Diabetic Retinopathy Severity Score Research Articles

Ultra-Widefield and Early Treatment Diabetic Retinopathy Study 7-Field Grading of Diabetic Retinopathy

High concordance in diabetic retinopathy (DR) outcomes between 7-field (7F) and ultra-widefield (UWF) images would allow for combining longitudinal assessments based on the 2 modalities both in clinical studies and clinical care. To compare 7F and UWF imaging with regard to DR severity and the associations of DR severity with risk factors, such as hemoglobin A1c, age, diabetes duration, and sex. This cross-sectional study describes the outcomes of the randomized clinical Diabetes Control and Complications Trial (DCCT) and its subsequent observational study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Of the 1441 participants with type 1 diabetes in the DCCT, 1375 were enrolled in the EDIC study. Of the 1171 participants who were active between March 2019 and December 2021, 200° UWF color imaging and 7F fundus photographs were obtained for 785 participants once at the same visit. Central graders assessed 7F-UWF with a 7F template masking the retinal periphery and the full UWF image (UWF-global). Data were analyzed from January 2022 to March 2023. Hemoglobin A1c was assessed quarterly during the DCCT and annually during the EDIC study using high-performance liquid chromatography. Retinopathy was determined independently for all imaging as mild, moderate, or severe nonproliferative DR (SNPDR) using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale for the 7F images and the global ETDRS grading scale for the UWF images. Panretinal and focal photocoagulation were self-reported or based on scarring location and pattern observed during grading. Proliferative DR (PDR) was defined by observed neovascularization or evidence of panretinal photocoagulation. Among the 785 participants included in this study, 420 (53%) were male and 365 (47%) were female. The mean (SD) age was 61 (7) years. DR grading between UWF-7F and 7F imaging was correlated for all outcomes, including for severe outcomes, such as SNPDR (κ, 0.73; concordance, 96%), PDR (κ, 0.74; concordance, 97%), scatter photocoagulation (κ, 0.97; concordance, 99%), and focal photocoagulation (κ, 0.71; concordance, 98%). Most DR severity scores were within 1 step (1410 of 1529 [92%]), and 3% (51 of 1529) were more than 2 steps apart (κ, 0.45; 95% CI, 0.42-0.49; weighted κ, 0.63; 95% CI, 0.60-0.67) on the ETDRS severity scale. DR severity assessed within the UWF-global area was higher compared to 7F (median [IQR] UWF-global score, 3 [2-3] vs median 7F level score, 2.0 [1-3]; P < .001), although the 2 modalities were correlated (1225 of 1508 [81%] 1-step agreement; weighted κ, 0.41). Standard ETDRS 7F and UWF evaluations of DR were comparable for ETDRS severity levels as previously reported by Diabetic Retinopathy Clinical Research Retina Network reports. In addition, these evaluations of DR were comparable for DCCT/EDIT study outcomes and major study conclusions, suggesting that use of UWF imaging is not likely to introduce relevant measurement biases in future longitudinal studies. ClinicalTrials.gov Identifiers: NCT00360815.

Comparison of Machine Learning Models to a Novel Score in the Identification of Patients at Low Risk for Diabetic Retinopathy

PurposeTo develop an easily applicable predictor of patients at low risk for diabetic retinopathy (DR). DesignAn experimental study on the development and validation of machine learning models and a novel retinopathy risk score to detect patients at low risk for diabetic retinopathy. SubjectsAll individuals aged 18 years or older who participated in the telemedicine retinal screening initiative through Temple University Health Systems from October 1, 2016 through December 31, 2020. The subjects must have documented evidence of their diabetes mellitus diagnosis as well as a documented hemoglobin A1C recorded in their chart within 6 months of the retinal screening photograph. MethodsThe charts of 1930 subjects (1590 evaluable) undergoing telemedicine screening for DR were reviewed, and 30 demographic and clinical parameters were collected. DR is a dichotomous variable where low risk is defined as no or mild retinopathy using the International Clinical Diabetic Retinopathy severity score. Five machine learning models (MLM) were trained to predict patients at low risk for DR using 1050 subjects and further underwent 10-fold cross validation to maximize its performance indicated by the area under the receiver operator characteristic curve (AUC). Additionally, a novel retinopathy risk score (RRS) is defined as the product of hemoglobin A1c closest to screening and years with diabetes mellitus. RRS was also applied to generate a predictive model. Main Outcome MeasuresThe performance of the trained machine learning models and the RRS model was compared using DeLong’s test. The models were further validated using a separate unseen test set of 540 subjects.The performance of the validation models were compared using DeLong’s test and chi-square tests. ResultsUsing the test set, the AUC for the RRS was not statistically different from four out of five MLM. The error rate for predicting low-risk patients using the RRS was significantly lower than the naive rate (0.097 vs 0.19; p<0.0001), and it was comparable to the error rates of the machine learning models. ConclusionThis novel retinopathy risk score is a potentially useful and easily deployable predictor of patients at low risk for DR.

Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

CHARACTERISTICS OF PARTICIPANTS IN DIABETIC RETINOPATHY CLINICAL RESEARCH CLINICAL TRIALS WHO WERE LOST TO FOLLOW-UP.

Our study describes the racial/ethnic composition and the broad health status/severity of disease of the cohorts of Diabetic Retinopathy Clinical Research clinical trials and compares the rates of noncompletion of the trial with the first data report (lost to follow-up). This study is a retrospective cohort study of participants in Diabetic Retinopathy Clinical Research Retina Network clinical trials who met our inclusion criteria. The primary outcome was the lost to follow-up rates and their associated risk factors. Eight clinical trials with 3,492 participants met our inclusion criteria. Participants who were lost to follow-up were more likely to be younger, Hispanic or Black, had Type 1 diabetes mellitus, had worse baseline best-corrected visual acuity, had higher hemoglobin A1c, had higher blood pressure, and had proliferative diabetic retinopathy (PDR) (Diabetic Retinopathy Severity Score >66). Participants who were lost to follow-up during Diabetic Retinopathy Clinical Research clinical trials tended to be younger, Hispanic or Black, and had worse diabetes and hypertension. This study highlights the importance of ensuring that a representative population is maintained through the end of the study period.

A 3-miRNA Risk Scoring Signature in Early Diabetic Retinopathy

The aim of our study was to investigate a comprehensive profile of streptozotocin (STZ)-induced early diabetic retinopathy (DR) mice to identify a risk scoring signature based on micorRNAs (miRNAs) for early DR diagnosis. RNA sequencing was performed to obtain the gene expression profile of retinal pigment epithelium (RPE) in early STZ-induced mice. Differentially expressed genes (DEGs) were determined with log2|fold change (FC)| > 1 and p value < 0.05. Functional analysis was carried out based on gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and the protein-protein interaction (PPI) network. We predicted the potential miRNAs via online tools and ROC curves were then conducted. Three potential miRNAs with AUC > 0.7 were explored via public datasets and a formula was further established to evaluate DR severity. In total, 298 DEGs (200 up-regulating and 98 down-regulating) were obtained through RNA sequencing. Hsa-miR-26a-5p, hsa-miR-129-2-3p and hsa-miR-217 were three predicted miRNAs with AUC > 0.7, suggesting their potential to distinguish healthy controls from early DR. The formula of DR severity score = 19.257 - 0.004 × hsa-miR-217 + 5.09 × 10-5 × hsa-miR-26a-5p - 0.003 × hsa-miR-129-2-3p was established based on regression analysis. In the present study, we investigated the candidate genes and molecular mechanisms based on RPE sequencing in early DR mice models. Hsa-miR-26a-5p, hsa-miR-129-2-3p and hsa-miR-217 could work as biomarkers for early DR diagnosis and DR severity prediction, which was beneficial for DR early intervention and treatment.

