Sea-fan retinal neovascularization associated with rickettsial retinitis: a case report.

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.

MICROVASCULAR CHANGES IN TREATMENT-NAÏVE NONEXUDATIVE MACULAR NEOVASCULARIZATION COMPLICATED BY EXUDATION.

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.

RETICULAR PSEUDODRUSEN DISAPPEARANCE AFTER DEVELOPMENT OF MACULAR NEOVASCULARIZATION.

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.

Iron Chelator Deferiprone Restores Iron Homeostasis and Inhibits Retinal Neovascularization in Experimental Neovascular Age-Related Macular Degeneration.

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.

A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy.

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-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-3399-270 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-3399-270 and IL-33109-270 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-3399-270 and IL-33109-270, 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.

FROM OUTER RETINAL NEOVACULARIZATION TO EXUDATIVE SUBRETINAL NEOVASCULARIZATION IN MACULAR TELANGIECTASIA TYPE 2.

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.

Isolated Retinal Neovascularization in Retinopathy of Prematurity: Clinical Associations and Prognostic Implications.

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.

Occult retinal neovascularization following intravitreal bevacizumab and laser treatment for retinopathy of prematurity.

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.

Atypical case of choroidal osteoma associated to polypoidal choroidal vasculopathy and preretinal neovascular membrane.

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.

Cytomegalovirus-Associated Non-Necrotizing Retinopathy, Occlusive Retinal Vasculitis, and Neovascularization.

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.

DEEP LEARNING FOR AUTOMATIC PREDICTION OF EARLY ACTIVATION OF TREATMENT-NAIVE NONEXUDATIVE MACULAR NEOVASCULARIZATIONS IN AGE-RELATED MACULAR DEGENERATION.

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.

SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages.

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.

The potential key role of choroidal non-perfusion and rod degeneration in the pathogenesis of macular neovascularization type 3.

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.

Factors associated with the development of exudation in treatment-naive eyes with nonexudative macular neovascularization.

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.

Reperfusion of retinal nonperfusion by neovascular-vascular anastomosis in proliferative diabetic retinopathy.

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.

Characteristics, Etiology, and Clinical Outcome of Retinal Vasculitis in Tertiary Hospital in Thailand.

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.

Limited Hyperoxia-Induced Proliferative Retinopathy (LHIPR) as a Model of Retinal Fibrosis, Angiogenesis, and Inflammation.

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.

Topographic distribution of retinal neovascularization in proliferative diabetic retinopathy using ultra-wide field angiography.

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 [DD2]) quadrant, followed by the IN (13.48 ± 8.59 DD2), IT (11.34 ± 8.37 DD2), and ST (11.3 ± 8.34 DD2) quadrants. Mean CNP area was maximum in patients with only neovascularization of disc (NVD; 64.99 ± 41.47 DD2), followed by both NVD and NVE (61.37 ± 35.61 DD2), and was minimum in patients with only NVE (36.44 ± 22.03 DD2). 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.

Oxygen-Induced Retinopathy in the Rat: An Animal Model to Study the Proliferative Retinal Vascular Pathology.

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.