Search

PURPOSE To compare the efficacy and safety of brolucizumab with aflibercept in patients with diabetic macular edema (DME). DESIGN Double-masked, 100-week, multicenter, active-controlled, randomized trials. METHODS Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in KITE (n = 360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if disease activity was identified at predefined assessment visits; aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in Diabetic Retinopathy Severity Scale score, and anatomical and safety outcomes. RESULTS At Week 52, brolucizumab 6 mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001), more subjects achieved central subfield thickness (CSFT)

Objectives: To identify clinical and morphological biomarkers associated with early onset of large submacular hemorrhage (SMH) secondary to neovascular age-related degeneration (nAMD) after anti-vascular endothelial endothelial growth factor (anti-VEGF) intravitreal injection (IVI). Methods: We retrospectively included patients presenting large SMH secondary to treated nAMD, for which at least 2 examinations, including spectral-domain optical coherence tomography (SD-OCT), were available prior to the onset of the SMH. Clinical characteristics, cardiovascular risk factors and treatment, as well as SD-OCT qualitative and quantitative variables were extracted at the 2 last examinations before SMH onset. History of previous SMH on the fellow eye was also documented. Early SMH onset at defined as 45 days since last IVI were compared. Results: Forty-six eyes of 46 patients were included in this study, of which 93% were undergoing pro-re-nata regimen with a monthly follow-up. Onion sign, persistence of exudative signs and increasing height of PED between the two last SD-OCT were associated with early SMH onset following last IVI. SMH was bilateral for 41% patients (19/46). In case of history of SMH on the fellow eye, the pre-existence of a RPE-tear before second SMH was significantly higher (p=0.029) in comparison to unilateral SMH. Conclusion: Persistence of exudative signs,, onion sign and increasing PED height despite anti-VEGF intravitreal injections between the two last examination, as well presence of RPE tear in case of history of an SMH on the fellow eye, should be considered as warning signs for SMH.

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.

To demonstrate two distinct pathways to geographic atrophy (GA) that originate from soft drusen/ pigment epithelial detachments (PEDs) and subretinal drusenoid deposits (SDDs), respectively, and are characterized by their final quantitative autofluorescence (qAF) levels.23 eyes of 18 patients with GA underwent spectral-domain optical coherence tomography (SD-OCT) and qAF imaging on the qAF-ready Heidelberg Spectralis. 52 GA Regions-of-interest (ROIs), or clusters of adjacent lesions, were selected, and the ROIs were divided into groups by the dominant iAMD precursors on prior serial tracked SD-OCT scans. Mean qAF values and structural SD-OCT findings of groups were compared.Group 1 lesions (soft drusen/PED precursors, 18/52) were isolated, with lower mean qAF (35.88 ± 12.75 units); group 3 lesions (SDD precursors, 12/52) were multilobular, with significantly higher mean qAF (71.62 ± 12.12 units, p 0.05). Group 2 lesions, (mixed precursors, 22/52) had intermediate mean qAF (58.13 ± 67.92 units). Significantly greater prevalence of split RPE/ Bruch's membrane complex in SDD-associated GA, suggesting basal laminar deposit (BLamD), than in drusen-associated lesions was the major structural difference.Quantitative autofluorescence (qAF) of GA lesions may reflect two distinct pathogenic pathways and structural outcomes, originating from soft drusen/PED and subretinal drusenoid deposits (SDDs), with the final qAF values lower or higher, respectively. Basal laminar deposit specifically in and adjacent to SDD-associated lesions may account for their greater autofluorescence. The potential importance of this paradigm is that it could direct, simplify and facilitate research on geographic atrophy by dividing the disease into two components that may be studied separately.

To investigate fellow eyes of newly diagnosed unilateral exudative Type 3 (T3) macular neovascularization (MNV) patients by assessing the presence and progression of a preclinical neovascular component during a 3-year follow-up.This is a longitudinal study involving three retinal referral centers. Patients affected by unilateral exudative treatment-naive T3 MNV were enrolled.Twenty-four eyes of 24 patients (79 ± 6 years old) were enrolled. Nine eyes (37%) displayed a nonexudative T3 MNV at baseline that developed exudation after a mean of 9 ± 9 months. Fifteen eyes that did not display a nonexudative Type 3 MNV at baseline. Five eyes (21%) did not display neovessels at baseline, but showed a nonexudative T3 after 13 ± 9 months, and exudation after 8 ± 3 months. Five eyes (21%) developed active exudative T3 MNV after 23 ± 9 months, with no detectable nonexudative stage at baseline. Five eyes (21%) did not show MNV, but progressed to geographic atrophy by 36 months of follow-up. Overall, T3 MNV in the fellow eye accounted for 79%, all developing exudation over 3 years of follow-up.The occurrence of a nonexudative T3 MNV is a frequent event in the fellow eye of patients newly diagnosed with unilateral exudative T3 MNV and it precedes the development of exudation over 3 years (prevalence of 37% and cumulative incidence of 79%). Optical coherence tomography angiography approach may be used to perform an early diagnosis and treatment of patients with T3 MNV.

