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Anti-vascular endothelial growth factor therapies have proven effective in treating retinal diseases but come with a high financial burden to the patient and health care system. Biosimilar drugs present an opportunity to decrease the cost of these important ophthalmic medications, and several ophthalmic biosimilars are expected to be approved and enter the market in the coming years. The objectives of this review are to educate ophthalmologists on the safety and efficacy of biosimilars in ophthalmology in the United States and European Union, review the biosimilar manufacturing and approval process, and describe the upcoming ophthalmic biosimilars.Two ranibizumab biosimilars are currently approved in the United States and European Union. Additional ranibizumab biosimilars, as well as biosimilars for aflibercept and bevacizumab, are currently in clinical development.Biosimilar use in ophthalmology is expected to grow with the patent expiration of two major anti-vascular endothelial growth factor drugs, ranibizumab and aflibercept, and the development of an ophthalmology-specific bevacizumab biosimilar. Financial savings from biosimilar use in ophthalmology have the potential to reduce economic burden, increase treatment adherence, and ultimately improve health outcomes.

Background Pigment epithelial detachments (PEDs) occur in association with various chorioretinal diseases. With respect to the broad clinical spectrum of PEDs we describe fundus autofluorescence (FAF) characteristics of PEDs. Methods Ninety-three eyes of 66 patients (mean age 71.9 ± 11.1) with uni- or bilateral PED ( ≥ 350 µm) were included in a retrospective cross-sectional study. PEDs were secondary to age-related macular degeneration (n = 79), central serous chorioretinopathy (n = 7), polypoidal choroidal vasculopathy (n = 2), pattern dystrophy (n = 3) or idiopathic PED (n = 2). FAF images were recorded using confocal scanning laser ophthalmoscopy (488 nm excitation wavelength, detection of emission >500 nm). Diagnosis of PED was confirmed using spectral-domain optical coherence tomography. A qualitative FAF grading system was established, and grading was performed by two independent readers. Results PEDs showed highly variable characteristics on FAF imaging. FAF within the area of PED was found to be irregular/granular (n = 59, 63.4%), increased (n = 28, 30.1%), decreased (n = 3, 3.2 %), or normal (n = 3, 3.2%). Accompanying FAF changes included condensation of macular pigment (n = 67, 72.0%), focally increased FAF at the PED apex (n = 14, 15.1%) or elsewhere (n = 52, 55.9%), focally decreased FAF (n = 23, 24.7%), a cartwheel-like pattern (n = 10, 10.8%), a doughnut sign (n = 6, 6.5%), and a halo of decreased FAF encircling the PED (completely n = 20, 21.5% or incompletely n = 20, 21.5%). Conclusions PEDs show a variety of abnormal patterns on FAF imaging. These changes in FAF signals may be secondary to morphological and metabolic alterations within corresponding retinal layers and do not necessarily correspond with the underlying PED subtype or a specific pathology.

Aims: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital. Methods: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement. Results: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59). Conclusions: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology. Precis: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways.

Purpose This trial was conducted to investigate the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration (nAMD). Design This was a prospective, multicenter, evaluation-masked, parallel-group, 48-week, phase III randomized study. Participants A total of 477 patients were randomly assigned to receive FYB201 (n = 238) or reference ranibizumab (n = 239). Methods Patients received FYB201 or ranibizumab 0.5 mg by intravitreal injection in the study eye every four weeks. Main Outcome Measures The primary end point was change from baseline in best corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 8 weeks prior to the third monthly intravitreal injection. Biosimilarity of FYB201 to its originator was assessed via a two-sided equivalence test, with an equivalence margin in BCVA of 3 ETDRS letters. Results BCVA improved in both groups, with a mean improvement of +5.1 (FYB201) and +5.6 (reference ranibizumab) ETDRS letters at week 8. The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was –0.4 ETDRS letters with a 90% confidence interval (CI) of –1.6 to 0.9. Primary end point was met as the 90% CI was within the predefined equivalence margin. Adverse events were comparable between treatment groups. Conclusions FYB201 is biosimilar to reference ranibizumab in terms of clinical efficacy and ocular and systemic safety in the treatment of patients with nAMD.