Ultra-Wide-Field Fluorescein Angiography Assessment of Non-Perfusion in Patients with Diabetic Retinopathy Treated with Anti-Vascular Endothelial Growth Factor Therapy

Purpose: To follow the evolution of peripheral ischemia by fluorescein angiography (FA) on ultra-wide-field (UWF) images in diabetic patients treated with anti-vascular endothelial growth factor (anti-VEGF) for macular edema. Methods: Prospective, non-interventional cohort study analyzing UWF-FA images of 48 patients with diabetic retinopathy (48 eyes) treated for diabetic macular edema. UWF-FA was performed at baseline and after one year of anti-VEGF therapy (M12). The primary endpoint was the change in the non-perfusion index. Results: Of the 48 patients included in this study, 25 completed the one-year follow-up, and 20 had FA images of sufficient quality to be interpreted. The non-perfusion index did not significantly change from baseline after one year of anti-VEGF treatment (0.7% of the non-perfused area at baseline versus 0.5% at M12; p = 0.29). In contrast, the diabetic retinopathy severity score improved significantly between baseline and M12. Conclusions: Anti-VEGF treatment with aflibercept for diabetic macular edema had no impact on the retinal perfusion assessed by FA, but it allowed for artificially improving diabetic retinopathy severity scores.

Examining the Relationship Between Diabetic Macular Edema, and Obstructive Sleep Apnea

PurposeThis prospective cohort study examined the relationship between diabetic macular edema (DME), diabetic retinopathy (DR) and obstructive sleep apnea (OSA) in patients after 1 year of treatment with anti-VEGF injection and/or continuous positive airway pressure (CPAP).Patients and MethodsThe study included adults with type 1 or 2 diabetes mellitus with diabetic retinopathy. Polysomnography metrics were measured at baseline. Ophthalmologic metrics were measured at baseline, six-month (6m) and twelve-month (12m) follow-up. All DME+ patients received standard care, and all OSA+ patients were advised continuous positive airway pressure (CPAP). Logistic regression between DR severity and OSA severity was performed. Analysis of variance (ANOVA) was performed between subgroups.ResultsSeventy-four eyes of 49 patients with DR were included. Prevalence of OSA was significantly higher in the DME+ group (70.7%) than DME- group (42.4%, p < 0.05). A significantly lower average minimum SaO2 was noted in OSA+DME+ (81.74%) than OSA+DME- eyes (88.23%, p < 0.05). Logistic regression analysis of ophthalmological and sleep metrics showed no correlation between DR and OSA severity. CPAP adherence was 20% (6/30) in the OSA+DME+ cohort and 36% (5/14) in the OSA+DME- cohort. At 12m, CPAP-adherent OSA+DME+ showed significantly lower DR severity score (1.00 ± 0.0) than CPAP non-adherent OSA+DME+ (1.36 ± 0.80, p = 0.042). No significant patterns were noted for visual acuity and mean central retinal thickness.ConclusionDME is associated with the presence of OSA. Minimum SaO2 is a significant OSA clinical variable for DME. DR severity is not associated with OSA severity. CPAP coupled with intravitreal anti-VEGF therapy may be helpful for reducing DR severity in DME+ eyes. Presence of OSA may diminish intravitreal anti-VEGF efficacy on anatomical (mean CRT) and functional (VA) outcomes of DME.

Comparison of early diabetic retinopathy staging in asymptomatic patients between autonomous AI-based screening and human-graded ultra-widefield colour fundus images

Learning ObjectivesUpon completion of this activity, participants will:Compare diabetic retinopathy (DR) severity scores of ophthalmologically asymptomatic people with diabetes between outputs from an artificial intelligence (AI)-based system and human-graded ultra-widefield (UWF) color fundus imaging, according to a clinical study.Compare manual 7F-mask gradings vs UWF full-field gradings and describe the correlation with patient characteristics, according to a clinical study.Describe clinical implications of the comparison between the DR severity scores of ophthalmologically asymptomatic people with diabetes outputs using outputs from an AI-based system and human-graded UWF color fundus imaging, according to a clinical study.Accreditation StatementsIn support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Springer Nature. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/eye; (4) view/print certificate.Credit hours1.0Release date:Expiration date:Post-test link:https://www.medscape.org/eye/posttest964708Authors/Editors disclosure informationS.S. has disclosed the following relevant financial relationships: Served as consultant or advisor for Allergan, Inc.; Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Heidelberg Pharma GmbH; Novartis Pharmaceuticals Corporation; Optos; Roche; Served as a speaker or a member of a speakers bureau for Allergan, Inc.; Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos; Roche; Received research funding from Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos; Is employed by or has an executive role as Data Monitoring Chair for Phase 2 study sponsored by Bayer HealthCare Pharmaceuticals; Scientific Committee Member of EyeBio Steering Committee for FOCUS sponsored by Novo Nordisk. Other: Trustee member for Macular Society Scientific/Research Advisory Committee Member for Sight UK, Retina UK, Macular Society.Journal CME author disclosure informationLaurie Barclay has disclosed no relevant financial relationships.

