视网膜静脉阻塞合并黄斑水肿治疗现状
Current Treatment Status of Retinal Vein Occlusion with Macular Edema
DOI: 10.12677/HJO.2021.104023, PDF, HTML, XML, 下载: 103  浏览: 450 
作者: 梁雪梅, 李 莉*:南宁爱尔眼科医院,广西 南宁
关键词: 视网膜静脉阻塞黄斑水肿治疗现状Retinal Vein Occlusion Macular Edema Treatment Status
摘要: 视网膜静脉阻塞是多种原因导致视网膜静脉回流受阻,血液循环障碍的常见视网膜血管疾病,具有显著的致盲性。RVO根据阻塞的部位不同分为视网膜分支静脉阻塞(BRVO)、视网膜中央静脉阻塞(CRVO)。RVO患者视力下降的主要原因是黄斑水肿和新生血管。视网膜中央静脉研究小组(CVOS)提出格栅样激光光凝已经不是CRVO继发黄斑水肿(Macular Edema, ME)视力下降的一种有效的治疗方法。在过去的10几年中,几项主要的随机对照临床试验研究了RVO-ME新的治疗方法。本文旨在为RVO-ME的治疗提供现有的循证方法。
Abstract: Retinal vein occlusions (RVO) are common retinal vascular disorders that have in common impaired venous return from the retinal circulation and blood circulation disorder, with the potential for significant vision-related morbidity. Retinal vein occlusions are classified as either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) based on the specific occlusion site. The main causes of vision loss in patients with RVO are associated with macular edema and neovascularization. The central vein occlusion study (CVOS) group demonstrated that grid laser photocoagulation is not an effective treatment for decreased vision due to CRVO-related macular edema. However, in the past ten years, several major randomized controlled clinical trials have investigated new therapeutic modalities for the treatment of macular edema secondary to RVO. This article aims to provide insight into current evidence based approaches to the treatment of RVO with macular edema.
文章引用:梁雪梅, 李莉. 视网膜静脉阻塞合并黄斑水肿治疗现状[J]. 眼科学, 2021, 10(4): 178-184. https://doi.org/10.12677/HJO.2021.104023

1. 前言

视网膜静脉阻塞(RVO)是我国第二大致盲性眼病(仅次于糖尿病视网膜病),通常与潜在的全身性疾病有关。RVO根据阻塞的部位不同分为视网膜分支静脉阻塞(BRVO)、视网膜中央静脉阻塞(CRVO)。RVO患者因血流中断引起的多种并发症导致视力下降的风险,包括黄斑水肿(Macular Edema, ME)、黄斑缺血、视神经病变、玻璃体积血,甚至牵引性视网膜脱离等 [1] [2]。虽然所有视网膜静脉阻塞在临床特征上都有许多共同之处,但它们在危险因素、预后,甚至治疗上是不同的。即使是同一个疾病过程中,也存在严重程度不同,例如一些患者可能完全没有症状,而另一些患者可能失去光感。因此,根据个体病情进行个性化治疗非常重要。本文拟对RVO继发黄斑水肿(RVO-ME)治疗进行综述。

2. 流行病学及危险因素

据估计,世界范围内BRVO的患病率为0.4%,CRVO约为0.08%,无性别差异,随着年龄的增长患病风险增加 [3]。40岁以上人群中RVO的患病率达1%~2%,BRVO的患病率是CRVO的4倍 [3]。单眼BRVO患者在3年内对侧眼发生RVO的风险为10% [4]。CRVO患者对侧眼的风险估计为每年1%,5年后增加到7% [5]。

RVO的主要危险因素包括高血压、动脉粥样硬化和糖尿病;也可能继发于其他过程,如炎症、血管痉挛或压迫 [6] [7]。但BRVO最常见的原因还是动静脉交叉部位的小动脉增厚造成静脉受压升高 [8]。CRVO的危险因素包括全身和眼部,高血压、糖尿病、心血管疾病、轻度体力活动和更少的酒精摄入患者CRVO的风险增加 [9]。CRVO也与开角型青光眼有关 [10]。

3. RVO-ME发病机制

RVO静脉血栓形成的确切发病机制尚不清楚。视网膜中央动脉粥样硬化可导致邻近的视网膜中央静脉受压,导致血流紊乱、内皮细胞损伤和血栓形成 [11]。黄斑水肿(ME)的机制主要是由于静脉血栓形成导致静脉引流不畅,视网膜大静脉扩张和迂曲,视网膜毛细血管压力增加。同时,这些变化触发血管内皮生长因子(VEGF-A)及炎性因子的上调和释放,炎性因子又可进一步促进VEGF-A的上调和释放,使毛细血管通透性增加,视网膜血流量减少,不同程度的缺血–缺氧,血液、液体和脂质渗出到视网膜,导致黄斑细胞外水肿 [12] [13]。近年来,越来越多的研究表明炎性介质上调在RVO-ME中起重要作用 [4] [5] [6] [7]。RVO视网膜缺血–缺氧,还可使小胶质细胞活化,触发中性粒细胞的浸润,加重血视网膜屏障的损伤,导致神经细胞损失 [14] [15];此外,炎性介质上调,Müller细胞功能异常,视网膜液体渗漏,引起黄斑细胞内水肿 [16]。同时,多个研究表明RVO患者玻璃体液及房水中细胞粘附分子(ICMA-1)、单核细胞驱化因子(MCP-1)、IL-6、IL-8及VEGF等炎性介质明显升高,与中央视网膜厚度成正相关 [17] [18] [19] [20] [21]。

