Pars Plana Vitrectomy for refractive Diabetic Macular Oedema with or without Internal Limiting Membrane Peeling: A systemic Review and Meta-Analysis

Pars Plana Vitrectomy for refractive Diabetic Macular Oedema with or without Internal Limiting Membrane Peeling: A systemic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Pars Plana Vitrectomy for refractive Diabetic Macular Oedema with or without Internal Limiting Membrane Peeling: A systemic Review and Meta-Analysis Jingpeng Miao, Yiyun Zeng, Xiaosi Chen, Zhizhong Gong, Xinyuan Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2582127/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective : To determine whether pars plana vitrectomy (PPV) combined with the internal limiting membrane (ILM) peeling technique improves the anatomic and functional outcomes of refractory diabetic macular oedema (DME) in comparison with PPV alone. Methods : All relevant articles published in English were retrieved from PubMed, google scholar, web of Science, scopes, and Cochrane library databases between January 1 st 1990 and September 28 2022. The meta-analysis was conducted using the Statistical software R 4.2.2. Results: Among 709 articles that were initially identified, 10 studies involving 1126 eyes with DME were found to be eligible for this meta-analysis and systematic review. Our results revealed that postoperative best corrected visual acuity (BCVA) was better in the non-peeling group than in the ILM peeling group (MD=-0.08, 95% CI: -0.12, -0.04, p <0.001), the improvement of BCVA was not significant between the two groups (RD=5.59, 95% CI: -4.81, 15.99, p =0.13). The random effects model showed that changes in central macular thickness were not significantly different between the ILM peeling group and the non-ILM peel group (MD=23.10, 95% CI: -53.82, 100.02, p =0.56). Conclusion : The functional and morphological clinical outcomes in the non-inferior group are equal to that of the ILM peeling group. Yet, further large-scale prospective, randomized, controlled trials are warranted to further validate the reported results. Health sciences/Medical research/Outcomes research Health sciences/Diseases/Eye diseases/Retinal diseases Pars plana vitrectomy refractive diabetic macular oedema internal limiting membrane peeling meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Diabetic retinopathy (DR) and diabetic macular oedema (DME) are the leading causes of blindness in the diabetic population, which may occur at any stage of DR[ 1 , 2 ]. The pathogenesis of DME is complex and controversial. Multiple cellular pathways, including inflammation and oxidation stress-inducing microangiopathy, such as loss of pericytes, thickening of the basement membrane, and loss of tight junctions of retinal capillary endothelium[ 3 ] triggered by hyperglycemia, have been hypothesized. DME is characterized by the breakdown of the blood-retinal barrier, cystic fluid accumulation, and disruption of normal retinal architecture. Central-involved DME accounts for more than 70% of DME and is the primary cause of visual impairment. Although anti-vascular endothelial growth factor (VEGF) therapy can achieve anatomic improvement in most cases, persistent macular oedema, also termed refractory DME, chronic, or recalcitrant DME was reported to be 30% by DRCR.net. Refractory DME refers to central retinal thickness (CRT) > 300µm or reduction in CRT < 10% after at least 3–6 anti-VEGF injections[ 4 ]. Management of refractory DME is challenging even with the most advanced treatment strategies. In recent years, pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) removal has been widely accepted by retinal surgeons. Release of the tractional forces at the vitreomacular interface may improve the resolution of the macular oedema and restore visual acuity[ 5 ]. However, there are still some controversies about ILM peeling during PPV. To date, no large and well-designed randomized prospective trials provided strong evidence about the clinical outcomes in terms of PPV alone or with ILM peeling; however, several studies with small samples provided some valuable insight. This study aimed to determine whether PPV combined with the ILM peeling technique improved the anatomic and functional outcomes of refractory DME compared with PPV alone. 2. Methods A prospective protocol for the present study was registered with (PROSPERO CRD 42022384842). The present study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Two independent ophthalmologists (J.M) and (Y.Z) screened all the published titles, abstracts, or full manuscripts for potentially eligible studies using comprehensive search strategies. Any disagreement was discussed with other authors (X.Z and X.C). 2.1 Study design Meta-analysis and systemic review. 2.2 Literature search PubMed, Medline, SpringerLink, the Cochrane Library, Google Scholar, and EMbase Medline database were searched for relevant English articles published between January 1st 1990 and September 28 2022, using the following key terms: ‘diabetic retinopathy’, ‘macular oedema’, ‘internal limiting membrane’, ‘inner limiting membrane’ and ‘vitrectomy’. The search was limited to the terms ‘management’ or ‘treatment’ or ‘trial’ or ‘randomized’ to focus on the findings of randomized or non-randomized clinical trials in the past decade. 2.3 Study selection Two authors (J.M and Y.Z) independently screened the titles, abstracts, or full texts of potentially eligible studies using the following inclusion and exclusion criteria. Disagreements were discussed with a third reviewer (X.C). Clinical studies that clearly assessed the effect of intermembrane peeling on clinical outcomes were included in this systemic review. 2.4 Eligibility criteria Inclusion criteria were the following: (1) studies that compared visual acuity and central retinal thickness of vitrectomy with or without ILM peeling concentrations between participants with T2DM and the comparably non-T2DM controls; (2) studies that provided sufficient data to calculate the effect sizes of interest; (3) at least 12 months follow up for evaluating of surgical outcomes; (4) lost rate < 10%. The exclusion criteria were as follows: (1) certain publication types (e.g., reviews, letters, case reports, comments); (2) the manuscripts published in languages other than English, and those containing secondary data from other published articles such as reviews, book chapters and conference papers on animal experiments, in vitro experiments, genetic research, and other basic medical research; (3) failure to report the associations between ILM peeling in PPV and PPV without ILM peeling; (4) the most recent version was evaluated for studies that were repeatedly published or their used data significantly overlapped. 