Quantitative Ultra-Widefield Angiography and Diabetic Retinopathy Severity: An Assessment of Panretinal Leakage Index, Ischemic Index and Microaneurysm Count.

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.

Compartmental Exudative Dynamics in Neovascular Age-Related Macular Degeneration: Volumetric Outcomes and Impact of Volatility in a Phase III Clinical Trial.

PURPOSE: To examine retinal feature dynamics in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-VEGF therapy and the relationship of these features with visual acuity. DESIGN: Post hoc analysis of the phase III, randomized, HAWK nAMD clinical trial. PARTICIPANTS: Participants randomized to the brolucizumab 6 mg or aflibercept 2 mg arms of the trial. METHODS: Spectral-domain OCT scans collected at 4-week intervals were analyzed using an automated machine learning-enhanced segmentation and feature-extraction platform with manual verification. Quantitative volumetric measures of retinal and exudative features were exported at multiple timepoints over 48 weeks. Volatility of exudative features was calculated as the standard deviation of each feature value during the maintenance phase (week 12-48) of treatment. These features were examined for their associations with anatomic and functional outcomes. MAIN OUTCOME MEASURES: Longitudinal intraretinal fluid (IRF) and subretinal fluid (SRF) volume, subretinal hyperreflective material (SHRM) volume, ellipsoid zone (EZ) integrity (EZ-retinal pigment epithelium [RPE] volume/thickness), and correlation with best-corrected visual acuity (BCVA). RESULTS: Intraretinal fluid, SRF, and SHRM demonstrated significant volumetric reduction from baseline with anti-VEGF therapy (P < 0.001 at each timepoint). Ellipsoid zone integrity measures demonstrated significant improvement from baseline (P < 0.001 at each timepoint). Both EZ integrity and SHRM measures correlated significantly with BCVA at all timepoints (EZ-RPE volume: 0.38 ≤ r ≤ 0.47; EZ-RPE central subfield thickness: 0.22 ≤ r ≤ 0.41; SHRM volume: -0.33 ≤ r ≤ -0.44). After treatment initiation, correlations of IRF and SRF volume with BCVA were weak or nonsignificant. Eyes with lower volatility of IRF, SRF, and SHRM volumes during the maintenance phase showed greater improvements in EZ integrity (all P < 0.01) and greater gains in BCVA (all P < 0.01) at week 48 compared with eyes with higher volatility in those exudative parameters. CONCLUSIONS: Quantitative measures of SHRM volume and EZ integrity correlated more strongly with BCVA than retinal fluid volumes during treatment. High volatility of exudative parameters, including SRF, during the maintenance phase of treatment was associated with loss of EZ integrity and BCVA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Longitudinal Quantitative Ultrawide-field Fluorescein Angiography Dynamics in the RUBY Diabetic Macular Edema Study.

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.

Longitudinal analysis of aqueous humour cytokine expression and OCT-based imaging biomarkers in retinal vein occlusions treated with anti-vascular endothelial growth factor therapy in the IMAGINE study.

BACKGROUND/OBJECTIVES: Retinal vein occlusion (RVO) is the second most common retinal vascular disorder. Despite promising advances with anti-VEGF therapy, select patients are unresponsive to therapy. A precision medicine-based approach for therapeutic decision-making based on underlying biomarkers may facilitate treatment based on the underlying pathway. This study aims to identify the baseline and longitudinal cytokine profiles of RVO-related macular oedema and correlating these expression profiles with higher order OCT features using a novel retinal segmentation and feature extraction platform. SUBJECTS/METHODS: The IMAGINE study is a post-hoc assessment of aqueous humour cytokines with correlation to higher level analysis of imaging studies. OCT scans underwent machine learning enhanced segmentation of the internal limiting membrane (ILM), ellipsoid zone (EZ) and retinal pigment epithelium (RPE), as well as evaluating volumetric fluid metrics. Samples of aqueous humour were obtained at baseline, as well as months 4 and 9 prior to treatment. These samples were analysed for the expression of multiple cytokines. Patients were divided into Responders and Non-Responders based on OCT profiles. Additionally, patients were categorised as a Rebounder if their CST increased by 50% after initial improvement. RESULTS: Twenty-six eyes were included. The OCT-based response schema identified 21 Responders (81%) and 5 Non-Responders (19%). VEGF levels directly correlated with intraretinal fluid volume and angiogenin was inversely correlated with fluid indices. Multiple cytokines, including ANGPTL4, were directly correlated with ellipsoid zone disruption. The baseline VEGF levels were significantly higher in all responders compared to Non-Responders (p = 0.02). Rebounders tended to have significantly decreased levels of angiogenin and TIMP-1 (p = 0.019, p = 0.015). CONCLUSIONS: Cytokine expression was linked to specific OCT features and treatment response in RVO. Identification of an imaging phenotype that could serve as a surrogate for underlying active disease pathways could enhance treatment decision-making and precision medicine.

