Studies on the pathogenesis of anterior ischemic optic neuropathy

The pathogenesis of nonarteritic anterior ischemic optic neuropathy (AION) was investigated, on the basis of clinical findings from a patient with nonarteritic AION and experimental study of the vascular architecture of the human optic nerve head. The patient's visual field examination revealed a wide Bjerrum scotoma. This visual field defect suggests that the mechanism of the onset of nonarteritic AION might be similar to that of glaucoma. Fluorescein fundus angiography (FFA) findings suggest that the peripapillary choroidal circulation might recover more easily from perfusion disturbance than the rest. Further, experimental study of the human optic nerve heads revealed that the circle of Zinn forms a complete vascular circle and that small branches from this circle extend to the peripapillary choroid or the optic nerve head, and that the intraneural vascular meshwork is less dense than that in the retrolaminar portion. Based upon the above clinical findings and experimental results, the pathogenesis of nonarteritic AION is postulated as follows: (1) The blood flow in the circle of Zinn is decreased by stenosis of the posterior ciliary artery (PCA). (2) Hypoperfusion is produced in the whole optic nerve head. (3) As in glaucoma, arcuate nerve fibers are first affected, resulting in the onset of nonarteritic AION with arcuate visual field defect or altitudinal defect.     

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.     

The blood supply of the optic nerve head and the evaluation of it - myth and reality

Evidence has gradually emerged that there is vascular insufficiency in the optic nerve head (ONH) in both anterior ischemic optic neuropathy (AION) and glaucomatous optic neuropathy (GON); thus both represent ischemic disorders of the ONH. Together these diseases constitute a major cause of blindness or seriously impaired vision in man. Consequently there has recently been great interest in the ONH circulation in health and disease and in how to evaluate it. Many studies of the subject have been published, with conflicting interpretations and claims. The basis of the inconsistent information seems to be confusion on some fundamental issues concerning the ONH circulation itself. The objective of this paper is to differentiate myths and misconceptions from reality about the ONH blood supply; to elucidate the reasons for disagreement on the blood supply of the ONH; and to evaluate the reliability and validity of various methods currently used to measure ONH blood flow.     

Endothelial dysfunction in glaucoma

Glaucoma is a group of ocular diseases characterized by optic neuropathy associated with loss of the retinal nerve fibre layer and re‐modelling of the optic nerve head, and a subsequent particular pattern of visual field loss. Increased intraocular pressure is the most important risk factor for the disease, but the pathogenesis of glaucoma is not monofactorial. Among other factors, ischaemia and vascular dysregulation have been implicated in the mechanisms underlying glaucoma. The vascular endothelium plays an important role in the regulation of ocular blood flow and pathological alterations of vascular endothelial cells may induce ischaemia and dysregulation. The present review summarizes our current evidence of endothelial dysfunction in glaucoma. This is of interest because endothelial dysfunction is a good prognostic factor for progression in several diseases. Although such data are lacking for glaucoma, endothelial dysfunction may provide an attractive target for therapeutic intervention in open‐angle glaucoma and other vascular disorders of the eye.     

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.     

Blood flow in the optic nerve head and factors that may influence it

In the recent past there has been great interest in the blood supply of the optic nerve head (ONH), how to evaluate ONH blood flow, and what factors influence it, in health and disease. This is because evidence has progressively accumulated that there is vascular insufficiency in the ONH in both anterior ischemic optic neuropathy (AION) and glaucomatous optic neuropathy (GON)-two major causes of blindness or of seriously impaired vision in man. For the management and prevention of visual loss in these two disorders, a proper understanding of the factors that influence the blood flow in the ONH is essential. The objective of this paper is, therefore, to review and discuss all these factors. The various factors that influence the vascular resistance, mean blood pressure and intraocular pressure are discussed, to create a better basic understanding of the ONH blood flow, which may help us toward a logical strategy for prevention and management of ischemic disorders of the ONH.     

Fluorescein angiography in chronic simple and low-tension glaucoma.

