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PubMedDate not supplied

The story of blindness in premature babies.

Perhaps on such a relaxed evening as this, one might reflect on the problem more freely and recall that all living matter is vulnerable to the injurious effects of oxygen and man is certainly no exception. It is strange indeed that the element upon which our very existence depends, should at the same time be so alien, and withstood only by the antioxidant defence mechanisms our cells have elaborated. We are born into and live in a poisonous atmosphere. Growing retinal vessels die because they have not yet acquired these defences and we all age and die because, it is thought, we lose them. As Gerschman so strikingly expressed it:--"The normal life span can be considered as a survival time for the organism exposed to 0.2 atmospheres of oxygen"--and that is air at sea level.

Animals↗
PubMed1994

Axial intensity distribution analysis of the human retina with a confocal scanning laser tomograph.

We have analysed the change of reflected light intensity along the optical axis or axial intensity distribution in images acquired with a confocal scanning laser tomographic system in human fundus examination. We hypothesized that confocal light detection units used in scanning laser tomographs register light originating from multiple layers within the human macula and that intraretinal structures might also be observable. To test this hypothesis we examined the axial intensity distribution in human maculas of normal volunteers, patients with cystic and other macular abnormalities and in an artificial retina in a plastic eye model. A total of over 140 patients and volunteers were examined. We analysed this distribution in 20 normal healthy volunteer eyes found the origin of the artifacts that cause retinal vessels to appear elevated. We examined four patients with cystic maculas and were able to detect the presence of two structures in axial direction contributing to the axial intensity distribution. A plastic eye model with a cellophane sheet covering a fluid pocket was developed to mimic the appearance of a large macular cyst. The axial intensity distribution analysis showed the presence of two distinct gaussian profiles. The results of this study show that confocal scanning laser tomographic imaging of the human fundus allows extraction of information regarding the axial position of intraretinal layers and that correction for the deeper retinal reflections may allow more precision in imaging of the retinal surface.

Adult↗
PubMed1999

Increased expression of endothelial antigen PAL-E in human diabetic retinopathy correlates with microvascular leakage.

AIMS/HYPOTHESIS: The Pathologische Anatomie Leiden-Endothelium (PAL-E) antigen is a marker for loss of the blood-brain barrier function in brain tumours. It is endothelium specific and is associated with the endothelial plasmalemmal vesicles (caveolae) involved in transcellular transport. To test whether blood-retinal barrier loss in diabetic retinopathy is associated with cellular changes in the endothelium, the expression of antigen PAL-E in relation to microvascular leakage in human diabetic retinopathy was investigated. METHODS: Immunohistochemical staining of frozen tissue sections of postmortem eyes obtained from 30 persons without and 41 persons with diabetes mellitus was carried out with monoclonal antibodies against PAL-E and CD31 and with antibodies against endogenous fibrinogen, albumin and IgG as indicators of vascular leakage. RESULTS: Patchy or uniform microvascular PAL-E staining was observed in the retina of 17 of the 41 eyes of diabetic patients and in 2 of the 30 normal control eyes. In the diabetic eyes, PAL-E staining co-localized with microvascular staining for endogenous fibrinogen, albumin and IgG. Strong staining for PAL-E was observed in sites without blood-tissue barriers, like the choroid. CONCLUSIONS/INTERPRETATION: In microvessels with an intact blood-retina barrier the endothelial antigen PAL-E is absent. Its expression is increased in retinal vessels of patients with diabetic retinopathy and correlates with microvascular leakage of plasma proteins. This phenotypic shift involving an antigen associated with caveolae suggests that dysfunction of the endothelium forms the cellular basis for microvascular leakage in diabetic retinopathy, rather than passive endothelial damage.

Adult↗
PubMed2002

The pathogenesis of diabetic retinopathy: old concepts and new questions.

Hyperglycaemia appears to be a critical factor in the aetiology of diabetic retinopathy and initiates downstream events including: basement membrane thickening, pericyte drop out and retinal capillary non-perfusion. More recently, focus has been directed to the molecular basis of the disease process in diabetic retinopathy. Of particular importance in the development and progression of diabetic retinopathy is the role of growth factors (eg vascular endothelial growth factor, placenta growth factor and pigment epithelium-derived factor) together with specific receptors and obligate components of the signal transduction pathway needed to support them. Despite these advances there are still a number of important questions that remain to be answered before we can confidently target pathological signals. How does hyperglycaemia regulate retinal vessels? Which growth factors are most important and at what stage of retinopathy do they operate? What is the preferred point in the growth factor signalling cascade for therapeutic intervention? Answers to these questions will provide the basis for new therapeutic interventions in a debilitating ocular condition.

