Clinical study of acupuncture plus Dang Gui Bu Xue Qu Feng Tang for benign essential blepharospasm

ZOU Yuelan (邹月兰), KONG Xiehe (孔谐和), GUO Xiaocong (郭潇聪), WANG Xuejun (王雪君), LI Xiaoying (李晓莹),HAN Rong (韩榕), ZHANG Xiaopeng (张小芃), YANG Guang (杨光), YANG Yanting (杨延婷), MA Xiaopeng (马晓芃),

1 Department of Ophthalmology, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai 200040, China

2 Shanghai Research Institute of Acupuncture and Meridian, Shanghai 200030, China

3 Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

4 Shanghai Qigong Research Institute, Shanghai 200030, China

Abstract

Keywords: Acupuncture Therapy; Acupuncture Medication Combined; Chinese Herbal Drugs; Dang Gui Bu Xue Qu Feng Tang; Blepharospasm; Clinical Trial

Benign essential blepharospasm (BEB) is a focal dystonic disorder characterized by excessive involuntary contraction of the periocular muscles[1]. It affects approximately 4-5 out of every 100 000 people and is more common in women[2-3]. Studies have found that patients with BEB are more frequently reported to have psychiatric disorders, such as severe anxiety, depressive symptoms, psychotic disorders, suicidal ideation, and despair, compared to the healthy population[4].

BEB belongs to the category of eyelid flickering in traditional Chinese medicine (TCM)[5]. According to TCM,this disease is mostly due to the deficiency of Qi and blood from the liver and spleen, which makes it unable to nourish the muscles and collaterals of the eyelids,resulting in the blepharospasm. Besides, the deficiency of blood generates wind, and wind shakes and pulls the eyelids, causing them to flicker. Acupuncture, herbal medicine, and their combination have been reported frequently in previous literature on TCM treatment of blepharospasm. Although these three therapies have shown good efficacy in short-term observations[6-9],there is a lack of objective quantitative assessment, so the results are somewhat biased and unable to provide reliable evidence for clinical treatment.

Therefore, this trial was conducted to observe the clinical efficacy of acupuncture, herbal medicine, and their combination for BEB using the internationallyrecognized BEB assessment scales, including Jankovic rating scale (JRS) and blepharospasm disability index(BSDI), in order to provide references for the clinical treatment of BEB.

1 Clinical Materials

1.1 Study type

This is a prospective, randomized, assessor- and statistician-blinded, controlled trial. The protocol and informed consent were approved by the Medical Ethics Committee of Shanghai General Hospital (Approval No.201925). The trial was registered in the Chinese Clinical Trial Registry (Identifier: ChiCTR1900023698). All participants provided written informed consent.

1.2 Diagnostic criteria in Western medicine

Diagnostic criteria in Western medicine referred to the diagnostic criteria of BEB in theDevelopment and Validation of a Clinical Guideline for Diagnosing Blepharospasm[10]. Involuntary eyelid contraction/closure due to orbicularis oculi spasms; with a particular spasm pattern; bilateral and synchronous spasms;presence of effective sensory trick; increased blinks at rest; and inability to voluntarily suppress the spasms.

1.3 Inclusion criteria

Those who were 18-70 years old and met the diagnostic criteria for BEB.

1.4 Exclusion criteria

Those with other neurodegenerative pathologies or severe systemic diseases; with a history of head or maxillofacial trauma or surgery; with other eye diseases;use of medications that affect dystonia in the last six months; allergic to metal; held unreasonable expectations.

1.5 Criteria for dropout

Those who developed serious adverse reactions during the trial and required other emergency measures; with condition worsened rapidly within a short period of time and required discontinuation;withdrew on their own during the trial; did not comply with treatment arrangements and refused to cooperate.

1.6 Sample size calculation and statistical analysis

The primary endpoint event was set as the change from baseline in the JRS total score. It was expected that the combination treatment group would further reduce the JRS total score by 0.8 point than either the acupuncture or herbal medicine group, with a common standard deviation of 1.2. Theαandβwere set at 0.05 and 0.20, respectively, and the grouping ratio was 1:1:1.The minimum number of valid sample cases needed for each group was calculated as 30 using the G-power software. Considering a dropout rate of ≤15%, 35 cases per group and 105 cases in total were needed.

