Baseline retinal vascular bed area on ultra-wide field fluorescein angiography correlates with the anatomical outcome of diabetic macular oedema to ranibizumab therapy: two-year analysis of the DAVE Study.

PURPOSE: To determine the relationship between baseline retinal non-perfusion area (NPA) and retinal vascular bed area (RVBA) on ultra-wide field fluorescein angiography (UWF FA) and long-term response to intravitreal ranibizumab therapy in diabetic macular oedema (DMO). METHODS: A post-hoc, 2-year observational case series. Baseline UWF FA images (Optos 200Tx) of 40 eyes from 29 patients with diabetes mellitus and treatment naïve DMO in the DAVE (NCT01552408) study were montaged and stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The retinal vasculature was automatically extracted to calculate RVBA. NPA was manually delineated by two masked certified graders. RVBA and NPA were computed in mm2 automatically by adjusting for peripheral distortion and then correlated with the severity of DMO. RESULTS: While global NPA at baseline was not correlated to retinal thickness measurements, baseline NPA in the superior retina was associated with the macular volume (MV) improvement (P = 0.022). Multivariate analysis revealed a smaller RVBA at baseline was correlated with a better MV outcome at two-year follow-up after adjusting for confounding factors (P = 0.049). CONCLUSION: Eyes with smaller baseline RVBA appear to have a better long-term anatomic outcome of DMO.

Multi-modal retinal scanning to measure retinal thickness and peripheral blood vessels in multiple sclerosis.

Our purpose was to investigate changes to the retina in multiple sclerosis (MS) using established and novel modes of retinal image acquisition and analysis. 72 participants with MS and 80 healthy volunteers underwent retinal scanning with optical coherence tomography (OCT) and ultra-widefield (UWF) scanning laser ophthalmoscopy (SLO), over a two-year period. Changes in retinal nerve fibre layer (RNFL) thickness, macular volume and retinal blood vessel diameter were measured and parameters were then tested for associations with MS. Measurements from OCT showed that individuals with MS had a thinner RNFL and reduced macular volume when compared to healthy volunteers. On UWF images, participants with MS had reduced arterial widths in the inferior nasal quadrant of both eyes and reduced venous widths in the inferior nasal quadrant of right eyes. Longitudinal analysis showed that participants with MS had an accelerated annual rate of RNFL thinning in several regions of the retina. In conclusion, the assessment of OCT showed thinning of the RNFL and macula in concordance with previous reports on MS, while analysis of blood vessels in the retinal periphery from UWF-SLO images revealed novel changes.

Clinical significance of metabolic quantification for retinal nonperfusion in diabetic retinopathy.

Diabetic retinopathy (DR) is characterized by microvascular changes including ischemia. Degradation and metabolic changes of various retinal cells occur during ischemia. Ischemic region containing more cells will lead to greater metabolic impairment. We analyzed the non-perfusion region (NPR) by integrating histologic mapping with ultra-widefield fluorescein angiography (UWF FA) images. We also investigated the correlations of the weighted ischemic index (ISI) considering the regional distribution of retinal cells with cytokines, macular edema (ME), and neovascularization (NV). In this study, 32 patients with treatment-naïve DR and 21 age-matched control participants were included. The difference between the non-weighted and weighted ISI of NPR with leakage was greatest at the posterior region. The weighted ISI of NPR with leakage was correlated with MCP-1, IL-8, IL-6, PlGF, and VEGF-A levels, while the non-weighted ISI of NPR with leakage was correlated with IL-8 and IL-6 levels. The presence of baseline ME or NV in patients with DR was associated with the weighted ISI, with a stronger association when cones and rods were weighted. The weighted ISI reflecting both metabolic activity and cell distribution demonstrated a better correlation with clinical features and was more valuable in NPR with leakage than non-weighted ISI, which previous studies conventionally used.

Choroidal vascular alterations evaluated by ultra-widefield indocyanine green angiography in central serous chorioretinopathy.

