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By systematically evaluating the clinical efficacy of oral TCM in treating vestibular migraine.
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Traditional Chinese Medicine can base on different syndrome types, combine TCM classification differentiation and disease differentiation, and treat the symptoms and diseases at the same time.
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Oral Traditional Chinese Medicine can improve vestibular migraine symptoms such as headache and dizziness, and can also improve nausea and vomiting, dry mouth and bitter taste, upset and irritability, restless sleep and other associated symptoms at night.
Abstract
Objective
Vestibular migraine is a common vertigo disease, and studies confirm that Traditional Chinese medical has unique advantages in treating vestibular migraine. However, there is no unified clinical treatment method and lacks objective outcome indicators. This study aims to provide evidence-based medical evidence by systematically evaluating the clinical efficacy of oral TCM in treating vestibular migraine.
Methods
Search journals related with clinical randomized controlled trials of oral traditional Chinese medicine for vestibular migraine in databases includes China Academic Journals full-text database (CNKI), China Biology Medicine disc (CBM), China Science and Technology Journal Database(VIP), Wangfang Medicine Online(WANFANG), PubMed, Cochrane library, EMBASE, MEDLINE, and OVID databases from their inceptions until September 2022. The quality of the included RCTs was assessed using the Cochrane risk of bias tool, then conduct the Meta analysis by using RevMan5.3.
Results
There were 179 papers left after selection. Moreover, according to the literature inclusion and exclusion criteria, 158 studies were filtered and the remaining 21 articles would be considered in this paper, which include 1650 patients in total and 828 of them were in the therapy group and 822 of them were in the control group.Furthermore,the therapy group outperformed the control group in terms of the total efficiency rate and TCM syndrome score, and the difference is statistically significant(P < 0.01). The number of vertigo attacks and the duration of each vertigo decreased compared to the control group, which difference is also statistically significant (P < 0.01). The funnel chart of the total efficiency rate was approximately symmetric and publication bias was low.
Conclusion
The oral traditional Chinese medicine is an effective way for vestibular migraine, which would help with the clinical symptoms, reduce the TCM syndrome score, decrease the number of vertigo attacks and the duration of each vertigo, and improve life quality of patients
Vestibular migraine(VM), also called migraine vertigo, is a common nervous system disease, which mainly causes repeated dizziness or migraine, and the symptoms might also contain sensitivity of light and sound [
GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016[J]. Lancet Neurol. 2018,17(11):954-976. doi: 10.1016/S1474-4422(18)30322-3. Erratum in: Lancet Neurol. 2021 Dec;20(12):e7. PMID: 30353868; PMCID: PMC6191530.
]. Studies have shown that vestibular migraine is the second most common cause of recurrent vertigo after benign paroxysmal positional vertigo, and the incidence of women is higher than that of men, the ratio can be as high as 5:1 [
(2019). Stroke and Vertigo Branch of Chinese Stroke Association, Vertigo Professional Committee of Neurologist Branch of Chinese Medical Doctor Association. Multidisciplinary expert consensus on the diagnosis and treatment of vestibular migraine [J].Chin J Internal Med. 58 (2): 102-107.
]. These facts have guiding significance for clinical.
Based on the Expert Consensus on the Diagnosis and Treatment of Vestibular Migraine (2018), there is currently no comprehensive diagnosis and treatment guideline, so its treatment recommendations should refer to the management model of migraine [
], which can treat vertigo and prevent migraines, but it has very limited effect. It not only has toxic side effects, but also fails to improve patients’ negative emotions [
]. Moreover, there is a high recurrence rate. In the case of the limitation of traditional treatment mode, TCM has played an important role. TCM has unique advantages in the treatment of vestibular migraine, which can base on different syndrome types, combine TCM classification differentiation and disease differentiation, and treat the symptoms and diseases at the same time [
]. It can also improve clinical efficacy and improve clinical symptoms. This paper aimed at providing higher-quality of clinical evidence of traditional Chinese medicine for VM, which could ideally guide clinical treatment by systematically evaluated the clinical efficacy of oral TCM for VM.
