糖尿病视网膜病变玻璃体切割术前康柏西普玻璃体腔注射时机对VEGF表达水平和视力恢复的影响

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文晓霞, 李红军, 谭德文, 方腾, 刘有娅, 蒋小均. 糖尿病视网膜病变玻璃体切割术前康柏西普玻璃体腔注射时机对VEGF表达水平和视力恢复的影响[J]. 中华眼视光学与视觉科学杂志, 2019,21(3): 181-186.
Xiaoxia Wen, Hongjun Li, Dewen Tan, Teng Fang, Youya Liu, Xiaojun Jiang. Effects of Timing of a Preoperative Intravitreal Injection of Conbercept on the Expression of VEGF and the Recovery of Visual Acuity in Patients with Diabetic Retinopathy[J]. CHINESE JOURNAL OF OPTOMETRY OPHTHALMOLOGY AND VISUAL SCIENCE, 2019,21(3): 181-186. 复制到剪切板

Doi: 10.3760/cma.j.issn.1674-845X.2019.03.005
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糖尿病视网膜病变玻璃体切割术前康柏西普玻璃体腔注射时机对VEGF表达水平和视力恢复的影响

文晓霞, 李红军, 谭德文, 方腾, 刘有娅, 蒋小均

重庆市开州区人民医院眼科 405499

通讯作者:李红军（ORCID：0000-0002-0283-0185）,Email：156717116@qq.com

第一作者：文晓霞（ORCID：0000-0002-9279-624X）,Email：460602916@qq.com

收稿日期: 2018-09-26

摘要

目的: 探讨糖尿病视网膜病变（DR）玻璃体切割术前康柏西普玻璃体腔注射时机对新生血管膜血管内皮生长因子（VEGF）表达水平及患者视力恢复的影响。方法: 前瞻性临床研究。将2015年5月至2017年5月重庆市开州区人民医院眼科收治的109例DR患者按随机数余数法分为A组（32例）、B组（43例）、C组（34例）,3组均行玻璃体切割术,A组术前不予玻璃体腔内注射康柏西普,B组术前3 d术眼玻璃体腔注射康柏西普,C组术前5 d术眼玻璃体腔注射康柏西普,观察3组手术情况,记录手术时间、术中出血量及医源性裂孔发生情况,所有患者术中留取视网膜下新生血管膜标本,测定VEGF表达水平;观察各组并发症发生率,比较手术前后不同时间患者最佳矫正视力（BVCA）的变化情况。数据采用单因素方差分析进行比较。结果: B、C组手术时间及术中出血量均少于A组（ P<0.05）,术中电凝止血率、医源性视网膜裂孔率均低于A组,术后玻璃体内出血发生率较A组低（ P<0.05）,术后角膜水肿、高眼压、前房炎性反应发生率均低于A组（ P<0.05）,但B、C组组间比较差异无统计学意义（ P>0.05）。B、C组新生血管膜VEGF阳性率低于A组,但B、C组组间比较差异无统计学意义（ P>0.05）。术后3、6个月,3组BCVA均上升（ P<0.05）,B、C组术后3、6个月BCVA高于A组（ P<0.05）,但组间比较差异无统计学意义（ P>0.05）。结论: DR患者术前玻璃体腔内注射康柏西普均可缩短手术时间,降低术中、术后并发症发生率,降低新生血管膜VEGF表达水平,促进患者术后视力恢复,但术前3 d或5 d注射效果并无明显差别。

关键词: 糖尿病视网膜病变; 康柏西普; 玻璃体切割术; 时机; 血管内皮生长因子

Effects of Timing of a Preoperative Intravitreal Injection of Conbercept on the Expression of VEGF and the Recovery of Visual Acuity in Patients with Diabetic Retinopathy

Xiaoxia Wen, Hongjun Li, Dewen Tan, Teng Fang, Youya Liu, Xiaojun Jiang

Department of Ophthalmology, the People's Hospital of Kaizhou District, Chongqing 405499, China

Corresponding author:Hongjun Li, Department of Ophthalmology, the People's Hospital of Kaizhou District, Chongqing 405499, China (Email: 156717116@qq.com)

