Change of retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in exudative age-related macular degeneration

Purpose:The study aimed to investigate the quantitative changes of retinal pigment epithelial (RPE) atrophy during a 24-month follow-up period of anti-vascular endothelial growth factor (VEGF) for exudative age-related macular degeneration (AMD).Results:The mean number of anti-VEGF treatments was 9.18. RPE atrophic area was 1.293 ± 1.298 mm² at baseline and enlarged to 2.394 ± 1.940 mm² after 24 months, which differed significantly (P = 0.001). Multiple regression analysis revealed that larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF treatments were associated with increased RPE atrophic areas.Conclusions:RPE atrophy progresses in eyes with exudative AMD during anti-VEGF treatment. Larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF injections were associated with an increased risk of progression of RPE atrophy the following treatment. These findings may be useful to clinicians using intravitreal anti-VEGF for the treatment of exudative AMD, both for selecting an appropriate treatment plan and for predicting the progression of RPE atrophy.     

干性年龄相关性黄斑变性患者视网膜色素上皮细胞损伤机制

年龄相关性黄斑变性(age-related macular degeneration,AMD)是中老年人视力障碍的重要原因之一。AMD分为2型:萎缩型(干性)和渗出型(湿性)。本文从光照损伤、脂褐素积累、氧化损伤、内质网应激4个方面,综述了干性AMD研究中基于视网膜色素上皮细胞损伤的相关研究进展,为进一步探索其发病机制提供依据和方向。     

One-year outcome after intravitreal ranibizumab for large, serous pigment epithelial detachment secondary to age-related macular degeneration

Aim

To report the effects of intravitreal ranibizumab therapy for large, serous pigment epithelial detachment (PED), secondary to age-related macular degeneration, and occupying more than 50% of the total lesion area.

Materials and methods

In a retrospective case series, visual acuity, ocular coherence tomography (OCT), and safety data were collected for 19 eyes of 19 patients, with serous PED and evidence of disease progression. Intravitreal ranibizumab of 0.5 mg was given with a loading phase of three consecutive monthly injections, followed by monthly review with further treatment, as indicated according to visual acuity and OCT findings. The change in visual acuity and maximum PED height from baseline to month 12 was determined.

Results

Moderate visual loss was avoided in 18/19 eyes (95%) at the 12-month examination. In all, 12 eyes (63%) had an increase in ETDRS letter score from baseline, and five eyes (26%) had a gain of 15 or more letters. Although there was a trend for the PED height to reduce with treatment, in none of the cases was the PED seen to resolve completely. There was no difference in functional or anatomical outcome between the avascular and vascularised serous PED. A single eye developed a retinal pigment epithelium rip, complicated by extensive sub-retinal haemorrhage, during the study period.

Conclusions

Visual acuity outcomes of intravitreal ranibizumab for large serous PED are comparable to those seen in multicentre, phase 3 trials of other lesion types, and were obtained without the need for either monthly, fixed treatment, or for continued treatment until the PED resolves.     

玻璃体腔注射雷珠单抗治疗非AMD脉络膜新生血管

目的：临床观察雷珠单抗( ranibizulab )治疗非年龄相关性黄斑变性( age-related lacular degeneration,AMD)脉络膜新生血管患者的疗效。
　　方法：回顾性分析2011-07/2015-04间在我院玻璃体腔注射ranibizulab治疗非AMD脉络膜新生血管的疗效及眼部与全身不良反应。治疗前后均进行裂隙灯的检查、最佳矫正视力的测定、荧光素眼底血管造影( fluorescein fundus angiography, FFA)、光学相干性断层扫描( optical coherence tolography,OCT),治疗后分别观察注射次数及术前和术后(末次随访时)患者的最佳矫正视力、黄斑区1 ll直径视网膜最大厚度。
　　结果：随访6lo~3a,治疗后平均视力(4.77±0.24)与治疗前(4.50±0.34)相比差异具有统计学意义(P<0.01),黄斑区1 ll直径最大厚度(317.62±55.05μl )较术前(421.63±139.37μl )相比差异具有统计学意义( P<0.01)。平均治疗次数为2.6±1.3次。患眼治疗后均未发生眼内炎、青光眼、视网膜脱离、葡萄膜炎等并发症及全身不良反应。
　　结论：Ranibizulab治疗非AMD脉络膜新生血管有效、不良反应低。     

