The role of cerebrospinal fluid pressure in glaucoma and other ophthalmic diseases: A review

Glaucoma is one of the most common causes of blindness in the world. Well-known risk factors include age, race, a positive family history and elevated intraocular pressures. A newly proposed risk factor is decreased cerebrospinal fluid pressure (CSFP). This concept is based on the notion that a pressure differential exists across the lamina cribrosa, which separates the intraocular space from the subarachnoid fluid space. In this construct, an increased translaminar pressure difference will occur with a relative increase in elevated intraocular pressure or a reduction in CSFP. This net change in pressure is proposed to act on the tissues within the optic nerve head, potentially contributing to glaucomatous optic neuropathy. Similarly, patients with ocular hypertension who have elevated CSFPs, would enjoy a relatively protective effect from glaucomatous damage. This review will focus on the current literature pertaining to the role of CSFP in glaucoma. Additionally, the authors examine the relationship between glaucoma and other known CSFP-related ophthalmic disorders.     

Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma

The pathogenesis of normal (intraocular) pressure glaucoma has remained unclear so far. As hospital‐based studies showed an association of normal‐pressure glaucoma with low systemic blood pressure, particularly at night, and with vasospastic symptoms, it has been hypothesized that a vascular factor may play a primary role in the pathogenesis of normal‐pressure glaucoma. That assumption may, however, be contradicted by the morphology of the optic nerve head. Eyes with normal‐pressure glaucoma and glaucomatous eyes with high‐intraocular pressure can show a strikingly similar appearance of the optic nerve head, including a loss of neuroretinal rim, a deepening of the optic cup, and an enlargement of parapapillary atrophy. These features, however, are not found in any (other) vascular optic neuropathy, with the exception of an enlargement and deepening of the optic cup in arteritic anterior ischaemic optic neuropathy. One may additionally take into account (i) that it is the trans‐lamina cribrosa pressure difference (and not the trans‐corneal pressure difference, i.e. the so‐called intraocular pressure) which is of importance for the physiology and pathophysiology of the optic nerve head; (ii) that studies have shown that the anatomy of the optic nerve head including the intraocular pressure, the anatomy and biomechanics of the lamina cribrosa and peripapillary sclera, retrobulbar orbital cerebrospinal fluid pressure and the retrobulbar optic nerve tissue pressure may be of importance for the pathogenesis of the highly myopic type of chronic open‐angle glaucoma; (iii) that studies have suggested a physiological association between the pressure in all three fluid filled compartments, i.e. the systemic arterial blood pressure, the cerebrospinal fluid pressure and the intraocular pressure; (iv) that an experimental investigation suggested that a low cerebrospinal fluid pressure may play a role in the pathogenesis of normal (intraocular) pressure glaucoma; and (v) that recent clinical studies reported that patients with normal (intraocular) pressure glaucoma had significantly lower cerebrospinal fluid pressure and a higher trans‐lamina cribrosa pressure difference when compared to normal subjects. One may, therefore, postulate that a low cerebrospinal fluid pressure may be associated with normal (intraocular) pressure glaucoma. A low systemic blood pressure, particularly at night, could physiologically be associated with a low cerebrospinal fluid pressure, which leads to an abnormally high trans‐lamina cribrosa pressure difference and as such to a similar situation as if the cerebrospinal fluid pressure is normal and the intraocular pressure is elevated. This model could explain why patients with normal (intraocular) pressure glaucoma tend to have a low systemic blood pressure, and why eyes with normal (intraocular) pressure glaucoma and eyes with high‐pressure glaucoma, in contrast to eyes with a direct vascular optic neuropathy, show profound similarities in the appearance of the optic nerve head.     

正常眼及三种视网膜疾病血管直径测量

目的 探讨正常眼、年龄相关性黄斑变性(age-related maculardegeneration,AMD)、糖尿病性视网膜病变(diabetic retinopathy,DR)和视网膜静脉阻塞(retinal vein occlusion,RVO)视网膜血管直径的变化规律.方法 将328只正常眼按年龄分成5组,应用计算机程序分别测量距离视盘边缘0.5～1.0视盘直径范围内六条最粗的视网膜动脉和静脉直径,比较其平均值.然后,以同样方法 测量AMD、DR和RVO三种视网膜疾病动静脉直径,并与同年龄正常人比较动静脉平均直径.结果 正常视网膜动静脉平均直径50岁以上较50岁以下减小.与同年龄正常人相比AMD、DR和RVO视网膜动脉平均直径减小,AMD和RVO视网膜静脉平均直径与同年龄正常人相比也减小,而DR视网膜静脉平均直径不变.结论 正常眼视网膜动静脉平均直径50岁以上变细.AMD、DR和RVO动脉平均直径也变细,AMD和RVO静脉平均直径变细,DR静脉平均直径不变.     

Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases

Neovascular age-related macular degeneration (NVAMD) is the most prevalent choroidal vascular disease, and diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the most prevalent retinal vascular diseases. In each of these, hypoxia plays a central role by stabilizing hypoxia-inducible factor-1 which increases production of vascular endothelial growth factor (VEGF) and other hypoxia-regulated gene products. High VEGF causes excessive vascular permeability, neovascularization, and in DR and RVO, promotes closure of retinal vessels exacerbating hypoxia and creating a positive feedback loop. Hence once VEGF expression is elevated it tends to remain elevated and drives disease progression. While other hypoxia-regulated gene products also contribute to pathology in these disease processes, it is remarkable how much pathology is reversed by selective inhibition of VEGF. Clinical trials have demonstrated outstanding visual outcomes in patients with NVAMD, DR, or RVO from frequent intraocular injections of VEGF-neutralizing proteins, but for a variety of reasons injection frequency has been substantially less in clinical practice and visual outcomes are disappointing. Herein we discuss the rationale, preclinical, and early clinical results of new approaches that provide sustained suppression of VEGF. These approaches will revolutionize the management of these prevalent retinal/choroidal vascular diseases.     

曲安奈德玻璃体腔注射治疗视网膜静脉阻塞和糖尿病视网膜病变继发黄斑水肿分析

目的 观察玻璃体腔注射曲安奈德(TA)治疗视网膜静脉阻塞(RVO)继发黄斑水肿和糖尿病性黄斑水肿的疗效以及二者疗效比较.方法 对经间接检眼镜、荧光素眼底血管造影(FFA)以及光学相干断层扫描(OCT)检查确诊的RVO继发黄斑水肿患者91例91只眼,其中中央视网膜静脉阻塞(CR-VO)55只眼(缺血型13只眼,非缺血型42只眼),分支视网膜静脉阻塞(BRVO)36只眼(缺血型10只眼,非缺血26眼).糖尿病性黄斑水肿患者67例73只眼,非增殖性糖尿病视网膜病变(PPDR)17只眼,增殖性糖尿病视网膜病变(PDR)56只眼,行TA玻璃体腔注射,治疗后随访3月至1年,对比分析术前术后的视力、眼底、FFA表现,观察OCT显示黄斑水肿高度.结果 最终随访RVO组视力提高者48只眼(52.7%),视力不变者39只眼(42.9%),视力下降者4只眼(4.40%).OCT形态恢复正常者50只眼(54.9%),改善者27只眼(29.7%),无改善者14只眼(15.4%).DR组视力提高者25(34.2%)只眼,,视力不变者45只眼(61.6%),视力下降者3只眼(4.11%).OCT形态恢复正常者24只眼(32.9%),改善者22只眼(30.1%),无改善者27只眼(37.0%).两组有效率行统计学分析,有显著性差异.RVO组24只眼术后出现一过性眼压升高,一眼白内障,一眼眼内炎,8只眼2次注射.DR组14眼术后出现一过性眼压升高,2只眼白内障,9只眼2次注射.结论 玻璃体腔注射TA是一种安全有效的治疗视网膜静脉阻塞继发黄斑水肿和糖尿病性黄斑水肿的方法,治疗视网膜静脉阻塞继发黄斑水肿的疗效好于糖尿病性黄斑水肿.     

玻璃体腔单次注射雷珠单抗治疗糖尿病黄斑水肿与视网膜静脉阻塞性黄斑水肿的短期疗效观察

目的评价玻璃体腔单次注射抗血管内皮细胞生长因子药物雷珠单抗治疗糖尿病黄斑水肿DME和视网膜静脉阻塞（RVO）性黄斑水肿的短期疗效。方法在安徽医科大学第一附属医院规律随访符合纳入和排除标准的DME和RVO黄斑水肿者23只眼。患眼给予玻璃体腔注射0.05 ml雷珠单抗注射液,治疗后2 d复查最佳矫正视力,治疗后4周进行复查最佳矫正视力、黄斑中心凹厚度、黄斑区平均厚度和Amsler表。结果治疗后2 d与治疗前相比,视力提高（t=4.632,P〈0.001）。治疗后4周与治疗前相比,黄斑中心凹厚度降低（t=10.165,P〈0.001）,黄斑区平均厚度降低（t=3.368,P=0.003）,视力提高（t=7.281,P〈0.001）。Amsler表阳性率下降（χ2=8.013,P=0.005）。差异均具有统计学意义。治疗后4周与治疗后2 d相比,视力提高,差别有统计学意义（t=5.271,P〈0.001）。黄斑中心凹厚度与Amsler表阳性率的相关性分析：无统计学意义（相关系数0.128,P=0.398）。结论玻璃体腔单次注射雷珠单抗对DME和RVO黄斑水肿在4周内有效。     