OCT-Derived Radiomic Features Predict Anti-VEGF Response and Durability in Neovascular Age-Related Macular Degeneration.

Purpose: No established biomarkers currently exist for therapeutic efficacy and durability of anti-VEGF therapy in neovascular age-related macular degeneration (nAMD). This study evaluated radiomic-based quantitative OCT biomarkers that may be predictive of anti-VEGF treatment response and durability. Design: Assessment of baseline biomarkers using machine learning (ML) classifiers to predict tolerance to anti-VEGF therapy. Participants: Eighty-one participants with treatment-naïve nAMD from the OSPREY study, including 15 super responders (patients who achieved and maintained retinal fluid resolution) and 66 non-super responders (patients who did not achieve or maintain retinal fluid resolution). Methods: A total of 962 texture-based radiomic features were extracted from fluid, subretinal hyperreflective material (SHRM), and different retinal tissue compartments of OCT scans. The top 8 features, chosen by the minimum redundancy maximum relevance feature selection method, were evaluated using 4 ML classifiers in a cross-validated approach to distinguish between the 2 patient groups. Longitudinal assessment of changes in different texture-based radiomic descriptors (delta-texture features) between baseline and month 3 also was performed to evaluate their association with treatment response. Additionally, 8 baseline clinical parameters and a combination of baseline OCT, delta-texture features, and the clinical parameters were evaluated in a cross-validated approach in terms of association with therapeutic response. Main Outcome Measures: The cross-validated area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were calculated to validate the classifier performance. Results: The cross-validated AUC by the quadratic discriminant analysis classifier was 0.75 ± 0.09 using texture-based baseline OCT features. The delta-texture features within different OCT compartments between baseline and month 3 yielded an AUC of 0.78 ± 0.08. The baseline clinical parameters sub-retinal pigment epithelium volume and intraretinal fluid volume yielded an AUC of 0.62 ± 0.07. When all the baseline, delta, and clinical features were combined, a statistically significant improvement in the classifier performance (AUC, 0.81 ± 0.07) was obtained. Conclusions: Radiomic-based quantitative assessment of OCT images was shown to distinguish between super responders and non-super responders to anti-VEGF therapy in nAMD. The baseline fluid and SHRM delta-texture features were found to be most discriminating across groups.

Bacillary Detachment in Neovascular Age-Related Macular Degeneration: Incidence, Clinical Features, and Response to Anti-VEGF Therapy.

OBJECTIVE: To evaluate the incidence of bacillary layer detachment among patients with neovascular age-related macular degeneration (nAMD) and their response to anti-VEGF therapy. DESIGN: Post hoc analysis of the OSPREY clinical trial, a prospective, double-masked, phase II study comparing 6-mg brolucizumab with 2-mg aflibercept over 56 weeks. PARTICIPANTS: Participants with treatment-naive nAMD at the initiation of the trial were included in the analysis (n = 81). METHODS: Spectral-domain OCT (SD-OCT) scans were obtained at 4-week intervals throughout the OSPREY study and were segmented automatically using a proprietary, machine learning-enabled higher-order feature-extraction platform. MAIN OUTCOME MEASURES: The presence of bacillary detachment, and in these eyes the effect of anti-VEGF therapy on change from baseline in visual acuity (VA), central subfield thickness (CST), retinal fluid volumes, subretinal hyper-reflective material (SHRM) volume, subretinal pigment epithelium (sub-RPE) fluid volume, and ellipsoid zone (EZ) integrity at week 56. RESULTS: Bacillary detachment was identified in 7.4% (6 of 81) eyes, which had higher fluid volumes, increased CST, EZ attenuation, and increased sub-RPE volume at baseline compared with eyes without bacillary detachment. Anti-VEGF treatment resulted in the resolution of bacillary detachment in 100% of the eyes. In eyes with bacillary detachment at baseline, the anti-VEGF treatment decreased CST, fluid burden, and SHRM volumes throughout the treatment course; however, there was no significant change from baseline in VA, sub-RPE volume, or EZ integrity throughout the 56-week course of anti-VEGF treatment. CONCLUSIONS: Bacillary detachment is an OCT signature that is identifiable in a notable proportion of nAMD eyes. Anti-VEGF therapy resulted in 100% resolution of bacillary detachment and significant decreases in CST and SHRM volume; however, improvements in VA may have been limited by persistent EZ attenuation.

