https://orcid.org/0000-0001-7800-881X
Figures
Abstract
Background
In recent years, an increasing number of patients with age-related macular degeneration (AMD) have received acupuncture treatment, but there has been no systematic review to evaluate the effect of acupuncture on patients with AMD.
Purpose
This meta-analysis aims to review the clinical efficacy of acupuncture in the treatment of AMD.
Methods
Randomized controlled trials up to September 4, 2022 were searched in the following databases: PubMed, Ovid Medline, Embase, Cochrane Library, The Chinese National Knowledge Infrastructure Database, VIP, Wanfang, and SINOMED. Two reviewers independently performed literature screening and data extraction. RevMan 5.4 was used for the meta-analysis.
Results
Nine of the 226 articles were finally included. A total of 508 AMD patients (631 eyes) were enrolled, including 360 dry eyes and 271 wet eyes. The results showed that acupuncture alone or as an adjunct therapy improved both the clinical efficacy and best-corrected visual acuity (BCVA) of AMD patients and reduced their central macular thickness. The certainty of the evidence ranged from "low" to "very low".
Conclusion
There is no high-quality evidence that acupuncture is effective in treating patients with AMD; patients with dry AMD may benefit from acupuncture treatment. Considering the potential of acupuncture treatment for AMD, it is necessary to conduct a rigorously designed randomized controlled trials to verify its efficacy.
Citation: Sun W, Zhao Y, Liao L, Wang X, Wei Q, Chao G, et al. (2023) Effects of acupuncture on age-related macular degeneration: A systematic review and meta-analysis of randomized controlled trials. PLoS ONE 18(3): e0283375. https://doi.org/10.1371/journal.pone.0283375
Editor: Shiying Li, Xiang’an Hospital of Xiamen University, CHINA
Received: March 20, 2022; Accepted: March 8, 2023; Published: March 23, 2023
Copyright: © 2023 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data can be found in the article.
Funding: This study was supported by The National Natural Science Foundation of China (NSFC), No.81874491. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
Age-related macular degeneration (AMD) is a disease that affects the macular area of the retina and causes progressive damage to central vision [1]. The early stage manifests as drusen and retinal pigment epithelium abnormalities, and the later stage manifests as dry AMD characterized by non-vascular proliferation or wet AMD characterized by choroidal neovascularization (CNV). Later, AMD can cause loss of central visual acuity of the patient, accompanied by severe visual impairment and even blindness [2]. Currently, AMD is the leading cause of irreversible blindness in developed countries [3, 4]. A meta-analysis involving a total of 129,664 participants worldwide showed that the overall global prevalence of early- and late-stage AMD in the adult population was 8.01% and 0.37%, respectively, with a total prevalence of 8.69% [5]. Considering that aging is the greatest risk factor for AMD, the number of people suffering from AMD will continue to increase [6]. By 2040, the number of AMD patients is expected to increase to 288 million [5].
The current treatment measures for AMD include anti-vascular endothelial growth factor (VEGF) injection therapy, antioxidant vitamins and minerals, photodynamic therapy, thermal laser photocoagulation surgery, etc [7, 8]. To date, there is no effective treatment for dry AMD patients other than appropriate antioxidant supplementation. Anti-VEGF therapy, the current first-line treatment, may reduce the odds of legal blindness caused by neovascular AMD [9]. However, a long-term follow-up study of patients initially receiving regular anti-VEGF agents showed that among patients who were followed up for more than 7 years, two-thirds lost most of their gains in visual acuity (VA) [10]. Currently, an increasing number of other treatment measures are causing concern. Relevant studies have shown that acupuncture may become an effective method for the treatment of AMD, which can improve the eye symptoms and visual acuity of patients [11, 12]. There are the following hypotheses about the mechanism of acupuncture treatment for AMD. Previous research revealed that acupuncture has obvious specificity for the macular area [13]. Acupuncture could improve microcirculation in the macular area by expanding the surrounding blood vessels after acting on the peripheral area of the eyes [14–16]. Clinical studies have further confirmed that acupuncture can reduce central macular thickness (CMT) and promote the absorption of fundus exudate [16–18]. In addition, relevant study have also shown that acupuncture may reduce serum VEGF levels in patients with wet AMD [19, 20]. Although many studies have revealed an intervention effect of acupuncture on AMD, there has been no review to scientifically evaluate the efficacy of acupuncture therapy. This review aims to evaluate the efficacy and safety of acupuncture in the treatment of AMD.
2. Methods
2.1. Study registration
This meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42020168611) and strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [21].
