Morphology-Dependent Recovery after Macular Hole Surgery: A Longitudinal Comparison of Bumpy and Smooth Morphologies

Morphology-Dependent Recovery after Macular Hole Surgery: A Longitudinal Comparison of Bumpy and Smooth Morphologies | 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 Morphology-Dependent Recovery after Macular Hole Surgery: A Longitudinal Comparison of Bumpy and Smooth Morphologies Hiroyuki Nakashizuka, Masanori Iwasaki, Ichihiko Takeuchi, Shosuke Yanagi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9169775/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Objectives To determine whether macular hole (MH) margin morphology (bumpy vs smooth) predicts postoperative recovery beyond MH size and surgical factors after full-thickness MH closure. Methods Retrospective cohort study of 111 eyes (107 patients) undergoing primary vitrectomy with follow-up at 3, 6, and 12 months. Preoperative OCT classified MH margins as bumpy (n = 59) or smooth (n = 52). Outcomes were ellipsoid zone (EZ) defect length and best-corrected visual acuity (BCVA; logMAR). Covariate-adjusted mixed-effects models with a morphology×time interaction estimated marginal means (EMMs). Models adjusted for minimum MH diameter, inverted flap technique, and high myopia for EZ; concomitant cataract surgery was additionally adjusted for BCVA. Results At baseline, bumpy eyes had larger minimum MH diameters, worse BCVA, and greater hole rim detachment (all P < 0.001). Adjusted EZ defect length was greater in the bumpy group at 3 months (EMM 404.2 vs 248.2 µm; P < 0.001) but not at 6 months (174.7 vs 133.1 µm; P = 0.362) or 12 months (73.9 vs 110.1 µm; P = 0.428). Adjusted BCVA was worse in the bumpy group at 3 months (0.279 vs 0.175; P = 0.006) but comparable at 6 months (0.194 vs 0.155; P = 0.311) and 12 months (0.143 vs 0.126; P = 0.656). Conclusions Bumpy MH-margin morphology is associated with delayed early structural and functional recovery; however, differences diminish over time, with convergence by 12 months. This catch-up pattern suggests bumpy morphology reflects a larger yet potentially reversible disturbance at the photoreceptor outer segment–retinal pigment epithelium interface rather than permanent photoreceptor loss. Health sciences/Medical research/Outcomes research Health sciences/Medical research/Biomarkers/Prognostic markers macular hole optical coherence tomography photoreceptor cells vitrectomy retinal pigment epithelium Figures Figure 1 Figure 2 Figure 3 Figure 4 Precis A preoperative bumpy macular hole margin does not necessarily predict poor visual or structural outcomes at 12 months; rather, it may represent a reversible alteration at the photoreceptor outer segment–retinal pigment epithelium interface. Introduction Full-thickness macular holes (MHs), which are characterised by the disruption of foveal architecture are a significant cause of central visual impairment that lead to decreased central vision. 1 , 2 Standard treatment for MH includes pars plana vitrectomy with internal limiting membrane (ILM) peeling or the inverted ILM flap technique, both of which achieve high anatomical closure rates and marked improvements in visual function. 3 – 5 However, the degree of postoperative functional recovery widely varies and influenced by the extent of recovery in the photoreceptor layer, as shown by optical coherence tomography (OCT) imaging. 6 , 7 Among the various OCT biomarkers that represent functional recovery, the ellipsoid zone (EZ), which is a hyperreflective band representing photoreceptor inner-segment integrity and mitochondrial alignment 8 – 11 has consistently demonstrated a strong correlation with postoperative visual outcomes. 12 Therefore, the preservation or timely recovery of EZ integrity is essential for visual acuity improvement following MH surgery. 6 , 7 , 13 Due to the recent advances in high-resolution spectral-domain OCT, distinct morphological features at the edges of MHs can be identified. These include a bumpy morphology, which is characterised by indentations in the photoreceptor layer along the inner hole contour, and a smooth morphology, which is characterised by a regular inner hole contour without such indentations. 14 However, previous studies have shown that the minimum MH diameter—an established determinant of postoperative anatomical and functional outcomes 15 – 18 —differs between bumpy and smooth morphologies. 14 , 19 , 20 Building on earlier observations linking MH-border morphology to postoperative outcomes, 14 we aimed to clarify the independent prognostic contribution of MH-margin morphology by accounting for potential confounders and to characterise morphology-specific recovery trajectories over time. Methods Study design and participants This retrospective study included 111 eyes from 107 patients who underwent successful MH closure at Nihon University Hospital between January 2015 and December 2024. A total of 14 retinal surgeons (H.N., M.I., K.M., H.K., M.Y., K.F., T.S., Y.W., H.O., C.S., T.S., T.H., Y.K. and K.T.) who were affiliated with the university hospital performed the surgeries included in this study. Notably, a portion of this cohort was previously included in separate studies addressing different research questions. 21 . 22 The inclusion criteria were as follows: Patients with primarily closed full-thickness MHs. Patients who underwent vitrectomy and ILM peeling with or without the inverted ILM flap technique. Eyes with available preoperative data and complete follow-up at 3, 6 and 12 months after surgery. The exclusion criteria were as follows: Patients with MH-associated retinal detachment. Patients with full- or partial-thickness MH with myopic foveoschisis. Patients with recurrent or traumatic MH. Patients with a history of ophthalmological surgery other than cataract surgery. Patients with significant ocular pathologies influencing study outcomes such as neovascular age-related macular degeneration, proliferative diabetic retinopathy, posterior patchy atrophy or macular oedema. Patients without essential baseline data. Ethical considerations This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Nihon University Hospital (approval number: 20211105). Written informed consent was obtained from all the patients before surgery. Surgical procedures All patients underwent standard 25- or 27-gauge pars plana vitrectomy using the Constellation system (Alcon, Fort Worth, TX, USA) along with a non-contact wide-angle viewing platform (Resight; Carl Zeiss, Jena, Germany). Following phacoemulsification and implantation of an intraocular lens, the vitreous cavity was stained with triamcinolone acetonide to visualise residual vitreous, and posterior vitreous detachment was induced when not preexisting. The ILM was then stained using 0.025% brilliant blue G and peeled. In some cases, the inverted ILM flap technique, wherein the peeled membrane is inverted over the MH to aid closure, 5 was performed at the discretion of the surgeon. In certain instances, viscoelastic material was applied over the flap. At the end of the surgery, tamponade was achieved using either room air, 17%–20% sulfur hexafluoride or 9%–11% octafluoropropane. Following surgery, patients were advised to maintain a prone position for 1–3 days based on the status of MH closure on OCT. Ocular parameters BCVA was evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart or conventional Landolt-C chart and all assessments were conducted under similar refractive correction conditions. Eyes were considered highly myopic if the axial length was ≥ 26.5 mm. The foveal structure was evaluated using a spectral-domain OCT (SPECTRALIS OCT2; Heidelberg Engineering, Heidelberg, Germany). All images were captured in high-speed acquisition mode, and only scans with a quality score of ≥ 20 were analysed. Line and radial scans were conducted with angular widths of 30° and 20°, respectively, using automatic real-time averaging of 100 and 22 frames. Preoperative radial B-OCT scans of the edges of the MH were used to categorise the foveal contour as either smooth or bumpy. A representative case with a smooth morphology is presented in Fig. 1 , and representative cases of MH with a bumpy morphology are presented in Figs. 2 . A smooth morphology was characterised by a moderately reflective inner contour without indentations that is continuous with the photoreceptor layer (asterisk in the top row of Fig. 1 ).