Diabetes Mellitus↗
PubMed2006

An igf-I gene polymorphism modifies the risk of diabetic retinopathy.

The role of IGF-I in the pathogenesis of diabetic retinopathy is unclear. We studied, prospectively, the relationship between an IGF-I gene polymorphism, retinal vessel diameters, and incident diabetic retinopathy in subjects with impaired glucose tolerance (IGT) or type 2 diabetes. In all 5,505 participants of the population-based Rotterdam Study (775 with IGT, 394 with type 2 diabetes, and 4,336 control subjects), fundus color transparencies were taken at baseline (between 1990 and 1993) and at follow-up (from 1997 to 1999). The wild-type genotype (i.e., carriers of the 192- or 194-bp alleles) was present in 72.7% of the participants, while 27.3% were variant carriers. Variant carriers with IGT or type 2 diabetes appeared to have larger retinal arteriolar and venular diameters at baseline than individuals with the wild-type genotype, but these differences did not reach statistical significance. This trend was especially observed in subjects who developed retinopathy at follow-up. In variant carriers with IGT/diabetes, an increase (odds ratio 1.8 [95% CI 1.0-3.2]; P = 0.04) in the risk of retinopathy was observed compared with participants with the wild-type genotype. In conclusion, our findings suggest that this IGF-I gene polymorphism is associated with an increased risk of diabetic retinopathy.

Aged↗
PubMed1985

Lipaemia retinalis in a 29-day-old infant with type 1 hyperlipoproteinaemia.

A 29-day-old infant born of consanguineous parents had type 1 hyperlipoproteinaemia associated with lipaemia retinalis. Biochemical analyses disclosed hypertriglyceridaemia, hyperchylomicronaemia, and lipoprotein lipase deficiency. Ophthalmoscopically all retinal vessels had the creamy appearance of lipaemia retinalis. The plasma lipoprotein levels and fundus condition became normal after her ingestion of fat was limited. To our knowledge this is the youngest patient reported with type 1 hyperlipoproteinaemia associated with lipaemia retinalis.

Dietary Fats↗
PubMed1979

[Ocular signs in cases of down's syndrome (author's transl)].

420 mongoloid children aged between one month and 14 years were examined in a special ophthalmology department for disabled children employing biomicroscopy, retinoscopy under atropine and, if possible, visual acuity testing. Epicanthal folds were present in 46%, mongoloid slanting of the lids in 72% of cases. A decrease in binocular vision was present in 40% of the children. Brushfield's spots were encountered in 86% of the patients in a circular arrangement, whilst in 7% only the temporal half of the iris was involved. Lens changes of a variable degree were present in altogether 55% of cases and an increase in the number of retinal vessels, as well as their radial arrangement, as described by Williams, were documented in 46% of the cases. A comparison of the incidence and degree of refractive anomalies in mongoloid and normal children was undertaken. The present findings are discussed and compared with the results of other investigators.

Adolescent↗
PubMed1998

Cilostazol, a selective cAMP phosphodiesterase inhibitor, dilates retinal arterioles and increases retinal and choroidal blood flow in rats.

The effects of cilostazol, a selective cyclic AMP (cAMP) phosphodiesterase inhibitor, on retinal and choroidal blood flow and retinal arteriole diameter were examined in anesthetized rats. The retinal and choroidal blood flow was measured using laser Doppler flowmetry, and the diameter of the retinal arterioles was measured using digital video microscopy. Cilostazol was administered by two routes; systemically via the intravenous route, and directly into the retinal vessels via the intra-arterial route. When administered intravenously, 1 mg/kg of cilostazol produced a biphasic blood flow response, composed of an initial decrease which was dependent on a depressor response of mean arterial pressure, and a subsequent slight but significant increase which was independent of changes in mean arterial pressure. When administered intra-arterially over a 2-min period, 40-55 and 400-440 microg of cilostazol both produced an increase in the blood flow in a dose-dependent manner, while a depressor effect was observed only at the dose of 400-440 microg. The diameter of the retinal arterioles was increased after the intra-arterial injection of cilostazol (400 microg). It is concluded that intra-arterially administered cilostazol induces vasodilation of the retinal arterioles of rats, which results in an increase in blood supply to the retina, independent of changes in mean arterial pressure.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Immunohistochemical detection of blood-retinal barrier breakdown in streptozotocin-diabetic rats.

