DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders.

This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and children (uveal melanoma and retinoblastoma, respectively). We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis. Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma. Loss of methylation of the oncogenic mir-17-92 cluster was detected in primary tissues but also in blood from patients.

DOME-SHAPED MACULA IN MYOPIC EYES: Twelve-Month Follow-up.

PURPOSE: To study the long-term clinical course of dome-shaped macula in myopic eyes and to evaluate treatment efficacy for subretinal fluid (SRF) as a related complication. METHODS: A retrospective, single-center consecutive case series study was conducted. The authors analyzed myopic eyes with dome-shaped macula in patients who presented for evaluation of decreased vision. Dome-shaped macula was defined as a convexity of the retina-choroidal macular complex seen on spectral domain optical coherence tomography images. All patients were followed for at least 12 months (mean, 25 months). Fluorescein angiography and/or indocyanine green angiography were performed in cases with SRF to rule out choroidal neovascularization. RESULTS: A total of 56 dome-shaped macula eyes from 36 patients were included in the study (bilateral in 55% of patients). Mean patient age was 56.9 ± 13.1 years. The mean spherical equivalent was -9.1 ± 6.0 diopters; 53% of eyes were considered highly myopic (>-6 diopters) and 47% of eyes were mildly myopic. In most cases (37 eyes; 66.1%), the dome-shaped macula was detected on vertical spectral domain optical coherence tomography scan patterns. No significant changes (P ≥ 0.1) were observed in mean best-corrected visual acuity or mean central foveal thickness from baseline to final follow-up. Subretinal fluid was present in 29 eyes (51.8%) at baseline, with no differences in best-corrected visual acuity in eyes with and without SRF (P ≥ 0.05). Nineteen of the 29 SRF eyes were treated: 8 underwent low-fluence photodynamic therapy, whereas 7 received bevacizumab, and 4 ranibizumab. No significant differences were found between treated and untreated SRF eyes in best-corrected visual acuity improvement (P ≥ 0.1), or complete resolution of SRF (P ≥ 0.1). Likewise, photodynamic therapy did not yield any significant benefit versus untreated eyes in best-corrected visual acuity or improvement of SRF. CONCLUSION: Dome-shaped macula is a condition associated with myopic eyes that seems to remain stable over time in terms of vision and macular profiles. It is often associated with chronic SRF, for which no effective treatment is current available. However, SRF does not seem to be a significant cause of visual impairment.

INCIDENCE AND RELATION WITH ANATOMICAL AND FUNCTIONAL VARIABLES OF POSTOPERATIVE MACULAR DISPLACEMENT IN RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To investigate the incidence of postsurgical retinal displacement in patients treated with pars plana vitrectomy for rhegmatogenous retinal detachment and to assess the influence of displacement on macular function. METHODS: Observational prospective study of 20 consecutive cases of rhegmatogenous retinal detachment who underwent 23-G pars plana vitrectomy with gas (C3F8 or SF6) tamponade, and prone resting. Three months after surgery, retinal displacement was evaluated by fundus autofluorescence. Macular function was evaluated with optical coherence tomography, multifocal electroretinogram, best-corrected visual acuity, and stereopsis. RESULTS: Postoperative retinal displacement was observed in 60% of cases. No correlation between the type of tamponade used and retinal displacement was observed. Similarly, no association between retinal displacement and postoperative stereopsis or visual acuity was found. A lower amplitude in P1 wave on the multifocal electroretinogram was observed in eyes with rhegmatogenous retinal detachment compared with the contralateral eye. However, no statistically significant differences between groups with or without retinal displacement were found. CONCLUSION: Retinal displacement in patients who undergo pars plana vitrectomy to treat rhegmatogenous retinal detachment is common. However, this displacement does not seem to affect macular function.

INTRAVITREAL DEXAMETHASONE IMPLANT FOR RADIATION MACULOPATHY SECONDARY TO PLAQUE BRACHYTHERAPY IN CHOROIDAL MELANOMA.

PURPOSE: To evaluate the efficacy of intravitreal dexamethasone implant 0.7 mg (Ozurdex) in radiation maculopathy secondary to plaque brachytherapy in choroidal melanoma. METHODS: Twelve eyes diagnosed of radiation maculopathy secondary to plaque brachytherapy and treated with intravitreal dexamethasone implant were included. Visual acuity, foveal thickness using spectral domain optical coherence tomography, and grade of macular edema, using Horgan classification, were evaluated. RESULTS: Mean age was 65.5 ± 28 years (range, 40-82 years). Mean follow-up was 8.2 ± 7.8 months (range, 2-28 months). Mean visual acuity before treatment was, in logarithm of the minimum angle of resolution scale, 1 ± 0.58 (range, 0.4-2) and mean final visual acuity 0.8 ± 0.58 (range, 0.2-2), showing a nonsignificant trend to improvement (P = 0.091; Wilcoxon's test). Foveal thickness before treatment was 416 ± 263 µm (range, 222-725 µm) and final foveal thickness 254 ± 170 µm (range, 145-750), showing a significant decrease (P = 0.016; Wilcoxon's test). Referring to Horgan classification, a significant reduction in grades before and after treatment was demonstrated (P = 0.007; Wilcoxon's test). CONCLUSION: Ozurdex is a useful treatment for radiation maculopathy associated to plaque brachytherapy for uveal melanoma, with a significant decrease in foveal thickness and a significant improvement in Horgan classification. This anatomical improvement was correlated with a moderate improvement in visual acuity.

