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PubMed1995

Comparative analysis of vascular endothelial growth factor receptors on retinal and aortic vascular endothelial cells.

Ischemic eye disease often results in ocular neovascularization, presumably due to the elaboration of growth factors. Diabetic retinopathy is a classic example in which dramatic retinal neovascularization arises after ischemic retinal damage. The characterization of vascular endothelial growth factor (VEGF) as an angiogenic molecule whose expression is markedly induced by hypoxia makes it a promising candidate for mediating ischemic retinal neovascularization. Thus, we have characterized the structure, binding, and regulation of VEGF receptors in bovine retinal (BREC) and aortic endothelial cells (BAEC). VEGF stimulated a 2.1-fold increase in BREC number and DNA content at 0.6 nmol/l VEGF (P < 1 x 10(-7)). Scatchard binding analysis demonstrated specific high-affinity VEGF receptors on BREC with a Kd of 4.9 +/- 0.6 x 10(-11) mmol/l, similar to that observed for BAEC at 5.1 +/- 0.4 x 10(-11) mmol/l. BREC, however, possess 1.5 x 10(5) high-affinity receptors/cell, threefold more than BAEC (P < 0.003) and more than any cell type reported previously. 125I-VEGF affinity cross-linking revealed complexes at 220 and 170 kDa in BREC, but only a 220-kDa band of lesser intensity in BAEC. Cross-linking was displaceable in a dose-dependent manner by VEGF (P < 0.01) but not by other hormones. Hypoxia increased VEGF receptor number 50% in BREC without altering affinity. Antiphosphotyrosine immunoblotting showed VEGF-stimulated tyrosine autophosphorylation of VEGF receptor bands at 225 and 220 kDa and another band at 80 kDa within 1 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Role of anterior retinal cryoablation in the management of neovascular glaucoma.

In a prospective study, the effect of anterior retinal cryoablation (ARC) in the management of neovascular glaucoma (NVG) was evaluated over two years, in 72 patients (74 eyes). The outcome of trabeculectomy/seton surgery preceded by 360 degrees ARC was also analysed in 12 eyes of 12 patients (6 eyes in each group). Following ARC, pain relief with dramatic regression of anterior chamber inflammatory reaction was observed in 95% of the patients (59 eyes). At the end of the follow up, as confirmed by iris fluorescein angiography, regression of neovascularization of the iris was documented in 93.5% (58 eyes) of the cases. Intraocular pressure control (< or = 22 mm Hg) was achieved in 82.3% (51 eyes) cases. IOP control of < or = 22 mm Hg was achieved in all the 6 eyes with the seton surgery following ARC. Similarly, control of IOP was successfully achieved in all the 6 eyes of patients with NVG with trabeculectomy with post operative course of 5-fluorouracil following ARC. ARC is strongly recommended in NVG, especially in eyes with media opacities and as a preliminary procedure for filtering surgery or drainage implant surgery.

Adolescent↗
PubMed2000

Optic disk neovascularization in a patient with cytomegalovirus retinitis associated with renal transplantation.

PURPOSE: To report the development of optic nerve head neovascularization during the recovery phase of cytomegalovirus (CMV) retinitis in a renal allograft recipient. CASE REPORT: A 46-year-old male renal allograft recipient developed CMV retinitis seven months after transplantation. At the time of the diagnosis, the patient was being immunosuppressed with prednisone, cyclosporine, and azathioprine, and was treated with repeated intravitreal and intravenous ganciclovir. Six weeks after the initiation of therapy, optic disk neovascularization developed. This was confirmed by fluorescein angiography, which showed no areas of retinal capillary nonperfusion. At this stage, active retinal lesions were partially resolved. Apart from intraocular inflammation, no other cause of neovascularization was detected. Over the following six months, optic disk neovascularization regressed spontaneously without causing vitreous hemorrhage or visual loss. There was no recurrence of CMV retinitis during follow-up. CONCLUSION: Optic disk neovascularization may develop in the healing phase of CMV retinitis in renal transplant recipients.

Cytomegalovirus Infections↗
PubMed1993

Baseline and early natural history report. The Central Vein Occlusion Study.

