Effects of Neuromuscular Electrical Stimulation on Hemiplegic Upper Limb of Stroke Survivors: A Meta-Analysis of Randomized Controlled Trials

Background: Whether NMES helps the recovery of upper limb function in patients with hemiparesis has not been confirmed. We conducted this meta-analysis to examine the effectiveness of neuromuscular electrical stimulation (NMES) for upper limb hemiparesis after stroke. Methods: Data sources such as Pubmed, Embase and Cochrane library databases were searched for all relevant studies that were carried out before December 1, 2018.We selected the randomized controlled trials (RCTs) which included chronic and acute stroke patients with upper extremity dysfunction. Then the intervention group which applied NMES was compared with a control group without NMES. Results: A total of 16 RCTs involving 691 patients were discerned from 248 searched articles. According to the forest plot ,NMES had a significant benefit on FMA-ue scale(SMD=0.44,95%CI 0.13 to 0.74,P=0.006).Also, NMES was positive for ARAT(SMD=0.31,95%CI 0.05 to 0.58,P=0.019)and MAL-AOU(SMD=0.59,95%CI 0.15 to1.04,P=0.009),but not for wrist MAS(SMD=-0.12,95%CI -0.43 to 0.19,P=0.434) or BI(SMD=0.51,95%CI -0.65 to 1.66,P=0.392). Conclusion: NMES application has beneficial impacts on upper extremity motor function in patients with stroke. This study suggests that NMES ought to be applied as a beneficial rehabilitation means in improving the upper function.

Conclusion: NMES application has beneficial impacts on upper extremity motor function in patients with stroke. This study suggests that NMES ought to be applied as a beneficial rehabilitation means in improving the upper function.

Background
Stroke accounts for at least 5% of all disability-adjusted life years (DALYs), and 10% of all deaths worldwide 1,2 . Overall, the total global burden of stroke is increasing, and the majority of this burden (over 75% stroke deaths and 81% of DALYs) comes 3 from low-and middle-income countries 3 . Importantly, over two-thirds of stroke deaths worldwide are in developing countries 4 . The most common complication among hemiplegic patients after stroke is the limitation in activity of the upper limb, and recovery is often observed to be poor 5 . Muscle paresis/weakness and hypertonia/spasticity can be impediments to motor function and cause pain 6 . The most frequently received complaint during upper limb physical treatment is the pain associated with passive exercise 5 .Under this condition, the application of NMES can stimulate muscles, change muscle paresis/weakness or hypertonia/spasticity to relieve pain from passive exercise. In addition, due to somatosensory changes, muscle fiber contents, the motor unit recruitment ability is reduced, also reducing its exercise capacity 7 . To facilitate recovery from this condition, NMES does not only alleviate disability through promoting the recovery of volitional movement (therapeutic effect),but also replace lost volitional movement (neuroprosthetic effect) 8 . Additionally, NMES therapy can also be used for strength training in disuse muscle atrophy caused due to long-term inactivity, surgery or injury, thereby maintaining muscle mass, improving joint mobility, promoting voluntary muscle control, and reducing paralysis 9 . NMES therapy is not the simply electrical stimulation, it also involved functional electrical stimulation (FES), therapeutic electrical stimulation (TES) , electromyogram (EMG) triggered NMES and so on 10 .
NMES contains the use of a battery-operated, small self-adhesive electrode, producing controllable stimulation, which drives the muscle contraction capacity from 20% to 40% 11,12 . This analysis was designed to examine the effectiveness of the NMES intervention in improving upper extremity motor function in hemiparesis 4 patients after stroke when compared to a control group.

Literature search
At the time of initial online retrieval, two independent investigators (ZWY and PSY) assessed the titles and abstracts of the articles and relevant references and then screened out the necessary data from accessible full-text articles. An online article search included two aspects: (i) Clinical studies published in the following electronic databases: PubMed, Embase, and Cochrane Library, (ii) several Chinese articles which found in the references [13][14][15] . All the studies included in this work were Inclusion and exclusion criteria: The purpose of this study was to explore the role of NMES in the recovery of upper limb function in stroke patient. Subjects of both sexes, aged more than 18 years, Inclusion criteria for selecting the articles included: (1) the design of selected trials were randomized controlled trials RCTs and participants were human, (2) the participants were clinically diagnosed as having acute or chronic hemiplegia after stroke with stable vital signs, (3) all experimental groups applied NMES such as FES, EMG-triggered NMES and, (4) at least one contrast group was included,(5) the study aim of the included trials were patients' upper limbs,(6) the parameters in the trials included at least the FMA-ue, ARAT, MAL-AOU or wrist MAS, and (7) the data of selected trials must included mean ± SD (or 95%CI) in order to conduct forest plot analysis.Additionally, the exclusion criteria were set as follows: (1) stroke survivors without hemiparesis, (2) age <18 years or pregnant, (3) lacking a contrast group and insufficient data even after contacting the author twice by e-mail, (4) intervention duration of <2 weeks, (5)the main measurement scales were not include FMA-ue or ARAT, and (6) the included trials focused only on lower limb studies.
Data extraction: Type of study design, characteristics of participants, number of patients, duration of intervention, main outcome measures, year of publication, gender, and type of interventions were extracted and showed in the Table1. Also included were the mean ± SD (or 95%CI) of all previously specified measures. Only data of the intervention period between 2 weeks and 24 weeks were extracted to control the relative heterogeneity. Emails were sent to the authors in order to obtain complete data in case they were incomplete.

