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PubMed1987

Structural characterization of neovascularization in adenovirus-12-induced retinal tumor.

In order to elucidate a relationship between newly formed micro-blood vessels in retinal tumor and blood-retina barrier, we studied light and electron microscopic and immunohistochemical findings of newly-formed micro-blood vessels in human adenovirus 12-induced retinoblastoma-like tumors in rats. In contrast to other experimentally induced tumors of the central nervous system, there was no evidence of formation of Weibel-Palade bodies and endothelial gaps in this experimental model of retinoblastoma, but factor VIII related antigen was evidently demonstrated. Increased pinocytotic vesicles suggested that the vast majority of these blood vessels did not retain the normal physiological barrier functions. The basement membrane of the micro-blood vessels was poorly developed. The morphological characteristics of the micro-blood vessels of this retinoblastoma-like tumor were compared with those of human retinoblastoma and other experimentally induced tumors of the central nervous system.

Adenoviruses, Human↗
PubMed1995

Effect of intravitreal administration of indomethacin on experimental subretinal neovascularization in the subhuman primate.

OBJECTIVE: To examine the effect of indomethacin, a cyclooxygenase (CO) inhibitor, on laser-induced subretinal neovascularization (SRN) in the monkey. The CO pathway of arachidonic acid metabolism plays an important role in angiogenesis, and the inhibition of CO is known to inhibit angiogenesis in the cornea and in certain tumors. MATERIALS AND METHODS: A cannula was implanted into the vitreous cavity of 11 eyes of six monkeys and connected to an osmotic minipump. Indomethacin (25 micrograms/d) was delivered into the vitreous through the cannula for 14 days (seven eyes). Vehicle alone was injected for 14 days as a control (four eyes). Argon laser photocoagulation was then performed (eight spots at the posterior pole in each eye) to induce SRN. Fundus photographs and fluorescein angiograms were taken periodically to document the evolution of SRN. Light and electron microscopic examination was performed on two eyes of each group 8 weeks after photocoagulation. RESULTS: Subretinal neovascularization developed from 2 to 4 weeks after photocoagulation. The incidence of SRN, indicated by fluorescein leakage, was significantly lower (P < .05) in the group treated with indomethacin (14.3%, eight of 56 lesions) than in the control group (37.5%, 12 of 32 lesions). After 8 weeks, no fluorescein leakage was found in either the control or indomethacin-treated groups. Scar formation was found on histologic examination in both groups. No histologic evidence of indomethacin toxicity was seen in the adjacent retina. CONCLUSIONS: Intravitreal administration of indomethacin inhibits the formation of laser-induced SRN in monkey eyes. This is consistent with the participation of the CO pathway in the process of SRN formation and suggests that this pathway could be a potential target in the treatment of SRN.

Animals↗
PubMed2006

Subretinal neovascular membrane in idiopathic intracranial hypertension.

PURPOSE: To define the prevalence, natural history, treatment, and prognosis of papilledema-related juxtapapillary subretinal neovascular membranes (SRNVMs). DESIGN: Retrospective observational case series. METHODS: We conducted a retrospective chart review. RESULTS: Of 1140 cases of idiopathic intracranial hypertension, six patients had juxtapapillary SRNVM. Three patients were observed, and their final visual acuities were 20/20, 20/50, and 20/200. Three SRNVM involved the fovea; two of the cases were treated with argon laser therapy, and one case was treated with photodynamic therapy. CONCLUSION: SRNVM in idiopathic intracranial hypertension is rare (0.53%). Most cases of juxtapapillary SRNVM are self-limited and regress, can be observed, and have a favorable visual prognosis. The progression of the SRNVM ophthalmoscopically or angiographically toward the fovea, however, might be an indication for laser treatment. Once subfoveal extension occurs, the visual outcome tends to be unfavorable. No patients had recurrence of SRNVM after the resolution of the papilledema.

Acetazolamide↗
PubMed1993

Evaluation of persistence of subretinal neovascular membranes using digitized angiographic analysis.

A study was conducted using the digitized fluorescein angiogram (DFA) system to evaluate adequacy of coverage of laser treatment for subretinal neovascular membranes (SRNVM) and to confirm that complete coverage lowers the incidence of persistent SRNVMs. Ten consecutive cases were evaluated with the DFA system after undergoing a single laser treatment. Three cases were judged to be adequately treated, and the remaining seven cases were judged to be inadequately treated. The DFA system was then used during photocoagulation in 16 consecutive cases to verify complete coverage of the SRNVM or to indicate the need for photocoagulation augmentation. Despite augmentation, 2 of the 16 cases remained inadequately treated. Overall, the cases that were adequately treated had a 12% (2/17) persistence rate, whereas those that were inadequately treated had a persistence rate of 67% (6/9). The data indicate that adequate coverage of SRNVMs is essential to prevent persistence.