(ref. 14) In contrast, a bumpy morphology was characterised by a poorly demarcated, moderately reflective inner contour with indentations that is continuous with the photoreceptor layer (asterisks in the top rows of Figs. 2 ). (ref. 14) To measure the narrowest width parallel to the retinal pigment epithelium (RPE), the minimum MH diameter was obtained from the horizontal OCT scan that crossed the foveal centre, which was measured using manual callipers. The extent of MH rim detachment was defined as the difference between the basal hole diameter and the minimum hole diameter (see the upper panels of Figs. 1 and 2 ). The EZ defect length was defined as the horizontal linear distance between the nasal and temporal endpoints of the disrupted EZ band on the same central B-scan image. EZ defects were measured at 3, 6 and 12 months postoperatively. Moreover, visual acuities in logarithm of the minimum angle of resolution (logMAR) were recorded at these time points. Out of four experienced retinal specialists (M.I., K.T., I.T. and R.Y.), two were selected to independently assess whether the MH morphology was bumpy or smooth. For any discrepancies, cases were re-evaluated until the graders reached a final agreement. For each case, the EZ defect length was measured by two of the four graders, and the mean of their readings was used in the statistical analyses. Main outcome measures Main outcome measures The primary outcome was EZ defect length measured by OCT at 3, 6 and 12 months after surgery. The secondary outcome was BCVA assessed at the same postoperative time points. Statistical analysis The ETDRS or decimal visual acuity was calculated in terms of the minimum resolution angle and converted to logMAR. Statistical analyses were performed using software R (v4.3.0) or Python (v3.14.3). Welch’s t -test was used to compare continuous variables between the two groups, while Fisher’s exact test was used for categorical variables. To account for repeated postoperative measurements within the same eye, linear mixed-effects models were fitted using the lme4 package. Models were specified to assess the longitudinal association between MH-margin morphology (bumpy vs. smooth) and postoperative outcomes (EZ defect length or logMAR visual acuity), including a morphology-by-month interaction. Covariates were included to control for potential confounding: minimum MH size, inverted flap technique, and high myopia were adjusted for the EZ analysis, with concomitant cataract surgery additionally included in the visual acuity analysis. Adjusted estimated marginal means (EMMs) and between-group differences were obtained, and P values for these differences were calculated using Wald tests. Statistical significance was set at p < 0.05. Continuous data are presented as mean ± standard deviation, and categorical data as percentages (of eyes). Results Baseline characteristics and surgical status Baseline characteristics and surgical details are summarised in Table 1 . The cohort included 111 eyes, including 59 (53.2%) with bumpy margins and 52 (46.8%) with smooth margins. The bumpy group had significantly larger minimum MH diameters, worse baseline visual acuity, and greater macular hole rim detachment (all p < 0.001). Other baseline characteristics, including age, sex, lens status and the presence of high myopia, did not differ significantly between groups. Likewise, the distribution of surgical techniques, including the use of the inverted flap technique, did not differ significantly between groups. Table 1 Baseline Characteristics and Surgical Status Category Overall (n = 111; 100%) bumpy (n = 59; 53.2%) smooth (n = 52; 46.8%) p-value Age (years) 64.9 ± 9.4 65.5 ± 10.3 64.2 ± 8.3 0.441 Male; Female n (%) 53 (47.7%); 58 (52.3%) 28 (47.5%); 31 (52.5%) 25 (48.1%); 27 (51.9%) 1.000 Minimum hole size (µm) 361.0 ± 155.2 422.3 ± 146.8 291.5 ± 134.9 < 0.001 lens status Phakia; IOL n (%) 99 (89.2%); 12 (10.8%) 53 (89.8%); 6 (10.2%) 46 (88.5%); 6 (11.5%) 1.000 High myopia (Axial length ≥ 26.5mm) n (%) 26 (23.4%) 12 (20.3%) 14 (26.9%) 0.502 Baseline visual acuity (logMAR) 0.524 ± 0.243 0.619 ± 0.250 0.417 ± 0.184 < 0.001 Extent of Macular hole rim detachment (µm) † 436.2 ± 298.2 534.8 ± 289.7 324.2 ± 268.9 < 0.001 Concomitant cataract surgery n (%) 95 (85.6%) 50 (84.7%) 45 (86.5%) 1.000 Inverted flap n (%) 69 (62.2%) 40 (67.8%) 29 (55.8%) 0.240 Postoperative EZ defect length Observed and adjusted postoperative EZ defect length values at 3, 6 and 12 months are illustrated in Fig. 3 . In the observed-data analysis, the bumpy group showed a larger EZ defect length at 3 and 6 months than the smooth group ( p < 0.001, p = 0.002; respectively), and between-group difference at 12 months remained borderline significant ( p = 0.071). In the covariate-adjusted linear mixed-effects model for postoperative EZ defect length, the adjusted EMM at 3 months was 248.2 µm (95% CI, 185.2–311.3) in the smooth group and 404.2 µm (95% CI, 345.3–463.2) in the bumpy group ( p < 0.001). At 6 months, the adjusted EMMs were 133.1 µm (95% CI, 70.0–196.2) for the smooth group and 174.7 µm (95% CI, 115.7–233.6) for the bumpy group ( p = 0.362). By 12 months, the adjusted EMMs were 110.1 µm (95% CI, 47.0–173.2) in the smooth group and 73.9 µm (95% CI, 15.0–132.9) in the bumpy group ( p = 0.428). The model showed a good fit (R² = 0.732), and the significant difference observed at 3 months was no longer present at later time points. Postoperative visual acuity Observed and adjusted postoperative visual acuity at 3, 6 and 12 months are shown in Fig. 4 . In the observed data, the bumpy group had significantly worse visual acuity at all time points ( p < 0.001, p = 0.002 and p = 0.014, respectively). In the covariate-adjusted linear mixed-effects model, the adjusted EMM at 3 months was 0.175 (95% CI, 0.122–0.227) in the smooth group and 0.279 (95% CI, 0.230–0.328) in the bumpy group ( p = 0.006). At 6 months, the adjusted EMMs were 0.155 (95% CI, 0.103–0.208) for the smooth group and 0.194 (95% CI, 0.145–0.243) for the bumpy group ( p = 0.311). By 12 months, the adjusted EMMs were 0.126 (95% CI, 0.074–0.179) in the smooth group and 0.143 (95% CI, 0.094–0.192) in the bumpy group ( p = 0.656). The model fit was strong (R² = 0.844), and the early difference observed at 3 months was no longer evident at later time points. These results were robust to covariate selection for both EZ defect length and visual acuity. Specifically, when the models were refitted with adjustment for minimum hole diameter only, the EMMs and the between-group differences at each time point remained unchanged (EZ defect