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Abstract Background The use of patient-reported outcome measures (PROMs) in clinical research increases and use of heterogeneous instruments reflects how well diverse traits are captured by a medical specialty. In order to reflect the heterogeneity of current PROM use in ophthalmology, we reviewed the available literature. Methods The medical literature database Web of Science was searched for the most cited articles in clinical ophthalmology. Titles, abstracts and full text articles were reviewed for the use of PROMs and a list of the 100 most cited articles using PROMs was obtained and stratified by year of publication. Results A total of 1,996 articles were screened. Seventy-seven out of the 100 articles identified included one PROM, and the average number of instruments was 1.5 ± 1.1. The most widely used PROMs were the National Eye Institute Visual Function Questionnaire (33%), the Ocular Surface Disease Index (14%) and the Medical Outcomes Study Short Form (13%). A simulation analysis suggested that the distribution of PROM use in ophthalmology study did not significantly differ from a power law distribution. Twenty-two percent and fifteen percent of articles did not reference and did not specify the PROM used, respectively. This rate decreased in the more recently published articles (p = 0.041). Conclusions Our data suggest that the heterogeneity of PROMs applied in ophthalmology studies is low. The selection of PROMs for clinical studies should be done carefully, depending on the research goal.

Abstract The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD.

Abstract Introduction The National Eye Institute Visual Function Questionnaire (NEI VFQ) is a common patient-reported outcome measure (PROM) in uveitis trials. Its psychometric properties using state-of-the-art scoring based on Rasch models, a latent trait model that improves accuracy of PROMs assessment, has not yet been investigated. Methods The study participants were recruited online from uveitis patient organizations, where individuals self-reported their uveitis diagnosis and visual acuity level. These participants then completed the NEI VFQ-25. The visual function (VF) and socioemotional (SE) subscales were psychometrically analysed in terms of item fit, targeting, internal consistency, dimensionality, and differential item functioning (DIF), using Rasch models. Criterion validity was examined based on associations between NEI VFQ person measures and recent visual acuity (VA) levels. Results Ninety-nine participants recruited online from uveitis patient organizations (68 women, 31 men; mean age 50 ± 15 years; 46.5% self-reported receiving systematic therapy for uveitis, 0.6% NEI VFQ-25 missing data) were included. The mean difficulty of items was lower than the average person ability. None of the items demonstrated misfit to an extent that would induce noise into the measurement. The consistency metrics person reliability and person separation index of the subscales were 0.85 and 2.34 (NEI VFQ-VF), 0.86 and 2.52 (NEI VFQ-SE), respectively. There was no evidence of multidimensionality and none of the items showed DIF by gender. The differences between item and person measures were 1.44 (NEI VFQ-VF) and 1.03 (NEI VFQ-SE). NEI VFQ-25 person measures were significantly lower in participants with visual impairment (all p values ≤ 0.007). Conclusion Rasch model-based scoring of the re-engineered NEI VFQ-25 demonstrates acceptable internal consistency, item fit and construct validity for assessing two key domains of quality of life in individuals self-reporting uveitis. The PROM was targeted at a higher level of difficulty than present in our heterogeneous sample.

Abstract Introduction Epidemiologic data on age-related macular degeneration (AMD) are mainly based on cohort studies, including both diagnosed and undiagnosed cases. Using health claims data allows estimating epidemiological data of diagnosed subjects with AMD within the health care system using diagnosis codes from a regional claims database (AOK PLUS) to estimate the prevalence and incidence of non-exudative and exudative AMD in Germany. Methods Patients with AMD were identified among AOK PLUS insured patients based on at least two outpatient, ophthalmologic or one inpatient H35.3 diagnoses for the years 2012 to 2021. Patients without continuous observation in a calendar year were excluded. Prevalence was assessed, and 1-year cumulative incidence was determined by the number of newly diagnosed patients divided by the number of individuals at risk. For 2020 and 2021, the AMD stage was assessed by diagnostic subcodes for non-exudative and exudative AMD, respectively. For 2012 to 2019, patient numbers were estimated based on the average proportions of non-exudative AMD and exudative AMD, respectively, in 2020 and 2021. Incidence and prevalence numbers were then extrapolated to Germany. Results Between 2012 to 2021, the prevalence of diagnosed AMD cases remained relatively stable among approximately 3.27 million AOK PLUS insured persons, ranging from 0.96% (minimum in 2021) to 1.31% (maximum in 2014) for non-exudative AMD, about twice as high as for exudative AMD (min–max: 0.53–0.72%). The age- and sex-adjusted projections amounted to 644,153 diagnosed non-exudative and 367,086 diagnosed German patients with exudative AMDs in 2021. The 1-year cumulative incidence for non-exudative and exudative AMD, respectively, ranged from 122,427–142,932 to 46,092–86,785 newly diagnosed cases. Conclusion The number of diagnosed cases with AMD in Germany has increased slightly over the past decade. For the first time, patient counts with non-exudative and exudative AMD were approximated for Germany based on a representative, large-scale database study.

