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Purpose: To longitudinally investigate the changes in intraretinal microvascular abnormalities (IRMAs) over time, employing swept-source optical coherence tomography angiography in eyes with diabetic retinopathy., Methods: In this retrospective, longitudinal study, we evaluated 12 × 12-mm swept-source optical coherence tomography angiography centered on the macula at baseline and last available follow-up visit for (1) IRMA changes during follow-up, defined as (a) stable, (b) regressed, (c) obliterated, and (d) progressed; and the (2) development of new neovascularization (NV) and their origins. Competing-risk survival analysis was used to assess the factors associated with these changes., Results: In total, 195 eyes from 131 participants with diabetic retinopathy were included. Stable, regressed, obliterated, and progressed IRMA were observed in 65.1%, 12.8%, 11.3%, and 19% of eyes with diabetic retinopathy, respectively. Anti-VEGF injections during the follow-up periods and a slower increase of foveal avascular zone were associated with IRMA regression (P < 0.001 and P = 0.039). Obliterated IRMA were correlated with previous panretinal photocoagulation (P < 0.001) and a lower deep capillary plexus vessel density at baseline (P = 0.007), as well as with follow-up anti-VEGF injections (P = 0.025). A higher baseline ischemia index (ISI) and panretinal photocoagulation during the follow-up periods were associated with IRMA progression (P = 0.049 and P < 0.001). A faster increase in ISI predicted the development of NV elsewhere (NVE) from veins (P < 0.001). No significant factors were found to be associated with NVE originating from IRMA., Conclusions: Changes in IRMA closely correlated with the severity of retinal ischemia and treatment. Notably, our study confirmed the potential, yet relatively rare, development of NVE from IRMA in a large cohort; however, the risk factors associated with this transformation require further exploration.

Extraretinal neovascularization is a hallmark of treatment-requiring retinopathy of prematurity (ROP). Optical coherence tomography angiography (OCTA) offers vascular flow and depth information not available from indirect ophthalmoscopy and structural OCT, but OCTA is only commercially available as a tabletop device. In this study, we used an investigational handheld OCTA device to study the vascular flow in and around retinal neovascularization in seven preterm infants with treatment-requiring ROP and contrasted them to images of vascular flow in six infants of similar age without neovascular ROP. We showed stages of retinal neovascularization visible in preterm infants from 32 to 47 weeks postmenstrual age: Intraretinal neovascularization did not break through the internal limiting membrane; Subclinical neovascular buds arose from retinal vasculature with active flow through the internal limiting membrane; Flat neovascularization in aggressive ROP assumed a low-lying configuration compared to elevated extraretinal neovascular plaques; Regressed neovascularization following treatment exhibited decreased vascular flow within the preretinal tissue, but flow persisted in segments of retinal vessels elevated from their original intraretinal location. These findings enable a pilot classification of retinal neovascularization in eyes with ROP using OCTA, and may be helpful in detailed monitoring of disease progression, treatment response and predicting reactivation., (© 2024. The Author(s).)

To investigate the fluorescein angiography (FA) findings and compare the extent of retinal vascularization in retinopathy of prematurity (ROP), recovered after intravitreal ranibizumab (IVR) monotherapy and those regressed spontaneously. Infants with a history of ROP who underwent FA between April 2018 and November 2021 were retrospectively included. The patients were divided into two groups based on whether they had received IVR (IVR group) or had ROP that regressed spontaneously without treatment (untreated group). The differences between the two groups in zone II ROP were also compared, to equalize the subgroups as much as possible in terms of disease severity. FA findings were recorded. The extent of vascularization was measured by the ratio of the distance from the center of the disk to the border of the vascularized zone (DB) and the distance from the center of the disk to the center of the fovea (DF). The width of the persistent avascular retina (PAR) was counted by disc diameters (DD). One hundred and ten eyes of 55 infants were included in the IVR group and 76 eyes of 38 babies in the untreated group. The ratio of abnormal shape of vessels was significantly higher in the IVR group than in the untreated group (50.9% vs. 35.5%; P = 0.038), while the linear choroidal filling pattern, tortuosity of vessels over the posterior pole, dye leakage, anomalous branching of vessels, circumferential vessels, arteriovenous shunt, abnormal capillary bed, and macular abnormalities were similarly. There was a smaller temporal DB/DF ratio (4.48 vs. 4.63; P = 0.003) and greater PAR (2.63 vs. 1.76; P < 0.001) in the IVR group compared to the untreated group. In zone II ROP, the progression of retinal vascularization was significantly larger in the IVR group than that in the untreated group (P = 0.003), while no statistical differences were observed in FA features, the DB/DF ratio, and PAR between the two subgroups. The residual vascular abnormalities and PAR may be common results of ROP regression. The DB/DF ratio of 4.0 temporally and 3.3 nasally could be used as the preliminary indicators for safe retinal vascularization in the completion of ROP regression., (© 2023. The Author(s).)

Purpose: To explore the condition of fellow eyes of patients with macular neovascularization Type 3 (MNV3) and to verify whether the retinal-choroidal anastomosis (RCA) develops equally in all MNV types., Methods: The contralateral eyes of 94 patients with MNV3, 96 patients with MNV1, and 96 patients with MNV2 were included. Multimodal imaging was performed. The MNV3 stage including the development of fibrosis and RCA over 24 months was determined., Results: In the contralateral eyes of patients of the solitary (one lesion) MNV3 group, 32 eyes (42.1%) showed early/intermediate age-related macular degeneration, 25 eyes (33%) showed MNV3, and 11 eyes (14.5%) experienced fibrosis, of which 4 eyes (5.2%) had a RCA, 7 eyes (9.2%) had atrophy after resolved MNV3, and 1 eye (1.3%) developed MNV1. In the multifocal (more than one lesion) MNV3 group, 2 eyes (11.1%) showed early/intermediate age-related macular degeneration, 9 eyes (50%) showed 15 MNV3 lesions, and 4 eyes (22.2%) showed fibrosis, of which 2 eyes (11.1%) manifested with a RCA and 3 eyes (16.7%) showed atrophy after resolved MNV3. The number of eyes with a RCA accounted for 40% of all eyes with fibrosis. The count of simultaneous bilateral multifocal MNV3 was 5 (55.6%). In the MNV1 and MNV2 groups, no eye developed a RCA. The incidence of RCAs in the scarred eyes in MNV3 was significantly higher (P < 0.0001)., Conclusion: Retinal-choroidal anastomosis is an exclusive clinical feature of MNV3. The development of the multifocal MNV3 is usually bilateral and simultaneous. The occurrence of fibrosis in MNV3 has decreased dramatically after the introduction of the antiangiogenic therapy., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

BACKGROUND The aim of this study was to assess use of lncRNAs as biomarkers in serum and aqueous humor of patients with diabetic macular edema (DME). MATERIAL AND METHODS Optical coherence tomography and fundus photography were used to analyze the retinal features of the patients. RT-qPCR was used to analyze the differential expression of lncRNA snhg5 in patients who have idiopathic macular hole (MH), DME, or refractory DME. The relationship between SNHG5 and the clinical characteristics of the patients was analyzed. The effect of SNHG5 on the hyperplasia and apoptosis of human retino-microvascular endothelial cells (HRMECs) and its mechanism were analyzed in vitro. RESULTS Patients with idiopathic MH developed retinal nerve epithelium rupture and retinal fundus thickening, and patients with DME or refractory DME showed significant macular edema with hemorrhaging. The refractory DME patients improved after treatment but still showed significant macular edema and multiple laser scarring. SNHG5 expression was not only low in the atrial fluid and plasma in DME patients, but also lower in the refractory DME group compared to the idiopathic MH patients. SNHG5 expression in the aqueous humor and plasma was negatively correlated with disease duration, body mass index, and levels of fasting blood glucose, glycated hemoglobin, proteinuria, and glycosuria. In the in vitro experiments, SNHG5 expression was significantly downregulated in high glucose-induced HMECs. After SNHG5 overexpression, cell proliferation, angiogenesis, and VEGF-A protein levels were distinctly downregulated. CONCLUSIONS SNHG5 correlates with the development of DME and is a potential target for therapy.

