ILM Peeling for Refractory Diabetic Macular Edema using intra-operative OCT

ILM Peeling for Refractory Diabetic Macular Edema using intra-operative OCT | 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 Case Report ILM Peeling for Refractory Diabetic Macular Edema using intra-operative OCT Thais Azeredo Bastos, Matheus Lopes da Silva, David Leonardo Cruvinel Isaac, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8595522/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 Diabetic macular edema (DME) is a vision-threatening condition and the leading cause of vision loss among working-age individuals. However, up to 23% of patients do not respond adequately to standard therapies. Previous studies have suggested that the internal limiting membrane (ILM) in diabetic patients tends to be thicker and contains a higher density of inflammatory cells, contributing to Müller cell traction, impaired diffusion of intravitreal anti-angiogenic agents, and perpetuation of the inflammatory process. Theoretically, ILM peeling may alleviate these factors, promoting anatomical and functional improvement. Herein, we describe the use of intraoperative optical coherence tomography (i-OCT) during pars plana vitrectomy combined with ILM peeling for the treatment of refractory DME without vitreomacular traction, in which satisfactory anatomical outcomes were achieved. Since i-OCT is a relatively recent technology, there remains limited evidence (particularly in the national context) regarding its benefits, its role in pre and intraoperative decision-making, and its impact on postoperative outcomes. We believe that, by enhancing surgical safety using i-OCT, PPV with ILM peeling is an effective treatment option for selected cases of refractory DME. Intraoperative Optic Coherence Tomography macular edema diabetic retinopathy vitrectomy ILM peeling Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Diabetes mellitus (DM) is a growing health issue worldwide 1 , and a challenge for many health care providers. Currently, there are approximately 20.7 million diabetic patients in Brazil (4th country in prevalence), of which 7.1 million have some degree of diabetic retinopathy 2 , of those, 2.1 million have a high risk of blindness 2 . Current estimates suggest that 20 to 30% of young Brazilians will develop diabetes over their lifetimes 3 . After 10 years of diagnosis, 25% of people with DM will develop diabetic macular edema (DME) 4 , a major cause of vision loss in working-age individuals and a significant threat to visual function 5 . The treatment of DME has evolved. In the past, photocoagulation was the first choice of treatement 6 . It has been replaced by intravitreal injections of corticosteroids and anti-VEGF, which are now the gold standard for the treatment of DME 7 , 8 . Up to 23% of patients, however, do not show significant improvement in both anatomic and visual function, called non-responders 9 . Pars plana vitrectomy (PPV), with or without peeling of the internal limiting membrane (ILM), has emerged as a promising surgical intervention 10 for such cases, especially in patients with refractory or recurrent macular edema and vitreous macular traction. Previous studies suggest at least 20% of decrease in the foveal thickness on OCT in about 80% of patients who underwent this treatment. 11 The Diabetic Retinopathy Clinical Reserach Network (DRCR.net) has conducted a study to evaluate the outcomes after PPV to treat DME 12 . Since then, the effectiveness of PPV in cases with vitreomacular traction or traction epiretinal membrane has been well established 12 . In these cases, there is a mechanical component contributing of the maintenance of the DME, which is releaved in the surgery. 8 However, it’s role for cases without traction is still debated. Another controversial point is the ILM peeling. On one hand, there are risks associated, such as the formation on an iartrogenic macular hole. On the other hand, the ILM peeling removes residual cortical vitreous, removing the tangencial and anterior-posterior traction. 8 Besides, the proposed physiopathology for this kind of treatment includes: 1) Enhancement of retinal oxygen levels, which suppress VEGF 10 , 13 . 2) Higher clearence rate of signaling proteins in the vitreous cavity, such as VEGF 14 , 15 . 3) Increase in the perifoveal blood flow velocity which has correlated with the improvement in visual acuity 16 . 4) difficult of intravitreal pharmacogical treatments penetrate trough thickened ILM mostly seen in post-mortem studies 17 . 