Prevention of Postoperative Proliferative Vitreoretinopathy in Complex Retinal Detachments with Serial Intravitreal Methotrexate Injections

Prevention of Postoperative Proliferative Vitreoretinopathy in Complex Retinal Detachments with Serial Intravitreal Methotrexate Injections | 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 Research Article Prevention of Postoperative Proliferative Vitreoretinopathy in Complex Retinal Detachments with Serial Intravitreal Methotrexate Injections Lucas Valadão de Brito Soares, Tiago Nelson Oliveira Rassi, Wener Passarinho Cella, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8933234/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Proliferative vitreoretinopathy (PVR) remains the leading cause of surgical failure after rhegmatogenous retinal detachment (RRD) repair. Methotrexate (MTX) has emerged as a potential antiproliferative adjunct, but evidence is limited. This study evaluated the safety and efficacy of serial intravitreal MTX injections administered throughout the critical postoperative period to prevent the onset of PVR-related redetachment in complex RRD. Methods This retrospective study included 49 eyes undergoing pars plana vitrectomy (PPV) for complex RRD, defined as PVR grade C, recurrent retinal detachment, or detachment associated with penetrating ocular trauma. All eyes received an intraoperative intravitreal MTX injection (400 µg/0.1 mL), followed by biweekly injections for up to 12 postoperative weeks. The primary outcome was single-surgery anatomic success (SSAS) at 12 weeks. Secondary outcomes included final retinal reattachment rate, changes in best-corrected visual acuity (BCVA), and safety outcomes. Results SSAS at 12 weeks was achieved in 85.7% of eyes. After reoperation in selected cases, the final retinal reattachment rate was 93.8%. Mean BCVA improved significantly by 1.29 ± 0.52 logMAR units at 3 months (95% CI, 1.05–1.53; p < 0.001). The most frequent adverse event was conjunctival hyperemia, which resolved after completion of the MTX protocol. No severe ocular or systemic MTX-related adverse events were observed. Conclusions Serial intravitreal MTX injections administered throughout the critical postoperative period demonstrated a favorable safety profile and were associated with high anatomic success rates and meaningful visual improvement in complex RRD. proliferative vitreoretinopathy rhegmatogenous retinal detachment intravitreal methotrexate pars plana vitrectomy retinal reattachment retinectomy Figures Figure 1 Figure 2 INTRODUCTION Proliferative vitreoretinopathy (PVR) remains the leading cause of surgical failure following primary repair of rhegmatogenous retinal detachment (RRD). Surgical management is the cornerstone of treatment: pars plana vitrectomy (PPV) is typically indicated for grades A and B, whereas grade C PVR, characterized by contractile retinal membranes, frequently requires extensive membrane peeling. In selected cases with significant retinal shortening, scleral buckling may be combined with PPV or performed as an isolated procedure, particularly in advanced grade C disease. 1 Despite continuous refinements in vitreoretinal surgical techniques, the incidence of PVR has remained relatively unchanged since the 1990s, ranging from approximately 5.7% to 11.7%, and often results in severe and irreversible visual impairment. 2 Given these limitations, pharmacologic strategies aimed at preventing or modulating PVR have been explored as adjuncts to surgery. Several agents have been investigated, including corticosteroids (dexamethasone, triamcinolone), antineoplastic agents (5-fluorouracil, daunorubicin), biologics (ranibizumab) 3 , retinoic acid 4 , and colchicine 5 . However, these therapies have demonstrated inconsistent efficacy and, in some cases, raised concerns regarding retinal toxicity, particularly in eyes with an attached macula at presentation. 6 More recently, intravitreal methotrexate (MTX) has emerged as a promising therapeutic option for PVR prevention. 7 MTX is a folic acid antagonist that inhibits DNA synthesis and repair, thereby suppressing cellular proliferation. It exerts potent antiproliferative and anti-inflammatory effects and has been widely used in the treatment of autoimmune diseases, transplant rejection, and malignancies. 8 In ophthalmology, MTX has been used for decades in the management of non-infectious uveitis and intraocular lymphoma. Intravitreal administration is considered safe at currently employed doses, as it minimizes systemic exposure and is generally associated with few and manageable adverse effects. 9 – 11 Nevertheless, evidence regarding the role of MTX as an adjunctive therapy for PVR remains conflicting. While some studies have reported favorable anatomic and functional outcomes, others have failed to demonstrate a significant benefit. It has been hypothesized that negative results may be related to undertreatment, including the use of lower doses, a limited number of injections, or insufficient treatment duration. . 12 13 The fibrotic response characteristic of PVR typically develops during the first 12 postoperative weeks, a critical period marked by cellular activation, migration, cytokine release, and extracellular matrix deposition. 6 , 14 Because a single intravitreal MTX injection does not provide sustained pharmacologic coverage throughout this interval 11 , repeated dosing has been proposed as a strategy to maintain therapeutic activity during the entire window of risk. Clinical studies employing biweekly dosing schedules have reported improved anatomic success rates compared with single-dose protocols. 15 , 16 Based on this rationale, the present study aimed to evaluate whether sustained intravitreal MTX exposure throughout the critical postoperative period could improve surgical outcomes in complex RRD. We administered MTX at a dose of 400 µg/0.1 mL every two weeks for up to 12 weeks following surgery. The primary objective was to assess single-surgery anatomic success (SSAS) at 12 weeks in patients with complex RRD undergoing PPV with intraoperative and serial postoperative MTX injections. Secondary outcomes included final retinal reattachment rates and visual function. METHODS Study Design and Ethics This retrospective observational study was conducted based on data extracted from electronic medical records. The study protocol was approved by the institutional Data Review Committee, and all procedures adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to inclusion. Participants We included patients who underwent PPV for RRD between February 2020 and April 2025. Cases were classified as complex retinal detachment if at least one of the following criteria was present: PVR grade C, recurrent retinal detachment due to PVR, or retinal detachment associated with penetrating ocular trauma. Additional inclusion criteria were completion of at least seven intravitreal MTX injections according to the study protocol and a minimum postoperative follow-up of 12 weeks. Eyes with incomplete follow-up or fewer than seven MTX administrations were excluded. All patients were examined and operated on by the same vitreoretinal surgeon (L.V.B.S.) at a single tertiary referral eye care center (Hospital de Referência Oftalmológica, HRO). PVR severity was classified according to the modified Retina Society Classification (1991). 17 Collected data included demographic information, preoperative ocular history, surgical details, and postoperative findings. Best-corrected visual acuity (BCVA) was measured preoperatively and postoperatively using a Snellen chart and subsequently converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analysis. Postoperative evaluation included optical coherence tomography (OCT) in all cases. Surgical Procedure All surgeries were performed using a 25-gauge Constellation Vision System (Alcon Laboratories Inc., Fort Worth, TX, USA). In phakic eyes, combined phacoemulsification with intraocular lens implantation was performed during the same surgical session. A standard bimanual pars plana vitrectomy with scleral depression was carried out to achieve meticulous vitreous base shaving, including removal of the anterior vitreous. Endolaser photocoagulation was applied to all identified retinal breaks. Scleral buckle placement (model S2971, style #42; Labtician Ophthalmics) was performed at the surgeon’s discretion in cases exhibiting significant anterior retinal shortening. Intraoperative dyes were used to facilitate tissue visualization: triamcinolone acetonide for identification of the posterior hyaloid, brilliant blue G for visualization of the internal limiting membrane (ILM), and trypan blue for staining of preretinal membranes associated with PVR. When ILM striae were observed, macular peeling was performed, extending to the vascular arcades. In cases of preretinal membranes located in the mid-periphery or peripheral retina, membrane peeling was carried out using 27-gauge forceps. Perfluorocarbon liquid (PFCL) was used intraoperatively to assist retinal flattening. If retinal contraction persisted despite membrane removal and PFCL infusion, intraoperative retinectomy was performed using endodiathermy and scissors. Following retinal reattachment under PFCL, a fluid-gas exchange was performed, and a final internal tamponade was achieved with silicone oil (Oxane 5700; Bausch & Lomb). Methotrexate Protocol At the conclusion of surgery, methotrexate (Tevametho 50 mg/2 mL; Teva Farmacêutica) was injected into the silicone oil tamponade at a dose of 400 µg/0.1 mL. Additional intravitreal MTX injections at the same dose were administered every two weeks until the 12th postoperative week, for a total of seven doses, provided no contraindications emerged during follow-up. Statistical Analysis Data were initially analyzed using descriptive statistics. Categorical variables were summarized as absolute and relative frequencies, while continuous variables were expressed as means, standard deviations, medians, and interquartile ranges, as appropriate. Associations between categorical variables were evaluated using Fisher’s exact test. Linear mixed-effects regression models were employed to assess the effects of diagnosis and intraoperative retinectomy on changes in visual acuity over time. When statistically significant differences were identified, post hoc comparisons were performed using Wald tests with Bonferroni correction. The assumption of normality for continuous variables was assessed using the Kolmogorov–Smirnov test. A two-sided significance level of 5% was adopted for all analyses. Statistical analyses were performed using SPSS software version 20.0 (IBM Corp., Armonk, NY, USA) and Stata software version 18 (StataCorp LLC, College Station, TX, USA). RESULTS A total of 49 eyes from 49 patients were included in the analysis. The mean patient age was 58.5 ± 13.6 years. Demographic and baseline ocular characteristics are summarized in Table 1. Overall, 32 patients (65.3%) were male, and 34 eyes (69.4%) presented with PVR grade C. Recurrent retinal detachment due to PVR was observed in 9 eyes (18.4%), and 6 eyes (12.2%) were associated with penetrating ocular trauma. Intraoperative retinectomy was performed in 8 eyes (16.3%). The mean follow-up duration was 14.7 ± 10.8 months. Pars plana vitrectomy was combined with scleral buckling in 38 cases (77.5%). All eyes received silicone oil tamponade (5000 cSt), with no evidence of silicone oil–related inflammation or toxicity. The first intravitreal MTX injection (400 µg/0.1 mL) was administered intraoperatively immediately after silicone oil placement, followed by biweekly injections until the 12th postoperative week, for a total of seven doses. Anatomic Outcomes The primary endpoint, SSAS, defined as retinal reattachment at 12 weeks without evidence of fibrotic membrane formation (Figure 1a–1c), was achieved in 42 of 49 eyes (85.7%). Seven eyes required additional surgical intervention for peeling of contractile membranes, resulting in a final anatomic reattachment rate of 93.8%. Three eyes exhibited persistent localized PVR without macular involvement despite reoperation. The distribution of SSAS according to diagnosis and intraoperative retinectomy status is shown in Table 2. No statistically significant association was found between SSAS and diagnostic category ( p = 0.355) or between SSAS and performance of intraoperative retinectomy ( p = 0.581). Visual Outcomes Overall, mean best-corrected visual acuity (BCVA) improved significantly at 3 months postoperatively ( p < 0.001), from 2.52 ± 0.58 logMAR (approximate Snellen equivalent 20/8000) preoperatively to 1.23 ± 0.84 logMAR (approximate Snellen equivalent 20/350). Mean BCVA values and corresponding 95% confidence intervals over time are illustrated in Chart 1, with subgroup analysis by diagnosis shown in Chart 2. Eyes undergoing intraoperative retinectomy achieved 100% SSAS. However, these cases demonstrated a trend toward poorer functional recovery, with a final mean BCVA of 1.74 logMAR (approximate Snellen equivalent 20/1200), as depicted in Chart 3. Visual acuity improved in 45 of 49 eyes and remained stable in the remaining cases. Detailed visual acuity changes stratified by diagnosis and retinectomy status are provided in Appendix 1. Intraocular Pressure and Postoperative Complications Mean intraocular pressure (IOP) during follow-up was 15.5 mmHg (median, 16.7 mmHg). One patient developed sustained IOP elevation beginning in the second postoperative month, which was refractory to topical hypotensive therapy. This patient subsequently underwent silicone oil removal combined with glaucoma valve implantation three months after the initial surgery. Postoperative hypotony, defined as an IOP below 6 mmHg, was observed in three eyes (6.1%). All hypotonic eyes maintained anatomic retinal attachment and did not develop subsequent PVR. Epiretinal membrane formation was observed in six eyes (12.2%), with only one case associated with foveal distortion requiring secondary membrane peeling. Cystoid macular edema occurred in three eyes (6.1%) and resolved with topical anti-inflammatory therapy, without the need for intravitreal corticosteroid injections. The distribution of postoperative complications is summarized in Table 3. Safety Outcomes Conjunctival hyperemia was observed in all patients during the postoperative period and resolved after completion of the MTX injection protocol. One patient experienced significant discomfort during the fourth-week injection and elected to discontinue treatment (Figure 2a–2d). A single case of corneal epithelial defect occurred during the third postoperative week and resolved with therapeutic contact lens placement, without interruption of subsequent MTX administrations. No severe ocular or systemic adverse events related to methotrexate were observed during the follow-up period. DISCUSSION To our knowledge, this study represents the largest retrospective single-arm cohort evaluating adjunctive serial intravitreal MTX (400 µg/0.1 mL) administered throughout the entire critical postoperative period in the surgical management of complex rhegmatogenous retinal detachment. The present findings demonstrate a favorable safety profile and were associated with high anatomic success rates and meaningful functional improvement. Eyes with retinal detachment complicated by PVR grade C or associated penetrating ocular trauma are known to have a poor prognosis and a high risk of postoperative redetachment, with reattachment rates ranging from 17% to 63%. In our cohort, serial MTX administration resulted in a SSAS rate of 85.7% and a final retinal reattachment rate of 93.8%. The rationale for sustained MTX exposure is supported by the treatment protocol used in this study, which combined intraoperative administration with biweekly injections up to the 12th postoperative week. This approach was designed to provide pharmacologic coverage during the period most susceptible to fibrocellular proliferation. Our results are consistent with those reported by Ullah et al., who achieved an SSAS rate of 79% using serial MTX injections during the postoperative period 16 . In contrast, El Baha et al. did not demonstrate a significant benefit of MTX in eyes with PVR grade C when the drug was administered as a single intraoperative dose, reporting SSAS rates of 87% in the control group and 74% in the MTX group 18 . These differences support the concept that treatment duration and dosing strategy may be critical determinants of therapeutic effect. Across the cohort, serial intravitreal MTX was associated with stable postoperative retinal architecture. All eyes undergoing intraoperative retinectomy achieved successful retinal reattachment, with well-demarcated laser scars and stable, non-contractile retinectomy margins. Importantly, no recurrent fibrotic membrane formation was observed along retinectomy edges. In addition, the overall incidence of postoperative epiretinal membrane formation was relatively low, supporting a sustained antiproliferative and anti-inflammatory effect of serial MTX exposure, as reflected in our anatomic outcomes. Although retinectomy was associated with universal anatomic success in this series, it correlated with poorer functional outcomes. This finding is consistent with previous reports indicating that extensive peripheral retinal excision, while effective in relieving traction, may compromise final visual acuity despite successful retinal reattachment. Nevertheless, overall visual function improved significantly in the study population, reinforcing the functional relevance of the anatomic stability achieved with this protocol. Prior studies have also reported functional benefits with postoperative MTX use. Gibson et al. observed improved visual acuity following MTX administration. However, most patients in their cohort had proliferative diabetic retinopathy, and only a minority had PVR associated with complex rhegmatogenous retinal detachment. Furthermore, MTX dosing and treatment duration were not standardized, ranging from 200 to 400 µg and from 6 to 16 weeks, respectively. 19 These differences limit direct comparison and underscore the importance of a standardized, protocol-driven approach such as that employed in the present study. Postoperative hypotony is a recognized complication of complex retinal detachment surgery, with reported incidences ranging from 8% to 40% and an association with poor visual outcomes. In the present cohort, hypotony occurred in only 6.1% of eyes. By inhibiting intraocular cellular proliferation, MTX may reduce the formation of contractile membranes at the level of the ciliary body, potentially contributing to this lower incidence. This observation contrasts with findings reported by Ullah et al., who noted a higher rate of postoperative epiretinal membrane formation when using a lower MTX dose of 200 µg/0.1 mL 16 , further supporting the relevance of dose selection. From a safety standpoint, serial intravitreal MTX was well tolerated. The most frequent adverse event was conjunctival hyperemia related to ocular surface irritation, which was mild, manageable with topical therapy, and resolved after completion of the injection cycle. A single corneal epithelial defect resolved without interruption of treatment. No clinical evidence of posterior segment toxicity was observed, consistent with the established ocular safety profile of MTX. 11 Several limitations must be acknowledged, including the retrospective, non-randomized design, the absence of a control group, and the heterogeneous nature of the cohort, which included both PVR grade C and penetrating ocular trauma cases that may involve distinct inflammatory mechanisms. 20 In addition, postoperative assessments were unblinded and performed by a single surgeon, which may introduce bias. These limitations preclude definitive causal inference. CONCLUSION Serial intravitreal methotrexate administered during the critical postoperative period was safe and associated with high anatomic success and significant functional improvement in complex rhegmatogenous retinal detachment. The low incidence of recurrent PVR and epiretinal membrane formation supports a sustained antiproliferative and anti-inflammatory effect. Although retinectomy improved anatomic outcomes, it was associated with poorer final visual acuity. Collectively, these findings support serial MTX at a dose of 400 µg/0.1 mL as a promising adjunctive strategy for reducing postoperative PVR and retinal redetachment, while reinforcing the need for prospective randomized controlled trials to validate these results. Abbreviations BCVA – Best-corrected visual acuity CI – Confidence interval ILM – Internal limiting membrane IOP – Intraocular pressure IQR – Interquartile range logMAR – Logarithm of the minimum angle of resolution MTX – Methotrexate OCT – Optical coherence tomography PFCL – Perfluorocarbon liquid PO – Postoperative PPV – Pars plana vitrectomy PVR – Proliferative vitreoretinopathy RRD – Rhegmatogenous retinal detachment SSAS – Single-surgery anatomic success Declarations Ethics approval and consent to participate The study adhered to the principles outlined in the Declaration of Helsinki and it was approved by the Ethics Committee of Hospital São Domingos. Written informed consent was obtained from all participants prior to enrollment. Consent for publication Written informed consent for publication was obtained from all participants prior to enrollment. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests All authors declare that they have no competing interests. Funding This study received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors ’ Contribution LVBS: conception, design, validation, analysis, and interpreted the data; performed surgery on the patients included in the study and drafted the manuscript; approved the submitted version. TNOR: analysis, and interpreted the data; approved the submitted version. MM: supervision and approved the submitted version. WPC: review and edit the manuscript, supervision; approved the submitted version. Acknowledgments Not applicable. References Pastor JC. Proliferative vitreoretinopathy. Surv Ophthalmol. 1998;43(1):3–18. Charteris D, Sethi C, Lewis G, Fisher S. Proliferative vitreoretinopathy: developments in adjunctive treatment and retinal pathology. Eye (Lond). 2002;16(4):369–374. Ghasemi Falavarjani K, Hashemi M, Modarres M, Hadavand Khani A. Intrasilicone oil injection of bevacizumab at the end of retinal reattachment surgery for severe proliferative vitreoretinopathy. Eye (Lond). 2014;28(5):576–580. Fekrat S, de Juan E Jr, Campochiaro PA. The effect of oral 13-cis-retinoic acid on retinal redetachment after surgical repair in eyes with proliferative vitreoretinopathy. Ophthalmology. 1995;102(3):412–418. Lemor M, Yeo JH, Glaser BM. Oral colchicine for the treatment of experimental traction retinal detachment. Arch Ophthalmol. 1986;104(8):1226–1229. Giuliari GP, Sadaka A. Proliferative vitreoretinopathy: current and emerging treatments. Clin Ophthalmol. 2012;6:1325–1333. Sadaka A, Sisk RA, Osher JM, Toygar O, Duncan MK, Riemann CD. Intravitreal methotrexate infusion for proliferative vitreoretinopathy. Clin Ophthalmol. 2016;10:1811–1817. Abdi F, Mohammadi S, Ghasemi Falavarjani K. Intravitreal methotrexate. J Ophthalmic Vis Res. 2021;16(2):260–267. Mitry D, Awan MA, Borooah S, Siddiqui MAR, Brogan K, Fleck BW, et al. Surgical outcome and risk stratification for primary retinal detachment repair. Br J Ophthalmol. 2012;96(5):730–734. Manna S, Banerjee R, Augsburger JJ, Al-Rjoub M, Donnell A, Correa ZM. Sustained-release methotrexate intraocular implant: pharmacokinetics and toxicity in rabbit eyes. Graefes Arch Clin Exp Ophthalmol. 2015;253(8):1297–1305. Aziz JH, Zaki MA, El-Shazly AAEF, Mamoun T, Helmy ROA, Hashem MH. Intravitreal methotrexate infusion for prophylaxis of proliferative vitreoretinopathy after pars plana vitrectomy. Med Hypothesis Discov Innov Ophthalmol. 2022;11(3):95–103. Amarnani D, Machuca-Parra AI, Wong LL, Marko CK, Stefater JA, Stryjewski TP, et al. Effect of methotrexate on an in vitro patient-derived model of proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2017;58(10):3940–3947. Palakurthi NK, Krishnamoorthy M, Augsburger JJ, Correa ZM, Banerjee RK. Kinetics of methotrexate for therapeutic treatment of intraocular lymphoma. Curr Eye Res. 2010;35(12):1105–1115. Takkar B, Temkar S, Gaur N, Venkatesh P, Chawla R, Kumar A. Retinal shortening: ultrasonic evaluation of proliferative vitreoretinopathy. Indian J Ophthalmol. 2017;65(11):1172. Benner JD, Dao D, Butler JW, Hamill KI. Intravitreal methotrexate for proliferative vitreoretinopathy. BMJ Open Ophthalmol. 2019;4(1):e000293. doi:10.1136/bmjophth-2019-000293. Ullah A, Toth CA, Burnett HW, Butler JW, Levy JH, Benner JD. Low-dose intravitreal methotrexate for proliferative vitreoretinopathy. Ophthalmol Retina. 2023;7(3):282–288. Machemer R, Aaberg TM, Freeman HM, et al. An updated classification of retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol. 1991;112(2):159–165. El Baha S, Leila M, Amr A, Lolah MMA. Outcomes of vitrectomy with or without intravitreal methotrexate for proliferative vitreoretinopathy. J Ophthalmol. 2021;2021:3648134. doi:10.1155/2021/3648134. Gibson L, Nguyen A, Ridgeway J, Omar M, Purvis C, Shihab Y, et al. Postoperative methotrexate to reduce reoperation rate and improve vision. Ophthalmol Retina. 2019;3(9):869–876. Jin Y. Traumatic proliferative vitreoretinopathy: clinical and histopathological observations. Ophthalmology. 2000;107(2):269–276. Tables Table 1. Demographic and ocular characteristics of the study population Variable n (%) or Mean ± SD Median (IQR) Sex Female 17 (34.7) – Male 32 (65.3) – Age (years) 58.5 ± 13.6 60.0 (50.5–66.5) Diagnosis PVR grade C 34 (69.4) – Re-detachment due to PVR 9 (18.4) – Penetrating ocular trauma 6 (12.2) – Intraoperative retinectomy No 41 (83.7) – Yes 8 (16.3) – Follow-up time (months) 14.7 ± 10.8 12.4 (5.1–22.3) Abbreviations: PVR, proliferative vitreoretinopathy; IQR, interquartile range (P25–P75). Table 2. Single-surgery anatomic success according to diagnosis and retinectomy Variable SSAS – No n (%) SSAS – Yes n (%) p value Overall 7/49 (14.3) 42/49 (85.7) – Diagnosis 0.355 PVR grade C 4/34 (11.8) 30/34 (88.2) Re-detachment due to PVR 1/9 (11.1) 8/9 (88.9) Penetrating ocular trauma 2/6 (33.3) 4/6 (66.7) Intraoperative retinectomy 0.581 No 7/41 (17.1) 34/41 (82.9) Yes 0/8 (0.0) 8/8 (100.0) p values obtained using Fisher’s exact test. Abbreviation: SSAS, single-surgery anatomic success. Table 3. Postoperative complications and ocular surface findings Variable n (%) Epiretinal membrane No 43 (87.8) Yes 6 (12.2) Cystoid macular edema No 46 (93.9) Yes 3 (6.1) Hypotony No 46 (93.9) Yes 3 (6.1) Corneal changes Epithelial defect 1 (2.0) Conjunctival hyperemia 49 (100.0) Charts Charts 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files PPV.mp4 Appendix.docx Chart123.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 21 Mar, 2026 Reviews received at journal 10 Mar, 2026 Reviews received at journal 08 Mar, 2026 Reviews received at journal 08 Mar, 2026 Reviewers agreed at journal 02 Mar, 2026 Reviewers agreed at journal 02 Mar, 2026 Reviewers agreed at journal 02 Mar, 2026 Reviewers invited by journal 02 Mar, 2026 Editor assigned by journal 01 Mar, 2026 Submission checks completed at journal 01 Mar, 2026 First submitted to journal 21 Feb, 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. 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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-8933234","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":599519123,"identity":"e4573cc3-43b3-471c-aeab-e8dbf5f53b36","order_by":0,"name":"Lucas Valadão de Brito Soares","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYBACPigtw8CQwMD4oQLIZGZuwKuFDUrzgLQwS5wBaWEkQQsDbxuITUiLRPLDjz/b7Hj425MfPpCcVxvN3w7U8qNiGx4tacbSvG3JPBJnnhkbFG47njvjMGMDY8+Z23i05DBIM5xh5mG4kWAmIbntWG4DUAszYxteLcw/f5yp55G/kf5NgnfOsdz5RGhhk+CpOMxjcCPHTIK3oSZ3A0EtPM/MrHkqjvMYnnlTbCxx7EDuRqCWg/j8ws+e/PjmD4NqObnj6Rsffqipy513/vDBBz8qcGtBB4fB5AGi1QNBHSmKR8EoGAWjYIQAAKrfVZgyCBRwAAAAAElFTkSuQmCC","orcid":"","institution":"Hospital de Referência Oftalmológica - Vision One","correspondingAuthor":true,"prefix":"","firstName":"Lucas","middleName":"Valadão de Brito","lastName":"Soares","suffix":""},{"id":599519124,"identity":"c4b3c61f-058b-4bd3-97c7-a7ac54e349b2","order_by":1,"name":"Tiago Nelson Oliveira Rassi","email":"","orcid":"","institution":"Federal University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Tiago","middleName":"Nelson Oliveira","lastName":"Rassi","suffix":""},{"id":599519125,"identity":"f0d6215c-acf2-4b05-9910-04aae1e77626","order_by":2,"name":"Wener Passarinho Cella","email":"","orcid":"","institution":"Hospital de Referência Oftalmológica - Vision One","correspondingAuthor":false,"prefix":"","firstName":"Wener","middleName":"Passarinho","lastName":"Cella","suffix":""},{"id":599519126,"identity":"cfa7535c-4658-4a70-add1-ed2aa6d38853","order_by":3,"name":"Mauricio Maia","email":"","orcid":"","institution":"Federal University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Mauricio","middleName":"","lastName":"Maia","suffix":""}],"badges":[],"createdAt":"2026-02-21 11:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8933234/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8933234/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104181567,"identity":"0f06400b-5c6e-46c7-92c5-c0195fe744a3","added_by":"auto","created_at":"2026-03-08 17:28:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3750852,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative case of primary rhegmatogenous retinal detachment with an inferior horseshoe tear, initially treated with pars plana vitrectomy and 20% sulfur hexafluoride (SF₆) gas tamponade, in a patient with a history of superior hemispheric retinal vein occlusion and prior superior laser photocoagulation. \u003cstrong\u003e1a.\u003c/strong\u003eFundus photograph obtained 10 days after the first surgery, showing initial postoperative appearance. \u003cstrong\u003e1b.\u003c/strong\u003e Recurrent retinal detachment due to PVR, managed with surgical reintervention two months after the initial vitrectomy; image shows the postoperative appearance two weeks after retinectomy (see supplementary surgical video:\u003ca href=\"https://vimeo.com/1110501077/41bc90a169?share=copy\"\u003e \u003c/a\u003e\u003ca href=\"https://vimeo.com/1110501077/41bc90a169?share=copy\"\u003ehttps://vimeo.com/1110501077/41bc90a169?share=copy\u003c/a\u003e). \u003cstrong\u003e1c.\u003c/strong\u003eFundus photograph obtained 12 weeks after reintervention, demonstrating adequate retinectomy healing with stable retinal attachment and no evidence of fibrotic membrane formation.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8933234/v1/cec4b38a13f8622930a815a8.jpg"},{"id":104181568,"identity":"4a03b642-0254-4b71-bf9a-e411536d6d04","added_by":"auto","created_at":"2026-03-08 17:28:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5412413,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative case of late fibrotic membrane formation associated with anterior proliferative vitreoretinopathy and subsequent hypotony, occurring after discontinuation of methotrexate treatment at postoperative week 4. \u003cstrong\u003e2a.\u003c/strong\u003e Second postoperative week, showing an attached retina without evidence of preretinal membranes. \u003cstrong\u003e2b.\u003c/strong\u003e Fourth postoperative week, demonstrating well-pigmented laser scars and absence of preretinal membrane formation. \u003cstrong\u003e2c.\u003c/strong\u003e Eighth postoperative week, with an attached retina and early fibrotic membrane development. \u003cstrong\u003e2d.\u003c/strong\u003e Twelfth postoperative week, showing progression of fibrotic membranes associated with ocular hypotony.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8933234/v1/6a277f3ac524902154d32d43.jpg"},{"id":104404148,"identity":"a6c60aad-1418-4d3a-b4e5-98a054b4aee6","added_by":"auto","created_at":"2026-03-11 12:19:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10032981,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8933234/v1/b2a6376e-fc32-45b7-b76d-6f6ec6449359.pdf"},{"id":104181570,"identity":"cd8b140c-8f94-4e4d-81fa-9bf36c04716e","added_by":"auto","created_at":"2026-03-08 17:28:39","extension":"mp4","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":104319940,"visible":true,"origin":"","legend":"","description":"","filename":"PPV.mp4","url":"https://assets-eu.researchsquare.com/files/rs-8933234/v1/c26d50d9632fe87384c7db43.mp4"},{"id":104181566,"identity":"9519b3d4-0325-47bd-b7bb-6e9ed19b6001","added_by":"auto","created_at":"2026-03-08 17:28:36","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20473,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-8933234/v1/a597478cbeca0d4c3032d6b6.docx"},{"id":104181569,"identity":"f1809416-77df-4376-914c-6fe5cafc156c","added_by":"auto","created_at":"2026-03-08 17:28:36","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":370956,"visible":true,"origin":"","legend":"","description":"","filename":"Chart123.docx","url":"https://assets-eu.researchsquare.com/files/rs-8933234/v1/6ee011d97abbbb52b8b2a938.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prevention of Postoperative Proliferative Vitreoretinopathy in Complex Retinal Detachments with Serial Intravitreal Methotrexate Injections","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eProliferative vitreoretinopathy (PVR) remains the leading cause of surgical failure following primary repair of rhegmatogenous retinal detachment (RRD). Surgical management is the cornerstone of treatment: pars plana vitrectomy (PPV) is typically indicated for grades A and B, whereas grade C PVR, characterized by contractile retinal membranes, frequently requires extensive membrane peeling. In selected cases with significant retinal shortening, scleral buckling may be combined with PPV or performed as an isolated procedure, particularly in advanced grade C disease.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Despite continuous refinements in vitreoretinal surgical techniques, the incidence of PVR has remained relatively unchanged since the 1990s, ranging from approximately 5.7% to 11.7%, and often results in severe and irreversible visual impairment.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eGiven these limitations, pharmacologic strategies aimed at preventing or modulating PVR have been explored as adjuncts to surgery. Several agents have been investigated, including corticosteroids (dexamethasone, triamcinolone), antineoplastic agents (5-fluorouracil, daunorubicin), biologics (ranibizumab)\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, retinoic acid\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, and colchicine\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, these therapies have demonstrated inconsistent efficacy and, in some cases, raised concerns regarding retinal toxicity, particularly in eyes with an attached macula at presentation.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMore recently, intravitreal methotrexate (MTX) has emerged as a promising therapeutic option for PVR prevention.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e MTX is a folic acid antagonist that inhibits DNA synthesis and repair, thereby suppressing cellular proliferation. It exerts potent antiproliferative and anti-inflammatory effects and has been widely used in the treatment of autoimmune diseases, transplant rejection, and malignancies.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In ophthalmology, MTX has been used for decades in the management of non-infectious uveitis and intraocular lymphoma. Intravitreal administration is considered safe at currently employed doses, as it minimizes systemic exposure and is generally associated with few and manageable adverse effects.\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNevertheless, evidence regarding the role of MTX as an adjunctive therapy for PVR remains conflicting. While some studies have reported favorable anatomic and functional outcomes, others have failed to demonstrate a significant benefit. It has been hypothesized that negative results may be related to undertreatment, including the use of lower doses, a limited number of injections, or insufficient treatment duration. .\u003csup\u003e12 13\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe fibrotic response characteristic of PVR typically develops during the first 12 postoperative weeks, a critical period marked by cellular activation, migration, cytokine release, and extracellular matrix deposition.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Because a single intravitreal MTX injection does not provide sustained pharmacologic coverage throughout this interval\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, repeated dosing has been proposed as a strategy to maintain therapeutic activity during the entire window of risk. Clinical studies employing biweekly dosing schedules have reported improved anatomic success rates compared with single-dose protocols.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBased on this rationale, the present study aimed to evaluate whether sustained intravitreal MTX exposure throughout the critical postoperative period could improve surgical outcomes in complex RRD. We administered MTX at a dose of 400 \u0026micro;g/0.1 mL every two weeks for up to 12 weeks following surgery. The primary objective was to assess single-surgery anatomic success (SSAS) at 12 weeks in patients with complex RRD undergoing PPV with intraoperative and serial postoperative MTX injections. Secondary outcomes included final retinal reattachment rates and visual function.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study was conducted based on data extracted from electronic medical records. The study protocol was approved by the institutional Data Review Committee, and all procedures adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to inclusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe included patients who underwent PPV for RRD between February 2020 and April 2025. Cases were classified as complex retinal detachment if at least one of the following criteria was present: PVR grade C, recurrent retinal detachment due to PVR, or retinal detachment associated with penetrating ocular trauma.\u003c/p\u003e\n\u003cp\u003eAdditional inclusion criteria were completion of at least seven intravitreal MTX injections according to the study protocol and a minimum postoperative follow-up of 12 weeks. Eyes with incomplete follow-up or fewer than seven MTX administrations were excluded.\u003c/p\u003e\n\u003cp\u003eAll patients were examined and operated on by the same vitreoretinal surgeon (L.V.B.S.) at a single tertiary referral eye care center (Hospital de Refer\u0026ecirc;ncia Oftalmol\u0026oacute;gica, HRO). PVR severity was classified according to the modified Retina Society Classification (1991).\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eCollected data included demographic information, preoperative ocular history, surgical details, and postoperative findings. Best-corrected visual acuity (BCVA) was measured preoperatively and postoperatively using a Snellen chart and subsequently converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analysis. Postoperative evaluation included optical coherence tomography (OCT) in all cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgical Procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll surgeries were performed using a 25-gauge Constellation Vision System (Alcon Laboratories Inc., Fort Worth, TX, USA). In phakic eyes, combined phacoemulsification with intraocular lens implantation was performed during the same surgical session.\u003c/p\u003e\n\u003cp\u003eA standard bimanual pars plana vitrectomy with scleral depression was carried out to achieve meticulous vitreous base shaving, including removal of the anterior vitreous. Endolaser photocoagulation was applied to all identified retinal breaks. Scleral buckle placement (model S2971, style #42; Labtician Ophthalmics) was performed at the surgeon\u0026rsquo;s discretion in cases exhibiting significant anterior retinal shortening.\u003c/p\u003e\n\u003cp\u003eIntraoperative dyes were used to facilitate tissue visualization: triamcinolone acetonide for identification of the posterior hyaloid, brilliant blue G for visualization of the internal limiting membrane (ILM), and trypan blue for staining of preretinal membranes associated with PVR. When ILM striae were observed, macular peeling was performed, extending to the vascular arcades. In cases of preretinal membranes located in the mid-periphery or peripheral retina, membrane peeling was carried out using 27-gauge forceps.\u003c/p\u003e\n\u003cp\u003ePerfluorocarbon liquid (PFCL) was used intraoperatively to assist retinal flattening. If retinal contraction persisted despite membrane removal and PFCL infusion, intraoperative retinectomy was performed using endodiathermy and scissors. Following retinal reattachment under PFCL, a fluid-gas exchange was performed, and a final internal tamponade was achieved with silicone oil (Oxane 5700; Bausch \u0026amp; Lomb).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethotrexate Protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the conclusion of surgery, methotrexate (Tevametho 50 mg/2 mL; Teva Farmac\u0026ecirc;utica) was injected into the silicone oil tamponade at a dose of 400 \u0026micro;g/0.1 mL. Additional intravitreal MTX injections at the same dose were administered every two weeks until the 12th postoperative week, for a total of seven doses, provided no contraindications emerged during follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were initially analyzed using descriptive statistics. Categorical variables were summarized as absolute and relative frequencies, while continuous variables were expressed as means, standard deviations, medians, and interquartile ranges, as appropriate.\u003c/p\u003e\n\u003cp\u003eAssociations between categorical variables were evaluated using Fisher\u0026rsquo;s exact test. Linear mixed-effects regression models were employed to assess the effects of diagnosis and intraoperative retinectomy on changes in visual acuity over time. When statistically significant differences were identified, \u003cem\u003epost hoc\u003c/em\u003e comparisons were performed using Wald tests with Bonferroni correction.\u003c/p\u003e\n\u003cp\u003eThe assumption of normality for continuous variables was assessed using the Kolmogorov\u0026ndash;Smirnov test. A two-sided significance level of 5% was adopted for all analyses. Statistical analyses were performed using SPSS software version 20.0 (IBM Corp., Armonk, NY, USA) and Stata software version 18 (StataCorp LLC, College Station, TX, USA).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 49 eyes from 49 patients were included in the analysis. The mean patient age was 58.5\u0026nbsp;\u0026plusmn;\u0026nbsp;13.6 years. Demographic and baseline ocular characteristics are summarized in Table 1. Overall, 32 patients (65.3%) were male, and 34 eyes (69.4%) presented with PVR grade C. Recurrent retinal detachment due to PVR was observed in 9 eyes (18.4%), and 6 eyes (12.2%) were associated with penetrating ocular trauma. Intraoperative retinectomy was performed in 8 eyes (16.3%). The mean follow-up duration was 14.7\u0026nbsp;\u0026plusmn;\u0026nbsp;10.8 months.\u003c/p\u003e\n\u003cp\u003ePars plana vitrectomy was combined with scleral buckling in 38 cases (77.5%). All eyes received silicone oil tamponade (5000 cSt), with no evidence of silicone oil\u0026ndash;related inflammation or toxicity. The first intravitreal MTX injection (400 \u0026micro;g/0.1 mL) was administered intraoperatively immediately after silicone oil placement, followed by biweekly injections until the 12th postoperative week, for a total of seven doses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnatomic Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint, SSAS, defined as retinal reattachment at 12 weeks without evidence of fibrotic membrane formation (Figure 1a\u0026ndash;1c), was achieved in 42 of 49 eyes (85.7%). Seven eyes required additional surgical intervention for peeling of contractile membranes, resulting in a final anatomic reattachment rate of 93.8%. Three eyes exhibited persistent localized PVR without macular involvement despite reoperation.\u003c/p\u003e\n\u003cp\u003eThe distribution of SSAS according to diagnosis and intraoperative retinectomy status is shown in Table 2. No statistically significant association was found between SSAS and diagnostic category (\u003cem\u003ep\u003c/em\u003e = 0.355) or between SSAS and performance of intraoperative retinectomy (\u003cem\u003ep\u003c/em\u003e = 0.581).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVisual Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, mean best-corrected visual acuity (BCVA) improved significantly at 3 months postoperatively (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), from 2.52\u0026nbsp;\u0026plusmn;\u0026nbsp;0.58 logMAR (approximate Snellen equivalent 20/8000) preoperatively to 1.23\u0026nbsp;\u0026plusmn;\u0026nbsp;0.84 logMAR (approximate Snellen equivalent 20/350). Mean BCVA values and corresponding 95% confidence intervals over time are illustrated in Chart 1, with subgroup analysis by diagnosis shown in Chart 2.\u003c/p\u003e\n\u003cp\u003eEyes undergoing intraoperative retinectomy achieved 100% SSAS. However, these cases demonstrated a trend toward poorer functional recovery, with a final mean BCVA of 1.74 logMAR (approximate Snellen equivalent 20/1200), as depicted in Chart 3. Visual acuity improved in 45 of 49 eyes and remained stable in the remaining cases. Detailed visual acuity changes stratified by diagnosis and retinectomy status are provided in Appendix 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntraocular Pressure and Postoperative Complications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean intraocular pressure (IOP) during follow-up was 15.5 mmHg (median, 16.7 mmHg). One patient developed sustained IOP elevation beginning in the second postoperative month, which was refractory to topical hypotensive therapy. This patient subsequently underwent silicone oil removal combined with glaucoma valve implantation three months after the initial surgery. Postoperative hypotony, defined as an IOP below 6 mmHg, was observed in three eyes (6.1%). All hypotonic eyes maintained anatomic retinal attachment and did not develop subsequent PVR.\u003c/p\u003e\n\u003cp\u003eEpiretinal membrane formation was observed in six eyes (12.2%), with only one case associated with foveal distortion requiring secondary membrane peeling. Cystoid macular edema occurred in three eyes (6.1%) and resolved with topical anti-inflammatory therapy, without the need for intravitreal corticosteroid injections. The distribution of postoperative complications is summarized in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConjunctival hyperemia was observed in all patients during the postoperative period and resolved after completion of the MTX injection protocol. One patient experienced significant discomfort during the fourth-week injection and elected to discontinue treatment (Figure 2a\u0026ndash;2d). A single case of corneal epithelial defect occurred during the third postoperative week and resolved with therapeutic contact lens placement, without interruption of subsequent MTX administrations. No severe ocular or systemic adverse events related to methotrexate were observed during the follow-up period.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo our knowledge, this study represents the largest retrospective single-arm cohort evaluating adjunctive serial intravitreal MTX (400 \u0026micro;g/0.1 mL) administered throughout the entire critical postoperative period in the surgical management of complex rhegmatogenous retinal detachment. The present findings demonstrate a favorable safety profile and were associated with high anatomic success rates and meaningful functional improvement.\u003c/p\u003e \u003cp\u003eEyes with retinal detachment complicated by PVR grade C or associated penetrating ocular trauma are known to have a poor prognosis and a high risk of postoperative redetachment, with reattachment rates ranging from 17% to 63%. In our cohort, serial MTX administration resulted in a SSAS rate of 85.7% and a final retinal reattachment rate of 93.8%. The rationale for sustained MTX exposure is supported by the treatment protocol used in this study, which combined intraoperative administration with biweekly injections up to the 12th postoperative week. This approach was designed to provide pharmacologic coverage during the period most susceptible to fibrocellular proliferation. Our results are consistent with those reported by Ullah et al., who achieved an SSAS rate of 79% using serial MTX injections during the postoperative period\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In contrast, El Baha et al. did not demonstrate a significant benefit of MTX in eyes with PVR grade C when the drug was administered as a single intraoperative dose, reporting SSAS rates of 87% in the control group and 74% in the MTX group\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. These differences support the concept that treatment duration and dosing strategy may be critical determinants of therapeutic effect.\u003c/p\u003e \u003cp\u003eAcross the cohort, serial intravitreal MTX was associated with stable postoperative retinal architecture. All eyes undergoing intraoperative retinectomy achieved successful retinal reattachment, with well-demarcated laser scars and stable, non-contractile retinectomy margins. Importantly, no recurrent fibrotic membrane formation was observed along retinectomy edges. In addition, the overall incidence of postoperative epiretinal membrane formation was relatively low, supporting a sustained antiproliferative and anti-inflammatory effect of serial MTX exposure, as reflected in our anatomic outcomes.\u003c/p\u003e \u003cp\u003eAlthough retinectomy was associated with universal anatomic success in this series, it correlated with poorer functional outcomes. This finding is consistent with previous reports indicating that extensive peripheral retinal excision, while effective in relieving traction, may compromise final visual acuity despite successful retinal reattachment. Nevertheless, overall visual function improved significantly in the study population, reinforcing the functional relevance of the anatomic stability achieved with this protocol.\u003c/p\u003e \u003cp\u003ePrior studies have also reported functional benefits with postoperative MTX use. Gibson et al. observed improved visual acuity following MTX administration. However, most patients in their cohort had proliferative diabetic retinopathy, and only a minority had PVR associated with complex rhegmatogenous retinal detachment. Furthermore, MTX dosing and treatment duration were not standardized, ranging from 200 to 400 \u0026micro;g and from 6 to 16 weeks, respectively.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e These differences limit direct comparison and underscore the importance of a standardized, protocol-driven approach such as that employed in the present study.\u003c/p\u003e \u003cp\u003ePostoperative hypotony is a recognized complication of complex retinal detachment surgery, with reported incidences ranging from 8% to 40% and an association with poor visual outcomes. In the present cohort, hypotony occurred in only 6.1% of eyes. By inhibiting intraocular cellular proliferation, MTX may reduce the formation of contractile membranes at the level of the ciliary body, potentially contributing to this lower incidence. This observation contrasts with findings reported by Ullah et al., who noted a higher rate of postoperative epiretinal membrane formation when using a lower MTX dose of 200 \u0026micro;g/0.1 mL\u003csup\u003e16\u003c/sup\u003e, further supporting the relevance of dose selection.\u003c/p\u003e \u003cp\u003eFrom a safety standpoint, serial intravitreal MTX was well tolerated. The most frequent adverse event was conjunctival hyperemia related to ocular surface irritation, which was mild, manageable with topical therapy, and resolved after completion of the injection cycle. A single corneal epithelial defect resolved without interruption of treatment. No clinical evidence of posterior segment toxicity was observed, consistent with the established ocular safety profile of MTX.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral limitations must be acknowledged, including the retrospective, non-randomized design, the absence of a control group, and the heterogeneous nature of the cohort, which included both PVR grade C and penetrating ocular trauma cases that may involve distinct inflammatory mechanisms.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e In addition, postoperative assessments were unblinded and performed by a single surgeon, which may introduce bias. These limitations preclude definitive causal inference.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eSerial intravitreal methotrexate administered during the critical postoperative period was safe and associated with high anatomic success and significant functional improvement in complex rhegmatogenous retinal detachment. The low incidence of recurrent PVR and epiretinal membrane formation supports a sustained antiproliferative and anti-inflammatory effect. Although retinectomy improved anatomic outcomes, it was associated with poorer final visual acuity. Collectively, these findings support serial MTX at a dose of 400 \u0026micro;g/0.1 mL as a promising adjunctive strategy for reducing postoperative PVR and retinal redetachment, while reinforcing the need for prospective randomized controlled trials to validate these results.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eBCVA\u003c/strong\u003e \u0026ndash; Best-corrected visual acuity\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e \u0026ndash; Confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eILM\u003c/strong\u003e \u0026ndash; Internal limiting membrane\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIOP\u003c/strong\u003e \u0026ndash; Intraocular pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIQR\u003c/strong\u003e \u0026ndash; Interquartile range\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003elogMAR\u003c/strong\u003e \u0026ndash; Logarithm of the minimum angle of resolution\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMTX\u003c/strong\u003e \u0026ndash; Methotrexate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOCT\u003c/strong\u003e \u0026ndash; Optical coherence tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePFCL\u003c/strong\u003e \u0026ndash; Perfluorocarbon liquid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePO\u003c/strong\u003e \u0026ndash; Postoperative\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePPV\u003c/strong\u003e \u0026ndash; Pars plana vitrectomy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePVR\u003c/strong\u003e \u0026ndash; Proliferative vitreoretinopathy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRRD\u003c/strong\u003e \u0026ndash; Rhegmatogenous retinal detachment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSSAS\u003c/strong\u003e \u0026ndash; Single-surgery anatomic success\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to the principles outlined in the Declaration of Helsinki and it was approved by the Ethics Committee of Hospital S\u0026atilde;o Domingos. Written informed consent was obtained from all participants prior to enrollment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from all participants prior to enrollment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u0026rsquo;\u0026nbsp;\u003cstrong\u003eContribution\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLVBS: conception, design, validation, analysis, and interpreted the data; performed surgery on the patients included in the study and drafted the manuscript; approved the submitted version.\u003c/p\u003e\n\u003cp\u003eTNOR: analysis, and interpreted the data; approved the submitted version.\u003c/p\u003e\n\u003cp\u003eMM: supervision and approved the submitted version.\u003c/p\u003e\n\u003cp\u003eWPC: review and edit the manuscript, supervision; approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePastor JC. Proliferative vitreoretinopathy. Surv Ophthalmol. 1998;43(1):3\u0026ndash;18.\u003c/li\u003e\n\u003cli\u003eCharteris D, Sethi C, Lewis G, Fisher S. Proliferative vitreoretinopathy: developments in adjunctive treatment and retinal pathology. Eye (Lond). 2002;16(4):369\u0026ndash;374.\u003c/li\u003e\n\u003cli\u003eGhasemi Falavarjani K, Hashemi M, Modarres M, Hadavand Khani A. Intrasilicone oil injection of bevacizumab at the end of retinal reattachment surgery for severe proliferative vitreoretinopathy. Eye (Lond). 2014;28(5):576\u0026ndash;580.\u003c/li\u003e\n\u003cli\u003eFekrat S, de Juan E Jr, Campochiaro PA. The effect of oral 13-cis-retinoic acid on retinal redetachment after surgical repair in eyes with proliferative vitreoretinopathy. Ophthalmology. 1995;102(3):412\u0026ndash;418.\u003c/li\u003e\n\u003cli\u003eLemor M, Yeo JH, Glaser BM. Oral colchicine for the treatment of experimental traction retinal detachment. Arch Ophthalmol. 1986;104(8):1226\u0026ndash;1229.\u003c/li\u003e\n\u003cli\u003eGiuliari GP, Sadaka A. Proliferative vitreoretinopathy: current and emerging treatments. Clin Ophthalmol. 2012;6:1325\u0026ndash;1333.\u003c/li\u003e\n\u003cli\u003eSadaka A, Sisk RA, Osher JM, Toygar O, Duncan MK, Riemann CD. Intravitreal methotrexate infusion for proliferative vitreoretinopathy. Clin Ophthalmol. 2016;10:1811\u0026ndash;1817.\u003c/li\u003e\n\u003cli\u003eAbdi F, Mohammadi S, Ghasemi Falavarjani K. Intravitreal methotrexate. J Ophthalmic Vis Res. 2021;16(2):260\u0026ndash;267.\u003c/li\u003e\n\u003cli\u003eMitry D, Awan MA, Borooah S, Siddiqui MAR, Brogan K, Fleck BW, et al. Surgical outcome and risk stratification for primary retinal detachment repair. Br J Ophthalmol. 2012;96(5):730\u0026ndash;734.\u003c/li\u003e\n\u003cli\u003eManna S, Banerjee R, Augsburger JJ, Al-Rjoub M, Donnell A, Correa ZM. Sustained-release methotrexate intraocular implant: pharmacokinetics and toxicity in rabbit eyes. Graefes Arch Clin Exp Ophthalmol. 2015;253(8):1297\u0026ndash;1305.\u003c/li\u003e\n\u003cli\u003eAziz JH, Zaki MA, El-Shazly AAEF, Mamoun T, Helmy ROA, Hashem MH. Intravitreal methotrexate infusion for prophylaxis of proliferative vitreoretinopathy after pars plana vitrectomy. Med Hypothesis Discov Innov Ophthalmol. 2022;11(3):95\u0026ndash;103.\u003c/li\u003e\n\u003cli\u003eAmarnani D, Machuca-Parra AI, Wong LL, Marko CK, Stefater JA, Stryjewski TP, et al. Effect of methotrexate on an in vitro patient-derived model of proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2017;58(10):3940\u0026ndash;3947.\u003c/li\u003e\n\u003cli\u003ePalakurthi NK, Krishnamoorthy M, Augsburger JJ, Correa ZM, Banerjee RK. Kinetics of methotrexate for therapeutic treatment of intraocular lymphoma. Curr Eye Res. 2010;35(12):1105\u0026ndash;1115.\u003c/li\u003e\n\u003cli\u003eTakkar B, Temkar S, Gaur N, Venkatesh P, Chawla R, Kumar A. Retinal shortening: ultrasonic evaluation of proliferative vitreoretinopathy. Indian J Ophthalmol. 2017;65(11):1172.\u003c/li\u003e\n\u003cli\u003eBenner JD, Dao D, Butler JW, Hamill KI. Intravitreal methotrexate for proliferative vitreoretinopathy. BMJ Open Ophthalmol. 2019;4(1):e000293. doi:10.1136/bmjophth-2019-000293.\u003c/li\u003e\n\u003cli\u003eUllah A, Toth CA, Burnett HW, Butler JW, Levy JH, Benner JD. Low-dose intravitreal methotrexate for proliferative vitreoretinopathy. Ophthalmol Retina. 2023;7(3):282\u0026ndash;288. \u003c/li\u003e\n\u003cli\u003eMachemer R, Aaberg TM, Freeman HM, et al. An updated classification of retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol. 1991;112(2):159\u0026ndash;165.\u003c/li\u003e\n\u003cli\u003eEl Baha S, Leila M, Amr A, Lolah MMA. Outcomes of vitrectomy with or without intravitreal methotrexate for proliferative vitreoretinopathy. J Ophthalmol. 2021;2021:3648134. doi:10.1155/2021/3648134.\u003c/li\u003e\n\u003cli\u003eGibson L, Nguyen A, Ridgeway J, Omar M, Purvis C, Shihab Y, et al. Postoperative methotrexate to reduce reoperation rate and improve vision. Ophthalmol Retina. 2019;3(9):869\u0026ndash;876.\u003c/li\u003e\n\u003cli\u003eJin Y. Traumatic proliferative vitreoretinopathy: clinical and histopathological observations. Ophthalmology. 2000;107(2):269\u0026ndash;276. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Demographic and ocular characteristics of the study population\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"285\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%) or Mean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e17 (34.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e32 (65.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e58.5 \u0026plusmn; 13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e60.0 (50.5\u0026ndash;66.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003ePVR grade C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e34 (69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eRe-detachment due to PVR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e9 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003ePenetrating ocular trauma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e6 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntraoperative retinectomy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e41 (83.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e8 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up time (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e14.7 \u0026plusmn; 10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e12.4 (5.1\u0026ndash;22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e PVR, proliferative vitreoretinopathy; IQR, interquartile range (P25\u0026ndash;P75).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Single-surgery anatomic success according to diagnosis and retinectomy\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"290\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSSAS \u0026ndash; No n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSSAS \u0026ndash; Yes n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e7/49 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e42/49 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0.355\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003ePVR grade C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e4/34 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e30/34 (88.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eRe-detachment due to PVR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e1/9 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e8/9 (88.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003ePenetrating ocular trauma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2/6 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e4/6 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntraoperative retinectomy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0.581\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e7/41 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e34/41 (82.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e0/8 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e8/8 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003ep\u003c/em\u003e values obtained using Fisher\u0026rsquo;s exact test.\u003cbr\u003e \u003cstrong\u003eAbbreviation:\u003c/strong\u003e SSAS, single-surgery anatomic success.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Postoperative complications and ocular surface findings\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"290\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 230px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpiretinal membrane\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e43 (87.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e6 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCystoid macular edema\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e46 (93.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypotony\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e46 (93.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCorneal changes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eEpithelial defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eConjunctival hyperemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 185px;\"\u003e\n \u003cp\u003e49 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Charts","content":"\u003cp\u003eCharts 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"proliferative vitreoretinopathy, rhegmatogenous retinal detachment, intravitreal methotrexate, pars plana vitrectomy, retinal reattachment, retinectomy","lastPublishedDoi":"10.21203/rs.3.rs-8933234/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8933234/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eProliferative vitreoretinopathy (PVR) remains the leading cause of surgical failure after rhegmatogenous retinal detachment (RRD) repair. Methotrexate (MTX) has emerged as a potential antiproliferative adjunct, but evidence is limited. This study evaluated the safety and efficacy of serial intravitreal MTX injections administered throughout the critical postoperative period to prevent the onset of PVR-related redetachment in complex RRD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 49 eyes undergoing pars plana vitrectomy (PPV) for complex RRD, defined as PVR grade C, recurrent retinal detachment, or detachment associated with penetrating ocular trauma. All eyes received an intraoperative intravitreal MTX injection (400 \u0026micro;g/0.1 mL), followed by biweekly injections for up to 12 postoperative weeks. The primary outcome was single-surgery anatomic success (SSAS) at 12 weeks. Secondary outcomes included final retinal reattachment rate, changes in best-corrected visual acuity (BCVA), and safety outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSSAS at 12 weeks was achieved in 85.7% of eyes. After reoperation in selected cases, the final retinal reattachment rate was 93.8%. Mean BCVA improved significantly by 1.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52 logMAR units at 3 months (95% CI, 1.05\u0026ndash;1.53; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The most frequent adverse event was conjunctival hyperemia, which resolved after completion of the MTX protocol. No severe ocular or systemic MTX-related adverse events were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSerial intravitreal MTX injections administered throughout the critical postoperative period demonstrated a favorable safety profile and were associated with high anatomic success rates and meaningful visual improvement in complex RRD.\u003c/p\u003e","manuscriptTitle":"Prevention of Postoperative Proliferative Vitreoretinopathy in Complex Retinal Detachments with Serial Intravitreal Methotrexate Injections","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 17:28:31","doi":"10.21203/rs.3.rs-8933234/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-22T03:33:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T14:29:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-08T18:24:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-08T06:26:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80977854873073708994297811240827896403","date":"2026-03-02T17:56:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"288414735502192713219450549095587420218","date":"2026-03-02T13:10:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271325832305611817908115149646926913740","date":"2026-03-02T11:42:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-02T10:24:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-02T03:14:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-01T19:16:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Retina and Vitreous","date":"2026-02-21T11:45:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9106429a-da92-4b89-ae3a-12b8cfba6c61","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-12T02:23:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 17:28:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8933234","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8933234","identity":"rs-8933234","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}