Diabetic Retinopathy Severity Scale Research Articles

CANBERRA, A Phase 2 Randomized Clinical Trial to Test the Therapeutic Potential of Oral Vicasinabin in Diabetic Retinopathy

ObjectiveNon-proliferative diabetic retinopathy (NPDR) is a progressive disease that can lead to blindness. Current therapies for NPDR are invasive and not extensively used or accessible until the disease progresses, pointing to the need for an early non-invasive treatment.The objective of CANBERRA was to assess the safety, tolerability, and efficacy of oral administration of vicasinabin (RG7774) on the severity of diabetic retinopathy (DR) in participants with moderately severe to severe NPDR and good vision. DesignCANBERRA was a global, multicentric randomized, double-masked, parallel-group, placebo-controlled, phase 2 study. The study duration was 36 months. 139 treatment-naïve participants with type 1 or type 2 diabetes mellitus and Diabetic Retinopathy Severity Scale (DRSS) levels of 47 or 53 in at least one eye. Eligible participants were randomized 1:1:1 to 36 weeks of daily oral placebo, vicasinabin 30mg, or vicasinabin 200mg. Participants were followed for an additional 12 weeks. Main OutcomeThe primary safety objective was to evaluate the safety and tolerability of vicasinabin by the frequency and severity of adverse events. The primary efficacy objective was to assess the effect of vicasinabin on the severity of DR, assessing the proportion of participants with at least 2-steps improvement in DRSS from baseline at week 36 in the study eye. ResultsResults are presented in the following order: placebo, vicasinabin 30mg, vicasinabin 200mg. 47, 48, and 44 participants were enrolled. Baseline characteristics were balanced. Adherence to treatment was approximately 90%, and pharmacokinetic analysis showed dose-dependent plasma exposure to vicasinabin. The primary efficacy endpoint was not met: the percentage of participants who improved their DRSS by at least two steps at week 36 from baseline were 7.9, 9.5, and 5.7, without statistically significant differences. The systemic and ocular safety profiles of vicasinabin were favorable, and adverse events distributed evenly across arms. Vicasinabin did not induce changes in glycemic control or any kidney function or cardiovascular parameters. Three patients in the placebo arm discontinued the study due to serious adverse events ConclusionsAt the doses tested, vicasinabin did not improve DRSS in participants with NPDR. The role of the cannabinoid system in diabetic retinopathy remains elusive

Diabetic Retinopathy Lesion Types and Distribution on Ultrawide Field Imaging and the Risk of Disease Worsening Over Time.

To evaluate the effect of diabetic retinopathy (DR) lesion type [hemorrhages and/or microaneurysms (H/Ma), intraretinal microvascular abnormalities (IRMA), new vessels elsewhere (NVE), venous beading], severity and distribution on disease worsening based on the Early Treatment Diabetic Retinopathy Study (ETDRS)-Diabetic Retinopathy Severity Scale (DRSS). Post-hoc analysis of a multi-center observational study of 544 eyes with nonproliferative DR and an ETDRS-DRSS score of Level 35-53. Disease worsening was defined as ETDRS-DRSS worsening by ≥2 steps from baseline or receipt of DR treatment over 4 years. DR lesions were evaluated based on the entire visible area in the ultrawide field color (UWF-color) and UWF-fluorescein angiography (UWF-FA) images. A significantly greater risk of disease worsening was associated with the presence of more severe lesion grades outside the ETDRS fields for H/Ma (HR:1.74 [95% CI:1.28-2.36]) on UWF-color; and for H/Ma (1.90 [1.38-2.61]), IRMA (1.68 [1.13-2.49]), and NVE (1.99 [1.36-2.93]) on UWF-FA. These results suggest that features on UWF-color and UWF-FA may provide additional prognostic value in determining the risk of disease worsening. The use of UWF-FA improves identification of DR lesions and disease progression. However, the optimal method of disease risk assessment on UWF imaging still needs to be determined.

Diabetic retinopathy screening with confocal fundus camera and artificial intelligence - assisted grading.