4. RVO-ME治疗

RVO患者视力下降的最常见并发症是黄斑水肿(ME)。几项具有里程碑意义的试验为改善BRVO和CRVO患者的视觉效果提供了指导,与自然病程相比,基线视力可以预测不进行治疗时的预后。相对性瞳孔传导阻滞(RAPD)的存在和毛细血管无灌注程度进一步影响BRVO和CRVO视力丧失 [22]。RVO-ME的治疗有病因治疗和对症治疗,后者主要包括视网膜激光光凝、抗VEGF和皮质类固醇激素。

4.1. 视网膜激光光凝治疗黄斑水肿

在20世纪80年代早期,国家眼科研究所首先探索使用激光治疗BRVO继发的ME。对非缺血型BRVO、视力20/40或更差、血管造影提示存在ME患者,随机行格栅样激光或观察,与观察组相比,进行激光治疗的患者视力提高2行以上(65% vs. 37%),且激光治疗的患者最终视力大于20/40的可能性高近2倍。BRVO-ME持续时间影响预后,发病时间大于12个月的患者恢复2行以上视力可能性小于发病时间小于12个月的患者(53% vs. 78%)。基于以上研究结果,黄斑格栅样激光光凝术成为与BRVO继发ME的标准治疗方法,至今仍是一些患者的合理选择 [23]。

关于CRVO-ME,激光治疗在整个试验人群中缺乏益处。然而,事后分析显示,激光可能降低较年轻的亚组视力恶化。一般来说,激光不用于治疗CRVO相关的黄斑水肿,因为有更有效的选择。最近,一些研究者探索了使用外周“靶向”激光光凝治疗无灌注区视网膜,以减轻抗VEGF治疗相关的经济负担。从理论上讲,周围缺血视网膜导致眼部VEGF水平的上调,激光治疗缺血区可关闭VEGF来源。然而,目前还没有研究证明使用外周激光治疗黄斑水肿有益处 [24] [25]。

4.2. 抗VEGF治疗黄斑水肿

血管内皮生长因子(VEGF)是一种增加血管通透性的炎症细胞因子,在RVO患眼中VEGF明显升高 [26]。抗VEGF已逐渐成为RVO-ME治疗的金标准。临床上使用的三种抗VEGF药物(雷珠单抗、阿柏西普及康柏西普)均是通过玻璃体腔注射治疗。雷珠单抗是人源化单克隆抗体,对VEGF-A分子具有活性,缺少抗体域的Fc部分,对心血管系统的副作用最小,也是目前唯一纳入RVO-ME治疗医保报销药品。

CRUISE试验比较了连续6个月玻璃体腔注射雷珠单抗组治疗CRVO-ME和观察组的疗效。雷珠单抗组显示明显的解剖和视觉改善 [27]。HORIZON试验是在CRUISE试验基础上延伸,最初随机分配到观察组的患者6个月后再进行积极治疗,尽管治疗后黄斑解剖和视力有轻微改善,但两组之间仍存在持续的差异 [28]。这表明,虽然不是急症,但黄斑水肿的早期治疗对于视力恢复很重要。

阿柏西普是VEGF分子竞争性受体。VIBRANT试验比较了每4周玻璃体腔注射阿柏西普与格栅样激光治疗的效果,结果表明每月注射阿柏西普后53%的患者视力有3行以上的改善,而激光组仅有27%。6个月后,激光组和注射组进行交叉,注射组改为每8周玻璃体腔注射治疗,视力得到维持。激光组通过每月连续注射得到改善,但视觉效果的改善并不如注射组,这支持了避免延迟开始治疗的建议 [29]。GALILEO/COPERNICUS试验对每个月进行阿柏西普注射和假注射进行比较。结果显示,56%的治疗眼和12%的假注射眼视力提高了3行以上 [30] [31]。

吴香瑞等 [32] 用Meta分析法评价视网膜激光光凝联合玻璃体腔注射雷珠单抗与单纯雷珠单抗治疗BRVO-ME的远期疗效及安全性;表明激光联合雷珠单抗相较单纯雷珠单抗治疗,在视力和黄斑中心凹厚度方面的远期结果无明显差异,在雷珠单抗的注药次数和安全性方面也无较大差距。

