糖尿病黄斑水肿的治疗现状

刘莉莉(综述),黄敏丽(审校)

(1.柳州市工人医院眼科,广西 柳州 545005； 2.广西医科大学第一附属医院眼科，南宁 530021)

糖尿病黄斑水肿的治疗现状

刘莉莉1(综述),黄敏丽2※(审校)

(1.柳州市工人医院眼科,广西 柳州 545005； 2.广西医科大学第一附属医院眼科，南宁 530021)

糖尿病黄斑水肿(diabetic macular edema，DME)严重损害糖尿病患者视力。其发病机制较为复杂，主要为黄斑区毛细血管周细胞和血管内皮细胞损伤、血视网膜屏障破裂、毛细血管扩张，液体和血浆成分自视网膜毛细血管内皮细胞及异常渗漏血管瘤渗出，导致视网膜水肿增厚，硬性渗出形成[1]。糖尿病患者中有10%～25%出现黄斑水肿，而患严重视网膜病变者伴DME比例较高[2]。DME治疗包括控制内科基础病及专科治疗：激光光凝、手术治疗、曲安奈德玻璃体腔注射、抗血管内皮生长因子(vascular endothelial growth factor，VEGF)玻璃体腔注射。现对DME的治疗现状予以综述。

1内科治疗

DME病程越长，全身并发症越重，预后越差，早期轻度的黄斑水肿可通过系统的内科治疗控制，进展为弥漫性黄斑水肿时，视力损害较难恢复。Matsuda等[3]将接受抗VEGF治疗的患者分成两组，糖化血红蛋白≤7%的患者经治疗后，最佳矫正视力有显著提高，糖化血红蛋白>7%的患者视力则无明显提高，治疗期间，血糖控制较好的患者黄斑中心凹厚度明显降低。

2激光光凝

激光长期以来作为糖尿病黄斑水肿的标准治疗，包括氩激光、红宝石激光、氪激光、多波长激光、掺钕钇铝石榴石(Neodymium-doped Yttrium Aluminium Garnet，ND:YAG)激光、阈下微脉冲半导体激光、帕斯卡(Pascal)激光器。激光治疗主要通过凝固效应也即是热效应，使缺血的区域成为瘢痕组织，新生血管因缺少充足的氧而消退，加强视网膜色素上皮细胞的交通作用，即激光破坏了感光细胞，从而减少了视网膜的耗氧量，减轻了内层视网膜的缺氧状态，引起视网膜小动脉的收缩，静脉压减小从而减少细胞的水肿[3]。黄斑水肿的光凝分为局部光凝、黄斑部格栅光凝、改良的格栅光凝。根据激光波长不同，黄斑水肿激光首选黄激光，其次为绿激光。美国早期糖尿病视网膜病变治疗研究组研究显示，黄斑部格栅光凝使患者3年内中度视力丧失风险减少50%[4]。黄斑部激光光凝对严重的弥漫性黄斑水肿效果欠佳，特别是合并大量硬性渗出，激光不能提高视力，短期内会因血视网膜屏障破坏加重而使水肿加重，从而引起视力减退。现不断有新的激光种类，据Lavinsky等[5]、Vujosevic等[6]报道阈下微脉冲半导体激光，阈下微脉冲半导体激光光凝时温度低于氩激光、氪激光，减轻脉络膜损害，保存病变表面一部分视网膜功能；Muqit等[7]报道近年来美国OptiMedia公司推出的Pascal激光器，发出的短脉冲将激光损害局限在视网膜色素上皮质。

3糖皮质激素治疗

糖皮质激素通过淋巴细胞、巨噬细胞、多形核白细胞、血管内皮细胞、成纤维母细胞等发挥眼部抗炎作用，抑制磷脂释放花生四烯酸，从而抑制由其转化的炎性介质：前列腺素、前列腺过氧化物、白三烯、血栓素等，下调VEGF的水平，降低血管通透性，促进水肿液吸收，抑制上皮细胞的增生及新生血管的形成，从而改善血视网膜屏障，达到治疗目的。

3.1曲安奈德玻璃体腔内注射Gillis等[8]将69眼(41例)纳入一项5年随机对照试验研究，34眼接受曲安奈德玻璃体腔内注射(intravitreous injection triamcinolone acetonide，IVTA),35眼接受安慰剂治疗。IVTA组经治疗后42%患眼视力提高5行，相比之下安慰剂组只有32%患者眼有提高。激素眼内应用可引起高眼压、加快白内障进展，玻璃体腔注药可引起眼内炎、玻璃体出血、视网膜脱离等。Beck等[9]及Elman 等[10-11]研究表明，弥漫性黄斑水肿患者经激素治疗后效果较好，眼压升高和白内障的进展则较明显。

