急性视网膜动脉缺血的防治研究进展

急性短暂性或永久性视网膜动脉缺血是需要及时诊断和治疗的眼部和全身急症。单眼一过性黑矇属于短暂性视网膜动脉缺血,并不会遗留永久性视功能损害。视网膜中央动脉阻塞和视网膜分支动脉阻塞在大部分患者均会遗留永久性视功能损害。目前的治疗方式包括降眼压、扩血管、高压氧、经静脉或动脉溶栓治疗等,但仍缺乏标准治疗方案。对高危人群应早期一级预防。急性视网膜动脉缺血患者发生继发卒中和不良心血管事件的风险高,应及时发现相关危险因素,积极治疗原发病,采取适当的二级预防措施改善预后。本文对急性视网膜动脉缺血事件的治疗和预防研究进展进行综述,以便为该类疾病的防治和研究提供参考。     

Changes in an electroretinogram and biochemical parameters of tear in simulated rabbit retinal ischemia

The pattern of functional impairments and the antioxidative and antiproteolytic status of tear were studied, by experimentally simulating retinal ischemia in rabbits and during treatment with Selecarten. Simulated retinal ischemia resulted in the development of persistent (up to 3 weeks) retinal electrogenetic disorder. Selecarten instillations produced a moderate neuroprotective effect, by positively affecting retinal function early after ischemia stimulation and accelerated the recovery of retinal electrogenesis late after laser coagulation of retinal vessels. The altered metabolic processes were characterized by an increase in the tear antiproteolytic potential. The antioxidative activity and the activity of a2-macroglobulin proteolysis inhibitor increased in the tears of Selecarten-treated rabbits.     

视网膜急性缺血后神经细胞损伤治疗的时间窗

目的:观察中西医结合综合疗法治疗发病时间较长的视网膜动脉阻塞的临床疗效,并探讨视网膜动脉阻塞治疗的时间窗。方法:采用常规疗法、联合中药、神经修复的综合方法治疗14例15眼连续就诊于中国中医科学院眼科医院一病区的患者,并对其进行回顾性研究,比较并分析治疗后7,14,30d视力结果及治疗前后视野结果。结果:患者13例14眼完成14d治疗,11例12眼完成30d治疗。治疗7d后15眼中有11眼(73.33%)视力改善,14d后14眼中11眼(78.57%)视力改善,治疗30d后12眼中有11眼(91.67%)视力改善。治疗7d与治疗前比较(P<0.01)、治疗14d与7d比较(P<0.05)、治疗30d与14d比较(P<0.05)视力均有显著的提高。14例中12例完成视野检查,治疗后视野平均敏感度较治疗前显著意义的改善(P<0.05)。结论:常规疗法、联合中药、神经修复的综合方法治疗视网膜动脉阻塞有较好疗效,尤其对发病后视网膜水肿未消失之前治疗价值更高,同时治疗时机也不应拘泥在传统概念的发病3d内,或许更长,比如60d。     

Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration

Ceramide and its metabolic derivatives are important modulators of cellular apoptosis and proliferation. Dysregulation or imbalance of their metabolic pathways may promote the development of retinal degeneration. The aim of this study was to identify the expression and regulation of key enzymes of the ceramide pathway in retinal pigment epithelial (RPE) cells. RT-PCR was used to screen the enzymes involved in ceramide metabolism that are expressed in RPE. Over-expression of neutral sphingomyelinase-2 (SMPD3) or sphingosine kinase 1 (Sphk1) in ARPE-19 cells was achieved by transient transfection of SMPD3 or Sphk1 cDNA subcloned into an expression vector. The number of apoptotic or proliferating cells was determined using TUNEL and BrdU assays, respectively. Neutral sphingomyelinase-1, neutral sphingomyelinase-2, acidic ceramidase, ceramide kinase, SphK1 and Sphk2 were expressed in both ARPE-19 and early passage human fetal RPE (fRPE) cells, while alkaline ceramidase 2 was only expressed in fRPE cells. Over-expression of SMPD3 decreased RPE cell proliferation and increased cell apoptosis. The percentage of apoptotic cells increased proportionally with the amount of transfected SMPD3 DNA. Over-expression of SphK1 promoted cell proliferation and protected ARPE-19 cells from ceramide-induced apoptosis. The effect of C₂ ceramide on induction of apoptosis was evaluated in polarized vs. non-polarized RPE cultures; polarization of RPE was associated with much reduced apoptosis in response to ceramide. In conclusion, RPE cells possess the synthetic machinery for the production of ceramide, sphingosine, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate (S1P). Over-expression of SMPD3 may increase cellular ceramide levels, leading to enhanced cell death and arrested cell proliferation. The selective induction of apoptosis in non-polarized RPE cultures by C₂ ceramide suggests that increased ceramide levels will preferentially affect non-polarized RPE, as are found in late age-related macular degeneration lesions, and may spare the normal RPE monolayer. SphK1 over-expression increased cellular S1P, which promoted cell proliferation and protected RPE from ceramide-induced apoptosis. Understanding the relationship between the metabolism of sphingolipids and their effects in RPE cell survival/death may help us to develop effective and efficient therapies for retinal degeneration.     

