Efficacy and Safety of Intravitreal Aflibercept Treat and Extend for Polypoidal Choroidal Vasculopathy in the ATLANTIC Study: A Randomized Clinical Trial.

IMPORTANCE: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. METHODS: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). RESULTS: Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2-12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7-9) injections, with a significant reduction of -93.0 [-154.0, -44.0] µm in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2-11] vs. 5 [2-13] letters (p = 0.98)), number of IVAIs (8.5 [7-9] vs. 8 [7-9] (p = 0.21)), change in CRT (-143 [-184; -47] vs. -89 [-123; -41.5] µm [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study. TRIAL REGISTRATION: The clinical trial was registered in ClinicalTrials.gov Identifier NCT02495181 and the European Union Drug Regulating Authorities Clinical Trials Database EudraCT No. 2015-001368-20.

Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium.

PURPOSE: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. DESIGN: Case-control study. PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts. METHODS: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations. RESULTS: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. CONCLUSIONS: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Retinal layer thicknesses and neurodegeneration in early age-related macular degeneration: insights from the Coimbra Eye Study.

PURPOSE: This study aims to analyze the retinal layers and choroidal thickness in a large set of eyes with early age-related macular degeneration (AMD), in order to detect differences by stage suggestive of early neurodegeneration, and to explore biomarkers of different phenotypes. METHODS: This study is a population-based, cross-sectional study. Patients from the incidence AMD study (NCT02748824) with early AMD (Rotterdam 2a, 2b, 3) were included. All performed spectral-domain optical coherence tomography (SD-OCT) (Spectralis, Heidelberg Engineering, Germany) and automatic segmentation of all retinal layers was obtained with built-in software. Manual correction was performed whenever necessary. The mean thicknesses (ETDRS grid) and volume of each layer were recorded. Subfoveal choroidal thickness was manually measured. Estimates for each layer thickness were calculated with linear mixed models and tested for pairwise differences between stages. Associations between layer thickness and microstructural findings were assessed by multivariate regression analysis. RESULTS: The final cohort comprised 346 eyes (233 patients): 82.66% (n = 286) in stage 2a, 5.49% (n = 19) in stage 2b, and 11.85% (n = 41) in stage 3. A global tendency for lower/inferior thickness of the neuroretinal layers was found comparing stage 3 to 2a: retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were inferior in the inner/outer ETDRS circles and the outer nuclear layer (ONL) and photoreceptors' segments layer in the central circle (p ≤ 0.002). The retinal pigment epithelium-Bruch's membrane (RPE/BrM) layer was thicker in stage 3 (p ≤ 0.001). Subretinal drusenoid deposits (SDD) were associated with thinner neuroretinal layers and choroid (p < 0.05). CONCLUSIONS: Our results showed in a large population-based dataset that several inner and outer neuroretinal layers were thinner with a higher stage in early AMD. These findings support the existence of early and progressive neurodegeneration. Neuronal retinal layer thicknesses might thus be used as quantitative biomarkers of disease progression in AMD. The presence of SDD is possibly associated to more prominent and faster neurodegeneration.

Polypoidal Choroidal Vasculopathy in Caucasians: Morphological Findings from Multimodal Retinal Imaging.

PURPOSE: The aim of the study was to characterize the morphological features of polypoidal choroidal vasculopathy (PCV) in a large Caucasian population. METHODS: We conducteda multicenter, cross-sectional study of treatment-naïve patients with PCV. Baseline fundus photography, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA) were assessed by trained medical graders. Typical PCV features were explored, and retinal thickness (RT) and choroidal thickness (CT) measurements were performed. RESULTS: Seventy-nine eyes of 73 patients (mean age, 72.6 ± 11.9 years) were included. ICGA identified macular polyps in 89.9% of cases. SD-OCT revealed mostly subretinal fluid (93.6%) and a retinal pigment epithelium (RPE) detachment in 91.4%, with sharp protrusion in 67.0% of cases. Polyp-like structures were seen in 74.3% of cases, mostly adherent to an elevated RPE (69.6%). Type 1 neovascularization (NV) was identified in 74.7% of patients, while 16.5% had a mixed NV. The mean macular CT was 220.9 ± 83.2 µm (range, 67.9-403.6). Diffuse and focal pachychoroid were observed in 26.6 and 30.4% of patients, respectively. Soft drusen were reported in 62.0% of cases, but retinal hemorrhage occurred in only 19.0% of cases. CONCLUSION: The morphological features of PCV in Caucasians are similar to those reported in Asians. Pachychoroid signs were found in nearly half of our cohort. However, the mean age at presentation, high prevalence of soft drusen, and low prevalence of large subretinal hemorrhages make PCV closer to age-related macular degeneration in this ethnic group.

