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Topical nepafenac inhibits ocular neovascularization.

PURPOSE: Topical nepafenac readily penetrates the cornea and is metabolized to amfenac, a potent cyclooxygenase (COX)-1 and COX-2 inhibitor. In this study, we tested the effect of topical nepafenac in three murine models of ocular neovascularization (NV). METHODS: A masked trial was performed to compare the topical effects of vehicle with one of several concentrations of nepafenac (0.01%, 0.03%, 0.1%, or 0.5%), 0.1% diclofenac, or 0.5% ketorolac tromethamine in mice with oxygen-induced ischemic retinopathy, mice with choroidal NV (CNV) due to laser-induced rupture of Bruch's membrane, or transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF transgenic mice). RESULTS: Mice treated with 0.1% or 0.5% nepafenac had significantly less CNV and significant less ischemia-induced retinal NV than did vehicle-treated mice. Nepafenac also blunted the increase in VEGF mRNA in the retina induced by ischemia. In rho/VEGF transgenic mice, nepafenac failed to inhibit neovascularization. In additional studies, compared with vehicle-treated mice, mice treated with 0.1% or 0.03% nepafenac had significantly less CNV, whereas eyes treated with 0.1% diclofenac showed no significant difference. Mice treated with 0.5% ketorolac tromethamine for 14 days had high mortality, but when evaluated after 7 days of treatment showed no difference from mice treated with vehicle for 7 days. CONCLUSIONS: Topical nepafenac inhibits CNV and ischemia-induced retinal neovascularization by decreasing production of VEGF. The absence of effect in rho/VEGF transgenic mice is consistent with this mechanism. Topical nepafenac may provide an effective new treatment for ocular neovascularization. The excellent corneal penetration of nepafenac certainly plays an important role in this effect. It is possible that other antiangiogenic agents are also amenable to topical application after formulations are identified that maximize their corneal penetration. Because of the many advantages of the topical route of delivery, this is a possible topic for exploration.

Administration, Topical↗

Bilateral choroidal hemangiomas and facial nevus flammeus.

Two patients presented with the rare combination of bilateral diffuse choroidal hemangiomas and bilateral facial nevus flammeus. In one eye of one patient, an associated serous retinal detachment was treated with xenon arc photocoagulation in an attempt to delimit the subretinal fluid. Clinicians should be aware of the subtle clinical findings of diffuse choroidal hemangiomas as well as the possibility of bilateral occurrence. Early recognition and treatment may prevent progression of total retinal detachment and neovascular glaucoma.

Adolescent↗

Anecortave acetate for the treatment of idiopathic perifoveal telangiectasia: a pilot study.

PURPOSE: To investigate the use of anecortave acetate, a new angiostatic cortisene, for the treatment of the leakage and/or neovascularization associated with idiopathic perifoveal telangiectasia (IPT) in an open label prospective pilot study. METHODS: Seven eyes of six patients were treated with posterior juxtascleral administration of anecortave acetate delivered adjacent to the macula using a specially designed curved cannula. A full clinical examination and fluorescein angiography were performed at baseline and at 3-month intervals. The primary efficacy outcome for this pilot study was the mean change in visual acuity (Early Treatment Diabetic Retinopathy Study) from baseline. RESULTS: The visual acuity remained unchanged in two eyes of two patients with nonproliferative disease after 24 months. The five eyes of four patients presenting with subretinal neovascularization, the proliferative stage of IPT, showed stabilization or improvement of lesion size, resolution of leakage, and stabilization of vision at last follow-up. CONCLUSION: The results of this study suggest that anecortave acetate may inhibit retinal and subretinal permeability as well as neovascular proliferation in patients with IPT. A larger study accordingly should be designed in the future to evaluate the effectiveness and treatment of IPT with this drug.

Adult↗

[Two cases of frosted retinal angiitis with central retinal vein occlusion].

