Acupuncture for blepharospasm: a systematic review and meta-analysis protocol


 Background

Blepharospasm is a disorder inducing bilateral eyelid closure due to irregular muscle contraction. Oral medications or surgical interventions currently still hardly achieve a great therapeutic effect. Acupuncture is indicated effective in improving blepharospasm, but its efficacy has not been comprehensively elucidated as a therapy, so a systematic evaluation on acupuncture for blepharospasm is desirable.
Methods

All randomised controlled trials related to acupuncture for blepharospasm will be screened from 9 databases, including 5 English databases (Cochrane Central Register of Controlled Trials, Web of Science, PubMed, MEDLINE, Excerpta Medica Database) and 4 Chinese databases (CNKI, Chinese Biomedical Literature Database, China Wanfang Database, and VIP Database). The primary outcomes include degree of blepharospasm, scores of BFM, UDRS, JRC, BSS, BDS, and BSDI. The incidence of adverse events will be also considered. Two reviewers will screen studies, extract data and assess the quality. Review Manager software 5.4.1 (provided by Cochrane, London, United Kingdom) will be used to assess risk of bias and synthesize data synthesis.
Discussion

Our study will investigate the efficacy and safety of acupuncture in treating blepharospasm, providing a summary to contribute to application of acupuncture.
Systematic review registration:
 CRD42020222489, registered on Dec 24, 2020.


Discussion
Our study will investigate the e cacy and safety of acupuncture in treating blepharospasm, providing a summary to contribute to application of acupuncture. Systematic review registration: CRD42020222489, registered on Dec 24, 2020.

Background
Blepharospasm is a focal dystonia in which agonist and antagonist muscles contract simultaneously, followed by involuntary eyelid closure [1] . Blepharospasm affects approximately 20 to 133 cases per million individuals and is more common in women [2][3][4] .The etiology of blepharospasm is not well understood until now. It can be divided into two types, benign essential blepharospasm (BEB) and secondary blepharospasm. Study shows that a positive family history of BEB is found in 20-30% of cases, probably due to genetic susceptibility [5] . Developing BEB is also determined by non-inherited risk factors, including eye strain [6][7] , psychiatric conditions [8] , head trauma [9] , keratoconjunctivitis/blepharitis and other ocular surface disease [10][11] . In ophthalmology, severe blepharospasm in patients with neurological symptoms is also known as Meige syndrome [12] .
Currently, there are already several treatment options available, including botulinum toxins injection [13] , oral medications such as benzodiazepines, anticholinergics, levodopa, baclofen, VMAT2 inhibitors (tetrabenazine), and surgical intervention [14] .However, there is no de nitive cure for blepharospasm due to its complex mechanisms. In recent years, some investigators have managed to apply acupuncture in the treatment of blepharospasm in clinical practice and experimental study with few side effects [15][16][17][18] . Acupuncture is effective for blepharospasm in some researches, but its e cacy is still under controversy.

Objectives
This study aims to evaluate the e cacy and safety of acupuncture for blepharospasm using system valuation and meta-analysis. It also provides a safer and more effective treatment for patients with blepharospasm.

Study registration
This protocol (registration number CRD42020222489) has been registered on the International Prospective Register of Systematic Reviews (PROSPERO). The protocol will strictly follow the guideline of Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols (PRISMA-P) [19] . The PRISMA-P checklist for our study is displayed in Additional le 1. If necessary, the authors will update the protocol during our research. 3. Types of blepharospasm are not restricted.

Types of intervention
Acupuncture therapies used in the observation group include body acupuncture, ear acupuncture, scalp acupuncture, re acupuncture, warming acupuncture and electroacupuncture. There is no limit on the length or frequency of treatment.
Control interventions include no treatment/wait list, sham control, or no active treatment (such as physical therapy, oral medications, surgery, injections, or other traditional medication). Studies that compare the effects of blepharospasm to herbal remedies will be excluded. If participants in the blepharospasm group received another aggressive treatment, only studies that included all control group participants receiving the same aggressive treatment as the combined intervention would be selected.

Change in level of consciousness.
3. Severe adverse events. Secondary outcomes 1. Comprehensive assessment of participant improvement (eg, proportion of overall improvement and subjective improvement).

Adverse events associated with blepharospasm or any other treatments.
Exclusion criteria 1. Diagnostic criteria is unclear .
2. The data are duplicated, or the data information is incomplete.
3. The research is a type of Non-RCTs or Quasi-RCTs. 4. The studies are observational or retrospective. 5. The study subjects are non-human. Other resources Searches will be also carried out on the Cochrane Central Register of Controlled Trials, the PROSPERO Register of Controlled Trials, and the Cochrane Complementary Medicine Field Specialized Register. If part of the data is incomplete, we will also obtain complete data information from the author by certain means.

Search strategy
Acupuncture and randomized controlled trial/RCT will be search teams. Multiple retrieval methods in Chinese and English databases will be conducted without publication restriction. The search strategy in PubMed is presented in Table1. Additionally, appropriate modi cations will be conducted in accordance with requirements.
The literature collection and data analysis Screening of literature Two researchers(HH, QH) will screen the studies in accordance with the inclusion and exclusion standard independently. The nal selection procedure will be demonstrated in Figure 1 according to the PRISMA guidelines.