To find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk., (© 2022. The Author(s).)

Objective: Vascular endothelial growth factor (VEGF) antagonists have been used for treating metastatic neoplasms. It has also been known that one of its side effects is to cause proteinuria and renal failure in the setting of thrombotic microangiopathy (TMA). The underlying mechanism is likely due to the inhibition of VEGF production in podocytes, resulting in diffuse fusion of foot processes and impaired glomerular endothelial fenestrations, and leading to massive proteinuria and subsequent glomerular endothelium injury. Intravitreal injection of VEGF antagonists (IIVA) has been also used to treat macular degeneration and diabetic retinal neo-vascular proliferation. The majority of patients tolerate the treatment well. However, IIVA can lead to renal dysfunction including proteinuria and gradual renal failure as a rare side effect. The goal of this study was to report two cases related to the nephrotoxicity of IIVA and review the literature associated with this topic., Case Report: The first diabetic patient had elevated serum creatinine at 3.25 mg/dl and proteinuria/creatinine ratio at 6.1 after 48-month treatment of IIVA. The first renal biopsy revealed thrombotic microangiopathy that was correlated with his increased serum creatinine and nephrotic range of proteinuria. The second diabetic patient had increased serum creatinine up to 1.89 mg/dl but low proteinuria. The second biopsy showed acute tubular necrosis that was correlated with his elevated serum creatinine., Conclusion: Intravitreal injection of VEGF antagonist can be associated with thrombotic microangiopathy and acute tubular necrosis, leading to renal dysfunction., (© 2021 by the Association of Clinical Scientists, Inc.)

Blood leakage from the vessels in the eye is the hallmark of many vascular eye diseases. One of the preclinical mouse models of retinal blood leakage, the very-low-density-lipoprotein receptor deficient mouse (Vldlr -/- ), is used for drug screening and mechanistic studies. Vessel leakage is usually examined using Fundus fluorescein angiography (FFA). However, interpreting FFA images of the Vldlr -/- model is challenging as no automated and objective techniques exist for this model. A pipeline has been developed for quantifying leakage intensity and area including three tasks: (i) blood leakage identification, (ii) blood vessel segmentation, and (iii) image registration. Morphological operations followed by log-Gabor quadrature filters were used to identify leakage regions. In addition, a novel optic disk detection algorithm based on graph analysis was developed for registering the images at different timepoints. Blood leakage intensity and area measured by the methodology were compared to ground truth quantifications produced by two annotators. The relative difference between the quantifications from the method and those obtained from ground truth images was around 10% ± 6% for leakage intensity and 17% ± 8% for leakage region. The Pearson correlation coefficient between the method results and the ground truth was around 0.98 for leakage intensity and 0.94 for leakage region. Therefore, we presented a computational method for quantifying retinal vascular leakage and vessels using FFA in a preclinical angiogenesis model, the Vldlr -/- model., (© 2021. The Author(s).)

Purpose: To describe the clinical and multimodal imaging features of bacillary layer detachment (BD), and its response to intravitreal anti-vascular endothelial growth factor therapy, in eyes with macular neovascularization., Methods: Retrospective, observational case series of 14 eyes (14 patients, 7 men) imaged with eyes (14 patients, 7 men) were imaged with spectral-domain optical coherence tomography, and either fluorescein angiography or optical coherence tomography angiography. Therapeutic response was monitored with serial imaging and best-corrected visual acuity assessments., Results: The mean age was 75 ± 13 (range: 45-96) years, with mean follow-up duration of 27 ± 21 (range: 1-56) months. Neovascular age-related macular degeneration was found in 71% (10/14) eyes. Type 2 macular neovascularization lesions were associated with BD in all 14 eyes. Subretinal hemorrhage was noted in 79% (11/14) eyes. BD promptly resolved after intravitreal antivascular endothelial growth factor therapy in all eyes. The baseline best-corrected visual acuity improved from logarithm of the minimum angle of resolution 0.84 ± 0.32 (Snellen equivalent 20/138) to logarithm of the minimum angle of resolution 0.48 ± 0.31 (Snellen equivalent 20/60) at the last follow-up, with treatment of the macular neovascularization., Conclusion: Type 2 macular neovascularization and subretinal hemorrhage are associated with BDs, which may be due to a rapid influx of exudative fluid into the potential space between the external limiting membrane and ellipsoid zone. Intravitreal antivascular endothelial growth factor therapy results in rapid resolution of BDs and visual improvement in most eyes.