2. Methods
2.1 Search strategy
Database search strategy is designed based on the handbook of reviews of Cochrane system, which mainly focused on computer search. Furthermore, Chinese databases such as China Academic Journals full-text database (CNKI), China Biology Medicine disc (CBM), China Science and Technology Journal Database (VIP) and Wangfang Medicine Online(WANFANG) and English databases such as PubMed, Cochrane library, EMBASE, MEDLINE, and OVID are considered.
Keywords set for Chinese databases are ‘vestibular migraine’, ‘migraine vertigo’, ‘traditional Chinese medicine’, ‘medicine herb’, ‘Chinese medicine’, ‘random’, ‘RCT’. The search strategy is that ‘vestibular migraine’ and ‘migraine vertigo’ are searched together with ‘traditional Chinese medicine’, ‘Chinese medicine’ and ‘medicine herb’. After refinement, the remaining studies are searched according to ‘random’, ‘RCT’ separately. English database retrieval combined the MESH term and free term, where MESH term are ‘vestibular migraine’, ‘Migraine vertigo’, ‘Drugs, Chinese Herbal’ and ‘Traditional Chinese Medicine’.
2.2 Diagnostic criteria
The diagnostic criteria of vestibular migraine refer to the diagnostic criteria of the International Classification of Headache Diseases, 3rd edition in 2018(ICHD-III) [
Headache Classification committee of the International Headache Society (IHS). (2018). The Internationial Classificati on of Headache Disorders, 3rd edition[J]. Cephalagia. 38:1-211. doi: 10.1177/0333102413485658. PMID: 23771276.
According to ICHD-III: migraine without aura or a history of present or past history of migraine with aura;
C.
Moderate or severe vestibular symptoms lasting 5 min to 72 h;
D.
At least 50% of attacks are accompanied by one or more of the following migraine symptoms；
(1)Headache meets at least 2 of the following 4 items:
I.Unilateral.
II.Pulsatile.
III.moderate or severe.
IV.Daily physical activity aggravates the headache.
(2) Sensitivity of light and sound；.
(3) Visual aura symptoms.
E.
Itcannot be better explained by other diagnoses of ICHD-III or other vestibular disorders.
2.3 Inclusion criteria
(1) Type of study: Randomized controlled trials evaluating oral traditional Chinese medicine in the treatment of vestibular migraine.
(2) Type of patient: Individuals that are diagnosed as vestibular migraine in clinical diagnosis disregarding the age, gender and nationality.
(3) Interventions: The control group used the normal Western medicine treatment or placebo, whereas the therapy group utilized the oral TCM or apply the oral TCM based on the control group. Chinese medicines include single medicines, compound prescriptions and proprietary Chinese medicines, etc.
(4)Literature period: relevant literature from their inceptions of database until January 2022.
(5) Outcome measure:
1)Primary outcome measure: Total clinical efficacy: The criteria for evaluating the clinical efficacy of VM was determined according to the Guiding principles of clinical research on new Chinese medicine treatment, which was divided into recovered completely, effective, effective to a certain extent and not effective [
Recovered Completely: After the treatment, the clinical symptom for example, dizziness basically disappeared. The total improvement rate of TCM is over 90%.
Effective: After the treatment, the dizziness is reduced significantly. However, there is still slightly vertigo but no sense of rotation and shaking of the patients themselves and surrounding objects. Therefore, daily life of patients was not affected. The total improvement rate of TCM is larger than 70%.
Effective to a certain extent: The vertigo or dizziness have decreased after treatment, but there is slightly feeling of rotation and shaking of patients themselves and the surroundings, which could affect their daily life. The total improvement rate of TCM is greater than 30%.
Not effective: There is no improvement with respect to the clinical symptoms or the clinical symptoms such as dizziness and vertigo were poorer than before. The total improvement rate of TCM is under 30%.
Nimodipine method: The total improvement rate of TCM = (The total score before treatment - The total score after treatment)/ The total score before treatment *100%.
