is related to the limited number of eyes analyzed by each study.1–3 Nevertheless, we feel that this topic is extremely important. In particular, the identification of a partial inner retinal sparing in the atrophic age-related macular degeneration subform can open the road to new therapeutic approaches: on the one hand diminishing the degenerative processes, and on the other leading to a potentially separate rehabilitative pathway. Further studies are warranted to ascertain the effects of current anti–vascular endothelial growth factor therapies on the inner retina layers. In essence, the long-neglected inner retina deserves to be thoroughly investigated even in age-related macular degeneration in an attempt to find new therapeutic options. ILARIA ZUCCHIATTI MAURIZIO BATTAGLIA PARODI LUISA PIERRO MARIA VITTORIA CICINELLI MARCO GAGLIARDI ` CASTELLINO NICCOLO FRANCESCO BANDELLO



1. Zucchiatti I, Parodi MB, Pierro L, et al. Macular ganglion cell complex and retinal nerve fiber layer comparison in different stages of age-related macular degeneration. Am J Ophthalmol 2015;160(3):602–607. 2. Lee HJ, Kim MS, Jo YJ, Kim JY. Ganglion cell-inner plexiform layer thickness in retinal diseases: repeatability study of spectral-domain optical coherence tomography. Am J Ophthalmol 2015;160(2):283–289. 3. Lee EK, Yu HG. Ganglion cell-inner plexiform layer and peripapillary retinal nerve fiber layer thicknesses in age-related macular degeneration. Invest Ophthalmol Vis Sci 2015;56(6):3976–3983.

Pro-permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; The Ozurdex for Retinal Vein Occlusion (ORVO) Study EDITOR: WE READ WITH GREAT INTEREST THE EXCELLENTLY ILLUS-

trated and comprehensive article by Campochiaro and associates,1 which correlated aqueous vasoactive protein changes with macular edema after dexamethasone implant in retinal vein occlusion (RVO). The authors explained the poor visual results of the RETAIN study2 (ie, unresolved macular edema observed after 4 years of anti– vascular endothelial growth factor [VEGF] injections, VOL. 161

with active disease in 50% of branch retinal vein occlusion [BRVO] patients and in 56% of the central retinal vein occlusion [CRVO] patients) by evolution or changes in the underlying disease process over time, indicating that propermeability factors other than VEGF may play a more important role. Of course, the vasoactive proteins detected in the aqueous1 might contribute to the pathogenesis of macular edema; however, other factors should be specifically considered and accounted for. The patients with RVO were eligible for the RETAIN study2 if they completed the BRAVO3 and CRUISE4 trials and had subsequent follow-up in the HORIZON study.5 The worsening of the visual function of the patients in the RETAIN study2 may have been caused by the reduced frequency of injections as well as the 2 periods of time during which the patients went without treatment. The first period occurred prior to the initiation of the BRAVO3 and CRUISE4 trials; that is, the BRVO and CRVO diagnoses were made within 12 months (mean 3.3 months) before study initiation, when VEGF was maximally expressed with subsequent progression of the ocular disease. The second period was the time elapsed from HORIZON study5 exit to entry in the RETAIN study2 (mean 92.7 days). These facts favored the delayed occurrence of a permanent retinal capillaropathy (eg, pigmentary changes in the fovea, poorly controlled severe recurrent macular edema, telangiectatic vessels with leakage, and epiretinal membrane formation). However, the condition is incurable owing to the ischemic and irreversible damage to the macular ganglion cell complex (consisting of a retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer), close to the foveola, with macular edema being a minor factor. The pro-permeability factors mentioned by Campochiaro and associates1 are maximally expressed in the ischemic lesions. These factors in turn amplify, through a vicious circle, the deterioration primarily caused by VEGF in the initially damaged macular ganglion cell complex. In 2015, we published a prospective clinical study6 on the 3-year outcomes of bevacizumab treatment at a dose _1 month of 2.5 mg per injection in patients with acute (< after the occlusion was diagnosed) central/hemicentral RVOs. Of these patients, 50% had ischemic central/hemicentral RVOs. The results of this study were the first evidence suggesting that early treatment, administered immediately after clinical onset of the venous occlusion, provides significant and sustained improvements in visual acuity and foveal thickness with inactive disease (dry retina and stable visual acuity for at least 6 months after the last injection) in most phakic patients with acute central/hemicentral RVOs. Therefore, this treatment option is a rational and viable therapeutic strategy. The sooner the treatment is started after RVO onset, the sooner the patient is likely to have gains in visual acuity and foveal thickness. Any delay in initiating therapy will adversely affect the restoration of visual functions, which are difficult to recover even with subsequent treatment.




Cluj-Napoca, Romania FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. Financial Disclosures: The following authors have no financial disclosures: Dan Calugaru, Mihai Calugaru. All authors attest that they meet the current ICMJE criteria for authorship.


1. Campochiaro PA, Hafiz G, Mir TA, et al. Pro-permeability factors after dexamethasone implant in retinal vein occlusion; the ozurdex for retinal vein occlusion (ORVO) study. Am J Ophthalmol 2015;160(2):313–321. 2. Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab. The RETAIN study. Ophthalmology 2014;121(1):209–219. 3. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology 2011;118(8):1594–1602. 4. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118(10):2041–2049. 5. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions. Long-term follow-up in the HORIZON trial. Ophthalmology 2012;119(4):802–809. 6. Calugaru D, Calugaru M. Intravitreal bevacizumab in acute central/hemicentral retinal vein occlusions: three-year results of a prospective clinical study. J Ocul Pharmacol Ther 2015;31(2):78–86.


RETAIN study,1 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 Calugaru 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 Calugarus (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 216

who had edema resolution and no longer needed injections1), we agree that delay in onset or lapses in antiVEGF treatment may contribute to progression of retinal nonperfusion, worsening of ischemia, and increased production of VEGF in patients with RVO.2 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 antiVEGF 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 Calugarus 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.



Baltimore, Maryland JANUARY 2016

Pro-permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; The Ozurdex for Retinal Vein Occlusion (ORVO) Study.

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