Fluorescein angiograms were performed on a group of low-tension glaucoma and chronic simple glaucoma patients with similar extent of visual field loss, under standardised conditions, to see whether differences attributable to chronic intraocular pressure elevation could be detected. There was no evidence for difference in circulation times between these two groups. There was no evidence that hypoperfusion of the peripapillary choroid contributed to optic nerve hypoperfusion. Low-tension glaucoma patients demonstrated focal sector hypoperfusion of the optic nerve in every case, while the chronic simple glaucoma patients demonstrated a wide range of optic nerve fluorescence, suggesting both focal and diffuse optic nerve head hypoperfusion. It was concluded that, while focal hypoperfusion of the optic nerve may reflect susceptible vasculature at the nerve head with or without intraocular pressure elevation, diffuse hypoperfusion suggested that prolonged intraocular pressure elevation may simultaneously affect the whole of the optic nerve head. This could be a direct effect on blood vessels or a mechanical effect with secondary vascular changes.     

Bilateral nonarteritic anterior ischemic neuropathy following acute angle-closure glaucoma in a patient with iridoschisis: case report

A 55-year-old woman was referred to our clinic because of a one-week history of visual loss and raised intraocular pressure in the left eye followed 4 days later by visual loss in the right eye. Slit-lamp examination showed bilateral conjunctival hyperemia, slight diffuse corneal edema, shallow anterior chamber and fixed and dilated pupil in both eyes. Splitting of the anterior layers of the iris with fibrillar degeneration extending for approximately one quadrant inferiorly was presented in each eye. Fundus examination showed optic disc edema with no vascular tortuosity and no cup in both eyes. The condition was treated as bilateral acute angle-closure glaucoma in a patient with irisdoschisis. After medical treatment and improvement of visual acuity, perimetry revealed a significant visual field defect especially in left eye; this case represents a rare concurrence of acute angle-closure glaucoma and bilateral nonarteritic ischemic optic neuropathy. Although most cases of elevated intraocular pressure, including acute angle-closure glaucoma, do not result in optic disc edema and irreversible vision loss, variations in the vascular supply of the nerve optic head along with others ocular systemic risk factors, may predispose certain individuals to nonarteritic ischemic optic neuropathy during periods of elevated intraocular pressure.     

Fluids in the anterior part of the optic nerve in health and disease

New techniques have recently made it possible to study the flow of fluids (blood, axoplasm, and interstitial fluid) in the anterior part of the optic nerve. Blood flow has been reviewed previously; axoplasm and interstitial fluid are considered in this review. General concepts of axoplasmic transport (anterograde and retrograde) are outlined, and the role of axoplasmic transport in the pathogeneses of optic disc edema of various types, in glaucoma, and in ischemic and toxic optic neuropathies is discussed. The probable sources of interstitial fluid in the anterior part of the optic nerve are capillaries in the nerve itself, peripapillary choroid, vitreous, cerebrospinal fluid and possibly axoplasm in the local axons; the flow is defined by various barrier systems. The role of the interstitial fluid in the pathogeneses of optic disc edema (and associated phenomena) and in serous retinal detachment in the macular region associated with optic disc pit is discussed. Its involvement in the process of diffusion of retrobulbar medication into the optic nerve and vitreous is also considered.     

原发性青光眼视神经损害的发生机制

关于原发性青光眼的发病机制,目前有许多学说,但每种学说都不能完全说明青光眼视神经损害的具体机制。综合分析发现,每个正常人或青光眼患者身上都具有致视神经损害因素和抗视神经损害因素,青光眼发生与否是这两种因素相斗争的结果。眼压虽然不是青光眼视神经损害的唯一因素,但仍然是青光眼最主要和最稳定的危险因素。另外,血循环因素和免疫因素也是导致青光眼视神经损害的重要原因。本文综合分析了近年来有关原发性青光眼视神经损害机制的研究,并以独特的视角分析了眼压对青光眼视神经损害的具体机制。     

