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 assessment of quantitative ultra-widefield ischaemic and vascular parameters in sickle cell retinopathy.

PURPOSE: To evaluate longitudinal quantitative ischaemic and vasculature parameters, including ischaemic index, vessel area, length and geodesic distance in sickle cell retinopathy (SCR) on ultra-widefield fluorescein angiography (UWFA). METHODS: Optimal UWFA images from two longitudinal timepoints of 74 eyes from 45 patients with SCR were aligned and a common region of interest was determined. A deep-learning augmented ischaemia and vascular segmentation platform was used for feature extraction. Geodesic distance maps demonstrating the shortest distance within the vascular masks from the centre of the optic disc were created. Ischaemic index, vessel area, vessel length and geodesic distance were measured. Paired t-test and linear mixed effect model analysis were performed. RESULTS: Overall, 25 (44 eyes) patients with HbSS, 14 (19 eyes) with HbSC, 6 (11 eyes) with HbSthal and other genotypes were included. Mean age was 40.1±11.0 years. Mean time interval between two UWFA studies was 23.0±15.1 months (range: 3-71.3). Mean panretinal ischaemic index increased from 10.0±7.2% to 10.9±7.3% (p<0.005). Mean rate of change in ischaemic index was 0.5±0.7% per year. Mean vessel area (p=0.020) and geodesic distance (p=0.048) decreased significantly. Multivariate analysis demonstrated baseline ischaemic index and Goldberg stage are correlated with progression. CONCLUSION: Longitudinal ischaemic index and retinal vascular parameter measurements demonstrate statistically significant progression in SCR. The clinical significance of these relatively small magnitude changes remains unclear but may provide insights into the progression of retinal ischaemia in SCR.

Predictive Assessment of Quantitative Ultra-Widefield Angiographic Features for Future Need for Anti-VEGF Therapy in Diabetic Eye Disease.

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.

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.