Background/objectives: Abnormal retinal neovascularization caused by ischemic retinal vein occlusion (RVO) is a frequent cause of visually significant vitreous hemorrhage. The early detection of new vessels may be challenging and often requires the use of invasive tests such as fundus fluorescein angiography (FA). We demonstrate the use of wide-field optical coherence tomography angiography (WF-OCTA) in the detection and characterization of neovascularization secondary to ischemic RVO., Subjects/methods: We conducted a retrospective observational case series of patients diagnosed with ischemic RVO between August 2018 and March 2019, who underwent WF-SS-OCTA imaging (PLEX Elite 9000, Carl Zeiss Meditec). We performed real-life montage imaging, covering the involved area and compared the findings of WF-SS-OCTA to standard clinical examination and when available, ultrawide-field fluorescein angiography (UWF-FA, Optos 200TX)., Results: In the included 39 eyes with ischemic RVO, neovascularization elsewhere (NVE) was encountered in 16 of 39 eyes (41%) on WF-OCTA and were characterized as sea-fan type vessels and nodular type vessels, based on their appearance and localization. NVE was identified in 4/39 eyes on standard clinical examination, equating to a detection rate of 10.3%. All were of a sea-fan morphology. In one case, NVE found on WF-OCTA was not observed on UWF-FA, which was a nodular type. Neovascularization of the disc (NVD) was detected in one eye., Conclusions: WF-OCTA may become a useful noninvasive tool in the detection of neovascularization in patients with ischemic RVO. Furthermore, the characterization of different morphologies of neovascularization detected by WF-OCTA could be of clinical relevance., (© 2020. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Diabetic macular edema (DME) is a major cause of vision loss in diabetics that is currently mainly treated by antivascular endothelial growth factor (VEGF) agents. The effect of these agents on macular perfusion (MP) is a current concern. Optical coherence tomography angiography (OCTA) is an imaging modality that allows noninvasive high-resolution retinal microvasculature imaging. Several recent studies evaluated the effect of anti-VEGF agents on the MP of DME patients using OCTA. Our aim is to provide a systematic review of these studies., Methods: Multiple databases were searched including PubMed, Ovid Medline, EMBASE, and Google Scholar for relevant studies published between January 2016 and November 2020 which were included in this review. Studies were compared regarding their design, the number of included patients, the machine and scanning protocol used, the inclusion and exclusion criteria, the number of injections given, the type of anti-VEGF agent used, the outcome measures assessed, and the effect of injections on different MP parameters., Results: A total of 16 studies were included. The studies assessed various OCTA parameters that define MP including the foveal avascular zone area and superficial and deep vascular density and yielded conflicting results. Seven studies showed stable or improved MP following treatment, while 7 studies showed worsening MP following treatment, and 2 studies showed inconclusive results. This could have been due to differences in study design, inclusion criteria, type of anti-VEGF agents used, treatment duration, and methods of image analysis and vascular density quantification. All identified studies were noncomparative case series, and 14 of them (87.5%) used the RTVue XR Avanti OCTA machine. Only one study compared OCTA to fluorescein angiography findings., Conclusion: Analysis of MP changes following VEGF inhibition for DME could benefit from a unified scanning protocol and analysis approach that uses similar study designs to eliminate potential sources of bias. This may provide more definitive conclusions regarding the effect of treatment on MP., Competing Interests: Ayman G. Elnahry declares that he has no conflict of interest. Gehad A. Elnahry declares that he has no conflict of interest., (Copyright © 2021 Ayman G. Elnahry and Gehad A. Elnahry.)

Importance: Adherence to screening for vision-threatening proliferative sickle cell retinopathy is limited among patients with sickle cell hemoglobinopathy despite guidelines recommending dilated fundus examinations beginning in childhood. An automated algorithm for detecting sea fan neovascularization from ultra-widefield color fundus photographs could expand access to rapid retinal evaluations to identify patients at risk of vision loss from proliferative sickle cell retinopathy., Objective: To develop a deep learning system for detecting sea fan neovascularization from ultra-widefield color fundus photographs from patients with sickle cell hemoglobinopathy., Design, Setting, and Participants: In a cross-sectional study conducted at a single-institution, tertiary academic referral center, deidentified, retrospectively collected, ultra-widefield color fundus photographs from 190 adults with sickle cell hemoglobinopathy were independently graded by 2 masked retinal specialists for presence or absence of sea fan neovascularization. A third masked retinal specialist regraded images with discordant or indeterminate grades. Consensus retinal specialist reference standard grades were used to train a convolutional neural network to classify images for presence or absence of sea fan neovascularization. Participants included nondiabetic adults with sickle cell hemoglobinopathy receiving care from a Wilmer Eye Institute retinal specialist; the patients had received no previous laser or surgical treatment for sickle cell retinopathy and underwent imaging with ultra-widefield color fundus photographs between January 1, 2012, and January 30, 2019., Interventions: Deidentified ultra-widefield color fundus photographs were retrospectively collected., Main Outcomes and Measures: Sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network for sea fan detection., Results: A total of 1182 images from 190 patients were included. Of the 190 patients, 101 were women (53.2%), and the mean (SD) age at baseline was 36.2 (12.3) years; 119 patients (62.6%) had hemoglobin SS disease and 46 (24.2%) had hemoglobin SC disease. One hundred seventy-nine patients (94.2%) were of Black or African descent. Images with sea fan neovascularization were obtained in 57 patients (30.0%). The convolutional neural network had an area under the curve of 0.988 (95% CI, 0.969-0.999), with sensitivity of 97.4% (95% CI, 86.5%-99.9%) and specificity of 97.0% (95% CI, 93.5%-98.9%) for detecting sea fan neovascularization from ultra-widefield color fundus photographs., Conclusions and Relevance: This study reports an automated system with high sensitivity and specificity for detecting sea fan neovascularization from ultra-widefield color fundus photographs from patients with sickle cell hemoglobinopathy, with potential applications for improving screening for vision-threatening proliferative sickle cell retinopathy.

Purpose: To investigate optical coherence tomography angiography (OCT-A) findings in recurrent type 3 macular neovascularisation (MNV)., Methods: In this retrospective cohort study, consecutive patients with type 3 MNV secondary to age-related macular degeneration underwent OCT-A at three different time points: baseline, after anti-vascular endothelial growth factor treatment with complete resolution of the exudative signs (ie, non-exudative stage) and at the recurrence of exudation (ie, recurrence stage). Demographics and clinical findings were analysed, including OCT-A features of type 3 MNV recurrence., Results: Twelve eyes (12 patients, mean age 78±7 years) were included. Using OCT-A, at baseline all type 3 MNVs showed the presence of detectable flow downgrowing from the deep vascular complex (DVC) to the retinal pigment epithelium (RPE)/sub-RPE space. 6/12 eyes (50%) showed anomalous flow under the RPE, while the other 6 eyes showed flow reaching the RPE without anomalous flow in the sub-RPE space. At the non-exudative stage (after treatment), BCVA and CMT significantly improved (p=0.004 and p=0.036), and flow inside the retinal lesions reduced; interestingly the connection to the RPE/sub-RPE space regressed. At the time of recurrence, all type 3 MNVs showed the presence of intra/sub-retinal exudation with restoration of the flow deepening from the DVC to the RPE/sub-RPE space., Conclusions: Detectable flow deepening from the DVC to the RPE/sub-RPE space using OCT-A is mandatory to have a new exudation secondary to recurrent type 3 MNV. Early detection of type 3 MNV recurrence by OCT-A characterisation may prompt retreatment and potentially prevent progression to late stages of the disease., Competing Interests: Competing interests: RS, EB and VC are consultants for ZEISS (Dublin, USA). FB is a consultant for: Alcon (Fort Worth,Texas,USA), Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc (Irvine, California, USA), Farmila-Thea (Clermont-Ferrand, France), Bayer Shering-Pharma (Berlin, Germany), Bausch + Lomb (Rochester, New York, USA), Genentech (San Francisco, California, USA), Hoffmann-La-Roche (Basel, Switzerland), Novagali Pharma (Évry, France), Novartis (Basel, Switzerland), Sanofi-Aventis (Paris, France), Thrombogenics (Heverlee,Belgium), Zeiss (Dublin, USA). EHS is a consultant for: Allergan Inc (Irvine, California, USA), Bausch + Lomb (Rochester, New York, USA), Bayer Shering-Pharma (Berlin, Germany), Novartis (Basel, Switzerland). GQ is a consultant for: Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc (Irvine, California, USA), Amgen (Thousand Oaks, USA), Bayer Shering-Pharma (Berlin, Germany), Heidelberg (Germany), KBH (Chengdu; China), LEH Pharma (London, UK), Lumithera (Poulsbo, USA), Novartis (Basel, Switzerland), Sandoz (Berlin, Germany), Sifi (Catania, Italy), Sooft-Fidea (Abano, Italy), ZEISS (Dublin, USA)., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Quantification of neovascularization changes in terms of neovascular complex (NVC) acquired from the optical coherence tomography angiography (OCTA) imaging is extremely important for diagnosis and treatment monitoring of proliferative diabetic retinopathy (PDR). However, only few vessel extraction methods have so far been reported to quantify neovascular changes in NVC with proliferative diabetic retinopathy PDR based on OCTA images., Methods: Here we propose an optimized approach to segment blood vessels, which is based on an improved vascular connectivity analysis (VCA) algorithm and combined with morphological characterization and elimination of noise and artifacts. The length and width of vessels are obtained in the quantitative assessment of microvascular network. The feasibility of the proposed method is further studied by a treatment monitoring and statistical analysis process, as we have monitored and statistically analyzed the changes of NVC based on sampled OCTA images of PDR patients (N = 14) after treatment by intravitreal injection of conbercept., Results: The proposed method has demonstrated better performance in accuracy compared with existing algorithms and can thus be used for PRD treatment monitoring. Following the PDR treatment monitoring study, our data has shown that from the 1st day to 7th day of treatment, the averaged (arithmetic mean) length of NVC has been substantially shortened by 36.8% (P < 0.01), indicating significant effects of treatment. Meanwhile, the averaged (arithmetic mean) width of NVC from the 1st day to 7th day of treatment has been increased by 10.2% (P < 0.05), indicating that most of the narrow neovascularization has been reduced., Conclusion: The results and analysis have confirmed that the proposed optimization process by the improved VCA method is both effective and feasible to segment and quantify the NVC with lower noise and fewer artifacts. Thus, it can be potentially applied to monitor the fibrovascular regression during the treatment period. Clinical Trial Registration This trial is registered with the Chinese Clinical Trial Registry (Registered 27 December 2017, http://www.chictr.org.cn , registration number ChiCTR-IPR-17014160).

