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In sickle cell retinopathy vascular involvement is most frequently recognised at the retinal periphery, but obstruction of perimacular arterioles and of major retinal vessels may also occur. This report describes a patient with homozygous sickle cell (SS) disease with recurrent occlusion of major retinal vessels associated with recurring transient impairment of visual function.
The eyes, kidneys and pancreas of mice (SJL/J) infected with encephalomyocarditis virus were examined by light and electron microscopy. Diabetic mice with the longest duration (6 months) of diabetes showed marked renal and ocular alterations. Fasting blood glucose levels were 17.8-21.9 mmol/l and glycosuria was present. Clinically, based on ophthalmoscopy and fluorescein angiography, retinal vessels were normal. Histologically, moderately decreased numbers of pericytes were noted following trypsin digestion. The basement membrane of inner retinal vessels showed significant thickening in diabetic mice. Corneal epithelial oedema was present and surface microvillus projections were decreased compared with control mice. The kidneys of the same animals showed nodular and diffuse glomerulosclerosis and mesangial thickening. Electron microscopy showed excessive accumulation of basement membrane-like material in the mesangium and the peripheral glomerular region. Histologically, moderate to advanced kidney disease was associated with relatively early retinopathy.
Adult rabbit retinal vessels underwent neovascularization in response to tumor implantation within the vitreous body. The neovascular response was presumably elicited by the tumor angiogenesis factor (TAF). The response of adult retinal vessels to an angiogenic stimulus raises the possibility that a similar substance may cause retinal neovascularization in humans, and that in normal conditions the vitreous may be able to suppress angiogenic activity.
The morphologic effects on the retina resulting from chronic lead exposure were assessed in neonatal rats. Newborn rats nursed from dams were given a low (0.115%) or a high (4.5%) concentration of lead in their diet. At day 21 the pups were weaned to the mother's diet. The retinas of the pups were studied by electron microscopy at various ages up to day 60. High and low lead concentrations produced necrosis of photoreceptor cells and cells of the inner nuclear layer. The high lead concentration, in addition, was associated with swelling of endothelial cells of the retinal vessels and narrowing of the lumen. Increased permeability of the retinal vessels and pigment epithelium to horseradish peroxidase was also observed under the high-dose condition. The authors conclude that lead can produce direct neuronal damage and, at high doses, produces retinal vascular lesions and alteration of the blood-retinal barrier.
The onset and progression of diabetic-like retinopathy has been investigated in age-matched male beagle dogs fed a 30% galactose diet. Examination of the intact retinal vessels, isolated by gentle trypsin digestion, reveals that the destruction of pericytes to form pericyte ghosts is the earliest observable retinal vessel change. This results in an irregular distribution of endothelial cell nuclei near pericyte ghosts and the subsequent formation of acellular capillaries containing neither endothelial cells or pericytes. This was followed by the histological appearance of microaneurysms and later, by the funduscopic appearance of intraretinal hemorrhages. Studies in similar galactose-fed dogs treated with aldose reductase inhibitors indicate that all of these changes are linked to the initial aldose reductase associated destruction of pericytes.
Since the retinal vessels have no sympathetic innervation, blood flow in response to raised blood pressure is dependent on autoregulation. To determine the effect of hypertension on retinal haemodynamics and the autoregulatory capacity of the retinal circulation under conditions of normoglycaemia and hyperglycaemia, retinal blood flow was measured before and after raising the systemic blood pressure in ten normal control subjects, ten diabetic subjects with blood glucose < 10 mmol l-1 and ten diabetic subjects with blood glucose > 15 mmol l-1. A controlled rise in systemic blood pressure was achieved using an intravenous infusion of tyramine. Retinal volume flow was determined from red cell velocity using laser Doppler velocimetry and from retinal vessel diameter measurements using digital image analysis of fundus photographs. With a 40% increase in mean arterial blood pressure (MAP), there was a significant increase in retinal blood flow of 32.9 +/- 7.1% in non-diabetic controls. In diabetics at the low blood glucose level, the increase in retinal blood flow was significant at 30% increase in MAP (23.6 +/- 8.7%, P = 0.032) and at 40% increase (49.9 +/- 12.03%, P = 0.004). Diabetics with high blood glucose failed to autoregulate at any of the increased levels of MAP (15% increase, 27.0 +/- 11.1%; 30% increase, 66.9 +/- 19.8%; and 40% increase, 101.9 +/- 21.4%; P < 0.022). The coefficients of autoregulation showed that in non-diabetic controls, retinal vascular autoregulation broke down with increases in MAP of between 30 and 40%. In diabetic subjects, it broke down between 15 and 30% in normoglycaemia and at less than 15% in hyperglycaemia. This study demonstrates an impairment in retinal vascular autoregulation in response to raised systemic blood pressure in diabetic subjects, more so at an elevated blood glucose level, thus providing a mechanism for the detrimental effect of hypertension on diabetic retinopathy.