]: It divided traditional Chinese medicine into 4 grades according to none, mild, moderate and severe. The main symptoms which include headache and dizziness are 0, 2, 4 and 6 scores respectively; while the secondary symptoms which include nausea,and vomiting, dry mouth, bitterness, irritability, restless sleep at night are 0, 1, 2 and 3 score respectively.
]: Dizziness handicap inventory(DHI) is applied to obtained the patients’ DHI index before and after the treatment, which are physical/P(28), emotional/E(36), and functional/F(36). The total score are 100. Moreover, the higher the score implies the severer dizziness of the patients.
2) Secondary outcome measure: The number of vertigo attacks and the duration time of vertigo.
2.4 Exclusion criteria:
(1) Non-randomized controlled trial, case observation study without control group such as literature review, Meta analysis, discussion, conference, non-clinical research of cell tissue or animal experiments.
(1)
Self-Cross-Control Study
(2)
Studies that were not meet the outcome measure or could not provide effective data
(3)
Researches that were detected or published repeatedly
2.5 Study selection and data extraction
Two researches selected studies individually based on inclusion and exclusion criteria. They first conducted preliminary screening mainly by checking the titles, abstracts and keywords. Furthermore, they would read full text for rescreening before conducting cross checking. If there is disagreement, it would be resolved through negotiation with a third party. If the third party still could not resolve it, then relevant professionals would be consulted. The main extraction: Name of authors, Year of publication, Number of people enrolled, Interventions and Outcome variables.
2.6 Literature quality assessment
The quality of the included paper was assessed based on the recommendations of the Cochrane website using a new ‘Risk of bias assessment’ tool developed by methodological experts, editors and systematic reviewers [
]. It includes 6 aspects: (1) random assignment (2) allocation concealment (3) blinding of subjects, investigators and testers (4) data completeness (5) selective reporting of outcomes (6) other sources of bias. Each research result would be divided into ‘Yes’(Low risk of bias), ‘No’(High risk of bias) and ‘Unclear’(Lack of relevant information or unclear about the bias) based on the six criteria above.
2.7 Statistical methods
Statistical software RevMan 5.3 was utilized for Meta analyzing results from studies included. For each result from included studies, it would be conducted heterogeneity test. If it is not statistically significant(P > 0.05, I^2 < 50%), it indicated that there was no statistically significant heterogeneity of this included paper, then it would be analyzed by fixed-effect model; if it is statistically significant(P < 0.05, I^2 > 50%), it inferred that there was statistically significant heterogeneity of the included study, and it should be be further analyzed the source of the heterogeneity to determine that whether the study could be analyzed by random-effects model. Dichotomous outcomes uses Relative Risk (RR) and its 95% confidence interval (CI) as the statistics of analysis of benefit. Continuous variable utilized Standardized Mean Difference (SMD) and 95% CI as the statistics of analysis of benefit.
3. Results
3.1 Literature search results
Based on search strategy, there were total 179 related papers after selection. By using a software, Note Express, to sort relevant studies, 68 papers were detected that they had been published or selected repeatedly, thus they were screened out. Moreover, the remaining papers would be further filtered by checking their titles and 46 researches were removed. There were 65 remaining papers whose full text would be read and performed the filtration according to the inclusion and exclusion criteria mentioned above. Finally, 21 papers would be included, shown in Fig. 1.
There were 21 randomised controlled trials included, with a total of 1650 cases, including 828 cases in the treatment group and 822 cases in the control group. There were 698 males and 952 females,and the age range is from 18 to 65 years old. The baselines of age and gender of each included study were basically balanced, indicating that the treatment and control group from each literature were comparable, shown in Table 1.
Table 1Study Characteristics.