Statistical analysis was performed by a third party unrelated to the trial. The per-protocol set was used for analysis, including those who completed all case report form (CRF) content. The baseline measurement data were expressed as mean ± standard deviation (±s),and the one-way analysis of variance (ANOVA) was used for comparisons among groups. The counting data were described by frequency, and between-group comparisons were made using Chi-square test.Within-group comparisons of JRS and BSDI scores were made using pairedt-test. Between-group comparisons were made using the analysis of covariance, with intervention as a fixed factor and the corresponding baseline score, and other baseline characteristics with significant between-group differences that occurred by chance during randomization as covariates. Intra-group comparison of each BSDI sub-score was performed using the non-parametric test. The Bonferroni approach was used to control the type 1 error rate. All the tests of effects were conducted at a two-sided alpha level of 0.05 using SPSS version 25.0 statistical software.

1.7 Randomization and blinding

All 105 participants were numbered in the order of appointment. Each participant was randomly assigned with equal probability to an acupuncture group, a herbal medicine group, or an acupuncture plus herbal medicine group via computer-generated randomization(SPSS version 25.0 statistical software). Set 1 as the acupuncture group, 2 as the herbal medicine group,and 3 as the acupuncture plus herbal medicine group.Slips of paper with 1, 2, or 3 written on them were placed in well-sealed opaque envelopes according to the randomization sequence that had been formed.Patients who were successfully screened were given an envelope sequentially, with treatment allocation hidden from the assessor and statistician and open to the acupuncturists. Patients in all three groups received treatment separately and were told not to discuss any treatment-related issues with the assessor at each assessment.

1.8 General data

At the end of the study, 10 of the 105 participants dropped out and 95 cases were finally included in the analysis, including 31 cases in the acupuncture group,34 cases in the herbal medicine group, and 30 cases in the acupuncture plus herbal medicine group, as detailed in Figure 1. Baseline characteristics of the three groups are shown in Table 1. There were no statistical differences in the general data (P＞0.05) except for the age (P＜0.05).

Figure 1. Clinical flow chart

Table 1. Baseline characteristics of the three groups

2 Treatment Methods

2.1 Acupuncture group

Acupoints: Bilateral Taiyang (EX-HN5), Cuanzhu (BL2),Sizhukong (TE23), Fengchi (GB20), Hegu (LI4),Yinlingquan (SP9), Sanyinjiao (SP6), Taichong (LR3),Benshen (GB13); Baihui (GV20), and Shenting (GV24).

Methods:The participants took a supine position.After sterilization, stainless steel disposable acupuncture needles (0.30 mm in diameter and 50 mm in length) were inserted. Acupuncturists lifted, thrust,and/or twisted the needles to make the patient get feelings of soreness, numbness, or distention (Deqi).The needles were retained for 30 min. The treatment was performed twice a week for four weeks.

2.2 Herbal medicine group

The herbal medicine group was given oral Dang Gui Bu Xue Qu Feng Tang.

Compositions:Huang Qi(Radix Astragali) 30 g,Dang Gui(Radix Angelicae Sinensis) 6 g,Bai Fu Zi(Rhizoma Typhonii Gigantei) 6 g,Jiang Can(Bombyx Batryticatus)6 g,Quan Xie(Scorpion) 3 g,Jing Jie(Herba Schizonepetae) 9 g, andFang Feng(Radix Saposhnikoviae) 10 g.

Modified according to different syndromes:Dang Shen(Radix Codonopsis) 15 g andBai Zhu(Rhizoma Atractylodis Macrocephalae) 15 g were added for heart-spleen Qi deficiency syndrome;Shu Di Huang(Radix Rehmanniae Preparata) 6 g andBai Shao(Radix Paeoniae Alba) 15 g for Yin-blood deficiency syndrome.

Methods:The herbs were decocted in water. Then the decoction was taken one dose daily for four weeks,with each dose divided into two portions taken in the morning and evening, respectively.

2.3 Acupuncture plus herbal medicine group

The acupuncture plus herbal medicine group received both the acupuncture and herbal medicine treatments. The methods and the course of treatment were the same as in the two groups mentioned above.

3 Observation of Therapeutic Efficacy

3.1 Observation items

3.1.1 Primary efficacy outcome (JRS score)[11]

The JRS was used to evaluate the severity and frequency of BEB. The JRS total score is 0-8 points and includes severity (0 point for no spasm; 4 points for severe functionally compromised blepharospasm that can involve the facial muscles) and frequency (0 point for no spasm; 4 points for functional “blindness”,persistent blepharospasm resulting in more than 50% of the time with eyes closed) sub-scores.

