Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease characterized by destruction of myelin in the central nervous system resulting in sensory and motor disorders.1 Multiple sclerosis symptoms include fatigue, poor balance, pain, muscle weakness, and spasticity.2 Spasticity is a significant problem for 60%–80% of patients with MS (PwMS).3
The term spasticity is inconsistently defined.4 The most commonly used definition was set by Lance5 in 1980 as “Spasticity is a motor disorder characterized by a velocity-dependent increase in muscle tone with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex”. The Lance's definition was elaborated by addition other features of spasticity as spasm and clonus.6 Spasticity in MS can worsen quality-of-life by increasing fatigue, pain, anxiety, disability, posture deficits, and high risk of fall.7,8 The fluctuation and progressive courses in MS make spasticity management more different and challenging than static conditions such as stroke and spinal cord injury.9,10
Spasticity management involves diverse approaches including physiotherapy (PT) interventions, transcranial magnetic stimulation, and antispastic medications as Baclofen (by oral or intrathecal administration), and botulinum toxin A.11,12 Physiotherapy interventions include a wide range of therapeutic approaches such as the following: exercise training, therapeutic standing, shock waves, electrical stimulation, and vibration. One international survey of patients living with spasticity found that the most common spasticity treatment is PT interventions.13 The PT interventions are intended to maintain the muscle length, prevent contracture, and change mechanical proprieties of the musculoskeletal system and plasticity within the central nervous system.14 Recent systematic reviews of systematic reviews15,16 found limited evidence with low quality for rehabilitation programs for spasticity in PwMS. This evidence was based on one Cochrane systematic review9 assessed the effects of nonpharmacological interventions. To date, there is no systematic review for the effectiveness of PT interventions for spasticity in PwMS. Therefore, the aim of the current review was to investigate systematically the effectiveness of PT interventions on spasticity in PwMS.
The review has been reported as recommended in preferred reporting items for systematic review and meta-analysis (PRISMA)17 (see Checklist, Supplemental Digital Content 1, https://links.lww.com/PHM/A619).
Type of studies are randomized clinical trials (RCTs), controlled trials, and interventional studies with pre-post design. Studies were limited to English language.
Type of participants is whether PwMS reported spasticity. Studies include participants with neurological conditions other than MS were excluded.
Type of interventions is any PT intervention either alone or in combination with pharmacological intervention or transcranial magnetic stimulation. We excluded articles that applied yoga or complementary medicine such as acupuncture and reflexology.
The studies that measure at least one of the following spasticity aspects: muscle tone, excitability of stretch reflex, muscle activity, clonus, spasm, tendon reflex, and self-perceived spasticity were included in type of outcomes. Secondary outcomes of interest were biomechanical analyses of gait and spastic limbs.
Data Searches and Studies Selection
A comprehensive search was undertaken until March 1, 2018, conducted in MEDLINE, SCOPUS, Cochrane Central Register of Controlled Trials, and PEDro databases. The reference lists of relevant articles were screened. The following key words and MeSH headings are used: multiple sclerosis, muscle spasticity, physiotherapy, rehabilitation, and management. The search strategy on MEDLINE is listed in the Appendix (Supplemental Digital Content 2, https://links.lww.com/PHM/A620) and adjusted slightly in the different databases. Studies selection was performed by two authors (M.E. and Z.H.) on the base of title and abstract. Full-text articles were then read.
Data Extraction and Data Items
Data extraction has been performed by three authors. Two authors (F.L. and Y.K.) extracted the following data: study design, sample size, MS course, level of disability, interventions details, spasticity outcomes, and main results. First-arm results were extracted in crossover trials. The disability level and ambulatory status were discriminated according to the used scale in each included article. The third author (M.E.) checked the extracted data. Disagreements were resolved by the authors' consequence. Corresponding authors were contacted to provide missing data.
Data were categorized and summarized by PT intervention, spasticity aspects, course of MS and ambulatory status, and using of antispastic medications.
Quality of Articles and Evidence-Based Practice
The PEDro scoring system was used to assess the methodological quality of RCTs,18 modified Downs and Black checklist for controlled studies.19 The maximum scores of PEDro and modified Downs and Black scales are 10 and 17, respectively. Low scores for studies would reflect the lower quality and greater potential of bias.
The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to assess quality of evidence-based practice. The GRADE quality of evidences was made by three authors (D.C., M.E., and Y.K.). Rating the quality of the included articles and the GRADE quality of evidences are described in details in the Appendix (Supplemental Digital Content 2, https://links.lww.com/PHM/A620).
