Accepted Manuscript

Effectiveness of Neuromuscular Electrical Stimulation on Lower Limb Hemiplegic

Patients following Chronic Stroke: A Systematic Review

Zhongqiu Hong, Minghong Sui, Zhiqiang Zhuang, Huihua Liu, Xiuyuan Zheng,
Chuanping Cai, Dongmei Jin, MD

PII: S0003-9993(18)30016-9
DOI: 10.1016/j.apmr.2017.12.019
Reference: YAPMR 57116

To appear in: ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 21 July 2017

Revised Date: 9 December 2017
Accepted Date: 13 December 2017

Please cite this article as: Hong Z, Sui M, Zhuang Z, Liu H, Zheng X, Cai C, Jin D, Effectiveness of
Neuromuscular Electrical Stimulation on Lower Limb Hemiplegic Patients following Chronic Stroke:
A Systematic Review, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2018), doi:
10.1016/j.apmr.2017.12.019.

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 ACCEPTED MANUSCRIPT
Running title: Neuromuscular Electrical Stimulation on Chronic Stroke Patients

Title: Effectiveness of Neuromuscular Electrical Stimulation on Lower Limb

Hemiplegic Patients following Chronic Stroke: A Systematic Review

Authors: Zhongqiu Hong1,a, Minghong Sui2,a, Zhiqiang Zhuang1, Huihua Liu1,

Xiuyuan Zheng1, Chuanping Cai3, Dongmei Jin1 MD

＊

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1
Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun

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Yat-sen University, No.107 West Yanjiang Road, Guangzhou, 510120, Guangdong,

China

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2
Department of Rehabilitation Medicine, Shenzhen Nanshan People’s Hospital (The

Sixth People’s Hospital of Shenzhen), Shenzhen University, Shenzhen, 518052,

Guangdng, China
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3
Department of Rehabilitation Medicine, the First People’s Hospital of Foshan,
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Foshan, 528000, Guangdong, China

Corresponding Author: Dongmei Jin, Department of Rehabilitation Medicine,

＊
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No.107 West Yanjiang Road, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,
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Guangzhou 510120, China, Tel: +86 20 81332037, E-mail: dmjin@126.com

a
These authors contributed equally to this work.
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Acknowledgements: None.
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Conflict of Interest: None.

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Funding: This work was supported by Grants from the National Natural Science
Foundation of China (Grant No. 81301676) and the Natural Science Foundation of
Guangdong Province (Grant No. 2017A030313663).
 ACCEPTED MANUSCRIPT

1 Effectiveness of Neuromuscular Electrical Stimulation on Lower Limb

2 Hemiplegic Patients following Chronic Stroke: A Systematic Review

3 Abstract
4 Objective: To investigate the effectiveness of neuromuscular electrical stimulation (NMES) with

5 or without other interventions in improving lower limb activity after chronic stroke.

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6 Data Source: Electronic databases including PubMed, EMBase, Cochrane Library, PEDro

7 (Physiotherapy Evidence Database) and PsycINFO were searched from the inception to January,

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8 2017.

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9 Study Selection: We selected the randomized controlled trials (RCTs) involving chronic stroke

10 survivors with lower limb dysfunction and comparing NMES or combined with other

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11 interventions with control of no electrical-stimulated treatment.

12 Data Extraction: The primary outcome was defined as lower limb motor function, and the
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13 secondary outcomes included gait speed, Berg Balance scale, Timed Up and Go, Six-Minute

14 Walk Test, Modified Ashworth Scale and Range of Motion .

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15 Data Synthesis: Twenty-one RCTs involving 1,481 participants were identified from 5,759
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16 retrieved articles. Pooled analysis showed that NMES had a moderate but statistically significant

17 benefits on lower limb motor function (SMD 0.42, 95% CI 0.26 to 0.58), especially when NMES
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18 combined with other interventions or treatment time within either 6 or 12 weeks. NMES also had

19 significant benefits on gait speed, balance, spasticity and range of motion but had no significant
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20 difference in walking endurance after NMES.

21 Conclusion: NMES combined with or without other interventions has beneficial effects in lower
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22 limb motor function in chronic stroke survivors. These data suggest that NMES should be a
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23 promising therapy to apply in chronic stroke rehabilitation to improve the capability of lower

24 extremity in performing activities.

25

26 Keywords: neuromuscular electrical stimulation; lower limb; stroke, motor function;

27 systematic review
28

29 Abbreviations

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30 NMES=neuromuscular electrical stimulation

31 FES=functional electrical stimulation

32 TENS=transcutaneous electrical nerve stimulation

33 ES=electrical stimulation

34 RCTs=randomized controlled trials

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35 PED=physiotherapy evidence database

36 ICF=international classification of functioning

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37 BBS=berg balance scale

38 TUG=time up and go

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39 6MWT=six-minute walk test

40 10MWT=10-meter walk test

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41 MAS=modified ashworth scale
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42 ROM=range of motion

43 SMD=standard mean difference

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44 MD=mean difference

45 FDS=foot drop stimulator

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46 AFO=ankle-foot orthosis
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47 PNS= peroneal nerve stimulation

48 CI = confidence interval
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49 m/s= meters per second

50 cm/s= centimeters per second

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51
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52

53 Stroke is a leading cause of disability with high mortality and morbidity. According to the

54 American Stroke Association (ASA) statistics, stroke has affected 7 million American adults,
[1, 2]
55 accounting for 3.0% of the population from 2007 and 2010 . It is generally known that many

56 stroke survivors suffer limb paralysis, abnormal gait, aphasia, and inability to take care of
[3]
57 themselves, incurring a large burden for survivors and society . For stroke patients with

58 hemiplegia, one of the most important goals is to restore and improve the motor function of lower

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[4]
59 limbs . Approximately 78% of adult survivors will regain walking ability [5], but will continue
[6, 7]
60 to experience problems such as gait abnormality, muscle spasms, and foot drop . With

61 hemiplegia contributing significantly to this inability to perform activities after stroke, improving
[8, 9]
62 motor function recovery after stroke becomes essential . To improve lower extremity motor

63 function following stroke, interventions shall focus on not only improving the impairment level,

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64 but addressing activity dysfunction such as gait speed, moving balance or coordination.