3.1.2 Secondary efficacy outcome (BSDI score)[11]

The BSDI is a self-rating scale used to assess the impact of blepharospasm on the patient's daily life. The BSDI consists of six items, including driving, reading,watching TV, shopping, walking, and doing daily activities, rated on a severity scale ranging from 0 to 4 points, with items not involved expressed as NA.

3.2 Results

3.2.1 Comparison of the primary efficacy outcome After four weeks of treatment, the JRS total scores,and severity and frequency sub-scores significantly decreased in all three groups (P＜0.01), (Table 2). In the model adjusted by age and the corresponding baseline scores, the change from baseline in the JRS total score was -1.13 [95% confidence interval (CI): -1.64, -0.61] in the acupuncture group, -1.11 (95% CI: -1.59, -0.64) in the herbal medicine group, and -1.91 (95% CI: -2.42,-1.39) in the acupuncture plus herbal medicine group,with statistically significant differences (P＜0.05). A greater reduction in the JRS total score was reported in participants receiving acupuncture plus herbal medicine versus acupuncture or herbal medicine alone (P＜0.05),but not in participants receiving acupuncture versus herbal medicine (P＞0.05). The acupuncture plus herbal medicine group had a greater decrease in the mean JRS severity sub-score than the herbal medicine group(P＜0.05). Yet, no significant difference was observed either in acupuncture plus herbal medicine versus acupuncture (P＞0.05) or in acupuncture versus herbal medicine (P＞0.05). The reduction in the JRS frequency sub-score among the three groups was not significantly different (P＞0.05). See Figure 2 to Figure 4 for details.

3.2.2 Comparison of the secondary efficacy outcome After the 4-week treatment, the BSDI scores significantly decreased in all three groups (P＜0.05),(Table 3). In the model adjusted by age and the corresponding baseline scores, the change from baseline in the BSDI score was -0.42 (95% CI: -0.54,-0.30) in the acupuncture group, -0.44 (95% CI: -0.50,-0.38) in the herbal medicine group, and -0.49 (95% CI:-0.61, -0.37) in the acupuncture plus herbal medicine group, with no statistically significant difference(P＞0.05), (Figure 5). Comparisons of each item score in BSDI between baseline and post-intervention were shown in Table 4. After four weeks of treatment, the acupuncture group had significantly lower BSDI driving and reading sub-scores versus baseline (P＜0.05); the herbal medicine group had a significantly lower BSDI driving sub-score versus baseline (P＜0.05); and the acupuncture plus herbal medicine group had significantly lower BSDI driving, reading, and watching TV sub-scores (P＜0.05).

Table 2. Comparisons of the JRS scores among the three groups ( ±s, point)

Table 2. Comparisons of the JRS scores among the three groups ( ±s, point)

Note: Compared with the same group before treatment, 1) P＜0.05

Group n Time Severity sub-score Frequency sub-score Total score Acupuncture 31 Before treatment 2.71±0.69 3.00±0.63 5.71±1.04 After treatment 2.10±1.221) 2.39±1.151) 4.48±2.171)Herbal medicine 34 Before treatment 2.35±0.77 3.18±0.39 5.53±1.02 After treatment 1.91±1.081) 2.50±1.101) 4.41±2.081)Acupuncture plus herbal medicine 30 Before treatment 2.40±0.62 3.20±0.41 5.60±0.97 After treatment 1.53±0.891) 2.30±0.881) 3.83±1.691)

Figure 2. Comparison of the change from baseline in JRS total score

Figure 3. Comparison of the change from baseline in the JRS severity sub-score

Figure 4. Comparison of the change from baseline in the JRS frequency sub-score

Table 3. Comparison of the BSDI score ( ±s, point)

Table 3. Comparison of the BSDI score ( ±s, point)

Note: Acu=Acupuncture group; Hm=Herbal medicine group;Acu+Hm=Acupuncture plus herbal medicine group

Group n Before treatment After treatment Acu 31 2.22±0.97 1.81±0.821)Hm 34 2.20±0.83 1.76±0.861)Acu+Hm 30 2.32±1.12 1.83±1.111)

Figure 5. Comparison of the change from baseline in the BSDI score

Table 4. Comparisons of each BSDI sub-score among the three groups ( ±s, point)

