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PubMed2004

Posterior segment manifestations of Rickettsia conorii infection.

PURPOSE: To characterize and analyze the posterior segment manifestations of Mediterranean spotted fever (MSF), an infectious disease caused by Rickettsia conorii. DESIGN: Prospective, noncomparative case series. PARTICIPANTS: Thirty patients (60 eyes) with serologically proven MSF at the acute stage. METHODS: Patients underwent complete ophthalmic examination, including dilated biomicroscopic fundus examination, fundus photography, and fluorescein angiography. Sequential follow-up examinations were performed in patients with evidence of posterior segment involvement. RESULTS: Of 30 patients, 25 (83.3%) had unilateral (n = 5) or bilateral (n = 20) posterior segment involvement related to MSF. Of those 25 patients, 16 (64%) had no ocular symptoms, and 9 (36%) had ocular complaints. Findings included mild vitreous inflammation (45 eyes [75%]), white retinal lesions (18 eyes [30%]), focal vascular sheathing (5 eyes [8.3%]), multiple arterial plaques (1 eye [1.7%]), intraretinal hemorrhages (14 eyes [23.3%]), white-centered retinal hemorrhages (2 eyes [3.3%]), subretinal hemorrhages (2 eyes [3.3%]), serous retinal detachment (3 eyes [5%]), macular star (2 eyes [3.3%]), cystoid macular edema (1 eye [1.7%]), optic disc edema (1 eye [1.7%]), branch retinal artery occlusion (1 eye [1.7%]), optic disc staining (30 eyes [50%]), retinal vascular leakage (27 eyes [45%]), delayed filling in a branch retinal vein (1 eye [1.7%]), and multiple hypofluorescent choroidal dots (10 eyes [16.7%]). One eye (1.7%) had retinal neovascularization at the 6-month follow-up examination. All posterior segment findings at the acute stage resolved in 3 to 10 weeks, and the final visual acuity was 20/20 in 42 of 45 affected eyes (93.3%). Retinal pigment epithelium changes developed in 9 eyes (15%), with resolved full-thickness white retinal lesions. No other abnormalities were noted in the eye with retinal neovascularization over a further follow-up of 6 months. CONCLUSION: Posterior segment involvement, frequently asymptomatic, is common in patients with acute MSF. Because the diagnosis can be easily overlooked, a careful dilated funduscopic examination, complemented by fluorescein angiography in selected cases, is recommended. Mild vitritis, retinal vasculitis, optic disc staining, white retinal lesions, retinal hemorrhages, and multiple hypofluorescent choroidal dots are the most common manifestations of MSF. Posterior segment changes in a patient with fever and/or skin rash living in or returning from a specific endemic area, especially during the spring or summer, strongly suggest R. conorii infection.

Adolescent↗
PubMed1998

Retinal arteriovenous malformation with fluctuating vision and ischemic central retinal vein occlusion and its sequelae: 25-year follow-up of a case.

A patient with a retinal arteriovenous malformation (AVM) had experienced episodic visual loss with spontaneous recovery for many years, followed by permanent visual loss secondary to central retinal vein occlusion. She subsequently progressed to development of retinal neovascularization extending onto the posterior vitreous face with recurrent vitreous hemorrhage requiring vitrectomy. A brief review of the literature is presented, and the cause of the fluctuations in vision and central retinal vein occlusion are discussed.

Adult↗
PubMed2006

Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration.

Oxidative stress has long been linked to the pathogenesis of neurodegenerative diseases; however, whether it is a cause or merely a consequence of the degenerative process is still unknown. We show that mice deficient in Cu, Zn-superoxide dismutase (SOD1) have features typical of age-related macular degeneration in humans. Investigations of senescent Sod1(-/-) mice of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young Sod1(-/-) mice to excess light induced drusen. The retinal pigment epithelial cells of Sod1(-/-) mice showed oxidative damage, and their beta-catenin-mediated cellular integrity was disrupted, suggesting that oxidative stress may affect the junctional proteins necessary for the barrier integrity of the retinal pigment epithelium. These observations strongly suggest that oxidative stress may play a causative role in age-related retinal degeneration, and our findings provide evidence for the free radical theory of aging. In addition, these results demonstrate that the Sod1(-/-) mouse is a valuable animal model to study human age-related macular degeneration.

