LAUSR

Dear Editor: We would like to address several challenges that have arisen from the study by Garweg et al. [1] which can be specifically summarized below. The first inclusion criterion for the patients in this series was the presence of choroidal neovascularization (CNV) confirmed angiographically, in the context of wet age-related macular degeneration (wAMD) requiring intravitreal therapy, as indicated by the loss of best-corrected visual acuity (BCVA) and the manifestation of intraretinal and subretinal fluid in optical coherence tomography. The wAMD patients were not investigated with regard to the possible presence of the following six angiographic subtypes of CNV, namely, the occult, minimally classic, predominantly classic, mixed CNV, the retinal angiomatous proliferation, and the polypoidal choroidal vasculopathy. The treatment would have had to be individualized according to the existing angiographic subtype [2]. Indocyanine green angiography should be a standard investigation for all patients with newly diagnosed wAMD, especially those with occult wAMD, to avoid missing this relevant subset. The final 10-year outcomes of this study were unsatisfactory. Specifically, the central retinal thickness (CRT) became much thinner (198 μm) than the normal CRT (315.2 μm) [3], and the BCVA decreased by 11.9 letters. These changes might be explained by development of the atrophic damages of the neurovascular maculopathy (scar formation and development of geographic atrophy) and/or by occurrence of the retinal angiomatous proliferation (vasogenic stage III), a distinct form of occult CNV associated with proliferation of intraretinal capillaries [4]. The fact that the loss of 11.9 letters occurred in wAMD patients after 10 years of treatment with a mean of 2.8 injections per year, while a loss by approximately seven letters appeared in patients after 4 years of treatment with a mean of 3.6 injections per year, suggesting insufficient treatment administered to patients. Therefore, a more intensive early treatment would have improved the long-term outcomes in this series. Most likely, there was a permanent vascular endothelial growth factor (VEGF) receptor 2-mediated breakdown of the inner blood-retinal barrier and a permanent VEGF receptor 1-mediated rupture of the retinal pigment epithelium junctions induced by long-term VEGF overexpression and high vitreous levels of placental growth factor in patients with wAMD. This permanent retinal capillaropathy caused by persistent subretinal or intraretinal fluid was temporarily relieved by reduction of edematous component with anti-angiogenic agents. However, the pathology was incurable because of irreversible ischemic changes to the macular ganglion cell complex, close to the foveola, with macular edema being a minor factor [5]. Importantly, the authors of this study did not consider the currently available recommendations [6] which stated that when early persistent retinal fluid was present, eyes treated with monthly aflibercept (Eylea, Regeneron Pharmaceuticals Inc., Tarrytown, NY) had better BCVA at week 52 than those treated with aflibercept less frequently or those treated with ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA). Moreover, a dry retina was more likely to be sustained in eyes treated with monthly aflibercept than in those treated with aflibercept every 2 months or ranibizumab every month. Conceivably, the design and the final outcomes of this study would have been different if the patients had been treated early after the exudative changes were detected with every 4-week anti-VEGF agent injections, instead of the presently employed regimens [7]. The comparison of the three treatment groups revealed that the patients in the combination group achieved the lowest loss of BCVA (approximately 10 letters) followed by those in the aflibercept and ranibizumab groups (approximately 12 and 14 * Mihai Călugăru [email protected]