PURPOSE: This study aims to evaluate choroidal vascular alterations in patients with central serous chorioretinopathy (CSC) using ultra-widefield (UWF) indocyanine green angiography (ICGA). METHODS: This was a retrospective case-control study conducted at a single tertiary eye center. In total, 36 eyes in patients with either unilateral (24 patients) or bilateral (six patients) treatment-naïve CSC and 30 eyes in 24 age-matched controls were evaluated. The number of quadrants with vortex vein engorgement on UWF ICGA was evaluated. Dilated choroidal vessels affecting the macula were regarded as extended vortex vein engorgement. Choroidal vascular hyperpermeability (CVH) area on late-phase ICGA was quantified using stereographic projection. The parameters were compared with clinical and optical coherence tomographic findings. RESULTS: Eyes with CSC had larger CVH area, thicker choroid, and more quadrants with vortex vein engorgement and extended vortex vein engorgement compared with control eyes (all P < 0.001). In patients with unilateral CSC, affected eyes had larger CVH area, thicker choroid, and more extended vortex vein engorgements compared with unaffected fellow eyes (all P < 0.001), but vortex vein engorgement did not significantly differ. CVH was significantly correlated with extended vortex vein engorgement (P < 0.001) and subfoveal choroidal thickness (P = 0.007). CONCLUSIONS: The increased number and binocular symmetry of engorged vortex veins suggest an anatomical predisposition for CSC. CVH area and extended vortex vein engorgement were indicators of choroidal outflow congestion. These parameters may serve as diagnostic clues or predictors of disease development in eyes with CSC.

Retinal vascular bed area on ultra-wide field fluorescein angiography indicates the severity of diabetic retinopathy.

AIMS: To quantify retinal vascular bed area (RVBA) in square millimetres on stereographically projected ultra-wide field (UWF) fluorescein angiography (FA) in eyes with diabetic retinopathy (DR). METHODS: A prospective, observational study. Baseline Optos 200Tx UWF FA images of 80 eyes with DR from the DAVE (NCT01552408) and RECOVERY (NCT02863354) studies were stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The early-phase FA frame was used to extract the retinal vasculature as a mask for calculating RVBA. The pixels of the retinal vasculature were automatically computed in square millimetres using manufacturer-provided software. RESULTS: Eighteen of 80 diabetic eyes were excluded because image quality and contrast were insufficient for automatic extraction of the retinal vasculature from the background fluorescence. The remaining 62 eyes were included in the final analysis. In comparison with age-matched and sex-matched normal controls, eyes with DR had a higher global RVBA for the entire retina (p<0.001), and RVBA correlated with DR severity (p<0.001), with a higher RVBA in eyes with proliferative DR (66.1±16.2 mm2) than in those with non-proliferative DR (56.2±16.6 mm2) or in normal controls (37.2±9.9 mm2). This tendency was also present in the posterior retina and mid-periphery but absent in the far-periphery. RVBA did not correlate with retinal ischaemia (p>0.05). CONCLUSIONS: Eyes with DR harboured a larger global RVBA for the entire retina than normal controls, and RVBA appeared to indicate DR severity. However, this biomarker was not observed to be a good indicator of retinal ischaemia.

Effects of refractive power on quantification using ultra-widefield retinal imaging.

BACKGROUND: Ultra-widefiled (UWF) retinal images include significant distortion when they are projected onto a two-dimensional surface for viewing. Therefore, many clinical studies that require quantitative analysis of fundus images have used stereographic projection algorithm, three-dimensional fundus image was mapped to a two-dimensional stereographic plane by projecting all relevant pixels onto a plane through the equator of the eye. However, even with this impressive algorithm, refractive error itself might affect the size and quality of images theoretically. The purpose of this study is to investigate the effects of refractive power on retinal area measurements (quantification) using UWF retinal imaging (Optos California; Dunfermline, Scotland, UK). METHODS: A prospective, interventional study comprised 50 healthy eyes. UWF images were acquired first without the use of a soft contact lens (CL) and then repeated with six CLs (+ 9D, +6D, +3D, -3D, -6D, and - 9D). Using stereographically projected UWF images, the optic disc was outlined by 15-17 points and quantified in metric units. We divided the subjects into three groups according to axial length: Groups A (22-24 mm), B (24-26 mm), and C (≥ 26 mm). The primary outcome was percentage change before and after use of the CLs. Secondary outcome was proportion of subjects with magnification effects, maximal changes > 10 %. RESULTS: The study population was 6, 28, and 16 eyes in each group. Overall changes for the measured area were not significantly different in the whole study population. Group C had a larger proportion of magnification effects compared to Groups A and B (50.0 %, 0 %, and 3.6 %, P = 0.020). Measured area with plus lenses was significantly higher in Group C (P < 0.001). CONCLUSIONS: The use of CLs might affect quantification of eyes with long axial length when using UWF images. Ophthalmologists should consider refractive error when measuring area in long eyes.

