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The clinical, pathological and genealogical features of Retinal Dysplasia in a family of Yorkshire terrriers were studied. The ocular changes were characterized by retinal detachment and retinal neovascularization. Dogs of three litters and their sire were affected. RD was suspected to be inherited as a recessive trait.
The permeability of the ocular blood vessels to sodium fluorescein (NaFl) was evaluated in neonatal and adult cats by fluorescence microscopy. The iris, ciliary body, and choroidal vessels were markedly permeable, whereas the mature and immature retinal vessels were impermeable. Since there is no apparent barrier to NaFl at the level of the iris vessels, the role of those vessels in aqueous formation is possibly significant. The fact that the immature retinal vessels are impermeable suggests that abnormal permeability to NaFl in retinal neovascularization is a consequence of pathology rather than immaturity.
The anti-angiogenic activity of pigment epithelium-derived factor (PEDF) has recently been discovered on the basis of its inhibition of ischemia-induced retinal neovascularization in an animal model of retinopathy of the premature. Moreover PEDF inhibits the migration and proliferation of various endothelial cells maintained in culture with FGF(2). Since vascular endothelial growth factor (VEGF) is the main angiogenic factor expressed in hypervascularized retinas, we investigated the functions of PEDF on retinal endothelial cells whose angiogenic phenotype is controlled or not by long term exposure to VEGF as observed in human pathologies such as diabetic retinopathy. Here, we observed that PEDF exerts opposite effects on endothelial cells depending on their phenotype. We determined that when PEDF inhibits endothelial cell growth, it inhibits VEGF-induced MAPK activation. However, in endothelial cells cultured with VEGF, PEDF has a synergistic action on cell proliferation with VEGF, and this corresponds to increased MAPK activation.
OBJECTIVE: To determine the safety and efficacy of the artificial silicon retina (ASR) microchip implanted in the subretinal space to treat vision loss from retinitis pigmentosa. METHODS: The ASR microchip is a 2-mm-diameter silicon-based device that contains approximately 5000 microelectrode-tipped microphotodiodes and is powered by incident light. The right eyes of 6 patients with retinitis pigmentosa were implanted with the ASR microchip while the left eyes served as controls. Safety and visual function information was collected. RESULTS: During follow-up that ranged from 6 to 18 months, all ASRs functioned electrically. No patient showed signs of implant rejection, infection, inflammation, erosion, neovascularization, retinal detachment, or migration. Visual function improvements occurred in all patients and included unexpected improvements in retinal areas distant from the implant. MAIN OUTCOME MEASURES: Subjective improvements included improved perception of brightness, contrast, color, movement, shape, resolution, and visual field size. CONCLUSIONS: No significant safety-related adverse effects were observed. The observation of retinal visual improvement in areas far from the implant site suggests a possible generalized neurotrophic-type rescue effect on the damaged retina caused by the presence of the ASR. A larger clinical trial is indicated to further evaluate the safety and efficacy of a subretinally implanted ASR.
A case of vitreous involvement in acute lymphoblastic leukemia associated with neovascularization of the optic nerve head is presented. The diagnosis was made from a vitreous biopsy specimen obtained by pars plana vitrectomy and prepared by a membrane filter and modified Papanicolaou stain technique. Fibrovascular membranes and leukemic cells were seen on microscopic examination of the vitreous biopsy specimen. Retinal neovascularization associated with acute lymphoblastic leukemia is discussed.
Advanced glycation end products (AGEs) are generated during long term diabetes and are correlated with the development of diabetic complications, such as retinopathy. Diabetic retinopathy is characterized by an increased retinal neovascularization due to the action of the angiogenic factor, vascular endothelial growth factor (VEGF). In this report, we show that injection of insulin and glycated albumin (Alb-AGE) to mice increases VEGF mRNA expression in eyes. Insulin and Alb-AGE stimulate VEGF mRNA and protein expression in retinal epithelial cells (ARPE-19). Alb-AGE-induced VEGF expression is not modulated by the use of antioxidants, N-acetyl-l-cysteine or pyrrolidinedithiocarbamate, or by an inhibitor of phosphatidylinositol 3-kinase (PI3K), wortmannin. However, using an inhibitor of ERK activation, U0126, we show that Alb-AGE stimulates VEGF expression through an ERK-dependent pathway. Accordingly, we found that Alb-AGE activated mitogen-activate protein kinase, ERK1/2, JNK1/2, but not p38, and that Alb-AGE did not activate PI3K and PKB. Moreover, Alb-AGE activated the transcription factor, hypoxia inducible factor-1 (HIF-1) DNA binding activity. This activation is mediated by an increase in accumulation of the HIF-1alpha protein through an ERK-dependent pathway. Thus, stimulation of VEGF expression by Alb-AGE, through the activation of HIF-1, could play an important role in the development of diabetic retinopathy.