大鼠急性视网膜缺血节细胞死亡时脑红蛋白的表达

目的 研究大鼠视网膜急性缺血中视网膜节细胞(RGCs)死亡时脑红蛋白(Nsb)的表达.方法 实验研究.采用特异性结扎大鼠视网膜动脉的方法造成视网膜急性缺血模型,按照结扎时间不同(0、15、30、60 min)分为A、B、C、D组,每组10只大鼠,均以左眼为实验眼.每组随机选取3只大鼠视网膜用于免疫印迹法检测,4只大鼠视网膜做HE染色节细胞计数及免疫组化染色荧光强度分析,3只大鼠做免疫电子显微镜观察.采用单因素方差分析对不同结扎时间Ngb蛋白定量及RGCs数目进行统计学分析,采用KSD-t检验进行两两比较.结果 视网膜完全结扎后,A、B、c、D组Ngb蛋白表达量分别为1.439±0.014、2.023±0.134、1.416±0.030及1.073±0.064;RGCs计数结果分别为4368±124、4296 ±96、4132±104、3973±115,组间比较差异有统计学意义(F=79.548,10.191,P<0.05).B组表达最高,之后逐渐降低,C组接近正常,此时与A组比较RGCs数量开始减少,D组Ngb的表达已明显低于A组,与A组比较RGCs数量进一步减少.在视网膜各层中,Ngb的表达以RGCs层为最高,其次为内丛状层与外丛状层.RGCs中Ngb主要分布在胞质,C组线粒体外室和线粒体嵴也发现有Ngb表达,而内核层及外核层细胞的胞质内始终未见Ngb的表达.结论 Ngb在大鼠RGCs急性缺血死亡时表达快速升高,主要表达于RGCs的胞质内,与RGCs的生存状态关系密切.     

Bilateral acute retinal necrosis.

In this paper 4 patients are described who had bilateral symmetrical confluent retinal swelling followed by apparent necrosis and sloughing of the retina into the vitreous. The disease was accompanied by signs of uveitis and the clinical appearance suggested inflammation rather than infarction as the pathogenic mechanism. No systemic abnormalities were found by which the aetiology could be identified.     

Ischemic preconditioning attenuates hypoperfusion after retinal ischemia in rats.

PURPOSE: Retinal blood flow (RBF) was measured in rats to test the hypotheses that hypoperfusion follows severe ischemia in the retina and that ischemic preconditioning (IPC) attenuates this change in blood flow. METHODS: Male Sprague-Dawley rats were anesthetized with halothane and mechanically ventilated by tracheostomy to maintain normocarbia and normoxia. Retinal ischemia was induced for 0, 5, 30, 60, 75, or 90 minutes. RBF was measured 60 and 150 minutes after the end of ischemia using the radioactive microsphere blood flow method, and electroretinography was performed during the first 120 minutes after ischemia to quantitate the extent of functional recovery. Additional groups received IPC (5 minutes of ischemia) 24 hours before 30, 60, or 75 minutes of ischemia. RESULTS: Control (0 minutes' ischemia) RBF was 22+/-3 ml/100 g per minute (mean +/- SE). At 60 minutes after 5, 30, 60, 75, or 90 minutes of ischemia, RBF was 15+/-2 (NS), 11+/-1, 8+/-2, 8+/-1, and 10+/-1 ml/100 g per minute, respectively (significance, P<0.05 versus control). At 150 minutes after 5, 30, 60, 75, or 90 minutes of ischemia, RBF was 18+/-3 (NS), 13+/-1, 12+/-3, 12+/-2, and 11+/-1 ml/100 g per minute respectively (significance, p<0.05 versus control). With prior IPC, RBF after 30 and 60 minutes of ischemia was 21+/-1 and 19+/-3 ml/100 g per minute (both NS compared with control; P<0.05 compared with 30 or 60 minutes of ischemia without IPC). When ischemia was 75 minutes in duration, IPC did not prevent postischemic hypoperfusion. The extent of recovery of the electroretinogram b wave was inversely related to the length of ischemia. CONCLUSIONS: Postischemic hypoperfusion is present in the rat retina 60 minutes after ischemia, does not resolve by 150 minutes after ischemia, and is attenuated by IPC when ischemia is 60 minutes or less in duration. Maintenance of postischemic perfusion in the retina may be one of the mechanisms involved in the neuroprotection afforded by IPC.     