Table 4. Comparisons of each BSDI sub-score among the three groups ( ±s, point)

Note: Acu=Acupuncture group; Hm=Herbal medicine group; Acu+Hm=Acupuncture plus herbal medicine group; compared with the same group before treatment, 1) P＜0.05

Group n Time Driving Reading Watching TV Shopping Walking Doing daily activities Acu 31 Before treatment 3.30±0.98 3.20±1.01 2.57±0.83 2.00±0.64 1.39±0.60 0.86±0.42 After treatment 2.72±0.991) 2.43±0.971) 2.28±0.91 1.48±0.73 1.19±0.61 0.76±0.43 Hm 34 Before treatment 3.21±1.07 3.03±1.00 2.71±0.74 1.93±0.68 1.49±0.77 0.83±0.38 After treatment 2.66±0.711) 2.56±1.03 2.30±0.82 1.25±0.54 1.06±0.58 0.73±0.39 Acu+Hm 30 Before treatment 3.37±0.82 3.35±0.92 2.87±0.71 2.06±0.71 1.38±0.61 0.89±0.45 After treatment 2.68±0.931) 2.53±0.991) 2.29±0.681) 1.51±0.71 1.20±0.62 0.77±0.40

4 Discussion

BEB is usually considered a sporadic disorder, but up to 27% of the patients have one or more family members with dystonia[12-13], suggesting a genetic predisposition for this disorder. However, no target gene has been determined. In recent years, functional magnetic resonance imaging (fMRI) studies have shown functional and gray matter abnormalities in several brain regions in patients with BEB[14-15], and abnormalities in the cortico-striato-pallido-thalamic loop may be associated with the pathophysiology of BEB[16-18], but the exact pathogenesis remains unclear.Currently, intramuscular injection of botulinum toxin is one of the conventional treatment options for BEB, and its efficacy depends on repeated administration.Patients may need to increase the dose to achieve the same effect over time, imposing a greater financial burden on the patients. The most common adverse effects include periorbital hematoma, ptosis, dry eye,blurred vision, and diplopia, and repeated injections carry a risk of neutralizing antibodies and are associated with adverse reactions such as dysphagia and dysphonia[19]. These are the reasons why many patients are reluctant to undergo this therapy, especially in patients in early stages of the disease with mild symptoms. Therefore, the search for effective treatments for BEB with fewer side effects has always been a difficult issue.

The etiology and pathogenesis of BEB are not new to TCM. The liver opens to the eyes and shares the same nature with wind and wood, so that it is prone to contract wind, leading to illnesses. Convulsion and flickering are the signs of wind. Yin-blood deficiency causes the wind to stir internally, pulling the eyelids and making them flicker. The eyelid belongs to the spleen.The deficient heart and spleen cannot provide sufficient Qi and blood. Then the tendons and flesh will not be nourished, resulting in eyelid flickering. Reinforcing blood to quench the wind, and tonifying the heart and spleen are the main treatment principle for this disease.In addition to Dang Gui Huo Xue Tang[20]and Gui Pi Tang[21]recommended in theOphthalmology ofTraditional Chinese Medicine, previous studies on the treatment of eyelid flickering also selected Tian Ma Gou Teng Tang[22], Ding Xian Wan[23], and Shao Chan Tang[24],all focusing on “quenching the wind”. Therefore, in this study, we proposed Dang Gui Bu Xue Qu Feng Tang for the treatment of BEB. In this herbal formula,Huang QiandDang Guiwere used to tonify the heart and spleen;Jing JieandFang Fengwere used to dispel the wind;Bai Fu Zi,Jiang Can, andQuan Xiewere selected to quench the wind and stop spasms.Dang ShenandBai Zhuwere added for heart-spleen Qi deficiency syndrome;Shu Di HuangandBai Shaowere added for Yin-blood deficiency syndrome. Acupuncture treatment is often based on the general principle that combines periocular acupoints with the acupoints for regulating the liver,heart and spleen[25]. In the present study, Taiyang(EX-HN5), Cuanzhu (BL2), and Sizhukong (TE23) were selected for unblocking the eye meridians and anti-spasmodic braking. Fengchi (GB20) is an essential acupoint for treating wind and can dispel wind and harmonize blood. Yinlingquan (SP9), Sanyinjiao (SP6),and Taichong (LR3) can regulate the liver and spleen,nourish and invigorate blood. Then the blood moves and the wind is eliminated. As the Yuan-Primary point of the Hand Yangming Meridian, Hegu (LI4) is a critical acupoint for treating diseases of the five senses. It has the effect of harmonizing Qi and blood of the eyes.Baihui (GV20), Benshen (GB13), and Shenting (GV24)were added to calm the heart and mind, and quench the wind, and to relieve the patients’ mental symptoms caused by long-term ocular discomforts. Further, the mean age and sex ratio of the BEB patients included in this study are consistent with the demographic characteristics of the disease. Therefore, the intervention method and the participants included in this study are representative, so the results can truly reflect the efficacy of acupuncture, herbal medicine,and their combination in the treatment of BEB.