Macular Microvascular Changes and Their Correlation With Peripheral Nonperfusion in Branch Retinal Vein Occlusion.

PURPOSE: To investigate the correlation between macular microvascular alterations on optical coherence tomography angiography (OCTA) and retinal ischemia on ultra-widefield fluorescein angiography (UWF FA) in eyes with branch retinal vein occlusion (BRVO). DESIGN: Cross-sectional study. METHODS: This prospective study was performed from September 2019 to June 2020 at Yeungnam University Medical Center. We included 60 patients with treatment-naïve BRVO. Two independent, masked graders analyzed OCTA parameters, including vessel density, skeletal density, and fractal dimension (FD), and UWF FA parameters, including retinal nonperfusion area (NPA) and ischemic index (ISI), from various concentric regions (perimacular region, 0.5-3 mm radius; near-peripheral region, 3-10 mm; midperipheral region, 10-15 mm; far-peripheral region, >15 mm). A repeated-measures analysis of variance test and a paired t test were performed for inter-visit and inter-regional comparisons, and Pearson correlation coefficient and multivariate regression analyses were performed to examine the correlation between UWF FA and OCTA parameters. RESULTS: The OCTA parameters from both the superficial and deep capillary plexuses (DCP) were significantly correlated with NPA and ISI in all concentric regions. Even after adjusting for several covariates, all OCTA parameters revealed a significant association with ISI on UWF FA. Moreover, OCTA parameters from DCP were significantly correlated with concentrations of placental growth factor and vascular endothelial growth factor. Although all OCTA parameters achieved excellent results of area under the curve (AUC) > 0.9 for detecting severe retinal ischemia, defined as ISI >10%, FD reduction in DCP was the most reliable parameter (AUC = 0.948, P < .001), and 5.39% was the best cut-off point for predicting ISI > 10%. CONCLUSIONS: OCTA is a useful noninvasive tool not only for evaluation of macular microvasculature but for supposition of peripheral nonperfusion in eyes with BRVO.

Relationship between distribution and severity of non-perfusion and cytokine levels and macular thickness in branch retinal vein occlusion.

We aimed to investigate the relationship between non-perfusion on ultra-widefield angiography (UWF FA) and aqueous cytokine levels and central macular thickness (CMT) in eyes with branch retinal vein occlusion (BRVO). Thirty-five eyes with treatment-naïve BRVO were included. Non-perfusion area (NPA) for partial and complete ischemia was manually segmented and the ischemic index (ISI) for each was calculated using stereographically projected UWF FA for four different retinal zones. Partial and complete ischemia had different regional predominance. Partial ischemia was predominant in the posterior regions, while complete ischemia was predominant in the periphery. And partial ischemic area, located posterior to far periphery, showed significant correlation with central macular thickness and concentrations of angiogenic and inflammatory cytokines, while complete ischemic area showed no correlation with any of the parameters. Taken together, partial but not complete ischemia, particularly in the more posterior retina, was associated with higher cytokine levels and more severe macular edema in eyes with BRVO. These findings would help us to better understand the different clinical significance of ischemia in BRVO depending on the severity and regional distribution.

Retinal Vascular Caliber Association with Nonperfusion and Diabetic Retinopathy Severity Depends on Vascular Caliber Measurement Location.