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 μm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 μm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

Purpose To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural OCT. Design Consensus meeting. Participants International group that included those with expertise in imaging and AMD basic science and histology, and those with Reading Center experience in AMD clinical trials. Methods As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA, risk of progression to GA, or both. Attendees undertook premeeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histologic features. Each of these different features were then discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees to refine the consensus definitions and descriptions further. Results Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypotransmission or hypertransmission), features frequently seen in eyes with atrophy (e.g., refractile drusen), and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits). Conclusions An international consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.

To report the prevalence and topographic distribution of structural characteristics in study participants with age-related macular degeneration (AMD) and controls in the cross-sectional study part of the MACUSTAR study (ClinicalTrials.gov Identifier: NCT03349801).European, multicenter cohort study.301 eyes of 301 subjects with early (n=34), intermediate (n=168) and late AMD (n=43), as well as eyes without any AMD features (n=56).In study eyes with intermediate AMD (iAMD), the presence of structural AMD biomarkers including pigmentary abnormalities (PA), pigment-epithelium detachment (PED), refractile deposits, reticular pseudodrusen (RPD), hyperreflective foci (HRF), incomplete/complete retinal pigment epithelium and outer retinal atrophy (i/cRORA)) and quiescent choroidal neovascularization (qCNV) was systematically determined in the prospectively acquired multimodal retinal imaging cross-sectional data set of MACUSTAR. Retinal layer thicknesses and the retinal pigment-epithelium drusen complex (RPEDC) volume were determined for the total study cohort in spectral-domain optical coherence tomography (SD-OCT) imaging using a deep-learning based algorithm.Prevalence and topographic distribution of structural iAMD features.A total of 301 study eyes of 301 subjects with a mean (± standard deviation) age of 71.2 ± 7.20 years (63.1% female) were included. Besides large drusen, the most prevalent structural feature in intermediate AMD (iAMD) study eyes were PA (57.1%), followed by HRF (51.8%) and RPD (22.0%). PED lesions were observed in 4.8%, vitelliform lesions in 4.2%, refractile deposits in 3.0% and qCNV in 2.4%. Direct precursor lesions for manifest retinal atrophy were detected in 10.7% (iRORA) and 4.2% (cRORA) in iAMD eyes. Overall, highest RPEDC volume with a median of 98.92 x 10Detailed knowledge of the prevalence and distribution of structural iAMD biomarkers is vital to identifying reliable outcome measure for disease progression. Longitudinal analyses are needed to evaluate their prognostic value for conversion to advanced disease stages.

Introduction: This retrospective analysis assessed geographic atrophy (GA) progression in fellow eyes from the Proxima B trial intermediate age-related macular degeneration (iAMD) subcohort using high-resolution multimodal imaging anchored on optical coherence tomography (OCT). Methods: Thirty-two patients from the Proxima B iAMD subcohort were assessed; all had GA with no macular neovascularization (MNV) in the contralateral eye. Imaging data, including color fundus photography, fluorescein angiography, near-infrared reflectance, fundus autofluorescence (FAF), and spectral-domain OCT, were obtained. Features preceding progression/conversion to advanced AMD (drusen, reticular pseudodrusen [RPD], MNV, incomplete/complete retinal pigment epithelium and outer retinal atrophy [iRORA/cRORA]) were assessed. Results: Of 30 fellow eyes with available follow-up images, 12 converted to GA (FAF), 2 converted to MNV, and 16 were nonconverters during the review period (median: 17.8 months). iRORA/cRORA features (present in all converters at baseline) were identified on OCT in eyes that progressed to GA. Median time interval from iRORA to cRORA and from cRORA to GA was 7 months each. GA development/progression was either drusen- or RPD-associated (n = 6 each). Eyes with baseline RPD showed faster GA progression versus eyes with drusen (1.49 vs. 0.38 mm2/year). Conclusions: RPD presence was associated with rapid GA lesion enlargement and may provide an early indication of faster GA progression.

Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332).Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12.Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] +0.29 z-score units [0.16, 0.42],PThese findings suggest that pegcetacoplan could slow GA progression and lead to a lesser thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration.