Immunohistochemical staining for albumin (69 kDa) and fibrinogen (340 kDa), as markers of blood-retinal barrier (BRB) breakdown of the retinas of streptozotocin-treated diabetic rats, was performed. The number of rats with BRB breakdown was three of nine at 6 months, four of seven at 12 months, and three of three at 18 months. Extravasation of albumin from the retinal vessels was detected in the retinas of rats maintained for 6, 12, and 18 months, while extravasation of fibrinogen was detected only in the retinas of rats maintained for 18 months. These findings suggested that the duration of diabetes has an influence on BRB breakdown and that each substance in the blood starts to permeate the vascular wall individually.

Animals↗
PubMed2005

Electrophysiological changes in lipaemia retinalis.

PURPOSE: To report the electrophysiologic findings in a patient with lipaemia retinalis. DESIGN: Observational case report. METHODS: An 11-year-old girl with diabetes had hyperlipidemia and presented for ophthalmologic consultation. Fundus examinations revealed milky discoloration of retinal vessels in both eyes. Laboratory testing disclosed hyperglycemia and markedly elevated level of triglycerides and cholesterol. Although the visual acuity was not affected, the electroretinograms showed decrease amplitudes of a- and b-wave in both cone and rod responses. RESULTS: After correction of blood sugar and lipids with insulin and diet control, the lipaemia retinalis resolved, and the impaired ERG response reversed within 1 week. CONCLUSIONS: Lipaemia retinalis usually resolves rapidly without visual impairment after correction of hyperlipidemia. The reversible deficits of electroretinogram response in lipaemia retinalis are reported for the first time. High level of triglycerides or cholesterol or both may impair retinal function. The mechanism of an impaired electroretinogram remained speculative.

Blood Glucose↗
PubMed1988

Topographical specificity in isolated retinal capillary basement membranes: a high-resolution scanning electron microscope analysis.

Numerous investigations have demonstrated that basement membranes (BMs) are composed of type IV collagen, laminin, heparan sulfate proteoglycan, nidogen, and possibly fibronectin. The precise proportion and supramolecular organization of these molecules within BMs is unclear, but is believed to be tissue-specific. In an effort to provide morphological evidence for BM specificity, we studied isolated bovine retinal capillary BMs by high-resolution SEM. Cryofractured specimens demonstrated that surfaces of BM leaflets and pericytic matrix (PCM) within the retinal capillary BM complex are composed of 20- to 100-nm granules and beaded fibrils arranged in patterns which are specific for each cell type. Subendothelial BMs and the subjacent PCM are composed of 20- to 30-nm granules loosely arranged and marked by numerous pits, features that are consistent with their TEM morphology and known susceptibility to proteolytic attack. These BMs also frequently exhibit large openings or fenestrations. These compare favorably with their fragmented image by TEM and probably represent BM discontinuities necessary for direct contact of pericytes and endothelial cells. Muller cell BMs are also composed of granules though they are much larger (40-100 nm) and more densely packed then those of subendothelial BMs. Moreover, they frequently contain interstitial collagen fibrils which could account for the tube-like structural rigidity exhibited by acellular retinal vessel BMs in SEM views. Data in the current study provide morphological evidence for direct contact of pericytes and endothelial cells in vivo and support the view that tissue specificity of BMs may be more exquisite than previously believed, extending even to surface topography of BM leaflets within capillary BM complexes.

Animals↗
PubMed2002

Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent ischemia-upregulated angiogenic protein that has been implicated in diabetic retinopathy. Intravitreal VEGF injections have not previously been shown to produce preretinal neovascularization. The purpose of this study was to further characterize the angiopathic changes that occur after intravitreal injections in a nonhuman primate and determine if preretinal neovascularization develops. DESIGN: Experimental animal study. METHODS: Vascular endothelial growth factor 165 was injected into the eyes of normal cynomolgus monkeys at regular intervals. As a control, normal eyes were injected with phosphate buffered saline. Color photography and fluorescein angiography were performed at regular intervals. The retinas were incubated for adenosine diphosphatase (ADPase) activity to visualize retinal vessels. The retinas were flat-embedded and areas of potential preretinal neovascularization were identified en bloc and serially sectioned. RESULTS: Areas of capillary nonperfusion and vessel dilation and tortuousity were seen by angiography. In serial sections, the nonperfused areas were found to be associated with endothelial cell hyperplasia in vessel lumens. Preretinal neovascularization originating only from superficial veins and venules was observed throughout peripheral retina, but was not seen in the posterior pole. Lacunae-like veins were subdivided by the process of intussusception and endothelial cell bridging. Arterioles demonstrated endothelial cell hyperplasia and microaneurysms. CONCLUSION: Intraocular injections of VEGF were sufficient to produce preretinal neovascularization in the nonhuman primate. Most vasculopathic structures were associated with endothelial cell hyperplasia. These results demonstrate that VEGF alone can produce many features of both nonproliferative and proliferative diabetic retinopathy including the previously undescribed development of preretinal neovascularization. This well-characterized VEGF-induced primate model of retinal neovascularization may be useful as a means of testing new treatments for retinal neovascularization.

