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Purpose: Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare genetic (CAPN5) autoimmune condition typically diagnosed in adulthood and characterized by a triad of inflammation, retinal degeneration, and neovascularization. We report novel multimodal imaging findings in children and young adults with ADNIV, and early treatment response to short-duration local and systemic corticosteroids., Design: Retrospective consecutive case series., Participants: Ten patients aged <25 years with ADNIV and available multimodal imaging., Methods: The medical records of patients aged <25 years with a diagnosis of ADNIV with ultrawidefield fluorescein angiography (UWFFA) and OCT data were reviewed., Main Outcome Measures: Ultrawidefield fluorescein angiography and OCT findings at baseline and after local corticosteroids., Results: Median age at presentation was 14 years (range, 9-24 years). OCT on presentation demonstrated cystoid macular edema in 8 of 20 eyes and symptomatic vitreoretinal interface disease in 2 of 20 eyes. Initial UWFFA demonstrated retinal vascular leakage (20/20 eyes, 100%), peripheral nonperfusion (13/20 eyes, 65%), and retinal neovascularization (6/20 eyes, 30%). Retinal vascular leakage improved with local corticosteroids, and neovascularization regressed with anti-VEGF therapy., Conclusions: Ultrawidefield fluorescein angiography findings of prefibrotic ADNIV reported in adults were also present in children and young adults. Early testing for a pathogenic CAPN5 variant in at-risk children and regularly scheduled screening for uveitis and retinal vasculitis with UWFFA and OCT may prompt earlier intervention. Short-duration local steroids are effective at treating retinal vascular leakage and macular edema but are not durable, suggesting a potential role for steroid-sparing immunosuppressive therapy. Early treatment may alter the natural history of disease., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Ischemic retinopathy is the major cause of vision-threatening conditions. Inflammation plays an important role in the pathogenesis of ischemic retinopathy. Formyl peptide receptor 1 (FPR1) has been reported to be implicated in the regulation of inflammatory disorders. However, the role of FPR1 in the progression of ischemic retinal injury has not been fully explained., Methods: The activation of FPR1 was measured by real-time PCR and western blotting in the retina of OIR. The effect of FPR1 on the expression of inflammatory cytokines and relevant pro-angiogenic factors was assessed between wild-type and FPR1-deficiency OIR mice. The impact of FPR1 on retinal angiogenesis was evaluated through quantifying retinal vaso-obliteration and neovascularization between FPR1 +/+ and FPR1 -/- OIR mice. At last, the neuronal effect of FPR1 on the ischemic retina was investigated by ERG between wild-type and FPR1-deficient OIR mice., Results: The expression of FPR1 significantly increased in the retina of OIR. Furthermore, FPR1 deficiency downregulated pro-inflammatory and pro-angiogenic factors. Ablation of FPR1 suppressed the retinal pathological neovascularization and promoted reparative revascularization, ultimately improving retinal neural function after ischemic injury., Conclusion: In ischemic retinopathy, FPR1 aggravates inflammation and inhibits reparative angiogenesis to exacerbate neuronal dysfunction.

Purpose: To assess differences in choriocapillaris (CC) and macular neovascularization (MNV) optical coherence tomography angiography quantitative parameters between long-term persistently nonexudative MNVs (NE-MNVs) and long-term activated NE-MNVs in age-related macular degeneration., Methods: Age-related macular degeneration patients with treatment-naïve NE-MNVs with >2 years of follow-up and no evidence of exudation within the first 6 months from diagnosis were retrospectively recruited. Two groups were considered according to the occurrence (EX group) or not (NE group) of exudation within the first 2 years of follow-up. Segmentation of the MNV and of the perilesional CC were obtained from enface optical coherence tomography angiography acquisitions at diagnosis and at 6-month follow-up. OCT B-scan images of the MNV were also collected. Fractal ratio was defined as the ratio between MNV fractal dimension (FrD) and CC FrD., Results: Fifty (50) eyes were included (20 EX group and 30 NE group). EX group showed higher flow deficit density and flow deficit number at the 6-month follow-up. It also showed higher MNV FrD, lower CC FrD, and higher fractal ratio at the 6-month follow-up. The fractal ratio significantly increased at 6-month acquisitions in the EX group, showing an area under the ROC curves of 0.887 (95% CI 0.869-0.922)., Conclusion: Fractal ratio at 6 months can predict exudation risk of MNV within 2 years from diagnosis. This suggests increased structural complexity of the NE-MNV accompanied by progressive capillary rarefaction of the perilesional CC as a key driving factor for the development of exudation in NE-MNV.

Purpose: To explore changes in reticular pseudodrusen (RPD) number and location after the development of macular neovascularization (MNV) in eyes with prior intermediate age-related macular degeneration, focusing on different retinal regions differently affected by MNV., Methods: This retrospective longitudinal study included intermediate age-related macular degeneration eyes with RPD that developed MNV. Reticular pseudodrusen were assessed at baseline when MNV was diagnosed (MNV stage) and after anti-vascular endothelial growth factor treatment. Three regions of interest were considered: MNV area, subretinal fluid (SRF) area, and a marginal area of 1,000 µm around SRF (marginal zone). Reticular pseudodrusen counts were compared with age- and sex-matched control eyes with RPD that did not develop MNV., Results: Reticular pseudodrusen number exhibited a significant decrease after MNV development in the MNV area (P = 0.048) and in the area with SRF (P = 0.078). A statistically significant decrease was also disclosed in the marginal area around SRF (P = 0.002), associated with larger SRF areas. Control eyes did not show any significant change in the RPD count., Conclusion: Reticular pseudodrusen reduction after MNV development suggests a complex interplay involving the MNV itself, the presence of SRF, and trophic changes. The results of this study highlight the role of MNV in retinal nutritional balance and provide intriguing results in the RPD life cycle.

Objective: Isolated retinal neovascularization (IRNV) is a common finding in patients with stage 2 and 3 retinopathy of prematurity (ROP). This study aimed to further classify the clinical course and significance of these lesions (previously described as "popcorn" based on clinical appearance) in patients with ROP as visualized with ultrawidefield OCT (UWF-OCT)., Design: Single center, retrospective case series., Participants: Images were collected from 136 babies in the Oregon Health and Science University neonatal intensive care unit., Methods: A prototype UWF-OCT device captured en face scans (>140°), which were reviewed for the presence of IRNV along with standard zone, stage, and plus classification. In a cross-sectional analysis we compared demographics and the clinical course of eyes with and without IRNV. Longitudinally, we compared ROP severity using a clinician-assigned vascular severity score (VSS) and compared the risk of progression among eyes with and without IRNV using multivariable logistic regression., Main Outcome Measures: Differences in clinical demographics and disease progression between patients with and without IRNV., Results: Of the 136 patients, 60 developed stage 2 or worse ROP during their disease course, 22 of whom had IRNV visualized on UWF-OCT (37%). On average, patients with IRNV had lower birth weights (BWs) (660.1 vs. 916.8 g, P = 0.001), gestational age (GA) (24.9 vs. 26.1 weeks, P = 0.01), and were more likely to present with ROP in zone I (63.4% vs. 15.8%, P < 0.001). They were also more likely to progress to stage 3 (68.2% vs. 13.2%, P < 0.001) and receive treatment (54.5% vs. 15.8%, P = 0.002). Eyes with IRNV had a higher peak VSS (5.61 vs. 3.73, P < 0.001) and averaged a higher VSS throughout their disease course. On multivariable logistic regression, IRNV was independently associated with progression to stage 3 (P = 0.02) and requiring treatment (P = 0.03), controlling for GA, BW, and initial zone 1 disease., Conclusions: In this single center study, we found that IRNV occurs in higher risk babies and was an independent risk factor for ROP progression and treatment. These findings may have implications for OCT-based ROP classifications in the future., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. All rights reserved.)