The Association of Fluid Volatility With Subretinal Hyperreflective Material and Ellipsoid Zone Integrity in Neovascular AMD.

Purpose: To evaluate the association of fluid volatility with ellipsoid zone (EZ) integrity and subretinal hyperreflective material (SHRM) volume during anti-vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD). Methods: This study was a post hoc analysis of the OSPREY study. Retinal volatility was quantified as the standard deviation across weeks 12 to 56 for six optical coherence tomography (OCT) metrics: central subfield thickness (CST), total fluid (TF) volume, subretinal fluid (SRF) volume, intraretinal fluid (IRF) volume, macular total retinal fluid index (TRFI), and central macular TRFI. Eyes with volatility ≤ 25th or ≥ 75th percentile values were compared. Results: Eyes with low volatility in several exudative metrics showed greater change from baseline in SHRM volume at week 12 than eyes with high volatility. During the maintenance phase (weeks 12-56), eyes exhibiting high SRF volatility demonstrated increased SHRM volume compared to eyes with low SRF volatility (P = 0.027). Eyes exhibiting high volatility in CST, TF, and SRF demonstrated less improvement in EZ total attenuation (P < 0.001, P = 0.033, and P = 0.043, respectively) than eyes with low volatility. Early exudative instability (i.e., between weeks 4-8 or weeks 8-12) in multiple parameters (i.e., CST, TF, IRF, macular TRFI, or central macular TRFI) was associated with greater volatility during the maintenance phase (P < 0.05). Conclusions: Greater volatility in exudative OCT metrics, particularly SRF volatility, was associated with a greater increase in SHRM and less improvement in EZ integrity, suggesting that volatility is detrimental to multiple anatomic features in nAMD. Early exudative instability during the loading phase of treatment was associated with longer-term volatility in exudation.

Risk Classification for Progression to Subfoveal Geographic Atrophy in Dry Age-Related Macular Degeneration Using Machine Learning-Enabled Outer Retinal Feature Extraction.

BACKGROUND AND OBJECTIVE: To evaluate the utility of spectral-domain optical coherence tomography biomarkers to predict the development of subfoveal geographic atrophy (sfGA). PATIENTS AND METHODS: This was a retrospective cohort analysis including 137 individuals with dry age-related macular degeneration without sfGA with 5 years of follow-up. Multiple spectral-domain optical coherence tomography quantitative metrics were generated, including ellipsoid zone (EZ) integrity and subretinal pigment epithelium (sub-RPE) compartment features. RESULTS: Reduced mean EZ-RPE central subfield thickness and increased sub-RPE compartment thickness were significantly different between sfGA convertors and nonconvertors at baseline in both 2-year and 5-year sfGA risk assessment. Longitudinal change assessment showed a significantly higher degradation of EZ integrity in sfGA convertors. The predictive performance of a machine learning classification model based on 5-year and 2-year risk conversion to sfGA demonstrated an area under the receiver operating characteristic curve of 0.92 ± 0.06 and 0.96 ± 0.04, respectively. CONCLUSIONS: Quantitative outer retinal and sub-RPE feature assessment using a machine learning-enabled retinal segmentation platform provides multiple parameters that are associated with progression to sfGA. [Ophthalmic Surg Lasers Imaging. 2022;53:31-39.].