length: p < 0.001, p = 0.398, and p = 0.392 at 3, 6, and 12 months, respectively; visual acuity: p = 0.004, 0.254, and 0.569 at the corresponding time points). Discussion This study evaluated whether preoperative MH-margin morphology (bumpy vs. smooth) provides prognostic information about postoperative recovery beyond MH size and surgical factors. Using covariate-adjusted longitudinal models, eyes with a bumpy morphology had worse early postoperative outcomes—both larger EZ defects and poorer visual acuity—at 3 months. However, these differences gradually diminished over time, and by 12 months, the adjusted outcomes were similar between the bumpy and smooth groups. The details of these findings are described below. In our results, eyes with bumpy margins showed worse early postoperative outcomes in terms of EZ defect length and visual acuity. Experimental studies in several mammalian models have demonstrated that retinal detachment deprives photoreceptors of oxygen and nutrients, inducing metabolic stress with mitochondrial perturbation and concurrent outer-segment swelling/loss, 10,14,23–26 which may be visualised on OCT as poorly demarcated, moderately reflective material accompanied by indentations of the photoreceptor layer, resembling a bumpy morphology. In our cohort, the extent of rim detachment was greater in the bumpy group. This finding supports the possibility that bumpy morphology partly reflects photoreceptor alterations secondary to more extensive detachment at the macular hole margin. Despite the early structural and functional deficits, the differences in both EZ defect length and visual acuity between groups diminished over time, with adjusted outcomes being comparable at later time points. The EZ band is considered to reflect the integrity of the mitochondria-rich photoreceptor inner segment (ellipsoid region). 8 – 11 Because renewal of the photoreceptor outer segment depends on healthy inner-segment function, the delayed but eventual catch-up seen in the bumpy group may indicate gradual restoration of inner-segment activity after photoreceptor–RPE reattachment. 7 , 23 , 27 , 28 This process may facilitate reconstitution of the outer segment–RPE interface and thereby reduce the initial structural deficit over time. 7 , 23 , 27 , 29 Experimental studies of retinal reattachment also suggest that photoreceptors can recover from metabolic stress after reattachment, which may be reflected in the restoration of the EZ band. 7 , 23 , 27 , 28 , 30 In this context, a bumpy morphology at the MH margin may represent partial outer segment loss or photoreceptor disorganisation at the outer segment–RPE interface, rather than irreversible damage to the photoreceptor layer. This interpretation aligns with reports associating supra-RPE granular deposits in full-thickness MHs with remnants of photoreceptor outer segments. 14 Limitations This study has several limitations. First, its retrospective design may introduce selection bias and unmeasured confounding. Second, the inverted ILM flap technique was not standardised, and the decision to perform it was at the discretion of each surgeon, which may have caused treatment selection bias. Third, the follow-up period was 12 months; therefore, long-term anatomical and functional outcomes beyond this period remain unknown. Despite these limitations, this study has several strengths. The cohort was relatively large, and there were multiple postoperative time points (3, 6 and 12 months), enabling a robust longitudinal analysis. Additionally, both anatomical and functional outcomes were evaluated, providing a comprehensive understanding of the recovery process. The use of covariate-adjusted linear mixed-effects models enabled precise estimation of recovery trajectories over time. This approach helped isolate the independent association of MH-margin morphology with postoperative outcomes. Conclusion In full-thickness MHs with successful closure, eyes with a bumpy morphology showed larger early postoperative EZ defects and poorer visual acuity compared to those with a smooth morphology. However, these differences gradually diminished over time, with outcomes becoming comparable by 12 months after surgery. This catch-up pattern, marked by convergence of both EZ defect length and visual acuity, suggests that bumpy morphology may indicate a larger, yet potentially reversible, disturbance at the photoreceptor outer segment–RPE interface rather than permanent photoreceptor loss. Abbreviations IOL intraocular lens logMAR logarithm of the minimum angle of resolution. Declarations Conflicts of Interest: Masanori Iwasaki received grants from Alcon. Hiroyuki Nakashizuka received grants from Alcon, Kowa Pharmaceutical, Senju Pharmaceutical, HOYA, Novartis Pharma and Santen Pharmaceutical. Hiroyuki Nakashizuka and Ryusaburo Mori received honoraria for lectures from Chugai Pharmaceutical, Santen Pharmaceutical, Senju Pharmaceutical, Novartis Pharma, Kowa Pharmaceutical, Bayer Yakuhin Ltd., Kyowa Kirin Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Ayaka Nakai received grants from JSPS KAKENHI (Grant Number 25K20214) and received honoraria for lectures from Chugai Pharmaceutical and Novartis Pharma. Yu Wakatsuki received grants from JSPS KAKENHI (Grant Number 21K16909). The sponsors had no role in the design or conduct of the study, data collection or analysis or preparation of the manuscript. Declaration of Generative AI and AI-assisted Technologies in the Writing Process During the preparation of this work the authors used ChatGPT (Open AI) to enhance the readability and proofread the English text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Funding No specific funding was received for this study. Author Contributions M.I. conceived and designed the study. M.I., K.T., I.T. and R.Y. collected the data and evaluated OCT morphology. M.I. and Y.I. performed the statistical analyses. M.I. drafted the manuscript. H.N., N.A., Y.W., K.T., R.M., and H.S. interpreted the data, revised the manuscript critically for important intellectual content, and approved the final version. Acknowledgements The authors acknowledge Yutaka Iguchi (Laboratory of Biology, Nagano, Japan) for his help with the statistical analysis. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request, subject to institutional and ethical restrictions. References Gass JDM. Idiopathic senile macular hole: its early stages and pathogenesis. 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The ability of rapid retinal reattachment to stop or reverse the cellular and molecular events initiated by detachment. Invest Ophthalmol Vis Sci. 2002;43:2412–2420 Additional Declarations There is no conflict of interest Cite Share Download PDF Status: Under Review Version 1 posted Review # 1 received at journal 25 Apr, 2026 Reviewer # 1 agreed at journal 25 Apr, 2026 Reviewers invited by journal 15 Apr, 2026 Editor assigned by journal 14 Apr, 2026 Submission checks completed at journal 23 Mar, 2026 First submitted to journal 19 Mar, 2026 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. 