Purpose: To estimate the impact of delayed care during the coronavirus disease 2019 (COVID-19) pandemic on the outcomes of patients with neovascular age-related macular degeneration (AMD)., Methods: Consecutive patients with diagnosis of neovascular AMD were consecutively enrolled between March 9, 2020, and June 12, 2020, (during and immediately after the Italian COVID-19 quarantine). During the inclusion (or pandemic) visit (V 0 ), patients received a complete ophthalmologic evaluation, including optical coherence tomography (OCT). Best-corrected visual acuity (BCVA) and OCT findings from the two preceding visits (V -1 and V -2 ) were compared with data at V 0 ., Results: One-hundred patients (112 eyes) were enrolled in this study. The time interval between following visits was 110.7 ± 37.5 days within V 0 and V -1 and 80.8 ± 39.7 days within V -1 and V -2 , respectively (P < 0.0001). BCVA was statistically worse at the V 0 visit as compared with the immediately preceding (V -1 ) visit (0.50 ± 0.43 LogMAR and 0.45 ± 0.38 LogMAR at the V 0 and V -1 visits, respectively; P = 0.046). On structural OCT, 91 out of 112 (81.2%) neovascular AMD eyes displayed the evidence of exudative disease activity at the V 0 visit, while 77 (68.7%) eyes exhibited signs of exudation at the V -1 visit (P = 0.022). No differences in terms of BCVA and OCT findings were detected between the V -1 and V -2 visits. In multiple regression analysis, the difference in BCVA between V 0 and V -1 visits was significantly associated with the interval time within these two visits (P = 0.026)., Conclusion: The COVID-19 pandemic-related postponement in patient care proved to be significantly associated with worse short-term outcomes in these patients.

Competing Interests: Competing interests: None declared.

Purpose: With the increasing prevalence of diabetes, fast, noninvasive identification of proliferative diabetic retinopathy (PDR) becomes essential. This study evaluated the utility of optical coherence tomography angiography (OCTA) to characterize intraretinal microvascular abnormalities (IRMA) and retinal neovascularization (NV)., Methods: Patients with severe non-PDR or PDR were imaged with fluorescein angiography and widefield swept-source OCTA (Zeiss Plex Elite 9000; Carl Zeiss Meditec, Dublin, CA). Regions suspicious for IRMA or retinal NV were identified and the OCTA, including flow overlay on the co-registered structural optical coherence tomography, and fluorescein angiography images were graded by two masked readers., Results: Ninety-six foci of irregular vasculature were analyzed, comprised of 70 IRMA and 26 retinal NV lesions from 14 eyes. Compared with fluorescein angiography, OCTA with flow overlay demonstrated specificity of 99% and sensitivity of 92% in identifying IRMA and NV. Neovascularization differed from IRMA on OCTA by demonstrating supraretinal flow breaching the internal limiting membrane and posterior hyaloid (P < 0.001). Intraretinal microvascular abnormalities were distinguished from NV by outpouching of the internal limiting membrane (P = 0.035). Vascular flow was reduced in the presence of fibrosis., Conclusion: Optical coherence tomography angiography, through flow overlay, has utility to image and differentiate IRMA and NV, which are key features distinguishing severe non-PDR and PDR, respectively. Noninvasive widefield OCTA may be a useful tool to diagnose high-risk diabetic retinopathy eyes.

Purpose: To further define the structural OCT features described as the "double-layer sign" suggestive of subclinical, nonexudative macular neovascularization (NE-MNV) in asymptomatic eyes with age-related macular degeneration (AMD)., Design: Cross-sectional observational study., Participants: Participants with large drusen (>125 μm) secondary to AMD in at least 1 eye., Methods: Participants in a "discovery" cohort, with known NE-MNV identified on swept-source (SS) OCT angiography (OCTA) and the "double-layer sign" on structural spectral-domain OCT (SD-OCT) imaging, were used to identify characteristic features of this sign. These features were then assessed by masked grading in an "evaluation" cohort of AMD eyes with large drusen to determine the predictive values for NE-MNV., Main Outcome Measures: Description of OCT features associated with an increased risk of NE-MNV and their diagnostic and predictive performance., Results: The discovery cohort of 4 eyes revealed that in retinal pigment epithelium (RPE) elevations with a greatest transverse linear dimension of 1000 μm or more, an irregular RPE layer with a height of predominantly less than 100 μm, and a nonhomogenous internal reflectivity as characteristic features of the double-layer sign when NE-MNV was present. We term these collective features as a shallow, irregular RPE elevation (SIRE). Features on OCT images from 233 eyes in the evaluation cohort that were associated significantly with NE-MNV when the RPE elevation was more than 1000 μm in length were: height of the RPE elevation, overall flat or variable morphologic features, RPE layer irregularity, and nonhomogeneous reflectivity (all P ≥ 0.032). Twenty-four eyes (10.3%) were identified with a SIRE. On SS-OCTA imaging, 6 of the 233 eyes were found to have definite NE-MNV, and all 6 graded positively for SIRE (sensitivity, 100%). The absence of SIRE was identified in 209 of 227 eyes without NE-MNV (specificity, 92.1%). The positive predictive value for SIRE was 25% and the negative predictive value was 100%., Conclusions: Eyes whose OCT images display a SIRE sign are at higher risk of having subclinical NE-MNV. SIRE can be used as a screening tool on routine structural OCT imaging. More frequent follow-up and diligent home monitoring is recommended for those with SIRE., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the characteristics of intraretinal microvascular abnormalities (IRMAs) before and after panretinal photocoagulation (PRP) for diabetic retinopathy (DR) by using optical coherence tomography angiography (OCTA)., Methods: Forty-six eyes of 29 patients with DR were included (26 eyes with severe nonproliferative diabetic retinopathy [SNPDR] and 20 eyes with proliferative diabetic retinopathy [PDR]). En face OCTA images of IRMAs in a 6 × 6-mm area were acquired by using Cirrus 5000 with AngioPlex. The morphological changes in IRMAs were evaluated before and after PRP. The changes in the IRMAs were divided into five subtypes: unchanged; tuft regression; reperfusion; mixed (combined tuft regression/reperfusion); and worsening (new appearance of tuft)., Results: Unchanged IRMAs were identified in 15 SNPDR eyes and 2 PDR eyes; all neovascularization (NV) had regressed after PRP. Tufts were more frequently observed in the PDR eyes (15/20, 75%) than in the SNPDR eyes (8/26, 31%) (P = 0.003), and two tufts tended to exceed the inner limiting membrane, which showed progression to NV before PRP. The reperfusion phenomenon was observed in 7/26 SNPDR eyes and 4/20 PDR eyes, including the mixed type, and showed two vascular patterns: abnormal (dilated, tortuous, and twisted) and normal vessels. The worsening type was observed in 1/26 SNPDR eye and 2/20 PDR eyes., Conclusions: OCTA enabled classification of IRMA into more detailed types. The unchanged and reperfusion types suggested that IRMAs had aspects of remodeling. However, IRMAs with tufts were observed in 75% of the PDR eyes, and the tufts had aspects of NV.