2.5 Data extraction In each eligible study, C.Z and L.Q independently extracted the necessary information from enrolled articles, including (1) basic information: article title, first and corresponding authors, journals, publication year, country/region, study period, and study design (study types, subjects allocation, blinding); (2) baseline characteristics of the research: sample size (number of subjects and eyes), gender, age range, average age, exposures (surgery types, if assistant with triamcinolone or indocyanine during the surgery), visual acuity, diagnosis; (3) post operation information such as duration of follow up, post-operation and improvement of visual acuity, reduction of the thickness of the central retina, incidence of post epiretinal membrane; (4) regression results: Odds ratio (OR), 95% confidence interval (CI), p -value, if several ORs were available in one study, the fully adjusted one was extracted. The values from all the studies were uniformed for the statistical analysis. 2.6 Statistical analysis Statistical software R 4.2.2 (R Foundation for Statistical Computing, Vienna) was used to perform a meta-analysis. The mean difference with a 95% CI in a random effect model was used to compare the primary and secondary clinical outcomes between the vitrectomy with ILM peeling and vitrectomy without ILM peeling. The I 2 statistics through the chi-square-based Q-test were used to evaluate the heterogeneity. I 2 denotes the promotion of the total variance across trials that can be attributed to trial differences rather than to sampling error. If p > 0.05 and I 2 ≤ 50%, a fixed-effects model was applied for the meta-analysis as the heterogeneity was considered low. p ≤ 0.05 and I 2 > 50% indicated high heterogeneity, and a random-effects model was used for the meta-analysis. A Traffic-light plot was applied to display the quality of the study, which was assessed by funnel plot. A p -value < 0.05 was considered as statistical significance. 2.7 Methodological quality or risk of bias assessment Bias assessment was evaluated in all the enrolled studies, including randomized trial (RCT)s and non-randomized studies of the effects of interventions (NRSI). The two reviewers simultaneously and independently evaluated the risks of bias for the included articles. Any disagreements in opinion were resolved through discussion or consultation of a senior professional if necessary. RCTs was assessed using the Cochrane risk-of-bias tool for randomized trials (ROBINS-2) in 3 studies. NRSI (7) was evaluated by the risk of bias in non-randomized studies-of interventions (ROBINS-I). Five items were designed by ROBINS-2 tool and ROBINS-I tool with multiple sections Y (Yes), PY (probably yes), PN (Probably no), N (No), and NI (no information). Enrolled studies were assessed and allocated to low-risk, middle-risk, and high-risk, according to the answers to each item. 3. Results 3.1 Study selection Initially, 709 articles were identified. Among these, 168 duplicated articles were removed, and 541 articles were assessed based on the title and abstract. The potential 395 relevant articles were thoroughly assessed for eligibility, and the full texts were downloaded for further evaluation. Finally, a total of 10 studies[ 6 – 15 ] were eligible for this meta-analysis and systematic review. The specific filtering process is described in Fig. 1 . 3.2 Characteristics of the studies The eligible 10 studies[ 6 – 15 ] included 1126 eyes with DME that were enrolled in this meta-analysis (485 eyes with ILM peeling, 641 eyes with no ILM peeling). Among these studies, 5 RCTs[ 6 – 10 ] and 5 non-randomized trials[ 11 – 15 ] were published from 2004 to 2015. The average patients’ age ranged from 54 to 73 years old. Six studies were conducted in Japan, Turkey, Greece, Germany, and the United Kingdom. The characteristics of these studies are listed in Table 1 . 3.3 Quality Assessment ROBINS-2 was used to assess the randomized trials and risk of bias, and ROBINS-I was used to assess the non-randomized trials. The opinion about each item of bias risk for included RCTs are illustrated in Fig. 2 , where most of the items were at ‘low risk’ based on the Cochrane handbook, which indicated that RCTs were of good quality. All non-randomized studies that scored ≥ 3 were identified as high quality. 3.4 Meta-analysis of Efficacy 3.4.1 Analysis of the best corrected visual acuity (BCVA) A total of 6 studies[ 6 – 9 , 11 , 12 ] (total 450 eyes) evaluated the changes of BCVA. There was no significant heterogeneity between the included studies ( I 2 = 34%, τ 2 = 0.0013, p = 0.18) in Fig. 3 A using a fixed effects model for meta-analysis. We compared the mean difference between post-operative and pre-operative BCVA between the ILM peeling group and non-peeling groups, finding that postoperative BCVA was better in the non-peeling group than in the ILM peeling group (MD=-0.08, 95% CI: -0.12, -0.04, p < 0.001). 3.4.2 Improvement of the best corrected visual acuity Five studies[ 6 – 9 , 13 ] (total 316 eyes) reported BCVA improvement post-operations between the ILM peeling and non-ILM peeling. There was no significant heterogeneity between included studies ( I 2 = 20%, τ 2 = 0.0022, p = 0.29). A fixed effects model analysis revealed that the improvement of BCVA was not significantly different between the ILM and non-ILM dissection group (RD = 5.59, 95% CI: -4.81, 15.99, p = 0.13) in Fig. 3 B. 3.4.3 Central macular thickness (CMT) Three studies [6, 7, 11] (total 176 eyes) showed CMT changes pre- and post-operation, as shown in Fig. 3 C. Yamamoto et al. [6] and Yamakoshi et al. [ 11 ] found that macular oedema vanished through the optical coherence tomography (OCT) manifestation of the reduction of CMT in the ILM peeling group, while Hoerauf et al. [7] found that CMT increased after surgery in the ILM group. There was significant heterogeneity across the studies ( I 2 = 90%, τ 2 = 4042.6900, p < 0.01) due to the variations in diagnostic criteria for macular oedema. CMT changes were not significantly different between the ILM peeling group and non-ILM peel group by random effects model (MD = 23.10, 95% CI: -53.82, 100.02, p = 0.56). 3.4.4 Publication Bias and Heterogeneity Begg's funnel plots of the BCVA mean difference and risk difference of postoperative clinical outcome revealed good symmetry, as shown in Fig. 4 . 4. Discussion The present meta-analysis revealed that postoperative BCVA was better in the non-peeling group than in the ILM peeling group; however, the improvement of BCVA and changes of CMT were not significantly different between the ILM and non-ILM dissection group, indicating that functional and morphological clinical outcomes in the non-ILM group were not inferior to that of ILM peeling group. The prevalence of persistent macular oedema after standard anti-VEGF and/or intravitreal steroids treatment varied from 23–40%[ 16 , 17 ]. Therefore, surgical intervention for DME has been considered an alternative option. Vitrectomy releases the pathological effects of the vitreous on the retina and restores the anatomical and functional outcomes of the macula in DME patients, especially with coexisting vitreomacular traction[ 18 , 19 ]. The rationale for the use of vitrectomy in the treatment of DME may be explained as follows: the elimination of mechanical traction on the vitreomacular interface and the removal of chemical mediators that aggravate the retinal vascular permeability, improving oxygen delivery to the retina[ 20 – 22 ]. Vitrectomy with ILM peeling