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Objective: 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., Design: 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)., Participants: 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., Methods: 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., Main Outcome Measures: 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., Results: 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)., Conclusions: 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., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the longitudinal change in quantitative ultrawide-field angiographic (UWFA) parameters and correlate them with functional outcomes and spectral domain-OCT metrics., Design: This study is a post hoc analysis of the phase II RUBY study: a prospective, randomized trial of patients with diabetic macular edema (DME) treated with either intravitreal aflibercept injection (IAI) or combined IAI/nesvacumab (antiangiopoietin 2 mAb)., Subjects: Subjects with DME that underwent UWFA across all treatment groups (n = 44)., Methods: A machine learning-enabled feature extraction system generated panretinal quantitative UWFA metrics, including leakage, ischemia, and microaneurysm (MA) burden. Zonal assessments were performed corresponding to the macula, midperiphery, and far periphery., Main Outcome Measures: Changes in ischemic area and index (proportion of nonperfusion in analyzable retina), leakage area and index (proportion of leakage in analyzable retina), and MA count at baseline, week 12, week 24, and week 36 were analyzed. Spectral-domain-OCT quantitative metrics, such as central subfield thickness, ellipsoid zone (EZ) integrity parameters, intraretinal fluid (IRF) volume, and subretinal fluid (SRF) volume were extracted via a machine learning-enhanced OCT feature extraction platform and analyzed. Additionally, the effect of these changes on best-corrected visual acuity (BCVA) was evaluated., Results: Mean panretinal leakage index, zonal leakage area, and panretinal MA count improved significantly between baseline and week 36. Panretinal ischemic index decreased between baseline and week 36, with some aspects showing significant improvement. Mean BCVA significantly improved from baseline to week 36. There was a significant inverse correlation between change in BCVA and change in macular leakage area. A direct correlation was observed between both baseline macular leakage area and panretinal leakage index with IRF volume, SRF volume, and EZ disruption on OCT., Conclusions: Assessment of UWFA parameters demonstrates a significant improvement in panretinal leakage index, leakage area, and MA burden in eyes treated with IAI with or without nesvacumab. A numeric reduction in panretinal ischemic index and area was noted. The analysis also shows the critical association of leakage with visual and OCT features. This highlights the potential role of UWFA in disease burden assessment, with leakage parameters serving as a primary end point., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME)., Methods: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response., Results: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05)., Conclusions: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response., Competing Interests: Competing interests: JRA, SA, LL, HJY, MH, JR: none; CCW, Adverum (research funding (F)), Alimera Sciences (consultant (C)) Allergan (C, F), Allegro (C), Apellis (C, F), Alynylam (C), Bayer (C), Clearside (C, F), DORC (C), EyePoint (C, F), Genentech/Roche (C, F), Kodiak (C), Neurotech (F), Notal Vision (C), ONL Therapeutics (C), Novartis (C, F), Polyphontonix (C), Regeneron (C, F, S), Regenxbio (C, F), Samsung (F), Santen (C, F); SKS: Regeneron (F), Allergan (F), Gilead (F), Bausch and Lomb (C), Santen (C), Leica (patent (P)); DMB, Adverum (F) Allergan (C, F), Apellis (F), Bayer (C), Biotime (C), Clearside (F), Chengdu Kanghong Biotechnology (C), Gemini (C), Genentech/Roche (C, F), Heidelberg (C), Novartis (C, F), OHR (C), Opthea (F), Optos (C), Zeiss (C), Regeneron (C, F), Regenxbio (C, F), Samsung (F), Santen (C), Senju (C); JPE: Aerpio (C, F), Alcon (C, F), Thrombogenics/Oxurion (C, F), Regeneron (C, F), Genetech (C, F), Novartis (C,F), Allergan (C, F), Roche (C), Leica (C, P), Zeiss (C), Santen (C)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To demonstrate the feasibility of a deep learning-based vascular segmentation tool for UWFA and evaluate its ability to automatically identify quality-optimized phase-specific images., Methods: Cumulative retinal vessel areas (RVA) were extracted from all available UWFA frames. Cubic splines were fitted for serial vascular assessment throughout the angiographic phases of eyes with diabetic retinopathy (DR), sickle cell retinopathy (SCR), or normal retinal vasculature. The image with maximum RVA was selected as the optimum early phase. A late phase frame was selected at a minimum of 4 min that most closely mirrored