5) deposits and chronic of inflammatory cells in the sub-ILM space in surgical peeled membranes of diabetic eyes. 18 Herein, we intend to report our experience with two cases of PPV using i-OCT for the treatment of refractory diabetic macular edema (DME) and that were followed for at least one year after surgery, as well as explore the role of PPV in the treatment of DME, its benefits, potential risks, and success rate as an alternative treatment option. In both of them, there were no epirretinal membrane, vitreous-macular traction or thickening of the posterior hyaloid on OCT. Besides the PPV, an ILM peeling was perfomed by an experienced retinal surgeon (MA) with direct visualization of intra-operative OCT (Artevo 800, Carl Zeiss Meditec, Jena, Germany). Cases presentation Both patients in our study had DM with chronic, refractory DME and reported progressive visual decline in both eyes (baseline BCVA≤ 20/200). They had previously undergone multiple intravitreal anti-VEGF injections, corticosteroid implants, and focal laser treatments without satisfactory anatomical or functional improvement. Optical coherence tomography (OCT) revealed intraretinal cystic spaces and disruption of the outer retinal layers, including the ellipsoid zone and external limiting membrane, findings consistent with chronic edema and degenerative retinal damage. It is important to note that neither case demonstrated vitreomacular interface abnormalities, such as vitreomacular traction or epiretinal membrane. Pars plana vitrectomy (PPV) was performed using intraoperative OCT (Artevo 800, Carl Zeiss Meditec, Jena, Germany). The i-OCT was employed during internal limiting membrane (ILM) peeling to ensure complete membrane removal and to rule out the presence of a macular hole (Fig. 1 ). The retinal tissue was fragile, and real-time OCT visualization during peeling allowed precise monitoring of each maneuver with the macular forceps and its immediate impact on the retinal surface, minimizing excessive traction. Whenever excessive traction was observed, that adhesion point was released, and the peeling was resumed from an adjacent area. (Fig. 2 ) Although the entire ILM peeling was guided by real-time i-OCT, a final scan consisting of five parallel sections was performed at the end of the surgery to confirm the absence of a macular hole, a potential complication of ILM peeling. Postoperatively, both patients showed progressive anatomical improvement on sequential OCT examinations. (Figs. 3 and 4 ) At two-year follow-up, complete resolution of the macular edema was observed. Although visual acuity did not improve, it remained stable throughout the follow-up period, whereas the fellow eyes of both patients experienced progressive visual decline over the same interval. Discussion The chronicity and degenerative finds on OCT may have contributed to the lack of significant improvement in visual acuity. The literature is heterogeneous regarding the functional success of vitrectomy in the treatment of diabetic macular edema. While some studies demonstrate both anatomical and visual improvement 8 , 19 , others show anatomical improvement without a corresponding gain in visual acuity 20 . Igicki M et al., showed that timing of surgery was strongly correlated with functional results 21 . In cases like the ones described in this study, the chronicity of the macular edema results in damage to the outer retina layers and the external limiting membrane, which restricts the improvement of visual function.In situations such as these, vitrectomy is intended to minimize progressive visual loss by stabilizing the condition. Besides, systemic factors such as HbA1c, blood pressure and renal function can influence the BCVA, limiting the prognosis of the treatments for DME 22 . The safety of PPV has been significantly improved, and surgical outcomes and patient recovery have been improved as a result of advancements in surgical techniques and instrumentation. Some of the technologies that are at the forefront of surgical innovation include intraoperative OCT, enhanced visualization methods, and small-gauge vitrectomy. The ILM peeling process is further complicated by the presence of intraretinal fluid, the reduced thickness of the retina above the cysts, and the composition of ILM in diabetic patients, which is thicker due to the overexpression of collagen, fibronectin, and laminin. The i-OCT facilitates the identification of excessive traction that could result in a macular hole by providing real-time surgeon monitoring of micromovements of the vitreous forceps and direct visualization of the peeling. This prompts a shift to an adjacent adhesion point in such cases. Once the entire ILM flap has been detached, this adhesion point is subsequently released with ease. The use of i-OCT is essential for identifying the ideal site to initiate the peeling, as it enables an initial scan of the entire macular area. It also allows visualization of any residual membranes or confirmation of their complete removal, thus avoiding the use of dyes or unnecessary maneuvers 23 , 24 . These advantages of intraoperative OCT (i-OCT) enhance surgical security and prevent the occurrence of macular holes, thereby improving the safety of the procedure. It is now more feasible to perform early peeling in patients with chronicity biomarkers. The utilization of contemporary pars plana vitrectomy (PPV) techniques has led to improved outcomes and shorter operative times than ever before 25 . The resolution of persistent macular edema after vitrectomy, whether complete or partial, varies from 70% to 100%, as indicated by a systematic review from 2003 12 . Although BCVA and anatomical success are not entirely correlated, anatomical success is still an essential metric for assessing the results of vitreoretinal surgeries 1 . In DME cases, vitrectomy has been demonstrated to achieve anatomic sucess 16 , 26 . Before surgery and during the postoperative follow-up 5 , patients with superior preoperative BCVA and reduced central retina thickness are anticipated to achieve superior visual outcomes. Removal of ILM is associated with greater reductions in retinal thickness, but without correlation with better visual outcomes. 