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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.

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.

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.

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.

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression.

Background: This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT). Methods: In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF8). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP), spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index. Results: Mean age of participants was 35±11 years with 49 (56%) female. Median qAF8 value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 µm (range 72-265) and median macular volume of 1.65 mm3 (range 1.13-2.19). Compared to persons without vision impairment, both reading performance and patient-reported visual function were significantly lower (p Conclusions: This trial design may serve as reference for future clinical trials as it explores the utility of qAF8 as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1. EudraCT registration: 2018-001496-20 (09/05/2019)

Sensitive and robust outcome measures of retinal function are pivotal for clinical trials in age-related macular degeneration (AMD). A recent development is the implementation of artificial intelligence (AI) to infer results of psychophysical examinations based on findings derived from multimodal imaging. We conducted a review of the current literature referenced in PubMed and Web of Science among others with the keywords 'artificial intelligence' and 'machine learning' in combination with 'perimetry', 'best-corrected visual acuity (BCVA)', 'retinal function' and 'age-related macular degeneration'. So far AI-based structure-function correlations have been applied to infer conventional visual field, fundus-controlled perimetry, and electroretinography data, as well as BCVA, and patient-reported outcome measures (PROM). In neovascular AMD, inference of BCVA (hereafter termed inferred BCVA) can estimate BCVA results with a root mean squared error of ~7-11 letters, which is comparable to the accuracy of actual visual acuity assessment. Further, AI-based structure-function correlation can successfully infer fundus-controlled perimetry (FCP) results both for mesopic as well as dark-adapted (DA) cyan and red testing (hereafter termed inferred sensitivity). Accuracy of inferred sensitivity can be augmented by adding short FCP examinations and reach mean absolute errors (MAE) of ~3-5 dB for mesopic, DA cyan and DA red testing. Inferred BCVA, and inferred retinal sensitivity, based on multimodal imaging, may be considered as a quasi-functional surrogate endpoint for future interventional clinical trials in the future.摘要: 对于年龄相关性黄斑变性(AMD)的临床试验来说, 敏感且强大的视网膜功能测量手段是至关重要的。近期的新进展是利用人工智能(AI)来解释多模式影像成像的心理物理检查结果。我们以“人工智能”和“机器学习”为关键词, 结合“视野测量”、“最佳矫正视力(BCVA)”、“视网膜功能”和“年龄相关性黄斑变性”, 对PubMed和Web of Science中的文献进行了综述。到目前为止, 基于人工智能的结构功能相关性的研究已被应用于传统的视野检查、FCP视野检查、视网膜电生理检查以及BCVA的检查和患者报告结果(PROM)的测量。对于新生血管性AMD, BCVA推理法(以下称为BCVA推测法)可以评估BCVA结果, 其均方根误差大约为7-11个字母, 这与实际视力评估的准确性相当。此外, 基于人工智能的结构功能相关性的研究可以成功推测FCP视野检查的结果, 包括中间视觉、暗适应(DA)青色和红色试验(以下称为灵敏度推测法)。通过增加短时间的FCP检查, 可以提高灵敏度推测法的准确性, 对于中间视觉法、暗适应青色法和暗适应红色法, 其平均绝对误差(MAE)约为3-5 dB。基于多模态成像的BCVA推测法和视网膜灵敏度推测法, 可被认为是未来干预性临床试验的功能评估手段的替代终点。.