Non-exudative macular and choroidal neovascularization (MNV and CNV) usually refers to the entity of treatment-naïve type 1 neovascularization in the absence of associated signs of exudation. Histopathological studies, dating back in the early 70s, identified the presence of non-exudative MNV, but the first clinical report of this finding was in the late 90s using indocyanine green angiography in eyes with age-related macular degeneration (AMD). With more advanced retinal imaging, there has been an ever increasing appreciation of non-exudative MNV associated with AMD and CNV with other macular disorders. However, consensus regarding the exact definition and the clinical management of this entity is lacking. Furthermore, there may be variation in the imaging features and clinical course suggesting that a spectrum of disease may exist. Herein, we review the large body of published work that has provided a better understanding of non-exudative MNV and CNV in the last decade. The prevalence, multimodal imaging features, clinical course, and response to treatment are discussed to elucidate further key insights about this entity. Based on these observations, this review also proposes a new theory about the origin and course of different sub-types of non-exudative MNV/CNV which can have different etiologies and pathways according to the clinical context of disease.

The authors present an unusual case of a 6-year-old boy with myopia and foveal hypoplasia who was diagnosed by optical coherence tomography angiography. This case report presents the importance of using optical coherence tomography angiography in the diagnosis of a different etiology. [ J Pediatr Ophthalmol Strabismus . 2022;59(2):e23–e24.]

Purpose: The lens-iris diaphragm retropulsion syndrome (LIDRS) corresponds to a brutal deepening of the anterior chamber during phacoemulsification. LIDRS is painful for the patient and sometimes causes intraoperative complications. This study was designed to assess the preoperative risk factors of LIDRS. Setting: Monocentric study in the university department of ophthalmology, Intercommunal Hospital Center, Creteil, France. Design: Prospective open-label observational study. Methods: Preoperative parameters of consecutive patients who underwent cataract surgery were recorded. LIDRS occurrence was evaluated during surgery and classified into 3 stages. Except for the first patient, a simple and rapid maneuver to separate the iris from the capsule (capsular touch) was performed in all patients with LIDRS. Results: LIDRS occurred in 101 out of 205 included eyes: mild in 73.2% (74/101) , marked in 16.8% (17/101) and severe in 9.9% (10/101). LIDRS eyes had a longer axial length (pConclusions: Myopia and prior vitrectomy were the main risk factors of LIDRS. The capsular touch allowed to resolve LIDRS in almost all eyes. Analysis of preoperative factors can help the surgeon to identify patients at risk and to prevent patient pain and intraoperative complications associated with LIDRS.

Purpose To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). Design AQUA was a multicenter, open-label, single-arm, phase 4 study. Participants Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. Methods Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. Main Outcome Measures The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. Results A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 μm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was –175.38 μm (SD, 132.62 μm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. Conclusions Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and High Density Lipoproteins (HDL) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relation to AMD in a large European dataset, and investigated whether this relationship is driven by certain sub fractions. DESIGN: (Pooled) analysis of cross-sectional data. PARTICIPANTS: 30,953 individuals aged 50+ participating in the E3 consortium; and 1530 individuals from the Rotterdam Study with lipid sub fraction data. METHODS: In E3, AMD features were graded per eye on fundus photographs using the Rotterdam Classification. Routine blood lipid measurements were available from each participant. Data on genetics, medication and confounders such as body mass index, were obtained from a common database. In a subgroup of the Rotterdam Study, lipid sub fractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random-effect were used to estimate the associations. MAIN OUTCOME MEASURES: early, late or any AMD, phenotypic features of early AMD, lipid measurements. RESULTS: HDL was associated with an increased risk of AMD, corrected for potential confounders (Odds Ratio (OR) 1.21 per 1mmol/L increase (95% confidence interval[CI] 1.14-1.29); while triglycerides were associated with a decreased risk (OR 0.94 per 1mmol/L increase [95%CI 0.91-0.97]). Both were associated with drusen size, higher HDL raises the odds of larger drusen while higher triglycerides decreases the odds. LDL-cholesterol only reached statistical significance in the association with early AMD (p=0.045). Regarding lipid sub fractions: the concentration of extra-large HDL particles showed the most prominent association with AMD (OR 1.24 [95%CI 1.10-1.40]). The CETP risk variant (rs17231506) for AMD was in line with increased-HDL levels (p=7.7x10-7); but LIPC risk variants (rs2043085, rs2070895) were associated in an opposite way (p=1.0x10-6 and 1.6x10-4). CONCLUSIONS: Our study suggests that HDL-cholesterol is associated with increased risk of AMD and triglycerides negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL sub fractions seem to be drivers in the relation with AMD, variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains a question to be answered.