2.2. Inclusion criteria
2.2.2. Types of participants.
Patients diagnosed with AMD by the investigators of the original study. Dioagnostic criteria inlucding at least one of the following:
1) Presence of at least intermediate-size drusen (≥63 μm in diameter); 2) Retinal pigment epithelium (RPE) abnormalities; 3) Presence of any of the following features: geographic atrophy of the RPE, CNV (wet), polypoidal choroidal vasculopathy, reticular pseudodrusen, or retinal angiomatous proliferation [8].
2.2.3. Types of interventions.
All types of acupuncture were included, including electroacupuncture, warm acupuncture, and scalp acupuncture. Interventions in the control group included sham acupuncture, no treatment, placebo, antioxidants or other treatments. To evaluate the efficacy of acupuncture as an adjunctive therapy, studies that compared acupuncture combined with other therapies with the other therapies were also included.
2.2.4. Outcome measures.
The primary outcomes were clinical efficacy rates and BCVA. The clinical efficacy rates were defined as the number of patients who showed improvement in VA and the absorption of fundus bleeding and exudate, and the improvements were assessed by clinicians based on the “Criteria of Diagnosis and Therapeutic Effect of Internal Diseases and Syndromes in Traditional Chinese Medicine (TCM)” [22] (S1 File in S1 Appendix). The secondary outcomes included changes in the CMT of the patients and adverse events.
2.3. Exclusion criteria
Studies involving any of the following were not included: 1) research that involved a comparison of different acupuncture techniques or a comparison of different acupuncture points; 2) treatments involving laser needle or hydro-acupuncture therapy; 3) duplicate published studies or case reports.
2.4. Search strategy
Relevant literature was searched in the following databases: PubMed, Ovid Medline, Embase, Cochrane Library, The Chinese National Knowledge Infrastructure Database, VIP, Wanfang, and SINOMED. The search time was from inception to September 4, 2022. In addition, relevant web pages were also manually searched (www.clinicaltrials.gov; www.clinicaltrialsregister.eu; trialsearch.who.int) for ongoing trials or unpublished clinical trial reports. The specific search strategy can be found in S1 Table in S1 Appendix.
2.5. Data extraction
Two reviewers conducted a literature search independently. After screening out the duplicate documents in EndNote software, a preliminary review was carried out by reading the titles and abstracts of the retrieved documents. The literature that satisfied the inclusion and exclusion criteria was read in full to determine its eligibility for further inclusion. Any differences between the two reviewers were resolved through communication and negotiation with an arbiter.
2.6. Quality assessment
The methodological quality of the included studies was evaluated according to the Cochrane risk-of-bias tool for randomized trials (RoB 2.0) as follows [23]: randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported result. Each item was classified as “low risk of bias”, “some problems”, and “high risk of bias”.
2.7. Data analysis
RevMan 5.4 was used for the meta-analysis. Continuous outcome variables were calculated by mean differences (MDs) or standard mean differences (SMDs) with 95% confidence intervals (CIs), and dichotomous outcome variables were calculated by risk ratios (RRs) with 95% CIs. When the heterogeneity of outcome variables was low (P > 0.10, I2 < 50%), the fixed-effect model was used; otherwise, the random-effect model was used. Publication bias assessment based on funnel plots was performed when the number of included studies was greater than 10. Subgroup analysis was performed by intervention type (with or without TCM), AMD type (dry or wet), or intervention course. Sensitivity analyses were performed to observe changes in synthetic results according to the following operations: 1) excluding low-quality studies; 2) excluding studies with small sample size; 3) excluding studies with the largest sample size; 4) excluding studies containing Chinese herbal medicine; 5) or switching between fixed and random effects models.
2.8. Quality of evidence
The quality of the pooled evidence for all the outcomes was judged by two independent reviewers according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [24]. The strength of evidence was graded as “high”, “moderate”, “low” or “very low” based on five assessment items: risk of bias, inconsistency, indirectness, imprecision, and other considerations.
3. Results
3.1. Literature search
A total of 226 articles were included, of which 102 studies were removed due to duplication. After reading the titles and abstracts, 15 articles remained (110 articles were removed, including 68 irrelevant articles, 26 reviews, 15 case reports and case series, and 1 mechanistic study). Of these, 4 included inappropriate comparisons, 1 was a comparison of different acupuncture manipulation techniques, and 1 was a comparison of different acupoints. Finally, nine studies were included [15–18, 25–29] (Fig 1). Excluded studies were listed in S1 Table in S1 Appendix.