PURPOSE: To evaluate the association of retinal nonperfusion and diabetic retinopathy (DR) severity with location of vascular caliber measurement using ultrawide field (UWF) imaging. DESIGN: Retrospective image review. PARTICIPANTS: Adults with diabetes mellitus. METHODS: All images from subjects with same-day UWF fluorescein angiography (FA) and color imaging were evaluated. Predominantly peripheral lesions (PPL) and DR severity were graded from UWF color images. Nonperfusion was quantified using UWF-FA in defined retinal regions [posterior pole (PP), mid-periphery (MP), far-periphery (FP)]. Retinal vessel calibers were measured at an optic disc centered inner and outer zone. MAIN OUTCOME MEASURES: Nonperfusion index (NPI) in the PP, MP and FP. Mean arteriole and venule diameter in the inner and outer zones. RESULTS: Two hundred eighty-five eyes of 193 patients (24.9% mild nonproliferative DR [NPDR], 22.8% moderate NPDR, 37.5% severe NPDR and 14.7% proliferative DR [PDR]) were reviewed. No significant associations between inner zone arteriolar diameter and retinal NPI overall or in any retinal region. In the outer zone, eyes with thinnest arteriolar calibers (quartile 1) were associated with a 1.7- to 2.4-fold nonperfusion increase across all retinal regions compared to the remaining eyes (P = 0.002 [PP] to 0.048 [FP]). In the outer zone, the percentage of eyes in the thinnest quartile of retinal arteriolar diameter increased with worsening DR severity (mild NPDR: 10% vs PDR: 31%, P = 0.007). This association was not observed when measured within the inner zone (P = 0.129). All venular caliber associations were not statistically significant when corrected for potentially confounding factors. Thinner outer zone retinal arteriolar caliber (quartile 1) was more common in eyes with PPL compared to eyes without PPL (34.1% vs 20.8%, P = 0.017) as were thicker outer venular calibers (quartile 4) (33% vs 21.3%, P = 0.036). Presence of PPL was associated with thinner outer zone arteriolar caliber (109.7 ± 26.5µm vs 123.0 ± 29.5µm, P = 0.001). CONCLUSIONS: The association of vascular caliber with nonperfusion and DR severity differs based upon the retinal location at which vascular caliber is measured. Peripheral arterial narrowing is associated with increasing nonperfusion, worsening DR severity and presence of PPL. In contrast, inner zone retinal arteriolar caliber is not associated with these findings.

Peripheral extent of the choroidal circulation by ultra-widefield indocyanine green angiography in healthy eyes.

AIM: To analyse the peripheral extent of choroidal circulation using ultra-widefield (UWF) indocyanine green angiography (ICGA) in healthy eyes. METHODS: UWF ICGA images of 55 eyes of 36 healthy subjects were captured using the Optos California (Optos, Dunfermline, United Kingdom) in this prospective observational study. Images were analysed to locate the peripheral extent of the visible choroidal circulation, and the boundary was marked in ImageJ (v1.52). Each pixel annotated as the border of the choroidal circulation was projected individually to its anatomically correct location on the three-dimensional model eye, and spherical trigonometry was applied (using the Optos software) to calculate its respective radial distance from the centre of the optic disc in metric units (corrected by stereographic projection) for each quadrant. RESULTS: The mean area of the peripheral extent was estimated to be 893.2 mm2 (95% CI: 844.2 to 942.3 mm2). The mean distance (range) of this boundary from optic nerve centre was 18.22 mm (95% CI: 14.0 to 23.14 mm). Multiple regression analysis with age, gender, axial length or ethnicity showed no relationship. There was excellent inter-grader reproducibility, with intraclass correlation coefficients of 0.95 (95% CI: 0.80 to 0.99, p<0.001) for distance and 0.99 (95% CI: 0.988 to 0.999, p<0.001) for area measurements. CONCLUSIONS: The peripheral choroidal boundary may be defined using UWF ICGA. Knowledge of the normal extent and its variability is essential to understand the impact of disease on the choroidal vasculature.

Quantitative analysis of choroidal vasculature in polypoidal choroidal vasculopathy using ultra-widefield indocyanine green angiography.