BACKGROUND: Frosted retinal angiitis usually occurs in children, and has a good prognosis. We report two cases of unilateral frosted retinal angiitis in adults. They resulted in visual degradation because of associated central retinal vein occlusion and neovascular glaucoma. CASES: Case 1 was a 36-year-old female. Almost all retinal veins and some retinal arteries had vasculitis in her right eye, and the veins were slightly dilated and sheathed. Case 2 was a 23-year-old female. Angle hypopyon was observed in her left eye. Retinal veins were dilated, meandered, and sheathed. Retinal hemorrhages were also observed. In both cases, systemic steroid therapy gradually improved the retinal vasculitis, but central retinal vein occlusions gradually developed, and in spite of systemic administration of urokinase and panretinal photocoagulation, neovascular glaucoma developed, and visual acuity became degraded in both cases. CONCLUSION: Two cases of frosted retinal angiitis complicated by retinal vein occlusion were reported. Careful observation of retinal blood flow is necessary in frosted retinal angiitis in adults.

Adult↗

Intravitreous anti-raf-1 kinase antisense oligonucleotide as an angioinhibitory agent in porcine preretinal neovascularization.

PURPOSE: To test the efficacy of a synthetic antisense oligonucleotide inhibitor of an intracellular signal transduction protein, C-raf-1 kinase, as an inhibitor of ocular neovascularization. METHODS: A 2'methoxyethyl, 2'deoxy chimeric 20-nucleotide sequence containing a uniform phosphorothioate backbone was synthesized which targets the 3'untranslated region of porcine C-raf-1 mRNA (ISIS 107189). Efficacy of mRNA inhibition was tested in vitro in porcine vascular endothelial cells and treated pigs by Northern blotting. In a pig model of intraocular neovascularization induced by branch retinal vein occlusion, intravitreal injection of ISIS 107189 compound (8 microM calculated intraocular concentration) at baseline and on days 14, 42, and 70, was tested against vehicle as control for inhibition of neovascularization. After enucleation on day 84, ocular tissues were analyzed for ISIS 107189 content by solid-phase extraction and capillary gel electrophoresis. Cryostat sections were immunostained for C-raf-1 kinase protein. RESULTS: The antisense oligonucleotide demonstrated high potency for inhibition of C-raf-1 kinase in the porcine cells lines. Levels of C-raf-1 kinase were also decreased in the retina of pigs following a single 180 microg dose. Pig eyes injected with the multiple doses of 180 microg oligonucleotide demonstrated a marked decrease in neovascularization due to branch retinal vein occlusion 12 weeks after treatment (p = 0.05, Mann-Whitney U-test). Posterior subcapsular cataracts were noted in the treated eyes. Concentrations of oligonucleotide in retina ranged from 2-12 microM in the treated eyes. Qualitative assessment of the expression of C-raf-1 kinase via immunohistostaining of frozen sections demonstrated inhibition of expression in the treated eyes compared to controls. CONCLUSIONS: ISIS 107189 successfully inhibited neovascularization in this model, which was correlated with an inhibition of expression of C-raf-1 kinase. While not proven in these studies, these results suggest that C-raf kinase may be important in angiogenesis. Antisense therapy has potential applicability in the therapy of ocular neovascular diseases.

Animals↗

Ocular ischemic syndrome.

BACKGROUND: The purpose of this study was to investigate the clinical features and management of ocular ischemic syndrome (OIS) and factors influencing its development. METHODS: Ten patients (12 eyes) with OIS underwent detailed medical and ocular histories, complete ophthalmic evaluation including fluorescein angiography, internal carotid artery evaluation by duplex ultrasonography, and management. The following outcome measures were considered: visual acuity, anterior segment neovascularization, lens status, retinal and choroidal changes, and carotid artery stenosis or occlusion. RESULTS: The mean age of the patients was 63 +/- 8 years. Presenting visual symptoms included gradual (82.5%) or sudden (17.5%) onset of vision loss. At initial visit, eyes with OIS had visual acuity less than or equal to counting fingers in 50%, iris neovascularization in 58%, and neovascular glaucoma in 42%. Initially associated systemic diseases in these patients included arterial hypertension (60%), diabetes mellitus (40%), coronary artery disease (20%), previous stroke (30%) and hemodialysis (10%). Complete occlusion or severe occlusion (70-99%) of the internal carotid artery was seen in 75% on the side of OIS. Panretinal photocoagulation did not prevent OIS from progressing but vitreous hemorrhage and rubeosis iris regressed. Carotid endarterectomy had some benefit in stabilizing or improving vision in patients with OIS. CONCLUSION: OIS has a poor visual prognosis. It is imperative that the clinician be aware of the signs and symptoms of carotid disease in order to facilitate prompt diagnosis and appropriate referral, because OIS may be the presenting sign of serious ischemic cerebrovascular and ischemic heart disease.