Abstract

Objective: To investigate the effects of the timing of a preoperative intravitreal injection of Conbercept on the expression of vascular endothelial growth factor (VEGF) and the recovery of visual acuity in patients with diabetic retinopathy (DR).Methods: In this prospective clinical study, 109 patients with DR treated in the People's Hospital of Kaizhou District, Chongqing, from May 2015 to May 2017 were randomly divided into A, B and C groups, 32 patients in group A, 43 patients in group B, 34 patients in group C. The three groups were treated by vitrectomy. Patients in group A were not treated with an intravitreal injection of Conbercept before surgery, patients in group B were treated with an intravitreal injection of Conbercept at 3 d before surgery, and patients in group C were treated with an intravitreal injection of Conbercept at 5 d before surgery. The surgery for the three groups was observed, and the surgical time, intraoperative blood loss and incidence of iatrogenic hiatus were recorded. The subretinal neovascular membrane specimens of all patients were collected during the surgery to determine the expression levels of VEGF. The incidence of complications was observed, and changes in the best corrected visual acuity (BCVA) at different times before and after surgery were compared. Data were analyzed using a one-way ANOVA.Results: The surgical times and intraoperative blood loss of groups B and C were shorter and less than those in group A ( P<0.05), and the rates of electric coagulation hemostasis during surgery, the incidence rates of the iatrogenic retinal hole and postoperative vitreous hemorrhage were lower than those in group A ( P<0.05). The incidence rates of corneal edema, high intraocular pressure and anterior chamber inflammatory reactions in groups B and C after surgery were lower than those in group A ( P<0.05), but there was no statistically significant difference between groups B and C ( P>0.05). The positive rates of VEGF in the neovascular membranes of group B and group C were lower than that in group A, but the difference between groups B and C ( P>0.05) was not significant. The BCVA of the three groups increased at 3 months and 6 months after surgery ( P<0.05), and the BCVA of groups B and C at 3 and 6 months after surgery was higher than that of group A ( P<0.05), without a statistically significant difference between groups B and C ( P>0.05).Conclusions: Intravitreal injections of Conbercept on the 3 d and 5 d before surgery can shorten the surgical time, reduce the incidence of intraoperative and postoperative complications, reduce the expression level of VEGF in the neovascular membrane, and promote the recovery of visual acuity in patients with DR after surgery, without a significant difference between injections 3 d or 5 d before surgery.

Keyword: diabetic retinopathy; Conbercept; vitrectomy; timing; vascular endothelial growth factor

文章图片

糖尿病视网膜病变（DR）是糖尿病严重微血管并发症^[1], 以血-视网膜屏障破坏、新生血管形成为病理特点, 主要表现为视力降低、视物模糊等, 且随病程的进展, 患者可能出现视细胞凋亡、视网膜纤维化, 造成永久性视力丧失^[2]。玻璃体切割术是目前治疗DR的有效手段, 但术中可能牵拉新生纤维化血管, 易造成出血, 增加医源性裂孔发生风险, 影响患者术后视力恢复。过去认为玻璃体切割术联合抗凝、抗血小板药物治疗可促进患者术后恢复^[3]。但近年来有研究者指出, 抗血小板聚集及抗凝类药物不仅无法改善患者视力水平, 同时可能增加患者视网膜出血发生风险^[4]。血管内皮生长因子（Vascular endothelial growth factor, VEGF）为有选择性的血管生成因子, 可促进内皮细胞有丝分裂及新生血管形成, 在DR发病及进展过程中发挥重要作用, 是引起视网膜纤维血管增殖的主要原因。而采用抗VEGF药物则可抑制新生血管生成, 防止血管渗漏, 提升手术效果。康柏西普属新型抗VEGF类药物, 可特异性阻断VEGF与VEGF受体结合, 抑制眼部异常血管增生, 且采用玻璃体腔内给药方式可提升眼内局部药物浓度, 促进药物透过血-眼屏障, 直达病灶, 提升疗效^[5]。但目前对DR患者玻璃体切割术前康柏西普用药时机的选择尚存在一定的争议。为探讨DR患者玻璃体切割术前康柏西普玻璃体腔注射时机对新生血管膜VEGF表达水平及患者视力恢复的影响, 现对重庆市开州区人民医院收治的DR患者展开了研究分析, 报告如下。

1 对象与方法

1.1 对象

纳入标准：①经眼科检查确诊的增殖性DR; ②单眼发病; ③糖尿病病程超过4年; ④病变处于V期, 拟行玻璃体切割术; ⑤患眼最佳矫正视力（BCVA）< 0.1; ⑥年龄> 18岁; ⑦入组前4周未服用其他抗VEGF药物; ⑧患者知情同意。

排除标准：①晶状体混浊超过Ⅲ 级者; ②合并心肝肾肺器质性功能障碍者; ③合并造血系统疾病者; ④合并严重精神疾病者; ⑤合并青光眼者; ⑥合并恶性肿瘤者或自身免疫功能障碍者; ⑦血糖控制不良者; ⑧妊娠或哺乳期女性; ⑨严重过敏体质者; ⑩依从性差, 无法配合治疗者。

