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[The existence of vasomotor nerve in the retina of the rabbit and monkey].

In the first stage of this study, peri- or intravascular unmyelinated nerve axon which was clearly different from that of the optic nerve was confirmed in the rabbit retina transmission electron microscopically. In the second stage, the correlation of these unmyelinated nerves and autonomic nerve was studied in rabbits and monkeys. For the purpose, wheat germ agglutinin horseradish peroxidase (WGA-HRP) was injected into the superior cervical ganglion. Electron microscopic observation of the retina 48 hrs after the injection of WGA-HRP showed deposit of its reaction product in the axon of the unmyelinated nerve located around the vascular wall and in the adventitia and smooth muscle cell in both rabbits and monkeys. This result clearly reveals the existence of an autonomic vasomotor in the retinal vessels at least in rabbits and monkeys.

Animals↗

Inflammatory response after scatter laser photocoagulation in nonphotocoagulated retina.

PURPOSE: Macular edema is one of the most serious adverse effects after retinal scatter laser photocoagulation. It has been suggested that the changes in the distribution of retinal blood flow or the inflammatory reaction after photocoagulation may be involved in the pathogenesis of macular edema, but little information is available about its exact mechanism. This study was designed to evaluate quantitatively leukocyte-endothelial cell interactions and vascular permeability in the nonphotocoagulated portions of the retina after partial scatter laser photocoagulation. METHODS: Argon laser photocoagulation was performed in one half of the retina in male pigmented rats (n = 90). In the other half of the retina, leukocyte dynamics after photocoagulation were evaluated in vivo with acridine orange digital fluorography. Retinal vessel permeability was quantified by using Evans blue dye. RESULTS: Scatter laser photocoagulation caused significant inflammatory leukocyte-endothelial interactions not only in the photocoagulated but also in the untreated half of the retina. In the nonphotocoagulated half of the retina, the number of leukocytes rolling along the major retinal veins increased after photocoagulation and peaked at 12 hours (14.3 +/- 4.5 cells/min per vessel). Leukocyte accumulation in the untreated half of the retina increased after photocoagulation, with a peak of 47.5 +/- 13.0 cells/mm(2) 24 hours after photocoagulation. Retinal vascular permeability in the untreated half of the retina gradually increased after photocoagulation. CONCLUSIONS: Scatter laser photocoagulation increased leukocyte rolling and subsequent accumulation in both the photocoagulated and the untreated portions of the retina. The accumulated leukocytes may be involved in the augmented vascular permeability in the untreated retina, resulting in retinal edema after photocoagulation.

Acridine Orange↗

Mechanisms in retinal vasculogenesis: an analysis of the spatial branching site correlation.

Starting from fractal dimension calculations of retinal vessel patterns, different growth models and related mechanisms have been suggested to simulate retinal vasculogenesis. A comprehensive view of this topic does not exist. In order to elucidate this question the spatial correlation of the vessel branching sites of the embryonic vessel pattern has been studied. During development of the retinal vasculature within the nerve fiber layer a modification of the branching characteristics can be observed. This result supports theories which suggest a close relation between the vessel propagation and the structure and surface characteristics of the invading vascular cells and the retinal tissue. Arterio-venous differentiation, however, may be dominated by diffusion processes.

Animals↗

[Effect of mannitol on human retinal blood flow].

The effect of hyperosmotic agents (20% mannitol) on the retinal circulation was evaluated in 14 eyes of 7 normal subjects. Laser speckle retinal blood flow velocimetry with simultaneous real-time measurement of retinal vessel diameter was used. Experiments were performed in a double-masked crossover design and each subject was given either 20% mannitol or physiological saline solution by intravenous drip. The retinal blood flow rate was measured just before the administration of the agents and after the intravenous drips. After the 20% mannitol administration, intraocular pressure was reduced and ocular perfusion pressure, retinal blood flow velocity, and retinal blood flow rate increased significantly (paired t-test, p < 0.01). There was not statistically significant difference between the retinal blood flow rate before and after the administration of physiological saline solution (p > 0.05), but the retinal blood flow velocity increased significantly (p < 0.05). The ratio between the retinal blood flow rate before and after the administration of 20% mannitol was statistically larger than that of physiological saline solution (p < 0.05).

Blood Flow Velocity↗

Local choroidal blood flow in the cat by laser Doppler flowmetry.