Polypoidal choroidal vasculopathy (PCV) is a common choroidal vascular disease particularly in Asians. However, the underlying pathogenesis of PCV is still yet to be fully elucidated, and the correlation between choroidal vasculature and treatment response of PCV are poorly understood. Accordingly, we sought to find clues to understand the pathogenesis and prognosis of PCV by quantitatively evaluating choroidal vasculature from the entire fundus using ultra-widefield (UWF) indocyanine green angiography (ICGA). In this study, 32 eyes from 29 patients with treatment naïve PCV and 30 eyes from 30 healthy control participants were enrolled. Choroidal vascular density (CVD) of PCV eyes was higher than normal eyes in majority regions including the periphery. CVD was positively correlated with choroidal thickness and choroidal hyperpermeability, supporting that the pathogenesis of PCV may include choroidal congestion and dilatation. Thicker choroid and higher CVD were also correlated with poor treatment response after anti-VEGF injections. The CVD, quantified from UWF ICGA can also be used as an effective image biomarker to predict the treatment response in PCV.

Fractal analysis of retinal vasculature in normal subjects on ultra-wide field fluorescein angiography.

AIM: To evaluate the fractal feature of the retinal vasculature of normal eyes on a stereographic projected and montaged ultra-wide field (UWF) fluorescein angiography (FA). METHODS: Prospective, observational, cross-sectional study. Totally 59 eyes of 31 normal subjects were imaged using the Optos 200Tx. Images obtained at different gaze angles stereographically projected and montaged. The early-phase UWF FA frames were processed to segment the retinal vasculature and the results were exported as binary masks. The fractal dimension (FD) was calculated using the box-counting method. RESULTS: The global FD for the entire retina was 1.6±0.04, with no difference between males and females (1.59±0.04 vs 1.61±0.04, P=0.084) or between right and left eyes (1.6±0.04 vs 1.6±0.05, P=0.61). FD was non-uniformly distributed among four quadrants (P<0.001) and decreased as the distance from the fovea increased (P<0.001). A negative association was observed between FD and age (R=-0.37, P=0.006), and this relationship was observed in the posterior and mid-peripheral retina (P<0.05) but absent in far-periphery (P>0.05). CONCLUSION: Fractal geometry is non-uniformly distributed across the retina in normal eyes and decreases from the fovea to the far-periphery. Subjects with an older age tend to have a smaller FD, however, the FD in the far-periphery does not appear to be influenced by age.

Association between hypertension and retinal vascular features in ultra-widefield fundus imaging.

Objective: Changes to the retinal vasculature are known to be associated with hypertension independently of traditional risk factors. We investigated whether measurements of retinal vascular calibre from ultra-widefield fundus imaging were associated with hypertensive status. Methods: We retrospectively collected and semiautomatically measured ultra-widefield retinal fundus images from a subset of participants enrolled in an ongoing population study of ageing, categorised as normotensive or hypertensive according to thresholds on systolic/diastolic blood pressure (140/90 mm Hg) measured in a clinical setting. Vascular calibre in the peripheral retina was measured to calculate the nasal-annular arteriole:venule ratio (NA-AVR), a novel combined parameter. Results: Left and right eyes were analysed from 440 participants (aged 50-59 years, mean age of 54.6±2.9 years, 247, 56.1% women), including 151 (34.3%) categorised as hypertensive. Arterioles were thinner and the NA-AVR was smaller in people with hypertension. The area under the receiver operating characteristic curve of NA-AVR for hypertensive status was 0.73 (95% CI 0.68 to 0.78) using measurements from left eyes, while for right eyes, it was 0.64 (95% CI 0.59 to 0.70), representing evidence of a statistically significant difference between the eyes (p=0.020). Conclusions: Semiautomated measurements of NA-AVR in ultra-widefield fundus imaging were associated with hypertension. With further development, this may help screen people attending routine eye health check-ups for high blood pressure. These individuals may then follow a care pathway for suspected hypertension. Our results showed differences between left and right eyes, highlighting the importance of investigating both eyes of a patient.

Distribution of peripheral lesions identified by mydriatic ultra-wide field fundus imaging in diabetic retinopathy.