Adult↗

Preretinal and optic nerve head neovascularization induced by photodynamic venous thrombosis in domestic pigs.

OBJECTIVE: To develop a reliable model of ischemic preretinal and optic nerve head neovascularization in young male domestic pigs. METHODS: Using laser-induced branch retinal venous obstruction assisted by photodynamic thrombosis with rose bengal, 15 of 15 treated eyes developed neovascularization of the optic nerve head and retina. All cases of neovascularization were followed up clinically for up to 12 weeks. RESULTS: Clinical, fluorescein angiographic, and histopathologic features were consistent with neovascular proliferation into the vitreous. CONCLUSIONS: Further evaluation of the long-term natural history, role of the degree of ischemia, and the effect of interventions for various types of ischemic retinopathy (eg, panretinal photocoagulation) is warranted. This model is simple and relatively inexpensive and allows easy clinical assessment.

Animals↗

Remodeling of the vascular channels in retinal angiomatous proliferations treated with intravitreal triamcinolone acetonide and photodynamic therapy.

BACKGROUND: The objective was to describe the remodeling of the vascular channels in stage II retinal angiomatous proliferation (RAP) treated by intravitreal injections of triamcinolone acetonide (TA) and subsequent photodynamic therapy (PDT). METHODS: Stage II RAP secondary to age-related macular degeneration was documented by dynamic digital fluorescein and indocyanine green angiography in 3 consecutive patients (3 eyes). All eyes were treated with intravitreal injection of TA (4 mg, 0.1 ml) followed by PDT 5-10 days later. RESULTS: Indocyanine green angiography (ICGA) revealed a complete remodeling of the vascular structure of the three RAPs after treatment. The feeding retinal artery, which shunted a major part of the blood flow from the original arteriole toward the intraretinal neovascular complex before treatment, regained a normal appearance after treatment. With RAP closure, the blood flow was again directed through the original retinal arteriole, and the connection to the RAP was no longer visible. CONCLUSIONS: Stage II RAPs are difficult lesions to treat. A real remodeling of the vascular lesion is achieved with the combined use of intravitreal TA and PDT. This finding corroborates the need for randomized clinical trials currently under way to evaluate this combination treatment in wet, age-related macular degeneration.

Aged↗

Anecortave acetate treatment for retinal angiomatous proliferation: a pilot study.

PURPOSE: The purpose of this study was to evaluate anecortave acetate treatment of retinal angiomatous proliferation (RAP), a neovascular form of age-related macular degeneration, with specific regard to inhibition of neovascularization and maintenance of vision. METHODS: Thirty-four patients with RAP with any stage of neovascularization were randomized 1:1:1 for treatment with three different quantities (30 mg, 15 mg, 3 mg) of anecortave acetate sterile suspension for juxtascleral administration. Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study chart), intraocular pressure measurement, biomicroscopy, funduscopy, digital fluorescein, and indocyanine green angiography were recorded at baseline and at 3 months. A 6-month retreatment interval was established for this study with a follow-up of 12 months. In selected patients optical coherence tomography was performed. The outcomes were mean changes in visual acuity and lesion size at 1 year. RESULTS: The detachment of the neurosensory retina and retinal pigment epithelium improved in all eyes, but all neovascular lesions increased in size. Vision loss occurred in the majority of study eyes (22 out of 34 eyes, 64.7%) independent of the concentration administered. CONCLUSION: The results suggest that a posterior juxtascleral injection of anecortave acetate reduces capillary permeability in patients with RAP. However, in spite of improvement of the exudation there is a progression of neovascularization and a significant loss of vision in all these patients. Like other monotherapeutic methods used to treat this variant of neovascular age-related macular degeneration, anecortave acetate alone does not appear to benefit these patients. Future studies should investigate a combination form of therapy.

