Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. METHODS: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. FINDINGS: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483). INTERPRETATION: SRT can reduce ranibizumab treatment burden without compromising vision. FUNDING: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Developing a Continuous Severity Scale for Macular Telangiectasia Type 2 Using Deep Learning and Implications for Disease Grading.

PURPOSE: Deep learning (DL) models have achieved state-of-the-art medical diagnosis classification accuracy. Current models are limited by discrete diagnosis labels, but could yield more information with diagnosis in a continuous scale. We developed a novel continuous severity scaling system for macular telangiectasia (MacTel) type 2 by combining a DL classification model with uniform manifold approximation and projection (UMAP). DESIGN: We used a DL network to learn a feature representation of MacTel severity from discrete severity labels and applied UMAP to embed this feature representation into 2 dimensions, thereby creating a continuous MacTel severity scale. PARTICIPANTS: A total of 2003 OCT volumes were analyzed from 1089 MacTel Project participants. METHODS: We trained a multiview DL classifier using multiple B-scans from OCT volumes to learn a previously published discrete 7-step MacTel severity scale. The classifiers' last feature layer was extracted as input for UMAP, which embedded these features into a continuous 2-dimensional manifold. The DL classifier was assessed in terms of test accuracy. Rank correlation for the continuous UMAP scale against the previously published scale was calculated. Additionally, the UMAP scale was assessed in the κ agreement against 5 clinical experts on 100 pairs of patient volumes. For each pair of patient volumes, clinical experts were asked to select the volume with more severe MacTel disease and to compare them against the UMAP scale. MAIN OUTCOME MEASURES: Classification accuracy for the DL classifier and κ agreement versus clinical experts for UMAP. RESULTS: The multiview DL classifier achieved top 1 accuracy of 63.3% (186/294) on held-out test OCT volumes. The UMAP metric showed a clear continuous gradation of MacTel severity with a Spearman rank correlation of 0.84 with the previously published scale. Furthermore, the continuous UMAP metric achieved κ agreements of 0.56 to 0.63 with 5 clinical experts, which was comparable with interobserver κ values. CONCLUSIONS: Our UMAP embedding generated a continuous MacTel severity scale, without requiring continuous training labels. This technique can be applied to other diseases and may lead to more accurate diagnosis, improved understanding of disease progression, and key imaging features for pathologic characteristics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

CHOROIDAL VASCULARITY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY AND ITS ASSOCIATION WITH RISK SINGLE-NUCLEOTIDE POLYMORPHISMS.

PURPOSE: To analyze the choroidal parameters of patients with chronic central serous chorioretinopathy (cCSC) and the association with central serous chorioretinopathy susceptibility genes. METHODS: The choroidal vascular index (CVI) was obtained by binarizing spectral domain optical coherence tomography enhanced depth images of patients with cCSC and healthy age-matched controls. Patients with cCSC were genotyped for three central serous chorioretinopathy susceptibility single-nucleotide polymorphisms: rs4844392 ( mir-29b-2/CD46 ), rs1329428 ( CFH ), and rs2379120 (upstream GATA5 ). RESULTS: One hundred three eyes with cCSC and 53 control eyes were included. There was a significant increase in the subfoveal choroidal area in both the affected (2.4 ± 0.6 mm 2 ) and fellow (2.2 ± 0.6 mm 2 ) eyes of patients with cCSC compared with controls (1.8 ± 0.5 mm 2 , P < 0.0001 and P < 0.0001). The CVI was reduced in patients with cCSC 63.5% ± 3.1% compared with controls 65.4% ± 2.3% ( P < 0.001) and also in the affected compared with the fellow eyes 64.6% ± 2.9% ( P < 0.01). There was a significant association between CVI in the cCSC group and presence of the risk single-nucleotide polymorphisms rs2379120 at GATA5 ( P < 0.01). CONCLUSION: The relative reduction of CVI in patients with cCSC may suggest a persistence of vessel hyperpermeability over dilation in chronic disease. GATA5 is associated with CVI in patients with cCSC and therefore may have a role in choroidal vascularity.