Adult↗
PubMedDate not supplied

Possible involvement of nitric oxide in the progression of diabetic retinopathy.

Abnormal nitric oxide (NO) synthesis has been implicated in the pathogenesis of diabetes mellitus. The aim of our study was to elucidate the relationship between the stages of diabetic retinopathy (DR) and the NO levels in aqueous humor and plasma. Using the chemiluminescence assay, we measured the concentrations of NO in aqueous humor and plasma samples obtained during intraocular surgery from 45 diabetic patients and 19 nondiabetic cataract patients. The patients with diabetes were classified into 4 groups: proliferative DR (PDR) with active neovascularization (active PDR; 9 cases), PDR with quiescent neovascularization (regressed PDR; 6 cases), background DR (BDR; 16 cases) and no DR (14 cases). We found that the aqueous NO levels (mean +/- SE) of the active PDR group (83.2 +/- 13.9 microM) were significantly higher than those of the BDR group (45.8 +/- 6.0 microM, p = 0.049) and the diabetics without DR (33.3 +/- 5.2 microM, p = 0.011), and, although not statistically significantly, they were also higher than those of the regressed PDR group (52.1 +/- 10.3 microM, p = 0.224). However, no significant differences were observed between any of the diabetic subgroups in the plasma NO levels (p = 0.345). We therefore concluded that NO present in the ocular tissues may play important roles in the progression of DR.

Aged↗
PubMed1993

Peripapillary subretinal neovascular membranes: the natural history.

We studied the natural course of peripapillary subretinal neovascular membranes in 20 eyes. The membranes were either idiopathic in nature or associated with underlying disease. We found that the visual prognosis was related to the behaviour of the membrane and to the patient's age. Patients under the age of 40 years had unilateral disease and a more favourable visual prognosis. Older patients had a uniformly poor visual prognosis and a high incidence of bilateral disease. Fifty-four per cent of patients over 45 years and 62% over 70 years of age had bilateral membranes. In those over the age of 70 years, 75% of untreated eyes lost vision to a level of 3/60 or less in both eyes. The probability of the second eye becoming involved in the older group of patients was 62%. The period of time elapsing between involvement of the first and second eye varied between simultaneous occurrence and a delay of 7 years.

Adult↗
PubMed2006

HTRA1 promoter polymorphism in wet age-related macular degeneration.

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.

Aged↗
PubMed1993

Randomized comparison of krypton versus argon scatter photocoagulation for diabetic disc neovascularization. The Krypton Argon Regression Neovascularization Study report number 1.

BACKGROUND: The Krypton Argon Regression of Neovascularization Study (KARNS) was designed to compare the efficacy of red krypton versus blue-green argon laser photocoagulation for the management of high-risk proliferative diabetic retinopathy. METHODS: A prospective, randomized clinical trial was performed in 24 clinical centers. Patients (n = 696, 907 eyes) with diabetes and neovascularization of the disc (NVD) of one-third disc area or greater in extent were assigned at random to either argon or krypton laser scatter (panretinal) photocoagulation. The major endpoint of the regression of NVD to less than one-third disc area in extent at 3 months was evaluated by comparisons of gradings of the fundus photographs obtained at baseline and follow-up. RESULTS: At 3 months' follow-up, the proportion of eyes with regression of NVD to less than or equal to one-third disc area in extent were 41.1% in the argon-treated group and 41.8% in the krypton-treated group (P = 0.92). The odds of regressing to this extent of NVD at 3 months for argon-treated eyes versus krypton-treated eyes was 0.98 (95% confidence interval, 0.74-1.31). CONCLUSION: Scatter laser photocoagulation with either krypton red or argon appears to be equally effective in the treatment of proliferative diabetic retinopathy with NVD.

Adolescent↗
PubMed2006

Differential expression of vitreous proteins in proliferative diabetic retinopathy.