27 Histopathological and immunohistochemical studies have demonstrated that the ILM in diabetic eyes often harbors increased glial fibrillary acidic protein (GFAP) expression, indicating Müller cell activation and gliosis, which is more pronounced in diabetic epiretinal membranes compared to idiopathic cases 28 . This supports the concept that Müller cell pathology and ILM alterations are more severe in diabetic retinopathy, potentially perpetuating edema. The internal limiting membrane corresponds, histologically, to the footplates of Müller cells, acting as a basement membrane. These cells, in turn, traverse all retinal layers, serving as part of its structural support. Since this membrane is thickened in patients with diabetic macular edema, it is possible that this increase in thickness and loss of elasticity generates some degree of traction on the entire Müller cell, which may contribute to maintaining retinal thickening and pharmacological non-response 29 . By removing the ILM, it is theorized that such traction would be relieved, allowing a reorganization of the layers. Another important point to consider is that, as previously discussed, these thickened membranes hinder the access and absorption of intravitreal anti-angiogenic drugs and, due to the large number of inflammatory cells they harbor, perpetuate the retinal inflammatory process, contributing to the persistence of edema 17 , 18 . ILM removal would facilitate the response to intravitreal medications in cases of edema recurrence and the need for re-treatment. 30 However, ILM peeling is not without consequences. Microstructural retinal changes, such as dimples, dissociated optic nerve fiber layer (DONFL), and thinning at the ILM edge, are common after ILM removal, reflecting both focal and zonal tissue shifts and possible Müller cell and nerve fiber layer disruption 31 , 32 . Long-term ultrastructural studies indicate that while the retina remains largely intact, the ILM does not regenerate as a continuous sheet, and some areas of the nerve fiber layer remain exposed, with glial wound healing occurring beneath the nerve fiber layer 32 . These changes may explain some of the functional and anatomical sequelae observed postoperatively. Our cases, in line with the literature, demonstrated anatomical success. One of them also showed that, in the event of edema recurrence, once ILM peeling has been performed, the response to anti-VEGF tends to be better and more long-lasting compared to the preoperative period. The lack of visual improvement is likely due to outer retinal damage, as its integrity correlates more strongly with visual acuity than retinal thickness itself. The limitations of this study were its limited statistical analysis and the small number of patients. The pioneering aspect of this work lies in reporting cases in which i-OCT was used, a still recent technology whose application has contributed to increased surgical safety, enabling the use of these approaches in earlier stages. With the evolution and refinement of technology, increasingly improved preoperative definition, quantification, and parameterization are expected. The analysis of biomarkers in the retina or in the internal limiting membrane itself that identify potential benefits of early peeling could shift the current paradigm regarding early surgical indication. In conclusion, PPV with ILM peeling is a alternative treatment for DME. Although the traditional and current indication is for refractory cases of DME, it may be more effective as a primary treatment for eyes with a shorter disease course than as a salvage option 26 . Besides, it is known that the anti-VEGF treatment represents a significant burden for patients, many of whom eventually discontinue therapy or fail to adhere to the recommended treatment intervals. The PPV presents itself as a cost-effective and long-lasting treatment option. Declarations Ethics approval and consent to participate This research was approved by the Ethics Research Committee of the Federal University of Goiás (number 78625824.0.0000.5083). The procedures used were in accordance with the tenets of the Declaration of Helsinki for research involving human beings. Consent for publication: Written informed consent was obtained from all participants included. Availability of data and materials: Not applicable. Competing interests: All authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: Not applicable Authors' contributions: TAB, ML, LPF, DLCI, AMBC, FTB, EN and MA participated in the design, interpretation of the studies and analysis of the data; LPF, DLCI, AMBC, FTB, EN and MA reviewed the manuscript; MA performed the surgery in all patients; TAB and ML wrote the manuscript. All authors read and approved the final manuscript. Acknowledgements: Not applicable. References Al-Lawati JA. Diabetes Mellitus: A Local and Global Public Health Emergency! Oman Med J. 2017 May;32(3):177-179. doi: 10.5001/omj.2017.34. PMID: 28584596; PMCID: PMC5447787. Brasil. Vigitel Brasil 2023: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico: estimativas sobre frequência e distribuição sociodemográfica de fatores de risco e proteção para doenças crônicas nas capitais dos 26 estados br. 