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Purpose: The purpose of this study was to provide a large, multi-center normative dataset for the Macular Integrity Assessment (MAIA) microperimeter and compare the goodness-of-fit and prediction interval calibration-error for a panel of hill-of-vision models., Methods: Microperimetry examinations of healthy eyes from five independent study groups and one previously available dataset were included (1137 tests from 531 eyes of 432 participants [223 women and 209 men]). Linear mixed models (LMMs) were fitted to the data to obtain interpretable hill-of-vision models. A panel of regression models to predict normative data was compared using cross-validation with site-wise splits. The mean absolute error (MAE) and miscalibration area (area between the calibration curve and the ideal diagonal) were evaluated as the performance measures., Results: Based on the parameters "participant age," "eccentricity from the fovea," "overlap with the central fixation target," and "eccentricity along the four principal meridians," a Bayesian mixed model had the lowest MAE (2.13 decibel [dB]; 95% confidence interval [CI] = 1.9-2.36 dB) and miscalibration area (0.13; 95% CI = 0.07-0.19). However, a parsimonious linear model provided a comparable MAE (2.17 dB; 95% CI = 1.93-2.4 dB) and a similar miscalibration area (0.14; 95% CI = 0.08-0.2)., Conclusions: Normal variations in visual sensitivity on mesopic microperimetry can be effectively explained by a linear model that includes age and eccentricity. The dataset and a code vignette are provided for estimating normative values across a large range of retinal locations, applicable to customized testing patterns.

Background/aims: To investigate the progression of quantitative autofluorescence (qAF) measures and the potential as clinical trial endpoint in ABCA4 -related retinopathy., Methods: In this longitudinal monocentre study, 64 patients with ABCA4 -related retinopathy (age (mean±SD), 34.84±16.36 years) underwent serial retinal imaging, including optical coherence tomography (OCT) and qAF (488 nm excitation) imaging using a modified confocal scanning laser ophthalmoscope with a mean (±SD) review period of 20.32±10.90 months. A group of 110 healthy subjects served as controls. Retest variability, changes of qAF measures over time and its association with genotype and phenotype were analysed. Furthermore, individual prognostic feature importance was assessed, and sample size calculations for future interventional trials were performed., Results: Compared with controls, qAF levels of patients were significantly elevated. The test-retest reliability revealed a 95% coefficient of repeatability of 20.37. During the observation time, young patients, patients with a mild phenotype (morphological and functional) and patients with mild mutations showed an absolute and relative increase in qAF values, while patients with advanced disease manifestation (morphological and functional), and homozygous mutations at adulthood revealed a decrease in qAF. Considering these parameters, required sample size and study duration could significantly be reduced., Conclusion: Under standardised settings with elaborated conditions towards operators and analysis to counterbalance variability, qAF imaging might be reliable, suitable for quantifying disease progression and constitutes a potential clinical surrogate marker in ABCA4 -related retinopathy. Trial design based on patients' baseline characteristics and genotype has the potential to provide benefits regarding required cohort size and absolute number of visits., Competing Interests: Competing interests: PLM received grants and personal fees from Novartis, grants from Bayer and grants Santen outside the submitted work. AT received personal fees from Allergan, grants and personal fees from Bayer, personal fees from Kanghong, personal fees from Heidelberg Engineering, grants and personal fees from Novartis, personal fees from Roche/Genentech, personal fees from Iveric Bio, personal fees from Apellis and personal fees from Thea outside the submitted work. FGH received grants, personal fees and non-financial support from Heidelberg Engineering, grants and personal fees from Novartis, grants and personal fees from Bayer, grants and personal fees from Acucela, grants and personal fees from Alcon, grants and personal fees from Allergan, grants, personal fees and non-financial support from Optos, personal fees from Boehringer Ingelheim and non-financial support from Carl Zeiss MediTec AG outside the submitted work. No other conflicting relationship exists for any author., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Supervised deep learning (DL) algorithms are highly dependent on training data for which human graders are assigned, for example, for optical coherence tomography (OCT) image annotation. Despite the tremendous success of DL, due to human judgment, these ground truth labels can be inaccurate and/or ambiguous and cause a human selection bias. We therefore investigated the impact of the size of the ground truth and variable numbers of graders on the predictive performance of the same DL architecture and repeated each experiment three times. The largest training dataset delivered a prediction performance close to that of human experts. All DL systems utilized were highly consistent. Nevertheless, the DL under-performers could not achieve any further autonomous improvement even after repeated training. Furthermore, a quantifiable linear relationship between ground truth ambiguity and the beneficial effect of having a larger amount of ground truth data was detected and marked as the more-ground-truth effect., (© 2023 Wiley-VCH GmbH.)

Purpose: The purpose of this study was to develop and validate a deep learning (DL) framework for the detection and quantification of reticular pseudodrusen (RPD) and drusen on optical coherence tomography (OCT) scans., Methods: A DL framework was developed consisting of a classification model and an out-of-distribution (OOD) detection model for the identification of ungradable scans; a classification model to identify scans with drusen or RPD; and an image segmentation model to independently segment lesions as RPD or drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with a self-reported diagnosis of age-related macular degeneration (AMD) and 250 UKBB controls. Drusen and RPD were manually delineated by five retina specialists. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), kappa, accuracy, intraclass correlation coefficient (ICC), and free-response receiver operating characteristic (FROC) curves., Results: The classification models performed strongly at their respective tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans classifier, the OOD model, and the drusen and RPD classification models). The mean ICC for the drusen and RPD area versus graders was 0.74 and 0.61, respectively, compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that the model's sensitivity was close to human performance., Conclusions: The models achieved high classification and segmentation performance, similar to human performance., Translational Relevance: Application of this robust framework will further our understanding of RPD as a separate entity from drusen in both research and clinical settings.

