Neovascularization In Proliferative Diabetic Retinopathy Research Articles

Clinical and imaging characteristics associated with foveal neovascularization in proliferative diabetic retinopathy.

To assess the prevalence of foveal neovascularization (FNV) and its associated clinical features in proliferative diabetic retinopathy (PDR) eyes. Cross-sectional observational study. Participants underwent ultra-widefield photography, optical coherence tomography (OCT), and swept-source OCT angiography (SS-OCTA). FNV was defined as a hyperreflective lesion breaching the internal limiting membrane and displaying flow signal on OCTA, within 1-mm of foveal avascular zone. Vascular metrics were obtained from the ARI Network portal. Ischemic index (ISI) and inner choroid flow deficit percentage were calculated using FIJI from 12 × 12 and 6 × 6-mm scans, respectively. Logistic regression models were used to compare eyes with and without FNV. We included 249 eyes of 164 patients (age: 58 [50-65] years). FNV was identified in 20 eyes (8%). Univariate logistic regression revealed significant associations between FNV and younger age (p = 0.03), higher maximal HbA1c (p = 0.04), worse visual acuity (VA) (p = 0.01), presence of disorganization of retinal inner layers (DRIL) (p = 0.01), no macular posterior vitreous detachment (PVD) (p = 0.03), neovascularization elsewhere (NVE) and at the disc (NVD) (p = 0.01 and p = 0.001), and greater ISI (p = 0.04). In multivariable analysis, a significant association remained between FNV and worse VA (p = 0.04), NVD (p < 0.001), DRIL (p < 0.001), and absence of macular PVD (p = 0.01). No associations were found with SS-OCTA vascular metrics. This study provides a comprehensive characterization of FNV in PDR. FNV was identified in 8% of our cohort, being more prevalent in younger patients with severe PDR, as evidenced by NVD and DRIL presence. The absence of macular PVD may explain its association with younger age. What is known • Neovascularization at the fovea occurs rarely in proliferative diabetic retinopathy. • OCT and OCT-angiography can be used to evaluate foveal neovascularization, which may be associated with choroidal vascular abnormalities. What is new • Foveal neovascularization was seen in 8% of eyes with proliferative diabetic retinopathy in this cohort. • Risk factors for foveal neovascularization included younger age, absence of macular posterior vitreous detachment, presence of neovascularization of the disc, and presence of disorganization of retinal inner layers. • We did not identify an association between foveal neovascularization and choroidal perfusion abnormalities in this study.

TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy

BackgroundStudies have shown that tet methylcytosine dioxygenase 2 (TET2) is highly expressed in diabetic retinopathy (DR), which reduces the DNA methylation of downstream gene promoters and activates the transcription. Abnormally expressed TET2 and downstream genes in a high-glucose environment are associated with retinal capillary leakage and neovascularization. Here, we investigated the downstream genes of TET2 and its potential association with neovascularization in proliferative diabetic retinopathy (PDR).MethodsGSE60436, GSE57362, and GSE158333 datasets were analyzed to identify TET2-related hypomethylated and upregulated genes in PDR. Gene expression and promoter methylation of these genes under high glucose treatment were verified. Moreover, TET2 knockdown was used to assess its impact on tube formation and migration in human retinal microvascular endothelial cells (HRMECs), as well as its influence on downstream genes.ResultsOur analysis identified three key genes (PARVB, PTPRE, ECM1) that were closely associated with TET2 regulation. High glucose-treated HRMECs exhibited increased expression of TET2 and ECM1 while decreasing the promoter methylation level of ECM1. Subsequently, TET2 knockdown led to decreased migration ability and tube formation function of HRMECs. We further found a decreased expression of PARVB, PTPRE, and ECM1, accompanied by an increase in the promoter methylation of ECM1.ConclusionsOur findings indicate the involvement of dysregulated TET2 expression in neovascularization by regulating the promoter methylation and transcription of downstream genes (notably ECM1), eventually leading to PDR. The TET2-induced hypomethylation of downstream gene promoters represents a potential therapeutic target and offers a novel perspective on the mechanism underlying neovascularization in PDR.Graphical

Foveal neovascularization in proliferative diabetic retinopathy: Characterization with OCTA