65 In recent years, neuromuscular electrical stimulation (NMES) techniques, including

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66 functional electrical stimulation (FES) and transcutaneous electrical nerve stimulation (TENS),

67 have been addressed to activate muscles during functional tasks with the goal of improving motor

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[10,11]
68 activity performance . Several previous studies demonstrated that NMES utilization could
[12-14] [12-14]
69 increase gait speed , decrease energy expenditure during walking and improve gait

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[12, 15]
70 symmetry . However, most emerging evidence in support of the effectiveness of NMES on
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71 improving lower extremity motor function originated from non-randomized controlled trials.

72 There remains a lack of clarity on the effectiveness of NMES in chronic stroke lower extremity
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73 rehabilitation although systematic reviews have been undertaken of the efficacy of FES for

74 increasing movement and activity after stroke. In 2006, Robbins et al. reported that FES resulted
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75 in 0.18 m/s (95% CI 0.08–0.28) faster walking speed than walking training alone or no
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[16]
76 intervention, based on a meta-analysis of three controlled trials in chronic stroke . In 2012,

77 Pereira et al. showed that FES resulted in 0.38 SMD (95% CI 0.08–0.68) further walking distance
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78 than walking training alone or no intervention in view of six controlled trials in the chronic phase
[17]
79 after stroke . More recently, Howllet et al. demonstrated that FES resulted in 0.40 SMD (95%
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80 CI 0.09–0.72) on activity as compared with no intervention or placebo, and performed a small

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81 effect on gait speed (WMD 0.08 m/s, 95% CI 0.02–0.15) relative to control group based on 18

82 controlled trials in stroke survivors [18]. However, there still have several unavoidable limitations:

83 none of them systematically determined the effect of NMES on lower limb activity in chronic

84 stroke hemiplegia; not all the included trials were randomized controlled trials (RCTs); and single

85 outcome measurement was reported without comprehensive evaluation of the effectiveness of

86 NMES.

87 Therefore, it is urgent not only to update previous studies by adopting more recent RCTs but

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88 also to further explore this issue. This systematic review aims to determine the effectiveness of

89 lower limb NMES compared with the control group in improving motor function outcomes after

90 chronic stroke.

91 Methods

92 Literature-search strategy

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93 A comprehensive literature search of electronic databases including PubMed, EMBase, Cochrane

94 Library, PEDro (Physiotherapy Evidence Database) and PsycINFO from the inception to January

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95 2017 was performed to identify relevant RCTs which were reported in English language. The

96 search terms of stroke, electric stimulation, and a string of words previously proposed were used

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97 individually or in combination. To raise the sensitivity of the search, words related to the

98 outcomes of interest were not included. In addition, reference lists of retrieved articles were

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99 searched as an additional source to identify other relevant studies. The complete search strategy
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100 was conducted with the PubMed database in Supplementary Appendix.

101 Eligibility criteria for literature selection

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102 To be included in this systematic review, the studies had to meet the following predefined criteria:

103 (1) type of study design was RCT and conducted in humans; (2) recruited participants were
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104 clinically diagnosed as stroke, either ischemic or hemorrhagic, and with mean stroke onset
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105 duration more than 6 months; (3) at least one intervention group utilized NMES, either alone or in

106 combination with other treatment techniques, and regardless of FES or TENS; (4) at least one
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107 comparison group was performed; and (5) at least one outcome reflected the ICF domain of

108 activity performances. However, the exclusion criteria were as follows: stroke survivors without
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109 lower limb dysfunction, crossover studies, lacking a comparison group and acquiring insufficient
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110 data even via contacting twice the author by e-mail.

111 Data extraction

112 Data from the original documents were abstracted independently by two investigators (ZQH and

113 MHS). Any disagreement encountered was resolved by the third author (DMJ). The following

114 data were systematically extracted from each eligible study: methodological design, number of

115 subjects, comparison groups, intervention protocol, and results of the outcomes. The primary

116 outcome was those measures which conducted motor function assessment. If more than one

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117 measures were used in an individual trial, gait analysis was considered as a priority outcome

118 measure because it is more appropriate to reflect lower extremity activity recovery; otherwise

119 10-meter walk test (10MWT) and various lower limb assessment scales were taken into

120 consideration. After that, reviewers (ZQZ and HHL) selected the more suitable assessment scale

121 to better reflect the task stimulation. Furthermore, the secondary outcomes were spatiotemporal

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122 parameters which consisted of walking distances assessed by 6-minute walk test (6MWT),

123 balance assessed by Berg balance scale (BBS) or Timed up and go (TUG), spasticity assessed by

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124 Modified Ashworth Scale (MAS) and range of motion assessed by goniometer. Authors were

125 contacted twice by email for original data if the published study data were insufficient for data

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126 analyses.

127 Methodological quality assessment

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128 The methodological quality of an individual study was independently evaluated with the
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129 Cochrane “Risk of bias” tool by two review authors (ZQH and ZQZ). The Cochrane “Risk of

130 bias” tool was described in the Cochrane Handbook for Systematic Reviews of Intervention
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[19]
131 (version 5.2.0) . Any disagreement was resolved through discussion with the third reviewer

132 (DMJ).
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133 Statistical analysis

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134 We referred to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions

135 5.2.0. For quantitative synthesis, pooled effect estimates were calculated by comparing the
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136 change from baseline to end of study in each group. Regarding the continuous outcomes, if the

137 unit of measurement was consistent across trials, the results were showed as the weighted mean
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138 difference (WMD) with 95% confidence intervals (95% CIs), and if the unit of measurement was
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139 inconsistent, the results were expressed as the standard mean difference (SMD) with 95% CI.