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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-9169775","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":623394106,"identity":"84c5ca3b-8d03-4255-8d96-30df3979144a","order_by":0,"name":"Hiroyuki Nakashizuka","email":"data:image/png;base64,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","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Nakashizuka","suffix":""},{"id":623394107,"identity":"f12db287-c5f9-432e-85da-7119750facb4","order_by":1,"name":"Masanori Iwasaki","email":"","orcid":"https://orcid.org/0000-0002-7397-8654","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masanori","middleName":"","lastName":"Iwasaki","suffix":""},{"id":623394108,"identity":"920d770d-01b8-48af-92f7-a8d457dc4c2d","order_by":2,"name":"Ichihiko Takeuchi","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ichihiko","middleName":"","lastName":"Takeuchi","suffix":""},{"id":623394109,"identity":"e8b6ad94-89b7-4c18-8f1c-add570c69da8","order_by":3,"name":"Shosuke Yanagi","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shosuke","middleName":"","lastName":"Yanagi","suffix":""},{"id":623394110,"identity":"793c90b0-6b57-48a9-ad15-9ca8d09d0cfd","order_by":4,"name":"Ayaka Nakai","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ayaka","middleName":"","lastName":"Nakai","suffix":""},{"id":623394111,"identity":"9a5bcce5-23c9-40df-813d-d8eae8edd7ae","order_by":5,"name":"Soichiro Odaka","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Soichiro","middleName":"","lastName":"Odaka","suffix":""},{"id":623394112,"identity":"01b9914f-3b98-46f6-8cd2-a4528640c4d6","order_by":6,"name":"Koyo Takase","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Koyo","middleName":"","lastName":"Takase","suffix":""},{"id":623394113,"identity":"93c77964-15f3-4e84-81d9-a0cc0c1644ee","order_by":7,"name":"Yu Wakatsuki","email":"","orcid":"","institution":"Nihon University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wakatsuki","suffix":""},{"id":623394114,"identity":"9db14184-f68f-443e-be45-2bfa45932bfa","order_by":8,"name":"Koji Tanaka","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Tanaka","suffix":""},{"id":623394115,"identity":"c173de5e-643c-4594-906e-e4769ba9eeb1","order_by":9,"name":"Ryusaburo Mori","email":"","orcid":"","institution":"Nihon University","correspondingAuthor":false,"prefix":"","firstName":"Ryusaburo","middleName":"","lastName":"Mori","suffix":""},{"id":623394116,"identity":"0a7eca34-e5fd-439f-9613-80768550dd0d","order_by":10,"name":"Hiroyuki Shimada","email":"","orcid":"","institution":"Nihon University","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Shimada","suffix":""}],"badges":[],"createdAt":"2026-03-19 13:06:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9169775/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9169775/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107868817,"identity":"2db910e4-b4ab-4f46-8293-df3d0da2ea71","added_by":"auto","created_at":"2026-04-27 07:34:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2543131,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative case of a full-thickness macular hole (MH) with a smooth morphology.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpectral-domain optical coherence tomography images of the left eye of a man in his 50s are shown. In the preoperative image, a smooth morphology is observed at the MH margin (top row, asterisk), characterised by a moderately reflective inner contour without indentations that is continuous with the photoreceptor layer (top row, white arrowhead). The basal hole diameter was 623 µm, and the minimum hole diameter was 259 µm, yielding an MH rim detachment extent of 364 µm (top row, double-headed white arrow indicating the distance). Visual acuity was 20/67. At 3 months postoperatively, the ellipsoid zone (EZ) defect appears reduced, with partial reconstitution of the EZ band at the fovea (middle row, white arrow), and visual acuity improved to 20/29. At 12 months postoperatively, the EZ band appears continuous at the fovea at the same site indicated at 3 months (bottom row, white arrow) and visual acuity was 20/25. Insets are shown at 150% magnification.\u003c/p\u003e","description":"","filename":"fig1smooth202603092.png","url":"https://assets-eu.researchsquare.com/files/rs-9169775/v1/dbe9719e0fea17dfbf6007db.png"},{"id":107617766,"identity":"ea003bff-2198-4a57-8d92-5f3167282b51","added_by":"auto","created_at":"2026-04-23 09:22:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2880953,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative case of a full-thickness macular hole (MH) with a bumpy morphology.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpectral-domain optical coherence tomography images of the left eye of a man in his 70s are shown (acquired in follow-up mode along the identical scan line). In the preoperative image, a bumpy morphology is observed at the MH margin (top row, asterisks) and is continuous with the photoreceptor layer (top row, white arrowhead). The bumpy morphology is characterised by poorly demarcated, moderately reflective material with indentations. These findings may suggest partial loss of the photoreceptor outer segments or disorganisation of photoreceptors at the outer segment–retinal pigment epithelium interface. The basal hole diameter was 1066 µm and the minimum hole diameter was 458 µm, yielding an MH rim detachment extent of 608 µm (top row, double-headed white arrow indicating the distance). Visual acuity was 20/133. At 3 months postoperatively, the foveal structure was partially restored (middle row, white arrow), and visual acuity improved to 20/50. By 12 months, the ellipsoid zone (EZ) band appears fully reconstituted and continuous at the fovea at the same location indicated at 3 months (bottom row, white arrow), with resolution of the irregularities observed at 3 months, and BCVA improved to 20/22. Insets are shown at 150% magnification.\u003c/p\u003e","description":"","filename":"fig2bumpy202603091.png","url":"https://assets-eu.researchsquare.com/files/rs-9169775/v1/8999c3a297806711e620d73b.png"},{"id":107617763,"identity":"358976a2-cec0-449a-a20b-82f9db62e62d","added_by":"auto","created_at":"2026-04-23 09:22:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":449257,"visible":true,"origin":"","legend":"\u003cp\u003eObserved (A) and adjusted (B) postoperative ellipsoid zone (EZ) defect length by MH-margin morphology (smooth vs. bumpy).\u003cbr\u003e\nPanel A shows observed values, with between-group comparisons at each postoperative time point assessed using Welch’s \u003cem\u003et\u003c/em\u003e-test. Panel B presents adjusted estimated marginal means (EMMs) from a covariate-adjusted linear mixed-effects model including minimum macular hole diameter, the inverted flap technique and high myopia. Between-group comparisons at each postoperative time point were performed using Wald tests. ***, p \u0026lt; 0.001; **, p \u0026lt; 0.01; *, p \u0026lt; 0.05; †, p \u0026lt; 0.10 (trend); n.s., not significant.\u003c/p\u003e","description":"","filename":"fig3EZ202602121.png","url":"https://assets-eu.researchsquare.com/files/rs-9169775/v1/5224fafebfa2f87487e6282e.png"},{"id":107617764,"identity":"42512907-8f30-4dd4-bb80-48e22a1fc9ba","added_by":"auto","created_at":"2026-04-23 09:22:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":493213,"visible":true,"origin":"","legend":"\u003cp\u003eObserved (A) and adjusted (B) postoperative visual acuity (logMAR) by MH-margin morphology (smooth vs. bumpy).\u003cbr\u003e\nPanel A shows observed values, with between-group comparisons at each postoperative time point assessed using Welch’s \u003cem\u003et\u003c/em\u003e-test. Panel B presents adjusted estimated marginal means (EMMs) from a covariate-adjusted linear mixed-effects model including minimum macular hole diameter, the inverted flap technique, high myopia and concomitant cataract surgery. Between-group comparisons at each postoperative time point were performed using Wald tests. ***, p \u0026lt; 0.001; **, p \u0026lt; 0.01; *, p \u0026lt; 0.05; †, p \u0026lt; 0.10 (trend); n.s., not significant.