Retinal Vascular Disease Research Articles

Fatty Acid-Binding Proteins 4 and 5 Are Involved in the Pathogenesis of Retinal Vascular Diseases in Different Manners.

This study reports on the pathological significance of the vitreous fatty acid-binding protein (Vt-FABP) 4 and 5, and vascular endothelial growth factor A (Vt-VEGFA) in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Subjects with PDR (n = 20), RVO (n = 10), and controls (epiretinal membrane, n = 18) who had undergone vitrectomies were enrolled in this study. The levels of Vt-FABP4, Vt-FABP5, and Vt-VEGFA were evaluated by enzyme-linked immunosorbent assays (ELISA). Retinal circulation levels were measured by a laser-speckle flow analyzer (LSFA) and other relevant data were collected. The Vt-FABP5 levels were significantly (p < 0.05) elevated in patients with RVDs compared to control patients. This elevation was more evident in patients with RVO than with PDR. Log Vt-FABP5 was significantly correlated negatively or positively with all the LSFA retinal circulation indexes or Log triglycerides (r = 0.31, p = 0.031), respectively. However, the elevations in the Vt-FABP4 and Vt-VEGFA levels were more evident in the PDR group (p < 0.05) and these factors were correlated positively with Log fasting glucose and negatively with some of the LSFA retinal circulation indexes. Multivariable regression analyses indicated that the LSFA blood flows of the optic disc at baseline was an independent effector with Log Vt-FABP5 other than several possible factors including age, gender, Log triglycerides, Log Vt-FABP4 and Log Vt-VEGFA. These current findings suggest that Vt-FABP5 is involved in the pathogenesis of RVD in a manner that is different from that for Vt-FABP4 and Vt-VEGFA, presumably by regulating retinal circulation.

Bevacizumab for blinding eye disease &#x2013; is it time for the PBS to list for off-label use?

Anti-vascular endothelial growth factor eye injections have become the most accepted and effective treatment for some of the leading causes of blindness. Aflibercept (Eylea; Bayer) is the most expensive item on the Pharmaceutical Benefits Scheme, (PBS) with ranibizumab (Lucentis; Roche/Novartis) ranked eighth. In 2011 the pharmaceutical cost for these treatments was A$237 million - now the figure is A$665 million and climbing. Bevacizumab (Avastin; Roche) is part of the original molecular lineage for a group of biologic agents, which were originally designed for cancer therapy. It is now administered worldwide on an off-label basis and in very large numbers for retinal vascular disease. It has a proven efficacy and safety profile. Bevacizumab is thirty times cheaper than the Therapeutic Goods Administration (TGA)-approved alternatives and its use could reduce PBS costs by hundreds of millions of dollars. Should the TGA be the sole arbiter in the approval of drugs, or should alternative bodies have some say in the approval of off-label usage under such compelling circumstances? Legislation for this approach has been approved in France, the UK, and Italy. Only by eliminating the legal risk to authorising bodies and physicians, and the financial disincentive to the patient associated with off-label use, will drugs such as bevacizumab be more widely adopted.

First person – Wenjing Liu

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Wenjing Liu is first author on ‘ LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling’, published in JCS. Wenjing is a PhD student in the lab of Xianjun Zhu at Sichuan Provincial People's Hospital, China, investigating the molecular mechanisms of retinal vascular diseases.