140 Statistical heterogeneity of effect size across trials was evaluated via using a standard Chi square

141 test with significance being set at P < 0.10, in which values above 25% and 50% were considered

142 as indicatives of moderate and high heterogeneity, respectively. The random effects model was set

143 for statistical analysis due to wide clinical and methodological variability across the trials.

144 Subgroup analyses were performed to further detect potential heterogeneity which might

145 influence the magnitude of measures of efficacy. Publication bias was conducted by using funnel

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146 plots and Egger’s test. All of the data analyses were calculated by means of using Review

147 Manager 5.2.0 (The Cochrane Collaboration, Oxford, England) and Stata version 12.0 (Stata Corp,

148 College Station, TX, USA). A value of P <0.05 was considered statistically significant.

149 Results

150 Characteristics of included studies

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151 A total of 21 RCTs [20-42] with 23 comparison groups involving 1,481 patients were identified for

152 the inclusion criteria by systematically screening from 5,759 potentially relevant publications

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[30, 36, 39]
153 (Figure 1). Of these eligible trials, three additional studies were searched from the
[24, 36]
154 reference list of published articles. Two trials had three arms and were counted as two

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155 separate comparison groups, respectively. Of 21 included studies, 11 studies investigated FES
[20,21,24-29, 38-42] [34,35]
156 applied in the lower limb , 2 studies investigated NMES , 2 studies

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[22,33] [23,30]
157 investigated FDS , 2 studies investigated unspecified ES , 2 studies investigated
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158 TENS[36, 37]
and the remaining two studies investigated implantable PNS [31,32]
. However, 21

159 studies reported different primary outcomes which were described as the synthesize analysis of
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160 the walking speed, walking distance and lower limb motor function assessment scales. Of 21
[20-26, 28,31-33, 36,
161 studies, 14 studies reported walking speed assessed by gait analysis and 10MWT
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37,42-44] [27,30, 38]

162 , 3 studies provided walking distance assessed by 6MWT , and the remaining 4
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[29,34,35,39]
163 studies adopted various motor function assessment scales . The secondary outcomes

164 were performed, encompassing the breadth of the International Classification of Function model.
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[21,24, 27, 28,30,33, 38]

165 Eight comparisons assessed walking endurance using 6MWT , 8 comparisons
[21,24,25, 29,30,33,34] [21,23,
166 assessed balance using BBS , 6 comparisons assessed mobility using TUG
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29,33,34, 37] [35-37, 39]

167 , 5 comparisons assessed spasticity using MAS , and 6 comparisons assessed
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[23,35, 36,41,42]
168 ROM using goniometer . Additionally, 14 studies applied electric stimulation with

169 stimulation frequencies ranged from 15 to 50 Hz, other 3 studies employed stimulation

170 frequencies ranged from 60 to 100 Hz, and 4 studies did not describe the stimulation

171 characteristics. The mean time of intervention was 12.86 weeks (ranged from 3 to 52 weeks) in

172 21 included studies.

173 Description of enrolled patients

174 Table 1 summarizes the baseline characteristics of enrolled participants. Baseline characteristics

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175 of studied patients varied among the included trials. Generally speaking, the mean age of enrolled

176 patients ranged from 49 to 71 years old, and 56% of patients were male. Across all studies,

177 patients who had suffered stroke regardless of hemorrhage or ischemia were included with the

178 mean time after stroke ranged from more than 6 to 108 months.

179 Risk of bias assessment

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180 Table 2 and Figure 2 summarize the risk of bias evaluation for the included studies. All studies

181 utilized adequate random sequence generation and were assessed as low risk, except one study [40]

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[22-24, 27, 38, 41]
182 which was assessed as unclear risk due to the missing information. Six studies

183 described details of allocation concealment. Four of them [23, 24, 38, 41] adopted sealed envelope and

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184 one study [22] used confidential random numbers tag, which were considered as low risk; however,

185 one study [27] was assessed as high risk due to the cross-matching allocation. All but two trials did

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186 not achieve participants’ and personnel’s blinding and were assessed as high risk. These two
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187 studies [30, 33] were assessed as low risk of bias because they provided double blinding protocol in
[20, 23, 26, 31-33, 35, 37-42]
188 detail. However, there were eleven studies reporting blinding of assessors,
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189 and were assessed as low risk bias. All but three studies were assessed as low risk of bias in
[23, 28, 41]
190 incomplete outcome data. These three studies were assessed as unclear risk of bias
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191 because they did not provide reasons for the drop-outs and intention-to-treat Analysis (ITT
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192 analysis). None of the included studies provided information on selective reporting due to lack of

193 research protocol so they were assessed as unclear risk bias. Baseline balance was performed in
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[22, 33, 35]

194 all studies except three studies and therefore these three studies were assessed as high

195 risk bias in other bias owing to baseline imbalance.