Animals↗
PubMed1989

Optic disc neovascularization in dominant exudative vitreoretinopathy.

Dominant exudative vitreoretinopathy (DEVR) is inherited retinal vascular disorder which is characterized by peripheral retinal neovascularization, tractional retinal detachment, subretinal, exudation, and vitreous fibrosis. A milder form of involvement characterized by capillary nonperfusion and straightening of the retinal vessels may be present in asymptomatic individuals. We describe a 15-year-old patient who presented with optic disc neovascularization, a finding not previously reported in association with DEVR. Angiographic evidence of DEVR in successive generations confirmed the diagnosis. The findings in mild and advanced DEVR are reviewed, and the pathogenesis of the capillary nonperfusion is discussed.

Adolescent↗
PubMedDate not supplied

A morphologic study of intravitreal membranes associated with intraocular hemorrhage in the dog.

Abstract We aimed to characterize intravitreal membranes in dogs and determine, if possible, associated predisposing conditions. Five globes in which intravitreal membranes were identified were evaluated. These originated from four Labrador Retrievers or Labrador-cross dogs and a Springer Spaniel. The ages of the dogs ranged from 4 to 11 years. Standard histology and immunohistochemical procedures for factor VIII-related antigen, smooth muscle actin (SMA), vimentin and glial fibrillary acidic protein (GFAP) were performed. Intravitreal membranes varied from loosely to highly organized. The extent of organization corresponded with increasing immunoreactivity for vimentin and GFAP, indicating their predominantly glial origin. They were never immunopositive for smooth muscle actin, nor were they vascularized. In all cases, they were associated with intravitreal hemorrhage. Additional common findings included epiretinal membranes, retinal neovascularization, preiridal fibrovascular membranes and glaucoma. Intravitreal membranes may be a sequelae of intravitreal hemorrhage. This in turn, may arise from new vessels associated with epiretinal or preiridial membranes, or hemorrhage associated with optic disc cupping or retinal neovascularization. All of these phenomena may accompany glaucoma.

Animals↗
PubMed2002

Side effects after radiotherapy of age-related macular degeneration with the Nijmegen technique.

BACKGROUND: In a randomized trial concerning radiotherapy for age-related macular degeneration, fluorescein angiograms were taken of controls and patients. In this study the frequency of side effects in eyes receiving radiotherapy with the Nijmegen technique is compared with the findings in the eyes of controls. METHODS: Patients receiving treatment were irradiated by two isocentric photon beams in four fractions of 6 Gy that were directed to the macular area at 30 degrees and -30 degrees with regard to the optical axis. The most recent fluorescein angiograms of the randomized eyes (32 treated and 31 control eyes) were scored by two independent researchers, using a scoring form with nine features of radiation retinopathy: nonperfusion, macular edema, microaneurysms, retinal hemorrhages, cotton-wool spots, perifoveal telangiectasis, vascular sheathing, retinal neovascularization, and radiation-associated choroidal neovasculopathy. The results were graded as: no retinopathy (grade 0), mild retinopathy (grade 1), moderate retinopathy (grade 2), and severe retinopathy (grade 3). RESULTS: In the treated group 6 patients (18.8%) were grade 1, 10 patients (31.2%) were grade 2 and 7 patients (21.9%) were grade 3. In the control group 9 patients (29.0%) were grade 1, 11 patients (35.5%)were grade 2 and 2 patients (6.5%) were grade 3. There were no patients with retinal neovascularization. CONCLUSION: With the Nijmegen technique a relatively high dose of radiation can be applied to a small retinal area. In only a minority of cases does some evidence of radiation retinopathy occur.