Caregiver Experience Survey of Anti-Vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema and Neovascular Age-Related Macular Degeneration.

INTRODUCTION: Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) require frequent anti-vascular endothelial growth factor (VEGF) treatment and monitoring visits. We aimed to understand the burden of treatment on caregivers. METHODS: This multinational, noninterventional study used a cross-sectional survey of adult patients with DME or nAMD treated with anti-VEGF injections in the USA, Canada, France, Italy, Spain, and the UK. The survey assessed caregivers' sociodemographic characteristics, patient relationships, patients' clinical history and treatment experiences, caregivers' experiences, and the Caregiver Reaction Assessment of caregiving burden. RESULTS: Caregivers for patients with DME (n = 30) and nAMD (n = 95) completed surveys. Mean ± standard deviation (SD) age was 64.0 ± 13.4 years, and most were female (71.2%), white (70.4%), married (66.4%), and from Europe (67.2%). Most were caring for their mother/father or partner/spouse (85.6%). Mean ± SD length of time as a caregiver was 9.1 ± 10.0 years. Caregivers estimated they provided support for 4.2 ± 2.9 days/week and 6.0 ± 7.1 h/day on average. Nearly half of caregivers (45.6%) reported some impairment in daily activities, and more than two-thirds (70.5%) of working caregivers (n = 44) reported work absenteeism due to anti-VEGF treatment/monitoring appointments. At least one treatment barrier was reported by 66.7% and 50.5% of caregivers of patients with DME and nAMD, respectively, which were related to coronavirus disease 2019- (38.4%), clinic- (18.4%), social-/health- (13.6%), treatment- (10.4%), or financial-related factors (4.8%). Caregiver Reaction Assessment scores indicated mild-to-moderate burden, with higher caregiver schedule disruption scores associated with an increasing number of anti-VEGF treatment/monitoring visits among DME caregivers (r = 0.61). CONCLUSION: Caregivers devote substantial time to caregiving, leading to schedule disruptions and absenteeism for some working caregivers. Positive and negative impacts on caregiver mental health were reported.

Patient Experience Survey of Anti-Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema.

INTRODUCTION: Understanding patient perspectives of treatment may improve adherence and outcomes. This study explored real-world patient experiences with anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD). METHODS: This multinational, non-interventional, quantitative, cross-sectional, observational survey assessed treatment barriers/burden, patient-reported visual functioning, and treatment satisfaction in DME and nAMD patients in the USA, the UK, Canada, France, Italy, and Spain. Treatment patterns and visual outcomes were extracted from medical charts. Regression models evaluated relationships between adherence, total missed visits, number of anti-VEGF injections, and clinical and patient-reported outcomes for visual functioning. Association between treatment satisfaction and aspects of burden were assessed. RESULTS: The survey was completed by 183 DME and 391 nAMD patients. Patients had moderately high vision-related functioning (25-item National Eye Institute Visual Functioning Questionnaire score: mean = 74.8) and were satisfied with their current treatment (mean total score: Macular Disease Treatment Satisfaction Questionnaire = 59.2; Retinopathy Treatment Satisfaction Questionnaire = 61.3). Treatment satisfaction scores were worse with higher time-related impacts of treatment (nAMD/DME), higher impacts on finances and daily life (nAMD), negative impacts on employment and lower expectations for treatment effectiveness (DME). Most patients reported ≥1 barrier (66.1% DME, 49.2% nAMD patients) related to treatment (35.0%), clinic (32.6%), and COVID-19 (21.1%). Moreover, 44.9% of patients reported some impairment in activities of daily living. Work absenteeism was observed among >60% of working patients. Nearly one-quarter (24.2%) of patients needed ≥1 day to recover from intravitreal injections; most reported ≥30 min of travel time (73.7%) and clinic wait time (54.2%). In unadjusted univariable analyses, treatment adherence (vs. nonadherence) was related to higher most recent visual acuity (ß = 8.98 letters; CI, 1.34-16.62) and lower odds of visual acuity below driving vision (≤69 letters) (OR = 0.50; CI, 0.25-1.00). CONCLUSION: More durable treatments with reduced frequency of injections/visits may reduce treatment burden and improve patient satisfaction, which may enhance adherence and visual outcomes.