Fluorescein leakage of the optic disc in glaucomatous optic neuropathy

Purpose To identify and quantify the role of capillary leakage of the optic nerve head in digital fluorescein angiography in normal subjects and patients with open-angle glaucoma.Methods We conducted a prospective cross-sectional study in the Department of Ophthalmology of the Technical University of Aachen. Thirty patients with primary open-angle glaucoma (POAG) and 30 healthy age-matched subjects were included. Fluorescein angiograms were performed using the scanning laser ophthalmoscope. The fluorescence of the optic nerve head and the surrounding retina (ratio of leakage) was measured using digital imaging analysis in the late phases of the angiogram (9–10 min).Results The ratio of optic nerve head fluorescence to retinal reference loci was significantly increased (p=0.01) in patients with glaucoma (POAG, 1.38±0.34) compared with normal subjects (1.20±0.19). Intraocular pressure (p=0.0001), visual field indices (mean deviation, p<0.0001; pattern standard deviation, p<0.0001; corrected pattern standard deviation, p<0.0001), and cup to disc ratios (p=0.02) differed significantly between the groups. Age and systolic and diastolic blood pressure showed no significant differences between groups.Conclusion Fluorescein angiography revealed significantly increased vascular leakage of glaucomatous optic nerve heads. An endothelial disruption and fluorescein leakage might be the result of mechanical stress at the level of the lamina cribrosa and/or a sign of ischemic damage. This measurement approach might enable us to judge the severity of optic nerve head leakage, and it is a potential way to evaluate therapeutic regimens.     

高原地区NAION的相关危险因素分析

非颞动脉炎性前部缺血性视神经病变(non-arteritic anterior ischemic opticneuropathy,NAION)是临床常见的由于供应视神经乳头的睫状后短动脉血流循环障碍而导致的视神经急性缺血、缺氧性病变。NAION是属于缺血性视神经病变(ischemic optic neuropathy,ION)最常见的一种,现就高原地区NAION的相关危险因素作一简单综述。     

Laser Doppler flowmetry and optic nerve head blood flow

PURPOSE: Ischemic disorders of the optic nerve head constitute an important cause of visual loss. The optic nerve head is supplied by two main sources of blood flow: the superficial layers by the central retinal artery and the deeper layers by the posterior ciliary arteries. This study was conducted in rhesus monkey eyes to obtain a better understanding of which part of the optic nerve head circulation is measured by laser Doppler flowmetry. METHODS: By means of a fundus camera-based laser Doppler flowmetry technique to measure blood flow in the optic nerve head tissue, laser Doppler flowmetry measurements were taken at baseline and then after experimental occlusion of central retinal artery (12 eyes), posterior ciliary arteries (nine eyes), and combined occlusion of central retinal artery and posterior ciliary arteries (nine eyes). Optic nerve head, choroidal, and retinal circulations were investigated by fluorescein fundus angiography after the various arterial occlusions. RESULTS: Average laser Doppler flowmetry flow during central retinal artery occlusion alone was significantly decreased (P<.001) by 39%+/-21% (mean +/- 95% confidence interval) compared with normal baseline. Combined occlusion of central retinal artery and posterior ciliary arteries reduced laser Doppler flowmetry flow even more markedly by 57%+/-27% (P<.0005), but the difference between this flow reduction and that with central retinal artery occlusion alone was not significant (P>.20). After posterior ciliary artery occlusion alone, however, measurements showed a nonsignificant increase in laser Doppler flowmetry flow of 17%+/-37%. CONCLUSIONS: The findings of this study suggest that the standard laser Doppler flowmetry technique is predominantly sensitive to blood flow changes in the superficial layers of the optic nerve head and less sensitive to those in the prelaminar and deeper regions, and their relative proportions are not known. In this laser Doppler flowmetry technique, the weaker Doppler signal from the deep layers cannot be separated from the dominant signal from the superficial layers to exclusively study the circulation in the deep layers; the latter circulation is of interest in optic nerve head ischemic disorders, including glaucoma. Emerging new optical modalities of the laser Doppler flowmetry technique may help in selectively measuring blood flow in the deeper layers.     