Synthesis of Analysis and Sensitivity Analysis
Meta-analysis was conducted if there were at least two studies that measure the effect of one PT intervention on one spasticity aspect. We computed effect size expressed as standardized mean difference20,21 in one of two ways: (1) the mean change from before to after the intervention in PT group minus the mean change in control group dived by the pooled change in stander deviation (SD) for the studies that contain control group for the comparison, or (2) the mean change from before to after intervention of PT group dived by the pooled change in SD for studies without control group for the comparison. The control group for the comparison was defined as no intervention, usual care, or equivalent dose of antispastic medications or transcranial magnetic stimulation groups. The aggregated or mean effect size was computed using a random effects model and adjusted for sample sizes (Hedges adjusted g)22 at 95% confidence interval. Heterogeneity in treatment effect was examined by calculating I2 index.23 The level of significant was set at P ≤ 0.05 for the Hedge g and I2. All statistical analyses were performed using comprehensive meta-analysis Version 3.3.070 software package (Biostat, NY).
A meta-analysis of high- and moderate-quality RCTs (RCTs without or with one limitation in included PEDro items, Appendix, Supplemental Digital Content 2, https://links.lww.com/PHM/A620) was performed as sensitivity analysis to reduce the heterogeneity of inclusion different methodological designs.
A total of 29 studies were included.24–52 Databases and hand searches provided 465 publications. After adjusting the duplication, 189 had been removed. Based on the title and abstract, 201 articles were excluded; 135 were noninterventional studies and 66 did not apply any PT intervention. Of the remaining 75, 46 articles did not meet the inclusion criteria. Finally, 29 trials were met the inclusion criteria and 25 were included in the meta-analyses (Fig. 1, Table 1). We excluded two studies very relevant to the inclusion criteria; one study reported that their participants with sever spasticity without determination the spasticity,53 and the other study assessed spasticity, pain, fatigue, strength, walking, and balance by one self-reported scale.54
The included studies were 16 RCTs and 13 non-RCTs, with a total of 799 participants. The sample size of studies ranged between 1 and 90. Eleven studies24,27–29,31,34,35,37,40,44,46 included relapsing-remitting and progressive MS, eight studies25,26,30,45,47,48,50,51 only progressive MS, and two studies32,36 only relapsing-remitting MS. Eight studies did not report the course of MS.33,38,39,41–43,49,52 One study42 did not report the level of disability, one study52 adapted Hauser Ambulation Index, and the remaining studies adapted expanded disability status scale to assess the level of disability and ambulatory status. Most of included articles did not make a distinction in the level of disability and included heterogeneous participants in disability level. Table 1 demonstrates demographic data, MS courses, level of disability, methodological design, and quality assessment in included articles.
The used spasticity outcomes were categorized to the following: (1) clinical scales as Ashworth Scale (AS), Modified Ashworth Scale (MAS), and Pendulum test for muscle tone, ankle clonus score, and patellar tendon reflex scale; (2) electrophysiological parameters for H-reflex excitability, or electromyography (EMG) muscle activity; and (3) self-reported spasticity outcomes as visual analog scale, Penn Spasm Frequency Score, and Multiple Sclerosis Spasticity Scale-88 (MSSS-88). Biomechanical measures were gait analyses, power generated and smoothness of movement, and goniometric measurements for passive and active range of motion. The participants in 25 articles were with lower-limb spasticity,24–28,31–33,35–50,52 whereas participants in two articles were with upper and lower-limb spasticity.29,30 Finally, two articles34–51 enrolled participants personally reported the spasticity without citation the location of the spasticity. Most of included articles assessed the spasticity by MAS and AS. Fifteen articles26,29–32,35–38,43,45,48–50,52 used more than one spasticity outcome. Spasticity outcomes and values at baseline for each included study are recorded in Table 2.
Effect of PT Interventions
The included PT interventions fit within the following five categories: exercise therapy, electrical stimulation, vibration, standing therapy, and radial shock wave therapy (RSWT). The completed intervention details and main finding regarding the effects of PT intervention on spasticity outcomes for each included study are in Table 2. In addition, Table 3 summarizes the concluded evidences for each PT intervention on different outcomes, results of meta-analyses, and GRADE level of evidence.
The exercise interventions have been set as one session to assess the acute effect or as exercise programs. One session of unloaded leg exercise36–38 or Bobath's exercises42 improved significantly ankle MAS and tibial nerve H-reflex excitability. The meta-analysis showed significant improvement in ankle MAS, but not in the H-reflex excitability (Fig. 2, Table 3).
The exercise programs were categorized as supervised outpatients training, inpatient and home based training, and robot-assisted and body weight–supported treadmill training. The outpatient exercises24,25,27,28,30,32,33,35 included active and passive stretch, strength, stability, balance, coordination, aquatic, endurance, walking, and mobilization exercise. The meta-analysis showed significant improvement of outpatient exercise on muscle tone and self-reported spasticity outcomes (Fig. 2, Table 3). The inpatient exercise26,34 was a part of multidisciplinary inpatient rehabilitation, home-based interventions29,31,50 contained education, exercise instructions, and home training. The meta-analysis showed no significant effect of inpatient and home-based exercise on muscle tone or self-reported spasticity outcomes (Fig. 2, Table 3). Four studies26,39–41 applied different types of robot-assisted and body weight supported treadmill training. The self-perceived spasticity26 and ankle range of motion39 were significantly improved, and the meta-analysis showed significant improvement in MAS (Fig. 2, Table 3).