the RVA from the selected early image. Trained image analysts evaluated the selected pairs., Results: A total of 13,980 UWFA sequences from 462 sessions were used to evaluate the performance and 1578 UWFA sequences from 66 sessions were used to create cubic splines. Maximum RVA was detected at a mean of 41 ± 15, 47 ± 27, 38 ± 8 s for DR, SCR, and normals respectively. In 85.2% of the sessions, appropriate images for both phases were successfully identified. The individual success rate was 90.7% for early and 94.6% for late frames., Conclusions: Retinal vascular characteristics are highly phased and field-of-view sensitive. Vascular parameters extracted by deep learning algorithms can be used for quality assessment of angiographic images and quality optimized phase selection. Clinical applications of a deep learning-based vascular segmentation and phase selection system might significantly improve the speed, consistency, and objectivity of UWFA evaluation., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Aim: To evaluate the potential of radiomics-based ultra-widefield fluorescein angiography (UWFA)-derived imaging biomarkers in retinal vascular disease for predicting therapeutic durability of intravitreal aflibercept injection (IAI)., Methods: The Peripheral and Macular Retinal Vascular Perfusion and Leakage Dynamics in Diabetic Macular Edema and Retinal Venous Occlusions During Intravitreal Aflibercept Injection (IAI) Treatment for Retinal Edema (PERMEATE) study prospectively evaluated quantitative UWFA dynamics in diabetic macular oedema or macular oedema secondary to retinal vascular occlusion. 27 treatment-naïve eyes were treated with 2 mg IAI q4 weeks for the first 6 months, and then administered q8 weeks. Morphological and graph-based attributes were used to model the spatial distribution of leakage areas, while tortuosity measures were used to model the vessel network disorder. Eyes were grouped based on functional tolerance of the first 8-week treatment interval challenge. 'Non-rebounders' (N=15) maintained/improved best-corrected visual acuity (BCVA) following the 8-week challenge. 'Rebounders' (N=12) exhibited worsened BVCA. The image biomarkers were used with a machine learning classifier to preliminarily evaluate their ability to predict BCVA stability., Results: Two new UWFA image-derived biomarkers were identified and extracted. The cross-validated area under the receiver operating characteristic curve (AUC) was 0.77±0.14 using baseline leakage distribution features and 0.73±0.10 for the UWFA baseline tortuosity measures. Additionally, the change in vascular tortuosity between month 4 and baseline yielded an AUC of 0.73±0.08. Three baseline clinical features of letter score, macular volume and central subfield thickness yielded a corresponding AUC of 0.42±0.09., Conclusions: Two computer-extracted UWFA radiomics-based descriptors were identified as potential biomarkers for predicting treatment durability and tolerance of longer treatment intervals. Conventional treatment parameters were not significantly different between these same groups., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Diabetic macular edema (DME) and retinal vein occlusion (RVO) are the leading causes of visual impairments across the world. Vascular endothelial growth factor (VEGF) stimulates breakdown of blood-retinal barrier that causes accumulation of fluid within macula. Anti-VEGF therapy is the first-line treatment for both the diseases; however, the degree of response varies for individual patients. The main objective of this work was to identify the (i) texture-based radiomics features within individual fluid and retinal tissue compartments of baseline spectral-domain optical coherence tomography (SD-OCT) images and (ii) the specific spatial compartments that contribute most pertinent features for predicting therapeutic response., Methods: A total of 962 texture-based radiomics features were extracted from each of the fluid and retinal tissue compartments of OCT images, obtained from the PERMEATE study. Top-performing features selected from the consensus of different feature selection methods were evaluated in conjunction with four different machine learning classifiers: Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Random Forest (RF), and Support Vector Machine (SVM) in a cross-validated approach to distinguish eyes tolerating extended interval dosing (non-rebounders) and those requiring more frequent dosing (rebounders)., Results: Combination of fluid and retinal tissue features yielded a cross-validated area under receiver operating characteristic curve (AUC) of 0.78±0.08 in distinguishing rebounders from non-rebounders., Conclusions: This study revealed that the texture-based radiomics features pertaining to IRF subcompartment were most discriminating between rebounders and non-rebounders to anti-VEGF therapy. Clinical Impact: With further validation, OCT-based imaging biomarkers could be used for treatment management of DME patients.

