, 0.4 to 0.75 as fair to good reliability, and greater than 0.75 as excellent reliability.27 ICC determination also established the responsiveness of the changes from baseline. Accordingly, the standard error of measurement (SEm) was also calculated using the formula: SEm = SD√(1 − ICC).28 Based on the SEm, the smallest real difference at the individual level (SRDi)26 was calculated using the following formula:29 SRDi = 2.77 SEm√2.

To assess the individual-level effects of the eccentric training, the 2-SD band method was employed to quantify the amount of change in RPT from baseline.19 A 2-SD band method was calculated for each participant based on the baseline measurements of RPT over 3 time points.

Even though the design of this study was set as single-system, changes from baseline in the amount of resistance to passive motion following the intervention were also analyzed at the group level by running 2-tailed paired t tests for continuous data expressed as mean (SD) (RPT, maximal strength, resting limb position, active ROM, passive ROM), or the nonparametric Wilcoxon signed-rank test for ordinal data (MAS and NRS scores), with significance set at P < .05.

2020 Volume 100 Number 7 Physical Therapy 1145

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

Table 1. Demographic and Clinical Features of the Participants at the Study Entrya

Participants Variable

1 2 3 4 5 6

Age, y 55 38 30 54 29 35

Disease, y 12 13 11 13 14 10

EDSS 4.5 5.0 4.5 5.0 2.0 5.0

MAS 1+ 2 2 1+ 1 1 Walking aids None None None None Walking stick AFO

aAFO = ankle foot orthosis; EDSS = Expanded Disability System Status; MAS = Modified Ashworth Scale.

Role of the Funding Source Fondazione Italiana Sclerosi Multipla (FISM 2018/R/9) and a grant for Multiple Sclerosis Innovation (GMSI 2018) supported this work. The funders played no role in the design, conduct, or reporting of this study.

Results All the participants (6 women; 40.2 [11.6] years old; mean weight: 60.4 [12.3] kg) had a definite diagnosis of relapsing remitting multiple sclerosis with a mean disease duration of 12.2 [1.5] years. They had moderate to severe disability (median EDSS: 4.8; range 2–5.5), normal cognitive functions, and depression ranging from minimal to mild, with the exception of participant #5, who exhibited a Beck Depression Inventory score of 22 (moderate to severe depression). All participants were receiving antispastic pharmacological treatment (baclofen orally) throughout the entire duration of the study, during which no relapses or changes in medications occurred. The intervention was well tolerated, with 100% adherence to the scheduled program and no adverse events reported by the participants. Overall, a delayed onset of muscular soreness in the trained muscles was reported in the 48 hours following the training sessions of the first week of intervention (median NRS score 4/10; range 2–5). However, none of the participants had to take pain medication or delay the following session due to muscular soreness. Main demographic and clinical features of the participants are reported in Table 1.

Resistance to Motor-Driven Passive Motion Data on RPT are reported at 90◦/s of angular velocity, which was found to be the lowest speed able to elicit the spastic reflex in all participants. Regarding the multiple assessments of RPT at baseline (Tab. 2), the ICC values calculated over the 3 assessment sessions at baseline were 0.98 (95% CI: 0.93–0.99), 0.99 (95% CI: 0.96–1.00) when comparing sessions 1 and 2, and 0.96 (95% CI: 0.70–0.99) when comparing sessions 1 versus 3 and session 2 versus 3.

The SEm ranged from 7% to 25%, with a median value of 15%, and the SRD ranged from 25.8% to 31%. Each

participant had therefore to exceed this range of improvement for the observed training-induced change in the resistive peak torque to be considered as meaningful and not due to a measurement error. Individual- and group-level results of the reliability analyses are reported for the RPT in Table 2. Following the eccentric training, the amount of resistance opposed by the spastic muscle(s) against the passive motion carried out by the isokinetic dynamometer, that is, the RPT, was found reduced in all the participants but 1 (Tab. 3). Figure 2 displays for each of the 6 participants the torque/angle isokinetic curve during passive mobilization at 90◦/s of angular velocity at baseline (PRE) and after the 6-week eccentric training (POST) carried out on the isokinetic device both for the unaffected and for the spastic limb. The graphs show that, at baseline, the unaffected limb is linearly moved by the isokinetic device throughout the predefined range of motion. By contrast, the spastic limb opposes a certain amount of resistance to passive motion, as shown by the opposite direction taken by the curve (downward rather than upward trend). The difference between the patterns exhibited by the 2 limbs was reduced following the 6-week eccentric training.