Purpose: To investigate macular curvature, including the evaluation of potential associations and the dome-shaped macular configuration, given the increasing myopia prevalence and expected associated macular malformations., Methods: The study included a total of 65,440 subjects with a mean age (± SD) of 57.3 ± 8.11 years with spectral-domain optical coherence tomography (OCT) data from a unique contemporary resource for the study of health and disease that recruited more than half a million people in the United Kingdom (UK Biobank). A deep learning model was used to segment the retinal pigment epithelium. The macular curvature of the OCT scans was calculated by polynomial fit and evaluated. Further, associations with demographic, functional, ocular, and infancy factors were examined., Results: The overall macular curvature values followed a Gaussian distribution with high inter-eye agreement. Although all of the investigated parameters, except maternal smoking, were associated with the curvature in a multilinear analysis, ethnicity and refractive error consistently revealed the most significant effect. The prevalence of a macular dome-shaped configuration was 4.8% overall, most commonly in Chinese subjects as well as hypermetropic eyes. An increasing frequency up to 22.0% was found toward high refractive error. Subretinal fluid was rarely found in these eyes., Conclusions: Macular curvature revealed associations with demographic, functional, ocular, and infancy factors, as well as increasing prevalence of a dome-shaped macular configuration in high refractive error including high myopia and hypermetropia. These findings imply different pathophysiologic processes that lead to macular development and might open new fields to future myopia and macula research.

Cynomolgus monkeys exhibit human-like features, such as a fovea, so they are often used in non-clinical research. Nevertheless, little is known about the natural variation of the choroidal thickness in relation to origin and sex. A combination of deep learning and a deterministic computer vision algorithm was applied for automatic segmentation of foveolar optical coherence tomography images in cynomolgus monkeys. The main evaluation parameters were choroidal thickness and surface area directed from the deepest point on OCT images within the fovea, marked as the nulla with regard to sex and origin. Reference choroid landmarks were set underneath the nulla and at 500 µm intervals laterally up to a distance of 2000 µm nasally and temporally, complemented by a sub-analysis of the central bouquet of cones. 203 animals contributed 374 eyes for a reference choroid database. The overall average central choroidal thickness was 193 µm with a coefficient of variation of 7.8%, and the overall mean surface area of the central bouquet temporally was 19,335 µm 2 and nasally was 19,283 µm 2 . The choroidal thickness of the fovea appears relatively homogeneous between the sexes and the studied origins. However, considerable natural variation has been observed, which needs to be appreciated., (© 2022. The Author(s).)

Background/aims: The reason for visual impairment in patients with nanophthalmos and posterior microphthalmos is not completely understood. Therefore, this study aims to investigate foveal structure, and the impact of demographic, clinical and imaging parameters on best-corrected visual acuity (BCVA) in these conditions., Methods: Sixty-two eyes of 33 patients with nanophthalmos (n=40) or posterior microphthalmos (n=22), and 114 eyes of healthy controls with high-resolution retinal imaging including spectral-domain or swept-source optical coherence tomography images were included in this cross-sectional case-control study. Foveal retinal layer thickness was determined by two independent readers. A mixed-effect model was used to perform structure-function correlations and predict the BCVA based on subject-specific variables., Results: Most patients (28/33) had altered foveal structure associated with loss of foveal avascular zone and impaired BCVA. However, widening of outer nuclear layer, lengthening of photoreceptor outer segments, normal distribution of macular pigment and presence of Henle fibres were consistently found. Apart from the presence of choroidal effusion, which had significant impact on BCVA, the features age, refractive error, axial length and retinal layer thickness at the foveal centre explained 61.7% of the variability of BCVA., Conclusion: This study demonstrates that choroidal effusion, age, refractive error, axial length and retinal layer thickness are responsible for the majority of interindividual variability of BCVA as well as the morphological foveal heterogeneity in patients with nanophthalmos or posterior microphthalmos. This might give further insights into the physiology of foveal development and the process of emmetropisation, and support clinicians in the assessment of these disease entities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To examine whether sociodemographic, and ocular factors relate to optical coherence tomography (OCT)-derived foveal curvature (FC) in healthy individuals., Methods: We developed a deep learning model to quantify OCT-derived FC from 63,939 participants (age range, 39-70 years). Associations of FC with sociodemographic, and ocular factors were obtained using multilevel regression analysis (to allow for right and left eyes) adjusting for age, sex, ethnicity, height (model 1), visual acuity, spherical equivalent, corneal astigmatism, center point retinal thickness (CPRT), intraocular pressure (model 2), deprivation (Townsend index), higher education, annual income, and birth order (model 3). Fovea curvature was modeled as a z-score., Results: Males had on average steeper FC (0.077; 95% confidence interval [CI] 0.077-0.078) than females (0.068; 95% CI 0.068-0.069). Compared with whites, non-white individuals showed flatter FC, particularly those of black ethnicity. In black males, -0.80 standard deviation (SD) change when compared with whites (95% CI -0.89, -0.71; P 5.2e10-68). In black females, -0.70 SD change when compared with whites (95% CI -0.77, -0.63; p 2.3e10-93). Ocular factors (visual acuity, refractive status, and CPRT) showed a graded inverse association with FC that persisted after adjustment. Macular curvature showed a positive association with FC. Income showed a linear trend increase in males (P for linear trend = 0.005)., Conclusions: We demonstrate marked differences in FC with ethnicity on the largest cohort studied for this purpose to date. Ocular factors showed a graded association with FC. Implementation of FC quantification in research and on the clinical setting can enhance the understanding of clinical macular phenotypes in health and disease.

Purpose: Virtual reality (VR) can be useful in explaining diseases and complications that affect children in order to improve medical communications with this vulnerable patient group. So far, children and young people's responses to high-end medical VR environments have never been assessed., Methods: An unprecedented number of 320 children and young people were given the opportunity to interact with a VR application displaying original ophthalmic volume data via a commercially available tethered head-mounted display (HMD). Participants completed three surveys: demographics and experience with VR, usability and perceived utility of this technology and the Simulator Sickness Questionnaire. The second survey also probed participants for suggestions on improvements and whether this system could be useful for increasing engagement in science., Results: A total of 206 sets of surveys were received. 165 children and young people (84 female) aged 12-18 years (mean, 15 years) completed surveys that could be used for analysis. 69 participants (47.59%) were VR-naïve, and 76 (52.41%) reported that they had previous VR experience. Results show that VR facilitated understanding of ophthalmological complications and was reasonably tolerated. Lastly, exposure to VR raised children and young people's awareness and interest in science., Conclusions: The VR platform used was successfully utilized and was well accepted in children to display and interact with volume-rendered 3D ophthalmological data. Virtual reality (VR) is suitable as a novel image display platform in ophthalmology to engage children and young people., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

The behavior of a particle in a solvent has been framed using stochastic dynamics since the early theory of Kramers. A particle in a chemical reaction reacts slower in a diluted solvent because of the lack of energy transfer via collisions. The flux-over-population reaction rate constant rises with increasing density before falling again for very dense solvents. This Kramers turnover is observed in this paper at intermediate and high temperatures in the backward reaction of the LiNC ⇌ LiCN isomerization via Langevin dynamics and mean first-passage times (MFPTs). It is in good agreement with the Pollak-Grabert-Hänggi (PGH) reaction rates at lower temperatures. Furthermore, we find a square root behavior of the reaction rate at high temperatures and have made direct comparisons of the methods in the intermediate- and high-temperature regimes, all suggesting increased ranges in accuracy of both the PGH and MFPT approaches.