Foveal neovascularization (FNV) is a rare clinical finding in conditions with vascular compromise, leading to ischemia of the retina. We present a case of proliferative diabetic retinopathy (PDR) with FNV, where optical coherence tomography angiography (OCTA) confirmed the architecture, extent, activity, and origin of a hemorrhage-like clump at the fovea. Digital Florescein Angiography (DFA) showed PDR (both eyes), but intra-retina microvascular abnormalities (IrMAs) or FNV could not be differentiated at the site of leak in right eye fovea. OCTA confirmed a FNV breaching the internal limiting membrane (ILM), protruding into vitreous, and determined its origin from superficial vascular plexus (SVC). Also, segmentation revealed flow voids in choriocapillaris slab, suggesting choroidal ischemia.

Volumetric Three-Dimensional Optical Coherence Tomography Angiography of Retinal Neovascularization in Proliferative Diabetic Retinopathy.

To evaluate structural and angiographic neovascularization in patients with proliferative diabetic retinopathy (PDR) using volumetric three-dimensional optical coherence tomography angiography (OCTA). This prospective, observational cross-sectional study included 29 eyes of 27 patients with PDR. The angiogenic structure, feeding vessel (epicenter), flow volume, and flow volume density (FVD) of the neovasculatures were evaluated using three-dimensional OCTA imaging. The flow area and the flow area density (FAD) were also measured using en face OCTA imaging. Sites of neovascularization were imaged successfully in 17 of the 29 eyes (58.6%). Three proposed types of neovascularization were identified on the basis of structural features seen on the three-dimensional OCTA images. Neovascularization of the adhesion type (9 of 17, 52.9%) adhered to the retinal vasculature. Those of the traction type (5 of 17, 29.4%) were partially separated from the retinal vascular plexus. Those of the mushroom type (3 of 17, 17.6%) were connected to the retinal vasculature via several epicenters. There was a significant difference between highly leaky (active) and faintly leaky (inactive) neovascularization for FVD, but not for flow area, flow volume, or FAD (P=0.01, 0.9, 0.6, and 0.1, respectively). Volumetric three-dimensional OCTA revealed three types of neovascularization in PDR, and may be useful for assessing neovascular activity and planning vitrectomies.

Long Noncoding RNA PPT2-EGFL8 Regulates Pathological Retinal Neovascularization in PDR by Functioning as a Competing Endogenous RNA.

Diabetic retinopathy (DR) is a common complication in patients with diabetes, and proliferative DR (PDR) has become an important cause of blindness; however, the mechanisms involved have not been fully elucidated. miRNAs and long noncoding RNAs can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: competing endogenous RNAs. We isolated total RNA of extracellular vesicles (EVs) in the serum of healthy individuals and individuals with diabetes without DR, non-PDR, or PDR, and performed deep sequencing. We found aberrantly low expression of PPT2-EGFL8 and significantly increased level of miR-423-5p. PPT2-EGFL8 adsorbs miR-423-5p as a molecular sponge and inhibits hypoxia-induced human retinal microvascular endothelial cells proliferation. In an oxygen-induced retinopathy (OIR) model and a streptozotocin-induced diabetes model, Egfl8-overexpression treatment reduces diabetes-related reactive gliosis, inflammation, and acellular capillaries and attenuates the development of pathological neovascularization. In addition, PPT2-EGFL8 targeting miR-423-5p plays an important role in hypoxia-induced peroxisome proliferator-activated receptor-β/δ (PPARD)/angiopoietin-like 4 (ANGPTL4) signaling activation, especially the expression of the C-terminal ANGPTL4 fragment. Finally, ANGPTL4 significantly induces retinal vessel breakage in the inner limiting membrane and facilitates retinal vessel sprouting into the vitreous in the OIR mice. Thus, either new biomarkers or new therapeutic targets may be identified with translation of these findings.