上述临床试验在短期内提供了治疗指导。但在临床实践中,与CRVO相关的黄斑水肿是一种慢性疾病,治疗护理负担很大。最直观的是当视网膜出现水肿时才进行治疗。然而,到底是联合治疗,补充激光,或在降级治疗都是有差别的。对于这些情况,多中心试验无法提供可靠的指导,需要医生根据临床情况进行判断。

4.3. 皮质类固醇激素治疗黄斑水肿

炎症在RVO的发病机制中起重要作用,有部分RVO-ME患者使用抗VEGF效果不明显,约30% RVO-ME患者VEGF水平在正常范围内,提示在部分患者中,VEGF不是疾病活动的主要炎症因子 [21]。2019年欧洲视网膜专家协会(EURETINA)指南指出:针对RVO-ME,抗炎治疗非常必要 [33]。

RVO相关ME的下一个里程碑式的治疗突破可能是标准护理和皮质类固醇治疗。SCORE研究小组对BRVO及CRVO使用标签外无防腐剂曲安奈德(1 mg和4 mg)玻璃体腔内注射(IVTA)进行比较。同时BRVO补充激光,CRVO则选择观察。在BRVO评分中,3行以上视力改善率相似,激光改善率为29%,IVTA 1 mg改善率为26%,IVTA 4 mg改善率为27%。但是4mg IVTA时不良事件发生率明显增加,35%的患者发生了白内障进展,41%的患者需要降眼压治疗。所有研究组OCT视网膜厚度在1年内均有改善,黄斑中心凹厚度的中位数减少相似。基于以上研究结果,建议将格栅样激光作为BRVO合并黄斑水肿患者的一线治疗 [34]。在CRVO评分中,与观察组相比,两组受试者视力提高3行以上均有更高比例(26%~27% vs. 7%)。与4 mg组相比,1 mg组出现白内障、白内障手术和眼压升高的几率更低。近年来,由于抗VEGF治疗的副作用少,疗效明确,不含防腐剂的IVTA越来越少用于临床 [34]。

2009年,美国食品药品监督管理局(FDA)批准了玻璃体内注射的地塞米松缓释剂(Ozurdex®) 0.7 mg用于RVO-ME的治疗。一项随机、多中心、对照临床试验GENEVA研究了两种剂量的玻璃体腔地塞米松(0.7 mg vs. 0.35 mg)植入对BRVO和CRVO患者的疗效 [35]。该研究包括34%的CRVO患者和66%的BRVO患者。所有受试者视力均为20/50及以下,OCT中心厚度大于299 μm。随机分成0.7 mg组、0.35 mg组及假注射组,观察注射后6个月内结果。在BRVO中,注射后30天视力提高3行的眼睛比例高于90天,表明随时间延长,治疗效果减弱。在6个月时,3组的视力和解剖结果均无差异。药物治疗组的高眼压更常见,4%的眼睛出现高眼压,而假注射组仅有0.7%。该研究还表明,RVO-ME早期治疗比延迟治疗更有利于视力的恢复。GENEVA研究事后亚组分析发现,在黄斑水肿发作90天内进行治疗的患者,比其他晚于这个时间治疗的患者更有可能得到视力改善,同时,重复注射地塞米松植入物会增加白内障和眼压升高的风险 [36]。

4.4. 抗VEGF联合地塞米松缓释剂治疗黄斑水肿

近年来,RVO-ME联合抗VEGF与傲迪适治疗的理念得到越来越多眼科医生的重视。然而,关于联合治疗的研究较少。一项非双盲的介入性研究在抗VEGF治疗后2周联合傲迪适玻璃体内注射,平均注射间隔135.5天。抗VEGF药物联合傲迪适植入物的治疗提供了一个可预测的效果持续时间,以及BCVA和中央视网膜厚度的显著改善 [37]。Mayer等 [38] 观察64只眼因RVO引起的黄斑水肿患者,对比三针抗VEGF规范注射后再联合地塞米松植入物和地塞米松植入物单药治疗的疗效和安全性,发现两种治疗方案在CRVO中没有差异,但是对于BRVO患者地塞米松植入物单药治疗效果更好。一篇关于抗VEGF药物联合皮质类固醇治疗RVO-ME的Meta分析显示 [39]:相比单纯抗VEGF药物,抗VEGF药物联合皮质类固醇激素治疗RVO-ME具有起效快、注射次数少、更加经济的特点。但不良反应发生率也更高,主要为高眼压及白内障。

5. 结论

RVO-ME治疗的最佳的给药策略仍在研究中。抗VEGF和傲迪适联合治疗起到互补作用,未来潜在的联合治疗策略,最佳的再治疗时间,治疗频率将是研究重点。

NOTES

*通讯作者。

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