3.2. Characteristics of the studies
All 9 RCTs were conducted in China. A total of 508 AMD patients (631 eyes) were enrolled, including 360 eyes with dry AMD and 271 eyes with wet AMD. The study period was from 2011 to 2020, and the patients were over 50 years old. Of the 9 studies, 3 studies consisted of patients with wet AMD [15, 16, 18], 4 studies consisted of patients with dry AMD [25–28], and the remaining 2 studies included patients with dry and wet AMD [17, 29]. Three studies compared acupuncture with antioxidants (vitamin E/C) [18, 25, 29]. Five studies compared acupuncture combined with medication therapy with the same medication therapy, in which all the medications were Chinese herbs [15–17, 26, 27]. One study compared an acupuncture group with a control group, and the control group was only observed regularly without any treatment [28]. All the studies involved true acupuncture with filiform needles. The course of treatment ranged from 20 days to 3 months. In terms of outcome indicators, 7 studies reported clinical effectiveness [15–18, 26, 27, 29], 5 studies reported BCVA [16–18, 25, 27], and 3 studies mentioned CMT [16–18]. Side effects were reported in only 2 studies [17, 28]. While the BCVA included in all studies were tested using international standard visual acuity charts, the recording method used was the five-point recording method or decimal recording method. Tables 1 & 2 list the specific information from the studies included.
3.3. Risk of bias assessment
All studies mentioned randomization, of which 4 studies used a random number table [15, 25, 28, 29] and 5 did not mention random methods. None of the studies mentioned allocation concealment. Considering that without sham acupuncture, the patients could not be blinded to the treatment, we think that blinded the acupuncture practitioner is equivalent to blinding. Three studies had a high risk of selective reporting [17, 26, 29]. All studies reported complete results with no significant missing data. Five studies were supported by government funding [15, 16, 18, 25, 28], and the remaining studies did not mention funding information. See Fig 2 for details.
A, literature quality evaluation; B, summary of the quality evaluation of the literature.
3.4. Outcome measurements
3.4.1. Clinical efficacy rates.
The clinical efficacy rates were evaluated in 7 studies [15–18, 26, 27, 29], and there was no heterogeneity in the outcome (I2 = 0%). The fixed-effect model showed that compared with the control, acupuncture significantly improved the clinical efficacy rates of the AMD patients (RR = 1.29, 95% CI: 1.17,1.42) (Fig 3A).
(A) Clinical response rates; (B) BCVA; (C) CMT.
3.4.2. BCVA.
BCVA was mentioned in 5 studies [16–18, 25, 27], with very high heterogeneity in the results (I2 = 89%). The random-effect model indicated that there was a significant difference between the acupuncture group and the control group in terms of BCVA (SMD = 0.95, 95% CI: 0.26,1.64) (Fig 3B).
3.4.3 CMT.
CMT was mentioned in three studies [16–18], with high heterogeneity in the results (I2 = 67%). The random-effect model suggested that the acupuncture group had reduced CMT compared with that in the control group (MD = - 32.74, 95% CI: - 60.96,-4.55). (Fig 3C).
3.4.4 Adverse events.
Adverse events were reported in only 2 studies [17, 28]. In one study, 10 of 22 patients in the acupuncture group had bleeding [28], while no side effects occurred in the control group. In another study, 3 patients in the control group and the acupuncture group each had nausea, vomiting, and flushing [17].
3.4.5 Sensitivity analysis and subgroup analysis.
Sensitivity analysis showed the stability of both Clinical efficacy rates and BCVA outcomes. When one study was removed [16], the difference in CMT between the two groups was no longer statistically significant.
Subgroup analysis showed that heterogeneity in BCVA and CMT outcomes disappeared when limiting the type of AMD to wet AMD, suggesting that heterogeneity was mainly related to the type of AMD. In addition, heterogeneity decreased to varying degrees when restricting the duration of the intervention (duration = 20–50 days) and the type of intervention (intervention includes TCM).
In the subgroup analysis of wet AMD or short intervention course (duration = 20–50 days), we noted changes in BCVA outcomes, with no statistically significant difference between the acupuncture group and the control group. See Tables 3 & 4 for details.
4. Discussion
4.1. Summary of evidence
The meta-analysis showed that compared with conventional treatment, acupuncture treatment increased the clinical efficacy and visual acuity of patients with AMD. In addition, acupuncture may have had a positive effect on the CMT of AMD patients. However, the certainty of the evidence was low due to concerns about the quality of the included studies.