Introduction: The study aimed to explore the psychometric properties of the National Eye Institute Visual Function Questionnaire (NEI VFQ) and Impact of Vision Impairment (IVI) profile in recessive Stargardt disease (STGD1)., Methods: The NEI VFQ-25 and IVI-28 were administered to individuals with STGD1. Responses were analyzed following psychometrically established dimension structures of the NEI VFQ (visual function [VF] subscale; socioemotional [SE] subscale) and of the IVI (functional [F] subscale; emotional [E] subscale). We analyzed internal consistency, dimensionality, item fit, and differential item functioning (DIF), using latent trait models. Criterion validity was assessed using Pearson correlation coefficients., Results: Seventy-one participants (42 females, 29 males; mean age, 44 ± 19 years) were included. Self-reported difficulty levels were lower than the mean difficulty of items in both instruments. Person reliability and person separation index of the instruments were 0.85 and 2.40 (NEI VFQ-VF), 0.69 and 1.49 (NEI-VFQ-SE), 0.88 and 2.77 (IVI-F), and 0.72 and 1.62 (IVI-E). No items showed misfit at a level distorting the measurement system. One IVI item showed DIF by gender but was retained as person measures were largely unaffected by its removal. NEI VFQ-VF and IVI-F as well as NEI VFQ-SE and IVI-E were positively correlated (r = 0.79 and 0.64, respectively)., Conclusion: The NEI VFQ and IVI have acceptable psychometric properties in STGD1 with the IVI allowing more sensitive person stratification. Targeting of questionnaires to individuals with STGD1 might be improved by including additional content domains specific to the disease., (© 2022 S. Karger AG, Basel.)

Purpose: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD)., Design: Development and validation of a deep-learning model for feature segmentation., Methods: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve., Results: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers., Conclusions: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

One-in-four ophthalmology trials are single-armed, which poses challenges to their interpretation. We demonstrate how real-world cohorts used as external/synthetic control arms can contextualize such trials. We herein emulated a target trial on the intention-to-treat efficacy of off-label bevacizumab (q6w) pro re nata relative to fixed-interval aflibercept (q8w) for improving week 54 visual acuity of eyes affected by neovascular age-related macular degeneration. The bevacizumab arm (n = 65) was taken from the ABC randomized controlled trial. A total of 4,471 aflibercept-treated eyes aligning with the ABC trial eligibility were identified from electronic health records and synthetic control arms were created by emulating randomization conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time-to-event analysis on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 ETDRS letters by week 54. The findings suggest off-label bevacizumab to be neither inferior nor superior to licensed aflibercept. Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed trials when analyzed in accord to the target trial framework. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? One-in-four randomized controlled trials in ophthalmology are single-armed, which poses challenges for interpreting their efficacy relative to standard of care. Recent conceptual advances in the methods of causal inference and in the emulation of target trials suggests that the standard-of-care arms representing the counterfactual intervention can be approximated with observational data. WHAT QUESTION DID THIS STUDY ADDRESS? How real-world cohorts representing the counterfactual intervention can aid the interpretation of single-armed ophthalmological trials. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed ophthalmological trials when undertaken in accord with the target trial framework. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? External counterfactual arms could reduce the time and cost to reach potential regulatory approval., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To investigate the interreader agreement for grading of retinal alterations in age-related macular degeneration (AMD) using a reading center setting., Methods: In this cross-sectional case series, spectral-domain optical coherence tomography (OCT; Topcon 3D OCT, Tokyo, Japan) scans of 112 eyes of 112 patients with neovascular AMD (56 treatment naive, 56 after three anti-vascular endothelial growth factor injections) were analyzed by four independent readers. Imaging features specific for AMD were annotated using a novel custom-built annotation platform. Dice score, Bland-Altman plots, coefficients of repeatability, coefficients of variation, and intraclass correlation coefficients were assessed., Results: Loss of ellipsoid zone, pigment epithelium detachment, subretinal fluid, and drusen were the most abundant features in our cohort. Subretinal fluid, intraretinal fluid, hypertransmission, descent of the outer plexiform layer, and pigment epithelium detachment showed highest interreader agreement, while detection and measures of loss of ellipsoid zone and retinal pigment epithelium were more variable. The agreement on the size and location of the respective annotation was more consistent throughout all features., Conclusions: The interreader agreement depended on the respective OCT-based feature. A selection of reliable features might provide suitable surrogate markers for disease progression and possible treatment effects focusing on different disease stages., Translational Relevance: This might give opportunities for a more time- and cost-effective patient assessment and improved decision making as well as have implications for clinical trials and training machine learning algorithms.

Machine learning has greatly facilitated the analysis of medical data, while the internal operations usually remain intransparent. To better comprehend these opaque procedures, a convolutional neural network for optical coherence tomography image segmentation was enhanced with a Traceable Relevance Explainability (T-REX) technique. The proposed application was based on three components: ground truth generation by multiple graders, calculation of Hamming distances among graders and the machine learning algorithm, as well as a smart data visualization ('neural recording'). An overall average variability of 1.75% between the human graders and the algorithm was found, slightly minor to 2.02% among human graders. The ambiguity in ground truth had noteworthy impact on machine learning results, which could be visualized. The convolutional neural network balanced between graders and allowed for modifiable predictions dependent on the compartment. Using the proposed T-REX setup, machine learning processes could be rendered more transparent and understandable, possibly leading to optimized applications.

