Optical Coherence Tomography Angiography in Central Retinal Vein Occlusion: Macular Changes and Their Correlation with Peripheral Nonperfusion at Ultra-Widefield Fluorescein Angiography.

INTRODUCTION: The aim of this study was to investigate the correlation between ischemic index (ISI) measured on ultra-widefield (UWF) fluorescein angiography (FA) images and macular parameters obtained by optical coherence tomography angiography (OCT-A) in eyes affected by central retinal vein occlusion (CRVO). METHODS: Retrospective study of data from 12 eyes affected by treatment-naïve CRVO. All patients underwent a comprehensive ocular examination including structural OCT, OCT-A, and UWF FA. Variables analyzed included best corrected visual acuity (BCVA) measured with the ETDRS chart; foveal avascular zone (FAZ) area at full-thickness OCT-A angiogram; perfusion density (PD) in the superficial (SCP) and deep capillary plexus (DCP); ISI; and central macular thickness (CMT). RESULTS: ISI showed a significant positive correlation with FAZ area (r = 0.63, p = 0.019) and a significant negative correlation with PD in the SCP (r = -0.62, p = 0.022), PD in the DCP (r = -0.66, p = 0.011), and BCVA (r = -0.75, p = 0.002). FAZ area also negatively correlated to PD in the SCP (r = -0.75, p = 0.002) and DCP (r = -0.64, p = 0.016). BCVA positively correlated to PD in the SCP (r = 0.67, p = 0.009) and DCP (r = 0.68, p = 0.008), while a negative correlation was found with FAZ area (r = -0.65, p = 0.013) and CMT (r = -0.70, p = 0.006). DISCUSSION/CONCLUSION: OCT-A macular parameters (namely, FAZ area and PD of SCP and DCP) significantly correlated with ISI, a quantitative way to assess peripheral retinal nonperfusion on UWF FA. Macular OCT-A analysis may help in assessing the need for additional UWF FA testing in eyes affected by CRVO.

Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: an extension trial.

PURPOSE: Our previous 1-year pilot study evaluated the efficacy of intravitreally injected activated protein C (APC) in 10 eyes with ischemic central retinal vein occlusion (CRVO). The reperfusion of the areas of retinal nonperfusion (RNP) exceeded 50% of the baseline in five (50%) eyes 1 year after the APC injection. The current study evaluated the long-term efficacy and safety of intravitreal APC. METHODS: The 10 eyes in the pilot study were included in this study. Other treatments were administered at the physicians' discretion after the pilot study. We evaluated visual acuity (VA), central retinal thickness (CRT) and perfusion status, and adverse events and severity over the long term. RESULTS: The median follow-up was 60 months (range, 48-68 months). Compared with baseline, the post-treatment VA improved significantly (P < 0.001) from 1.39 to 1.06 logarithm of the minimum angle of resolution. The CRT improved significantly (P < 0.001) from 1090 to 195 µm at the last visit. The RNP areas decreased from an average 29.7 disc areas (DAs) at baseline to an average 16.5 DAs at the last examination (mean, 40 ± 6.5 months after the first APC treatment). No adverse events were related to intravitreal APC. CONCLUSION: No complications were associated with intravitreal APC, the clinical course improved, and improved RNP was maintained for the long term, suggesting that intravitreal APC may be an alternative treatment for CRVO.

The prognostic value of peripheral retinal nonperfusion in diabetic retinopathy using ultra-widefield fluorescein angiography.