Safety Assessment of an A-Scan Ultrasonic System for Ophthalmic Use.

OBJECTIVES: This study describes the safety assessment of an A-scan ultrasonic system for ophthalmic use. The system is an investigational medical device for automatic cataract detection and classification. METHODS: The risk management was based on the International Organization for Standardization (ISO) standard DIN EN ISO 14971:2009-10 and International Electrotechnical Commission (IEC) standard IEC 60601-2-37. The calibration of the ultrasonic field was conducted according to the standards IEC 62127-1:2007 and IEC 62359:2010. The uncertainty on measurements was delineated in agreement with the guide JCGM 100:2008. RESULTS: After risk management, all risks were qualitatively classified as acceptable. The mechanical index (0.08 ± 0.05), soft tissue thermal index (0.08 ± 0.08) and spatial-peak temporal-average intensity (0.56 ± 0.59 mW/cm2 ) were under the maximum index values indicated by the US Food and Drug Administration guidance, Marketing Clearance of Diagnostic Ultrasound Systems and Transducers (0.23, 1, and 17 mW/cm2 , respectively). CONCLUSIONS: This study presents a practical approach for the safety assessment of A-scan ultrasonic systems for ophthalmic use. The safety evaluation of a medical device is mandatory before its use in clinical practice. However, the safety monitoring throughout its life cycle should also be considered, since many device components may deteriorate over time and use.

Incidence of Age-Related Macular Degeneration in the Central Region of Portugal: The Coimbra Eye Study - Report 5.

PURPOSE: To describe the 6.5-year incidence and progression of age-related macular degeneration (AMD) in a coastal town of central Portugal. METHODS: Population-based cohort study. Participants underwent standardized interviews and ophthalmological examination. Color fundus photographs were graded according to the International Classification and Grading System for AMD and ARM. The crude and age-standardized incidence of early and late AMD was calculated, and progression was analyzed. RESULTS: The 6.5-year cumulative incidence of early AMD was 10.7%, and of late AMD it was 0.8%. The incidence of early AMD was 7.2, 13.1 and 17.7% for participants aged 55-64, 65-74 and 75-84 years (p < 0.001). The late AMD incidence was 0.3, 0.9 and 2.8% for the corresponding age groups (p = 0.003). The age-standardized incidence was 10.8% (95% CI, 10.74-10.80%) for early and 1.0% (95% CI, 1.00-1.02%) for late AMD. The incidence of both neovascular AMD and geographic atrophy was 0.4%. Progression occurred in 17.2% of patients. CONCLUSION: The early AMD incidence in a coastal town of central Portugal was found to be similar to that of major epidemiological studies of European-descent populations; however, the incidence of late AMD was lower, and further analysis on risk factors will be conducted.

Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).

PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.

Systemic and Ocular Determinants of Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in the European Eye Epidemiology (E3) Population.