Diabetic Macular Edema (DME) and macular edema secondary to retinal occlusion (RVO) are the two most common retinal vascular causes of visual impairment and leading cause of worldwide vision loss. The blood-retinal barrier is the key barrier for maintaining fluid balance within the retinal tissue. Vascular Endothelial Growth Factor (VEGF) has a significant role in the permeability of the blood-retinal barrier, which also leads to appearance of leakage foci. Intravitreal anti-VEGF therapy is the current gold standard treatment and has been demonstrated to improve macular thickening, improve vision acuity and reduce vascular leakage. However, treatment response and required dosing interval can vary widely across patients. Given the role of the blood-retinal barrier and vascular leakage in the pathogenesis of these disorders, the goal of this study was to present and evaluate new computer extracted features relating to morphology, spatial architecture and tortuosity of vessels and leakages from baseline ultra-widefield fluorescein angiography (UWFA) images. Specifically, we sought to evaluate the role of these computer extracted features from baseline UWFA images. Notably, these UWFA images were obtained from IRB-approved PERMEATE clinical trial [1], [2] to distinguish eyes tolerating extended dosing intervals (n = 16) who are referred to as non-rebounders and those who require more frequent dosing (n = 12) and are called rebounders based on visual acuity loss with extended dosing challenges. A total of 64 features encapsulating different morphological and geometrical attributes of leakage patches including the anatomical (shape, size, density, area, minor and major axis, orientation, area, extent ratio, perimeter, radii) and geometrical characteristics (the proximity of each leakage foci to main vessels, to other leakage foci and to optical disc) as well as 54 tortuosity features (tortuosity of whole vessel network, local tortuosity of vessels in the vicinity of leakage foci) were extracted. The most significant and predictive biomarkers related to treatment response were proximity of leakage nodes to major and minor eye vessels as well as local vasculature tortuosity in the vicinity of the leakages. The imaging features were then used in conjunction with a Linear Discriminant Analysis (LDA) classifier to distinguish rebounders from non-rebounders. The 3-fold cross-validated Area Under Curve (AUC) was found to be 0.82 for the morphological based features and 0.85 for the tortuosity based features. Our findings suggest higher variation in leakage node proximity to retinal vessels in eyes tolerating extended interval dosing. In contrast, eyes with increased local vascular tortuosity demonstrated less tolerance of increased dosing interval. Moreover, a class activation map generated by a deep learning model identified regions that corresponded to regions of leakages proximal to the vessels, providing confirmation of the validity of predictive image features extracted from these regions in this study.

Purpose: To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME)., Design: Prospective, randomized phase 2 trial (PRIME)., Methods: A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI., Results: Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P = .01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P = .49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P = .03). Two eyes developed a PDR event at week 52 following 5 months of quiescence., Conclusions: The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To describe longitudinal retinal fluid dynamics on spectral domain OCT and to identify imaging biomarkers that predict the worsening of DME with interval extension during anti-vascular endothelial growth factor (VEGF) therapy., Design: A post hoc sub-analysis of phase III, VISTA-DME study., Methods: Eyes received either intravitreal aflibercept injection 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly injections (2q8), and eyes imaged with the Cirrus HD-OCT system were included. The macular cube was analyzed for 10 time-points from baseline through week 100. Retinal OCT images were evaluated using a novel software platform to extract retinal fluid features for calculation of volumetric fluid parameters, including the retinal fluid index (RFI): the percentage of retinal volume that was occupied by intraretinal fluid., Results: Fifty-five eyes were included in the 2q4 group, and 58 eyes were included in the 2q8 group. Early RFI