Triple-DRNet: A triple-cascade convolution neural network for diabetic retinopathy grading using fundus images

Diabetic Retinopathy (DR) is a universal ocular complication of diabetes patients and also the main disease that causes blindness in the world wide. Automatic and efficient DR grading acts a vital role in timely treatment. However, it is difficult to effectively distinguish different types of distinct lesions (such as neovascularization in proliferative DR, microaneurysms in mild NPDR, etc.) using traditional convolutional neural networks (CNN), which greatly affects the ultimate classification results. In this article, we propose a triple-cascade network model (Triple-DRNet) to solve the aforementioned issue. The Triple-DRNet effectively subdivides the classification of five types of DR as well as improves the grading performance which mainly includes the following aspects: (1) In the first stage, the network carries out two types of classification, namely DR and No DR. (2) In the second stage, the cascade network is intended to distinguish the two categories between PDR and NPDR. (3) The final cascade network will be designed to differentiate the mild, moderate and severe types in NPDR. Experimental results show that the ACC of the Triple-DRNet on the APTOS 2019 Blindness Detection dataset achieves 92.08%, and the QWK metric reaches 93.62%, which proves the effectiveness of the devised Triple-DRNet compared with other mainstream models.

Therapeutic effect of ultra-long-lasting human C-peptide delivery against hyperglycemia-induced neovascularization in diabetic retinopathy.

Rationale: Neovascularization is a hallmark of the late stages of diabetic retinopathy (DR) leading to blindness. The current anti-DR drugs have clinical disadvantages including short circulation half-lives and the need for frequent intraocular administration. New therapies with long-lasting drug release and minimal side effects are therefore needed. We explored a novel function and mechanism of a proinsulin C-peptide molecule with ultra-long-lasting delivery characteristics for the prevention of retinal neovascularization in proliferative diabetic retinopathy (PDR). Methods: We developed a strategy for ultra-long intraocular delivery of human C-peptide using an intravitreal depot of K9-C-peptide, a human C-peptide conjugated to a thermosensitive biopolymer, and investigated its inhibitory effect on hyperglycemia-induced retinal neovascularization using human retinal endothelial cells (HRECs) and PDR mice. Results: In HRECs, high glucose conditions induced oxidative stress and microvascular permeability, and K9-C-peptide suppressed those effects similarly to unconjugated human C-peptide. A single intravitreal injection of K9-C-peptide in mice resulted in the slow release of human C-peptide that maintained physiological levels of C-peptide in the intraocular space for at least 56 days without inducing retinal cytotoxicity. In PDR mice, intraocular K9-C-peptide attenuated diabetic retinal neovascularization by normalizing hyperglycemia-induced oxidative stress, vascular leakage, and inflammation and restoring blood-retinal barrier function and the balance between pro- and anti-angiogenic factors. Conclusions: K9-C-peptide provides ultra-long-lasting intraocular delivery of human C-peptide as an anti-angiogenic agent to attenuate retinal neovascularization in PDR.

Contributory factors for developing foveal neovascularization in proliferative diabetic retinopathy

Foveal neovascularisation (NV) in proliferative diabetic retinopathy (PDR) is uncommon. The study aim is to analyse a series of cases of foveal NV in PDR and ascertain the factors leading to its development. In this retrospective case-control study, optical coherence tomography (OCT) and OCT-angiography (OCTA) images of PDR cases with/without foveal NV diagnosed on fluorescein angiography were analysed. From 124 consecutive PDR eyes, foveal NV was identified in 12 (10%) eyes. Eyes with foveal NV showed thin choroid (p = 0.001), increased FAZ area and reduced vessel density at the macula compared to control group on OCT and OCTA. After regression analysis, an increased FAZ in the superficial capillary plexus slab (p = 0.002) was associated with foveal NV development. Our case series suggest that foveal NV is an uncommon finding, occurring due to reduced choroidal and inner retinal perfusion at the macula. Further studies are required to assess the treatment outcomes in such eyes.

Characterizing Flow and Structure of Diabetic Retinal Neovascularization after Intravitreal Anti-VEGF Using Optical Coherence Tomography Angiography: A Pilot Study.