To compare widefield optical coherence tomography angiography (OCTA) to ultra-widefield fluorescein angiography (UWFA) in the assessment of nonperfusion in retinal vein occlusion (RVO).A cross-sectional study of 43 eyes of 43 patients with RVO examined using both widefield OCTA (PLEX Elite, Carl Zeiss Meditec, Dublin, CA) with a panoramic montage of five 12 × 12-mm images and UWFA (Optos, 200°). Qualitative analysis was performed according to nonperfusion areas (cutoff: three disk areas) on widefield OCTA. The quantitative analysis assessed the vascular density on the widefield OCTA and ischemic index on UWFA.The ischemic index on UWFA and vascular density in the superficial and deep plexus correlated significantly (P = 0.019, r = 0.357 and P0.013, r = 0.375, respectively). The qualitative classification on widefield OCTA and ischemic index on UWFA correlated significantly (P0.001, r = 0.618). For the detection of marked nonperfusion (ischemic index ≥ 25%), widefield OCTA had a sensitivity of 100% and a specificity of 64.9%.The presence of nonperfusion on UWFA correlated with widefield OCTA. Optical coherence tomography angiography could help to identify high-risk RVO patients who might benefit from a further evaluation using fluorescein angiography.

Importance Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD. Objective To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. Design, Setting, Participants This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P

Zweck: Mit der vorliegenden Studie sollten die 9-Jahres-Ergebnisse der Behandlung der myopen choroidalen Neovaskularisation (mCNV) mit Ranibizumab als Monotherapie beurteilt werden. Methoden: Es handelt sich um eine retrospektive, nicht randomisierte Multicenterstudie zur Beurteilung der Langzeitergebnisse einer mindestens 9-jährigen Behandlung der mCNV mit Ranibizumab als Monotherapie gemäß einem streng bedarfsbasierten Therapieschema. Ergebnisse: In die Studie wurden 17 Augen von 17 Patienten (12 Frauen; Durchschnittsalter 57,9 ± 7,7 Jahre) eingeschlossen. Die mittlere Nachbeobachtungsdauer betrug 112,4 ± 3,9 Monate (Spanne: 108-120). Die mittlere Differenz in der bestkorrigierten Sehschärfe (BCVA) zwischen dem Ausgangswert und der letzten Nachuntersuchung lag bei +1,2 ± 15,6 ETDRS (Early Treatment for Diabetic Retinopathy Study)-Buchstaben (p = 0,004, Ausgangswert vs. 12 und 24 Monate). Die mittlere Gesamtzahl intravitrealer Injektionen bei jedem Patienten betrug 1,24 ± 1,70 pro Jahr (Spanne: 2-25). Während der 9-jährigen Nachbeobachtung wurden keine systemischen Nebenwirkungen im Zusammenhang mit der Arzneimitteltherapie beobachtet. Schlussfolgerungen: Die Langzeit-Monotherapie mit Ranibizumab bewirkt nach 9-jähriger Behandlung bei fast allen Augen eine gegenüber Studienbeginn unveränderte oder verbesserte BCVA. Übersetzung aus Ophthalmologica 2018;239:133-142 (DOI: 10.1159/000485112)

