Properties of Patient-Reported Outcome Measures in Recessive Stargardt Disease.

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.

Optical Coherence Tomography-Angiography in Geographic Atrophy.

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.

Feasibility and Safety of a Coaxial Dual-Wavelength Optical Coherence Tomography Apparatus.

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.

SPECTRAL FUNDUS AUTOFLUORESCENCE EXCITATION AND EMISSION IN ABCA4-RELATED RETINOPATHY.

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.

PROGRESSION OF ABCA4-RELATED RETINOPATHY: Prognostic value of demographic, functional, genetic, and imaging parameters.

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.

MESOPIC AND DARK-ADAPTED TWO-COLOR FUNDUS-CONTROLLED PERIMETRY IN GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

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.

Retinal imaging including optical coherence tomography angiography for detecting active choroidal neovascularization in pseudoxanthoma elasticum.

IMPORTANCE: The diagnostic accuracy of different retinal imaging modalities to detect active choroidal neovascularization (CNV) in pseudoxanthoma elasticum (PXE) is essential to enable a correct diagnosis but is currently poorly understood. BACKGROUND: Optical coherence tomography (OCT), fluorescein angiography (FA) and OCT angiography (OCT-A) are employed in daily practice, but a systematic comparison of these imaging techniques is lacking. DESIGN: Retrospective, observational study. PARTICIPANTS: Twenty patients (31 eyes) with PXE. METHODS: OCT, FA and OCT-A imaging was performed in each eye and graded separately by independent readers. MAIN OUTCOME MEASURES: Diagnostic accuracy, sensitivity and specificity to detect CNV-activity of each modality and longitudinal change of CNV size measured by OCT-A. RESULTS: OCT showed the highest diagnostic accuracy (kappa = 0.57) in comparison to OCT-A or FA (kappa = 0.39 and 0.37, respectively). OCT-A, OCT and FA showed a diagnostic sensitivity of 0.9, 0.85 and 0.6, and a diagnostic specificity of 0.45, 0.72 and 0.82, respectively. Evaluation of longitudinal OCT recordings (24 eyes) resulted in optimal sensitivity and specificity (kappa = 1.0). Although median CNV size assessed using OCT-A remained stable on longitudinal measures of seven eyes, two eyes showed a distinct increase over time despite anti-vascular endothelial growth factor treatment. CONCLUSIONS AND RELEVANCE: The systematic use of OCT, FA and OCT-A imaging can facilitate the diagnostic accuracy for detection and follow-up of CNV activity in PXE. While structural OCT is of high value, especially when longitudinal follow-up images are available, FA and OCT-A data might contribute to diagnostic accuracy in more complex cases.

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases.

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.

CHOROIDAL ALTERATIONS IN ABCA4-RELATED RETINOPATHY.

PURPOSE: To investigate choroidal alterations in ABCA4-related retinopathy. METHODS: Mean choroidal thickness and subfoveal choroidal thickness were measured in the right eyes of 40 patients with ABCA4-related retinopathy using enhanced-depth imaging optical coherence tomography. The right eyes of 65 age-matched healthy subjects were used for comparison. RESULTS: Compared with controls, patients with ABCA4-related retinopathy revealed a reduced subfoveal choroidal thickness ([mean ± SEM] 347 ± 10 µm vs. 302 ± 12 µm; P = 0.006) and mean choroidal thickness (315 ± 9 µm vs. 275 ± 10 µm; P = 0.005). This difference was mainly due to choroidal thinning in eyes with reduced photopic and/or scotopic amplitudes on full-field electroretinography. Atrophy of the retinal pigment epithelium (RPE) was associated with a thinner choroid compared with eyes without RPE atrophy (subfoveal choroidal thickness: 277 ± 17 µm vs. 341 ± 16 µm; mean choroidal thickness: 252 ± 13 µm vs. 313 ± 13 µm; both, P ≤ 0.001), but choroidal thinning was not restricted to the area of RPE atrophy. Choroidal thickness was similar to controls when RPE atrophy and functional loss were limited to the central retina. There was no association between visual acuity and choroidal thickness. CONCLUSION: The results indicate choroidal alterations in widespread ABCA4-related retinopathy, especially when associated with atrophy of the RPE. The absence of focal choroidal thinning in areas of RPE atrophy is suggestive for a diffusible factor from the RPE sustaining the choroidal structure.

M-sequences in ophthalmic electrophysiology.

The aim of this review is to use the multimedia aspects of a purely digital online publication to explain and illustrate the highly capable technique of m-sequences in multifocal ophthalmic electrophysiology. M-sequences have been successfully applied in clinical routines during the past 20 years. However, the underlying mathematical rationale is often daunting. These mathematical properties of m-sequences allow one not only to separate the responses from different fields but also to analyze adaptational effects and impacts of former events. By explaining the history, the formation, and the different aspects of application, a better comprehension of the technique is intended. With this review we aim to clarify the opportunities of m-sequences in order to motivate scientists to use m-sequences in their future research.