纳入2015年5月至2017年5月重庆市开州区人民医院眼科收治的109例DR患者作为研究对象。按随机数余数法分为A、B、C组, A组患者术前不注射康柏西普, B组患者术前3 d注射康柏西普, C组患者术前5 d注射康柏西普。A组纳入患者32例, B组纳入患者43例, C组纳入患者34例。本研究遵循赫尔辛基宣言。

1.2 方法

3组均接受玻璃体切割术。A组：术前不予康柏西普玻璃体腔内注射, 直接行玻璃体切割术。采用美国博士伦一体式玻璃体切割仪, 行23G巩膜三通道玻璃体切割术, 常规球后麻醉, 23G巩膜通道, 行玻璃体切割, 清除玻璃体积血, 剥离新生血管膜, 复位视网膜, 常规行视网膜激光凝术, 合并白内障者行白内障超声乳化手术治疗, 手术顺利剥离纤维增殖膜未伴视网膜脱离或轻度视网膜脱离者玻璃腔内填充气体顶压视网膜, 发生视网膜脱离者玻璃体内注射硅油压迫视网膜, 术后3~6个月取硅油。 B组：术前3 d术眼玻璃体腔内注射康柏西普。采用盐酸奥布卡因点眼行表面麻醉, 消毒铺巾, 开睑器开睑, 结膜囊消毒, 0.9%氯化钠溶液冲洗, 注射器抽取0.05 ml康柏西普, 自颞上象限距角巩膜约3.5 mm睫状体处垂直穿刺, 注入康柏西普, 注射完毕后拔针, 压迫进针处, 氧氟沙星眼膏点眼, 术眼常规包扎。C组术前5 d玻璃体腔内注射康柏西普, 方法同B组。3组受试期间均未用其他同类药物干预。

1.3 观察指标

①手术情况观察。统计各组手术时间、术中出血（积液盒平均红细胞数× 10⁶/ml）情况, 并记录术中使用电凝止血及医源性视网膜裂孔发生率。②术后情况观察。均记录各组术后玻璃体内出血（早期：术后1个月内; 晚期：术后1个月后）情况, 统计再次手术治疗所占比例, 记录各组术后高眼压、视网膜增殖、角膜水肿等并发症发生率。③VEGF水平测定。各组术中均采用内界膜镊撕除新生血管膜, 多聚甲醛固定、脱水, 二甲苯透明, 连续切片, 采用免疫组化法测定新生血管膜VEGF水平, 采用辣根过氧化物酶标记的链霉卵白素染色法, 光学显微镜下观察, 均以PBS替代一抗为阴性对照, 以细胞浆内出现红色颗粒为VEGF阳性, 采用网格测试法计算阳性细胞百分率, 选取高倍视野观察100个细胞中阳性细胞计数, 每个标本均取3个视野, 取均值。④视力恢复情况观察。术前, 术后3、6个月均行眼科检查, 测定患者BCVA的变化, BCVA采用国际标准视力表测定。

1.4 统计学方法

前瞻性临床研究。数据均采用SPSS 20.0软件分析, 计数资料采用χ ²和Fisher检验, 计量资料符合正态分布, 方差齐, 以均数± 标准差表示, 采用单因素方差分析进行检验, 组内行LSD-t检验。以P< 0.05为差异有统计学意义。

2 结果

2.1 术前基线特征

3组患者年龄、性别、病程、视力、术前空腹血糖比较差异均无统计学意义（P> 0.05）, 具有可比性, 见表1。

表1 各组糖尿病视网膜病变患者玻璃体切割术前基线特征 Table 1 Baseline demographics and characteristics of diabetic retinopathy patients before vitrectomy

2.2 各组手术时间及术中出血量比较

B、C组手术时间及术中出血量均少于A组, 差异均有统计学意义（P< 0.05）, 但B、C组组间比较差异无统计学意义（P> 0.05）, 见表2。

表2 各组糖尿病视网膜病变患者玻璃体切割手术时间及术中出血量比较 Table 2 Comparison of operative time and blooding volume between each diabetic retinopathy group during vitrectomy

2.3 各组术中及术后情况比较

B、C组术中电凝止血发生率、医源性视网膜裂孔发生率、术后玻璃体内出血发生率、角膜水肿发生率、高眼压发生率、前房炎性反应发生率均低于A组, 差异有统计学意义（P< 0.05）, 但B、C组组间差异无统计学意义（P> 0.05）, 各组早期玻璃体内出血及术后再次手术所占比例比较差异无统计学意义（P> 0.05）, 见表3。