A Cost-Effectiveness Analysis of Intravitreal Aflibercept for the Prevention of Progressive Diabetic Retinopathy

To calculate costs required to prevent center-involved diabetic macular edema (CI-DME) or proliferative diabetic retinopathy (PDR), and to improve the diabetic retinopathy severity score (DRSS) with intravitreal anti-VEGF injections, as reported for aflibercept in 2 randomized control trials. Cost-effectiveness analysis modeling based on published data. None. Results from PANORAMA and the Diabetic Retinopathy Clinical Research Network Protocol W were analyzed. Parameters collected included DRSS, risk reduction of PDR, risk reduction of CI-DME, and the number of treatments required. Costs were modeled based on 2020 Medicare reimbursement data practice settings of hospital-based facility and nonfacility. Cost to prevent cases of PDR and CI-DME and to improve DRSS stage. Over 2 years in Protocol W, the cost required to prevent 1 case of PDR was $83 000 ($72 400) in the facility (nonfacility) setting; in PANORAMA, the corresponding 2-year costs were $89 400 ($75 000) for the 2-mg aflibercept every 16 weeks (2Q16) arm, and $91 200 ($89 900) for the 2-mg aflibercept every 8 weeks as needed (2Q8PRN) arm. To prevent 1 case of CI-DME with vision loss in Protocol W, the cost was $154 000 ($133 000). For all CI-DME, with and without vision loss, in PANORAMA, the costs to prevent a case were $70 900 ($59 500) for the 2Q16 arm and $90 000 ($88 800) for the 2Q8PRN arm. In Protocol W, the overall accumulated total for cost/DRSS unit change at the 2-year point for facility (nonfacility) setting was $2700 ($2400)/DRSS. In the first year alone, it was $2100 ($1800)/DRSS and in the second year, it was $6100 ($5300)/DRSS. There is a considerable cost associated with the prevention of PDR and CI-DME with intravitreal aflibercept injections. A price per unit of change in DRSS is a new parameter that might serve as a benchmark in future utility analyses that could be used to bring the perspective to cost-utility considerations.

Real-Time Diabetic Retinopathy Severity Score Level versus Ultra-Widefield Leakage Index-Guided Management of Diabetic Retinopathy: Two-Year Outcomes from the Randomized PRIME Trial.

The prospective PRIME trial applied real-time, objective imaging biomarkers to determine individualized retreatment needs with intravitreal aflibercept injections (IAI) among eyes with diabetic retinopathy (DR). 40 eyes with nonproliferative or proliferative DR without diabetic macular edema received monthly IAI until a DR severity scale (DRSS) level improvement of ≥2 steps was achieved. Eyes were randomized 1:1 to DRSS- or PLI- guided management. At the final 2-year visit, DRSS level was stable or improved compared to baseline in all eyes, and mean PLI decreased by 11% (p = 0.73) and 23.6% (p = 0.25) in the DRSS- and PLI-guided arms. In both arms, the percent of pro re nata (PRN) visits requiring IAI was significantly higher in year 2 versus 1 (p < 0.0001). The percent of PRN visits receiving IAI during year 1 was significantly correlated with the percent of PRN visits with IAI during year 2 (p < 0.0001). Through week 104, 77.4% of instances of DRSS level worsening in the DRSS-guided arm were preceded by or occurred alongside an increase of PLI. Overall, consistent IAI re-treatment interval requirements were observed longitudinally among individual patients. Additionally, PLI increases appeared to precede DRSS level worsening, highlighting PLI as a valuable biomarker in the management of DR.