Introduction: For ophthalmologic research, the systematic correlation of clinical data with data obtained from postmortem tissue donation is of great benefit. In this respect, the establishment of an eye donation registry represents a prerequisite for the acquisition of such data. Methods: A total of 300 patients were interviewed at a tertiary referral center in Germany by means of a standardized questionnaire. Binary questions were evaluated by percentage; Likert-scaled questions (1 = does apply; 5 = does not apply) were analyzed by the median and 25th (Q25) and 75th (Q75) percentiles. Results: The majority of patients (77.0%) would agree to donate their eyes for research purposes. When asked about reasons against an eye donation, 60.9% of all patients only stated reasons in the category “addressable” (e.g., not enough awareness of the topic). The vast majority of patients considered it appropriate for an ophthalmologist to approach them on the issue of postmortem eye donation (median 1, Q25 1, Q75 1). Conclusion: Overall, patients had a positive attitude towards postmortem eye donation for research purposes. Importantly, reasons given against postmortem eye donation were often related to misconceptions and were potentially addressable. These results underline the fundamental willingness of ophthalmological patients in Germany to donate their eyes postmortem for research purposes.

Background/aimsThe prospective, non-interventional ORCA module of the OCEAN study (Observation of Treatment Patterns with Lucentis in Approved Indications) evaluated the qualiy of spectral domain-optical coherence tomography (SD-OCT) image interpretation and treatment decisions by clinicians in Germany and the impact on visual outcomes over 24 months in patients with neovascular age-related macular degeneration (nAMD).Methods2286 SD-OCT scans of 205 eyes were independently evaluated by clinicians and reading centres (RCs) regarding signs of choroidal neovascularisation (CNV) activity, including presence of intraretinal fluid, subretinal fluid, and/or increase in pigment epithelial detachments. Agreement between clinicians and RCs was calculated. Treatment decisions by clinicians and the impact on treatment outcomes were evaluated.ResultsCNV activity was detected by RCs on 1578 scans (69.0%) and by clinicians on 1392 scans (60.9%), with agreement in 74.9% of cases. Of the 1578 scans with RC detected CNV activity, anti-vascular endothelial growth factor injections were performed by clinicians in only 35.5% (560/1578). In 19.7% of cases (311/1578), lack of treatment was justified by patients request, termination criteria or chronic cystoid spaces without other signs for CNV activity. In 44.8% of cases (707/1578) with RC detected CNV activity, clinicians claimed no treatment was necessary despite having correctly detected CNV activity in about 2/3 of these cases. In 34% of cases with presumed undertreatment, visual acuity declined in the following visit.ConclusionAlthough broad agreement on CNV activity parameters was observed between clinicians and RCs, correct identification of CNV activity did not always lead to the initiation of (re-)treatment. To preserve vision over time, correct interpretation of SD-OCT scans and careful retreatment decisions are required.Trial registration numberNCT02194803.

BACKGROUND Empirical models have been an integral part of everyday clinical practice in ophthalmology since the introduction of the Sanders-Retzlaff-Kraff (SRK) formula. Recent developments in the field of statistical learning (artificial intelligence, AI) now enable an empirical approach to a wide range of ophthalmological questions with an unprecedented precision. OBJECTIVE Which criteria must be considered for the evaluation of AI-related studies in ophthalmology? MATERIAL AND METHODS Exemplary prediction of visual acuity (continuous outcome) and classification of healthy and diseased eyes (discrete outcome) using retrospectively compiled optical coherence tomography data (50 eyes of 50 patients, 50 healthy eyes of 50 subjects). The data were analyzed with nested cross-validation (for learning algorithm selection and hyperparameter optimization). RESULTS Based on nested cross-validation for training, visual acuity could be predicted in the separate test data-set with a mean absolute error (MAE, 95% confidence interval, CI of 0.142 LogMAR [0.077; 0.207]). Healthy versus diseased eyes could be classified in the test data-set with an agreement of 0.92 (Cohen's kappa). The exemplary incorrect learning algorithm and variable selection resulted in an MAE for visual acuity prediction of 0.229 LogMAR [0.150; 0.309] for the test data-set. The drastic overfitting became obvious on comparison of the MAE with the null model MAE (0.235 LogMAR [0.148; 0.322]). CONCLUSION Selection of an unsuitable measure of the goodness-of-fit, inadequate validation, or withholding of a null or reference model can obscure the actual goodness-of-fit of AI models. The illustrated pitfalls can help clinicians to identify such shortcomings.