Abstract As most rare diseases, intermediate uveitis lacks reliable endpoints necessary for randomized clinical trials. Therefore, we investigated longitudinal changes of retinal and choriocapillaris perfusion on optical coherence tomography angiography (OCT-A) in intermediate uveitis and their prognostic value for future best corrected visual acuity (BCVA) and central retinal thickness (CRT). In this retrospective, longitudinal cohort study eyes of patients with intermediate uveitis were imaged by swept-source OCT-A (macula-centered 3 × 3 mm; PLEX Elite 9000, Zeiss) and stratified into clinically stable, worsened and improved based on changes in clinical parameters. Superficial (SRL) and deep retinal layers (DRL) were automatically analyzed for vessel density (VD) and choriocapillaris layer for non-perfused area (CCNPA) using ImageJ. Mixed-effects regression analysis controlling for age, sex, and OCT-A signal strength index (SSI) was used to evaluate the prognostic value of OCT-A parameters. 91 eyes (62 stable, 12 worsened, and 17 improved) were included in the analysis and mean follow-up time was 296 days. Longitudinal changes of VD were different between all three groups (p = 0.002 for SRL and p = 0.017 for DRL). Clinically worsened eyes showed a decrease in VD (− 0.032 ± 0.055 for SRL and − 0.027 ± 0.025 for DRL), whereas clinically improved eyes showed an increase in VD (0.037 ± 0.039 for SRL and 0.001 ± 0.023 for DRL). No difference was found for CCNPA. When controlling for age, sex, and SSI, observed differences held true in clinically worsened eyes for DRL (p = 0.011) and in clinically improved eyes for SRL (p = 0.002). An increase of CCNPA in clinically worsened eyes (p = 0.03) compared to clinically stable and improved eyes was evident. Predictive analysis revealed an association of VD in SRL and DRL at baseline with BCVA at follow-up (p = 0.039 and p = 0.047, respectively) and of VD in SRL at baseline with CRT at follow-up (p = 0.046). Alterations in retinal perfusion on OCT-A in intermediate uveitis are partly reversible and OCT-A VD may serve to predict future BCVA and CRT. Thus, perfusion parameters on OCT-A might aid monitoring and serve as prognostic imaging-biomarker.

Abstract Background With a rising prevalence of age-related eye diseases, prevention and early diagnosis of these conditions are key goals of public eye health. Disease-related knowledge in the general public supports these goals but there is little data available. Thus, we have assessed knowledge of cataract, glaucoma, age-related macular degeneration (AMD) and diabetic eye disease in the German adult general population in a cross-sectional study and identified target groups for health education interventions. Methods Knowledge assessment content was identified based on a literature review, expert input, and a list of items was generated after a qualitative selection process. The resulting 16-item instrument (4 items per condition) was administered to 1,008 participants from a survey panel, demographically representative of the adult German population. Test properties were evaluated based on a Rasch model and multiple correspondence analysis (MCA). Binary-logistic regression analysis was performed to investigate associations with age, sex, education level, employment status, marital status, income, reported health status, visual difficulties, and recent general practitioner (GP) and ophthalmologist consultations. Results Replies were correct for a median of 9 out of 16 (range 2 – 16) items, which differed between conditions (p

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability.

Abstract Age-related macular degeneration (AMD) is a leading cause of severe vision loss worldwide, with a global prevalence that is predicted to substantially increase. Identifying early biomarkers indicative of progression risk will improve our ability to assess which patients are at greatest risk of progressing from intermediate AMD (iAMD) to vision-threatening late-stage AMD. This is key to ensuring individualized management and timely intervention before substantial structural damage. Some structural biomarkers suggestive of AMD progression risk are well established, such as changes seen on color fundus photography and more recently optical coherence tomography (drusen volume, pigmentary abnormalities). Emerging biomarkers identified through multimodal imaging, including reticular pseudodrusen, hyperreflective foci, and drusen sub-phenotypes, are being intensively explored as risk factors for progression towards late-stage disease. Other structural biomarkers merit further research, such as ellipsoid zone reflectivity and choriocapillaris flow features. The measures of visual function that best detect change in iAMD and correlate with risk of progression remain under intense investigation, with tests such as dark adaptometry and cone-specific contrast tests being explored. Evidence on blood and plasma markers is preliminary, but there are indications that changes in levels of C-reactive protein and high-density lipoprotein cholesterol may be used to stratify patients and predict risk. With further research, some of these biomarkers may be used to monitor progression. Emerging artificial intelligence methods may help evaluate and validate these biomarkers; however, until we have large and well-curated longitudinal data sets, using artificial intelligence effectively to inform clinical trial design and detect outcomes will remain challenging. This is an exciting area of intense research, and further work is needed to establish the most promising biomarkers for disease progression and their use in clinical care and future trials. Ultimately, a multimodal approach may yield the most accurate means of monitoring and predicting future progression towards vision-threatening, late-stage AMD.