Screening for diabetic retinopathy (DR) by ophthalmologists is costly and labour-intensive. Artificial Intelligence (AI) for automated DR detection could be a clinically and economically alternative. We assessed the performance of a confocal fundus imaging system (DRSplus, Centervue SpA), coupled with an AI algorithm (RetCAD, Thirona B.V.) in a real-world setting. 45° non-mydriatic retinal images from 506 patients with diabetes were graded both by an ophthalmologist and by the AI algorithm, according to the International Clinical Diabetic Retinopathy severity scale. Less than moderate retinopathy (DR scores 0, 1) was defined as non-referable, while more severe stages were defined as referable retinopathy. The gradings were then compared both at eye-level and patient-level. Key metrics included sensitivity, specificity all measured with a 95% Confidence Interval. The percentage of ungradable eyes according to the AI was 2.58%. The performances of the AI algorithm for detecting referable DR were 97.18% sensitivity, 93.73% specificity at eye-level and 98.70% sensitivity and 91.06% specificity at patient-level. DRSplus paired with RetCAD represents a reliable DR screening solution in a real-world setting. The high sensitivity of the system ensures that almost all patients requiring medical attention for DR are referred to an ophthalmologist for further evaluation.

Assessment of Baseline Ultrawidefield Fluorescein Angiographic Quantitative Leakage Parameters with Ultrawidefield Fundus Features and Clinical Parameters in Diabetic Retinopathy in Protocol AA

PurposeEvaluate quantitative leakage parameters on ultra-widefield fluorescein angiography (UWF-FA) images and explore their association with Diabetic Retinopathy Severity Scale (DRSS), predominantly peripheral lesions (PPLs), visual acuity, and clinical characteristics. DesignA post-hoc analysis of baseline UWF-FA images in the DRCR Retina Network observational study Protocol AA. ParticipantsN = 575 eyes from 384 adults across 38 sites in the US and Canada with gradable UWF-FA. MethodsA machine learning-enhanced feature extraction platform provided initial leakage segmentation of UWF-FA images sequentially reviewed and corrected by two certified readers for segmentation accuracy. UWF-FA leakage was measured in five retinal zones: panretinal (whole retina), central macular (3-disc diameter fovea-centered circle), posterior pole (6-disc diameter fovea-centered circle), peripheral (outside 6-disc diameter circle) and widefield far peripheral (outside 9-disc diameter circle); associations with clinical factors were evaluated with marginal beta regression models. Main Outcome MeasuresUWF-FA leakage index, calculated as the area with leakage divided by the analyzable retinal area. ResultsThe mean quantitative leakage index was 3.5% for panretinal, 6.6% for macular, 4.8% for posterior pole, 3.3% for peripheral and 2.8% for wide-field far peripheral retinal zones. Panretinal leakage was associated with DRSS (mean 2.2% for no to mild NPDR, 3.4% for moderate NPDR, 4.2% for moderately severe NPDR, 4.8% for severe NPDR and 5.1% for PDR; P<.001), HbA1c (3.2% for HbA1c <8% vs. 3.8% for HbA1c ≥8%; P=.01 for continuous HbA1c), visual acuity (3.3% for 20/25 or better vs. 4.7% for 20/32 or worse; continuous P<.001), and UWF-FA-PPL types of IRMA (4.3% vs. 3.3%; P=.005) or NVE (5.7% vs. 3.4%; P=.003). DRSS was also statistically significant for leakage within all retinal zones (P<.001); eyes with non-central DME versus no DME had higher mean leakage in the central macular (11.2% vs. 5.9%; P=0.005) and posterior pole regions (9.2% vs. 4.2%; P=.002). ConclusionQuantitative UWF-FA leakage analysis identified associations between leakage and DRSS, visual acuity, and presence of DME. In the future, quantitative UWF-FA leakage parameters may be explored as potential biomarkers for disease progression risk.

Evaluation of an AI algorithm trained on an ethnically diverse dataset to screen a previously unseen population for diabetic retinopathy.

This study aimed to determine the generalizability of an artificial intelligence (AI) algorithm trained on an ethnically diverse dataset to screen for referable diabetic retinopathy (RDR) in the Armenian population unseen during AI development. This study comprised 550 patients with diabetes mellitus visiting the polyclinics of Armenia over 10 months requiring diabetic retinopathy (DR) screening. The Medios AI-DR algorithm was developed using a robust, diverse, ethnically balanced dataset with no inherent bias and deployed offline on a smartphone-based fundus camera. The algorithm here analyzed the retinal images captured using the target device for the presence of RDR (i.e., moderate non-proliferative diabetic retinopathy (NPDR) and/or clinically significant diabetic macular edema (CSDME) or more severe disease) and sight-threatening DR (STDR, i.e., severe NPDR and/or CSDME or more severe disease). The results compared the AI output to a consensus or majority image grading of three expert graders according to the International Clinical Diabetic Retinopathy severity scale. On 478 subjects included in the analysis, the algorithm achieved a high classification sensitivity of 95.30% (95% CI: 91.9%-98.7%) and a specificity of 83.89% (95% CI: 79.9%-87.9%) for the detection of RDR. The sensitivity for STDR detection was 100%. The study proved that Medios AI-DR algorithm yields good accuracy in screening for RDR in the Armenian population. In our literature search, this is the only smartphone-based, offline AI model validated in different populations.