According to TCM theory, inner eye tissue is closely related to meridians, which are the distribution network of essential substances of qi, blood, and body fluids throughout the body. The macula is yellowish on the unshaded fundus or eyeball, so it is considered to belong to the foot Taiyin Spleen Channel [30]. The spleen has the function of controlling the normal operation of blood in the meridians. Once the spleen-qi movement is not comfortable, it will impair the spleen’s ability to control the blood flow, which will cause the macular blood to flow out of the blood vessels. Of the twelve channels, only the liver channel is directly connected to the eyes. Therefore, the liver channel plays an important role in connecting the eyes with the liver, which can communicate the flow of qi and blood between the two organs. In the TCM system, the liver is the main reservoir of blood and the eyes need to be nourished by blood. In addition, liver qi is also closely related to eye function. Only when the liver-qi is comfortable can the eyes perform optimally [30]. Therefore, Qi and blood are very important for the eyes, and regulating qi and blood has become an important principle in the treatment of AMD in TCM theory.
In TCM theory, acupoints are specific parts of the body surface that reflect the state of human organs and regulate their physiological functions. Through acupuncture to stimulate the acupoint of the meridians, the human qi machinery is regulated, so as to ease the movement of qi and blood of the meridians, so that the eyes can get the nourishment of qi and blood, and finally treat the discomfort of the eyes. In addition, acting on acupoints around the eye is also believed to stimulate the movement of qi and blood in the eye and treat eye diseases. For example, the acupoint around the eyes, Jingming Point (BL1). As the first point of the bladder meridian, BL1 receives the ascending qi and blood from the bladder meridian and supplies it to the eyes. The eye receives the supply of qi and blood and therefore can see clearly. At present, acupuncture treatment of AMD mostly uses a combination of periocular and systemic acupuncture points [31].
Relevant histological studies have found that local acupoints may include high-density nerve endings, nerve and vascular components, and mast cells with sensory stimulation functions [32]. Acupuncture treatment of AMD mostly uses a combination of periocular and systemic acupuncture points. When the points are stimulated by acupuncture, in addition to the local release of biological factors to regulate local effects, acupuncture also transmits somatosensory information to the central nervous system by stimulating the nerves connected to the skin and muscles, thereby regulating the function of the autonomic nervous system [32, 33].
Oxidative stress is known to be one of the important pathogenesis of AMD [34]. The photoreceptor cells and retinal pigment epithelium (RPE) cells in the retina need to be metabolized in a high oxygen environment to fully exert their physiological functions, but at the same time, this will lead to a large accumulation of reactive oxygen species (ROS). In addition, due to the presence of a large number of unsaturated fatty acids and photoreceptor cytochromes, the macular region exhibits characteristics including high oxygen consumption and sensitivity to light radiation, which will further generate ROS [34, 35]. The increased level of ROS not only directly damages the components of RPE cells and photoreceptor cells such as proteins and lipids, thereby impairing their physiological functions, but also stimulates RPE cells to produce VEGF and hypoxia-inducible factor 1 to stimulate CNV generation [34, 36].
Several studies have found that acupuncture has the effect of maintaining redox homeostasis, which is achieved by modulating the imbalance between pro-oxidants and antioxidants [37]. Acupuncture can reduce oxidative stress and injury by inhibiting the production of ROS, reducing the ratio of the redox state of plasma glutathione/oxidized glutathione, and increasing the expression of redox effector [32, 33, 38, 39]. In addition, the regulatory effects of acupuncture on autophagy [40], inflammatory factors [41], and complement levels [42] may also play a role in delaying the progression of AMD.
Some studies have reported positive effects of acupuncture in AMD patients. Krenn et al. found in an observational study that acupuncture may have a positive effect on the vision of AMD patients [11]. Li et al. found that acupuncture improved the visual acuity of patients and reduced the levels of the macular nerve fiber layer, retinal neuroepithelium layer, pigment epithelium, and choroid capillary composite layer. Further, a 3-month follow-up showed that the improvement effect on visual acuity and macular retinal structure was still be maintained [12]. Other studies have also reported positive effects of acupuncture in patients with dry or wet AMD, including improving visual prognosis [43–45], alleviating ocular symptoms (e.g., visual distortion, blurred vision, visual fatigue, shadow occlusion) [43, 44], and enhancing the quality of life of the patients [45]. Similarly, our meta-analysis showed that acupuncture improved clinical efficacy rates and BCVA in AMD patients, and sensitivity analysis showed stability for both outcomes. However, when limiting the duration of intervention to 20–50 days, we did not observe significant improvements in BCVA and CMT in the acupuncture group compared to the control group, suggesting that prolonged intervention may be necessary for the efficacy of acupuncture. In addition, a subgroup analysis of wet AMD patients showed no improvement in BCVA and CMT with acupuncture, despite its ability to improve clinical efficiency in patients with wet AMD. It should be noted that the limitation of the number of studies in the subgroup analysis reduces the certainty of this conclusion. None of the studies mentioned the follow-up of patients’ visual acuity; therefore, we cannot provide evidence to support the effects of acupuncture on the long-term vision prognosis of patients.
