Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases

Neovascular age-related macular degeneration (NVAMD) is the most prevalent choroidal vascular disease, and diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the most prevalent retinal vascular diseases. In each of these, hypoxia plays a central role by stabilizing hypoxia-inducible factor-1 which increases production of vascular endothelial growth factor (VEGF) and other hypoxia-regulated gene products. High VEGF causes excessive vascular permeability, neovascularization, and in DR and RVO, promotes closure of retinal vessels exacerbating hypoxia and creating a positive feedback loop. Hence once VEGF expression is elevated it tends to remain elevated and drives disease progression. While other hypoxia-regulated gene products also contribute to pathology in these disease processes, it is remarkable how much pathology is reversed by selective inhibition of VEGF. Clinical trials have demonstrated outstanding visual outcomes in patients with NVAMD, DR, or RVO from frequent intraocular injections of VEGF-neutralizing proteins, but for a variety of reasons injection frequency has been substantially less in clinical practice and visual outcomes are disappointing. Herein we discuss the rationale, preclinical, and early clinical results of new approaches that provide sustained suppression of VEGF. These approaches will revolutionize the management of these prevalent retinal/choroidal vascular diseases.     

Photocoagulation for retinal vein occlusion

The role of photocoagulation in retinal vein occlusion (RVO) has been studied since 1974. The most serious complications of central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) are: (i) visual deterioration, most commonly due to macular edema, and (ii) the development of ocular neovascularization (NV), particularly neovascular glaucoma (NVG), with hazardous consequences for vision and even the eye itself.Before discussing the role of photocoagulation in the management of NV and macular edema in RVO, it is crucial to gain a basic scientific understanding of the following relevant issues: classification of RVO, ocular NV in RVO, and the natural history of macular edema and visual outcome of RVO. These topics are discussed.In CRVO, ocular NV is a complication of ischemic CRVO but not of nonischemic CRVO. Photocoagulation has been advocated to prevent and/or treat the development of ocular NV and NVG. Since NVG is the most dreaded, intractable and blinding complication of ischemic CRVO, the role of photocoagulation and its management are discussed. Findings of three randomized, prospective clinical trials dealing with photocoagulation in ischemic CRVO are discussed.The role of photocoagulation in the management of ocular NV and macular edema in BRVO, and three randomized, prospective clinical trials dealing with those are discussed.Recent advent of intravitreal anti-VEGF and corticosteroid therapies has drastically changed the role of photocoagulation in the management of macular edema and NV in CRVO and BRVO. This is discussed in detail.     

Management of retinal vascular diseases: a patient-centric approach

Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases.     

Methods for making animal models of retinal vein occlusion

Retinal vein occlusion (RVO) is divided into branch retinal vein occlusion and central retinal vein occlusion. It is characterized by retinal vein dilatation and tortuosity, blood flow stasis, bleeding and edema. It is often accompanied by macular edema (ME) and neovascularization. Neovascular glaucoma is the most serious complications. RVO is the second most common cause of visual loss classified under retinal vascular disorders after diabetic retinopathy. So far, the number of patients suffering from retinal vein occlusion has increased, but the pathogenesis of retinal vein occlusion has not been fully understood and there are no treatments that are very long-lasting. The research of animal models on the pathogenesis and treatment of the RVO is very important. Therefore, this article gives a briefly review to the animals and model making methods used in retinal vein occlusion experiments, and discusses the advantages and disadvantages of various RVO animal models.     

视网膜静脉阻塞动物模型的制作方法

视网膜静脉阻塞(RVO)分为视网膜分支静脉阻塞和视网膜中央静脉阻塞,是以视网膜静脉扩张迂曲、血流瘀滞、出血和水肿为特征的病变,常并发黄斑水肿和新生血管,新生血管型青光眼是其最严重的并发症。视网膜静脉阻塞对视力危害较大,是仅次于糖尿病性视网膜病变的第二大致盲性眼病。目前为止,视网膜静脉阻塞的患病人数增多,但其发病机制尚未完全明了,而且也无长久有效的治疗方法。实验室中动物模型对视网膜静脉阻塞发病机制和治疗方法的研究至关重要,因此本文对视网膜静脉阻塞实验中使用的动物及模型的制作方法做了简要综述,并对各种视网膜静脉阻塞动物模型的优缺点进行讨论。     