Background/aims: To evaluate the applicability of mesopic light sensitivity measurements obtained by fundus-controlled perimetry (FCP, also termed 'microperimetry') as clinical trial endpoint in Stargardt disease (STGD1)., Methods: In this retrospective, monocentre cohort study, 271 eyes of 136 patients (age, 37.1 years) with STGD1 and 87 eyes of 54 healthy controls (age, 41.0 years) underwent mesopic FCP, using a pattern of 50 stimuli (achromatic, 400-800 nm) centred on the fovea. The concurrent validity of mesopic FCP testing using the MAIA device (CenterVue, Italy), the retest variability and its determinants, and the progression of sensitivity loss over time were investigated using mixed-model analyses. The main outcomes were the average pointwise sensitivity loss in dependence of patients' demographic, functional and imaging characteristics, the intrasession 95% coefficient of repeatability, and the pointwise sensitivity loss over time., Results: Pointwise sensitivity loss was on average (estimate (95% CI)) 13.88 dB (12.55 to 15.21) along the horizontal meridian and was significantly associated with the electrophysiological subgroup, presence/absence of foveal sparing, best-corrected visual acuity and disease duration. The 95% coefficient of repeatability was 12.15 dB (10.78 to 13.38) and varied in dependence of the underlying mean sensitivity and local sensitivity slope. The global progression rate for the sensitivity loss was 0.45 dB/year (0.13 to 0.78) and was higher for the central and inner ETDRS subfields compared with more peripheral regions., Conclusions: Mesopic light sensitivity measured by FCP is reliable and susceptible for functional changes. It constitutes a potential clinical outcome for both natural history studies as well as future interventional studies in patients with STGD1., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate lipofuscin-related quantitative autofluorescence measures and their association with demographic characteristics, retinal structure, retinal function and genotype in ABCA4-related retinopathy (Stargardt disease 1)., Design: Cross-sectional study with age-matched healthy control subjects., Methods: A total of 77 patients with ABCA4-related retinopathy and 110 control subjects underwent quantitative fundus autofluorescence (qAF) imaging using a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to measure qAF as surrogate for lipofuscin accumulation. Measures of qAF were correlated with demographic characteristics, structural alterations on optical coherence tomography and fundus autofluorescence imaging, retinal function assessed by full-field electroretinography (ERG) and fundus-controlled perimetry, and genotype., Results: Most patients (76.6%) had qAF levels >95% prediction interval of the age-related control group, with best discrimination between cases and control subjects in younger patients. Reduced discrimination based on qAF measures was associated with mild disease, more advanced disease with dark flecks, or older age because of the physiological age-related increase in qAF and a ceiling effect in patients. Nullizygous patients presented with high qAF levels earlier in life compared with those with at least 1 milder ABCA4 variant. Within the sectors of qAF measurements, at approximately 7-9° eccentricity, increased qAF without flecks or with only bright flecks was associated with topographically related preserved retinal thickness and fundus-controlled perimetry results, and with normal full-field ERG recordings. All 3 parameters were increasingly abnormal with the development of dark flecks and decreasing qAF., Conclusions: The accumulation of lipofuscin depends on the severity of ABCA4 variants, precedes other structural changes, and may remain without clinically relevant effect on retinal function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Spatially-resolved retinal function can be measured by psychophysical testing like fundus-controlled perimetry (FCP or 'microperimetry'). It may serve as a performance outcome measure in emerging interventional clinical trials for macular diseases as requested by regulatory agencies. As FCP constitute laborious examinations, we have evaluated a machine-learning-based approach to predict spatially-resolved retinal function ('inferred sensitivity') based on microstructural imaging (obtained by spectral domain optical coherence tomography) and patient data in recessive Stargardt disease. Using nested cross-validation, prediction accuracies of (mean absolute error, MAE [95% CI]) 4.74 dB [4.48-4.99] were achieved. After additional inclusion of limited FCP data, the latter reached 3.89 dB [3.67-4.10] comparable to the test-retest MAE estimate of 3.51 dB [3.11-3.91]. Analysis of the permutation importance revealed, that the IS&OS and RPE thickness were the most important features for the prediction of retinal sensitivity. 'Inferred sensitivity', herein, enables to accurately estimate differential effects of retinal microstructure on spatially-resolved function in Stargardt disease, and might be used as quasi-functional surrogate marker for a refined and time-efficient investigation of possible functionally relevant treatment effects or disease progression.

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., (© 2020 S. Karger AG, Basel.)

Purpose: To evaluate the feasibility and safety of a coaxial dual-wavelength optical coherence tomography (OCT) device (marked as Hydra-OCT)., Methods: Healthy participants without ocular pathology underwent retinal imaging using the Hydra-OCT allowing for simultaneous measurement of retinal scanning of 840 and 1,072 nm wavelength. Before and after measurement, best-corrected visual acuity and patients' comfort were assessed. Representative OCT images from both wavelengths were compared by 5 independent graders using a subjective grading scheme., Results: A total of 30 eyes of 30 participants (8 females and 22 males) with a mean age of 26.5 years (range from 19 to 55 years) were included. Dual-wavelength image acquisition was made possible in each subject. The participant's effort and comfort assessment using the Hydra-OCT imaging revealed an equivalent value as compared to the commercially available OCT machine. No adverse events were reported, and visual acuity was not altered by the Hydra-OCT. Imaging between the systems was comparable., Conclusions: This study provides evidence for the feasibility and safety of a coaxial dual-wavelength OCT imaging method under real-life conditions. The novel Hydra-OCT imaging device may offer additional insights into the pathology of retinal and choroidal diseases., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Purpose: To systematically and longitudinally investigate the characteristics of flecks in ABCA4-related retinopathy under different fundus autofluorescence (AF) excitation and emission spectra., Methods: A total of 132 eyes of 66 patients with ABCA4-related retinopathy were investigated using multimodal AF imaging and spectral domain optical coherence tomography. Autofluorescence imaging with blue (BAF), green (GAF), and near-infrared (NIR-AF) excitation wavelengths obtained by a confocal scanning laser ophthalmoscope was compared with AF imaging obtained by an innovative confocal light-emitting diode-based retinal imaging system (Color-AF) that allows for separation of short (green emission fluorescent component) and long (red emission fluorescent component) autofluorescence emission components., Results: Color-AF, BAF, and GAF, overall, revealed similar presentation of hyperautofluorescent flecks. Flecks that showed predominantly red emission fluorescent component matched with hyperautofluorescent flecks in NIR-AF. Over the observation time of 5 to 14 months, flecks showed a transition in the AF emission spectrum to shorter wavelengths (red emission fluorescent component to green emission fluorescent component), associated with a progressed disruption of overlaying outer retinal bands in optical coherence tomography. Newer hyperautofluorescent flecks usually revealed predominantly red emission fluorescent component., Conclusion: By separation of the AF spectra, the remodeling of fluorophores and associated structural changes can be monitored over time indicating a novel and susceptible surrogate marker for disease progression and potential therapeutic effects.

