BACKGROUND AND OBJECTIVES:The aim of this study was to identify the rate of early visual acuity poor responders in patients with neovascular age-related macular degeneration (AMD) after the first intravitreal injection of ranibizumab (Lucentis; Genentech, South San Francisco, CA) and to determine potential predictors for early response.PATIENTS AND METHODS:Patients with choroidal neovascularization secondary to AMD were evaluated before and 1 month after their first ranibizumab treatment. Early poor responders were defined as eyes gaining less than five letters 1 month after the first injection.RESULTS:Following the first ranibizumab injection, 58% of 84 patients gained five or more letters. Beyond 42% poor responders, 31% displayed foveal retinal pigment epithelium (RPE) atrophy and 89% a loss of the external limiting membrane (ELM) integrity at baseline. However, the amount of intra- and subretinal fluid, pigment epithelial detachment (PED), and subfoveal fibrosis showed a similar distribution between gainers and poor responders.CONCLUSION:Early poor responders present with more RPE atrophy, as well as a loss of the ELM integrity at baseline optical coherence tomography. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:326-332.].

Physiological stress response and oxidative damage are factors for aging processes and, as such, are thought to contribute to neovascular age-related macular degeneration (AMD). Paraoxonase 1 (PON1) is an enzyme that plays an important role in oxidative stress and aging. We investigated association of DNA sequence variants (SNP) within the upstream regulatory region of the PON1 gene with neovascular AMD in 305 patients and 288 controls. Four of the seven tested SNPs (rs705379, rs705381, rs854573, and rs757158) were more frequently found in AMD patients compared to controls (P = 0.0099, 0.0295, 0.0121, and 0.0256, respectively), and all but one (SNP rs757158) are in linkage disequilibrium. Furthermore, haplotype TGGCCTC conferred protection (odds ratio (OR) = 0.76, (CI) = 0.60-0.97) as it was more frequently found in control individuals, while haplotype CGATGCT increased the risk (OR = 1.55, CI = 1.09-2.21) for AMD. These results were also reflected when haplotypes for the untranscribed and the 5'untranslated regions (5'UTR) were analyzed separately. To assess haplotype correlation with levels of gene expression, the three SNPs within the 5'UTR were tested in a luciferase reporter assay. In retinal pigment epithelium-derived ARPE19 cells, we were able to measure significant differences in reporter levels, while this was not observed in kidney-derived HEK293 cells. The presence of the risk allele A (SNP rs705381) caused an increase in luciferase activity of approximately twofold. Our data support the view that inflammatory reactions mediated through anti-oxidative activity may be relevant to neovascular age-related macular degeneration.

Objective: To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME).Design: Twenty-four-month, open-label, multicenter, Phase IIIb extension study.Participants: Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension.Methods: All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best-corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension.Main Outcome Measures: Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA.Results: Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: +7.9 letters, -140.6 mu m, and 5.6 , respectively; prior ranibizumab plus laser: +6.7 letters, -133.0 mu m, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (+5.4 letters, -126.6 mu m, and 4.3, respectively), with an average of 4.1 ranibizumab injections.Conclusions: Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year.

Objective: Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome.Methods: Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr).Results: 204 eyes were included. A change of +5.0 [-1;+11] letters and +1.5 [-5.5;+9.5] was observed with a median of 4 [3;7] and 10 [7;14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01).Conclusions: Our data suggest that clinical decisions regarding treatment may be guided by observing patients' initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value.