volatility with a central macular RFI increase by ≥5 points from week 4 to 8 (P = .004, odds ratio [OR] 31.3, 95% confidence interval [CI] 3.0 to 329) and cumulative RFI volatility with an aggregate increase in macular RFI by ≥10 points from those timepoints with increased RFI between baseline to week 20, P = .005, OR 10.2, 95% CI 2.1 to 51.3) were both significant predictors for the worsening of DME and visual acuity when the treatment interval was extended to 8 weeks in the 2q8 group., Conclusions: Early fluid dynamics as measured by (1) early RFI volatility and (2) cumulative RFI instability with aggregate increased RFI were associated with intolerance of interval extension., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To identify biomarkers for predicting response to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular edema (DME) and evaluate any links between cytokine expression and optical coherence tomography (OCT) phenotype., Design: The IMAGINE is a post hoc image analysis and cytokine expression assessment of the Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE) randomized clinical trial., Methods: Subjects were categorized as anatomical responders or nonresponders, and within the responder group as rebounders and non-rebounders based on quantitative, longitudinal OCT criteria. Retinal layer and fluid features were extracted using an OCT machine-learning augmented segmentation platform. Responders were further sub-classified by rapidity of response. Aqueous concentrations of 54 cytokines were measured at multiple timepoints. Expression was compared between responder groups and correlated with OCT imaging biomarkers., Results: Of the 24 eyes studied, 79% were anatomical responders with 38% super responders, 17% early responders, and 25% slow responders. Twenty-one percent were nonresponders. Super responders had increased baseline vascular endothelial growth factor (VEGF) (880.0 pg/mL vs 245.4 pg/mL; P = .012) and decreased monocyte chemotactic protein-1 (MCP-1) (513.3 pg/mL vs 809.5 pg/mL; P = .0.042) concentrations compared with nonresponders. Interleukin-6 (-24.9 pg/mL vs 442.8 pg/mL; P = .032) concentrations increased among nonresponders during therapy. VEGF concentrations correlated with central subfield thickness (r = 0.49; P = .01). Panmacular retinal volume correlated with increased interleuckin-6 (r = 0.47; P = .02) and decreased MCP-1 (r = -0.45; P = .03). Matrix metallopeptidase-1 correlated with subretinal fluid volume (r = 0.50; P = .01)., Conclusions: OCT imaging biomarkers correlated with both intraocular cytokines and responsiveness to anti-VEGF therapy, which indicated a possible link to underlying pathways and their relevance to DME prognosis. Baseline concentrations of VEGF and MCP-1 are associated with anatomic response to anti-VEGF therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Characterization of leakage indices on ultra-widefield fluorescein angiography in proliferative diabetic retinopathy treated with intravitreal aflibercept., Methods: Prospective study enrolling subjects for treatment of proliferative diabetic retinopathy randomized 1:1 to receive 2-mg intravitreal aflibercept every 4 weeks (2q4) or every 12 weeks (2q12). Ultra-widefield fluorescein angiography images obtained at baseline, 24, and 48 weeks were analyzed using a semiautomated leakage segmentation platform. Panretinal and zonal leakage indices were calculated., Results: Forty eyes of 40 subjects were included, and mean age was 48 ± 12.1 years. Mean number of injections was 11 ± 1.7 in the 2q4 arm and 4 ± 0.4 in the 2q12 arm. Median baseline leakage index in the 2q4 and 2q12 groups was 5.1% and 4.3%, respectively (P = 0.28). At 24 and 48 weeks, the 2q4 group significantly improved to 1.1% (-79%, P < 0.0001). At Week 24, the 2q12 group demonstrated nonsignificant improvement (3.4%; -21%, P = 0.47); by Week 48, improvement was significant (1.4%; -68%, P = 0.02). The 2q4 group resulted in lower leakage index compared with the 2q12 group at 24 weeks (1.1% vs. 3.4%, respectively; P = 0.008), but by 48 weeks, leakage index was similar between both groups (1.1% vs. 1.4%, respectively; P = 0.34)., Conclusion: Proliferative diabetic retinopathy treated with intravitreal aflibercept demonstrated significant leakage index reductions at 1 year. Monthly dosing provided more rapid reduction in leakage index compared with quarterly dosing., Trial Registration: RECOVERY study (NCT02863354); https://clinicaltrials.gov/ct2/show/NCT02863354.