Abstract Background Visual impairment is an independent risk factor for falling. Whether this extends to patient-reported visual difficulties has not been assessed to date. We have evaluated whether patient-reported visual difficulties in low-contrast and low luminance situations are a risk factor for falls and concerns about falling. Methods Baseline assessments in outpatients with varying degrees of visual impairment aged ≥ 60 years included the Vision Impairment in Low Luminance (VILL) questionnaire and socio-demographic data; prospective follow-up assessments included falls over 12 months, the Falls Efficacy Scale (FES-I) and the VILL. The VILL was scored using Rasch models, and the FES-I was categorized following published guidelines. Associations were investigated using logistic regression analysis, controlling for age, visual acuity and known risk factors of falling. Results We included 112 participants (74 women, mean age 70 ± 7 years). Twenty-seven participants recalled any falls and eleven recalled multiple falls at follow-up. Higher VILL reading subscale and mobility subscale scores at baseline were significantly associated with reporting less multiple falls at follow-up (OR 0.559 [0.333–0.936], p = 0.027 and OR 0.595 [0.377–0.940], p = 0.026). VILL scores were significantly associated with concerns about falling (high versus low: p ≤ 0.004, reading, mobility and emotional subscales; high versus moderate: p = 0.004, emotional subscale). Conclusions Patient-reported visual difficulties under low illumination and in low-contrast conditions are predictive of multiple falls in the future, have an additional predictive value over established risk scores, and are associated with concerns to fall. Current fall risk assessments may benefit from the inclusion of such assessments, e.g. the VILL questionnaire.

Abstract Cerebral embolization is a known complication of transcatheter aortic valve implantation (TAVI) but the effect of the procedure on the ocular perfusion is currently unclear. Thus, we investigated post-procedural morphologic and perfusion changes of the retina and choroid, using optical coherence tomography angiography (OCTA) and color fundus photography (CFP) in a prospective cohort study. Ophthalmic examinations were conducted pre- and post-TAVI. OCTA images were analyzed quantitatively based on vessel density and skeleton density of the superficial and deep retinal plexus as well as the signal intensity and flow deficits in the choriocapillaris. CFP images were assessed for presence of acute retinal ischemia, optic nerve swelling, vessel emboli, hemorrhages and cotton wool spots. Data was analyzed using linear mixed models. Twenty patients (9 women; 11 men) at a mean age of 81 ± 6 years were included. Pre- and post-interventional ocular imaging data were available for 32 eyes. The analysis revealed a significant impairment of the choriocapillaris perfusion after TAVI with an increased proportion of flow deficits (p = 0.044). When controlling for blood pressure, the average size of choriocapillaris flow voids was significantly increased (systolic and diastolic, p = 0.039 and 0.029). Qualitatively, focal areas of retinal ischemia were detected on OCTA in 33% of participants. Silent emboli or cotton wool spots were identified on CFP in 21%. Our findings indicate a reduced choroidal perfusion as well as areas of retinal ischemia and embolization in a considerable proportion of patients following TAVI. Pending confirmation in a larger sample, these complications merit monitoring as well as inclusion in consent procedures for TAVI.

Abstract Drusen are an important biomarker for age-related macular degeneration (AMD). Their accurate segmentation based on optical coherence tomography (OCT) is therefore relevant to the detection, staging, and treatment of disease. Since manual OCT segmentation is resource-consuming and has low reproducibility, automatic techniques are required. In this work, we introduce a novel deep learning based architecture that directly predicts the position of layers in OCT and guarantees their correct order, achieving state-of-the-art results for retinal layer segmentation. In particular, the average absolute distance between our model’s prediction and the ground truth layer segmentation in an AMD dataset is 0.63, 0.85, and 0.44 pixel for Bruch's membrane (BM), retinal pigment epithelium (RPE) and ellipsoid zone (EZ), respectively. Based on layer positions, we further quantify drusen load with excellent accuracy, achieving 0.994 and 0.988 Pearson correlation between drusen volumes estimated by our method and two human readers, and increasing the Dice score to 0.71 ± 0.16 (from 0.60 ± 0.23) and 0.62 ± 0.23 (from 0.53 ± 0.25), respectively, compared to a previous state-of-the-art method. Given its reproducible, accurate, and scalable results, our method can be used for the large-scale analysis of OCT data.

Fundus autofluorescence (FAF) is a prompt and non-invasive imaging modality helpful in detecting pathological abnormalities within the retina and the choroid. This narrative review and case series provides an overview on the current application of FAF in posterior and panuveitis. The literature was reviewed for articles on lesion characteristics on FAF of specific posterior and panuveitis entities as well as benefits and limitations of FAF for diagnosing and monitoring disease. FAF characteristics are described for non-infectious and infectious uveitis forms as well as masquerade syndromes. Dependent on the uveitis entity, FAF is of diagnostic value in detecting disease and following the clinical course. Currently available FAF modalities which differ in excitation wavelengths can provide different pathological insights depending on disease entity and activity. Further studies on the comparison of FAF modalities and their individual value for uveitis diagnosis and monitoring are warranted.

Abstract Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991–0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757–0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD. Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017.