Changes in retinal nerve fiber layer thickness after acute primary angle closure

PURPOSE: To evaluate the changes in retinal nerve fiber layer (RNFL) thickness in the first 16 weeks after acute primary angle closure (APAC) using scanning laser polarimetry (SLP). DESIGN: Prospective, observational case series. PARTICIPANTS: Thirty-seven Asian subjects with APAC. METHODS: For all cases, APAC had resolved after treatment, and the study was conducted during the follow-up period after the acute episode. Using the GDx Nerve Fiber Analyzer (Laser Diagnostic Technologies, San Diego, CA), the RNFL was assessed in both eyes 2 weeks after APAC, and again after 16 weeks. The SLP parameters were compared between week 2 and week 16 within affected and fellow eyes. A multiple logistic regression analysis was carried out to analyze factors likely to influence RNFL outcome. MAIN OUTCOME MEASURES: Superior and inferior average RNFL thickness. RESULTS: The mean age of study subjects was 60.1+/-10.3 years (range, 46-91 years), and most subjects were female (68%) and Chinese (86%). In APAC eyes, the superior average RNFL thickness decreased from 63.8+/-13.6 microm to 61.4+/-11.2 microm (P = 0.04) and the inferior average RNFL thickness decreased from 69.5+/-14.4 microm to 66.3+/-12.6 microm (P = 0.005). There was also a decrease in inferior ratio (P = 0.008) and ellipse modulation (P = 0.02). In the fellow eyes, there was no difference found between week 2 and week 16 for any of the SLP parameters studied. Logistic regression analysis showed no significant association between developing a 10% reduction in either superior or inferior RNFL thickness with age, gender, history of ischemic risk factors, duration of symptoms during APAC, the level of presenting intraocular pressure (IOP), or the development of a rise in IOP between study visits. CONCLUSIONS: After an episode of APAC, superior and inferior average RNFL thickness was found to decrease significantly from week 2 to week 16.     

缺血-再灌注大鼠视网膜TPA变化与视网膜水肿的关系

目的　探讨缺血-再灌注对大鼠视网膜分泌组织型纤溶酶原激活物(TPA)的影响及其与视网膜水肿的关系。方法　采用提高眼压法造成视网膜缺血后,恢复眼压形成血流再灌注。实验分正常对照组、缺血 1h再灌注 1h组、缺血 1h再灌注 2h组、缺血 2h再灌注 1h组和缺血 2h再灌注 2h组。每组各取 10例测试视网膜组织TPA的活性和含水量。结果　缺血-再灌注后,大鼠视网膜组织TPA的活性和含水量随缺血和再灌注时间的延长而升高(P<0 01)。 结论　缺血-再灌注可引起视网膜组织TPA的活性升高和视网膜水肿,是视网膜组织结构和功能损伤的因素之一。     

Chickenpox-associated acute retinal necrosis syndrome.

Acute retinal necrosis (ARN) syndrome usually occurs as the result of secondary reactivation of latent, previously acquired, varicella-zoster or herpes simplex virus. The authors report four patients who developed a mild form of ARN within 1 month (5 to 28 days) after the onset of chickenpox. In contrast to typical cases of ARN, these cases were less severe, with retinitis limited to two quadrants or less (three patients), no retinal detachment (four patients), minimal vitreitis (four patients), and no loss of visual acuity (four patients). Thus, ARN may occur during the course of primary varicella-zoster infection.     

