In the introduction of our manuscript, we cited the RETAIN study, which showed that with a mean follow-up of 49 months after the initiation of anti–vascular endothelial growth factor (VEGF) treatment, only 50% of branch retinal vein occlusion (BRVO) patients and 44% of central retinal vein occlusion (CRVO) patients no longer required injections to control edema. We also noted that in many patients, injections of a VEGF antagonist seemed less effective over time, suggesting evolution or change in the disease process such that other pro-permeability factors may play a more important role. Drs Dan and Mihai Călugăru refer to these observations as poor visual outcome, and suggest that they may occur from delays in the onset and/or lapses in anti-VEGF treatment that could lead to permanent damage and a vicious cycle.

While we do not agree with all terminology used by the Călugărus (for instance, the need for continued treatment should not be equated with a poor visual outcome, because the mean final vision was 20/32 in BRVO patients who were still requiring anti-VEGF injections after 4 or more years of treatment, the same as that in BRVO patients who had edema resolution and no longer needed injections ), we agree that delay in onset or lapses in anti-VEGF treatment may contribute to progression of retinal nonperfusion, worsening of ischemia, and increased production of VEGF in patients with RVO. Thus, we agree that it is prudent to initiate anti-VEGF treatment early and to avoid recurrent edema if possible. One way to try and achieve this is with a treat-and-extend protocol, and if the interval between treatments can be extended to more than 3–4 months, it is reasonable to try withholding an injection to determine if injections are no longer needed. However, there are some RVO patients who have recurrent edema despite prolonged monthly anti-VEGF injections. It is possible that such patients have such high levels of VEGF that the levels cannot be neutralized by monthly anti-VEGF injections, but an alternative possibility is that there are 1 or more other pro-permeability factors contributing to edema. Likewise, patients who seem to be less responsive to anti-VEGF injections over time may be experiencing increased production of VEGF or production of 1 or more other pro-permeability factors.

If the comments by the Călugărus are meant to suggest that VEGF is currently the only proven contributor to macular edema in patients with RVO, then we agree. However, if these comments are meant to suggest that it is absolutely clear that VEGF is the only contributor and it is pointless to search for other possible contributors, we disagree. Our study has demonstrated that some patients with RVO have elevated levels of other pro-permeability factors that are reduced in association with edema reduction after injection of a dexamethasone implant. Causality is not demonstrated by an association and we state that our study does not prove involvement of any factors, but rather identifies candidates for further investigation. Additional studies are needed to test whether these candidates or others contribute to macular edema in some RVO patients.