Fundus Retinal Vessels Image Segmentation Method Based on Improved U-Net

ObjectivesAlthough the segmentation of retinal vessels in the fundus is of great significance for screening and diagnosing retinal vascular diseases, it remains difficult to detect the low contrast and the information around the lesions provided by retinal vessels in the fundus and to locate and segment micro-vessels in the fine-grained area. To overcome this problem, we propose herein an improved U-Net segmentation method NoL-UNet. Material and methodsThis work introduces NoL-UNet. First of all, the ordinary convolution block of the U-Net network is changed to random dropout convolution blocks, which can better extract the relevant features of the image and effectively alleviate the network overfitting. Next, a NoL-Block attention mechanism added to the bottom of the encoding-decoding structure expands the receptive field and enhances the correlation of pixel information without increasing the number of parameters. ResultsThe proposed method is verified by applying it to the fundus image datasets DRIVE, CHASE_DB1, and HRF. The AUC for DRIVE, CHASE_DB1 and HRF is 0.9861, 0.9891 and 0.9893, Se for DRIVE, CHASE_DB1 and HRF is 0.8489, 0.8809 and 0.8476, and the Acc for DRIVE, CHASE_DB1 and HRF is 0.9697, 0.9826 and 0.9732, respectively. The total number of parameters is 1.70M, and for DRIVE, it takes 0.050s to segment an image. ConclusionOur method is statistically significantly different from the U-Net method, and the improved method shows superior performance with better accuracy and robustness of the model, which has good practical application in auxiliary diagnosis.

The Molecular Mechanism of Long Non-Coding RNA (LncRNA) Regulation of Notch Signaling in Glucose-Induced Apoptosis of Human Retinal Vascular Endothelial Cell.

Diabetes, a global health concern, affects the health of more than 500 million adults. The absence of Notch protein can cause an imbalance in the retinal vascular environment and cause retinal vascular disease. Long noncoding RNA (lncRNA) is known to be involved in the regulation of many signaling pathways. We hope to understand the specific mechanism of apoptosis in retinal vascular endothelial cells (RVECs) by exploring the regulatory effect of lncRNA on the Notch pathway. In this study, we found that RVECs treated with glucose showed increased levels of Notch transcript and protein expression. The lentiviral interference with Notch RNAi reversed this response. When Notch activity decreased, oxidative stress also decreased, accompanied by increased levels of Caspase-9 and Caspase-3 and an increased rate of apoptosis. Therefore, we believe that Notch is involved in the development of diabetic retinopathy and loss of expression promotes apoptosis of human RVECs. By inhibiting the Notch pathway, lncRNA promotes apoptosis of human RVECs in a high-glucose environment.

Exploring neovascular age-related macular degeneration and diabetic macular edema and advances in treatment

Retinal and choroidal vascular diseases are principal causes of blindness for adults in developed countries around the world. Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) are 2 significant contributors to this global vision loss and confer substantial social and economic burdens on patients and society. Anti-vascular endothelial growth factor intravitreal injection therapy has dominated as the standard of care treatment for over 15 years, but poor adherence and high treatment burden have led to suboptimal visual outcomes in the real world compared with the clinical trial results. New treatments are emerging that expand the therapeutic targets and use innovative delivery mechanisms with longer durability to ease the treatment burden. Understanding the benefits and drawbacks of these therapies is key to designing new treatment pathways that improve visual outcomes while decreasing the treatment burden on patients and healthcare institutions.

Retinopathy of Prematurity - Update on Classification, Screening, and Therapy

Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness. This proliferative retinal vascular disease affects only prematurely born infants. Major risk factors include low gestational age and prolonged postnatal oxygen supplementation. ROP screening allows for timely identification of treatment-requiring infants and thus significantly reduces the risk of severe visual impairment and blindness from ROP. Current treatment options comprise retinal laser coagulation and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. We provide a review of scientific data and current treatment recommendations, with special attention to the updated German guideline on ROP screening, the statement of the German ophthalmological societies on anti-VEGF therapy of ROP, and the new third edition of the International Classification of Retinopathy of Prematurity (ICROP3).

DIABETES -THE URGENCY TO DEVELOP AND IMPLEMENT MULTI-SECTORAL STRATEGIES TO COMBAT THE GROWING EPIDEMIC

Diabetes is a major cause of morbidity and mortality, though these outcomes are not due to the immediate effects of the disorder. They are instead related to the diseases that develop as a result of chronic diabetes mellitus. These include diseases of large blood vessels,microvascular disease, and&#x0D; peripheral ,coronary heart diseases, arterial disease) and small blood vessels (microvascular disease, including retinal and renal vascular disease), as well as diseases of the nerves.&#x0D; Keywords: DM type II, multy sectoral strategies

Application of Improved U-Net Convolutional Neural Network for Automatic Quantification of the Foveal Avascular Zone in Diabetic Macular Ischemia.