PURPOSE: To analyze the distribution of diabetic retinopathy (DR) lesions in an Indian population using ultra-wide field (UWF) fundus imaging. METHODS: Seven hundred fifteen subjects (1406 eyes) with diabetic retinopathy in India were enrolled in this multicenter, prospective, observational study using UWF pseudocolor imaging with Optos Daytona Plus (Optos plc, Dunfermline, Scotland, UK). Images were transmitted to Doheny Image Reading Center, Los Angeles, CA, for grading. The ETDRS grid was overlaid on stereographic projections of UWF images, and images were graded independently by 2 masked graders. Lesion distribution was graded as predominantly central (PCL) or predominantly peripheral (PPL) according to previous criteria, considering both lesion number and area. An image was graded as PPL if > 50% of the lesion area was seen in at least one peripheral field as compared with the corresponding ETDRS field. Diabetic retinopathy severity was also assessed based on the International Classification of Diabetic Retinopathy (ICDR) grading scale. The main outcome measures were lesion distribution (PPL versus PCL): overall and within specific fields in eyes with various grades of DR. RESULTS: Lesion distribution was rated to be PPL in 37% of eyes and PCL in 63% of eyes (P < 0.003). The frequency of a PPL distribution varied significantly across all ICDR severity levels, with frequencies of mild non-proliferative DR (NPDR) (30.9%), moderate NPDR (40.3%), severe NPDR (38.5%) and PDR (34.9%), P = 0.005. When assessing which individual fields were rated to show a PPL distribution, the frequency was greatest in field 4 and least in field 7. For any grade of DR, temporal fields showed the greatest PPL frequency, followed in order by the superior, inferior, and nasal fields (P < 0.001). Only 3.5% of eyes showed PPL distribution in all five peripheral fields. CONCLUSIONS: One-third of the UWF images showed a PPL distribution in this cohort with the temporal quadrant having the widest distribution of PPL. As the PPL distribution varied significantly between various grades of DR, UWF imaging may prove to be important for screening of referral warranted retinopathy.

Distribution and Location of Vortex Vein Ampullae in Healthy Human Eyes as Assessed by Ultra-Widefield Indocyanine Green Angiography.

PURPOSE: To study the number and distribution of vortex ampullae in healthy eyes using ultra-wide field (UWF) indocyanine green angiography (ICGA). DESIGN: Prospective, observational study. PARTICIPANTS: Thirty-six eyes of 36 healthy participants with no evidence of ocular or systemic disease. METHODS: The UWF ICGA images (central and peripheral steered) were captured using the Optos California (Optos, Dunfermline, United Kingdom) instrument. The images were projected stereographically to correct for peripheral distortion and obtain accurate measurements. All images were graded and analyzed for number, location, and distance of the vortex vein ampullae from the center of optic nerve. MAIN OUTCOME MEASURES: Mean number and the distance of ampullae from the center of optic nerve in all quadrants. RESULTS: The mean number of ampullae observed by UWF ICGA was 8.0±2.1 (range, 5-13). The mean distance of a vortex vein ampulla from the optic nerve was 14.2±1.1 mm (range, 10.3-17.7 mm). The frequency of ampullae was higher in the superior and inferior quadrants than the nasal and temporal quadrants. Ampullae were never observed in the 3- or 9-o'clock meridians. Multiple regression analysis showed no relationship with age, gender, axial length, or ethnicity. Excellent intergrader reproducibility was found between graders with an intraclass correlation coefficient (distance measurements: intraclass correlation coefficient, 0.99; 95% CI, 0.979-0.999; P < 0.001; number of ampullae: intraclass correlation coefficient, 0.99; 95% CI, 0.988-0.999; P < 0.001). CONCLUSIONS: The number of discrete vortex vein ampullae that can be discerned by UWF ICGA in healthy individuals is greater frequently and substantially than the 4 that are traditionally thought to drain the major quadrants. Considerable variability in the number and position of the ampullae may be apparent in healthy individuals.

Relationship Between Retinal Fractal Dimension and Nonperfusion in Diabetic Retinopathy on Ultrawide-Field Fluorescein Angiography.