miRNA-146a在视网膜色素上皮细胞老化及老年性黄斑变性中的功能研究

目的 检测miRNA-146a(miR-146a)在视网膜色素上皮细胞(retinal pigment epithelial cells,RPE)衰老及老年性黄斑变性(age-related macular degeneration,AMD)中的表达水平,并探讨其通过抑制VEGF-A表达,参与调控AMD病变进程的机制.方法 qRT-PCR检测年龄为2个月、8个月、12个月、18个月和24个月小鼠的RPE及75岁晚期“湿”性AMD患者眼球中miR-146以及VEGF-A的mRNA表达水平.Western Blotting检测VEGF-A蛋白表达水平.在ARPE-19细胞系中转染miR-146a,通过qRT-PCR及Western Blotting检测miR-146a对VEGF-A mRNA及蛋白水平的影响.结果 在自然衰老的RPE中,miR-146的表达呈现随年龄增加逐渐上升的趋势,与2个月的小鼠相比,在18个月及24个月的小鼠中miR-146a水平上升约8倍及24倍.而VEGF-A的表达呈现下降趋势,与对照相比,24个月的小鼠RPE中的VEGF-A相对水平由2个月时的1.5倍降为0.8倍.但是在AMD患者中,病灶部位的miR-146a较病灶旁侧表达下降14.5倍,VEGF-A表达上升.在ARPE-19细胞中过表达miR-146a抑制了VEGF-A的mRNA及蛋白表达水平.结论 本实验结果将miR-146a与RPE衰老及AMD的发生联系在一起,未来有可能成为RPE衰老及AMD早期诊断的新的分子标记物,为制定临床治疗策略提供参考.     

Retinal pigment epithelial tears after intravitreal bevacizumab injection for exudative age-related macular degeneration

Purpose: To determine the incidence of and the risk factors for the development of retinal pigment epithelial (RPE) tears after intravitreal bevacizumab (Avastin) injection for the treatment of exudative age‐related macular degeneration (AMD). Methods: A retrospective, multicentre, consecutive interventional case series of all patients with subfoveal exudative AMD treated with intravitreal bevacizumab between August 2005 and April 2007. The main outcome measures were pre‐ and post‐RPE tear visual acuity and choroidal neovascular membrane lesion types, incidence of tears and time from first injection until development of the tear. Results: A total of 920 eyes with exudative AMD were treated with intravitreal bevacizumab. Fifteen eyes from 15 patients developed a RPE tear for an incidence of 1.6%. The average patient age was 79 years. Fourteen of the fifteen eyes (93%) had an occult subfoveal choroidal neovascular membrane. Forty‐seven per cent (7/15) of the RPE tears occurred within the first 6 weeks of treatment, and all tears occurred within the first 18 weeks of treatment initiation. The mean pre‐injection visual acuity was 20/100 with a mean post‐tear visual acuity of 20/200. In all 10 eyes in which the tear involved the fovea, the final visual acuity was poor. Six of the 15 eyes continued with bevacizumab/ranibizumab (Lucentis) injections after tear development, and four of these six eyes continued to have visual improvement. Conclusion: RPE tears occur after intravitreal bevacizumab injections for exudative AMD in approximately 1.6% of eyes and can cause severe vision loss. Maintenance of therapy may help preserve vision after RPE tear development.     

Retinal pigment epithelial tears after intravitreal bevacizumab injection for exudative age-related macular degeneration

We report a series of retinal pigment epithelial (RPE) tears after intravitreal bevacizumab therapy for choroidal neovascularization associated with age-related macular degeneration (ARMD). Retinal pigment epithelial tears were estimated to occur at an incidence of 1.6% in this patient population at our institution. Ophthalmologists should be aware of this rare but serious finding associated with exudative macular degeneration therapy.     

Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

Purpose

There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD.

Methods

For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography.

Results

Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC.

Conclusions

MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production. Therefore, sub-lytic MAC might have a significant role in generating a pro-inflammatory microenvironment, contributing to the development of AMD. Enhanced vitronectin might be a protective mechanism against MAC deposition. In addition, the increased expression of gelatinolytic MMPs and pro-angiogenic VEGF may be associated with neovascular processes and late AMD.     