The electrical stimulation was as functional electrical stimulation (FES) or transcutaneous electrical nerve stimulation (TENS). There was a significantly acute improvement of FES47,48 in MAS (Table 3). Two studies46,47 found that different effects of FES program on MAS, generated power, and smoothness of pedaling movement were improved significantly after a FES program.47 The meta-analysis showed no significant improvement of FES programs on MAS (Fig. 3, Table 3).
Three studies43–45 discussed the effect of TENS. First one43 compared two different durations of TENS (1 hr/d or 8 hrs/d). The TENS did not improve quadriceps AS, patellar tendon reflex, or ankle clonus in both groups. Eight hours group significantly improved in Penn Spasm Frequency Score. The other two studies44,45 found significant improvement in gastronomes muscle tone and EMG activity. The meta-analysis of the three studies showed significant improvement in ankle MAS (Fig. 3, Table 3).
The vibration interventions were as focal muscle vibration (FMV) or whole-body vibration.
Two studies25,28 found different effects of addition FMV to exercise programs on MAS, and the meta-analysis found nonsignificant improvement in MAS (Fig. 3, Table 3). The FMV led to significant improvement in gait analyses represented by first step length and double support time.28
Only muscle spasm item in MSSS-88 improved after whole-body vibration in one study, and other items of MSSS-88 and MAS were not improved.52
Two studies50,51 discussed the effects of therapeutic standing on Oswestry standing frame. The studies did not reveal improvement in MAS or Penn Spasm Score but demonstrated significant improvement in ankle and hip passive range of motion.
Radial Shock Wave Therapy
One study49 found that the four sessions of RSWT over planter extensor muscles improved ankle MAS but not H-reflex excitability. One RSWT session did not reveal benefits.
Adverse Events and Side Effects
Nine articles reported no adverse events or side effects due to exercise therapy,24,25,27,29,30,33 electrical stimulation,44,46 or RSWT.49 Five articles noted minor side effects or adverse events after exercise training,31,40,41 whole-body vibration,52 and standing therapy,51 but their participants were able to complete the intervention. The remaining studies did not report on adverse events or side effects.
Six studies measured spasticity outcomes at 3 wks,28 4 wks,35,49 6 wks,39 1 mo and 3 mos,30 and 16 and 18 wks25 of follow-up. There was significant improvement at follow-up measures in favor of outpatient exercises,30,35 FMV,25,28 and robot-ankle training.39 There is no follow-up improvement for RSWT.49
Thirteen studies did not report the status of antispastic medications. The participants in five articles28,36,37,41,47 have not received antispastic medications during the studies, whereas the participants in 10 articles25,26,29–31,33,38,45,46,49 received antispastic medications. Three studies25,30,33 found that the exercise enhanced the efficacy of antispastic medications. One study found that the TENS better than oral Baclofen.44
Progressive MS and Nonambulatory PwMS
The articles that included exclusively progressive forms of MS or nonambulatory PwMS revealed significant improvements on spasticity outcomes in favor of outpatient exercise training,25,30 robot training and body weight supported treadmill training,26,40,41 functional electrical stimulation,46–48 and TENS,45 whereas nonsignificant improvement in favor of standing therapy or home exercise training.26,44
Quality of Included Articles
The PEDro score for included RCTs ranged from 3 to 8, whereas modified Down and Black checklist ranged from 12 to 15 (Table 1). Only four studies based their sample size on statistical power calculations.26,27,43,44 The difference in the sample sizes between study groups was significant in one study.35 The postallocation withdrawals were higher than 15% in five studies32–34,49,52 and two of them33,34 reported complete information on participants who withdrew and the reasons of withdrawing.
The sensitivity analysis showed significant improvement of outpatient exercise therapy on MAS (Hedge's = 0.642, 95% CI = 0.330–0.955, P = 0.003) and nonsignificant improvement of inpatient exercise on visual analog scale (Hedge's = 0.034, 95% CI −0.537–0.607, P = 0.908).
This is the first systematic review aimed to clarify the effectiveness of PT interventions on spasticity among PwMS. It incorporated 16 RCTs, and 13 non-RCTs discussed the effects of exercise training, electrical stimulation, vibration, standing therapy, and RSWT. The inclusion of non-RCTs was due to the limitation in the available RCTs respect to the diversity in PT interventions and MS characteristics. To reduce the influence of inclusion of non-RCTs, we adapted to use GRADE approach for the quality of evidence and performed sensitivity analysis. The included PT interventions showed different evidences of benefits and nonbenefits on spasticity outcomes (Table 3). The previous Cochrane review10 of nonpharmacological interventions found low-quality evidence of benefits for exercise programs and no evidence of benefits of TENS or whole-body vibration on spasticity in PwMS based on four studies.