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.Which criteria must be considered for the evaluation of AI-related studies in ophthalmology?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).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]).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.HINTERGRUND: Empirische Modelle sind seit Einführung der SRK(Sanders-Retzlaff-Kraff)-Formel im klinischen Alltag der Augenheilkunde etabliert. Rezente Entwicklungen im Bereich des statistischen Lernens („künstliche Intelligenz“ [KI]) ermöglichen jetzt ein empirisches Vorgehen für vielfältigste ophthalmologische Fragestellungen bei bislang unerreichter Präzision.Welche Kriterien müssen für die Bewertung von Arbeiten zum Thema KI in der Augenheilkunde berücksichtigt werden?Es erfolgen die beispielhafte Vorhersage des Visus (stetige Zielgröße) und Klassifikation von gesunden und kranken Augen (diskrete Zielgröße) anhand von retrospektiven optischen Kohärenztomographiebilddaten (50 Augen von 50 Patienten, 50 gesunde Augen von 50 Probanden). Die Daten wurden mit verschachtelter Kreuzvalidierung (zur Lernalgorithmusauswahl und Hyperparameteroptimierung) analysiert.Durch verschachtelte Kreuzvalidierung ließ sich der Visus im separaten Testdatensatz mit einem mittleren absoluten Fehler (MAE, [95 %-CI, Konfidenzintervall]) von 0,142 LogMAR [0,077; 0,207] vorhersagen. Kranke und gesunde Augen ließen sich im Testdatensatz mit einer Konkordanz von (Kappa nach Cohen) 0,92 klassifizieren. Die beispielhafte inkorrekte Lernalgorithmus- und Variablenauswahl resultierte in einem MAE von 0,229 LogMAR [0,150; 0,309] für den Testdatensatz. Erst durch Vergleich mit dem MAE des Nullmodells (0,235 LogMAR [0,148; 0,322]) wurde die Überanpassung offensichtlich.Die Auswahl einer ungeeigneten Kennzahl für die Anpassungsgüte, inadäquate Validierung oder Unterschlagen eines Null- oder Referenzmodells kann die tatsächliche Anpassungsgüte von KI-Modellen verschleiern. Die illustrierten Fallstricke können Klinikern und Forschern helfen, solche Unzulänglichkeiten zu erkennen.

Fundus-controlled perimetry (FCP, also called 'microperimetry') allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.

Purpose The aim of the study was to investigate optical coherence tomography angiography (OCTA) as a high-resolution in vivo imaging modality for monitoring therapeutic response to different vascular endothelial growth factor inhibitors in the rat model of laser-induced choroidal neovascularization (CNV). Further, OCTA findings were compared with fluorescein angiography (FA) and fluorescence microscopy. Methods Laser treatment at day (D)0 was followed by intravitreal injection of aflibercept, AF564, and NaCl in dark agouti rats. Imaging with OCTA and FA was performed at D2, D7, D14, and D21. OCTA was compared to FA as well as confocal imaged flat mounts and analysis included quantification of CNV area, pixel intensity, vessel density, and number of vessel junctions. Results Within laser lesions, neovascularization were visible especially in deeper retinal layers on OCTA, but not on FA images. Using OCTA, mean CNV area (D21) at the level of the outer nuclear layer (ONL) was 0.017 mm² following aflibercept administration, 0.016 mm² following AF564 and 0.026 mm² following NaCl injection (P = 0.04 and P = 0.03). Similar differences between treatment groups were determined by FA and histology, although the overall CNV area was always larger on FA due to dye leakage (P ≤ 0.0001, all layers). Conclusions Compared to FA, OCTA imaging allows for a more precise and quantitative analysis of new blood vessel formation and therapeutic response to vascular endothelial growth factor (VEGF)-inhibitors, whereas it does not permit assessment of leakage. Translational relevance These findings suggest that OCTA may be particularly useful for the investigation of new treatment targets in the animal model.

Purpose To longitudinally evaluate vision-related quality of life (VRQoL) in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Methods Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. Results A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. In the multivariable cross-sectional analysis, predictors of the VRQoL composite score were BCVA, GA size, and low-luminance visual acuity (LLVA) for the better eye and BCVA, foveal sparing status, and LLVA for the worse eye (cross-validated R2 = 0.32). In the longitudinal analysis, a similar prediction accuracy for VRQoL was determined (cross-validated R2 = 0.28). Prediction accuracy for VRQoL did not improve when follow-up time was added as an independent variable. Conclusions Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

