Electroacupuncture for Poststroke Spasticity: A Systematic Review and Meta-Analysis

Electroacupuncture for Poststroke Spasticity: A Systematic Review and Meta-Analysis

Accepted Manuscript Electro-acupuncture for post-stroke spasticity: a systematic review and meta-analysis Yiyi Cai, MMed, Claire Shuiqing Zhang, PhD, ...

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Accepted Manuscript Electro-acupuncture for post-stroke spasticity: a systematic review and meta-analysis Yiyi Cai, MMed, Claire Shuiqing Zhang, PhD, Shaonan Liu, MMed, Zehuai Wen, MD, Anthony Lin Zhang, PhD, Xinfeng Guo, PhD, Chuanjian Lu, PhD, Charlie C. Xue, PhD PII:

S0003-9993(17)30257-5

DOI:

10.1016/j.apmr.2017.03.023

Reference:

YAPMR 56867

To appear in:

ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 4 February 2017 Revised Date:

22 March 2017

Accepted Date: 24 March 2017

Please cite this article as: Cai Y, Zhang CS, Liu S, Wen Z, Zhang AL, Guo X, Lu C, Xue CC, Electroacupuncture for post-stroke spasticity: a systematic review and meta-analysis, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2017), doi: 10.1016/j.apmr.2017.03.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Running head: Electro-acupuncture decreases spasticity

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Title: Electro-acupuncture for post-stroke spasticity: a systematic review and meta-analysis

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Authors: Yiyi Cai1,2, MMed, Claire Shuiqing Zhang1, PhD, Shaonan Liu2, MMed, Zehuai Wen2, MD,

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Anthony Lin Zhang1, PhD, Xinfeng Guo2, PhD, Chuanjian Lu2,1*, PhD, Charlie C. Xue1,2* , PhD

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Sciences, RMIT University, Melbourne, Australia

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University of Chinese Medicine), Guangdong Provincial Academy of Chinese Medical Sciences, and The

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Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China

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China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical

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Guangdong Provincial Hospital of Chinese Medicine (The Second Affiliated Hospital of Guangzhou

*Corresponding author 1: Charlie Changli Xue, School of Health and Biomedical Sciences, RMIT

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University, PO Box 71, Bundoora, VIC. 3083, Australia, Tel: +61-399257360, Fax: +61 399256539, E-mail:

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[email protected]

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*Corresponding author 2: Chuanjian Lu, Guangdong Provincial Hospital of Chinese Medicine,

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Guangzhou, 510120, China, Tel: +862081887233, Fax: +8620-81874903, E-mail:

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[email protected]

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Keywords: stroke, muscle spasticity, acupuncture, traditional Chinese medicine, meta-analysis

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Acknowledgements: This work was supported by Guangdong Provincial Science and Technology

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Department and the Guangdong Provincial Academy of Chinese Medical Sciences (GPACMS) (Grant No.

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2012A032500009); and partially supported by a grant from the International Science and Technology

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Cooperation Project of the Ministry of Science and Technology of China (Grant No. 2012DFA31760) and

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the China-Australia International Research Centre for Chinese Medicine, funded by the Guangdong

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Provincial Academy of Chinese Medical Sciences and Guangdong Provincial Hospital of Chinese Medicine

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(GPACMS and GPHCM), Guangdong China and RMIT University, Australia.

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The authors declare no conflicts of interest.

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Electro-acupuncture for post-stroke spasticity: a systematic review and meta-

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analysis

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Abstract

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Objective: To evaluate the effects and safety of electro-acupuncture (EA) for stroke patients

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with spasticity.

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Data Sources: Five English (PubMed, EMBASE, CINAHL, Cochrane Central Register of

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Controlled Trials and AMED) and four Chinese databases (CBM, CNKI, CQVIP and

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Wanfang) were searched from their inception to September 2016.

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Data Selection: Randomized controlled trials were included if they measured spasticity with

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Modified Ashworth Scale in stroke patients and investigated the add-on effects of electro-

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acupuncture to routine pharmacotherapy and rehabilitation therapies.

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Data Extraction: Information on patients, study design, treatment details and outcomes

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assessing spasticity severity, motor function and activity of daily living were extracted.

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Data Synthesis: In total, 22 trials met the search criteria and were included involving 1,425

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participants. The estimated add-on effects of EA to reduce spasticity in upper limb measured

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by MAS (SMD: -0.57[-0.84, -0.29]) and improve overall motor function measured by FMA

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(MD: 10.60[8.67, 12.53]) were significant. It was also found that for spasticity in lower limb,

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lower-limb motor function and activity of daily living, significant add-on effects of EA were

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also shown (SMD: -0.88[-1.42, -0.35], MD:4.42[0.06, 8.78] and MD: 6.85[3.64, 10.05]

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respectively), though with high heterogeneity. For upper-limb motor function, no significant

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add-on effects of EA was received.

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Conclusions: Electro-acupuncture combined with conventional routine care has the potential

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of reducing spasticity in upper and lower limb and improving overall and lower extremity

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ACCEPTED MANUSCRIPT motor function and activity of daily living for spasticity patients within 180 days post stroke.

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Further studies of high methodological and reporting quality are needed to confirm the effects

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and safety of electro-acupuncture, and to explore the adequate and optimal protocol of EA for

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post-stroke spasticity incorporating a group of comprehensive outcome measures in different

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populations.

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Key Words: stroke, spasticity, acupuncture, systematic review, meta-analysis

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List of abbreviations: Acupuncture Points

AMED

Allied and Complementary Medicine Database

BI

Barthel Index

CBM

Chinese Biomedical Database

CENTRAL

Cochrane Central Register of Controlled Trials

CINAHL

Cumulative Index to Nursing and Allied Health Literature

CMFM

Gross Motor Function Measure

CNKI

Chinese National Knowledge Infrastructure (full text)

CQVIP

Chongqing VIP Database (full text)

CT EA FMA

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Acupoints

Composite Spasticity Scale

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Computed Tomography

Electro-acupuncture

Fugl-Meyer Assessment of Sensorimotor Recovery

ITT analysis

Intention-to-treat Analysis

MAS

Modified Ashworth Scale

MCID

Minimal Clinical Important Difference

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ACCEPTED MANUSCRIPT Mean Difference

MDD

Minimal Detectable Difference

MRI

Magnetic Resonance Imaging

RC

routine care

RevMan

Review Manager

SMD

Standardized Mean Difference

STRICTA

Standards for Reporting Intervention in Clinical Trials of Acupuncture

Wanfang

Wanfang Database (full text)

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Stroke has become a significant burden across the globe with one-third sufferers left

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permanently disabled 1. Spasticity is one of the most commonly seen complications after

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stroke, affecting around 20-50% of survivors 2-4. Post-stroke spasticity not only adversely

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affects physical functions, such as walking, difficulty in changing positions, but also

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negatively impacts quality of life, including negative effects resulting from pressure ulcers

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and difficulty in bowel and bladder care, et al 5-8.

