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Aims: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital., Methods: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement., Results: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59)., Conclusions: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology., Precis: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

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.)

Introduction: For ophthalmologic research, the systematic correlation of clinical data with data obtained from postmortem tissue donation is of great benefit. In this respect, the establishment of an eye donation registry represents a prerequisite for the acquisition of such data., Methods: A total of 300 patients were interviewed at a tertiary referral center in Germany by means of a standardized questionnaire. Binary questions were evaluated by percentage; Likert-scaled questions (1 = does apply; 5 = does not apply) were analyzed by the median and 25th (Q25) and 75th (Q75) percentiles., Results: The majority of patients (77.0%) would agree to donate their eyes for research purposes. When asked about reasons against an eye donation, 60.9% of all patients only stated reasons in the category "addressable" (e.g., not enough awareness of the topic). The vast majority of patients considered it appropriate for an ophthalmologist to approach them on the issue of postmortem eye donation (median 1, Q25 1, Q75 1)., Conclusion: Overall, patients had a positive attitude towards postmortem eye donation for research purposes. Importantly, reasons given against postmortem eye donation were often related to misconceptions and were potentially addressable. These results underline the fundamental willingness of ophthalmological patients in Germany to donate their eyes postmortem for research purposes., (© 2020 S. Karger AG, Basel.)

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: This retrospective analysis assessed geographic atrophy (GA) progression in fellow eyes from the Proxima B trial intermediate age-related macular degeneration (iAMD) subcohort using high-resolution multimodal imaging anchored on optical coherence tomography (OCT)., Methods: Thirty-two patients from the Proxima B iAMD subcohort were assessed; all had GA with no macular neovascularization (MNV) in the contralateral eye. Imaging data, including color fundus photography, fluorescein angiography, near-infrared reflectance, fundus autofluorescence (FAF), and spectral-domain OCT, were obtained. Features preceding progression/conversion to advanced AMD (drusen, reticular pseudodrusen [RPD], MNV, incomplete/complete retinal pigment epithelium and outer retinal atrophy [iRORA/cRORA]) were assessed., Results: Of 30 fellow eyes with available follow-up images, 12 converted to GA (FAF), 2 converted to MNV, and 16 were nonconverters during the review period (median: 17.8 months). iRORA/cRORA features (present in all converters at baseline) were identified on OCT in eyes that progressed to GA. Median time interval from iRORA to cRORA and from cRORA to GA was 7 months each. GA development/progression was either drusen- or RPD-associated (n = 6 each). Eyes with baseline RPD showed faster GA progression versus eyes with drusen (1.49 vs. 0.38 mm2/year)., Conclusions: RPD presence was associated with rapid GA lesion enlargement and may provide an early indication of faster GA progression., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Purpose: Based on exudative activity, choroidal neovascularization (CNV) in age-related macular degeneration (AMD) can be classified as "active" aCNV, pretherapied "silent" sCNV (i.e., a treatment-free interval >12 weeks), or treatment-naïve "quiescent" qCNV. We evaluated the qualitative and quantitative optical coherence tomography angiography (OCTA) features of these CNV subgroups., Methods: The presence of small-caliber vessels, peripheral arcades, and a -perilesional OCTA signal attenuation as well as values for vessel length, density, and branching index were evaluated for each CNV network in a 6 × 6 mm OCTA scan pattern., Results: Fifty-one eyes of 51 patients with AMD (age 75.9 ± 7.5 years; 20 males [39.2%]) were included. The qCNV subgroup (n = 8) showed the highest prevalence of qualitative and quantitative values for OCTA activity criteria, reaching significance with regard to small-caliber vessels (p = 0.003), peripheral arcades (p = 0.039), vessel length (p = 0.020), and branching index (p < 0.001) when compared to the aCNV (n = 32) and sCNV (n = 11) subgroups. Qualitative criteria were inversely associated with the number of previous anti-VEGF injections (each p < 0.03), while quantitative metrics also suggested lower values., Conclusions: These findings suggest that OCTA may be supportive in the phenotypical differentiation of CNV lesions secondary to AMD, while the assessed structural changes appeared to be more indicative of previously administered anti-VEGF therapy than current exudative activity., (© 2019 S. Karger AG, Basel.)