Geographic atrophy (GA) represents the non-exudative late stage of age-related macular degeneration and constitutes a leading cause of legal blindness in the developed world. It is characterized by areas of loss of outer retinal layers including photoreceptors, degeneration of the retinal pigment epithelium, and rarefication of the choriocapillaris. As all three layers are functionally connected, the precise temporal sequence and relative contribution of these layers towards the development and progression of GA is unclear. The advent of optical coherence tomography angiography (OCT-A) has allowed for three-dimensional visualization of retinal blood flow. Using OCT-A, recent studies have demonstrated that choriocapillaris flow alterations are particularly associated with the development of GA, exceed atrophy boundaries spatially, and are a prognostic factor for future GA progression. Furthermore, OCT-A may be helpful to differentiate GA from mimicking diseases. Evidence for a potential protective effect of specific forms of choroidal neovascularization in the context of GA has been reported. This article aims to give a comprehensive review of the current literature concerning the application of OCT-A in GA, and summarizes the opportunities and limitations with regard to pathophysiologic considerations, differential diagnosis, study design, and patient assessment.

Purpose To investigate the association between retinal microstructure and cone- and rod-function in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) using artificial-intelligence-(AI) algorithms. Design Prospective, observational case series Methods Forty-one eyes of 41 patients (75.8±8.4 years; 22 female) from a tertiary referral hospital were included (Directional-Spread-in-Geographic-Atrophy (DSGA) natural history study; NCT02051998). Mesopic, dark-adapted (DA) cyan and red sensitivity were assessed using fundus-controlled perimetry (“microperimetry”); retinal microstructure using spectral-domain optical-coherence-tomography (SD-OCT), fundus autofluorescence (FAF) and near-infrared-reflectance (IR) imaging. Layer-thicknesses and -intensities and FAF- and IR-intensities were extracted for each test-point. We evaluated the cross-validated mean absolute error (MAE) for random-forest-based predictions of retinal sensitivity with and without patient-specific training-data and the increase mean-squared error (%IncMSE) as measure of feature-importance. Results Retinal sensitivity was predicted with a MAE of 4.64 dB for mesopic, 4.89 dB for DA cyan and 4.40 dB for DA red testing in absence of patient-specific data. Partial addition of patient-specific sensitivity data to the training sets decreased the MAE to 2.89 dB, 2.86 dB and 2.77 dB. For all three types of testing, the outer nuclear layer-thickness constituted the most important predictive feature (35.0, 42.22 and 53.74 %IncMSE). Spatially-resolved mapping of “inferred sensitivity” revealed regions with differential degrees of mesopic and DA cyan sensitivity loss outside of the GA lesions. Conclusions “Inferred sensitivity” accurately reflected retinal function in patients with GA. Mapping of “inferred sensitivity” could facilitate monitoring of disease progression and serve as “quasi functional” surrogate outcome in clinical trials, especially in consideration of retinal regions beyond areas of GA.

PURPOSE: To examine the feasibility and utility of dark-adapted two-color fundus-controlled perimetry (FCP) in patients with cuticular, reticular, and soft drusen, and to compare FCP data to microstructural spectral-domain optical coherence tomography (SD-OCT) data. METHODS: Forty-four eyes (24 eyes of 24 patients with drusen, age 69.4 ± 12.6 years; 20 normal eyes of 16 subjects, 61.7 ± 12.4 years) underwent duplicate mesopic, dark-adapted cyan and dark-adapted red FCP within 14° of the central retina (total of 12 936 threshold tests) using the Scotopic Macular Integrity Assessment (S-MAIA, CenterVue, Padova, Italy) device. FCP data were registered to SD-OCT data to obtain outer nuclear layer, inner and outer photoreceptor segment, and retinal pigment epithelium drusen complex (RPEDC) thickness data spatially corresponding to the stimulus location and area (0.43°). Structure-function correlations were assessed using mixed-effects models. RESULTS: Mean deviation values for eyes with cuticular, soft, and reticular drusen were similar for mesopic (-2.1, -3.4, and -3.6 dB) and dark-adapted red (-1.4, -2.6, and -3.3 dB) FCP. For the dark-adapted cyan FCP (0.1, -1.9, and -5.0 dB) and for the cyan-red sensitivity difference (+1.0, +0.5, and -2.4 dB), the mean deviation values differed significantly in dependence of the predominant drusen type (one-way ANOVA; p CONCLUSIONS: In contrast to mesopic FCP, dark-adapted two-color FCP allowed for meaningful differential testing of rod and cone function in patients with drusen indicating predominant cone dysfunction in eyes with cuticular drusen and predominant rod dysfunction in eyes with reticular drusen. RPEDC thickness was the strongest predictor of the evaluated SD-OCT biomarkers for point-wise sensitivity.