Animals↗
PubMed1999

Models for the description of angioscotomas.

To describe small scotomas in visual field examinations several statistical models are proposed and applied to the evaluation of angioscotoma in 13 ophthalmologically normal subjects. A special perimetric grid is used where thresholds can be estimated along a line of narrow-spaced test points which crosses the predicted location of the retinal vessel. A two-stage analysis employs single estimations to fit a threshold curve by means of a special parametric description of the luminance difference sensitivity threshold as a function of stimulus position. An alternative model incorporates the threshold as a function of position into the probabilistic description of the binary response (stimulus seen/not seen).

Adult↗
PubMed2004

Mouse model of post-surgical breakdown of the blood-retinal barrier.

PURPOSE: Post-surgical macular edema is an important clinical problem resulting from breakdown of the blood-retinal barrier (BRB) after surgery. This study was designed to develop a mouse model of post-surgical BRB breakdown. METHODS: Two 25-gauge needles, one for infusion and one for aspiration, were inserted through the limbus and into the lens of one eye of adult male C57BL/6 mice. The anterior portion of the lens was aspirated and the fellow eye was untreated. At several time points after surgery, the integrity of the BRB was assessed quantitatively, using [3H]mannitol as a tracer, or qualitatively, using immunohistochemical staining for albumin. RESULTS: Eyes with partial lens extraction had a significant increase in retinal vascular leakage one day after surgery, which persisted two and three days after surgery, but by five days, was not significantly different from controls. Immunohistochemical staining for albumin demonstrated that the breech in the barrier was sufficient to allow passage of a 60kDa protein into the retina, and was localized predominantly to retinal vessels. CONCLUSIONS: Partial lens extraction in mice results in BRB breakdown (primarily the inner BRB) that is highly reproducible in the severity of leakage and its time course. This provides a valuable tool for investigation of the molecular pathogenesis and new treatment approaches for post-surgical breakdown of the BRB.

Animals↗
PubMed1992

Ultrastructural pathology of experimental autoimmune uveitis. Quantitative evidence of activation and possible high endothelial venule-like changes in retinal vascular endothelium.

BACKGROUND: Experimental autoimmune uveitis (EAU) is a highly organ-specific autoimmune disease in which the target is the retinal photoreceptors. It is well recognized as a model of uveoretinitis in humans. The mechanisms that control the homing of sensitized lymphocytes and other leukocytes to the retina is unknown. The aim of this study was to investigate changes in the retinal vasculature that may be involved with aiding leukocyte-endothelial cell interactions and subsequent extravasation of leukocytes into the retina. EXPERIMENTAL DESIGN: Lewis rats immunized with S-antigen were used to produce EAU. The retinal vasculature was assessed by morphologic (light and electron microscopy) and morphometric techniques at various stages in the generation and course of the disease (days 3, 7, 11, 14, 21, 28 and 49 postimmunization) for evidence of endothelial cell (EC) activation and leukocyte-EC interaction. Image analysis of the retinal vessels at the electron microscopic level was performed to detect alterations in the thickness and irregularity of the EC surface, both considered to be important in lymphocyte homing in the high endothelial venules (HEVs) of lymphoid tissues. Control values were obtained from normal eyes, pertussis-only treated animals, and normal lymph node HEVs. RESULTS: The clinical and histopathologic changes in the eyes were consistent with previous descriptions of EAU and included perivasculitis, focal mononuclear infiltrate in the outer retina, and choroid with destruction of the photoreceptor outer segments and eventually loss of large portions of the outer retina. During the course of EAU, a significant proportion of retinal venules underwent both qualitative and quantitative morphologic changes including EC activation evident as increased cytoplasmic organelles, a 230% average increase in mean EC thickness, and a concomitant 4-fold increase in irregularity of the EC, that produced plump irregular EC with deep intercellular clefts. These alterations were maximal at day 21, however from day 11 onward, large numbers of lymphocytes and monocytes were observed adhering to or lodged in the clefts of plump EC, migrating through the EC cytoplasm, or lying beneath the EC. CONCLUSIONS: The characteristics acquired by the retinal venules during EAU are reminiscent of HEVs. This study suggests that tissue-specific changes in the endothelial cells of retinal venules may be responsible for the homing of S-antigen specific autoreactive lymphocytes to the target organ in this model of retinal autoimmunity.