Importance: Correlates for Bruch membrane alterations are needed for interventional trials targeting the Bruch membrane in pseudoxanthoma elasticum (PXE)., Objectives: To quantify mesopic and scotopic light sensitivity and identify its microstructural correlates associated with a diseased Bruch membrane in patients with PXE., Design, Setting, and Participants: A prospective, single-center, cross-sectional case-control study was conducted at a tertiary referral center from January 31, 2018, to February 20, 2020. Twenty-two eyes of 22 patients with PXE and 40 eyes of 40 healthy individuals were included. Data analysis was completed March 15, 2020., Exposures: Mesopic and dark-adapted 2-color fundus-controlled perimetry (microperimetry) and multimodal retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and OCT angiography were performed. Perimetry thresholds were analyzed using mixed models, and structure-function correlation with SD-OCT data was performed using machine learning., Main Outcomes and Measures: Observed dark-adapted cyan sensitivity loss as measure of rod photoreceptor dysfunction, as well as mean absolute error between predicted and observed retinal sensitivity to assess the accuracy of structure-function correlation., Results: Of the 22 patients with PXE included in this study, 15 were women (68%); median age was 56.5 years (interquartile range, 50.4-61.2). These patients exhibited mesopic (estimate, 5.13 dB; 95% CI, 2.89-7.38 dB), dark-adapted cyan (estimate, 9.08 dB; 95% CI, 6.34-11.82 dB), and dark-adapted red (estimate, 7.05 dB; 95% CI, 4.83-9.27 dB) sensitivity losses. This sensitivity loss was also evident in 9 eyes with nonneovascular PXE (mesopic: estimate, 3.21 dB; 95% CI, 1.28-5.14 dB; dark-adapted cyan: 5.93 dB; 95% CI, 3.59-8.27 dB; and dark-adapted red testing: 4.84 dB; 95% CI, 2.88-6.80 dB), showing a distinct centrifugal pattern of sensitivity loss with preserved function toward the periphery. Retinal function could be predicted from microstructure with high accuracy (mean absolute errors, of 4.91 dB for mesopic, 5.44 dB for dark-adapted cyan, and 4.99 dB for dark-adapted red). The machine learning-based analysis highlighted an association of a thinned inner retina and putative separation of the pigment-epithelium-photoreceptor complex with sensitivity loss., Conclusions and Relevance: In this study, among 22 patients with PXE, those with and without choroidal neovascularization exhibited reductions of retinal sensitivity being most pronounced in dark-adapted cyan testing. This finding suggests that pathologic characteristics of this Bruch membrane disease may be dominated by rod photoreceptor degeneration and/or dysfunction. A putative pigment-epithelium-photoreceptor separation may further impair rod function, while inner retinal abnormalities appear to be correlated with overall dysfunction.

Purpose: To investigate the prognostic value of demographic, functional, genetic, and imaging parameters on retinal pigment epithelium atrophy progression secondary to ABCA4-related retinopathy., Methods: Patients with retinal pigment epithelium atrophy secondary to ABCA4-related retinopathy were examined longitudinally with fundus autofluorescence imaging. Lesion area, perimeter, circularity, caliper diameters, and focality of areas with definitely decreased autofluorescence were determined. A model was used to predict the lesion enlargement rate based on baseline variables. Sample size calculations were performed to model the power in a simulated interventional study., Results: Sixty-eight eyes of 37 patients (age range, 14-78 years) with a follow-up time of 10 to 100 months were included. The mean annual progression of retinal pigment epithelium atrophy was 0.89 mm. The number of atrophic areas, the retina-wide functional impairment, and the age-of-onset category constituted significant predictors for future retinal pigment epithelium atrophy growth, explaining 25.7% of the variability. By extension of a simulated study length and/or specific patient preselection based on these baseline characteristics, the required sample size could significantly be reduced., Conclusion: Trial design based on specific shape-descriptive factors and patients' baseline characteristics and the adaption of the trial duration may provide potential benefits in required cohort size and absolute number of visits.

Purpose: To investigate the development and progression of retinal pigment epithelial and outer retinal atrophy (RORA) secondary to maternally inherited diabetes and deafness (MIDD)., Design: Retrospective observational case series., Methods: Thirty-six eyes of 18 patients (age range, 22.4-71.6 years) with genetically proven MIDD and serial optical coherence tomography (OCT) images were included. As proposed reference standard to diagnose and stage atrophy, OCT images were longitudinally evaluated and analyzed for presence and precursors of RORA. RORA was defined as an area of (1) hypertransmission, (2) disruption of the retinal pigment epithelium, (3) photoreceptor degeneration, and (4) absence of other signs of a retinal pigment epithelial tear., Results: The majority of patients revealed areas of RORA in a circular area around the fovea of between 5° and 15° eccentricity. Over the observation time (range, 0.5-8.5 years), evidence for a consistent sequence of OCT features from earlier disease stages to the end stage of RORA could be found, starting with loss of ellipsoid zone and subretinal deposits, followed by loss of external limiting membrane and loss of retinal pigment epithelium with hypertransmission of OCT signal into the choroid, and leading to loss of the outer nuclear layer bordered by hyporeflective wedges. Outer retinal tabulations seemed to develop in regions of coalescent areas of RORA., Conclusions: The development and progression of RORA could be tracked in MIDD patients using OCT images, allowing potential definition of novel surrogate markers. Similarities to OCT features in age-related macular degeneration, where mitochondrial dysfunction has been implicated in the pathogenesis, support wide-ranging benefits from proof-of-concept studies in MIDD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