Aged↗

[Eales' syndrome. Clinical aspects, therapeutic indications and course of 29 cases].

Biomicroscopic examination of these cases showed vitreous hemorrhages in 18 eyes, retinal hemorrhages in 18 eyes, periphlebitis in 16 eyes, equatorial neovascularization in 16 eyes, macular involvement in 9 eyes (macular-cystoïd edema or macular pucker), prepapillary neovascularization in 15 eyes. Fluorescein retinal angiography was performed when it was possible. Follow up of these eyes upon and over six months, treated by corticotherapy for 11 eyes, retinal photocoagulation for 32 eyes, and vitrectomy for 9 eyes, led to separate non evolutive entities (30 eyes) from evolutive entities (6 eyes). Complications happened in 15 eyes, 4 eyes ended with neovascular glaucoma. 40 eyes maintained ambulatory or calibrated acuity.

Adolescent↗

Eales disease--an update.

Eales disease, first described by Henry Eales in 1880, remains an enigma. The disease, observed more commonly in the Indian subcontinent than in the rest of the world, occurs in young healthy adult males, initially presenting as retinal periphlebitis and later as retinal ischemia that may lead to vascular alterations and neovascularization. Recurrent vitreous hemorrhage with or without retinal detachment is the common sequelae. In recent years, immunological, molecular biological, and biochemical studies have indicated the role of human leukocyte antigen, retinal autoimmunity, mycobacterium tuberculosis genome, and free radical mediated damage in the etiopathogenesis of this disease. However, its etiology appears to be multifactorial. The management depends on the stage of the disease and consists of medical treatment with oral corticosteroids in the active inflammatory stage and laser photocoagulation in the advanced retinal ischemia and neovascularization stages. The results of vitreoretinal surgery have been found to be satisfactory in case of vitreous hemorrhage with or without retinal detachment.

Diagnosis, Differential↗

Optical coherence tomography: its clinical use for the diagnosis, pathogenesis, and management of macular conditions.

BACKGROUND: Optical coherence tomography (OCT) is a noninvasive, noncontact transpupillary imaging technology that can image retinal structures in vive with a resolution of up to 10 microns. Anatomic layers within the retina can be differentiated and retinal thickness measured. The objective is to demonstrate clinical viability and useful interpretation of macular images derived from a commercially available OCT instrument. METHODS: A Stratus OCT (Zeiss-Humphrey, Dublin, California) imaging system was used to evaluate several pathological presentations of the macula in selected patients. Conditions illustrated in this case series were macular holes, epiretinal membranes, macular edema, idiopathic central serous choroidopathy, detachments of pigment epithelium and sensory retina, choroidal neovascular membranes, and retinal vascular occlusions. CONCLUSIONS: Acquired OCT images achieved structural information regarding anatomical characteristics of the conditions scanned. A cross-sectional resolution of 10 microns was accomplished, which is 10 times greater than current ultrasound. OCT provides important information that may be critical in the diagnosis and management of some ocular conditions. Its high-resolution scans may contribute to the better understanding of disease pathogenesis, as well as assistance in or confirmation of a diagnosis. This imaging technology provides important information beyond what can be seen on clinical examination, and offers a useful adjunct to other diagnostic imaging tools such as fundus photography, fluorescein angiography, and indocyanine green angiography.

Aged↗

PCR-positive tubercular retinal vasculitis: clinical characteristics and management.