Spasticity management is a complex approach.55,56 Inadequate treatments may worsen the spasticity and level of function.7 Despite of the most included articles did not report on safety of PT interventions, the reported adverse events, side effects, and withdrawals were minor and rare. The PT interventions seem a safe option for spasticity in PwMS. Previous reviews confirmed the safety of exercise, TENS, and whole-body vibration in MS rehabilitation.57–60 The nonintervention or usual care control participants in four included articles24,27,29,31 reported worsening in spasticity outcomes. However, spasticity may be beneficial by counteracting muscle weakness, thereby increasing stability of the lower limbs.61 A cross-sectional study62 found planter flexor weakness worse walking more than planter flexor spasticity in PwMS. Therefore, the goal of spasticity management must be always function safely focused.
Most enrolled participants were with lower-limb spasticity that is associated with posture instability, gait impairments, and high risk of falls.63,64 The PT interventions that target posture, gait control, and spasticity are required in MS rehabilitation protocols. The PT interventions should focus on the control of medio-lateral and anterior-posterior sway by improving antigravity muscles strength, reducing calf muscle spasm, and enhancing ankle dorsflexion range of motion.8,63 One included article27 used core stabilization exercises and reported significant improvement in muscle tone, balance, and walking.
The best available quality evidences of benefits were for robot gait training on self-perceived spasticity and outpatient exercise programs on muscle tone. The outpatient exercise improved also self-reported spasticity outcomes. Home-based and inpatient exercise did not show significant improvements on spasticity outcomes. The superiority of outpatient programs is in line with the previous studies.22,65 It is possible that home-based and inpatients programs lack sufficient interactions as outpatient programs. The management of MS requires collaborative communications and active participations by PwMS.66 The participants in home exercise and inpatients trials were with higher disability. Recovery mediates by motor training is thought to be based on plastic changes in injured motor network.67,68 Functional magnetic resonance imaging studies69,70 show that exercise interventions can enhance regional brain volume, structural connectivity, and myelination-related process in PwMS. The unloaded exercises and passive movements and positioning showed acute significant effects on spasticity outcomes. Physiotherapy specialists should initiate the exercise training with light exercises to reduce spasticity and spastic pattern. Patient's physical function, endurance, disability level, heart rate and blood pressure, perceived exertion, and the resistance of cycling exercises were considered to set the exercise programs in six included exercise articles (Table 2). Two included articles25,30 applied short pauses during the stretch to prevent contractures. High-intensity stretch may worsen the spasticity. A biomechanical analysis71 found that stretches of planter flexor muscles in weight bearing positions led to increase in muscle activation and postural activity compared with nonweight bearing positions in PwMS. According to the available evidence and nature of MS, we suggest that the outpatient exercise is the most beneficial PT intervention for spasticity with careful considerations to preliminary exercise tests, functional goals, and correlated MS symptoms.
The electrical stimulation studies showed evidences of benefits on muscle tone, EMG muscle activity, biomechanical proprieties of the movement, and self-reported spasm. There is no effect on clonus or tendon reflex. The review results show similar effects of FES and TENS that is in agreement with a previous RCT.72 The improvement after electrical stimulation was explained by its actions on facilitation of Ib inhibitory pathway, on increasing sensory stimuli, and specific plasticity of spinal cord pathways.73,74 The TENS was recommended as treatment option for spasticity.75 Previous reviews found that the TENS was effective on spasticity when it was used with active therapy such as exercise and task-related training.76,77 We recommended using electrical stimulation as adjacent therapy to motor training programs.78 The use of electrical stimulations primary to motor training may be more effective by reducing spasticity immediately and increasing sensory stimuli. Modulation of spasticity may depend on the frequency of electrical stimulation.79 However, the electrical stimulations included studies that did not explain the criteria for selection stimulation parameters and durations.
The FMV led to significant improvement in gait first step length and double-support time but not in muscle tone in the current analysis. An excluded article53 found that the FMV improves sever gait impairments in PwMS. These articles applied the vibration over spastic and nonspastic muscles at different parameters. A vibratory stimulus to spastic muscles induces presynaptic inhibition of Ia afferents and decreases the monosynaptic reflex excitability.80 However, Clinical trials81,82 confirmed that FMV over nonspastic muscles (agonist) reduced muscle tone in spastic muscles (antagonist). Whole-body vibration did not improve lower-limb MAS or MSSS-88 in this review. Therapeutic standing improved significantly hip and ankle range of motion, but not self-perceived spasm or AS in the included standing studies.50,51 It is hypothesized that prolonged stretching with weight bearing in standing might be more effective than intermittent stretch.83 However, there was no difference between standing and stretch exercises on spasticity outcomes.52 Previous reviews found inconclusive evidence for the effects of whole-body vibration or standing on spasticity.84,85 Radial shock wave therapy improved MAS but not H-reflex in the included RSWT study.49 The improvement in MAS was after four sessions but not after one session or at 4-wk follow-up. Similarly, RCTs86,87 recorded that three sessions of RSWT had more beneficial effects than one session. Contradictory, previous analysis88 found that the RSWT improved MAS at 4-wk follow-up. The lack of RSWT effects on H-reflex and at acute and long-term measurements support that mechanical stimuli by RSWT act on nonreflex hypertonia aspects, for example, stiffness and extensibility on muscle-tendon unit.89 The effect of PT modalities regarding the parameters and treatment duration is not clear. Further studies are needed to establish these interventions effects on spasticity and conclude optimum parameters.