Results from a meta-analysis of 3 studies showed that compared with the control, acupuncture reduced the CMT more in the AMD patients. However, the lack of included literature and the high heterogeneity of outcomes greatly limit the certainty of this evidence. CMT is an important indicator of OCT for observing the morphological structure and pathological changes of the macular area. An increase in CMT is related to the deterioration of retinal function and can damage visual acuity in AMD patients [46–49]. Acupuncture can reduce CMT, which may be related to the expansion of the surrounding blood vessels, thereby improving the microcirculation in the macular region [16–18]. This microcirculation can not only improve the nutrient supply to the working cells in the fundus [50] but also promote the absorption of hemorrhage and edema caused by CNV to restore the normal shape and function of the macular area. Only two studies reported side effects [17, 28]. The failure to mention the qualifications of the acupuncturists and the small number of research samples make their finding extremely uncertain. We noted that one of the studies reported 10 cases of bleeding at the site of acupuncture [28]. After further communication with the author, the bleeding occurred when the needle was withdrawn and could be stopped after a cotton swab was pressed against the bleeding site for around 10 seconds. It is necessary to standardize the extraction process of acupuncture needles. In reports of acupuncture treatment of other eye diseases, acupuncture was a relatively safe treatment method [51–53], and its safety in application to AMD treatment still needs further research.
All the included studies were conducted in China, so the global inference is limited. The population involved in this study was over 50 years old; considering that cases of AMD between the ages of 40 and 50 are not uncommon [54], we cannot assume that our results apply to all age groups. In addition, we reviewed the related technologies for acupuncture treatment in AMD. None of the studies provided detailed information on the acupuncture practitioners. Our senior acupuncture review authors (WQP and ZJ) found that most of the studies (88.9%) selected appropriate acupoints because these acupoints were used by professionally trained and experienced clinicians for a long time. Seven studies used a sufficient frequency and treatment time. Nine studies mentioned specific acupuncture techniques, which can ensure the reproducibility of the acupuncture implementation. None of the included studies guaranteed that participants or acupuncturists had been blinded successfully. The quality of evidence was limited by the high risk of co-intervention bias (performance bias), failure to use intentional analysis (attrition bias), and the inconsistency (high heterogeneity; I2 = 89%, for BCVA; I2 = 67%, for CMT) and imprecision (335 samples for BCVA, 201 samples for CMT) of studies involving BCVA and CMT. Therefore, no evidence was highly certain. The quality of our evidence ranged from “low” to “very low” according to the GRADE evaluation system (S2 Table in S1 Appendix).
4.2 Limitations
First, the quality of included studies is of concern, with many studies failing to mention allocation concealment, or blinding of participants or personnel, limiting our understanding of the evidence. Second, although we implemented an adequate and detailed search strategy, the possibility of publication bias cannot be ruled out, which means that some result values may be amplified, especially in the presence of selective reporting bias in some included studies. Also, most studies used clinical efficacy rates as an outcome measure rather than BCVA or other international standard vision outcomes, failing to thoroughly assess the efficacy of acupuncture.
5. Conclusion
Limited evidence suggests that patients with AMD may benefit from acupuncture, especially those with dry AMD. Considering the potential of acupuncture treatment, it is necessary to carry out a rigorously designed RCT to verify its efficacy.
Acknowledgments
All authors of this manuscript would like to express our sincere gratitude to the ophthalmologist of Beijing University of Chinese Medicine Oriental Hospital for reviewing acupuncture techniques.
References
- 1. Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet. 2018;392(10153):1147–1159. pmid:30303083
- 2. Bourne RR, Jonas JB, Flaxman SR, Keeffe J, Leasher J, Naidoo K, et al. Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990–2010. Br J Ophthalmol. 2014;98(5):629–638. pmid:24665132
- 3. Friedman DS, O’Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–572. pmid:15078675
- 4. GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. Lancet Glob Health. 2021;9(2):e144–e160. pmid:33275949
- 5. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106–116. pmid:25104651
- 6. Blasiak J. Senescence in the pathogenesis of age-related macular degeneration. Cell Mol Life Sci. 2020;77(5):789–805. pmid:31897543
- 7. Ammar MJ, Hsu J, Chiang A, Ho AC, Regillo CD. Age-related macular degeneration therapy: a review. Curr Opin Ophthalmol. 2020;31(3):215–221. pmid:32205470
- 8. Flaxel CJ, Adelman RA, Bailey ST, Fawzi A, Lim JI, Vemulakonda GA, et al. Age-Related Macular Degeneration Preferred Practice Pattern®. Ophthalmology. 2020;127(1):1–65.
