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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 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.

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.

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.

Gesetzliche Vorgaben zur Qualitatssicherung (QS) haben angesichts groser Patientenzahlen und fehleranfalliger Tatigkeiten auch eine grose Bedeutung fur die moderne Augenheilkunde. Der Beitrag diskutiert die Notwendigkeit und Formate der QS am Beispiel der intravitrealen operativen Medikamenteneingabe (IVOM). Die rechtlichen Rahmenbedingungen werden kurz referenziert, Verbesserungspotenziale des Status quo diskutiert. Erste Instrumente der Qualitatskontrolle wurden fur die IVOM-Therapie umgesetzt. Allerdings werden wichtige Qualitatsindikatoren (Zahl der Behandlungen pro Patient/Jahr, „loss of follow-up“, Funktionsverlauf) in Deutschland noch nicht flachendeckend evaluiert und konnen so fur eine standige Verbesserung und QS-Berichte nicht berucksichtigt werden. Bisher werden im Bereich der Basisdiagnostik und Verlaufskontrolle nicht alle beteiligten Augenarzte berucksichtigt; eine Beschrankung der QS allein auf Ophthalmochirurgen dient der Qualitat ebenso wenig wie die Blockade wissenschaftlicher Untersuchungen innerhalb von Selektivvertragen durch einzelne Krankenkassen. Fur die Qualitatssicherung der bildgebenden Diagnostik in der Augenheilkunde gibt es eine Notwendigkeit fur ahnliche Masnahmen, wie sie mit Stichproben und Ringversuchen in den radiologischen Disziplinen erfolgen. Die Kommunikation transparenter Qualitatsindikatoren kann das Risiko reduzieren, dass Prozess- und Ergebnisqualitat zu stark von Zufall, Kostendruck oder Bequemlichkeit beeinflusst werden. Die Hersteller von Software und Diagnostikgeraten sollten sich daran orientieren, dass der Austausch von Voxel-orientierten Bildformaten in der Radiologie mittlerweile immer weniger durch proprietare Formate behindert wird.

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.

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.

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 Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a non-invasive imaging modality to investigate the human retina. This study compares FLIO lifetimes in different degenerative retinal diseases. Methods Included were eyes with retinal pigment epithelium (RPE) and/or photoreceptor atrophy due to Stargardt disease (n = 66), pattern dystrophy (n = 18), macular telangiectasia type 2 (n = 49), retinitis pigmentosa (n = 28), choroideremia (n = 26), and geographic atrophy (n = 32) in age-related macular degeneration, as well as 37 eyes of 37 age-matched healthy controls. Subjects received Heidelberg Engineering FLIO, autofluorescence intensity, and optical coherence tomography imaging. Amplitude-weighted mean FLIO lifetimes (τm) were calculated and analyzed. Results Retinal FLIO lifetimes show significant differences depending on the disease. Atrophic areas in geographic atrophy and choroideremia showed longest mean FLIO lifetimes. τm values within areas of RPE and outer nuclear layer atrophy were significantly longer than within areas with preserved outer nuclear layer (P < 0.001) or non-atrophic areas (P < 0.001). Conclusions FLIO is able to contribute additional information regarding differences in chronic degenerative retinal diseases. Although it cannot replace conventional autofluorescence imaging, FLIO adds to the knowledge in these diseases and may help with the correct differentiation between them. This may lead to a more in-depth understanding of the pathomechanisms related to atrophy and types of progression. Translational Relevance Differences between atrophic retinal diseases highlighted by FLIO may indicate separate pathomechanisms leading to atrophy and disease progression.

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.

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 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.