Identifying the severity of diabetic retinopathy by visual function measures using both traditional statistical methods and interpretable machine learning: a cross-sectional study.

AIMS/HYPOTHESIS: To determine the extent to which diabetic retinopathy severity stage may be classified using machine learning (ML) and commonly used clinical measures of visual function together with age and sex. METHODS: We measured the visual function of 1901 eyes from 1032 participants in the Northern Ireland Sensory Ageing Study, deriving 12 variables from nine visual function tests. Missing values were imputed using chained equations. Participants were divided into four groups using clinical measures and grading of ophthalmic images: no diabetes mellitus (no DM), diabetes but no diabetic retinopathy (DM no DR), diabetic retinopathy without diabetic macular oedema (DR no DMO) and diabetic retinopathy with DMO (DR with DMO). Ensemble ML models were fitted to classify group membership for three tasks, distinguishing (A) the DM no DR group from the no DM group; (B) the DR no DMO group from the DM no DR group; and (C) the DR with DMO group from the DR no DMO group. More conventional multiple logistic regression models were also fitted for comparison. An interpretable ML technique was used to rank the contribution of visual function variables to predictions and to disentangle associations between diabetic eye disease and visual function from artefacts of the data collection process. RESULTS: The performance of the ensemble ML models was good across all three classification tasks, with accuracies of 0.92, 1.00 and 0.84, respectively, for tasks A-C, substantially exceeding the accuracies for logistic regression (0.84, 0.61 and 0.80, respectively). Reading index was highly ranked for tasks A and B, whereas near visual acuity and Moorfields chart acuity were important for task C. Microperimetry variables ranked highly for all three tasks, but this was partly due to a data artefact (a large proportion of missing values). CONCLUSIONS/INTERPRETATION: Ensemble ML models predicted status of diabetic eye disease with high accuracy using just age, sex and measures of visual function. Interpretable ML methods enabled us to identify profiles of visual function associated with different stages of diabetic eye disease, and to disentangle associations from artefacts of the data collection process. Together, these two techniques have great potential for developing prediction models using untidy real-world clinical data.

Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis.

