Factors associated with topographic changes of the optic nerve head induced by acute intraocular pressure reduction in glaucoma patients

Purpose

To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG).

Methods

Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient''s systemic and ocular characteristics.

Results

A total of 42 patients were included (mean age, 66.7±11.8 years). After a mean IOP reduction of 47.3±11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P<0.01), but not in mean cup depth (P=0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r²=0.17, P<0.01) and diabetes diagnosis (r²⩾0.21, P<0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r²=0.30, P<0.01). Age, race, disc area, and CCT were not significant (P⩾0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P<0.01).

Conclusions

Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.     

鼠青光眼模型的眼压测量方法

青光眼是主要的致盲眼病之一,对于该病病因、病理、预防、诊断和治疗的研究都需要青光眼动物模型。近年青光眼鼠模型应用报道越来越多。但由于鼠眼较小,对其眼压测量有一定特殊性,我们对鼠青光眼模型的眼压测量方法,尤其是各种方法的原理、特点进行综述。     

Optic nerve blood flow in glaucoma

Background : Glaucomatous optic neuropathy often occurs in the absence of elevated intraocular pressure and, conversely, elevated intraocular pressure may occur without associated damage of the optic nerve. These findings challenge the simple explanation of intraocular pressure being the sole cause of neural loss and have led to theories of ischaemic causes of the morbidity. This paper reviews the vascular anatomy of the optic disc, the factors that control its blood flow and the existing techniques for measurement of the blood flow. It also briefly discusses the possible role of apoptosis in glaucomatous visual loss. Method : Literature review. Conclusions : The posterior ciliary artery circulation is the main source of the blood supply to the optic nerve head with additional lesser supply via the central retinal artery and the choroidal circulation. There is considerable individual variation in the distribution of this circulation and complex regulatory systems govern its function. It is likely that microcirculatory changes in the vascular supply of the optic disc play a role in glaucoma, either as the primary abnormality or as a co‐factor that increases susceptibility to damage from increased intraocular pressure through impaired auto‐regulation. Clinical trials are currently in progress for the treatment of glaucoma with systemically administered agents that are antagonists of the receptors that mediate glutamine toxicity, a factor in the process of apoptosis.     

Temporary elevation of the intraocular pressure by cauterization of vortex and episcleral veins in rats causes functional deficits in the retina and optic nerve

PURPOSE: To evaluate visual function in rats with chronic elevation of intraocular pressure (IOP). METHODS: Chronic ocular hypertension was induced in the left eye of 14 adult Brown Norway rats by cauterizing 3 vortex veins and 2 major episcleral veins; the right eye served as a non-operated control. A control group (n=5) was sham operated on the left eye. Prior to surgery, the IOP was measured with a Tonopen, the pupil light reflex (PLR) evaluated with a custom-made computerized pupillometer and electroretinograms (ERGs) were recorded simultaneously from both eyes post surgically: IOP was measured on weeks 1, 3, 5 and 8 post-operatively, pupil light reflexes on weeks 1, 4 and 8 post-operatively, and ERGs on weeks 4 and 8 post-operatively. Sixty five days postoperatively, rats were euthanized and optic nerves and eye globes were prepared for histological analysis. RESULTS: Seven days after surgery 5/14 rats developed significant elevation of the IOP in operated eyes (control eyes: 25.1+/-0.5mmHg; operated eyes: 34.1+/-0.6mmHg; mean+/-SEM; p=0.0004; Paired t-test). Elevation of the IOP was sustained at 3 (p=0.002) and 5 (p=0.007) weeks postoperatively. However, IOP values did not significantly differ between control and operated eyes 8 weeks postoperatively (p=0.192, Paired t-test). Sham operated animals showed no elevation of the IOP 7 days postoperatively. When the ratio between consensual and direct PLR (PLR(ratio)=consensual/direct PLR; pupil of unoperated eye recorded) was examined in rats which developed elevation of the IOP, preoperative values were 92.2+/-4% (mean+/-SEM), 1 week postoperatively 65+/-4% (significantly different from preoperative values, p<0.05 Repeated Measures ANOVA with Dunnett's Multiple Comparison test, n=5), 4 weeks postoperatively 60.6+/-3.2% (p<0.01, n=5). By 8 weeks postoperatively, pupil responses had essentially recovered 75.4+/-6.9% (p>0.05, n=5). Rats whose IOP values did not rise after surgery and sham operated rats did not develop pupil deficits 4 weeks postoperatively. Rats with elevated IOP displayed a significant decrease in ERG amplitudes in operated eyes at 4 weeks (a-wave(operated)/a-wave(control) (a-wave ratio)=42+/-14% (mean+/-SEM); b-wave(operated)/b-wave(control) (b-wave ratio)=43+/-16%) but not at 8 weeks postoperatively (a-wave ratio=88+/-8.4%; b-wave ratio=82.9+/-9%). Sham operated and rats whose IOP values remained non-elevated after surgery did not develop ERG deficits 4 weeks after surgery. Histological analysis did not reveal any damage in the eyes of animals with elevated intraocular ocular pressure with the exception of one rat, which still had ERG and pupil deficits at the end of experiment. CONCLUSIONS: Development of ERG and PLR deficits are proportional to the elevation of the IOP in the rat model of chronic ocular hypertension. Functional monitoring of the ERG and PLR are useful objective techniques for the detection of retina and optic nerve deficits.     