Wide-Field Optical Coherence Tomography in Patients with Diabetic Macular Edema.

Background: The goal of the study was to analyze variations in central, perifoveal, and peripheral retinal thickness (RT) and choroidal thickness (CT) in patients with diabetic macular edema (DME) measured with ultra-wide-field optical coherence tomography (UWF-OCT). Additionally, correlations between RT and CT in the central, perifoveal, and peripheral sectors and the presence of selected systemic factors were evaluated. Methods: A total of 74 consecutive adult diabetic patients with DME and 75 healthy controls were included. Study participants were divided into three groups: DME patients without panretinal photocoagulation (PRP; 84 eyes), DME patients after PRP (56 eyes), and healthy controls (125 eyes). RT and CT were analyzed in three zones: a central circle of 3 mm diameter (central), a ring contained between a centered 9 mm circle and the central 3 mm circle (perifoveal), and a second, more peripheral ring between centered 18 mm and 9 mm circles (peripheral). Additionally, DME subgroups were analyzed according to the correlation of RT and CT with age, axial length, best corrected visual acuity (BCVA), diabetes duration, insulin therapy duration, body mass index (BMI), glycosylated hemoglobin (HbA1c) values, intravitreal injection (IVI) count, and the advancement of retinopathy assessed by the simplified diabetic retinopathy severity scale (DRSS). Results: The increase in RT in the far peripheral sectors in DME patients was not significant. The increases in central and perifoveal RT and lower values of CT in PRP-naive DME patients were strongly associated with poorer BCVA. Patients with DME after PRP presented with BCVA improvements significantly related to the number of IVIs. The amount of DME and RT in peripheral sectors were both independent of systemic factors such as BMI, duration of diabetes, duration of insulin intake, retinopathy severity, and HbA1c levels. Conclusions: Peripheral retinal sectors in DME patients are less affected in terms of increase in their thickness compared to central ones. Functional and morphological associations of DME with UWF-OCT testing refer to central and perifoveal sectors.

Biosimilar Candidate CT-P42 in Diabetic Macular Edema: 24-Week Results from a Randomized, Active-Controlled, Phase III Study

ObjectiveTo demonstrate the therapeutic similarity of CT-P42 compared to reference aflibercept (Eylea®) in adult patients with diabetic macular edema (DME). DesignRandomized, active-controlled, double-masked, Phase III clinical trial ParticipantsPatients with a diagnosis of either type 1 or 2 diabetes mellitus (DM) with DME involving the center of the macula. MethodsPatients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 mL) by intravitreal injection every 4 weeks (5 doses) then every 8 weeks (4 doses) in the main study period. Results up to Week 24 are reported herein. Main Outcome MeasuresThe primary endpoint was mean change from baseline at Week 8 in best corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the two-sided 95% confidence interval (CI) (global assumptions) and two-sided 90% CI (US Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set. ResultsOverall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). BCVA improved from baseline to Week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the pre-defined equivalence margin of ±3 letters (95% CI −0.73, 1.88 [global]; 90% CI −0.52, 1.67 [FDA]). Through Week 24, other efficacy results for the two groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing at least one treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups. ConclusionsThis study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 mL) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Efficacy and safety of intravitreal injection of conbercept for moderate to severe nonproliferative diabetic retinopathy