yields a sustained anatomical and functional effectiveness with a lower rate of DME recurrence; however, there is still a lack of large-scale prospective, randomized, controlled trials clarifying the efficacy of the PPV combined with ILM-peeling for non-tractional DME. The discrepancy of vitrectomy with ILM peeling in functional and structural prognosis suggests that the cellular and microcirculatory impairment is the pathological inducer in the macular area, which could occur pre- or post-surgical intervention. Several prospective researchers included in the present study used indocyanine green (ICG) as an adjuvant method to aid ILM peeling. This agent is correlated with inner retinal toxicity, subsequently affecting surgical prognosis, especially at concentrations of ≥ 0.1%[ 23 ]. Although ILM peeling removes the ILM barrier as well as local astrocyte proliferation, it can also induce the apoptosis of neuron cells[ 24 ]. Furthermore, the iatrogenic injury, such as tiny hemorrhages on superficial macular tissue during the initiating engagement of the ILM and parafovea micro scotoma were almost inevitable, leading to functional impairment of macula[ 25 , 26 ]. ILM peeling means more complicated operative procedures, longer exposure duration of the macula to lamplight, higher probability of gas or silicone oil tamponade, and even more intraocular pressure fluctuation compared with PPV alone. The functional prognosis is different for the visual outcome of ILM peeling for idiopathic epiretinal membrane and DME[ 27 ]. Furthermore, OCT cannot be used to distinguish intra- or extra-cellular oedema. The thickened retina cannot be used as an indicator of the prognosis of the function and morphology. Most cases that received vitrectomy have already failed to respond to the other treatment, and irreversible impairment of photoreceptors has already occurred before PPV, which can explain the lack of significant difference in the BCVA improvement between the two groups. Case selection bias may exist in those enrolled studies. Intravitreal triamcinolone has been implicated in DME, especially in combination with other therapies[ 28 ]. As a confounder, triamcinolone could magnify the likelihood of bias; however, it could not be homogenized in our data collection. Those studies that used triamcinolone to aid during vitrectomy were excluded from this meta-analysis. A condensed paramacular vitreous pocket in the macular can be found to be attached to the ILM, and the exact preoperatively state is very complicated[ 29 ]. The selective bias of patients with different vitreous morphology presents a difficulty for enrollment of patients, which could somewhat explain the lack of well-designed trials to elucidate the effects of ILM peeling. The present meta-analysis has some limitations. The study design discrepancy and complicated patient situation led to study heterogeneity. There were variabilities in enrolled studies, including the intervention window of DME, the duration of macular oedema, the pre-operative glycated hemoglobin level, the long-term glucose control after the operation, blood pressure, the cardiac or renal function, pan-retinal photocoagulation, the extent of ischemic damage, pre-operative lens status, accompanied cataract extraction, an opacity of lens in a follow-up visit, the age of patients and follow-up periods etc. Also, these factors were not standardized. Non-randomized studies occupied a small percentage, and most of the studies only included relatively small sample sizes, which could diminish the statistical significance and present clinical value. Finally, although standard criteria were used for study selection, this meta-analysis is still limited by the study design and exclusion of those studies published in other languages. In summary, our results indicated that vitrectomy with ILM peeling did not have advantages in post-operative BCVA, BCVA improvement, and morphological changes. Further large-scale prospective, randomized, controlled trials are warranted to further validate the reported results. Abbreviations BCVA: best corrected visual acuity CI: confidence interval CMT: Central macular thickness CRT: central retinal thickness DME: diabetic macular oedema DR: diabetic retinopathy ICG: indocyanine green ILM: internal limiting membrane MD: mean difference NRSI: non-randomized studies of the effects of interventions OR: odds ratio PPV: pars plana vitrectomy PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses RCT: randomized trial RD: risk difference ROBINS-I：risk of bias in non-randomized studies-of interventions ROBINS-2：Cochrane risk-of-bias tool for randomized trials T2DM: diabetes mellitus type 2 VEGF: vascular endothelial growth factor Declarations Acknowledgements This work was supported by the National Natural Science Foundation of China [Grant 81570850 and 82070988] and the Ministry of Science and Technology Foundation of China [Grant 2016YFC1305604]. Statement of Conflict of Interest All authors in this manuscript indicate that there are no relevant conflicts of interest to disclose. Funding This work was supported by the National Natural Science Foundation of China [Grant 81570850; Grant 81170859 and 82070988] and the Ministry of Science and Technology Foundation of China [Grant 2016YFC1305604]. Author Contributions XZ contributed to conception and design of the study, drafted and revised the manuscript and perform statistical analysis. JM, YZ and XC organized the database, performed the experiments and statistical analysis and drafted the manuscript. XZ, JP, YZ and ZG performed the statistical analysis. All authors contributed to manuscript revision, read, and approved the submitted version. References Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular oedema and related vision loss. Eye and vision 2, 1-25 (2015). Ting DSW, Cheung GCM, Wong TY. 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Table Table 1 is available in the Supplementary Files section. Additional Declarations There is no conflict of interest Supplementary Files Table1.xlsx Table 1 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2582127","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":182503790,"identity":"24f1a594-1188-4cce-8aa7-ae19a617eb8b","order_by":0,"name":"Jingpeng Miao","email":"","orcid":"https://orcid.org/0000-0003-4217-5389","institution":"Beijing Tongren Eye Centre,Beijing Institute of Ophthalmology,Beijing Tongren Hospital, Capital Medical University，Beijing Retinal and Choroidal Vascular Diseases Study Group","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jingpeng","middleName":"","lastName":"Miao","suffix":""},{"id":182503791,"identity":"61001fe5-30a8-4936-8fe9-086a9373e744","order_by":1,"name":"Yiyun Zeng","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yiyun","middleName":"","lastName":"Zeng","suffix":""},{"id":182503792,"identity":"50e5eae0-167c-4a69-b8d4-a761bbdedfc1","order_by":2,"name":"Xiaosi Chen","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaosi","middleName":"","lastName":"Chen","suffix":""},{"id":182503793,"identity":"3c6557c1-2968-4c07-8cb5-27311dc9b0a1","order_by":3,"name":"Zhizhong