烧灼大鼠表层巩膜静脉法诱导慢性青光眼模型的研究

目的 利用大鼠建立慢性青光眼模型。方法 选用成年Wistar大鼠，左眼为实验眼，右眼为对照眼，找到实验眼的4条表层巩膜静脉，烧灼其中3条。定期测量和记录双眼眼压，观察眼前节情况；测量和比较双眼角膜水平直径大小。分别于烧灼后2、4、6个月时摘除双侧眼球。观察大鼠视网膜及视盘的组织形态学改变、双眼视网膜厚度和视网膜神经节细胞数目变化。结果 (1)一次性实验操作可使眼压持续升高至少6个月。(2)眼前节无明显并发症。(3)实验期间，角膜水平直径大小无改变。(4)视网膜厚度明显变薄，视网膜神经节细胞数明显减少，视盘凹陷逐渐扩大和加深。结论 通过烧灼大鼠表层巩膜静脉可获得长期眼压中度升高的慢性青光眼模型。     

Glutamate level in optic nerve head is increased by artificial elevation of intraocular pressure in rabbits

Neurons can be damaged by the activation of glutamate receptors, but whether glutamate is related to the development of glaucomatous optic neuropathy is still controversial. The purpose of this study was to measure the acute changes in the glutamate levels in the optic nerve head (ONH) of rabbits induced by an artificial elevation of the intraocular pressure (IOP). A concentric microdialysis probe was inserted into the ONH of rabbits via the pars plana. The probe was perfused with Ringer's solution, and the levels of glutamate in 10-min dialysate samples were measured repeatedly using high-performance liquid chromatography. After the glutamate level was stabilized for at least 60 min, the IOP was adjusted to three levels; 120 mm Hg (n=11), 60 mm Hg (n=12), and 15 mm Hg (control group; n=11). The IOP was altered by changing the height of a bottle of Ringer's solution, which was connected to the anterior chamber by a 23-gauge needle. The IOP levels were maintained for 60 min, and the glutamate levels were determined every 10 min during the 60 min. The mean basal levels of glutamate in the 10-min dialysate were not significantly different among the three groups. The glutamate levels remained unchanged and stable in the controls, but elevation of the IOP significantly increased the level of the glutamate in the dialysate (IOP60, P=0.012; and IOP120, P=0.005: repeated measures ANOVA). Elevation of the IOP causes an increase in the glutamate levels in the ONH of rabbits. This suggests a possible interaction between glutamate metabolism and the IOP in the ONH.     