Purpose: Currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration (iAMD). The MACUSTAR Consortium, a public-private research group funded by the European Innovative Medicines Initiative intends to close this gap., Procedures: Development of study protocol and statistical analysis plan including predictive modelling of multimodal endpoints based on a review of the literature and expert consensus., Results: This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. Current patient-reported outcome measures (PROMs) are not acceptable to regulators and may not capture the functional deficit specific to iAMD with needed precision, justifying development of novel PROMs for iAMD. The total sample size will be n = 750, consisting mainly of subjects with iAMD (n = 600)., Conclusions: As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD., (© 2018 S. Karger AG, Basel.)

Purpose: To evaluate two different spectral-domain optical coherence tomography (SD-OCT) scan patterns in eyes with intermediate age-related macular degeneration (AMD) for the longitudinal assessment of drusen volume., Methods: The data of 38 eyes of 38 AMD patients (age 69.97 ± 6.08 years) were included. The longitudinal drusen volume over 4 years was analyzed by annual SD-OCT raster scanning (field size 20 × 15°). Two raster scan patterns (A/B) differed in the distance between neighboring B-scans (240 vs. 30 µm) and in the number of averaged frames (4 vs. 15)., Results: The mean drusen volume at baseline was 0.213 ± 0.100 mm3 (pattern A) and 0.219 ± 0.103 mm3 (pattern B) (p = 0.937). Linear mixed-effect models showed no significant difference for the change within 4 years for both pattern A (p = 0.8) and pattern B (p = 0.8)., Conclusions: The results indicate that the performance of interpolation algorithms may be sufficient to balance for less dense raster scanning with regard to quantification of longitudinal drusen volume, which can be used as a surrogate marker for AMD progression in future clinical trials., (© 2018 S. Karger AG, Basel.)

Purpose: To assess the natural disease progression of high myopia in Caucasians considered at risk for the development of myopic choroidal neovascularization (mCNV)., Methods: Subjects were recruited in 25 clinical sites between June 2014 and June 2016. Main inclusion criteria included axial length of ≥26 mm, best-corrected visual acuity ≥0.05 decimal equivalent and presence of at least one out of five predefined morphological disease risk criteria. These were (1) subfoveal choroidal thinning < 50 µm, (2) enhanced choroidal curvature length > 6,300 µm, (3) lacquer cracks, (4) patchy atrophy > 5 mm2 and (5) preexisting mCNV in the fellow eye (German Clinical Trial Register DRKS00007761)., Results: A total of 150 participants (66% females) with a mean age of 57.2 (±12.7) years (range 21.9-86.2 years) were included. The disease criteria most frequently encountered were choroidal thinning (33.3%) and lacquer cracks (32.7%). Enhanced choroidal curvature length was detected in only 8 subjects and always occurred in combination with other disease criteria. Presence of patchy atrophy was found to be more common in older subjects (p = 0.0012) and also associated with a more severe disease manifestation., Conclusion: The baseline data of this study indicate that enhanced choroidal curvature might be less common in Caucasians than in Asian populations. Further, disease severity in patients with high myopia is relatively high in the presence of patchy atrophy., (© 2018 S. Karger AG, Basel.)