PURPOSE: To develop a procedure using a noninvasive technique that will allow the investigation of choroidal blood flow (ChBF) regulation in discrete regions of the cat eye. Validation of this procedure will provide a method to study intrinsic, neural, and pharmacologic factors that regulate regional ChBF. METHODS: The technique to measure ChBF is based on laser Doppler flowmetry. However, in contrast to conventional laser Doppler flowmetry, which uses fiber-optic probes in direct contact with the tissue to deliver the laser beam and detect the scattered light, with this technique the beam is delivered through a fundus camera and the scattered light is detected in the retinal image plane of the camera. Measurements were made in 34 anesthetized cats under conditions that would ensure that the flow measured represented ChBF in the choriocapillaris: the laser beam was aimed at retinal intervascular sites in the tapetal region of the fundus; the Doppler shift power spectrum of the light scattered by the red blood cells had the shape and frequency range typical for a microvascular bed; and the recorded flow did not decrease by more than 5% when the cat was given 100% O2 to breathe for 4 minutes. The responses to various physiologic and pharmacologic stimuli were tested and compared with those obtained from retinal vessels. RESULTS: Intravenous infusions of acetylcholine increased ChBF in a dose-response fashion, whereas sympathetic nerve stimulation at various frequencies decreased ChBF as predicted by previous studies. By comparison, retinal blood flow was negligibly affected by these two stimuli. In contrast to retinal blood flow, ChBF was unaffected by diffuse luminance flicker. ChBF was found to be pulsatile. The mean of the pulsatile component of ChBF represented approximately 34% of mean ChBF, a value similar to those derived from ChBF measurements in minipigs and retinal blood flow in the cat. CONCLUSIONS: This study demonstrates that laser Doppler flowmetry is a valid technique for obtaining local, noninvasive, and continuous recordings of relative ChBF. Tested under steady-state conditions for blood pressure, heart rate, and acid-base balance, ChBF is stable for long periods of time, allowing the investigation of the effect of various physiologic stimuli and pharmacologic agents on this flow.

Acetylcholine↗

[Williams-Beuren syndrome: diagnosis and ocular manifestations].

A 24-year-old woman presented with a Williams-Beuren Syndrome which included a characteristic facies, cardiovascular dysfunction and neurologic troubles. Ophthalmic examination showed a stellate pattern of the iris and tortuosities of the retinal vessels. Knowledge of these ocular manifestations could help early diagnosis.

Adult↗

[Lymphangioma of the conjunctiva].

A 23-year-old female presented with a yellow-brownish, asymptomatic tumour of the bulbar conjunctiva in her left eye. The lesion had been detected 5 years previously and had grown since then. Prior to presentation there were 2 episodes of intratumoral hemorrhage. Funduscopy revealed tortuous vessels on the left. Complete tumour excision was performed. Histology showed numerous channels lined by a flat endothelium, and inflammatory cells in the fibrous septae. A diagnosis of a conjunctival lymphangioma was established. The tortuosity of the retinal vessels was probably associated by chance or caused by an undetected orbital lymphangioma.

Adult↗

Aplasia of the optic nerve.

A case of unilateral true aplasia of the optic nerve in an otherwise normal and healthy child is presented. Twenty-eight previously reported cases of aplasia have been reviewed and classified according to criteria which we have presented. Only six of these cases, including the present case, represent true aplasia, manifested by total blindness and complete absence of the optic disc and retinal vessels.

Blindness↗

Perfluorooctylbromide (PFOB) as a vitreous substitute in non-human primates.

We evaluated the toxicity of perfluorooctylbromide in the primate eye as a short-term postoperative vitreous substitute. Four eyes of 4 African green monkeys underwent complete vitrectomy and vitreous replacement with 1.5-2.0 ml of PFOB. One additional animal received BSS as a control vitreous substitute in one eye. Animals were examined twice weekly for clarity and consistency of the vitreous replacement substance. Anterior segment and lenses remained clear in all eyes, although in the immediate postoperative period one eye became inflamed and had a culture-negative vitritis. The other eyes showed a minimal anticipated postoperative vitreous inflammation. Emulsification of the PFOB began within 3 days of injection and progressed up to 3 weeks, precluding fundus examination and fluorescein angiography after 2 weeks. Eyes were enucleated and light microscopy performed at 2 days, 10 days, 33 days, and 45 days. No toxic effects to the retinal cells were detectable by histological examination, but perivasculitis of retinal vessels was noted at 45 days. Indirect examination was normal up to 10 days; thereafter, the fundus view was obscured by the emulsified PFOB. Because of cellular migration into the vitreous cavity and retinal perivasculitis, observed histologically, PFOB seems most suitable for intraoperative rather than postoperative use.

Animals↗

Serous macular detachment secondary to distant retinal vascular disorders.

