Intraocular Neovascularization Research Articles

Expeditious resolution of disc and iris neovascularization

Intraocular neovascularization is seen commonly as a response to retinal ischemia or less commonly due to inflammation. Inflammatory iris neovascularization responds well to topical steroids, whereas retinal neovascularization associated with uveitic conditions responds to systemic steroids or periocular depot injections. This case highlights an unusually rapid resolution of disc neovascularization along with iris neovascularization just with topical steroids in a middle-aged lady diagnosed with bilateral panuveitis and retinal vasculitis. We presume it may be due to a spontaneous decrease in posterior segment inflammation or due to systemic vascular remodeling.

Incidence and Risk Factors for Secondary Glaucoma in Eyes with Uveal Melanoma

To estimate incidence of and analyze risk factors for developing secondary glaucoma in eyes with uveal melanoma before and after diagnosis. A cross-sectional, population-based cohort study. Seven hundred eighty-one patients (median age, 64 years; range, 14-93) consecutively diagnosed with uveal melanoma from 1997 to 2012 in a national ocular oncology service, 708 (91%) of whom received ruthenium (50%) or iodine (50%) brachytherapy. Patient, tumor, treatment, and follow-up data were collected prospectively. Frequency and associations of melanoma-related glaucoma at tumor diagnosis were assessed. Incidence of developing secondary glaucoma after diagnosis was estimated by Kaplan-Meier analysis. Independent risk factors were modeled using Cox regression. Melanoma-related glaucoma and related risk factors. Forty-five patients (5.8%; 95% confidence interval [CI], 4.2-7.6) had tumor-related secondary glaucoma at diagnosis, 34 (76%) from a narrow-to-closed angle (25 had direct angle invasion) and 10 (22%) from anterior neovascularization. Synchronous metastases were common in patients with initial secondary glaucoma (11% vs. 1.2% with incident glaucoma, P= 0.005). Patients with secondary glaucoma were often male (58% vs. 48% without glaucoma; P= 0.010) and had larger tumors (median thickness, 9.1 vs. 4.0 mm; P < 0.001) involving the ciliary body (43% vs. 21%; P < 0.001) with retinal detachment (53% vs. 30%; P < 0.001). One hundred and sixty-eight patients 165 of which were treated with brachytherapy developed incident tumor- or treatment-related secondary glaucoma a median of 1.7 years (range, 0.1-13.6) after tumor diagnosis. Cumulative proportion of developing secondary glaucoma was 23% (95% CI, 20-27) at 5 years. The most common mechanism was neovascularization in 119 patients (71%; 95% CI, 63-78). By multivariable regression, initial retinal detachment 3 to 4 quadrants (hazard ratio [HR], 2.18; P < 0.001), initial intraocular pressure 17 mmHg or higher (HR, 1.64; P= 0.01), and tumor thickness predicted incident secondary glaucoma. Secondary glaucoma at initial uveal melanoma diagnosis predicts high risk of synchronous metastases. Although anterior neovascularization is the most common mechanism for secondary glaucoma after diagnosis, other mechanisms such as angle narrowing and anterior chamber hemorrhage are not infrequent. Initial retinal detachment and intraocular pressure with tumor thickness could inform interim assessments of intraocular pressure and neovascularization.

Etiology, pathogenesis, and diagnosis of neovascular glaucoma.

Neovascular glaucoma is defined as iris and/or anterior chamber angle neovascularization associated with increased intraocular pressure. It is a secondary glaucoma that is most frequently caused by severe retinal ischemia. The most common diseases responsible for the development of neovascular glaucoma are diabetic retinopathy, ischemic central retinal vein occlusion, and ocular ischemic syndrome. Uncommon causes include ocular radiation, ocular tumors, uveitis and other miscellaneous conditions. Vascular endothelial growth factor is an important and likely predominant agent involved in the pathogenesis of intraocular neovascularization and neovascular glaucoma. The evolution of clinical and histopathological changes from predisposing conditions to the occurrence of rubeosis iridis and neovascular glaucoma is divided into four stages: prerubeosis, preglaucoma, open angle glaucoma, and angle-closure glaucoma.

Clinical observation of ranibizumab combined with surgery in the treatment of neovascular glaucoma with vitreous hemorrhage.