Quantitative Assessment of the Severity of Diabetic Retinopathy

To determine whether a quantitative approach to assessment of the severity of diabetic retinopathy (DR) lesions on ultrawide field (UWF) images can provide new parameters to predict progression to proliferative diabetic retinopathy (PDR). One hundred forty six eyes from 73 participants with DR and 4 years of follow-up data were included in this post hoc analysis, which was based on a cohort of 100 diabetic patients enrolled in a previously published prospective, comparative study of UWF imaging at the Joslin Diabetes Center. Diabetic Retinopathy Severity Score level was determined at baseline and 4-year follow-up visits using mydriatic 7-standard field Early Treatment Diabetic Retinopathy Study (ETDRS) photographs. All individual DR lesions (hemorrhage [H], microaneurysm [ma], cotton wool spot [CWS], intraretinal microvascular abnormality [IRMA]) were manually segmented on stereographic projected UWF. For each lesion type, the frequency/number, surface area, and distances from the optic nerve head (ONH) were computed. These quantitative parameters were compared between eyes that progressed to PDR in 4 years and eyes that did not progress. Univariable and multivariable logistic regression analyses were performed to identify parameters that were associated with an increased risk for progression to PDR. A total of 146 eyes of 73 subjects were included in the final analysis. The mean age of the study cohort was 53.1 years, and 42 (56.8%) subjects were female. The number and surface area of H/ma's and CWSs were significantly (P ≤ .05) higher in eyes that progressed to PDR compared with eyes that did not progress by 4 years. Similarly, H/ma's and CWSs were located further away from the ONH (ie, more peripheral) in eyes that progressed (P < .05). DR lesion parameters that conferred a statistically significant increased risk for proliferative diabetic retinopathy in the multivariate model included hemorrhage area (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.25-5.53), and greater distance of hemorrhages from the ONH (OR, 1.24; 95% CI, 0.97-1.59). Quantitative analysis of DR lesions on UWF images identifies new risk parameters for progression to PDR including the surface area of hemorrhages and the distance of hemorrhages from the ONH. Although these risk factors will need to be confirmed in larger, prospective studies, they highlight the potential for quantitative lesion analysis to inform the design of a more precise and complete staging system for diabetic retinopathy severity in the future. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Aflibercept Reduces Retinal Hemorrhages and Intravitreal Microvascular Abnormalities But Not Venous Beading: Secondary Analysis of the CLARITY Study

Approximately 50% of patients receiving anti-vascular endothelial growth factor (VEGF) therapy show significant improvement in diabetic retinopathy severity score (DRSS), in particular at DRSS level 47 to 53 (moderately severe to severe nonproliferative diabetic retinopathy). Level 47 to 53 consists of 3 main features: deep hemorrhages (DH), venous beading (VB), and intraretinal microvascular abnormalities (IRMAs). It is unclear whether these features respond to anti-VEGF therapies differently. Post hoc analysis of Intravitreal Aflibercept versus Panretinal Photocoagulation in Patients with Proliferative Diabetic Retinopathy (CLARITY) study. Treatment-naïve participants randomized to intravitreal aflibercept. We reanalyzed the fundus images at baseline, week 12, and week 52 to assess the changes of the 3 main features in DRSS level 47 to 53 in those patients who were treatment naïve and had received aflibercept. Changes in DH, VB, and IRMA after aflibercept therapy at weeks 12 and52. Fifty-five treatment-naïve eyes at baseline that received aflibercept were included in the study. Severe DH and severe IRMA improved in approximately 75% of eyes at week 12 and mostly remained improved at week 52; VB remained unchanged in all eyes at week 12. From 12 weeks, 32 eyes that had received injections showed improved or stable DH compared with 7 eyes that did not receive injections, and DH deteriorated in 6 eyes with no further injections compared with 4 eyes that had received more injections (P= 0.0072). Similarly, 15 eyes that continued to receive injections from week 12 showed improved or stable IRMA compared with 4 who did not receive injections (P= 0.006). Worsening of IRMA was seen in 5 eyes with no further injections compared with 4 eyes that continued to receive injections. The improvements in DH and IRMA are more likely to be maintained if less than 16 weeks have elapsed since the last anti-VEGF injection. Aflibercept seems to improve DH and IRMA after just 3 injections. As soon as the frequency of injections were reduced, DH and IRMA can deteriorate again. It is unclear whether these results can be translated to patients without PDR.