This study explored whether rotational three-dimensional (3D) visualization of optical coherence tomography angiography (OCTA) volume data may yield valuable information regarding type 3 macular neovascularization (MNV). In this retrospective, cross-sectional study, we collected data from 15 eyes (13 patients) with treatment-naïve type 3 MNV in their post-nascent stage and age-related macular degeneration (AMD). Subjects were imaged with the SS-OCT system (PLEX Elite 9000, Carl Zeiss Meditec Inc., Dublin, CA, USA). The OCTA volume data were processed with a prototype volume projection removal algorithm and then analyzed using volumetric visualization techniques in order to obtain a 3D visualization of the region occupied by type 3 MNV. The two-dimensional and three-dimensional OCTA images were investigated. Mean ± SD age was 75.1 ± 7.4 years. BCVA was 0.42 ± 0.21 LogMAR in the study eyes. Considering the cohort of analyzed eyes, on rotational 3D OCTA images, a total of 35 neovascular lesions (vs 22 lesions detected on 2D OCTA images) rising from the deep vascular complex and variably spanning the outer retinal layers and eventually reaching the RPE/sub-RPE space were detected. Nine of 35 lesions had a saccular shape, while the remaining cases had a filiform shape. On rotational 3D OCTA images, these lesions were inclined on the three planes, instead of perpendicular to the RPE/Bruch's membrane. In conclusion, this study used an algorithm to obtain rotational three-dimensional visualization of type 3 MNV. This approach seems to increase the detection rate for these lesions and to be useful to offer new insight into type 3 MNV.

Objective: Comparison of retinal neovascularizations of the disc (NVD) and elsewhere (NVE) in optical coherence tomography angiography (OCTA) and fluorescein angiography (FA) in patients with proliferative diabetic retinopathy., Materials and Methods: 15 consecutive patients were included in this study. All patients received an OCTA with a 3 × 3 mm scan of the region of interest with the ZEISS OCT Cirrus 5000 with the AngioPlex module. The size of the neovascularization (NV) was determined manually in OCTA and FA and compared between the two methods., Results: 20 eyes of 15 patients with proliferative diabetic retinopathy with an average age of 57 years were included. The mean size of NVDs was 3.44 mm 2 in OCTA and 3.75 mm 2 in FA, the mean size of NVDs was 1.06 mm 2 in OCTA and 1.54 mm 2 in FA. Taking into account a generally larger area measured in the FA, the two methods showed good overall agreement., Conclusion: There was a good agreement for the size of the NVs in both methods. OCTA can be used as a simple and non-invasive method to visualize retinal neovascularizations., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To assess the ability of optical coherence tomography (OCT) alone and in combination with OCT angiography (OCTA) to differentiate polypoidal choroidal vasculopathy (PCV) from neovascular age-related macular degeneration, as compared to fluorescein angiography and indocyanine green angiography., Methods: This is a cross-sectional study. All participants had a standardized history, clinical examination including measurement of best-corrected visual acuity, slit-lamp biomicroscopy, and indirect fundus examination, and underwent standardized imaging (color photography, fluorescein and indocyanine green angiography, OCT, and OCTA) after predefined protocols. We used a 2-step approach (Step 1: spectral domain OCT; Step 2: addition of OCTA) combining structural OCT and OCTA to differentiate 50 treatment-naive eyes with PCV, choroidal neovascularization, and retinal angiomatous proliferation and compared with the diagnosis based on fluorescein angiography and indocyanine green angiography. Spectral domain OCT signs used to diagnose PCV included presence of two out of three of any retinal pigment epithelium detachment (pigment epithelial detachment/double-layer sign), notched or narrow-peaked pigment epithelial detachment, or round subretinal pigment epithelium structure. Optical coherence tomography angiography signs used to diagnose PCV included presence of a localized subretinal pigment epithelium hyperflow signal in the cross-sectional OCTA and/or presence of a focal hyperflow sign in en face OCTA based on outer retina slab., Results: Based on fluorescein angiography and indocyanine green angiography, the diagnosis was choroidal neovascularization in 24 eyes, PCV in 23 eyes, and retinal angiomatous proliferation in 3 eyes. Based on spectral domain OCT signs, PCV was diagnosed in 19/23 (82.6%) eyes; however, specificity of OCT was only 51.9%. Cross-sectional OCTA showed a diffuse hyperflow signal in all 24 (100.0%) eyes with choroidal neovascularization, whereas a localized subretinal pigment epithelium hyperflow signal was detected in 19/23 (82.6%) eyes with PCV. En face OCTA only detected a nodular hyperflow signal in 10/23 eyes (43.5%) with PCV. Combination of OCT and OCTA achieved 82.6% sensitivity and 100.0% specificity for differentiating PCV from choroidal neovascularization/retinal angiomatous proliferation., Conclusion: Cross-sectional OCTA is more sensitive than en face OCTA in detecting flow signal in polyps. Combination of structural OCT and OCTA can be used to screen for PCV with a high level of sensitivity and specificity.

