Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15–40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment (both thermal therapy for retinal vascular diseases and photodynamic therapy for eAMD), abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes.

A subset of patients do not have resolution of macular edema after treatment with intravitreal bevacizumab. Such patients may respond to treatment with an intravitreal dexamethasone implant.

Ahmed valve placement through the pars plana during vitrectomy is an effective option for managing complex cases of glaucoma without the use of the pars plana clip.

PurposeTo test the efficacy of the intravitreal dexamethasone (DEX) implant in patients with retinal vein occlusions (RVOs) who have failed multiple anti-vascular endothelial growth factor (anti-VEGF) treatments.MethodsA randomized exploratory study of ten patients with branch RVO or central RVO who received at least two previous anti-VEGF treatments and had persistent or unresponsive cystoid macular edema. Treatment with the DEX implant was either every 4 months or pro re nata (PRN) depending on their group assignment for 1 year. Multifocal electroretinography and microperimetry were the primary end points, with high-resolution optical coherence tomography and best-corrected visual acuity as the secondary end points.ResultsAll patients in both the every 4 month and PRN cohorts who completed the study received the three maximal injections of DEX; therefore, the data from both cohorts were combined and reported as a case series. On average, the multifocal electroretinography amplitude increased significantly from 5.11±0.66 to 24.19±5.30 nV/deg2 at 12 months (P<0.005), mean macular sensitivity increased from 7.67±2.10 to 8.01±1.98 dB at 4 months (P=0.32), best-corrected visual acuity increased significantly from 51.0±5.1 to 55.4±5.1 early treatment of diabetic retinopathy study letters at 2 months (P<0.05), and central retinal thickness decreased from 427.6±39.5 to 367.1±37.8 μm at 4 months (P<0.05). Intraocular pressure increased significantly in one patient, with that patient requiring an additional glaucoma medication for management. Additionally, cataract progression increased significantly (P<0.05) in this patient population and partially limited analysis of other end points.ConclusionDEX should be considered as a treatment option in patients with RVOs who have failed anti-VEGF therapy, as the results of this study demonstrated an improvement in retinal morphology and macular function. Cataract progression did occur following multiple consecutive injections; however, steroid-induced glaucoma was not a limiting factor.

PurposeTo assess whether combination therapy (CT) reduces retreatments when compared to ranibizumab monotherapy (RM), while safely maintaining similar vision outcomes.MethodsIn this 24-month trial, patients with age-related macular degeneration (AMD) were randomized to 1) quarter-fluence or 2) half-fluence triple therapy (verteporfin photodynamic therapy [vPDT] + ranibizumab + dexamethasone), 3) half-fluence double therapy (vPDT + ranibizumab), or 4) RM. The primary outcomes were number of retreatment visits and change from baseline in visual acuity (VA) at 12 months.ResultsOne hundred sixty-two subjects enrolled. There were 4.0 (P=0.02), 3.2 (P<0.001), 4.1 (P=0.03), and 5.7 retreatment visits through month 12, and 5.9 (P=0.03), 4.3 (P<0.001), 5.9 (P=0.02) and 8.7 through month 24, in groups 1, 2, 3, and 4, respectively (P-value comparing with RM). Month 12 VA score change from baseline (95% confidence interval) was +3.6 (−0.9 to +8.1), +6.8 (+2.4 to +11.1), +5.0 (+0.6 to +9.3), and +6.5 (+1.7 to +11.4), respectively.ConclusionCT resulted in significantly fewer retreatment visits than a RM regimen at months 12 and 24. VA results appeared similar although wide confidence intervals preclude conclusions regarding vision outcomes.