Purpose: To characterize the longitudinal panretinal retinal vascular dynamics in diabetic macular edema (DME) and retinal vein occlusion (RVO) over a 12-month period while being treated with intravitreal aflibercept injections (IAIs)., Design: Prospective open-label study (clinicaltrials.gov identifier, NCT02503540)., Participants: Thirty-one treatment-naive eyes with foveal-involving retinal edema secondary to DME and RVO., Methods: Participants received 2 mg IAI every 4 weeks for the first 6 months, followed by 2 mg every 8 weeks. Ultra-widefield fluorescein angiography (UWFA; California Optos [Optos, Dunfermline, United Kingdom]) and spectral-domain OCT (Cirrus; Zeiss, Oberkochen, Germany) scans were obtained and analyzed using a novel quantitative assessment platform. Visual acuity, central subfield thickness, and adverse events also were collected., Main Outcome Measures: The primary end point was the mean change in panretinal leakage index at month 12 from baseline as measured by UWFA., Results: Mean age was 67.1 years. At month 12, visual acuity significantly improved by a mean of 18.4±21.4 letters (P < 0.0001), and central subfield thickness also improved significantly, with a mean reduction of 301.3±250.3 μm (P < 0.0001). Mean panretinal leakage index improved significantly, decreasing from 3.4% at baseline to 0.5% at month 6 (P <0.0001) and 0.4% at month 12 (P < 0.0001). Panretinal ischemic index did not demonstrate any significant change but showed a nonsignificant increase from 5.5% at baseline to 6.1% at month 6 (P = 0.315) and 8.7% at month 12 (P = 0.193). Eyes with DME showed a decrease in leakage index from 3.5±2.7% at baseline to 1.6±0.8% at month 12 (P = 0.018) and overall stability in ischemic index from 5.0±4.1% at baseline to 4.7±3.5% at month 12 (P = 0.689). Participants with RVO showed a decrease in leakage index from 3.3±1.1% at baseline to 0.02±0.03% at 12 months (P < 0.0001) and a nonsignificant increase in ischemic index from 5.9±4.5% at baseline to 12.6±9.8% at month 12 (P = 0.172)., Conclusions: Intravitreal aflibercept injections resulted in a dramatic reduction in panretinal leakage index. Panretinal ischemic index did not improve and trended toward worsening., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the relationship between diabetic macular edema (DME) and quantitative ultra-widefield fluorescein angiography (UWFA) metrics of ischemia, leakage, and microaneurysms., Design: Retrospective image analysis study., Participants: Eyes with diabetic retinopathy that had undergone spectral-domain OCT, UWFA, and ultra-widefield fundus photography., Methods: OCT images were analyzed to determine the presence or absence of DME, central subfield thickness (CST), and subretinal fluid. Using a semiautomated analysis platform, UWFA images were segmented for ischemia, leakage, and microaneurysms with manual correction as needed. Clinical variables, including age, gender, race, hemoglobin A1C levels, blood pressure, cholesterol levels, use of blood thinners, smoking status, and lens status also were evaluated., Main Outcome Measures: Factors associated with the presence and severity of DME., Results: A total of 304 eyes (156 right eyes, 148 left eyes) from 178 diabetic patients were analyzed in the study. Panretinal leakage index, microaneurysm count, and ischemic index were not significantly different between eyes with and without DME in univariate assessment. Zonal assessments of macular microaneurysms and macular leakage index values revealed that eyes with DME showed a significantly higher microaneurysm count (P = 0.001) and leakage index (P < 0.0001) in the posterior pole compared with eyes without DME. Severity of macular thickening (i.e., CST) was associated significantly with macular leakage index and posterior pole microaneurysm count (P = 0.0002 and P = 0.03, respectively). In addition to posterior pole leakage index and microaneurysm count, DME was associated with older age (P < 0.01), higher systolic blood pressure (P < 0.001), and white race (P = 0.03). Multivariate assessment confirmed the independent association of presence of DME with macular leakage index and macular microaneurysm count (P < 0.01)., Conclusions: Quantitative measures of leakage index and microaneurysm count in the posterior pole on UWFA images were associated with the presence and severity of DME. Panretinal analyses were not linked to DME as strongly. Additional research is needed to determine the role of quantitative UWFA in predicting DME development and characterizing patient prognosis., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study., Design: A post hoc subanalysis