PurposeThis study aimed to assess the effectiveness and safety of intravitreal injection of conbercept (IVC) in treating moderate to severe nonproliferative diabetic retinopathy (NPDR), with or without accompanying diabetic macular edema.MethodsIn this longitudinal retrospective study, 35 patients (50 eyes) with moderate to severe NPDR and Diabetic Retinopathy Severity Scale (DRSS) scores between 43 and 53 were treated at the Department of Ophthalmology, First Affiliated Hospital of Kunming Medical University, from October 2018 to January 2023. Treatment protocol included three monthly IVC injections followed by a pro re nata (PRN) regimen over a two-year follow-up period. Outcome measures were best-corrected visual acuity (BCVA), intraocular pressure, central macular thickness (CMT), extent of hard exudate (HE), and changes in DRSS scores. DRSS scores before and after treatment were analyzed using the Wilcoxon rank-sum test. Both systemic and ocular adverse events were meticulously documented to ascertain safety.ResultsFrom baseline to the final follow-up, the mean BCVA improved from 0.41 ± 0.39 to 0.23 ± 0.20 logMAR (p&amp;lt;0.05). The mean CMT decreased from 306.22 ± 77.40 to 297.97 ± 88.15 μm (p = 0.385). At 24 months, DRSS scores improved by ≥1 stage in 40 eyes (80%), ≥ 2 stages in 28 eyes (56%), ≥3 stages in 10 eyes (20%), and remained stable in 6 eyes (12%). The DRSS scores at each follow-up interval demonstrated statistically significant improvement from baseline (p&amp;lt;0.05). In 15 of 27 eyes (55.56%) with diabetic macular edema (DME), there was a significant reduction in the mean area of HE from baseline (p&amp;lt;0.05). No serious systemic adverse events were observed.ConclusionIVC is an effective and safe treatment for moderate to severe NPDR, demonstrating significant improvements in DRSS scores.

A pilot cost-analysis study comparing AI-based EyeArt® and ophthalmologist assessment of diabetic retinopathy in minority women in Oslo, Norway

BackgroundDiabetic retinopathy (DR) is the leading cause of adult blindness in the working age population worldwide, which can be prevented by early detection. Regular eye examinations are recommended and crucial for detecting sight-threatening DR. Use of artificial intelligence (AI) to lessen the burden on the healthcare system is needed.PurposeTo perform a pilot cost-analysis study for detecting DR in a cohort of minority women with DM in Oslo, Norway, that have the highest prevalence of diabetes mellitus (DM) in the country, using both manual (ophthalmologist) and autonomous (AI) grading. This is the first study in Norway, as far as we know, that uses AI in DR- grading of retinal images.MethodsOn Minority Women’s Day, November 1, 2017, in Oslo, Norway, 33 patients (66 eyes) over 18 years of age diagnosed with DM (T1D and T2D) were screened. The Eidon - True Color Confocal Scanner (CenterVue, United States) was used for retinal imaging and graded for DR after screening had been completed, by an ophthalmologist and automatically, using EyeArt Automated DR Detection System, version 2.1.0 (EyeArt, EyeNuk, CA, USA). The gradings were based on the International Clinical Diabetic Retinopathy (ICDR) severity scale [1] detecting the presence or absence of referable DR. Cost-minimization analyses were performed for both grading methods.Results33 women (64 eyes) were eligible for the analysis. A very good inter-rater agreement was found: 0.98 (P < 0.01), between the human and AI-based EyeArt grading system for detecting DR. The prevalence of DR was 18.6% (95% CI: 11.4–25.8%), and the sensitivity and specificity were 100% (95% CI: 100–100% and 95% CI: 100–100%), respectively. The cost difference for AI screening compared to human screening was $143 lower per patient (cost-saving) in favour of AI.ConclusionOur results indicate that The EyeArt AI system is both a reliable, cost-saving, and useful tool for DR grading in clinical practice.

RELIABILITY OF CLINICAL GRADING OF DIABETIC RETINOPATHY COMPARED WITH GRADING OF ULTRA-WIDEFIELD IMAGES.

To evaluate the reliability of clinical grading of diabetic retinopathy (DR) severity compared with grading on ultra-widefield pseudocolor fundus (UWF-CF) and ultra-widefield fluorescein angiography (UWF-FA) images and their relative detection of sight-threatening DR and referable DR. A total of 184 diabetic eyes were analyzed. UWF-CF and UWF-FA images were graded based on the International Clinical Diabetic Retinopathy severity scale. Agreement between clinical and UWF-based severity grading was evaluated using Cohen's kappa coefficient. The rate of sight-threatening DR and referable DR was evaluated for each grading method. Moderate agreement was found between clinical grading and UWF-CF (k = 0.456, P < 0.001) and between UWF-CF and UWF-FA (k = 0.443, P < 0.001). The agreement between clinical grading and UWF-FA was fair (k = 0.397, P < 0.001). UWF-based grading identified a higher DR grade in 56 eyes (30%) on UWF-CF and 85 eyes (46.2%) on UWF-FA. Compared with clinical grading, UWF-FA detected a higher rate of sight-threatening DR (44%; 81/184 vs. 22.3%; 41/184), while UWF-CF detected more referable eyes (58.1%; 107/184 vs. 45.65%; 84/184). Ultra-widefield pseudocolor fundus is a valuable tool for identifying referable eyes and can be a useful, noninvasive adjunct to clinical grading. The results suggest that UWF-FA is particularly useful for detecting unsuspected sight-threatening DR in eyes with clinically referable DR.