Aim: Biallelic ABCC6 mutations cause pseudoxanthoma elasticum, a systemic disease characterised by calcification of elastic tissue and a specific retinal phenotype. In this study, we investigated if monoallelic ABCC6 mutations are also associated with retinal alterations., Methods: In this prospective, cross-sectional, monocentre case-control study, carriers of monoallelic ABCC6 mutations were investigated and compared with age-matched controls. The retinal phenotype was characterised using fundus photography, fundus autofluorescence, confocal near-infrared reflectance imaging, spectral domain optical coherence tomography and in selected cases late-phase indocyanine green angiography., Results: Thirty-eight subjects carrying monoallelic ABCC6 mutations (mean age 70.2 years, range 50-90, 26 female) were examined and compared with 77 age-matched controls (mean age 69.9 years, range 50-93, 43 female). Retinal alterations were more frequently found in carriers of monoallelic ABCC6 mutations compared with controls (50% vs 33.8%, p=0.107) with increasing prevalence at older age. Typical findings were peripapillary atrophy (37% vs 23%, p=0.184), pattern dystrophy-like changes (24% vs 12%, p=0.109), reticular pseudodrusen (21% vs 5%, p=0.019), small angioid streaks (8% vs 1%, p=0.105), choroidal neovascularisations and atrophic lesions (both 8% vs 0%, p=0.034). Late-phase indocyanine green angiography showed a reduced cyanescence centred to the posterior pole in 11 of 14 examined subjects with monoallelic ABCC6 mutations., Conclusion: The findings of this study indicate a possible ocular ABCC6 haploinsufficiency phenotype. Due to its late-onset and phenotypic similarities, misinterpretation as age-related macular degeneration is possible., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Full-field electroretinogram (ERG) and best corrected visual acuity (BCVA) measures have been shown to have prognostic value for recessive Stargardt disease (also called " ABCA4 -related retinopathy"). These functional tests may serve as a performance-outcome-measure (PerfO) in emerging interventional clinical trials, but utility is limited by variability and patient burden. To address these limitations, an ensemble machine-learning-based approach was evaluated to differentiate patients from controls, and predict disease categories depending on ERG ('inferred ERG') and visual impairment ('inferred visual impairment') as well as BCVA values ('inferred BCVA') based on microstructural imaging (utilizing spectral-domain optical coherence tomography) and patient data. The accuracy for 'inferred ERG' and 'inferred visual impairment' was up to 99.53 ± 1.02%. Prediction of BCVA values ('inferred BCVA') achieved a precision of ±0.3LogMAR in up to 85.31% of eyes. Analysis of the permutation importance revealed that foveal status was the most important feature for BCVA prediction, while the thickness of outer nuclear layer and photoreceptor inner and outer segments as well as age of onset highly ranked for all predictions. 'Inferred ERG', 'inferred visual impairment', and 'inferred BCVA', herein, represent accurate estimates of differential functional effects of retinal microstructure, and offer quasi-functional parameters with the potential for a refined patient assessment, and investigation of potential future treatment effects or disease progression.

Clinical science and medical imaging technology are traditionally displayed in two dimensions (2D) on a computer monitor. In contrast, three-dimensional (3D) virtual reality (VR) expands the realm of 2D image visualization, enabling an immersive VR experience with unhindered spatial interaction by the user. Thus far, analysis of data extracted from VR applications was mainly qualitative. In this study, we enhance VR and provide evidence for quantitative VR research by validating digital VR display of computed tomography (CT) data of the orbit. Volumetric CT data were transferred and rendered into a VR environment. Subsequently, seven graders performed repeated and blinded diameter measurements. The intergrader variability of the measurements in VR was much lower compared to measurements in the physical world and measurements were reasonably consistent with their corresponding elements in the real context. The overall VR measurements were 5.49% higher. As such, this study attests the ability of VR to provide similar quantitative data alongside the added benefit of VR interfaces. VR entails a lot of potential for the future research in ophthalmology and beyond in any scientific field that uses three-dimensional data.