Background: Rickettsial disease has been commonly associated with retinitis, retinal vasculitis, and optic nerve involvement, but the development of retinal neovascularization has been very rarely reported. We herein describe a case of rickettsial retinitis complicated with the development of sea-fan retinal neovascularization documented with multimodal imaging, including fundus photography, SS-OCT, fluorescein angiography, and SS-OCT angiography., Case Presentation: A 26-year-old female with a history of fever one week earlier presented with sudden decreased vision in the left eye. Best-corrected visual acuity (BCVA) was 20/2000 and the patient was diagnosed with rickettsial retinitis along the superotemporal retinal vascular arcade associated with serous retinal detachment and retinal hard exudates. The indirect immunofluorescence test was positive for Rickettsia conorii, and the patient was treated with oral doxycycline (200 mg/day) and oral prednisone (0.75 mg/kg/day, with gradual tapering). Four weeks after presentation, the retinal infiltrate and associated serous retinal detachment had resolved, but retinal hard exudates had increased. A large sea-fan preretinal fibrovascular neovascularization became apparent along the superotemporal retinal vascular arcade, but there was no associated retinal ischemia on fluorescein angiography. The patient received an adjunctive single intravitreal injection of 1.25 bevacizumab. Sequential follow-up examinations showed shrinking of sea-fan retinal neovascularization, a complete resolution of retinal hard exudates, and the development of a self-limited vitreous hemorrhage. On last follow-up, 30 months after intravitreal bevacizumab injection, BCVA was 20/25., Conclusion: Patients with rickettsial retinitis may develop a sea-fan retinal neovascularization, with subsequent vitreous hemorrhage, putatively through inflammatory mechanisms. Multimodal imaging including OCT, fluorescein angiography, and OCT-angiography, is highly useful for accurate diagnosis and reliable monitoring of the evolution of retinitis, retinal neovascularization, and other retinal changes. The use of a combination therapy with oral doxycycline and corticosteroids and intravitreal anti-VEGF can improve outcomes., (© 2024. The Author(s).)

Purpose: To describe the outcomes from treatment of macular neovascularization in an eye affected by late-onset retinal degeneration., Methods: A 72-year-old female patient presented with a history of decreased vision since several years. The patient was previously diagnosed with age-related macular degeneration and treated with anti-vascular endothelial growth factors., Results: Clinical examination of the retina and ultra-widefield color fundus photographs showed extensive atrophy in both eyes. The left eye showed macular neovascularization on fluorescein angiography, subretinal fluid on optical coherence tomography, and correspondent hemorrhages on the color fundus photography. Aflibercept anti-vascular endothelial factor treatment was used to treat the macular neovascularization in the left eye., Conclusion: We report a case of genetically confirmed late-onset retinal degeneration (heterozygous pathogenic mutation p.Ser163Arg in one C1QTN5 allele) with advanced degeneration of the retina complicated by macular neovascularization, which responded well to treatment with a single aflibercept injection.

Purpose: Retinal neovascularization is a significant feature of advanced age-related macular degeneration (AMD) and a major cause of blindness in patients with AMD. However, the underlying mechanism of this pathological neovascularization remains unknown. Iron metabolism has been implicated in various biological processes. This study was conducted to investigate the effects of iron metabolism on retinal neovascularization in neovascular AMD (nAMD)., Methods: C57BL/6J and very low-density lipoprotein receptor (VLDLR) knockout (Vldlr-/-) mice, a murine model of nAMD, were used in this study. Bulk-RNA sequencing was used to identify differentially expressed genes. Western blot analysis was performed to test the expression of proteins. Iron chelator deferiprone (DFP) was administrated to the mice by oral gavage. Fundus fluorescein angiography was used to evaluate retinal vascular leakage. Immunofluorescence staining was used to detect macrophages and iron-related proteins., Results: RNA sequencing (RNA-seq) results showed altered transferrin expression in the retina and RPE of Vldlr-/- mice. Disrupted iron homeostasis was observed in the retina and RPE of Vldlr-/- mice. DFP mitigated iron overload and significantly reduced retinal neovascularization and vascular leakage. In addition, DFP suppressed the inflammation in Vldlr-/- retinas. The reduced signals of macrophages were observed at sites of neovascularization in the retina and RPE of Vldlr-/- mice after DFP treatment. Further, the IL-6/JAK2/STAT3 signaling pathway was activated in the retina and RPE of Vldlr-/- mice and reversed by DFP treatment., Conclusions: Disrupted iron metabolism may contribute to retinal neovascularization in nAMD. Restoring iron homeostasis by DFP could be a potential therapeutic approach for nAMD.

Background: Around 30% of nonexudative macular neovascularizations exudate within 2 years from diagnosis in patients with age-related macular degeneration. The aim of this study is to develop a deep learning classifier based on optical coherence tomography (OCT) and OCT angiography (OCTA) to identify nonexudative macular neovascularizations at risk of exudation., Methods: Patients with age-related macular degeneration showing OCTA and fluorescein angiography-documented nonexudative macular neovascularization with a 2-year minimum imaging follow-up were retrospectively selected. Patients showing OCT B-scan-documented macular neovascularization exudation within the first 2 years formed the EX GROUP while the others formed the QU GROUP. ResNet-101, Inception-ResNet-v2, and DenseNet-201 were independently trained on OCTA and OCT B-scan images. Combinations of the six models were evaluated with major and soft voting techniques., Results: Eighty-nine eyes of 89 patients with a follow-up of 5.7 ± 1.5 years were recruited (35 EX GROUP and 54 QU GROUP). Inception-ResNet-v2 was the best performing among the three single convolutional neural networks. The major voting model resulting from the association of the three different convolutional neural networks resulted in an improvement of performance both for OCTA and OCT B-scan (both significantly higher than human graders' performance). The soft voting model resulting from the combination of OCTA and OCT B-scan-based major voting models showed a testing accuracy of 94.4%. Peripheral arcades and large vessels on OCTA en face imaging were more prevalent in the QU GROUP., Conclusion: Artificial intelligence shows high performances in identifications of nonexudative macular neovascularizations at risk for exudation within the first 2 years of follow-up, allowing better customization of follow-up timing and avoiding treatment delay. Better results are obtained with the combination of OCTA and OCT B-scan image analysis.

Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-33 95-270 , IL-33 99-270 , IL-33 109-270 , and IL-33 112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-33 95-270 , IL-33 99-270 , IL-33 109-270 , and IL-33 112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-33 99-270 could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3'-mRNA sequencing and signaling studies indicated that IL-33 99-270 and IL-33 109-270 were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-33 99-270 and IL-33 109-270 , significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33 -/- mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: To describe the progression from outer retinal neovascularization (ORNV) to exudative subretinal new vessels (SRNVs) in idiopathic macular telangiectasia type 2., Methods: A total of 135 patients (270 eyes) imaged with optical coherence tomography angiography were included., Main Outcome Measures: Ellipsoid zone loss, outer retinal hyperreflectivity, ORNV, and SRNVs. Outer retinal neovascularization was defined as a flow signal passing through the outer plexiform layer, with or without vertical linear outer retinal hyperreflectivity on the optical coherence tomography B-scan. Subretinal new vessels were defined as an abnormal capillary network with a peripheral anastomotic arcade seen on en face optical coherence tomography angiography and a convex hyperreflectivity at the retinal pigment epithelium., Results: Subretinal new vessels were observed in 38/270 eyes (14%). Subretinal new vessels were at a fibrotic stage in 24/38 eyes and at an exudative stage in 6/38 eyes, and a progression from ORNV to SRNVs was documented in 8/38 eyes. All cases showed an ellipsoid zone loss. In seven eyes (2.5%), SRNVs were also associated with subepithelial neovascularization. No retinochoroidal anastomosis was detected. The visual acuity dropped when SRNVs were present., Conclusion: In this case series, SRNVs were found in 14% of eyes. In all cases, they were associated with an ellipsoid zone loss and with outer retinal hyperreflectivity. A progression from ORNV to SRNVs was observed.

Purpose: To identify the predictive factors for development of exudation in patients with treatment-naïve nonexudative macular neovascularization (MNV)., Methods: We retrospectively analyzed 61 treatment-naïve patients with nonexudative MNV who had not received treatment for nonexudative MNV before the exudation developed. Baseline characteristics and changes in MNV were evaluated using multivariate modeling to determine the potential risk factors for exudative conversion., Results: Exudation development was identified in 31.1% (19/61 eyes) of the study eyes during the 46.2 ± 8.2-month mean follow-up period. The mean period of development of exudation from the baseline was 21.5 ± 6.7 months. Multivariate Cox regression analysis identified that older age (hazard ratio [HR] of 1.380, 95% confidence interval [CI] 1.129-1.688, P = 0.008), larger MNV area at baseline (HR of 1.715, CI 1.288-2.308; P = 0.006), increase of MNV area by doubling (HR of 4.992, CI 1.932-9.246; P = 0.002), and retinal pigment epithelium (RPE) elevation more than 100 μm (HR of 1.017, CI 1.006-1.233; P = 0.015) were associated with increased risk of the development of exudation., Conclusion: Older age, larger MNV area, increasing MNV area, and higher RPE elevation were associated with an increased risk of exudative conversion in patients with treatment-naïve nonexudative MNV. Identifying these risk factors may be helpful in establishing treatment strategies and monitoring patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To report a case series of human immunodeficiency virus (HIV)-negative patients with healed cytomegalovirus retinitis presenting with proliferative retinopathy (in the form of neovascularisation elsewhere)., Methods: Retrospective case series. Multimodal imaging was performed at each follow-up visit., Results: Three patients with non-HIV immune dysfunction were followed up after healing of CMV retinitis. All three developed neovascularisation. Patient 1 after 4 months presented with vitreous haemorrhage for which pars plana vitrectomy was performed. Patient 2 developed neovascularization at disc and neovascularisation elsewhere 4 months after resolution, and patient 3 despite being affected by bilateral CMV retinitis, presented with unilateral neovascularization at 14 month after resolution of retinitis., Conclusion: Increased incidence of this rare entity could be attributed to partial immune dysfunction in non-HIV patients, limited area of retinitis with a more aggressive occlusive vasculitis. Extensive occlusion with more area of viable retina for angiogenic factor production explains this phenomena. It emphasizes the need for continued follow-up even after healing and to differentiate it from reactivation of retinitis and immune recovery uveitis. Abbreviation: CMV: cytomegalovirus; HIV: human immunodeficiency virus; BCVA: best corrected visual acuity.

Macular neovascularization type 3 (MNV3) is a multifactorial disease with distinct epidemiological, clinical, pathomorphological and topographical characteristics. This review of the literature discusses the latest experimental and clinical outcomes that could explain the pathogenesis of retinal neovascularization. Although patients with MNV3 are usually older than those with MNV1 or 2, their lesions do not coexist with, precede, or follow other types in the same eye. The regional distribution of MNV3 lesions is characterized as confined to the parafoveal macula without any involvement of the rod-free foveal area. Focal outer retinal atrophy and choroidal non-perfusion are the main structural features that occur prior to the development of retinal neovascularization. Also, histological and experimental studies of MNV3 and other non-neovascular age-related macular degeneration diseases complicated with MNV3-like lesions strongly suggest rod degeneration contributes to the pathogenesis. Therefore, the retinal neovascularization in MNV3 has a different pathogenesis from the choroidal neovascularization in MNV1 and 2 and emerging evidence indicates that choroidal non-prefusion and rod degeneration play a key role in the pathogenesis of MNV3. Accordingly, we suggest a sequence of pathological events that start with choroidal non-perfusion due to advanced age followed by hypoxia of the outer retina at the parafoveal area. This induces a remarkable degeneration of rods that triggers the growth of retinal neovascularization due to the imbalance of the angiogenic factors in the outer retina., (© 2024. The Author(s).)

Purpose: We describe a case of vitreous haemorrhage and retinal neovascularization secondary to peripheral retinal ischemia associated with disseminated melanoma., Methods: A retrospective case report., Results: A 48-year-old man presented with vitreous haemorrhage in the right eye, peripheral retinal ischemia, and retinal neovascularization in both eyes. CT and MRI scans were suggestive of disseminated malignancy and an ultrasound-guided biopsy of the abdominal mass confirmed metastatic melanoma. Immune checkpoint inhibitor therapy with ipilimumab/nivolumab was initiated. Regarding his ocular status, the vitreous haemorrhage cleared spontaneously, visual acuity improved to 6/7.5 and the patient underwent bilateral peripheral scatter laser photocoagulation to stabilize the retinopathy. The patient passed away 1 year after the initial presentation., Conclusion:  Our patient presented with melanoma and peripheral retinal ischaemia, leading to retinal neovascularization and vitreous haemorrhage. Therefore, melanoma should be considered as a differential diagnosis when investigating the aetiology of peripheral retinal ischaemia.