Effectiveness of artificial intelligence for diabetic retinopathy screening in community in Binh Dinh Province, Vietnam.

The objective of this study is to evaluate the sensitivity, specificity, and accuracy of artificial intelligence (AI) for diabetic retinopathy (DR) screening in community in Binh Dinh Province in Vietnam. This retrospective, descriptive, cross-sectional study assessed the DR screening efficacy of EyeArt system v2.0 by analyzing 2332 nonmydriatic digital fundus pictures of 583 diabetic patients from hospitals and health centers in Binh Dinh province. First, we selected thirty patients with 120 digital fundus pictures to perform the Kappa index by two eye doctors who would be responsible for the DR clinical feature evaluation and DR severity scale classification. Second, all digital fundus pictures were coded and then sent to the two above-mentioned eye doctors for the evaluation and classifications according to the International Committee of Ophthalmology's guidelines. Finally, DR severity scales with EyeArt were compared with those by eye doctors as a reference standard for EyeArt's effectiveness. All the data were analyzed using the SPSS software version 20.0. Values (with confidence interval 95%) of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated according to DR state, referable or not and vision-threatening DR state or not. P < 0.05 was considered statistically significant. The sensitivity and specificity of EyeArt for DR screening were 94.1% and 87.2%. The sensitivity and specificity for referable DR and vision-threatening DR were 96.6%, 90.1%, and 100.0%, 92.2%. Accuracy for DR screening, referable DR, and vision-threatening DR were 88.9%, 91.4%, and 93.0%, respectively. EyeArt AI was effective for DR screening in community.

Efficacy and Safety of Brolucizumab for Diabetic Macular Edema

Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME). To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME. This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021. Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks. Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52. A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 μm; aflibercept, -196.5 μm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion. In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified. ClinicalTrials.gov Identifier: NCT03917472.

Image preprocessing‐based ensemble deep learning classification of diabetic retinopathy

AbstractDiabetic retinopathy (DR) can cause irreversible eye damage, even blindness. The prognosis improves with early diagnosis. According to the International Classification of Diabetic Retinopathy Severity Scale (ICDRSS), DR has five stages. Modern, cost‐effective techniques for automatic DR screening and staging of fundus images are based on deep learning (DL). To obtain higher classification accuracy, the combination of several diverse individual DL models into one ensemble could be used. A new approach to model diversity in an ensemble is proposed by manipulating the training input data involving original and four variants of preprocessed image datasets. There are publicly available datasets with labels for all five stages, but some contain poor‐quality images. In contrast, this algorithm was trained on images from a six‐class DDR dataset, including the class of poor‐quality ungradable images, to enhance the classification performance. The solution was evaluated on the APTOS dataset, containing only ICDRSS classes. Classification results of the ensemble model were presented on two different ensemble convolutional neural network (CNN) models, based on Xception and EfficientNetB4 architectures using two fusion approaches. Our proposed ensemble models outperformed all other single deep learning architectures regarding overall accuracy and Cohen's Kappa, with the best results using the EfficientNetB4 architecture.

Non-Invasive Treatment of Early Diabetic Macular Edema by Multiwavelength Photobiomodulation with the Valeda Light Delivery System.