Background/Aims. This study evaluates changes of flow and structure of diabetic retinal neovascularization (NV) treated with intravitreal antivascular endothelial growth factor (VEGF) agents using optical coherence tomography angiography (OCTA). With OCTA, retinal blood vessels are visualized at high resolution to separately look at flow and structure information without the need for dye injection. We introduce a new measurement method including and combining information of flow and structure. Methods. Retrospective observational case series. Patients with proliferative diabetic retinopathy (PDR) were treated with intravitreal antiVEGF injections. Retinal NV were repeatedly imaged using swept-source OCTA (Zeiss PlexElite 9000) at baseline, after initial treatment block with 3-4 monthly injections, and during a follow-up period of up to 51 weeks. Change of size and flow density of the structural and angio area of NV was assessed. Results. Nine NV in eight eyes of five patients were analyzed with a median follow-up time of 45 weeks. After the initial treatment block, en face structural area regressed, 18.7% ± 39.0% (95% CI 44.2–6.8%, p=0.26), and en face angio area regressed, 51.9% ± 29.5% (95% CI 32.6 to 71.2%, p=0.007). Flow density within the en face structural area decreased by 33% ± 19.2% (95% CI 20.5–45.5%, p=0.0077). Flow density within the en face angio area decreased by mean 17.9% ± 25.2% (95% CI 1.4–34.4%, p=0.066). In two fellow eyes, NV recurrence could be observed before the onset of vitreous bleeding in one. Conclusion. Our study introduces a new quantitative measurement for NV in PDR, combining structure and flow measurement. The structure area remained after treatment, while its flow density and angio area regressed. We propose this measurement method as a more physiological and possibly more comparable metrics.

Pattern and distribution of neovascularization in proliferative diabetic retinopathy on fundus fluorescein angiography: A growing paradigm

BackgroundThe objective of this study was to evaluate pattern and distribution of neovascularization of optic disc (NVD) and elsewhere (NVE) in proliferative diabetic retinopathy (PDR). MethodsA cross-sectional study was conducted among freshly detected cases of PDR. Fundus fluorescein angiographic images of 61 eyes were assessed. Parameters studied for NVD were their number and location and for NVE were their number, location, type of leak, and distance from center of optic disc. ResultsOf 61 eyes, 29 eyes (47.5%) had NVD with a total of 49 leaks. Of these 49 NVD leaks, the maximum was concentrated in the superotemporal quadrant with 21 leaks (42.9%; 95%CI 28.8–57.8%). Of 61 eyes, 50 eyes (82%) had NVE with 97 leaks. Of 97 NVE leaks, 41 were found in the superotemporal quadrant (42.3%; 95%CI 32.3–52.7%). Maximum NVE was found within the circle of radius 3–6 mm centered on optic disc (p value = 0.001) with no leaks in central macula. Of 29 eyes with NVD, only 7 eyes had >1/3 area of disc involvement. Also, of 18 eyes with concurrent NVD and NVE, only 2 eyes had >1/3 area of disc involvement which is a high-risk characteristic of PDR. ConclusionNeovascular lesions have a predilection for superotemporal part for both NVD and NVE. NVE leaks were almost double the number of NVD leaks. Maximum NVE leaks were found at posterior pole with no central macular involvement. This study provides comprehensive data and further adds to knowledge of neovascularization for early diagnosis and management of PDR.

Optical Coherence Tomography Angiography Findings in Proliferative Diabetic Retinopathy