Purpose: To report a rare case of cytomegalovirus (CMV)-associated non-necrotizing viral retinopathy, occlusive retinal vasculitis, papillitis, and retinal neovascularization in a young 41-year-old woman., Methods: Case report., Results: The patient presented with features of papillitis, peripapillary cotton-wool spots, pre-retinal hemorrhages, and occlusive vasculitis. Her visual acuity was 20/100 in the left eye. She developed a worsening of the disease upon initiation of systemic corticosteroids. Her serum immunoglobulins (Ig) (both IgG and IgM) were highly positive for CMV. Anterior chamber paracentesis was positive for CMV DNA using real-time polymerase chain reaction. After stopping systemic corticosteroids, she was initiated on oral valganciclovir, with rapid resolution of the vasculitis and cotton-wool spots. After three months, the patient developed retinal neovascularization and underwent pan-retinal photocoagulation. However, her uveitis was inactive, and her visual acuity improved to 20/25., Conclusions: Non-necrotizing viral retinopathy has been associated with either varicella zoster virus (VZV) or herpes simplex virus (HSV). Our case highlights that CMV can also lead to non-necrotizing retinopathy and must be suspected in patients who may be negative for VZV and HSV. Appropriate anti-viral treatment can prevent severe vision loss in these patients.

Purpose: To report a very rare and atypical case of an elderly Caucasian female patient who developed perilesional multiple polypoidal choroidal vasculopathy (PCV) as a probable complication of choroidal osteoma (CO), associated to preretinal neovascular membrane overlying the lesion., Methods: Observational case report., Case Observation: A 60-year-old Caucasian woman presented with blurred vision in her right eye (RE). Fundus examination revealed a round white-yellowish calcified deep lesion in the juxta-papillary superior area, measuring 4 disc-diameters, with well-defined scalloped margins and an irregular surface. B-scan ultrasonography and orbital tomography confirmed the diagnosis of choroidal osteoma (CO). Further investigation with multimodal imaging including infracyanine green angiography, fluorescein angiography, swept source optical coherence tomography and angiography highlighted the presence of multiple aneurysmal choroidal dilations around the CO, corresponding to PCV. We also noted the presence of a preretinal neovascular membrane overlying the CO. The patient was monitored with regular follow-up since no signs of activity were detected on multimodal imaging., Conclusion: Our case report represents an exceptional and atypical association between pre-retinal neovascularization, PCV and choroidal osteoma. While the mechanisms underlying the development of PCV and pre-retinal neovascularization in the setting of CO are not well understood, it is imperative for ophthalmologists to recognize this association as a potential cause of sudden vision loss in patients with CO, and to consider appropriate diagnostic and management strategies., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: We present a patient with retinopathy of prematurity (ROP) who developed worsening plus disease after complete regression of stage 3 ROP. The use of fundus fluorescein angiography (FFA) aided the visualization of occult neovascularization that caused the disease progression., Case Presentation: The patient was at high risk for ROP due to low birth weight of 690 g and gestational age of 25 weeks. After the diagnosis of stage 3 ROP in zone I without plus disease, she was treated initially with bilateral intravitreal bevacizumab (IVB) and followed by laser photocoagulation 5 weeks later. Despite the resolution of ROP stage, the plus disease worsened. Neither systemic risk factors nor skip laser areas were observed. Hence, FFA was performed and subsequently identified occult neovascularization with active leakage. Additional IVB and laser treatment in the capillary dropout area inside vascularized retina were added. The plus disease improved but mild arteriolar tortuosity persisted., Conclusions: Worsening of plus disease after completion of laser ablation and IVB with complete regression of stage 3 ROP is rare. Systemic risk factors such as continuous oxygen therapy and cardiovascular disease should be ruled out. FFA aided in identifying occult neovascularization and prompted further treatment., (© 2024. The Author(s).)

Purpose: To assess the real clinical utility of widefield OCT angiography (WF-OCTA) for detecting retinal neovascularization (RNV) in eyes with proliferative diabetic retinopathy (PDR)., Design: A retrospective cross sectional study., Participants: Consecutive eyes clinically suspected of PDR by physicians at a tertiary eye center between March 2021 and November 2022., Methods: All eyes underwent ultrawidefield fluorescein angiography (UWF-FA) (California, Optos) and WF-OCTA (S1, Canon) with a 23 × 20 mm scan area. Two independent graders detected individual RNV lesions using UWF-FA and used them as the ground truth. Widefield OCT angiography images were first evaluated to determine whether the images successfully illustrated retinal vasculature, regardless of the image quality index or the presence of vitreous hemorrhage. The graders then identified the RNV lesions with WF-OCTA. We detected RNV by utilizing both the entire retinal slab, including flow signals in the retina, and the custom vitreoretinal interface slab, defined as flow signals from 20 μm below the internal limiting membrane (ILM) to 2000 μm above the ILM. We evaluated the applicability to real clinical practice by not correcting segmentation errors., Main Outcome Measures: The success rate of imaging and the detection rate of RNV using WF-OCTA., Results: Initially, 69 consecutive patients who underwent UWF-FA were identified. Of these, 114 eyes from 57 (83%) patients underwent both UWF-FA and WF-OCTA. Of the 114 eyes, 108 (95%) produced gradable WF-OCTA images. Using UWF-FA, the graders identified 175 RNV lesions in 40 eyes. Widefield OCT angiography achieved a sensitivity of 95% and specificity of 88% for detecting eyes with RNV. At the level of individual RNV lesions, graders detected 156 RNV lesions with WF-OCTA, with 118 of these confirmed by UWF-FA (true positive). Among the 57 false-negative lesions, the primary causes were being out of the scan range (26 lesions) and segmentation errors (21 lesions)., Conclusions: Widefield OCT angiography imaging had a high success rate, achieving a sensitivity of 95% and a specificity of 88% for detecting eyes with RNV in a real clinical setting. Despite a 67% detection rate for individual RNV lesions, WF-OCTA may serve as a valuable noninvasive method for RNV detection in eyes with diabetic retinopathy., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis., Competing Interests: Declaration of interests Y.S. and T.W. are inventors on patent applications relating to this work filed by Boston Children’s Hospital., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Retinal nonperfusion is a significant cause of vision loss in patients with proliferative diabetic retinopathy (PDR). Therefore, reperfusion of a nonperfusion has been a matter of strong interest, but few previous studies have demonstrated the potential benefits of reperfusion., Case Reports: Here, we report longitudinal optical coherence tomography angiographic analysis of two cases of PDR, in which the retinal neovascularization (RNV) that developed in response to retinal ischemia formed anastomoses with pre-existing physiological retinal vessels, resulting in both superficial and deep capillary reperfusion within the nonperfusion. We named this interesting finding "neovascular-vascular anastomosis." Retinal reperfusion due to neovascular-vascular anastomosis differed from recanalization, defined as reperfusion of once-occluded blood vessels, and has not been reported previously., Conclusion: Our observation highlights the potential of RNV to rescue retinal ischemia by the formation of neovascular-vascular anastomoses., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To analyze characteristics, etiology, and outcome of retinal vasculitis in Central Thailand., Methods: A retrospective cohort study., Results: Retinal vasculitis was found in 10% of uveitis, 74 from 741 uveitis, noninfectious (64.9%) and infectious group (35.1%). The most common cause was Behcet's disease (48.6%). Behcet's disease was the most common cause of all types of vascular leakage on angiography, including capillary (80.4%), venous (56.3%), and arterial leakage (56%). Final visual acuity was 0.86 ± 0.97 logMAR. Cataract was the most frequent complication (42.5%). Acute clinical course ( p = .025) and retinal neovascularization ( p = .031) were associated with infectious group. Forty-three percent of vasculitis complicated by ischemia required photocoagulation (33%) and anti-VEGF injection (17%). Furthermore, 17% of vasculitis underwent vitrectomy., Conclusion: One-half of the retinal vasculitis in Central Thailand were Behcet's disease. Acute onset and retinal neovascularization may suggest infectious etiology. Retinal ischemia should be cautious and undergo early interventions to prevent sight-threatening complications.