Reticular Pseudodrusen in Sorsby Fundus Dystrophy.

PURPOSE: To investigate the association of reticular pseudodrusen (RPD) with Sorsby fundus dystrophy (SFD). DESIGN: Prospective, monocenter, cross-sectional case series. SUBJECTS: Sixteen patients of 4 unrelated families with SFD caused by mutations in TIMP3. METHODS: All subjects underwent multimodal imaging including near-infrared (NIR) reflectance and fundus autofluorescence with a confocal scanning laser ophthalmoscope and spectral-domain optical coherence tomography (SD OCT). MAIN OUTCOME MEASURES: Prevalence, topographic distribution, and phenotype of RPD. RESULTS: Mean age of the investigated patients was 56.8 years (range, 23-78 years). Reticular pseudodrusen were identified frequently in SFD patients in the sixth decade of life (5 of 7 [71%]) and were absent in younger (n = 3) or older (n = 6) patients. They were most abundant in the superior quadrant and spared the foveal region. Reticular pseudodrusen appeared as yellowish round to oval (dot subtype; n = 5) or confluent, wriggled (ribbon subtype; n = 3) lesions, sometimes forming irregular networks. Reticular pseudodrusen were hyporeflective on NIR reflectance and hypofluorescent on fundus autofluorescence imaging. They appeared as subretinal deposits on SD OCT imaging. Other lesions, such as peripheral pseudodrusen and soft drusen, were present less frequently. CONCLUSIONS: Reticular pseudodrusen are a frequent finding in patients with SFD. Although SFD patients with RPD are younger, distribution and phenotype of RPD are similar to those observed in patients with age-related macular degeneration. The association of RPD with SFD implicates a role of Bruch's membrane, the Bruch's membrane-retinal pigment epithelium interface, or both in the pathogenesis of RPD.

Multicenter Normative Data for Mesopic Microperimetry.

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.

Human selection bias drives the linear nature of the more ground truth effect in explainable deep learning optical coherence tomography image segmentation.

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.

Progression, reliability, predicting parameters and sample size calculations for quantitative fundus autofluorescence measures in ABCA4-related retinopathy.

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.

Quantification and Predictors of OCT-Based Macular Curvature and Dome-Shaped Configuration: Results From the UK Biobank.

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 monkey's choroid reference database derived from hybrid deep learning optical coherence tomography segmentation.

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 µm2 and nasally was 19,283 µm2. 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.

Foveal Curvature and Its Associations in UK Biobank Participants.

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.

Estimating excess visual loss from neovascular age-related macular degeneration in the UK during the COVID-19 pandemic: a retrospective clinical audit and simulation model.

OBJECTIVES: To report the reduction in new neovascular age-related macular degeneration (nAMD) referrals during the COVID-19 pandemic and estimate the impact of delayed treatment on visual outcomes at 1 year. DESIGN: Retrospective clinical audit and simulation model. SETTING: Multiple UK National Health Service (NHS) ophthalmology centres. PARTICIPANTS: Data on the reduction in new nAMD referrals were obtained from four NHS Trusts comparing April 2020 with April 2019. To estimate the potential impact on 1-year visual outcomes, a stratified bootstrap simulation model was developed drawing on an electronic medical records dataset of 20 825 nAMD eyes from 27 NHS Trusts. MAIN OUTCOME MEASURES: Simulated mean visual acuity and proportions of eyes with vision ≤6/60, ≤6/24 and ≥6/12 at 1 year under four hypothetical scenarios: 0-month, 3-month, 6-month and 9-month treatment delays. Estimated additional number of eyes with vision ≤6/60 at 1 year nationally. RESULTS: The number of nAMD referrals dropped on average by 72% (range 65%-87%). Simulated 1-year visual outcomes for 1000 nAMD eyes with a 3-month treatment delay suggested an increase in the proportion of eyes with vision ≤6/60 from 15.5% (13.2%-17.9%) to 23.3% (20.7%-25.9%), and a decrease in the proportion of eyes with vision ≥6/12 (driving vision) from 35.1% (32.1%-38.1%) to 26.4% (23.8%-29.2%). Outcomes worsened incrementally with longer modelled delays. Assuming nAMD referrals are reduced to this level for 1 month nationally, these simulated results suggest an additional 186-365 eyes with vision ≤6/60 at 1 year. CONCLUSIONS: We report a large decrease in nAMD referrals during the COVID-19 lockdown and provide an important public health message regarding the risk of delayed treatment. As a conservative estimate, a treatment delay of 3 months could lead to a >50% relative increase in the number of eyes with vision ≤6/60 and 25% relative decrease in the number of eyes with driving vision at 1 year.

Foveal structure and visual function in nanophthalmos and posterior microphthalmos.

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.

A Deep Learning Framework for the Detection and Quantification of Reticular Pseudodrusen and Drusen on Optical Coherence Tomography.

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.