In klinischen Studien bestehen im Vergleich zur klinischen Routine hohere Anforderungen, was einen zeitlichen Mehraufwand bedingt. Ziel dieser Arbeit ist die vollumfangliche Zeiterfassung an den deutschen ophthalmologischen Studienzentren. Mit 3 Fragebogen wurden bei den Mitgliedern der „Arbeitsgemeinschaft DOG Klinische Studienzentren“ der geschatzte Zeitaufwand fur die studienbezogenen Tatigkeiten, fur die Administration und prospektiv die tatsachliche Verwendung der Arbeitszeit abgefragt. Fur Letzteres wurde von jedem Mitarbeiter 3 Wochen lang zu jeder vollen Stunde ein Fragebogen ausgefullt („work sampling“). Die Fragebogen wurden von 9 der 11 angefragten Zentren ausgefullt. Insgesamt wurden 5504 Arbeitsstunden protokolliert. An einem durchschnittlichen Arbeitstag betrug der mittlere Aufwand fur Dokumentation und Administration jeweils 4 h. Signifikant waren auch operative Eingriffe (2,8 h), augenarztliche Untersuchungen (2,5 h) und Einwilligungsgesprache (1,5 h). Die protokollierte Dauer von Visusmessung, Einwilligung und Dokumentationen passte gut zu den Angaben aus den Fragebogen. Operative Eingriffe, augenarztliche Untersuchungen und die Handhabung von Bioproben wurden in der Dauer unterschatzt. Ein erheblicher Teil des Zeitaufwandes fallt fur Dokumentation an. Administrative Aufgaben sind ahnlich bedeutsam. Der uberraschend hohe Zeitbedarf fur operative Eingriffe, Untersuchungen und Handhabung von Bioproben resultiert wahrscheinlich aus Tatigkeiten zur Vor- und Nachbereitung, was im Kontext einer Vollkostenrechnung berucksichtigt werden muss. Viele administrative Tatigkeiten lassen sich zudem nicht ausreichend uber „case payments“ abbilden, sodass Zusatzvergutungen fur den kostendeckenden Betrieb eines ophthalmologischen Studienzentrums erforderlich sind.

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 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.

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.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm2/year (median, ∼1.78 mm2/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.

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 summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN: Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS: A panel of retina specialists. METHODS: During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES: Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS: Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS: A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.

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 compare the intermodality and interreader agreement for geographic atrophy (GA) lesion size quantification in green-light fundus autofluorescence (GAF; excitation = 518 nm) versus combined blue-light fundus autofluorescence (BAF; excitation = 488 nm) and near-infrared reflectance (NIR; 820 nm) -based grading. Methods Confocal scanning laser ophthalmoscopy (cSLO) GAF, BAF, and NIR images of 40 eyes from 29 patients (mean age 79.7 years) with GA secondary to AMD were recorded according to a standardized protocol. GA areas were analyzed in GAF, BAF combined with NIR (BAF+NIR), or BAF alone, by four independent readers using semiautomated software (RegionFinder; Heidelberg Engineering, Heidelberg, Germany). A mixed-effects model was used to assess the effect of image modality on the measured square-root lesion area. The coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were assessed for the square-root lesion area, lesion perimeter, and circularity. Results GAF-based measurements were on average 0.062 mm (95% confidence interval [CI] 0.04-0.08 mm) larger than BAF+NIR-based measurements and 0.077 mm (95% CI 0.06 - 0.10 mm) larger than BAF-based measurements. Interreader agreement was highest for GAF-based analysis ([CR, ICC] 0.196 mm, 0.995) followed by BAF+NIR (0.232 mm, 0.992) and BAF alone (0.263 mm, 0.991). The same was noted for the lesion perimeter and circularity. Post hoc review revealed that interreader differences were associated with media opacification interfering with lesion boundary demarcation to a larger extent in BAF than in GAF. Conclusions cSLO-based GAF and combined BAF+NIR imaging with semiautomated lesion delineation allow for an accurate and reproducible quantification of GA. The slightly better interreader agreement using cSLO GAF suggests that its use may be preferable in clinical trials examining the change in lesion size as a clinical endpoint.

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.