正常眼压性青光眼与视盘血流灌注的关系

正常眼压性青光眼（normal tension glaucoma, NTG）是青光眼中的特殊类型,发病隐匿,机制未明,可能与视神经乳头血流灌注异常有关,如系统性低血压、全身或局部血管狭窄、眼部血流量下降、视神经乳头血流调控异常等,并最终导致视乳头和巩膜筛板血流灌注降低,发生NTG。（国际眼科纵览,2019, 43： 411-415）     

应用OCT探究眼压与筛板参数的关系

筛板的变形与血流减少一直被视作青光眼视神经轴突损伤的首发因素.病理性眼压升高与青光眼的发生发展间有紧密关系.通过OCT技术衡量筛板及周边参数随眼压变化来研究青光眼发病机制受到了广泛关注.研究表明筛板深度(LCD)、筛板前表面厚度(PTT)、筛板曲率指数(LCCI)以及视盘血管密度等参数均与眼压具有相关性.眼压升高可对筛...     

Color doppler imaging of ocular blood flow after topical ketanserin.

The authors investigated the effect of ketanserin 0.5% eye drops on intraocular pressure and orbital blood flow in some healthy volunteers. Ketanserin is a selective antagonist of serotonin S(2) receptors; moreover, it produces an alpha(1)-blocking effect. It causes a systemic reduction of blood pressure and capillary vasodilatation. Three hours after topical administration of ketanserin 0.5%, the intraocular pressure was decreased by about 14% from the baseline. At the same time, we observed by color Doppler imaging that the mean percent increase in the peak systolic velocity in the ophthalmic artery (OA) was 5.18% (p < 0.161) and 23.18% (p < 0.001) in the posterior ciliary arteries (PCAs). The mean resistance index of the OA was in contrast reduced by 1.16% (p < 0.669) and by 32.14% (p < 0.003) in the PCAs. These data show that ketanserin 0.5% eye drops may be useful not only to decrease intraocular pressure but also to improve blood flow in the PCAs that supply the optic nerve head.     

Papilläre Hämodynamik bei Patienten mit Normaldruckglaukom und Papillenrandblutungen

Background. Optic disc hemorrhages in patients with normal-pressure glaucoma (NPG) are usually regarded as a sign of vascular dysfunction and as an indicator for glaucoma damage progression. Methods. Optic nerve head blood flow was measured in 21 patients suffering from NPG with acute optic disc hemorrhages by scanning laser Doppler flowmetry at various locations of the optic disc. Intraocular pressure and mean deviation of the visual field were also monitored. Two groups served as control: 21 patients with NPG matched for age, sex, and stage of the disease and in addition the contralateral eye without any hemorrhages. Results. Optic nerve head blood flow as a mean of several locations was significantly lower in eyes with optic disc hemorrhages than in controls and differed significantly from the contralateral eye. Conclusion. Optic nerve blood flow was lower in NPG eyes with optic disc hemorrhages than in the contralateral eye and in controls.     

Optic nerve blood flow in glaucoma: effect of systemic hypertension

PURPOSE: To investigate optic nerve head blood flow in patients with glaucoma and to assess the effect of systemic hypertension. METHODS: This study included 24 eyes of 24 patients with primary open-angle glaucoma. Eleven of these patients had a history of systemic hypertension. Results in patients with glaucoma were compared with those of 13 eyes of 13 age-matched normal controls. Determinations of relative optic nerve head blood velocity, volume, and flow were obtained with laser Doppler flowmetry in the superotemporal and inferotemporal neuroretinal rim and also in the cup. Means of the velocity, volume, and flow of these three measurement sites were calculated for each subject. RESULTS: Mean overall optic nerve head blood flow was 29% lower in glaucoma patients than in normal controls (t test, P < .001). This decrease in flow was mainly caused by a decrease of 23% in mean blood velocity (P < .001). Mean flow in glaucoma patients without systemic hypertension was 26% lower than that of glaucoma patients with hypertension (Tukey honest significant difference test, P = .05). A significant direct correlation was observed between mean flow and mean blood pressure (R = 0.51, P < .02). CONCLUSIONS: Optic nerve blood flow is reduced in glaucoma patients. Glaucoma patients without systemic hypertension have lower optic nerve blood flow than those with hypertension. Our results raise concerns that treatment of systemic hypertension may further decrease optic nerve blood flow in glaucoma patients.     