Influence of pigment epithelial detachment on visual acuity in neovascular age-related macular degeneration

Pigment epithelial detachment (PED), the anatomical separation of the retinal pigment epithelium from the Bruch membrane, is common in many chorioretinal diseases, including neovascular age-related macular degeneration. PED is present in about 30% to 80% of neovascular age-related macular degeneration patients based on the CATT, EXCITE, and VIEW studies. The influence of PED on visual acuity is controversial as a result of inconsistent results reported by various studies. With advances in imaging technologies, it is possible to evaluate not only the presence or absence of PED, but also detailed quantitative parameters, such as height, width, greatest linear diameter, area, volume, and reflectivity within the PED. We performed a comprehensive literature review to evaluate the relationship of PED with visual acuity. In summary, the presence or persistence of a PED may still be compatible with relatively good visual acuity. There is no strong evidence that the presence of a PED or aspects of its morphology has a significant impact on visual acuity. The presence of a PED may be predictive of the need for more regular treatment. More well-designed studies with standardized PED definitions and classifications are needed to evaluate the relationship between PED and visual acuity.     

Retinal pigment epithelial tear following intravitreal ranibizumab injections for neovascular age-related macular degeneration

Background To report the development of retinal pigment epithelial (RPE) tear after intravitreal injection of ranibizumab (Lucentis, Novartis, Basel, Switzerland). Methods Case report with presentation of the fundus photography, fluorescein angiography (FA) and optical coherence tomography (OCT) findings. Results A 70-year-old man received intravitreal injections of ranibizumab for the treatment of occult choroidal neovascularisation (CNV) with fibrovascular pigment epithelial detachment due to age-related macular degeneration. One day after the third intravitreal ranibizumab injection, fundus examination showed a RPE defect at the foveal region. FA and OCT confirmed the presence of RPE tear sparing the fovea. No further progression of the RPE tear was observed after withholding subsequent ranibizumab injection and his right eye visual acuity remained at 20/100 at 3 months from the last injection. Conclusions As with other anti-vascular endothelial growth factor treatment for CNV, RPE tear might occur after intravitreal ranibizumab injection even after previous uneventful intravitreal injections.     

康柏西普治疗老年性黄斑变性的研究现状

老年性黄斑变性( AMD)已经成为发达国家老年人致盲的主要原因之一。随着AMD患者的逐年增加,这也成为眼科防盲研究中重要的课题之一。其病因并不完全清楚,但许多研究表明血管内皮生长因子( VEGF)在其发病中起了重要作用。随着抗VEGF药物的研发与应用,目前已有多种药物应用于该病,本文主要介绍康柏西普在老年性黄斑变性中的应用。     

Bilateral same-session intravitreal injections of anti-vascular endothelial growth factors

AIM: To document the indications, safety and possible complications of bilateral same-session intravitreal anti-vascular endothelial growth factor (VEGF) injections performed in the ophthalmic operating room.METHODS:A retrospective case series study. Consecutive records of seventy four patients receiving simultaneous bilateral intravitreal injections of either ranibizumab or bevacizumab, between September 2010 and September 2013, were reviewed and the outcomes were assessed. Data collected included number of injections, indications for injections, pre-injection and post-injection visual acuity (VA), pre-injection and post-injection intraocular pressure and ocular and systemic complications/complaints after each injection.RESULTS: A total of 342 injections were administered to 74 patients, with a mean of 4.62 injections per patient. Seventy-three patients received bevacizumab (Avastin; Genentech Inc., South San Francisco, California, USA) alone, and only one patient received both bevacizumab and ranibizumab (Lucentis; Genentech Inc.) distributed between the injections. Pre- and post-injection VA follow-up measurements were available for 65 patients. Mean follow up period was 22mo. The indications for initiating therapy were choroidal neovascular membrane from age-related macular degeneration (3 patients) and diabetic macular edema (71 patients). The mean Snellen VA before each injection was 6/22. The next post-injection follow-up mean Snellen VA was 6/20. One patient had a painful, culture-positive endophthalmitis in one eye 3d after bilateral bevacizumab. Another patient had a painless subconjunctival hemorrhage in one eye. No other ocular or systemic adverse side effects/complaints have been registered in this study group.CONCLUSION:Bilateral same-session intravitreal injections using a separate povidone-iodine preparation, speculum, needle, and syringe for each eye are well-tolerated. None of the subjects in this study requested to switch to alternating unilateral injections. Proper patient counseling as to the risk of complications with this procedure is necessary.     