OBJECTIVES: To evaluate panretinal photocoagulation for ischemic central vein occlusion and macular grid-pattern photocoagulation for macular edema with reduced visual acuity due to central vein occlusion and to further define the natural history of central vein occlusion. DESIGN: A multicenter randomized controlled clinical trial supported by the National Eye Institute, Bethesda, Md. PATIENTS: A total of 728 eyes from 725 patients were entered into one or more of four study groups: perfused, nonperfused, indeterminate perfusion, and macular edema. RESULTS: Follow-up of study patients is still in progress and no results are available for the randomized groups (nonperfused and macular edema). Thirty-eight (83%) of 46 evaluable eyes in the indeterminate group eventually demonstrated at least 10 disc areas of nonperfusion (28 eyes) or developed iris and/or angle neovascularization before retinal status could be determined (10 eyes). Four-month follow-up information is available for 522 of the 547 eyes in the perfused group. Thirty of these 522 eyes demonstrated iris and/or angle neovascularization at or before the 4-month follow-up visit. An additional 51 eyes had developed evidence of at least 10 disc areas of nonperfusion by the time of the 4-month visit. CONCLUSIONS: These findings confirm the importance of frequent follow-up examinations, including undilated slit-lamp examination of the iris, and gonioscopy in the management of all patients with recent onset of central vein occlusion.

Adult↗
PubMed2000

Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina.

Fibroblast growth factor-2 (FGF2) is a potent mitogen for vascular endothelial cells and exogenous administration of FGF2 stimulates angiogenesis. However, increased expression of FGF2 in the retina does not cause angiogenesis. One possible explanation is that FGF2 may not be capable of initiating angiogenesis unless it is administered in pharmacologic levels or there is coexpression of another angiogenic factor. Alternatively, there may be control mechanisms that sequester FGF2 in vivo, preventing it from manifesting its in vitro angiogenic activity. We tested the first hypothesis by crossing mice that express FGF2 in the retina with mice that express vascular endothelial growth factor (VEGF) in the retina. Surprisingly, despite comparable levels of VEGF expression, mice that expressed both FGF2 and VEGF had significantly less neovascularization than mice that expressed VEGF alone. The second hypothesis was tested by treating Rho/FGF2 transgenic mice with low-intensity laser photocoagulation that disrupts photoreceptors, but does not rupture Bruch's membrane, or intense laser that ruptures Bruch's membrane. In Rho/FGF2 transgenics, but not wild type mice, choroidal neovascularization developed in areas of low-intensity laser. Both wild type and transgenic mice developed choroidal neovascularization in areas of intense laser that ruptured Bruch's membrane, but the area of neovascularization was significantly greater in transgenics. These data suggest that increased retinal expression of FGF2 is angiogenic only when it is accompanied by cell injury that overcomes sequestration control mechanisms.

Animals↗
PubMed1992

An atypical fulminant course of choroidal osteoma in two siblings.

We studied two cases of bilateral choroidal osteoma in an otherwise healthy 5-year-old boy and his only sibling, a 7-year-old sister. Both children were known to have normal fundus appearances at younger ages. The tumor showed slow growth in all four eyes, but severe visual acuity loss developed in three eyes because of neovascular complications that could not be effectively treated by photocoagulation. Secondary retinal cysts developed in three eyes.

Child↗
PubMed1986

Diagnosis and management of ocular complications of sickle hemoglobinopathies: Part V.

Sickle cell retinopathy in its advanced form is complicated by preretinal neovascularization, vitreous hemorrhage, and retinal detachment. Treatment of neovascularization can be performed with photocoagulation. Complications such as retinal breaks, retinal detachments, and choroidally fed neovascularization may result from such treatment. The risks vs. the benefits of various types of photocoagulation are currently being evaluated. Cryotherapy also may be used to treat neovascularization. It is currently being used in eyes with media that are too hazy to permit photocoagulation. It is used commonly during scleral buckling and vitrectomy procedures. In eyes with decreased visual acuity secondary to prolonged vitreous hemorrhage, pars plana vitrectomy can be utilized to produce optically clear media. Complications (including erythrocyte-induced glaucoma), however, may be severe. Retinal detachment can be treated by scleral buckling, but the markedly increased risk of anterior segment ischemia in patients with sickle cell hemoglobin necessitates preoperative, intraoperative, and postoperative prophylactic measures to minimize the risk of this potentially devastating complication. In eyes with retinal detachment with cloudy media and severe vitreous traction, combined scleral buckling and vitrectomy may be necessary. These eyes are extremely fragile, and a successful result is currently obtained in only about 50% of such cases. Hyphemas in patients with sickle cell hemoglobinopathies, whether traumatically or surgically induced, may have devastating effects on the eye. If elevated IOP results decreased vascular perfusion of the eye may cause irreversible damage to the retina and optic nerve. Most antiglaucoma medications, when used in the sickle cell patient, have a narrow margin of safety. Therefore, early surgical intervention for the treatment of sickle cell hyphemas is currently being evaluated.