Background: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) can reduce oedema, improve vision, and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. In the previous update of this review, we found moderate-quality evidence that, at 12 months, aflibercept was slightly more effective than ranibizumab and bevacizumab for improving vision in people with DMO, although the difference may have been clinically insignificant (less than 0.1 logarithm of the minimum angle of resolution (logMAR), or five Early Treatment Diabetic Retinopathy Study (ETDRS) letters, or one ETDRS line). Objectives: The objective of this updated review was to compare the effectiveness and safety of the different anti-VEGF drugs in RCTs at longer followup (24 months). Search methods: We searched various electronic databases on 8 July 2022. Selection criteria: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham, or no treatment in people with DMO. Data collection and analysis: We used standard Cochrane methods for pairwise meta-analysis and we augmented this evidence using network meta-analysis (NMA) methods. We used the Stata 'network' meta-analysis package for all analyses. We used the CINeMA (Confidence in Network Meta-Analysis) web application to grade the certainty of the evidence. Main results: We included 23 studies (13 with industry funding) that enrolled 3513 people with DMO (median central retinal thickness (CRT) 460 microns, interquartile range (IQR) 424 to 482) and moderate vision loss (median best-corrected visual acuity (BCVA) 0.48 logMAR, IQR 0.42 to 0.55. One study that investigated ranibizumab versus sham and one study that mainly enrolled people with subclinical DMO and normal BCVA were not suitable for inclusion in the efficacy NMA. Consistent with the previous update of this review, we used ranibizumab as the reference drug for efficacy, and control (including laser, observation, and sham) as the reference for systemic safety. Eight trials provided data on the primary outcome (change in BCVA at 24 months, in logMAR: lower is better). We found no evidence of a difference between the following interventions and ranibizumab alone: aflibercept (mean difference (MD) -0.05 logMAR, 95% confidence interval (CI) -0.12 to 0.02; moderate certainty); bevacizumab (MD -0.01 logMAR, 95% CI -0.13 to 0.10; low certainty), brolucizumab (MD 0.00 logMAR, 95% CI -0.08 to 0.07; low certainty), ranibizumab plus deferred laser (MD 0.00 logMAR, 95% CI -0.11 to 0.10; low certainty), and ranibizumab plus prompt laser (MD 0.03 logMAR, 95% CI -0.04 to 0.09; very low certainty). We also analysed BCVA change at 12 months, finding moderate-certainty evidence of increased efficacy with brolucizumab (MD -0.07 logMAR, 95%CI -0.10 to -0.03 logMAR), faricimab (MD -0.08 logMAR, 95% CI -0.12 to -0.05), and aflibercept (MD -0.07 logMAR, 95 % CI -0.10 to -0.04) compared to ranibizumab alone, but the difference could be clinically insignificant. Compared to ranibizumab alone, NMA of six trials showed no evidence of a difference with aflibercept (moderate certainty), bevacizumab (low certainty), or ranibizumab with prompt (very low certainty) or deferred laser (low certainty) regarding improvement by three or more ETDRS lines at 24 months. There was moderate-certainty evidence of greater CRT reduction at 24 months with brolucizumab (MD -23 microns, 95% CI -65 to -1 9) and aflibercept (MD -26 microns, 95% CI -53 to 0.9) compared to ranibizumab. There was moderate-certainty evidence of lesser CRT reduction with bevacizumab (MD 28 microns, 95% CI 0 to 56), ranibizumab plus deferred laser (MD 63 microns, 95% CI 18 to 109), and ranibizumab plus prompt laser (MD 72 microns, 95% CI 25 to 119) compared with ranibizumab alone. Regarding all-cause mortality at the longest available follow-up (20 trials), we found no evidence of increased risk of death for any drug compared to control, although effects were in the direction of an increase, and clinically relevant increases could not be ruled out. The certainty of this evidence was low for bevacizumab (risk ratio (RR) 2.10, 95% CI 0.75 to 5.88), brolucizumab (RR 2.92, 95% CI 0.68 to 12.58), faricimab (RR 1.91, 95% CI 0.45 to 8.00), ranibizumab (RR 1.26, 95% CI 0.68 to 2.34), and very low for conbercept (RR 0.33, 95% CI 0.01 to 8.81) and aflibercept (RR 1.48, 95% CI 0.79 to 2.77). Estimates for Antiplatelet Trialists Collaboration arterial thromboembolic events at 24 months did not suggest an increase with any drug compared to control, but the NMA was overall incoherent and the evidence was of low or very low certainty. Ocular adverse events were rare and poorly reported and could not be assessed in NMAs. Authors' conclusions: There is limited evidence of the comparative efficacy and safety of anti-VEGF drugs beyond one year of follow-up. We found no clinically important differences in visual outcomes at 24 months in people with DMO, although there were differences in CRT change. We found no evidence that any drug increases all-cause mortality compared to control, but estimates were very imprecise. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated, and the individuals exposed to these drugs may be less healthy than trial participants.

Review and comparison of retinal vessel calibre and geometry software and their application to diabetes, cardiovascular disease, and dementia.

Developments in retinal imaging technologies have enabled the quantitative evaluation of the retinal vasculature. Changes in retinal calibre and/or geometry have been reported in systemic vascular diseases, including diabetes mellitus (DM), cardiovascular disease (CVD), and more recently in neurodegenerative diseases, such as dementia. Several retinal vessel analysis softwares exist, some being disease-specific, others for a broader context. In the research setting, retinal vasculature analysis using semi-automated software has identified associations between retinal vessel calibre and geometry and the presence of or risk of DM and its chronic complications, and of CVD and dementia, including in the general population. In this article, we review and compare the most widely used semi-automated retinal vessel analysis softwares and their associations with ocular imaging findings in common systemic diseases, including DM and its chronic complications, CVD, and dementia. We also provide original data comparing retinal calibre grading in people with Type 1 DM using two softwares, with good concordance.