3.2缓释型玻璃体腔内植入物为提高眼内操作安全性，缓释型玻璃体腔内植入物成为新的给药途径。它可减少玻璃体内腔注射次数，保持玻璃体腔内的药物浓度，减少玻璃体腔内注射引起的术中、术后并发症。

3.2.1缓释型地塞米松植入物美国眼力健公司生产的缓释型地塞米松植入物(地塞米松0.7 mg)作用时间可达6个月[12-13]。一项回顾性研究[14]显示，9例持续黄斑水肿患者经地塞米松植入物治疗，最佳矫正视力(best corrected visual acuity，BCVA)均有提高；Boyer等[15]研究表明，地塞米松植入物治疗对已行玻璃体切割术的DME患者同样有效。优点在于可自行眼内降解，避免再次手术。

3.2.2氟轻松非生物降解型给药系统由美国博士伦公司生产，用25号针头植入玻璃体腔，可存留3年之久。局限性为不能眼内降解，需手术取出。Campochiaro等[16-17]研究显示，随访24个月及36个月时与假注射组相比，氟轻松治疗组BCVA均有明显提高，高眼压和白内障的进展较假注射组明显。

4抗VEGF

糖尿病患者眼内视网膜内VEGF水平明显增加，促进血管内白细胞黏附，启动炎症反应，血管通透性增加，黄斑水肿。抗VEGF药物有抗新生血管形成，减少渗出、减轻水肿，稳定及提高视力作用。目前常用的抗VEGF药物有哌加他尼纳、兰尼单抗、贝伐单抗，阿柏西普。

4.1哌加他尼纳哌加他尼纳是一种核糖核受体，其特异性结合到VEGF-A165异构体(眼部主要的VEGF蛋白)，是最早运用于DME治疗的抗VEGF药物。一项Macugen治疗DME的随机对照试验[18]中提示，低浓度的Macugen(0.3 mg)治疗较安慰剂对照组在BCVA和黄斑中心厚度上均有显著提高，高浓度(1 mg、3 mg)与低浓度相比差异无统计学意义。另一项随机对照试验[19]中随访第54周，Macugen治疗组患者视力提高较安慰剂组明显，2年的随访期，Macugen治疗组视力持续改善。其抗VEGF作用有限，价格高，目前应用较少。

4.2兰尼单抗兰尼单抗于2006年在美国上市。它是人源化的重组抗体片段(Fab，或结合抗体片段)，可对抗所有VEGF亚型[20]。Massin等[21]研究中，第12个月时兰尼单抗治疗组BCVA明显高于安慰剂组；Nguyen等[22-23]和Do等[24]的研究中兰尼单抗组BCVA改善较激光组明显，与联合治疗组相比差异无统计学意义。

4.3贝伐单抗贝伐单抗为全长的重组人源化重组抗体，对VEGF A亚型有效。在眼科新生血管性疾病如湿性年龄相关黄斑病变，中心性渗出性脉络膜视网膜病变、变性近视黄斑区视网膜所形成的脉络膜新生血管、新生血管性青光眼等方面应用越来越广泛。Kook等[25]一个回顾性研究中，对慢性弥漫性黄斑水肿患者经24个月反复玻璃体腔内注射贝伐单抗后，水肿明显改善，对慢性缺血性黄斑水肿患者亦有效。贝伐单抗有增加心血管风险，对于危重患者慎用。

4.4阿柏西普阿柏西普与VEGF-A亚型有更强亲和力。眼内半衰期长。阿柏西普在治疗年龄相关性黄斑病变时和兰尼单抗疗效相同[26]。一项双盲随机对照试验Ⅱ期临床试验[27-28]中，将4种不同剂量、不同给药次数的阿柏西普组和激光组做比较，24周时阿柏西普组的BCVA均有提高，52周时阿柏西普组BCVA仍有提高。

5手术治疗

5.1玻璃体切除术学者认为由于玻璃体的机械作用和生理作用，增加血管的通透性，导致DME的发生、发展[29]。伴有玻璃体后脱离患者中DME的发生率低于无后脱离患者[30]，自发玻璃体后脱离可使DME好转[30-31]。玻璃体切除术解除玻璃体机械性牵引，视网膜通过玻璃体腔向缺血无灌注区运氧能力增强，提高含氧量，促进微血管收缩，减轻了水肿。手术适应证为玻璃体积血，增殖膜形成、弥漫性黄斑水肿，无法行视网膜光凝者； Kadonosono等[32]称玻璃体切除术后增加黄斑中心凹毛细血管血流量。此外，去除玻璃体有助于减少眼内有毒物质及细胞因子，如组胺、自由基清除剂和VEGF[33]。