The aim was to explore the clinical efficacy of ranibizumab combined with surgical treatment of neovascular glaucoma with vitreous hemorrhage. A total of 15 patients (17 affected eyes) who had neovascular glaucoma (NVG) with vitreous hemorrhage in our hospital were enrolled. After admission, the patient was given levofloxacin eye drops, 4 times a day. Three days later, the patients received intravitreal injection of ranibizumab. Then, trabeculectomy and vitrectomy were performed. The detailed clinical data, such as type of diseases, intraocular pressure (IOP), and best corrected visual acuity (BCVA), were collected before and after surgery. Visual acuity remained stable or improved in thirteen effected eyes and decreased in effected three eyes. Within 30days after discharge, one effected eye recurred iris neovascularization with slightly higher IOP; then, the patient received intravitreal injection of ranibizumab again and neodymium-doped yttrium aluminum garnet (YAG) therapy. One patient (one effected eye) was given intravitreal ranibizumab injection again because of uncontrollable IOP and recurrence of neovascularization on iris surface and angle after operation; then, the patient received cyclophotocoagulation. Vitreous cavity hemorrhage occurred again in 3 patients after operation; then, these patients received the vitreous cavity lavage again. After trabeculectomy, inflammatory exudation or a small amount of bleeding could be seen in the anterior chamber of 6 young patients. Intravitreal injection of ranibizumab can effectively promote the rapid regression of intraocular neovascularization and help to control the IOP and improve postoperative visual acuity.

Vascular endothelial growth factor inhibitors (anti-VEGF) use in Nigeria: The way forward

Intraocular neovascularization is a serious, blinding complication of diverse ischemic retinal vascular disorders. The treatment includes the use of vascular endothelial growth factors inhibitors (anti-VEGF), which are administered via intraocular injections. The commonly used anti-VEGF include bevacizumab, ranibizumab, and aflibercept. Although ranibizumab and aflibercept are approved for intraocular application, bevacizumab is used “off-label.” This article reviews the advantages and drawbacks of the anti-VEGF use and the implications for Nigeria where eye diseases requiring anti-VEGF treatment are also prevalent.

Prevention of intraocular pressure elevation following intravitreal injections

Determining the role of vascular endothelial growth factor (VEGF) in the pathogenesis of intraocular neovascularization prompted the development of anti-VEGF therapy. In general, these intravitreal injections (IVI) are considered relatively safe. One of the side effects that can occur after IVI of anti-VEGF agents is ocular hypertension, it can be acute or persistent. Numerous studies investigating the prevention of ophthalmic hypertension have been carried out in connection with the proven risk of short-term intraocular pressure (IOP) elevation after anti-VEGF injections. Scientific literature describes several methods of preventing intraocular pressure spikes after IVI: prophylactic medications, anterior chamber paracentesis, scleral decompression. Despite the significant number of publications, there is no universal consensus on the necessity of prevention measures for IVI of anti-VEGF drugs since the clinical benefits of slightly reducing the short-term IOP spikes remain unclear. This literature review analyzes the prospects of preventing ocular hypertension after IVI of anti-VEGF agents.

Prospects and Challenges of Anti-VEGF Drug Treatment for Pathological Angiogenesis of the Retina

The number of patients with exudative age-related macular degeneration, diabetic retinopathy and retinal vein occlusion is expected to rise in proportion with the aging of the population and increasing diabetes patients. Also, they are the most common diseases caused by intraocular neovascularization and are often difficult to treat. Currently, anti-vascular endothelial growth factor (VEGF) therapy has been developed and has demonstrated excellent results in treating macular edema, and many patients have avoided blindness. Unfortunately, there are problems with cases that do not respond to the anti-VEGF drugs and complications of administration. It is necessary to deepen the understanding of the physiological and pathological retinal roles of VEGF and to optimize the anti-VEGF therapy. There are also no drugs indicated for the regression of neovascularization itself. The solution to this problem is to develop novel therapies targeting other than VEGF. In this symposium review, we introduce the roles of VEGF in the ischemic retina and anti-angiogenic factors as promising therapeutic targets.

Primary Tumour Type, Clinical Features, Treatment and Outcome of Patients with Iris Metastasis

ABSTRACT Purpose To describe the primary tumour type, clinical features, treatment and outcome of patients with Iris metastasis. Methods Retrospectively analyzed articles published from 1934 to 2019 in the PubMed database. Results In total, 133 eyes of 125 patients with iris metastatic carcinoma were retrieved. The average age at metastasis diagnosis of the patients was 56 ± 15 years; 60 left eyes and 49 right eyes were involved. The most common primary tumors were lung carcinoma (42%) and breast carcinoma (15%). Approximately one-third of the patients were first diagnosed in the ophthalmology department before the primary tumor was detected. Twenty-two percent of iris metastases were discovered before and 33% were discovered after systemic metastasis. The most common complaints were blurred vision and pain. The clinical features included iris masses, neovascularization and keratic precipitates. 57 patients (64%, N = 90) had an elevated intraocular pressure. Local administration of radiation therapy or intraocular injections of anti-VEGF drugs relieved eye discomfort and controlled the high intraocular pressures. Conclusions Iris nodules with increased intraocular pressure and neovascularization may indicate iris metastasis. Lung cancer is the most common primary tumor.