Purpose: This case report describes a central retinal vein occlusion in a healthy 12-year-old girl who developed retinal neovascularization at 24 years of age. To the knowledge of the authors, this is the longest time between a reported pediatric central retinal vein occlusion event and neovascularization., Methods: The patient underwent a full history, physical examination, and laboratory workup to determine potential risk factors contributing to the vascular event. Fundus photographs, optical coherence tomography, and fluorescein angiography were performed throughout the patient's treatment course., Results: Family history was noncontributory, but laboratory testing revealed a mildly elevated homocysteine level and homozygous C677T mutation in methylenetetrahydrofolate reductase. As a result, she was started on folate supplementation. The patient has had no further ocular or systemic thrombotic events to date., Conclusion: Pediatric patients presenting with central retinal vein occlusion should undergo a systemic workup and require long-term follow-up to avoid complications, such as intraocular hemorrhage, tractional retinal detachments, and neovascular glaucoma.

Purpose: To present two cases of concomitant retinal neovascularization (RNV) in acquired peripheral retinoschisis and analyze its characteristics on optical coherence tomography angiography and based on a literature review., Methods: This was an observational, retrospective case study., Results: Case 1 presented with bullous retinoschisis and RNV near the schisis cavity. Optical coherence tomography angiography revealed no angioflow into the retinal arterioles of the cavity. An arterial filling delay to the retinoschisis with extensive leakage from the RNV was noted on fluorescein angiography. Case 2 involved the superficial retinoschisis and telangiectatic vessels inside the schisis cavity. Optical coherence tomography angiography revealed damage to the superficial capillary plexus of the cavity, absence of angioflow to the inner schisis layer, and increased angioflow to the RNV. Fluorescein angiography showed focal leakage from the RNV and diffuse leakage from telangiectasia. No vision-threatening complications were identified in either patient up to the last follow-up, subsequent to laser photocoagulation., Conclusion: Acquired peripheral retinoschisis is associated with RNV. Inner retinal ischemia caused by hemodynamic resistance or a damaged superficial capillary plexus can interrupt angioflow to the inner schisis retinal layer on optical coherence tomography angiographic findings and develop RNV inside or outside the retinoschisis.

The progression to fibrosis and traction in retinopathy of prematurity (ROP) and other ischemic retinopathies remains an important clinical and surgical challenge, necessitating a comprehensive understanding of its pathogenesis. Fibrosis is an unbalanced deposition of extracellular matrix components responsible for scar tissue formation with consequent tissue and organ impairment. Together with retinal traction, it is among the main causes of retinal detachment and vision loss. We capitalize on the Limited Hyperoxia Induced Retinopathy (LHIPR) model, as it reflects the more advanced pathological phenotypes seen in ROP and other ischemic retinopathies. To model LHIPR, we exposed wild-type C57Bl/6J mouse pups to 65% oxygen from P0 to P7. Then, the pups were returned to room air to recover until later endpoints. We performed histological and molecular analysis to evaluate fibrosis progression, angiogenesis, and inflammation at several time points, from 1.5 months to 9 months. In addition, we performed in vivo retinal imaging by optical coherence tomography (OCT) or OCT Angiography (OCTA) to follow the fibrovascular progression in vivo. Although the retinal morphology was relatively preserved, we found a progressive increase in preretinal fibrogenesis over time, up to 9 months of age. We also detected blood vessels in the preretinal space as well as an active inflammatory process, altogether mimicking advanced preretinal fibrovascular disease in humans.

Purpose: To analyze the topographic distribution of neovascularization (NV) and capillary nonperfusion (CNP) using ultra-wide field fluorescein angiography (UWFFA) in patients with proliferative diabetic retinopathy (PDR)., Methods: This was a prospective, single-center, observational study in which all patients who presented between March 2019 and December 2020 and satisfied the inclusion criteria were recruited. In our study, patients with treatment-naïve PDR without any fibrovascular proliferation underwent UWFFA. The images were analyzed qualitatively for the topographic distribution of NV and the CNP area was quantified. The number of lesions picked by UWFFA was compared with 7 standard field (7SF) image using overlay of 7SF. The main outcome measure was characteristics of neovascularization, such as the number, location, and area of CNP, measured using UWFFA, which was considered with 95% confidence intervals (CI)., Results: Two hundred and fifty-three eyes of 187 patients with a mean age of 56.03 ± 8 years were included. Mean neovascularization elsewhere (NVE) was 2.91 ± 3.43. Maximum NVEs were seen in the superotemporal (ST; 0.9 ± 1.13) quadrant, followed by the inferotemporal (IT; 0.7 ± 1.08), inferonasal (IN; 0.66 ± 1.02) and superonasal (SN; 0.66 ± 1.01) quadrants. Maximum CNP area was seen in the SN (13.75 ± 8.83 disc diameter square [DD 2 ]) quadrant, followed by the IN (13.48 ± 8.59 DD 2 ), IT (11.34 ± 8.37 DD 2 ), and ST (11.3 ± 8.34 DD 2 ) quadrants. Mean CNP area was maximum in patients with only neovascularization of disc (NVD; 64.99 ± 41.47 DD 2 ), followed by both NVD and NVE (61.37 ± 35.61 DD 2 ), and was minimum in patients with only NVE (36.44 ± 22.03 DD 2 ). Eighty-one (32%) eyes out of 253 had NVE and 189 (75%) out of 253 had CNP area outside 7SF (overlay) of Early Treatment Diabetic Retinopathy Study (ETDRS)., Conclusion: Diabetic NV lesions and CNP areas are distributed asymmetrically throughout the retina and are not restricted to the posterior pole. Compared to conventional 7SF imaging, UWFFA reveals significantly more retinal vascular pathology in patients with PDR.