Abstract Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial–drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of − 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of − 22.35 ± 3.28 AU (p

Abstract Clinical discrimination of posterior uveitis entities remains a challenge. This exploratory, cross-sectional study investigated the green (GEFC) and red emission fluorescent components (REFC) of retinal and choroidal lesions in posterior uveitis to facilitate discrimination of the different entities. Eyes were imaged by color fundus photography, spectrally resolved fundus autofluorescence (Color-FAF) and optical coherence tomography. Retinal/choroidal lesions’ intensities of GEFC (500–560 nm) and REFC (560–700 nm) were determined, and intensity-normalized Color-FAF images were compared for birdshot chorioretinopathy, ocular sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and punctate inner choroidopathy (PIC). Multivariable regression analyses were performed to reveal possible confounders. 76 eyes of 45 patients were included with a total of 845 lesions. Mean GEFC/REFC ratios were 0.82 ± 0.10, 0.92 ± 0.11, 0.86 ± 0.10, and 1.09 ± 0.19 for birdshot chorioretinopathy, sarcoidosis, APMPPE, and PIC lesions, respectively, and were significantly different in repeated measures ANOVA (p

Abstract Cerebral small vessel disease (CSVD) is an important contributor to cognitive impairment and stroke. Previous research has suggested associations with alterations in single retinal layers. We have assessed changes of all individual retinal layers in CSVD using high-resolution optical coherence tomography (OCT) for the first time. Subjects with recent magnetic resonance imaging (MRI) underwent macular and peripapillary retinal imaging using OCT for this case–control study. Number and volume ratio index (WMRI) of white matter lesions (WML) were determined on MRI. Data were analyzed using multiple linear regression models. 27 CSVD patients and 9 control participants were included. Ganglion cell layer (GCL) volume was significantly reduced in patients with CSVD compared to age-matched controls (p = 0.008). In patients with CSVD, larger foveal outer plexiform layer (OPL) volume and decreased temporal peripapillary retinal nerve fiber layer (RNFL) thickness were significantly associated with a higher WMRI in linear regression when controlling for age (p ≤ 0.033). Decreased foveal GCL volume and temporal-inferior RNFL thickness at Bruch’s membrane opening (MRW), and increased temporal MRW were associated with a higher WML burden (p ≤ 0.037). Thus, we identified alterations in several OCT layers in individuals with CSVD (GCL, OPL, MRW and RNFL). Their potential diagnostic value merits further study.

Abstract Both retinal atrophy measured through optical coherence tomography and plasma neurofilament light chain (NfL) levels are markers of neurodegeneration, but their relationship is unknown. Therefore, we assessed their determinants and association in 4369 participants of a population‐based study. Both plasma NfL levels and inner retinal atrophy increased exponentially with age. In the presence of risk factors for neurodegeneration (including age, smoking, and a history of neurological disorders), plasma NfL levels were associated with inner retinal atrophy and outer retinal thickening. Our findings indicate that inner retinal atrophy can reflect neuroaxonal damage as mirrored by rising plasma NfL levels.

Abstract Cerebral small vessel disease (CSVD) is associated with changes in the retinal vasculature which can be assessed non-invasively with much higher resolution than the cerebral vasculature. To detect changes at a microvascular level, we used optical coherence tomography angiography which resolves retinal and choroidal vasculature. Participants with CSVD and controls were included. White matter lesions were determined on magnetic resonance imaging (MRI). The retinal and choroidal vasculature were quantified using swept-source optical coherence tomography angiography. Data were analysed using linear regression. We included 30 participants (18 females; patients, n = 20; controls, n = 10) with a mean age of 61 ± 10 years. Patients had a higher mean white matter lesion index and number of lesions than controls (p ≤ 0.002). The intraindividual deviation of choriocapillaris reflectivity differed significantly between age-matched patients (0.234 ± 0.012) and controls (0.247 ± 0.011; p = 0.029). Skeleton density of the deep retinal capillaries was significantly associated with the number of lesions on MRI (β = − 5.3 × 108, 95%-confidence interval [− 10.3 × 108; − 0.2 × 108]) when controlling for age. The choroidal microvasculature and the deep retinal vascular plexus, as quantified by optical coherence tomography angiography, are significantly altered in CSVD. The value of these findings in diagnosing or monitoring CSVD need to be assessed in future studies.

Abstract Retinal assessments have been discussed as biomarkers for brain atrophy. However, available studies did not investigate all retinal layers due to older technology, reported inconsistent results, or were based on small sample sizes. We included 2872 eligible participants of the Rhineland Study with data on spectral domain–optical coherence tomography (SD–OCT) and brain magnetic resonance imaging (MRI). We used multiple linear regression to examine relationships between retinal measurements and volumetric brain measures as well as fractional anisotropy (FA) as measure of microstructural integrity of white matter (WM) for different brain regions. Mean (SD) age was 53.8 ± 13.2 years (range 30–94) and 57% were women. Volumes of the inner retina were associated with total brain and grey matter (GM) volume, and even stronger with WM volume and FA. In contrast, the outer retina was mainly associated with GM volume, while both, inner and outer retina, were associated with hippocampus volume. While we extend previously reported associations between the inner retina and brain measures, we found additional associations of the outer retina with parts of the brain. This indicates that easily accessible retinal SD-OCT assessments may serve as biomarkers for clinical monitoring of neurodegenerative diseases and merit further research.