BACKGROUND: Inflammation of retinal vessels is a known association of systemic tuberculosis. Patients with retinal vasculitis are subjected to extensive but unrewarding systemic workup. Polymerase chain reaction (PCR) is now commonly used to detect DNA of infective organisms including Mycobacterium tuberculosis. This study was undertaken to characterize the clinical characteristics of PCR-positive tubercular retinal vasculitis, so as to determine the clinical presentation, associated systemic features, management, and course of this form of vasculitis. METHODS: The clinical records of 13 patients seen between 1997 and 1999 with the diagnosis of PCR-positive tubercular retinal vasculitis from the aqueous or vitreous humor were reviewed. Recorded data included age, sex, race, visual acuity, anterior and posterior segment findings, and results of diagnostic evaluations. All received antituberculosis therapy with or without concomitant corticosteroids. Laser scatter photocoagulation was done in eyes with neovascularization. One eye with vitreous hemorrhage was subjected to pars plana vitrectomy. RESULTS: There were 9 (69.2%) male and 4 (30.7%) female patients with a median age of 20 years. The disease was bilateral in seven. The most consistent finding was the presence of vitritis in all the eyes followed by vitreous snowball opacities in 17 eyes (89.4%), neovascularization in 11 eyes (57.8%), retinal hemorrhages in 10 eyes (52.6%), neuroretinitis in 10 eyes (52.6%), focal choroiditis in 9 eyes (47.3%), vitreous/preretinal hemorrhage in 5 eyes (26.3%), and serous retinal detachment in 3 eyes (15.7%). Over a median follow-up of 12 months, all showed resolution of vasculitis with no recurrences. CONCLUSIONS: Polymerase chain reaction-positive tubercular retinal vasculitis had varied associated fundus findings. Its recognition is important so as to order only relevant diagnostic tests.

Adolescent↗

Vascular shunt of the optic disc resembling neovascularization in a diabetic patient with optic disc drusen.

PURPOSE: To report an insulin-dependent diabetic patient who was referred by the diabetic screening clinic as having proliferative diabetic retinopathy who was found to have bilateral optic disc drusen with optociliary shunt resembling neovascularization on the disc. METHODS: Complete ocular evaluation including a fluorescein angiography was performed. RESULTS: Fundus examination showed signs of mild nonproliferative diabetic retinopathy in the right eye and the presence of well-defined optic disc drusen in both eyes with a peculiar vascular abnormality resembling neovascularization on the right disc. The central retinal vein pulsation was normal on digital examination. Autofluorescence confirmed the presence of the optic disc drusen in both eyes. Fluorescein angiography showed no leakage from the optociliary shunt. The vascular abnormality has remained stable for 2 years. CONCLUSIONS: This case highlights the correlation of optic disc drusen and optociliary shunts which in diabetic patients can be misdiagnosed as neovascularization.

Diabetes Mellitus, Type 1↗

Inhibition of ocular angiogenesis by an adenovirus carrying the human von Hippel-Lindau tumor-suppressor gene in vivo.

PURPOSE: The purpose of this study was to investigate the effect of the von Hippel-Lindau (VHL) protein on VEGF gene expression in vitro and to determine whether adenovirus-mediated VHL intraocular gene transfer inhibits the development of angiogenesis in a monkey model of multiple branch retinal vein occlusion (BRVO). METHODS: A recombinant adenovirus vector adVHL was constructed to deliver the human VHL gene. Total RNA prepared from various kinds of cells transduced with adLacZ (control) or adVHL under normoxic or hypoxic conditions was subjected to Northern blot analyses. Either adLacZ or adVHL was delivered by preretinal injection in monkeys. The effects of adLacZ or adVHL on ocular neovascularization in laser-induced multiple BRVO was evaluated in color photographs and with fluorescein angiography (FA). RESULTS: VHL expression in adVHL-transduced cells was confirmed at the transcript and protein levels. VHL overexpression significantly decreased the levels of VEGF transcripts in human aortic endothelial cells (HAECs); retinal pigment epithelium (RPE) cells; and RCC 786-O cells, renal carcinoma cells lacking VHL expression under normoxia. In contrast, VHL had no effect on the hypoxia-mediated increase in VEGF expression in these cells, although basal levels of VEGF expression were substantially reduced. Color photographs and FA revealed that retinal neovascularization and iris rubeosis accompanied by multiple BRVO in a monkey model were obviously suppressed by VHL overexpression. Northern blot analysis and immunostaining for VHL and VEGF indicated that VHL transfer obviously suppressed VEGF gene expression in VHL-transduced tissues such as retina or RPE. CONCLUSIONS: The results showed that adenovirus expressing VHL led to a significant reduction in VEGF expression in vitro under normoxic or hypoxic conditions. adVHL effectively inhibited angiogenesis in retina and iris in laser-induced multiple BRVO in monkey eyes. These data suggest that gene therapy based on VHL gene delivery has potential in the treatment of human ocular neovascularization.