Diabetes is associated with ocular complications including diabetic macular edema (DME). Current therapies are invasive and include repeated intravitreal injections and laser therapy. Photobiomodulation (PBM) is a treatment (Tx) that utilizes selected wavelengths of light to induce cellular benefits including reduction of inflammation and edema. This single-center, open-label, post-hoc analysis explored the utility of multiwavelength PBM in subjects with DME. Analysis included review of data from patients undergoing standard clinical care with an approved and marketed PBM medical device, the Valeda® Light Delivery System. Subjects with early-stage DME with good vision (Best-corrected visual acuity (BCVA) > 20/25, logMAR > 0.1) were evaluated in clinic and treated with one series of multiwavelength PBM (Tx delivered 3x/week over 3-4 weeks; total of 9 Tx sessions). Clinical, anatomical, and safety parameters were assessed in addition to subjective quality of life. A total of 30 eyes (19 subjects) were analyzed. Subjects were predominately male (68.4%) with a mean age of 56 ± 14 years. Reductions in central retinal thickness (CRT), resolution of intraretinal fluid (IRF) and improvement in diabetic retinopathy severity scale scores were observed following PBM treatment in select patients. Baseline BCVA remained stable over the follow-up observation period of 3 months post-PBM. Approximately 64% of patients reported subjective improvements in their ocular condition and decreased influence in everyday life. Detailed OCT evaluations confirmed no safety issues related to phototoxicity up to 16 months. Early-stage DME subjects treated with Valeda multiwavelength PBM showed improvements in clinical and anatomical parameters. The Valeda multiwavelength PBM approach demonstrates a favorable safety profile with no signs of phototoxicity following an independent OCT review. PBM therapy may offer an alternative, non-invasive treatment strategy with a unique mechanism and modality for patients with early-stage DME.

Ocular and Systemic Risk Factors for Disease Worsening Among Patients with NPDR: Post Hoc Analysis of the PANORAMA Trial

PurposeIdentify baseline systemic and ocular characteristics associated with nonproliferative diabetic retinopathy (NPDR) worsening, and the impact of intravitreal aflibercept injection (IAI) on these associations. DesignPost hoc analysis of PANORAMA. ParticipantsPatients with moderately severe to severe NPDR enrolled in the prospective PANORAMA phase 3 trial. MethodsAssociations between baseline systemic and ocular factors with events indicative of NPDR worsening at Week 100 were evaluated by multivariable analysis in sham-treated eyes. NPDR worsening was defined as development of (1) vision-threatening complications (VTCs; comprising PDR and/or anterior segment neovascularization), (2) center-involved diabetic macular edema (CI-DME), or (3) ≥ 2-step Diabetic Retinopathy Severity Scale (DRSS) worsening. Impact of IAI on identified baseline factors was evaluated using univariable analysis in combined IAI groups. Main Outcomes MeasuresBaseline systemic and ocular factors associated with events indicative of NPDR worsening at Week 100. The cumulative incidence and risk of developing such events at Week 100 among sham versus IAI-treated eyes. ResultsUsing multivariable analyses among sham-treated eyes, 5 baseline factors associated with increased risk of NPDR worsening were identified: fluorescein leakage, retinal nonperfusion area, thicker central subfield thickness, eosinophil level, and proteinuria. Considering baseline fluorescein leakage area as a prognostic indicator in detail, the risk of developing VTCs alone, VTCs and/or CI-DME, or ≥ 2-step DRSS worsening increased with increasing fluorescein leakage area in the sham group (all P < 0.05). Considering baseline retinal nonperfusion area as a prognostic indicator in detail, the risk of developing VTCs alone, CI-DME alone, or VTCs and/or CI-DME increased with increasing baseline retinal nonperfusion area in the sham group (all P < 0.05). In contrast, among IAI-treated eyes, increasing baseline fluorescein leakage or retinal nonperfusion areas did not increase the risks of NPDR worsening. ConclusionsWithin the PANORAMA trial, increased areas of fluorescein leakage and retinal nonperfusion at baseline were identified as key ocular biomarkers associated with events indicative of NPDR worsening among sham-treated patients. IAI treatment appeared to mitigate the effect of these baseline risk factors and reduced the likelihood of NPDR worsening.

Assessment of early diabetic retinopathy severity using ultra-widefield Clarus versus conventional five-field and ultra-widefield Optos fundus imaging

To compare early diabetic retinopathy (DR) severity level and the abilities in detecting early DR lesions among conventional five-field, ultrawide-field (UWF) Optos, and UWF Clarus fundus imaging methods. This was a single-center, prospective, clinic-based, and comparative study. In total, 157 consecutive patients with diabetes mellitus were enrolled in this study. All patients underwent comprehensive ophthalmological examinations. Following mydriasis, each eye was examined with conventional five-field, UWF Optos, and UWF Clarus fundus imaging methods. The initial UWF images were overlaid with a template mask that obscured the retina, which created a five-field view from UWF images (covered UWF images). The covered UWF images were then graded, after which the template mask was removed, and the original UWF images were also evaluated. All images were graded using the International Clinical DR severity scale. DR grades were compared and analyzed by weighted kappa statistics among the three fundus imaging methods. In total, 157 consecutive patients with diabetes (302 eyes) were enrolled in this study. Weighted kappa statistics for agreement were 0.471 (five-field vs. covered Optos), 0.809 (five-field vs. covered Clarus), 0.396 (covered Optos vs. covered Clarus), 0.463 (five-field vs. Optos), 0.521 (five-field vs. Clarus 133°), 0.500 (five-field vs. Clarus 200°), 0.323 (Optos vs. Clarus 133°), and 0.349 (Optos vs. Clarus 200°). The area under curve of covered Clarus images was higher than that of conventional five-field images at three different thresholds. Compared with conventional five-field and Optos fundus imaging methods, Clarus fundus imaging methods exhibited excellent performance in assessing early DR severity. Thus, Clarus fundus imaging methods were superior for early detection of DR.