表3 各组糖尿病视网膜病变患者玻璃体切割术中及术后情况及手术并发症发生率比较 Table 3 Comparison of intraoperative and postoperative complications between each diabetic retinopathy group underwent vitrectomy

2.4 各组新生血管膜VEGF阳性率比较

B、C组新生血管膜VEGF阳性率低于A组, 差异有统计学意义（P< 0.05）, 但B、C组组间差异无统计学意义（P> 0.05）。各组术中取材新生血管膜VEGF表达见图1。

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图1. 各组糖尿病视网膜病变患者玻璃体切割术中取材新生血管膜VEGF表达（HE, × 400）
A：术前未注射康柏西普者新生血管膜VEGF表达; B：术前3 d注射康柏西普者新生血管膜VEGF表达; C：术前5 d注射康柏西普者新生血管膜VEGF表达Figure 1. VEGF expression in the neovascular membrane of each diabetic retinopathy group that underwent vitrectomy (HE, × 400)
A: VEGF expression in the neovascular membrane of patient did not treated with an intravitreal injection of Conbercept before surgery. B: VEGF expression in the neovascular membrane of patient with an intravitreal injection of Conbercept at 3 d before surgery. C: VEGF expression in the neovascular membrane of patient with an intravitreal injection of Conbercept at 5 d before surgery.

2.5 各组术后不同时间BCVA比较

术后3、6个月, 3组BCVA均上升, 与术前比较差异有统计学意义（P< 0.05）, 术后3、6个月B、C组BCVA高于A组, 差异有统计学意义（P< 0.05）, 但B、C组组间差异无统计学意义（P> 0.05）, 见表4。

表4 各组糖尿病视网膜病变患者玻璃体切割术后不同时间BCVA比较 Table 4 Comparison of BCVA at different postoperative time between each diabetic retinopathy group underwent vitrectomy

3 讨论

DR系以血管新生为特点的增殖性眼底病变, 以增生性DR多见^[6]。玻璃体手术是目前治疗DR的首选方式, 手术重点在于剥离视网膜新生血管膜, 解除增殖牵引, 避免视网膜机械损伤^[7]。但DR常伴玻璃体积血、纤维膜增生, 新生血管纤维化增殖牵引可能导致严重出血, 在剥离过程中可能增加手术出血, 影响术野, 造成医源性视网膜裂孔, 增加手术并发症的发生风险, 影响术后患者视力恢复, 严重者可能引起牵拉性视网膜脱离及继发性青光眼, 影响患者生活质量^[8]。近年来, 较多报道均发现, 玻璃体手术术前应用抗VEGF药物可促进新生血管萎缩, 减少术中出血, 改善手术视野, 简化手术, 缩短手术时间, 降低手术并发症发生率^{[9, 10]}。本研究中, A组单纯应用玻璃体切割术, B、C组分别于术前3 d、术前5 d辅助应用抗VEGF药物康柏西普玻璃体腔内注药治疗, 结果发现, B、C组手术时间较A组短, 术中出血量较A组少, 同时B、C组术中电凝止血使用率降低, 医源性视网膜裂孔发生率降低, 与肖紫云等^[11]的结论相符。分析主要原因可能为：术前康柏西普玻璃体腔内注射可抑制血管渗漏, 减轻组织水肿, 降低术中剥离新生血管膜难度, 明显降低对视网膜组织的牵拉损伤, 并降低视网膜裂孔发生风险; 同时康柏西普的应用可有效抑制新生血管增生, 避免进一步出血及渗出, 简化手术, 减少术中电凝止血使用率, 缩短手术时间。

Wang等^[12]表示, DR患者采用玻璃体切割术治疗虽可挽救部分视力, 但玻璃体出血的发生严重影响患者预后, 导致视力降低, 增加高眼压、视网膜脱离的发生风险, 严重者可能失明。沈强等^[13]研究发现, DR患者玻璃体切割术后VEGF水平上升, 可进一步刺激新生血管生成, 引起玻璃体内再发生出血。有学者对行玻璃体切割术的DR患者进行术后随访发现, 有超过60%的患者术后早期发生玻璃体内出血^[14]。本研究发现, 术前辅助应用抗VEGF药物的患者术后玻璃体内出血发生率均低于单纯应用手术治疗的患者, 主要与玻璃体腔内注射康柏西普具备显著的抗VEGF生成作用有关。康柏西普与VEGF亲和力强, 且结构稳定, 代谢速度慢, 药效周期长, 可有效抑制新生血管形成, 抑制纤维增生, 促进新生血管、血管膜萎缩, 减少出血性渗漏, 降低玻璃体出血发生率。同时进行新生血管膜VEGF免疫组化监测发现, B、C组术中VEGF阳性率低于A组, VEGF为血管内皮细胞特异性促有丝分裂素, 可促进视网膜色素上皮细胞有丝分裂, 增加血管渗透性, 近年来被发现VEGF参与DR血管病变过程, 可导致视网膜血管渗漏, 促进新生血管生成^[15]。术前接受康柏西普注射后患者VEGF阳性率降低, 主要与康柏西普抗VEGF形成作用有关。此外, 进行术后视力监测发现, B、C组术后不同时间BCVA均高于A组, 主要与术前应用康柏西普可抑制新生血管形成, 提高手术治疗效果, 减少视网膜出血及增殖风险, 降低术后再出血发生率有关, 有助于促进患者术后视力恢复。