Most included articles include heterogeneous participants in MS course and disability level. Patients with MS with greater disability have greater impairment in balance, fatigue, cognitive, and psychological status that will make spasticity management more challenged.90 The review shows positive results of PT interventions especially outpatient exercise training, robot-assisted and body weight–supported treadmill training, and electrical stimulation on spasticity outcomes in progressive and/or nonambulatory (severer disability) PwMS. These positive results in addition to the heterogeneity indicate that PT interventions can be a treatment option for spasticity in all stable PwMS. Previous reviews91–93 and international progressive MS alliance94 have reinforced the need to specific adequate quality researches to clear the effects of PT interventions in progressive and nonambulatory MS populations.
Spasticity measurement is difficult, because there are no direct measures.95 The most used outcomes were AS and MAS. Measures of spasticity are not exclusively dependent on muscle tone.95 Moreover, a meta-analyses (Fig. 2A) and some of included studies show that MAS but not H-reflex was improved in favor of PT interventions that support the MAS is not able to discriminate between reflex and nonreflex hypertonia.96 Range of motion, movement biomechanical analysis, clonus, or tendon reflex were assessed in small number of included articles. Assessment of range of motion was sensitive to change after antispastic therapies.97 One study98 found that a simple biomechanical analysis for acceleration and smoothness of voluntary movement revealed a significant reduction in spasticity after Baclofen therapy in PwMS that was not detected by MAS. Only 9 of 17 included articles that adapted more than 1 spasticity outcome showed similar results on different scales. Cross-sectional studies98–102 found poor correlations between different spasticity outcomes that make it difficult to find a reliable and sensitive outcome measure the spasticity as one clinical phenomenon. Thus, no solid conclusions can be drawn on the effect of PT interventions on overall spasticity. This review did not consider outcomes of daily life because the spasticity is not only the cause of defects in quality-of-life or functional level among PwMS but also the heterogeneity in disability levels in included articles.
The included evidence was limited, and the major quality of evidences was very low. The weakness in quality of evidences was primarily due to serious risks of bias, lack of power sample size, and the heterogeneity (Appendix, Supplemental Digital Content 2, https://links.lww.com/PHM/A620). The concluded evidence for the most of PT interventions was based on one or two studies. The included articles were heterogeneous and badly reported in the PT interventions, results, and MS characteristics. The estimate of the effectiveness of PT interventions is not fully clear, and further researches are very likely to change the current evidences. Power RCTs explain that the effects of PT interventions on clinical, electrophysiological, and self-reported spasticity outcomes in homogeneous MS populations are required to better understand the effectiveness on overall spasticity. An important area of future research involves testing the correlations between improvement in spasticity and functional level or quality of life. We recommended future interventional trials to carefully consider and clearly report the procedures regarding on that choice of PT interventions, intensity, and parameters of used interventions. The importance of and difficulty in spasticity definition, pathophysiology, measures, and management demand more precise and informative researches.
Physiotherapy interventions showed some benefits on spasticity outcomes. Physiotherapy interventions can be a safe and beneficial option for spasticity in PwMS. The best available evidences were for beneficial effects of exercise therapy especially robot gait training and outpatient exercise programs on self-perceived spasticity and muscle tone respectively. No firm conclusion can be drawn on overall spasticity. Further researches in different spasticity aspects are needed.
1. Noseworthy JH, Lucchinetti C, Rodriguez M, et al.: Multiple sclerosis. N Engl J Med
2. Compaston A, Coles A: Multiple sclerosis. Lancet
3. Rizzo MA, Hadjimichael OC, Preiningerova J, et al.: Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler
4. Malhotra S, Pandyan AD, Day CR, et al.: Spasticity, an impairment that is poorly defined and poorly measured. Clin rehabil
5. Lance JW: The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology
6. Pandyan AD, Gregoric M, Barnes MP, et al.: Spasticity: clinical perceptions, neurological realities and meaningful measurement. Disabil Rehabil
7. Milinis K, Tennant A, Young CA, et al.: Spasticity in multiple sclerosis: associations with impairments and overall quality of life. Mult Scler Relat Disord