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196 The primary outcome

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197 The primary outcome was the lower limb motor function which consisted of gait speed, walking

198 distance and motor function assessment scales. The outcomes were reported by 21 studies with 23

199 comparisons. Sixteen comparisons provided data of gait speed which was assessed either gait

200 analysis or 10MWT, 3 comparisons provided data of walking distance by 6MWT and 4

201 comparisons evaluated gait activity by lower limb assessment scales. Due to difference in the

202 measurement methods, SMD with 95% CI and random effect model were performed. Overall,

203 pooled analysis of 23 comparisons showed a statistically significant improvement in lower

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204 extremity motor function with NMES compared with control group (0.42 [95% CI, 0.26 to 0.58;

205 I2 34%]; Figure 3). Further subgroup analyses based on type of intervention and therapy time of

206 NMES were conducted. The subgroup analysis showed that NMES combined with other

207 treatment technique interventions resulted in significant improvement in gait activity (0.47 [95%

208 CI, 0.28 to 0.67; I2 29%]; Figure 4a), while NMES alone did not (0.25 [95% CI, -0.02 to 0.52; I2

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209 32%]; Figure 4a). Furthermore, another one subgroup analysis of therapy time of NMES

210 demonstrated that NMES therapy applied within 6 weeks or 12 weeks resulted in significant

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211 improvements in gait activity, respectively (0.51 [95% CI, 0.28 to 0.74; I2 0%] and 0.49 [95% CI,

212 0.19 to 0.79; I2 35%]; Figure 4b), while NMES therapy applied within 24 weeks did not (0.20

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213 [95% CI, -0.09 to 0.50; I2 52%]; Figure 4b).

214 The secondary outcomes

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215 Gait speed
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216 A total of 18 comparisons assessed the efficacy of NMES therapy on gait speed by gait analysis

217 and 10MWT, but 16 comparisons provided data suitable for meta-analysis. Of 16 comparisons, 14
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218 comparisons used gait analysis to evaluate gait speed and other two used 10MWT to assess gait

219 speed. Due to inconsistent unit of outcomes, the results were expressed as the SMD and used a
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220 random effect model. Meta-analysis of 16 comparisons reporting gait speed showed significant
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221 improvement compared with control group (0.41 [95% CI, 0.22 to 0.61; I2 41%]; Figure 5).

222 Further analysis to investigate the potential effectiveness of NMES on gait speed, a consistent
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223 measurement unit analysis was performed by using WMD. Eight of 14 comparisons reporting

224 unit of gait speed with meters per second (m/s) demonstrated an increase in gait speed compared
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225 with control group (0.05 [95% CI, 0.00 to 0.09; I2 54%]; Figure 6a). The other 6 comparisons
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226 using centimeters per second (cm/s) showed a significant increase in gait speed compared with

227 control group (5.82 [95% CI, 3.47 to 8.18; I2 39%]; Figure 6b).

228 Balance

229 BBS and TUG both have high reliability and validity to estimate balance on the clinical

230 rehabilitation assessment. Meta-analysis of BBS result showed a significant improvement with

231 NMES compared with control group (3.17 [95% CI, 1.31 to 5.02; I2 87%]; Figure 7a).

232 Meta-analysis of 6 comparisons reporting TUG showed a statistically significant reduction in

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233 balance with NMES relative to control group (-2.96 [95% CI, -4.34 to -1.59; I2 0%]; Figure 7b).

234 Spasticity and ROM

235 Spasticity was assessed by MAS from 5 comparisons in this article. NMES resulted in a

236 significant reduction in spasticity (-0.70 [95% CI, -0.96 to -0.44; I2 55%]; Figure 8). Furthermore,

237 meta-analysis of 5 comparisons reporting range of motion showed a statistically significant

enhancement in ROM with NMES relative to control group (3.21 [95% CI, 1.07 to 5.34; I2 61%];

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238

239 Figure 9).

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240 Walking endurance

241 Walking endurance was evaluated by 6MWT which is regarded as a commonly used

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242 activity-level measure to assess functional walking capability. Eight comparisons reported

243 walking endurance with 6MWT, but there was no significant difference between NMES group

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244 and control group (5.84 [95% CI, -2.60 to 14.29; I2 0%]; Figure 10).
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245 Publication bias of literature

246 The funnel plot was performed to examine publication bias for the primary outcomes with 21
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247 studies. Egger’s approach applied for the primary outcomes, showing the potential publication

248 bias (P=0.004; Figure S1). The publication bias was more likely to be generated from the large
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249 effects of two trials [20, 33] in this systematic review. The larger effects of these two trials were
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250 attributable to the greater non-significant improvement of lower limb motor function achieved in

251 the trials. Once these two trials were removed, the results of Egger’s test was not significant
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252 (P=0.096; Figure S2).

253 Discussion
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254 This systematic review of 21 RCTs involving 1,481 participants demonstrated NMES combined
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255 with other treatment technique had significant effects on improving lower extremity motor

256 function compared with control group in chronic stroke survivors, but a non-significant

257 improvement in motor function was found when NMES was applied alone. More importantly,

258 subgroup analyses indicated that treatment time of application NMES within 6 or 12 weeks

259 resulted in a significant improvement in motor function whereas treatment time within 24 weeks

260 was not significantly improved. Furthermore, the results of the secondary outcomes showed

261 application of NMES resulted in significant increases in gait speed, BBS and ROM and

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262 significant reductions in TUG and MAS, but a non-significant increase in 6MWT.

263 Generally speaking, the mechanism of FES contributing to lower limb motor function recovery

264 in patients with post stroke may be explained from following two aspects. One aspect is the

265 orthotic effect which means electrical stimulation can produce hemiplegic limb movement caused
[43]
266 by muscle contraction time. Kottink et al. conducted a systematic evaluation of eight articles

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267 about the effects of FES in stroke patients with FES device and used gait speed as evaluation

268 outcome. The results of this research indicated FES resulted in significant improvement of

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[16]
269 patient's walking speed. The other aspect is the delayed effect. Robbins et al. demonstrated

270 that after a period of treatment of electrical stimulation, lower limb activity capability is still

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271 significantly improved compared with the control group. It was reported that the mechanism of

272 delayed effects may relate to the plasticity of the brain and, therefore, purpose and repetition of

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273 active exercise training can enhance the movement of hemiplegic limbs. Smith et al. [44] and Han
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[45]
274 et al. found that electrical stimulation might affect physiological functions of brain by

275 activating the main motor area and supplementary motor area, and finally lead to the reduction of
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276 intracortical inhibition and the increase of the amplitude of motor evoked potentials. Smith et al.

