The Effectiveness and Safety of Moxibustion for Peripheral Facial Paralysis A Protocol for Systematic Review and Meta-Analysis

Shanshan Xiang Jiangxi University of Traditional Chinese Medicine Ting Fang Jiangxi University of Traditional Chinese Medicine Changan Ren Jiangxi University of Traditional Chinese Medicine Junnan Qi Jiangxi University of Traditional Chinese Medicine Zheng Guo Jiangxi University of Traditional Chinese Medicine Fushui Liu (  lfstcm@163.com ) Jiangxi University of Traditional Chinese Medicine https://orcid.org/0000-0002-8304-0889 Wenlong Yang Jiangxi University of Traditional Chinese Medicine


Introduction
Peripheral facial paralysis(PFP) is a common clinical condition in which facial expression muscle paralysis is caused by facial nerve dysfunction, and also a cause of face disability and resulting in lower quality of life [1][2] . Otherwise a prospective study indicated that PFP may have a negative impression to people's mental health [3] . On the basis of epidemiological survey, the incidence of different populations is about 11.5 to 53.3 per 100,000 people [4] . And research shows that suffers moderate to severe facial dissymmetry may persist impacting on PFP patients quality of life, which data in approximately 15-25% [5][6] . Based on the literatures, the majority of patients diagnosed with PFP is between the ages of 20 and 40, with a higher incidence in men than women [7] . According to clinical observations, the PFP can occur in any season, but autumn and winter are the peak seasons [7] .
Clinically, the clinical symptoms of PFP include inability to move the expression muscles, shallowing or disappearing off the frontal lines and nasolabial fold on the affected side, crooked mouth corners to the good side, incomplete eyelid closure, poor whistling, and bulging cheeks [8] . The main pathological feature is characterized by edema and facial nerve primary or secondary ischemia cause nerve compression and hypoxia [9] . The overwhelming majority of causing PFP is idiopathic Bell's palsy [10] , followed by traumatic causes accidental trauma leading to temporal bone fractures [9] . Currently, the treatments of PFP include oral steroids, antiviral therapy combined antiviral-steroid treatment, facial nerve decompression surgical and physical therapy [11][12][13][14] . However, there are still debate on the effectiveness of these interventions and often accompanied by varying degrees of side-effects [11,12,15,16] . Consequently, PFP sufferers require alternative treatments.
Moxibustion is a method of treatment originally in traditional Chinese medicine(TCM), which is the moxa sticks burned on the skin. According to theory of TCM, moxibustion is a kind of warm stimulus, which can warm the meridians and dispel cold, promote blood circulation and relieving pain. Some Chinese studies by RCTs or clinical observations [17][18][19] suggest that the moxibustion has the potential to be an effective and safe therapy for PFP, such as improving facial expression, adjusting the facial nerve function, improving face symptoms [20] .
With the deepening of research, it has been proved that moxibustion is effective on over 300 diseases, by accommodating circulatory, nervous system, immunologic function, and facilitating the formation of adaptation of huamn organisms [21] . Moxibustion is applied more widely to treat PFP, and its curative effect is positive in the clinical research of TCM. Therefore, the review is based on an evidence-based methodology to evaluate the effectiveness and safety of moxibustion in the treatment of PFP, to provide a scienti c basis for the clinicians treat PFP.

Objective
The objective of this review is to conclude the clinical evidence on the effectiveness and safety of moxibustion for the treatment of PFP and to provide credible proposals for clinicians.

Protocol registration
The protocol for the systematic review and meta-analysis(SR-MA) documented in PROSPERO 2020 CRD42020207068, which could available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42020207068. The protocol is draw up following the principles that guide the SR-MA protocol (PRISMA-P) statement in the Cochrane Handbook [22] . If there are any changes on the protocol, we will describe them in detail in the nal draft.

Participants of studies
We will include PFP patients who have been diagnosed by clinicians, on the basis of the diagnostic criteria of PFP established by the American Academy of Neurology (AAN) or the Neurology Society of Chinese Medical Association. There will be no restriction on country, occupation, race, age, and gender.

Interventions of studies
Depending on the purpose of our review, RCTs with moxibustion in the treatment group will be included. The treatment group with moxibustion in spite of the shape, size and type of moxa, length of time. The intervention group can treat with moxibustion or associate other interventions, while comparison group will only include other treatments.

Study selection
The search results will be imported into NoteExpress 3.2.0, excluding duplicate literature by it. Before literature selection, all reviewers will discuss and decide the selection criteria together. Firstly, two reviewers will exclude articles which did not meet the inclusion criteria by reading the title and abstract individually. Then they will read the rest of the studies in full text to make the ultimate decision. If there are disagreements, we will discuss or negotiate with the three reviewer to reach a consensus. The process of document screening is shown in Figure 1.

Data extraction and analysis
3.5.1. Data management and extraction Two reviewers will independently design an extraction form to collect general information from including RCTs, including author, country, year of publication, diagnostic criteria, sample size, intervention(s), control(s), treatment cycle(s), outcome measure(s), adverse events and other informations. In cases of any disagreement, we will consult and discuss with the three reviewer. When the RCTs' requisite data are incomplete or missing, we will contact the rst or corresponding author via e-mail for obtaining the data.