Adenoviruses, Human↗

Fluorescein angiography and its prognostic significance in central retinal vein occlusion.

To determine the prognostic value of fluorescein angiograms in central retinal occlusion 75 patients presenting within the first three months of their initial visual symptoms were studied prospectively. The prognosis was found to be best (complete or partial resolution) in eyes with good capillary perfusion, an intact perifoveal capillary arcade, and leakage only from terminal venules and veins. A broken perifoveal capillary arcade and much capillary leakage, even in the absence of obvious capillary closure, were precursors of permanent macular oedema. All eyes with extensive capillary closure developed severe complications such as thrombotic glaucoma and neovascularization (pre-retinal fibrosis), and all became blind. Macular transit time and leakage from arteries and veins were not used as prognostic features. Fluorescein angiography during the first month of the initial visual symptoms was of prognostic value only in those cases with poor prognosis. The three-month angiogram was an accurate indicator of the visual outcome in all cases.

Capillaries↗

Intravitreal triamcinolone acetonide for cataract surgery with iris neovascularization.

A 73-year-old patient with proliferative diabetic retinopathy presented with marked iris neovascularization and dense cataract that prevented retinal laser coagulation. To prevent postoperative progression of the iris neovascularization, the patient had standard cataract surgery with implantation of a foldable posterior chamber lens in combination with an intravitreal injection of 25 mg triamcinolone acetonide. During the 5.5-month follow-up, visual acuity increased from 0.10 to 0.20. With no additional retinal ablative treatment, the iris neovascularization markedly regressed within the first 5 postoperative weeks, after which a peripheral retinal laser treatment was performed, resolving the iris neovascularization. Intraocular pressure was within the normal range.

Aged↗

Retinal hemorrhage after photodynamic therapy in patients with subfoveal choroidal neovascularization caused by age-related macular degeneration.

PURPOSE: To report the frequency and the evolution of the extensive retinal hemorrhages that can appear within 48 h after the application of photodynamic therapy. METHODS: Two hundred and fifteen individual eyes of 194 consecutive patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration who underwent photodynamic treatment were included in the study. The visual acuity was measured before and after treatment. Color and red-free photographs were taken. Fluorescein angiography and optical coherence tomography (OCT) were also performed in order to describe the macular hemorrhages. RESULTS: Four out of 215 eyes developed macular hemorrhage within 48 h after the photodynamic therapy. Before treatment one of the four patients had classic CNV, one predominantly classic and two patients occult CNV without any classic component. In all four cases, the hemorrhage after photodynamic therapy (PDT) was extensive, it extended beyond the arcades and it was not absorbed during the follow-up period, which ranged from 11 to 21 months. The greatest linear dimension of the hemorrhage was extremely high (>12,000 microm). CONCLUSION: Extensive macular hemorrhage was observed in 1.86% of the studied cases. The hemorrhage was not related to the type of the CNV lesion before treatment. The size and the appearance of hemorrhage within 48 h after treatment support the view that the hemorrhage is a direct consequence of the photodynamic therapy and not related to the natural course of the disease.

Aged↗