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Treatment for spasticity is not selected sorely based on the severity of spasticity. Most

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clinical guidelines prioritise non-pharmacological interventions, such as stretching and

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splinting, in the management of spasticity 9-15. Oral medications including baclofen, or

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invasive therapies, such as botulinum injection and chemical neurolysis, should be considered

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for moderate or severe cases; while intrathecal baclofen is usually considered in severe

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generalized spasticity when no response is achieved with conservative options 16-18. However,

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though with current treatment, moderate to severe disability was observed in more than half

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of stroke patients with spasticity 19. The relatively short-term effects and heavy financial

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ACCEPTED MANUSCRIPT burden with current therapies are attached to great concern 20, 21. Besides, some unwanted

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risks with oral anti-spasticity medications, such as increase in muscle weakness, might limit

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their use 22. Due to the above mentioned limitations and uncertainty in clinical practice, to

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achieve a better control of spasticity with less adverse events, stroke patients with spasticity

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are in need of new therapies.

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Acupuncture has been practised in China for a long time and increasingly popular in western

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countries in recent decades 23. When electrical stimulation is applied through a small electric

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current passing between pairs of acupuncture needles, it is then known as electro-acupuncture

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(EA) 24. Compared to manual acupuncture, EA can provide a constant stimulation, whose

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intensity, frequency and duration are quantifiable 24. Therefore, on one hand, EA enables

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clinicians to apply a standardized treatment in clinical practice. On the other hand, when

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intervention could be specifically defined, studies on different parameters would be possible,

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and a relatively higher reporting quality may be achieved. A cross-over clinical trial had

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suggested that EA combined with traditional rehabilitation therapies could reduce spasticity

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of the wrist joint in chronic stroke survivors 25. However, no published systematic review

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focused specifically on the effects of EA for post-stroke spasticity. Although the results of

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three published systematic reviews with meta-analyses of acupuncture for post-stroke

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spasticity suggested positive add-on effects of EA, their results could not be confirmed

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partially due to the small number of the included studies 23, 26.

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Compared to published systematic review, we conducted a more comprehensive search of

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five English and four Chinese databases and updated the search time to September 2016, with

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an aim to evaluate the add-on effects and safety of EA for post-stroke spasticity.

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Methods

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Literature search

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Nine databases were searched from their inception to September 2016. English databases

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included PubMed, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials

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(CENTRAL) and Allied and Complementary Medicine Database (AMED); and Chinese

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databases included Chinese Biomedical Database (CBM), Chinese National Knowledge

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Infrastructure (CNKI), Chongqing VIP Database (CQVIP) and Wanfang Database (Wanfang).

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The following online clinical trial registration websites were also searched: Chinese Clinical

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Trial Registry and International Clinical Trials Registry Platform. The key words and subject

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terms are of three groups “acupuncture”, “post-stroke spasticity” and “clinical trial” (see

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Appendix S1). We also hand searched studies from references of included studies and related

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systematic reviews and presented the results under the category of other sources in PRISMA

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flow chart (Figure 1).

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Study selection

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Two reviewers (YC, CZ) independently reviewed the titles and abstracts of trials for

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inclusion. Full texts of articles were retrieved if there was doubt about inclusion. Any

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disagreement was resolved by discussion with a third author (SL).

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Inclusion criteria 5

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Studies were included if the following criteria were met: (1) randomized controlled trials with results measuring spasticity; (2) stroke confirmed by Computed Tomography (CT) or

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Magnetic Resonance Imaging (MRI); (3) patients with one or multiple times of strokes; (4)

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comparing any type of routine care (RC) combined with EA, to the same RC without EA (or

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with pseudo EA); (5) spasticity severity measured by Modified Ashworth Scale (MAS) as the

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primary outcome measure, with or without any of the following secondary or safety outcome

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measures: Fugl-Meyer Assessment of Sensorimotor Recovery (FMA), Barthel Index (BI) and

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adverse events.

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Exclusion criteria

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Studies were excluded if they: (1) investigated patients with stroke symptoms caused by

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tumour, subdural haemorrhage, trauma or poisoning; (2) adopted complex treatment without

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specifying the add-on effects of EA (i.e. EA plus massage plus rehabilitation vs.

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rehabilitation); (3) compared different forms of acupuncture.

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Data extraction and management

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Information on patients, study design and results were extracted independently by two

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reviewers (YC, CZ) using a self-developed data extraction form and checked by the third

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author (SL). For dichotomous data, the number of participants experiencing the events (such

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as adverse events) and the total number of participants in each arm of the trial were extracted.

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For continuous data, mean change of scores with standard deviation at the end of treatment

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and follow-up phases in each arm were extracted. Authors were contacted via emails or 6

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phone calls if important data were unclear or unavailable, or duplication of data was

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suspected.

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Assessment of methodological quality

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The methodological quality of the included studies was assessed using the Cochrane “Risk of

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bias” tool, as described in the Cochrane Handbook for Systematic Reviews of Interventions

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(version 5.1.0). Quality assessment was performed by two independent reviewers (YC, CZ)

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and disagreement was resolved through discussion with the third member (SL).

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Statistical analysis

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The Cochrane Review Manager software (RevMan 5.3)a was used for meta-analysis. If an

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outcome measure for continuous data was evaluated using the same instrument, mean

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difference (MD) was calculated; while standardized mean difference (SMD) was used for the

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same outcome using different scales range. Results of treatment effects from individual

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studies were pooled for meta-analyses with randomized effect model. Subgroup analyses

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were planned in regards of spasticity severity at baseline, whether patients were with first

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stroke onset, number of acupuncture points (acupoints) used for EA, EA stimulation time,

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length of treatment period and length of post-stroke period. A P value less than 0.05 was

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considered as statistically significant for effect estimation. Sensitivity analyses were

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performed taking account of the risk of bias to assess the reliability of the results.

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Examination of any potential publication bias using a funnel plot and Egger’s linear

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regression test was planned if 10 or more randomized controlled trials were identified in one

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meta-analysis.

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Results

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Search results

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Our search identified 31,833 studies (Figure 1). Full texts of 84 possibly relevant papers were

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obtained, with 22 clinical trials 22, 27-47 meeting the selecting criteria included for meta-

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analysis.