\u003c/p\u003e","description":"","filename":"fig4VA202602121.png","url":"https://assets-eu.researchsquare.com/files/rs-9169775/v1/d5c0d87c6f27cad5fe7721bc.png"},{"id":107871683,"identity":"0efb1c32-b51f-415d-b467-4a62d0055521","added_by":"auto","created_at":"2026-04-27 07:53:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7172834,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9169775/v1/64b83331-c6a1-4b5b-ad28-1c76d0edbfc1.pdf"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Morphology-Dependent Recovery after Macular Hole Surgery: A Longitudinal Comparison of Bumpy and Smooth Morphologies","fulltext":[{"header":"Precis","content":"\u003cp\u003eA preoperative bumpy macular hole margin does not necessarily predict poor visual or structural outcomes at 12 months; rather, it may represent a reversible alteration at the photoreceptor outer segment–retinal pigment epithelium interface.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eFull-thickness macular holes (MHs), which are characterised by the disruption of foveal architecture are a significant cause of central visual impairment that lead to decreased central vision.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Standard treatment for MH includes pars plana vitrectomy with internal limiting membrane (ILM) peeling or the inverted ILM flap technique, both of which achieve high anatomical closure rates and marked improvements in visual function.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e However, the degree of postoperative functional recovery widely varies and influenced by the extent of recovery in the photoreceptor layer, as shown by optical coherence tomography (OCT) imaging.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAmong the various OCT biomarkers that represent functional recovery, the ellipsoid zone (EZ), which is a hyperreflective band representing photoreceptor inner-segment integrity and mitochondrial alignment\u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e has consistently demonstrated a strong correlation with postoperative visual outcomes.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Therefore, the preservation or timely recovery of EZ integrity is essential for visual acuity improvement following MH surgery.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDue to the recent advances in high-resolution spectral-domain OCT, distinct morphological features at the edges of MHs can be identified. These include a bumpy morphology, which is characterised by indentations in the photoreceptor layer along the inner hole contour, and a smooth morphology, which is characterised by a regular inner hole contour without such indentations.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, previous studies have shown that the minimum MH diameter\u0026mdash;an established determinant of postoperative anatomical and functional outcomes\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u0026mdash;differs between bumpy and smooth morphologies.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBuilding on earlier observations linking MH-border morphology to postoperative outcomes,\u003csup\u003e14\u003c/sup\u003e we aimed to clarify the independent prognostic contribution of MH-margin morphology by accounting for potential confounders and to characterise morphology-specific recovery trajectories over time.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis retrospective study included 111 eyes from 107 patients who underwent successful MH closure at Nihon University Hospital between January 2015 and December 2024. A total of 14 retinal surgeons (H.N., M.I., K.M., H.K., M.Y., K.F., T.S., Y.W., H.O., C.S., T.S., T.H., Y.K. and K.T.) who were affiliated with the university hospital performed the surgeries included in this study. Notably, a portion of this cohort was previously included in separate studies addressing different research questions.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The inclusion criteria were as follows:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with primarily closed full-thickness MHs.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients who underwent vitrectomy and ILM peeling with or without the inverted ILM flap technique.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEyes with available preoperative data and complete follow-up at 3, 6 and 12 months after surgery.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe exclusion criteria were as follows:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with MH-associated retinal detachment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with full- or partial-thickness MH with myopic foveoschisis.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with recurrent or traumatic MH.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with a history of ophthalmological surgery other than cataract surgery.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with significant ocular pathologies influencing study outcomes such as neovascular age-related macular degeneration, proliferative diabetic retinopathy, posterior patchy atrophy or macular oedema.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients without essential baseline data.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003e This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Nihon University Hospital (approval number: 20211105). Written informed consent was obtained from all the patients before surgery.\u003c/p\u003e\n\u003ch3\u003eSurgical procedures\u003c/h3\u003e\n\u003cp\u003eAll patients underwent standard 25- or 27-gauge pars plana vitrectomy using the Constellation system (Alcon, Fort Worth, TX, USA) along with a non-contact wide-angle viewing platform (Resight; Carl Zeiss, Jena, Germany). Following phacoemulsification and implantation of an intraocular lens, the vitreous cavity was stained with triamcinolone acetonide to visualise residual vitreous, and posterior vitreous detachment was induced when not preexisting. The ILM was then stained using 0.025% brilliant blue G and peeled. In some cases, the inverted ILM flap technique, wherein the peeled membrane is inverted over the MH to aid closure,\u003csup\u003e5\u003c/sup\u003e was performed at the discretion of the surgeon. In certain instances, viscoelastic material was applied over the flap. At the end of the surgery, tamponade was achieved using either room air, 17%\u0026ndash;20% sulfur hexafluoride or 9%\u0026ndash;11% octafluoropropane. Following surgery, patients were advised to maintain a prone position for 1\u0026ndash;3 days based on the status of MH closure on OCT.\u003c/p\u003e\n\u003ch3\u003eOcular parameters\u003c/h3\u003e\n\u003cp\u003eBCVA was evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart or conventional Landolt-C chart and all assessments were conducted under similar refractive correction conditions. Eyes were considered highly myopic if the axial length was \u0026ge;\u0026thinsp;26.5 mm.\u003c/p\u003e \u003cp\u003eThe foveal structure was evaluated using a spectral-domain OCT (SPECTRALIS OCT2; Heidelberg Engineering, Heidelberg, Germany). All images were captured in high-speed acquisition mode, and only scans with a quality score of \u0026ge;\u0026thinsp;20 were analysed. Line and radial scans were conducted with angular widths of 30\u0026deg; and 20\u0026deg;, respectively, using automatic real-time averaging of 100 and 22 frames.