Assessing the risk of bias in included studies
Two reviewers will independently evaluate the methodological quality of included RCTs which base on the Cochrane Risk of Bias Assessment tool of Cochrane Reviewer's Handbook 5.0.24 [23] , as following: randomly generated sequence number, allocation sequence concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. The trial will be classi ed into each aspect " high, low or unclear risk ". The rating results will be cross-checked by two reviewers, and all disagreements will consult with the three reviewer.

Synthesis of results
RevMan 5.3 software will be prepare to conduct meta-analysis. If the result of overall effect test is P < 0.5, it means that difference is statistically signi cant. On the contrary, the difference is not statistically signi cant between the experimental group and control group. As for the index of effect size, we will use the Weighted Mean Difference (WMD) and 95% con dence intervals(CI) to evaluate the continuous variables, while using rate ratio(RR)and 95% CI for dichotomous variables. The results will be presented in the form of forest maps.
3.5.4. Heterogeneity test I 2 will be applied to assess the heterogeneity for included RCTs. When P>0.1 and I 2 ≤50, it is indicated that the merged studies with a lower heterogeneity, we will use the xed-effects model. Oppositely, it means that the heterogeneity of the merged studies is higher, we will choose the xed-effects model. When heterogeneity is apparent, we will perform subgroup analysis or sensitivity analysis to explore the source of heterogeneity and its impact on the research results.

Evaluation of reporting bias
When the number of eligible RCTs≥10, publication bias will be evaluated by funnel plot developed by Egger [24] . If the funnel plot appeared to be symmetric, showing that studies are lower with publication bias; If to be asymmetric, showing that studies are higher with publication bias.
3.5.5. Analysis of sensitivity If heterogeneity is signi cant in combination of different research data, we will conduct sensitivity analysis in line with sample size, methodological components, quality of RCTs, and study characteristics. Sensitivity analysis will be applied to assess whether the results are stable.
3.5.6. Analysis of subgroup If the data of eligible RCTs are reliable, we will conduct subgroup analysis based on age, course, frequency of treatment, treatment cycle, interventions for the control group and so on. For instance, if included RCTs were divided into 2 subgroups basis of different moxibustion type, and the 2 subgroups put on heterogeneity test which had been proved to be homogeneous. If the data of the 2 subgroups were apparent heterogeneity, it revealed that moxibustion type was the source of heterogeneity. Conversely, it showed that the type has little impact on the study results.
3.5.7. Grading the quality of evidence Two reviewers will independently assess the quality of eligible RCTs evidence by the software of GRADE pro ler 3.6. The speci c quality of the included RCTs will be evaluated in 5 dimensions (inconsistency, limitations, imprecision, indirectness, and publication bias), and ultimately the quality of RCTs outcome measure will be de ned as 4 levels, expressed as high, moderate, low, or very low [25] .

Discussion
Peripheral Facial Paralysis(PFP) is a disease with multiple pathogenic factors and complicated nosogenesis. However, the exact pathogenesis of PFP remains controversial. Clinically, most PFP cases have been uncovered without determining a exact causation. Therefore, a new study analyze the actuality of theories regarding the causes of PFP in ve aspect: cold stimulation,ischemia, anatomical, viral infection, and in ammation [26] . Currently, it is generally agreed that in ammation and edema of the facial nerve leading to entrapment within the facial canal, which also is main pathological manifestations of early PFP [26] . According to pathological manifestations of PFP, the most commonly accepted theories that cold stimulation lead to the microenvironment change of the facial microvascular neuron, which also an important factor causes in ammation and edema of the facial nerve [27,28] .
Moxibustion, as one of the oldest traditional therapies, has been used to treat various diseases including PFP for many years. Moxibustion is a warm stimulus produced by burning moxa, which with the effect of removing pathogenic wind and dampness [29] . Literature research showed that moxibustion which can expand the diameter of face capillaries, improve blood circulation, and relieve facial nerve and blood vessel spasm [30] . Moxibustion can inhibits the release of in ammation at the branch of the facial nerve, which plays a criticla role in eliminate the in ammation and edema of facial nerve [31,32] .
PFP is a disease which in uences a persons life via causing face modality change. Conventional treatments and operative intervention are helpful but at same time have their limitations. Recently, some clinical reports have showed that using moxibustion for PFP could contribute to both modality and functional aspects. However, there is no SR-MA on the effectiveness of moxibustionin the treatment of PFP so far. Based on the latest data, we hope that this study will provide clinicians and other workers with new ideas and programs for the treatment of PFP, and ultimately make thorugh with the objective of reducing the physical damage and mental distort of patients.

Declarations
Ethics approval and consent to participate No ethics approval is required for this systematic review because we will be using information from published documents. Our ndings will be published in a peer-reviewed journal according to the PRISMA guidelines.
Availability of data and materials Not applicable.

Consent for publication
Not applicable.

Declaration of Competing Interest
The authors have no con icts of interest to declare. Table   Due to technical limitations, table 1 is only available   Table1ThesearchstrategyforPubmed.pdf