Included Paper
Sample Size
Grouping Method
Baseline(age and gender)
Interventions
Control group
Treatment Group
Treatment Group
Control group
Outcome Measures
Male/
Male/
female
female
Gao,2019
11/22
15/20
Random-numbers Table
Consistent
Shenqi Banxia Baizhu Tianma Decoction
Flunarizine Hydrochloride Capsules
1, 3
Zhang,2016
20/17
21/18
Random-numbers Table
Consistent
Chaihu Qinlian Decoction
Betahistine Mesilate Tablets
1, 3, 4, 5, 6
Li,2018
18/16
16/17
Random-numbers Table
Consistent
Changyuan Dingxuan Decoction
Flunarizine Hydrochloride Capsules
1, 2, 3, 4, 5, 6
Wang,2021
17/20
19/19
Random-numbers Table
Consistent
Modified Zexie Decoction
Flunarizine Hydrochloride Capsules
1, 3
Sun,2021
12/21
11/23
Random-numbers Table
Consistent
Qufeng zhixuan Decoction
Flunarizine Hydrochloride Capsules
1, 2, 3, 4, 5, 6
Gao,2020
1218
17/13
Random-numbers Table
Consistent
Control group + Xifeng Jianpi Huatan Treatment
Flunarizine Hydrochloride Capsules
1, 2, 3
Gu,2021
15/15
14/16
Random-numbers Table
Consistent
Control group + Yiqi Congming Decoction
Flunarizine Hydrochloride Capsules
1, 2, 4, 5
Sun,2018
25/37
26/36
Randomization
Consistent
Control group + Siwu Decoction
Flunarizine Hydrochloride Capsules
1, 2, 4
Gao,2021
14/16
12/18
Randomization
Consistent
Control group + Xifeng Jianpi Huatan Treatment + Acupuncture
Li, J.J. (2018). Clinical effect of calamus soup in vestibular migraine (evidence of sputum stasis) [D]. Changchun University of Traditional Chinese Medicine.
Tang PL. Clinical effect of nourishing serum brain granules and preventing hyperhepatic vestibular migraine [D]. Chengdu University of Traditional Chinese Medicine. 2020. DOI:10.26988/d.cnki.gcdzu. 2020.000461.
Xu JM. Clinical study on the treatment of liver and kidney Yin deficiency type vestibular migraine [D]. Shandong University of Traditional Chinese Medicine. 2021. DOI:10.27282/d.cnki.gsdzu. 2021.000576.
Li, J.J. (2018). Clinical effect of calamus soup in vestibular migraine (evidence of sputum stasis) [D]. Changchun University of Traditional Chinese Medicine.
] did not fully report the outcome results due to the patients drop-out. None of the 21 studies reported selective outcomes and other biases, shown in Fig. 2 and Fig. 3.
There were 21 studies, including 1650 patients, and 828 of them were in the treatment group, and 822 of them were in the control group. Heterogeneity test showed that there was heterogeneity among the 21 studies (P < 0.05, I^2 = 51%), therefore a random effect model was applied. Meta analysis implies it is statistically significant in the difference between the control group and the treatment group in improving the total clinical effective rate (RR = 1.21, 95 %CI[1.14,1.30], P < 0.01), shown in Fig. 4.
There were 12 studies, including 892 patients, and 446 of them were in the treatment group, and 446 patients were in the control group. The heterogeneity test shows that there was heterogeneity among the 12 studies (P < 0.001, I^2 = 94%), therefore a random effect model was applied. Meta analysis implies it is statistically significant in the difference between the control group and the treatment group in improving the TCM syndrome score (SMD = −1.47, 95 %CI [−2.09,−0.86], P < 0.01), shown in Fig. 5.
There were 14 researches, including 1022 patients, and 514 of them were in the treatment group, and 508 of them were in the control group. The heterogeneity test suggested there was heterogeneity among the 14 studies (P < 0.001, I^2 = 96%), thus a random effect model was utilized. Meta analysis shows that there was statistically significant difference between the treatment group and the control group in improving vertigo disorders (SMD = −0.97, 95 %CI[−1.67,−0.28], P < 0.01), shown in Fig. 6.