Panretinal photocoagulation plus intravitreal conbercept for diabetic retinopathy in real world: a retrospective study

BackgroundTo evaluate outcomes of panretinal photocoagulation (PRP) plus intravitreal conbercept (IVC) for diabetic retinopathy (DR) in real world and explore risk factors for patients with poor reactivity and presence of vision-threatening complications after combination treatment.MethodsRetrospective review of DR patients received PRP plus IVC over 6 months. The main outcome was improvement ≥ 2 steps in ETDRS diabetic retinopathy severity scale (DRSS) levels. Different strategies for eyes receiving IVC within or over 1 month after PRP were analyzed. For patients with DRSS improvement < 2 steps and presence of vision-threatening adverse events, a binary logistic regression method was used to select risk factors.ResultsSixty one eyes were involved in this study. After treated with combination therapy with a median number of 3 injections, 44% of eyes improved ≥ 2 steps in DRSS levels. A total of 14 eyes (23%) occurred vision-threatening adverse events. No significant difference was found in eyes receiving conbercept within or over 1 month after PRP. Duration of diabetes (OR 0.849, 95%CI 0.734–0.982, P = 0.027), GFR (OR 0.961, 95%CI 0.933–0.990, P = 0.010) and baseline DRSS levels (OR 3.290, 95%CI 1.483–7.295, P = 0.003) were independent risk factors for DRSS improvement < 2 steps after treatment. Occurrence of vision-threatening complications was only related to high DRSS levels (OR 3.668, 95%CI 1.710–7.868, P = 0.001).ConclusionsThe combination therapy was effective for most patients with DR in real world. Eyes received PRP combined with earlier or later conbercept was demonstrated no significant difference for outcomes. For patients with poor renal function, high DRSS levels or occurred DR at the early stage of diabetes, follow-up should be strengthened.

Longitudinal Quantitative Ultrawidefield Angiographic Features in Diabetic Retinopathy Treated with Aflibercept from the Intravitreal Aflibercept as Indicated by Real-Time Objective Imaging to Achieve Diabetic Retinopathy Improvement Trial

To report longitudinal trends of quantitative ultrawidefield fluorescein angiography (qUWFA) biomarkers in the Intravitreal Aflibercept as Indicated by Real-Time Objective Imaging to Achieve Diabetic Retinopathy Improvement (PRIME) diabetic retinopathy (DR) clinical trial. Post hoc analysis of the PRIME prospective randomized DR clinical trial comparing intravitreal aflibercept treatment based on the DR severity score (DRSS) or quantitative leakage index for DR improvement (ClinicalTrials.gov identifier: NCT03531294). Patients were enrolled with a DRSS level of 47A to 71A and best-corrected visual acuity of 20/800 or better. Key exclusion criteria were previous intravitreal injection, panretinal photocoagulation, vitrectomy, central-involving macular edema, or vitreous hemorrhage. A previously validated, machine learning-based qUWFA analysis platform was used for panretinal leakage index assessment and differentiation of generalized and perivascular leakage phenotypes. Additionally, microaneurysm count and ischemic index were quantified in panretinal and macular regions. The trends in these biomarkers and therapeutic response were studied over 1 year. Longitudinal trends of qUWFA biomarkers. The impact of these qUWFA metrics on treatment response was assessed by studying their associations with time to 2-step DRSS improvement and number of treatment-free days. Forty eyes from 40 subjects with DR were enrolled. Lower baseline generalized leakage was noted in eyes that attained the 2-step DRSS improvement in < 16 weeks (1.9% vs. 2.8%; P= 0.026). Baseline macular perivascular-generalized leakage ratio had a significant correlation with the number of treatment-free days (r= 0.4; P= 0.012). At the end of 1 year, therapy significantly reduced the mean panretinal (3.9% vs. 5.8%; P= 0.002) and macular (6.2% vs. 12.2%; P= 0.008) generalized leakage indices compared with baseline, as well as the mean panretinal perivascular leakage index (1.5% vs. 2.3%; P= 0.002). The mean panretinal ischemic index demonstrated a small but likely clinically insignificant decrease from 12.5% at baseline to 11.6% at year 1 (P= 0.016). Down-trending leakage indices and microaneurysm counts were demonstrated over 1 year of anti-VEGF therapy. At baseline, DR eyes with lower generalized leakage responded to therapy more rapidly. Eyes with greater perivascular leakage relative to generalized leakage showed a longer-lasting anti-VEGF treatment response. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Correlation of Risk Factors with the Severity of Diabetic Retinopathy at a Rural Health Facility in Sindh Pakistan