综上所述, 术前不同时间应用康柏西普均可降低DR患者玻璃体切割术手术难度, 缩短手术时间, 减少术中出血, 减少手术相关并发症的发生率, 同时有助于降低VEGF水平, 促进患者术后视力恢复。

利益冲突申明 本研究无任何利益冲突

作者贡献声明 文晓霞、李红军：收集数据, 参与选题、设计及资料的分析和解释; 撰写论文; 根据编辑部的修改意见进行修改。谭德文、方腾：参与选题、设计和修改论文的结果、结论。刘有娅、蒋小均：参与选题、设计、资料的分析和解释; 修改论文中关键性结果、结论; 根据编辑部的修改意见进行核修

The authors have declared that no competing interests exist.

参考文献

文献选项

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2015

0.0

... 糖尿病视网膜病变（DR）是糖尿病严重微血管并发症^[1],以血-视网膜屏障破坏、新生血管形成为病理特点,主要表现为视力降低、视物模糊等,且随病程的进展,患者可能出现视细胞凋亡、视网膜纤维化,造成永久性视力丧失^[2] ...

2016

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2014

0.0

... 过去认为玻璃体切割术联合抗凝、抗血小板药物治疗可促进患者术后恢复^[3] ...

2017

0.0

... 但近年来有研究者指出,抗血小板聚集及抗凝类药物不仅无法改善患者视力水平,同时可能增加患者视网膜出血发生风险^[4] ...

2017

0.0

... 康柏西普属新型抗VEGF类药物,可特异性阻断VEGF与VEGF受体结合,抑制眼部异常血管增生,且采用玻璃体腔内给药方式可提升眼内局部药物浓度,促进药物透过血-眼屏障,直达病灶,提升疗效^[5] ...

2013

0.0

... 3 讨论DR系以血管新生为特点的增殖性眼底病变,以增生性DR多见^[6] ...

2016

0.0

曾苗, 宋艳萍, 丁琴. 玻璃体腔注射康柏西普治疗病理性近视脉络膜新生血管疗效观察. 中华眼底病杂志, 2016, 32(1): 17-21.

Objective To evaluate the efficacy of intravitreal injections of conbercept in choroidal neovascularization (CNV) secondary to pathologic myopia (PM). Methods A retrospective case series of 37 eyes of 37 patients affected with CNV secondary to PM treated by intravitreal injections of Conbercept. All the patients were examined with best-corrected visual acuity (BCVA) of Early Treatment Diabetic Retinopathy Study (ETDRS) chart, central macular thickness (CMT) of optical coherence tomography （OCT）at baseline. The initial average letters of ETDRS BCVA was 49.86±8.87, CMT was (306.38±31.01) μm. All eyes were treated with intravitreal Conbercept 0.05 ml (10 mg/ml). Follow-up visits were performed monthly after injection. The mean follow-up time was 16.8 months. Injections were repeated according to the situation of BCVA, CMT, subretinal fluid and CNV leakage in follow-up. All eyes received an average of 4.8 injections. BCVA, CMT and ophthalmoscope examination were assessed monthly. The relationship of BCVA improvement and CMT reduction with the data at baseline and number of treatments were analyzed by Spearman Rho correlation respectively. Results During the 1, 3, 6 and 12 months after treatment, the mean BCVA were all improved with statistically significant difference (t=17.629, P＜0.01)．At 12 months，15 eyes (45.9%) had improvement of 15 letters or more, 32 eyes (86.5%) had improvement of 5 letters or more, and 1 eye (2.7%) had decreased more than 5 letters. During the 1, 3, 6 and 12 months after treatment, the mean CMT were all decreased with statistically significant difference (F=43.726, P＜0.01). At 12 months，the retinal fluid of 34 eyes (91.9%) were absorbed completely; 33 eyes (89.2%) had angiographic closure at that time. There was no significant relevance between BCVA improvement and sex, age and course of the disease (P＞0.05), but a significant negative correlation was found between the BCVA improvement and BCVA at baseline, injection times (P＜0.05). There was no significant relevance between CMT reduction and sex, age, course of the disease and injection times (P＞0.05), but a significant positive correlation was found between CMT reduction and CMT at baseline (P＜0.05). There were no systemic or ocular serious side effects during the follow up. Conclusions Intravitreal injections of Conbercept showed BCVA improvement and CMT reduction. It appeared to be effective and safe for choroidal neovascularization secondary to pathologic myopia. Intravitreal Conbercept for CNV secondary to PM showed BCVA improvement, CMT reduction and safety.