8. Sosnoff JJ, Shin S, Motl RW: Multiple sclerosis and postural control: the role of spasticity. Arch Phys Med Rehabil
9. Amatya B, Khan F, La Mantia L, et al.: Non pharmacological interventions for spasticity in multiple sclerosis. Cochrane Database Syst Rev
10. Picelli A, Vallies G, Chemello E, et al.: Is spasticity always the same? An observational study comparing the features of spastic equinus foot in patients with chronic stroke and multiple sclerosis. J Neurol Sci
11. Galea MP: Physical modalities in the treatment of neurological dysfunction. Clin Neurol Neurosurg
12. Shakespeare D, Boggild M, Young C: Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev
13. Barnes M, Kocer S, Murie Fernandez M, et al.: An international survey of patients living with spasticity. Disabil Rehabil
14. Adams MM, Hicks AL: Spasticity after spinal cord injury. Spinal Cord
15. Khan F, Amatya B, Bensmail D, et al.: Non-pharmacological interventions for spasticity in adults: an overview of systematic reviews. Ann Phys Rehabil Med
16. Khan F, Amatya B: Rehabilitation in multiple sclerosis: a systematic review of systematic reviews. Arch Phys Med Rehabil
17. Liberati A, Altman DG, Tetzlaff J, et al.: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol
18. Maher CG, Sherrington C, Herbert RD, et al.: Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther
19. Downs SH, Black N: The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health
20. Cohen J: Statistical Power Analysis for the Behavioral Sciences
. 2nd ed. Hillsdale, NJ, Lawrence Erlbaum Associates, 1988
21. Snook EM, Motl RW: Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair
22. Borenstein M, Hedges L, Higgins J, et al.: Comprehensive Meta-Analysis Version 2
. Englewood NJ, Biostat, 2005
23. Higgins JPT, Green S, editors: Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Library
. Chichester, UK: John Wiley & Sons, Ltd, 2011
24. Negahban H, Rezaie S, Goharpey S: Massage therapy and exercise therapy in patients with multiple sclerosis: a randomized controlled pilot study. Clin Rehabil
25. Paoloni M, Giovannelli M, Mangone M, et al.: Does giving segmental muscle vibration alter the response to botulinum toxin injections in the treatment of spasticity in people with multiple sclerosis? A single-blind randomized controlled trial. Clin Rehabil
26. Pompa A, Morone G, Iosa M, et al.: Does robot-assisted gait training improve ambulation in highly disabled multiple sclerosis people? A pilot randomized control trial. Mult Scler
27. Tarakci E, Yeldan I, Huseyinsinoglu BE, et al.: Group exercise training for balance, functional status, spasticity, fatigue and quality of life in multiple sclerosis: a randomized controlled trial. Clin Rehabil
28. Spina E, Carotenuto A, Aceto MG, et al.: The effects of mechanical focal vibration on walking impairment in multiple sclerosis patients: a randomized, double-blinded vs placebo study. Restor Neurol Neurosci
29. Ehling R, Edlinger M, Hermann K, et al.: Successful long-term management of spasticity in patients with multiple sclerosis using a software application (APP): a pilot study. Mult Scler Relat Disord
30. Giovannelli M, Borriello G, Castri P, et al.: Early physiotherapy after injection of botulinum toxin increases the beneficial effects on spasticity in patients with multiple sclerosis. Clin Rehabil
31. Hugos CL, Bourdette D, Chen Y, et al.: A group-delivered self-management program reduces spasticity in people with multiple sclerosis: a randomized, controlled pilot trial. Mult Scler J Exp Transl Clin
32. Mori F, Ljoka C, Magni E, et al.: Transcranial magnetic stimulation primes the effects of exercise therapy in multiple sclerosis. J Neurol
33. Brar SP, Smith MB, Nelson LM, et al.: Evaluation of treatment protocols on minimal to moderate spasticity in multiple sclerosis. Arch Phys Med Rehabil
34. Storr LK, Sørensen PS, Ravnborg M: The efficacy of multidisciplinary rehabilitation in stable multiple sclerosis patients. Mult Scler
35. Sosnoff J, Motl RW, Snook EM, et al.: Effect of a 4-week period of unloaded leg cycling exercise on spasticity in multiple sclerosis. NeuroRehabilitation
36. Sosnoff JJ, Motl RW: Effect of acute unloaded arm versus leg cycling exercise on the soleus H-reflex in adults with multiple sclerosis. Neurosci Lett
37. Motl RW, Snook EM, Hinkle ML, et al.: Effect of acute leg cycling on the soleus H-reflex and modified Ashworth scale scores in individuals with multiple sclerosis. Neurosci Lett
38. Motl RW, Snook EM, Hinkle ML: Effect of acute unloaded leg cycling on spasticity in individuals with multiple sclerosis using anti-spastic medications. Int J Neurosci
39. Lee Y, Chen K, Ren Y, et al.: Robot-guided ankle sensorimotor rehabilitation of patients with multiple sclerosis. Mult Scler Relat Disord
40. Kozlowski AJ, Fabian M, Lad D, et al.: Feasibility and safety of a powered exoskeleton for assisted walking for persons with multiple sclerosis: a single-group preliminary study. Arch Phys Med Rehabil