Comparison of Diabetic Retinopathy Lesions Identified Using Ultrawide Field Imaging and Optical Coherence Tomography Angiography.

INTRODUCTION: Optical coherence tomography (OCT) angiography (OCTA) has the potential to influence the diagnosis and management of diabetic eye disease. This study aims to determine the correlation between diabetic retinopathy (DR) findings on ultrawide field (UWF) color photography (UWF-CP), UWF fluorescein angiography (UWF-FA), and OCTA. METHODS: This is a cross-sectional, prospective study. One hundred and fourteen eyes from 57 patients with diabetes underwent mydriatic UWF-CP, UWF-FA, and OCTA. DR severity was assessed. Ischemic areas were identified on UWF-FA using ImageJ and the nonperfusion index (NPI) was calculated. Diabetic macular edema (DME) was assessed using OCT. Superficial capillary plexus vessel density (VD), vessel perfusion (VP), and foveal avascular zone (FAZ) area were automatically measured on OCTA. Pearson correlation coefficient between the imaging modalities was determined. RESULTS: Forty-five eyes were excluded due to non-DR findings or prior laser photocoagulation; 69 eyes were analyzed. DR severity was associated with larger NPI (r = 0.55944, p < 0.0001) even after distinguishing between cones (Cone Nonperfusion Index [CPI]: r = 0.55617, p < 0.0001) and rods (Rod Nonperfusion Index [RPI]: r = 0.55285, p < 0.0001). In eyes with nonproliferative DR (NPDR), NPI is correlated with DME (r = 0.51156, p = 0.0017) and central subfield thickness (CST) (r = 0.67496, p < 0.0001). UWF-FA macular nonperfusion correlated with NPI (r = 0.42899, p = 0.0101), CPI (r = 0.50028, p = 0.0022), and RPI (r = 0.49027, p = 0.0028). Central VD and VP correlated with the DME presence (r = 0.52456, p < 0.0001; r = 0.51952, p < 0.0001) and CST (r = 0.50133, p < 0.0001; r = 0.48731, p < 0.0001). Central VD and VP were correlated with macular nonperfusion (r = 0.44503, p = 0.0065; r = 0.44239, p = 0.0069) in eyes with NPDR. Larger FAZ was correlated with decreased central VD (r = -0.60089, p = 0.0001) and decreased central VP (r = -0.59224, p = 0.0001). CONCLUSION: UWF-CP, UWF-FA, and OCTA findings provide relevant clinical information on diabetic eyes. Nonperfusion on UWF-FA is correlated with DR severity and DME. OCTA metrics of the superficial capillary plexus correlate with the incidence of DME and macular ischemia.

Comparison of 2-Field and 5-Field Mydriatic Handheld Retinal Imaging in a Community-Based Diabetic Retinopathy Screening Program.