PURPOSE: To investigate the prognostic value of peripheral retinal nonperfusion in patients with diabetic retinopathy using ultra-widefield fluorescein angiography (UWFA). METHODS: A cross-sectional study included 78 treatment-naïve eyes with nonproliferative and proliferative diabetic retinopathy (NPDR and PDR). Eyes were divided into three groups: mild/moderate NPDR (n = 31), severe NPDR (n = 31), and PDR (n = 16). Three nonperfusion variables were calculated reflecting the proportion of nonperfused to visible retina based on initial UWFA: central nonperfusion (CNP) index, peripheral nonperfusion (PNP) index, and PNP ratio. The relationships between these indices and central subfield thickness (CST) and spectacle-corrected visual acuity (SCVA) were evaluated. RESULTS: CNP and PNP indices were significantly higher in the PDR group vs. mild/moderate NPDR group (p = 0.007 and 0.008, respectively) but not in the PDR group vs. severe NPDR group (p = 0.149 and p = 0.535, respectively). A significant linear correlation was found between the CNP and PNP indices in both severe NPDR and PDR groups (R2 = 0.141, p = 0.041, and R2 = 0.311, p = 0.025, respectively). Nonperfusion predominance was not statistically correlated with the presence of macular edema (p = 0.058) or disorganization of retinal inner layers (p = 1). In the severe NPDR group, there was a moderately positive correlation between CNP index and CST (rs = 0.496, p = 0.019) and no correlation between CNP index and SCVA when controlling for CST (p = 0.160). In the PDR group, a strong negative correlation between PNP ratio and CST was found (rs = -0.659, p = 0.014), but no correlation was observed between CNP index, CST, and SCVA. In the PDR group, a positive correlation was found between PNP index, PNP ratio, and SCVA (rs = 0.549, p = 0.027, and rs = 0.626, p = 0.010, respectively), even after controlling for CST (rs = 0.599, p = 0.040). CONCLUSIONS: Higher amounts of retinal nonperfusion are seen in patients with more severe retinopathy. Increased CNP is associated with macular thickening and subsequent vision loss. Having predominantly PNP was independently associated with worse VA, regardless of macular thickness. Further studies are needed to investigate the role of PNP in vision loss in diabetic retinopathy.

[Selective panretinal laser photocoagulation in ischemic central retinal vein occlusion]. / Selektivnaya panretinal'naya lazernaya koagulyatsiya pri ishemicheskikh okklyuziyakh tsentral'noi veny setchatki.

PURPOSE: To compare the effectiveness and safety of panretinal laser photocoagulation targeting far-periphery (sPRP) versus conventional panretinal laser photocoagulation (cPRP) in patients with ischemic central retinal vein occlusion (iCRVO) in terms of the degree of macular edema. MATERIAL AND METHODS: The study included eight (5 males and 3 females, mean age 59.4±17.2 years) and seven (6 males and 1 female, mean age 75.7±9.1 years) patients in sPRP and cPRP groups, respectively. iCRVO was defined as a CRVO case with baseline best corrected visual acuity (BCVA) of <0.2, central retinal thickness (CRT) of >500 µm and severe intraretinal hemorrhages. sPRP included dense photocoagulation of far-periphery over 360˚ and standard photocoagulation of the mid-periphery. Primary outcome measures were CRT and macular volume at the end of the follow-up. BCVA served as the secondary outcome measure. RESULTS: The median of the follow-up period was 9.5 months (ranged from 1.5 to 19 months). In the sPRP group, at the end of the follow-up both CRT and macular volume significantly decreased from 892.0±149.4 µm to 391.8±131.2 µm (p<0.001) and from 16.6±4.1 mm3 to 9.7±1.4 mm3, respectively (p=0.008). In the cPRP group, at the end of the follow-up CRT and macular volume changes were statistically insignificant: from 761.0±162.1 µm to 705.0±181.8 µm (p=0.46) and from 13.6± 3.2 mm3 to 11.8±1.7 mm3, respectively (p=0.38). At the end of the follow-up, cPRP group did not have changes in BCVA, while in the sPRP group BCVA increased statistically significantly from 1.45±0.6 LogMAR (≈0.06) to 1.1±0.6 LogMAR (≈0.14) (p=0.03). There were no adverse events or complications associated with laser treatment in any of the study patients. CONCLUSION: This study demonstrates the superiority of sPRP compared with cPRP for treatment of patients with iCRVO, showing that selective laser treatment of the far-periphery results in significant reduction of macular edema associated with severe retinal ischemia.

Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: A meta-analysis of randomised trials.

PURPOSE: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. RESULTS: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. CONCLUSION: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO REGISTRATION: CRD42022314418.

Macular Perfusion Deficits on OCT Angiography Correlate with Nonperfusion on Ultrawide-field Fluorescein Angiography in Diabetic Retinopathy.

OBJECTIVE: To evaluate the correlation between nonperfusion parameters on OCT angiography (OCTA) and ultrawide-field fluorescein angiography (UWF-FA) in subjects with diabetes mellitus (DM). DESIGN: Prospective, cross-sectional study. SUBJECTS: Subjects with DM and a wide range of diabetic retinopathy (DR) severity seen at a tertiary referral center. METHODS: We used averaged 3 × 3 mm OCTA scans to measure geometric perfusion deficit (GPD), vessel density, and vessel length density in the full retina, superficial capillary plexuses (SCPs), and deep capillary plexuses (DCPs). Nonperfusion was manually delineated on UWF-FA to quantify central, peripheral, and total retinal nonperfusion (mm2 and % area). MAIN OUTCOME MEASURES: Correlation between OCTA parameters and UWF-FA nonperfusion, and accuracy of these OCTA and UWF-FA parameters in detecting clinically referable eyes, using receiver operating characteristic (ROC) curve analysis, sensitivity, specificity, and area under the ROC curve (AUC). RESULTS: The study included 67 eyes (12 eyes with no signs of DR, 8 mild, 22 moderate, 14 severe nonproliferative DR, and 11 treatment-naive proliferative DR). There was a fair-to-moderate correlation between either central or total retinal nonperfusion on UWF-FA (mm2) and GPD in the SCP (r = 0.482 and r = 0.464, respectively) and DCP (r = 0.470 and r = 0.456, respectively). Receiver operating characteristic analysis showed the DCP GPD significantly superior to other OCTA parameters at the DCP with the largest overall AUC on OCTA for distinguishing referable DR (0.905). Furthermore, the GPD parameter had the largest AUC in each respective capillary layer compared with other parameters. Overall, the total UWF-FA nonperfusion area showed a comparable AUC (0.907) and performed significantly better than peripheral nonperfusion (P = 0.041). Comparing the AUC values between GPD and UWF-FA nonperfusion parameters showed no significant difference in discerning referable DR. CONCLUSIONS: Nonperfusion as quantified on OCTA (3 × 3 mm) correlated with UWF-FA parameters and both were comparable in detecting referable DR. These macular OCTA metrics, particularly DCP GPD, have the potential for gauging the overall ischemic status of the retina, with an important clinical role in identifying eyes with clinically referable DR. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Association of Diabetic Lesions and Retinal Nonperfusion Using Widefield Multimodal Imaging.

PURPOSE: To evaluate the association of microvascular lesions on ultrawidefield (UWF) color fundus (CF) images with retinal nonperfusion (RNP) up to the midperiphery on single-capture widefield (WF) OCT angiography (OCTA) in patients with diabetic retinopathy (DR). DESIGN: Cross-sectional study. SUBJECTS: Seventy-five eyes of 50 patients with mild to severe nonproliferative DR (NPDR) and proliferative DR (PDR) were included in this analysis. METHODS: ETDRS level and presence of predominantly peripheral lesions (PPLs) were assessed on UWF-CF images acquired with a Zeiss Clarus 700. Single-capture 65°-WF-OCTA was performed using a PlexElite prototype (Carl Zeiss Meditec, Inc.). A custom grid consisting of a central ETDRS grid extended by 2 rings reaching up to the midperiphery was overlaid to subdivide retinal areas visible on WF-OCTA en face images. Retinal nonperfusion was measured in each area and in total. Nonperfusion index (NPI) was calculated from total RNP. On UWF-CF images, the number of microaneurysms, hemorrhages, neovascularizations, and areas with intraretinal microvascular abnormalities (IRMAs) were evaluated using the same grid. MAIN OUTCOME MEASURES: Association of diabetic lesions with RNP was calculated using Spearman correlations (rs). RESULTS: Median RNP on WF-OCTA was 0 mm2 (0-0.9), 4.9 mm2 (1.9-5.4), 23.4 mm2 (17.8-37), and 68.4 mm2 (40.8-91.7) in mild, moderate, and severe NPDR and PDR, respectively. We found a statistically significant correlation (P < 0.01) of overall RNP (rs = 0.96,) and NPI (rs = 0.97) on WF-OCTA with ETDRS level. Number of grid-fields affected by IRMAs on CF images was highly associated with NPI (rs = 0.86, P < 0.01). Intraretinal microvascular abnormalities and RNPs had similar topographic distributions with high correlations in affected areas. Eyes with PPLs (n = 43 eyes, 57%) on CF images had a significantly higher NPI (P = 0.014) than eyes without PPLs. CONCLUSION: The combination of UWF-CF imaging and single-capture WF-OCTA allows precise and noninvasive analysis of the retinal vasculature up to the midperiphery in patients with DR. The presence and extent of IRMAs on CF images may serve as an indicator for underlying RNP, which is more pronounced in eyes with PPLs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal Ischaemia in Diabetic Retinopathy: Understanding and Overcoming a Therapeutic Challenge.