Computational Imaging Biomarker Correlation with Intraocular Cytokine Expression in Diabetic Macular Edema: Radiomics Insights from the IMAGINE Study.

Purpose: Various pathways and cytokines are implicated in pathogenesis of diabetic macular edema (DME). Computational imaging biomarkers (CIBs) of vessel tortuosity from ultra-widefield fluorescein angiography (UWFA) and texture patterns from OCT images have been associated with anti-vascular endothelial growth factor (VEGF) therapy treatment response in DME. This analysis was a radiogenomic assessment of the association between underlying cytokines, UWFA, and OCT-based DME CIBs. Design: Biclustering analysis based on UWFA and OCT CIBs to identify a common imaging phenotype across patients with subsequent assessment of underlying cytokine signatures and treatment response attributes. Participants: The IMAGINE DME study was a post hoc study of cytokine expressions that included 24 eyes with sufficient baseline aqueous humor samples and an in-depth assessment of the imaging studies obtained during the phase I/II DmeAntiVEgf study (DAVE) that measured different cytokine expressions. Methods: A total of 151 graph or morphologic features quantifying leakage shape, size, density, interobject distance, and architecture of leakage spots and 5 vessel tortuosity features were extracted from the baseline UWFA scans, and 494 texture-based radiomics features were extracted from each of the fluid and retinal tissue compartments of OCT images. Biclustering enables simultaneous clustering of patients and features and was used to aggregate patients in terms of their commonality of phenotypes (based on similar imaging attributes) and to identify commonality in terms of cytokine expression and treatment response to anti-VEGF therapy. Main Outcome Measures: Identification of eyes with similar imaging phenotypes to evaluate commonalities of patterns and underlying cytokine expression. Results: Strong correlations between VEGF and 7 UWFA leakage morphologic features (Pearson correlation coefficient [PCC], 0.45-0.51; P < 0.05), 1 vascular tortuosity-based UWFA feature (PCC, 0.45; P = 0.00016), and 2 OCT-derived intraretinal fluid texture features (PCC, 0.58-0.63; P < 0.05) were identified. Strong correlation between intraretinal fluid features and other cytokines (PCC, 0.41-0.59; P < 0.05) were also observed. Conclusions: This study identified groups of eyes with similar imaging phenotypes as defined by UWFA and OCT CIBs that demonstrated similar treatment response patterns and cytokine expression, including a strong association between VEGF with UWFA-derived leakage morphologic and vessel tortuosity features.

Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression.

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.

Machine Learning-Based Automated Detection and Quantification of Geographic Atrophy and Hypertransmission Defects Using Spectral Domain Optical Coherence Tomography.

The current study describes the development and assessment of innovative, machine learning (ML)-based approaches for automated detection and pixel-accurate measurements of regions with geographic atrophy (GA) in late-stage age-related macular degeneration (AMD) using optical coherence tomography systems. 900 OCT volumes, 100266 B-scans, and en face OCT images from 341 non-exudative AMD patients with or without GA were included in this study from both Cirrus (Zeiss) and Spectralis (Heidelberg) OCT systems. B-scan and en face level ground truth GA masks were created on OCT B-scan where the segmented ellipsoid zone (EZ) line, retinal pigment epithelium (RPE) line, and bruchs membrane (BM) line overlapped. Two deep learning-based approaches, B-scan level and en face level, were trained. The OCT B-scan model had detection accuracy of 91% and GA area measurement accuracy of 94%. The en face OCT model had detection accuracy of 82% and GA area measurement accuracy of 96% with primary target of hypertransmission on en face OCT. Accuracy was good for both devices tested (92-97%). Automated lesion size stratification for CAM cRORA definition of 250um minimum lesion size was feasible. High-performance models for automatic detection and segmentation of GA area were achieved using OCT systems and deep learning. The automatic measurements showed high correlation with the ground truth. The en face model excelled at identification of hypertransmission defects. The models performance generalized well across device types tested. Future development will include integration of both models to enhance feature detection across GA lesions as well as isolating hypertransmission defects without GA for pre-GA biomarker extraction.

Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study.

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.