INTRODUCTION: The purpose of this study was to compare 2-field (2F) and 5-field (5F) mydriatic handheld retinal imaging for the assessment of diabetic retinopathy (DR) severity in a community-based DR screening program (DRSP). METHODS: This was a prospective, cross-sectional diagnostic study, evaluating images of 805 eyes from 407 consecutive patients with diabetes acquired from a community-based DRSP. Mydriatic standardized 5F imaging (macula, disc, superior, inferior, temporal) with handheld retinal camera was performed. 2F (disc, macula), and 5F images were independently assessed using the International DR classification at a centralized reading center. Simple (K) and weighted (Kw) kappa statistics were calculated for DR. Sensitivity and specificity for referable DR ([refDR] moderate nonproliferative DR [NPDR] or worse) and vision-threatening DR ([vtDR] severe NPDR or worse) for 2F compared to 5F imaging were calculated. RESULTS: Distribution of DR severity by 2F/5F images (%): no DR 66.0/61.7, mild NPDR 10.7/14.4, moderate NPDR 7.9/8.1, severe NPDR 3.3/5.6, proliferative DR 5.6/4.6, ungradable 6.5/5.6. Exact agreement of DR grading between 2F and 5F was 81.7%, within 1-step 97.1% (K = 0.64, Kw = 0.78). Sensitivity/specificity for 2F compared 5F was refDR 0.80/0.97, vtDR 0.73/0.98. The ungradable images rate with 2F was 16.1% higher than with 5F (6.5 vs. 5.6%, p < 0.001). CONCLUSIONS: Mydriatic 2F and 5F handheld imaging have substantial agreement in assessing severity of DR. However, the use of mydriatic 2F handheld imaging only meets the minimum standards for sensitivity and specificity for refDR but not for vtDR. When using handheld cameras, the addition of peripheral fields in 5F imaging further refines the referral approach by decreasing ungradable rate and increasing sensitivity for vtDR.

Multimodal Retinal Imaging in Patients with Diabetes Mellitus and Association with Cerebrovascular Disease.

INTRODUCTION: This study aimed to evaluate the association between macular optical coherence tomography angiography (OCT-A) metrics, characteristics of ultrawide field (UWF) imaging, and cerebrovascular disease in patients with diabetes mellitus (DM) with different stages of diabetic retinopathy (DR). METHODS: 516 eyes of 258 DM patients were enrolled in two centers (Milan and Belfast). UWF color fundus photos (CFPs) were obtained with Optos California (Optos, PLC) and graded for both DR severity and predominantly peripheral lesions presence (>50% of CFP lesions) by two independent graders. OCT-A (3 × 3 mm), available in 252 eyes of 136 patients, was used to determine perimeter, area, and circularity index of the foveal avascular zone and vessel density (VD); perfusion density (PD); fractal dimension on superficial, intermediate (ICP), and deep capillary plexuses; flow voids (FVs) in the choriocapillaris. RESULTS: Out of 516 eyes, 108 eyes (20.9%) had no DR, and 6 eyes were not gradable. The remaining 402 eyes were as follows: 10.3% (53) had mild nonproliferative DR (NPDR), 38.2% (197) had moderate NPDR, 11.8% (61) had severe NPDR, and 17.6% (91) had proliferative DR. A worse DR stage was associated with a history of stroke (p = 0.044). Logistic regression analysis after taking into account sex, type of DM, age, DM duration, and OCT-A variables found that PD and VD on ICP were significantly associated with presence of stroke and DR severity. CONCLUSION: OCT-A metrics show an association with the presence of cerebrovascular complications, providing potentially useful parameters to estimate vascular risk in patients with DM.

Comparisons of Handheld Retinal Imaging with Optical Coherence Tomography for the Identification of Macular Pathology in Patients with Diabetes.