补精益视片对大鼠慢性高眼压模型视网膜损害的影响

目的　观察补精益视片对大鼠慢性高眼压（ｅｌｅｖａｔｅｄｉｎｔｒａｏｃｕｌａｒｐｒｅｓｓｕｒｅ,ＥＩＯＰ）模型视网膜损害的干预作用,探讨其作用机理。方法　将３０只ＳＤ大鼠随机分为３组:对照组、给药组、模型组,每组１０只。采用烙闭上巩膜静脉法对给药组、模型组ＳＤ大鼠建立慢性ＥＩＯＰ模型,观察补精益视片对慢性ＥＩＯＰ大鼠眼压和视网膜病理形态学变化的影响。结果　给药组、模型组大鼠在造模后即刻直至造模后８周与造模前相比眼压均升高,差异均有统计学意义（均为Ｐ＜０．０１）,说明ＥＩＯＰ模型造模成功。造模后８周眼压与造模后即刻相比,给药组有降低趋势,差异有统计学意义（Ｐ＜０．０１）,模型组差异无统计学意义（Ｐ＞０．０５）。造模后８周,视网膜神经节细胞（ｒｅｔｉｎａｌｇａｎｇｌｉｏｎｃｅｌｌｓ,ＲＧＣｓ）数量给药组（１４．５７±１．９７）与模型组（１０．７６±２．１９）均明显低于对照组（１７．４７±１．９７）,差异均有统计学意义（Ｐ＜０．０５,Ｐ＜０．０１）;视网膜厚度模型组为（１５０．８３±１７．９１）μｍ低于对照组的（２１９．７２±３２．２４）μｍ,差异有统计学意义（Ｐ＜０．０１）,给药组为（２１５．５１±５１．２３）μｍ,与对照组相比差异无统计学意义（Ｐ＞０．０５）;给药组ＲＧＣｓ数量及视网膜厚度均优于模型组,差异均有统计学意义（均为Ｐ＜０．０１）。ＲＧＣｓ超微结构显示给药组较模型组明显改善。结论　补精益视片能保护ＳＤ大鼠慢性ＥＩＯＰ模型视功能,表现为降低眼压、提高ＲＧＣｓ数量、增加视网膜厚度、改善ＲＧＣｓ超微结构。     

青光眼模型视神经损伤的评估方法

对青光眼动物模型视神经损伤的评估有利于青光眼发病机制和治疗方法的研究.目前主要从视网膜神经节细胞(retinal ganglion cell,RGC)计数、视网膜内层厚度测定和球后视神经轴突计数三方面进行评估.几种评估方法各有优缺点.RGC的凋亡直接反映视神经损伤的程度,视网膜全铺片染色计数RGC方法操作较简单,但视网膜铺片各层细胞易于重叠;逆行荧光染料标记需进行颅内手术且染料可能泄露到邻近小胶质细胞,导致不准确的计数;视网膜厚度测量不能直接反映视神经损伤的程度;视神经轴突计数难度相对较高;体视学方法可直接计数RGC,但需要熟悉相关体视学公式及方法,目前在该领域的报道较少.     

慢性高眼压青光眼动物模型的构建和鉴定

目的:建立大鼠慢性高眼压模型,观察眼压、病理和视功能改变.方法:SD大鼠45只,麻醉后使用532二极管激光行右眼角膜缘360°光凝,角膜缘激光斑为80～100个,大鼠角膜缘颞侧、颞上及颞下巩膜浅层静脉3条,每条静脉光凝3～4个斑点,功率0.45W/0.7s.左眼为对照眼,3d后测量眼压,部分眼压升高不明显者,进行同样的二次光凝.Tono-penXL眼压计监测3,7,30,60,90,180d麻醉状态下的眼压.激光术后60,180d取大鼠各5只,40g/L多聚甲醛灌注固定,摘取双侧眼球和视神经,分别进行冰冻和石蜡切片,采用HE染色、尼氏染色、甲苯胺蓝染色,光镜下观察房角变化,不同时间视网膜节细胞计数,比较视神经髓鞘密度的变化.60,180d大鼠10只,使用TEC-350V视觉电生理仪行F-VEP检查;然后6mo大鼠5只,进行逆行荧光金标记RGCs,7d后40g/L多聚甲醛灌注固定,全视网膜铺片,荧光显微镜下比较视网膜节细胞数量变化.结果:大鼠高眼压模型成功38只,平均最高眼压在激光后30d,平均值为25.0±4.1mmHg,对照眼17.1±3.2mmHg,180d时眼压基本恢复正常.病理改变:实验眼前房角明显变窄,小梁网间隙压缩、变窄,甚至部分闭锁,消失,少量梭形成纤维细胞聚集,组织致密、硬化,而小梁细胞减少,虹膜部分卷曲,水肿、肥厚出现明显异常.逆行荧光金视网膜铺片和视网膜切片尼氏染色见实验眼视网膜节细胞数量有明显的减少;尼氏染色切片每400倍视野总平均数,60d组对照眼为41±10.6个,实验眼为35±11.2个,180d组对照眼为40±9.8个,实验眼为34±11.0个,周边视网膜平均值减少最为显著,均值相差可达8个神经节细胞;180d时模型眼视神经甲苯胺蓝染色显示的髓鞘密度明显降低;视功能检查:高眼压大鼠模型60,180d的实验眼和对照眼均可引出典型的和重复性好的NPN波形,60d时实验眼AP1(N1-P1振幅)均值降低,为13.03±3.11ms,对照眼为21.14±3.10ms,两者具有显著性差异(P＜0.05),波幅值降低持续至180d仍未恢复;LP1(P1峰潜伏期)60d时无明显变化,180d时则明显延迟,实验眼为74.47±8.05μV,对照眼为59.73±4.16μV,与对照组比较有显著性差异(P＜0.05).结论:使用532-二极管激光角巩膜缘小梁网及巩膜浅层静脉光凝能成功升高眼内压,眼压升高近8mmHg;病理显示视网膜神经节细胞数显著减少,以周边视网膜为著;视神经髓鞘密度亦显著地减少;视觉电生理检测,F-VEP的AP1振幅降低,LP1波峰潜伏期延迟非常显著.     