Purpose: To investigate the imaging characteristics of early Type 3 neovascularization and propose a new pathophysiologic sequence for early disease., Methods: Patients were evaluated with a comprehensive ophthalmologic examination to include fundus photography, optical coherence tomography, optical coherence tomography angiography, fluorescein angiography, and volume-rendered optical coherence tomography angiography. Relevant literature was also reviewed., Results: There were 10 eyes of 9 patients who had a mean age of 87 (range 79-93) years and 7 were women. The patients were seen to have distributed areas of cystoid macular edema, not necessarily contiguous with areas of fluorescein or optical coherence tomography angiographic evidence of neovascularization, which colocalized with each other. Areas of hemorrhage were not necessarily contiguous with observed neovascularization. In some patients, massive amounts of edema were imaged, although the associated neovascular invasion was small and did not reach deeper portions of the retina. These findings were readily responsive to intravitreal injections of anti-vascular endothelial growth factor (VEGF) medication. Review of published literature showed conflicting pathophysiologic proposals, which did not abide with contemporaneous imaging findings., Conclusion: Type 3 neovascularization likely grows in response to increased cytokine levels, particularly VEGF, in a permissive environment. Elevated levels of VEGF have been shown to cause hemorrhage, edema, and telangiectasis in the macula, suggesting some of the manifestations of Type 3 neovascularization are related to increased tissue VEGF levels and not necessarily to the neovascularization alone. A proposal based on imaging and histopathologic findings and known physiologic effects of VEGF is presented.

Joint high-resolution multimodal photoacoustic microscopy (PAM) and optical coherence tomography (OCT) was developed to improve the efficiency for visualizing newly developed retinal neovascularization (RNV) and to monitor the dynamic changes of retinal vein occlusion (RVO) in living rabbits. The RNV and RVO models were created in New Zealand rabbits by Rose Bengal laser-induced RVO. Dual modalities imaging equipment, including color fundus photography, fluorescein angiography (FA), OCT, and PAM, was used to image and assess the changes of retinal vasculature. In vivo experimental results exhibited that not only the treatment boundaries and the position of the occluded vasculature but also the structure of individual RNV were markedly observed using PAM platform with great resolution and high image contrast. The laser light energy of 80 nJ was used to induce photoacoustic signal, which is approximately half the energy of the American National Standards Institute safety limit. A cross-sectional structure of RNV was identified with the OCT modality. Furthermore, vibrant transformations in the RNV and the retinal morphology were examined at different times after laser occlusion: days 4, 28, 35, 49, and 90. PAM revealed high contrast and high resolution vascular imaging of the retina and choroid with amplified penetration depth. Through the present custom-built imaging system, both RNV and RVO can be reconstructed and observed in two and three dimensions. A unique dual modality A unique dual modality PAM and OCT can help precisely visualize and distinguish individual microvessels, microvessel depth, and the surrounding anatomy. Thus, the proposed multimodal ocular imaging platform may offer a potential equipment to enhance classification of microvasculature in a reliable and proficient manner in larger rabbit eyes.

Background: The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization., Methods: Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and, using enhanced ray casting, were converted to 3D volumes to which color filter was applied., Results: Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks, and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stages 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF., Conclusions: The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.

Purpose: To report the case 70-year-old patient presenting with preretinal, abnormal vascularization accompanying an idiopathic epiretinal membrane (ERM), identified by optical coherence tomography angiography., Methods: Observational case report of one patient., Results: The authors describe the case of a patient presenting with an ERM on the right eye since March 2011, diagnosed by fundus biomicroscopy and spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany). At the last follow-up visit, the patient had a Snellen best-corrected visual acuity of 20/32 in her right eye and 20/20 in her left eye. Although on spectral domain optical coherence tomography the aspect on the right eye was unchanged since prior examination, optical coherence tomography angiography (Angiovue; Optovue, Fremont, CA) was able to reveal a high-flow, abnormal vascular network in the preretinal manual segmentation corresponding to the ERM., Conclusion: Spectral domain optical coherence tomography, routinely performed in these patients, may underestimate the presence of abnormal vascularization, as both preretinal neovascular complexes and thick ERMs appear as hyperreflective structures. Optical coherence tomography angiography allows a fast and depth-resolved visualization of these abnormal vascular complexes inside idiopathic ERMs. Diagnosis of a vascularized epiretinal structure could be noteworthy before decision of retinal surgery.

Background and Objective: To quantify the size and location of nonperfusion associated with posterior segment neovascularization (NV) in proliferative diabetic retinopathy (PDR) using ultra-widefield fluorescein angiography., Patients and Methods: Cross-sectional study of 18 eyes with PDR. The total image area, areas of nonperfusion, buds of posterior segment neovascularization (either neovascularization of the disc or elsewhere), and the distances from each bud to the nearest area of nonperfusion and to the disc were measured., Results: Nonperfused areas with associated neovascularization were significantly larger than areas without neovascularization (32.0% ± 5.24% of the retinal image vs. 3.3% ± 0.92%; P < .001) and were more likely to be posteriorly located. Nonperfusion encompassing greater than 23% of the total angiographic image had more associated neovascular buds (9.64 ± 2.16 vs. 0.86 ± 0.29; P < .0001), which were closer to the disc (7.53 mm ± 0.27 mm vs. 9.24 mm ± 0.64 mm; P = .014)., Conclusion: A threshold size of nonperfusion greater than 23% of the retinal image is associated with posterior segment neovascularization and may serve as an indicator of risk for the development of PDR. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:86-92.]., (Copyright 2019, SLACK Incorporated.)

The development of in vivo retinal fundus imaging in mice has opened a new research horizon, not only in ophthalmic research. The ability to monitor the dynamics of vascular and cellular changes in pathological conditions, such as neovascularization or degeneration, longitudinally without the need to sacrifice the mouse, permits longer observation periods in the same animal. With the application of the high-resolution confocal scanning laser ophthalmoscopy in experimental mouse models, access to a large spectrum of imaging modalities in vivo is provided. Recently developed optical coherence tomography angiography allows even noninvasive in vivo blood flow analysis.

Competing Interests: There are no conflicts of interest

Purpose: To illustrate errors in the automated segmentation image analysis of optical coherence tomography angiography after laser photocoagulation therapy for Type 2 neovascularization., Methods: This case report describes a patient with extrafoveal Type 2 neovascularization treated with argon laser photocoagulation evaluated before and after treatment by optical coherence tomography angiography., Results: Disrupted retinal layers after laser photocoagulation therapy lead to segmentation errors., Conclusion: Images of optical coherence tomography angiography are prone to degradation by artifacts in cases in which there is disruption of the retinal layers. Clinicians must be aware of these errors because they can be misinterpreted as active Type 2 neovascularization. Improvement in optical coherence tomography angiography image analysis to minimize automated segmentation errors needs to be further explored.