In view of the large number of patients and error-prone activities, legal requirements for quality assurance (QA) are of great importance for modern ophthalmology.This article discusses the need and formats of QA using the example of intravitreal operative medication injection therapy (IVOM).The legal framework conditions are briefly referenced and improvement potentials of the status quo are discussed.The first quality control instruments were implemented for IVOM therapy; however, important quality indicators (number of treatments per patient/year, loss of follow-up, course of function) are not yet evaluated nationwide in Germany and cannot therefore be taken into account for continuous improvement and QA reports. To date, not all ophthalmologists involved have been under review in the field of basic diagnostics and follow-up. Limiting QA to ophthalmic surgeons alone does not improve quality and many statutory health insurances actively prevent scientific investigations within selective contracts.For the QA of imaging diagnostics, similar proficiency measures (random samples, round robin testing) are required in ophthalmology as in radiological disciplines. The communication of transparent quality indicators can reduce the risk in the medium term. The quality of treatment and results must not be left to chance, cost pressure or convenience. The manufacturers of software and diagnostic equipment should be oriented towards radiology, where the exchange of voxel-oriented image formats is now less and less hindered by proprietary formats.

Purpose: To investigate residual sensitivity within geographic atrophy (GA) secondary to age-related macular degeneration. Methods: Mesopic and dark-adapted (DA) cyan and red light sensitivity (Goldmann III) were investigated using fundus-controlled perimetry (microperimetry). Test points were placed within GA along an “iso-hull” with a distance of −0.645° to the atrophy boundary. The false-positive response rate was determined with suprathreshold stimuli to the optic disc (Heijl-Krakau method) and used to compute the expected sensitivity measurements for the assumption of absolute scotomata. The outermost visible retinal layer on spectral-domain optical coherence tomography at the location of each test point was determined. Results: Thirty eyes of 36 patients (75.55 ± 7.93 years; 19 female) from the prospective natural history study Directional Spread in Geographic Atrophy (NCT02051998), with a total of 1380 threshold determinations were analyzed. The measured sensitivities were significantly (P < 0.01) higher than the expected values for absolute scotomata (mean ± standard error of +6.92 ± 0.86 dB for mesopic, +2.57 ± 0.56 dB for DA cyan, and +4.93 ± 0.74 dB for DA red testing). For mesopic testing and DA red testing, the presence of a residual outer nuclear layer had a significant effect on this discrepancy (P < 0.001). There was no effect of fixation stability or any other reliability index on this discrepancy. Conclusions: Measured sensitivities within the inner junctional zone of GA may not be purely explained by patient-specific false-positive response rates or other reliability indices. The marked influence of the outer retinal configuration on measured sensitivity may be indicative of residual cone function within GA at the inner junctional zone.

Age-related macular degeneration (AMD) is clinically divided into early and late stages. The term "dry" AMD is widely used when there are no "exudative" changes in the ocular fundus. There are numerous studies on the epidemiology of AMD. Most studies differentiate between early and late forms of AMD, but without further differentiation of the "dry" late form. In addition, different studies may employ different classifications of AMD, which inevitably leads to deviations in epidemiological data on AMD. New classification systems take into account microstructural changes that can be detected by high resolution in vivo imaging of the retina. A new consensus classification of AMD-associated atrophy will allow future studies to be conducted according to uniform definitions.Klinisch 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.