Estimation of axon counts in a rat model of glaucoma: comparison of fixed-pattern sampling with targeted sampling

Background: Full axon counting of optic nerve cross‐sections represents the most accurate method to quantify axonal damage, but such analysis is very labour intensive. Recently, a new method has been developed, termed targeted sampling, which combines the salient features of a grading scheme with axon counting. Preliminary findings revealed the method compared favourably with random sampling. The aim of the current study was to advance our understanding of the effect of sampling patterns on axon counts by comparing estimated axon counts from targeted sampling with those obtained from fixed‐pattern sampling in a large collection of optic nerves with different severities of axonal injury. Methods: Chronic ocular hypertension was induced in adult Sprague‐Dawley rats for 1–7 weeks by translimbal laser photocoagulation of the trabecular meshwork. Axonal damage on resin‐embedded cross‐sections was estimated using three different methods: (i) semi‐quantitative damage grading; (ii) semi‐quantitative, automated axon counting using targeted sampling; and (iii) semi‐quantitative, automated axon counting using fixed‐pattern sampling. Results: Estimated axon counts, as generated by targeted sampling and fixed‐pattern sampling, correlated equally well with the semi‐quantitative grading scheme. Estimated counts obtained with targeted sampling were not statistically different from those yielded by fixed‐pattern sampling. Bland–Altman analysis showed a good agreement between the two methods. Conclusions: The results of our study validate the use of both fixed‐pattern sampling and targeted sampling for estimation of axonal damage but do not indicate that the latter method is superior for detection of axon loss in animals with minor damage.     

青光眼视神经保护治疗的研究进展

青光眼是由于眼压升高引起视乳头损害和视野缺损的一种致盲性眼病,其病理基础是视网膜神经节细胞及其轴突的进行性丢失。过去大量的研究都集中在降低眼压方面,现在视神经保护治疗作为一种通过阻止神经元死亡治疗青光眼的新策略已被普遍接受。我们从NMDA受体拮抗剂、神经营养因子、热休克蛋白、免疫系统等方面,总结了目前青光眼视神经保护治疗的研究进展。     

补精益视片对大鼠慢性高眼压模型视网膜p-Akt表达的影响

目的　观察补精益视片对大鼠慢性高眼压（ｅｌｅｖａｔｅｄｉｎｔｒａｏｃｕｌａｒｐｒｅｓｓｕｒｅ,ＥＩＯＰ）模型ｐ-Ａｋｔ表达的干预作用,探讨其作用机理。方法　将３０只ＳＤ大鼠随机分为３组:对照组、模型组、给药组,模型组和给药组采用烙闭上巩膜静脉法建立ＳＤ大鼠慢性ＥＩＯＰ模型,给药组每天予１．８ｇ·ｋｇ－１体质量补精益视片混悬液灌胃,对照组、模型组每天予３ｍＬ生理盐水灌胃,连续给药８周,并于８周末处死大鼠,观察各组大鼠眼压、视网膜ｐ-Ａｋｔ表达的情况。结果　模型组、给药组大鼠造模后即刻直至造模后８周与造模前眼压相比均升高,差异均有统计学意义（均为Ｐ＜０．０１）;造模后８周眼压与造模后即刻相比,给药组有降低趋势,差异有统计学意义（Ｐ＜０．０１）,模型组无降低趋势,差异无统计学意义（Ｐ＞０．０５）。造模后８周视网膜ｐ-Ａｋｔ表达免疫组织化学分析示:给药组总面积、平均光密度和积分光密度分别为（７４６３１．８１±１２８４１．３０）μｍ２,９３９．２６±１７５．１７和３７８１４．９６±５８２２．７１,与模型组的（３７９４７．２６±８０５０．５１）μｍ２、４８１．４５±１６１．０２和１８９０７．６４±４３６７．２９相比,差异均有显著统计学意义（均为Ｐ＜０．０１）;给药组平均黑度为１３８．５５±８．５８,虽高于模型组的１３６．５２±３．８１,但差异无统计学意义（Ｐ＞０．０５）。结论　补精益视片通过降低眼压、上调视网膜ＰＩ３Ｋ／Ａｋｔ信号转导通路中ｐ-Ａｋｔ的表达而保护慢性ＥＩＯＰ模型ＳＤ大鼠的视功能。     