Wuhan General Hospital of Guangzhou Military Command，Wuhan 430070，China

目的观察玻璃体腔注射康柏西普治疗病理性近视(PM)继发黄斑部脉络膜新生血管（CNV）的临床疗效及安全性。方法回顾性系列病例研究。经最佳矫正视力（BCVA）、眼部A型超声、光相干断层扫描（OCT）、荧光素眼底血管造影联合吲哚青绿血管造影等检查确诊的PM继发黄斑部CNV的37例患者37只眼纳入研究。采用早期糖尿病视网膜病变治疗研究视力表行BCVA检查；OCT测量黄斑中心视网膜厚度（CMT）。患眼平均BCVA为（49.86±8.87）个字母，平均CMT为（306.38±31.01） μm。均行玻璃体腔注射10 mg/ml的康柏西普0.05 ml(含康柏西普0.5 mg)治疗。治疗后每一个月随访1次，平均随访时间16.8个月。根据每一个月随访所见的BCVA、CMT、视网膜下积液、CNV渗漏等变化情况确定是否需重复治疗。患眼平均治疗次数为4.8次。对比观察治疗前后BCVA、CMT的变化以及随访期间眼部与全身不良反应发生情况；分析治疗后BCVA提高及CMT下降与患者年龄、性别、治疗次数、治疗前BCVA或CMT值的相关性。 结果 治疗后1、3、6、12个月患眼平均BCVA均较治疗前明显提高，差异有统计学意义（F=17.629，P＜0.01）。治疗后12个月，BCVA提高超过15个字母者15只眼，占45.9%；提高超过5个字母者32只眼，占86.5%；下降超过5个字母者1只眼，占2.7%。治疗后1、3、6、12个月患眼平均CMT均较治疗前明显降低，差异有统计学意义（F=43.726,P＜0.01）。治疗后12个月，视网膜积液完全吸收34只眼，占91.9%；视网膜积液未完全吸收3只眼，占8.1%。黄斑部CNV病灶渗漏消失33只眼，占89.2%；黄斑部CNV病灶渗漏未消失4只眼，占10.8%。相关性分析结果显示，治疗后BCVA提高字母数与性别、年龄、病程无明显相关（P＞0.05）；与治疗前BCVA及注射次数呈负相关（P＜0.05）。治疗后CMT下降值与性别、年龄、病程、注射次数均无明显相关（P＞0.05）；与治疗前CMT值呈正相关（P＜0.05）。随访期间均未发生视网膜脱离、眼内炎、白内障及持续性眼压升高等与药物、注射相关的眼部和全身不良事件。结论玻璃体腔注射康柏西普治疗PM继发黄斑部CNV可提高患眼BCVA，降低CMT。无与治疗相关的不良事件发生。

... 玻璃体手术是目前治疗DR的首选方式,手术重点在于剥离视网膜新生血管膜,解除增殖牵引,避免视网膜机械损伤^[7] ...

2015

0.0

陈小红, 陈梅珠, 王云鹏. 增生型糖尿病视网膜病变患眼玻璃体腔注射雷珠单抗治疗前后房水血管内皮生长因子和色素上皮衍生因子的浓度变化. 中华眼底病杂志, 2015, 31(6): 560-563. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.012.