Purpose: To describe foveal sparing (FS) in central retinal dystrophies (RD). Methods: Participants for this retrospective study were identified from the retinal dystrophy database of the Department of Ophthalmology at Radboud University Medical Center. FS was defined as an intact foveal structure surrounded by at least 180° of chorioretinal atrophy, and a best-corrected visual acuity (BCVA) of 20/200 Snellen). Eligible eyes were identified using fundus autofluorescence (FAF) images, and FS was confirmed using near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography when available. Clinical and demographic data were extracted from medical records. We performed quantification of FS and chorioretinal atrophic areas using semiautomated software on fundus autofluorescence and NIR images. We calculated the chronologic change using eye-wise linear regression. Results: We identified 36 patients (56 eyes) with FS. RDs included: Stargardt disease (STGD1;20 patients), central areolar choroidal dystrophy (CACD; 7 patients), mitochondrial retinal dystrophy (MRD; 6 patients), pseudo-Stargardt pattern dystrophy (PSPD; 3 patients). Median age at first presentation was 60 (interquartile range [IQR] 54-63) years. Median BCVA at first presentation ranged from 20/25 Snellen in STGD1, to 20/38 Snellen in MRD. Progression of the chorioretinal atrophic area ranged from 0.26 (0.25-0.28) mm/year in PSPD, to 0.14 (0.11-0.22) in CACD. Change in FS area over time was similar between the different dystrophies. Conclusions: The presence of FS in different RDs suggests a disease-independent mechanism that prolongs the survival of the fovea. The associated preservation of BCVA is important for the individual prognosis and has implications for the design of therapeutic trials for RDs.

Purpose To analyze longitudinal thickness changes of retinal layers in comparison with established risk factors in eyes with age-related macular degeneration (AMD) with regard to their prognostic value for conversion into advanced AMD stages. Design Prospective, longitudinal natural history study. Participants Ninety-one eyes of 91 patients with AMD (73.3±7.3 years; 62 female patients [50.4%]) of the Molecular Diagnostic of Age-related Macular Degeneration (MODIAMD) study without exudative or nonexudative late-stage AMD in the study eye at baseline. Methods At each annual follow-up visit, all subjects underwent ophthalmic examination with assessment of best-corrected visual acuity (BCVA) and retinal imaging, including spectral-domain OCT (SD-OCT), over a study period of 6 years. Purpose To analyze longitudinal thickness changes of retinal layers in comparison with established risk factors in eyes with age-related macular degeneration (AMD) with regard to their prognostic value for conversion into advanced AMD stages. Main Outcome Measures Qualitative structural AMD features and SD-OCT–based quantitative thickness changes of different retinal layers, such as the retinal pigment epithelium-drusen complex (RPEDC), were assessed by multimodal imaging. Their prognostic relevance regarding disease conversion was determined using Cox regression (cloglog link function). Results In the multivariable analysis, the presence of focal hyperpigmentation, almost reaching statistical significance, showed the strongest effect regarding the development of nonexudative late-stage AMD (hazard ratio [HR], 5.88; 95% confidence interval [CI], 0.69–50.2; P = 0.052) followed by the presence of refractile drusen (HR, 4.82; 95% CI, 1.33–17.44; P = 0.0164). A thickening of the RPEDC was the only assessed retinal layer that exhibited a significant effect on the development of nonexudative advanced AMD (HR, 1.03; 95% CI, 1.0–1.07; P = 0.0393), whereas no association was observable for the other retinal layers. Neither qualitative nor quantitative markers were significant predictors for the development of exudative late-stage AMD (P > 0.05). Conclusions The results indicate that the development of both exudative and nonexudative AMD is associated with distinct prognostic features. However, compared with the assessment of qualitative AMD features, the quantification of retinal layers on average across the central retina had less prognostic impact. Further studies are needed to identify and validate robust biomarkers in early AMD stages.