Animals↗
PubMed1982

Effects of changes in arterial Po2 and Pco2 on the electroretinogram in the cat.

Changes in components of the electroretinogram during hyperoxia, hypoxia, and hypercapnia were studied to demonstrate retinal vascular autoregulation by electrophysiologic means. Autoregulation of the retinal arterial network is shown to stabilized the b-wave during hyperoxia (arterial PO2 of 395 mm Hg). During marked hypoxia, under ventilation with 10% and 5% O2, the b-wave decreased, indicating failure of autoregulation at the corresponding arterial PO2 levels of 30 and 26 mm Hg. During hypercapnia, possible autoregulatory effects were counteracted by a low arterial pH, which decreased the b-wave amplitude. The findings provide new electrophysiologic evidence for autoregulation of the retinal vessels. The c-wave during changes in arterial PO2 and PCO2 underwent changes that correlate inversely with fluctuations in blood pressure that occurred during ventilation with test gas mixtures. Considering the linear relationship between blood pressure and choroidal flow, we suggest that the latter influences the amplitude of the c-wave.

Animals↗
PubMedDate not supplied

[Fundus-oriented perimetry. Evaluation of a new visual field examination method for detecting angioscotoma].

BACKGROUND: Conventional automated perimeters usually work with a given set of grids and thus are normally not adapted to individual conditions. This fact restricts efficiency of this method not only for any single examination but also for follow-up studies. MATERIALS AND METHODS: A new method (patent pending) is introduced which superimposes an individual perimetric grid--corrected in respect to orientation, position and size--onto a patient's fundus image. A recently developed software realizes this procedure in a comfortable manner: the digitized fundus image is loaded into the computer by e.g. photo-CD or disc, depicted on a control monitor and mirrored if necessary. Assuming a central fixation, the foveola is translationally shifted to the center of the perimetric grid by the help of a crosshair. The blind spot which has been previously determined with kinetic perimetry is then superimposed onto the optic disc of the fundus image using a rotation and zoom function. In this way, it is possible to adapt the perimetric grid directly to the underlying individual fundus findings: thus, stimuli can be spatially concentrated or more frequently tested in special regions of interest. Additionally, test points can be dragged away from delicate positions to avoid artifacts. Examinations were carried out on a high resolution colour VDU of the Tübingen Electronic Campimeter (TCC). Alternatively, suited bowl perimeters can be used. RESULTS: In order to test the precision of the superimposing procedure, fundus oriented perimetry was performed to detect angioscotomata in 13 ophthalmologically normal subjects. Using dark stimuli (12'), visual field defects in the expected region, caused by retinal vessels, could be detected in 7 cases (= 54%). The resulting attenuation of differential light sensitivity in this circumscribed region was up to 12 dB. CONCLUSIONS: By means of a morphologically adapted, individual arrangement of stimulus locations fundus-oriented perimetry enables detection of even minute (angio-) scotomata.

Adult↗
PubMed1975

Effect of calcium bodesilate (doxium) on circulatory disorders of the retina with special emphasis on diabetic retinopathy.

The authors examined the effect of calcium dobesilate (Doxium ¿) on 85 subjects with diabetic retinopathy, occlusion of the central vein of the retina and other retinopathies of vascular origin. Capillary resistance measured on the skin and conjunctiva showed, as compared with 100 healthy subjects, a significant decrease. The efficacy of long-term treatment with Doxium was highly significant in restoring CR to normal. Visual acuity improved in 45.8% of simple DR cases, and became stabilized in 27.5% of cases with malignant DR. Hyperpermeability of retinal vessels decreased in 60% of simple DR cases. It is pointed out that glaucoma did not develop in cases of venous occlusion and the diagnostic value of capillary resistance measurement in diabetes. As a highly effective vasoprotective drug, Doxium¿ is the treatment of choice in all retinopathies of vascular etiology.

Adolescent↗