BACKGROUND: Retinal ischaemia is present to a greater or lesser extent in all eyes with diabetic retinopathy (DR). Nonetheless, our understanding of its pathogenic mechanisms, risk factors, as well as other characteristics of retinal ischaemia in DR is very limited. To date, there is no treatment to revascularise ischaemic retina. METHODS: Review of the literature highlighting the current knowledge on the topic of retinal ischaemia in DR, important observations made, and underlying gaps for which research is needed. RESULTS: A very scarce number of clinical studies, mostly cross-sectional, have evaluated specifically retinal ischaemia in DR. Interindividual variability on its natural course and consequences, including the development of its major complications, namely diabetic macular ischaemia and proliferative diabetic retinopathy, have not been investigated. The in situ, surrounding, and distance effect of retinal ischaemia on retinal function and structure and its change over time remains also to be elucidated. Treatments to prevent the development of retinal ischaemia and, importantly, to achieve retinal reperfusion once capillary drop out has ensued, are very much needed and remain to be developed. CONCLUSION: Research into retinal ischaemia in diabetes should be a priority to save sight.

Reduced Vessel Density in the Mid-Periphery and Peripapillary Area of the Superficial Capillary Plexus in Non-Proliferative Diabetic Retinopathy.

Our aim in this study was to assess the vessel density (VD) and vessel skeleton density (VSD) in the nasal area of the superficial capillary plexus (SCP) of diabetic subjects without diabetic retinopathy (DR), or in those with a non-proliferative diabetic retinopathy (NPDR), and to evaluate the relationship between the VD and VSD and the severity of DR. In this prospective study, the VD and VSD in the SCP were measured and analyzed on 6 × 6-mm macular and nasal optical coherence tomography angiography scans. The three concentric circles of the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid were used and divided into zones numbered from 1 to 9 in the macular area and from 1 to 8 in the nasal area. The VD was significantly lower in the nasal peripapillary area (p = 0.0028), and both the VD and VSD were significantly lower in the macular area (p = 0.0131 and p = 0.0132, respectively) in patients with more severe DR. The SD was significantly lower in zones 5 (p = 0.0315) and 6 (p = 0.0324) in the nasal grid in patients with more severe DR. We showed a lower superficial capillary flow in the nasal periphery and peripapillary area in patients with more severe DR.

Final Outcomes from the Randomized RECOVERY Trial of Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy.