Gong","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhizhong","middleName":"","lastName":"Gong","suffix":""},{"id":182503794,"identity":"1dc10ad9-2be9-4912-b451-6ff84a44c7cd","order_by":4,"name":"Xinyuan Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYNCCCgkeNvbGxocfiNdyxkaGn+dws7EE0ToY29JsJGektwnwEKNad9rxZ9I8bId5DG4+bGOQYLCT020goMXsdkKyMQ8PUMvtxLYHBQzJxmYHCGs5+JhHAqyl3UCC4UDiNsJaEhuA6kEOO9gmwUOclmTGxzwJaTySMxiJ1pLGbDjngA0PP08iMJANiPJL+jOJt/8k7NnYjz98+KHCTo6gFhBgQkSHARHKQYDxB5EKR8EoGAWjYIQCAL0dQktTkTS7AAAAAElFTkSuQmCC","orcid":"","institution":"Beijing Tongren Eye Centre,Beijing Institute of Ophthalmology,Beijing Tongren Hospital, Capital Medical University，Beijing Retinal and Choroidal Vascular Diseases Study Group","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xinyuan","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2023-02-13 12:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2582127/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2582127/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":34358417,"identity":"7dfd5878-516b-4bd9-929b-2a11b7e47b59","added_by":"auto","created_at":"2023-03-16 14:20:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":824621,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe PRISMA flow diagram showing the study selection process.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2582127/v1/ef8d0213d2d4950a4a811b5c.jpg"},{"id":34358408,"identity":"abd1a9de-8347-4dae-ac4b-d816016a877d","added_by":"auto","created_at":"2023-03-16 14:20:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1100318,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuality assessment using ROBINS-2 (A) and ROBINS-I (B).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eROBINS-I: risk of bias in non-randomized studies of interventions; ROBINS-2: Cochrane risk-of-bias tool for randomized trials.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2582127/v1/89ccc174242fc92fc0a17ef8.jpg"},{"id":34358411,"identity":"c103c10e-43ae-41ff-8fd9-891963ff0f3e","added_by":"auto","created_at":"2023-03-16 14:20:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1215777,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot showing the mean difference of BCVA (A) and CMT (C), risk difference of BCVA improvement (B) between the ILM peeling and non-peeling groups before and after surgery.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBCVA: best corrected visual acuity; CMT: Central macular thickness; MD: mean difference; RD: risk difference; CI: confidence interval; PPV: Pars plana vitrectomy; ILM: internal limiting membrane.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2582127/v1/965e5e4e049a2da2de3406f4.jpg"},{"id":34358415,"identity":"6f4a90c0-77f4-429a-b674-f173f8125d86","added_by":"auto","created_at":"2023-03-16 14:20:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":673207,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plots of the publication bias analysis for the mean difference of BCVA (A) and BCVA improvement (B).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBCVA: best corrected visual acuity.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2582127/v1/046883d1b3185ac8d86cd620.jpg"},{"id":40865634,"identity":"9041f369-4c34-4b3d-b7bd-dec8deeaf044","added_by":"auto","created_at":"2023-08-01 07:35:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":719780,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2582127/v1/16716479-ede0-4b87-869e-70f462264a90.pdf"},{"id":34359598,"identity":"3b4bed0f-8e75-403f-ad60-78e0e4c24e84","added_by":"auto","created_at":"2023-03-16 14:28:46","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12519,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2582127/v1/b57c08c93bea16b5958a8b59.xlsx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Pars Plana Vitrectomy for refractive Diabetic Macular Oedema with or without Internal Limiting Membrane Peeling: A systemic Review and Meta-Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDiabetic retinopathy (DR) and diabetic macular oedema (DME) are the leading causes of blindness in the diabetic population, which may occur at any stage of DR[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The pathogenesis of DME is complex and controversial. Multiple cellular pathways, including inflammation and oxidation stress-inducing microangiopathy, such as loss of pericytes, thickening of the basement membrane, and loss of tight junctions of retinal capillary endothelium[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] triggered by hyperglycemia, have been hypothesized. DME is characterized by the breakdown of the blood-retinal barrier, cystic fluid accumulation, and disruption of normal retinal architecture. Central-involved DME accounts for more than 70% of DME and is the primary cause of visual impairment.\u003c/p\u003e \u003cp\u003eAlthough anti-vascular endothelial growth factor (VEGF) therapy can achieve anatomic improvement in most cases, persistent macular oedema, also termed refractory DME, chronic, or recalcitrant DME was reported to be 30% by DRCR.net. Refractory DME refers to central retinal thickness (CRT)\u0026thinsp;\u0026gt;\u0026thinsp;300\u0026micro;m or reduction in CRT\u0026thinsp;\u0026lt;\u0026thinsp;10% after at least 3\u0026ndash;6 anti-VEGF injections[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Management of refractory DME is challenging even with the most advanced treatment strategies. In recent years, pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) removal has been widely accepted by retinal surgeons.\u003c/p\u003e \u003cp\u003eRelease of the tractional forces at the vitreomacular interface may improve the resolution of the macular oedema and restore visual acuity[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, there are still some controversies about ILM peeling during PPV. To date, no large and well-designed randomized prospective trials provided strong evidence about the clinical outcomes in terms of PPV alone or with ILM peeling; however, several studies with small samples provided some valuable insight. This study aimed to determine whether PPV combined with the ILM peeling technique improved the anatomic and functional outcomes of refractory DME compared with PPV alone.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eA prospective protocol for the present study was registered with (PROSPERO CRD 42022384842). The present study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Two independent ophthalmologists (J.M) and (Y.Z) screened all the published titles, abstracts, or full manuscripts for potentially eligible studies using comprehensive search strategies. Any disagreement was discussed with other authors (X.Z and X.C).\u003c/p\u003e\n\u003cdiv class=\"Section2\" id=\"Sec3\"\u003e\n \u003ch2\u003e2.1 Study design\u003c/h2\u003e\n \u003cp\u003eMeta-analysis and systemic review.