Spectral domain optical coherence tomography cross-sectional image of optic nerve head during intraocular pressure elevation

AIM: To analyze changes of the optic nerve head (ONH) and peripapillary region during intraocular pressure (IOP) elevation in patients using spectral domain optical coherence tomography (SD-OCT).METHODS: Both an optic disc 200×200 cube scan and a high-definition 5-line raster scan were obtained from open angle glaucoma patients presented with monocular elevation of IOP (≥30 mm Hg) using SD-OCT. Additional baseline characteristics included age, gender, diagnosis, best-corrected visual acuity, refractive error, findings of slit lamp biomicroscopy, findings of dilated stereoscopic examination of the ONH and fundus, IOP, pachymetry findings, and the results of visual field.RESULTS: The 24 patients were selected and divided into two groups:group 1 patients had no history of IOP elevation or glaucoma (n=14), and group 2 patients did have history of IOP elevation or glaucoma (n=10). In each patient, the study eye with elevated IOP was classified into group H (high), and the fellow eye was classified into group L (low). The mean deviation (MD) differed significantly between groups H and L when all eyes were considered (P=0.047) and in group 2 (P=0.042), not in group 1 (P=0.893). Retinal nerve fiber layer (RNFL) average thickness (P=0.050), rim area (P=0.015), vertical cup/disc ratio (P=0.011), cup volume (P=0.028), inferior quadrant RNFL thickness (P=0.017), and clock-hour (1, 5, and 6) RNFL thicknesses (P=0.050, 0.012, and 0.018, respectively), cup depth (P=0.008), central prelaminar layer thickness (P=0.023), mid-inferior prelaminar layer thickness (P=0.023), and nasal retinal slope (P=0.034) were significantly different between the eyes with groups H and L.CONCLUSION:RNFL average thickness, rim area, vertical cup/disc ratio, cup volume, inferior quadrant RNFL thickness, and clock-hour (1, 5, and 6) RNFL thicknesses significantly changed during acute IOP elevation.     

The damage patterns of retinal nerve fiber layer in acute and chronic intraocular pressure elevation in primary angle closure glaucoma

 Purpose: To observe the differences of damage patterns of retinal nerve fiber layer (RNFL) between acute and chronic intraocular pressure (IOP) elevation in primary angle closure glaucoma (PACG) using optical coherence tomography (OCT). Methods: Twenty four patients (48 eyes) with unilateral acute PACG (APACG) attack in the 6 months after remission and 36 patients (64 eyes) with chronic PACG (CPACG) were included in this prospective study. For all cases, IOP has been controlled less than 21 mm Hg after treatment. Using stratus OCT, the RNFL thickness was assessed in eyes with PACG within 3 days, 2 weeks, 1, 3 and 6 month after IOP controlled. Repeated measures ANOVA was used to examine the time course of changes after IOP controlled in RNFL thickness in both acute attack and unaffected fellow eyes of APACG and eyes with CPACG. Results: The mean RNFL thickness (μm) for the APACG-attacked eyes increased significantly within 3 days (121.49±23.84) after acute strike and then became thinner along with time (107.22±24.72 at 2 week, 93.58±18.37 at 1 month, 84.10±19.89 at 3 month and 78.98±19.17 at 6 month). In APACG-attacked eyes, there were significant differences of average RNFL thickness among 5 different times after IOP was controlled (P ＜ 0.001). In the APACG unaffected fellow eyes and CPACG eyes, there were no significant differences in mean RNFL thickness among 5 different times (F = 0.450, P = 0.104 in APACG unaffected fellow eyes and F = 1.558, P = 0.200 in CPACG eyes). There was significant difference for interaction between time periods and groups (F = 1.912,P = 0.003). Conclusion:  RNFL damage patterns are different under different IOP elevated courses. In APACG, RNFL was found to be swollen and thickening right after acute attack and then becomes thinning and atrophy along with the time, while RNFL was found to be diffused thinness in CPACG.     