视网膜静脉阻塞机制及危险因素研究进展

视网膜静脉阻塞(RVO)是第二大视网膜血管疾病，其病理生理机制复杂，除血管机械压迫外，炎症和内皮素也都被证实参与RVO的发病，但具体机制尚不明确。既往文献证明高血压、糖尿病和血脂异常是老年人群中最常见的危险因素，而近期研究发现凝血异常和血液流变学异常在50岁以下人群中更为常见。眼部危险因素也越来越受到重视，包括青光眼、高校正眼压及眼底血管异常。不同危险因素间存在协同关系，早期识别并且干预能有效降低RVO的发病率。本文旨在对近期相关研究进行综述，对现有机制理论进行总结，为发掘潜在药物靶点提供研究思路，同时为疾病危险因素识别和管理提供参考。     

Exudative retinal detachment subsequent to retinal vein occlusion.

Previous studies have shown the possible development of exudative retinal detachment (ERD) as a complication of retinal vein occlusion (RVO). Considering 473 consecutive cases of RVO, only 3 cases of ERD with peculiar clinical aspects were discovered. In the first case, the ERD followed a branch RVO, but it developed in the opposite quadrant, with a late occurrence of venous retinal collaterals. In the second case, the ERD developed after a central RVO, having a retinoschisis aspect, with the subsequent occurrence of optic disk collateral vessels. In the third case, the ERD was secondary to a hemicentral RVO and involved the entire macular area. The pathogenesis of the ERD subsequent to RVO is still debated. Our experience seems to indicate that the ERD pathogenesis is linked not only to an inability of the draining vascular system, but also to an impairment in the function of the retinal pigment epithelium.     

从EURETINA最新指南看视网膜静脉阻塞诊疗策略的变化

视网膜静脉阻塞(retinal vein occlusion,RVO)是严重危及视功能的常见疾病,在临床治疗策略和方案上并未完全形成共识,国内至今也未见相关指南和共识发表,近期新的国际指南发布对RVO治疗方法和管理策略有了更为全面、清晰的推荐和建议,了解并解读相关指南可为临床实践提供参考,对规范和指导诊疗提供帮助。     

Ischemic retinal vein occlusion: characterizing the more severe spectrum of retinal vein occlusion

Retinal vein occlusion (RVO)-including central RVO, branch RVO, and hemicentral and hemispheric RVO—is the second most common vascular cause of visual loss, surpassed only by diabetic retinopathy. The presence and extent of retinal ischemia in RVO is associated with a worse prognosis. On this basis, most previously conducted studies considered ischemic retinal vein occlusion (iRVO) and non-iRVO as separate entities based on set thresholds of existing retinal ischemia as determined by fundus fluorescein angiography. Other diagnostic technologies have been used specifically in the differentiation of ischemic central retinal vein occlusion and nonischemic central retinal vein occlusion. To date, there is no fully accepted definition for iRVO. Some clinicians and researchers may favor establishing a clear differentiation between these forms of RVO; others may prefer not to consider iRVO as a separate entity. Whatever the case, retinal ischemia in RVO confers a higher risk of visual loss and neovascular complications; thus, it should be determined as accurately as possible in patients with this disease and be considered in clinical and experimental studies. Most recently conducted clinical trials evaluating new treatments for macular edema secondary to RVO included none or only few patients with iRVO based on previous definitions (i.e., few patients with sizeable areas of retinal ischemia were recruited in these trials), and thus it is unclear whether the results observed in recruited patients could be extrapolated to those with retinal ischemia. There has been scant research aiming at developing and/or testing treatments for retinal ischemia, as well as to prevent new vessel formation as a result of RVO. We provide a detailed review of the knowledge gathered over the years on iRVO, from controversies on its definition and diagnosis to the understanding of its epidemiology, risk factors and pathogenesis, the structural and functional effects of this disease in the eye and its complications, natural history, and outcomes after treatment. In each section, the definition of iRVO used is given so, independently of whether iRVO is considered a separate clinical entity or a more severe end of the spectrum of RVO, the information will be useful to clinicians to determine patient's risk, guide therapeutic decisions, and counsel patients and for researchers to design future studies.     

Medical treatment of retinal vein occlusions

The medical treatment of retinal vein occlusion (RVO) is comprised of three main stages: identification and therapy of the detectable risk factors, specific treatment aimed at the occlusive form and treatment of RVO complications. Even though the possible medical management of RVO includes several treatments, the most interesting approaches have been: anticoagulant/antiaggregating agents, troxerutin, corticosteroid, fibrinolytic/thrombolytic agents, and hemodilution. Overall, the medical approach to RVO is still awkward and unsatisfactory. Randomized clinical trials are needed to assess the degree of efficacy of the medical treatment of the specific forms of RVO.     