Purpose: Based on exudative activity, choroidal neovascularization (CNV) in age-related macular degeneration (AMD) can be classified as “active” aCNV, pretherapied “silent” sCNV (i.e., a treatment-free interval >12 weeks), or treatment-naïve “quiescent” qCNV. We evaluated the qualitative and quantitative optical coherence tomography angiography (OCTA) features of these CNV subgroups. Methods: The presence of small-caliber vessels, peripheral arcades, and a ­perilesional OCTA signal attenuation as well as values for vessel length, density, and branching index were evaluated for each CNV network in a 6 × 6 mm OCTA scan pattern. Results: Fifty-one eyes of 51 patients with AMD (age 75.9 ± 7.5 years; 20 males [39.2%]) were included. The qCNV subgroup (n = 8) showed the highest prevalence of qualitative and quantitative values for OCTA activity criteria, reaching significance with regard to small-caliber vessels (p = 0.003), peripheral arcades (p = 0.039), vessel length (p = 0.020), and branching index (p < 0.001) when compared to the aCNV (n = 32) and sCNV (n = 11) subgroups. Qualitative criteria were inversely associated with the number of previous anti-VEGF injections (each p < 0.03), while quantitative metrics also suggested lower values. Conclusions: These findings suggest that OCTA may be supportive in the phenotypical differentiation of CNV lesions secondary to AMD, while the assessed structural changes appeared to be more indicative of previously administered anti-VEGF therapy than current exudative activity.

IMPORTANCE: Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. OBJECTIVE: To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. DESIGN, SETTING, AND PARTICIPANTS: This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). MAIN OUTCOMES: The correlation between square root–transformed geographic atrophy growth rate and 7 596 219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. MAIN OUTCOMES AND MEASURES: Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. RESULTS: A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10(−8)) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10(−7)) as the most likely progression-associated genes. CONCLUSIONS AND RELEVANCE: These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.

Purpose To probabilistically forecast needed anti-vascular endothelial growth factor (anti-VEGF) treatment frequency using volumetric spectral domain-optical coherence tomography (SD-OCT) biomarkers in neovascular age-related macular degeneration from real-world settings. Methods SD-OCT volume scans were segmented with a custom deep-learning-based analysis pipeline. Retinal thickness and reflectivity values were extracted for the central and the four inner Early Treatment Diabetic Retinopathy Study (ETDRS) subfields for six retinal layers (inner retina, outer nuclear layer, inner segments [IS], outer segments [OS], retinal pigment epithelium-drusen complex [RPEDC] and the choroid). Machine-learning models were probed to predict the anti-VEGF treatment frequency within the next 12 months. Probabilistic forecasting was performed using natural gradient boosting (NGBoost), which outputs a full probability distribution. The mean absolute error (MAE) between the predicted versus actual anti-VEGF treatment frequency was the primary outcome measure. Results In a total of 138 visits of 99 eyes with neovascular AMD (96 patients) from two clinical centers, the prediction of future anti-VEGF treatment frequency was observed with an accuracy (MAE [95% confidence interval]) of 2.60 injections/year [2.25-2.96] (R2 = 0.390) using random forest regression and 2.66 injections/year [2.31-3.01] (R2 = 0.094) using NGBoost, respectively. Prediction intervals were well calibrated and reflected the true uncertainty of NGBoost-based predictions. Standard deviation of RPEDC-thickness in the central ETDRS-subfield constituted an important predictor across models. Conclusions The proposed, fully automated pipeline enables probabilistic forecasting of future anti-VEGF treatment frequency in real-world settings. Translational relevance Prediction of a probability distribution allows the physician to inspect the underlying uncertainty. Predictive uncertainty estimates are essential to highlight cases where human-inspection and/or reversion to a fallback alternative is warranted.

Die optische Koharenztomographie (OCT) hat im Management von Patienten mit Makula- und Netzhauterkrankungen mittlerweile einen wichtigen Stellenwert eingenommen. Neben vielen Vorteilen dieses nichtinvasiven bildgebenden Verfahrens sind in der zunehmend breiten Anwendung auch Limitationen und Fallstricke zu beachten. Im vorliegenden Beitrag werden mogliche Fehlerquellen in der Durchfuhrung und Interpretation von OCT-Aufnahmen diskutiert. Damit soll ein Beitrag zu einem zielgerichteten und sinnvollen Einsatz im klinischen Alltag geleistet werden.