In this study, the efficacy of acupuncture, herbal medicine, and their combination in the treatment of BEB was observed and compared using a randomized controlled approach and quantitative indicators. JRS and BSDI are two most applied scale assessment methods for blepharospasm and have been repeatedly validated for their reliability[11,26]. All three treatments were found to have some efficacy. A reduction of ≥2 points in the JRS total score or ≥0.7 point in the BSDI score is generally considered clinically meaningful[11].The best efficacy in this study was only a reduction of 1.91 and 0.49 points in the acupuncture plus herbal medicine group, with limited clinical significance of the 4-week treatment. However, botulinum toxin type A,the most commonly used intervention in Western medicine for BEB, only reduces 0.93 point on average at 4-6 weeks after injection versus placebo control[27]. The JRS severity sub-score (reduction in spasm magnitude)was reduced by 0.54 point (acupuncture), 0.45 point(herbal medicine), and 0.93 point (acupuncture plus herbal medicine) in this study. The effect size of the combination treatment still deserves attention, and the efficacy of acupuncture has been reported to increase further at 4-8 weeks[28]. Therefore, the combination of acupuncture and herbal medicine, a safe and economical intervention, is worthy of being an effective supplementary or alternative therapy of the conventional treatment of BEB.

Regarding the reduction in the JRS total score, the acupuncture plus herbal medicine group was greater than either the acupuncture or herbal medicine group,which is consistent with the results of previous studies[6-7], indicating that both acupuncture and herbal medicine contribute to the efficacy. Further analysis of the JRS sub-scores showed that the acupuncture plus herbal medicine group was superior to the herbal medicine group but not superior to the acupuncture group comparing the improvement in the spasm magnitude, while the acupuncture plus herbal medicine group was not significantly different from either the acupuncture or herbal medicine group in the improvement of the spasm frequency. It is suggested that the efficacy of the combination of acupuncture and herbal medicine is mainly reflected in the spasm magnitude, which may mainly originate from acupuncture. BAO F F,et al[28]used specific instruments to measure lower eyelid tension in patients with BEB,and the tension decreased from 812.76 Pa to 549.69 Pa after four weeks of acupuncture treatment. We speculate that the ameliorative effect of acupuncture on the magnitude of spasms may be related to the decrease in eyelid tension.

There are some limitations to this study. First, it is an open-label designed trial and lacks a placebo control to exclude the placebo effect of individual therapies.Second, the observation period is relatively short, with no follow-up performed.

The results of this study showed that four weeks of acupuncture, herbal medicine (Dang Gui Bu Xue Qu Feng Tang) and their combination were all effective in treating BEB. The combination treatment was superior to either acupuncture or herbal medicine alone, while the efficacy did not differ between acupuncture and herbal medicine alone. Further, a longer intervention with follow-up visits should be performed in the future study to observe the long-term efficacy in order to provide references for TCM treatment of BEB.

Conflict of Interest

Author MA Xiaopeng is a member of the Editorial Board of Journal of Acupuncture and Tuina Science, and author YANG Guang is the editor serving for Journal of Acupuncture and Tuina Science. The paper was handled by other editors and has undergone rigorous peer review process. Authors MA Xiaopeng and YANG Guang were not involved in the journal’s review or decisions related to this manuscript..

Acknowledgments

This work was supported by Shanghai Municipal Health Commission (上海市卫生和计划生育委员会项目, No.2018LP027); Youth Project of National Natural Science Foundation of China (国家自然科学基金青年项目, No.81904302).

Statement of Informed Consent

The protocol and informed consent were approved by the Medical Ethics Committee of Shanghai General Hospital (Approval No. 201925). Informed consent was obtained from all individual participants.

Received: 14 December 2020/Accepted: 27 April 2021