Comparison of montage with conventional stereoscopic seven-field photographs for assessment of ETDRS diabetic retinopathy severity

BackgroundThe ETDRS stereoscopic seven-field (7F) has been a standard imaging and grading protocol for assessment of diabetic retinopathy (DR) severity score in many clinical trials. To the best of our knowledge, the comparison between montage and stereoscopic 7F has not been reported in the literature. Therefore, the main purpose of this study is to compare agreement between montage and stereoscopic seven-field (7F) photographs in the assessment of DR severity.MethodsStereoscopic 7F photographs were captured from subjects with DR. Montages of monoscopic 7F images were created using Adobe Photoshop CS6 Extended©. The best quality image of each stereo pair was selected and placed on a 150 × 125-inch canvas field according to the standard location from field 1 to 7. All the fields were aligned following the vessels and overlaid using the built-in blending tool. The resulting montage was utilized for grading and compared with grading on stereoscopic 7F photographs. Three independent graders were asked to assess DR severity on stereoscopic 7F photographs and montage. Severity level agreement between stereo 7F and montage was cross-tabulated and the agreement of DR severity levels between stereoscopic 7-field images and montage was analyzed using κ intergrader agreement; statistical significance was set at p < 0.05.ResultsA total of 50 eyes were included in the study. There was a substantial agreement between stereoscopic 7F and montage (κ = 0.745, κweighted = 0.867) in assessment of DR severity. Of 50 eyes, 80% of the cases showed complete agreement, and 100% of the cases had agreement within one-step. There was a moderate agreement among graders, and κ-value ranged from 0.4705 to 0.5803.ConclusionIn this study, we found a substantial agreement in assessing DR severity score employing non-stereoscopic montage and stereoscopic 7F photographs.

Deep learning algorithm predicts diabetic retinopathy progression in individual patients

The global burden of diabetic retinopathy (DR) continues to worsen and DR remains a leading cause of vision loss worldwide. Here, we describe an algorithm to predict DR progression by means of deep learning (DL), using as input color fundus photographs (CFPs) acquired at a single visit from a patient with DR. The proposed DL models were designed to predict future DR progression, defined as 2-step worsening on the Early Treatment Diabetic Retinopathy Diabetic Retinopathy Severity Scale, and were trained against DR severity scores assessed after 6, 12, and 24 months from the baseline visit by masked, well-trained, human reading center graders. The performance of one of these models (prediction at month 12) resulted in an area under the curve equal to 0.79. Interestingly, our results highlight the importance of the predictive signal located in the peripheral retinal fields, not routinely collected for DR assessments, and the importance of microvascular abnormalities. Our findings show the feasibility of predicting future DR progression by leveraging CFPs of a patient acquired at a single visit. Upon further development on larger and more diverse datasets, such an algorithm could enable early diagnosis and referral to a retina specialist for more frequent monitoring and even consideration of early intervention. Moreover, it could also improve patient recruitment for clinical trials targeting DR.

The Clinical Importance of Changes in Diabetic Retinopathy Severity Score

To investigate the clinical importance of changes in diabetic retinopathy severity score (DRSS) in patients with diabetic macular edema (DME) treated with intravitreal ranibizumab. Post hoc analysis of the phase III RIDE and RISE studies of ranibizumab for treatment of DME. Four hundred sixty-eight eyes treated with ranibizumab from randomization with gradable DRSS on baseline fundus photographs. Visual and anatomic outcomes were examined in eyes grouped according to DRSS change from baseline to month24. Mean best-corrected visual acuity (BCVA) letter score change, proportion of patients with 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letter score change, mean contrast sensitivity change, proportion of patients with resolved macular edema, and leakage on fluorescein angiography. Most (56.8%) patients treated with ranibizumab experienced 1-step or more improvement in DRSS from baseline to month 24; 40.0% had no change, and 3.2% experienced DRSS worsening. Patients with DRSS stability or improvement had greater mean BCVA letter score changes (+15.1,+14.2,+11.3, and+11.2 letters for ≥3-step improvement, ≥2-step improvement, 1-step improvement, and no DRSS change, respectively) compared with+5.0 letters in patients who had any DRSS worsening. Best-corrected visual acuity letter score gain of 15 letters or more was more common in patients with 2-step or 3-step or more DRSS improvement (51.9% and 44.6%, respectively) compared with those with a 1-step DRSS improvement, no change, or worsening (37.9%, 39.6%, and 26.7%, respectively). A loss of 15 letters or more in BCVA was more common in patients with any DRSS worsening (13.3%) compared with patients who had stable or improved DRSS (0%-2.8%). Resolution of macular edema was more common in patients with DRSS improvement: 84.2%, 87.7%, and 92.3% of patients with 1-step, 2-step or more, and 3-step or more improvement in DRSS achieved central foveal thickness of 250μm or less, compared with 65.2% and 53.3% of patients who had no DRSS change or any DRSS worsening. These findings provide further support that improvement in DRSS is a clinically important outcome that should be evaluated as a measure of treatment effectiveness in future studies of diabetic eye disease.