Recombinant adeno-associated viral (AAV) vectors have become powerful gene delivery tools for the treatment of retinal degeneration in a variety of animal models that mimic corresponding human diseases. AAV vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. In the sheltered environment of the retina, AAV vectors are able to maintain high levels of transgene expression in the retinal pigmented epithelium (RPE), photoreceptors, or ganglion cells for long periods of time after a single treatment. Each cell type can be specifically targeted by choosing the appropriate combination of AAV serotype, promoter, and intraocular injection site. The focus of this review is on examples of AAV-mediated gene therapy in those animal models of inherited retinal degeneration caused by mutations directly affecting the interacting unit formed by photoreceptors and the RPE. In each case discussed, expression of the therapeutic gene resulted in significant recovery of retinal structure and/or visual function. Because of the key role of the vasculature in maintaining a healthy retina, a summary of AAV gene therapy applications in animal models of retinal neovascular diseases is also included.
BACKGROUND: It has been shown that scatter photocoagulation induces regression of retinal neovascularization, but the mechanism for this effect is not completely understood. The main focus of our research is to determine the mechanism for the beneficial effects of photocoagulation. In the present study, we quantified the expression of growth factors and transcription factors that inhibit or induce angiogenesis in photocoagulated human retinal pigment epithelial (RPE) cells in vitro. METHODS: RPE cells were grown to confluence, and RNA was isolated from the RPE cells with or without photocoagulation. The following growth factors, their receptors and transcription factors were examined by reverse transcription polymerase chain reaction (RT-PCR): transforming growth factor (TGF)-beta 1, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor (KDR/flk-1), hypoxia-inducible factor (HIF)-1, ETS-1, nuclear factor kappa B (NF-kappa B), interleukin-8 (IL-8). RESULTS: Laser photocoagulation increased the expression of TGF-beta 1. Expression of angiogenic factors bFGF, VEGF, IL-8 and their transcription factor, ETS1, was also increased. However, the up-regulation of these factors was observed early (6 h) after photocoagulation. Seventy-two hours after photocoagulation, when RPE cells were repaired, the expression of VEGF, IL-8, ETS-1, and NF-kappa B was decreased to the levels before photocoagulation. CONCLUSIONS: These results suggest that TGF-beta produced by photocoagulated RPE cells and the down-regulation of angiogenic factors in repaired RPE cells, in all likelihood, play an important role in the processes that occur after laser photocoagulation.
PURPOSE: To present seven patients who developed retinopathy while receiving high-dose interferon alfa-2b therapy for adjuvant treatment of high-risk melanoma. METHODS: Retrospective case series. RESULTS: Seven patients developed a retinopathy while receiving high-dose interferon alfa-2b therapy for adjuvant treatment of high-risk melanoma. Five patients had normal visual acuity, but retinopathy with cotton- wool spots and/or retinal hemorrhages with the retinopathy resolved after stopping treatment after detection. Two patients developed severe retinopathy with vision loss to counting fingers and hand motions without resolution of the retinopathy. The duration of the maintenance treatment before detection of the retinopathy for all patients ranged from 6 to 26 weeks. The total dose received at time of detection of retinopathy ranged from 816 to 1770 million units. Confounding factors included hypertension, thrombocytopenia, anemia, and a history of prior chemotherapy in one patient. Also, one patient received an investigational ganglioside vaccine, one had a history of radiation treatment to the brain, and six received paroxetine. CONCLUSIONS: Patients receiving interferon alfa-2b are at risk for developing an associated retinopathy. The risk appears to be greater with higher dosage therapy. In addition, severe vision loss can be seen with interferon alfa-2b-associated retinopathy. The effect of treatment with selective serotonin reuptake inhibitors, such as paroxetine, in increasing the incidence of this complication is unknown. Patients need to be monitored until the retinopathy is resolved to screen for sequelae, including retinal neovascularization.
Using panretinal fluorescein angiography, three patterns (A, B, C) of capillary nonperfusion were identified in 308 eyes with proliferative diabetic retinopathy. Statistical analysis showed that there was a significant association with different retinal complications and clinical parameters. Pattern A (83.7%: midperipheral location of capillary nonperfusion) occurs in type I and II diabetes and is associated with early retinal neovascularization and focal macular edema. Pattern B (8.1%: capillary exclusions disseminated on the whole retina) is typical of young type-I diabetics and is complicated by early disc new vessels and ischemic maculopathy. Pattern C (8.1%: capillary nonperfusion confined to the peripheral retina) is observed in type-I diabetic females and associated with multiple, retinal new vessels, without maculopathy. This study also demonstrated that eyes with pattern B retinal ischemia respond less well to laser treatment than eyes with other pattern types. Various pathogenetic factors could lead to these three distinct types of proliferative diabetic retinopathy.