PURPOSE: To identify vitreous proteins that were differentially expressed in patients suffering from proliferative diabetic retinopathy with active neovascularization. METHODS: The vitreous samples of 15 active proliferative diabetic retinopathy patients were analyzed by two-dimensional gel electrophoresis and mass spectrometry, and the results were compared with those from age-matched patients with macular hole. RESULTS: Twenty-five protein spots were identified in the two-dimensional gel electrophoresis gels. Eight proteins (pigmented epithelium derived factor, serine protease inhibitor, apolipoprotein A-IV precursor, prostaglandin-H2 D-isomerase, a(1)-antitrypsin precursor, ankyrin repeat domain 15 protein, alpha2-HS-glycoprotein, and beta V spectrin) in the 25 spots were expressed significantly differently between the macular hole and proliferative diabetic retinopathy patients (p value < 0.05). Five proteins were upregulated in the proliferative diabetic retinopathy patients, and three were downregulated (p value < 0.05). CONCLUSIONS: We constructed vitreous protein profiles for proliferative diabetic retinopathy patients and identified eight candidate proteins believed to be involved in the pathogenesis of proliferative diabetic retinopathy.

Aged↗
PubMedDate not supplied

[A device for fluorescence diagnosis and photodynamic therapy of eye diseases, by using photosense].

By having a high photodynamic effectiveness and an ability of fluorescence, a Photosense photosensibilizer provides a way of combining photodynamic therapy (PDT) and monitoring its control within a session, which enhances the efficiency of treatment for the subretinal neovascular membrane. A slit lamp-based apparatus complex has been developed to employ the methods of fluorescence diagnosis (FD) and PDT, by applying this photosensitizer. The complex comprises an optical adapter that focusing laser radiation on the fundus of the eye in a range of 100-1000 microm, a video adapter that includes color and high-sensitive monochromic video cameras, as well as a personal computer and software that processes video information from the high-sensitive camera and displays the obtained images in real time. The original system of filters provides an image of the eye fundus in the fluorescent and usual color light at once during a FR procedure. The spatial resolution of the developed apparatus was tested on the test object specially devised for these purposes, which was 10 microm. The sensitivity of the complex is sufficient to record slightly fluorescent objects on the fundus of the eye.

Fluorescence↗
PubMed2006

MMP-2 and MMP-9 secretion by rpe is stimulated by angiogenic molecules found in choroidal neovascular membranes.

PURPOSE: Matrix metalloproteinases (MMP)-2 and -9 play an important role in the pathogenesis of choroidal neovascularization (CNV). Retinal pigment epithelial cells (RPE) are an important source of MMPs in the outer retinal environment, however little is known about the local factors that modulate MMP secretion in these cells. The purpose of this study was to determine the effects of CNV involved growth factors and the extracellular matrix molecule fibronectin on MMP-2 and -9 secretion by cultured human RPE. METHODS: MMP-2 and -9 secretion was studied using gelatin zymography, Western blot, and ELISA assay of RPE culture supernatants. The effects of stimulating the cells for 36 hours with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bGFG), tumor necrosis factor-alpha (TNF-alpha), or fibronectin (FN), all angiogenic factors found in CNV membranes, was determined. RESULTS: Resting RPE cells secreted MMP-2 but not MMP-9. Stimulation with TNF-alpha induced secretion of MMP-9 and increased the secretion of MMP-2. MMP-2 secretion was also increased by stimulation with FN and VEGF, but not bFGF. CONCLUSION: The results indicated that the angiogenic molecules VEGF, FN, and TNF-alpha stimulate MMP-2 and -9 secretion from RPE and thus further promote CNV.

Angiogenic Proteins↗
PubMed1999

External beam radiotherapy for subretinal neovascularization in age-related macular degeneration: is this treatment efficient?

PURPOSE: Control of the natural course of subretinal neovascularization (SRNV) in age-related macular degeneration (AMD) is difficult. Only a subset of patients is suitable for laser coagulation. This prospective study aimed to determine the efficacy and individual benefit of external beam radiotherapy (EBRT). METHODS AND MATERIALS: The prospective trial included 287 patients with subfoveal neovascularization due to AMD which was verified by fluorescein angiography. Patients have been treated between January 1996 and October 1997. All patients received a total dose of 16 Gy in 2-Gy daily fractions with 5-6 MeV photons based on computerized treatment planning in individual head mask fixation. This first analysis is based on 73 patients (50 women, 23 men, median age 74.3 years), with a median follow-up of 13.3 months and a minimum follow-up of 11 months. RESULTS: All patients completed therapy and tolerability was good. First clinical control with second angiography was performed 6 weeks after irradiation, then in 3-month intervals. Eighteen patients with SRNV refusing radiotherapy served as a control group and were matched with 18 irradiated patients. After 7 months median visual acuity (VA) was 20/160 for the irradiated and 20/400 for the untreated patients. One year after radiotherapy final median VA was 20/400 in both groups. CONCLUSION: These results suggest that 16 Gy of conventionally fractionated external beam irradiation slows down the visual loss in exudative AMD for only a few months. Patients' reading vision could not be saved for a long-term run.