Purpose: This study is aimed to adapt a three-dimensional (3-D) in vitro angiogenesis model to the ophthalmology field using retinal endothelial cells (REC). This system is applied to assess the angiogenic capacity of aqueous humor (AH) from patients with ocular disorders, and to test the effect of VEGF inhibitor (aflibercept) on induced angiogenesis., Methods: Human REC and umbilical vein endothelial cells (HUVEC) and pericytes were co-cultured in a gel matrix with 25-200 ng/ml pro-angiogenic growth factors (GF). AH from patients with cataract, glaucoma or proliferative diabetic retinopathy (PDR) was tested in the REC-pericyte co-culture. Aflibercept was then introduced to the co-culture containing PDR AH. The surface area and total tubule length were measured using Image J., Results: Optimal GF concentrations at 200 ng/ml induced angiogenesis by REC as well as HUVEC, while vessel formation by both cell types was strongly reduced using 25-50 ng/ml GF. Addition of AH from the PDR patient triggered tubule formation by REC at low GF concentration. Aflibercept, however, significantly inhibited angiogenesis induced by PDR AH, but showed no significant influence on other conditions., Conclusion: REC can be applied efficiently in the 3-D in vitro angiogenesis model as a diagnostic tool to assess the AH angiogenic status and to validate new anti-angiogenic therapeutic compounds prior to clinical trial.

Purpose: To investigate the early development of spontaneous retinal neovascularization in the murine retina by a multifunctional optical coherence tomography approach. To characterize involved tissue changes in vivo and describe structural and functional changes over time., Methods: A multifunctional optical coherence tomography (OCT) system providing 3-fold contrast comprising reflectivity, polarization sensitivity, and OCT angiography (OCTA) was utilized to image very-low-density lipoprotein receptor (VLDLR) knockout mice. Baseline measurements were acquired as early as postnatal day 14 and a follow-up of neovascularization development was performed until the age of 3 months. Control mice were imaged accordingly and a multiparametric image analysis was performed to characterize different stages of pathologic vascular growth. Histology was conducted at the endpoint of the experiment. An interventional pilot experiment was conducted to investigate the effect of the anti-vascular endothelial growth factor (VEGF) agent aflibercept on the development of retinal neovascularization., Results: Onset of neovascularization was imaged at baseline, and significant changes were encountered in the retina over time, including reduced retinal thickness, increase of lesion volume, migration of pigmented structures, and presence of abnormal blood flow in the outer retina. Multifunctional image contrast was correlated to ex vivo histology. Microscopic analysis of retinal flat mounts and cross-sectional samples confirmed the changes observed in in vivo structural and functional OCT images. Administration of an anti-VEGF agent resulted in a significantly reduced lesion volume., Conclusions: Longitudinal, multifunctional OCT imaging of infant VLDLR-/- mouse retinas enabled a multiparametric, in vivo staging of neovascularization formation from before lesion onset until their manifestation.

This study reports the short-term efficacy and safety of intravitreal conbercept injections for neovascularization at the disc (NVD) in patients with proliferative diabetic retinopathy (PDR). Conbercept is a recombinant fusion protein with a high affinity for all isoforms of vascular endothelial growth factor (VEGF)-A, placental growth factor and VEGF-B. A prospective case series study was conducted in 15 patients (15 eyes). Patients had complete ocular examinations and received a 0.5 mg intravitreal conbercept injection followed by supplemental pan-retinal photocoagulation (PRP). Optical coherence tomography angiography (OCTA) was performed before and after treatment. Before treatment, the mean NVD area was 1.05 ± 0.33 mm 2 , and it decreased to 0.56 ± 0.17 mm 2 after an interval of 7.5 d (p = 0.000). One eye required vitrectomy during follow-up. Recurrent NVD was observed in 2 eyes, which resolved after repeated injections. The remaining 12 eyes were stable over a mean follow-up period of 8.3 months. The mean area of the NVD in 14 patients without vitrectomy was 0.22 ± 0.11 mm 2 (p = 0.000) at the last visit. Intravitreal conbercept injections combined with intensive PRP are an effective and safe treatment for PDR with NVD. Quantitative information on NVD can be obtained with OCTA, which may be clinically useful in evaluating the therapeutic effect.

Ocular neovascularization is a common pathological feature in diabetic retinopathy and neovascular age-related macular degeneration that can lead to severe vision loss. We evaluated the therapeutic efficacy of a novel endogenous inhibitor of angiogenesis, the calreticulin anti-angiogenic domain (CAD180), and its functional 112-residue fragment, CAD-like peptide 112 (CAD112), delivered using a self-complementary adeno-associated virus serotype 2 (scAAV2) in rodent models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. The expression of CAD180 and CAD112 was elevated in human umbilical vein endothelial cells transduced with scAAV2-CAD180 or scAAV2-CAD112, respectively, and both inhibited angiogenic activity in vitro. Intravitreal gene delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly inhibited ischemia-induced retinal neovascularization in rat eyes (CAD180: 52.7% reduction; CAD112: 49.2% reduction) compared to scAAV2-mCherry, as measured in retinal flatmounts stained with isolectin B4. Moreover, the retinal structure and function were unaffected by scAAV2-CAD180 or scAAV2-CAD112, as measured by optical coherence tomography and electroretinography. Moreover, subretinal delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly attenuated laser-induced choroidal neovascularization in mouse eyes compared to scAAV2-mCherry, as measured by fundus fluorescein angiography (CAD180: 62.4% reduction; CAD112: 57.5% reduction) and choroidal flatmounts (CAD180: 40.21% reduction; CAD112: 43.03% reduction). Gene delivery using scAAV2-CAD180 or scAAV2-CAD112 has significant potential as a therapeutic option for the management of ocular neovascularization.

Purpose: We establish and characterize the chronic retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-α-aminoadipic acid (AAA) in a rabbit model and investigate the extent and duration of inhibitory actions induced by IVT aflibercept on the RNV., Methods: Rabbits received a single IVT injection of AAA, with weekly follow-up fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT). After 10 weeks, they received a single IVT aflibercept or control injection. RNV leakage was quantified from FA by image analysis with Photoshop. Some eyes were collected for histologic analysis., Results: IVT AAA produced neuronal degeneration over a large fraction of the retina. RNV formed in the damaged area and by 10 weeks exhibited stable morphology and leakage, which persisted for at least 65 weeks. Control IVT injections did not affect RNV leakage, but IVT aflibercept completely blocked RNV leakage. The inhibition was reversible (i.e., the leakage returned as the drug cleared), and the duration of antileak effects with 500 μg aflibercept was approximately 8 weeks. Partial regression of the pathologic vasculature also occurred with aflibercept, with reestablishment as the drug cleared., Conclusions: This model mimics a chronic human disease in its stability and persistence, and the antileak action of aflibercept is fully reversible with a dose-dependent duration. Therefore, this large eye model is uniquely suitable for investigations into the efficacy and duration of action of novel formulations and pharmacotherapies for retinal vascular diseases, and for studying the underlying pathobiology of retinal angiogenesis.