Purpose: To assess the intrasession test-retest reliability of scotopic cyan and scotopic red fundus-controlled perimetry (FCP) in normal subjects using a modified MAIA "microperimeter" (macular integrity assessment) device., Methods: Forty-seven normal eyes of 30 subjects (aged 33.8 years) underwent duplicate mesopic (achromatic stimuli, 400-800 nm), scotopic cyan (505 nm), and scotopic red (627 nm) FCP, using a grid of 49 stimuli over 14° of the central retina. Test-retest reliability for pointwise sensitivity (PWS), stability of fixation, reaction time and test duration were analyzed using mixed-effects models., Results: PWS test-retest reliability was good among all 3 types of retinal sensitivity assessments (coefficient of repeatability of 4.75 dB for mesopic, 5.26 dB for scotopic cyan, and 4.06 dB for scotopic red testing). While the mean sensitivity decreased with eccentricity for both mesopic and scotopic red testing, it was highest at 7° eccentricity for the scotopic cyan assessment (p < 0.001)., Conclusions: The modified MAIA device allows for reliable scotopic FCP in normal subjects. Our findings suggest that testing of scotopic cyan sensitivity largely reflects rod function., (© 2016 S. Karger AG, Basel.)

Purpose: To analyze and model visual acuity (VA) in geographic atrophy (GA) secondary to age-related macular degeneration (AMD)., Methods: The course of VA was analyzed using Turnbull's estimator in 226 eyes with uni- or bilateral GA due to AMD (151 patients; mean age 74.0 ± 7.6 years; mean follow-up time 33.4 ± 23.4 months) from the natural history FAM (Fundus-Autofluorescence Imaging in AMD) study. The variables 'age at baseline', 'gender', 'lesion size', 'diagnosis of the fellow eye', 'status of the fovea', 'focality of the lesion' and 'pattern' were evaluated for effects on predicting VA using linear mixed-effects models., Results: Mean VA at baseline was 0.6 (Snellen 20/80) ± 0.4 logMAR [range -0.1 to 1.8 (20/17 to hand motions)], showing an estimated mean increase of 0.181 (95% CI 0.152-0.210) and 0.256 (0.214-0.300) after 2 and 4 years of follow-up, respectively. The percentage of eyes with a loss of ≥3 lines was 34% by 2 years and 47% by 4 years. Linear mixed model analysis suggested that 65% of VA variability could be explained by the assessed predictor variables. The strongest effect was found for the 'status of the fovea' (0.69 logMAR units between 'definitively spared fovea' and 'definitive foveal involvement', p < 0.001). The second strongest effect was identified for 'total lesion size' (effects between 0.02 and 0.09 logMAR units for each mm depending on foveal involvement, p < 0.001, square root transformed values)., Conclusions: These findings underscore the importance of GA lesion characteristics as these have the strongest impact on VA. Natural history data and modeling VA to other variables will be helpful for refining outcome parameters and estimating possible benefits of therapeutic interventions., (© 2016 S. Karger AG, Basel.)

Purpose: To assess the clinical application of multicolor imaging by confocal scanning laser ophthalmoscopy (cSLO)., Methods: Retinal imaging was performed in 76 patients including cSLO multicolor imaging (SPECTRALIS SD-OCT, Heidelberg Engineering, Heidelberg, Germany) and color fundus photography (CFP)., Results: The use of confocal optics, reduced light scatter and automated eye tracking enable high-resolution cSLO reflectance images. Compared to CFP, the appearance of pigment alterations and hemorrhages were some of the differences observed. Various artifacts including those derived from optical media alterations need to be considered when interpreting images. Specific pathological findings including epiretinal membranes, fibrovascular proliferations, and reticular pseudodrusen may be better visualized on multicolor images., Conclusions: When using multicolor imaging, ophthalmologists need to be mindful about differences in the appearance of pathological changes and artifacts. Multicolor imaging may offer information over and above conventional CFP; it can be performed through undilated pupils and is less affected by media opacities., (© 2016 S. Karger AG, Basel.)