To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naïve patients with neovascular age-related macular degeneration (AMD).Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis.Patients with active choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) of 24-73 Early Treatment Diabetic Retinopathy Study letters in the study eye were enrolled.Patients (n = 1888) were randomized in a 1:1:1 ratio to study eye treatment with abicipar 2 mg every 8 weeks after 3 initial doses at baseline and weeks 4 and 8 (Q8), abicipar 2 mg every 12 weeks after 3 initial doses at baseline and weeks 4 and 12 (Q12), or ranibizumab 0.5 mg every 4 weeks (Q4).The primary efficacy end point was proportion of patients with stable vision (defined as15-letter loss in BCVA from baseline) in the study eye at week 52. Secondary end points included change from baseline in BCVA and central retinal thickness (CRT) at week 52. Safety measures included adverse events (AEs).The proportion of patients with stable vision at week 52 was 93.2%, 91.3%, and 95.8% in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively, with both abicipar Q8 and Q12 noninferior to ranibizumab Q4. Week 52 mean change from baseline in BCVA was 7.5, 6.4, and 8.4 letters and in CRT was -144, -145, and -144 μm in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. Incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3%, respectively. The IOI AEs were typically mild or moderate in severity and treated with topical corticosteroids; 62 of 192 patients (32.3%) received oral and/or injectable corticosteroids.Abicipar Q8 and Q12 were both noninferior to ranibizumab Q4 in the primary end point of stable vision at week 52. Intraocular inflammation was more frequent with abicipar. Quarterly and Q8 abicipar reduce nAMD disease and treatment burden compared with monthly treatment.

Purpose To analyze the frequency and phenotypic variation of AMD in subjects with high myopia (HM), and to describe the clinical course and response to treatment of neovascularization (NV). Methods Patients with HM were identified at five retina tertiary referral centers. Inclusion criteria were myopic patients aged 55 years or more with axial lengths equal or greater than 25.5 mm. Results A total of 874 eyes from 442 HM subjects older than 55 years were identified and 104 eyes of 54 patients (72 ± 11 years) were included in the study and followed up for 23.5 ± 19.5 months. The estimated AMD frequency in HM subjects over 55 years was 11.9% (95% confidence interval; 9.8%-14.0%). A total of 34 of 104 eyes were diagnosed with drusen, 22 with reticular pseudodrusen (RPD), 28 with both drusen and RPD, and 20 with geographic atrophy. Neovascularization was detected in 52 eyes (50%), and type 1 was the most frequent form (39 eyes, 75%). Overall, NV was treated with 4.6 ± 2.6 anti-VEGF injections. Eyes with treatment-naive NV at baseline (n = 34) required 3.8 ± 1.5 anti-VEGF injections during the first year of treatment. This exceeded the injection number in the purely myopic population (1.8 to 3.6 injections for the first year). Conclusions This study provides evidence to suggest that older patients with HM are at a significant risk of the dry and neovascular forms of AMD. NV in eyes with HM and AMD required more injections in the first year compared to NV in HM eyes without AMD.

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 mu m in the Rotterdam Study I to 104.7 +/- 12.5 mu m in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (beta = -0.38 mu m/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (10P) (beta = -0.36 mu m/mmHg; 95% CI, -0.56 to -0.15), visual impairment (beta = -5.50 mu m; 95% CI, -9.37 to -1.64), and history of systemic hypertension (beta = -0.54 mu m; 95% CI, -1.01 to -0.07) and stroke (beta = -1.94 mu m; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (beta = -3.11 mu m; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (beta = 1.39 mu m/diopter; 95% CI, 1.19-1.59) and smoking (beta = 1.53 mu m; 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. (C) 2018 by the American Academy of Ophthalmology

Manuscript no. 2016-1147 Supplemental material is available at www.aaojournal.org/; International audience; [u]Purpose:[/u] Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. [u]Design:[/u] Meta-analysis of prevalence data. [u]Participants:[/u] A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. [u]Methods:[/u] AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). [u]Main Outcome Measures:[/u] Prevalence of early and late AMD, BCVA, and number of AMD cases. [u]Results:[/u] Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1% -5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged >= 85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer >= 80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. [u]Conclusion:[/u] We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans.