277 observed there were obvious functional activities in the corresponding regions of a brain after
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[44]
278 using FES to stimulate the lower limb in healthy people . Arienzo et al. applied FES to
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279 stimulate the tibial nerve in healthy people and found there was a significant change in the

280 supplementary motor area by fMRI [46]. Moreover, Kimberley et al. also detected that the cerebral
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281 cortex signal significantly increased when FES was applied in stroke patients [47].

282 Gait speed is considered as a vital important indication of function and level of disability and
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[48-50]
283 the primary means of classifying ambulation status after stroke . More recently, several
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284 previous reviews evaluated gait speed using a pooled mean difference analysis between FES
[16]
285 group and control group. Robbins et al. applied FES or TENS in gait speed after stroke, and

286 found a pooled mean difference of 0.18 m/s (95% CI, 0.08-0.28; P <0.01) to favor FES versus

287 control. In addition, they also found stroke survivors in the acute or subacute period (onset <6

288 months) had a large effect size whereas a moderate effect size in chronic subjects (onset >6

289 months). Another article authored by Howltee et al. [18] showed a significant increase of 0.08 m/s

290 (95% CI, 0.02-0.15; P=0.01) in 61% stroke survivors with mean time more than 6 months. In this

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291 review, we found chronic stroke survivors randomized to NMES group had a significant

292 improvement in gait speed compared with control group by pooled analysis (SMD 0.41, 95% CI,

293 0.22 to 0.61; P <0.0001). Furthermore, data results indicated a small increase of 0.05-0.06 m/s in

294 gait speed compared with control group. As for this small effect size of gait speed distinct from

295 previous meta-analysis, the possible explanation was that earlier intervention resulted in greater

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296 gait speed changes. Nevertheless, it was noted that chronic post stroke survivors did experience

297 not only increased gait speed, but also achieved balance, spasticity and range of motion, which

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298 confirmed the previous findings that NMES treatment may potentially improve outcomes for

299 chronic post-stroke hemiplegia.

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300 When performed a sensitivity analysis of therapy time of NMES application, we found that

301 therapy time of NMES within 6 or 12 weeks showed significant benefits on lower extremity

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302 motor function recovery, but treatment time within 24 weeks showed no significant efficacy. This
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303 surprising finding may be explained as follows: the trials with treatment time within 6 weeks or

304 12 weeks both utilized NMES versus no interventions or placebo rather than AFOs, which may
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305 have not adequate time to figure out a total effect difference between FDS and AFOs. O'Dell et

306 al.[51] found measures showed a continuous linear increase in total effective gait speed for at least
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307 42 weeks of FDS utilization, and the percentage of subjects achieving clinically meaningful
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308 changes continued to increase. Therefore, three of four studies with treatment time between 26 to

309 30 weeks showing no significant total effect difference between FDS and AFOs groups may be
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310 interpreted as lacking enough time to observe a significant difference between FDS and AFOs.

311 However, another study [21] reported that 12 months (52 weeks) treatment of application peroneal
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312 nerve functional electrical stimulation (PNFES) had non-inferior to AFOs for all primary
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313 endpoints. The reason why that the PNFES and AFOs were equally beneficial is that so long-term

314 treatments for foot drop caused a non-significant total effect difference between the PNFES group

315 and the AFOs group.

316 However, our findings showed NMES with or without other interventions had significant

317 improvements in other indicators, including BBS, TUG, MAS and ROM, but had no significant

318 effects on 6MWT. Confronted with this inconsistent result, we found significant effects of NMES
[33]
319 on 6MWT when removing one study reported by Kluding et al. (WMD 12.09, 95% CI,

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320 0.57-23.62; P=0.04). The reason is that 60% of participants enrolled in this study had foot drop so

321 they received either a new or modified brace before randomization in addition to receiving

322 physiotherapy intervention to achieve enrollment standard. Thus, this might have contributed to

323 the unexpected improvements in 6MWT for the control group.

324 Study limitations

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325 Our review has several limitations. First, the strongest source of bias may be from the lack of

326 blinding of therapists and participants in the clinical trials because it is so difficult to blind them

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327 during the delivery of an intervention such as FES that data may be easily influenced by
[48]
328 observation bias . Second, we performed the primary outcome using SMD. One of the main

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329 problems associated with this is that an estimation of the benefits of NMES in real terms cannot
[53]
330 be expressed . Moreover, lacking sufficient data may limit our further examination of the

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331 therapeutic effects of NMES from main outcomes. To better investigate the association between
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332 NMES and lower limb motor function, we evaluated gait speed, balance, spasticity and range of

333 motion with available data from the retrieved studies as far as possible. Therefore, it is possible
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334 that the estimated effects of NMES may be larger than the true benefits, which were potentially

335 affected by small trial bias with small number of participants in several included studies [54]. Third,
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336 our results showed significant evidence of publication bias in our retrieved studies because of
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337 different interventions or inconsistent measurements. Hence, we attempted to perform several

338 sensitivity analyses to figure out the potential sources of publication bias. Finally, due to strict
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339 inclusion criteria of our review, future research should focus on determining the effectiveness of

340 FES and TENS in patients in the chronic stages of stroke recovery.
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341 Conclusion
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342 In summary, NMES combined with other interventions had beneficial effects on improving lower

343 extremity motor function, including gait speed, balance, spasticity and range of motion in chronic

344 stroke survivors, especially who had received 6 or 12 weeks’ NMES treatment duration. Our

345 findings may provide implications for future stroke rehabilitation for both clinicians and

346 researchers included in this review. In future research, the conduction of large scale and

347 high-quality RCTs is needed to establish its true efficacy.

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348 References
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420 28. Daly JJ, Zimbelman J, Roenigk KL, et al. Recovery of coordinated gait: randomized

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423 2011;25(7):588-96.