PURPOSE: To correlate fractal dimension (FD) of the retinal vasculature with the extent of retinal nonperfusion area in diabetic retinopathy (DR) on ultrawide-field fluorescein angiography (FA). DESIGN: Cross-sectional study. METHODS: Baseline Optos 200Tx ultrawide-field FA images of 80 eyes with DR from the DAVE (NCT01552408) and RECOVERY (NCT02863354) studies were stereographically projected at the Doheny Image Reading Center. The retinal vasculature was extracted from an early-phase FA frame by exploiting the elongated nature of the vessels and then skeletonized for calculation of FD using a box-counting method. The nonperfusion area was delineated by 2 independent, reading center-certified graders who were masked to the study groups and who were using a standardized protocol and then computed in millimeters squared. RESULTS: While no difference in FD was observed for the entire retina in DR compared with normal control subjects, a significantly smaller FD was found in the far-periphery of the DR eyes (P < .001). FD for the entire retina was negatively associated with global nonperfusion area (R = -0.44; P < .001), and this relationship was also present within the 3 concentric retinal zones (posterior: R = -0.31, P = .016; midperiphery: R = -0.35, P = .007; and far periphery: R = -0.31, P = .015). CONCLUSIONS: Peripheral FD on ultrawide-field FA is reduced in DR eyes compared with normal eyes and is correlated with severity of retinal nonperfusion. FD can be calculated automatically without the need for correction of peripheral distortion, and therefore it may prove to be a useful surrogate biomarker when precise quantification of nonperfusion is not feasible.

SEVERITY OF DIABETIC MACULAR EDEMA CORRELATES WITH RETINAL VASCULAR BED AREA ON ULTRA-WIDE FIELD FLUORESCEIN ANGIOGRAPHY: DAVE Study.

PURPOSE: To quantify retinal nonperfusion area and retinal vascular bed area (RVBA) in mm on ultra-widefield fluorescein angiography in eyes with diabetic macular edema (DME) and explore their relationship with the severity of DME. METHODS: Prospective, observational case series. Baseline ultra-widefield fluorescein angiography images of 40 eyes from 29 patients with treatment-naive DME who participated in the DAVE study (NCT01552408) were stereographically projected at Doheny Image Reading Center. The retinal vasculature was automatically extracted to calculate RVBA. Nonperfusion area was manually delineated by two masked certified graders. Retinal vascular bed area and nonperfusion area were computed in mm automatically by adjusting for peripheral distortion and then correlated with the severity of DME. RESULTS: The global RVBA for the entire retina in eyes with DME was increased compared with healthy controls (54.7 ± 16.6 mm vs. 37.2 ± 9.9 mm, P < 0.001) and correlated with the severity of DME (P < 0.05). Retinal ischemia (nonperfusion area) was nonuniformly distributed and not related to DME extent (P > 0.05). CONCLUSION: Eyes with DME have an increased RVBA compared with healthy controls. The severity of DME appears to be related to global RVBA, but not to retinal ischemia.

Distribution of Nonperfusion and Neovascularization on Ultrawide-Field Fluorescein Angiography in Proliferative Diabetic Retinopathy (RECOVERY Study): Report 1.

PURPOSE: To explore the distribution of nonperfusion area (NPA) on ultrawide-field fluorescein angiography (UWF FA) in proliferative diabetic retinopathy (PDR) and its relationship with the presence of neovascularization of the optic disc (NVD) and distribution of neovascularization elsewhere (NVE). DESIGN: Prospective, observational case series. METHODS: Baseline Optos 200Tx UWF FA images of 38 eyes with treatment-naïve early-stage PDR from the RECOVERY (NCT02863354) study were stereographically projected at the Doheny Image Reading Center. Two independent/masked certified graders manually delineated the NPA and the total visible retinal area (TRA). NPA and TRA were then computed in square millimeters using the manufacturer software. Ischemic index (ISI) was calculated by dividing NPA by TRA. NPA and ISI were correlated with the presence and distribution of neovascularization in the corresponding zones. RESULTS: Eyes with NVD appeared to have more severe global NPA than those without (P = .026). Although the ISI appeared to increase with increasing distance from the foveal center (P < .001), NVE was more likely to be located in the posterior pole than the midperiphery or far-periphery (P < .001). Presence of NVE in the posterior polar retina appeared to demonstrate more severe ischemia in the posterior pole and midperiphery than those without (P < .05), but interestingly, was not correlated with the severity of overall global ischemia or of ischemia in the far-periphery alone (P > .05). CONCLUSIONS: Whereas the presence of NVD was associated with the severity of global ischemia, the distribution of NVE did not appear to be influenced by the distribution of ischemia.