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ILM peeling in nontractional diabetic macular edema: review and metanalysis. Int Ophthalmol. 2018 Dec;38(6):2709-2714. doi: 10.1007/s10792-017-0761-6. Epub 2017 Oct 31. PMID: 29090356. Pignatelli F, Niro A, Fallico M, Passidomo F, Gigliola S, Nacucchi A, Bonfiglio V, Reibaldi M, Addabbo G, Avitabile T. Mid-term safety and effectiveness of macular peeling one month after intravitreal dexamethasone implant for tractional diabetic macular edema. Sci Rep. 2023 Apr 12;13(1):5990. doi: 10.1038/s41598-023-32780-5. PMID: 37045880; PMCID: PMC10097727. Hsieh TH, Wang JK, Chen FT, Chen YJ, Wang LU, Huang TL, Chang PY, Hsu YR. Three-Dimensional Quantitative Analysis of Internal Limiting Membrane Peeling Related Structural Changes in Retinal Detachment Repair. Am J Ophthalmol. 2025 Jan;269:94-104. doi: 10.1016/j.ajo.2024.08.022. Epub 2024 Aug 24. PMID: 39187230. Hisatomi T, Notomi S, Tachibana T, Sassa Y, Ikeda Y, Nakamura T, Ueno A, Enaida H, Murata T, Sakamoto T, Ishibashi T. Ultrastructural changes of the vitreoretinal interface during long-term follow-up after removal of the internal limiting membrane. Am J Ophthalmol. 2014 Sep;158(3):550-6.e1. doi: 10.1016/j.ajo.2014.05.022. Epub 2014 May 27. PMID: 24878309. Additional Declarations No competing interests reported. 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-8595522","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":588282639,"identity":"055cc929-506c-41a7-9f91-308b79641b5f","order_by":0,"name":"Thais Azeredo Bastos","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYDACCQaGAyDaAMK1AWLGxgP4dPAgaWFsYGBIA2lpIKiFAUnLYTAHrxZ76eaHB38wbJM3Zz/+/MGHP+ft1rYfBtpSYxON0xaZYwaHeRhuG+7syTFsnNl2O3nbmUSglmNpuQ04HZZgAHTMbcYNB3IYm3kbbiebHQBqYWw4jEdL+gegw27bbzj//GEzz59zyWbnHxLSkmNwAOiwxA03EgybedgO2JndIGTLjZyCwzwGt5N3znhjOHNmW3KC2Q2gLQl4/MI+I33zxx8Vt22386c/+PDhj5292fn0hw8+1Njg1AIBBghmIlhlAl7laMCeFMWjYBSMglEwMgAAnxBqRbOPbRQAAAAASUVORK5CYII=","orcid":"","institution":"Cerof - UFG","correspondingAuthor":true,"prefix":"","firstName":"Thais","middleName":"Azeredo","lastName":"Bastos","suffix":""},{"id":588282641,"identity":"8859d3c6-3b97-47b8-a8fd-897aceca24c6","order_by":1,"name":"Matheus Lopes da Silva","email":"","orcid":"","institution":"Cerof - UFG","correspondingAuthor":false,"prefix":"","firstName":"Matheus","middleName":"Lopes da","lastName":"Silva","suffix":""},{"id":588282643,"identity":"15dcef14-75e7-44d3-8562-18625cf194ab","order_by":2,"name":"David Leonardo Cruvinel Isaac","email":"","orcid":"","institution":"Cerof - UFG","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"Leonardo Cruvinel","lastName":"Isaac","suffix":""},{"id":588282652,"identity":"8393184f-713d-48e4-90a9-07eb186571cb","order_by":3,"name":"Antônio Marcelo Barbante Casella","email":"","orcid":"","institution":"Londrina State University","correspondingAuthor":false,"prefix":"","firstName":"Antônio","middleName":"Marcelo Barbante","lastName":"Casella","suffix":""},{"id":588282657,"identity":"20cb12b6-2428-44d7-8d0c-ac34424f487c","order_by":4,"name":"Fabrício Tadeu Borges","email":"","orcid":"","institution":"Centro Brasileiro da Visão – CBV","correspondingAuthor":false,"prefix":"","firstName":"Fabrício","middleName":"Tadeu","lastName":"Borges","suffix":""},{"id":588282668,"identity":"5342bde0-237d-4707-af7a-c2540e17a306","order_by":5,"name":"Eduardo Novais","email":"","orcid":"","institution":"Centro Oftalmológico Città","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"","lastName":"Novais","suffix":""},{"id":588282673,"identity":"36ebb8b5-0b32-4e25-b0e3-a2abf0939a5d","order_by":6,"name":"Marcos Ávila","email":"","orcid":"","institution":"Cerof - UFG","correspondingAuthor":false,"prefix":"","firstName":"Marcos","middleName":"","lastName":"Ávila","suffix":""}],"badges":[],"createdAt":"2026-01-13 20:38:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8595522/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8595522/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102440088,"identity":"32cab7d5-958a-46ba-a5dd-dc113edc3831","added_by":"auto","created_at":"2026-02-11 16:45:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":612033,"visible":true,"origin":"","legend":"\u003cp\u003eReal-time intraoperative OCT showing the ILM being peeled without evidence of macular hole formation or residual membranes.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8595522/v1/e31063ebf8d989b3148e8bc9.png"},{"id":102745814,"identity":"f24f62ab-c942-4b39-9561-c205005faa2d","added_by":"auto","created_at":"2026-02-16 08:54:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":828352,"visible":true,"origin":"","legend":"\u003cp\u003eIntraoperative OCT showing retinal traction during ILM peeling, which did not lead to macular hole formation. The i-OCT enhances procedural safety and assists the surgeon in making informed surgical decisions.