Objective To analyze the concentrations of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in aqueous humor of patients with proliferative diabetic retinopathy (PDR) before and after intravitreal injection of ranibizumab. Methods Twenty-five eyes of 20 PDR patients were collected as the PDR group. Twenty-five eyes of 21 senile cataract patients were collected as the control group. There were no statistical significance in gender (χ2=0.223), age (Z=-1.555) and intraocular pressure (Z=-0.225) between the two groups (P＞0.05). Samples of aqueous humor (0.1 ml) were collected just before and 7 days after the injection of ranibizumab in PDR group. Samples of aqueous (0.1 ml) humor were collected just before cataract surgery in control group. The concentrations of VEGF and PEDF in the aqueous humor were measured by enzyme-linked immunosorbent assay. Results The VEGF and PEDF concentration in the aqueous humor were reduced significantly after intravitreal injection of ranibizumab in PDR group (Z=-4.072, -4.319; P＜0.05). The concentrations of VEGF and PEDF in the aqueous humor before intravitreal injection of ranibizumab in PDR group were significantly higher than the control group (Z=-5.228, 4.706; P＜0.05). The VEGF concentration in the aqueous humor after intravitreal injection of ranibizumab in PDR group were similar to control group (Z=-1.557, P＞0.05). However, the concentration of PEDF in the aqueous humor after intravitreal injection of ranibizumab in PDR group still higher than control group (Z=-2.475, P＜0.05). The ratio of VEGF/PEDF before and after intravitreal injection of ranibizumab was statistically different (Z=-2.058，P＜0.05), but was the same between PDR group and control group (Z=-0.456, -0.844; P＞0.05). The aqueous humor concentrations of VEGF and PEDF were not significantly correlated with each other, neither in PDR group (r=-0.195, -0.174; P＞0.05) nor in control group (r=-0.286, P＞0.05). Conclusions Aqueous humor concentrations of VEGF and PEDF are significantly elevated in eyes with PDR. Intravitreal injection of ranibizumab significantly decreased the VEGF and PEDF in the aqueous humor after 7 days.

Department of Ophthalmology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou 350025, China

目的观察增生型糖尿病视网膜病变（PDR）患眼玻璃体腔注射雷珠单抗（IVR）治疗前后房水血管内皮生长因子（VEGF）和色素上皮衍生因子（PEDF）的浓度变化。方法临床确诊为PDR的20例患者25只眼（PDR组）及老年性白内障患者（对照组）21例25只眼纳入研究。两组患者的性别（χ2=0.223）、年龄（Z=-1.555）、眼压（Z=-0.225）比较，差异无统计学意义（P＞0.05）。PDR组患眼行常规IVR治疗；对照组患眼常规行白内障超声乳化手术。PDR组患眼于IVR治疗前及IVR治疗后7 d、对照组患眼于手术前各抽取房水0.1 ml，采用酶联免疫吸附测定法检测房水VEGF、PEDF浓度。对两组患眼房水VEGF、PEDF浓度行相关性分析。结果 IVR治疗后PDR组患眼房水VEGF、PEDF浓度较IVR治疗前明显降低，差异有统计学意义（Z=-4.072、-4.319，P＜0.05）。IVR治疗前PDR组患眼房水VEGF、PEDF浓度较对照组明显升高，差异有统计学意义（Z=-5.228、4.706，P＜0.05）。与对照组比较，IVR治疗后PDR组患眼房水VEGF浓度无明显变化，差异无统计学意义（Z=-1.557， P＞0.05）；而PEDF浓度仍偏高，差异有统计学意义（Z=-2.475，P＜0.05）。IVR治疗前后PDR组患眼房水VEGF/PEDF浓度比值比较，差异有统计学意义（Z=-2.058，P＜0.05）。IVR治疗前后PDR组患眼房水VEGF/PEDF浓度比值分别与对照组比较，差异均无统计学意义（Z=-0.456、-0.844，P＞0.05）。相关性分析结果显示，IVR治疗前后PDR组患眼房水VEGF和PEDF浓度之间均无明显相关性（r =-0.195、-0.174，P＞0.05）；对照组患眼房水VEGF和PEDF浓度之间也无明显相关性（r=-0.286，P＞0.05）。结论 PDR患眼房水中VEGF和PEDF浓度显著增高；经IVR治疗后，房水VEGF、PEDF浓度明显降低。

... 但DR常伴玻璃体积血、纤维膜增生,新生血管纤维化增殖牵引可能导致严重出血,在剥离过程中可能增加手术出血,影响术野,造成医源性视网膜裂孔,增加手术并发症的发生风险,影响术后患者视力恢复,严重者可能引起牵拉性视网膜脱离及继发性青光眼,影响患者生活质量^[8] ...

2013

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... 近年来,较多报道均发现,玻璃体手术术前应用抗VEGF药物可促进新生血管萎缩,减少术中出血,改善手术视野,简化手术,缩短手术时间,降低手术并发症发生率^[9,10] ...