Purpose: To assess the value of en face OCT for detecting clinically unsuspected retinal neovascularization (RNV) in patients with nonproliferative diabetic retinopathy (NPDR)., Design: A retrospective, cross-sectional study., Participants: Treatment-naïve patients clinically graded as NPDR in an ongoing prospective observational OCT angiography (OCTA) study at a tertiary care center., Methods: Each patient underwent imaging of 1 eye with a spectral-domain OCTA, generating a 17 × 17-mm widefield image by montaging four 9 × 9-mm scans. Two independent graders examined a combination of en face OCT, en face OCTA with a custom vitreoretinal interface slab, and cross-sectional OCTA to determine the presence of RNV. We measured the area of RNV flow within RNV lesions on en face OCTA., Main Outcome Measures: Detection rate of clinically occult RNV with OCT and OCTA., Results: Of 63 enrolled eyes, 27 (43%) were clinically graded as severe NPDR, 16 (25%) as moderate NPDR, and 20 (32%) as mild NPDR. Using the combination of en face OCT, en face OCTA, and cross-sectional OCTA, the graders detected 42 RNV lesions in 12 (19%) eyes, of which 8 (67%) were graded as severe NPDR, 2 (17%) as moderate NPDR, and 2 (17%) as mild NPDR. The sensitivity of en face OCT alone for detecting eyes with RNV was similar to that of en face OCTA alone (100% vs. 92%; P = 0.32), whereas the specificity of en face OCT alone was significantly lower than that of en face OCTA alone (32% vs. 73%; P < 0.001). For detecting individual RNV lesions, the en face OCT was 100% sensitive, compared with 67% sensitivity for the en face OCTA (P < 0.001). The area of RNV lesions that manual grading with en face OCTA alone missed was significantly smaller than that of manually detectable RNV (Mean [standard deviation] RNV flow area, 0.015 [0.020] mm 2 vs. 0.16 [0.36] mm 2 ; P < 0.001)., Conclusion: The combination of en face OCT and OCTA can detect clinically occult RNV with high sensitivity. For screening these small lesions, en face OCT may be a useful imaging modality., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Retinal neovascularization (RNV) is an intractable pathological hallmark of numerous ocular blinding diseases, including diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. However, current therapeutic methods have potential side effects and limited efficacy. Thus, further studies on the pathogenesis of RNV-related disorders and novel therapeutic targets are critically required. Long non-coding RNAs (lncRNAs) have various functions and participate in almost all biological processes in living cells, such as translation, transcription, signal transduction, and cell cycle control. In addition, recent research has demonstrated critical modulatory roles of various lncRNAs in RNV. In this review, we summarize current knowledge about the expression and regulatory functions of lncRNAs related to the progression of pathological RNV., Methods: We searched databases such as PubMed and Web of Science to gather and review information from the published literature., Conclusions: In general, lncRNA MEG3 attenuates RNV, thus protecting the retina from excessive and dysregulated angiogenesis under high glucose stress. In contrast, lncRNAs MALAT1, MIAT, ANRIL, HOTAIR, HOTTIP, and SNHG16, have been identified as causative molecules in the pathological progression of RNV. Comprehensive and in-depth studies of the roles of lncRNAs in RNV indicate that targeting lncRNAs may be an alternative therapeutic approach in the near future, enabling new options for attenuating RNV progression and treating RNV-related retinal diseases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic retinopathy (DR) is one of the leading causes of vision loss worldwide. There are numerous animal models available for developing new ocular therapeutics and drug screening and to investigate the pathological processes involved in DR. Among those animal models, the oxygen-induced retinopathy (OIR) model, though originally developed as a model for retinopathy of prematurity, has also been used to investigate angiogenesis in proliferative DR with the phenomenon of ischemic avascular zones and pre-retinal neovascularization it demonstrated. Briefly, neonatal rodents are exposed to hyperoxia to induce vaso-obliteration. Upon removal from hyperoxia, hypoxia develops in the retina that eventually results in neovascularization. The OIR model is mostly used in small rodents such as mice and rats. Here, we describe a detailed experimental protocol of rat OIR model and the subsequent assessment of abnormal vasculature. By illustrating the vasculoprotective and anti-angiogenic activities of the treatment, OIR model might advance to a new platform for investigating novel ocular therapeutic strategies for DR., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Diabetic retinopathy (DR) is the most common microangiopathic complication of diabetes mellitus, representing a major cause of visual impairment in developed countries. Proliferative DR (PDR) represents the last stage of this extremely complex retinal disease, characterized by the development of neovascularization induced by the abnormal production and release of vascular endothelial growth factor (VEGF). The term VEGF includes different isoforms; VEGF-A represents one of the most important pathogenic factors of DR. Anti-VEGF intravitreal therapies radically changed the outcome of DR, due to combined anti-angiogenic and anti-edematous activities. Nowadays, several anti-VEGF molecules exist, characterized by different pharmacological features and duration. With respect to PDR, although anti-VEGF treatments represented a fundamental step forward in the management of this dramatic complication, a big debate is present in the literature regarding the role of anti-VEGF as substitute of panretinal photocoagulation or if these two approaches may be used in combination. In the present review, we provided an update on VEGF isoforms and their role in DR pathogenesis, on current anti-VEGF molecules and emerging new drugs, and on the current management strategies of PDR. There is an overall agreement regarding the relative advantage provided by anti-VEGF, especially looking at the management of PDR patients requiring vitrectomy, with respect to laser. Based on the current data, laser approaches might be avoided when a perfectly planned anti-VEGF therapeutic strategy can be adopted. Conversely, laser treatment may have a role for those patients unable to guarantee enough compliance to anti-VEGF injections.Key messagesVEGF increased production, stimulated by retinal hypoperfusion and ischaemia, is a major pathogenic factor of neovascular complication onset in diabetic retinopathy and of DR stages progression.Nowadays, several anti-VEGF molecules are available in clinical practice and other molecules are currently under investigation. Each anti-VEGF molecule is characterized by different targets and may interact with multiple biochemical pathways within the eye.All the data agreed in considering anti-VEGF molecules as a first line choice for the management of diabetic retinopathy. Laser treatments may have a role in selected advanced cases and for those patients unable to guarantee enough compliance to intravitreal treatments schemes.

Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia-specific Transforming Growth Factor-β (Tgfβ) receptor knock out mouse model and human iPSC-derived microglia to examine the role of Tgfβ signaling in activated microglia during retinal NV. Using a tamoxifen-inducible, microglia-specific Tgfβ receptor type 2 (Tgfβr2) knockout mouse [Tgfβr2 KO (ΔMG)] we show that Tgfβ signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfβ signaling represses expression of the pro-angiogenic factor, Insulin-like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen-induced retinopathy (OIR) we show that Tgfβ signaling in activated microglia plays a role in hypoxia-induced NV where a loss in Tgfβ signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC-derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor-β1 (Tgfβ1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfβ signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfβ signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Purpose: To summarize all reported cases of Henle fiber layer (HFL) hemorrhage in the absence of subretinal neovascularization (SRNV) in patients with macular telangiectasia type 2 (MacTel2) and to propose a mechanism for the right-sided predominance of this unique presentation., Design: Perspective., Methods: Collection, review, and analysis of all cases in the literature and in the authors' databases of HFL hemorrhage in MacTel2, including analysis of baseline and follow-up multimodal retinal imaging findings of selected cases. Elucidation of the complex interplay of systemic venous pressure with the deep retinal capillary plexus and hypothesis regarding the right-sided predilection of HFL hemorrhage complicating MacTel2., Results: Ten patients presented with a unilateral, characteristic radial macular hemorrhage within the HFL that affected only the right eye in all cases. Absence of SRNV was confirmed by fluorescein angiography and/or optical coherence tomography angiography. The hemorrhage resolved spontaneously in at least 7 of the 10 eyes. The HFL hemorrhage may plausibly be explained by dysfunction of the deep capillary plexus in MacTel2 combined with an acute rise in central venous pressure, for which the right side may be at increased risk., Conclusions: HFL hemorrhage can complicate MacTel2 in the absence of SRNV, and the radial pattern of blood affecting only the right eye is remarkable. The right eye predominance may be multifactorial in etiology. Related factors may include the right-sided predilection of MacTel2 and/or increased right-sided dural sinus drainage related to normal anatomical variation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To report a rare presentation of ocular von Hippel-Lindau disease associated with a massive epiretinal vascular proliferation over the macula removed by vitrectomy and submitted to histological analysis., Methods: Interventional case report., Results: A 13-year-old woman with von Hippel-Lindau disease reported progressive visual loss in the right eye over the preceding 6 months. Best-corrected visual acuity was 20/100 in the right eye. Fundoscopy showed retinal neovascularization (RNV) with macular traction and a small superotemporal hemangioblastoma. Spectral-domain optical coherence tomography confirmed increased macular thickness and macular traction secondary to RNV. Bevacizumab was injected intravitreally, resulting in partial regression of RNV. Five days after the injection, the patient underwent complete removal of fibrovascular proliferation via pars plana vitrectomy, followed by peripheral tumor photocoagulation. The specimen was subjected to histopathological and immunohistochemical analyses. At 2 years of follow-up, vision had improved to 20/30, and anatomical improvement was confirmed on both fundoscopy and spectral-domain optical coherence tomography., Conclusion: Ocular von Hippel-Lindau disease may be associated with RNV and macular traction. In such cases, RNV is likely responsive to anti-vascular endothelial growth factor and may be removed surgically along a cleavage plane between the tissue proliferation and the inner retina. In the reported case, the procedure was found to be safe and associated with macular anatomical improvement and vision recovery.

Background: Retinopathy of prematurity (ROP) remains the leading cause for blindness in children. Limited hyperoxia induced proliferative retinopathy (L-HIPR) was recently introduced as a potential animal model for ROP and persistent fetal vasculature; however, the detailed pathological changes remain unclear., Methods: To model L-HIPR, we placed C57BL/6J mice in 65% oxygen from birth to post-natal day 7 (P7). We examined eyes at intervals between P12 and P30. Retinal morphometry, thickness, and preretinal fibrosis were quantified at different time points on histological sections stained with hematoxylin and eosin (H&E) and Masson Trichrome, respectively. Vascular development, angiogenesis, inflammation, and pericyte coverage were analyzed using immunohistochemistry staining in retinal flat mounts and cross sections., Results: In L-HIPR, the hyaloidal vessels persisted until the latest time point in this study, P30 and began to invaginate the peripheral then central retina starting at P12. Central retinal distortion was noted beginning at P17, while the peripheral retina demonstrated a trend of thinning from P12 to P30. We found that L-HIPR was associated with delayed and abnormal retinal vascular development with subsequent retinal inflammation, pericyte loss and preretinal fibrosis., Conclusion: Our study presents a detailed analysis of the L-HIPR animal model demonstrating vitreoretinal pathologic changes, preretinal fibrosis and persistent hyaloidal vessels into adulthood. Based on our findings, we suggest that the persistence and peculiar stepwise migration of the hyaloidal vessels into the retina may provide a potential rescue mechanism for inner retinal development that deserves further study., Competing Interests: The authors have declared that no competing interests exist.

For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti-vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic factors that promote disease progression. To identify these factors, we performed multiplex ELISA angiogenesis arrays on aqueous fluid from PDR patients who responded inadequately to anti-VEGF therapy and/or PRP and identified plasminogen activator inhibitor-1 (PAI-1). PAI-1 expression was increased in vitreous biopsies and neovascular tissue from PDR eyes, limited to retinal vascular cells, regulated by the transcription factor hypoxia-inducible factor (HIF)-2α, and necessary and sufficient to stimulate angiogenesis. Using a pharmacologic inhibitor of HIF-2α (PT-2385) or nanoparticle-mediated RNA interference targeting Pai1 , we demonstrate that the HIF-2α/PAI-1 axis is necessary for the development of retinal neovascularization in mice. These results suggest that targeting HIF-2α/PAI-1 will be an effective adjunct therapy for the treatment of PDR patients.

Background/aims: To explore whether the existence and pattern of distribution of macular haemorrhage or exudate can be valuable diagnostic markers for macular neovascularization type 3 (MNV3) in patients with neovascular age-related macular degeneration., Methods: Eighty-three eyes of 83 consecutive treatment naïve patients with stage 3 MNV3 were enrolled. The diagnosis was based on fluorescein angiography (FA) and optical coherence tomography (OCT). Subretinal and intraretinal haemorrhage and dense exudates were evaluated on colour fundus photography. Fluorescein angiography (FA) images and OCT scans were used to identify the axial location of the haemorrhage. 83 patients with MNV1 and 83 with MNV2 were included as two control groups., Results: In the MNV3 group, 62 (75%) eyes had intraretinal haemorrhage and 52 (63%) had dense exudates. 73 (88%) eyes had intraretinal haemorrhage and/or dense exudates. 41 (49%) had both pathologies. The intraretinal haemorrhage was flame shaped over the lesion and punctate or semi-punctate further away from it and directed to the fovea. No subretinal haemorrhage was noticed. In the MNV1 and MNV2 groups, 11 (13%) and 24 (29%) eyes had subretinal haemorrhage or dense exudates, respectively. No intraretinal haemorrhage was seen in the two control groups. The prevalence of exudates and haemorrhage (irrespective of its location) was greater in MNV3 than in MNV1 or 2 (p < 0.0001)., Conclusion: The existence and pattern of distribution of intraretinal haemorrhage is pathognomonic of MNV3. It makes (alone or with dense exudates) the diagnose MNV3 possible using fundoscopy or colour fundus photo and without further diagnostic expenditure., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To document enlarged neovascularization elsewhere (NVE) quantitatively and morphologically using widefield swept-source (SS) OCT angiography (OCTA) with vitreoretinal interface (VRI) slab images., Design: Retrospective, observational imaging study., Participants: The study included 46 NVE examples in 25 eyes of 21 consecutive patients who demonstrated severe proliferative diabetic retinopathy with NVE between March 2018 and June 2020 at Osaka University Hospital., Methods: All patients underwent ophthalmologic examination, including ultra-widefield fluorescein angiography and widefield SS OCTA scans., Main Outcome Measures: We evaluated the area and the vascular density (VD) of NVE lesions detected on five 12 × 12-mm 2 or two 15 × 9-mm 2 SS OCTA panoramic VRI slab images obtained at the first and final visits., Results: At baseline, the mean NVE area on OCTA was 1.85 ± 2.81 mm 2 , and the VD of the NVE lesions was 73.9 ± 14.6%. At the final visit, the mean NVE area on OCTA was 2.14 ± 3.14 mm 2 , and the mean VD of the NVE lesions was 65.3 ± 17.1%. The average NVE size change (square millimeters per month) was associated significantly with the ischemic index (P = 0.009). Growth of NVE area was classified into 2 patterns: round (61.8%) and ramified (38.2%). The round group tended to have a larger ischemic index at baseline than the ramified group (P = 0.0375)., Conclusions: We quantified the size and density of NVE lesions over time. The NVE size increase was associated significantly with the severity of ischemic changes. Furthermore, the round growth pattern was correlated significantly with the ischemic index. These findings suggest that the morphologic features of NVE are associated with more severe ischemia., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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.