Practical Lessons from Protocol I for the Management of Diabetic Macular Edema.

Protocol I, a multicenter randomized clinical trial, compared the visual outcomes of patients treated with 0.5 mg intravitreal ranibizumab with either prompt or deferred (by 24 weeks laser), 4 mg intravitreal triamcinolone with prompt laser, or sham injection with prompt laser for the treatment of center-involving diabetic macular edema (DME). A total of 854 adult patients with type I or II diabetes and any level of non-proliferative diabetic retinopathy or proliferative retinopathy with adequate panretinal photocoagulation, with best-corrected visual acuity (BCVA) of 78 to 24 ETDRS letters (Snellen equivalent of 20/32 to 20/320) and visual loss attributed to macular edema, or retinal thickening with central subfield thickness of at least 250 µm by OCT were enrolled. The main outcomes relevant for practicing clinicians are as follows. (1) Intravitreal ranibizumab treatment provides superior visual outcomes compared to conventional laser treatment. (2) Adjunctive laser treatment does not appear to provide substantial visual benefit compared to ranibizumab treatment alone, but may reduce the number of injections required to resolve DME. Deferral of laser is likely beneficial in patients with worse initial visual acuity. (3) Intravitreal triamcinolone provides similar visual outcomes compared to intravitreal ranibizumab in pseudophakic patients but is associated with a clinically important increased risk of increased intraocular pressure (IOP), need for glaucoma medications, and need for glaucoma surgery. (4) Delayed initiation of intravitreal ranibizumab therapy provides improved visual outcome among patients initially treated with conventional laser photocoagulation or triamcinolone, but the magnitude of the benefit is not as great as is observed when ranibizumab treatment is initiated promptly. (5) The number of ranibizumab injections required to achieve the desired visual outcome decreases substantially after the first year, with the majority of patients not requiring further treatment after 3 years. (6) Patients who do not have a rapid response to ranibizumab still display long-term benefit to continued therapy, although perhaps less than those with immediate improvement. (7) Intravitreal ranibizumab is not only effective in reducing retinal edema and improving BCVA among patients with DME, it is also a disease modifying therapy and induces improvement of the diabetic retinopathy severity score by 2 or more steps in approximately one third of patients. Triamcinolone injection also induces improvement in diabetic retinopathy severity in DME patients, but perhaps to a lesser degree. (8) No increased risk of systemic adverse events was observed among patients treated with intravitreal ranibizumab compared to sham-injected controls or triamcinolone-treated patients, but the low frequency of adverse events, restrictive enrollment criteria, and specific posology employed in this study limit the generalization of this conclusion to patients routinely encountered in clinical practice. (9) There was no clinically important increased risk of major ocular complications among patients treated with intravitreal ranibizumab (including the risk of glaucoma), although endophthalmitis is a potentially devastating outcome should it occur. In addition to the risk of endophthalmitis, intravitreal triamcinolone injection was associated with clinically important increased risk of cataract progression and increased IOP.

Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression

To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME). A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial. Subjects (n= 144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites. Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID)+ monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID+ monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID+ monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks. Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS). At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4±24.2 μm) compared with the ranibizumab monotherapy group (-110.4±17.2 μm; P= 0.008) and was 6.2±13.0 μm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0±11.2 μm and 29.2%, respectively, in the combination group versus 392.1±17.1 μm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3±1.3 in the combination group, 5.7±1.2 in the ranibizumab monotherapy group, and 1.5±1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained ≥10 or ≥15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events. Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone.