When appraising the results through visual inspection, based on the 2-SD band method, the posttraining curves of 5 participants (#1, #2, #3, #4, and #6) were found to be at least 2 SDs below the baseline values, thus indicating a significant reduction at the individual level in the amount of resistance to passive mobilization. For participant #5, a nonsignificant reduction in the RPT was observed.

Comparing the training-induced percentage change in the resistive peak torque with the SRDi range calculated at baseline (25.8%–31%), 5 participants (#1, #2, #3, #4, and #6) of the 6 participants were found to exceed this threshold, whereas 1 patient (#5) did not.

Resistance to Manual Passive Mobilization Following the 6-week eccentric training, 5 of the participants (#1, #2, #3, #4, and #6) reported a subjective reduction in self-perceived severity of spasticity, as

1146 Physical Therapy Volume 100 Number 7 2020

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

Table 2. Reliability of the Resistive Peak Torque Measured During Passive Isokinetic Extensions of the Affected Elbow Flexors at Baseline

Resistive Peak Torque,a Nm Participants

Test 1-Day Retest 1-Week Retest

1 12.9 (9.2) 12.2 (8.9) 12.3 (9.0)

2 17.4 (11.9) 17.0 (12.1) 17.2 (11.5)

3 22.5 (14.0) 20.7 (12.6) 17.0 (11.6)

4 8.7 (5.8) 6.2 (4.2) 8.5 (5.9)

5 6.5 (3.6) 6.4 (4.0) 6.5( 4.1)

6 11.0 (6.2) 10.3 (6.2) 9.8 (5.7)

1–6 13.2 (6.2) 12.1 (5.8) 11.9 (4.5)

aThe resistive peak torque was calculated as the difference between the torques recorded from the nonspastic and spastic elbow flexors, respectively. Values are means (SD) in newton meters (Nm); all torques recorded at 90◦/s of isokinetic angular velocity.

Table 3. Resistive Peak Torques Measured During Passive Isokinetic Extension of the Nonspastic and Spastic Elbow Flexors Before (PRE) and After (POST) the 6-Week Period of Eccentric Traininga

PRE POST

Participants Nonspastic Torque, Nm

Spastic Torque, Nm

RPT, Nm Nonspastic Torque, Nm

Spastic Torque, Nm

RPT, Nm RPT PRE to POST

Change, %

1 18.3 (5.7) 5.4 (3.7) 12.9 (9.2) 16.9 (6.1) 9.8 (1.9) 7.1 (5.4) −45%b , c

2 18.0 (5.7) 0.6 (6.5) 17.4 (11.9) 17.0 (6.5) 10.6 (2.5) 6.5 (5.3) −62.7%b , c

3 18.7 (5.6) −4.2 (8.4) 22.5 (14) 18.2 (6.1) 11.6 (2.6) 6.6 (4.7) −70.7%b , c

4 16.0 (5.5) 7.3 (1.5) 8.7 (5.8) 15.2 (6.1) 10.1 (2.8) 5.1 (3.7) −41.4%b , c

5 18.9 (3.2) 12.4 (1.9) 6.5 (3.6) 18.2 (3.5) 10.8 (1.3) 7.4 (2.2) 13.8%

6 17.1 (5.6) 6.1 (1.6) 11.0 (6.2) 16.3 (6.3) 10.1 (2.8) 6.2 (3.9) −43.6%b , c

1–6d 17.8 (1.1) 4.5 (5.8) 13.2 (5.9) 17 (1.2) 10.5 (0.7) 6.5 (0.8) −41.6 (29.6) P = .018

aValues are means (SD) in newton meters (Nm). All torques recorded at 90◦/s of isokinetic angular velocity. RPT = resistive peak torque calculated as the difference between the torques recorded from the nonspastic and spastic elbow flexors, respectively. bPRE to POST change in resistive peak torque exceeding the smallest real difference (SRDi) cutoff for clinically meaningful change. cSignificant change from baseline according to the 2-SD band method calculated for each participant at baseline over 3 time points. d1–6 = group-level results as assessed by 2-tailed paired t tests; significance set at P < .05.

assessed by the 0 to 10 NRS. Participants #1, #2, #3, and #4 reported a reduction by at least 1 point. No change was detected in the clinician-rated MAS scores (Tab. 4).

Maximal Strength Following the eccentric training, maximal voluntary isometric strength of the elbow flexors measured at the optimal muscle length (intermediate ROM) increased in all the participants (+30.9 [9.1]%; 95% CI: 20.3-41.4; P = .0006; Tab. 4).