Aged↗
PubMed2000

Retinal vasculitis occurring with common variable immunodeficiency syndrome.

PURPOSE: To report severe retinal vasculitis causing decreased vision in three patients with the common variable immunodeficiency syndrome. METHOD: Case report. Three patients with common variable immunodeficiency syndrome developed decreased vision secondary to retinal vasculitis. Fluorescein angiography was performed in all three patients. Peribulbar injections were given in one patient, and two patients were treated with oral steroids and cyclosporin. RESULTS: All three patients were young and had classic common variable immunodeficiency syndrome. Bilateral retinal vasculitis and diffuse retinal edema were present in all three patients, and two patients had retinal neovascularization in the absence of ischemia. No evidence of intraocular infection was present, and none was detected systematically. Visual acuity decreased in five of the six eyes and was responsive to treatment in only one patient (both eyes). CONCLUSION: Retinal vasculitis may be another autoimmune manifestation of common variable immunodeficiency syndrome.

Capillary Permeability↗
PubMed2003

VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier.

Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF-TRAP(R1R2), in models for these disease processes. VEGF-TRAP(R1R2) is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF-TRAP(R1R2) strongly suppressed choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane. Subcutaneous injection of VEGF-TRAP(R1R2) also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF-induced breakdown of the blood-retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF-TRAP(R1R2) significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF-TRAP(R1R2) may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema.

Animals↗
PubMed2005

Inhibition of retinal and choroidal neovascularization by a novel KDR kinase inhibitor.

PURPOSE: Inhibition of vascular endothelial growth factor (VEGF) signaling has shown great promise for the treatment of ocular neovascular disease. Current anti-VEGF therapies in late-stage development, while efficacious, require dosing by frequent intravitreal injections that are inconvenient to patients. VEGF signaling inhibitors that demonstrate more convenient dosing regimens could lead to the improved treatment of neovascular diseases such as wet age related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). Here we describe the assessment of a KDR (VEGFR2) kinase inhibitor in two well-established models of ocular neovascularization following oral administration. METHODS: A novel KDR kinase inhibitor was dosed by oral gavage for 12 days at 0, 10, 30, or 100 mg/kg in an adult male Brown Norway rat laser induced choroidal neovascularization (CNV) model. The areas of CNV lesions were quantitated by fluorescence image analysis of FITC-dextran perfused animals. The kinase inhibitor was also assessed in a rat oxygen induced retinopathy (OIR) model in which neonatal rats were placed in an oxygen chamber that delivered alternating 24 h cycles of 50% and 10% oxygen for 14 days. After 14 days of oxygen treatment, the animals were returned to room air and dosed orally for 7 days with 0, 10, or 30 mg/kg kinase inhibitor. The extent of retinal neovascularization was assessed by counting pre-retinal neovascular nuclei on histological sections. RESULTS: At doses of 100 mg/kg, the KDR kinase inhibitor resulted in a 98% reduction in lesion size in the rat CNV model. 30 mg/kg doses of the inhibitor showed a 70% and 80% reduction in lesion size in the laser CNV and OIR models, respectively. CONCLUSIONS: Oral dosing of the described KDR kinase inhibitor effectively inhibits neovascularization in two well-established animal models of ocular neovascularization. These data suggest that compounds of this class may prove to be useful for the treatment of a variety of ocular neovascular diseases using a convenient oral dosing regimen.

Administration, Oral↗
PubMed1990

Macroaneurysms associated with retinal branch vein occlusion.

We reviewed the clinical findings, color photographs, and fluorescein angiograms of 147 patients (154 involved eyes) who participated in the Branch Vein Occlusion Study through the Bascom Palmer Eye Institute for the presence of macroaneurysms within or adjacent to the zone of branch vein occlusion. Four distinct categories of macroaneurysms included arterial, venous, capillary, and collateral-associated types. We identified 59 lesions among 25 of the 154 (16.2%) affected eyes. Intraretinal lipid exudation and hemorrhage were commonly observed around the lesions, but these complications usually did not affect visual acuity. Macroaneurysms were associated with capillary nonperfusion on fluorescein angiography. Retinal neovascularization occurred in eight of 25 eyes (32%) with macroaneurysms.