Background/AimsTo analyse the retest reliability of visual field indices and to describe patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry (FCP) in macular diseases.MethodsSeventy-seven eyes (30 eyes with macular diseases and 47 normal eyes) underwent duplicate mesopic and dark-adapted two-colour FCP (Scotopic Macular Integrity Assessment, CenterVue). Non-weighted (mean defect, loss variance), variability-weighted (mean deviation, pattern standard deviation (PSD)) and graphical (cumulative defect (Bebie) curves) indices were computed. Reproducibility (coefficient of repeatability, CoR) of these indices was assessed. Cluster analysis was carried out to identify patterns of visual field deficits.ResultsThe intrasession reproducibility was lower for the mean defect as compared with the mean deviation (CoR (dB) 2.67 vs 2.57 for mesopic, 1.71 vs 1.45 for dark-adapted cyan, 1.94 vs 1.87 for dark-adapted red testing) and lower for the square-root loss variance as compared with the PSD (CoR (dB) 1.48 vs 1.34, 0.77 vs 0.65, 1.23 vs 1.03). Hierarchical cluster analysis of the indices disclosed six patterns of visual field deficits (approximately unbiased P value>0.95) with varying degrees of global versus focal defect and rod versus cone dysfunction. These were also reflected by the cumulative defect curves.ConclusionFCP with mesopic and dark-adapted two-colour testing allows for reproducible assessment of different types of retinal sensitivity, whereby mean deviation and PSD exhibited the better retest reliability of the tested indices. Distinct patterns of retinal dysfunction can be identified using this setup, reflecting variable degrees of rod and cone dysfunction in different macular diseases. Dark-adapted two-colour FCP provides additional diagnostic information and allows for refined structure–function correlation in macular diseases.

Purpose: To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. Methods: A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. Results: For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R2 value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R2 value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in geographic atrophy progression in previously unknown patients and 39.1% in patients with previous observation. Conclusion: These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

To assess the longitudinal association between outer retinal microstructure and mesopic as well as scotopic retinal sensitivity in patients with drusen secondary to intermediate age-related macular degeneration (iAMD).Prospective, longitudinal natural history study.Fifty-nine eyes of 54 patients with large drusen (125 μm) associated with iAMD and 27 age-matched healthy control eyes.Participants underwent spectral-domain OCT and both mesopic and scotopic fundus-controlled perimetry (FCP). Annual follow-up visits were performed over a 3-year period.Pointwise correlation of retinal sensitivity stimuli to corresponding standardized (Z score) pointwise retinal thickness. Linear mixed-effect models were applied to analyze longitudinally the association of pointwise retinal thickness changes, follow-up time, or both with retinal function.At baseline, mean pointwise sensitivity in patients was reduced by -1.67 dB (95% confidence interval [CI], -2.22 to -1.12) for mesopic and by -2.34 dB (95% CI, -2.85 to -1.84) for scotopic testing compared with controls with a pointwise sensitivity change of -0.35 dB/year (95% CI, -0.43 to -0.28) for mesopic and +0.20 dB/year (95% CI, 0.12-0.29) for scotopic testing, respectively (P0.001). Retinal thickness analysis in patients revealed a significantly thinner outer nuclear layer (ONL) by -0.49 standard deviation (SD; 95% CI, -0.70 to -0.28 SD) and a significant thicker retinal pigment epithelium-drusen complex (RPEDC) by +3.22 SD (95% CI, 2.27-4.17 SD) at baseline, respectively (P0.001). During follow-up, retinal thickness thickened further by +0.51 SD/year (RPEDC) and thinned by -0.03 SD/year (ONL; P = 0.045) and -0.34 SD/year (inner and outer photoreceptor segments) in patients, respectively (P 0.001). Structure-function analysis showed a significant association of the ONL and the RPEDC thickness change with both types of FCP sensitivity testing (P0.001). Besides, follow-up time had a significant (independent) effect on mesopic and scotopic retinal sensitivity (P0.001).The longitudinal structure-function correlation demonstrated a progressive quantifiable degeneration of the outer retina in iAMD associated with photoreceptor dysfunction. Because longitudinal sensitivity changes could not be explained by structural changes alone, an unmet need remains for additional refined parameters on retinal structure to predict retinal function.