Abstract Neovascular age-related macular degeneration (nAMD) is a progressive retinal disease that often leads to severe and permanent vision loss. Early initiation of anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to preserve vision in nAMD patients. Concurrently, treatment outcomes in real-world are inferior to those reported in clinical trials. The most likely reasons observed are fewer treatment-intensity in routine clinical practice than in clinical trials. The other possibility could be the delay in starting treatment and the re-treatment interval. Although a negative impact of aforementioned parameters seems obvious, quantitative impact measures remain elusive in a real-world setting due to a lack of an ‘optimal treatment’ control group. To overcome this shortcoming, we developed, validated, and applied a model to assess and quantify the impact of anti-VEGF administration variables on visual acuity development in a prospective nAMD patient cohort. The model was further applied to probe the impact of the COVID-19 pandemic on visual progressions in nAMD patients. The presented model paves the way to systematically explore and evaluate realistic interventions in the current treatment paradigm, that can be adopted in routine clinical care.

Abstract Peripheral arterial disease (PAD) is caused by atherosclerosis and is a common disease of the elderly leading to excess morbidity and mortality. Early PAD diagnosis is important, as the only available causal therapy is addressing risk factors like smoking, hypercholesterolemia or hypertension. However, current diagnostic techniques often do not detect early stages of PAD. We theorize that PAD’s underlying cause atherosclerosis can be detected on color fundus photography (CFP) images with a convolutional neural network architecture, which might aid earlier PAD diagnosis and improve disease monitoring. In this explorative study a deep attention-based Multiple Instance Learning (MIL) architecture is used to capture retinal imaging biomarkers on CFP images of 135 examinations. To capture subtle variations in vascular structures, higher image resolution can be utilized by partitioning the CFP into patches. Our architecture converts each patch into a feature vector, and determines its relative importance via an automatically computed attention weight. Our best model achieves an ROC AUC score of 0.890. Visualizing these attention weights provides insights about the network’s decision and suggests ocular involvement in PAD. Statistical analysis confirms that the optic disc and the temporal arcades are weighted significantly higher (p

Abstract The purpose of this prospective case–control study was to assess whether parameters of retinal and choriocapillaris perfusion are altered in patients with peripheral arterial disease (PAD). Patients with PAD and healthy controls were imaged with swept-source optical coherence tomography angiography (OCT-A). Macula centered 3 × 3 mm OCT-A scans were acquired, binarized and perfusion was evaluated for vessel density (VD) and choriocapillaris non-perfused area. Clinical examination and non-invasive assessment included Fontaine staging, ankle-brachial-pressure-index (ABI) and vascular color-coded Doppler sonography. Fifty-two patients with PAD and 23 healthy controls were included. Superficial retinal VD was reduced in patients compared to controls (difference = − 0.013, p = 0.02), decreased with higher Fontaine stage (p = 0.01) and correlated with ABI (r = 0.42, p

Abstract Smartphone-based fundus imaging (SBFI) is a low-cost approach for screening of various ophthalmic diseases and particularly suited to resource limited settings. Thus, we assessed how best to upskill alternative healthcare cadres in SBFI and whether quality of obtained images is comparable to ophthalmologists. Ophthalmic assistants and ophthalmologists received a standardized training to SBFI (Heine iC2 combined with an iPhone 6) and 10 training examinations for capturing central retinal images. Examination time, total number of images, image alignment, usable field-of-view, and image quality (sharpness/focus, reflex artifacts, contrast/illumination) were analyzed. Thirty examiners (14 ophthalmic assistants and 16 ophthalmologists) and 14 volunteer test subjects were included. Mean examination time (1st and 10th training, respectively: 2.17 ± 1.54 and 0.56 ± 0.51 min, p

Abstract Background Recruiting asymptomatic participants with early disease stages into studies is challenging and only little is known about facilitators and barriers to screening and recruitment of study participants. Thus we assessed factors associated with screening rates in the MACUSTAR study, a multi-centre, low-interventional cohort study of early stages of age-related macular degeneration (AMD). Methods Screening rates per clinical site and per week were compiled and applicable recruitment factors were assigned to respective time periods. A generalized linear mixed-effects model including the most relevant recruitment factors identified via in-depth interviews with study personnel was fitted to the screening data. Only participants with intermediate AMD were considered. Results A total of 766 individual screenings within 87 weeks were available for analysis. The mean screening rate was 0.6 ± 0.9 screenings per week among all sites. The participation at investigator teleconferences (relative risk increase 1.466, 95% CI [1.018–2.112]), public holidays (relative risk decrease 0.466, 95% CI [0.367–0.591]) and reaching 80% of the site’s recruitment target (relative risk decrease 0.699, 95% CI [0.367–0.591]) were associated with the number of screenings at an individual site level. Conclusions Careful planning of screening activities is necessary when recruiting early disease stages in multi-centre observational or low-interventional studies. Conducting teleconferences with local investigators can increase screening rates. When planning recruitment, seasonal and saturation effects at clinical site level need to be taken into account. Trial registration ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017.