ObjectivesThe foveal avascular zone (FAZ) is a biomarker for quantifying diabetic macular ischemia (DMI), to automate the identification and quantification of the FAZ in DMI, using an improved U-Net convolutional neural network (CNN) and to establish a CNN model based on optical coherence tomography angiography (OCTA) images for the same purpose. Methods The FAZ boundaries on the full-thickness retina of 6 × 6 mm en face OCTA images of DMI and normal eyes were manually marked. Seventy percent of OCTA images were used as the training set, and ten percent of these images were used as the validation set to train the improved U-Net CNN with two attention modules. Finally, twenty percent of the OCTA images were used as the test set to evaluate the accuracy of this model relative to that of the baseline U-Net model. This model was then applied to the public data set sFAZ to compare its effectiveness with existing models at identifying and quantifying the FAZ area. Results This study included 110 OCTA images. The Dice score of the FAZ area predicted by the proposed method was 0.949, the Jaccard index was 0.912, and the area correlation coefficient was 0.996. The corresponding values for the baseline U-Net were 0.940, 0.898, and 0.995, respectively, and those based on the description data set sFAZ were 0.983, 0.968, and 0.950, respectively, which were better than those previously reported based on this data set. Conclusions The improved U-Net CNN was more accurate at automatically measuring the FAZ area on the OCTA images than the traditional CNN. The present model may measure the DMI index more accurately, thereby assisting in the diagnosis and prognosis of retinal vascular diseases such as diabetic retinopathy.

Recommendations for OCT Angiography Reporting in Retinal Vascular Disease: A Delphi Approach by International Experts

Purpose:To develop a consensus nomenclature for reporting OCT angiography (OCTA) findings in retinal vascular disease (e.g., diabetic retinopathy, retinal vein occlusion) by international experts.Design:Delphi-based survey.Subjects, Participants, and/or Controls:Twenty-five retinal vascular disease and OCTA imaging experts.Methods, Intervention, or Testing:A Delphi method of consensus development was used, comprising 2 rounds of online questionnaires, followed by a face-to-face meeting conducted virtually. Twenty-five experts in retinal vascular disease and retinal OCTA imaging were selected to constitute the OCTA Nomenclature in Delphi Study Group for retinal vascular disease. The 4 main areas of consensus were: definition of the parameters of “wide-field (WF)” OCTA, measurement of decreased vascular flow on conventional and WF-OCTA, nomenclature of OCTA findings, and OCTA in retinal vascular disease management and staging. The study end point was defined by the degree of consensus for each question: “strong consensus” was defined as ≥85% agreement, “consensus” as 80% to 84%, and “near consensus” as 70% to 79%.Main Outcome Measures:Consensus and near consensus on OCTA nomenclature in retinal vascular disease.Results:A consensus was reached that a meaningful change in percentage of flow on WF-OCTA imaging should be an increase or decrease ≥30% of the absolute imaged area of flow signal and that a “large area” of WF-OCTA reduced flow signal should also be defined as ≥30% of the absolute imaged area. The presence of new vessels and intraretinal microvascular abnormalities, the foveal avascular zone parameters, the presence and amount of “no-flow areas,” and the assessment of vessel density in various retinal layers should be added for the staging and classification of diabetic retinopathy. Decreased flow ≥30% of the absolute imaged area should define an ischemic central retinal vein occlusion. Several other items did not meet consensus requirements or were rejected in the final discussion round.Conclusions:This study provides international consensus recommendations for reporting OCTA findings in retinal vascular disease, which may help to improve the interpretability and description in clinic and clinical trials. Further validation in these settings is warranted and ongoing. Efforts are continuing to address unresolved questions.