Resting Limb Position, Passive and Active ROM Table 4 summarizes data by participant and at the group level. At the POST-evaluation, electrogoniometry of the spastic side revealed reduced flexion at rest in the spontaneous position of the upper limb in all participants.

At the group-level analysis, resting limb position was found significantly improved (−35.5 [12.4]%; 95% CI: 23.8-49.8; P = .0008).

Both passive ROM (+4.6%; P = .005) and active ROM (+11.8%; P = .009) were found to be significantly increased (Tab. 4).

Discussion To our knowledge, the present proof-of-concept single-system case series employed eccentric training for the first time primarily to modulate spastic hypertonia, unlike previous studies in neurological populations that used similar protocols to increase muscle strength in stroke survivors11 and in children with cerebral palsy.10 We

2020 Volume 100 Number 7 Physical Therapy 1147

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

Figure 2. Effects of a 6-week eccentric training on the isokinetic spastic resistive moment recorded bilaterally: individual results. Moment/angle isokinetic curve at 90◦/s of angular velocity is shown for each participant at baseline (PRE, left panels) and after the 6-week eccentric training (POST, right panels) carried out on the isokinetic device. Data are reported for the unaffected limb (continuous line) and the affected limb (dotted line). Graph axes are optimized for each case.

1148 Physical Therapy Volume 100 Number 7 2020

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

Table 4. Muscle Strength, Goniometric and Qualitative Measures of Muscle Hypertonia in Persons With Multiple Sclerosis Presenting Spasticity of Elbow Flexors Before and After 6 Weeks of Eccentric Training of the Spastic Musclesa

Participants Outcomes Assessed

1 2 3 4 5 6 1–6

Spastic elbow flexors MVIC, (Nm)

PRE 27.4 33.9 40.6 30.2 48.2 37.6 36.3 (7.5)

(95% CI: 28.4 to 44.2)

POST 38.8 46.3 48.5 41.1 58.1 49.4 47.0 (6.8)

(95% CI: 39.8 to 54.2)

P .0006

Resting limb position, (deg)

PRE 17 24 30 12 18 17 19.7 (6.3)

(95% CI: 13.0 to 26.3)

POST 9 14 22 7 15 9 12.7 (5.5)

(95% CI: 6.9 to 18.5)

P .001

PROM, (deg)

PRE 110 102 105 107 111 114 108.2 (4.3)

(95% CI: 103.6 to 112.7)

POST 113 109 113 110 113 121 113.2 (4.2)

(95% CI: 108.7 to 117.6)

P .005

AROM, (deg)

PRE 87 74 90 92 101 101 90.5 (9.7)

(95% CI: 80.3 to 100.7)

POST 104 93 101 99 103 103 101.2 (4.8)

(95% CI: 96.1 to 106.2)

P value .009

MAS (score)

PRE 1+ 2 2 1+ 1 1 1.5 (0.6) (95% CI: 0.9 to 2.1)

POST 1 2 2 1 1 1 1.3 (0.5)

(95% CI: 0.8 to 1.9)

P >.05

NRS (score)

PRE 7.1 6.1 6.9 5.8 5 3.6 5.7 (1.3)

(95% CI: −0.2 to 11.7)

POST 5 4.2 5 4.5 5 3.1 4.5 (0.7)

(95% CI: −0.3 to 9.2) P .01

aOutcome measures are reported at individual level and at group level (mean [SD] and 95% CI). Data were analyzed with 2-tailed paired t tests except for MAS and NRS scores, which were processed by Wilcoxon signed rank tests. AROM = active range of motion; MAS = Modified Ashworth Scale; MVIC = maximal voluntary isometric contraction; Nm = newton meter; NRS = Numerical Rating Scale related to patient-reported perception of spasticity burden; POST = outcome measures assessed after 6 weeks of eccentric training; PRE = outcome measures assessed at baseline; PROM = passive range of motion.

also showed that eccentric training is a feasible and safe way to manage spasticity-related resistance to passive motion in people with multiple sclerosis. Moreover, the eccentric training induced reductions in the resistance to passive motion of the spastic elbow flexor muscles, as measured objectively by isokinetic dynamometry, in self-reported perception of spasticity severity, in spasticity-free elbow ROM, and in the spontaneous resting limb positioning. Finally, as expected, the intervention also significantly improved maximal strength of the spastic muscles.