Purpose: To characterize preretinal neovascularizations (NV) and their corresponding branching routes in proliferative diabetic retinopathy (PDR) with optical coherence tomography angiography (OCTA) and compare the findings with fluorescein angiography (FA). Methods: In patients with PDR, angiograms were acquired with spectral-domain OCTA (CIRRUS 5000, OCTA AngioPlex^TMCarl Zeiss Meditec, Inc.) and FA (Zeiss FF450PlusIR fundus camera or Spectralis HRA-OCT SLO, Heidelberg Engineering Inc.) and were consecutively evaluated. Neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) were analyzed with 6 × 6 and 8 × 8 mm OCTA flow images and B-scans with flow registration. Segmentations of the vitreoretinal interface (VRI) and superficial retina were performed for analysis. Two independent investigators examined OCTA findings and compared them to corresponding FA. Results: Forty-two eyes of 30 patients with PDR were analyzed. A total of 76 NV with their corresponding proliferation routes were visualized and characterized, with 55 (72.4%) proliferating along the posterior hyaloid membrane (PHM), 14 (18.4%) along the epiretinal membrane, and 7 (9.2%) along the fibrovascular membrane. The posterior vitreous was partially detached in 37 of 42 eyes (88.1%), completely detached in 1 of 42 eyes (2.4%), and adherent in 1 of 42 eyes (2.4%). In 38 of 42 cases, OCTA was superior (n = 23) or equivalent (n = 15) to FA in detecting NV and provided a more detailed information of the neovascular vessels. In 4 of 42 study eyes, OCTA was inferior to FA. Conclusions: OCTA is a useful tool to detect NV in PDR. In comparison to FA, OCTA has the advantages that it is noninvasive and the image capture takes only seconds. We were able to identify all NV and characterize their corresponding proliferation routes in the VRI, the superficial retina slab, or the B-scan with flow registration. Through evading the masking effect of dye leakage in FA, OCTA is capable of better visualization of NV. FA, however, remains essential for the detection of all NV, since OCTA supplies a smaller detection field. Additionally, we identified the PHM as the main proliferating route of diabetic NV (72.4%), marking it as an important structure for sprouting vessels in neoangiogenesis in PDR.

Association of the Pattern of Retinal Capillary Non-Perfusion and Vascular Leakage with Retinal Neovascularization in Proliferative Diabetic Retinopathy.

Purpose:To explore the correlation between retinal capillary non-perfusion and the distribution of retinal neovascularization and vascular leakage (VL) in patients with proliferative diabetic retinopathy (PDR).Methods:Ultra-widefield angiograms of 96 eyes of 69 patients with PDR were reviewed for the proportion of non-perfused area to total gradable area, and for the presence of neovascularization and VL.Results:Retinal neovascularization was distributed as such: neovascularization elsewhere (NVE), 57.3%; neovascularization of the disc (NVD), 11.5%; both neovascularization of the disc and elsewhere (NVED), 31.3%. The proportion of non-perfused retina, so-called ischemic index, was greater in eyes with NVED compared to eyes with NVE only, but not when compared to NVD only. Overall, 83% of eyes had VL. The presence and the extent of VL correlated with the proportion of the ischemic index. While VL and ischemic index were more severe in the mid-periphery and far-periphery, the majority of NVE was located in the posterior pole.Conclusions:The presence of both NVD and NVE is associated with a greater ischemic index than NVE alone. Although both VL and ischemic index is significantly higher in peripheral zones, the majority of neovascularization occurs at the posterior pole.

Near-infrared reflectance imaging of neovascularization in proliferative diabetic retinopathy

BackgroundBlood is one of the main absorbers in the near-infrared spectrum and thus retinal vessels appear dark in near-infrared reflectance (NIR) images. Proliferative diabetic retinopathy (PDR) is characterized by abnormal neovascularization which also absorbs light and appears dark against a lighter fundus background. We analyzed neovascularization in PDR using NIR imaging, by observing changes in the neovascular complexes (NVCs) contrast and reflectivity over time.MethodsRetrospective case series of 20 eyes of 17 patients with PDR who underwent NIR imaging with optical coherence tomography (OCT) using the Spectralis System. NVCs presence and activity was determined using clinical, tomographic and angiographic criteria. At baseline, all NVCs were qualitatively graded in the NIR image into 3 groups (absent, present and inactive and present and active) and their evolution over time was registered as progression, regression or same status.ResultsTwenty-seven NVCs were imaged, of which, 52% were neovascularization of the disc (NVD) and 48% were elsewhere (NVE). Consecutive NIR images were obtained from baseline to up to 5 time-points with a mean follow-up of 3.2 ± 1.7 years. All eyes underwent laser treatment and 30% had additional intravitreal therapy. Using NIR imaging, NVCs were classified at baseline as absent, present and inactive and present and active, respectively in 11, 4 and 85% of cases. NIR identified active neovascularization as hyporeflective irregular dark vessels originating from the retinal venules in NVE or from the disc in NVD. In all groups during follow-up, progression was identified as the development of new vascular hyporeflective dark fronds while regression was shown by reduced dark perfusion. Five eyes developed a wolf’s jaw configuration with vascular hyporeflective new vessels and hyperreflective tissue from extensive fibrosis. Fibrosis was more apparent in later images, reaching 86%. In 3 cases (11%), the NVC was no longer seen in NIR, although was still identifiable on OCT over the NVC area.ConclusionsNIR is a non-invasive imaging modality commonly performed alongside OCT and frequently overlooked which can be useful to evaluate NVCs in PDR. Changes in NVC contrast and reflectivity due to blood perfusion can help in the detection and monitoring of diabetic proliferative disease and aid clinicians in daily practice.