Aged↗
PubMedDate not supplied

[The first results of phase IIA of clinical studies of photodynamic therapy for subretinal neovascular membranes with photosense].

The subretinal neovascular membrane (SNM) is a common complication of diseases, such as senile macular degeneration, myopia, pseudohistoplasmic syndrome, and many others. There is no algorithm of treatment for this pathology in today's ophthalmological care; however, many authors have arrived at the conclusion that photodynamic therapy (PDT) plays a major role in solving this difficult problem. Fifteen (18 eyes) patients, including 8 (8 eyes) patients diagnosed as having senile macular degeneration and SNM and 7 (10 eyes) patients diagnosed as having complicated high-grade myopia, and 3 were diagnosed as having bilateral SNM. The Russian agent Photosense, 0.05 mg/kg, was used as a photosensitizer. PDT was performed on day 3 after administration of the agent according to the peak of accumulation and the maximum laser concentration gradient at a wavelength of 675 nm and a light dose of 120 J/cm2. Good functional and angiographic results may be observed after the first 3 months of a prospective controlled open-labeled study of the efficiency of PDT with Photosense; however, longer follow-ups and larger groups of patients are required to make a final assessment of this treatment.

Adult↗
PubMed1995

Modified vitreous surgery for subretinal neovascularization and hemorrhage.

PURPOSE: To modify vitreous surgery for subretinal neovascularization (SRNV) and to determine the effects of this operation. METHODS: Six patients with SRNV were performed with this operation. The methods of examination before and after operation included: testing the best-corrected visual acuity before operation and 1, 3 or 6 months after operation; 30 degrees and macular 10 degrees Humphrey visual field examination; FFA examination preoperatively and 1, 3 or 6 months postoperatively. Modified surgery procedure is: a preventive buckling; pars plana vitrectomy; peeling the vitreous cortical; no intraocular diathermy; small retinotomy; subretinal surgery; air-fluid exchange. RESULTS: SRNV was taken off in 4 cases. Subretinal hemorrhage was washed in 2 cases. After 4 to 7 months follow-up, the visual acuity was improved in 4 cases, unchanged in 2 cases. The visual field was improved in 4 cases, unchanged in 1 case, decraesed in 1 case. The complications included macular hole due to surgery in 1 case and subretinal hemorrage in 1 case. CONCLUSION: The surgery criteria were: 1) massive subretinal hemorrhage; 2) some patients of SRNV included: FFA evidence they showed the membrane is beneath fovea, the best V. A is 20/100 or lower, and can't be treated by laser and the patient consent. This modified subretinal operation is safe, and effective for massive hemorrhage and some SRNVS.

Adult↗
PubMed2001

[Study of subretinal neovascular membranes secondary to degenerative myopia].

PURPOSE: To study the type, size, location and posterior time evolution of the subretinal neovascular membranes (SRNM) secondary to degenerative myopia (DM) and its relationship with the degree of myopic ametropia. METHODS: We studied 65 patients (130 eyes) with MD who were divided into three groups according to their refraction. A complete ophthalmologic examination, including a fluorescein angiography (FAG), was performed for all the patients. Based on this test, 55 SRNA were identified, and were classified into two types according to the fluorescein angiography results. Their position was described in relationship to the foveal avascular zone (FAZ) and their size was measured. RESULTS: 55 (42.3%) of the 130 eyes presented SRNM, which was bilateral in 16.32% of the patients. Based on the FAG criteria, 41 eyes (74.54%) presented type 1 SRNM, 60% (33 eyes) presented subfoveal membranes and the size was greater than 1,500 microns in more than 75%. The development of the SRNM showed no relationship with the myopic ametropia degree (P<0.2500). The follow-up time was 24.61+/-7.63. CONCLUSIONS: No relationship between the appearance of the development of the SRNM and the myopia degree has been found. These are generally small sized, have poor dye diffusion and are frequently located in the foveal zone. The visual acuity loss is often sudden and maintained over time.

Adult↗
PubMedDate not supplied

Colocalization of Tie2, angiopoietin 2 and vascular endothelial growth factor in fibrovascular membrane from patients with retinopathy of prematurity.