The visual inspection of the single responses to eccentric training exhibited by each participant revealed a clear pattern toward reduction in the amount of resistance offered by the spastic muscle groups against the passive motor-driven limb mobilization, in all participants. The 2-SD band method, which is the preferred statistical benchmark in single-system design research, evidenced that 5 of the 6 participants (all exhibiting spasticity of the elbow flexors) improved significantly and exceeded the SRD, which is the smallest change that surpasses the measurement error and can thus be recognized as

2020 Volume 100 Number 7 Physical Therapy 1149

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

clinically meaningful at the level of the individual patient.26 ,30

Regarding the possible reasons why 1 participant (#5) did not respond to the intervention, this participant exhibited a Beck Depression Inventory score of 22, which, despite lying below the cutoff for exclusion (≥28), fell into the 19 to 29 range, which represents a moderate to severe level of depression. These mood alterations could have led to reduced attention and motivation during the training sessions, possibly affecting the participant’s involvement in the study, which could be even more relevant if we consider that the execution of eccentric contractions is highly demanding and requires full patient-therapist interaction and collaboration.

Evidence is accumulating on the benefits of eccentric protocols, that is, the lengthening of an active muscle while it is contracting under load,5 in musculoskeletal disorders, where it has been widely shown to induce consistent gains in strength along with structural changes of soft tissues. In particular, eccentric contractions exert a lengthening action on sarcomeres and collagens, which has been demonstrated to have therapeutic implications in orthopedic conditions and also in neurological disorders characterized by spasticity-induced alterations such as contractures at the joint, tendon, and muscle levels.10 ,11

Because of this lengthening action, eccentric training affects the overall length range and the length-tension relationship of a muscle, inducing a sustained shift in the angle of peak torque and in the curve width, so that the range over which torque can be sustained above 50% of maximum (curve width) is significantly wider than that obtained with the conventionally employed concentric actions.10 ,31 Such effects have been explained by the training-induced increase in the number of sarcomeres in series to maximize muscle efficiency.32 In addition, lengthening eccentric actions have the potential to counteract the contracture due to hypertonia of the targeted muscles by reducing the active insufficiency of the spastic muscle(s), that is, the too-shortened condition of the sarcomere, which prevents multijoint muscles from achieving the optimal production of strength.9 In line with these findings, we found that the observed reduction in the resistance to passive motion was associated with significant improvements in strength of the spastic elbow flexors and resting limb position. Furthermore, subjective perception of spasticity was found to be reduced by 1 point (−21%, on NRS), which achieved the cutoff previously outlined for a clinically meaningful reduction in patient-reported spasticity (−20%) in people with multiple sclerosis.33 However, no changes were detected in the clinician-rated impression of spasticity, as assessed by MAS testing. The minimal clinical important change in the MAS score has been established in stroke survivors as a decrease by approximately 1 point following focal pharmacological interventions, such as botulinum injections,34 and by 0.5 points following rehabilitation,

which corresponds to a 10% decrease in the score.35 ,36

None of the participants in this study achieved or surpassed this threshold. Even though failure to exceed the cutoff for clinically meaningful difference can be interpreted as a limited magnitude of effect of the intervention administered, responsiveness of MAS scores has been reported as controversial due to high variability across the studies, results of which tend to range from poor to marked responsiveness to change following rehabilitation.36 For these reasons, establishing new end points, such as the RPT proposed here, is relevant and necessary to appraise the effectiveness of interventions to manage spasticity.

Study Limitations A number of factors are acknowledged that might limit the validity of the study findings. First, given the study design chosen (single-system case series), no cause-effect relationship between the intervention and any observed changes can be directly drawn or claimed, because a case series only serves the purpose of documenting changes in a participant’s performance over time when exploring the effects of specific and/or innovative treatments for particular problems.15 ,16 Secondly, the specific AB design chosen further limits the causal inferences that can be drawn between the intervention administered and the observed effects,19 due to the lack of a follow-up period after the training completion, and to the limited number of assessments (in our study 3 at baseline and only 2 at the post). Upcoming properly planned, randomized controlled trials comparing eccentric training with best practice in the exercise-based management of spasticity will contribute to look causally into effectiveness issues, with the recommendation to complement the laboratory-based RPT, which is only 1 component of the complex of signs contributing to spasticity, with a core set of functional outcomes. Third, the observed reductions in the resistance to passive robotic movement were detected after a period of slow eccentric contractions (30◦/s of angular speed) at submaximal to maximal intensity (approximately 70%–80% of the maximal baseline strength). Future dose-response studies will have to clarify these practical points, also considering that spasticity is velocity-dependent and that fast muscle contractions, including eccentric ones, can result in exacerbated reflexes and spasms. Finally, the present findings were obtained in the elbow flexor muscles and should not be generalized straightaway to other upper and or lower limb districts.