Influence of Glycosylated Hemoglobin on the Efficacy of Ranibizumab for Diabetic Macular Edema: A Post Hoc Analysis of the RIDE/RISE Trials

To investigate the influence of glycosylated hemoglobin (HbA1c) on treatment outcomes in patients with diabetic macular edema (DME) receiving intravitreal ranibizumab. Post hoc analysis of 2 identical phase III clinical trials assessing the efficacy and safety of intravitreal ranibizumab in DME over 36 months (RIDE: NCT00473382/RISE: NCT00473330). A total of 483 adults with vision loss from DME treated with ranibizumab were included in this analysis from RIDE/RISE. Participants received monthly intravitreal ranibizumab (0.3 or 0.5 mg). Differences in visual and anatomic outcomes, and diabetic retinopathy (DR) severity score, between subgroups of patients with baseline HbA1c ≤7% versus HbA1c >7% at 36 months. There were 195 patients in RIDE/RISE who were treated with ranibizumab with a baseline HbA1c ≤7% and 288 patients with a baseline HbA1c >7% included in this analysis. The mean improvement in visual acuity (VA) at 36 months was +13 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in patients with baseline HbA1c ≤7% compared with +11 ETDRS letters in the patients with a baseline HbA1c >7% (P = 0.17). After adjustment for baseline central foveal thickness (CFT) and duration of diabetes, the mean CFT reduction was -268 μm in patients with a baseline HbA1c ≤7% and -269 μm in patients with a baseline HbA1c >7% (P = 0.98; 95% confidence interval, -22.93 to 23.54). The proportion of patients with a ≥2-step improvement in DR severity score was 38% in patients with baseline HbA1c ≤7% compared with 41% in the patients with a baseline HbA1c >7% (P = 0.53). There was no correlation of baseline HbA1c with any visual or anatomic parameter. The improvement in VA, anatomic reduction of macular edema, and improvement in DR severity score with ranibizumab treatment seem to be independent of baseline HbA1c.

Journal of Diabetes News

Journal of Diabetes News

Phosphate, fibroblast growth factor 23 and retinopathy in chronic kidney disease: the Chronic Renal Insufficiency Cohort Study

Elevated circulating concentrations of phosphate and fibroblast growth factor 23 (FGF23) contribute to the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Retinopathy is a common manifestation of microvascular disease in CKD, but its associations with phosphate and FGF23 have not been studied. We tested the hypothesis that higher serum phosphate is associated with more severe retinopathy in individuals with CKD, independent of FGF23 and known risk factors for retinopathy. We tested the associations of serum phosphate and plasma FGF23 with retinopathy in a cross-sectional analysis of 1800 participants in the Chronic Renal Insufficiency Cohort Study who underwent fundus photography. Retinopathy severity was graded according to the Early Treatment of Diabetic Retinopathy Severity score, and retinal venous and arterial diameters were measured. Mean estimated glomerular filtration rate (eGFR) was 46.5 ± 15.4 mL/min/1.73 m(2), mean serum phosphate was 3.7 ± 0.6 mg/dl and median plasma C-terminal FGF23 was 133 RU/mL (interquartile range 87.2, 217.8 RU/mL). In multivariable ordinal logistic regression models, higher serum phosphate was associated with greater retinopathy severity independent of hypertension, diabetes, CKD severity and FGF23 [adjusted odds ratio of being in one higher category of retinopathy severity: 1.19 per 1 standard deviation increase; 95% confidence interval (CI) 1.05, 1.36; P = 0.007]. Presence of diabetes or hypertension did not modify the results. Higher serum phosphate was also independently associated with greater retinal venous diameter (multivariable-adjusted 1.70 µm increase per 1 standard deviation increase in phosphate; 95% CI 0.46, 2.93; P = 0.007). FGF23 levels were not independently associated with retinopathy severity or retinal venous diameter, and neither FGF23 nor phosphate was associated with retinal arterial diameter. Among individuals with moderate-to-severe CKD, higher serum phosphate but not FGF23 was independently associated with more severe retinopathy and microvascular retinal venous dilatation.