To analyze the intersession repeatability of structural biomarkers in eyes with early and intermediate age-related macular degeneration (iAMD) within the cross-sectional part of the observational multicenter MACUSTAR study.Certified site personnel obtained multimodal imaging data at two visits (38 ± 20 [mean ± standard deviation] days apart), including spectral-domain optical coherence tomography (SD-OCT). One junior reader performed systematic and blinded grading at the central reading center, followed by senior reader review. Structural biomarkers included maximum drusen size classification (63 to ≤125 µm vs.125 µm), presence of large pigment epithelium detachments (PEDs), reticular pseudodrusen (RPD), vitelliform lesions, and refractile deposits. Intrasession variability was assessed using Cohen's κ statistics.At the first visit, 202 study eyes of 202 participants were graded as manifesting with either early (n = 34) or intermediate (n = 168) AMD. Grading of imaging data between visits revealed perfect agreement for the maximum drusen size classification (κ = 0.817; 95% confidence interval, 0.70-0.94). In iAMD eyes, perfect to substantial agreement was determined for the presence of large PEDs (0.87; 0.69-1.00) and RPD (0.752; 0.63-0.87), while intersession agreement was lower for the presence of vitelliform lesions (0.649; 0.39-0.65) and refractile deposits (0.342; -0.029-0.713), respectively.Multimodal retinal imaging analysis between sessions showed a higher repeatability for structural biomarkers with predefined cutoff values than purely qualitative defined parameters.A high repeatability of retinal imaging biomarkers will be important to implement automatic grading approaches and to establish robust and meaningful structural clinical endpoints for future interventional clinical trials in patients with iAMD.

Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized.To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss.This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr110-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy.Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines.In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr110-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr110-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr110-risk and Chr10-risk. Eyes in the Chr110-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years).These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials.

Das ORCA-Modul der nichtinterventionellen OCEAN-Studie untersucht den Einsatz der bildgebenden Diagnostik in der klinischen Versorgung bei Patienten unter VEGF(„vascular endothelial growth factor“)-Hemmer-Behandlung. In der vorliegenden Arbeit werden zum Zeitpunkt der Basisvisite die Ubereinstimmung zwischen der dokumentierten Diagnose des Behandlers und der Auswertung durch Reading Center sowie Effekte auf den weiteren Verlauf analysiert. Insgesamt wurden 396 Patienten (Alter 75,4 Jahre) eingeschlossen, bei denen die Indikation zur Ranibizumab-Therapie aufgrund eines diabetischen Makulaodems (DMO), einer neovaskularen altersabhangigen Makuladegeneration (nvAMD) oder eines retinalen Venenverschlusses (RVV) durch die Behandler gestellt wurde. Uber 24 Monate erfolgte die systematische Erfassung von Patienten- und Untersuchungsdaten, Behandlungen sowie der Befundung bildgebender Diagnostik durch den Behandler. Zusatzlich erfolgte die Auswertung der Netzhautbildgebung durch 3 Reading Center. Bei 338 von 396 (85,4 %) Studienaugen wurde die Diagnose des Behandlers bei Therapiebeginn von den Reading Centern bestatigt (DMO 87,5 %, nvAMD 82,3 %, RVV 94,9 %). Bei 17 von 58 Augen mit diskrepanter Diagnose bestand zumindest Konsensus hinsichtlich der Indikation zur VEGF-Hemmer-Therapie. Insgesamt umfassten die ermittelten Differenzialdiagnosen eine Vielzahl von unterschiedlichen Netzhauterkrankungen. Augen mit ubereinstimmender Diagnose zeigten im Verlauf von bis zu 3 Monaten einen deutlicheren Visusanstieg (6,4 vs. 2,7 Buchstaben, p = 0,05) und einen starkerer Ruckgang der zentralen Netzhautdicke (−112,3 vs. −24,4 µm, p