The 2-Year Leakage Index and Quantitative Microaneurysm Results of the RECOVERY Study: Quantitative Ultra-Widefield Findings in Proliferative Diabetic Retinopathy Treated with Intravitreal Aflibercept.

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.

Longitudinal Higher-Order OCT Assessment of Quantitative Fluid Dynamics and the Total Retinal Fluid Index in Neovascular AMD.

Purpose: The purpose of this study was to evaluate the feasibility of assessing quantitative longitudinal fluid dynamics and total retinal fluid indices (TRFIs) with higher-order optical coherence tomography (OCT) for neovascular age-related macular degeneration (nAMD). Methods: A post hoc image analysis study was performed using the phase II OSPREY clinical trial comparing brolucizumab and aflibercept in nAMD. Higher-order OCT analysis using a machine learning-enabled fluid feature extraction platform was used to segment intraretinal fluid (IRF) and subretinal fluid (SRF) volumetric components. TRFI, the proportion of fluid volume against total retinal volume, was calculated. Longitudinal fluid metrics were evaluated for the following groups: all subjects (i.e. treatment agnostic), brolucizumab, and aflibercept. Results: Mean IRF and SRF volumes were significantly reduced from baseline at each timepoint for all groups. Fluid feature extraction allowed high-resolution assessment of quantitative fluid burden. A greater proportion of brolucizumab participants achieved true zero and minimal fluid (total fluid volume between 0.0001 and 0.001mm3) versus aflibercept participants at week 40. True zero fluid during q12 brolucizumab dosing was achieved in 36.6% to 38.5%, similar to the 25.6% to 38.5% during the corresponding q8 aflibercept cycles. TRFI was significantly reduced from baseline in all groups. Conclusions: Higher-order OCT analysis demonstrates the feasibility of fluid feature extraction and longitudinal volumetric fluid burden and TRFI characterization in nAMD, supporting a unique opportunity for fluid burden assessment and the impact on outcomes. Translational Relevance: Detection and characterization of disease activity is vital for optimal treatment of nAMD. Longitudinal assessment of fluid dynamics and the TRFI provide important proof of concept for future automated tools in characterizing disease activity.

Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material, and Subretinal Pigment Epithelium Disease in Neovascular Age-Related Macular Degeneration.

PURPOSE: To assess longitudinally the effect of anti-vascular endothelial growth factor (VEGF) treatment on ellipsoid zone (EZ) integrity, subretinal hyperreflective material (SHRM), and the sub-retinal pigment epithelium (sub-RPE) compartment in eyes with neovascular age-related macular degeneration (nAMD). DESIGN: Post hoc analysis of the OSPREY clinical trial, a prospective, double-masked, phase 2 study comparing brolucizumab 6 mg with aflibercept 2 mg over 56 weeks. PARTICIPANTS: Participants with treatment-naïve nAMD at the initiation of the trial were included in the analysis. METHODS: Eyes were evaluated with spectral-domain OCT at 4-week intervals in the OSPREY trial (n = 81). Spectral-domain OCT scans collected from each visit were segmented automatically using a proprietary, machine learning-enabled higher-order feature-extraction platform for retinal layer, SHRM, and sub-RPE boundary lines, which were evaluated and corrected as needed by masked trained graders. The current analysis focused only on patients evaluated with the Cirrus (Zeiss) platform (n = 28). MAIN OUTCOME MEASURES: Outcome measures included change from baseline in EZ-RPE (i.e., photoreceptor outer segment) volume, EZ-RPE central subfield thickness (CST), total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume. The correlation between each of these measures and best-corrected visual acuity (BCVA) at each visit was evaluated. RESULTS: EZ-RPE volume and EZ-RPE CST showed significant increases, and total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume showed significant decreases from baseline at each visit from weeks 4 through 56 (P < 0.05 at each visit). Ellipsoid zone integrity measures and SHRM volume correlated significantly with BCVA at most visits (P < 0.05). No significant correlation was found between total sub-RPE volume and BCVA. CONCLUSIONS: EZ integrity, SHRM, and sub-RPE disease features in eyes with nAMD showed improvement as early as week 4 of anti-VEGF treatment. EZ integrity measures and SHRM volume were predictors of visual acuity over the first year of treatment.