The Efficacy of Traditional Chinese Medical Exercise for Parkinson’s Disease: A Systematic Review and Meta-analysis

Background and Objective Several studies assessed the efficacy of traditional Chinese medical exercise in the management of Parkinson’s disease (PD), but its role remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the effect of traditional Chinese medical exercise for PD. Methods Seven English and Chinese electronic databases, up to October 2014, were searched to identify relevant studies. The PEDro scale was employed to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.1 software. Results Fifteen trials were included in the review. Tai Chi and Qigong were used as assisting pharmacological treatments of PD in the previous studies. Tai Chi plus medication showed greater improvements in motor function (standardized mean difference, SMD, -0.57; 95% confidence intervals, CI, -1.11 to -0.04), Berg balance scale (BBS, SMD, -1.22; 95% CI -1.65 to -0.80), and time up and go test (SMD, -1.06; 95% CI -1.44 to -0.68). Compared with other therapy plus medication, Tai Chi plus medication also showed greater gains in motor function (SMD, -0.78; 95% CI -1.46 to -0.10), BBS (SMD, -0.99; 95% CI -1.44 to -0.54), and functional reach test (SMD, -0.77; 95% CI -1.51 to -0.03). However, Tai Chi plus medication did not showed better improvements in gait or quality of life. There was not sufficient evidence to support or refute the effect of Qigong plus medication for PD. Conclusions In the previous studies, Tai Chi and Qigong were used as assisting pharmacological treatments of PD. The current systematic review showed positive evidence of Tai Chi plus medication for PD of mild-to-moderate severity. So Tai Chi plus medication should be recommended for PD management, especially in improving motor function and balance. Qigong plus medication also showed potential gains in the management of PD. However, more high quality studies with long follow-up are warrant to confirm the current findings.

Integrated Database, Weipu Database for Chinese Technical Periodicals and Wan Fang Data. The following keywords were used: Parkinson, Parkinson's disease, Parkinsonism, traditional Chinese medical exercise, Tai Chi, Qigong, Wuqinxi, Baduanjin and Yijinjing. WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Chinese Dissertation Fulltext Database were also searched to identify unpublished studies. And we contacted experts in relevant field. The literature search was performed independently by two authors (S Jiao and ZY Lv), and disagreements were resolved by discussion.

Study Selection
Two authors (Y Yang and WQ Qiu) independently identified and selected the studies based on standardized manner. The studies that met the following criteria were included: (1) study design: randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs); (2) the target population was diagnosed as PD in any stage; (3) traditional Chinese medical exercise was practiced alone or combined with stable medication, such as Madopar, compared to placebo, no intervention and any other therapies with or without stable medication; (4) the primary outcomes were motor function assessed by Unified Parkinson's Disease Rating Scale III (UPDRS III), health related quality of life assessed by Parkinson's Disease Questionnaire-39  or Activities of Daily Living (ADL), balance assessed by Berg Balance Scale (BBS), Functional Reach Test (FRT) or Time Up and Go Test (TUG) and gait assessed by gait velocity, stride/step length, or 6-Minute Walking Test (6-MWT); (5) the studies contain available data for the meta-analysis; (6) the paper was available in either English or Chinese. Any disagreement was settled by discussion or by consulting a third author (J Teng).

Data Extraction
Two authors (Y Yang and WQ Qiu) independently performed data extraction from the eligible studies. The following information was extracted: (1) study source and study design; (2) patients characteristics: sample size, age, gender and disease stage; (3) details of the interventions: type, duration, dose and frequency; (4) main outcomes and (5) length of follow-up. For the crossover study, the first phase of the study was adopted for the sake of prohibiting carryover effects. The primary author was contacted by e-mails when the relevant data was not reported. Any disagreement was settled by discussion or by consulting a third author (YL Hao).

Quality Assessment
Two authors (Y Yang and S Jiao) independently assessed the methodological quality of eligible studies using PEDro scale. The PEDro score has a fair-to-good reliability for the physiotherapy studies in systematic reviews [20,21]. And higher scores represent a better quality. The necessary information in eligible studies was supplemented by contacting the corresponding authors. There was no disagreement between the authors regarding PEDro scores.

Data Synthesis and Analysis
Meta-analysis was conducted with Cochrane Collaboration software (Review Manager Version 5.1). D-value of the pre and post treatment was used as the change of curative effect. As for three or four-armed studies, the similar control groups have be merged with computational formula provided by the Cochrane handbook to create a single pair-wise comparison. For continuous data, standardized mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated for all eligible trials. The I 2 statistic, a quantitative measure of inconsistency across studies, was employed in assessing heterogeneity. Heterogeneity was regarded high if the I 2 is greater than 75%. Detailed subgroup analyses were performed to compare Tai Chi/Qigong plus medication with medication alone or other therapy plus medication. Publication bias was assessed using funnel plot if the group included more than 10 studies.
Gait. One study reported that Qigong plus medication did not show greater improvements than medication alone in gait velocity or step length [15]. Gait endurance was assessed by 6-MWT in 2 trials [13,29] and the meta-analysis was performed. The aggregated result showed that there was no significant difference between Qigong plus medication and other therapy plus medication (SMD, -0.09; 95% CI -1.07 to 0.89; p = 0.85, Fig 9) [13,29].
Quality of life. One study assessed the quality of life in patients with PD by PDQ-39, and reported that Qigong plus medication showed better effect than aerobic exercise plus medication (PDQ-39 mean changes: 2.8 versus -3.2) [13].  The Effect of Traditional Chinese Medical Exercise on PD

Adverse Events
No serious adverse events were reported during the Tai Chi/Qigong training in eligible studies. Only one study reported that there were few back pain and ankle sprain [14].