Introduction: We conducted a multimodal, cross-sectional evaluation., Methods: Eyes were divided into 4 study groups: controls, early/intermediate age-related macular degeneration (AMD), fellow eyes of retinal angiomatous proliferation (RAP), and RAP eyes. Patients were evaluated with spectral-domain optical coherence tomography (OCT), enhanced depth imaging-OCT, and OCT angiography (OCTA). OCTA images were processed to generate maps of the vessel density and perfusion density of the superficial and deep retinal layers (SRL and DRL) and the choriocapillaris level (CL). The thickness of the outer nuclear layer and choroid was manually assessed., Results: We included 135 eyes of 100 patients (51 controls, 30 AMD, 42 RAP, and 12 fellow eyes). The fellow eyes showed a significantly lower vascular perfusion of the SRL, DRL, and CL (p < 0.02) than the early/intermediate AMD and control eyes did. Similarly, RAP eyes presented a lower vascular perfusion of the DRL and CL (p < 0.05). Besides, structural analyses of the fellow eyes and RAP eyes revealed a significantly higher prevalence of macular pigmentary changes, atrophy of the retinal pigment epithelium, hyperreflective "clumps" above flat drusen, amongst others, than early/intermediate AMD and control eyes (p < 0.05)., Conclusion: We present the first report on the OCTA analysis of the fellow eye of patients with RAP. The reduced perfusion density and vessel density observed contributes, in association with clearly defined structural changes, to a wider characterization of RAP as a distinctive phenotype., (© 2017 S. Karger AG, Basel.)

Inflammatory optic disc neovascularisation (NVD) has been treated with periocular or systemic steroids, immunosuppressants, panretinal photocoagulation and bevacizumab. However, the role of intravitreal ranibizumab in inflammatory NVD has not been explored in the peer-reviewed indexed literature. In case 1, NVD and associated subhyaloid haemorrhage showed rapid and dramatic regression after intravitreal ranibizumab. Recurrence was noted 8 weeks after injection which was managed by oral steroids. In case 2, intravitreal ranibizumab led to partial resolution of NVD. The addition of steroids, azathioprine and panretinal photocoagulation led to further fibrosis of the neovascularisation. Ranibizumab may be an important adjunct to anti-inflammatory therapy in the management of inflammatory NVD., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Visualizing ocular vasculature is important in clinical ophthalmology because ocular circulation abnormalities are early signs of ocular diseases. Photoacoustic microscopy (PAM) images the ocular vasculature without using exogenous contrast agents, avoiding associated side effects. Moreover, 3D PAM images can be useful in understanding vessel-related eye disease. However, the complex structure of the multi-layered vessels still present challenges in evaluating ocular vasculature. In this study, we demonstrate a new method to evaluate blood circulation in the eye by combining in vivo PAM imaging and an ocular surface estimation method based on a machine learning algorithm: a random sample consensus algorithm. By using the developed estimation method, we were able to visualize the PA ocular vascular image intuitively and demonstrate layer-by-layer analysis of injured ocular vasculature. We believe that our method can provide more accurate evaluations of the eye circulation in ophthalmic applications.

Purpose: To study the cross-sectional and en face optical coherence tomography angiography (OCTA) findings in Type 3 neovascularization (NV)., Methods: Optical coherence tomography angiography imaging of 27 eyes of 23 patients with Type 3 NV was analyzed with 9 eyes having consecutive follow-up OCTA studies., Results: Type 3 NV appeared as a linear high-flow structure on cross-sectional OCTA corresponding to a high-flow tuft of vessels seen on en face OCTA. Cross-sectional OCTA seemed to enable the distinction between vascular and nonvascular intraretinal hyperreflective foci. Two patterns of flow were observed; Pattern 1 (11%): a flow signal confined to the neurosensory retina and Pattern 2 (74%): a flow signal extending through the retinal pigment epithelium. No definitive retinal-choroidal anastomosis was observed; however, projection artifacts confounded the interpretation of deeper structures. An increase in the intensity of the high-flow tuft was seen during the progression or recurrence of Type 3 NV. Intravitreal anti-vascular endothelial growth factor therapy caused a reduction in the intensity of the high-flow tuft which was not sustained., Conclusion: Compared with conventional imaging, OCTA may improve detection and delineation of vascular changes occurring in Type 3 NV. Cross-sectional and en face OCTA may prove useful in studying the pathogenesis and guiding the management of these lesions.

Purpose: To report 2-year treatment outcomes with intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) in routine clinical practice., Design: Retrospective, nonrandomized, interventional case series., Methods: Retrospective analysis of electronic medical record (EMR) notes (OpenEyes) and paper case notes and review of spectral-domain optical coherence tomography (SDOCT) imaging of patients with consecutively treated eyes with previously untreated nAMD. Patients were commenced on aflibercept injections in 1 or both eyes from October 1, 2013 to December 31, 2013. Data including age, sex, visual acuity (VA) measured on Early Treatment Diabetic Retinopathy Study charts, injection episodes, and complications were recorded. Additionally, SDOCT data, including presence or absence of macular fluid and automated central subfield macular thickness (CSMT) at year 1 and 2, were recorded., Results: Of the 109 eyes of 102 patients treated, data from 94 eyes of 88 patients were available at 2-year follow-up (86% of patients). In the analysis of 2-year outcomes, there were 58 women (65.9%); the mean (± standard deviation) age was 77.5 ± 8 years. Over the 2 years, these eyes received a median of 12 (mean, 11.4 ± 4) injections at a median of 100 (mean, 99.3 ± 5.3) weeks of follow-up. The mean VA changed from 55.9 ± 15 letters at baseline to 61.3 ± 16.9 letters (VA gain 5.4 letters) at 1 year and to 61 ± 17.1 letters (VA gain 5.1 ± 14.9 letters) at 2 years. The reduction in CSMT was 79 μm with absence of macular fluid in 72.7% of the 88 eyes with SDOCT data available at 2-year follow-up., Conclusions: The VA and SDOCT results compare favorably with outcomes seen in randomized controlled trials. The results suggest that good long-term outcomes can be achieved using aflibercept for nAMD in clinical settings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the utility of ultrahigh speed, swept source optical coherence tomography angiography in visualizing retinal microvascular and choriocapillaris (CC) changes in diabetic patients., Methods: The study was prospective and cross-sectional. A 1,050 nm wavelength, 400 kHz A-scan rate swept source optical coherence tomography prototype was used to perform volumetric optical coherence tomography angiography of the retinal and CC vasculatures in diabetic patients and normal subjects. Sixty-three eyes from 32 normal subjects, 9 eyes from 7 patients with proliferative diabetic retinopathy, 29 eyes from 16 patients with nonproliferative diabetic retinopathy, and 51 eyes from 28 diabetic patients without retinopathy were imaged., Results: Retinal and CC microvascular abnormalities were observed in all stages of diabetic retinopathy. In nonproliferative diabetic retinopathy and proliferative diabetic retinopathy, optical coherence tomography angiography visualized a variety of vascular abnormalities, including clustered capillaries, dilated capillary segments, tortuous capillaries, regions of capillary dropout, reduced capillary density, abnormal capillary loops, and foveal avascular zone enlargement. In proliferative diabetic retinopathy, retinal neovascularization above the inner limiting membrane was visualized. Regions of CC flow impairment in patients with proliferative diabetic retinopathy and nonproliferative diabetic retinopathy were also observed. In 18 of the 51 of eyes from diabetic patients without retinopathy, retinal mircrovascular abnormalities were observed and CC flow impairment was found in 24 of the 51 diabetic eyes without retinopathy., Conclusion: The ability of optical coherence tomography angiography to visualize retinal and CC microvascular abnormalities suggests it may be a useful tool for understanding pathogenesis, evaluating treatment response, and earlier detection of vascular abnormalities in patients with diabetes.