Damage patterns of retinal nerve fiber layer in acute and chronic intraocular pressure elevation in primary angle closure glaucoma

AIM: To observe the differences of damage patterns of retinal nerve fiber layer (RNFL) between acute and chronic intraocular pressure (IOP) elevation in primary angle closure glaucoma (PACG) using optical coherence tomography (OCT). METHODS: Twenty-four patients (48 eyes) with unilateral acute PACG (APACG) attack in the 6 months after admission and 36 patients (64 eyes) with chronic PACG (CPACG) were included in this prospective study. For all cases, IOP has been controlled under 21mmHg after treatment. Using stratus OCT, the RNFL thickness was assessed in eyes with PACG within 3 days, 2 weeks, 1, 3 and 6 months after IOP was controlled. Repeated measures ANOVA was used to examine the changes of RNFL thickness at different time after IOP being controlled in both acute attack eyes and unaffected fellow eyes of APACG and eyes with CPACG. RESULTS: The mean RNFL thickness for the APACG- attacked eyes increased significantly within 3 days (121.49±23.84)μm after acute onset and then became thinner along with time [(107.22±24.72)μm at 2 weeks,(93.58±18.37)μm at 1 month, (84.10±19.89)μm at 3 months and (78.98±19.17)μm at 6 months]. In APACG-attacked eyes, there were significant differences of average RNFL thickness at 5 different times after IOP was controlled (P＜0.001). In the APACG unaffected fellow eyes and CPACG eyes, there were no significant differences in mean RNFL thickness at 5 different times(F=0.450, P=0.104 in APACG unaffected fellow eyes and F=1.558, P=0.200 in CPACG eyes). There was significant difference for interaction between time periods and groups (F=1.912, P=0.003). CONCLUSION: RNFL damage patterns are different under different IOP elevated courses. In APACG, RNFL was found to be swollen and thickening right after acute attack and then becomes thinning and atrophy along with the time, while RNFL was found to be diffused thinness in CPACG.     

The use of cyclodialysis to limit exposure to elevated intraocular pressure in rat glaucoma models

Elevated intraocular pressure (IOP) is the most common risk factor for glaucoma and pressure control is the goal of current clinical glaucoma therapy. Yet, recent clinical studies have documented that, even after therapeutic lowering of IOP, glaucomatous visual field loss can progress in many patients. Experimental elevation of IOP in the rat is commonly used to model human glaucomatous injury. However, there currently is no rodent model for the clinical situation of glaucomatous progression in eyes with apparently controlled IOP. The purpose of this study was to evaluate the ability of surgical cyclodialysis to produce both prolonged, non-injurious reduction of IOP in rat eyes and to stably normalize IOP in eyes with experimental pressure elevation. To perform cyclodialysis, a blunted spatula was fashioned from a hypodermic needle and used to separate a portion of the ciliary body from the sclera, opening a channel into the suprachoroidal space to allow aqueous outflow. Experimental IOP elevation was produced in rats by unilateral injection of hypertonic saline. Cyclodialysis in normal eyes resulted in an average 40 +/- 4% reduction in IOP, without marked hypotony. IOP lowering could be sustained for at least 6 months. The risk of retinal or optic nerve injury following a single cyclodialysis procedure was minimal as evidenced by unaltered levels of four injury-responsive retinal mRNAs and by normal optic nerve morphology. Cyclodialysis in eyes with experimental IOP elevation resulted in IOP normalization that was sustained for durations of 7 and 21 days in 88% and 53% of eyes, respectively. In addition, in eyes with the same cumulative dose of elevated IOP prior to the procedure, successful IOP normalization by cyclodialysis resulted in significantly less optic nerve injury than that seen in eyes in which IOP control was ineffective (p = 0.03). These studies show that cyclodialysis provides a simple, non-injurious method to reduce experimentally elevated IOP in rats that can be used to model the clinical situation of eyes previously damaged by pressure. This tool offers new opportunities for identifying and studying the molecular processes associated with glaucomatous progression and for testing potential neuroprotective therapies in a clinically relevant situation.     

Optic nerve damage in glaucoma: II. Insufficiency of blood flow

Ladies and gentlemen, our case rests. I do not contend that ischemia is the sole mechanism by which the optic nerve becomes damaged in glaucoma. But can one seriously doubt that it plays an important role?