PURPOSE: The tyrosine kinase receptor Tie2 and its ligands, the angiopoietins (Angs), play important roles in vascular integrity and neovascularization, modulating vascular endothelial growth factor (VEGF) activity. To elucidate the potential role of Angs and the Tie2 system in retinopathy of prematurity (ROP), we have investigated the expression of Angs, Tie2 and VEGF within fibroproliferative membranes in ROP. METHODS: Fibroproliferative membranes were obtained from 38 cases with stage 5 ROP at the time of vitrectomy. Membranes were fixed in formalin and embedded in paraffin. Each specimen was serially sectioned for immunohistochemistry. Polyclonal antibodies specific for Ang1, Ang2, Tie2 and VEGF were used for immunostaining. Immunoreactivity for von Willebrand factor (factor VIII) was also assessed to confirm the identity of vascular endothelial cells. RESULTS: Positive staining for Tie2 was observed in 23 of 38 specimens (60.5%). Tie2 was localized in vascularized regions of fibrovascular membranes and was co- expressed with VEGF and factor VIII. Ang2 stained positively in 18 of 38 (47.3%) serial sections where Tie2 was present, and was also co-expressed with VEGF and factor VIII. Ang1 was not generally observed in these specimens (3/38). CONCLUSIONS: VEGF and Ang2-Tie2 interactions may play an important role in the pathogenesis of ROP.

Angiogenesis Inducing Agents↗
PubMed2000

Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration.

Accumulating evidence has shown the importance of vascular endothelial growth factor (VEGF) in chorioretinal angiogenesis. However, whether or not VEGF is indeed critical for the pathogenesis of subretinal neovascularization (SRN) in adulthood, which is a serious complication of age-related macular degeneration, has to be further investigated. We constructed an adenovirus expressing an entire ectodomain of the human VEGF receptor/flt-1 fused to Fc portion of human IgG (Adflt-ExR): this soluble receptor is secreted from Adflt-ExR-transfected cells. We studied the effect of Adflt-ExR on the formation of experimental SRN. Experimental SRN was induced by intense photocoagulation on the retina in pigmented rats and Adflt-ExR was injected into the femoral muscle. The formation of SRN assessed by fluorescein angiography was more significantly inhibited for 7 days in the Adflt-ExR-treated rats than in the control rats who received either an adenovirus vector encoding LacZ gene or balanced salt solution (BSS). The serum concentration of this soluble receptor increased for 7 days and thereafter gradually decreased. An immunohistochemical study disclosed the fibroblast cell proliferation and inflammatory cell infiltration to be reduced in the photocoagulation spot of Adflt-ExR-treated rats. VEGF plays a crucial role in the formation of SRN and VEGF soluble receptor gene transfection can inhibit SRN. This method will contribute to future gene therapy for age-related macular degeneration.

Adenoviridae↗
PubMed1999

Radiotherapy for isolated occult subfoveal neovascularisation in age related macular degeneration: a pilot study.

BACKGROUND/AIMS: Teletherapy has been proposed as a possible treatment for choroidal neovascular membranes (CNV), secondary to age related macular degeneration (AMD) not amenable to laser photocoagulation. The aim of this prospective study has been to investigate the effect of teletherapy on isolated occult choroidal neovascular membranes of subfoveal location. METHODS: 28 AMD patients presenting with retrofoveal isolated occult CNV demonstrated by fluorescein angiography were treated by external beam radiation. A complete ophthalmological examination, fluorescein angiography, and indocyanine green angiography (ICG) were performed within 15 days before treatment and repeated at follow up. A total dose of 16 Gy was applied in four sessions of 4 Gy using a 4 MeV photon beam. Follow up ranged from 6 to 9 months (mean follow up 6.4 months). RESULTS: Visual acuity was found to be stable in 68% of the cases. The decrease in visual acuity was of 3-6 lines in 18% and of more than 6 lines in 10% of the eyes at last examination. On fluorescein angiography the size of the lesion area was found to be stable in 67%, decreased in 13%, and increased in 20% of the cases. On ICG angiography the size of the CNV was stable in 93% and increased in 7% of the cases. All the eyes experiencing a visual acuity decrease showed either no change or an increase in size of the membrane on fluorescein angiography and/or on ICG. CONCLUSION: According to this study with strict inclusion criteria, external beam radiotherapy seems to have a beneficial effect on the evolution of isolated occult subfoveal CNV.

Aged↗