of a phase III, prospective clinical trial., Participants: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8)., Methods: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point., Main Outcome Measures: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA)., Results: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 μm to 31.6 μm, P < 0.001; 2q8: 25.2 μm to 31.4 μm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits., Conclusions: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the relationship between the diabetic retinopathy (DR) severity and quantitative ultra-widefield angiographic metrics, including leakage index, ischemic index, and microaneurysm count., Design: Retrospective image analysis study., Methods: Eyes with DR that had undergone ultra-widefield fluorescein angiography (UWFA) with associated color photography were identified. All eyes were laser-naive and had not received any intravitreal pharmacotherapy within 6 months of UWFA. Each eye was graded for DR severity. Quantitative angiographic parameters were evaluated with a semiautomated analysis platform with expert reader correction, as needed. Angiographic parameters included panretinal leakage index, ischemic index, and microaneurysm count. Clinical characteristics analyzed included age, gender, race, hemoglobin A1C level, hypertension, systolic blood pressure, diastolic blood pressure, and smoking history., Main Outcome Measures: Association of DR severity with panretinal leakage index, ischemic index, and microaneurysm count., Results: Three hundred thirty-nine eyes were included with mean age of 62±13 years. Forty-two percent of eyes were from women and 57.5% were from men. Distribution of DR severity was as follows: mild NPDR in 11.2%, moderate NPDR in 23.9%, severe NPDR in 40.1%, and PDR with 24.8%. Panretinal leakage index [mild NPDR (mean = 0.51%), moderate NPDR mean = 1.20%, severe NPDR (mean = 2.75%), and PDR (mean = 5.84%); P<2×10 -16 ], panretinal ischemic index [mild NPDR (mean = 0.95%, moderate NPDR (mean = 1.37%), severe NPDR (mean = 2.80%), and PDR (mean = 9.53%); P<2×10 -16 ], and panretinal microaneurysm count [mild NPDR (mean = 36), moderate NPDR (mean = 129), severe NPDR (mean = 203), and PDR (mean = 254); P<5×10 -7 ] were strongly associated with DR severity. Multivariate analysis demonstrated that ischemic index and leakage index were the parameters associated most strongly with level of DR severity., Conclusions: Panretinal leakage index, panretinal ischemic index, and panretinal microaneurysm count are associated with DR severity. Additional research is needed to understand the clinical implications of these parameters related to progression risk, prognosis, and implications for therapeutic response., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the relationship between vitamin D status and diabetic retinopathy., Methods: A clinic-based, cross-sectional study was conducted at Emory University, Atlanta, Georgia. Overall, 221 patients were classified into 5 groups based on diabetes status and retinopathy findings: no diabetes or ocular disease (n = 47), no diabetes with ocular disease (n = 51), diabetes with no background diabetic retinopathy (n = 41), nonproliferative diabetic retinopathy (n = 40), and proliferative diabetic retinopathy (PDR) (n = 42). Patients with type 1 diabetes and those taking >1,000 IU of vitamin D daily were excluded from the analyses. Study subjects underwent dilated funduscopic examination and were tested for hemoglobin A1c, serum creatinine, and 25-hydroxyvitamin D [25(OH)D] levels between December 2009 and March 2010., Results: Among the study groups, there was no statistically significant difference in age, race, sex, or multivitamin use. Patients with diabetes had lower 25(OH)D levels than did those without diabetes (22.9 ng/mL versus 30.3 ng/mL, respectively; P<.001). The mean 25(OH)D levels, stratified by group, were as follows: no diabetes or ocular disease = 31.9 ng/mL; no diabetes with ocular disease = 28.8 ng/mL; no background diabetic retinopathy = 24.3 ng/mL; nonproliferative diabetic retinopathy = 23.6 ng/mL; and PDR = 21.1 ng/mL. Univariate analysis of the 25(OH)D levels demonstrated statistically significant differences on the basis of study groups, race, body mass index, multivitamin use, hemoglobin A1c, serum creatinine level, and estimated glomerular filtration rate. In a multivariate linear regression model with all potential confounders, only multivitamin use remained significant (P<.001)., Conclusion: This study suggests that patients with diabetes, especially those with PDR, have lower 25(OH)D levels than those without diabetes.