玻璃体腔注射雷珠单抗治疗糖尿病黄斑水肿与视网膜静脉阻塞性黄斑水肿的疗效对比

目的观察对比玻璃体腔注射雷珠单抗治疗糖尿病黄斑水肿（DME）与视网膜静脉阻塞性黄斑水肿（RVO-ME）的疗效。方法2013年5月至2014年12月在安徽医科大学第一附属医院眼科门诊确诊为DME 及RVO-ME的患者,共26例（33只眼）,其中DME 17只眼,RVO-ME 16只眼。患眼接受玻璃体腔注射雷珠单抗（0．5 mg／0．05 ml）治疗,治疗前和治疗后1 d、2周、4周定期门诊回访观察最佳矫正视力（BCVA）及中央黄斑厚度（CST）。比较雷珠单抗治疗两组治疗前和治疗后的BCVA及CST改变情况。结果 DME组与RVO-ME组治疗后1 d、2周、4周的BCVA均较治疗前明显提高,差异均有统计学意义（P ＜0．05）。DME组与RVO-ME组治疗后4周的CST均较治疗前明显改善,差异均有统计学意义（P ＜0．05）。DME组与RVO-ME组之间在BCVA及CST方面比较,差异均无统计学意义（P ＞0．05）。结论玻璃体腔注射雷珠单抗治疗DME及RVO-ME均可减轻黄斑水肿和改善视力,两者治疗效果无明显差异。     

小梁切除术联合视网膜光凝术治疗新生血管性青光眼

目的 探讨复合小梁切除术联合视网膜光凝术治疗新生血管性青光眼的疗效.方法 回顾性分析视网膜中央静脉阻塞继发新生血管性青光眼患者9例,行复合小梁切除术,术后1周予全视网膜光凝术.记录术前及术后3个月、12个月患者视力、眼压、虹膜及房角新生血管检查,眼底视网膜新生血管消退及无灌注区情况.结果 术后12个月患者视力提高8眼,1眼无明显提高.术后眼压：5例患者眼压控制在21mmHg以下;4例眼压控制欠佳,需要局部使用降眼压药物,其中2例使用一种局部降眼压药物后眼压控制在21mmHg以下,另外2例眼压不能控制.虹膜及房角新生血管消退.眼底3个月和12个月后行荧光血管造影显示新生血管消退,无水肿,毛细血管无灌注区消失.结论 复合小梁切除术联合全视网膜光凝术是一种治疗视网膜中央静脉阻塞继发的新生血管性青光眼的有效的方法.     

Retinal venous pulsation: Expanding our understanding and use of this enigmatic phenomenon

Retinal vein pulsation was first noted soon after the invention of the ophthalmoscope 170 years ago and was seen to change with cerebrospinal fluid pressure (CSFP) variation in the 1920s. The classical explanation for vein pulsation was that the cardiac cycle induced systolic peak in intraocular pressure (IOP) tended to intermittently collapse the retinal vein close to its exit in the central optic disk, causing pulsation to be counter-phase to IOP. Recently, improved ophthalmodynamometry and video recording techniques have allowed us to explore the fundamentals of retinal vein pulsation. This demonstrates that retinal venous collapse is in phase with both IOP and CSFP diastole, indicating the dependence upon CSFP pulse. We describe in some detail the mathematical and physical models of Starling resistors and how their results can be applied to understand the physiology of retinal vein pulsation. We discuss various techniques for measuring retinal venous pulsation, including a novel modified photo-plethysmographic technique developed in our laboratory. With these techniques, non-invasive measurement of CSFP is beginning to look feasible. Venous pulsation properties also have significant prognostic value in predicting long-term outcomes for both glaucoma and central retinal vein occlusion, as well as utility in other retinal vasculopathies and orbital disease. We demonstrate the potential use of modified photo-plethysmographic images in assessing these various disorders. A revised understanding of retinal vein pulse wave transmission along with improved measurement techniques may generate useful clinical tools for assessing these disorders.     

Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ocular hypertension

As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors that may play a protective role in glaucoma. β‐amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans‐lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucoma mainly through a lower trans‐lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure‐independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including β‐amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic β‐amyloid pathway in glaucoma.     

糖尿病视网膜病变中大视杯发生率探讨

目的 研究糖尿病视网膜病变中大视杯的发生率,对结果进行分析,探讨其发生机制.方法 选择糖尿病视网膜病变患者104例208只眼,进行视盘眼底彩照,图像分析仪测定其C/D比值,根据分析结果进行分组,C/D≤0.3组和C/D≥0.6组.比较两组间的眼压和视网膜循环时间之间的差异.结果 糖尿病视网膜病变中C/D≤0.3的占51.92%;C/D≥0.6的占14.90%.C/D≤0.3组和C/D≥0.6组的眼压分别为(14.91±2.15)mmHg;(13.70±2.73)mmHg(P＞0.05)差异无统计学意义;C/D≥0.6组的视网膜循环时间为(2.69±1.58)S,较C/D≤0.3组(1.90+0.58)S明显延迟(P＜0.05),差异有统计学意义.结论 糖尿病视网膜病变中C/D比值大于0.6的比率显著高于一般人群.造成C/D比值增加的因素考虑以视网膜缺血为主,而非眼压增高所致,说明视网膜血液循环障碍对C/D比值的扩大有一定影响.     

Study of clinical applications and safety for Pascal® laser photocoagulation in retinal vascular disorders

Purpose: To establish safe laser parameter standards for 10–30 ms Pascal^® laser in clinical practice and to evaluate clinical and visual outcomes using this 532‐nm multi‐spot photocoagulation system. Methods: Retrospective observational case series of 313 patients treated between 2006 and 2008. Evaluation of eight groups: A – panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR); B – focal laser treatment for clinically significant diabetic macular oedema; C – grid laser for diffuse diabetic macular oedema; D – sector PRP for ischaemic branch retinal vein occlusions (I‐BRVO); E – full PRP for ischaemic central retinal vein occlusions (I‐CRVO); F – macular laser treatment for macular oedema secondary to non‐ischaemic BRVO; G – full PRP for rubeosis iridis and/or neovascular glaucoma (NVG) secondary to I‐BRVO, I – CRVO or PDR; H – laser retinopexy for retinal breaks/degenerations. Results: Mean LogMAR visual acuity for all procedures improved postlaser (p = 0.065), and laser prevented visual loss in 85% eyes. Topical anaesthesia was only required. At mean follow‐up of 5 months, 72% procedures had a successful clinical outcome. Significantly higher powers were required for PRP using Pascal^® compared to conventional laser (p = 0.001) in PDR, I‐BRVO, I‐CRVO and NVG. Sixty‐seven per cent of patients (15/20) were successfully treated with single‐session 20‐ms PRP using a mean 1952 burns. There were no laser‐associated adverse effects or ocular complications associated with multi‐spot PRP or macular Pascal^® arrays. Conclusions: The clinical efficacy using 10‐ to 30‐ms pulse duration Pascal^® laser is comparable to conventional standard protocols used for the treatment of vascular retinal disorders. Higher power, 10‐ to 30‐ms pulse duration laser may be safely and effectively used in clinical practice.     

内皮素系统与视网膜静脉阻塞的相关性研究现状

视网膜静脉阻塞(RVO)以视网膜静脉血流受阻、纡曲扩张和视网膜出血、水肿以及新生血管形成为主要特征,其发病机制尚不完全明确。近期研究发现,内皮素(ET)系统中ET-1、ETA受体、ETA信号通路可能通过刺激血管收缩导致视网膜静脉压增高以及诱导TNF-α、IL-6、IL-1β等促炎因子表达等方式参与RVO的发生发展。深入了解ET系统与RVO发生发展的相关性,可为进一步研究RVO发病机制提供新的思路。     

The effect of isosorbide-mononitrate eye drops on the human intraocular pressure and aqueous humor dynamics

Summary In a randomized, double-masked, single drop study the effect of topical isosorbid-mononitrate (ISMO) 0.5% eye drops, the main metabolite of isosorbid-dinitrate, widely used in the treatment of coronary heart diseases, was studied in patients suffering from open angle glaucoma or ocular hypertension. There was no statistically significant IOP change within 8 hours posttreatment after topical administration of ISMO 0.5%. There were no side effects after application of the ophthalmic solution of ISMO 0.5%. There were no significant changes in blood pressure and pulse rate either.A 2% ophthalmic solution of ISMO was investigated with respect to a response on the aqueous humor dynamics in 10 healthy volunteers. Anterior chamber fluorophotometry revealed a mean increase in aqueous flow of 39% within 3 hours after topical application (p < 0.01). However, in comparison to the placebo treated fellow eyes there were no statistical significant difference in aqueous humor flow during the time of investigation. There was a statistical significant reduction of IOP during the same time period (p < 0.03) in all treated eyes.     