Real-life experience of ranibizumab therapy for neovascular age-related macular degeneration from Turkey

AIM: To report the real-life experience and clinical results of intravitreal ranibizumab injections to neovascular age-related macular degeneration (nAMD) in a single institution in Turkey. METHODS: A total of 101 eyes of 89 patients with nAMD treated with intravitreal ranibizumab injection, followed up for at least 24mo between 2009 and June 2014, which were evaluated retrospectively. A pro re nata (PRN) treatment protocol was performed after the patients had received three, monthly loading injections. Best corrected visual acuity (BCVA) and central macular thickness measurements were evaluated at baseline and 3, 6, 12, 18, and 24mo. Number of injections and visits were also recorded. RESULTS: Of the 89 patients, 34 (38.2%) were male and 55 (61.8%) were female and the mean age was 74.0±9.5 (52-91)y. The mean follow-up period was 24.82±4.4 (24-29)mo. Mean number of visits was 8.4±1.12 (7-12) in the first year and 6.6±1.33 (4-12) in the second year. The mean number of injections was 5.8±1.6 (3-10) and 4.2±2.2 (0-9) in the first and second year, respectively. The mean BCVA was 59±15.8 letters at baseline by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The mean BCVA at 3, 12, and 24mo was 70.3±15.9, 67.9±14.3 and 67.3±16.9 letters, respectively. Improvement in visual acuity for each of the visits from baseline was found to be statistically significant (P<0.01). Visual acuity in 9 eyes at month 3, 7 eyes at month 12, and 13 eyes at month 24 did not change. The mean central macular thickness (CMT) was 437.99±164.78 μm at baseline. The mean CMT was 348.05±138.47 μm, 349.27±139.79 μm, and 344.13±146.30 μm at months 3, 12, and 24, respectively. The decrease in CMT for each of the visits from baseline was found to be statistically significant (P<0.01). CONCLUSION: Anatomical and functional achievement are obtained in our study, but the mean number of injections and visits are found to be lower than the findings reported in randomized controlled clinical trials in the literature. However, the mean number of injections and visits in our study are compatible with the findings reported in real-life experience studies in the literature.     

丛生蛋白参与年龄相关性黄斑变性的作用机制

丛生蛋白是玻璃膜疣的主要蛋白成分之一。近年来研究发现丛生蛋白与衰老密切相关,不仅通过对补体系统的调节参与年龄相关性黄斑变性（ａｇｅ-ｒｅｌａｔｅｄｍａｃｕｌａｒｄｅｇｅｎ-ｅｒａｔｉｏｎ,ＡＭＤ）炎症反应发生机制,也与氧化还原反应密切相关,是ＡＭＤ发生过程中氧化应激反应的感受器。本文就丛生蛋白参与ＡＭＤ作用机制的研究进展进行综述。     

湿性年龄相关性黄斑变性的治疗进展

年龄相关性黄斑变性( age-related macular degeneration, AMD)是WHO现阶段三大防盲重点眼病之一,是50岁以上人群主要的致盲眼病之一,65岁以上的人群中,约2%因患本病而导致单眼失明,随着人口老龄化,我国AMD的患病率也在增加。 AMD就其临床表现分为干性 AMD和湿性AMD,湿性AMD对患者的视力危害最大,目前AMD的治疗很多(主要是针对湿性AMD),主要包括激光治疗、药物治疗、手术治疗、基因治疗等,以下对近年来湿性AMD的治疗作一综述。     