PURPOSE: Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR). DESIGN: Prospective, randomized clinical trial with treatment crossover in the second year. SUBJECTS: Eyes with PDR and RNP. METHODS: At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing. MAIN OUTCOME MEASURES: Change in total RNP area (mm2) through year 2. Secondary outcomes included Diabetic Retinopathy Severity Scale (DRSS) scores; best-corrected visual acuity; central subfield thickness; additional measures of RNP, including ischemic index (ISI); and adverse event incidence. Means and 95% confidence intervals were calculated. RESULTS: Among all subjects, from baseline to year 2, the mean RNP increased from 235 mm2 to 402 mm2 (P < 0.0001), and the ISI increased from 25.8% to 50.4% (P < 0.0001). Increases in the mean RNP (P < 0.0001) and ISI (P < 0.0001) were also observed from year 1 to year 2. The mean total RNP increased from 264 mm2 at baseline to 386 mm2 (P < 0.0001) at year 2 in arm 1 and from 207 mm2 at baseline to 421 mm2 (P < 0.0001) at year 2 in arm 2 (P = 0.023, arm 1 vs. arm 2). Increases in the mean RNP for both treatment arms (P < 0.0001) were also specifically observed within year 2 (P = 0.32, arm 1 vs. arm 2). Compared with baseline, the DRSS scores at the end of year 2 improved in 82% (n = 27) of subjects and remained stable in 18% (n = 6), with no subjects experiencing worsening; at 2 years, the DRSS scores had improved by 2 or more steps in 65% (n = 11) and 81% (n = 13) of subjects in arms 1 and 2, respectively. CONCLUSIONS: Through year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

[Ischemia and laser photocoagulation in retinal vein occlusion]. / Ischämie und Lasertherapie bei retinalen venösen Verschlüssen.

BACKGROUND: Retinal vein occlusions (RVO) are associated with retinal ischemia to a highly variable extent. An ischemic retina may lead to the development of neovascularization and further to secondary complications such as neovascular glaucoma, vitreous hemorrhage or tractional retinal detachment. Numerous factors such as vascular endothelial growth factor (VEGF) and other cytokines are produced in the ischemic area, which cause macular edema. Before the introduction of intravitreal drug injections (IVI), retinal laser photocoagulation was the leading form of treatment. Macular laser photocoagulation was applied in the form of focal laser or grid laser in patients with branch retinal vein occlusion (BRVO) to treat macular edema. In patients with ischemic RVO, panretinal laser photocoagulation (PRP) was recommended for treatment of secondary neovascular complications. The value of laser treatment in the management of patients with RVO changed after the introduction of IVI treatment. AIM: This article presents a review of the current study results and the recommendations for performing laser photocoagulation of the central and peripheral retina in patients with RVO. CONCLUSION: Conventional focal or grid laser photocoagulation has been replaced by IVI treatment in the management of macular edema secondary to BRVO; however, macular laser treatment can still be considered in patients with BRVO if the macular edema persists despite the use of available IVI drugs. The use of central laser photocoagulation in these cases is based on the findings of fluorescein angiography. Disseminated panretinal laser photocoagulation is still indicated in RVO patients who have large areas of nonperfusion, have developed neovascularization and/or late complications. Targeted laser photocoagulation of the peripheral areas of nonperfusion has recently been recommended by several authors and is expected to improve not only the visual outcome of IVI treatment, but more importantly to also reduce the duration of treatment and the number of re-injections needed. Clear evidence for targeted laser treatment is not yet available and is a focus of currently ongoing prospective randomized studies.

Bilateral Adie's Pupil following Laser Treatment of the Ischemic Peripheral Retina for Uveitis: A Case Report.