PURPOSE: To investigate systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in the European population. DESIGN: Cross-sectional meta-analysis. PARTICIPANTS: A total of 16 084 European adults from 8 cohort studies (mean age range, 56.9±12.3-82.1±4.2 years) of the European Eye Epidemiology (E3) consortium. METHODS: We examined associations with pRNFLT measured by spectral-domain OCT in each study using multivariable linear regression and pooled results using random effects meta-analysis. MAIN OUTCOME MEASURES: Determinants of pRNFLT. RESULTS: Mean pRNFLT ranged from 86.8±21.4 µm in the Rotterdam Study I to 104.7±12.5 µm in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (ß = -0.38 µm/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (IOP) (ß = -0.36 µm/mmHg; 95% CI, -0.56 to -0.15), visual impairment (ß = -5.50 µm; 95% CI, -9.37 to -1.64), and history of systemic hypertension (ß = -0.54 µm; 95% CI, -1.01 to -0.07) and stroke (ß = -1.94 µm; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (ß = -3.11 µm; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (ß = 1.39 µm/diopter; 95% CI, 1.19-1.59) and smoking (ß = 1.53 µm; 95% CI, 1.00-2.06 for current smokers compared with never-smokers). CONCLUSIONS: In addition to previously described determinants such as age and refraction, we found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. These may be of clinical relevance, especially in glaucoma monitoring of patients with newly occurring vascular comorbidities.

Ranibizumab for High-Risk Proliferative Diabetic Retinopathy: An Exploratory Randomized Controlled Trial.

PURPOSE: To compare the efficacy and safety of intravitreal ranibizumab (IVR) in monotherapy or associated with panretinal photocoagulation (PRP) versus conventional PRP, for high-risk proliferative diabetic retinopathy (PDR) without vitreoretinal traction. PROCEDURES: Multicenter randomized trial, with 3 treatment arms: PRP versus IVR alone and PRP + IVR combined treatment. Follow-up was performed at months 3, 6 and 12. RESULTS: Thirty-five subjects were randomized and 32 used for analysis. Complete regression of neovessels elsewhere occurred in 100% (PRP + IVR), 75% (IVR) and 69.2% (PRP) and for neovessels of the disk in 44.4% (PRP + IVR), 37.5% (IVR) and 30.8% (PRP). During the 1-year duration of treatment, there was no need for laser rescue treatment in IVR-treated eyes. CONCLUSIONS: This trial suggests that the use of IVR is safe and may have a beneficial effect in the treatment of eyes with high-risk PDR. MESSAGE: Ranibizumab appears to have a place in the treatment of PDR.

Prevalence of Age-Related Macular Degeneration in Portugal: The Coimbra Eye Study - Report 1.

PURPOSE: To evaluate the age- and gender-specific prevalence of early and late age-related macular degeneration (AMD) in a Portuguese population-based sample. METHODS: All patients aged ≥55 years of a Portuguese primary health-care unit were recruited for a cross-sectional population-based study. Responders underwent complete ophthalmological examination and digital fundus imaging. Early and late AMD was defined according to the International Age-Related Macular Epidemiological Study Group Classification, and the adopted staging for AMD was the same as that used in the Rotterdam study. The age- and gender-adjusted prevalence of early and late forms of AMD was calculated. RESULTS: Of the 4,370 eligible subjects, 3,000 underwent study procedures (68.6% response rate) and 2,975 were included in the analysis; they had a mean age of 68.9 ± 8.6 years. The overall prevalence of early and late AMD was 15.53% (95% CI 14.25-16.88) and 0.67% (95% CI 0.41-1.04), respectively. Neovascular AMD (NV-AMD) and geographic atrophy (GA) accounted for 0.44% (95% CI 0.23-0.75) and 0.27% (95% CI 0.12-0.53) of individuals, respectively. The highest prevalence of advanced AMD was among those aged ≥75 years (1.13% for NV-AMD; 0.63% for GA). CONCLUSIONS: To our knowledge, this is the first AMD epidemiological study in a Portuguese population. The early forms of the disease had a similar prevalence to that of other large-scale population-based cohorts, but late AMD was less frequent than previously reported.

Retinal layer location of increased retinal thickness in eyes with subclinical and clinical macular edema in diabetes type 2.