424 29. Hwang DY, Lee HJ, Lee GC, Lee SM. Treadmill training with tilt sensor functional electrical
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426 with chronic stroke: A randomized controlled trial. Technol Health Care 2015;23(4):443-52.
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427 30. Janssen TW, Beltman JM, Elich P, et al. Effects of electric stimulation-assisted cycling
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429 31. Kottink AI, Hermens HJ, Nene AV, Tenniglo MJ, Groothuis-Oudshoorn CG, IJzerman MJ.

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431 footdrop: a randomized controlled trial. Phys Ther 2008;88(4):437-48.

432 32. Kottink AI, Tenniglo MJ, de Vries WH, Hermens HJ, Buurke JH. Effects of an implantable

433 two-channel peroneal nerve stimulator versus conventional walking device on spatiotemporal

434 parameters and kinematics of hemiparetic gait. J Rehabil Med 2012;44(1):51-7.

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435 33. Kluding PM, Dunning K, O'Dell MW, et al. Foot drop stimulation versus ankle foot orthosis

436 after stroke: 30-week outcomes. Stroke 2013;44(6):1660-9.

437 34. Lee D, Lee G, Jeong J. Mirror Therapy with Neuromuscular Electrical Stimulation for

438 improving motor function of stroke survivors: A pilot randomized clinical study. Technol Health

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440 35. Mesci N, Ozdemir F, Kabayel DD, Tokuc B. The effects of neuromuscular electrical

441 stimulation on clinical improvement in hemiplegic lower extremity rehabilitation in chronic

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443 36. Ng SS, Hui-Chan CW. Transcutaneous electrical nerve stimulation combined with

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445 2007;38(11):2953-9.

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446 37. Park J, Seo D, Choi W, Lee S. The effects of exercise with TENS on spasticity, balance, and
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453 dorsiflexor muscle: effects on dorsiflexor strength, plantarflexor spasticity, and motor recovery in
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455 40. Sabut SK, Sikdar C, Mondal R, Kumar R, Mahadevappa M. Restoration of gait and motor
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457 2010;32(19):1594-603.

458 41. Sheffler LR, Taylor PN, Gunzler DD, Buurke JH, Ijzerman MJ, Chae J. Randomized

459 controlled trial of surface peroneal nerve stimulation for motor relearning in lower limb

460 hemiparesis. Arch Phys Med Rehabil 2013;94(6):1007-14.

461 42. Sheffler LR, Taylor PN, Bailey SN, et al. Surface peroneal nerve stimulation in lower limb

462 hemiparesis: effect on quantitative gait parameters. Am J Phys Med Rehabil 2015;94(5):341-57.

463 43. Kottink AI, Oostendorp LJ, Buurke JH, Nene AV, Hermens HJ, IJzerman MJ. The orthotic

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464 effect of functional electrical stimulation on the improvement of walking in stroke patients with a

465 dropped foot: a systematic review. Artif Organs 2004;28(6):577-86.

466 44. Smith GV, Alon G, Roys SR, Gullapalli RP. Functional MRI determination of a dose-response

467 relationship to lower extremity neuromuscular electrical stimulation in healthy subjects. Exp

468 Brain Res 2003;150(1):33-9.

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469 45. Han BS, Jang SH, Chang Y, Byun WM, Lim SK, Kang DS. Functional magnetic resonance

470 image finding of cortical activation by neuromuscular electrical stimulation on wrist extensor

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471 muscles. Am J Phys Med Rehabil 2003;82(1):17-20.

472 46. Arienzo D, Babiloni C, Ferretti A, et al. Somatotopy of anterior cingulate cortex (ACC) and

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473 supplementary motor area (SMA) for electric stimulation of the median and tibial nerves: an

474 fMRI study. Neuroimage 2006;33(2):700-5.

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475 47. Kimberley TJ, Lewis SM, Auerbach EJ, Dorsey LL, Lojovich JM, Carey JR. Electrical
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476 stimulation driving functional improvements and cortical changes in subjects with stroke. Exp

477 Brain Res 2004;154(4):450-60.

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478 48. Perry J, Garrett M, Gronley JK, Mulroy SJ. Classifcation of walking handicap in the stroke

479 population. Stroke 1995;26:982–9.

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480 49. Lord SE, McPherson K, McNaughton HK, Rochester L, Weatherall M. Community
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481 ambulation after stroke: how important and obtainable is it and what measures appear predictive?

482 Arch Phys Med Rehabil 2004;85:234–9.

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483 50. Nadeau S, Arsenault AB, Gravel D, Bourbonnais D. Analysis of the clinical factors

484 determining natural and maximal gait speeds in adults with a stroke. Am J Phys Med Rehabil
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485 1999;78:123–30
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486 51. O'Dell MW, Dunning K, Kluding P, et al. Response and prediction of improvement in gait

487 speed from functional electrical stimulation in persons with poststroke drop foot. PM R

488 2014;6(7):587-601

489 52. chulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of

490 methodological quality associated with estimates of treatment effects in controlled trials. JAMA

491 1995;273(5):408-12.

492 53. Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence of trial sample size on treatment

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493 effect estimates: meta-epidemiological study. BMJ 2013;346:f2304.

494 54. Johnston BC, Thorlund K, Schünemann HJ, et al. Improving the interpretation of quality of

495 life evidence in meta-analyses: the application of minimal important difference units. Health Qual

496 Life Outcomes 2010;8:116.

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519 Figure Legends

Figure 1 Flowchart of process for selection of articles.

Figure 2 Risk of bias assessment of included studies.

Figure 3 Pool analysis the effectiveness of neuromuscular electrical stimulation on lower limb

motor function by SMD (95% CI) from 23 comparisons (n=1239)

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Figure 4 Sensitivity analyses the effectiveness of neuromuscular electrical stimulation on lower

limb motor function based on type of interventions (a) and duration of interventions (b) by SMD

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(95% CI) from 23 comparisons (n=1239), respectively.

