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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.)

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).)

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.

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.)

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 quantify lipofuscin-associated fundus autofluorescence in patients with pseudoxanthoma elasticum (PXE), a model disease for Bruch's membrane pathology., Methods: In this prospective, monocenter, cross-sectional case-control study, 49 patients with PXE (mean age: 46 years, range 18-62) underwent quantitative fundus autofluorescence (qAF) imaging with a modified scanning laser ophthalmoscope containing an internal fluorescent reference for normalization of images. The mean qAF values of a circular ring centered on the fovea (qAF8) were measured and compared to 108 healthy controls (mean age 40 years, range 18-64)., Results: Overall, patients with PXE showed lower qAF8 values compared to controls (difference from controls -23%, 95% confidence interval [CI] -29% to -16%, P < 0.001). The reduction was most pronounced in patients older than 40 years (-30%, 95% CI -36% to -23%, P < 0.001) and was negatively correlated with the extent of Bruch's membrane calcification (r = -0.49, 95% CI: -0.67 to -0.22). The topographic distribution revealed a greater reduction of qAF values toward the optic disc than temporally compared to controls (P < 0.001). The phenotype of patients with reduced qAF values was characterized by pattern-dystrophy-like changes (71%; 10 of 14), reticular pseudodrusen (71%; 10 of 14) and limited areas of atrophy (29%, 4 of 14)., Conclusions: Reduced qAF8 values are a characteristic finding in patients with PXE, indicating that Bruch's membrane disease may result in a modification of the accumulation, distribution, or composition (or a combination thereof) of lipofuscin in retinal pigment epithelial cells.

Purpose: To optimize the perceptibility of Haidinger brushes (HB) and to investigate its association with visual acuity and macular pigment density., Methods: In this prospective cross-sectional study, each subject underwent best-corrected visual acuity (BCVA) testing, funduscopy, and assessment of macular pigment optical density (MPOD) using the two-wavelength fundus autofluorescence method. Haidinger brush visibility was tested with a rotating linear polarizer and a controllable three-color light-emitting diode (LED) panel as light source. A simple model of macular pigment absorption was used to predict HB visibility as a function of stimulus wavelength and MPOD., Results: All control eyes (n = 92) and 34% of the 198 eyes of subjects with macular disease (age-related macular degeneration, n = 40; macular telangiectasia type 2, n = 52; Stargardt disease, n = 58; other retinal dystrophies, n = 48) perceived HB when an optimized test setup (464-nm LED light) was applied. The degree of psychophysical perception and the dependency on different wavelengths were in accordance with the absorptance model. In eyes of subjects with macular disease, minimum thresholds of MPOD and BCVA required for HB perception were identified. Subjects with macular telangiectasia type 2 showed lowest values of MPOD and were mostly unable to perceive HB despite relatively preserved BCVA., Conclusions: Macular pigment and a relatively preserved foveal function are necessary for the perception of HB. Haidinger brushes are usually not perceived by subjects with macular telangiectasia type 2, likely due to their characteristic foveal depletion of macular pigment.

Background: Optical coherence tomography angiography (OCT-A) allows noninvasive, depth-selective visualization of retinal and choroidal vascular networks by detecting the endoluminal blood flow. This results in three-dimensional high-resolution images which are not possible by regular fluorescein angiography in this spatial resolution. Thus, OCT-A can be used to visualize the microperfusion of retinal and choroidal vessels and their alterations due to diverse pathologies and during the course of therapy. Based on several clinical case reports this article gives an overview of the wide range of applications of OCT-A., Methods: The OCT-A images were obtained with the Spectralis OCT-2 prototype (Heidelberg Engineering, Heidelberg, Germany). This device provides an increased A scan rate of 70 kHz, which allows the generation of high-resolution OCT volume scans., Results: The areas of application are manifold and include neovascular age-related macular degeneration, diabetic retinopathy, retinal vascular occlusion, inflammatory diseases and telangiectasia of various etiologies. The resulting images and their interpretation differ significantly from regular fluorescein angiography. Knowledge of these differences and of the limitations of this novel diagnostic device are of importance for its clinical application. For certain indications, OCT-A may be used as a substitute for invasive fluorescein angiography and provides more detailed information, particularly due to the absence of blockage phenomena, such as pooling or staining., Conclusion: The use of OCT-A allows visualization of the microperfusion of the retinal and choroidal vascular networks and their alterations due to diverse diseases in high resolution and with segmentation of different anatomical layers. The exact interpretation of the three-dimensional OCT-A images and their clinical application are currently under clinical evaluation.

Background: Optical coherence tomography angiography (OCT-A) is a new diagnostic non-invasive method by which the vascular structures of the retina and choroid can be visualized three-dimensionally without need for using fluorescence dyes. The technology of OCT-A is an advancement of the OCT. By means of more powerful software and hardware used for OCT-A not only morphological but also retinal and choroidal vascular perfusion analyses can be performed. In this article, the principles and applications of OCT-A are discussed and compared to other non-invasive diagnostic devices for visualization of the retinal and choroidal blood circulation., Methods: This article is based on a selective literature review and analyses of own data., Results: The advantages of OCT-A include easy application without the need for mydriasis or intravenous injection of fluorescence dyes and also the exact three-dimensional localization of vascular changes. In the case of retinal pathologies there is a considerable difference between software-assisted automatic segmentation and the real architecture of the retina, which must be taken into consideration in the clinical interpretation., Conclusion: Of all noninvasive devices for visualization of the retinal and choroidal circulation, OCT-A is the only one which can already be implemented into the clinical routine. With this novel imaging device retinal and choroidal alterations can be visualized in a depth- selective manner and without masking affects, such as pooling or staining phenomena.