视网膜静脉阻塞患者中原发性开角型青光眼发病比例的研究

背景 有研究表明,高加索人视网膜静脉阻塞(RVO)与原发性开角型青光眼(POAG)的产生存在关联,但目前鲜见关于亚洲人群RVO患者中POAG发病比例的报道. 目的 观察以医院人群为基础的RVO患者中POAG的发病比例.方法 采用横断面观察性研究设计,连续纳入2011年10月至2013年5月在北京大学第三医院眼科确诊且病程在1年以内的RVO患者375例,患者均接受房角镜检查,POAG的诊断参照国际地域性和流行病学眼科学学会的青光眼诊断标准.根据眼底彩色照片和FFA将RVO分为视网膜中央静脉阻塞(CRVO)型、半侧视网膜静脉阻塞(HRVO)型和视网膜分支静脉阻塞(BRVO)型;按照静脉阻塞的部位分为动静脉交叉RVO(AV-RVO)型、视盘RVO(OC-RVO)型、无视盘水肿的视神经RVO(NONHS-RVO)型及有视盘水肿的视神经RVO(ONHS-RVO)型.分别统计不同RVO类型患者中POAG的发病比例.结果 共317例患者纳入青光眼筛查并完成各检查项目,应答率为84.5％.POAG在RVO患者中的发病比例为8.2％,其中在CRVO型中的比例为7.1％,在HRVO型中为23.5％,在BRVO型中为6.2％.OC-RVO型患者和NONHS-RVO型患者中POAG的发病比例分别为27.9％和13.2％,明显高于AV-RVO和ONHS-RVO中的4.7％和1.3％,差异均有统计学意义(均P＜0.05). 结论 中国RVO患者中POAG的发病比例是正常人群的3～4倍;OC-RVO型和NONHS-RVO型患者中POAG的发病比例较高,提示RVO的发病可能与POAG的视盘结构改变密切相关.     

Medical treatment of retinal vein occlusions

The medical treatment of retinal vein occlusion (RVO) is comprised of three main stages: identification and therapy of the detectable risk factors, specific treatment aimed at the occlusive form and treatment of RVO complications. Even though the possible medical management of RVO includes several treatments, the most interesting approaches have been: anticoagulant/antiaggregating agents, troxerutin, corticosteroid, fibrinolytic/thrombolytic agents, and hemodilution. Overall. the medical approach to RVO is still awkward and unsatisfactory. Randomized clinical trials are needed to assess the degree of efficacy of the medical treatment of the specific forms of RVO.     

抗血管内皮生长因子药物治疗对视网膜静脉阻塞黄斑水肿患者视网膜毛细血管影响的研究现状

玻璃体腔注射抗VEGF药物是目前治疗视网膜静脉阻塞(RVO)黄斑水肿的主要手段,其能明显抑制新生血管,减轻水肿,提高患者视力。但VEGF是血管内皮细胞的存活因子,其是否会导致视网膜缺血进展以及是否对视网膜毛细血管产生影响值得临床关注。就目前来看,大多学者认为,从拱环形态改变以及浅层、深层视网膜毛细血管层量化黄斑中心凹无血管区面积、视网膜无灌注区大小及黄斑区视网膜血流密度等方面观察,抗VEGF药物治疗RVO黄斑水肿并不会加重视网膜毛细血管的闭塞。并且,这些指标的变化可能与患者需要治疗的次数、视力预后等有一定的关系。今后随着OCT血管成像的逐渐普及以及抗VEGF药物治疗次数和时间的延长,期待更大样本、更长随访时间的研究深入分析抗VEGF药物治疗对RVO黄斑水肿患者视网膜毛细血管的确切影响。     

视网膜静脉阻塞继发黄斑水肿发病机制及黄斑水肿影响视功能的研究进展

视网膜静脉阻塞(RVO)是一种常见的视网膜血管疾病,其继发的黄斑水肿(ME)是引起患者视力下降的主要原因。RVO继发ME的发病机制复杂,目前尚未充分阐明,有许多细胞和细胞因子参与其中,使进入和转出视网膜液体之间的平衡被打乱,进而形成ME。本文就RVO继发ME的发病机制以及ME影响视功能的机制展开综述。     

No excess of factor V:Q506 genotype but high prevalence of anticardiolipin antibodies without antiendothelial cell antibodies in retinal vein occlusion in young patients

Factor V:Q506 (factor V Leiden) is associated with venous thrombosis and has been reported to be a risk factor for retinal vein occlusion (RVO). Anticardiolipin antibodies (ACA), also associated with RVO, are a marker for the prothrombotic condition antiphospholipid syndrome, in which antiendothelial antibodies (AECA) are also frequently present. This study reviewed 45 younger patients 10 GPL units); in 6 of these, the titre was >20 GPL units (population reference range = 0-10 GPL units). No patient had antiendothelial cell reactivity. The low-titre ACA may therefore represent a non-specific response to vascular injury.     