Data extraction and management
The data will be extracted by QH and NG. Each study is evaluated in terms of the type of design, randomisation, inclusion or exclusion standard, the characteristics of participants, intervention measures, outcomes measures, and the quality of study. Encountering differences, they will turn to YLZ for veri cation.
Quality assessment of the studies included Two researchers (HH, RXL) will evaluate the included literature quality. According to Cochrane Handbook for Systematic Reviews of Interventions [22] , 7 aspects of bias risk will be assessed: 1. whether the sequence is randomly generated; 2. whether allocation concealment is adopted; 3. whether participants and personnel implement the blind method; 4. whether the blind method is used to evaluate the results; 5. whether the outcome data are complete; 6. whether the selective outcome has been reported; 7. other bias: follow-up, con icts of interest, non-intention-to-treat or per-protocol analysis, etc.
The study quality will be described as "bias of low risk," "bias of high risk," and "uncertainty of bias risk."

Measures of treatment effect
The odds ratio (OR) is used as the effect size if the data type is binary, while the standardized mean difference (SMD) and its 95% con dence interval (CI) is adopted as the effect size if the data type is quantitative.

Management of missing data
The missing data will be acquired through contacting rst authors. The incomplete data will be deleted if they cannot be obtained. If necessary, the potential in uence of missing data on the conclusions of the research would be clari ed in the section of 'Discussion'.

Heterogeneity analysis
The Cochran Q statistic and the I 2 statistic will be used to evaluate the heterogeneity across studies. If I 2 >50%, heterogeneity exiting, a random-effects model (REM) will be selected. If I 2 < 50%, indicating no signi cant heterogeneity, a xed-effects model (FEM) will be adopted.

Assessment of publication biases
Egger's and Beg's tests will be conducted to assess publication bias in a meta-analysis through funnel plot asymmetry. P value <.05 refers to signi cant publication bias.

Subgroup analysis
In case of su cient studies (>10), the the heterogeneity source will be clari ed by the mothod of subgroup analysis based on acupoint therapy combined with other treatments. The study with low quality will be excluded to assure the reliability of the funding.

Sensitivity analysis
Sensitivity analysis will be performed to assesses the reliability of the conclusions and indicate the impact of the protocol deviations on results. If the stability is poor, the analysis model, inclusion and exclusion criteria will be adjusted to increase stability.

Data synthesis
The RevMan 5.4.1 software will be used to analyse the data. The X 2 test and I 2 test will indicate the application of a FEM or a REM. Substantial statistical heterogeneity not found, a systematic narrative synthesis will be performed to summarize and analyse the ndings of the studies included.

Grading of quality of evidence
The evidence quality will be conducted according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [23] in terms of inconsistency, limitation, imprecision, indirectness, and the publication bias. The system classi es evidence into high, moderate, low, and very low.

Ethics and dissemination
We will publish this review in peer-reviewed journals, or address it in meetings. The individual participant data will be excluded, so it is not necessary to acquire the ethical approval or informed consent.

Discussion
At present, the mainstream treatment for blepharospasm is botulinum toxins injection, which has many side effects, such as the presence of apraxia of eyelid opening and dose-dependent effects [24][25] . Consequently, it is urgent to look for a feasible, safe and effective treatment for blepharospasm. In traditional Chinese medicine, blepharospasm is usually caused by the de ciency of blood in the liver and spleen or the de ciency of both the heart and spleen. The treatment should be based on heart, liver and spleen, and acupuncture is often used to tonify Qi and blood [26][27] . A considerable number of studies have shown the e cacy of acupuncture in the treatment of blepharospasm.
This systematic review elucidates the function of acupuncture for blepharospasm. Conclusions may bene t patients clinicians and policy makers. This review comprises identi cation, the inclusion of study, the extraction of the data, and the synthesis of the data. It has some limitations such as considerable heterogeneity caused by various forms of acupuncture and the poor quality of included studies. Ethics approval is not required because individual data are not included. The ndings of this systematic review will be disseminated through peer-reviewed publication or conference presentations.

Consent for publication
Not applicable Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current protocol.

Competing interests
The sponsors are not involved in design, execution, or whiting the study. All authors involved in this work have no con icts of interest.

Funding:
This work was supported by the Sichuan Province Science and Technology Support Program, grant number (2019YFH0117).
Author contributions HH, QH, NG contributed equally to this work and are co rst authors. Contributors HH and YLZ contributed to the conception of the study. The manuscript protocol was drafted by HH, and was revised by YLZ, QH, NG. HH and QH developed the search strategies, and QH, NG will implement them. RXL, WWZ will extract data of included studies, assess the risk of bias and complete the data synthesis. YLZ will arbitrate the disagreements and ensure that no errors are introduced during the study. All authors approved the publication of the protocol. RCT(ti,ab) #24 #7 and #11 and #20 and #24 MeSh = medical subject headings, RCT = randomized controlled trial.