Adie's pupil is a neurological condition of unknown origin with unusual, asymmetric presentation known as anisocoria with the enlarged pupil failing to react to light. It is believed that this pupillary abnormality results from damage to the ciliary ganglion or postganglionic short ciliary nerves. Affected individuals (usually female) may be symptomatic with photophobia or difficulty reading in the diseased eye. Although most Adie's pupil cases are idiopathic, previous studies have associated photocoagulation and uveitis with symptom onset. To the best of our knowledge, there have been no reports of specific means of preventing Adie's pupil. We describe a patient who experienced varying severities of Adie's pupil after separate laser treatments of the ischemic peripheral retina for uveitis. Fluorescein angiography revealed peripheral retinal nonperfusion in the bilateral eyes of a 37-year-old Japanese female who had been suffering from posterior uveitis. To avoid proliferative changes, 360° laser photocoagulation of the retinal nonperfusion region located in the far periphery was first delivered to the left eye over 2 sessions. Soon after treatment, the patient complained of acute photophobia and blurred vision in the treated eye. Ocular examination revealed left pupil dilation and poor light sensitivity, although the pupil was reactive to a close stimulus. The left pupil also displayed positive denervation sensitivity based on the dilute pilocarpine (0.125%) test. Adie's pupil was diagnosed based on these observations. Three months later, similar, albeit milder, findings were observed in her right eye after 360° peripheral laser photocoagulation that was more conservatively performed over 4 sessions. Four months after the first treatment, her subjective visual function had improved, and the pupil diameter had decreased to a normal size in both eyes without additional treatment. We encountered a patient whose severity of Adie's pupil was apparently reduced by more conservative laser photocoagulation of the ischemic peripheral retina.

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.

Automated segmentation of retinal nonperfusion area in fluorescein angiography in retinal vein occlusion using convolutional neural networks.

PURPOSE: Retinal vein occlusion (RVO) is the second most common cause of vision loss after diabetic retinopathy due to retinal vascular disease. Retinal nonperfusion (RNP), identified on fluorescein angiograms (FA) and appearing as hypofluorescence regions, is one of the most significant characteristics of RVO. Quantification of RNP is crucial for assessing the severity and progression of RVO. However, in current clinical practice, it is mostly conducted manually, which is time-consuming, subjective, and error-prone. The purpose of this study is to develop fully automated methods for segmentation of RNP using convolutional neural networks (CNNs). METHODS: FA images from 161 patients were analyzed, and RNP areas were annotated by three independent physicians. The optimal method to use multi-physicians' labeled data to train the CNNs was evaluated. An adaptive histogram-based data augmentation method was utilized to boost the CNN performance. CNN methods based on context encoder module were developed for automated segmentation of RNP and compared with existing state-of-the-art methods. RESULTS: The proposed methods achieved excellent agreements with physicians for segmentation of RNP in FA images. The CNN performance can be improved significantly by the proposed adaptive histogram-based data augmentation method. Using the averaged labels from physicians to train the CNNs achieved the best consensus with all physicians, with a mean accuracy of 0.883±0.166 with fivefold cross-validation. CONCLUSIONS: We reported CNN methods to segment RNP in RVO in FA images. Our work can help improve clinical workflow, and can be useful for further investigating the association between RNP and retinal disease progression, as well as for evaluating the optimal treatments for the management of RVO.

Retinal nonperfusion in optical coherence tomography angiography.

BACKGROUND: Retinal nonperfusion (NP) is a biomarker for assessment of the severity of diabetic retinopathy and retinal vein occlusion. However, various conditions mimic the retinal NP flow void signals that are observed in optical coherence tomography angiography (OCTA). METHODS: In this review, the possible mechanisms for these similar void flow signals in OCTA were summarized, and the discrepancies between the evaluations of retinal NP with fluorescein angiography and OCTA were also investigated and evaluated in terms of size and morphology. RESULTS AND CONCLUSION: Vascular occlusion, resulting in retinal ischemia, leads to a flow void signal, indicating retinal NP in OCTA images. In addition, displacement of retinal vessels secondary to cystoid macular edema presents a false NP signal and produces a flow void signal similar to that of retinal NP in OCTA. Finally, various pathological conditions can coexist in the same retinal disease, with one of these factors playing a major role. Understanding the various causes of retinal NP in OCTA will be beneficial in conducting appropriate pathological investigations and making appropriate treatment and management choices.

Effect of anti-VEGF treatment on nonperfusion areas in ischemic retinopathy.