Die YAG-Laser-Vitreolyse stellt ein innovatives Therapieverfahren zur Behandlung von storenden Glaskorpertrubungen dar. Voraussetzung ist eine kritische Indikationsstellung nach eingehender Anamneseerhebung, intensiver klinischer Untersuchung und ausfuhrlicher Risikoaufklarung mit realistischer Erwartungshaltung des Patienten. Die Morphologie von Glaskorpertrubungen und die damit subjektiv wahrgenommenen Beeintrachtigungen sind vielfaltig. Dynamische Veranderungen uber die Zeit sind moglich. Nicht alle sind zur Laserbehandlung geeignet. Eine Klassifizierung nach dem histoanatomischen Ursprungsort von Glaskorpertrubungen kann eine Entscheidungshilfe bei der Indikationsstellung sein. Im Vergleich zu anderen YAG-Laser-Behandlungen in der Ophthalmologie unterscheidet sich die YAG-Laser-Vitreolyse v. a. darin, dass besondere technische Voraussetzungen erforderlich sind. Zudem ist die Behandlung aufwendiger, erfordert entsprechende Erfahrung und Kenntnisse des Behandlers und sollte mit groser Sorgfalt durchgefuhrt werden.

Purpose To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). Design Consensus meeting. Participants Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. Methods As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. Main Outcome Measures A consensus classification system for atrophy and OCT-based criteria to identify atrophy. Results OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. Conclusions A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

Purpose: To evaluate two different spectral-domain optical coherence tomography (SD-OCT) scan patterns in eyes with intermediate age-related macular degeneration (AMD) for the longitudinal assessment of drusen volume. Methods: The data of 38 eyes of 38 AMD patients (age 69.97 ± 6.08 years) were included. The longitudinal drusen volume over 4 years was analyzed by annual SD-OCT raster scanning (field size 20 × 15°). Two raster scan patterns (A/B) differed in the distance between neighboring B-scans (240 vs. 30 µm) and in the number of averaged frames (4 vs. 15). Results: The mean drusen volume at baseline was 0.213 ± 0.100 mm3 (pattern A) and 0.219 ± 0.103 mm3 (pattern B) (p = 0.937). Linear mixed-effect models showed no significant difference for the change within 4 years for both pattern A (p = 0.8) and pattern B (p = 0.8). Conclusions: The results indicate that the performance of interpolation algorithms may be sufficient to balance for less dense raster scanning with regard to quantification of longitudinal drusen volume, which can be used as a surrogate marker for AMD progression in future clinical trials.