PURPOSE: To identify the retinal layer predominantly affected in eyes with subclinical and clinical macular edema in diabetes type 2. METHODS: A cohort of 194 type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20/35) were examined with Cirrus spectral-domain optical coherence tomography (OCT) at the baseline visit (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers of the eyes with subclinical and clinical macular edema was compared with a sample of 31 eyes from diabetic patients with normal OCT and an age-matched control group of 58 healthy eyes. RESULTS: From the 194 eyes in the study, 62 had subclinical macular edema and 12 had clinical macular edema. The highest increases in retinal thickness (RT) were found in the inner nuclear layer (INL; 33.6% in subclinical macular edema and 81.8% in clinical macular edema). Increases were also found in the neighboring layers. Thinning of the retina was registered in the retinal nerve fiber, ganglion cells and inner plexiform layers in the diabetic eyes without macular edema. CONCLUSIONS: The increase in RT occurring in diabetic eyes with macular edema is predominantly located in the INL but extends to neighboring retinal layers indicating that it may be due to extracellular fluid accumulation.

One-year progression of diabetic subclinical macular edema in eyes with mild nonproliferative diabetic retinopathy: location of the increase in retinal thickness.

PURPOSE: To characterize the 1-year progression of retinal thickness (RT) increase occurring in eyes with subclinical macular edema in type 2 diabetes. METHODS: Forty-eight type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (NPDR; levels 20 and 35 in the Early Treatment Diabetic Retinopathy Study) classified as presenting subclinical macular edema at baseline completed the 1-year follow-up period, from a sample of 194 followed in a 12-month observational and prospective study (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers in these eyes was performed, followed by verification and correction by a human grader. RESULTS: The highest increase in RT over the 1-year follow-up period for the 48 eyes/patients with subclinical macular edema was found in the inner nuclear layer (INL). Progression to clinical macular edema was also associated with increased thickening of other retinal layers aside from the INL. The microvascular disease activity shown by microaneurysm (MA) turnover ≥6 was associated with progression from subclinical to clinical macular edema. CONCLUSIONS: Increases in RT occurring over a period of 1 year in diabetic eyes with mild NPDR and subclinical macular edema occur mainly in the INL. The development of clinical macular edema appears to be associated with increased thickening of other retinal layers and microvascular disease activity.

Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to Predict Progression to Clinical Macular Edema: An Attempt of Composite Grading of Macular Edema.

PURPOSE: To characterize the relevance of macular thickness changes in the inner and outer rings in the progression of macular edema in eyes/patients with diabetes type 2. METHODS: A total of 374 type 2 diabetic patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20-35) were included in a 12-month prospective observational study to identify retinopathy progression. Retinal thickness analyses were performed in 194 eyes/patients using Cirrus SD- OCT and 166 eyes/patients using Spectralis SD-OCT. The DRCR.net classification of subclinical and clinical macular edema was used. A composite grading of macular edema is proposed in this study. RESULTS: A total of 317 eyes/patients completed the study. SD-OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Increased thickness of the central subfield is the best predictor for the development of clinical macular edema, with 85.7% sensitivity and 71.9% specificity (OR: 2.57, 95% CI: 0.82-7.99). However, the involvement of the inner and outer rings is a cumulative predictor of progression to clinical macular edema (OR: 8.69, 95% CI: 2.85-26.52). CONCLUSIONS: A composite OCT grading of macular edema taking into account the retinal thickness changes in the inner and outer macular rings offers a simple way to characterize macular edema, with added clinical value.

Choroidal thickness in diabetic retinopathy: the influence of antiangiogenic therapy.

PURPOSE: To analyze the effect of anti-vascular endothelial growth factor agents (anti-VEGF) in submacular choroidal thickness (CT) of diabetic retinopathy (DR) patients. METHODS: Cross-sectional study, which included 25 DR patients (50 eyes) divided in 2 groups, according to DR stage and previous treatments: nonproliferative DR and diffuse diabetic macular edema in both eyes, submitted to macular laser in both eyes and anti-VEGF injection only in 1 eye (nonproliferative diabetic retinopathy + diabetic macular edema group, n = 11); and proliferative DR in both eyes, treated with panretinal photocoagulation in both eyes and anti-VEGF injection only in 1 eye (proliferative diabetic retinopathy group, n = 14). In the study visit, all patients underwent optical coherence tomography with enhanced depth imaging protocol. Choroidal segmentation was performed manually. The medium CT in central macular area (CCT) and the CT in centrofoveal B-scan were obtained automatically. RESULTS: The 25 eyes treated with anti-VEGF showed a reduction on CCT (P = 0.002) and subfoveal CT (P = 0.004), compared with the fellow eyes treated with laser only. Independent evaluation of PDR group revealed similar results (CCT, P = 0.02; subfoveal CT, P = 0.03). In nonproliferative diabetic retinopathy + diabetic macular edema group, CCT was also significantly thinner in eyes treated with anti-VEGF (P = 0.04). A correlation between the number of injections and a thinner CT was found in this group (P = 0.03) and in the evaluation of all eyes together (P = 0.03). CONCLUSION: Diabetic eyes treated with anti-VEGF agents have reduced CT.