Purpose To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). Design Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. Participants Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N = 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n = 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n = 32). Methods Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. Main Outcome Measures Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). Results At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were −13.88 (1.40) and −7.64 (1.20) in Proxima A, −9.49 (1.29) and −7.57 (1.26) in Proxima B fellow eye CNV cohort, and −11.48 (3.39) and −8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. Conclusions The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.

Purpose To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data. Design Consensus meeting. Participants An international panel of retina specialists, imaging and image reading center experts, and ocular pathologists. Methods During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components. Main Outcome Measures A consensus classification of neovascular AMD. Results The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated. Conclusions The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.

BackgroundTo characterise early stages of geographic atrophy (GA) development in age-related macular degeneration (AMD) and to determine the prognostic value of structural precursor lesions in eyes with intermediate (i) AMD on the subsequent GA progression.MethodsStructural precursor lesions for atrophic areas (lesion size at least 0.5 mm² in fundus autofluorescence images) were retrospectively identified based on multimodal imaging and evaluated for association with the subsequent GA enlargement rates (square-root transformed, sqrt). A linear mixed-effects model was used to account for the hierarchical nature of the data with a Tukey post hoc test to assess the impact of the local precursor on the subsequent GA progression rate.ResultsA total of 39 eyes with GA of 34 patients with a mean age of 74.4±6.7 (±SD) years were included in this study. Five precursor lesions (phenotypes 1–5) preceding GA development were identified: large, sub-retinal pigment epithelial drusen (n=19), reticular pseudodrusen (RPD, n=10), refractile deposits (n=4), pigment epithelial detachment (n=4) and vitelliform lesions (n=2). Precursor lesions exhibited a significant association with the subsequent (sqrt) GA progression rates (p=0.0018) with RPD (phenotype 2) being associated with the fastest GA enlargement (2.29±0.52 (±SE) mm/year.ConclusionsThe results indicate the prognostic relevance of iAMD phenotyping for subsequent GA progression highlighting the role of structural AMD features across different AMD stages.

Purpose: To investigate the association between the presence of type 1 choroidal neovascularization (CNV) and the localized progression of atrophy in age-related macular degeneration (AMD). Design: Analysis of patients’ data collected in the context of 2 noninterventional, prospective studies conducted at the Department of Ophthalmology, University of Bonn, Germany. Participants: A total of 98 eyes diagnosed with AMD of 59 patients (40 female, 19 male) with a mean (±standard deviation) age at baseline of 76.60±6.65 years and median (interquartile range) review period of 1.17 years (1.01–1.55) were included. Eyes were subdivided into 3 categories based on multimodal imaging and ocular history: retinal pigment epithelium (RPE) atrophy with treatment-naïve quiescent CNV (n=7), RPE atrophy with a history of exudative CNV (n=10), and RPE atrophy without evidence of coexisting CNV (n=81). Methods: Retinal pigment epithelium atrophy was delineated on the basis of serial fundus-autofluorescence and infrared-reflectance images. If CNV was detected by OCT angiography (OCTA), its location and dimension were spatially mapped to RPE atrophy. The localized progression of RPE atrophy in topographic relation to the CNV lesion was then analyzed using mixed-effects logistic regression. The spatial overlap (Dice coefficient) between predicted and observed RPE atrophy progression was evaluated to estimate the model accuracy. Main Outcome Measures: Odds ratio (OR) for localized RPE atrophy progression in areas overlying type 1 CNV. Results: The prediction model achieved a high overlap between predicted and observed RPE atrophy progression with a cross-validated Dice coefficient of 0.87 (95% confidence interval [CI], 0.85–0.89) reflecting a high accuracy. The odds for future RPE atrophy involvement were reduced by a factor of 0.21 (95% CI, 0.19–0.24) in the presence of treatment-naïve quiescent type 1 CNV and by a factor of 0.46 (95% CI, 0.41–0.51) in the presence of exudative type 1 CNV. Conclusions: The results indicate that there is markedly reduced RPE atrophy progression in areas co-localizing with quiescent and exudative type 1 CNV. This observation is compatible with a potential protective effect of type 1 CNV on the RPE and overlying neurosensory retina. These results may have relevant clinical implications for the management of CNV and lead to new therapeutic strategies to prevent atrophy progression.