In recent years, retinal ischemia such as that which occurs in diabetic retinopathy (DR) and retinal vein occlusion (RVO) has become a hotspot of ischemic retinopathy research. High levels of vascular endothelial growth factor (VEGF) are recognized as a major cause of macular edema (ME) in DR and RVO. High concentrations of VEGF in the vitreous can lead to serious retinal ischemia and hypoxia and form retinal nonperfusion areas (NPAs). Different levels of retinal ischemia can represent disease severity and progression. Anti-VEGF therapy as the first-line treatment for ME has been found to be effective in improving vision, but there are still disputes about whether anti-VEGF therapy could improve retinal ischemia and achieve reperfusion of previously developed retinal NPAs. Here, we review and summarize studies of the effects of anti-VEGF drugs on retinal ischemia, especially NPAs.

Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT.

BACKGROUND: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. OBJECTIVE: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. DESIGN: This was a three-arm, double-masked, randomised controlled non-inferiority trial. SETTING: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. PARTICIPANTS: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. INTERVENTIONS: The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). MAIN OUTCOME MEASURES: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of -5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. RESULTS: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows - ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval -2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference -1.73 letters, 95% confidence interval -6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was -3.96 letters, 95% confidence interval -8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means -1.8, 95% confidence interval -2.9 to -0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000-30,000 per quality-adjusted life-year. LIMITATIONS: The comparison of aflibercept and bevacizumab was a post hoc analysis. CONCLUSION: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. FUTURE WORK: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13623634. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

The eye functions like a camera. The retina, at the back of the eye, is the camera film, and the centre, the macula, allows us to see fine details. Approximately 6500 people each year in England and Wales are affected by fluid leaking out of congested tiny blood vessels, causing macular swelling or oedema. The cause is blockage of the main vein that normally drains blood from the retina. Three drugs, injected into the eye in tiny amounts every 4­8 weeks, have been shown to improve the vision of people with this condition. Two drugs, ranibizumab (0.5 mg/0.05 ml Lucentis^®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea^®; Bayer AG, Leverkusen, Germany), are licensed for UK use, but the third, bevacizumab (1.25 mg/0.05 ml Avastin^®; F. Hoffmann-La Roche AG, Basel, Switzerland), is not, even though it is much cheaper and used extensively worldwide. To our knowledge, no trials have compared the three drugs over the typical 2-year treatment period. This multicentre, Phase III, double-masked, randomised controlled non-inferiority trial comparing the clinical effectiveness and cost-effectiveness of intravitreal therapy with ranibizumab (Lucentis) versus aflibercept (Eylea) versus bevacizumab (Avastin) for macular oedema due to central retinal Vein Occlusion (LEAVO) was designed to compare ranibizumab, aflibercept and bevacizumab in this type of macular oedema. The trial showed that all three drugs improved vision a lot, but bevacizumab improved vision to a slightly lesser degree than the other two drugs. All patients should be aware of these findings before considering their treatment options. A comparison of the costs and benefits of ranibizumab, aflibercept and bevacizumab, using data from the trial and other sources, found that all three led to similar improvements in quality of life. Because aflibercept and ranibizumab are so much more expensive, they may be poor value for money. If patients, their representatives and funders all agree, it may be possible to treat this type of macular oedema with bevacizumab, which is cheaper, keeping the other agents available if needed.

Deep Learning-Based Segmentation and Quantification of Retinal Capillary Non-Perfusion on Ultra-Wide-Field Retinal Fluorescein Angiography.