Diabetes Mellitus (DM) and the resulting Diabetic Retinopathy (DR) is a significant health problem around the World. In 2019, the total number of diabetics worldwide was 463 million, and 35% had some DR. Objectives: To determine the correlation between the severity of Diabetic Retinopathy (DR) and the known risk factors. Methods: Analytical cross-sectional study design was used with convenience sampling in a primary, multispecialty day care health facility under the Baqai Foundation (Khushal Nagar) in a rural area of Sindh from 2020 - 2022. A total of 133 patients had some DR according to the International Classification of Diabetic Retinopathy Severity Scale (ICDRSS), which correlated with the different risk factors. Spearman rank correlation was used, and the result was considered significant when the P value was &lt;.05. Results: The results showed a significant positive correlation between the severity of DR with Age, Random Blood Sugar, Hypertension, and Smoking. Glycated hemoglobin and hyperlipidemia were not significantly correlated, mainly because of the small sample size. (23 and 14 respectively). The patients who tried to have Lipid Profile and Glycated Hemoglobin done had stage four or five of ICDRSS. Conclusions: Most risk factors studied were positively correlated with the severity of DR. Besides the intended study, the findings highlighted the non-awareness of patients about DR and its consequences. Awareness campaigns and screening programs for DR and its risk factors are urgently required and tailored to our circumstances.

Longitudinal bidirectional associations between diabetic retinopathy and diagnosed depression: Results from a Danish nationwide registry-based cohort study

ObjectiveDiabetic retinopathy (DR) is a feared complication and a leading course of visual impairment, but the connection between DR and depression including the direction has never been studied in a nationwide cohort. We aimed to assess, whether the associations between DR and diagnosed depression are bidirectional. MethodsWe performed a national register-based cohort study of individuals with type 2 diabetes, who attended diabetic eye screening between January 2013 and June 2022. Level of DR was extracted from the Danish Registry of Diabetic Retinopathy. The severity of DR was assessed according to the International Clinical Diabetic Retinopathy severity scale. Diagnosed depression was ascertained by physician diagnostic codes of unipolar depression (F32), recurrent depression (F33) or dysthymia (F34.1) from the Danish National Patient Register. We estimated presence of diagnosed depression according to DR level at index date and risk of diagnosed depression during follow-up using multivariable logistic and Cox regression, respectively. Secondly, we assessed whether diagnosed depression at index date could predict incident DR. ResultsWe included 240,893 individuals with type 2 diabetes with baseline rates of diagnosed depression ranging from 5.2 to 6.0 % for DR level 1–4. At index date, individuals with type 2 diabetes and DR were less likely to have a history of diagnosed depression (multivariable adjusted OR, 0.77 [95 % CI 0.73–0.82]). In 226,523 individuals with type 2 diabetes followed for 1,159,755 person-years, 1.7 % developed at least one episode of diagnosed depression.In a model adjusted for age and sex, individuals with DR at index date had an increased risk of incident diagnosed depression compared to those without DR (HR 1.25 [95 % CI 1.16–1.36]). Adjusting for marital status, use of glucose-, lipid- and blood pressure lowering medication, HbA1c, diabetic neuropathy and Charlson comorbidity index waived the above risk (multivariable adjusted HR 1.02 [95 % CI 0.93–1.12]).Furthermore a previous history of diagnosed depression was not associated with increased risk of incident DR (multivariable adjusted HR 0.89 [95 % CI 0.77–1.03]). ConclusionIn this nationwide cohort study, individuals with DR at first screening were 23 % less likely to have a history of depression, but our data did not support a bidirectional association between DR and depression. Selection bias may have occurred as diagnosed depression is a known barrier for attending DR-screening.