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8595522/v1/8cd2ea9e4154ced11594283a.png"},{"id":102440089,"identity":"5f80f37b-82eb-4069-9356-c5a15f350bee","added_by":"auto","created_at":"2026-02-11 16:45:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1540673,"visible":true,"origin":"","legend":"\u003cp\u003eCase 1, right eye: Color retinography and OCT images of: A) Pre-operative; B) 4 days after surgery C) One year after surgery D) Two years after surgery\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8595522/v1/2a03b13dd5931933f92084fd.png"},{"id":102440090,"identity":"008164b5-a14b-4b1a-9598-6a57c2cf19fa","added_by":"auto","created_at":"2026-02-11 16:45:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1690936,"visible":true,"origin":"","legend":"\u003cp\u003eCase 2, left eye: A) OCT before surgery, showing a large intraretinal cyst, disorganization of internal retinal layers, and irregularity of outer retinal layers; B) OCT one month after surgery, the cyst has disappeared, with little intraretinal fluid left. C) Fluorescein angiography before the surgery and (D) one month after surgery. Note the reduction in macular fluorescein leakage.\u003c/p\u003e","description":"","filename":"figure4..png","url":"https://assets-eu.researchsquare.com/files/rs-8595522/v1/70ca4e9d59b4a9c0e5ee47bf.png"},{"id":104399716,"identity":"bc1fd8ca-66e0-46f3-9adb-30c7ff855e1e","added_by":"auto","created_at":"2026-03-11 12:07:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6467967,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8595522/v1/25d2c17f-1a93-45d9-84f9-2cbe2d19b596.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"ILM Peeling for Refractory Diabetic Macular Edema using intra-operative OCT","fulltext":[{"header":"Background","content":"\u003cp\u003eDiabetes mellitus (DM) is a growing health issue worldwide\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, and a challenge for many health care providers. Currently, there are approximately 20.7\u0026nbsp;million diabetic patients in Brazil (4th country in prevalence), of which 7.1\u0026nbsp;million have some degree of diabetic retinopathy\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, of those, 2.1\u0026nbsp;million have a high risk of blindness\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Current estimates suggest that 20 to 30% of young Brazilians will develop diabetes over their lifetimes\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. After 10 years of diagnosis, 25% of people with DM will develop diabetic macular edema (DME)\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, a major cause of vision loss in working-age individuals and a significant threat to visual function\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe treatment of DME has evolved. In the past, photocoagulation was the first choice of treatement\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. It has been replaced by intravitreal injections of corticosteroids and anti-VEGF, which are now the gold standard for the treatment of DME\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Up to 23% of patients, however, do not show significant improvement in both anatomic and visual function, called non-responders\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Pars plana vitrectomy (PPV), with or without peeling of the internal limiting membrane (ILM), has emerged as a promising surgical intervention\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e for such cases, especially in patients with refractory or recurrent macular edema and vitreous macular traction. Previous studies suggest at least 20% of decrease in the foveal thickness on OCT in about 80% of patients who underwent this treatment.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe Diabetic Retinopathy Clinical Reserach Network (DRCR.net) has conducted a study to evaluate the outcomes after PPV to treat DME\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Since then, the effectiveness of PPV in cases with vitreomacular traction or traction epiretinal membrane has been well established \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In these cases, there is a mechanical component contributing of the maintenance of the DME, which is releaved in the surgery.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, it’s role for cases without traction is still debated.\u003c/p\u003e \u003cp\u003eAnother controversial point is the ILM peeling. On one hand, there are risks associated, such as the formation on an iartrogenic macular hole. On the other hand, the ILM peeling removes residual cortical vitreous, removing the tangencial and anterior-posterior traction.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Besides, the proposed physiopathology for this kind of treatment includes: 1) Enhancement of retinal oxygen levels, which suppress VEGF \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. 2) Higher clearence rate of signaling proteins in the vitreous cavity, such as VEGF \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. 3) Increase in the perifoveal blood flow velocity which has correlated with the improvement in visual acuity \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. 