HGF and VEGF-A and Their Receptors Show Expression and Angiogenic Effects on Human Choroidal Endothelial Cells: Implications for Treatments of Neovascular Age-Related Macular Degeneration

Intraocular neovascularisation is associated with common blinding conditions including neovascular age-related macular degeneration (nAMD). Vascular endothelial growth factor (VEGF) is central in driving choroidal neovascularisation in this disease. Many clinical therapies target VEGF-A with intravitreal anti-VEGF drugs, which, however, have limited efficacy and require repeated, prolonged treatment. Other cytokines are known to be involved, including hepatocyte growth factor (HGF), which is shown to have a role in the early stages of nAMD. We investigated the effect of HGF and its co-operation with VEGF-A on human choroidal endothelial cells (CEC). The expression of HGF and related molecules in CEC was investigated using immunofluorescence, Western blotting and flow cytometry. In vitro assays for proliferation, tubule formation and migration were used to assess the potential role of HGF in neovascularisation. Primary human CEC expressed HGF, VEGF-A and their receptors MET and VEGF receptor 2 (VEGFR2). HGF increased CEC proliferation, tubule formation and migration; the increased proliferation and migration appeared to be additive with that achieved with VEGF-A. This study provides insight into growth factor co-operation in CEC signalling and indicates that simultaneous blockage of multiple growth factors or common downstream signalling pathways may provide a more sustained treatment response, enhancing treatments in nAMD.

Pathophysiological mechanisms of diabetic retinopathy

Aim. To evaluate pathophysiological mechanisms in diabetic retinopathy.Material and methods. Factors of diabetic retinopathy pathogenesis, scientific reviews.Results. The evaluation of pathophysiological mechanisms in diabetic retinopathy found that early stages are characterized by histopathological changes, which include loss of pericytes, basement membrane thickening, haemodynamic alterations leading to reduced vascular integrity. The later stages of diabetic retinopathy are characterized by complications, which include visual impairment, primarily due to macular edema and proliferative diabetic retinopathy. Also, the severity of retinopathy was associated with poorer metabolic control, demonstrated by elevated HbA1c. Diabetic complications accompany the accumulation of advanced glycation end products in diabetic tissues. Increased accumulation of these products has been reported in epiretinal membranes by the use of the immunohistochemical technique. The binding of advanced glycation end products to a high-affinity receptor in pericytes exerts selective toxicity resulting in their death. Vascular endothelial growth factor exerts an important role in intraocular neovascularization due to ischemic retinopathy.Conclusions. Early stages of diabetic retinopathy are characterized by his topathological changes which include loss of pericytes, basement membrane thickening, haemodynamic alterations leading to reduced vascular integrity. The later stages of diabetic retinopathy are characterized by complications, which include visual impairment, primarily due to macular edema and proliferative diabetic retinopathy. The binding of advanced glycation end products to a high-affinity receptor in pericytes exerts selective toxicity resulting in their death.

Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders

Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.

Intraocular VEGF Deprivation Induces Inflammatory and Fibrogenic Response in Retina