- 9. Bressler NM, Doan QV, Varma R, Lee PP, Suñer IJ, Dolan C, et al. Estimated cases of legal blindness and visual impairment avoided using ranibizumab for choroidal neovascularization: non-Hispanic white population in the United States with age-related macular degeneration. Arch Ophthalmol. 2011;129(6):709–717. pmid:21670337
- 10. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K. Seven-year outcomes in ranibizumab treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292–2299. pmid:23642856
- 11. Krenn H. Acupuncture may improve vision in patients with age-related macular degeneration (AMD): An observational study. Revista Internacional de Acupuntura. 2009;3(1):26–29.
- 12. Li G, Shao Y, Yin J. Early age-related macular degeneration treated with emayaoling acupuncture technique: a randomized controlled trial. Zhongguo Zhen Jiu. 2017;37(12):1294–1298. pmid:29354994
- 13. Wong S, Ching R. The use of acupuncture in ophthalmology. Am J Chin Med. 1980;8(1–2):104–153. pmid:7395794
- 14. Bittner AK, Seger K, Salveson R, Kayser S, Morrison N, Vargas P, et al. Randomized controlled trial of electro-stimulation therapies to modulate retinal blood flow and visual function in retinitis pigmentosa. Acta Ophthalmol. 2018;96(3):e366–e376. pmid:29130647
- 15. Yao J, Li S, Guo CW. Clinical observation on acupuncture and medicine in treating age-related macular degeneration. Shanxi J TCM. 2015;16(01):41–42+45. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2015&filename=SHAN201501016&uniplatform=NZKPT&v=xmuAmdkybnNIFmEpuJEAPUZwmWGnVOef9GERd4MEEBZlBWS-wgV_mkR5ZTyAyR3W
- 16. Yang YQ, An ZW, Yang XR, Wang QL, YinYN , Liu YJ. Effect of Yiqi Yangyin Sanjie Tongluo Method Combined with Acupuncture on wet Age-related Macular Degeneration. Hebei J TCM. 2019;34(02):23–25+47. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2019&filename=HZYX201902007&uniplatform=NZKPT&v=Wp03yDHZH4xuuIozBx_HkW6MRtN93MEvCjNsrCdiZkAf_ipzJD3crT2AtchzuTLH
- 17. Wang ZJ, Wang H. Efficacy of the Huangban Fuming decoction plus acupuncture on AMD. Clinical Journal of Chinese Medicine.2019;11(28):61–63. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=ZYLY201928025&uniplatform=NZKPT&v=GZipsRl9Y634kjoasAp-5RpNCkw1IGWaEDzw6qxtXAjfKC_KmkjDh8-ncPeznPby
- 18. Liu JL, Zhu Y, LiJ , Song Y, Chen X. Clinical study of acupuncture combined with Wulingsan in the treatment of wet age-related macular degeneration. Hebei J TCM. 2016;38(10):1547–1549+1553. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2017&filename=HBZY201610030&uniplatform=NZKPT&v=Q43StBfZXM4q-7yPJyW2HWrDhyU7OnMUjgYHVunwCEmxkNmSXkuOcb3Bmvh94W2z
- 19. Qin L, Pang L, Ou Y. Effect of acupuncture combined with iontophoresis of Danshen injection on wet age-related macular degeneration. Hebei J TCM. 2018;40(07):1093–1096. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2018&filename=HBZY201807032&uniplatform=NZKPT&v=ETDkXDUuVky4E_sYwyA0aXrUPegJwa9Pj2OIJAXi-cdpzfHIdMO75u9FsxYABBuB
- 20. Li T. Curative Effect of Using Huangban Fuming Decoction Combined with Acupuncture in the Treatment of AMD and the Influence on Macular Edema, Subjective Symptoms, Serum VEGF, PDGF and ES Levels. Sichuan J TCM. 2018;36(12):174–177. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2019&filename=SCZY201812064&uniplatform=NZKPT&v=WvCetyQZ32k-L0VuZr6BELwumJe6ecg-tt-2PVBQZrTLG0qdtpS25TYY15-08zZk
- 21. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. pmid:33782057
- 22.
National Administration of Traditional Chinese Medicine. Criteria of diagnosis and therapeutic effect of internal diseases and syndromes in traditional Chinese medicine: Nanjing University Press; 1994. pp. 110–113.