4) difficult of intravitreal pharmacogical treatments penetrate trough thickened ILM mostly seen in post-mortem studies\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. 5) deposits and chronic of inflammatory cells in the sub-ILM space in surgical peeled membranes of diabetic eyes.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHerein, we intend to report our experience with two cases of PPV using i-OCT for the treatment of refractory diabetic macular edema (DME) and that were followed for at least one year after surgery, as well as explore the role of PPV in the treatment of DME, its benefits, potential risks, and success rate as an alternative treatment option.\u003c/p\u003e \u003cp\u003eIn both of them, there were no epirretinal membrane, vitreous-macular traction or thickening of the posterior hyaloid on OCT. Besides the PPV, an ILM peeling was perfomed by an experienced retinal surgeon (MA) with direct visualization of intra-operative OCT (Artevo 800, Carl Zeiss Meditec, Jena, Germany).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Cases presentation","content":"\u003cp\u003eBoth patients in our study had DM with chronic, refractory DME and reported progressive visual decline in both eyes (baseline BCVA≤ 20/200). They had previously undergone multiple intravitreal anti-VEGF injections, corticosteroid implants, and focal laser treatments without satisfactory anatomical or functional improvement.\u003c/p\u003e\u003cp\u003eOptical coherence tomography (OCT) revealed intraretinal cystic spaces and disruption of the outer retinal layers, including the ellipsoid zone and external limiting membrane, findings consistent with chronic edema and degenerative retinal damage. It is important to note that neither case demonstrated vitreomacular interface abnormalities, such as vitreomacular traction or epiretinal membrane.\u003c/p\u003e\u003cp\u003ePars plana vitrectomy (PPV) was performed using intraoperative OCT (Artevo 800, Carl Zeiss Meditec, Jena, Germany). The i-OCT was employed during internal limiting membrane (ILM) peeling to ensure complete membrane removal and to rule out the presence of a macular hole (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cp\u003eThe retinal tissue was fragile, and real-time OCT visualization during peeling allowed precise monitoring of each maneuver with the macular forceps and its immediate impact on the retinal surface, minimizing excessive traction. Whenever excessive traction was observed, that adhesion point was released, and the peeling was resumed from an adjacent area. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cp\u003eAlthough the entire ILM peeling was guided by real-time i-OCT, a final scan consisting of five parallel sections was performed at the end of the surgery to confirm the absence of a macular hole, a potential complication of ILM peeling. Postoperatively, both patients showed progressive anatomical improvement on sequential OCT examinations. (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) At two-year follow-up, complete resolution of the macular edema was observed. Although visual acuity did not improve, it remained stable throughout the follow-up period, whereas the fellow eyes of both patients experienced progressive visual decline over the same interval.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe chronicity and degenerative finds on OCT may have contributed to the lack of significant improvement in visual acuity. The literature is heterogeneous regarding the functional success of vitrectomy in the treatment of diabetic macular edema. While some studies demonstrate both anatomical and visual improvement\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, others show anatomical improvement without a corresponding gain in visual acuity\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Igicki M et al., showed that timing of surgery was strongly correlated with functional results\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In cases like the ones described in this study, the chronicity of the macular edema results in damage to the outer retina layers and the external limiting membrane, which restricts the improvement of visual function.In situations such as these, vitrectomy is intended to minimize progressive visual loss by stabilizing the condition. Besides, systemic factors such as HbA1c, blood pressure and renal function can influence the BCVA, limiting the prognosis of the treatments for DME\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe safety of PPV has been significantly improved, and surgical outcomes and patient recovery have been improved as a result of advancements in surgical techniques and instrumentation. Some of the technologies that are at the forefront of surgical innovation include intraoperative OCT, enhanced visualization methods, and small-gauge vitrectomy. The ILM peeling process is further complicated by the presence of intraretinal fluid, the reduced thickness of the retina above the cysts, and the composition of ILM in diabetic patients, which is thicker due to the overexpression of collagen, fibronectin, and laminin.