Aged↗
PubMed2000

Quantitative MR imaging study of intravitreal sustained release of VEGF in rabbits.

PURPOSE: To determine whether sustained elevation of vascular endothelial growth factor (VEGF) in the vitreous cavity causes retinal hyperpermeability [blood-retinal barrier (BRB) breakdown] before the development of retinal neovascularization (NV) and to document the kinetics of the integrity of BRB breakdown versus time. METHODS: Poly(L-lactide-co-glycolide)based devices loaded with VEGF were implanted intravitreally in rabbit eyes. Contrast-enhanced magnetic resonance imaging (MRI) methods were used to identify and quantitate the retinal permeability at various time points after implantation. This was done with the newly developed MR tracer AngioMARK (Epix Medical, Boston, MA). After the MRI measurements, fundus photography and fluorescein angiography (FA) also were performed on the same set of animals. RESULTS: At 3 days after implantation, the MR images showed a significant retinal leakage into the vitreous cavity (BRB breakdown) of the VEGF-implanted eyes. To quantitate this leakage, the permeability surface area product (PS) was measured. At 3 days, the mean PS product was 1.25 +/-0.25 x 10(-5) cm3/min. Based on the VEGF in vitro release study, this 3-day BRB breakdown corresponded to a total sustained release of 7.42 +/- 0.54 microg/ml of VEGF. The fundus and FA photographs of these VEGF-implanted eyes taken at 4 days after implantation also showed a considerable level of retinal vascular dilation and tortuosity. By 12 days after implantation, the mean PS product decreased to 5.83 +/- 1.38 x 10(-6) cm3/min. However, the retinal NV was observed only after the second week after implantation. By this time, a total of 10.70 +/- 0.92 microg/ml of VEGF was released in a sustained fashion. Also, after the retinal NV development, retinal detachment also was observed. The control eyes, however, which were implanted with blank devices, remained unchanged and normal during the entire course of this study (PS = 5.57 +/- 0.66 x 10(-7) cm3/min). CONCLUSIONS. The findings indicate that sustained delivery of elevated amounts of VEGF in the vitreous cavity induces a BRB breakdown even earlier than 3 days after implantation. This was achieved after a total sustained release of 7.42 +/- 0.54 microg/ml of VEGF. This retinal leakage regressed by more than half by the time the retinal NV developed. Furthermore, a retinal detachment occurred after this retinal NV. These results are similar to proliferative diabetic retinopathy (PDR). The sustained elevation of VEGF in the vitreous cavity of rabbit eyes is potentially a good model to test VEGF antagonists to treat or prevent PDR in humans. The quantifiable change of BRB breakdown by the contrast-enhanced MRI method is ideal to assess the therapeutic intervention in vivo without killing the animal and may prove to be clinically useful in humans.

Animals↗
PubMed1998

Upregulation of the vascular endothelial growth factor/vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat.

Vascular endothelial growth factor (VEGF) is a major contributor to retinal neovascularization. The possible participation of VEGF and its high-affinity tyrosine kinase receptors, flk-1 and flt-1, in early background diabetic retinopathy was studied in the streptozotocin-induced diabetic rat model of experimental retinopathy using in situ hybridization, blotting techniques, and immunohistochemistry. Diabetic retinopathy was assessed by quantitative morphometry of retinal digest preparations. The number of acellular capillaries increased 2.7-fold in diabetic animals with diabetes' duration of 6 months compared with nondiabetic controls. VEGF expression was not detectable by in situ hybridization in nondiabetic rats but was highly increased in the ganglion cell layer and in the inner and outer nuclear layers of retinas from diabetic animals. VEGF protein was extractable only from diabetic retinas, and a strong immunolabeling was detected in vascular and perivascular structures. Increased flk-1 and flt-1 mRNA levels were also found in the ganglion cell and both nuclear layers of diabetic samples only. Dot blot and Western blot analyses confirmed the increase in flk-1 mRNA and protein in diabetic retinas. Also, flk-1 immunoreactivity was associated with vascular and nonvascular structures of the inner retinas from diabetic animals. These data obtained from a rodent model in which retinal neovascularization does not occur support the concept that the VEGF/VEGF receptor system is upregulated in early diabetic retinopathy.