PURPOSE: To report tomographic features of macular edema associated with distant retinal vascular disorders. METHODS: Six eyes with macular edema (three with extramacular branch retinal vein occlusion and three with Coats disease) underwent fluorescein angiography to detect dye leakage and optical coherence tomography to evaluate the macular features and measure the foveal height (distance between inner retinal surface and retinal pigment epithelium) and the retinal thickness (thickness of neurosensory retina) at the central fovea. RESULTS: Fluorescein angiography showed widespread nonperfusion and retinal vein staining in the eyes with a branch retinal vein occlusion not involving the macula. In eyes with Coats disease, nonperfused areas, telangiectatic retinal vessels, and aneurysms were seen in the peripheral fundus on fluorescein angiography. In one eye with Coats disease, telangiectatic vessels and aneurysms were seen in the nasal mid periphery of the optic disk. There was no dye leakage in the macular area in any eyes. Optical coherence tomography showed subretinal fluid and retinal swelling at the fovea in all eyes. The foveal height ranged from 300 to 697 microm (mean, 478 microm) and retinal thicknesses ranged from 170 to 280 microm (mean, 233 microm). CONCLUSION: Distant retinal vascular leakage causes serous retinal detachment in the macula. The macula is predisposed to collect subretinal fluid although retinal vascular leakage is far from the macula.

Adolescent↗

Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy.

The polyol (sorbitol) pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the polyol pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the polyol pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy.

Aged↗

Fundus morphology assessed by digital image analysis in children with fetal alcohol syndrome.

BACKGROUND: Fetal alcohol syndrome (FAS) is associated with anomalies of the eye ground. The aim of this study was to evaluate the development of fundus morphology in children with FAS from early childhood to adolescence. METHODS: Funds photographs were evaluated by digital image analysis in 16 children with FAS. Age at the baseline study was between 0.25 and 14 years, and the median follow-up period was 7 years (range: 0.5 to 12). Sixteen sex- and age-matched healthy children were used as controls. RESULTS: Children with FAS had a smaller optic disc area, lower frequency of excavations, greater tortuosity of retinal vessels, and a smaller number of vascular branching points compared with the controls. There were no significant differences in the funds abnormalities between the first and last examinations. CONCLUSION: No interval change of retinal funds morphology was found at follow up, suggesting that the ocular abnormalities associated with FAS remain unchanged during childhood.

Adolescent↗

Experimental percutaneous cannulation of the supraorbital arteries: implication for future therapy.

PURPOSE: There is some evidence to suggest that thrombolysis has a beneficial effect in retinal vessel occlusion. However, there is concern that this therapeutic approach carries the risk of hemorrhage. Retrograde cannulation of the supraorbital arteries followed by irrigation with fibrinolytic agents may have the potential to minimize the risk of major complications. The study was conducted to investigate the anatomic and sonographic features of the supraorbital arteries. METHODS: This cadaver dissection study was performed on the orbits of 12 cadaveric specimens. In each orbit, the supraorbital region was dissected, followed by cannulation of the supraorbital vessels and injection of ink. In six orbits, the orbital vessels and the distribution of the injected ink were investigated. Continuous-wave Doppler sonographic analysis of the supratrochlear and the supraorbital artery was performed in 40 orbits of 20 volunteers to measure the distance between the arteries and the midline. RESULTS: Cannulation with retrograde injection of ink was successfully performed in both the supratrochlear and the supraorbital arteries. The supratrochlear artery exhibited a more superficial course and a larger diameter than the supraorbital artery (1.08 +/- 0.19 mm vs. 0.86 +/- 0.19 mm [SD]). Dissection to the orbital apex revealed a spread of ink into the ophthalmic and the central retinal arteries. The average distance between the exit of the supratrochlear artery and the midline was found to be 16.4 +/- 1.7 mm (range, 13-20). The average distance between the exit of the supraorbital artery and the midline measured 26.5 +/- 2.6 mm (range, 23-35). CONCLUSIONS: The findings of this anatomic and sonographic study support the concept of percutaneous supraorbital vessel cannulation as a potential approach to thrombolysis in retinal vessel occlusion. The supratrochlear artery appears to provide the most reliable access route.

Adult↗

Hypercholesterolemia induces leukocyte entrapment in the retinal microcirculation of rats.