Classification of Regions of Nonperfusion on Ultra-widefield Fluorescein Angiography in Patients with Diabetic Macular Edema.

PURPOSE: To classify retinal nonperfusion regions (NPRs) in patients with diabetic macular edema (DME) and assess the relationship with severity of DME. DESIGN: Prospective, observational case series. METHODS: Forty eyes of 29 patients with treatment-naïve center-involved macular edema secondary to diabetes mellitus were included (The DAVE study, NCT01552408) in this analysis. Ultra-widefield fluorescein angiography (UWF FA) images were transmitted to the Doheny Image Reading Center, where they were corrected using stereographic projection to adjust for peripheral distortion. Two independent, certified graders manually evaluated the NPR and classified the nonperfusion as being associated with leakage or without leakage. The size of these 2 subtypes of NPR were computed in mm2 and assessed across the entire retina and within 3 concentric retinal zones. The relationship between subtype of NPR and the severity of DME was assessed. RESULTS: In 40 eyes with treatment-naïve DME, visual acuity was significantly correlated with central macular thickness (CMT) and macular volume (MV). The NPR with leakage was positively correlated with CMT (R = 0.408, P = .009) and MV (R = 0.399, P = .011), whereas the NPR without leakage was negatively correlated with CMT (R = -0.468, P = .002) and MV (R = -0.473, P = .002). The NPR with leakage in the posterior region was significantly greater compared to the mid-periphery and the far periphery (P < .001), whereas the NPR without leakage was significantly greater in the mid-periphery compared with the far periphery or the posterior region (P = .001). CONCLUSION: In patients with DME, the severity of DME appears to be positively correlated with NPR with leakage but negatively correlated with NPR without leakage. These findings may have implications for the pathophysiology of DME and the design of protocols for targeted laser in these eyes.

Ultra-Wide-Field Fluorescein Angiography-Guided Normalization of Ischemic Index Calculation in Eyes With Retinal Vein Occlusion.

Purpose: The purpose of this study was to compare the use of central and montaged ultra-wide-field fluorescein angiography (UWFFA) images for calculating the area of nonperfusion (NP) and ischemic index (ISI) in patients with retinal vein occlusion (RVO) and macular edema (ME) and to correlate these measurements with best-corrected visual acuity (BCVA) and central macular thickness (CMT). Methods: Thirty eyes of 30 RVO patients with recurrent ME were enrolled. Baseline UWFA images were sent to the Doheny Image Reading Center for quantitative analysis by certified graders. The association between ISI from the various zones and BCVA and CMT was examined by Spearman rank correlation and compared. Generalized linear models (GLMs) were used to analyze associations between BCVA and disease status. Results: The NP area and ISI for central and montaged images were not significantly different for any retinal zone. A modest but statistically significant negative linear correlation was observed between BCVA and ISI, ranging from r = -0.3825 in the perimacular area (PMA) to r = -0.584 in the far peripheral area (FPA). On GLM analysis, both PMA (ß = -1.059; 95% confidence interval: -1.74 to -0.378) and FPA (ß = -0.505; 95% confidence interval: -0.988 to -0.021) were significant independent predictors of BCVA. We found no correlation between ISI from the various zones and CMT in this cohort. Conclusions: Montaging of UWFFA images may not be required to adequately quantify and represent areas of NP in eyes with RVO. NP in both the PMA and peripheral retina appear relevant to visual function, highlighting the importance of evaluating the retinal periphery in these individuals.