Purpose.: Neovascular age-related macular degeneration (AMD) resulting in decreased central vision severely impairs affected individuals. Current standard treatment is an intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Genetic factors that influence AMD and that affect the outcome of ranibizumab treatment were sought within a sample of Swiss patients. Methods.: Changes in visual acuity (VA) after initiation of anti-VEGF treatment were observed during 12 months, and percentiles of VA were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2, and VEGFA) as well as not yet reported AMD-associated genes (KDR, LRP5, and FZD4) were determined, and their frequencies were compared. Results.: Of the 309 eyes included in the study, 243 completed VA assessment. On average, 3.9 ±2.6 ranibizumab injections were administered. Based on the change in visual acuity, two responder groups were established: 63 eyes were assigned to the poor responders (≤25th percentile) and 63 eyes to the good responders (≥75th percentile). Individuals with genotype CC of p.Y402H in CFH had a decreased chance of positive treatment outcome compared with those with the CT and TT genotypes (P = 0.005 and P = 0.006). In this study, the genotype combination of AG at CFH with CT at FZD4 (SNP rs10898563) promised an increased chance of positive treatment outcome (P = 0.004). Furthermore, the association with the known genetic susceptibility loci CFH, HTRA1, and AMRS2 were confirmed, and a risk-conferring polymorphism in one new locus, LRP5, was identified. Conclusions.: Genetic predisposition may account for the variability in response to anti-VEGF treatment.

OBJECTIVE:To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). DESIGN:A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. PARTICIPANTS:We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. METHODS:Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). MAIN OUTCOME MEASURES:Mean average change in BCVA from baseline to month 1 through 12 and safety. RESULTS:Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. CONCLUSIONS:Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.

To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).Mean average change in BCVA from baseline to month 1 through 12 and safety.Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.

Background: Retinal hemorrhages have been described as a component of high altitude retinopathy (HAR) in association with altitude illness. In this prospective high altitude study, we aimed to gain new insights into the pathophysiology of HAR and explored whether HAR could be a valid early indicator of altitude illness.Methodology/Principal Findings: 28 mountaineers were randomly assigned to two ascent profiles during a research expedition to Mt. Muztagh Ata (7546 m/24,751 ft). Digital fundus photographs were taken prior to expedition at 490 m (1,607 ft), during expedition at 4497 m (14,750 ft = base camp), 5533 m (18,148 ft), 6265 m (20,549 ft), 6865 m (22,517 ft) and 4.5 months thereafter at 490 m. Number, size and time of occurrence of hemorrhages were recorded. Oxygen saturation (SpO(2)) and hematocrit were also assessed. 79% of all climbers exhibited retinal hemorrhages during the expedition. Number and area of retinal bleeding increased moderately to medium altitudes (6265 m). Most retinal hemorrhages were detected after return to base camp from a high altitude. No post-expeditional ophthalmic sequelae were detected. Significant negative (SpO(2) Beta: -0.4, p<0.001) and positive (hematocrit Beta: 0.2, p = 0.002, time at altitude Beta: 0.33, p = 0.003) correlations with hemorrhages were found.Conclusions/Significance: When closely examined, a very large amount of climbers exhibit retinal hemorrhages during exposure to high altitudes. The incidence of retinal hemorrhages may be greater than previously appreciated as a definite time lag was observed between highest altitude reached and development of retinal bleeding. Retinal hemorrhages should not be considered warning signs of impending severe altitude illness due to their delayed appearance.