Vitreoretinal Interface Slab in OCT Angiography for Detecting Diabetic Retinal Neovascularization

To compare neovascularization identified in proliferative diabetic retinopathy (PDR) eyes by widefield swept-source (SS) OCT angiography (OCTA) using vitreoretinal interface (VRI) slab images, composed by automated and manual segmentation, with that identified by fluorescein angiography (FA). Retrospective study. Forty-two eyes of 30 treatment-naïve PDR patients who visited the outpatient clinic of the Department of Ophthalmology, Shinshu University, from June 2018 through October2019. All patients underwent comprehensive ophthalmologic examinations, including SS-OCTA and FA. Neovascularization detected by en face SS-OCTA 15× 15-mm VRI slab images and by FA in the same 15× 15-mm areas were compared in terms of number and structure. Among 100 neovascularizations detected by FA, 73 also were visualized as neovascularization in SS-OCTA VRI slab images using automated segmentation. The sensitivity of VRI slab images for detecting neovascularization was 73%. Among the remaining 27 neovascularizations detected only by FA, but not by VRI slab, 15 were intraretinal microvascular abnormalities with fluorescence leakage, 1 was a diabetic papillopathy, and 11 were flat neovascularizations on the internal limiting membrane surface that were missed because of segmentation error. Conversely, among the 98 neovascularizations detected on VRI slab images, 25 were not detected as neovascularizations by FA. They included 9 small neovascularizations that exhibited too little leakage on FA and 16 false-positive results that were the result of segmentation errors. After reconstruction of SS-OCTA VRI slab images by means of manual segmentation, the sensitivity of VRI slab images for detecting neovascularizations increased to 84%. The efficacy of SS-OCTA VRI slab images for detecting neovascularizations in PDR was comparable with that of FA. Swept-source OCTA VRI slab images may be better than FA for identifying intraretinal microvascular abnormalities and diabetic papillopathy from neovascularizations. Notably, however, FA and SS-OCTA VRI slab images demonstrated differences in identification efficacy in cases of small and flat neovascularizations. Further exploration of SS-OCTA technology is warranted to address this issue.

The Inhibitory Effects of Gold Nanoparticles on VEGF-A-Induced Cell Migration in Choroid-Retina Endothelial Cells.

Background: Vascular endothelial growth factor (VEGF) is upregulated by hypoxia and is a crucial stimulator for choroidal neovascularization (CNV) in age-related macular degeneration and pathologic myopia, as well as retinal neovascularization in proliferative diabetic retinopathy. Retinal and choroidal endothelial cells play key roles in the development of retinal and CNV, and subsequent fibrosis. At present, the effects of gold nanoparticles (AuNPs) on the VEGF-induced choroid-retina endothelial (RF/6A) cells are still unknown. In our study, we investigated the effects of AuNPs on RF/6A cell viabilities and cell adhesion to fibronectin, a major ECM protein of fibrovascular membrane. Furthermore, the inhibitory effects of AuNPs on RF/6A cell migration induced by VEGF and its signaling were studied. Methods: The cell viability assay was used to determine the viability of cells treated with AuNPs. The migration of RF/6A cells was assessed by the Transwell migration assay. The cell adhesion to fibronectin was examined by an adhesion assay. The VEGF-induced signaling pathways were determined by western blotting. Results: The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay revealed no cytotoxicity of AuNPs on RF/6A cells. AuNPs inhibited VEGF-induced RF/6A cell migration in a concentration-dependent manner but showed no significant effects on RF/6A cell adhesion to fibronectin. Inhibitory effects of AuNPs on VEGF-induced Akt/eNOS were found. Conclusions: These results suggest that AuNPs are an effective inhibitor of VEGF-induced RF/6A cell migration through the Akt/eNOS pathways, but they have no effects on their cell viabilities and cell adhesion to fibronectin.