INTRODUCTION: Handheld retinal imaging cameras are relatively inexpensive and highly portable devices that have the potential to significantly expand diabetic retinopathy (DR) screening, allowing a much broader population to be evaluated. However, it is essential to evaluate if these devices can accurately identify vision-threatening macular diseases if DR screening programs will rely on these instruments. Thus, the purpose of this study was to evaluate the detection of diabetic macular pathology using monoscopic macula-centered images using mydriatic handheld retinal imaging compared with spectral domain optical coherence tomography (SDOCT). METHODS: Mydriatic 40°-60° macula-centered images taken with 3 handheld retinal imaging devices (Aurora [AU], SmartScope [SS], RetinaVue 700 [RV]) were compared with the Cirrus 6000 SDOCT taken during the same visit. Images were evaluated for the presence of diabetic macular edema (DME) on monoscopic fundus photographs adapted from Early Treatment Diabetic Retinopathy Study (ETDRS) definitions (no DME, noncenter-involved DME [non-ciDME], and center-involved DME [ciDME]). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each device with SDOCT as gold standard. RESULTS: Severity by ETDRS photos: no DR 33.3%, mild NPDR 20.4%, moderate 14.2%, severe 11.6%, proliferative 20.4%, and ungradable for DR 0%; no DME 83.1%, non-ciDME 4.9%, ciDME 12.0%, and ungradable for DME 0%. Gradable images by SDOCT (N = 217, 96.4%) showed no DME in 75.6%, non-ciDME in 9.8%, and ciDME in 11.1%. The ungradable rate for images (poor visualization in >50% of the macula) was AU: 0.9%, SS: 4.4%, and RV: 6.2%. For DME, sensitivity and specificity were similar across devices (0.5-0.64, 0.93-0.97). For nondiabetic macular pathology (ERM, pigment epithelial detachment, traction retinal detachment) across all devices, sensitivity was low to moderate (0.2-0.5) but highly specific (0.93-1.00). CONCLUSIONS: Compared to SDOCT, handheld macular imaging attained high specificity but low sensitivity in identifying macular pathology. This suggests the importance of SDOCT evaluation for patients suspected to have DME on fundus photography, leading to more appropriate referral refinement.

Inclusion of diabetic retinopathy screening strategies in national-level diabetes care planning in low- and middle-income countries: a scoping review.

BACKGROUND: Diabetes is a major public health concern, with approximately 80% of the burden falling on low- and middle-income countries (LMICs). Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, and early detection through diabetic eye screening programmes is essential to prevent visual impairment and blindness. Careful planning at a national level is crucial for effective implementation of such programmes. METHODS: A scoping review was conducted, and the protocol was published previously to explain the methods in detail. Data were collected from databases and searches, including grey literature. Furthermore, consultations were conducted with key informants from LMICs. RESULTS: Lower-middle-income countries (29/50, 58%) and upper-middle-income countries (27/59, 45.8%) are making more progress than low-income countries (4/29, 13.8%) in terms of DR policy planning. However, no identified data for published policies have actually implemented national DR policies. Compared to low-income and lower-middle-income countries, upper-middle-income countries are making the most progress in implementing national diabetic eye screening programmes; however, their progress is still slow, with only 5/59 (8.5%) having such programmes. CONCLUSION: There are significant gaps in the literature, with no data reported for 78/138 (56.5%) LMICs. Further research is clearly needed to support and document DR policy development in LMICs.

Exploring association between pseudoexfoliation syndrome and ocular aging.

PURPOSE: Within a population-based follow-up study, to examine the 10-year incidence of pseudoexfoliation syndrome (PEX), possible risk factors for PEX and its association with ocular aging of the cornea, lens and retina. METHODS: The baseline examination was conducted in 2006 on a random sample of 1,033 adult participants from Kaunas city (Lithuania) population of whom 631 had ophthalmic examination data at attendance of the 10-year follow-up in 2016. Detailed examination of the anterior and posterior segment of the eye was carried out. After diagnostic mydriasis PEX was diagnosed by the presence of typical grayish-white exfoliation material on the anterior capsule surface of the lens. The participants were divided to PEX and non-PEX groups. RESULTS: PEX prevalence increased from 9.8 to 34.2% from baseline to 10-year follow-up. Nuclear cataract was common both in the PEX group (66.7%) and in those without PEX (72.2%), but this difference did not reach statistically significantly increased risk of developing cataract in those with PEX (OR 1.2; p = 0.61). Central corneal thickness (CCT) was thinner in the PEX group (529 ± 34 µm) and in the oldest group (525 ± 36 µm) (p < 0.001). Compared to baseline, corneal curvature (CC) became flatter in both groups (7.6 ± 0.27 vs 7.7 ± 0.26 mm; p < 0.001) during the follow-up, but the difference did not reach significance between groups. Corneal astigmatism was most commonly with-the-rule in both groups (37 (50.0%) vs 148 (68.5%); p > 0.05). Age, sex and PEX had no influence on age-related macular degeneration distribution. CONCLUSION: The prevalence of PEX increased significantly with age in our population, with those with PEX having thinner and flatter corneae, but no difference in cataract and age-related macular degeneration characteristics.