Purpose: To assess the relationship between serum insulin-like growth factor I (IGF-I) and diabetic retinopathy., Methods: This was a clinic-based cross-sectional study conducted at the Emory Eye Center. A total of 225 subjects were classified into four groups, based on diabetes status and retinopathy findings: no diabetes mellitus (no DM; n=99), diabetes with no background diabetic retinopathy (no BDR; n=42), nonproliferative diabetic retinopathy (NPDR; n=41), and proliferative diabetic retinopathy (PDR; n=43). Key exclusion criteria included type 1 diabetes and disorders that affect serum IGF-I levels, such as acromegaly. Subjects underwent dilated fundoscopic examination and were tested for hemoglobin A1c, serum creatinine, and serum IGF-I, between December 2009 and March 2010. Serum IGF-I levels were measured using an immunoassay that was calibrated against an international standard., Results: Between the groups, there were no statistical differences with regards to age, race, or sex. Overall, diabetic subjects had similar serum IGF-I concentrations compared to nondiabetic subjects (117.6 µg/l versus 122.0 µg/l; p=0.497). There was no significant difference between serum IGF-I levels among the study groups (no DM=122.0 µg/l, no BDR=115.4 µg/l, NPDR=118.3 µg/l, PDR=119.1 µg/l; p=0.897). Among the diabetic groups, the mean IGF-I concentration was similar between insulin-dependent and non-insulin-dependent subjects (116.8 µg/l versus 118.2 µg/l; p=0.876). The univariate analysis of the IGF-I levels demonstrated statistical significance in regard to age (p=0.002, r=-0.20), body mass index (p=0.008, r=-0.18), and race (p=0.040)., Conclusions: There was no association between serum IGF-I concentrations and diabetic retinopathy in this large cross-sectional study.

Purpose: To evaluate the safety and effect of bevacizumab pretreatment on the incidence of recurrent vitreous hemorrhage and visual acuity after vitrectomy for proliferative diabetic retinopathy., Methods: This was a consecutive, retrospective, and comparative cohort study. Patients undergoing vitrectomy from September 2006 through November 2007 at the Emory Eye Center for complications of proliferative diabetic retinopathy were identified and reviewed. A total of 33 eyes pretreated with bevacizumab and 104 untreated eyes were observed for postoperative vitreous hemorrhage and final visual acuity., Results: Patients in the bevacizumab group were significantly younger than those in the untreated group (average age, 46.4 vs. 58.4 years) and were more likely to have 20-gauge instrumentation (58% vs. 36%). An average of 9.6 days passed between injection and surgery. Early (4-6 weeks) rebleed rates were 15% versus 13% in the bevacizumab and untreated groups, respectively, and not statistically different. Preoperative (7/200 vs. count finger at 4'), 1-month postoperative (20/200(-3) vs. 20/150), and 3-month postoperative visual acuity (20/100(-3) vs. 20/100(+2)) were not statistically different between groups. No statistical difference was found in rebleed rates regarding the gauge of vitrectomy., Conclusion: Bevacizumab pretreatment for diabetic vitrectomy was not associated with any observed complications but did not influence rates of postoperative vitreous hemorrhage or final visual acuity in this retrospective series. The overall incidence of postoperative early vitreous hemorrhage in this series was 13% and seems lower than historically reported rates.

The objective of this study was to identify biomarkers that predict a future need for anti-VEGF therapy in diabetic retinopathy (DR). Eyes with DR that underwent ultra-widefield angiography (UWFA) and had at least a 1 year follow-up were grouped based on future anti-VEGF treatment requirements: (1) not requiring treatment, (2) immediate treatment (within 3 months of UWFA), and (3) delayed treatment (after 3 months of UWFA). Quantitative UWFA features and clinical factors were evaluated. Random forest models were built to differentiate eyes requiring immediate and delayed treatment from the eyes not requiring treatment. A total of 173 eyes were included. The mean follow-up was 22 (range: 11–43) months. The macular leakage index, panretinal leakage index, presence of DME, and visual acuity were significantly different in eyes requiring immediate (n = 38) and delayed (n = 34) treatment compared to eyes not requiring treatment (n = 101). Random forest model differentiating eyes requiring immediate treatment from eyes not requiring treatment demonstrated an AUC of 0.91 ± 0.07. Quantitative angiographic features have potential as important predictive biomarkers of a future need for anti-VEGF therapy in DR and may serve to guide the frequency of a follow-up. [ABSTRACT FROM AUTHOR]