PURPOSE: To evaluate leukocyte dynamics in the retinal microcirculation of hypercholesterolemic rats in vivo using acridine orange digital fluorography. METHODS: 18 male pigmented rats were divided into 3 groups according to their diet; (A) control diet (0.1% cholesterol) for 8 weeks, (B) control diet for an initial 4 weeks followed by a high-cholesterol (HC) diet (5% cholesterol) for another 4 weeks and (C) HC diet for 8 weeks. Leukocyte dynamics were observed with acridine orange digital fluorography. The diameter of major retinal vessels and the number of leukocytes trapped in the retina were evaluated quantitatively. RESULTS: Both groups B and C showed approximately 4-fold higher serum cholesterol levels than in group A. The diameters of retinal arteries and veins were not significantly different among the three groups. Also, no rolling leukocytes were observed in any of the groups. In the retinal microcirculation at 30 minutes after acridine orange injection, the density of trapped leukocytes in both groups B and C was significantly greater than in group A (23.19 +/- 2.13, 28.56 +/- 1.96 and 13.67 +/- 1.45 cells/mm(2), respectively, p < 0.01). Furthermore, group C exhibited a significantly greater number of trapped leukocytes than in group B (p < 0.01). CONCLUSION: Enhanced leukocyte entrapment in the retinal microcirculation was induced in the early stage of hypercholesterolemia. Entrapment was increased as the period of hypercholesterolemia was prolonged. Leukocyte accumulation in the retina may be an early vascular dysfunction leading to arteriosclerosis in hypercholesterolemia.

Acridine Orange↗

Vascular occlusion in diabetic retinopathy. A qualitative and quantitative histopathological study.

The retinal vessels from seven diabetic patients and from six age-matched normal controls were studied qualitatively and quantitatively using various histological staining techniques. In diabetic patients the walls of retinal arterioles and capillaries showed significantly more staining than normals for periodic acid Schiff (neutral glycoproteins), Sirius red (connective tissue), and for Alcian blue at pH 2.6, pH 5.8 and at pH 5.8 combined with MgCl22 in concentrations less than 0.9 M (acid mucopolysaccharides). In the retina from diabetic patients there was no difference between the number of capillaries staining with these dyes in areas of vascular occlusion, and in adjacent control areas. Furthermore, in areas of vascular occlusion, the material accumulated centrally to occlude the lumen of ghost vessels did not stain with any of the dyes used. A homogenous material, accumulated in the outer retina in areas of vascular occlusion in the retina from diabetic patients, only stained with Alcian blue at pH 5.8 combined with MgCl2 in concentrations less than 0.4 M, suggesting a different molecular composition from the Alcian blue material accumulated in the retinal vascular walls. The findings are in accordance with the knowledge that basement membranes of retinal vessels are thickened in diabetes mellitus. However, the findings also indicate that basement membrane thickening cannot fully account for vascular occlusion in diabetic retinopathy.

Aged↗

Aplasia of the optic nerves.

At birth, a full term baby showed marked cyanosis and respiratory distress, resulting from transposition of the great vessels. In spite of intensive care, and of balloon septostomies, the child died at the age of five days. The right eye was small and had an almost fully opaque cornea, together with other abnormalities of the anterior segment; the left eye was slightly larger, with a clear cornea. Both eyes showed varying degress of retinal dysplasia, and foci of microcystoid change. Macroscopically, and on histological examination of serial sections, the central retinal vessels were completely absent (a focus of neovascularisation in the vitreous of the right eye was apparently of choroidal origin). Furthermore, no optic discs, retinal ganglion cells and nerve fibres could be demonstrated. The optic nerves were missing. The findings are discussed.

Adult↗

Microscopic visualization of the retina by angiography with high-molecular-weight fluorescein-labeled dextrans in the mouse.

Methods currently available for the examination of the retinal vasculature of laboratory animals have significant drawbacks. Fluorescein angiography of rodent eyes is hampered by a poor view of the peripheral retina and difficulty in performing fundus photography. Methods of staining or filling retinal vessels are unreliable, labor-intensive, or have high backgrounds. We have developed a novel technique that is quick, simple, and accurate. Fluorescein-labeled 2 million molecular weight dextrans are used to fill the retinal vasculature of mice in vivo, followed by removal of the retina, fixation in paraformaldehyde, and examination of the vascular pattern in whole mount preparations by fluorescence microscopy. We found that fluorescein and fluorescein-labeled low-molecular-weight dextrans (40,000-500,000) are not suitable as they leak out of the vasculature to stain the entire retina in whole mount preparations. By contrast, fluorescein-labeled 2 million molecular weight dextrans remain in the vasculature for many months without diffusion or decay. Under low magnification, the entire retinal vasculature can be visualized at one time. By focusing from one plane to another, the superficial, connecting, or deep vascular layers are delineated. The background fluorescence is very low. We have successfully used this technique in over 20 mice per day to document retinal angiogenesis in a model of oxygen-induced proliferative retinopathy.

Animals↗

Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor.

The most common cause of new blindness in young patients is retinal neovascularization, and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment, but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study, we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family, along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization.

Administration, Oral↗