Animals↗
PubMed2003

Spatial pattern and temporal evolution of retinal oxygenation response in oxygen-induced retinopathy.

PURPOSE: To determine the spatial pattern and temporal evolution of the change in retinal partial oxygen pressure (DeltaPO(2)) associated with a murine oxygen-induced retinopathy (OIR) model of retinal neovascularization (NV). METHODS: On P7, newborn C57BL/6 mice were exposed to 75% oxygen until postnatal day (P)12, followed by recovery in room air until P17 or P34. Control mice remained in room air until P17 or P34. At P17 and P34, functional magnetic resonance imaging (MRI) and a carbogen inhalation challenge was used to measure retinal DeltaPO(2). Retinal avascularity, distance from the optic nerve head to the vascular edge in the peripheral retina, and NV incidence and severity were measured in retinas stained with adenosine diphosphatase (ADPase). RESULTS: In P17 and P34 controls and in P34 OIR animals, retinas were fully vascularized without evidence of NV. In P17 OIR mice, there was a large central retinal capillary-free zone (22% +/- 3% of the entire retinal area, mean +/- SD) and 4 clockhours (range 1-7) of retinal NV at the border of the peripheral vascular and central acapillary retina in 100% (36/36) of the mice. In P17 OIR mice, retinal DeltaPO(2) over the vascularized far peripheral retina was not significantly (P > 0.05) different from the P17 control but was supernormal (P < 0.05) over the central capillary-free retina. However, no differences (P > 0.05) in retinal DeltaPO(2) were found between the P34 control and OIR groups. CONCLUSIONS: A reversible supernormal DeltaPO(2) was found only over the central acapillary retina during the appearance of retinal NV in a mouse OIR model. The present data show the applicability of carbogen-challenge functional MRI to the study of retinal DeltaPO(2) in vivo in eyes that are too small for the use of existing techniques.

Animals↗
PubMed1994

Extraretinal neovascularization induced by hypoxic episodes in the neonatal rat.

PURPOSE: To test the hypothesis that hypoxia induces retinal neovascularization. METHODS: To produce relative hypoxia in the avascular retina, newborn rats were exposed for 11 days to 80% oxygen interrupted daily by short episodes in room air. Episodes in room air lasted 1/2 hour or 1 hour followed by abrupt reintroduction, or 1/2 hour followed by progressive reintroduction to 80% oxygen lasting 3 hours to prolong the period of hypoxia. At the end of the 11 days of interrupted oxygen exposure, the animals were left in room air for 6 days. RESULTS: The incidence of neovascularization exhibited a dose-response relationship to the period out of 80% oxygen. Periods of approximately 3 hours produced neovascularization (in at least one eye) in 94% of the animals. The total area of the peripheral avascular retina was larger in animals exposed to prolonged periods of hypoxia than in those exposed for shorter periods. The incidence of neovascularization was strongly associated with the total area of the peripheral avascular retina and occurred in the inferior quadrant in 78% of the cases. Additional features of stage 3 retinopathy of prematurity (ROP), including arteriovenous shunts and ridges, were observed in some retinas. CONCLUSIONS: These data demonstrate that hypoxic episodes can induce extraretinal neovascularization in the rat and suggest that brief periods of oxygen deficiency could exacerbate progression of ROP. With the high incidence and predictability of localization of neovascularization, this model could be useful for the study of angiogenesis and for evaluation of antiangiogenic or antioxidant substances.

Animals↗
PubMed2001

c-abl is required for the development of hyperoxia-induced retinopathy.