IMPORTANCE: As a disabling and frequent disease, geographic atrophy secondary to age-related macular degeneration (AMD) constitutes an important study subject. Emerging clinical trials require suitable end points. The characterization and validation of reading performance as a functional outcome parameter is warranted. OBJECTIVE: To prospectively evaluate reading performance in geographic atrophy and to assess its association with established visual function assessments and structural biomarkers. DESIGN, SETTING, AND PARTICIPANTS: The noninterventional, prospective natural history Directional Spread in Geographic Atrophy study included patients with geographic atrophy secondary to AMD who were recruited at the University Hospital in Bonn, Germany. Participants were enrolled from June 2013 to June 2016. Analysis began December 2019 and ended January 2021. MAIN OUTCOMES AND MEASURES: Reading acuity and reading speed were assessed using Radner charts. Longitudinal fundus autofluorescence and infrared reflectance images were semiautomatically annotated for geographic atrophy, followed by extraction of shape-descriptive variables. Linear mixed-effects models were applied to investigate the association of those variables with reading performance. RESULTS: A total of 150 eyes of 85 participants were included in this study (median [IQR] age, 77.9 [72.4-82.1] years; 51 women [60%]; 34 men [40%]). Reading performance was impaired with a median (IQR) monocular reading acuity of 0.9 (0.4-1.3) logarithm of the reading acuity determination and a reading speed of 52.8 (0-123) words per minute. In the multivariable cross-sectional analysis, best-corrected visual acuity, area of geographic atrophy in the central Early Treatment Diabetic Retinopathy Study (ETDRS) subfield, classification of noncenter vs center-involving geographic atrophy, and area of geographic atrophy in the inner-right ETDRS subfield showed strongest associations with reading acuity (cross-validated R(2) for reading acuity = 0.69). Regarding reading speed, the most relevant variables were best-corrected visual acuity, low-luminance visual acuity, area of geographic atrophy in the central ETDRS subfield, in the inner-right ETDRS subfield, and in the inner-upper ETDRS subfield (R(2) for reading speed = 0.67). In the longitudinal analysis, a similar prediction accuracy for reading performance was determined (R(2) for reading acuity = 0.73; R(2) for reading speed = 0.70). Prediction accuracy did not improve when follow-up time was added as an independent variable. Binocular reading performance did not differ from reading performance in the better-seeing eye. CONCLUSIONS AND RELEVANCE: The association of reading acuity and speed with visual functional and structural biomarkers supports the validity of reading performance as a meaningful end point in clinical trials. These findings suggest that measures in clinical and low-vision care for patients with geographic atrophy should focus primarily on the better-seeing eye.

PURPOSE To evaluate the impact of the vitreoretinal interface architecture, in specific the angle between the posterior vitreous cortex and the internal limiting membrane, on vitreomacular traction (VMT) resolution in eyes treated with intravitreally injected ocriplasmin (Jetrea). METHODS Retrospective, multicenter cohort study and exploratory data analysis. Spectral domain optical coherence tomography assessments were performed before scheduled ocriplasmin injections. General (age and sex) as well as ocular variables (lens status, presence of epiretinal membrane formations, horizontal diameter of VMT, central retinal thickness, and in particular various prespecified angles between the posterior vitreous cortex and internal limiting membrane) were analyzed to evaluate their impact on successful VMT resolution. RESULTS Fifty-nine eyes of 59 patients were included. Univariate analysis of age (odds ratio [OR]: 0.881; 95% CI: [0.812-0.955]; P = 0.0022) and lens status (OR: 11.03; 95% CI: [2.23-54.57]; P = 0.0033) had a significant impact on successful VMT resolution, whereas sex (OR: 0.668; 95% CI: [0.126-2.065]; P = 0.4906), epiretinal membrane formation (OR: 0.581; 95% CI: [0.168-2.006]; P = 0.3903), horizontal diameter of VMT (OR: 0.99930; 95% CI: [0.99825-1.00035]; P = 0.1886), and central retinal thickness (OR: 0.9985; 95% CI: [0.9934-1.00436]; P = 0.56) failed. The angle at 500 μm apart from the fovea centralis, irrespective if measured nasally (OR: 1.135; 95% CI: [1.013-1.272]; P = 0.0289) or temporally (OR: 1.099; 95% CI: [1.001-1.208]; P = 0.0485), showed a significant correlation with VMT resolution. CONCLUSION The angle between the posterior vitreous cortex and the internal limiting membrane 500 μm apart from the fovea centralis correlates with VMT resolution and may be a clinically useful marker for selection of patients to be treated with ocriplasmin. This observation needs to be proven in a prospective confirmatory investigation.