Anemia, Sickle Cell↗
PubMed1984

Ocular vasodilation and angiogenesis in Potter's syndrome.

At autopsy we examined eight eyes of six infants with Potter's syndrome, an idiopathic multisystem condition with a constellation of ocular anomalies, to explore its ocular component more fully and systematically. A striking abnormality in some cases was the presence of dilated intraocular blood vessels, and these were sometimes associated with retinal and preretinal neovascularization reminiscent of the vasoproliferative stage of retrolental fibroplasia. Since oxygen therapy cannot be implicated in these cases, other causes, either genetic or environmental, must be sought. The presence of nonretinal ocular vascular anomalies, such as iris capillary dilation, peripapillary angioma formation, and vascular anomalies in nonocular tissue, point to a generalized derangement in the control of ocular angiogenesis. Our study indicated that an understanding of the pathogenesis of the vascular anomalies in Potter's syndrome is clearly relevant to other more common retinopathies that are associated with neovascularization.

Abnormalities, Multiple↗
PubMed1988

Role of the vitreous in branch retinal vein occlusion.

We analyzed the vitreous findings in 62 patients (62 eyes) with major branch retinal vein occlusion to determine whether vitreous examination was useful in predicting the development of retinal or disk neovascularization, or both. In 18 eyes with no or partial posterior vitreous detachment and large areas of capillary nonperfusion (5 disk diameters or more), ten eyes (55.6%) eventually developed neovascularization. Only three of the remaining 44 eyes (6.8%) developed neovascularization. The probability of this development was greater in eyes with no partial posterior vitreous detachment at the initial vitreous examination (P = .0177, Cox's regression analysis), and in those with large areas of nonperfusion (P = .0097, Cox's regression analysis).

Aged↗
PubMed2006

Role of vascular endothelial growth factor in ocular angiogenesis.

VEGF-A is a critical regulator of ocular angiogenesis and vascular permeability and is involved in the pathogenesis of several ocular diseases involving neovascularization or increased vascular permeability, such as neovascular AMD, diabetic ME, and diabetic retinopathy. Currently available therapies for neovascular AMD, such as laser photocoagulation, PDT with verteporfin, and pegaptanib sodium, slow visual loss but do not improve vision for most patients. In contrast, an emerging anti-VEGF agent, ranibizumab, improved vision in 25% to 34% of treated patients in one clinical trial, rather than slowing visual loss and is the first treatment for neovascular AMD to demonstrate visual improvement in a substantial number of patients. This represents a major advance in the treatment of ocular diseases involving neovascularization or increased vascular permeability and provides hope to patients with these debilitating diseases. Since the submission of this article, ranibizumab was approved by the FDA for the treatment of neovascular AMD.

Animals↗
PubMed2005

Transient serous retinal detachment in classic and occult choroidal neovascularization after photodynamic therapy.

PURPOSE: To quantify transient serous retinal detachment in classic and occult choroidal neovascularization (CNV) after photodynamic therapy (PDT). DESIGN: Prospective consecutive case series. METHODS: Consecutive patients with classic and occult CNV were examined by optical coherence tomography before PDT and at 2 and 7 days after PDT. RESULTS: In classic CNV (n = 6), retinal elevations increased from 217 (SD 42) microm before PDT to 626 (SD 157) microm 2 days after PDT and decreased to 240 (SD 36) microm 7 days after treatment. In occult CNV (n = 4), the mean retinal elevation of 266 (SD 41) microm before PDT increased to 544 (SD 94) microm 2 days after PDT and decreased to 259 (SD 40) microm 7 days after treatment. CONCLUSION: Cross-sectional optical coherence tomography imaging revealed transient subretinal fluid accumulation in classic as well as in occult CNV after PDT. The subretinal location possibly relates to an outer blood-retinal barrier breakdown after PDT.

Blood-Retinal Barrier↗
PubMed1995

Clinicopathologic correlation of spontaneous retinal pigment epithelial tears with choroidal neovascular membranes in age-related macular degeneration.