Backgrounds: Anti-VEGF reagents have become the first-line treatment to patients with intraocular neovascularization, although accumulative clinical data point to strong association between VEGF deprivation and adverse effects in ocular system, the underlying mechanisms remain to be explored. Methods: We employed recombinant adeno-associated virus encoding soluble Fms-related tyrosine kinase-1 (rAAV.sFLT-1) for sustained VEGF neutralization. The functional effects of sFLT-1 were confirmed both in vitro and in vivo. The retinal tissues and functions were analyzed by fundus photography, optical coherence tomography (OCT), TUNEL assay, immunofluorescence staining, fluorescence in situ hybridization (FISH) and electroretinography. Moreover, high throughput RNA-seq analysis was performed to interrogate gene expression profiles of the retina. Findings: In vitro, sFLT-1 was co-precipitated with VEGF165. rAAV-mediated expression of sFLT-1 was maintained for at least three months post-intravitreal injection in mice. rAAV.sFLT-1 treatment effectively suppressed laser-induced choroidal neovascularization, an indication of VEGF deprivation. Furthermore, we showed that intraocular deprivation of VEGF induced retinal degeneration and gliosis. Functional deficit in retinal response to visual stimulation was also recorded by electroretinogram in rAAV.sFLT-1 treated eyes. Moreover, RNA-seq analysis of the VEGF-deprived retina revealed 5356 differentially expressed genes, which suggests potential mechanisms for VEGF deprivation induced retinal pathogenesis. Interpretation: Our findings demonstrate that sustained intraocular VEGF deprivation induced substantial molecular changes, which paves way to elucidation of pathogenic mechanisms for adverse effects associated with VEGF deprivation in clinical practice and identification of potential therapeutic targets. Funding: National Natural Science Foundation of China (No. 817008280; 81470640), National Key R&D Program of China (No. 2017YFA0105300), Program for Eastern Young Scholar at Shanghai Institutions of Higher Learning (No. QD2016003), Shanghai Rising-Star Program (No. 17QA1402800), Science and Technology Commission of Shanghai Municipality (No. 16411952900, 16dz2251500, 17140902800). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: Animal procedures were approved by the Shanghai Jiao Tong University Institutional Review Board. All animal experiments conformed to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research.

Vascular endothelial growth factor inhibition and proliferative diabetic retinopathy, a changing treatment paradigm?

Prior to the development of panretinal photocoagulation (PRP) in the 1970s, proliferative diabetic retinopathy (PDR) was the most common cause of blindness in diabetic patients. The diabetic retinopathy study demonstrated that PRP could decrease severe visual loss from PDR by 50%. Since then and for the past four decades, PRP has been the treatment of choice for eyes with PDR. In the past decade, vascular endothelial growth factor (VEGF) inhibition has become the treatment of choice for diabetic macular edema (DME). When treated intensively with anti-VEGF drugs, about one-third of eyes with DME experience an improvement in their diabetic retinopathy severity scale. Randomized clinical trials comparing ranibizumab to PRP and aflibercept to PRP have shown that VEGF inhibitors cause regression of intraocular neovascularization but need to be given on a fairly regular basis. Despite these promising results, concerns about treatment adherence have surfaced. Patients with PDR that are treated solely with anti-VEGF drugs and somehow interrupt their treatment are at a high risk of developing irreversible blindness. Combination treatment of PRP plus an anti-VEGF drug may be the treatment of choice for PDR.

Autophagy: a potential target for the treatment of intraocular neovascularization

The formation of neovascularization is a common pathological feature of many ocular vascular diseases, and is an important cause of vision loss in patients. Neovascularization can cause retinal hemorrhage, vitreous hemorrhage, and other serious complications, leading to loss of vision. The treatment of intraocular neovascularization is the focus of ophthalmology research. In recent years, some studies have found that autophagy is closely related to vascular endothelial growth factor and the formation of neovascularization. Autophagy is expected to become a new target for the treatment of intraocular neovascularization. Therefore, this article reviews the research on autophagy and the formation of intraocular neovascularization.

Diverse roles of macrophages in intraocular neovascular diseases: a review.

Macrophages are involved in angiogenesis, and might also contribute to the pathogenesis of intraocular neovascular diseases. Recent studies indicated that macrophages exert different functions in the process of intraocular neovascularization, and the polarization of M1 and M2 phenotypes plays extremely essential roles in the diverse functions of macrophages. Moreover, a large number of cytokines released by macrophages not only participate in macrophage polarization, but also associate with retinal and choroidal neovascular diseases. Therefore, macrophage might be considered as a novel therapeutic target to the treatment of pathological neovascularization in the eye. This review mainly summarizes diverse roles of macrophages and discusses the possible mechanisms in retinal and choroidal neovascularization.

Development of Multigenic Lentiviral Vectors for Cell-Specific Expression of Antiangiogenic miRNAs and Protein Factors.

Generation of lentivirus (LV)-based vectors holding multiple gene cassettes for coexpression of several therapeutic factors provides potent tools in both gene delivery studies as well as in gene therapy. Here we describe the development of such multigenic LV gene delivery vectors enabling cell-specific coexpression of antiangiogenic microRNA (miRNA) and protein factors and, if preferred, a fluorescent reporter, from RNApol(II)-driven expression cassettes orientated in a back-to-back fashion. This configuration may contribute to the development of new combination therapies for amelioration of diseases involving intraocular neovascularization including exudative age-related macular degeneration (AMD).

Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases.

Numerous benefits have been attributed to dietary long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), including protection against cardiac arrhythmia, triglyceride-lowering, amelioration of inflammatory, and neurodegenerative disorders. This review covers recent findings indicating that a variety of these beneficial effects are mediated by "omega-3 epoxyeicosanoids", a class of novel n-3 LC-PUFA-derived lipid mediators, which are generated via the cytochrome P450 (CYP) epoxygenase pathway. CYP enzymes, previously identified as arachidonic acid (20:4n-6; AA) epoxygenases, accept eicosapentaenoic acid (20:5n-3; EPA) and docosahexaenoic acid (22:6n-3; DHA), the major fish oil n-3 LC-PUFAs, as efficient alternative substrates. In humans and rodents, dietary EPA/DHA supplementation causes a profound shift of the endogenous CYP-eicosanoid profile from AA- to EPA- and DHA-derived metabolites, increasing, in particular, the plasma and tissue levels of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP). Based on preclinical studies, these omega-3 epoxyeicosanoids display cardioprotective, vasodilatory, anti-inflammatory, and anti-allergic properties that contribute to the beneficial effects of n-3 LC-PUFAs in diverse disease conditions ranging from cardiac disease, bronchial disorders, and intraocular neovascularization, to allergic intestinal inflammation and inflammatory pain. Increasing evidence also suggests that background nutrition as well as genetic and disease state-related factors could limit the response to EPA/DHA-supplementation by reducing the formation and/or enhancing the degradation of omega-3 epoxyeicosanoids. Recently, metabolically robust synthetic analogs mimicking the biological activities of 17,18-EEQ have been developed. These drug candidates may overcome limitations of dietary EPA/DHA supplementation and provide novel options for the treatment of cardiovascular and inflammatory diseases.

Central retinal artery occlusion without underlying chronic ocular ischemic syndrome may lead to neovascular glaucoma

The prevalence and etiology of neovascular glaucoma (NVG) as a complication of central retinal artery occlusion (CRAO) is a debated issue. According to some authors, NVG associated with CRAO always involves underlying chronic ocular ischemic syndrome (COIS) as a primum movens for CRAO. However, we describe 5cases of NVG following CRAO with no underlying COIS, confirmed by carotid Doppler studies and ultrasound color Doppler imaging (USCDI) of the ophthalmic artery (OA). We conducted a single-center retrospective analysis of the medical records of 5consecutive patients who developed NVG following non-arteritic CRAO between July2010 and July2014. Five patients were included. All 5patients were examined at the emergency room. The 5patients had normal intraocular pressure and no intraocular neovascularization upon initial examination. They had no hemodynamically significant internal carotid artery stenosis, and the ophthalmic artery USCDI was normal. These 5patients developed NVG subsequently to the CRAO. In our patients, carotid Doppler studies and USCDI of the OA ruled out COIS. Thus, COIS did not cause the NVG. CRAO may therefore lead to neovascular glaucoma without underlying COIS.

Recent Update on the Role of Chinese Material Medica and Formulations in Diabetic Retinopathy.

Diabetes mellitus is one of the most frequent endocrine disorders, affecting populations worldwide. Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes in patients aged 20 and over. Major complications of DR include intraocular neovascularization, inter-retinal edema, hemorrhage, exudates and microaneurysms. Therefore, timely medical attention and prevention are required. At present, laser-assisted therapy and other operational procedures are the most common treatment for DR. However, these treatments can cause retinal damage and scarring. Also, use of the majority of traditional medicines is not supported by clinical evidence. However, due to accumulating scientific evidence, traditional natural medications may assist in delaying or preventing the progression of DR. This review focuses on evidence for the role of traditional natural medicines and their mechanisms of action and pharmacological test results in relation to the progression of DR.

VEGF and Intraocular Neovascularization: From Discovery to Therapy.

I am honored and humbled to be one of the awardees of the 2014 A. Champalimaud Vision Award. I offer my heartfelt thanks to the Champalimaud Foundation President, Leonor Beleza, and to the Award Committee Members for this wonderful recognition. I feel especially fortunate to have had the opportunity to witness my scientific discoveries move from the bench to the clinic. Scientific discovery is hugely exciting, but the ability to translate that work into potentially helping someone lead a better life is even more fulfilling. This Award is dedicated to the patients.