41. Giesser B, Beres-Jones J, Budovitch A, et al.: Locomotor training using body weight support on a treadmill improves mobility in persons with multiple sclerosis: a pilot study. Mult Scler
42. Rösche J, Rüb K, Niemann-Delius B, et al.: Effects of physiotherapy on F-wave-amplitudes in spasticity. Electromyogr Clin Neurophysiol
43. Miller L, Mattison P, Paul L, et al.: The effects of transcutaneous electrical nerve stimulation (TENS) on spasticity in multiple sclerosis. Mult Scler
44. Shaygannejad V, Janghorbani M, Vaezi A, et al.: Comparison of the effect of baclofen and transcutaneous electrical nerve stimulation for the treatment of spasticity in multiple sclerosis. Neurol Res
45. Armutlu K, Meriç A, Kirdi N, et al.: The effect of transcutaneous electrical nerve stimulation on spasticity in multiple sclerosis patients: a pilot study. Neurorehabil Neural Repair
46. Backus D, Burdett B, Hawkins L, et al.: Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory. Int J MS Care
47. Szecsi J, Schlick C, Schiller M, et al.: Functional electrical stimulation assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome—a pilot study. J Rehabil Med
48. Krause P, Szecsi J, Straube A: FES cycling reduces spastic muscle tone in a patient with multiple sclerosis. NeuroRehabilitation
49. Marinelli L, Mori L, Solaro C, et al.: Effect of radial shock wave therapy on pain and muscle hypertonia: a double-blind study in patients with multiple sclerosis. Mult Scler
50. Baker K, Cassidy E, Rone-Adams S: Therapeutic standing for people with multiple sclerosis: Efficacy and feasibility. Int J Ther Rehabil
51. Hendrie WA, Watson MJ, McArthur MA: A pilot mixed methods investigation of the use of Oswestry standing frames in the homes of nine people with severe multiple sclerosis. Disabil Rehabil
52. Schyns F, Paul L, Finlay K, et al.: Vibration therapy in multiple sclerosis: a pilot study exploring its effects on tone, muscle force, sensation and functional performance. Clin Rehabil
53. Camerota F, Celletti C, Di Sipio E, et al.: Focal muscle vibration, an effective rehabilitative approach in severe gait impairment due to multiple sclerosis. J Neurol Sci
54. Skjerbæk AG, Møller AB, Jensen E, et al.: Heat sensitive persons with multiple sclerosis are more tolerant to resistance exercise than to endurance exercise. Mult Scler
55. Pfleger CC, Flachs EM, Koch-Henriksen N: Social consequences of multiple sclerosis (1): early pension and temporary unemployment—a historical prospective cohort study. Mult Scler
56. Pfleger CC, Flachs EM, Koch-Henriksen N: Social consequences of multiple sclerosis. Part 2. Divorce and separation: a historical prospective cohort study. Mult Scler
57. Heine M, van de Port I, Rietberg MB, et al.: Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev
58. Sitjà Rabert M, Rigau Comas D, Fort Vanmeerhaeghe A, et al.: Whole-body vibration training for patients with neurodegenerative disease. Cochrane Database Syst Rev
59. Sawant A, Dadurka K, Overend T, et al.: Systematic review of efficacy of TENS for management of central pain in people with multiple sclerosis. Mult Scler Relat Disord
60. Pilutti LA, Platta ME, Motl RW, et al.: The safety of exercise training in multiple sclerosis: a systematic review. J Neurol Sci
61. Henze T, Rieckmann P, Toyka KV, et al.: Symptomatic treatment of multiple sclerosis. Multiple Sclerosis Therapy Consensus Group (MSTCG) of the German Multiple Sclerosis Society. Eur Neurol
62. Wagner JM, Kremer TR, Van Dillen LR, et al.: Plantarflexor weakness negatively impacts walking in persons with multiple sclerosis more than plantarflexor spasticity. Arch Phys Med Rehabil
63. Pau M, Coghe G, Corona F, et al.: Effect of spasticity on kinematics of gait and muscular activation in people with multiple sclerosis. J Neurol Sci
64. Balantrapu S, Sosnoff JJ, Pula JH, et al.: Leg spasticity and ambulation in multiple sclerosis. Mult Scler Int
65. Pappalardo A, D'Amico E, Leone C, et al.: Inpatient versus outpatient rehabilitation for multiple sclerosis patients: effects on disability and quality of life. Mult Scler Demyelinating Disord
66. Giovannoni G, Rhoades RW: Individualizing treatment goals and interventions for people with MS. Curr Opin Neurol
67. Flachenecker P: Clinical implications of neuroplasticity - the role of rehabilitation in multiple sclerosis. Front Neurol
68. Mori F, Ljoka C, Nicoletti CG, et al.: CB1 receptor affects cortical plasticity and response to physiotherapy in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm
69. Lin TW, Kuo YM: Exercise benefits brain function: the monoamine connection. Brain Sci
70. Taubert M, Lohmann G, Margulies DS, et al.: Long-term effects of motor training on resting-state networks and underlying brain structure. Neuroimage
71. Ofori J, Freeman J, Logan A, et al.: An investigation of commonly prescribed stretches of the ankle plantar flexors in people with multiple sclerosis. Clin Biomech (Bristol, Avon)