Abstract Quantifying intraocular inflammation is crucial in managing uveitis patients. We assessed the minimum B-scan density for reliable automated vitreous intensity (VI) assessment, using a novel approach based on optical coherence tomography (OCT). OCT volume scans centered on the macula were retrospectively collected in patients with uveitis. Nine B-scans per volume scan at fixed locations were automatically analyzed. The following B-scan selections were compared against the average score of 9 B-scans per volume scan as a reference standard: 1/3/5/7 central scans (1c/3c/5c/7c), 3 widely distributed scans (3w). Image data of 49 patients (31 females) were included. The median VI was 0.029 (IQR: 0.032). The intra-class-correlation coefficient of the VI across the 9 B-scans was 0.923. The median difference from the reference standard ranged between 0.001 (7c) and 0.006 (1c). It was significantly lower for scan selection 3w than 5c, p(adjusted) = 0.022, and lower for selection 7c than 3w, p(adjusted) = 0.003. The scan selections 7c and 3w showed the two highest areas under the receiver operating curve (0.985 and 0.965, respectively). Three widely distributed B-scans are sufficient to quantify VI reliably. Highest reliability was achieved using 7 central B-scans. Automated quantification of VI in uveitis is reliable and requires only few OCT B-scans.

Abstract To investigate sensitive outcome measures based exclusively on abnormal points in microperimetry testing of eyes with intermediate age-related macular degeneration (iAMD). 25 eyes of 25 subjects with iAMD had undergone 2 successive tests of mesopic microperimetry with the Macular Integrity Assessment Microperimeter (MAIA), using a custom grid of 33 points spanning the central 14 degrees of the macula. Each point was defined as abnormal if its threshold sensitivity was lower than 1.65 standard deviations (SD) (5%) or 2 SD (2.5%) than the expected threshold in healthy eyes according to the MAIA internal database. Among the 25 eyes there were 11.8 ± 9 and 8.4 ± 8.2 abnormal points at

Abstract Background Systematically review the evidence describing the impact of anti–vascular endothelial growth factor (anti-VEGF) therapy on neovascular age-related macular degeneration (nAMD) patient outcomes and healthcare resource utilization. Methods A systematic literature review was completed using Medline and EMBASE for publications prior to July 2018, and proceedings from major ophthalmology conferences (January 2016 to July 2018). The search strategy combined terms for nAMD with terms for anti-VEGF and study design. The review focused on publications describing the impact of anti-VEGF on blindness, visual impairment, vision-related quality of life (VRQoL), mortality, and costs. The search targeted data collected in epidemiological or observational studies to reflect real-world outcomes but also considered modeling-based approaches. Results The use of anti-VEGF in clinical practice was associated with significant reduction in the incidence of blindness by nAMD. Population-based analyses reported reduction in incidence among the general population of 47% (9.1 cases/100,000 in 2006 to 4.8 cases/100,000 in 2011). Among patients aged ≥50 years, a reduction of 50% was observed (52.2 cases/100,000 in 2000 to 25.7 cases/100,000 in 2010). In some cases, the odds of decreased vision (defined as decline from normal to moderate, moderate to severe, or severe to blindness) fell by 41% following introduction of anti-VEGF. Patients’ VRQoL improved with treatment, with patients reporting a positive impact shortly after treatment was initiated. Change on National Eye Institute 25-Item Visual Function Questionnaire score from baseline to month 12 ranged from 0.7 to 4.4. Although nAMD patients report signs of depression and anxiety, the evidence suggests that there is no association between the use of anti-VEGF and the prevalence or diagnosis of depression. The introduction of anti-VEGF led to increased overall treatment costs due to replacement of existing less frequently administered treatments (e.g. photodynamic therapy) and increased number of patients treated (prior to anti-VEGF, only ~ 20% of patients were eligible for treatment). Conclusions The introduction of anti-VEGF agents has been associated with a positive impact on patient-relevant outcomes, including a significant reduction in incidence of blindness and visual impairment by nAMD. Anti-VEGF agents replaced less-effective treatments, improving patient outcomes and broadening the patient population eligible for treatment.

Abstract Background There is an unmet need for treatment options in intermediate age-related macular degeneration (iAMD). However, for any new interventions to be tested in clinical trials, novel currently unavailable clinical endpoints need to be developed. Thus, the MACUSTAR study aims to develop and evaluate functional, structural, and patient-reported candidate endpoints for use in future iAMD trials. Methods The protocol describes a low-interventional clinical multicenter study employing a novel two-part design. The cross-sectional part (total duration, 1 month) and the longitudinal part (total duration, 36 months) include participants with iAMD and control groups with early/late/no AMD. The cross-sectional part’s primary objective is a technical evaluation of functional, structural, and patient-reported candidate outcomes. The longitudinal part’s primary objective is to assess the prognostic power of changes in functional, structural, and patient-reported outcomes for progression from iAMD to late AMD. All data will be used to support a biomarker qualification procedure by regulatory authorities. Discussion The MACUSTAR study characterizes and evaluates much needed novel functional, structural, and patient-reported endpoints for future clinical trials in iAMD and will improve our understanding of the natural history and prognostic markers of this condition. Trial registration ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017