Effects of lomerizine, a novel Ca2+ channel blocker, on the normal and endothelin-1-disturbed circulation in the optic nerve head of rabbits.

We examined the effects of lomerizine, a new diphenylmethylpiperazine Ca2+ channel blocker, on the normal circulation in the optic nerve head and long posterior ciliary artery, and on endothelin-1-induced hypoperfusion in the optic nerve head in anesthetized rabbits using a hydrogen gas clearance method and laser Doppler flowmetry. These effects were compared with those of nilvadipine and pranidipine. Lomerizine (0.1 and 0.3 mg/kg, i.v.) significantly increased tissue blood flow in the optic nerve head and the putative blood flow in the long posterior ciliary artery with smaller reduction of blood pressure (0.3 mg/kg, i.v.) and without change in heart rate. On the other hand, nilvadipine (0.003 and 0.01 mg/kg, i.v.) and pranidipine (0.003 and 0.01 mg/kg, iv.) each significantly increased blood flow and lowered blood pressure. Moreover, lomerizine (0.1 and 0.3 mg/kg, i.v.) and nilvadipine (0.01 mg/kg, i.v.), when administered 5 min before an endothelin-1 injection (10(-6) M, 100 microl), inhibited the hypoperfusion in the optic nerve head. These results suggest that lomerizine improves the ocular circulation with minimal cardiovascular side effects. Therefore, lomerizine may have clinical potential for the treatment of eye diseases associated with local circulatory disturbances, such as normal-tension glaucoma.     

Absolute filling defects of the optic disc in fluorescein angiograms in glaucoma--a retrospective clinical study

BACKGROUND: Analysis of clinical importance of the size of filling defects in fluorescein angiograms in primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), ocular hypertension and subjects with physiological excavations in comparison to visual field loss, optic nerve head morphology and hemodynamics. PATIENTS AND METHODS: 75 patients (POAG, NTG, ocular hypertension) and 10 healthy subjects with physiological excavations were included in this study. In digitized video fluorescein angiograms (Scanning Laser Ophthalmoscope) the size of absolute filling defects of the optic disc was quantified in the early venous phase and expressed by percentage of the optic disc. Visual fields were obtained by conventional static perimetry (Humphrey 24-2) and graded in stages of glaucoma visual field defects (Aulhorn I-V). Optic disc excavations were evaluated as cup-to-disc-area-ratios. RESULTS: The filling defects correlated with the visual-field loss stages of Aulhorn and the visual field indices MD (mean deviation), PSD (pattern standard deviation) and CPSD (corrected pattern standard deviation). There was no correlation with the index SF (short-term fluctuation) and with systemic hemodynamics (blood pressure, perfusion pressure) or the IOP. Absolute filling defects correlated with the cup-to-disc-area-ratio in NTG. The absolute filling defects were larger in patients with glaucoma (POAG, NTG) in comparison to patients without glaucomatous visual field loss (ocular hypertension, glaucoma-like discs). No difference of filling defects was found in the glaucoma group (POAG, NTG). Patients with NTG had larger excavations and lower systolic blood pressures than patients with POAG. CONCLUSION: The size of fluorescein filling defects may be useful as a parameter for the evaluation of an ischemic lesion of the optic nerve head. Absolute filling defects may differentiate POAG from ocular hypertension and NTG from glaucoma-like discs without field defects. The results support the hypothesis that in POAG and NTG disturbances of the circulation result in similar filling defects of the optic disc and visual field loss.