Purpose: To evaluate longitudinal variations of reticular drusen (RDR) in age-related macular degeneration using confocal scanning laser ophthalmoscopy (cSLO), near-infrared reflectance (NIR) and spectral-domain optical coherence tomography (SD-OCT) imaging., Methods: Eighteen eyes of 12 patients with RDR (median observational time 5 months, range 3-10) were included. Changes over time in the en face cSLO NIR images, the identical SD-OCT B scan (simple approach) and the dense SD-OCT volume scans (11 µm between B scans, detailed approach) for 5 preselected RDR lesions were analysed, respectively., Results: Nineteen of 90 (21%) lesions were no longer detectable at the follow-up examination with the simple SD-OCT approach (increase 7/decrease 48/unchanged 15/not gradable 1). By contrast, no disappearance of single lesions was noted for both cSLO (3/8/61/18) and detailed SD-OCT image analysis (67/22/1/0). Within the dense SD-OCT volume scan, a median change of individual lesion height of 10 µm/year was determined., Conclusions: The findings indicate a recordable progression of RDR lesions in lateral and vertical dimensions. Using dense SD-OCT volume scans, individual RDR lesion progression can be quantified and may be applied in future longitudinal studies., (© 2014 S. Karger AG, Basel.)

Aim: To evaluate the variation of peripheral alterations in different retinal diseases over a period of >3 years by using wide-field fundus autofluorescence (FAF) scanning laser ophthalmoscopy (SLO)., Methods: A total of 26 eyes from 13 patients (median age 66 years, range 19-80) with age-related macular degeneration and other retinal degenerations were examined. In 2009, the Optos P200CAF prototype and from 2012 onwards, the Optos 200Tx (Optos plc, Scotland) were used for wide-field FAF SLO (excitation 532 nm)., Results: The area involvement in outer retinal pathological alterations, such as atrophy and mottling of the retinal pigment epithelium far beyond the vascular arcades, was readily and better visualized within one image frame using wide-field FAF as compared to pseudocolor SLO of the same device. Over time, progression of existing and the development of de novo peripheral lesions were recorded with a concomitant enlargement of central lesions. In two cases (unilateral paravenous pigmented choroidal atrophy and suspected phenocopy of retinal dystrophy), no longitudinal changes of the topographic distribution of peripheral FAF intensities were noted., Conclusions: Wide-field FAF SLO allows the mapping of dynamic changes at the outer retina far beyond the vascular arcades. While its ability to detect and monitor these changes appears to be better than that of pseudocolor imaging, wide-field FAF SLO may not only be helpful to assess more widespread retinal dysfunction, but may also be useful for longitudinal assessments in natural history studies and interventional clinical trials., (© 2015 S. Karger AG, Basel.)

Purpose: To investigate the use of imaging and quantitative measurement capabilities of a modified fundus camera in a rat model of laser-induced choroidal neovascularization., Methods: Following induction of experimental choroidal neovascularization, Dark Agouti rats underwent serial in vivo imaging with a fundus camera (FF450plus, Carl Zeiss MediTec, Jena, Germany), including color, reflectance and fluorescence imaging., Results: A custom-made setting allowed high-resolution imaging. Change of fluorescence intensity following intravenous or intravitreal dye injection could be quantitatively monitored over time. Hardware binning resulted in an improved signal-to-noise ratio and a reduction of flash light intensity. Simultaneous fluorescence imaging following injection of two different dendritic polygylcerol sulfate dyes could be demonstrated., Conclusion: This study demonstrates the use and optimizations of a fundus camera for various in vivo imaging modalities in rats. Molecular imaging of the eye may allow for better insights into cellular dysfunction and optimization of therapeutic strategies., (© 2013 S. Karger AG, Basel.)

Advances in retinal imaging technology have largely contributed to the understanding of the natural history, prognostic markers and disease mechanisms of geographic atrophy (GA) due to age-related macular degeneration. There is still no therapy available to halt or slow the disease process. In order to evaluate potential therapeutic effects in interventional trials, there is a need for precise quantification of the GA progression rate. Fundus autofluorescence imaging allows for accurate identification and segmentation of atrophic areas and currently represents the gold standard for evaluating progressive GA enlargement. By means of high-resolution spectral-domain optical coherence tomography, distinct microstructural alterations related to GA can be visualized., (Copyright © 2011 S. Karger AG, Basel.)