\u003c/p\u003e\n \u003ch2\u003e\u003cspan\u003e\u003cstrong\u003e2.2 Literature search\u003c/strong\u003e\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003ePubMed, Medline, SpringerLink, the Cochrane Library, Google Scholar, and EMbase Medline database were searched for relevant English articles published between January 1st 1990 and September 28 2022, using the following key terms: \u0026lsquo;diabetic retinopathy\u0026rsquo;, \u0026lsquo;macular oedema\u0026rsquo;, \u0026lsquo;internal limiting membrane\u0026rsquo;, \u0026lsquo;inner limiting membrane\u0026rsquo; and \u0026lsquo;vitrectomy\u0026rsquo;. The search was limited to the terms \u0026lsquo;management\u0026rsquo; or \u0026lsquo;treatment\u0026rsquo; or \u0026lsquo;trial\u0026rsquo; or \u0026lsquo;randomized\u0026rsquo; to focus on the findings of randomized or non-randomized clinical trials in the past decade.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec4\"\u003e\n \u003ch2\u003e2.3 Study selection\u003c/h2\u003e\n \u003cp\u003eTwo authors (J.M and Y.Z) independently screened the titles, abstracts, or full texts of potentially eligible studies using the following inclusion and exclusion criteria. Disagreements were discussed with a third reviewer (X.C). Clinical studies that clearly assessed the effect of intermembrane peeling on clinical outcomes were included in this systemic review.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec5\"\u003e\n \u003ch2\u003e2.4 Eligibility criteria\u003c/h2\u003e\n \u003cp\u003eInclusion criteria were the following: (1) studies that compared visual acuity and central retinal thickness of vitrectomy with or without ILM peeling concentrations between participants with T2DM and the comparably non-T2DM controls; (2) studies that provided sufficient data to calculate the effect sizes of interest; (3) at least 12 months follow up for evaluating of surgical outcomes; (4) lost rate\u0026thinsp;\u0026lt;\u0026thinsp;10%. The exclusion criteria were as follows: (1) certain publication types (e.g., reviews, letters, case reports, comments); (2) the manuscripts published in languages other than English, and those containing secondary data from other published articles such as reviews, book chapters and conference papers on animal experiments, in vitro experiments, genetic research, and other basic medical research; (3) failure to report the associations between ILM peeling in PPV and PPV without ILM peeling; (4) the most recent version was evaluated for studies that were repeatedly published or their used data significantly overlapped.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec6\"\u003e\n \u003ch2\u003e2.5 Data extraction\u003c/h2\u003e\n \u003cp\u003eIn each eligible study, C.Z and L.Q independently extracted the necessary information from enrolled articles, including (1) basic information: article title, first and corresponding authors, journals, publication year, country/region, study period, and study design (study types, subjects allocation, blinding); (2) baseline characteristics of the research: sample size (number of subjects and eyes), gender, age range, average age, exposures (surgery types, if assistant with triamcinolone or indocyanine during the surgery), visual acuity, diagnosis; (3) post operation information such as duration of follow up, post-operation and improvement of visual acuity, reduction of the thickness of the central retina, incidence of post epiretinal membrane; (4) regression results: Odds ratio (OR), 95% confidence interval (CI), \u003cem\u003ep\u003c/em\u003e-value, if several ORs were available in one study, the fully adjusted one was extracted. The values from all the studies were uniformed for the statistical analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003e2.6 Statistical analysis\u003c/h2\u003e\n \u003cp\u003eStatistical software R 4.2.2 (R Foundation for Statistical Computing, Vienna) was used to perform a meta-analysis. The mean difference with a 95% CI in a random effect model was used to compare the primary and secondary clinical outcomes between the vitrectomy with ILM peeling and vitrectomy without ILM peeling. The \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e statistics through the chi-square-based Q-test were used to evaluate the heterogeneity. \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e denotes the promotion of the total variance across trials that can be attributed to trial differences rather than to sampling error. If \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026le;\u0026thinsp;50%, a fixed-effects model was applied for the meta-analysis as the heterogeneity was considered low. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.05 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% indicated high heterogeneity, and a random-effects model was used for the meta-analysis. A Traffic-light plot was applied to display the quality of the study, which was assessed by funnel plot. A \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistical significance.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003e2.7 Methodological quality or risk of bias assessment\u003c/h2\u003e\n \u003cp\u003eBias assessment was evaluated in all the enrolled studies, including randomized trial (RCT)s and non-randomized studies of the effects of interventions (NRSI). The two reviewers simultaneously and independently evaluated the risks of bias for the included articles. Any disagreements in opinion were resolved through discussion or consultation of a senior professional if necessary. RCTs was assessed using the Cochrane risk-of-bias tool for randomized trials (ROBINS-2) in 3 studies. NRSI (7) was evaluated by the risk of bias in non-randomized studies-of interventions (ROBINS-I). Five items were designed by ROBINS-2 tool and ROBINS-I tool with multiple sections Y (Yes), PY (probably yes), PN (Probably no), N (No), and NI (no information). Enrolled studies were assessed and allocated to low-risk, middle-risk, and high-risk, according to the answers to each item.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection\u003c/h2\u003e \u003cp\u003eInitially, 709 articles were identified. Among these, 168 duplicated articles were removed, and 541 articles were assessed based on the title and abstract. The potential 395 relevant articles were thoroughly assessed for eligibility, and the full texts were downloaded for further evaluation. Finally, a total of 10 studies[\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] were eligible for this meta-analysis and systematic review. The specific filtering process is described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Characteristics of the studies\u003c/h2\u003e \u003cp\u003eThe eligible 10 studies[\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] included 1126 eyes with DME that were enrolled in this meta-analysis (485 eyes with ILM peeling, 641 eyes with no ILM peeling). Among these studies, 5 RCTs[\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and 5 non-randomized trials[\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] were published from 2004 to 2015. The average patients\u0026rsquo; age ranged from 54 to 73 years old. Six studies were conducted in Japan, Turkey, Greece, Germany, and the United Kingdom. The characteristics of these studies are listed in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Quality Assessment\u003c/h2\u003e \u003cp\u003eROBINS-2 was used to assess the randomized trials and risk of bias, and ROBINS-I was used to assess the non-randomized trials. The opinion about each item of bias risk for included RCTs are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, where most of the items were at \u0026lsquo;low risk\u0026rsquo; based on the Cochrane handbook, which indicated that RCTs were of good quality. All non-randomized studies that scored\u0026thinsp;\u0026ge;\u0026thinsp;3 were identified as high quality.