Study quality assessment:
ZWY and PSY assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions 16 . As per this guide; the study quality assessment was divided into six aspects: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias. Each aspect of the risk of bias involved 3 evaluation results: low, unclear, or high. The outcomes of assessment were illustrated in the Results section. In addition, Funnel plots, Egger's test and Begg's test were applied to assess the publication bias of literature.

6
Statistical analysis: We applied the Stata version 12.0 (Stata Corporation, College Station, TX, USA) to analyze these trials. Only continuous variables were available and were extracted in this analysis. Among all, 16 RCTs data were all Mean ± SD and two were 95%CI 17,18 . The Chi-squared and I-square (I 2 ) tests were used to analyse trial statistical heterogeneity. The random-effects model was used to study the obvious heterogeneity (P < 0.1 and I 2 > 50%) 19 ; in other cases, a fixed-effect model was conducted. We assumed the heterogeneity exist among selected trials and applied random-effects model to verify it. If not, fixed-effect model was conducted. When P-value<0.05, it implied that the statistical significance existed between the intervention and control group. In addition, when the SMD value was closing to 0 (P > 0.05), it showed that no statistical significance existed. And a "significant finding" means that the SMD value was far from 0(P < 0.05). Subgroup analyses were conducted based on the duration of intervention (≤4weeks and 4weeks) and area (North America, Europe, and Asia).

Summary of included studies
On initial online search and relevant references, 248 articles were included. Filter by title, abstract, repetition, and content, most of the unqualified articles have been filtered out. Careful assessment of 21 full-text articles led to the exclusion of 2 studies 20, 21 because of lacking a control group, another 3 studies 22-24 were excluded due to incomplete data. Therefore, a total of 16 randomized controlled trials (RCTs) with 691 acute or chronic individuals fulfilled the inclusion criteria and 7 were applied to this meta-analysis. The detailed screening process was showed in the form of PRISMA diagram 25 in Fig 1. The summary of the basic characteristics of the included studies is presented in Table 1. The 5 studies 13-15, 17, 26 were performed in China, and 2 were conducted in Japan 27, 28 and 3 were conducted in America 18,29,30  Data quality: The assessment regarding the risk of bias among each trial is shown in Supplementary file S1. Amongst all, these selected trials were different in study quality: besides 12 17,18,26,[28][29][30][31][32][33][34][35][36] blind trials were at low risk of bias, one study 27 was assessed as high risk of bias out of not blind. 2 35, 36 trials adopted concealed allocation, which were regarded as low risk of bias. Also, all of the involved trials were at an unclear risk of bias in selective reporting. One study 34 was at high risk of bias due to incomplete outcome data. Moreover, 6 studies 17, 18, 28, 31, 33, 35 were at low risk of bias due to random sequence generation by computer or pseudorandom number sequence. One study 36 was at high risk of bias 8 for free of other sources of bias.

Publication bias of literature
To evaluate the publication bias, Funnel plots, Egger's test and Begg's test were conducted successively, except the condition that selected trials were less than 10 in each meta-analysis. In this meta-analysis, only the FMA-ue scale met the above standard ,which involved total 16 trials. So the Begg 's and Egger's approaches can be assessed (P=0.224)( in Fig 3), and was deemed to show no publication bias. The best recovery period is around the first 10 weeks after the occurrence of stroke, with chances of spontaneous neurological recovery 38,39 , and 4% to 27% poststroke spasticity usually occurs during1-4 week's post-stroke, so we selected 4 weeks as a boundary 40 . In addition, the experiments by Fang et al (2004) 13 and Li et al (2009) 15 considered the duration of the rehabilitation as an intervention period, so the typical intervention period was not mentioned but definitely more than 4 weeks . In this analysis, SMD was used to measure the experimental data instead of WMD due to the mean difference was too large and exceeded 10 times in the value of scales.

Discussion
After further analysis, we figured out that the trial of Hua Fang 13 contributed to the relatively high heterogeneity in BI score.And the heterogeneity would be reduced by 20% after dropping this trial. Usually, the major negative reaction of muscle discomfort was detected which was caused due to excessive muscle stimulation and improper adaptation to electrical stimulation. And this negative effect could be reduced by adjusting the NMES parameters and intensity 41 . However, during NMES therapy in these selected trials, no adverse effect was reported.
There are still some limitations in this analysis; the findings should be interpreted cautiously. First, we involved 3 trials [13][14][15] , which were published in China not in SCI journals, low assessment may affect the overall results of the analysis, and the impact of NMES may have been assessed to be greater than actual, due to small bias. In addition, the relatively small sample size may give an uncorrected conclusion. Besides these selected RCTs, one trial 14 used NMES as a the control group and contra laterally controlled functional electrical stimulation (CCFES) was considered as the experimental group. But in this study ,NMES group was selected as the intervention group. Finally, bias exists due to lack of blinded experimenters and participants. This is because it is difficult to get rid of observation bias during an intervention such as EMG-triggered NMES and so on.

Conclusion
To conclude, NMES has a positive influence on improving upper limb motor function, involving FMA-ue, ARAT and MAL-AOU in hemiplegic patients, specific to NMES therapy within 4 weeks. Our study may offer therapists a guide for future hemiparesis rehabilitation in patients after stroke. However, further studies including larger size and higher quality trials are needed to determine its true efficacy.

Ethics approval and consent to participate
Not applicable.

Competing interests
Authors have no competing interests.

Funding
The article processing charge was funded by the Natural Science Foundation of

Availability of data and materials
The tables and figures supporting the conclusions of this article are included within the article.

Authors' contributions
WYZ and SYP contributed to the conception and design of the study. WYZ