To describe the appearance of acute syphilitic posterior placoid chorioretinitis, a rare ocular manifestation of syphilis, on spectral domain optical coherence tomography (SD OCT) both before and after treatment.Ophthalmic examination and imaging studies of 30 eyes of 19 confirmed cases were analyzed both at the time of presentation and at each follow-up visit. Patients with SD OCT and fluorescein angiography at the time of presentation, and at least three documented follow-up visits after initiation of therapy, were included in the study. Standard treatment of neurosyphilis was given to each patient, including 4 million units of penicillin G administered intravenously every 4 hours for 14 days.Fundus examination and imaging studies were consistent with previous reports and confirmed the diagnosis of acute syphilitic posterior placoid chorioretinitis. In 13 eyes (43.3%), baseline SD OCT scans were performed within 1 to 2 days of presentation and revealed a small amount of subretinal fluid, disruption of the inner segment/outer segment junction, and hyperreflective thickening of the retinal pigment epithelium (RPE). All 30 eyes were again scanned between Days 7 and 9 after presentation and revealed loss of the inner segment/outer segment and OS/RPE bands, and irregular hyperreflectivity of the RPE with prominent nodular elevations but without subretinal fluid. Early disruption of the external limiting membrane and punctate choroidal hyperreflectivity were seen in 1 of the 30 eyes (3.3%) and 14 of the 30 eyes (46.6%), respectively. Vision improved and the outer retinal abnormalities normalized in 28 of the 30 eyes (93.3%) after the treatment of neurosyphilis. The external limiting membrane, inner segment/outer segment band, and/or linear outer segment/RPE junction remained substantially abnormal despite treatment in 2 eyes left with 20/200 vision.Patients with acute syphilitic posterior placoid chorioretinitis show characteristic outer retinal abnormalities on SD OCT imaging, including disruption of the inner segment/outer segment band, nodular thickening of the RPE with loss of the linear outer segment/RPE junction, and, in some cases, loss of the external limiting membrane, accumulation of subretinal fluid, and punctate hyperreflectivity in the choroid. Vision improved and these abnormalities reversed after treatment of neurosyphilis in most of the patients. Persistently, poor vision despite treatment was associated with long-term loss or disruption of outer retinal anatomy on SD OCT.

To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD).Six-month, phase 1/2, prospective, multicenter, double-masked, randomized, ascending single-dose, active-controlled, parallel-group study.A total of 194 treatment-naive patients, aged ≥50 years, with primary subfoveal choroidal neovascularization secondary to AMD.Patients received a single intravitreal injection of RTH258 0.5 mg (n = 11), 3.0 mg (n = 31), 4.5 mg (n = 47), or 6.0 mg (n = 44), or ranibizumab 0.5 mg (n = 61).The primary efficacy end point was the change from baseline to month 1 in central subfield thickness (CSFT) measured by spectral-domain optical coherence tomography. The secondary efficacy end point was the duration of treatment effect measured as time from the initial injection to receipt of post-baseline therapy (PBT) guided by protocol-defined criteria. Adverse events (AEs) were recorded throughout the study.RTH258 demonstrated noninferiority compared with ranibizumab in mean change in CSFT from baseline to month 1 for the 4.5- and 6.0-mg dose groups (margin: 40 μm, 1-sided alpha 0.05). The difference in CSFT change at month 1 comparison with ranibizumab was 22.86 μm (90% confidence interval [CI], -9.28 to 54.99) and 19.40 μm (95% CI, -9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. The median time to PBT after baseline therapy was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. Changes in best-corrected visual acuity with RTH258 were comparable to those observed with ranibizumab. The most frequent AEs reported for the RTH258 groups were conjunctival hemorrhage, eye pain, and conjunctival hyperemia; the majority of these events were mild in intensity.This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.

Tariq Aslam,1 Cécile Delcourt,2 Frank Holz,3 Alfredo García-Layana,4 Anita Leys,5 Rufino M Silva,6 Eric Souied7 1Manchester Royal Eye Hospital, Manchester, UK; 2University ofBordeaux, Bordeaux, France; 3University of Bonn, Bonn, Germany; 4Clínica Universidad de Navarra, Pamplona, Spain; 5University Hospitals, Leuven, Belgium; 6University of Coimbra, Coimbra, Portugal; 7Université Paris Est Créteil, Créteil, FrancePurpose: To evaluate ophthalmologists’ opinion of, and use of, micronutritional dietary supplements 10years after publication of the first Age-Related Eye Disease Study (AREDS) study.Methods: Participation was solicited from 4,000European ophthalmologists. Responding physicians were screened, and those treating at least 40patients with age-related macular degeneration (AMD) per month and prescribing nutrition supplements at least 4times per month were admitted and completed a 40-item questionnaire.Results: The surveyed sample included 112general ophthalmologists and 104retinal specialists. Most nutritional supplements (46%) were initiated when early/intermediate AMD was confirmed, although 18% were initiated on confirmation of neovascular AMD. Clinical studies were well known: 90% were aware of AREDS, with 88% aware of AREDS1and 36% aware of the, as-yet-unpublished, AREDS2studies. Respondents considered lutein, zeaxanthin, zinc, omega-3, and vitamins to be the most important components of nutritional supplements, with the results of AREDS2already having been taken into consideration by many. Ophthalmologists anticipate more scientific studies as well as improved product quality but identify cost as a barrier to wider uptake.Conclusion: Micronutrition is now part of the routine management of AMD for many ophthalmologists. Ophthalmologists choosing to use nutritional supplements are well-informed regarding current scientific studies. Keywords: age-related macular degeneration, micronutrition, nutritional supplementation

Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Genetic heterogeneity of LCA has been suspected since the report by Waardenburg of normal children born to affected parents. In 1995, we localized the first disease causing gene, LCA1, to chromosome 17p13 and confirmed the genetic heterogeneity. In 1996, we ascribed LCA1 to mutations in the photoreceptor-specific guanylate cyclase gene (retGC1). RetGC1 is an essential protein implicated in the phototransduction cascade, especially in the recovery of the dark state after the excitation process of photoreceptor cells by light stimulation. In 1997, mutations in a second gene were reported in LCA, the RPE65 gene, which is the first specific retinal pigment epithelium gene. The protein RPE65 is implicated in the metabolism of vitamin A, the precursor of the photoexcitable retinal pigment (rhodopsin). Finally, a third gene, CRX, implicated in photoreceptor development, has been suspected of causing a few cases of LCA. Taken together, these three genes account for only 27% of LCA cases in our series. The three genes encode proteins that are involved in completely different physiopathologic pathways. Based on these striking differences of physiopathologic processes, we reexamined all clinical physiopathological discrepancies and the results strongly suggested that retGC1 gene mutations are responsible for congenital stationary severe cone-rod dystrophy, while RPE65 gene mutations are responsible for congenital severe but progressive rod-cone dystrophy. It is of tremendous importance to confirm and to refine these genotype-phenotype correlations on a large scale in order to anticipate the final outcome in a blind infant, on the one hand, and to further guide genetic studies in older patients on the other hand.

PURPOSE: To report clinical features and molecular genetic study in three unrelated families in which age-related macular degeneration was observed in grandparents of patients with Stargardt disease. METHODS: A complete ophthalmologic examination including best-corrected visual acuity measurement, fundus examination, and fluorescein angiography was performed on all members of the three families. The entire coding sequence of the ABCR gene was analyzed using a combination of single strand conformation polymorphism and direct sequence analysis of the 50 exons. RESULTS: Compound heterozygous missense mutations were observed in patients with Stargardt disease (Arg212Cys, Arg1107Cys, Gly1977Ser, Arg2107His, and le2113Met). Heterozygous missense mutations were observed in the grandparents with age-related macular degeneration (Arg212Cys and Arg1107Cys). CONCLUSIONS: We report phenotype and genotype findings in three unrelated families segregating patients with Stargardt disease and age-related macular degeneration. The hypothesis that the Arg212Cys and Arg1107Cys ABCR gene mutations could be susceptibility factors for age-related macular degeneration is discussed. We speculate that the relatives of patients affected with Stargardt disease who are carriers of heterozygous ABCR gene mutations may have a higher risk of developing age-related macular degeneration.

SummaryCongenital nystagmus (CN) is a common oculomotor disorder (frequency of 1/1,500 live births) characterized by bilateral uncontrollable ocular oscillations, with onset typically at birth or within the first few months of life. This condition is regarded as idiopathic, after exclusion of nervous and ocular diseases. X-linked, autosomal dominant, and autosomal recessive modes of inheritance have been reported, but X-linked inheritance is probably the most common. In this article, we report the mapping of a gene for X-linked dominant CN (NYS1) to the short arm of chromosome X, by showing close linkage of NYS1 to polymorphic markers on chromosome Xp11.4-p11.3 (maximum LOD score of 3.20, over locus DXS993). Because no candidate gene, by virtue of its function, has been found in this region of chromosome Xp, further studies are required, to reduce the genetic interval encompassing the NYS1 gene. It is hoped that the complete gene characterization will address the complex pathophysiology of CN.