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Descriptive analysis

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All the included studies were conducted in China from 2003 to 2016 involving 1,425

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participants (Table 1). The sample size of the included studies ranged from 37 to 132 with the

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average age being 65. Participants’ baseline characteristics varied among the included studies.

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Eight of them only included patients with first-ever stroke. The post-stroke period ranged

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from one day to four years. For spasticity severity at baselines, MAS≥1 was reported in

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eleven studies. As for selection of acupoints, most of the reported acupoints were located at

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the posterior aspect of arm and forearm and posterior and lateral aspects of thigh and leg. On

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average, eight points were used for EA among studies. But the rationale of selecting these

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acupoints was not stated in any of the included study. Treatment frequency was reported once

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ACCEPTED MANUSCRIPT to twice per day for a period of three to 12 weeks. Diverse comprehensive rehabilitation

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programs, including Bobath therapy and Rood approach, were reported as co-intervention in

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the included trials (Table S1). Seventeen of the included studies reported rehabilitation

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duration for each treatment section, which ranged from 20 to 120 minutes with a treatment

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period of 3 to 12 weeks (Table S1). None of the included studies used pseudo-EA (manual

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acupuncture with pseudo electro stimulation) as control. MAS was the most frequently

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reported outcome measure (22 studies), followed by BI (11 studies) and FMA (10 studies)

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(Table 1).

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Risk of bias Assessment

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Nine studies 28-31, 34, 39, 41, 46, 47 used adequate random sequence generation and were assessed

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as low risk; others were assessed as unclear risk in this domain due to lack of information.

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None of the included studies described details of allocation concealment. Therefore all were

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assessed as unclear risk of bias. None of the included studies attempted to achieve

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participants’ and personnel’s blinding but three trials 40, 41, 44 reported blinding of assessors.

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All but two trials 31, 39 were assessed as low risk of bias in incomplete outcome data. These

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two trials assessed as unclear risk of bias because they did not provide reason for the drop-

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outs and intention-to-treat Analysis (ITT analysis) was not applied. Information on selective

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reporting cannot be assessed in all studies due to lack of research protocol and were assessed

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as unclear bias, except one study was assessed high risk of bias for not reporting the results of

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Composite Spasticity Scale (CSS) and Gross Motor Function Measure (CMFM) 22. Baseline

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balance was presented in all studies except one 35, thus, this study was assessed high risk of

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bias in “other bias” due to baseline imbalance. Details of the risk of bias assessment were

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presented in Figure 2.

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Effects of interventions

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Change of MAS

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Thirteen of the included trials 22, 28, 30-33, 36, 37, 39, 42, 45-47 reported MAS without specifying

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which joints or regions for measurement. Significant between-group difference in MAS was

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seen with high heterogeneity when comparing EA plus RC to RC alone (SMD: -1.16, [-1.70,

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-0.61], I²=93%) (Figure 3, Table S2). Similar results were found in meta-analysis of MAS in

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upper and lower limbs comparing EA plus RC to RC alone (4 studies 27, 29, 35, 43, SMD: -0.57,

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[-0.84, -0.29], I²=0% and 5 studies 27, 38, 40, 43, 44, SMD: -0.88, [-1.42, -0.35], I²=78%

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respectively) (Figure 3). In addition, two studies 34, 41 measured MAS of different joints and

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reported the results separately, so their data were not pooled.

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Subgroup analyses were conducted based on: 1) spasticity severity measured by MAS; 2)

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whether participants were after their first onset of stroke; 3) the number of acupoints; 4) EA

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stimulation time; and 5) the length of treatment period; 6) the length of post-stroke period.

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Some of the pre-defined subgroup analyses could not be conducted due to the limited number

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of included studies (Table S2).

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It was worth noting that in the subgroup of EA treatment duration less than 30 minutes,

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adding EA was not beneficial for MAS (unspecified region) (SMD: -1.23 [-2.54, 0.08], 10

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I²=96%). All other subgroup analyses consistently showed favourable effects towards the

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combination of EA and RC. Only two subgroups on the outcome of MAS in lower limb

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showed no heterogeneity (I2=0%), which were: patients with baseline MAS ≥ 1 level, or

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when more than 10 acupoints were used in electro-acupuncture treatment (Table S2).

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Change of FMA

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For the total FMA motor function scores, the effects of combining EA and RC were

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significantly better than those using RC alone 28, 37, 42, 45 (4 studies, MD: 10.60 [8.67, 12.53],

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I²=0%) (Figure 4).

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Subgroup analysis of FMA in upper limb showed that of the two studies recruited patients

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with baseline MAS ≥ 1 level, the heterogeneity reduced, and the treatment effects was in

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favour of the combination of EA and RC (2 studies 29, 34, MD: 4.43, [2.44, 6.43], I²=0%).

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While for the two studies 46, 47 that did not specify baseline MAS score, no add-on effect of

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EA was detected, and the heterogeneity was very high (MD: 21.86, [-6.29, 50.00], I2=100%).

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Besides, two studies 34, 46 recruiting patients within 180 days showed superior effects adding

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EA to RC for FMA in upper limb with low heterogeneity (MD: 6.93, [5.01, 8.85], I2=0%).

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But no add-on effects of EA were observed in the subgroup where patients with longer than

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180 days of post-stroke period were included (MD: 20.06 [-11.61, 51.73], I²=100%) (Table

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S2). Other subgroup analyses related to FMA were not applied due to limited number of

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included studies.

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Change of BI

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Eleven included trials reported results of BI or MBI 28, 30-32, 34, 37, 38, 42, 43, 45, 47, but only seven

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of them reported the version of BI, so were pooled for meta-analysis 28, 30-32, 37, 42, 45. There 11

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was greater improvement of BI scores in participants with EA than those without it (7 studies,

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MD 6.85, [3.64, 10.05] (Figure 5). But the heterogeneity was also high (I²=80%).

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With regards to subgroup analysis of BI, in the subgroup including patients with a post-stroke

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period longer than 180 days, adding EA showed no benefit (2 studies 30, 37, 6.62 [-3.79, 17.02],

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I²=92%). Results of other subgroups favoured adding EA to RC. And heterogeneity could be

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reduced to 0% and 2% in the subgroups where baseline MAS was not specified, or when only

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patients after their first stroke onset were recruited, and those applied with EA stimulation

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time less than 30 minutes (Table S2).

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Adverse events and outcomes in follow-up

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No data on adverse events were reported in all included studies and none of the included

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trials involved a period of follow-up.

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Sensitivity analysis

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For MAS in lower limb, sensitivity analysis with low risk of bias in outcome assessors

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reduced heterogeneity to 0%, while for other outcome measures, the cause of high

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heterogeneity could not be detected.