Retinal neovascularization (RNV), a pathological process shared among diabetic retinopathy, retinopathy of prematurity and other retinopathies, has been widely studied, but the mechanism remains unclear. In this study, the mechanism by which the interleukin (IL)-23/IL-17 axis regulates RNV in oxygen-induced retinopathy (OIR) model mice and in cell experiments in vitro was characterized. In the retinas of OIR mice, IL-23/IL-17 axis activation was increased and regulated RNV formation, and this effect was accompanied by increased macrophage recruitment and nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome activation. Moreover, inhibiting the IL-23/IL-17 axis reduced the number of macrophage and the expression and activation of NLRP3 inflammasome. On the other hand, recombinant (r) IL-23p19 and rIL-17A promoted the expression and activation of NLRP3 inflammasome, and the proliferation and migration of macrophages. Furthermore, macrophage elimination decreased the activation of IL-23/IL-17 axis and the expression and activation of NLRP3 inflammasome. In summary, our experiments showed that the IL-23/IL-17 axis promoted the formation of RNV by activating the NLRP3 inflammasome in retinal macrophages of an OIR mouse model., (© 2021 John Wiley & Sons Ltd.)

Background: Retinal neovascularization (RNV) membranes can lead to a tractional retinal detachment, the primary reason for severe vision loss in end-stage disease proliferative diabetic retinopathy (PDR). The aim of this study was to characterize the molecular, cellular and immunological features of RNV in order to unravel potential novel drug treatments for PDR., Methods: A total of 43 patients undergoing vitrectomy for PDR, macular pucker or macular hole (control patients) were included in this study. The surgically removed RNV and epiretinal membranes were analyzed by RNA sequencing, single-cell based Imaging Mass Cytometry and conventional immunohistochemistry. Immune cells of the vitreous body, also known as hyalocytes, were isolated from patients with PDR by flow cytometry, cultivated and characterized by immunohistochemistry. A bioinformatical drug repurposing approach was applied in order to identify novel potential drug options for end-stage diabetic retinopathy disease., Results: The in-depth transcriptional and single-cell protein analysis of diabetic RNV tissue samples revealed an accumulation of endothelial cells, macrophages and myofibroblasts as well as an abundance of secreted ECM proteins such as SPARC, FN1 and several types of collagen in RNV tissue. The immunohistochemical staining of cultivated vitreal hyalocytes from patients with PDR showed that hyalocytes express α-SMA (alpha-smooth muscle actin), a classic myofibroblast marker. According to our drug repurposing analysis, imatinib emerged as a potential immunomodulatory drug option for future treatment of PDR., Conclusion: This study delivers the first in-depth transcriptional and single-cell proteomic characterization of RNV tissue samples. Our data suggest an important role of hyalocyte-to-myofibroblast transdifferentiation in the pathogenesis of diabetic vitreoretinal disease and their modulation as a novel possible clinical approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boneva, Wolf, Hajdú, Prinz, Salié, Schlecht, Killmer, Laich, Faatz, Lommatzsch, Busch, Bucher, Stahl, Böhringer, Bengsch, Schlunck, Agostini and Lange.)

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.)

The microRNAs miR-17-5p and miR-20a-5p play important roles on angiogenesis; however, it is arguable whether they regulate the formation of retinal blood vessels in retinopathy of prematurity (ROP). We used a mouse model of oxygen-induced retinopathy (OIR) to simulate the development of retinas in mice suffering from ROP, and the expression levels of miR-20a-5p, miR-17-5p, hypoxia-inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF) were measured by RT-qPCR and Western blotting. Cell proliferation, apoptosis, and angiogenesis in the OIR model mice were measured using MTT assays, flow cytometry, and Matrigel assays, respectively. The interaction between HIF-1α/VEGF and miR-20a-5p/miR-17-5p were further validated using dual-luciferase reporter assays, biotin-labeled RNA-pulldown, and RNA immunoprecipitation (RIP) assays. In our OIR model, retinal angiogenesis in the mice was associated with down-regulation of miR-20a-5p and miR-17-5p, as well as up-regulation of HIF-1α and VEGF. In addition, the miR-20a-5p and miR-17-5p inhibited cell proliferation and angiogenesis through regulating HIF-1α and VEGF in the retinal cells of the OIR model mice. Moreover, it was found that miR-20a-5p and miR-17-5p bind to HIF-1α and VEGF at the 3'UTR, and there was a combined effect between miR-20a-5p and miR-17-5p on the regulation of HIF-1α and VEGF. It is worth noting that miR-17-5p and miR-20a-5p can preferentially regulate HIF-1α, then act on VEGF, thereby affecting the angiogenesis associated with ROP.

Genistein, a natural tyrosine kinase inhibitor, may act as an intraocular antiangiogenic agent. Its therapeutical use, however, is limited by its nonlinear pharmacokinetics. We aimed to determine genistein's kinetics and retinal tissue distributions in normal and diabetic rats. We developed an isocratic, reverse-phase C18 HPLC system to measure genistein concentration in blood and retinas of streptozotocin (65 mg/kg IV)-diabetic and non-diabetic rats receiving two types of genistein-rich diet (150 and 300 mg/kg) for ten days. Genistein's decay exhibited a two-compartmental open model. Half-lives of distribution and elimination were 2.09 and 71.79 min, with no difference between groups. Genistein steady-state concentration in blood for 150 and 300 mg/kg diet did not differ between diabetic (0.259 ± 0.07 and 0.26 ± 0.06 μg/ml) and non-diabetic rats (0.192 ± 0.05 and 0.183 ± 0.09 μg/ml). In retina, genistein concentration was significantly higher in diabetic rats (1.05 ± 0.47 and 0.997 ± 0.47 μg/gm wt. vs. 0.087 ± 0.11 and 0.314 ± 0.18 μg/gm wt., p < 0.05). The study determined that increasing genistein dose did not change its bioavailability, perhaps due to the poor aqueous solubility. The retina's increased genistein could be due to increased permeability of blood-retinal barrier that occurs early in diabetes., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. All rights reserved.)