PURPOSE: To study changes in retinal glial cell components in areas of vascular occlusion secondary to diabetic retinopathy. MATERIAL: The retina from ten eyes of six diabetic patients and from five eyes of five normal controls were studied for immunoreactivity to glial fibrillary acid protein and vimentin (glial cells), S-100 protein (perivascular glial cells), carbonic anhydrase isoenzyme II and CD-57 antigen (Müller cells), and CD-68 antigen (microglia). RESULTS: The study showed increased immunoreactivity to S-100 protein, corresponding to perivascularly located glial cells in the retina from diabetic patients, except for areas of vascular occlusion where this immunoreactivity was absent. Furthermore, the material invading the lumen of former retinal vessels in areas of vascular occlusion showed immunoreactivity to CAH-II and CD-57, suggesting that this material represents ingrowth of retinal Müller cells. CONCLUSIONS: The findings suggest that at least two types of changes in retinal glial cells are involved in the pathophysiology of diabetic retinopathy, i.e. 1) Reactive changes in the perivascular glial cells in the retina, and 2) Müller cell ingrowth into the former lumen of occluded retinal vessels.
AIMS/HYPOTHESIS: The growth of retinal vessels is associated with a number of disease conditions, including diabetic retinopathy and proliferative vitreo-retinopathy. In this study we describe a model of human retinal angiogenesis and show how this may be used to explain the mechanisms that are associated with the growth of new retinal vessels. METHODS: A 4 mm diameter disc of retinal tissue was placed within a fibrin matrix and the appearance was monitored daily by light microscopy. Immunohistochemical techniques were used for the detection of, glial fibrillary acidic protein, CD68, the Ki-67 antigen, vascular endothelial growth factor, monocarboxylate transporter type 1 and von Willebrand's factor. RESULTS: Vessels were evident extending from the periphery of the explant and the activation of endothelial cells was shown by immuno-peroxidase staining of paraffin embedded sections of the explants for the expression of the Ki-67 antigen, a marker of cell proliferation. The expression of glial fibrillary acidic protein and von Willebrand's factor increased with duration in culture and the presence of activated macrophages or microglia or both was shown by positive immunoreactivity for CD68 and Ki-67 and were identified by day 3. The presence of endogenous vascular endothelial growth factor and the activation of monocarboxylate transporter type 1 by vascular endothelial growth factor, showed the involvement of specific growth factors. CONCLUSION/INTERPRETATION: The explant model provides evidence for the involvement of macrophages and glial fibrillary acidic protein activation in human retinal angiogenesis and for the expression of monocarboxylate transporter type 1, which is likely to be important in the use of lactate in the hypoxic retina.
Fifty male rats were made diabetic by a single injection of streptozotocin and were killed at periods varying from 1 to 12 mo. Ten saline-injected rats and three rats treated with 3-O-methylglucose and streptozotocin served as controls. Intraluminal changes in retinal vessels were studied by electron microscopy. In diabetic rats maintained for 9-12 mo, microthrombus formation was observed in the various sized retinal vessels at the histologic and ultrastructural level. The microthrombi were mainly composed of aggregated platelets and fibrin strands. However, there was no definite evidence of detachment or loss of the endothelial cells. This microthrombus formation may play an important role in the development of diabetic retinopathy.
Diabetic retinal microangiopathy is characterized by increased permeability, leukostasis, microthrombosis, and apoptosis of capillary cells, all of which could be caused or compounded by activation of complement. In this study, we observed deposition of C5b-9, the terminal product of complement activation, in the wall of retinal vessels of human eye donors with 9 +/- 3 years of type 2 diabetes, but not in the vessels of age-matched nondiabetic donors. C5b-9 often colocalized with von Willebrand factor in luminal endothelium. C1q and C4, the complement components unique to the classical pathway, were not detected in the diabetic retinas, suggesting that C5b-9 was generated via the alternative pathway, the spontaneous activation of which is regulated by complement inhibitors. The diabetic donors showed a prominent reduction in the retinal levels of CD55 and CD59, the two complement inhibitors linked to the plasma membrane by glycosylphosphatidylinositol anchors, but not in the levels of transmembrane CD46. Similar complement activation in retinal vessels and selective reduction in the levels of retinal CD55 and CD59 were observed in rats with a 10-week duration of streptozotocin-induced diabetes. Thus, diabetes causes defective regulation of complement inhibitors and complement activation that precede most other manifestations of diabetic retinal microangiopathy. These are novel clues for probing how diabetes affects and damages vascular cells.