Reliable outcome measures are required for clinical trials investigating novel agents for preventing progression of capillary non-perfusion (CNP) in retinal vascular diseases. Currently, accurate quantification of topographical distribution of CNP on ultrawide field fluorescein angiography (UWF-FA) by retinal experts is subjective and lack standardisation. A U-net style network was trained to extract a dense segmentation of CNP from a newly created dataset of 75 UWF-FA images. A subset of 20 images was also segmented by a second expert grader for inter-grader reliability evaluation. Further, a circular grid centred on the FAZ was used to provide standardised CNP distribution analysis. The model for dense segmentation was five-fold cross-validated achieving area under the receiving operating characteristic of 0.82 (0.03) and area under precision-recall curve 0.73 (0.05). Inter-grader assessment on the 20 image subset achieves: precision 59.34 (10.92), recall 76.99 (12.5), and dice similarity coefficient (DSC) 65.51 (4.91), and the centred operating point of the automated model reached: precision 64.41 (13.66), recall 70.02 (16.2), and DSC 66.09 (13.32). Agreement of CNP grid assessment reached: Kappa 0.55 (0.03), perfused intraclass correlation (ICC) 0.89 (0.77, 0.93), non-perfused ICC 0.86 (0.73, 0.92), inter-grader agreement of CNP grid assessment values are Kappa 0.43 (0.03), perfused ICC 0.70 (0.48, 0.83), non-perfused ICC 0.71 (0.48, 0.83). Automated dense segmentation of CNP in UWF-FA images achieves performance levels comparable to inter-grader agreement values. A grid placed on the deep learning-based automatic segmentation of CNP generates a reliable and quantifiable method of measurement of CNP, to overcome the subjectivity of human graders.

Nonperfused Peripheral Retinal Area in Eyes with Chronic Rhegmatogenous Retinal Detachment.

We report two cases of chronic rhegmatogenous retinal detachment with a nonperfused peripheral retinal area. Case 1 was an 84-year-old woman who presented with a bullous retinal detachment of the inferior retina and a best-corrected visual acuity of 20/500. A small horseshoe tear was detected in the peripheral superior retina. Fluorescein angiography showed a wide area of nonperfused retina in the inferior retina. The retina was successfully reattached by scleral buckling surgery. Case 2 was a 40-year-old woman who presented with a shallow retinal detachment involving the macula. There were multiple retinal breaks at the pars plana that were secondary to blunt trauma. Fluorescein angiography revealed a wide area of nonperfused retina in the inferior peripheral retina. She underwent scleral buckling surgery, and the retina was successfully reattached. Our findings indicate that clinicians should examine the peripheral retina carefully especially with fluorescein angiography to search for nonperfused areas in eyes with chronic rhegmatogenous retinal detachment.

A Custom-Made Semiautomatic Analysis of Retinal Nonperfusion Areas After Dexamethasone for Diabetic Macular Edema.

Purpose: To evaluate the changes of retinal capillary nonperfusion areas and retinal capillary vessel density of the superficial capillary plexus (SCP) and deep capillary plexus in patients with diabetes with diabetic macular edema treated with an intravitreal dexamethasone implant (IDI). Methods: We enrolled 28 patients with diabetic retinopathy and diabetic macular edema candidates to IDI. All patients underwent widefield optical coherence tomography angiography with PLEX Elite 9000 device with 15 × 9 mm scans centered on the foveal center at baseline, 1 month, 2 months, and 4 months after IDI. In all the patients, the variation of the retinal capillary nonperfusion areas and of the retinal vessel density of the SCP and deep capillary plexus were calculated using an automatic software written in Matlab (MathWorks, Natick, MA). Results: During follow-up, SCP showed a statistically significant reduction of ischemic areas at 1 month after IDI (P = 0.04) and slightly increased not significantly thereafter (P = 0.15). The percentage of nonperfusion areas changed from 11.4% at baseline, to 6.3% at 1 month, 8.1%, at 2 months, and 10.2% at 4 months. The whole vessel density of SCP slightly increased (not significantly) from 35.30% at baseline to 38.00% at 1 month, and then decreased to 37.85% at 2 months and 36.04% at 4 months (P = 0.29). Retinal capillary nonperfusion areas and retinal vessel density at the deep capillary plexus did not change significantly (P = 0.31 and P = 0.73, respectively). Conclusions: Widefield optical coherence tomography angiography showed a decrease in retinal capillary nonperfusion areas after dexamethasone implant suggesting a possible drug-related reperfusion of retinal capillaries particularly evident in the early period. Translational Relevance: A custom-made automatic analysis of retinal nonperfusion areas may allow a better and precise evaluation of ischemic changes after intravitreal therapy.