A study of the prevalence and severity of retinopathy of prematurity in East of Iran during 2015–2017: A descriptive cross-sectional study

IntroductionRetinopathy of prematurity (ROP) is a retinal vascular disease in preterm infants, which can cause partial defects in visual acuity or lead to serious defects including retinal detachment and blindness. In most cases, ROP can be prevented and treated if detected early. In this study, the prevalence of ROP and some factors affecting the severity of this disease have been examined. MethodThis cross-sectional study was implemented on 253 premature infants referred to Khatam-Al-Anbia hospital in Mashhad in 2015–2017 period for ROP screening. The sampling was performed using census method. The data-gathering tool was a demographic questionnaire and a checklist for recording the stage of the disease, follow-up and treatment of the patients. ResultsThe sample consisted of 104 female infants (41.1%) and 149 male infants (58.9%). The mean gestational age of infants was 32.1 ± 2.9 weeks and the mean birth weight was 1697.2 ± 566.5 g. Of the sample, 112 (44.3%) had some degrees of ROP and only 1.98% were in need of treatment. In the first examination, the severity of retinopathy in both eyes of infants was the highest in infants with gestational age of less than 32 weeks, and the lowest in infants older than 34 weeks (P < 0.001). There was a significant correlation between ROP severity and gestational age (p ≥ 0.001). The severity of retinopathy in natural pregnancy was also lower than assisted reproduction techniques (P < 0.001). In this study, there was no significant relationship between ROP severity and gender (p ≥ 0.10). ConclusionIn general, the prevalence of ROP in our sample was relatively high. Considering that the severity of ROP was found to be related to the gestational age of infants, and since early diagnosis is the key to ROP treatment, it is suggested to administer ROP screening for all infants with a gestational age of less than 34 weeks or premature infants born by assisted reproduction techniques.

Evaluation of Capillary and Other Vessel Contribution to Macular Perfusion Density Measured with Optical Coherence Tomography Angiography.

Parafoveal circulation of the superficial retinal capillary plexus is usually measured with vessel density, which determines the length of capillaries with circulation, and perfusion density, which calculates the percentage of the evaluated area that has circulation. Perfusion density also considers the circulation of vessels larger than capillaries, although the contribution of these vessels to the first is not usually evaluated. As both measurements are automatically generated by optical coherence tomography angiography devices, this paper proposes a method for estimating the contribution of vessels larger than capillaries by using a coefficient of determination between vessel and perfusion densities. This method can reveal a change in the proportion of perfusion density from vessels larger than capillaries, even when mean values do not differ. This change could reflect compensatory arterial vasodilatation as a response to capillary dropout in the initial stages of retinal vascular diseases before clinical retinopathy appears. The proposed method would allow the estimation of the changes in the composition of perfusion density without the need for other devices.

Unilateral peripheral vascular retinal disease associated with a developmental arcade vessel anomaly in adult-onset Coats’ disease

Unilateral peripheral vascular retinal disease associated with a developmental arcade vessel anomaly in adult-onset Coats’ disease

Structure and function of the retina of low-density lipoprotein receptor-related protein 5 (Lrp5)-deficient rats

Loss-of-function mutations in the Wnt co-receptor, low-density lipoprotein receptor-related protein 5 (LRP5), result in familial exudative vitreoretinopathy (FEVR), osteoporosis-pseudoglioma syndrome (OPPG), and Norrie disease. CRISPR/Cas9 gene editing was used to produce rat strains deficient in Lrp5. The purpose of this study was to validate this rat model for studies of hypovascular, exudative retinopathies. The retinal vasculature of wildtype and Lrp5 knockout rats was stained with Giffonia simplifolia isolectin B4 and imaged by fluorescence microscopy. Effects on retinal structure were investigated by histology. The integrity of the blood-retina barrier was analyzed by measurement of permeability to Evans blue dye and staining for claudin-5. Retinas were imaged by fundus photography and SD-OCT, and electroretinograms were recorded. Lrp5 gene deletion led to sparse superficial retinal capillaries and loss of the deep and intermediate plexuses. Autofluorescent exudates were observed and are correlated with increased Evans blue permeability and absence of claudin-5 expression in superficial vessels. OCT images show pathology similar to OCT of humans with FEVR, and retinal thickness is reduced by 50% compared to wild-type rats. Histology and OCT reveal that photoreceptor and outer plexiform layers are absent. The retina failed to demonstrate an ERG response. CRISPR/Cas9 gene-editing produced a predictable rat Lrp5 knockout model with extensive defects in the retinal vascular and neural structure and function. This rat model should be useful for studies of exudative retinal vascular diseases involving the Wnt and norrin pathways.