Purpose: To assess the intrasession test-retest reliability of scotopic cyan and scotopic red fundus-controlled perimetry (FCP) in normal subjects using a modified MAIA “microperimeter” (macular integrity assessment) device. Methods: Forty-seven normal eyes of 30 subjects (aged 33.8 years) underwent duplicate mesopic (achromatic stimuli, 400-800 nm), scotopic cyan (505 nm), and scotopic red (627 nm) FCP, using a grid of 49 stimuli over 14° of the central retina. Test-retest reliability for pointwise sensitivity (PWS), stability of fixation, reaction time and test duration were analyzed using mixed-effects models. Results: PWS test-retest reliability was good among all 3 types of retinal sensitivity assessments (coefficient of repeatability of 4.75 dB for mesopic, 5.26 dB for scotopic cyan, and 4.06 dB for scotopic red testing). While the mean sensitivity decreased with eccentricity for both mesopic and scotopic red testing, it was highest at 7° eccentricity for the scotopic cyan assessment (p < 0.001). Conclusions: The modified MAIA device allows for reliable scotopic FCP in normal subjects. Our findings suggest that testing of scotopic cyan sensitivity largely reflects rod function.

There is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term "geographic atrophy." Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals.We reviewed the nominal definition of the term "geographic atrophy" and conducted a search of the ophthalmologic literature focusing on preceding terminologies and the first citations of the term "geographic atrophy" secondary to age-related macular degeneration.According to the nominal definition, the term "geography" stands for a detailed description of the surface features of a specific region, indicating its relative position. However, it does not necessarily imply that the borders of the region must be sharply demarcated or related to any anatomical structures. The term "geographical areas of atrophy" was initially cited in the 1960s in the ophthalmologic literature in the context of uveitic eye disease and shortly thereafter also for the description of variants of "senile macular degeneration." However, no direct explanation could be found in the literature as to why the terms "geographical" and "geographic" were chosen. Presumably the terms were used as the atrophic regions resembled the map of a continent or well-defined country borders on thematic geographical maps. With the evolution of the terminology, the commonly used adjunct "of the retinal pigment epithelium" was frequently omitted and solely the term "geographic atrophy" prevailed for the nonexudative late-stage of age-related macular degeneration itself. Along with the quantification of atrophic areas, based on different imaging modalities and the use of both manual and semiautomated approaches, various and inconsistent definitions for the minimal lesion diameter or size of atrophic lesions have also emerged.Reconsideration of the application of the term "geographic atrophy" in the context of age-related macular degeneration seems to be prudent given ongoing advances in multimodal retinal imaging technology with identification of various phenotypic characteristics, and the observation of atrophy development in eyes under antiangiogenic therapy.

To correlate partial outer retinal thickness with scotopic and mesopic fundus-controlled perimetry in patients with reticular drusen (RDR).Observational case series with controls of similar age.Twenty eyes from 18 patients with RDR (mean age 75.8 years) and 20 eyes from 20 healthy controls (mean age 75.5 years) were included. Scotopic and mesopic fundus-controlled perimetry was performed in patients. The localized partial outer retinal thickness at the site of test stimuli was determined as the distance between the outer border of the outer plexiform layer and the inner border of the ellipsoid zone and topographically corrected according to measurements in controls.The mean partial outer retinal thickness in patients was 65.8 μm over areas with RDR and 76.4 μm (P.0001) over nonaffected retinal areas. Mesopic and scotopic sensitivity were reduced corresponding to areas with RDR (mean scotopic 12.8 dB and mean mesopic 17.2 dB) as compared to nonaffected retinal areas (18.2 dB and 18.4 dB) (P.001, P = .001). On average, a reduction of partial outer retinal thickness by 1 μm was associated with a decrease of scotopic function of 0.96 dB.The extent of outer retinal thinning in the presence of RDR is spatially associated with the extent of impairment in scotopic retinal function, indicating a direct structural-functional correlation of structural changes to loss of rod function. High-resolution retinal imaging in combination with scotopic fundus-controlled perimetry allows for a more refined structure-function correlation in diseases with a presumed higher vulnerability of rod compared with cone function.