BACKGROUND: A correlation of the clinical and histopathologic features of age-related macular degeneration (AMD), complicated by choroidal neovascular membrane (CNVM) with spontaneous tears of retinal pigment epithelial (RPE) detachment, has not been reported. METHODS: Two patients with vision loss from AMD and spontaneous pigment epithelial detachment tears, involving the fovea with serous or hemorrhagic neurosensory retinal detachments, were examined clinically. The surgically excised CNVM from each patient was examined with light microscopy. RESULTS: The authors present two patients with clinicopathologic correlation of the ophthalmoscopic, fluorescein angiographic, and pathologic findings of spontaneous pigment epithelial detachment tears. In the surgical specimens from these two eyes, the removed tissue, presumed to be the spontaneous RPE tear with CNVMs, demonstrated a fibrovascular membrane surrounding RPE with adjacent abnormally thickened basement membrane. The RPE-basement membrane complex was folded redundantly and scrolled beneath itself. CONCLUSION: The authors found RPE-basement membrane abnormalities and CNVMs associated with clinically evident spontaneous pigment epithelial detachment tears. These findings support the current theories of their pathogenesis.

Aged↗
PubMed2002

Neuropeptide Y expression in a mouse model of oxygen-induced retinopathy.

BACKGROUND: Neuropeptide Y (NPY) is a potent vaso-constrictor and angiogenic agent that is found in the retina. The goal of this study was to determine the expression of NPY and its receptors, NPY Y1 and NPY Y2, in a mouse model of oxygen-induced retinopathy. METHODS: Retinal NPY, NPY Y1, and NPY Y2 mRNA expression were evaluated using reverse transcriptase-polymerase chain reaction. Neuropeptide Y cellular localization was determined using immunohistochemistry. RESULTS: Retinal NPY mRNA expression was increased by 2.3-fold from P7 to P12, and 2.8-fold from P7 to P17 in oxygen-reared animals. Retinal NPY Y1 was increased 1.9-fold from P7 to P12 in room-air-reared animals. There was no change in NPY Y1 expression following exposure to oxygen. Retinal NPY Y2 expression in oxygen-reared animals increased by 2.8-fold from P7 to P12 and by 2.7-fold from P12 to P17. There was no change in NPY Y2 expression in room-air-reared animals. Retinal NPY and NPY Y2 expression increased concomitant with vasoconstriction and neovascularization seen in this model by evaluation of retinal whole mounts. Neuropeptide Y protein was detectable by immunohistochemistry mainly between the inner and outer nuclear layers and increased with hyperoxic exposure at P12 and also increased during the period of relative retinal hypoxia at P17. CONCLUSIONS: Retinal NPY and NPY Y2 receptor expression are altered in the development of oxygen-induced retinopathy of the mouse, during both the hyperoxic vasoconstrictive phase and the period of retinal neovascularization. Alteration in the production of NPY and the NPY Y2 receptor may be avenues for potential modification in the development of retinopathy.

Animals↗
PubMed1998

What is the role of radiation in the treatment of subfoveal membranes: review of radiobiologic, pathologic, and other considerations to initiate a multimodality discussion.

BACKGROUND: Single-dose-fraction conformal proton beam and multiple-fraction X ray dose schedules have been used to treat subfoveal neovascular membranes. All schedules successfully controlled membrane progression, stabilized vision in most patients, and increased visual acuity in some. Conformal protons also decreased the radiation dose to healthy tissues outside the designated volume (16 mm in diameter). It appears that radiation therapy could be useful and cost-effective, but neither the optimal time-dose schedule single or multiple dose fractions nor the type of radiation proton conformal beam or x-ray therapy are defined. METHODS: By means of an extensive literature survey, we reviewed the rationale for using radiation to treat subfoveal neovascularization, examined a paradigm of radiation interaction with tissue, reviewed the histopathology of neovascular membranes, and documented the role of growth factors in the pathophysiology of the disease. Accepting that the eye is an extracranial brain extension, and that its microvasculature has properties similar to brain microvessels, we reviewed the radiobiologic response of brain microvessels. We also revisited the controversy concerning the efficacy of single-dose-fraction vs. multifraction schedules. RESULTS: This paper outlines parameters within which radiation therapy's role might be defined, and proposes a clinical radiation-biology scoring program to evaluate radiation effects, based on the SOMA concept. CONCLUSION: A prospective, controlled clinical trial is feasible and is indicated to determine radiation therapy's role in managing the proliferative component of age-related macular degeneration.

Aged↗
PubMed1997

Ocular growth in newborn rabbit eyes implanted with a poly(methyl methacrylate) or silicone intraocular lens.