\u003c/p\u003e \u003cp\u003eThe i-OCT facilitates the identification of excessive traction that could result in a macular hole by providing real-time surgeon monitoring of micromovements of the vitreous forceps and direct visualization of the peeling. This prompts a shift to an adjacent adhesion point in such cases. Once the entire ILM flap has been detached, this adhesion point is subsequently released with ease. The use of i-OCT is essential for identifying the ideal site to initiate the peeling, as it enables an initial scan of the entire macular area. It also allows visualization of any residual membranes or confirmation of their complete removal, thus avoiding the use of dyes or unnecessary maneuvers\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. These advantages of intraoperative OCT (i-OCT) enhance surgical security and prevent the occurrence of macular holes, thereby improving the safety of the procedure. It is now more feasible to perform early peeling in patients with chronicity biomarkers. The utilization of contemporary pars plana vitrectomy (PPV) techniques has led to improved outcomes and shorter operative times than ever before\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The resolution of persistent macular edema after vitrectomy, whether complete or partial, varies from 70% to 100%, as indicated by a systematic review from 2003\u003csup\u003e12\u003c/sup\u003e. Although BCVA and anatomical success are not entirely correlated, anatomical success is still an essential metric for assessing the results of vitreoretinal surgeries\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn DME cases, vitrectomy has been demonstrated to achieve anatomic sucess\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Before surgery and during the postoperative follow-up\u003csup\u003e5\u003c/sup\u003e, patients with superior preoperative BCVA and reduced central retina thickness are anticipated to achieve superior visual outcomes. Removal of ILM is associated with greater reductions in retinal thickness, but without correlation with better visual outcomes.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHistopathological and immunohistochemical studies have demonstrated that the ILM in diabetic eyes often harbors increased glial fibrillary acidic protein (GFAP) expression, indicating M\u0026uuml;ller cell activation and gliosis, which is more pronounced in diabetic epiretinal membranes compared to idiopathic cases\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. This supports the concept that M\u0026uuml;ller cell pathology and ILM alterations are more severe in diabetic retinopathy, potentially perpetuating edema.\u003c/p\u003e \u003cp\u003eThe internal limiting membrane corresponds, histologically, to the footplates of M\u0026uuml;ller cells, acting as a basement membrane. These cells, in turn, traverse all retinal layers, serving as part of its structural support. Since this membrane is thickened in patients with diabetic macular edema, it is possible that this increase in thickness and loss of elasticity generates some degree of traction on the entire M\u0026uuml;ller cell, which may contribute to maintaining retinal thickening and pharmacological non-response\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. By removing the ILM, it is theorized that such traction would be relieved, allowing a reorganization of the layers.\u003c/p\u003e \u003cp\u003eAnother important point to consider is that, as previously discussed, these thickened membranes hinder the access and absorption of intravitreal anti-angiogenic drugs and, due to the large number of inflammatory cells they harbor, perpetuate the retinal inflammatory process, contributing to the persistence of edema\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. ILM removal would facilitate the response to intravitreal medications in cases of edema recurrence and the need for re-treatment.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, ILM peeling is not without consequences. Microstructural retinal changes, such as dimples, dissociated optic nerve fiber layer (DONFL), and thinning at the ILM edge, are common after ILM removal, reflecting both focal and zonal tissue shifts and possible M\u0026uuml;ller cell and nerve fiber layer disruption\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Long-term ultrastructural studies indicate that while the retina remains largely intact, the ILM does not regenerate as a continuous sheet, and some areas of the nerve fiber layer remain exposed, with glial wound healing occurring beneath the nerve fiber layer\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. These changes may explain some of the functional and anatomical sequelae observed postoperatively.\u003c/p\u003e \u003cp\u003eOur cases, in line with the literature, demonstrated anatomical success. One of them also showed that, in the event of edema recurrence, once ILM peeling has been performed, the response to anti-VEGF tends to be better and more long-lasting compared to the preoperative period. The lack of visual improvement is likely due to outer retinal damage, as its integrity correlates more strongly with visual acuity than retinal thickness itself.