5.2视网膜内界膜剥离术糖尿病眼内界膜中的纤维连接蛋白、层粘连蛋白、胶原蛋白水平提高[34-35],视网膜内界膜剥离术作为一种治疗黄斑裂孔新兴方法，适用于玻璃体积血、光学相干断层扫描或术中发现黄斑水肿的患者。玻璃体切除术联合视网膜内界膜术疗效显著。一项研究报道玻璃体切割术并发症：视网膜裂孔(9.6%)，视网膜裂孔(9.6%)，视网膜前膜(9%)，视网膜脱离，新生血管性青光眼和虹膜红变(各1.9%)[36]。

6联合治疗

联合治疗成为学者研究的方向。玻璃体腔内注射药物联合激光，可以有效减轻黄斑水肿，亦可减轻玻璃体腔内注射的风险。

6.1曲安奈德和激光的联用Chung等[37]研究表明，相比单用IVTA治疗，IVTA+黄斑部格栅光凝治疗，极大地改善难治性黄斑水肿患者的视力，且并发症更少。Aydin等[38]研究显示，IVTA先或与黄斑部格栅光凝同时治疗弥漫性黄斑水肿均较单独黄斑部格栅光凝疗效明显。

6.2激光和抗VEGF药物联用Maia等[39]将激光和IVTA 联合应用治疗非增殖期糖尿病和弥漫性黄斑水肿，最佳矫正视力的提高和中心凹厚度、黄斑容积降低较单用光凝治疗明显。Gillies等[40]研究表明，联合治疗组患眼视力提高较单独激光治疗组明显，但高眼压及白内障进展较单独激光组高。目前IVTA应用于人工晶体眼及曾行玻璃体切割术眼时，易引起眼压的升高。Mitchell等[41]研究表明，IVR及激光的联合组最佳矫正视力改善优于单用激光组。在之前Nguyen等[22-23]和Do等[24]研究显示，IVTA组合与联合组提高最佳矫正视力的差异无统计学意义，但联合治疗组最佳矫正视力及黄斑水肿均有改善，同时亦减少频繁眼内注药。

7结语

DME治疗方法中，基础病治疗尤为重要。激光长期以来作为DME治疗标准，近年来随着对DME发病机制的研究进展，新的治疗方法不断出现，如玻璃体腔内注射糖皮质激素和抗VEGF治疗，药物的联合治疗或是激光和药物的联合治疗，玻璃体切除术，这些方法各有优缺点。我国已进入老龄化社会，糖尿病患者日渐增多，需采取安全、经济、有效方法预防和治疗DME。

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摘要：糖尿病黄斑水肿是由于高血糖所引起的眼部并发症，是造成糖尿病患者视力严重损害的原因之一。DME是一种多因素引起的复杂的病理过程，传统的治疗方法主要是黄斑部激光治疗。早期糖尿病视网膜病变研究组认为激光治疗对于临床有意义的黄斑水肿是有效的。近年来，DME治疗方法有了迅速进展，如手术治疗、眼内注射药物治疗。其中新型的眼内注射药物已成为伴有中心视力下降的DME一线治疗。

关键词：糖尿病; 糖尿病黄斑水肿; 激光治疗; 药物治疗; 手术

The Treatment of Diabetic Macular EdemaLIULi-li1,HUANGMin-li2. (1.DepartmentofOphthalmology,LiuzhouWorker′sHospital,Liuzhou545005,China; 2.DepartmentofOphthalmology,theFirstAffiliatedHospital,GuangxiMedicalUniversity,Nanning530021,China)

Abstract:Diabetic macular edema(DME),a serious eye complication caused by hyperglycemia,is one of the main causes of visual impairment in diabetic patients.DME is a complex pathological process caused by multiple factors.Conventional treatment is mainly based on laser photocoagulation.The study on early treatment for diabetic retinopathy showed that macular laser photocoagulation was beneficial for eyes with clinically significant macular edema.The treatment for DME is rapidly evolving in recent years,such as surgical treatment,intraocular pharmacotherapy.New drugs,given by intraocular injection,have become first line treatment for DME with loss of vision.

Key words:Diabetes; Diabetic macular edema; Laser photocoagulation; Drug therapy; Surgery

收稿日期：2014-10-18修回日期：2014-12-28编辑：相丹峰

doi：10.3969/j.issn.1006-2084.2015.15.036

中图分类号：R774.5； R587.2

文献标识码：A

文章编号：1006-2084(2015)15-2786-04