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Meta-analysis of Efficacy\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1 Analysis of the best corrected visual acuity (BCVA)\u003c/h2\u003e \u003cp\u003eA total of 6 studies[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] (total 450 eyes) evaluated the changes of BCVA. There was no significant heterogeneity between the included studies (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;34%, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0013, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.18) in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA using a fixed effects model for meta-analysis. We compared the mean difference between post-operative and pre-operative BCVA between the ILM peeling group and non-peeling groups, finding that postoperative BCVA was better in the non-peeling group than in the ILM peeling group (MD=-0.08, 95% CI: -0.12, -0.04, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2 Improvement of the best corrected visual acuity\u003c/h2\u003e \u003cp\u003eFive studies[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] (total 316 eyes) reported BCVA improvement post-operations between the ILM peeling and non-ILM peeling. There was no significant heterogeneity between included studies (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;20%, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0022, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.29). A fixed effects model analysis revealed that the improvement of BCVA was not significantly different between the ILM and non-ILM dissection group (RD\u0026thinsp;=\u0026thinsp;5.59, 95% CI: -4.81, 15.99, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.13) in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.4.3 Central macular thickness (CMT)\u003c/h2\u003e \u003cp\u003eThree studies\u003csup\u003e[6, 7, 11]\u003c/sup\u003e (total 176 eyes) showed CMT changes pre- and post-operation, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC. Yamamoto \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e[6]\u003c/sup\u003e and Yamakoshi \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] found that macular oedema vanished through the optical coherence tomography (OCT) manifestation of the reduction of CMT in the ILM peeling group, while Hoerauf \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e[7]\u003c/sup\u003e found that CMT increased after surgery in the ILM group. There was significant heterogeneity across the studies (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;90%, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;4042.6900, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) due to the variations in diagnostic criteria for macular oedema. CMT changes were not significantly different between the ILM peeling group and non-ILM peel group by random effects model (MD\u0026thinsp;=\u0026thinsp;23.10, 95% CI: -53.82, 100.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.56).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.4.4 Publication Bias and Heterogeneity\u003c/h2\u003e \u003cp\u003eBegg's funnel plots of the BCVA mean difference and risk difference of postoperative clinical outcome revealed good symmetry, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe present meta-analysis revealed that postoperative BCVA was better in the non-peeling group than in the ILM peeling group; however, the improvement of BCVA and changes of CMT were not significantly different between the ILM and non-ILM dissection group, indicating that functional and morphological clinical outcomes in the non-ILM group were not inferior to that of ILM peeling group.\u003c/p\u003e \u003cp\u003eThe prevalence of persistent macular oedema after standard anti-VEGF and/or intravitreal steroids treatment varied from 23\u0026ndash;40%[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, surgical intervention for DME has been considered an alternative option.\u003c/p\u003e \u003cp\u003eVitrectomy releases the pathological effects of the vitreous on the retina and restores the anatomical and functional outcomes of the macula in DME patients, especially with coexisting vitreomacular traction[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The rationale for the use of vitrectomy in the treatment of DME may be explained as follows: the elimination of mechanical traction on the vitreomacular interface and the removal of chemical mediators that aggravate the retinal vascular permeability, improving oxygen delivery to the retina[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Vitrectomy with ILM peeling yields a sustained anatomical and functional effectiveness with a lower rate of DME recurrence; however, there is still a lack of large-scale prospective, randomized, controlled trials clarifying the efficacy of the PPV combined with ILM-peeling for non-tractional DME.\u003c/p\u003e \u003cp\u003eThe discrepancy of vitrectomy with ILM peeling in functional and structural prognosis suggests that the cellular and microcirculatory impairment is the pathological inducer in the macular area, which could occur pre- or post-surgical intervention. Several prospective researchers included in the present study used indocyanine green (ICG) as an adjuvant method to aid ILM peeling. This agent is correlated with inner retinal toxicity, subsequently affecting surgical prognosis, especially at concentrations of \u0026ge;\u0026thinsp;0.1%[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Although ILM peeling removes the ILM barrier as well as local astrocyte proliferation, it can also induce the apoptosis of neuron cells[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Furthermore, the iatrogenic injury, such as tiny hemorrhages on superficial macular tissue during the initiating engagement of the ILM and parafovea micro scotoma were almost inevitable, leading to functional impairment of macula[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. ILM peeling means more complicated operative procedures, longer exposure duration of the macula to lamplight, higher probability of gas or silicone oil tamponade, and even more intraocular pressure fluctuation compared with PPV alone.\u003c/p\u003e \u003cp\u003eThe functional prognosis is different for the visual outcome of ILM peeling for idiopathic epiretinal membrane and DME[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Furthermore, OCT cannot be used to distinguish intra- or extra-cellular oedema. The thickened retina cannot be used as an indicator of the prognosis of the function and morphology. Most cases that received vitrectomy have already failed to respond to the other treatment, and irreversible impairment of photoreceptors has already occurred before PPV, which can explain the lack of significant difference in the BCVA improvement between the two groups. Case selection bias may exist in those enrolled studies.