The requirement for the nonreceptor tyrosine kinase c-abl in the pathogenesis of retinopathy of prematurity (ROP) was examined using the mouse model for ROP and c-abl-deficient mice. Hyperoxia-induced retinal neovascularization was observed in wild-type and heterozygous mice but animals that were homozygous null for c-abl did not develop a vasoproliferative retinopathy in response to hyperoxia. Two gene products, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF), have been implicated in the pathogenesis of ROP. The mRNA expression of ET-1 and VEGF was assessed in mice maintained in normoxia and in hyperoxia-exposed mice. ET-1 mRNA levels were unchanged in wild-type mice throughout the hyperoxia treatment, suggesting that ET-1 mRNA expression is not regulated by the increase in inspired oxygen. In wild-type mice maintained in room air, VEGF mRNA levels rose threefold from postnatal day 6 (P6) to P17. When wild-type mice were treated with the hyperoxia regimen, a fivefold decrease in VEGF mRNA expression was observed from P7 to P16. However, retinal VEGF expression in hyperoxia-treated homozygous null mice did not decrease and remained at control levels. These data suggest that c-abl is required for the hyperoxia-induced retinal neovascularization and hyperoxia-induced decrease in VEGF mRNA levels.

Animals↗
PubMed2003

Adult human hematopoietic cells provide functional hemangioblast activity.

The murine adult hematopoietic stem cell is able to function as a hemangioblast, contributing both to blood reconstitution and to blood vessel repair in response to ischemic injury. We developed a novel mouse xenotransplantation model of retinal neovascularization to test human hematopoietic cell plasticity. Immunocompromised nonobese diabetic (NOD)/scid mice underwent myeloablative conditioning and transplantation with human CD34+ umbilical cord blood. After multilineage reconstitution was established, retinal ischemia was induced to promote neovascularization. Our results demonstrate human retinal neovascularization, thus revealing the functional hemangioblast activity of human hematopoietic cells.

Adult↗
PubMed2005

Two-port pars plana vitrectomy surgery: a prospective interventional case series.

BACKGROUND AND OBJECTIVE: Current literature review fails to disclose any series describing the use of two-port vitrectomy in adult patients. This study was performed to determine the feasibility and efficacy of pars plana vitrectomy surgery using two (rather than three or four)-port access for treatment of diabetic patients with nonclearing vitreous haemorrhage due to retinal neovascularization. DESIGN: Interventional prospective case series: to measure ability to allow for long-term resolution of chronic uncomplicated vitreous haemorrhage in diabetic patients, and to study the frequency and nature of complications associated with this technique. METHODS: Two-port pars plana vitrectomy (with endolaser treatment and membrane delamination if necessary) was performed in a prospective series of 12 consecutive diabetic patients with nonclearing vitreous haemorrhage due to retinal neovascularization. RESULTS: Successful removal of vitreous haemorrhage resulted in all patients. No visually significant intraoperative complications occurred. Best postoperative visual acuity correlated with lenticular and macular perfusion status. CONCLUSION: Two-port pars plana vitrectomy is an efficient (and potentially safer and faster) alternative to the standard three-port vitrectomy in selected patients.

Adult↗
PubMed2001

[Retrospective analysis of argon laser for treating retinal periphlebitis].

OBJECTIVES: This article was to investigate the curative effect of argon laser photocoagulation for retinal periphlebitis treatment, and then to discuss the stage of the treatment. METHODS: According to the condition of vitreous hemorrhage and the range of retinal neovascularization, 31 cases (34 eyes) were divided into the light group and the heavy group, and the therapeutic effective rate, the condition of visual acuity and vitreous hemorrhage were compared. RESULTS: The therapeutic effective rate was 64.71%, there was significant difference in effective rate and prognosis of visual acuity between two groups (P < 0.01). After laser treatment, the morbidity of vitreous hemorrhage in heavy group decreased from 100% to 18.70%. CONCLUSION: Argon laser photocoagulation is an effective method for treating retinal periphlebitis and early treatment is recommended.

Adolescent↗