Discussion
This is the first comprehensive systematic review and meta-analysis to assess the effect of traditional Chinese medical exercise in the management of PD. Tai Chi and Qigong were used as assisting pharmacological treatments of PD in the previous studies. The positive finding was that Tai Chi plus medication showed greater gains than medication alone or other therapy plus medication in motor function and balance. However, there was not sufficient evidence on the efficacy of Tai Chi plus medication in improving gait or quality of life. Although some trials reported beneficial effect of Qigong plus medication for PD, the aggregated results did not support or refute it.
The positive finding of this systematic review should be available for patients with PD of mild-to-moderate severity due to most patients diagnosed as Hoehn and Yahr stage I to III [13,15,[22][23][24][25][26][27][28]31]. All eligible patients can finish Tai Chi or Qigong exercise independently.  The Effect of Traditional Chinese Medical Exercise on PD And traditional Chinese medical exercise is based on the ability to stand and move independently. Therefore, these assisting pharmacological exercises should be recommended for PD patients of mild-to-moderate severity, especially in improving motor function and balance.
The last systematic reviews of Tai Chi for PD concur with our positive findings [17,18]. One supported that Tai Chi plus medication resulted in promising gains in mobility and balance for PD patients at an early stage [18]. However, there were serious limitations in this review. Firstly, two control interventions were considered as no intervention [15] and routine physical exercise [24] respectively, but stable medications were not changed during the study according to the author's reply. Secondly, some subgroup analyses only included one trial. It was not valid because the meta-analysis should be performed based at least on two studies. What's more, the similar control groups should be combined to create a single pair-wise comparison according to Cochrane handbook, but it was not performed in this review. The other review concluded that Tai Chi was a valid complementary and alternative therapy for PD, especially on motor function and balance [17]. However, Tai Chi as an assisting pharmacological treatment was not compared with medication alone or other therapy plus medication. In our review, detailed subgroup analyses were performed to compare Tai Chi plus medication with medication alone or other therapy plus medication.
Our result of Qigong for PD was supported by previous review [39]. The evidence was insufficient to support Qigong plus medication for PD due to limited number of studies. However, the beneficial finding of current review was that Qigong plus medication showed potential gains for PD. Two trials reported that Qigong plus medication showed better effect than medication alone in Webster scale [11,12], and one study reported that Qigong plus medication was superior to aerobic exercise plus medication in UPDRS III and PDQ-39 [13]. What's more, it has been reported that Qigong has beneficial effects in improving physical performance, figure, quality of life, etc. [40][41][42]. Consequently, Qigong may be a valid assisting pharmacological treatment of PD. Further high quality RCTs are required to confirm current beneficial finding.
In previous studies, only Tai Chi and Qigong were focused, but other traditional Chinese medical exercises should also be investigated, such as Baduanjin and Wuqinxi. Li and his colleagues have reported beneficial effects of Baduanjin exercise in physical flexibility of healthy older [43]. Baduanjin has been recommended as a safe and feasible treatment option for patients with knee OA in disability, stiffness and quality of life [44]. Wuqinxi exercise may be a valid alternative treatment for low back pain in improving dysfunction [45], and for knee OA in balance function [46]. So Baduanjin and Wuqinxi exercise may be a valid assisting pharmacological treatment for PD.
Assuming that traditional Chinese medical exercise was beneficial for PD, some complex neurophysiological mechanisms may provide possible rationales [47][48][49][50]. Intensive exercise showed beneficial effects on neural plasticity, neuroprotection and preventing neural degeneration [47]. Especially, some animal studies have reported that intensive exercise may promote neurogenesis, dopamine synthesis and release in the striatum [51,52]. And such neural changes may affect behavioral recovery in individuals with PD [53,54]. In relevant studies, the intervention was generally considered as intensive exercise when involving 2-3 hours of exercise per week for 6-14 weeks (a total of 12-42 hours of treatment) [47]. In our systematic review, all eligible studies employed intensive traditional Chinese medical exercise (a total of 12-300 hours) for PD. And the intensive Tai Chi/Qigong also showed beneficial effects in improving motor function and balance. In addition, repetitive traditional Chinese medical exercise may also promote development of new motor programs which allow faster reactions responding to postural challenge [55]. And these new motor programs, which promoted behavioral recovery, may be due to making new synaptic connections.
There were some potential limitations in our systematic review: 1) there was the degree of uncertainty in locating relevant studies because of limited retrieving resources, language barrier, publication bias, etc. 2) there were few studies in some subgroup analyses because of strict eligibility criteria, which may bias the aggregated results. However, low eligibility criteria would conduct more doubtful results. 3) PEDro score was less than 6 in 5 studies. They were not considered as high quality, but they contributed valuable information to the evidence of Tai Chi/Qigong for PD. So they were included in our review. 4) synthetic results may be affected by different parameters (duration, frequency, dosage, etc.) of Tai Chi/Qigong exercise. 5) the follow-up effect of Tai Chi/Qigong for PD was not investigated in current studies. So further studies of Tai Chi/Qigong for PD should include long-term follow-up. 6) few adverse events were reported in included studies, but it was not concluded that Tai Chi/Qigong exercise was safe.

Conclusions
In the previous studies, Tai Chi and Qigong were used as assisting pharmacological treatments of PD. The current systematic review showed positive evidence of Tai Chi plus medication for PD of mild-to-moderate severity. So Tai Chi plus medication should be recommended for PD management, especially in improving motor function and balance. Qigong plus medication also showed potential gains in the management of PD. However, more high quality studies with long follow-up are warrant to confirm the current findings. And relevant mechanism research of traditional Chinese medical exercise for PD is also required.