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Reporting quality of the included studies

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Meanwhile, we compared the key items reported in the included trials with those

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recommended by the Standards for Reporting Intervention in Clinical Trials of Acupuncture

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(STRICTA) guidelines and found that only the style of acupuncture, the needle stimulation,

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the number of treatment sessions and the frequency and duration of treatment were reported

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by all the included studies (Table S3). Variation to acupoint selection, details of needling and

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other interventions, as well as precise description of the control methods were available in

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most of the included studies. However, in terms of reasoning for treatment provided and

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depth of insertion, only four studies reported these items respectively (Table S3). As for

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practioner background and rationale for the control therapy, there is only one study reported

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for each of the two items (Table S3). And the setting and context of treatment was mentioned

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in none of the included studies.

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Publication bias

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For MAS of unspecified region, the funnel plot was asymmetric around the mean effect size

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line (Figure S1). Then we conducted the Egger’s test, whose results indicated potential

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publication bias (P=0.003). Publication bias might result from smaller studies showing no

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effect under-reported in the literature. However, in our meta-analysis it is more likely to be

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generated from the large effects of two trials 36, 37. The larger effects in these two trials are

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attributable to the greater reduction of MAS achieved in the trials. When these two trials were

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removed from the analysis, the results of Egger’s test was not significant (P=0.098).

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The limited number of trials for meta-analysis of other outcome measures prohibited a

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meaningful funnel plot to detect publication bias.

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Discussion

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Summary of main findings

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The results suggested that adding EA to RC for post-stroke spasticity might be superior to RC

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alone in terms of muscle spasticity reduction measured by MAS, overall and lower-limb

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improvement of motor function, as well as activity of daily living. Adverse event information

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was provided by none of the included trials.

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Clinical importance of results

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Since the add-on effect of EA for reduction of spasticity measured by MAS was analysed

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with SMD, the MDD of MAS could not be applied to the explanation of the results.

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Therefore, we only compared between-group differences for MAS. As for FMA, both the

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MDD and MCID of FMA in upper extremity were explored as around 5.2 points 48, 49. But

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neither MDD nor MCID for the whole motor function or lower limb was available. In terms

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of FMA in upper limb, no significant difference between EA plus RC compared to RC alone

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was detected though with high heterogeneity (Figure 4). With regards to BI, MCID for

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chronic stage of stroke patients was not available. The MDD of BI was investigated as 4.02

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points 50. Therefore, we used 4.02 points in BI for the interpretation of our results to clinical

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practice. But the result of our meta-analysis did not support a clinically meaningful

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improvement of BI with EA adding to RC.

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The interpretation of our results comparing to MCID and MDD could be possibly illustrated

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by several reasons: First, apart from spasticity, motor function and activity of daily living of

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stroke patients might be affected by various factors, such as muscle strength, sensation

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disorders; second, the add-on effects of EA to RC might be too small to impact on the

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changes of FMA and BI; last but not least, the relatively low quality and small number of the

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included studies and total sample size limited our confidence in the results.

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Indications to clinical practice

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As for MAS in unspecified region, patients with EA stimulation time less than 30 minutes did

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not receive benefit adding EA to RC. Meanwhile, for FMA in upper limb, superior add-on

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effects of EA could be detected only in the subgroup where patients’ baseline MAS scores

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were more than one level and the subgroup with a post-stroke period no more than 180 days.

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And adding EA to RC could not benefit those with a post-stroke period longer than 180 days

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for BI.

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Moreover, this review attempted to explore an adequate and even optimal EA treatment

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protocol and provided indications for clinical practice and scientific research onwards.

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Specifically, the results suggested that applying EA to patients who had stroke less than 180

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days, with a baseline MAS ≥1, or applied with EA for no less than 30 minutes, might

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contribute to better effects of EA. But the above results of subgroup analysis could not be

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confirmed due to the limitation in the number and the methodological quality of the included

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studies, as well as the high heterogeneity of the results. 15

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Though the electrical stimulation frequency reported in most of the included studies was

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below 20 Hz, the optimal frequency needs further exploration because of the uncertain impact

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of EA on muscles with different frequencies 51, 52. The number of acupoints being electro-

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stimulated among the included studies ranged from 2 to 14 and 8 was the average number

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(Table 1). Twenty studies reported patient response, such as “Deqi” sensation (a composite of

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unique needling sensations, including soreness, numbness, distension, heaviness felt by

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patients at the acupoint, with the practitioner’s feeling of mild needle grasping) 53 or muscle

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contraction during acupuncture treatment (Table S3). And the reasoning for treatment

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provided was available in only four of the included study. Although it is recommended to at

350

least conduct a subgroup analysis including only studies with adequate protocol of EA

351

treatment 54, it could hardly be done in our systematic review due to lack of clinical

352

consensus and empirical evidence of adequate EA protocol. However, compared to criteria on

353

adequacy of acupuncture applied to studies on other conditions, such as fibromyalgia 55 and

354

low back pain 54, the number of points needled and the treatment frequency suggest the dose

355

might be adequate.

SC

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356

RI PT

341

Measurement of spasticity

358

This review did not explore the underlying mechanism on how EA works in reducing

359

spasticity. The conventional understanding of the pathophysiology of post-stroke spasticity

360

can be summarized as the abnormal processing of proprioceptive input in the spinal cord

361

resulting in the hyper-excitability of stretch reflex 56. Due to the complexity of the underlying

362

pathophysiologic basis of spasticity with neural and non-neural components 56, it is difficult

363

to measure the change of spasticity with one single outcome measure. Currently, MAS was

364

the most frequently and widely reported outcome measure, though it might not cover all key

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16

ACCEPTED MANUSCRIPT aspects of spasticity as a velocity-dependent increase in muscle tone and might underestimate

366

the effects of the intervention because of the limited ability to assess the minor change of

367

spasticity 57. Future study might need to incorporate a comprehensive group of outcome

368

measures, including quantitative measures, such as surface EMG 58, 59 and

369

electrophysiological evaluation 60 .

370

RI PT

365

Control methods for electro-acupuncture trials

372

Since positive treatment effects of pseudo and sham acupuncture had been observed and

373

raised concerns over research of acupuncture 61-64, the treatment effects of acupuncture might

374

be underestimated when compared with pseudo or sham acupuncture. Therefore, subgroup

375

analysis of studies with and without pseudo or sham acupuncture is needed when conducting

376

systematic reviews of acupuncture. However, in our systematic review, neither pseudo

377

acupuncture nor sham acupuncture was applied to any of the included study.