Purpose To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. Design Consensus meeting. Participants Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. Methods As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. Main Outcome Measures Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. Results OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. Conclusions An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

Zusammenfassung Einleitung Retinale arterielle Verschlüsse (RAV) führen bei betroffenen Patienten häufig zu einer dramatischen und irreversiblen Visusreduktion. Bis dato existiert keine evidenzbasierte Standardtherapie. Die systemische Lysetherapie kann nach der Leitlinie zu retinalen arteriellen Verschlüssen der DOG, RG und BVA bis zu einem Zeitfenster von 4 h 30 min angewendet werden. Methoden Wir berichten über 2 Patienten, bei denen ein RAV im Zeitfenster mit einer intravenösen Lysetherapie behandelt wurde. Ergebnisse Bei Patient 1 wurde eine systemische Lysetherapie bei einem Verschluss der A. temporalis inferior 4 h 15 min nach Symptombeginn angewendet. Unmittelbar im Anschluss an die Therapie berichtete der Patient von einer deutlichen Symptombesserung. Drei Monate nach der Therapie bestand eine gute retinale Funktion bei dezenter Atrophie der neurosensorischen Netzhaut. Bei Patient 2 kam es 2 h 30 min nach Symptombeginn bei einem Verschluss der A. temporalis inferior zu einer weiteren Verschlechterung des Visus auf Lichtscheinwahrnehmung mit Zeichen eines Zentralarterienverschlusses (ZAV). Eine notfallmäßige Lysetherapie, die 3 h später durchgeführt wurde, ergab eine deutliche Visusbesserung mit Erhalt des Gesichtsfeldes im inferioren Bereich. Bei beiden Patienten kam es unmittelbar im Anschluss an die Lysetherapie zu einer deutlichen Befundbesserung: Patient 1, rechtes Auge: BCVA initial: 0,5; BCVA 3 Tage nach Lysetherapie: 1,0; keine Defekte im Goldmann-Gesichtsfeld. Patient 2, linkes Auge: BCVA initial: 0,4; dann beobachteter Visusabfall auf Lichtscheinwahrnehmung, BCVA 4 Wochen nach Lysetherapie: 0,6. Schlussfolgerung Zwei Patienten mit akuten arteriellen retinalen Verschlüssen konnten mit einer systemischen Lysetherapie erfolgreich behandelt werden.

Purpose The non-interventional OCEAN study (NCT02194803) evaluated frequency and monitoring of ranibizumab injections for retinal vein occlusion (RVO) in routine practice in Germany. Methods RVO patients (including branch and central RVO (BRVO/CRVO)) receiving ranibizumab were included. Best-corrected visual acuity (BCVA) testing, imaging and treatment were performed at the investigators' discretion and documented over 24 months. Results Overall, 744 RVO patients (27% BRVO, 16% CRVO, remaining unspecified RVO) were included. For 74% of patients, data were available for the 12-month visit and for 56% for the 24-month visit. Mean baseline BCVA was 52.0 Early Treatment for Diabetic Retinopathy Study (ETDRS) letters (BRVO: 55.9, CRVO: 43.9). BCVA improved rapidly within the first 3 months, reaching 64.3 letters at 12 months and 64.7 at 24 months. CRVO patients showed less improvement than those with BRVO. Patients received a median of 4 (5) injections over 12 (24) months, with 100% of patients receiving injections at baseline, 70% at Month 1 and 81% at Month 2. Overall, 40% of patients demonstrated a ≥15 letter increase within the first 3 months (42% BRVO, 46% CRVO). Patients with low initial BCVA (

Purpose: To compare ischemia-related clinical outcomes in patients treated with either ranibizumab pro re nata (PRN) or single dexamethasone implant in the Branch Retinal Vein Occlusion (COMRADE-B)...

ZusammenfassungKlinisch wird die altersabhängige Makuladegeneration (AMD) in Früh- und Spätstadien eingeteilt. Der Begriff „trockene“ AMD wird häufig verwendet, wenn keine „exsudativen“ Veränderungen am Augenhintergrund vorliegen. Es existiert eine Vielzahl von Studien zur Epidemiologie der AMD. Dabei wird in den meisten Studien zwischen AMD-Früh- und -Spätformen unterschieden, allerdings ohne eine weitere Differenzierung der „trockenen“ AMD-Spätform. Zudem stellt sich die Herausforderung unterschiedlicher Klassifikationen der AMD in verschiedenen Studien, was zwangsläufig zu Abweichungen in den epidemiologischen Daten bei der AMD führt. Neue Klassifikationssysteme berücksichtigen mikrostrukturelle Veränderungen, die mittels hochauflösender In-vivo-Bildgebung der Netzhaut detektiert werden können. Eine neue Konsensusklassifikation der AMD-assoziierten Atrophie soll ermöglichen, zukünftige Studien nach einheitlichen Definitionen durchzuführen.