Degree of decrease in central retinal thickness predicts visual acuity response to intravitreal ranibizumab in diabetic macular edema.

PURPOSE: To characterize factors that may be associated with optimal or suboptimal response to ranibizumab intravitreal injections in diabetic macular edema (DME). METHODS: Fifty-nine eyes with DME treated with ranibizumab were included. All underwent best-corrected visual acuity (BCVA) assessment and optical coherence tomography (OCT) at baseline, 3 and 6 months. Central retinal thickness (CRT) was assessed at each visit, and OCT images were classified according to their morphological patterns. RESULTS: A mean BCVA increase of 4.78 and 5.52 letters, and a CRT decrease of 80.25 and 106.12 µm were found after 3 and 6 months of treatment (p < 0.001). BCVA improvement was found to be dependent on baseline BCVA and the degree of CRT decrease. Twenty-six eyes (44%) showing a CRT decrease ≥ 20% improved BCVA by 10.3 ± 13.0 letters, whereas 33 eyes (56%) with a CRT decrease <20% had BCVA improvement of 1.8 ± 7.2 letters (odds ratio = 3.31). CONCLUSIONS: The degree of CRT decrease obtained by spectral-domain OCT identifies well the optimal responders to intravitreal ranibizumab and predicts BCVA improvement after treatment.

Genetic variants in ICAM1, PPARGC1A and MTHFR are potentially associated with different phenotypes of diabetic retinopathy.

PURPOSE: To explore phenotype-genotype correlations that may contribute to a better understanding of diabetic retinopathy (DR). PROCEDURES: An exploratory association study was performed to identify genetic variants associated with non-proliferative DR (NPDR) in 307 type 2 diabetic patients who were previously stratified into 3 different phenotypes of NPDR progression. The 307 patients were genotyped for 174 single nucleotide polymorphisms of 11 candidate genes (ACE, AGER, AKR1B1, ICAM1, MTHFR, NOS1, NOS3, PPARGC1A, TGFB1, TNF and VEGFA). RESULTS: Significant associations were observed for PPARGC1A rs16874120 with phenotype A (odds ratio, OR = 0.60, 95% confidence interval, CI 0.36-0.99), ICAM1 rs1801714 with phenotype B (OR = 3.32, 95% CI 1.05-10.50) and both PPARGC1A rs10213440 (OR = 2.00, 95% CI 1.07-3.73) and MTHFR rs1801133 (OR = 1.84, 95% CI 1.08-3.11) with phenotype C. CONCLUSIONS: RESULTS indicate that specific gene variants in ICAM1, PPARGC1A and MTHFR are associated with different NPDR phenotypes, being likely candidates to explain different disease mechanisms underlying the different phenotypes. This is the first study to show correlations between specific gene variants and NPDR phenotypes, opening new perspectives on DR.

Progression of myopic maculopathy after treatment of choroidal neovascularization.