\u003c/p\u003e \u003cp\u003eIntravitreal triamcinolone has been implicated in DME, especially in combination with other therapies[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. As a confounder, triamcinolone could magnify the likelihood of bias; however, it could not be homogenized in our data collection. Those studies that used triamcinolone to aid during vitrectomy were excluded from this meta-analysis. A condensed paramacular vitreous pocket in the macular can be found to be attached to the ILM, and the exact preoperatively state is very complicated[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The selective bias of patients with different vitreous morphology presents a difficulty for enrollment of patients, which could somewhat explain the lack of well-designed trials to elucidate the effects of ILM peeling.\u003c/p\u003e \u003cp\u003eThe present meta-analysis has some limitations. The study design discrepancy and complicated patient situation led to study heterogeneity. There were variabilities in enrolled studies, including the intervention window of DME, the duration of macular oedema, the pre-operative glycated hemoglobin level, the long-term glucose control after the operation, blood pressure, the cardiac or renal function, pan-retinal photocoagulation, the extent of ischemic damage, pre-operative lens status, accompanied cataract extraction, an opacity of lens in a follow-up visit, the age of patients and follow-up periods etc. Also, these factors were not standardized. Non-randomized studies occupied a small percentage, and most of the studies only included relatively small sample sizes, which could diminish the statistical significance and present clinical value. Finally, although standard criteria were used for study selection, this meta-analysis is still limited by the study design and exclusion of those studies published in other languages.\u003c/p\u003e \u003cp\u003eIn summary, our results indicated that vitrectomy with ILM peeling did not have advantages in post-operative BCVA, BCVA improvement, and morphological changes. Further large-scale prospective, randomized, controlled trials are warranted to further validate the reported results.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBCVA: best corrected visual acuity\u003c/p\u003e\n\u003cp\u003eCI:\u0026nbsp;confidence interval\u003c/p\u003e\n\u003cp\u003eCMT: Central macular thickness\u003c/p\u003e\n\u003cp\u003eCRT:\u0026nbsp;central retinal thickness\u003c/p\u003e\n\u003cp\u003eDME: diabetic macular oedema\u003c/p\u003e\n\u003cp\u003eDR:\u0026nbsp;diabetic retinopathy\u003c/p\u003e\n\u003cp\u003eICG:\u0026nbsp;indocyanine green\u003c/p\u003e\n\u003cp\u003eILM:\u0026nbsp;internal limiting membrane\u003c/p\u003e\n\u003cp\u003eMD: mean difference\u003c/p\u003e\n\u003cp\u003eNRSI:\u0026nbsp;non-randomized studies of the effects of interventions\u003c/p\u003e\n\u003cp\u003eOR:\u0026nbsp;odds ratio\u003c/p\u003e\n\u003cp\u003ePPV:\u0026nbsp;pars plana vitrectomy\u003c/p\u003e\n\u003cp\u003ePRISMA:\u0026nbsp;Preferred Reporting Items for Systematic reviews and Meta-Analyses\u003c/p\u003e\n\u003cp\u003eRCT:\u0026nbsp;randomized trial\u003c/p\u003e\n\u003cp\u003eRD: risk difference\u003c/p\u003e\n\u003cp\u003eROBINS-I：risk of bias in non-randomized studies-of interventions\u003c/p\u003e\n\u003cp\u003eROBINS-2：Cochrane risk-of-bias tool for randomized trials\u003c/p\u003e\n\u003cp\u003eT2DM: diabetes mellitus type 2\u003c/p\u003e\n\u003cp\u003eVEGF: vascular endothelial growth factor\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China [Grant 81570850 and 82070988] and the Ministry of Science and Technology Foundation of China [Grant 2016YFC1305604].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eConflict of Interest \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors in this manuscript indicate that there are no relevant conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China [Grant 81570850; Grant 81170859 and 82070988] and the Ministry of Science and Technology Foundation of China [Grant 2016YFC1305604].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXZ contributed to conception and design of the study, drafted and revised the manuscript and perform statistical analysis. JM, YZ and XC organized the database, performed the experiments and statistical analysis and drafted the manuscript. XZ, JP, YZ and ZG performed the statistical analysis. All authors contributed to manuscript revision, read, and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular oedema and related vision loss. Eye and vision 2, 1-25 (2015).\u003c/li\u003e\n\u003cli\u003eTing DSW, Cheung GCM, Wong TY. Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. Clinical \u0026amp; experimental ophthalmology 44, 260-277 (2016).\u003c/li\u003e\n\u003cli\u003eBandello F, Lattanzio R, Zucchiatti I, Del Turco C. Pathophysiology and treatment of diabetic retinopathy. Acta diabetologica 50, 1-20 (2013).\u003c/li\u003e\n\u003cli\u003eMadjedi K, Pereira A, Ballios BG, Arjmand P, Kertes PJ, Brent M, et al. Switching between anti-VEGF agents in the management of refractory diabetic macular oedema: A systematic review. Survey of Ophthalmology (2022).\u003c/li\u003e\n\u003cli\u003ePars plana vitrectomy for refractory diabetic macular oedema. Seminars in ophthalmology; 2003. Taylor \u0026amp; Francis.\u003c/li\u003e\n\u003cli\u003eYamamoto T, Hitani K, Sato Y, Yamashita H, Takeuchi S. Vitrectomy for diabetic macular oedema with and without internal limiting membrane removal. Ophthalmologica 219, 206-213 (2005).\u003c/li\u003e\n\u003cli\u003eHoerauf H, Bruggemann A, Muecke M, Luke J, Muller M, Stefansson E, et al. Pars plana vitrectomy for diabetic macular oedema. Internal limiting membrane delamination vs posterior hyaloid removal. A prospective randomized trial. Graefes Arch Clin Exp Ophthalmol 249, 997-1008 (2011).\u003c/li\u003e\n\u003cli\u003eBahadir M, Ertan A, Mertoglu O. Visual acuity comparison of vitrectomy with and without internal limiting membrane removal in the treatment of diabetic macular oedema. Int Ophthalmol 26, 3-8 (2005).\u003c/li\u003e\n\u003cli\u003eKumagai K, Hangai M, Ogino N, Larson E. Effect of internal limiting membrane peeling on long-term visual outcomes for diabetic macular oedema. Retina 35, 1422-1428 (2015).\u003c/li\u003e\n\u003cli\u003eShiba T, Kamura Y, Yagi F, Sato Y. Comparison of surgical procedures for vitreous surgery in diabetic macular oedema. Jpn J Ophthalmol 53, 120-124 (2009).\u003c/li\u003e\n\u003cli\u003eYamakoshi T, Kachi S, Sugita J, Asami T, Ishikawa K, Ito Y, et al. Triamcinolone-assisted removal of internal limiting membrane enhances the effect of vitrectomy for diabetic macular oedema. Ophthalmic Res 41, 203-209 (2009).