Purpose: To investigate quantitatively lipofuscin-associated fundus autofluorescence in patients with macular and cone/cone-rod dystrophies (MD/CCRDs)., Design: Prospective, single-center, case-control study., Participants: Two hundred thirty patients with MD/CCRDs who had undergone genetic testing and 110 control participants without any eye disease., Methods: Participants were examined using quantitative fundus autofluorescence (qAF) imaging with a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference (modified Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Mean qAF values were obtained by averaging measurements from an 8-segment ring centered on the fovea (qAF 8 ) and compared with controls., Main Outcome Measures: The qAF 8 levels., Results: Elevated qAF 8 values were a frequent finding (n = 105 [45%]) and associated with ABCA4 (n = 73 [70%]), PRPH2 (n = 9 [9%]), CERKL (n = 3 [3%]), PROM1 (n = 2 [2%]), CRX (n = 1 [1%]), and CDHR1 (n = 1 [1%]) mutations. Reduced qAF 8 values were rare (n = 15 [7%]) and found predominantly among patients with MERTK (n = 3 [20%]) and RDH5 (n = 2 [13%]) mutations. Patients with normal qAF 8 values (n = 110 [48%]) showed high genotypic heterogeneity. For various genes including ABCA4, PRPH2, CDHR1, and PROM1, higher qAF 8 measures were associated with specific phenotypes and genotypes. For instance, qAF 8 values were normal in PRPH2-related central areolar chorioretinal dystrophy but increased in PRPH2-related Stargardt-like retinopathy. Accordingly, high qAF 8 levels were associated with specific genetic causes and mutation detection rates in characteristic but genetically heterogenous clinical phenotypes, such as a Stargardt-like flecked fundus, bull's eye maculopathy, or pattern dystrophy. In genetically unsolved cases (16 with elevated, 35 with normal, 7 with reduced qAF values), qAF 8 was used to support or reject ambiguous results of genetic testing, to suggest underlying pathogenic pathways, and to predict disease in otherwise healthy participants., Conclusions: Quantitative fundus autofluorescence imaging revealed characteristic qAF levels in association with certain gene mutations and in participants without detected mutations. These findings indicate that qAF may facilitate differential diagnostics of MD/CCRDs and may offer novel pathogenetic insights that may be of particular value for the assessment of future treatment approaches., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the prognostic value of demographic, functional, and imaging parameters on retinal pigment epithelium (RPE) atrophy progression secondary to maternally inherited diabetes and deafness (MIDD) and to evaluate the application of these factors in clinical trial design., Design: Retrospective observational case series., Methods: Thirty-five eyes of 20 patients (age range, 24.9-75.9 years) with genetically proven MIDD and demarcated RPE atrophy on serial fundus autofluorescence (AF) images were included. Lesion size and shape-descriptive parameters were longitudinally determined by 2 independent readers. A linear mixed-effect model was used to predict the lesion enlargement rate based on baseline variables. Sample size calculations were performed to model the power in a simulated interventional study., Results: The mean follow-up time was 4.27 years. The mean progression rate of RPE atrophy was 2.33 mm 2 /year, revealing a dependence on baseline lesion size (+0.04 [0.02-0.07] mm 2 /year/mm 2 , P < .001), which was absent after square root transformation. The fovea was preserved in the majority of patients during the observation time. In the case of foveal involvement, the loss of visual acuity lagged behind central RPE atrophy in AF images. Sex, age, and number of atrophic foci predicted future progression rates with a cross-validated mean absolute error of 0.13 mm/year and to reduce the required sample size for simulated interventional trials., Conclusions: Progressive RPE atrophy could be traced in all eyes using AF imaging. Shape-descriptive factors and patients' baseline characteristics had significant prognostic value, guiding appropriate subject selection and sample size in future interventional trial design., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To investigate histopathologic, immunohistochemical, and electron microscopic findings in 8 keratoplasty specimens with a history of corneal collagen crosslinking (CXL) for keratoconus. Five new (hitherto unreported) and 3 previously published specimens were analyzed., Methods: Corneal buttons of 8 keratoconus corneas (5-114 months after CXL) were compared with 5 keratoconus specimens without CXL and 5 normal corneas for morphological alterations. Corneal buttons were evaluated by light microscopy and immunohistochemistry using antibodies against CD34, PGP 9.5, nestin, telomerase reverse transcriptase, and Ki67 as well as by transmission electron microscopy., Results: Keratoconus corneas after CXL showed a significant keratocyte loss (except 1 specimen with an increased keratocyte number), whereas keratoconus corneas without CXL revealed a higher keratocyte density compared with healthy controls. Keratocyte loss could be clinically correlated with corneal opacification and corneal perforation. In corneas after CXL, the remaining keratocytes appeared more polymorphic and revealed a different expression of surface markers similar to keratocytes in corneal scars. The presence of proteoglycans, nerves, and endothelial cells was unaffected by CXL., Conclusions: CXL may cause permanent keratocyte loss or repopulation of altered keratocytes, resulting in clinical complications such as corneal opacification or perforation. Despite its good safety profile and high effectiveness in progressive keratoconus, CXL should be performed in accordance with current guidelines strictly adhering to protocol and safety standards.

Purpose: To investigate retinal sensitivity in the junctional zone of geographic atrophy (GA) secondary to age-related macular degeneration using patient-tailored perimetry grids for mesopic and dark-adapted two-color fundus-controlled perimetry., Methods: Twenty-five eyes with GA of 25 patients (prospective, natural-history Directional Spread in Geographic Atrophy study [DSGA; NCT02051998]) and 40 eyes of 40 normal subjects were included. Patient-tailored perimetry grids were generated using annotated fundus autofluorescence data. Customized software positioned test-points along iso-hulls surrounding the GA boundary at distances of 0.43°, 0.86°, 1.29°, 2.15°, and 3.01°. The grids were used for duplicate mesopic and dark-adapted two-color (cyan and red) fundus-controlled perimetry. Age-adjusted reference-data were obtained through regression analysis of normative data followed by spatial interpolation., Results: The mean sensitivity loss for mesopic testing decreased with the distance to GA (-10.3 dB [0.43°], -8.2 dB [0.86°], -7.1 dB [1.29°], -6.8 dB [2.15°], and -6.6 dB [3.01°]; P < 0.01). Dark-adapted cyan sensitivity loss exceeded dark-adapted red sensitivity loss for all iso-hulls (-14.8 vs. -11.7 dB, -13.5 vs. -10.1 dB, -12.8 vs. -9.1 dB, -11.6 vs. -8.2 dB, -10.7 vs. -8.0 dB; P < 0.01)., Conclusion: Patient-tailored fundus-controlled perimetry grids allowed for testing of retinal function in the junctional zone of GA with high spatial resolution. A distinct decrease in mesopic sensitivity loss between 0.43° (125 µm) and 1.29° (375 µm) was observed that leveled off at more distant test-points. In proximity to the GA boundary, the results indicate that rod exceeded cone dysfunction.

Purpose: To evaluate the functional relevance and structural correlates of autofluorescence (AF) alterations under short-wavelength (SW) and near-infrared (NIR) excitation light in ABCA4 -related retinopathy., Methods: In this prospective, cross-sectional case series, 88 eyes of 44 patients with ABCA4 -related retinopathy (mean age, 37.6 years; range, 9-77 years) underwent SW-AF and NIR-AF imaging. The AF images were graded for disease characteristic patterns by two independent readers and correlated with alterations in optical coherence tomography (OCT) and impairment of retinal sensitivity along a foveo-papillary line assessed by fundus-controlled microperimetry., Results: A centrifugal sequence of AF patterns from atrophic lesions to homogeneous background was found for both AF modalities. The eccentricity of each AF pattern in NIR-AF was larger compared to those in SW-AF ( P < 0.001). Increasing eccentricity of each pattern correlated with increasing retinal sensitivity. The distant border of the zone of hyperfluorescent flecks in SW-AF and hypoautofluorescent flecks in NIR-AF correlated with the margins of the ellipsoid zone loss in OCT ( r = 0.979 and r = 0.971, P < 0.001). The expansion of hypofluorescent flecks in SW-AF was associated with the boundaries of external limiting membrane loss ( r = 0.933, P < 0.001)., Conclusions: SW-AF and NIR-AF revealed a characteristic sequence of AF patterns that correlated with functional and structural alterations, suggesting different stages in disease progression., Translational Relevance: Alterations in NIR-AF exceeded those in SW-AF images, substantiating the hypothesis of different AF origins and suggesting NIR-AF as surrogate marker for early disease-related changes., (Copyright 2019 The Authors.)