OBJECTIVE:To report 5-year outcomes from a clinical trial of intravitreal triamcinolone acetonide (IVTA) in eyes with diabetic macular edema (DME) and impaired vision despite previous laser treatment. DESIGN:Prospective, double-masked, randomized clinical trial. After completing the 2-year visit, all eyes, including those initially randomized to receive placebo, received IVTA according to prospectively defined guidelines. PARTICIPANTS AND CONTROLS:A total of 69 eyes (41 patients) were entered into the study, with 34 eyes initially receiving active treatment and 35 eyes receiving placebo. Five-year data were available for 44 of 67 eyes (66%). For the 23 eyes with missing 5-year data, of which 13 received placebo and 10 received IVTA, the last observation was carried forward. INTERVENTION:Intravitreal injection of 0.1 ml of 40 mg/ml triamcinolone acetonide with adjunctive laser therapy where appropriate. MAIN OUTCOME MEASURES:Improvement of best-corrected logarithm of the minimum angle of resolution visual acuity by >or=5 letters after 5 years compared with baseline and 2 years, and incidence of adverse events. Secondary outcome was the change in central macular thickness. RESULTS:Improvement of >or=5 letters after 5 years was found in 14 of 33 eyes (42%) initially treated with IVTA compared with 11 of 34 eyes (32%) initially treated with placebo (z(GEE) = 0.81, P = 0.4). Foveal thickness decreased by 30 microm (95% confidence interval, -47 to 107 microm) less in the initial-IVTA group than in the initial-placebo group at 5 years (z(GEE) = 0.76, P = 0.45); 5 of 11 eyes (45%) from the initial-IVTA group that were phakic at commencement of the third year required cataract surgery. A similar number of eyes from each group required ongoing treatment from the third year onward with both laser and IVTA, indicating that IVTA treatment for 2 years does not lead to reduction in the risk of recurrent edema. CONCLUSIONS:The majority of eyes that initially improved with IVTA maintained their gain after 5 years. No new safety concerns were identified. IVTA treatment may be considered in carefully selected cases of impaired vision caused by advanced DME that are unresponsive to other interventions.

PURPOSE:To identify and quantitate specific changes in optical coherence tomography (OCT) images of patients with type 2 idiopathic perifoveal telangiectasia (IPT).METHODS:In a prospectively designed, observational, case-control study, 28 eyes of 14 consecutive patients with IPT were examined with OCT and compared with eyes of 14 unaffected control subjects. Light reflectivity profiles of raw scan data of OCT images were quantitatively analyzed for differences in distance between different retinal reflectivity layers and their respective reflectivities. Maculae were examined in four separate regions: (1) central fovea, (2) nasal perifovea, (3) temporal perifovea, and (4) outside the fovea.RESULTS:Retinal thinning, shortening of the photoreceptor outer segments and loss of reflectivity of the photoreceptor ellipsoid region were found in the central foveal region as well as the nasal and temporal perifoveal regions in eyes with IPT. In addition, increased reflectivity of the outer nuclear layer was found in a sharply demarcated area of the inferotemporal perifoveal region in all affected eyes. Retinal tissue located more than 2000 mum away from the foveola was indistinguishable from that in normal eyes.CONCLUSIONS:Quantitative OCT analysis shows unique and specific changes in the photoreceptors of the central macula in IPT which can be detected from first clinical presentation. These changes may be of use as an additional diagnostic tool. Correlation of the findings in the outer nuclear layer with histologic studies may help identify the nature of the reflectivity increase and define more clearly the type of damage sustained by the photoreceptors in this condition.

PURPOSE To test the hypothesis that hyporeflective spaces in the neuroretina found on optical coherence tomography (OCT) examination have different optical reflectivities according to whether they are associated with exudation or degeneration. METHODS Retrospective analysis of eyes with idiopathic perifoveal telangiectasia (IPT), diabetic macular edema (DME), idiopathic central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), or cone dystrophy (CD) and eyes of healthy control subjects. OCT scans were performed. Raw scan data were exported and used to calculate light reflectivity profiles. Reflectivity data were acquired by projecting three rectangular boxes, each 50 pixels long and 5 pixels wide, into the intraretinal cystoid spaces, centrally onto unaffected peripheral RPE, and onto the prefoveolar vitreous. Light reflectivity in the retinal pigment epithelium (RPE), vitreous, and intraretinal spaces for the different retinal conditions and control subjects were compared. RESULTS Reflectivities of the vitreous and the RPE were similar among the groups. Hyporeflective spaces in eyes with exudation (DME, RP, and CSC) had higher reflectivity compared with the mean reflectivity of the vitreous, whereas the cystoid spaces in the maculae of the eyes without exudation (CD and IPT) had a lower reflectivity than did the normal vitreous. CONCLUSIONS Analysis of the light reflectivity profiles may be a tool to determine whether the density of hyporeflective spaces in the macula is greater or less than that of the vitreous, and may be a way to differentiate degenerative from exudative macular disease.