72. Sivaramakrishnan A, Solomon JM, Manikandan N: Comparison of transcutaneous electrical nerve stimulation (TENS) and functional electrical stimulation (FES) for spasticity in spinal cord injury - a pilot randomized cross-over trial. J Spinal Cord Med
73. Motta-Oishi AA, Magalhães FH, Mícolis de Azevedo F: Neuromuscular electrical stimulation for stroke rehabilitation: is spinal plasticity a possible mechanism associated with diminished spasticity? Med Hypotheses
74. Chen SC, Chen YL, Chen CJ, et al.: Effects of surface electrical stimulation on the muscle-tendon junction of spastic gastrocnemius in stroke patients. Disabil Rehabil
75. Fernández-Tenorio E, Serrano-Muñoz D, Avendaño-Coy J, et al.: Transcutaneous electrical nerve stimulation for spasticity: a systematic review. Neurologia
76. Mills PB, Dossa F: Transcutaneous electrical nerve stimulation for management of limb spasticity: a systematic review. Am J Phys Med Rehabil
77. Stein C, Fritsch CG, Robinson C, et al.: Effects of electrical stimulation in spastic muscles after stroke: systematic review and meta-analysis of randomized controlled trials. Stroke
78. Etoom M, Khraiwesh Y, Foti C: Transcutaneous electrical nerve stimulation for spasticity. Am J Phys Med Rehabil
79. Koyama S, Tanabe S, Takeda K, et al.: Modulation of spinal inhibitory reflexes depends on the frequency of transcutaneous electrical nerve stimulation in spastic stroke survivors. Somatosens Mot Res
80. Katz R: Presynaptic inhibition in humans: a comparison between normal and spastic patients. J Physiol Paris
81. Casale R, Damiani C, Maestri R, et al.: Localized 100 Hz vibration improves function and reduces upper limb spasticity: a double-blind controlled study. Eur j Phys Rehabil Med
82. Etoom M, Marchetti A: Effect of a focal muscle vibration above triceps brachii muscle on upper limb spasticity in a patient with chronic spinal cord injury: a case report. Int J Physiother Res
83. Bovend'Eerdt TJ, Newman M, Barker K, et al.: The effects of stretching in spasticity: a systematic review. Arch Phys Med Rehabil
84. Huang M, Liao LR, Pang MY: Effects of whole body vibration on muscle spasticity for people with central nervous system disorders: a systematic review. Clin Rehabil
85. Newman M, Barker K: The effect of supported standing in adults with upper motor neurone disorders: a systematic review. Clin Rehabil
86. Li TY, Chang CY, Chou YC, et al.: Effect of radial shock wave therapy on spasticity of the upper limb in patients with chronic stroke: a prospective, randomized, single blind, controlled trial. Medicine
87. Park DS, Kwon DR, Park GY, et al.: Therapeutic effect of extracorporeal shock wave therapy according to treatment session on gastrocnemius muscle spasticity in children with spastic cerebral palsy: a pilot study. Ann Rehabil Med
88. Lee JY, Kim SN, Lee IS, et al.: Effects of extracorporeal shock wave therapy on spasticity in patients after brain injury: a meta-analysis. J Phys Ther Sci
89. Gonkova MI, Ilieva EM, Ferriero G, et al.: Effect of radial shock wave therapy on muscle spasticity in children with cerebral palsy. Int J Rehabil Res
90. Sandroff BM, Pilutti LA, Benedict RH, et al.: Association between physical fitness and cognitive function in multiple sclerosis: does disability status matter? Neurorehabil Neural Repair
91. Campbell E, Coulter EH, Mattison PG, et al.: Physiotherapy rehabilitation for people with progressive multiple sclerosis: a systematic review. Arch Phys Med Rehabil
92. Toomey E, Coote SB: Physical rehabilitation interventions in nonambulatory people with multiple sclerosis: a systematic review. Int J Rehabil Res
93. Edwards T, Pilutti LA: 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
94. Fox RJ, Thompson A, Baker D, et al.: Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS. Mult Scler
95. Pandyan AD, Johnson GR, Price CI, et al.: A review of the properties and limitations of the Ashworth and modified Ashworth Scales as measures of spasticity. Clin Rehabil
96. Vattanasilp W, Ada L, Crosbie J: Contribution of thixotropy, spasticity, and contracture to ankle stiffness after stroke. J Neurol Neurosurg Psychiatry
97. Skold C, Levi R, Seiger A: Spasticity after traumatic spinal cord injury: nature, severity, and location. Arch Phys Med Rehabil
98. Wininger M, Craelius W, Settle J, et al.: Biomechanical analysis of spasticity treatment in patients with multiple sclerosis. Ther Adv Neurol Disord
99. Platz T, Eickhof C, Nuyens G, et al.: Clinical scales for the assessment of spasticity, associated phenomena, and function: a systematic review of the literature. Disabil Rehabil
100. Lechner HE, Frotzler A, Eser P: Relationship between self- and clinically rated spasticity in spinal cord injury. Arch Phys Med Rehabil
101. Craven BC, Morris AR: Modified Ashworth scale reliability for measurement of lower extremity spasticity among patients with SCI. Spinal Cord
102. Kohan AH, Abootalebi S, Khoshnevisan A, et al.: Comparison of modified Ashworth scale and Hoffmann reflex in study of spasticity. Acta Med Iran