视网膜静脉阻塞性黄斑水肿复发因素的研究进展

视网膜静脉阻塞（RVO）是一种常见的视网膜血管疾病,其继发的黄斑水肿是RVO最常见的并发症,也是引起RVO患者视力下降的主要原因。RVO继发性黄斑水肿的发病因素复杂,并且容易复发,针对其复发因素的分析,目前尚未充分阐明,患者黄斑区结构和血流的变化以及眼内细胞因子的变化等都可能参与其中。本文就RVO继发性黄斑水肿的复发因素进行综述。     

Factors associated with retinal-vein occlusion in Hispanics

Sixty-eight foreign-born Hispanic patients with angiography-proven retinal-vein occlusion (RVO) and 50 age-, sex-, and race-matched controls were evaluated for systemic disease. Thirty of the RVO patients had central retinal-vein occlusion, and 38 had branch retinal-vein occlusion. Hypertension, the most commonly associated factor, was present in 66.2% of the RVO patients in contrast to 18% of the controls (P less than .001). Other factors which were more common in the RVO population included open-angle glaucoma (19.1% vs 8%), diabetes mellitus (16.2% vs 12%), and atherosclerotic heart disease (14.7% vs 10%); these, however, were not statistically significant (P greater than .05). Hyperlipidemia was present in 12% of the controls and 10.3% of the RVO group (P greater than .50). This is in direct contrast to reports of nonHispanic populations where hyperlipidemia has been reported to be present in up to 60% of RVO patients.     

2019年《EURETINA视网膜静脉阻塞诊疗指南》解读

视网膜静脉阻塞(retinal vein occlusion,RVO)是继糖尿病视网膜病变后常见的眼底血管性疾病。2011年发表的《视网膜静脉阻塞管理专家共识》对RVO的诊疗进行了全面的阐述。2019年8月,欧洲视网膜专家协会(European Society of Retina Specialists,EURETINA)则在2011年专家共识基础上更新了RVO诊疗指南,总结了大型临床试验结果,采纳更强证据等级的数据资料对RVO的诊疗进行了规范。2019年指南形式上采用了"基本原理-证据-推荐"的结构,对RVO进行全面总结。本文对该指南内容进行解读。     

慎重审视激光诱导脉络膜视网膜静脉吻合术在视网膜静脉阻塞治疗中的作用

视网膜静脉阻塞(retinal vein occluSion，Rvo)是一种常见的致盲性眼病，目前尚无满意的治疗方法。近年研究发现，采用激光诱导脉络膜视网膜静脉吻合术(laser-induced chorioretinal venous anastomosis,LCRVA)治疗非缺血型RVO的初步结果令人满意，但也伴发一些并发症，有些可严重威胁视功能。LCRVA的激光参数和治疗技术还未标准化，适应证有待规范。在没有得到随机临床试验验证之前，必须权衡这一疗法的利弊，慎重使用。     

视网膜静脉阻塞引起黄斑水肿的药物治疗进展

视网膜静脉阻塞(retinal vein occlusion,RVO)是临床上常见的眼底血管病,其高发性和对视力的危害性仅次于糖尿病性视网膜病变。RVO的特点是视网膜静脉扩张迂曲,沿静脉分布区域的视网膜出血、水肿和渗出,累及黄斑区时引起黄斑水肿(macular oedema,MO),久之将导致严重的中心视力损害。RVO疾病已被命名有100多年,但是一直以来RVO引起的MO的治疗比较困难。随着治疗方法的不断推新,特别是长效皮质类固醇及近年来的抗血管内皮生长因子类药物的应用,使该病的治疗效果有了较大的改观。我们从RVO引起MO的机制、糖皮质激素和抗血管内皮生长因子药物的作用机制及治疗进展等方面进行阐述,并提出了RVO的未来治疗展望。