Treatment responses for branch retinal vein occlusion predicted by semi-automated fluorescein angiography quantification

BackgroundsBranch retinal vein occlusion (BRVO) is one of the most important causes of visual loss in retinal vascular diseases. The aim of this study is to predict the treatment response of anti-vascular endothelial growth factor (anti-VEGF) therapy in BRVO using semi-automated quantified fluorescein angiography (FA) features.MethodsThis retrospective case-control study enrolled patients with BRVO who are receiving anti-VEGF therapy and have been followed up for > 1 year. Those receiving < 5 anti-VEGF injections in the first year were classified as the responsive group, while those receiving ≥5 injections were the refractory group. The FA images were subjected to semi-automated pre-processing. Fluorescein leakages at the 5-min image were represented by mean gray value over parafoveal and perifoveal regions. FA leakages and central retinal thickness (CRT) on optical coherence tomography (OCT) were used for predicting the treatment response and compared using area under receiver operating characteristic curve (AUC).ResultsEighty-nine patients (56 males, 33 females, mean age 62.5 ± 10.9 years) with BRVO were enrolled. Of the 89 eyes, 47 (53%) were in the responsive group and 42 (47%) were in the refractory group. The refractory group had a significantly higher number of anti-VEGF injections in the first year (5.9 ± 1.6 versus 2.4 ± 1.2, p < 0.001) when compared with that of the responsive group. It had thicker pre-treatment CRT (p = 0.011), post-treatment best CRT (p < 0.001) and CRT at 1-year (p < 0.001). It also had a higher mean gray value over the parafoveal (p < 0.001) and the perifoveal (p < 0.001) regions. The mean gray value over perifoveal (AUC 0.846) and parafovel (AUC 0.818) had significantly larger AUC than that of the pre-treatment OCT (AUC 0.653; p = 0.005 and p = 0.016, respectively) when predicting treatment response.ConclusionThe refractory group had a more severe fluorescein leakage over the parafoveal and the perifoveal regions than the responsive group had. Semi-automated quantified FA leakage can be used as a biomarker for the prediction of anti-VEGF treatment response in macular edema due to BRVO.

Deep learning-based classification of retinal vascular diseases using ultra-widefield colour fundus photographs

ObjectiveTo assess the ability of a deep learning model to distinguish between diabetic retinopathy (DR), sickle cell retinopathy (SCR), retinal vein occlusions (RVOs) and healthy eyes using ultra-widefield colour fundus...

Retinal Vascularization Abnormalities Studied by Optical Coherence Tomography Angiography (OCTA) in Type 2 Diabetic Patients with Moderate Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most severe and frequent retinal vascular disease that causes significant visual loss on a global scale. The purpose of our study was to evaluate retinal vascularization in the superficial capillary plexus (SCP), the deep capillary plexus (DCP) and the choriocapillaris (CC) and changes in the foveal avascular zone (FAZ) by optical tomography angiography (OCTA) in patients with type 2 diabetes mellitus (DM2) with moderate DR but without diabetic macular oedema (DME). Fifty-four eyes of DM2 with moderate DR (level 43 in the ETDRS scale) and without DME and 73 age-matched healthy eyes were evaluated using OCTA with swept-source (SS)-OCT to measure microvascularization changes in SCP, DCP, CC and the FAZ. The mean ages were 64.06 ± 11.98 and 60.79 ± 8.62 years in the DM2 and control groups, respectively. Visual acuity (VA) was lower in the DM2 patients (p = 0.001), OCTA showed changes in the SCP with a significant diminution in the vascular density and the FAZ area was significantly higher compared to healthy controls, with p < 0.001 at the SCP level. The most prevalent anatomical alterations were peripheral disruption in the SCP (83.3%), microaneurysms (MA) in the SCP and in the DCP (79.6% and 79.6%, respectively) and flow changes in the DCP (81.5%). A significant positive correlation was observed between the DM2 duration and the FAZ area in the SCP (0.304 with p = 0.025). A significant negative correlation was also found between age and CC central perfusion (p < 0.001). In summary, a decrease in the vascular density in DM2 patients with moderate DR without DME was observed, especially at the retinal SPC level. Furthermore, it was found that the FAZ was increased in the DM2 group in both retinal plexuses and was greater in the SCP group.

