Introduction: The aim of the study was to evaluate risk factors for recalcitrance to topical therapy of post-surgical macular edema (PSME) after rhegmatogenous retinal detachment (RRD) repair and its response to intravitreal dexamethasone implant (DEX-I). Methods: This two-center retrospective study reviewed the charts of pseudophakic patients who had undergone vitrectomy for RRD and experienced PSME within 6 months of surgery. A regression model analyzed the relationship between the recalcitrance of PSME to topical therapy and independent variables, including clinical data, surgical steps, and OCT parameters recorded at 1 month after surgery. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of eyes with responsive and recalcitrant PSME to topical therapy, the latest treated with DEX-I, were compared over follow-up. Results: Of the 361 eyes screened, 42 (11.7%) experienced PSME. Among those, all the eyes with recalcitrant PSME (21/42) received at least one DEX-I (1.38 ± 0.49 implant). The mean follow-up was 11.9 ± 0.3 months. Disrupted retinal outer layers (p = 0.02) and hyperreflective foci (HRF) (p = 0.01) were linked to recalcitrant PSME. An increased risk for recalcitrance was observed in the presence of HRF (OR: 7.69; IC: 1.31–44.9; p = 0.02). Over follow-up, BCVA and CMT were significantly (p < 0.01) worse in implanted eyes that experienced the more significant fluctuation of CMT (189.2 ± 104.7 µm (range: 58–409 µm); p < 0.01) with a reimplant rate of 42.8%. No one of the implanted eyes experienced ocular hypertension requiring intervention or other complications. Conclusion: HRF were found to be a risk factor for recalcitrance to topical therapy of PSME. Limited response to DEX-I was observed in such cases.

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