Purpose: Ellipsoid zone (EZ) and outer retinal integrity are strongly linked to visual prognosis, but quantitative normative data is lacking. This study evaluates the EZ, outer retina, and inner retina in eyes without macular disease across a wide age spectrum. Methods: An IRB-approved study was performed for eyes without macular pathology undergoing Spectral Domain Optical Coherence Tomography (SD-OCT) scans on the Cirrus HD-OCT system (Carl Zeiss Meditec, Oberkochen, Germany). Scans were analyzed using a previously described automated EZ mapping tool with line-by-line manual verification. Segmentation included internal limiting membrane (ILM), outer nuclear layer/Henle fiber layer complex (ONL/HFL), EZ, and the retinal pigment epithelium (RPE). The output included metrics for the inner retina (ILM-OPL/HFL), outer retina (ONL/HFL-RPE), EZ-RPE area and volume, and en face EZ mapping. EZ-RPE attenuation on en face mapping was defined as EZ-RPE thickness < 20 um, and total attenuation was 0 um. Imaging parameters were assessed for the group and compared to age, sex, visual acuity and spherical equivalent. Results: 167 eyes from 167 subjects were included. Mean age was 49.7 years (range 10–84 years). The mean foveal retinal thickness was 200.58 ± 19.22 um. Mean inner retinal thickness was 21.47 ± 13.60 um. Mean outer retinal thickness was 179.11 ± 18.52 um. Mean EZ-RPE thickness was 50.58 ± 6.01um. The mean EZ-RPE volume was 1.20 ± 0.10 mm3. Mean EZ attenuation percentage per macular map area was 0.87% ± 1.13% and mean percentage total attenuation was 0.12% ± 0.14%. Total and inner retinal thickness metrics decreased with age. Mean outer retinal thickness increased with age. EZ-RPE parameters were unchanged with age. However, EZ attenuation was negatively correlated with age. Conclusion: This study provides important information for inner and outer retinal parameters. Future research on quantitative EZ integrity can utilize this data for comparison. [ABSTRACT FROM AUTHOR]

The management of retinal diseases relies heavily on digital imaging data, including optical coherence tomography (OCT) and fluorescein angiography (FA). Targeted feature extraction and the objective quantification of features provide important opportunities in biomarker discovery, disease burden assessment, and predicting treatment response. Additional important advantages include increased objectivity in interpretation, longitudinal tracking, and ability to incorporate computational models to create automated diagnostic and clinical decision support systems. Advances in computational technology, including deep learning and radiomics, open new doors for developing an imaging phenotype that may provide in-depth personalized disease characterization and enhance opportunities in precision medicine. In this review, we summarize current quantitative and radiomic imaging biomarkers described in the literature for age-related macular degeneration and diabetic eye disease using imaging modalities such as OCT, FA, and OCT angiography (OCTA). Various approaches used to identify and extract these biomarkers that utilize artificial intelligence and deep learning are also summarized in this review. These quantifiable biomarkers and automated approaches have unleashed new frontiers of personalized medicine where treatments are tailored, based on patient-specific longitudinally trackable biomarkers, and response monitoring can be achieved with a high degree of accuracy. [ABSTRACT FROM AUTHOR]

Eyes with proliferative diabetic retinopathy (PDR) have been shown to improve in the leakage index and microaneurysm (MA) count after intravitreal aflibercept (IAI) treatment. The authors investigated these changes via automatic segmentation on ultra-widefield fluorescein angiography (UWFA). Forty subjects with PDR were randomized to receive either 2 mg IAI every 4 weeks (Arm 1) or every 12 weeks (Arm 2) through Year 1. After Year 1, Arm 1 switched to quarterly IAI and Arm 2 to monthly IAI through Year 2. By Year 2, the Arm 1 leakage index decreased by 43% from Baseline (p = 0.03) but increased by 59% from Year 1 (p = 0.04). Arm 2 decreased by 61% from Baseline (p = 0.008) and by 31% from Year 1 (p = 0.12). Both cohorts exhibited a significant decline in MAs from Baseline to Year 2 (871 to 410; p < 0.001; 776 to 207; p < 0.001, respectively). Subjects with an improved leakage and MA count showed a more significant improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. Moreover, central subfield thickness (CST) was positively associated with changes in the leakage index. In conclusion, the leakage index and MA counts significantly improved from Baseline following IAI treatment, and monthly injections provided a more rapid and sustained reduction in these parameters compared with quarterly injections. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case study of a 63-year-old man who has diabetic macular oedema (DME) and treated with vitrectomy and dexamethasone implant which required surgical repositiong due to post injection foveal adhesion.