Widefield Swept-Source Optical Coherence Tomography Angiography of Proliferative Diabetic Retinopathy.

To demonstrate the utility of widefield swept-source optical coherence tomography angiography (SS-OCTA) for the diagnosis and management of proliferative diabetic retinopathy (PDR). Consecutive patients with vision-threatening diabetic retinopathy were imaged with widefield SS-OCTA using the 12 mm × 12 mm scan pattern. Twenty-four eyes of 12 patients underwent SS-OCTA imaging. In all 24 eyes, the en face total retinal flow images detected areas of decreased retinal perfusion, and the en face vitreoretinal interface (VRI) slabs detected foci of retinal neovascularization (NV). NV was treated and followed using the VRI images. Widefield SS-OCTA is a useful, noninvasive technology for the detection and monitoring of NV in PDR. Features of interest, such as areas of decreased retinal perfusion, increased retinal thickness, and NV, can be identified from different en face slabs extracted from a single 12 mm × 12 mm scan. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:474-484.].

Distribution of Diabetic Neovascularization on Ultra-Widefield Fluorescein Angiography and on Simulated Widefield OCT Angiography

Areas of neovascularization (NV) in proliferative diabetic retinopathy (PDR) on ultra-widefield (UWF) fluorescein angiography (FA) were identified and compared with a simulated widefield (WF) swept-source OCT angiography (SS-OCTA) field of view to determine whether the WF SS-OCTA field of view was sufficient for detection of NV in PDR. Retrospective, consecutive case series. All patients with PDR and UWF FA imaging at the Bascom Palmer Eye Institute over a period of 5.5 years were identified. UWF FA images were reviewed and sites of NV were identified either as NV of the disc or NV elsewhere. Sites of NV elsewhere were classified by disc-centered retinal quadrants. A simulated WF SS-OCTA montage field of view was overlaid on the UWF FA images to determine whether sites of NV would have been identified by this simulated WF SS-OCTA field of view. A total of 651 eyes with PDR from 433 patients had at least 1UWF FA with NV. Of the 651 eyes, 50% were treatment-naïve, 9.8% had NV of the disc only, 41.8% had NV elsewhere only, and 48.4% had both NV of the disc and NV elsewhere. NV elsewhere was most prevalent in the superotemporal quadrant and the least prevalent in the nasal quadrants. When the simulated WF SS-OCTA field of view was overlaid on the UWF FA, 98.3% of all eyes, 99.4% of treatment-naive eyes, and 97.2% of previously treated eyes had NV within the WF SS-OCTA field of view. In those eyes with a repeat UWF FA within 6 to 18months of the first FA, the distribution of NV did not change in either the treatment-naive or previously treated eyes. NV elsewhere in PDR was most prevalent superotemporally, and 99.4% of treatment-naïve eyes had NV within the simulated WF SS-OCTA field of view. Combined with previous research using WF SS-OCTA to identify NV in PDR, these findings suggest that WF SS-OCTA may be the only imaging modality needed for the diagnosis and longitudinal management of PDR.

ARTERIAL OXYGEN SATURATION IN NEOVASCULARIZATIONS IN PROLIFERATIVE DIABETIC RETINOPATHY.

Retinal neovascularizations in proliferative diabetic retinopathy have been proposed to develop from larger retinal venules. However, angiographic evidence suggests that the new vessels may originate from both arterioles and venules, and the vitreous oxygen tension near retinal neovascularizations is similar to that of retinal arterioles. An assessment of the oxygen saturation in neovascularizations may help characterizing the vascular origin of these vessels in proliferative diabetic retinopathy. Dual wavelength oximetry was used to study the oxygen saturation in arterioles, venules, and retinal neovascularizations in 40 eyes from 40 patients with proliferative diabetic retinopathy. The oxygen saturation was significantly lower in retinal venules than in arterioles and neovascularizations (P < 0.0001), and after a correction for the influence of vessel diameter, there was no significant difference between the oxygen saturation in retinal arterioles and neovascularizations (P = 0.71). Age at onset and duration of diabetes mellitus contributed significantly to the variation in oxygen saturation of the venules, whereas none of the clinical background parameters contributed to the variation in oxygen saturation in arterioles and neovascularizations. The oxygen saturation in retinal neovascularizations in proliferative diabetic retinopathy is similar to that of the arterioles. Neovascularizations may act as shunts to bypass areas of capillary occlusion.