Recent developments of temperature‐responsive polymers for ophthalmic applications

AbstractBlindness is one of the most feared disabilities. From cataracts and glaucoma to age‐related macular degeneration and retinal vascular diseases, ocular diseases have adverse impacts on patients and pose a huge burden to the healthcare system. The World Health Organization estimates that out of 2.2 billion people with visual impairment, almost half of the cases can be prevented or has yet to be addressed. This presents an urgent clinical and societal need to be met. Temperature‐sensitive hydrogels are one of the most biocompatible materials, which can be applied into the eye. By exploiting physiological temperature as a stimulus for in situ gel formation, control of the mechanical properties, rate of drug release, and biomechanical interactions can be tuned. They are very versatile and have immense potential in ocular applications by acting as vitreous substitutes in retinal surgery or topical eye drops and lenses for ocular discomfort and inflammation. In this article, we provide a review of the recent developments in temperature‐responsive polymers in ophthalmic therapy in the past 5 years including retinal detachment, retinal vascular diseases, dry eyes, cataracts, age‐related macular degeneration, and glaucoma.

Semi-Automated Quantification of Retinal and Choroidal Biomarkers in Retinal Vascular Diseases: Agreement of Spectral-Domain Optical Coherence Tomography with and without Enhanced Depth Imaging Mode.

Background: We compared with and without enhanced depth imaging mode (EDI) in semi-automated quantification of retinal and choroidal biomarkers in optical coherence tomography (OCT) in patients with diabetic retinopathy (DR) or retinal vein occlusion (RVO) complicated by macular edema. We chose to study three OCT biomarkers: the numbers of hyperreflective foci (HF), the ellipsoid zone reflectivity ratio (EZR) and the choroidal vascularity index (CVI), all known to be correlated with visual acuity changes or treatment outcomes. Methods: In a single examination, one eye of each patient (n = 60; diabetic retinopathy: n = 27, retinal vein occlusion: n = 33) underwent macular 870 nm spectral domain-OCT (SD-OCT) B-scans without and with EDI mode. Semi-automated quantification of HF, EZR and CVI was applied according to preexisting published protocols. Paired Student’s t-test or Wilcoxon rank-sum test was used to test for differences in subgroups. Intraclass correlation coefficient (ICC) and Bland–Altman plots were applied to describe the agreement between quantification in EDI and conventional OCT mode. The effect of macular edema on semi-automated quantification was evaluated. Results: For the entire cohort, quantification of all three biomarkers was not significantly different in SD-OCT scans with and without EDI mode (p > 0.05). ICC was 0.78, 0.90 and 0.80 for HF, EZR and CVI. The presence of macular edema led to significant differences in the quantification of hyperreflective foci (without EDI: 80.00 ± 33.70, with EDI: 92.08 ± 38.11; mean difference: 12.09, p = 0.03), but not in the quantification of EZR and CVI (p > 0.05). Conclusion: Quantification of EZR and CVI was comparable whether or not EDI mode was used. In conclusion, both retinal and choroidal biomarkers can be quantified from one single 870 nm SD-OCT EDI image.

Central Retinal Vein Occlusion: A Brief Overview

Retinal vein occlusion is a common retinal vascular disease and cause of visual loss. Depending on the location of obstruction, it can be classified into central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) and hemi-retinal vein occlusion (HRVO). The condition is labelled as CRVO if the blockage of central retinal vein takes place at the lamina cribrosa. Based on the area of capillary non-perfusion, CRVO can be sub-divided into ischaemic and non-ischaemic types. Ischaemic CRVO is defined by the Central Retinal Vein Occlusion Study (CVOS) as CRVO with fluorescein angiographic evidence of >10 disc areas of capillary nonperfusion on seven-field fundus fluorescein angiography.