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Differences from previous systematic reviews

380

Compared to three existing systematic reviews on acupuncture for stroke 23, 26, 65, our study is

381

different in the following main areas. First, previous systematic reviews did not specifically

382

evaluate the add-on effects of EA for post-stroke spasticity. Second, we conducted a more

383

comprehensive search in five English and four Chinese databases. Because of the

384

characteristics of Chinese characters, the indexing of key words and subjects could not be

385

clearly defined. Search terms should therefore not be limited to the standard, but a more

386

general and comprehensive combination of similar words and phrases with synonyms, which

387

might contribute to a much larger number of hits of search results in this systematic reviews

388

compared to the previously published ones. Third, we updated the search up to September

389

2016 with more up-to-date evidence in English and Chinese databases.

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ACCEPTED MANUSCRIPT 390

391

Study limitations

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RI PT

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Methodological quality

395

The limited methodological quality of the included studies prevented us from drawing a firm

396

conclusion on the effects of EA for post-stroke spasticity with respect to spasticity reduction,

397

improvement of motor function as well as activity of daily living. It is important for a

398

randomized controlled trial to apply proper randomization and allocation. But we noted that

399

only 40.9 % of the included studies used proper randomization method to reduce selection

400

bias and none of them reported adequate allocation concealment, either might result from low

401

methodological quality of the studies or low report quality and might lead to exaggeration of

402

the estimated efficacy 66. Apart from randomization and allocation concealment, insufficient

403

blinding may also contribute to overestimation of the effects 67. Pseudo-EA or sham EA was

404

used in none of the included trials. Admittedly, blinding of participants and personnel is

405

difficult in clinical trials of non-pharmacotherapy. But the attempt to reduce performance bias

406

with sham EA, pseudo-EA or placebo EA is needed in future research. In addition, blinding

407

assessors could help reduce the detection bias with regards to non-objective outcome

408

measures, including MAS, FMA and BI. However, there are only 3 studies in this systematic

409

review reported clearly the methods used for blinding assessors, limiting our confidence on

410

the results of this meta-analysis.

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411 412

High heterogeneity in results

18

ACCEPTED MANUSCRIPT Besides, high heterogeneity across studies was observed in some of the meta-analyses in this

414

systematic review. To gain a broad perspective on the overall evidence of EA for post-stroke

415

spasticity, randomized controlled trials of different basic characteristics and EA treatment

416

protocols were included in the systematic review, which may lead to clinical heterogeneity.

417

We also conduct subgroup and sensitivity analysis. But the cause of the high heterogeneity

418

could not be well addressed (Table S2).

RI PT

413

419

Assessment of safety

421

To evaluate the safety of EA for post-stroke spasticity is also one of the objectives of this

422

systematic review, but none of the included trials addressed the long-term effects or adverse

423

events. Although EA is widely accepted as relatively safe if applied appropriately by

424

competent practitioners even with some mild adverse events, including localised pain or

425

slight bleeding from needling 28, none of the included studies reported adverse event during

426

their treatment period, nor any follow-up observation was available in the included studies.

427

The lack of reporting adverse events suggested poor reporting quality. Therefore, evaluation

428

of the safety of EA for post-stroke spasticity could not be confirmed based on currently

429

included studies of the systematic review.

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420

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430 431

Reporting quality

432

In terms of the report quality of the included studies, none of the included studies addressed

433

all the key items recommended by the STRICTA. Therefore, future clinical trials are

434

recommended to be registered prospectively and improve reporting quality according the

435

STRICTA and the CONSORT statement to provide transparency of the study design, practice

436

and analysis 68, 69.

437 19

ACCEPTED MANUSCRIPT 438

Besides, 13 of the 22 included did not specify which region was measured in their reporting

439

of MAS, making the interpretation of results less clinically relevant (Figure 3). Outcome

440

measures need to be described in detail in future studies to improve reporting quality.

441

Generalization of results

443

Since participants were restricted to Chinese population, generalization of the results to non-

444

Chinese populations needs further evidence. Besides, contracture could inevitably develop in

445

stroke patients with chronic spasticity 70, where acupuncture might have a different impact 71.

446

Caution is needed in generalization of the results to a general stroke population with both

447

spasticity and contracture.

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448 449

Conclusions

450

TE D

451

This systematic review suggested that EA combined with conventional RC has the potential

453

of reducing spasticity in upper and lower limb and improving overall and motor function in

454

lower extremity and activity of daily living for spasticity patients within 180 days post stroke.

455

Further studies of high methodological and reporting quality are needed to confirm the effects

456

and safety of EA, and to explore the adequate and optimal protocol of EA for post-stroke

457

spasticity incorporating a group of comprehensive outcome measures in different populations.

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459

Suppliers

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a. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic

461

Cochrane Centre, the Cochrane Collaboration, 2014. Available at:

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http://community.cochrane.org/tools/review-production-tools/revman-5 20

ACCEPTED MANUSCRIPT 463

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statement. PLoS medicine 2010;7(6):e1000261.

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formation. Clinical orthopaedics and related research 1988(233):7-18.

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ACCEPTED MANUSCRIPT Legends of figures and tables:

661

Figure 1 PRISMA Flow Chart

662

Figure 2 Risk of Bias Summary

663

Figure 3 Forest plot of MAS

664

Figure 4 Forest plot of FMA

665

Figure 5 Forest plot of BI

666

Table 1 Basic Characteristics of the included studies

667

Table S1 Summary of rehabilitation treatment

668

Table S2 Summary of main results and subgroup analyses

669

Table S3 Key Items of Electro-acupuncture Treatment Protocol Reported in the Included

670

Studies

671

Figure S1 Funnel plot of MAS (Unspecified Region)

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ACCEPTED MANUSCRIPT Table 1 Basic Characteristics of the included studies First onset of stroke

Spasticity severity

Time from stroke onset (days) ≥30

Comparis ons

Acupoints

Number of Electrostimulated acupoints

Whether “Deqi” was achieved

Electrical stimulation frequency (Hz)

EA+Reha b vs Rehab

10

Yes

10

Not mentio ned 0-60

EA+Reha b vs Rehab EA+Reha b vs Rehab

LI11, LI4, LI15, SJ5, GB30, GB31, ST36, GB39, BL60, DU20 Scalp acupoints (not specified)

Needle retentio n time (minutes ) 30

Cai, 201147

60 (30/30)

5379

53.3

Not mentioned

Not mentio ned

Not mentione d

Cheng, 201529

37 (18/19)

4070

51.4

40 (20/20)

1880

62.5

Not mentio ned Yes

MAS: 1-3

Fan, 201522

Cerebral infarction & hemorrhage Cerebral infarction & hemorrhage

2 (not specified)