PURPOSE: To examine eye growth in lensectomized infant rabbits implanted with a poly(methyl methacrylate) (PMMA) or a silicone intraocular lens (IOL). SETTING: S:t Eriks Eye Hospital, Karolinska Institute, Stockholm, Sweden. METHODS: Two groups of 3-week-old rabbits were used. In Group 1 (n = 13), lensectomy was performed in both eyes. In one randomly selected eye, a +30 diopter (D) heparin-surface-modified (HSM) PMMA IOL was implanted in the capsular bag; the other eye was left aphakic. In Group 2 (n = 10), a +21 D HSM PMMA IOL was implanted in one randomly selected eye and a +21 D silicone IOL was implanted in the other. Axial length, corneal diameter, corneal thickness, and intraocular pressure (IOP) were measured in all eye preoperatively and 1, 2, and 3 months after surgery. The wet mass of the after-cataract was measured 3 months after surgery. The ciliary body with the ciliary processes and the peripheral retina were examined histologically after formalin fixation. The two IOL types were compressed to 7.0 MM, corresponding to the diameter of the 3-week-old rabbit lens. RESULTS: In Group 1, the axial length was significantly decreased in the eye with an HSM PMMA IOL compared with the fellow aphakic eye (P < .01, two-way analysis of variance [ANOVA]). No significant difference in corneal diameter, corneal thickness, or IOP was found between the eyes. The wet mass of the dissected after-cataract was significantly less in the eye implanted with an IOL. Two animals had an elevated IOP with secondary glaucoma in their aphakic eye and were excluded from the study. In Group 2, axial length in eyes with the HSM PMMA IOL was less than in the eyes with the silicone IOL (P < .25, two-way ANOVA). No difference in corneal diameter, corneal thickness, or IOP was found. The amount of after-cataract was not altered. Histologically, the eyes with the HSM PMMA IOL showed retinal degeneration, neovascularization of the ciliary body accompanied by a large number of inflammatory cells, and tumid ciliary processes. The eyes with the silicone IOL showed only minor changes. The aphakic eyes presented even less histological change. The compression test demonstrated that three time the compression force was needed to squeeze the HSM PMMA lens than the silicone IOL. CONCLUSION: The results suggest that in the young rabbit eye, implanting a regular size HSM PMMA IOL destroys intraocular tissues and reduces eye growth significantly. Replacing the PMMA IOL with a silicone IOL improves the ocular growth.

Animals↗
PubMed2006

Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.

PURPOSE: To report the biologic effect of intravitreal bevacizumab in patients with retinal and iris neovascularization secondary to diabetes mellitus. DESIGN: Interventional, consecutive, retrospective, case series. PARTICIPANTS: Forty-five eyes of 32 patients with retinal and/or iris neovascularization secondary to diabetes mellitus. METHODS: Patients received intravitreal bevacizumab (6.2 microg-1.25 mg). Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography. MAIN OUTCOME MEASURES: Change in fluorescein angiographic leakage of the proliferative diabetic retinopathy (PDR). Secondary outcomes included changes in Snellen VA. RESULTS: No significant ocular or systemic adverse events were observed. All patients with neovascularization demonstrated by fluorescein angiography (44/44 eyes) had complete (or at least partial) reduction in leakage of the neovascularization within 1 week after the injection. Complete resolution of angiographic leakage of neovascularization of the disc was noted in 19 of 26 (73%) eyes, and leakage of iris neovascularization completely resolved in 9 of 11 (82%) eyes. The leakage was noted to diminish as early as 24 hours after injection. In addition to the reduction in angiographic leakage, the neovascularization clinically appeared to involute in many patients with a reduction in the caliber or presence of perfused blood vessels. In 2 cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow uninjected eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection. Recurrence of fluorescein leakage varied. Recurrent leakage was seen as early as 2 weeks in one case, whereas in other cases, no recurrent leakage was noted at last follow-up of 11 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab is well tolerated and associated with a rapid regression of retinal and iris neovascularization secondary to PDR. A consistent biologic effect was noted, even with the lowest dose (6.2 microg) tested, supporting proof of concept. The observation of a possible therapeutic effect in the fellow eye raises concern that systemic side effects are possible in patients undergoing treatment with intravitreal bevacizumab (1.25 mg), and lower doses may achieve a therapeutic result with less risk of systemic side effects. Further study is indicated.

Adult↗