2017

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2017

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... 本研究中,A组单纯应用玻璃体切割术,B、C组分别于术前3 d、术前5 d辅助应用抗VEGF药物康柏西普玻璃体腔内注药治疗,结果发现,B、C组手术时间较A组短,术中出血量较A组少,同时B、C组术中电凝止血使用率降低,医源性视网膜裂孔发生率降低,与肖紫云等^[11]的结论相符 ...

2013

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... Wang等^[12]表示,DR患者采用玻璃体切割术治疗虽可挽救部分视力,但玻璃体出血的发生严重影响患者预后,导致视力降低,增加高眼压、视网膜脱离的发生风险,严重者可能失明 ...

2012

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沈强, 张学东, 宗元娟, 等. 玻璃体腔注射环孢菌素A对糖尿病大鼠血视网膜屏障的保护作用及机制. 中华眼底病杂志, 2012, 28(3): 254-257. DOI: 10.3760/cma.j.issn.1005-1015.2012.03.011.

Objective To investigate the protective effect and mechanism of intravitreal injection with cyclosporin-A(CsA) on blood-retinal barrier (BRB) in diabetic rats. Methods A total of 48 Sprague-Dawley male mice at the age of 8-10 weeks were divided into normal group, diabetes mellitus (DM) group, CsA group and DMSO group, with 12 rats in each group. The rats in DM, CsA group and DMSO group were induced with streptozotocin (STZ) injection creating a diabetic retinopathy model. The same volume of citric sodium citrate buffer was injected into the rats in the normal group. Immunohistochemical staining was used to detect the BRB permeability, Western blot was used to measure the protein expression of intercellular adhesion molecule (ICAM-1). Enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of vascular endothelial growth factor 72 hours after injection. Results Compared with the normal group, the BRB permeability, ICAM-1 and VEGF expression were significantly increased in DM group ( F =29.350, 29.240, 9.658; P ＜0.01). Compared with the DM group, the BRB permeability, ICAM-1 and VEGF expression were significantly decreased in CsA group ( t =3.174, 5.000, 3.352; P ＜0.05); but there was no obvious change of above indexes in DMSO group ( t =0.420, 0.561, 0.312; P ＞0.05). Conclusion Intravitreal injection of CsA has protective effects on BRB in diabetic rats. Down-regulated expression of ICAM-1 and VEGF may be the mechanism.

目的观察和探讨玻璃体腔注射环孢菌素A（CsA）对糖尿病（DM）大鼠血视网膜屏障（BRB）的影响及其作用机制。方法 8~10周龄健康Sprague-Dawley雄性大鼠48只，随机分为正常对照组、DM组、CsA组及二甲基亚砜（DMSO）组，每组12只。对DM、CsA及DMSO组大鼠进行一次性腹腔注射链脲佐菌素（STZ）溶液建模，正常对照组大鼠腹腔注射等量的柠檬酸钠缓冲液。注射后72 h，采用免疫组织化学染色法检测视网膜内外渗的内源性白蛋白评价BRB的渗透性；蛋白质免疫印迹法（Western blot）检测视网膜细胞间粘附分子（ICAM-1）的蛋白表达；酶联免疫吸附试验（ELISA）检测视网膜血管内皮生长因子（VEGF）的表达。结果与正常对照组相比，DM组大鼠视网膜外渗的白蛋白增多，视网膜内ICAM-1、VEGF表达明显升高，差异均有统计学意义（ F =29.350，29.240，9.658； P ＜0.01）。与DM组相比，CsA组大鼠视网膜外渗的白蛋白减少，视网膜内ICAM-1、VEGF表达明显下降，差异均有统计学意义（ t =3.174，5.000，3.352； P ＜0.05）；DMSO组大鼠视网膜外渗的白蛋白、视网膜内ICAM-1及VEGF表达均无明显变化，差异无统计学意义（ t =0.420，0.561，0.312； P ＞0.05）。结论玻璃体腔注射CsA对DM大鼠BRB具有保护作用。其机制可能与CsA降低ICAM-1及VEGF的表达有关。

... 沈强等^[13]研究发现,DR患者玻璃体切割术后VEGF水平上升,可进一步刺激新生血管生成,引起玻璃体内再发生出血 ...

2013

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... 有学者对行玻璃体切割术的DR患者进行术后随访发现,有超过60%的患者术后早期发生玻璃体内出血^[14] ...

2013

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... 同时进行新生血管膜VEGF免疫组化监测发现,B、C组术中VEGF阳性率低于A组,VEGF为血管内皮细胞特异性促有丝分裂素,可促进视网膜色素上皮细胞有丝分裂,增加血管渗透性,近年来被发现VEGF参与DR血管病变过程,可导致视网膜血管渗漏,促进新生血管生成^[15] ...