Yes

60-80

7

Yes

Not mentione d

0-21

EA+Reha b vs Rehab

Not available

Not mentione d MAS ≥ 1

<7

14-147

EA+Reha b vs Rehab EA+Reha b vs Rehab

HT1, LI15, LU5, PC7, SJ4, SJ10, BL62, KI6, LR8, SP10, ST34, ST41 Scalp acupoints (details unavailable), LI4, LR3, ST36, DU20 LI10, LI14, LI15, SJ5

Guo, 200345

57 (29/28)

4079

70.2

Cerebral infarction & hemorrhage

Yes

Guo, 201546

58 (28/30)

3273

63.8

Cerebral infarction

Yes

Huang, 201631

68 (33/35)

3480

53.0

Not mentioned

No

Li, 200743

58 (29/29)

5375

60.3

Not mentioned

Not mentio ned

MAS > 2

60-180

Li, 201144

60 (30/30)

3569

60.0

Not mentioned

Not mentio ned

Not mentione d

10-90

Liu, 201628

80 (40/40)

3575

41.3

Cerebral infarction & hemorrhage

Yes

Not mentione d

EA+Reha b+Baclofe n vs Rehab+Ba clofen EA+Reha b vs Rehab

AC C

MAS: 0-4

20-60

Treatment frequency (times/day; days/week)

Length of treatment

Outcome Measures

1 time/day; 5 days/week

4 weeks

MAS, MBI, FMA, RSB

20

1 time/day; 6 days/week

6 weeks

MAS, FMA, RSB

Not mentioned

30

1 time/day 7 days/week

30 days

MAS, FMA, BBS

Yes

30

30

1 time/day; 5 days/week

4 weeks

4

Yes

2

30

1 time/day; 6 days/week

3 weeks

MAS, MBI, FMA, CNS, secondary complications MAS, FMA

LI4, LI10, LI15, SJ5, SJ10, SJ14, GB34, SP9, SP10, EX-LE28 LI4, LI11, LI14, LI15, SJ5, BL36, BL37, BL40, ST36, ST40, LR3

10

Not mentione d

2

Not mention ed

1 time/day 6 days/week

4 weeks

MAS, BI, RSB

11

Not mentione d

1-10

25

1 time/day; 7 days/week

8 weeks

MAS, BI

ST36, ST37, ST39, GB34, BL62, KI6, GB41

7

Yes

Not mentioned

30

1 time/day; 7 days/week

30 days

LI10, LI11, SJ5, SJ8, SJ11, SJ12, SJ13, BL37, BL40, GB34, GB39

4

Yes

“Low frequency” (not specified)

30

1 time/day; 7 days/week

30 days

MAS, MMT, CarrShepherd walking and balance scores MAS, FMA, BI

EA+Reha b vs Rehab

RI PT

Stroke type

SC

Gende r (% male)

M AN U

Age (yea rs)

TE D

Sample size (I/C)

EP

Author, year

ACCEPTED MANUSCRIPT Table 1 (Continued) First onset of stroke

Spasticity severity

Time from stroke onset (days) 0-180

Comparis ons

Acupoints

Number of Electrostimulated acupoints

Whether “Deqi” was achieved

Electrical stimulation frequency (Hz)

EA+Reha b vs Rehab

ST36, GB34, BL62, ST41, KI3, KI6, BL57, LR3

4 (not specified)

Yes

20-30

Needle retentio n time (minutes ) 30

Lu, 200340

40 (20/20)

5574

62.5

Not mentioned

Not menti oned

Not mentioned

Lu, 201041

90 (30/30/3 0)

5280

60.0

Not mentioned

Not menti oned

Lu, 201142

60 (30/30)

4075

71.7

Cerebral infarction & hemorrhage

Wang, 200739

63 (31/32)

1875

Not mentio ned

Wu, 200838

60 (30/30)

4675

Wu, 201137

60 (30/30)

AS:1-3 Brunstrom :2-3

14 60

EA1+Reh ab vs Rehab vs EA2+Reh ab

14

Not mentione d

2

Yes

Not mentioned

14180

EA+Reha b vs Rehab

Yes

Cerebral infarction & hemorrhage

Not menti oned

Not mentioned

Not menti oned

13

61.7

Cerebral infarction & hemorrhage

Yes

Not mentioned

301461

EA+Reha b+Baclofe n vs Rehab+Ba clofen EA+Reha b vs Rehab

4176

55.0

Cerebral infarction & hemorrhage

Not menti oned

MAS > 0

>15

4076

61.7

Cerebra infarction

Not menti oned

MAS:1-4

DU16, DU14, DU4, DU3, SJ13, SJ11, LI10, SJ5, EX-UE8, SJ3, BL36, BL37, GB34, ST40 meridian sinew nodal points of limbs (details unavailable) LI15, SI9, EXUE12, LI14, SJ10, LI10, SJ5, ST31, ST32, SP10, GB34, ST40, GB39 LI10, SJ5, SJ10, EX-UE9, BL40, BL57, GB34, LR3, ST31, ST36, EXLE28 DU20, DU24, BG13, EX-HN1, GB20, LR3, KI6, SP9, LI15, LI11, LI10, SJ5, LI4, ST32, ST34, ST36, SP6, BL62, EXLE28 LI10, LI11, LI14, LI15, LI4, SJ5, SP10, GB34, ST40, SP6, ST41

Xing, 201536

60 (30/30)

EA+Reha b vs Rehab

AC C 14180

EA+Reha b vs Rehab

Treatment frequency (times/day ×days/week)

Length of treatment

Outcome Measures

1 time/day; 7 days/week

12 weeks

30

1 time/day; 5 days/week

4 weeks

MAS, MMT, Carr-Shepherd walking and balance scores MAS

Not mentioned

30

2 times/day; 6 days/week

4 weeks

MAS, FMA, BI

Yes

100

40

1 time/day 7 days/week

4 weeks

MAS

Not available

Not mentione d

Not mentioned

30

1 time/day; 6 days/week

4 weeks

MAS, BI

Not available

Yes

Not mentioned

30

1 time/day; 7 days/week

12 weeks

MAS, FMA, BI

11

Not mentione d

Not mentioned

30

1 time/day; 7 days/week

30 days

MAS, CSI

RI PT

Stroke type

SC

Gende r (% male)

Not available

M AN U

Age (yea rs)

TE D

Sample size (I/C)

EP

Author, year

ACCEPTED MANUSCRIPT Table 1 (Continued) Stroke type

First onset of stroke

Spasticity severity

Comparis ons

Acupoints

Number of Electrostimulated acupoints

Whether “Deqi” was achieved

Electrical stimulation frequency (Hz)