Treatment patterns and persistence rates with anti-vascular endothelial growth factor treatment for diabetic macular oedema in the UK: A real-world study.

INTRODUCTION: Anti-vascular endothelial growth factors (anti-VEGFs) are considered standard of care therapy for diabetic macular oedema (DME). This study examined treatment patterns and outcomes in patients with DME treated with anti-VEGF therapy. METHODS: Using anonymized electronic medical record data collected from three UK sites, this retrospective cohort study assessed rates of anti-VEGF intravitreal injections in adults with treatment-naïve DME who received their first treatment between 1 September 2010 and 31 July 2018. The proportion of patients with at least one interval of at least 12 weeks between injections; the distribution of injection intervals; the discontinuation rates; and the number of anti-VEGF injection-, injection-free- and total visits were assessed during the first and second years of treatment. RESULTS: Overall, 1606 patient eyes with DME were included, with no minimum follow-up. During the first and second year of treatment, 63.2% and 73.1% of eyes had at least one anti-VEGF injection interval of at least 12 weeks, respectively. In the first and second years of treatment, the mean (standard deviation) numbers of injections were 7.7 (1.9) and 5.6 (2.2), with 14.2 (5.7) and 13.4 (6.4) total clinic visits, and 6.6 (5.0) and 7.8 (5.8) injection-free visits, respectively. In total, 27.8% of patient eyes discontinued treatment during the first 2 years. CONCLUSIONS: The high number of clinic visits and high discontinuation rates demonstrate a significant unmet need for a treatment to enable sustainable extended injection intervals, while maintaining visual acuity. This could improve patient adherence and health-related quality of life for patients with DME.

Five-year cumulative incidence and progression of age-related macular degeneration: results from the German population-based Gutenberg Health Study (GHS).

PURPOSE: Age-related macular degeneration (AMD) is a major cause of visual impairment and blindness. This study evaluates the incidence and progression of AMD in a large German cohort. METHODS: The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany that includes 15,010 participants between 35 and 74 years of age. The baseline examination, including fundus photography, was conducted between 2007 and 2012, and the 5-year follow-up examination was performed between 2012 and 2017. AMD grading of fundus photographs was performed according to the Rotterdam Eye Study classification. The 5-year cumulative incidence and progression of AMD were calculated. Poisson regression analysis was conducted to investigate factors associated with the cumulative incidence and progression of AMD. RESULTS: Six-thousand-eight-hundred-eighty-eight participants (49.8%, n = 3427 female) were included in the analysis. AMD prevalence was 8.5% [95% CI: 7.9-9.2%] at baseline and 10.3% [95% CI: 9.6-11.1%] at follow-up. The cumulative 5-year-incidence was 2.0% [1.7-2.4%]. AMD progression within 5 years was seen in 18.1% [95% CI: 15.1-21.5%] of the participants. AMD incidence and AMD progression were associated with higher age, for each 10-year increase in age, the risk of AMD doubles (RR = 2.30), and the risk of progression of the disease is increased by 1.6. while AMD incidence also with pseudophakic status. CONCLUSIONS: In summary, this population-based sample provides substantial epidemiologic data from a large German cohort, including data on progression and cumulative incidence of macular degeneration in younger age groups. AMD progression over 5 years is common in the German population, 18.1% of subjects with AMD showed progression in at least one eye in this time frame and is associated with higher age. Nevertheless, although usually defined to occur over the age of 50, in this cohort AMD occurred in 0.5% and AMD progression occurred in 5.4% of those already affected in the youngest age group before 50 years of age.

The Feasibility of Using Ultra-Widefield Retinal Imaging to Identify Ocular Pathologies amongst Those with Systemic Medical Disease Attending a Tertiary Healthcare Facility at a University Hospital.

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.

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy.

Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 µg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.