Figure 5 Pool analysis the effectiveness of neuromuscular electrical stimulation on gait speed by

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SMD (95% CI) from 16 comparisons (n=1020)

Figure 6 Subgroup analyses the effectiveness of neuromuscular electrical stimulation on gait

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speed based on unit of measurement of m/s (a) from 8 comparisons (n=438) and cm/s (b) from 6
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comparisons (n=166) by WMD (95% CI).

Figure 7 Pool analysis the effectiveness of neuromuscular electrical stimulation on balance based
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on BBS (a) from 8 comparisons (n=708) and TUG (b) from 6 comparisons (n=697) by WMD

(95% CI).
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Figure 8 Pool analysis the effectiveness of neuromuscular electrical stimulation on spasicity

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based on MAS from 5 comparisons (n=200) by WMD (95% CI).

Figure 9 Pool analysis the effectiveness of neuromuscular electrical stimulation on range of

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motion based on goniometer from 5 comparisons (n=219) by WMD (95% CI).

Figure 10 Pool analysis the effectiveness of neuromuscular electrical stimulation on walking

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endurance based on 6MWT from 8 comparisons (n=738) by WMD (95% CI).

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Figure S1 Funnel plot of the primary outcomes (N=21).

Figure S2 Correction funnel plot of the primary outcomes (N=19).

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Table 1 Characteristic of included trials in meta-

meta-analysis (N=23)
Enrolled Interventions
Author,Year Comparators Number(I/C) Age(I/C) Post-
Post-stroke Main Outcomes Interventi
Masculine on
Numbe (I/C) (M±SD) Duration(I/C)(M Measure Times
r ±SD)
Bethoux,2015 495 FES AFO 242/2 147/157 63.87±11.33/64.3 6.9±6.41/6.86±6 6MWT 10MWT 52 weeks

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[24,25] 53 ±12.01 .64* TUG
Buridge,1997 32 ODFS PT PT 16/16 10/13 52.3±14.3/61.3±8. 3.58/4.92* 10MWT 13 weeks

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[26] 6
Cheng,2010 [27] 15 ES motor General 8/7 5/7 52.87±8.74/58.43 33.6±37.9/33.6± GA 4 weeks
training exerise ±5.06 28.1

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Cho,2015 [28] 21 FES(GM TA) TT RPT 10/11 7/5 57.0±9.1/57.8±7.9 22.5±12.6/21.6± 6MWT GA 4 weeks
TT RPT 6.7 BBS

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Cho ,2015 [28] 21 FES(TA) TT TT RPT 10/11 7/5 53.3±9.2/57.8±7.9 22.5±14.1/21.6± 6MWT GA 4 weeks
RPT 6.7 BBS

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Chung,2014 [29] 18 FES GT 9/9 7/7 60.0±7.5/56.6± 25.4±3.2/24.9 GA BBS 6 weeks
7.6 ±3.1
Cozean,1988 19 FES RPT RPT 10/9 6/6 52/62 >1/> GA 6 weeks

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[30] 1*
Daly,2006 [31] 32 FES BWSTT Non-FNS 14/15 11/11 57.7±11.9/63.6±1 3.6±3.8/3.3±2. 6MWT 12 weeks

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BWSTT 0.4 1*
Daly,2011 [32] 53 FES BWSTT BWSTT 20/24 15/17 59/62 2.8±3.3/2.6±3. 6MWT GA 12 weeks

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0*
Hwang,2015 32 FES TT TT Placebo 15/15 9/8 50.0±7.55/49.47± 94.07±18.95/192.5 10MWT TUG 4 weeks
[33] 5.01 3±18.79 BBS
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Janssen,2008 12 ES LCE LCE 6/6 3/3 54.2±10.7/55.3 12.3±5.4/18.3 6MWT BBS 6 weeks
[34] ±10.4 ±9.9
Kottink,2008 29 Walking 13/12 10/ 55.2±11.36/52.87 9.07±9.29/5.67± 26 weeks
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Implantable PNS GA
[35] device 7 ±9.87 4.64*
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Kottink,2012 23 Implantable PNS Walking 9/12 7/7 55.6±13.16/53.33 9.0±10.04/6.15± GA 26 weeks

[36] device ±10.55 4.81*
Kulding,2013 197 FDS PT AFO PT 74/88 51/67 60.71±12.24/61.5 4.77±5.29/4.34± 6MWT GA 30 weeks
[37] 8±10.98 4.1* TUG BBS
Lee,2016 [38] 27 NMES MT CPT 14/13 7/7 55.71±6.70/53.62 36.79±26.07/42.5 6MWT MAS 4 weeks
CPT ±6.29 4±33.9 TUG BBS
Mesci,2009 [39] 40 NMES CRP CRP 20/20 12/11 62.6±7.5/59.1±8.6 9.45±4.8/7.3±4. MAS ROM 4 weeks
42
Ng,2007 [40] 88 TNES TRT Placebo 21/20 16/17 58.4±7.1/57.1±7.8 5.0±3.0/4.7±4. GA MAS 4 weeks
TRT 1* ROM
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Ng#,2007 [40] 88 TNES RPT 19/20 17/17 56.4±9.1/57.3±8.6 6.2±4.1/5.2±2. GA MAS 4 weeks
9* ROM
Park,2013 [41] 34 TNES TE TE 15/14 12/ 71.2±3.46/71.14± 18.66±2.46/18.57 GA TUG MAS 6 weeks
8 3.82 ±1.74
Peurala,2005 45 FES GT GT 15/15 13/13 53.3±8.9/51.2±7.9 2.6±2.4/2.4±2. 6MWT 10MWT 3 weeks

PT
[42] 6*
Sabut,2011 [43] 51 FES CPT CPT 27/24 4/2 49.1±8.8/50.1±10. 17.3±18.8/18.2± MAS ROM 12 weeks
4 11.8

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Sabut,2010 [44] 30 FES PT PT 16/14 12/12 49.5±8.9/47.1±12. 20/1 GA MAS 12 weeks
4 5 ROM

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Sheffler,2015 110 PNS (FES ) UC 39/45 NA 52.8±12.2/53.2±1 44.7±97.5/44.9± GA 24 weeks
[45,46] 0.1 79.2
*Data indicates years, §Data indicates days.Cho# and Cho are two different trials in one article.Ng# and Ng are two different trials in one article.