Xue, 200835

56 (28/28)

N/A

82.1

Not mentioned

Yes

Yan, 201034

81 (40/41)

4075

49.4

Cerebral infarction

Not mention ed

Not mentione d MAS ≥ 1

EA+Reha b vs Rehab EA+Reha b vs Rehab

LI11, LI15, LI10, LI4, SP10, SP9, SP6, KI3 PC2, EX-UE21, LU5, PC3, HT3, LU6, LU7, HT5, LI4, SI3, ST32, ST34, ST36, GB34, SP10, SP9, SP5, GB40, SP6, GB39 Scalp acupoints (not specified)

8

Not mentione d Yes

Yang, 200733

80 (42/38)

<75

62.5

Cerebral infarction

Yes

Not mentione d

14-90

EA+Reha b vs Rehab

Yao, 201232

132 (66/66)

5869

59.1

Not mention ed

MAS ≥ 1

≤90

EA+Reha b vs Rehab

Yu, 200727

60 (30/30)

≤80

60.0

Not mention ed.

MAS ≥ 1

30-120

EA+Reha b vs Rehab

Zhang, 201530

65 (34/31)

4675

63.1

Cerebral infarction & hemorrhag e Cerebral infarction & hemorrhag e Cerebral infarction & hemorrhag e

Not mention ed

MAS: 1-4

30-365

EA+Reha b vs Rehab

AC C

EP

Time from stroke onset (days) Not mentio ned Not mentio ned

4

RI PT

Gende r (% male)

SC

Age (yea rs)

Treatment frequency (times/day ×days/week)

Length of treatment

Outcome Measures

10-100

Needle retention time (minutes ) 30

1 time/day; 6 days/week

4 weeks

MAS, FMA

100

30

1 time/day 5 days/week

6 weeks

MAS, FMA, MBI

“High frequency” (not specified) Not mentioned

20

1 time/day; 6 days/week

4 weeks

MAS

20

1 time/day; 7 days/week

30 days

MAS, BI

Not available

Not mentione d

LI11, SJ5, SJ6, LI4, LI10, BL37, BL40, ST36, SP6, ST40, LR3

Not available

Yes

LI15, LI11, LI10, SJ5, LI4, GB31, ST34, ST36, GB34, ST40, GB39, SP6, SP9 LI4, LI11, LI15, SJ5, BL40, BL57, GB40, SP6, SP9, ST41

4 (not specified)

Not mentione d

1

Not mention ed

1 time/day; 6 days/week

30 days

MAS

8 or 10

Yes

Not mentioned

30

1 time/day; 7 days/week

4 weeks

MAS, BI, Motor Assessment Scale

M AN U

Sample size (I/C)

TE D

Author, year

Notes: I: intervention group, C: controlled group; Rehab: rehabilitation; RSB: recovery stage of Brunnstrom, CSI: Composite spasticity index, BBS: Berg Balance Scale.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

1

Appendix S1 Search Strategy

ACCEPTED MANUSCRIPT

Search Search Strategy #1

stroke OR brain infarction OR intracranial embolism and thrombosis OR intracranial hemorrhages OR cerebrovascular accident OR cerebral infarction OR intracranial haemorrhage OR cerebral muscle spasticity OR muscle hypertonia OR muscle tonus OR spasm OR dystonia OR paraparesis, spastic* OR high tone OR hypermyotonia OR contracture

#3

RI PT

#2

acupuncture OR Meridians OR electro-acupuncture OR auriculotherapy OR ear acupuncture OR

SC

acupuncture, ear OR acupuncture therapy OR acupuncture analgesia OR acupuncture points OR electro-acupuncture OR electro acupuncture OR electro-stimulation OR electro stimulation random* AND controlled trial random* AND controlled trial

#5

#1 AND #2 AND #3 AND #4

AC C

EP

TE D

2

M AN U

#4

1

ACCEPTED MANUSCRIPT Table S1 Summary of rehabilitation treatment Author, year Cai, 201147

Rehabilitation period

each treatment section

times/day

days/week

40 minutes

1

7

4 weeks

60 minutes

not available

not available

6 weeks

22

120 minutes

1

5

30 days

Guo, 2003

45

40 minutes

1

5

4 weeks

Guo, 2015

46

not available

not available

not available

3 weeks

4 weeks

Fan, 2015

Huang, 2016

60 minutes

1

6

43

45 minutes

1

7

44

Li, 2007

8 weeks

not available

not available

30 days

30-45 minutes

1

7

30 days

Lu, 2003

40

30 minutes

1

7

Lu, 2010

41

not available

not available

42

30 minutes

1

not available

not available

Liu, 2016

Lu, 2011

Wang, 2007

39

38

30 minutes

Wu, 201137

30 minutes

Xing, 201536

30 minutes

35

45 minutes

34

60 minutes

Xue, 2008 Yan, 2010

Yang, 2007 Yao, 2012 Yu, 2007

33

32

27

not available

4 weeks

6

4 weeks

not available

4 weeks

6

4 weeks

1

7

12 weeks

1

5

30 days

1

6

4 weeks

1

5

6 weeks

1

6

4 weeks

1

7

30 days

not available

2

6

30 days

30 minutes

1

7

4 weeks

45 minutes 20-30 minutes

AC C

EP

Zhang, 2015

30

12 weeks

1

TE D

Wu, 2008

SC

not available

28

M AN U

Li, 2011

31

RI PT

Cheng, 2015

29

Rehabilitation frequency

Rehabilitation duration in

ACCEPTED MANUSCRIPT Table S2 Summary of main results and subgroup analyses

Number of acupoints

EA stimulation time

Length of treatment period

Yes unspecified ≥ 10 < 10 & unspecified < 30 min

-1.23 [-2.54, 0.08], I²=96%, 3 (141/139)

≥ 30 min

-1.14 [-1.79, -0.50], I²=92%, 10 (301/299)

> 4 weeks

-1.47 [-2.75, -0.18], I²=96%, 5 (186/186)

-0.99 [-1.51, -0.47], ≤ 4 weeks I²=87%, 8 (256/252) -0.95 [-1.58, -0.31], ≤ 180 days I²=93%, 9 (318/317) Post-stroke period -1.64 [-2.70, -0.59], > 180 days I²=92%, 4(124/121) Notes: I: intervention group, C: control group.