Aim of the study was to compare optical coherence tomography angiography (OCT-A) and conventional fluorescein angiography (FA) for quantitative analysis of the retinal and choroidal vasculature in the animal model of laser-induced choroidal neovascularization (CNV). Therefore, Dark Agouti rats underwent argon laser photocoagulation to induce CNV at D0. In vivo imaging using combined confocal scanner laser ophthalmoscopy (cSLO)-based FA and OCT-A (Heidelberg Engineering GmbH, Heidelberg, Germany) was performed before and immediately after laser treatment as well as at day 2, 7, 14 and 21. OCT-A en-face images were compared to cSLO images obtained by conventional FA topographic uptake recorded using a series of different pre-defined focus settings. For a quantitative comparison of CNV imaging by OCT-A and FA, CNV area, vessel density, number of vessel junctions, total vessel length and number of vessel end points were analyzed. Subsequent ex vivo analyses of the CNV included immunofluorescence staining of vessels in retinal and RPE/choroidal/scleral flatmount preparations. We found, that OCT-A allowed for high-resolution non-invasive imaging of the superficial, intermediate and deep retinal capillary plexus as well as the choroidal blood vessels in rats. Compared with OCT-A, visualization of CNV progression by invasive FA was less accurate, in particular the deep vascular plexus was visualized in more detail by OCT-A. The area of neovascularization was mainly detected in the deep retinal vascular plexus, outer nuclear layer (ONL), ellipsoid zone (EZ) and the choroid. Within the laser lesions, signs of CNV formation occurred at day 7 with progression in size and number of small vessels until day 21. Due to leakage and staining effects, CNV areas appeared significantly larger in FA compared to OCT-A images (p ≤ 0.0001 for all tested layers). Vessel density, number of vessel junctions, total vessel length and number of vessel end points were significantly higher in intermediate vascular plexus (IVP) and deep vascular plexus (DVP) in OCT-A compared to FA images. Overall, CNV area in flatmounts was similar to OCT-A results and much smaller compared to the area of dye leakage by FA. This study demonstrates that in vivo OCT-A imaging in small animals is feasible and allows for precise analysis of the formation of new blood vessel formation in the animal model of laser-induced CNV. Given its superior axial resolution, sensitivity and non-invasiveness compared to conventional FA imaging, OCT-A opens the door for a more detailed evaluation of CNV development in such a model and, thus, enables the analysis of the response to novel therapeutic interventions in longitudinal in vivo studies.

Spatially-resolved mapping of rod- and cone-function may facilitate monitoring of macular diseases and serve as a functional outcome parameter. However, mesopic and dark-adapted two-color fundus-controlled perimetry (FCP, also called “microperimetry”) constitute laborious examinations. We have devised a machine-learning-based approach to predict mesopic and dark-adapted (DA) retinal sensitivity in eyes with neovascular age-related macular degeneration (nAMD). Extensive psychophysical testing and volumetric multimodal retinal imaging data were acquired including mesopic, DA red and DA cyan FCP, spectral-domain optical coherence tomography and confocal scanning laser ophthalmoscopy infrared reflectance and fundus autofluorescence imaging. With patient-wise leave-one-out cross-validation, we have been able to achieve prediction accuracies of (mean absolute error, MAE [95% CI]) 3.94 dB [3.38, 4.5] for mesopic, 4.93 dB [4.59, 5.27] for DA cyan and 4.02 dB [3.63, 4.42] for DA red testing. Partial addition of patient-specific sensitivity data decreased the cross-validated MAE to 2.8 dB [2.51, 3.09], 3.71 dB [3.46, 3.96], and 2.85 dB [2.62, 3.08]. The most important predictive feature was outer nuclear layer thickness. This artificial intelligence-based analysis strategy, termed “inferred sensitivity”, herein, enables to estimate differential effects of retinal structural abnormalities on cone- and rod-function in nAMD, and may be used as quasi-functional surrogate endpoint in future clinical trials.

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.