\u003c/p\u003e \u003cp\u003ePreoperative radial B-OCT scans of the edges of the MH were used to categorise the foveal contour as either smooth or bumpy. A representative case with a smooth morphology is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and representative cases of MH with a bumpy morphology are presented in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A smooth morphology was characterised by a moderately reflective inner contour without indentations that is continuous with the photoreceptor layer (asterisk in the top row of Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).(ref. 14) In contrast, a bumpy morphology was characterised by a poorly demarcated, moderately reflective inner contour with indentations that is continuous with the photoreceptor layer (asterisks in the top rows of Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). (ref. 14)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo measure the narrowest width parallel to the retinal pigment epithelium (RPE), the minimum MH diameter was obtained from the horizontal OCT scan that crossed the foveal centre, which was measured using manual callipers. The extent of MH rim detachment was defined as the difference between the basal hole diameter and the minimum hole diameter (see the upper panels of Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The EZ defect length was defined as the horizontal linear distance between the nasal and temporal endpoints of the disrupted EZ band on the same central B-scan image. EZ defects were measured at 3, 6 and 12 months postoperatively. Moreover, visual acuities in logarithm of the minimum angle of resolution (logMAR) were recorded at these time points.\u003c/p\u003e \u003cp\u003eOut of four experienced retinal specialists (M.I., K.T., I.T. and R.Y.), two were selected to independently assess whether the MH morphology was bumpy or smooth. For any discrepancies, cases were re-evaluated until the graders reached a final agreement. For each case, the EZ defect length was measured by two of the four graders, and the mean of their readings was used in the statistical analyses.\u003c/p\u003e\n\u003ch3\u003eMain outcome measures\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eMain outcome measures\u003c/div\u003e \u003cp\u003eThe primary outcome was EZ defect length measured by OCT at 3, 6 and 12 months after surgery. The secondary outcome was BCVA assessed at the same postoperative time points.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe ETDRS or decimal visual acuity was calculated in terms of the minimum resolution angle and converted to logMAR. Statistical analyses were performed using software R (v4.3.0) or Python (v3.14.3). Welch\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test was used to compare continuous variables between the two groups, while Fisher\u0026rsquo;s exact test was used for categorical variables. To account for repeated postoperative measurements within the same eye, linear mixed-effects models were fitted using the lme4 package. Models were specified to assess the longitudinal association between MH-margin morphology (bumpy vs. smooth) and postoperative outcomes (EZ defect length or logMAR visual acuity), including a morphology-by-month interaction. Covariates were included to control for potential confounding: minimum MH size, inverted flap technique, and high myopia were adjusted for the EZ analysis, with concomitant cataract surgery additionally included in the visual acuity analysis. Adjusted estimated marginal means (EMMs) and between-group differences were obtained, and P values for these differences were calculated using Wald tests.\u003c/p\u003e \u003cp\u003eStatistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Continuous data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and categorical data as percentages (of eyes).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics and surgical status\u003c/h2\u003e \u003cp\u003eBaseline characteristics and surgical details are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The cohort included 111 eyes, including 59 (53.2%) with bumpy margins and 52 (46.8%) with smooth margins. The bumpy group had significantly larger minimum MH diameters, worse baseline visual acuity, and greater macular hole rim detachment (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Other baseline characteristics, including age, sex, lens status and the presence of high myopia, did not differ significantly between groups. Likewise, the distribution of surgical techniques, including the use of the inverted flap technique, did not differ significantly between groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics and Surgical Status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall (n\u0026thinsp;=\u0026thinsp;111; 100%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ebumpy (n\u0026thinsp;=\u0026thinsp;59; 53.2%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003esmooth (n\u0026thinsp;=\u0026thinsp;52; 46.8%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.441\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale; Female n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (47.7%);\u003c/p\u003e \u003cp\u003e58 (52.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (47.5%);\u003c/p\u003e \u003cp\u003e31 (52.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (48.1%);\u003c/p\u003e \u003cp\u003e27 (51.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinimum hole size (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e361.0\u0026thinsp;\u0026plusmn;\u0026thinsp;155.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e422.3\u0026thinsp;\u0026plusmn;\u0026thinsp;146.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e291.5\u0026thinsp;\u0026plusmn;\u0026thinsp;134.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elens status Phakia; IOL n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99 (89.2%);\u003c/p\u003e \u003cp\u003e12 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (89.8%);\u003c/p\u003e \u003cp\u003e6 (10.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (88.5%);\u003c/p\u003e \u003cp\u003e6 (11.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh myopia (Axial length\u0026thinsp;\u0026ge;\u0026thinsp;26.5mm) n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (23.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (20.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (26.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.502\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline visual acuity (logMAR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.524\u0026thinsp;\u0026plusmn;\u0026thinsp;0.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.619\u0026thinsp;\u0026plusmn;\u0026thinsp;0.250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.417\u0026thinsp;\u0026plusmn;\u0026thinsp;0.184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of Macular hole rim detachment (\u0026micro;m) \u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e436.2\u0026thinsp;\u0026plusmn;\u0026thinsp;298.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e534.8\u0026thinsp;\u0026plusmn;\u0026thinsp;289.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e324.2\u0026thinsp;\u0026plusmn;\u0026thinsp;268.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant cataract surgery n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 (85.