Conclusions Eccentric contractions proved feasible and safe in the management of spasticity of the elbow flexor muscles in people with multiple sclerosis. A training period of 6 weeks was sufficient to reduce spastic hypertonia and weakness of the spastic muscles. These objective effects translated into a subjective reduction of spasticity as perceived by patients, and into increased spasticity-free

1150 Physical Therapy Volume 100 Number 7 2020

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

ROM, with better positioning of the affected limb. The present preliminary findings encourage an extension of the study to confirm the observed results over a larger number of participants through a properly planned, randomized controlled trial where eccentric training is compared with other active exercise-based interventions.

Author Contributions and Acknowledgments

Concept/idea/research design: A. Manca, F. Deriu Writing: A. Manca, F. Deriu Data collection: G. Martinez, E. Aiello, L. Ventura Data analysis: A. Manca, G. Martinez, E. Aiello, L. Ventura, F. Deriu Project management: F. Deriu Fund procurement: A. Manca, F. Deriu Providing participants: E. Aiello Providing facilities/equipment: F. Deriu Consultation (including review of manuscript before submitting):

A. Manca, G. Martinez, E. Aiello, L. Ventura, F. Deriu

The authors are indebted to Mrs Daphne Yeager, BA, for the language revision of the manuscript.

Ethics Approval

This study was approved by the institutional Bioethics Committee of the Local Health Authority (ASL n.1-Sassari, Italy; Prot. number 2420/CE 2016). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

This work was supported by Fondazione Italiana Sclerosi Multipla (FISM 2018/R/9) and by a grant for Multiple Sclerosis Innovation (GMSI 2018).

Clinical Trial Registration

A convenience sample of 6 people with multiple sclerosis with moderate-to-severe degree of spasticity was selected within the framework of a larger randomized controlled trial (clinicaltrials.gov: NCT02010398) for which a degree of spasticity greater than or equal to moderate was set as an exclusion criterion.

Disclosures

The authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.

DOI: 10.1093/ptj/pzaa055

References 1 Rizzo MA, Hadjimichael OC, Preiningerova J, Vollmer TL.

Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler. 2004;10:589–595.

2 Beard S, Hunn A, Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess. 2003;7iii, ix–x:1–111.

3 O’Dwyer NJ, Ada L, Neilson PD. Spasticity and muscle contracture following stroke. Brain. 1996;119:1737–1749.

4 Amatya B, Khan F, La Mantia L, Demetrios M, Wade DT. Non pharmacological interventions for spasticity in multiple sclerosis. Cochrane Database Syst Rev. 2013;CD009974. doi:10.1002/14651858.CD009974.pub2.

5 LaStayo PC, Woolf JM, Lewek MD, Snyder-Mackler L, Reich T, Lindstedt SL. Eccentric muscle contractions: their contribution to injury, prevention, rehabilitation, and sport. J Orthop Sports Phys Ther. 2003;33:557–571.

6 Lindstedt SL, LaStayo PC, Reich TE. When active muscles lengthen: properties and consequences of eccentric contractions. News Physiol Sci. 2001;16:256–261.

7 Enoka RM. Eccentric contractions require unique activation strategies by the nervous system. J Appl Physiol. 1996;81: 2339–2346.

8 Lambert CP, Archer RL, Evans WJ. Muscle strength and fatigue during isokinetic exercise in individuals with multiple sclerosis. Med Sci Sports Exerc. 2001;33:1613–1619.

9 Gajdosik RL, Hallett JP, Slaughter LL. Passive insufficiency of two-joint shoulder muscles. Clin Biomech. 1994;9: 377–378.

10 Reid S, Hamer P, Alderson J, Lloyd D. Neuromuscular adaptations to eccentric strength training in children and adolescents with cerebral palsy. Dev Med Child Neurol. 2010;52:358–363.

11 Clark DJ, Patten C. Eccentric versus concentric resistance training to enhance neuromuscular activation and walking speed following stroke. Neurorehabil Neural Repair. 2013;27:335–344.

12 Robineau S, Nicolas B, Gallien P, et al. Eccentric isokinetic strengthening in hamstrings of patients with multiple sclerosis. Ann Phys Rehabil Med. 2005;48:29–33.