Purpose To determine the minimal optical coherence tomography B-scan density for reliable detection of intraretinal and subretinal fluid. Methods Spectral domain optical coherence tomography raster scanning (Spectralis; Heidelberg Engineering, Heidelberg, Germany) using a scan field of 20° × 20° of 97 B-scans with an interscan distance (ISD) of 60 μm was performed in 150 eyes of 150 consecutive patients at monitoring visits for intravitreal anti-vascular endothelial growth factor therapy. Using custom software, every other B-scan was repeatedly deleted to generate additional data sets with an ISD of 120 μm (49 B-scans), 240 μm (25 B-scans), and 480 μm (13 B-scans). Two independent reviewers evaluated the data sets for the presence of cystoid spaces of intraretinal fluid and subretinal fluid. Results Treatment diagnoses were neovascular age-related macular degeneration (68.0%), macular edema secondary to retinal vein occlusion (20.7%), diabetic macular edema (10.7%), and other retinal diseases (4.0%). Using the source data sets with an ISD of 60 μm, intraretinal fluid was detected in 56.0%, subretinal fluid in 19.3%, and either/both in 68.7%. Compared with these results, the sensitivity of detection of intraretinal fluid and/or subretinal fluid using an ISD of 120 μm, 240 μm, and 480 μm was 99.0% (95% confidence interval, 94.7-100.0; P = 0.5), 97.1% (91.7-99.4; P = 0.1), and 87.4% (79.4-93.1; P = 0.0001), respectively. Conclusion An increase of ISD up to 240 μm does not significantly impair the detection of treatment-relevant exudative retinal changes in monitoring during intravitreal therapy of macular diseases. These findings are relevant for the choice of optical coherence tomography B-scan density in both routine clinical care and interventional clinical studies.

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the industrialized world. AMD is characterized by accumulation of extracellular deposits, namely drusen, along with progressive degeneration of photoreceptors and adjacent tissues. AMD is a multifactorial disease encompassing a complex interplay between ageing, environmental risk factors and genetic susceptibility. Chronic inflammation, lipid deposition, oxidative stress and impaired extracellular matrix maintenance are strongly implicated in AMD pathogenesis. However, the exact interactions of pathophysiological events that culminate in drusen formation and the associated degeneration processes remain to be elucidated. Despite tremendous advances in clinical care and in unravelling pathophysiological mechanisms, the unmet medical need related to AMD remains substantial. Although there have been major breakthroughs in the treatment of exudative AMD, no efficacious treatment is yet available to prevent progressive irreversible photoreceptor degeneration, which leads to central vision loss. Compelling progress in high-resolution retinal imaging has enabled refined phenotyping of AMD in vivo. These insights, in combination with clinicopathological and genetic correlations, have underscored the heterogeneity of AMD. Hence, our current understanding promotes the view that AMD represents a disease spectrum comprising distinct phenotypes with different mechanisms of pathogenesis. Hence, tailoring therapeutics to specific phenotypes and stages may, in the future, be the key to preventing irreversible vision loss.

To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD).Interreader agreement study.Twelve readers from 6 reading centers.After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy.Interreader agreement based on Gwet's first-order agreement coefficient (ACSubstantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (ACAssessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

The Acknowledgements section in the original version of this Article was incomplete. ""This research was supported by the Else Kröner-Fresenius Foundation/German Scholars Organization (EKFS/GSO 16) to RF, the BONFOR GEROK Program, Faculty of Medicine, University of Bonn, (Grant No. O-137.0028) to MW, the GEROK Program, Faculty of Medicine, University of Bonn, (Grant No. O-137.0026) to ST and the German Ministry of Education and Research (BMBF), FKZ 13N10349. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report."" now reads: ""This research was supported by the Else Kröner-Fresenius Foundation/German Scholars Organization (EKFS/GSO 16) to RF, the BONFOR GEROK Program, Faculty of Medicine, University of Bonn, (Grant No. O-137.0028) to MW, the GEROK Program, Faculty of Medicine, University of Bonn, (Grant No. O-137.0026) to ST and the German Ministry of Education and Research (BMBF), FKZ 13N10349. The work of Shekoufeh Gorgi Zadeh was supported by a grant from Deutsche Forschungsgemeinschaft (DFG), grant number SCHM 2966/2-1. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report."" The original Article has been corrected.