AIMS/BACKGROUND: Association of choroidal neovascularization with pigment epithelial detachment is not an uncommon feature. Since this condition usually has a poor visual outcome, new treatments should be developed. METHODS: We studied the anatomical and visual results of 11 eyes with this association as a manifestation of an Exudative Age Related Macular Degeneration which were treated with diode laser photocoagulation guided by indocyanine green angiography. The average follow up time was 25.5 months (from 12 to 48 months). RESULTS: Complete closure with complete resolution of the exudates and flattening of the detachment was observed in five eyes (45%). Visual acuity in the final examination improved or remained stable in 6 cases (55%). CONCLUSION: These results indicate that diode laser photocoagulation guided by indocyanine green angiography is at least as effective as conventional lasers with shorter wavelengths for treatment of vascularized pigment epithelial detachments in Age Related Macular Degeneration.
BACKGROUND AND OBJECTIVE: To report the incidence and clinical characteristics of retinal breaks and/or rhegmatogenous retinal detachment (RRD) in patients with branch retinal vein occlusion (BRVO). PATIENTS AND METHODS: We reviewed the clinical records of 230 eyes of 214 patients with BRVO and identified eyes with retinal breaks and/or RRD. Patients had at least 6 months of follow-up. RESULTS: Seven of 230 eyes (3%) had retinal breaks and 3 eyes (1.3%) had RRD. One of the eyes with RRD had subclinical retinal detachment. All 7 eyes had ischemic disease documented by fluorescein angiography. Two of 7 eyes had concurrent retinal neovascularization. Four eyes with breaks, but without RRD, and the eye with subclinical RRD were managed by argon green laser. Two eyes with RRD were managed successfully with scleral buckling surgery and postoperative supplemental argon green laser. The mean follow-up period was 14.8 +/- 8.3 months. CONCLUSIONS: Patients with BRVO should be monitored closely for possible retinal break formation and RRD development.
Differences between the rabbit and human retinal circulation, and the use of the rabbit eye in a model of experimental retinal neovascularization, necessitates a complete description of the normal vascular structure in the rabbit and its relationship to adjacent tissue, particularly the glia. The gliovascular relationships in the rabbit were studied by scanning and transmission electron microscopy. Utilizing gas compression of the vitreous to clear the wings of overlying vitreous, the authors were able to make detailed observations of retinal surface by scanning electron microscopy. Glial sheaths surrounding a large number of medium size and smaller vessels were observed. The glial sheaths contained cells which were ultrastructurally similar to Müller cells. No isolated glial tufts were observed in avascular areas. Finally, small, smooth-surfaced cells were found adjacent to many vessels. The exact nature and function of these cells remains unknown.
Retinopathy of prematurity (ROP) is a neovascularizing disease of the retina affecting premature infants. Much of our current knowledge regarding development of both normal and abnormal blood vessels in the retina has been obtained from animal models of retinopathy. The retina is an excellent organ for studying angiogenesis, since the progress of blood vessel growth can be monitored by angiography or fundoscopy. Also, the entire retinal vasculature can be viewed in flat-mounted retinal preparations. Although these animal models were previously used to study the gross aspects of vasculogenesis and angiogenesis, they are increasingly being used to identify the genes and molecular mechanisms involved in these processes. Knowledge gained from these studies can be applied to non-ocular angiogenic conditions. This paper provides historical perspective on the development and use of animal models of retinal neovascular disease since the 1950's and on the key studies that have led to our current understanding about the pathogenesis these conditions.
Long-term follow-up of 135 eyes that had initially-successful vitreous surgery for complications of proliferative diabetic retinopathy indicates that most of these eyes remain visually and anatomically stable and do not develop new retinal neovascularization. The nature and incidence of important complications during the early and later postoperative periods are discussed.
OBJECTIVE: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. METHODS: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsin-elastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. RESULTS: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactose-fed groups. CONCLUSIONS: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization.
Retinal neovascularization and macular edema are central features of diabetic retinopathy, the major cause of blindness in the developed world. Current treatments are limited in their efficacy and are associated with significant adverse effects. Characterization of the molecular and cellular processes involved in vascular growth and permeability has led to the recognition that the angiogenic growth factor and vascular permeability factor vascular endothelial growth factor (VEGF) plays a pivotal role in the retinal microvascular complications of diabetes. Therefore, VEGF represents an exciting target for therapeutic intervention in diabetic retinopathy. This review highlights the current understanding of the mechanisms that regulate VEGF gene expression and mediate its biological effects and how these processes may become altered during diabetes. The cellular and molecular alterations that characterize experimental models of diabetes are considered in relation to the influence of high glucose-mediated oxidative stress on VEGF expression and on the mechanisms of VEGF's actions under hyperglycemic induction. Finally, potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological effects in the diabetic retina are considered.
Three patients with idiopathic central serous chorioretinopathy (ICSC) and bullous retinal detachment (RD) were examined at least 2 years after the onset of the disease in one patient and over 10 years in the other two patients. There were large areas of retinal pigment epithelium (RPE) degeneration in each patient. Interestingly, there was loss of retinal vascular trees in the inferior peripheral retina where the subretinal fluid presumably persisted for a long time. In one patient, there was a retinal neovascularization with sea-fan formation along the border of the vascular loss. To the authors' knowledge, this finding has not been described in the literature.