Longitudinal Wide-Field Swept-Source OCT Angiography of Neovascularization in Proliferative Diabetic Retinopathy after Panretinal Photocoagulation

Wide-field swept-source (SS) OCT angiography (OCTA) was compared with ultrawide-field (UWF) fluorescein angiography (FA) for evaluating neovascularization (NV) before and after panretinal photocoagulation (PRP) in eyes with treatment-naive proliferative diabetic retinopathy (PDR). Prospective, observational, consecutive case series. Patients with treatment-naive PDR. Patients were imaged using the SS OCTA 12× 12-mm field of view (PLEX Elite 9000; Carl Zeiss Meditec, Inc, Dublin, CA) at baseline and at 1 week, 1 month, and 3 months after PRP. Select eyes were imaged with 5 SS OCTA 12× 12-mm scans to create posterior pole montages. Ultrawide-field fundus photography and UWF FA were obtained at baseline and 3 months after PRP. Neovascularization visualized using wide-field SS OCTA and UWF FA. From January through May 2018, wide-field SS OCTA was performed on 20 eyes with treatment-naive PDR from 15 patients. The en face SS OCTA 12× 12-mm vitreoretinal interface (VRI) slab images showed NV at baseline in 18 of 20 eyes (90%). Of the remaining 2 eyes, the posterior pole montage captured peripheral NV in one eye, and in the other eye, no evidence of NV was detected with either UWF FA or SS OCTA. After PRP, both SS OCTA and FA demonstrated similar progression or regression of NV, but SS OCTA provided more detailed visualization of the vascular changes. Neovascularization in PDR can be identified at baseline and imaged serially after PRP using wide-field SS OCTA. In patients with a high clinical suspicion for PDR, wide-field SS OCTA likely will betheonlyimaging method needed for diagnosis and longitudinal evaluation of NV.

Mechanistic Evaluation of Panretinal Photocoagulation Versus Aflibercept in Proliferative Diabetic Retinopathy: CLARITY Substudy.

PurposeThe purpose of this study was to study the effects of panretinal photocoagulation (PRP) and intravitreal aflibercept on retinal vessel oxygen saturations, area of retinal nonperfusion, and area of neovascularization in proliferative diabetic retinopathy.MethodsThis is a prospective randomized single center study. Forty patients with proliferative diabetic retinopathy were randomized to PRP or intravitreal aflibercept treatment for 52 weeks. Retinal oximetry and ultra-widefield angiography were performed at baseline and week 52. Ultra-widefield color fundus imaging was performed at baseline, week 12, and week 52. The outcomes were retinal arterio-venous oximetry differences (AVD), area of retinal nonperfusion, and area of neovascularization in disc areas (DA).ResultsThe AVD in the PRP group increased from 36.7% at baseline to 39.7%, whereas it decreased from 33.4% to 32.5% in the aflibercept group. The difference in AVD between groups at week 52 was 4.0% (95% confidence interval, −0.08, 8.8; P = 0.10). The baseline mean area of retinal nonperfusion of 125.1 DA and 131.2 DA in the PRP and aflibercept groups increased to 156.1 DA and 158.4 DA, respectively, at week 52 (P = 0.46). The median baseline area of neovascularization decreased from 0.98 DA to 0.68 DA in the PRP group and from 0.70 DA to 0 DA in the aflibercept group at week 12 (P = 0.019). At week 52, this measured 0.24 DA in the PRP group and 0 DA in the aflibercept group (P = 0.45).ConclusionsIntravitreal aflibercept achieved an earlier and complete regression of neovascularization in proliferative diabetic retinopathy compared with PRP. There were no significant differences in global change in intravascular oxygen saturation or areas of retinal nonperfusion between the two groups by 52 weeks.