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FES=functional electric stimulation, AFO=ankle-foot orthosis, ODFS=odstock dropped foot stimulator, ES=electric stimulation, PT=physiotherapy,
TT=treadmill training, GM=gluteus medius, TA= tibialis anterior, RPT=regular physical therapy, BWSTT=body weight–supported treadmill training,

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LCE=leg cycling exercise, PNS=peroneal nerve stimulation, FDS= foot drop stimulator, MT=mirror therapy, CPT=conventional physical therapy,
CRP=conventional rehabilitation program, TNES=transcutaneous electrical nerve stimulation, TRT=task-related training, TE=therapeutic exercise, GT=
gait trainer exercise, UC=usual care. 6MWT=6-minute walk test, 10MWT=10-Meter Walk Test , TUG=Timed up and go, BBS=Berg balance scale, GA=gait

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analysis, MAS=modified ashworth scale, ROM=range of motion.

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Table 2.Quality of trials included in the systematic review according to the Cochrane Risk-of-Bias Tool (N=21)

Allocation Blinding of Assessor Incomplete Selective

Sequence Other Bias
Study (Author, Year) Concealment Patients Blinding Outcome Data Reporting
Generation

Bethoux et al,2015 Low NR High Low Low NR Low

Buridge et al,1997 Low Low High NR Low NR High
Cheng et al,2010 Low Low High Low NR NR Low
Cho et al,2015 Low NR High NR Low NR NR
Chung,2014 Low Low High NR Low NR Low

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Cozean et al,1988 Low NR High Low Low NR Low
Daly et al,2006 Low High High NR Low NR Low
Daly et al,2011 Low NR High NR NR NR Low

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Hwang et al,2015 Low NR High NR Low NR Low
Janseen et al,2008 Low NR Low NR Low NR Low
Kottink et al,2008 Low NR High Low Low NR Low

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Kottink et al,2012 Low NR High Low Low NR Low
Kulding et al,2013 Low NR Low Low Low NR High
Lee et al,2016 Low NR High NR Low NR Low

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Mesci etal,2009 Low NR High Low Low NR High
Ng et al,2007 Low NR High NR Low NR Low
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Park et al,2013 Low NR High NR Low NR Low
Peurala et al,2005 Low Low High Low Low NR Low
Sabut et al,2010 NR NR High Low Low NR Low
Sabut et al,2011 Low NR High
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Low Low NR Low

Sheffler et al,2015 Low Low High Low NR NR Low
NR indicates not reported.
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Search strategy for PubMed database

“Stroke”[Mesh] OR “Stroke” OR “Strokes” OR “Apoplexy” OR “CVA

(Cerebrovascular Accident)” OR “CVAs (Cerebrovascular Accident)” OR
“Cerebrovascular Accident” OR “Cerebrovascular Accidents” OR “Cerebrovascular
Apoplexy” OR “Apoplexy, Cerebrovascular” OR “Cerebrovascular Stroke” OR
“Cerebrovascular Strokes” OR “Stroke, Cerebrovascular” OR “Strokes,

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Cerebrovascular” OR “Vascular Accident, Brain” OR “Brain Vascular Accident” OR
“Brain Vascular Accidents” OR “Vascular Accidents, Brain” OR “Cerebral Stroke”
OR “Cerebral Strokes” OR “Stroke, Cerebral” OR “Strokes, Cerebral” OR “Stroke,

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Acute” OR “Acute Stroke” OR “Acute Strokes” OR “Strokes, Acute” OR
“Cerebrovascular Accident, Acute” OR “Acute Cerebrovascular Accident” OR “Acute
Cerebrovascular Accidents” OR “Cerebrovascular Accidents, Acute”

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AND

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“Electrical Stimulation”[Mesh] OR “Electrical Stimulation” OR “Electrical
Stimulations” OR “Stimulation, Electrical” OR “Stimulations, Electrical” OR
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“Stimulation, Electric” OR “Electric Stimulations” OR “Stimulations, Electric” OR
“ElectricStimulation Therapy” [Mesh] OR “Stimulation Therapy, Electric” OR
“Therapy, Electric Stimulation” OR “Electrotherapy” OR “Therapeutic Electric
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Stimulation” OR “Electric Stimulation, Therapeutic” OR “Stimulation, Therapeutic

Electric” OR “Electrical Stimulation Therapy” OR “Stimulation Therapy, Electrical”
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OR “Therapy, Electrical Stimulation” OR “Therapeutic Electrical Stimulation” OR

“Electrical Stimulation, Therapeutic” OR “Stimulation, Therapeutic Electrical” OR
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“Neuromuscular Electrical Stimulation” OR “Functional Electrical Stimulation”

AND
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(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized

controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR
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single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR (“clinical
trial”[tw]) OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND
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(mask*[tw] OR blind*[tw])) OR (“latin square”[tw]) OR placebos [mh] OR

placebo*[tw] OR random*[tw] OR research design [mh] OR comparative study [mh]
OR evaluation studies [mh]OR follow-up studies [mh] OR prospective studies [mh]
OR control*[tw] OR prospectiv*[tw] OR volunteer*[tw]) NOT (animal [mh]).