- 23. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. pmid:31462531
- 24. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490. pmid:15205295
- 25. Xia Y, Liu R, Sun JJ, Xin SE, Cui HS, Liu SM. Clinical Study of Deep Needling at Orbital Points as Main Treatment for Age-related Macular Degeneration.Shanghai J Acupunct Moxibustion. 2014;33(05):421–423. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2014&filename=SHZJ201405019&uniplatform=NZKPT&v=Y9diiuQwJTWLbthxnD263lI6spm09LZr3lNQkKBUojl8-zKEY-L88AF6MlVA8W4A
- 26. Wang WY, Zhou HY, Zhou LN. Clinical study of acupuncture combined with jianpi-yiqi decoction in the treatment of atrophic age-related macular degeneration.Electronic Journal of Clinical Medical Literature. 2017;4(61):11913+11916. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2018&filename=LCWX201761026&uniplatform=NZKPT&v=F5G-cdZQ6fVEPGs-wJ9yiw6om6yxBFII8F1HrU9XIu9dM-ORChfNzNsCS1ed7G2p
- 27. Qin H, Xue JS, Gao YX, Zhao Y. Clinical study of acupuncture combined with Chaihuguizhiganjiang decoction in the treatment of dry age-related macular degeneration. Xinjiang J TCM.2020;38(06):30–31. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2021&filename=XJZY202006012&uniplatform=NZKPT&v=LhAydnmS9EJz-q1TRjfpgsKqUNNybXIJfhW3Wsl303s50SoH5TOMTGPh41DE7-vi
- 28. Xia Y, Liu R, Sun J, XIN SE, CUI HS, LIU SM. Clinical study on acupuncture for quality of life in patients with age-related macular degeneration. J Acupunct Tuina Sci. 2013;11(6). Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDHIS2&filename=ZJTN201306008&uniplatform=NZKPT&v=VVvkBl8H6pMInMR3lu3Sz-sgnB41npDR4r5WbM-hlY1Zce5tQWB7_627TZwlEYx-
- 29. Jiao N J. Observation on therapeutic effect of age-related macular degeneration treated with acupuncture. Zhongguo zhen jiu. 2011;31(1):43–45. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2011&filename=ZGZE201101019&uniplatform=NZKPT&v=D_zySGnSb_mJ8APAwg5EqYgcuoRXT3vZW5ntg7RROu9HOH5n2d3hlPnbJSYiTz_G pmid:21355157
- 30. Li Y, Li X, Li X, Zeng Z, Strang N, Shu X, et al. Non-neglectable therapeutic options for age-related macular degeneration: A promising perspective from traditional Chinese medicine. J Ethnopharmacol. 2022;282:114531. pmid:34474141
- 31. Ni Y, Yang J, Wang J, Xu X. Treatment of epiphora due to insufficiency of lacrimal passage by acupuncture at Jingming. J Tradit Chin Med. 1999;19(2):108–110. pmid:10681866
- 32. Li F, He T, Xu Q, Lin LT, Li H, Liu Y, et al. What is the Acupoint? A preliminary review of Acupoints. Pain Med. 2015;16(10):1905–1915. pmid:25975413
- 33. Wen J, Chen X, Yang Y, Liu J, Li E, Liu J, et al. Acupuncture Medical Therapy and its Underlying Mechanisms: A Systematic Review. Am J Chin Med. 2021;49(1):1–23. pmid:33371816
- 34. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000;45:115–134. pmid:11033038
- 35. Brown EE, DeWeerd AJ, Ildefonso CJ, Lewin AS, Ash JD. Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors. Redox Biol. 2019;24:101201. pmid:31039480
- 36. Datta S, Cano M, Ebrahimi K, Wang L, Handa JT. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res. 2017;60:201–218. pmid:28336424
- 37. Liu CZ, Zhou SF, Guimarães SB, Cho WC, Shi GX. Acupuncture and oxidative stress. Evid Based Complement Alternat Med. 2015;2015:424762. pmid:25873980
- 38. Yang FM, Yao L, Wang SJ, Guo Y, Xu ZF, Zhang CH, et al. Current Tracking on Effectiveness and Mechanisms of Acupuncture Therapy: A Literature Review of High-Quality Studies. Chin J Integr Med. 2020;26(4):310–320. pmid:30707414
- 39. Su XT, Wang L, Ma SM, Cao Y, Yang NN, Lin LL, et al. Mechanisms of Acupuncture in the Regulation of Oxidative Stress in Treating Ischemic Stroke. Oxid Med Cell Longev. 2020;2020:7875396. pmid:33178387
- 40. Pu YP, Wang PQ. Effect of eye acupuncture on autophagy in brain tissue of rats with cerebral ischemia-reperfusion injury. Zhen Ci Yan Jiu. 2021;46(2):100–105. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2021&filename=XCYJ202102003&uniplatform=NZKPT&v=6DeQU_HV2YE6T7U4fKhYCz4uPSEa83qWZCCvbdHs-cxGAAGl4unJ1sJ0YMBq5Opy pmid:33788429
- 41. Ding N, Wei Q, Deng W, Sun X, Zhang J, Gao W. Electroacupuncture Alleviates Inflammation of Dry Eye Diseases by Regulating the α7nAChR/NF-κB Signaling Pathway. Oxid Med Cell Longev. 2021;2021:6673610.