Not available

FMA (lower limb) (MD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

Barthel Index (MD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

10.6 [8.67, 12.53], I²=0%, 4 (129/128)

13.32 [-6.53, 33.17], I²=100%, 4 (116/120)

4.42 [0.06, 8.78], I²=90%, 3 (88/89)

6.85 [3.64, 10.05], I²=80%, 7 (262/260)

RI PT

FMA (upper limb) (MD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

SC

MAS unspecified

-1.24 [-2.43, -0.04], I²=96%, 5 (183/182) -1.11 [-1.69, -0.54], I²=89%, 8 (259/256) -0.48 [-0.90, -0.06], I²=75%, 6 (189/186) -1.80 [-2.77, -0.83], I²=95%, 7 (253/252) -1.45 [-2.22, -0.68], I²=94%, 9 (313/312) -0.56 [-1.09, -0.03], I²=77%, 4 (129/126)

-0.88 [-1.42, -0.35], I²=78%, 5 (137/137) -0.43 [-0.79, -0.06], I²=0%, 2 (59/59) -1.22 [-1.99, -0.45], I²=79%, 3 (78/78)

FMA (motor function) (MD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

Not available

M AN U

First onset of stroke

MAS ≥ 1

-0.57 [-0.84, -0.29], I²=0%, 4 (105/106)

4.43 [2.44, 6.43], I²=0%, 2 (58/60) 21.86 [-6.29, 50.00], I²=100%, 2 (58/60)

Not available

Not available

Not available

Not available

Not available

Not available

Not available

-0.43 [-0.79, -0.06], I²=0%, 2 (59/59) -1.22 [-1.99, -0.45], I²=79%, 3 (78/78)

Not available

Not available

Not available

Not available

Not available

TE D

Spasticity severity

-1.16 [-1.70, -0.61], I²=93%, 13 (442/438)

MAS (lower limb) (SMD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

Not available

EP

All studies

MAS (upper limb) (SMD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

AC C

Meta-analysis groups

MAS (unspecified region) (SMD, 95%CI, I2, No. of studies (No. of participants of I/C groups))

Not available

Not available

Not available

Not available

Not available

Not available

5.07 [1.23, 8.91], I²=79%, 4 (163/162) 9.42 [7.30, 11.55], I²=0%, 3 (99/98) 9.42 [7.30, 11.55], I²=0%, 3 (99/98) 5.07 [1.23, 8.91], I²=79%, 4 (163/162) 6.05 [2.38, 9.72], I²=84%, 5 (203/202) 9.93 [3.19, 16.68], I²=46%, 2 (59/58) 3.83 [1.59, 6.07], I²=2%, 2 (99/101) 8.33 [3.97, 12.68], I²=80%, 5 (163/159)

Not available

Not available

Not available

6.93 [5.01, 8.85], I²=0%, 2 (68/71) 20.06 [-11.61, 51.73], I²=100%, 2 (48/49)

Not available

Not available

7.92 [2.73, 13.10], I²=87%, 3 (136/136) 5.79 [1.65, 9.94], I²=67%, 4 (126/124) 6.97 [3.56, 10.37] , I²=74%, 5 (198/199) 6.62 [-3.79, 17.02] , I²=92%, 2 (64/61)

ACCEPTED MANUSCRIPT

Table S3 Key Items of Electro-acupuncture Treatment Protocol Reported in the Included Studies 1. Acupuncture rationale

29

Cheng 2015 22

Fan 2015

45

Guo 2003

46

Guo 2015

31

Huang 2016

1c) Extent to

2a) Number

2b) Names of

2c) Depth

2d) Response

2e) Needle

2f) Needle

2g) Needle

acupuncture

for treatment

which treatment

of needle

points used

of insertion

sought

stimulation

retention time

type

provided

was varied

insertions

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

No

No

No

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

No

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

43

Yes

No

Yes

Yes

44

Yes

No

Yes

Yes

Li 2007 Li 2011

28

Yes

Yes

Yes

Yes

40

Yes

No

Yes

Yes

41

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

No

No

No

No

Yes

Yes

Yes

Yes

Lu 2003 Lu 2010

42

Lu 2011

Wang 2007

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

No

No

Yes

Yes

No

Wu 201137

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Xing 2015

Yes

No

Yes

Yes

Yes

No

No

Yes

Yes

No

Xue 200835

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

No

34

Yan 2010

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yang 200733

Yes

No

No

No

No

Yes

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Yes

No

Yes

Yes

No

Yes

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

No

Wu 2008

36

32

Yao 2012

Yu 200727 30

Zhang 2015

EP

Yes

38

AC C

39

TE D

Liu 2016

RI PT

Cai 2011

1b) Reasoning

SC

47

1a) Style of

M AN U

Studies

2. Details of needling

ACCEPTED MANUSCRIPT

Table S3 (Continued) 3. Treatment regimen

4. Other components of treatment

5. Practitioner

6. Control or comparator interventions

background 3b) Frequency and

4a) Details of other

4b) Setting and

5) Description of

6a) Rationale for the control

6b) Precise

treatment

duration of treatment

interventions administered

context of

participating

or comparator in the context

description of the

sessions

sessions

to the acupuncture group

treatment

acupuncturists

of the research question

control or comparator

Yes

Yes

Yes

No

No

No

Yes

Cheng 2015

Yes

Yes

Yes

No

Yes

No

Yes

Fan 201522

Yes

Yes

Yes

No

No

No

Yes

Yes

Yes

Yes

No

No

No

No

Yes

Yes

Yes

No

No

No

Yes

Huang 2016

Yes

Yes

Yes

No

No

No

Yes

Li 200743

Yes

Yes

Yes

No

No

No

Yes

44

Yes

Yes

Yes

No

No

No

Yes

No

No

No

Yes

No

No

No

No

No

No

No

Yes

No

No

Yes

Yes

No

No

No

Yes

No

No

No

Yes

No

No

No

Yes

No

No

No

No

Yes

Yes

No

No

No

Yes

Yes

No

No

No

Yes

Guo 2003

Guo 201546 31

Li 2011

Liu 201628

Yes

Yes

Yes

40

Lu 2003

Yes

Yes

Yes

Lu 201041

Yes

Yes

Yes

42

Yes

Yes

Yes

Lu 2011

Wang 200739

Yes

Yes

Yes

Yes

Yes

37

Yes

Yes

Yes

Wu 2008 Wu 2011

36

Xing 2015

AC C

Yes

38

SC

45

M AN U

29

TE D

Cai 201147

RI PT

3a) Number of

EP

Studies

Yes

Yes

35

Yes

Yes

34

Yes

Yes

Yang 2007

Yes

Yes

Yes

No

No

No

Yes

32

Yes

Yes

Yes

No

No

No

Yes

Yes

Yes

Yes

No

No

No

Yes

Yes

Yes

Yes

No

No

No

Yes

Xue 2008 Yan 2010

33

Yao 2012

27

Yu 2007

30

Zhang 2015

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT