This study is a retrospective, multicenter, observational study of patients with RVO and ERM who underwent PPV and ERM peeling with or without cataract phacoemulsification between July 2012 and January 2021. Patients were included from the San Raffaele Scientific Institute (Milano, Italy), the Second Department of Ophthalmology, the University of Athens (Athens, Greece), the Ospedale Maggiore Policlinico (Milano, Italy), and the Lariboisière University Hospital, Université de Paris (Paris, France). The study adhered to the tenets of the Declaration of Helsinki (1964) and received the approval of the local institutional review boards.
The decision to pursue PPV and ERM removal was made on a personal basis, considering each patient's history of macular edema, response to previous intravitreal therapies, expectations, and compliance to visits and treatments. Overall, ERM peeling was performed in patients with RVO and history of macular edema with a suboptimal response to previous therapeutic strategies, non-improving visual acuity, or persistence/recurrence of macular thickening despite treatments. All the eyes had evident ERM on optical coherence tomography (OCT) scans encompassing the fovea and obliterating the foveal depression. Patients with retinal diseases other than RVO (e.g., age-related macular degeneration, diabetic retinopathy), those with RVO-related complications causing irreversible visual loss (e.g., retinal detachment or neovascular glaucoma), and those with a history of intraocular surgery except for uncomplicated phacoemulsification before ERM peeling were excluded.
Patients’ charts were reviewed at the time of ERM peeling (baseline) and 3, 6, 12, 24, and 36 months after surgery; a range of 2 months for each time point was allowed due to the study's retrospective nature. The following variables were recorded at baseline: age, gender, history of glaucoma, diabetes mellitus, and cardiovascular comorbidities (systemic hypertension, deep vein thrombosis, arterial occlusive disease), interval between RVO diagnosis and PPV, previous intravitreal treatments (both anti-vascular endothelial growth factor [VEGF] agents and dexamethasone [DEX] implants), and presence of macular edema. Regarding surgery, parameters collected included the date of the surgery, phacoemulsification at the time of PPV, induction of PVD, inner limiting membrane (ILM) peeling, tamponade agent at the end of PPV, and occurrence of peri- or postoperative complications. History of intravitreal injections after the surgical procedure was also recorded.
Best-corrected visual acuity (BCVA) values, measured on decimal charts, and spectral-domain OCT (SD-OCT, Spectralis HRA+OCT, Heidelberg, Germany) scans were recorded at each visit. The OCT software automatically calculated the central macular thickness (CMT). The SD-OCT scans were scrutinized by four trained graders (MVC, IC, MN, AS) for external limiting membrane (ELM)/ellipsoid zone (EZ) damage under the fovea (in case the two outer hyperreflective bands corresponding to the ELM and EZ were interrupted or absent) and the presence of disorganization of the retinal inner layers (DRIL), defined as the loss of clear tomographic boundaries between the four innermost retinal layers [13,14,15].
Statistical calculations were carried out with the open-source R programming language. Continuous variables were reported as the median and interquartile range (IQR) or mean ± standard deviation (SD), and categorical variables as frequency and proportions. The BCVA was converted into logMAR and used as a continuous variable; a value of 2.0 logMAR was given to counting fingers, and a value of 2.3 logMAR was given to hand motion .
As the primary outcome, the clinical factors associated with the longitudinal BCVA and CMT variation after ERM removal were investigated. For this purpose, linear mixed models with a repeated-measures design were used, in which the eye identification number was the random factor to account for multiple measures performed in the same eye, and the explored covariate was the main effect variable. The interaction between the visit and the main effect variable was included in each model. Regression estimates and 95% confidence intervals (CI) were computed. The estimated marginal means at different time points were compared with a Bonferroni correction. The analyses were repeated separately evaluating eyes with CRVO and BRVO.
For the secondary outcome, improvement in BCVA of at least one line (i.e., reduction in BCVA of 0.1 logMAR) and disappearance of macular edema on SD-OCT after ERM removal (i.e., OCT not showing any sign of intraretinal or subretinal fluid) were considered as events, and the date on which the event was first recorded in the patients’ charts was collected. Kaplan–Meier survival curves were plotted, and median survival time was estimated. Since improvement in BCVA of at least one line was recorded in 95% of eyes, risk factor analysis was not performed. On the other hand, the clinical factors associated with disappearance of macular edema on SD-OCT after ERM removal were investigated with univariable Cox proportional hazard models. For each variable, the hazard ratio (HR) and 95% CI were reported. The patients who presented without macular edema at the time of ERM removal were excluded from survival regression models.
As the tertiary outcome, the presence of macular edema, the need for and the number of intravitreal injections (either anti-VEGF or steroids), and the rate of ELM/EZ and DRIL on OCT were compared between before and after ERM removal between paired t test or chi-square tests.
The cutoff point for statistical significance was set at p < 0.05 (two-sided).