Interleukin-13 and age-related macular degeneration

AIM: To identify the effects of interleukin (IL)-13 on retinal pigment epithelial (RPE) cells and the IL-13 level in aqueous humor of age-related macular degeneration (AMD) patients. METHODS: IL-13 levels in aqueous humor specimens from AMD patients were detected with enzyme-linked immunosorbent assay (ELISA). ARPE-19 cells were treated with 10 ng/mL IL-13 for 12, 24, and 48h. The cell proliferaton was evaluated by the MTS method. The mRNA and protein levels of α-SMA and ZO-1 were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot respectively. The expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) were assessed by ELISA. RESULTS: IL-13 levels in the aqueous humor of patients with AMD were significantly higher than those in the control (167.33±17.64 vs 27.12±5.65 pg/mL; P<0.01). In vitro, IL-13 of high concentrations (10, 15, and 20 ng/mL) inhibited ARPE-19 cell proliferation. α-SMA mRNA in ARPE-19 cell were increased (1.017±0.112 vs 1.476±0.168; P<0.001) and ZO-1 decreased (1.051±0.136 vs 0.702±0.069; P<0.001) after treated with 10 ng/mL IL-13 for 48h. The protein expression of α-SMA and ZO-1 also showed the same tendency (α-SMA: P=0.038; ZO-1: P=0.008). IL-13 significantly reduced the level of TNF-α (44.70±1.67 vs 31.79±3.53 pg/mL; P=0.005) at 48h, but the level of TGF-β2 was significantly increased from 34.44±2.92 to 57.61±6.31 pg/mL at 24h (P=0.004) and from 61.26±1.11 to 86.91±3.59 pg/mL at 48h (P<0.001). While expressions of VEGF didn’t change after IL-13 treatment. CONCLUSION: IL-13 in vitro inhibit ARPE-19 cell proliferation and expression in the aqueous may be associated with AMD.     

微小RNA与年龄相关性黄斑变性发病的关系

微小RNA (miRNA)是指一种小的内源性非编码RNA分子,其异常表达与年龄相关性黄斑变性(age-related macular degeneration,AMD)发生发展密切相关.miRNA在AMD的炎性反应、氧化应激损伤、淀粉样蛋白及脉络膜新生血管形成等病变过程中贯穿始终.这些发现可能为AMD的早期诊断、治疗及预后判断提供新的可能性.     

湿性年龄相关性黄斑变性发病机制及治疗

湿性年龄相关性黄斑变性（AMD）是导致老年人视力受损甚至失明的重要原因,以黄斑区新生血管为主要病理特征,其发病与年龄、环境、遗传、氧化应激、脂质代谢、免疫机制等多因素相关。血管内皮生长因子（VEGF）已被证实是导致湿性AMD的重要因子。因此,抗VEGF药物是湿性AMD治疗领域中里程碑性的进展,但该治疗方法仍有诸多不足,如需要多次注射、部分患者对治疗应答欠佳甚至无应答、可能发生进行性纤维化等并发症。目前,许多新药正在被开发用来解决现有抗VEGF药物治疗的弊端。通过检索国内外相关文献及报道,我们对湿性AMD的分型、发病机制、治疗等的研究进展进行述评。     

Clinical efficacy of intravitreal corticoid as an adjunctive therapy to anti-VEGF treatment of neovascular age-related macular degeneration: a Meta-analysis

AIM: To evaluate the efficacy and safety of intravitreal corticoid as an adjunctive therapy to anti-vascular endothelial growth factor (VEGF) treatment of neovascular age-related macular degeneration (nvAMD). METHODS: Four databases including PubMed, Embase, Cochrane Library, and the clinicaltrials.gov were comprehensively searched for studies comparing intravitreal corticoid plus anti-VEGF (IVC/IVA) vs anti-VEGF monotherapy (IVA) in patients with nvAMD. GRADE profiler was used to assess the quality of outcomes. Best-corrected visual acuity (BCVA), central macular thickness (CMT) and adverse events including the occurrence of severe elevation of intraocular pressure (IOP) and the progress of cataract were extracted from the eligible studies. Review Manager (RevMan) 5.3 was used to analyze the data. RESULTS: There was no statistic difference of mean change in BCVA at 6 and 12mo between IVC/IVA and IVA group [95% confidence interval (CI): -2.28 to 4.24, P=0.55; 95%CI: -3.01 to 8.70, P=0.34]. No statistic difference was found in the change of CMT between two groups at 6mo time point (95%CI: -17.98 to 16.42, P=0.93) while the CMT reduction in IVC/IVA group was significantly more obvious than IVA group at 12mo time point [mean difference (MD)=-44.08, 95%CI: -80.52 to -7.63, P=0.02]. The risk of occurrence of severe elevation of IOP in the IVC/IVA group was higher than that in the IVA group (95%CI: 1.92 to 9.48; P=0.0004). Cataract progression risk was calculated no statistic difference between two groups (95%CI: 0.74 to 4.66; P=0.18). CONCLUSION: No visual or anatomical benefits are observed in IVC/IVA group at 6mo. At 12mo, the CMT of the IVC/IVA group is significantly lower than that of the IVA group. Risk of severe elevation of IOP is significantly higher when treated by IVC/IVA.