There were 12 studies, including 1015 patients, and 508 of them were in the control group and 507 of them were in the treatment group. The heterogeneity test indicated that there was heterogeneity among the five studies (P < 0.001, I^2 = 94%), so a random effect model was used. Meta analysis shows that there was a statistically significant difference between the treatment group and the control group in improving the number of vertigo attacks (SMD = −1.14, 95 %CI[−1.68,−0.61], P < 0.01), as shown in Fig. 7.
Eight studies were included and there were 640 cases, including 321 of them were in the treatment group and 319 cases were in the control group. The heterogeneity test implies that there was heterogeneity among the eight studies(P < 0.05, I^2 = 94%), so a random effect model was used. Meta analysis suggested there was a statistically significant difference between the treatment group and the control group in improving the duration of vertigo (SMD = −0.95, 95 %CI[−1.62,−0.28], P < 0.01), shown in Fig. 8.
A funnel plot was plotted based on the total clinical efficiency in outcome measures, shown in Fig. 9. It suggested that the left side and the right side were basically symmetric, indicating low publication bias, where it could be considered that the TCM could improve the clinical efficacy of vestibular migraine, improve the quality of patients’ life, and furthermore, the results were reliable.
Fig. 9The funnel plot of the total clinical efficacy.
Chinese medicine has unique advantages in treating the VM, since there was study showed that oral TCM could improve significantly the TCM syndrome, clinical efficacy, clinical symptoms, and the quality of patients’ life [
] suggested in their study that the oral TCM Wendan decoction could reduce the the TCM syndrome score, and improve the clinical efficacy. DUyanhua, et al. [
] discovered that the oral TCM Tianmagouteng drink could improve greatly the clinical efficacy, decrease the TCM syndrome and vertigo disorder score, reduce the number of vertigo attacks and duration of vertigo, and it could also reduce the occurrence of adverse reactions.
Vestibular migraine is characterized by dizziness or migraine, which belong to the category of ‘vertigo’ and ‘Partial head wind pain’ in the traditional medicine science of Chinese. Modern Chinese medicine believes that VM is mainly caused by internal wind and external wind, and the pathogenesis is mostly wind, fire, phlegm, blood stasis, and deficiency [
], which is the evidence of deficiency, so the treatment should focus on promoting blood circulation and removing blood stasis, calming the liver and suppressing wind, and nourishing Qi and blood.
Among the literatures included in this study, the most frequently used traditional Chinese medicines are Chuanxiong, Gegen. Both of them are products for activating qi and promoting blood circulation, and dredging the meridians. Chuanxiong can activate blood and qi, dispel wind and relieve pain. It is called “sacred medicine in blood”. Shen Nong’s Materia Medica records that it can treat stroke, headache, cold pain, and muscle spasm. In Medical Qiyuan, it is said Chuanxiong canvreplenish blood, and treat headache due to blood deficiency”. Modern pharmacology shows that Chuanxiong can anti-thrombotic and anti-cerebral ischemia [
]. Gegen is one of the medicines of the Yangming meridian. Modern pharmacological studies have shown that puerarin, the active ingredient of Gegen has a protective effect on neuronal apoptosis induced by oligosaccharide Aβ. It can inhibit neuronal apoptosis, increase the content of monoamine transmitters in brain tissue, and up-regulate the main protein levels of cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor (CREB-BDNF) signaling pathway in brain tissue, thereby exerting neuroprotective effect [
]. Therefore, Chuanxiong and Pueraria played an important role in the treatment of vestibular migraine.
This study included 21 relevant researches, which results implies, the treatment group outperformed the control group significantly (P < 0.01) in improving the total clinical efficacy and reducing the TCM syndrome. The treatment group performed better than the control group in reducing the number of vertigo attacks and the duration of vertigo (P < 0.01). In terms of TCM syndromes, TCM has played a unique advantage. From the results of this study, oral TCM can improve symptoms such as headache and dizziness, and can also improve nausea and vomiting, dry mouth and bitter taste, upset and irritability, restless sleep and other associated symptoms at night, which greatly improving the quality of life of patients.