Apolipoprotein E (ApoE) is a polymorphic protein that plays a central part in plasma metabolism of lipids and in central nervous system lipid homeostasis. Our purpose was to evaluate the potential role of ApoE polymorphism in the occurrence of exudative age-related macular degeneration associated with drusen, which contain lipids.We analyzed apolipoprotein E genotypes in 116 unrelated patients with exudative age-related macular degeneration in one eye and hard drusen (n = 39) or soft drusen (n = 77) in the other eye, and compared the results with those of age-matched and sex-matched control subjects (n = 168). Apolipoprotein E alleles were detected by a ploymerase chain reaction-based method.A lower frequency of the epsilon4 allele carriers was observed in the exudative age-related macular degeneration group compared with control subjects (12.1% vs 28.6%, respectively; P.0009). The epsilon4 allele was less frequent in the age-related macular degeneration group compared with control subjects (0.073 vs 0.149, respectively; P.006). This decreased frequency of the epsilon4 allele was mainly observed in the soft drusen subgroup compared with control subjects (0.045 vs 0.149, respectively; P.0009).This lower relative frequency of the epsilon4 allele supports the hypothesis that the ApoE gene is a genetic protective factor identified in age-related macular degeneration.

We discuss the role of the optical coherence tomography (OCT) in the diagnosis of challenging macular disorders through the presentation of four clinical cases. The first example describes a case of photic maculopathy secondary to uncomplicated cataract surgery. The OCT revealed a hyporeflective space (a ‘partial-thickness hole') and was particularly useful to make the correct diagnosis and follow the spontaneous disease progression. The second example describes a case of posttraumatic photoreceptor disruption. The OCT showed a focal disruption of the inner segment/outer segment junction in the foveal region and was a very useful tool in the diagnosis. The third example describes a case of spontaneous retinal pigmented epithelium rip in nonexudative age-related macular degeneration in which OCT was very useful to exclude choroidal neovascularization and visualize the retinal pigmented epithelium rip. The fourth example shows the usefulness of OCT for diagnosis and follow-up of the vitelliform macular dystrophy preclinical stage: in this phase there is initially a thicker and more reflective appearance of the Verhoeff‘s membrane.

Purpose To screen for mutations in the rhodopsin, peripherin/RDS, and ROM1 genes in a family affected with retinitis punctata albescens. Because clinical heterogeneity was observed in this family, with some members affected with retinitis punctata albescens and one member affected with features typical of retinitis pigmentosa, we analyzed the apolipoprotein E gene to elucidate this unusual intrafamilial heterogeneity. Methods The coding sequences of these genes were analyzed with a combination of single-strand conformation polymorphism and direct sequence analysis. Haplotypes of the apolipoprotein E gene were analyzed by polymerase chain reaction and enzymatic digestion. Results The Argl35Trp mutation in the rhodopsin gene was observed in all affected members of this family, but no mutation was detected in the peripherin/RDS or ROM1 genes. The e4 allele of the apolipoprotein E gene apparently cosegregated with the albescens phenotype in this family. Conclusions The albescent phenotype in retinal dystrophy appears to not be caused exclusively by a peripherin/RDS gene mutation, and we suggest that the apolipoprotein E gene may play a role in the albescent phenotype.

Age related macular degeneration (AMD) is the leading cause of vision loss in the elderly in developed countries. Genetic factors play a major role in this multifactorial and polygenic disease. Genomewide analysis identified two loci on 1q25-31 and 10q26 chromosomes associated with AMD, and association studies highlighted the implication of SNPs located in the complement H factor gene (CFH) on 1q25-31 and in PLEKHA1-HTRA1-LOC387715 on 10q26 in the disease. Homozygous carriers for the at-risk alleles of the CFH, HTRA1, and LOC387715 genes have an increased risk to develop exudative AMD with odds ratio of 6.2, 6.9, et 7.3 respectively. Moreover, other genes involved in the complement cascade, namely the genes of the C2, C3 component, and factor B, are associated to the disease. The SCARB1 gene has also recently been associated to AMD. Genotype-phenotype correlations have been performed in AMD patients and found that occult CNV are more often associated to CFH at-risk allele and classic CNV to HTRA1 at-risk allele. This last allele seems also linked to more severe forms of the disease. These new major genetic factors could lead to a new clinical approach of AMD and to the discovery of new therapeutic targets.