Abstract Background Attrition due to death and non-attendance are common sources of bias in studies of age-related diseases. A simulation study is presented to compare two methods for estimating the survivor average causal effect (SACE) of a binary exposure (sex-specific dietary iron intake) on a binary outcome (age-related macular degeneration, AMD) in this setting. Methods A dataset of 10,000 participants was simulated 1200 times under each scenario with outcome data missing dependent on measured and unmeasured covariates and survival. Scenarios differed by the magnitude and direction of effect of an unmeasured confounder on both survival and the outcome, and whether participants who died following a protective exposure would also die if they had not received the exposure (validity of the monotonicity assumption). The performance of a marginal structural model (MSM, weighting for exposure, survival and missing data) was compared to a sensitivity approach for estimating the SACE. As an illustrative example, the SACE of iron intake on AMD was estimated using data from 39,918 participants of the Melbourne Collaborative Cohort Study. Results The MSM approach tended to underestimate the true magnitude of effect when the unmeasured confounder had opposing directions of effect on survival and the outcome. Overestimation was observed when the unmeasured confounder had the same direction of effect on survival and the outcome. Violation of the monotonicity assumption did not increase bias. The estimates were similar between the MSM approach and the sensitivity approach assessed at the sensitivity parameter of 1 (assuming no survival bias). In the illustrative example, high iron intake was found to be protective of AMD (adjusted OR 0.57, 95% CI 0.40–0.82) using complete case analysis via traditional logistic regression. The adjusted SACE odds ratio did not differ substantially from the complete case estimate, ranging from 0.54 to 0.58 for each of the SACE methods. Conclusions On average, MSMs with weighting for exposure, missing data and survival produced biased estimates of the SACE in the presence of an unmeasured survival-outcome confounder. The direction and magnitude of effect of unmeasured survival-outcome confounders should be considered when assessing exposure-outcome associations in the presence of attrition due to death.

Traditional endpoints assessing visual function are limited by their responsiveness to interventions restoring or maintaining vision. An alternative concept is assessing instrumental activities of daily living (IADL). Herein, we review all available vision-specific IADL instruments relevant for vision restoration trials and report data for the most promising instrument. Six relevant instruments exist: The Low Vision Functional Status Evaluation (LVFSE), Timed IADL (TIADL), Melbourne Low-Vision Activities of Daily Living Index (MLVAI), Assessment of Disability Related to Vision (ADREV), Functional Low-Vision Observer Rated Assessment (FLORA), and Very Low Vision IADL (IADL-VLV). Both internal consistency and test-retest data were available for the LVFSE, MLVAI, and IADL-VLV. In a sample from a low-vision clinic (n = 51; age 57 ± 16 years), we report additional validation data on the IVI-VLV including test–retest reliability (intraclass correlation coefficient 0.981 [0.961; 0.991]). The LVSFE was noticeably less reliable than the MLVAI and the IADL-VLV. Content and construct validity data were available for the LVFSE, TIADL, MLVAI, ADREV, and IADL-VLV, but only the MLVAI and IADL-VLV were developed for an ultra-low vision context. Ceiling effects were present across instruments. Thus, of all appropriate IADL instruments related to vision, the IADL-VLV and MLVAI best meet existing requirements for use in vision restoration trials, e.g., in gene therapies or visual prostheses in inherited retinal diseases, but require further validation.

Abstract Background Real-world data (RWD) has been a valuable addition to the scientific literature regarding treatment pathways, clinical outcomes and characteristics of patients with retinal diseases in recent years. Registries, observational studies and patient databases are often used for real-world research. However, there is limited information for each data source on the design, consistency, data captured, limitations and usability for assessing research questions. Using a systematic approach, we identified RWD sources for patients with retinal diseases and assessed them for completeness of data relating to different outcomes. Methods A systematic literature review was carried out to identify RWD sources for patients with retinal disease. Potentially relevant articles published between 2006 and 2016 were screened following electronic searches in Embase and MEDLINE. Congress and supplementary searches were undertaken to identify RWD sources that may not be referenced in full publications. For each data source, availability and quantity of data on baseline status, clinical outcomes, treatment and management, safety, and patient-reported and economic burden were assessed using a bespoke completeness assessment tool based on International Consortium for Health Outcomes Measurement guidelines for macular degeneration. Completeness of data for each area of interest in each data source was assessed and rated using a ‘good–moderate–poor’ rating system based on availability and quantity of available data. Each data source was then given an overall score based on its score for each of the 7 areas of interest. Results A total of 128 RWD sources from 32 countries were identified. Of the identified sources, 64 sources from 16 countries of interest were analyzed. Most of these sources provided information on baseline status and clinical outcomes and treatment, but few collected data on economic and patient-reported burden. Of the RWD sources analyzed, 10 scored highly in the overall completeness assessment, collecting data on most or all of the areas of interest; these sources are considered to be robust data sources for performing ophthalmology real-world studies. Conclusions The study provides a comprehensive list of RWD sources for patients with retinal disease, many of which will be useful for conducting real-world studies in the field of ophthalmology.