The Blood-Retinal Barrier (BRB) is a situation of restricted permeability which is present between the blood and the retina. This barrier has a well defined anatomic substrate, particular permeability characteristics and appears to play a role of major importance in the pathophysiology and therapeutics of retinal disease. The BRB phenomenon operates fundamentally at two levels, retinal vessels and chorioepithelial interface, forming which may be better called an inner BRB and an outer BRB. The main structures involved are, for the inner BRB, the endothelial membrane of the retinal vessels, and for the outer BRB, the retinal pigment epithelium. 'Zonulae occludentes' are present in these membranes forming complete belts around the cells, sealing off the spaces between them. Other structures appear to play an accessory role. Both barriers show an apparent predominance of processes of active transport over mechanisms of passive transfer, these being extremely restricted. Much information on the pathophysiology of the BRB mechanism has been obtained from studies of its experimental breakdown. In this way, a breakdown of the inner BRB may be induced by acute distension of the vessel walls, ischaemia, chemical influences, defects in the endothelial cells and failure of the active transport system, whereas experimental ischaemia, mechanical distension of the pigment epithelial membrane, defects in the pigment epithelium and failure of the active transport systems can cause a breakdown of the outer BRB. The increased permeability of the inner BRB, and of the outer BRB, appears to be related to changes in the vascular endothelial membrane and retinal pigment epithelium, respectively. In clinical ophthalmology there are two methods for the diagnosis of breakdown of the BRB, fundus fluorescein angiography and vitreous fluorophotometry. Vitreous fluorophotometry being capable of detecting functional alterations of the barrier before any pathological changes are apparent. There is evidence of an intimate relationship between breakdown of the BRB and almost every retinal disease, particularly the vascular retinopathies and the pigment epitheliopathies. Diabetic retinopathy, hypertensive retinopathy, retinal vein obstruction, blood diseases, trauma or surgery to the eye, temporary arterial obstruction, perivasculitis, Behçet's and Coats' diseases, retinoblastoma, hemangioblastoma and retinal neovascularization are examples of situations where a breakdown of the inner BRB has been demonstrated. On the other hand, examples of breakdown of the outer BRB include situations of choroidal ischaemia, detachment of the pigment epithelium, choroidal neovascularization, photocoagulation, retinal detachment, Koyanagi's disease, central serous choroidopathy, multifocal inner choroiditis and acute placoid pigment epitheliopathy.
PURPOSE: To examine the course of development of vascular disorders in the Royal College of Surgeons (RCS) rat and how these may lead to retinal ganglion cell loss. METHODS: Whole-mount retinae from RCS rats were first stained for neurofilament protein and then for NADPH-diaphorase staining. A separate group of RCS rats was injected with Type II Peroxidase and the retinae were subsequently processed for peroxidase histochemistry. RESULTS: The first changes in the deep vascular plexus occur as the photoreceptor layer is lost and it comes into close proximity to the retinal pigment epithelial (RPE) cell layer. RPE cells migrate onto retinal vessels, and at such locations vascular complex develop. These are first found ventral to the optic nerve head and then gradually progress over most of the retina. The inner retinal vessels that supply the complexes cross the optic nerve fiber layer and appear to be under tension. They ligate axons, which leads to retinal ganglion cell loss. CONCLUSIONS: These observations show vascular changes can have secondary repercussions for neurons distant from the primary lesion.
A vascular abnormality of the retina of a rhesus monkey was studied with fluorescein angiography, microvascular examination after silicone rubber injection, and histological examination. Fluorescein angiography revealed that this abnormality was an arteriovenous shunt. Microvascular examination showed a vascular abnormality on the sclera and an end-to-end communication of the arteriovenous malformation that was a continuation of abnormally large central retinal vessels observed just before their insertion into the optic nerve in the orbit. Histologic examination proved that the arteriovenous shunt originated from the central retinal vessels in the orbit; that degeneration of the retina and the choroid was extensive near the abnormal vessels; that the abnormal vessels had normal endothelium and adventitia but remarkably widened media; and that the cavernous hamangioma-like structure in the optic disk was clearly distinguishable from a cavernous hamangioma.