PURPOSE: To evaluate the long-term progression of myopic maculopathy and functional outcome after treatment of myopic choroidal neovascularization (CNV) with photodynamic therapy (PDT) and/or intravitreal ranibizumab (IVR). METHODS: Retrospective study with a cross-sectional evaluation. Eyes were assigned to 4 groups (PDT, IVR, PDT + IVR, dry myopic maculopathy) and evaluated with best-corrected visual acuity, color fundus photography and spectral-domain optical coherence tomography. Chorioretinal atrophy progression was quantified. RESULTS: Fifty-four eyes were included with a mean follow-up of 80.6 ± 28.0 months. The prevalence of diffuse, patchy and macular atrophy increased during the follow-up, in contrast with tessellated fundus, lacquer cracks and active CNV. Progression of macular atrophy was significant in the 3 treatment groups (p < 0.05) and predictive of visual acuity. It depended on age, degree of myopia and presence of staphyloma, but not on the type of treatment. CONCLUSIONS: The long-term functional outcome of eyes with myopic CNV is more dependent on the progression of macular atrophy, and not on the type of treatment.

Animal model for in-vivo Nuclear Cataract. Lens hardness and elasticity assessment.

Age-related cataract is the most frequent cause of blindness in the world being responsible for 48% of blindness and affecting more than 10% of the working population. Currently there is no objective data of the lens biomechanical properties so the process by which the cataract affects the lens's properties (e.g. hardness and elasticity) is still unclear. A modified animal model was produced to create different severities of nuclear cataract. Different doses of sodium selenite were injected in two different moments of the rat' eyes maturation resulting in 12, 13 and 11 rats with incipient, moderate and severe cataract, respectively. The nucleus and cortex's hardness and the stiffness were measured using NanoTest™. Statistically significant differences were found between healthy and cataractous lenses. Statistically significant differences were also found between the different nuclear cataract degrees (p = 0.016), showing that the lens' hardness increases with cataract formation. The nucleus shows a higher hardness increase with cataract formation (p = 0.049). The animal model used in this study allowed for the first time the characterization of the lens's hardness and elasticity in two regions of the lens, in healthy and cataractous lenses.

Macular thickness measured by stratus optical coherence tomography in patients with diabetes type 2 and mild nonproliferative retinopathy without clinical evidence of macular edema.

To evaluate macular thickness in eyes with mild nonproliferative diabetic retinopathy (NPDR), patients with diabetes type 2, NPDR level 20 or 35, and without evidence of clinical macular edema underwent best-corrected visual acuity assessment, color fundus photography and Stratus optical coherence tomography. Mean center point thickness (CPT) and mean central subfield (CSF) thickness were compared with those of a healthy control population. 410 eyes/patients aged 61.2 ± 8.3 years, and with glycosylated hemoglobin of 7.9 ± 1.5% were included. Mean CPT and CSF were 186.6 ± 28.4 and 215.2 ± 25 µm, respectively, significantly increased compared to healthy subjects (p < 0.001). CSF thickness was abnormally increased in 17.6% of the patients, with values within the normal range in 79.5%, and abnormally decreased in 2.9%. CPT and CSF thickness were significantly thicker in men. No systemic factors showed a significant association. A significant increase in the macular thickness was found in eyes/patients with mild NPDR without clinical macular edema; however, only 17.6% of the eyes/patients had abnormally increased values and less than 3% abnormally decreased values.

Subclinical macular edema as a predictor of progression to clinically significant macular edema in type 2 diabetes.

OBJECTIVE: To examine the relationship between subclinical diabetic macular edema (DME) and the development of clinically significant macular edema (CSME) in nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes. METHODS: A prospective, monocenter, observational study was designed to follow patients/eyes with type 2 diabetes and NPDR (Early Treatment Diabetic Retinopathy Study levels 20 and 35) with no prior laser treatment for 2 years or until development of CSME. Ophthalmologic examinations, including best-corrected visual acuity, fundus photography and optical coherence tomography (OCT), were performed at baseline, 6 months and a final visit. RESULTS: A total of 348 patients completed study follow-up; 26 eyes developed CSME. Six out of 32 eyes/patients presenting subclinical DME at baseline developed CSME (18.7%), while 20 out of 316 eyes without subclinical DME developed CSME (6.3%). Eyes/patients with subclinical DME presented a risk for DME progression 3.686 times higher than that of eyes/patients without subclinical DME (95% confidence interval 1.221-7.988). CONCLUSIONS: Subclinical DME in eyes with NPDR identified by center point thickness measured on a Stratus OCT is a good predictor of CSME development.