Abstract Purpose Most definitions of visual impairment focus on the status of the better-seeing eye only, but this approach might underestimate the influence of the worse-seeing eye on the vision-related quality of life (VRQoL). Methods We assessed distance-corrected visual acuity in both eyes and VRQoL using the “National Eye Institute 25-Item Visual Function Questionnaire” (NEI VFQ-25) in the German population-based Gutenberg Health Study. We calculated the Rasch-based visual functioning scale (VFS) and socioemotional scale (SES). We categorized the visual acuity of the better-seeing eye (BE) and worse-seeing eye (WE) as follows: (1) no visual impairment (VI) ( 0.5 logMAR). Next, the subjects were categorized as follows: both eyes with no VI (no/no), the better-seeing eye with no VI and the worse-seeing eye with mild VI (no/mild), no VI/severe VI (no/severe), both eyes with mild VI (mild/mild), light VI/severe VI (mild/severe), and both eyes with severe VI (severe/severe). We calculated the median scores for VFS and SES. We used linear regression to estimate the combined influence of BE/WE on VFS and SES. Results We included 11,941 participants (49.9% female, age range: 35–74 years) with information on VRQoL and visual acuity. The median VFS/SES scores were 90/100 (no/no VI group), 84/97 (no/mild group), 81/94 (no/severe group), 70/90 (mild/mild group), 67/74 (mild/severe group), and 63/76 (severe/severe group). These differences were supported by the regression analysis results. Conclusion Relying on the function of the better-seeing eye considerably underestimates the impact of visual impairment on VRQoL.

Abstract Smartphone-based fundus photography (SBFP) allows for a cheap and mobile fundus examination with the potential to revolutionize eye care especially in low income settings. The purpose of this study was to assess the impact of pupil dilation on image quality in optic nerve head (ONH) imaging and vertical cup-to-disc ratio (vCDR) evaluation with SBFP. Eyes with glaucoma or suspected to have glaucoma were imaged with conventional digital fundus photography (CFP) and SBFP undilated and following dilation, all monoscopically. SBFP was possible in 74% of eyes without dilation and in 98% following dilation. Better image quality on SBFP was achieved with dilation and complete visualization of the optic disc rim was possible in 46% of images without dilation and on 94% of images with dilation. VCDR measurements on images obtained following dilation highly correlated with measurements on CFP (coefficient of correlation r = 0.91, p

Abstract Background To estimate the burden of diseases, it is important to consider patient-reported outcomes including Quality of Life (QoL). The aim of this study is to provide population-based reference data for the National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25), stratified by sex and age. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany, including 15,010 participants aged between 35 and 74. The baseline examination was conducted between 2007 and 2012. To overcome known shortcomings of the NEI VFQ-25, we calculated the previously proposed visual functioning scale and the socio-emotional scale based on Rasch-transformed person-level data. We present mean values, standard deviations and percentiles for age decades stratified by sex. We used a linear regression model to assess the influence of age, sex, socioeconomic status, distance-corrected visual acuity (better-seeing eye) and the absolute difference in distance-corrected visual acuity of both eyes on vision-related QoL. Results NEI VFQ-25 data are available from 12,231 participants (82%). Both the long-form visual functioning scale (LFVFS) and the long-form socio-emotional scale (LFSES) showed a clear age dependency, with an average LFVFS score of 92.8 for men and 90.5 for women in the youngest age group and 85.7 and 83.4 in the oldest age group, and a LFSES score of 98.3 for men and 98.1 in women in the youngest and 94.7 and 94.5 in the oldest decade. The largest difference was observed between the youngest age group (35–44 years) and the 45–54 years group. Men tended to have slightly higher scores than women. In the multivariable linear regression analysis, age (per 5 years −0.42), female sex (−1.57), worse distance-corrected visual acuity of the better eye (per 0.1 increase in logMAR −2.92) and the difference between both eyes (per 0.1 increase in logMAR −0.87) were associated with a reduced LFVFS score (all p

In the original publication of this article [1], the incorrect causal diagram was submitted as Fig. 1.

Pseudoxanthoma elasticum (PXE) is an inherited multi-system disorder characterized by ectopic mineralization and fragmentation of elastic fibres in the skin, the elastic laminae of blood vessels and Bruch membrane in the eye. Biallelic mutations in the ABC transporter gene ABCC6 on chromosome 16 are responsible for the disease.The pathophysiology is incompletely understood. However, there is consent that a metabolic alteration leads to dysfunction in extracellular calcium homeostasis and subsequent calcification of connective tissues rich in elastic fibres. This review summarizes and aims at explaining the variety of phenotypic ocular findings in patients with PXE. Specialised imaging techniques including white light fundus photography, blue light autofluorescence, near-infrared confocal reflectance imaging, high resolution optical coherence tomography, fluorescein and indocyanin green angiography have revealed characteristic lesions at the ocular fundus of PXE patients. These include the classic signs of angioid streaks, peau d’orange, comet lesions and choroidal neovascularisations (CNV), but also the more recently recognised features such as chorioretinal atrophy, subretinal fluid independent from CNV, pattern dystrophy-like changes, debris accumulation under the retinal pigment epithelium, and a decreased fluorescence on late phase indocyanine green angiography.