- 42. Hou PW, Hsu HC, Lin YW, Tang NY, Cheng CY, Hsieh CL. The History, Mechanism, and Clinical Application of Auricular Therapy in Traditional Chinese Medicine. Evid Based Complement Alternat Med. 2015;2015:495684. pmid:26823672
- 43. Xu H, Liu J, Xu SW, Zong L, Zhang R. Analysis on literature of acupuncture and moxibustion treatment of intractable eye diseases. Zhongguo Zhen Jiu. 2008;28(8):625–628. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2008&filename=ZGZE200808034&uniplatform=NZKPT&v=E0zQb2FrKzl4jCqu3kdCdLlUmXtHD_9QOc767CgE0Y4h4KAxi34rMROeHBCISZ-y pmid:18767593
- 44. Zhu JL, Ju ZY, Liu YL, Li Y, Xia Y, Liu SM. Clinical Observation of Acupuncture for Dry Macular Degeneration. Shanghai J Acupunct Moxibustion.2018;37(06):630–634. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2018&filename=SHZJ201806008&uniplatform=NZKPT&v=DJxgm3wPDHfJGNoXTg-_WMFujoDDOgr96hTeg67SYfxWe8zgYMzilL2pIJ1QEkRd
- 45. Zheng J, Liu WT, Min ZJ, Qu CY, Zhang R, Xu H. Therapeutic Observation of Comprehensive Acupuncture for Wet Age-related Macular Degeneration. Shanghai J Acupunct Moxibustion. 2015;34(04):335–337. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2015&filename=SHZJ201504024&uniplatform=NZKPT&v=0NJbcHpxGP5t31PG4o2E-lnIzoumokID0LlHSS11US_kM2-M-1sl9Z0Je5qL0M4W
- 46. Shin YI, Kim JM, Lee MW, Jo YJ, Kim JY. Characteristics of the Foveal Microvasculature in Asian Patients with Dry Age-Related Macular Degeneration: An Optical Coherence Tomography Angiography Study. Ophthalmologica. 2020;243(2):145–153. pmid:31645037
- 47. Claessens D, Schuster AK. Correlation of Quantitative Metamorphopsia Measurement and Central Retinal Thickness in Diabetic Macular Edema and Age-Related Exsudative Macular Degeneration. Klin Monbl Augenheilkd. 2019;236(7):877–884.
- 48. Puell MC, Hurtado-Ceña FJ, Pérez-Carrasco MJ, Contreras I. Association between central retinal thickness and low luminance visual acuity in early age-related macular degeneration. Eur J Ophthalmol. 2020;1120672120968740. pmid:33153337
- 49. Wu BH, Wang B, Wu HQ, Chang Q, Lu HQ. Intravitreal conbercept injection for neovascular age-related macular degeneration. Int J Ophthalmol. 2019;12(2):252–257. pmid:30809481
- 50. Tai HQ. Experimental study on acupuncture treatment of glaucoma in rabbits. Journal of Anhui University of Chinese Medicine. 2001;(06):29–30. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2001&filename=AHZY200106013&uniplatform=NZKPT&v=N_BFnqO__afDU5n-ZVeyjy7n_foOyB5NkAboNOXGQwQ52qvw_iswJ59RBBE_ftgg
- 51. Wei QB, Ding N, Wang JJ, Wang W, Gao WP. Acupoint selection for the treatment of dry eye: A systematic review and meta-analysis of randomized controlled trials. Exp Ther Med. 2020;19(4):2851–2860. pmid:32256769
- 52. Ang L, Song E, Jun JH, Choi TY, Lee MS. Acupuncture for treating diabetic retinopathy: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 2020;52:102490. pmid:32951739
- 53. Law SK, Wang L, Li T. Acupuncture for glaucoma. Cochrane Database Syst Rev. 2020;2(2):CD006030. pmid:32032457
- 54. Klein R, Klein BEK, Linton KLP. Prevalence of Age-related Maculopathy: The Beaver Dam Eye Study. Ophthalmology. 2020;127(4S):S122–S132. pmid:32200811