PURPOSE: To assess hemodynamic changes in two patients with severely affected retinal circulation. METHODS: A 62-year-old man with central retinal artery occlusion and a 46-year-old woman with branch retinal vein occlusion were studied by fluorescein angiography with a scanning laser ophthalmoscope (SLO). Fluorescein angiography with SLO revealed hypofluorescent clumps of different sizes and hyperfluorescent dots in large retinal vessels. The velocities of the hypofluorescent clumps were calculated between two points on the same vessel, and movements of the hypofluorescent clumps and the hyperfluorescent dots were investigated. RESULTS: The velocities of the hypofluorescent clumps were slow and varied in the same vessel. The velocities of the hypofluorescent clumps increased at the sites with narrow calibers. The hypofluorescent clumps occasionally changed size in the bloodstream. The hypofluorescent clumps flowed along the walls of retinal vessels. Distance between consecutive hypofluorescent clumps was wide. Some vessels filled with hypofluorescent clumps were also detected. Rolling hyperfluorescent dots were seen in fluorescent plasma. CONCLUSIONS: The hypofluorescent clumps were concluded to be packed erythrocytes and the hyperfluorescent dots corresponded to leukocytes and platelets moving in the vessels. Fluorescein angiography with SLO is a useful method for evaluating hemodynamic changes using the hypofluorescent clumps in severely affected retinal circulation.
We constructed a new fluorescein fundus angiography system using a speedy and sensitive fundus camera and an argon laser apparatus as the illumination source. The system consists of a fluorescein fundus camera, a high-speed camera, a digital recorder, an argon laser apparatus, and a cathode ray tube(CRT)monitor. The frame speed was 200 frames/s. It was possible to record high speed fluorescein angiography with lower illumination by using an argon laser as the illumination source. This system allowed us to measure the rate of blood flow in the retinal vessels because it easily detected the dye front in the retinal vessels.
The diameter of the large retinal vessels is an important factor in retinal microcirculation. A system configuration was developed that uses SLO images to measure the diameter of retinal branch vessels off-line. The place for measurement is defined in the image by the investigator, and the diameter is measured automatically. The mean standard deviation of the diameter of arterial vessels was 2.37% and for veins 3.43% by repeat measurement in sequential pictures by optimal scanner settings. The reproduction of vessel diameters was unsatisfactorily for repeat examinations. The course of these results may be changes in the fundus image connected with changes in the position of the scanner-bulbus (e.g., new examination, poor fixation). The scanner-bulbus position is not yet precisely defined and not reproducible enough.
27 eyes of 20 premature and full-term infants were subjected to trypsin digestion, and a study was made of the extension of the temporal retinal vessels and of the formation of the radial peripapillary capillaries (RPCs) and the capillary-free zone in the macula. The advancing borders of the temporal retinal vessels exhibited a V-shaped appearance in cases of 23-29 weeks in gestational age. The RPCs were observed in cases after the 27th week of gestation. The capillary-free zone in the macula was observed in cases after the 25th week of gestation. There were two eyes having extremely small and incomplete capillary-free zones: in one eye a vascular network was present in the region corresponding to the center of the macula. It was thought that the vascular network in the temporal horizontal aspect of the macula is formed by anastomosis of the superior and inferior temporal vessels, and that the capillary-free zone in the macula develops secondarily as the result of retraction of the capillaries.
Basic fibroblast growth factor (FGF2) is constitutively expressed in the retina and its expression is increased by a number of insults, but its role in the retina is still uncertain. This study was designed to test the hypothesis that altered expression of FGF2 in the retina affects the development of retinal neovascularization. Mice with targeted disruption of the Fgf2 gene had no detectable expression of FGF2 in the retina by Western blot, but retinal vessels were not different in appearance or total area from wild-type mice. When FGF2-deficient mice were compared with wild-type mice in a murine model of oxygen-induced ischemic retinopathy, they developed the same amount of retinal neovascularization. Transgenic mice with a rhodopsin promoter/Fgf2 gene fusion expressed high levels of FGF2 in retinal photoreceptors but developed no retinal neovascularization or other abnormalities of retinal vessels; in the ischemic retinopathy model, they showed no significant difference in the amount of retinal neovascularization compared with wild-type mice. These data indicate that FGF2 expression is not necessary nor sufficient for the development of retinal neovascularization. This suggests that agents that specifically antagonize FGF2 are not likely to be useful adjuncts in the treatment of retinal neovascularization and therapies designed to increase FGF2 expression are not likely to be complicated by retinal neovascularization.