\u003c/p\u003e \u003cp\u003eThe limitations of this study were its limited statistical analysis and the small number of patients. The pioneering aspect of this work lies in reporting cases in which i-OCT was used, a still recent technology whose application has contributed to increased surgical safety, enabling the use of these approaches in earlier stages.\u003c/p\u003e \u003cp\u003eWith the evolution and refinement of technology, increasingly improved preoperative definition, quantification, and parameterization are expected. The analysis of biomarkers in the retina or in the internal limiting membrane itself that identify potential benefits of early peeling could shift the current paradigm regarding early surgical indication.\u003c/p\u003e \u003cp\u003eIn conclusion, PPV with ILM peeling is a alternative treatment for DME. Although the traditional and current indication is for refractory cases of DME, it may be more effective as a primary treatment for eyes with a shorter disease course than as a salvage option\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Besides, it is known that the anti-VEGF treatment represents a significant burden for patients, many of whom eventually discontinue therapy or fail to adhere to the recommended treatment intervals. The PPV presents itself as a cost-effective and long-lasting treatment option.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis research was approved by the Ethics Research Committee of the Federal University of Goi\u0026aacute;s (number\u0026nbsp;78625824.0.0000.5083). The procedures used were in accordance with the tenets of the Declaration of Helsinki for research involving human beings.\u003c/p\u003e\n\u003cp\u003eConsent for publication:\u0026nbsp;Written\u0026nbsp;informed consent was obtained from all participants included.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: Not applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests:\u003c/p\u003e\n\u003cp\u003eAll authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003eFunding: Not applicable\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003eTAB, ML, LPF, DLCI, AMBC, FTB, EN and MA \u0026nbsp;participated in the design, interpretation of the studies and analysis of the data; LPF, DLCI, AMBC, FTB, EN and MA \u0026nbsp;reviewed the manuscript; MA performed the surgery in all patients; TAB and ML \u0026nbsp; wrote the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAl-Lawati JA. Diabetes Mellitus: A Local and Global Public Health Emergency! Oman Med J. 2017 May;32(3):177-179. doi: 10.5001/omj.2017.34. PMID: 28584596; PMCID: PMC5447787.\u003c/li\u003e\n \u003cli\u003eBrasil. Vigitel Brasil 2023: vigil\u0026acirc;ncia de fatores de risco e prote\u0026ccedil;\u0026atilde;o para doen\u0026ccedil;as cr\u0026ocirc;nicas por inqu\u0026eacute;rito telef\u0026ocirc;nico: estimativas sobre frequ\u0026ecirc;ncia e distribui\u0026ccedil;\u0026atilde;o sociodemogr\u0026aacute;fica de fatores de risco e prote\u0026ccedil;\u0026atilde;o para doen\u0026ccedil;as cr\u0026ocirc;nicas nas capitais dos 26 estados br. 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PMID: 24878309.\u003c/li\u003e\n\u003c/ol\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":"Intraoperative Optic Coherence Tomography, macular edema, diabetic retinopathy, vitrectomy, ILM peeling","lastPublishedDoi":"10.21203/rs.3.rs-8595522/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8595522/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDiabetic macular edema (DME) is a vision-threatening condition and the leading cause of vision loss among working-age individuals. However, up to 23% of patients do not respond adequately to standard therapies. Previous studies have suggested that the internal limiting membrane (ILM) in diabetic patients tends to be thicker and contains a higher density of inflammatory cells, contributing to M\u0026uuml;ller cell traction, impaired diffusion of intravitreal anti-angiogenic agents, and perpetuation of the inflammatory process. Theoretically, ILM peeling may alleviate these factors, promoting anatomical and functional improvement. Herein, we describe the use of intraoperative optical coherence tomography (i-OCT) during pars plana vitrectomy combined with ILM peeling for the treatment of refractory DME without vitreomacular traction, in which satisfactory anatomical outcomes were achieved. Since i-OCT is a relatively recent technology, there remains limited evidence (particularly in the national context) regarding its benefits, its role in pre and intraoperative decision-making, and its impact on postoperative outcomes. We believe that, by enhancing surgical safety using i-OCT, PPV with ILM peeling is an effective treatment option for selected cases of refractory DME.\u003c/p\u003e","manuscriptTitle":"ILM Peeling for Refractory Diabetic Macular Edema using intra-operative OCT","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 16:45:31","doi":"10.21203/rs.3.rs-8595522/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":"f24e4660-c575-4a0d-8186-e6d9068e6ad7","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T05:55:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-11 16:45:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8595522","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8595522","identity":"rs-8595522","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}