Importance: Acute retinopathy may partly explain variable disease manifestation and vision loss in patients with pseudoxanthoma elasticum (PXE). The diagnosis of this likely autoimmune process may inform patient counseling and treatment approaches., Objective: To characterize acute retinopathy in patients with PXE as a disease manifestation that may be associated with profound visual impairment., Design, Setting, and Participants: This single-center case series was conducted from May 2013 to October 2018. It used the patient database of the Department of Ophthalmology at the University of Bonn, a referral center for PXE in Germany. Patients at this center with genetically confirmed PXE and who met the inclusion criteria were included (n = 9). Patients underwent multimodal retinal imaging, including fundus photography, fundus autofluorescence (AF), optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA); in select cases, electroretinography as well as antiretinal and anti-retinal pigment epithelium (RPE) antibody testing were also used., Main Outcomes and Measures: Clinical presentation and disease course., Results: Nine patients (8 [89%] female; mean [range] age, 43 [19-55] years) with acute retinopathy were identified in a cohort of 167 consecutive patients with PXE (frequency of 5%). Symptoms ranged from light sensations or metamorphopsia to profound vision loss. Visual acuity was reduced in 6 patients (67%), ranging from a best-corrected visual acuity of 20/30 to perception of hand movements at manifestation. All patients revealed characteristic fundus features with temporary appearance of partly confluent outer retinal whitish dots at the posterior pole, which corresponded to areas of hyperautofluorescence on fundus AF, loss of the ellipsoid band on OCT, and associated scotomata. The FA and late-phase ICGA imaging showed associated hyperfluorescence and hypocyanescence. Electroretinography revealed a variable reduction of amplitudes. Changes were fully reversible within 1 month in 3 of 8 patients with available follow-up data. Of the remaining 5 patients, 3 had a prolonged and likely permanent vision loss (observation period, 1-64 months) mainly owing to central subretinal hyperreflective material originating from angioid streaks. In 4 (67%) of 6 tested, antiretinal and/or anti-RPE antibodies were detected., Conclusions and Relevance: Acute retinopathy in patients with PXE may occur, with symptoms ranging from short-term, reversible alterations to irreversible vision loss; these findings contribute to understanding the variable ocular disease progression in PXE and provide insights into the autoimmune phenomena of the posterior pole.

Aims: To systematically describe the clinical and histopathological features of a case series of conjunctival carcinomatous lesions underlying as-and also masquerading-pyogenic granuloma., Methods: Nine cases of conjunctival carcinomatous lesions underlying a pyogenic granuloma (which were clinically predominant) were retrospectively identified. Patients' records were analysed for demographic data, clinical appearance and the postoperative course. Formalin-fixed paraffin-embedded specimens were routinely processed and stained with H&E and periodic acid-Schiff. Immunohistochemical stains for cytokeratin were performed in selected cases., Results: All nine tumours were located in the conjunctiva (bulbar, tarsal, limbal conjunctiva) of patients between 44 and 80 years. The lesions exhibited clinical features of pyogenic granuloma which dominated the clinical appearance. Additional features comprised a papillomatous appearance of the adjacent conjunctiva, a more whitish aspect of the lesion and a history of squamous cell carcinoma (SCC) respectively surgery for other entities. Histopathological analysis revealed a carcinomatous lesion (conjunctival intraepithelial neoplasia or SCC) at the base of a classic pyogenic granuloma in all nine cases. Surgical removal (R0 resection) was performed. Three cases received adjuvant mitomycin C or interferon α2b treatment. Two lesions locally recurred within 2 years after initial presentation., Conclusion: Carcinomatous lesions may be accompanied by a pyogenic granuloma which may dominate the clinical pictures. As the tumour is usually located at the base of the lesion, a complete surgical excision followed by histopathological analysis is mandatory for each lesion appearing as conjunctival pyogenic granuloma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To report the clinical and molecular findings in patients with retinal dystrophy associated with the c.783G>A variant in CDHR1., Methods: The retinal phenotype of 10 patients with CDHR1-related retinopathy was characterized by multimodal imaging including color fundus photography, optical coherence tomography (OCT), and blue- and near-infrared fundus autofluorescence imaging. Functional testing included electroretinography, visual acuity, and visual field testing., Results: Six patients homozygous for the c.783G>A variant in CDHR1 showed a retinal phenotype resembling central areolar choroidal dystrophy (CACD) on multimodal imaging. Retinal function outside an area of slowly progressive macular atrophy remained relatively preserved. In contrast, biallelic severe/truncating CDHR1 mutations result in retina-wide retinal degeneration in addition to macular atrophy, with overall severely reduced retinal function. Patients compound heterozygous for the c.783G>A mutation and a truncating mutation in CDHR1 showed an intermediate phenotype. All patients except one with biallelic severe CDHR1 mutations were asymptomatic in the first four decades of life, irrespective of their individual CDHR1 mutations. Analysis of blood RNA from patients with the c.783G>A variant revealed in-frame skipping of exon 8 in vivo, predicting a partial deletion of CDHR1 ectodomains 2 and 3., Conclusions: Patients with biallelic c.783G>A CDHR1 mutations demonstrate a retinal phenotype consistent with autosomal recessive CACD. The apparently silent dbSNP-annotated c.783G>A CDHR1 variant (rs147346345) has a relatively high minor allele frequency (0.31%), with homozygous individuals annotated in the general population, and it may therefore have been disregarded in many next-generation sequencing (NGS)-based studies. The differential diagnosis includes PRPH2-associated CACD and age-related macular degeneration.

Importance: Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next-generation sequencing may be increased by a reasonable preselection of RP-patients., Background: To systematically evaluate and compare features of genetically solved and unsolved RP-patients., Design: Retrospective, observational study., Participants: One-hundred and twelve consecutive RP-patients who underwent extensive molecular genetic analysis., Methods: Characterization of patients based on multimodal imaging and medical history., Main Outcome Measures: Differences between genetically solved and unsolved RP-patients., Results: Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease-onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years-of-age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing., Conclusions and Relevance: The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP-patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease-causing mutations and may impact patient counselling., (© 2019 Royal Australian and New Zealand College of Ophthalmologists.)