\u003c/li\u003e\n\u003cli\u003eKamura Y, Sato Y, Isomae T, Shimada H. Effects of internal limiting membrane peeling in vitrectomy on diabetic cystoid macular oedema patients. Jpn J Ophthalmol 49, 297-300 (2005).\u003c/li\u003e\n\u003cli\u003eStefaniotou M, Aspiotis M, Kalogeropoulos C, Christodoulou A, Psylla M, Ioachim E, et al. Vitrectomy results for diffuse diabetic macular oedema with and without inner limiting membrane removal. European journal of ophthalmology 14, 137-143 (2004).\u003c/li\u003e\n\u003cli\u003eKumagai K, Furukawa M, Ogino N, Larson E, Iwaki M, Tachi N. Long-term follow-up of vitrectomy for diffuse nontractional diabetic macular oedema. Retina 29, 464-472 (2009).\u003c/li\u003e\n\u003cli\u003ePatel JI, Hykin PG, Schadt M, Luong V, Fitzke F, Gregor ZJ. Pars plana vitrectomy with and without peeling of the inner limiting membrane for diabetic macular oedema. Retina 26, 5-13 (2006).\u003c/li\u003e\n\u003cli\u003eBlinder KJ, Dugel PU, Chen S, Jumper JM, Walt JG, Hollander DA, et al. Anti-VEGF treatment of diabetic macular oedema in clinical practice: effectiveness and patterns of use (ECHO Study Report 1). Clinical ophthalmology (Auckland, NZ) 11, 393 (2017).\u003c/li\u003e\n\u003cli\u003eBaker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, et al. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular oedema involving the center of the macula and good visual acuity: a randomized clinical trial. Jama 321, 1880-1894 (2019).\u003c/li\u003e\n\u003cli\u003eNetwork DRCR. Vitrectomy outcomes in eyes with diabetic macular oedema and vitreomacular traction. Ophthalmology 117, 1087 (2010).\u003c/li\u003e\n\u003cli\u003eBonnin S, Sandali O, Bonnel S, Monin C, El Sanharawi M. Vitrectomy with internal limiting membrane peeling for tractional and nontractional diabetic macular oedema: long-term results of a comparative study. Retina 35, 921-928 (2015).\u003c/li\u003e\n\u003cli\u003eAdelman R, Parnes A, Michalewska Z, Parolini B, Boscher C, Ducournau D. Strategy for the management of diabetic macular oedema: the European vitreo-retinal society macular oedema study. BioMed research international 2015, (2015).\u003c/li\u003e\n\u003cli\u003eShah SU, Maturi RK. Therapeutic options in refractory diabetic macular ooedema. Drugs 77, 481-492 (2017).\u003c/li\u003e\n\u003cli\u003eRomano MR, Allegrini D, Della Guardia C, Schiemer S, Baronissi I, Ferrara M, et al. Vitreous and intraretinal macular changes in diabetic macular oedema with and without tractional components. Graefe\u0026apos;s Archive for Clinical and Experimental Ophthalmology 257, 1-8 (2019).\u003c/li\u003e\n\u003cli\u003eRomano MR, Ilardi G, Ferrara M, Cennamo G, Parolini B, Mariotti C, et al. Macular peeling-induced retinal damage: clinical and histopathological evaluation after using different dyes. Graefe\u0026apos;s Archive for Clinical and Experimental Ophthalmology 256, 1573-1580 (2018).\u003c/li\u003e\n\u003cli\u003eWolf S, Schnurbusch U, Wioedemann P, Grosche J, Reichenbach A, Wolburg H. Peeling of the basal membrane in the human retina: ultrastructural effects. Ophthalmology 111, 238-243 (2004).\u003c/li\u003e\n\u003cli\u003eMaberley DA, Beelen M, Smit J, Meenink T, Naus G, Wagner C, et al. A comparison of robotic and manual surgery for internal limiting membrane peeling. Graefe\u0026apos;s Archive for Clinical and Experimental Ophthalmology 258, 773-778 (2020).\u003c/li\u003e\n\u003cli\u003eDeltour J-B, Grimbert P, Masse H, Lebreton O, Weber M. Detrimental effects of active internal limiting membrane peeling during epiretinal membrane surgery: microperimetric analysis. Retina 37, 544-552 (2017).\u003c/li\u003e\n\u003cli\u003eDucloyer J-B, Ivan J, Poinas A, Lebreton O, Bonissent A, Fossum P, et al. Does internal limiting membrane peeling during epiretinal membrane surgery induce microscotomas on microperimetry? Study protocol for PEELING, a randomized controlled clinical trial. Trials 21, 1-12 (2020).\u003c/li\u003e\n\u003cli\u003eHwang S, Kang SW, Kim KT, Noh H, Kim SJ. Three-year outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular oedema. Scientific Reports 11, 1-8 (2021).\u003c/li\u003e\n\u003cli\u003eSchaal KB, Pang CE, Pozzoni MC, Engelbert M. The premacular bursa\u0026apos;s shape revealed in vivo by swept-source optical coherence tomography. Ophthalmology 121, 1020-1028 (2014). \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pars plana vitrectomy, refractive diabetic macular oedema, internal limiting membrane peeling, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-2582127/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2582127/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: To determine whether pars plana vitrectomy (PPV) combined with the internal limiting membrane (ILM) peeling technique improves the anatomic and functional outcomes of refractory diabetic macular oedema (DME) in comparison with PPV alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: All relevant articles published in English were retrieved from PubMed, google scholar, web of Science, scopes, and Cochrane library databases between January 1\u003csup\u003est\u003c/sup\u003e 1990 and September 28 2022. The meta-analysis was conducted using the Statistical software R 4.2.2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Among 709 articles that were initially identified, 10 studies involving 1126 eyes with DME were found to be eligible for this meta-analysis and systematic review. Our results revealed that postoperative best corrected visual acuity (BCVA) was better in the non-peeling group than in the ILM peeling group (MD=-0.08, 95% CI: -0.12, -0.04, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001), the improvement of BCVA was not significant between the two groups (RD=5.59, 95% CI: -4.81, 15.99, \u003cem\u003ep\u003c/em\u003e=0.13). The random effects model showed that changes in central macular thickness were not significantly different between the ILM peeling group and the non-ILM peel group (MD=23.10, 95% CI: -53.82, 100.02, \u003cem\u003ep\u003c/em\u003e=0.56).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The functional and morphological clinical outcomes in the non-inferior group are equal to that of the ILM peeling group. Yet, further large-scale prospective, randomized, controlled trials are warranted to further validate the reported results.\u003c/p\u003e","manuscriptTitle":"Pars Plana Vitrectomy for refractive Diabetic Macular Oedema with or without Internal Limiting Membrane Peeling: A systemic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-16 14:20:41","doi":"10.21203/rs.3.rs-2582127/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b1ea0fd3-4c84-4465-9931-7fd53f713f6e","owner":[],"postedDate":"March 16th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":19827915,"name":"Health sciences/Medical research/Outcomes research"},{"id":19827916,"name":"Health sciences/Diseases/Eye diseases/Retinal diseases"}],"tags":[],"updatedAt":"2023-09-14T10:51:10+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-16 14:20:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2582127","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2582127","identity":"rs-2582127","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}