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (84.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (86.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInverted flap n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (62.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (67.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (55.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePostoperative EZ defect length\u003c/h2\u003e \u003cp\u003eObserved and adjusted postoperative EZ defect length values at 3, 6 and 12 months are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In the observed-data analysis, the bumpy group showed a larger EZ defect length at 3 and 6 months than the smooth group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002; respectively), and between-group difference at 12 months remained borderline significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.071).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the covariate-adjusted linear mixed-effects model for postoperative EZ defect length, the adjusted EMM at 3 months was 248.2 \u0026micro;m (95% CI, 185.2\u0026ndash;311.3) in the smooth group and 404.2 \u0026micro;m (95% CI, 345.3\u0026ndash;463.2) in the bumpy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At 6 months, the adjusted EMMs were 133.1 \u0026micro;m (95% CI, 70.0\u0026ndash;196.2) for the smooth group and 174.7 \u0026micro;m (95% CI, 115.7\u0026ndash;233.6) for the bumpy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.362). By 12 months, the adjusted EMMs were 110.1 \u0026micro;m (95% CI, 47.0\u0026ndash;173.2) in the smooth group and 73.9 \u0026micro;m (95% CI, 15.0\u0026ndash;132.9) in the bumpy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.428). The model showed a good fit (R\u0026sup2; = 0.732), and the significant difference observed at 3 months was no longer present at later time points.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePostoperative visual acuity\u003c/h2\u003e \u003cp\u003eObserved and adjusted postoperative visual acuity at 3, 6 and 12 months are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In the observed data, the bumpy group had significantly worse visual acuity at all time points (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014, respectively).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the covariate-adjusted linear mixed-effects model, the adjusted EMM at 3 months was 0.175 (95% CI, 0.122\u0026ndash;0.227) in the smooth group and 0.279 (95% CI, 0.230\u0026ndash;0.328) in the bumpy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). At 6 months, the adjusted EMMs were 0.155 (95% CI, 0.103\u0026ndash;0.208) for the smooth group and 0.194 (95% CI, 0.145\u0026ndash;0.243) for the bumpy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.311). By 12 months, the adjusted EMMs were 0.126 (95% CI, 0.074\u0026ndash;0.179) in the smooth group and 0.143 (95% CI, 0.094\u0026ndash;0.192) in the bumpy group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.656). The model fit was strong (R\u0026sup2; = 0.844), and the early difference observed at 3 months was no longer evident at later time points.\u003c/p\u003e \u003cp\u003eThese results were robust to covariate selection for both EZ defect length and visual acuity. Specifically, when the models were refitted with adjustment for minimum hole diameter only, the EMMs and the between-group differences at each time point remained unchanged (EZ defect length: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, p\u0026thinsp;=\u0026thinsp;0.398, and p\u0026thinsp;=\u0026thinsp;0.392 at 3, 6, and 12 months, respectively; visual acuity: p\u0026thinsp;=\u0026thinsp;0.004, 0.254, and 0.569 at the corresponding time points).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study evaluated whether preoperative MH-margin morphology (bumpy vs. smooth) provides prognostic information about postoperative recovery beyond MH size and surgical factors. Using covariate-adjusted longitudinal models, eyes with a bumpy morphology had worse early postoperative outcomes\u0026mdash;both larger EZ defects and poorer visual acuity\u0026mdash;at 3 months. However, these differences gradually diminished over time, and by 12 months, the adjusted outcomes were similar between the bumpy and smooth groups. The details of these findings are described below.\u003c/p\u003e \u003cp\u003eIn our results, eyes with bumpy margins showed worse early postoperative outcomes in terms of EZ defect length and visual acuity. Experimental studies in several mammalian models have demonstrated that retinal detachment deprives photoreceptors of oxygen and nutrients, inducing metabolic stress with mitochondrial perturbation and concurrent outer-segment swelling/loss,\u003csup\u003e10,14,23\u0026ndash;26\u003c/sup\u003e which may be visualised on OCT as poorly demarcated, moderately reflective material accompanied by indentations of the photoreceptor layer, resembling a bumpy morphology. In our cohort, the extent of rim detachment was greater in the bumpy group. This finding supports the possibility that bumpy morphology partly reflects photoreceptor alterations secondary to more extensive detachment at the macular hole margin.\u003c/p\u003e \u003cp\u003eDespite the early structural and functional deficits, the differences in both EZ defect length and visual acuity between groups diminished over time, with adjusted outcomes being comparable at later time points. The EZ band is considered to reflect the integrity of the mitochondria-rich photoreceptor inner segment (ellipsoid region).\u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Because renewal of the photoreceptor outer segment depends on healthy inner-segment function, the delayed but eventual catch-up seen in the bumpy group may indicate gradual restoration of inner-segment activity after photoreceptor\u0026ndash;RPE reattachment.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e This process may facilitate reconstitution of the outer segment\u0026ndash;RPE interface and thereby reduce the initial structural deficit over time.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Experimental studies of retinal reattachment also suggest that photoreceptors can recover from metabolic stress after reattachment, which may be reflected in the restoration of the EZ band.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this context, a bumpy morphology at the MH margin may represent partial outer segment loss or photoreceptor disorganisation at the outer segment\u0026ndash;RPE interface, rather than irreversible damage to the photoreceptor layer. This interpretation aligns with reports associating supra-RPE granular deposits in full-thickness MHs with remnants of photoreceptor outer segments.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study has several limitations. First, its retrospective design may introduce selection bias and unmeasured confounding. Second, the inverted ILM flap technique was not standardised, and the decision to perform it was at the discretion of each surgeon, which may have caused treatment selection bias. Third, the follow-up period was 12 months; therefore, long-term anatomical and functional outcomes beyond this period remain unknown.