PDR术后继发新生血管性青光眼围手术期血压和血糖波动性的研究

目的:研究增殖性糖尿病视网膜病变(proliferative diabetic retinopathy,PDR)行玻璃体切除硅油取出术后继发新生血管性青光眼(neovascular glaucoma,NVG)围手术期血压、血糖的波动性.方法:回顾性分析增殖性糖尿病视网膜病变行23G玻璃体切除、联合白内障超声乳化、人工晶状体植入、硅油充填术的271例271眼,行硅油取出术后继发新生血管性青光眼的14例14眼,对照组(none neovascular glaucoma,NNVG)为随机抽取同期手术后未继发NVG的同年龄、同手术方式、排除对侧眼做对比,分析发生NVG的时间、围手术期血压、血糖变异性,随访时间为手术后1 ～ 12mo,用SPSS 11.0统计学软件分析本组新生血管性青光眼的发病率、发病时间、围手术期血糖、血压、糖化血红蛋白(Hbc％)的变异性.结果:患者271例14眼继发NVG,占5.2％;男10眼(71.4％),女4眼(28.6％);年龄49 ～ 68(平均57.07)岁;继发NVG的时间为玻璃体切除术后107 ～ 135d,硅油取出术后7 ～ 45(平均31.78)d;糖尿病史10 ～ 15(平均13.2)a.NVG组:围手术期空腹血糖波动4.0 ～10.2(平均8.52±3.24)mmol/L,变异系数0.48.NNVG组:围手术期空腹血糖波动5.0 ～8.2(平均7.22±0.24)mmol/L,变异系数0.43,两组变异系数差异有显著差异(P＜0.05).Hbc％ NVG组:(10.52±0.27)％,NNVG组:(7.60±1.34)％,两组比较差异有统计学意义(P＜0.05).NVG组:围手术期收缩压140 ～180(平均152.3±15.1)mmHg,变异系数0.099,舒张压50 ～ 110(平均92.3±11.1)mmHg,变异系数0.11;NNVG组:围手术期收缩压120 ～150(平均131.4±0.1)mmHg,变异系数0.061,舒张压80～100(平均87.3±8.1)mmHg,变异系数0.08;两组相比,变异系数有差异(P＜0.05),NVG组围手术期空腹血糖的变异性明显大于NNVG组.而两组之间昼夜血压的变异性相比,NVG组白天的收缩压(systolic blood pressure,SBP)以及夜晚的舒张压(diastolic blood pressure,DBP)的变异性均大于NNVG组,均有统计学意义(P＜0.05).14例患者取油术与玻璃体切除硅油注入手术围手术期血糖的变异性、血压的变异性相比无统计学意义.结论:PDR继发NVG患者围手术期空腹血糖的变异性、白天收缩压、夜间舒张压的变异性大,最早可发生在硅油取出术后1wk.     

Retina in a dish: Cell cultures,retinal explants and animal models for common diseases of the retina

For many retinal diseases, including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), the exact pathogenesis is still unclear. Moreover, the currently available therapeutic options are often unsatisfactory. Research designed to remedy this situation heavily relies on experimental animals. However, animal models often do not faithfully reproduce human disease and, currently, there is strong pressure from society to reduce animal research. Overall, this creates a need for improved disease models to understand pathologies and develop treatment options that, at the same time, require fewer or no experimental animals.Here, we review recent advances in the field of in vitro and ex vivo models for AMD, glaucoma, and DR. We highlight the difficulties associated with studies on complex diseases, in which both the initial trigger and the ensuing pathomechanisms are unclear, and then delineate which model systems are optimal for disease modelling. To this end, we present a variety of model systems, ranging from primary cell cultures, over organotypic cultures and whole eye cultures, to animal models. Specific advantages and disadvantages of such models are discussed, with a special focus on their relevance to putative in vivo disease mechanisms. In many cases, a replacement of in vivo research will mean that several different in vitro models are used in conjunction, for instance to analyze and validate causative molecular pathways. Finally, we argue that the analytical decomposition into appropriate cell and tissue model systems will allow making significant progress in our understanding of complex retinal diseases and may furthermore advance the treatment testing.