Blepharoptosis After Repeated Intravitreal Anti-VEGF Injections: A Prospective Study

Overview

Intravitreal anti-VEGF injections are a mainstay of treatment for retinal diseases such as neovascular age-related macular degeneration, diabetic macular edema and retinal vein occlusion, and usually require repeated administration over years. During each injection an eyelid speculum holds the lids open and the upper eyelid is exposed to repeated mechanical stretch. Aponeurotic ptosis after intraocular surgery is well described, but evidence on blepharoptosis after repeated intravitreal injections is limited and conflicting. This single-center prospective observational study enrolls 60 patients who are starting intravitreal anti-VEGF therapy in one eye only; the untreated fellow eye of each patient serves as an internal control. Upper eyelid position and function are assessed with margin reflex distance-1 (MRD-1), margin reflex distance-2 (MRD-2) and levator function at baseline and at months 1, 3, 6 and 12. The primary endpoint is the difference between the injected eye and the fellow eye in the change in MRD-1 from baseline to month 12.

Design: prospective, single-center, longitudinal, non-interventional observational study conducted in the Department of Ophthalmology, University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey. No study-driven intervention is performed. The decision to treat, the anti-VEGF agent (ranibizumab, aflibercept or bevacizumab), the injection interval and the total number of injections are determined solely by the treating retina specialist on clinical grounds. Injections are given under routine sterile conditions, topical anesthesia and with an eyelid speculum, as in standard practice; the study therefore evaluates the combined exposure of injection plus speculum use and cannot isolate the speculum-specific mechanical effect. The injected eye is the study eye and the non-injected fellow eye is the control eye; each participant serves as their own control. All participants are assessed at baseline and at months 1, 3, 6 and 12. At every visit, for both eyes, MRD-1, MRD-2 and levator function are measured by the same examiner where possible using a standard technique. MRD-1 is the distance in millimetres between the corneal light reflex and the upper eyelid margin in primary gaze; MRD-2 is the distance between the corneal light reflex and the lower eyelid margin; levator function is the upper eyelid excursion from downgaze to upgaze with frontalis action neutralised. The cumulative number of intravitreal injections, the agent used and the number of eyelid speculum uses are recorded at each visit. Clinically significant blepharoptosis is defined as an MRD-1 of 2 mm or less and/or a decrease of 2 mm or more from baseline, evaluated separately for each eye at every visit. Sample size: based on a paired comparison of the change in MRD-1. Using the 0.60 mm (SD 0.61) MRD-1 reduction at 12 months reported by Bermudez-Castellanos et al., and assuming a conservatively clinically meaningful difference of 0.50 mm with a standard deviation of paired differences of 1.00 mm (dz = 0.50), a two-sided alpha of 0.05 and 90% power require a minimum of 44 evaluable participants; allowing for approximately 25% attrition over 12 months, the target enrollment is 60. Statistical analysis: normality by the Shapiro-Wilk test; between-eye change compared by paired t-test or Wilcoxon signed-rank test; repeated measures across the five timepoints by repeated-measures ANOVA or the Friedman test; frequency of clinically significant blepharoptosis compared between eyes by the McNemar test; associations between the number of injections or speculum uses and the change in eyelid measurements by Pearson or Spearman correlation; a sensitivity analysis compares eyelid measurement change among anti-VEGF agents. Two-sided p \< 0.05 is considered significant. Analyses are performed in SPSS.