13 Hayes HA, Gappmaier E, LaStayo PC. Effects of high- intensity resistance training on strength, mobility, balance, and fatigue in individuals with multiple sclerosis: a randomized controlled trial. J Neurol Phys Ther. 2011;35: 2–10.

14 Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173.

15 Riddoch J, Lennon S. Single subject experimental design: one way forward? Phys Ther. 1994;80:215–218.

16 Hunter SM, Crome P, Sim J, Pomeroy VM. Effects of mobilization and tactile stimulation on recovery of the hemiplegic upper limb: a series of replicated single-system studies. Arch Phys Med Rehabil. 2008;89:2003–2010.

17 Gleeson NP, Mercer TH. The utility of isokinetic dynamometry in the assessment of human muscle function. Sports Med. 1996;21:18–34.

18 Armstrong LE, Winant DM, Swasey PR, Seidle ME, Carter AL, Gehlsen G. Using isokinetic dynamometry to test ambulatory patients with multiple sclerosis. Phys Ther. 1983;63: 1274–1279.

19 Backman CL, Harris SR. Case studies, single-subject research, and N of 1 randomized trials: comparisons and contrasts. Am J Phys Med Rehabil. 1999;78:170–176.

20 Schmit BD, Dewald JP, Rymer WZ. Stretch reflex adaptation in elbow flexors during repeated passive movements in unilateral brain-injured patients. Arch Phys Med Rehabil. 2000;81:269–278.

21 Ploutz-Snyder LL, Clark BC, Logan L, Turk M. Evaluation of spastic muscle in stroke survivors using magnetic resonance imaging and resistance to passive motion. Arch Phys Med Rehabil. 2006;87:1636–1642.

2020 Volume 100 Number 7 Physical Therapy 1151

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021

Eccentric Training to Manage Spasticity

22 Sinkjaer T, Toft E, Larsen K, Andreassen S, Hansen HJ. Non-reflex and reflex mediated ankle joint stiffness in multiple sclerosis patients with spasticity. Muscle Nerve. 1993;16:69–76.

23 Starsky AJ, Sangani SG, McGuire JR, Logan B, Schmit BD. Reliability of biomechanical spasticity measurements at the elbow of people poststroke. Arch Phys Med Rehabil. 2005;86:1648–1654.

24 Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67: 206–207.

25 Proske U, Morgan DL. Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol. 2001;537:333–345.

26 Lexell JE, Downham DY. How to assess the reliability of measurements in rehabilitation. Am J Phys Med Rehabil. 2005;84:719–723.

27 Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ, USA: Lawrence Erlbaum Associates; 1988.

28 Weir JP. Quantifying test-retest reliability using the intraclass correlation coefficient and the SEM. J Strength Cond Res. 2005;19:231–240.

29 Portney LG, Watkins MP. Foundations of Clinical Research: Applications to Practice. 3rd ed. Upper Saddle River, NJ, USA: Pearson/Prentice Hall; 2008.

30 Dvir Z. Difference, significant difference and clinically meaningful difference: the meaning of change in rehabilitation. J Exerc Rehabil. 2015;11:67.

31 Brockett CL, Morgan DL, Proske U. Human hamstring muscles adapt to eccentric exercise by changing optimum length. Med Sci Sports Exerc. 2001;33:783–790.

32 Morgan DL, Proske U. Popping sarcomere hypothesis explains stretch-induced muscle damage. Clin Exp Pharmacol Physiol. 2004;31:541–545.

33 Farrar JT, Troxel AB, Stott C, Duncombe P, Jensen MP. Validity, reliability, and clinical importance of change in a 0–10 numeric rating scale measure of spasticity: a post hoc analysis of a randomized, double-blind, placebo-controlled trial. Clin Ther. 2008;30:974–985.

34 Shaw L, Rodgers H, Price C, et al. BoTULS investigators. BoTULS: A multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type a. Health Technol Assess. 2010;14:1–113.

35 Mangold S, Schuster C, Keller T, Zimmermann-Schlatter A, Ettlin T. Motor training of upper extremity with functional electrical stimulation in early stroke rehabilitation. Neurorehabil Neural Repair. 2009;23:184–190.

36 Scurr JC, Abbott V, Ball N. Quadriceps EMG muscle activation during accurate soccer instep kicking. J Sports Sci. 2011;29: 247–251.

1152 Physical Therapy Volume 100 Number 7 2020

D ow

nloaded from https://academ

ic.oup.com /ptj/article/100/7/1142/5816579 by A

P TA

M em

ber A ccess user on 17 February 2021