Overall, the oral TCM has certain effect in preventing the VM. In additionally, it could improve the clinical efficacy remarkably, reduce the TCM syndrome, and decrease the number of vertigo attacks and duration of vertigo. However, the literature included in this study was heterogeneous. The reason might be that, first, dizziness handicap inventory is a widely used symptomatic assessment in the clinical history of vertigo. Though it is a reliable and effective quantitative assessment tool for life disabilities caused by vertigo, it is also an assessment of the subjective feeling of vertigo patients, so the quantitative standard has a certain degree of subjectivity. Accordingly, there would be bias in the assessment results to a certain extent. Second, Chinese medicine (decoction) and oral preparation (fluorizine hydrochloride Capsules, etc.) have different dosage forms, so it is difficult to hide and blind the distribution, which increases the selection bias and decreases the quality of the studies. Finally, the sample size included is small, no details of sample size calculation are provided, and the literature quality is poor, which reduces the statistical efficacy of the analysis and leads to high heterogeneity.
5. Limitations
This study evaluated systematically the clinical efficacy of the oral TCM for the VM, which showed that the oral TCM could improve remarkably the clinical efficacy, decrease the TCM syndrome, and reduce the number of vertigo attacks and the duration of vertigo. Whereas, this study also has certain limitation. Firstly, factors such as different TCM prescription, treatment frequency and duration may cause heterogeneity among various studies. Secondly, the clinical efficacy evaluation standard of the researches included in this study is mainly based on scales, so it would have subjectivity to a certain extent. Finally, none of the included articles mentioned allocation concealment and blinding, and three studies had low article quality due to subject shedding. In addition, the methodological and applied method reports of the included literature in this study were of poor quality, and there was a certain risk of bias, and only published literature was retrieved, so there was a certain publication bias.
6. Conclusion
The results from this study indicated that compared to other treatment, the oral traditional medicine has obvious advantages in treating vestibular migraine, which are that it can significantly improve clinical efficacy, decrease the TCM syndrome scores, reduce the number of vertigo attacks, shorten the duration of vertigo, and improve the life quality. These facts have guiding significance for clinical. Due to certain limitations of this study, rigorously designed, large-scale, multicenter RCTs are needed for evaluating the clinical efficacy of the oral TCM in the treatment of the VM to provided more reliable evidence.
Funding
Shanghai Pilot Construction Project of TCM Diagnosis and Treatment Model Innovation [ZY (2018-2020) -FWTX-6013]; Three-year Action Plan for TCM Strong Excellence in Hongkou District, Shanghai (HGY-YSZK-2018-10).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to thank all the researchers in our working group.
Availability of data and materials
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
References:
GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016[J]. Lancet Neurol. 2018,17(11):954-976. doi: 10.1016/S1474-4422(18)30322-3. Erratum in: Lancet Neurol. 2021 Dec;20(12):e7. PMID: 30353868; PMCID: PMC6191530.
(2019). Stroke and Vertigo Branch of Chinese Stroke Association, Vertigo Professional Committee of Neurologist Branch of Chinese Medical Doctor Association. Multidisciplinary expert consensus on the diagnosis and treatment of vestibular migraine [J].Chin J Internal Med. 58 (2): 102-107.
Headache Classification committee of the International Headache Society (IHS). (2018). The Internationial Classificati on of Headache Disorders, 3rd edition[J]. Cephalagia. 38:1-211. doi: 10.1177/0333102413485658. PMID: 23771276.
Li, J.J. (2018). Clinical effect of calamus soup in vestibular migraine (evidence of sputum stasis) [D]. Changchun University of Traditional Chinese Medicine.
Xu JM. Clinical study on the treatment of liver and kidney Yin deficiency type vestibular migraine [D]. Shandong University of Traditional Chinese Medicine. 2021. DOI:10.27282/d.cnki.gsdzu. 2021.000576.
Tang PL. Clinical effect of nourishing serum brain granules and preventing hyperhepatic vestibular migraine [D]. Chengdu University of Traditional Chinese Medicine. 2020. DOI:10.26988/d.cnki.gcdzu. 2020.000461.
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