Involvement of oxygen free radicals in experimental retinal ischemia and the selective vulnerability of retinal damage.

Protective effects of CV-3611, a free radical scavenger, on retinal ischemic injury in the rat and on glutamate-induced cytotoxicity in a cell line were evaluated. Transient retinal ischemia was induced by raising intraocular pressure of rats to 110 mm Hg for 45 min, and the electroretinogram (ERG) was measured to evaluate retinal function. No ERG could be recorded immediately after reperfusion, and thereafter the ERG gradually recovered. Recovery of the a-wave latency and the amplitudes of the a and b waves in the CV-3611-treated (10 mg/kg, p.o.) group were significantly better than those in the control group up to 24 h after reperfusion. In both the control and CV-3611 group, the b wave showed better recovery than the a wave up to 6 h after reperfusion, while the relationship was reversed after 24-hour reperfusion. Glutamate (10 mM)-induced cytotoxicity in the N18-RE-105 cell, a neural retina-neuroblastoma hybridoma, was quantified by measuring lactate dehydrogenase. Three and 10 microM of CV-3611 significantly attenuated the glutamate-induced cytotoxicity in N18-RE-105 cells. Thus, the radical scavenger (CV-3611) promoted the recovery of retinal function after ischemia-reperfusion injury and ameliorated glutamate-induced cytotoxicity. These results suggest that oxygen free radicals play an important role in the early phase of retinal ischemic injury. Moreover, differential recovery processes of the a and b waves after ischemia suggest that the selective vulnerability of the retina to ischemia could change functionally during the period of reperfusion.     

Changes in axial length after retinal detachment surgery.

PURPOSE: To evaluate changes in axial length and corneal curvature after an encircling procedure combined with segmental buckling. MATERIALS AND METHODS: We prospectively analysed cases with rhegmatogenous retinal detachment treated with an encircling band and scleral buckling surgery, comparing the pre-and postoperative ultrasonographic measurements of axial length and corneal curvature, and patients' age and sex in relation to the axial length of the eyeballs. We studied 74 patients (25 female, 49 male, aged 14-78 years, mean 46.7 years), who underwent retinal detachment surgery in 1995 and 1996. RESULTS: Axial eye length was significantly increased by surgery (median 0.77 mm one month after surgery). One year after treatment the elongation of the eye had decreased by 0.20 mm. The average increase of corneal curvature was 0.22 D one month after surgery, and 0.43 D at one year. The distribution of axial length showed a significant preponderance of eyes with a longer axial length among males. CONCLUSIONS: Encircling with a scleral buckling procedure with moderate indentation causes axial elongation of the eye.     

Multimodal imaging in acute retinal ischemia: spectral domain OCT, OCT-angiography and fundus autofluorescence

AIM: To describe retinal findings of various imaging modalities in acute retinal ischemia. METHODS: Fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), OCT-angiography (OCT-A) and fundus autofluorescence (FAF) images of 13 patients (mean age 64y, range 28-86y) with acute retinal ischemia were evaluated. Six suffered from branch arterial occlusion, 2 had a central retinal artery occlusion, 2 had a combined arteriovenous occlusions, 1 patient had a retrobulbar arterial compression by an orbital haemangioma and 2 patients showed an ocular ischemic syndrome. RESULTS: All patients showed increased reflectivity and thickening of the ischemic retinal tissue. In 10 out of 13 patients SD-OCT revealed an additional highly reflective band located within or above the outer plexiform layer. Morphological characteristics were a decreasing intensity with distance from the fovea, partially segmental occurrence and manifestation limited in time. OCT-A showed a loss of flow signal in the superficial and deep capillary plexus at the affected areas. Reduced flow signal was detected underneath the regions with retinal edema. FAF showed areas of altered signal intensity at the posterior pole. The regions of decreased FAF signal corresponded to peri-venous regions. CONCLUSION: Multimodal imaging modalities in retinal ischemia yield characteristic findings and valuable diagnostic information. Conventional OCT identifies hyperreflectivity and thickening and a mid-retinal hyperreflective band is frequently observed. OCT-A examination reveals demarcation of the ischemic retinal area on the vascular level. FAF shows decreased fluorescence signal in areas of retinal edema often corresponding to peri-venous regions.