Autofluorescence and axial length as prognostic factors for outcomes of macular hole retinal detachment surgery in high myopia.

PURPOSE: To evaluate the results of fundus autofluorescence and axial length as prognostic factors for surgical outcome of macular hole retinal detachment in high myopic patients. METHODS: This is a retrospective, interventional, nonrandomized study. Patients were treated with posterior vitrectomy, internal limiting membrane peeling, and silicone oil tamponade. Best-corrected visual acuity, axial length, fundus autofluorescence, and spectral domain optical coherence tomography images were obtained. RESULTS: Fifteen eyes from 15 patients (mean age, 69.4 years) were evaluated. The mean refractive error was -19 diopters, and the mean axial length was 29.9 mm. The mean best-corrected visual acuity (logMAR) improved from 2.17 to 1.42 (P = 0.02) after a mean follow-up of 19.3 months. Spectral domain optical coherence tomography scans showed retinal detachment resolution in 13 eyes (86.6%) and macular hole closure in 9 eyes (60%). Fundus autofluorescence showed macular hypoautofluorescence with foveal involvement (mean area of 9.7 mm2) in 10 eyes (66.6%). Postoperative best-corrected visual acuity was significantly worse in these eyes (P = 0.009). Axial length >30 mm was found in the 2 cases with recurrent retinal detachment and in 4 of the 6 cases without macular hole closure (66.6%). CONCLUSION: Macular hole retinal detachment in high myopic patients can be successfully treated with vitrectomy, internal limiting membrane peeling, and silicone oil. Axial length >30 mm and macular hypoautofluorescence with foveal involvement seem to be prognostic factors for a worse anatomical and visual outcome.

One-year results of a flexible regimen with ranibizumab therapy in macular degeneration: relationship with the number of injections.

PURPOSE: To evaluate the efficacy and safety of a flexible regimen with intravitreal injections of ranibizumab in patients with naive choroidal neovascularization secondary to age-related macular degeneration and to determine whether the final outcome is related to the number of injections. METHODS: Prospective, noncomparative, consecutive case series study. We included 90 eyes of 88 patients that were initially treated with 3 consecutive monthly intravitreal injections of ranibizumab, and thereafter, follow-up visits were progressively spread out to a maximum of 8 weeks apart in the absence of visual acuity loss and signs of lesion activity. The primary end points were changes in visual acuity (Early Treatment Diabetic Retinopathy Study letters), foveal thickness measured by spectral-domain optical coherence tomography, and lesion size (LS) measured by fluorescein angiography. RESULTS: The median visual acuity improved from 53 letters at baseline to 60 letters at Month 1 (P < 0.0001), 63 letters at Month 3 (P < 0.0001), and 60 letters at Month 12 (P < 0.0001). A significant reduction was also observed in foveal thickness and LS (P < 0.0001). The mean number of injections was 4.4, and the mean number of visits was 8.0. Treatment consisted of 3 injections for 40% of patients, and 60% of patients received more than 3 injections. No significant association was observed between the visual acuity improvement and the number of injections. No relevant side effects were observed. CONCLUSION: A flexible regimen with ranibizumab therapy is efficacious and safe in patients with neovascular age-related macular degeneration, reducing both the burden of injections and follow-up visits. The visual acuity improvement was independent of the number of injections.

Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy.

PURPOSE: The purpose of this study was to determine the efficacy and safety of intravitreal infliximab in the treatment of choroidal neovascularization secondary to age-related macular degeneration in patients who are nonresponders to antivascular endothelial growth factor therapy. METHODS: Prospective, noncomparative, interventional case series. The primary inclusion criteria for patients consisted of previous treatment with five or more intravitreal injections of bevacizumab and/or ranibizumab, visual loss, angiographic leakage, and intraretinal and/or subretinal fluid on spectral domain optical coherence tomography. At Day 0, a single intravitreal injection of infliximab (2 mg/0.05 mL) was administered. Best-corrected visual acuity testing measured with Early Treatment Diabetic Retinopathy Study charts and spectral domain optical coherence tomography scans were performed on Days 0, 3, 7, 30, 60, and 90. Fluorescein angiography was performed at days 0 and 90. The development of systemic antibodies against infliximab (human antichimeric antibodies) was not sought. Main outcome measures were changes in best-corrected visual acuity, foveal thickness, and lesion size. RESULTS: We included four patients. At Day 90, the best-corrected visual acuity change was -18, +3, +4, and -4 letters, respectively. Intraretinal and/or subretinal fluid on spectral domain optical coherence tomography scans was not significantly reduced in any case. Lesion size was not reduced in any case. Two patients developed intraocular inflammation with high intraocular pressure 3 and 5 weeks after the infliximab injection, respectively. One case was controlled with topical medication, and one case required posterior vitrectomy. CONCLUSION: Intravitreal infliximab showed no significant visual or anatomical benefit for the treatment of choroidal neovascularization secondary to age-related macular degeneration in patients who were nonresponders to antivascular endothelial growth factor therapy. In addition, half of the cases developed intraocular inflammation.