\u003c/p\u003e \u003cp\u003eDespite these limitations, this study has several strengths. The cohort was relatively large, and there were multiple postoperative time points (3, 6 and 12 months), enabling a robust longitudinal analysis. Additionally, both anatomical and functional outcomes were evaluated, providing a comprehensive understanding of the recovery process. The use of covariate-adjusted linear mixed-effects models enabled precise estimation of recovery trajectories over time. This approach helped isolate the independent association of MH-margin morphology with postoperative outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn full-thickness MHs with successful closure, eyes with a bumpy morphology showed larger early postoperative EZ defects and poorer visual acuity compared to those with a smooth morphology. However, these differences gradually diminished over time, with outcomes becoming comparable by 12 months after surgery. This catch-up pattern, marked by convergence of both EZ defect length and visual acuity, suggests that bumpy morphology may indicate a larger, yet potentially reversible, disturbance at the photoreceptor outer segment\u0026ndash;RPE interface rather than permanent photoreceptor loss.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintraocular lens\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003elogMAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elogarithm of the minimum angle of resolution.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of Interest:\u003c/h2\u003e\n\u003cp\u003eMasanori Iwasaki received grants from Alcon. Hiroyuki Nakashizuka received grants from Alcon, Kowa Pharmaceutical, Senju Pharmaceutical, HOYA, Novartis Pharma and Santen Pharmaceutical. Hiroyuki Nakashizuka and Ryusaburo Mori received honoraria for lectures from Chugai Pharmaceutical, Santen Pharmaceutical, Senju Pharmaceutical, Novartis Pharma, Kowa Pharmaceutical, Bayer Yakuhin Ltd., Kyowa Kirin Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Ayaka Nakai received grants from JSPS KAKENHI (Grant Number 25K20214) and received honoraria for lectures from Chugai Pharmaceutical and Novartis Pharma. Yu Wakatsuki received grants from JSPS KAKENHI (Grant Number 21K16909). The sponsors had no role in the design or conduct of the study, data collection or analysis or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Generative AI and AI-assisted Technologies in the Writing Process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work the authors used ChatGPT (Open AI) to enhance the readability and proofread the English text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNo specific funding was received for this study.\u003c/p\u003e\n\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\n\u003cp\u003eM.I. conceived and designed the study. M.I., K.T., I.T. and R.Y. collected the data and evaluated OCT morphology. M.I. and Y.I. performed the statistical analyses. M.I. drafted the manuscript. H.N., N.A., Y.W., K.T., R.M., and H.S. interpreted the data, revised the manuscript critically for important intellectual content, and approved the final version.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors acknowledge Yutaka Iguchi (Laboratory of Biology, Nagano, Japan) for his help with the statistical analysis.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request, subject to institutional and ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGass JDM. Idiopathic senile macular hole: its early stages and pathogenesis. 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Am J Ophthalmol. 2012;153:111\u0026ndash;119.e1. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ajo.2011.09.011\u003c/span\u003e\u003cspan address=\"10.1016/j.ajo.2011.09.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewis GP, Charteris DG, Sethi CS, Leitner WP, Linberg KA \u0026amp; Fisher SK. The ability of rapid retinal reattachment to stop or reverse the cellular and molecular events initiated by detachment. Invest Ophthalmol Vis Sci. 2002;43:2412\u0026ndash;2420\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"macular hole, optical coherence tomography, photoreceptor cells, vitrectomy, retinal pigment epithelium","lastPublishedDoi":"10.21203/rs.3.rs-9169775/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9169775/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjectives\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo determine whether macular hole (MH) margin morphology (bumpy vs smooth) predicts postoperative recovery beyond MH size and surgical factors after full-thickness MH closure.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRetrospective cohort study of 111 eyes (107 patients) undergoing primary vitrectomy with follow-up at 3, 6, and 12 months. Preoperative OCT classified MH margins as bumpy (n\u0026thinsp;=\u0026thinsp;59) or smooth (n\u0026thinsp;=\u0026thinsp;52). Outcomes were ellipsoid zone (EZ) defect length and best-corrected visual acuity (BCVA; logMAR). Covariate-adjusted mixed-effects models with a morphology\u0026times;time interaction estimated marginal means (EMMs). Models adjusted for minimum MH diameter, inverted flap technique, and high myopia for EZ; concomitant cataract surgery was additionally adjusted for BCVA.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAt baseline, bumpy eyes had larger minimum MH diameters, worse BCVA, and greater hole rim detachment (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Adjusted EZ defect length was greater in the bumpy group at 3 months (EMM 404.2 vs 248.2 \u0026micro;m; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but not at 6 months (174.7 vs 133.1 \u0026micro;m; P\u0026thinsp;=\u0026thinsp;0.362) or 12 months (73.9 vs 110.1 \u0026micro;m; P\u0026thinsp;=\u0026thinsp;0.428). Adjusted BCVA was worse in the bumpy group at 3 months (0.279 vs 0.175; P\u0026thinsp;=\u0026thinsp;0.006) but comparable at 6 months (0.194 vs 0.155; P\u0026thinsp;=\u0026thinsp;0.311) and 12 months (0.143 vs 0.126; P\u0026thinsp;=\u0026thinsp;0.656).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBumpy MH-margin morphology is associated with delayed early structural and functional recovery; however, differences diminish over time, with convergence by 12 months. This catch-up pattern suggests bumpy morphology reflects a larger yet potentially reversible disturbance at the photoreceptor outer segment\u0026ndash;retinal pigment epithelium interface rather than permanent photoreceptor loss.\u003c/p\u003e","manuscriptTitle":"Morphology-Dependent Recovery after Macular Hole Surgery: A Longitudinal Comparison of Bumpy and Smooth Morphologies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 09:22:18","doi":"10.21203/rs.3.rs-9169775/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-04-25T09:45:57+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-25T09:18:35+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-04-15T06:51:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-14T14:43:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-23T14:25:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Eye","date":"2026-03-19T13:02:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0fc45888-a392-4675-8981-240d7ede777f","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66343201,"name":"Health sciences/Medical research/Outcomes research"},{"id":66343202,"name":"Health sciences/Medical research/Biomarkers/Prognostic markers"}],"tags":[],"updatedAt":"2026-04-23T09:22:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 09:22:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9169775","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9169775","identity":"rs-9169775","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}