Radiation-induced neovascular glaucoma: A devastating disease.

Neovascular glaucoma (NVG) is a potentially blinding form of secondary glaucoma, with radiation being one of the rare causes. This report is aimed to discuss a case of NVG caused secondary to radiotherapy (RT) given for a nasal malignancy. A 50-year-old male presented with enophthalmos, dry eye, and NVG 3 years after receiving RT for chondrosarcoma of nasal and paranasal cavities. He was given topical antiglaucoma medications, retinal laser, and intravitreal bevacizumab injection and thus prevented the eye from becoming a painful blind eye. The radiation oncologist and ear, nose, and throat specialists have to liaise closely with ophthalmologist when patients receive radiation involving the eye in the treatment field to prevent, diagnose, and treat this devastating condition.

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR-proNGF pathway.

Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.

Pars plana insertion of glaucoma shunt in eyes with refractory neovascular glaucoma: Case report.

RATIONALE: Neovascular glaucoma (NVG) is one of the most aggressive types of glaucoma in clinical practice. The outcomes are unsatisfactory despite the successful trabeculectomy with glaucoma shunt insertion. PATIENT CONCERNS: EX-PRESS Glaucoma Filtration Device (Alcon Laboratories, Fort Worth, TX), which is used in open-angle glaucoma surgery, could minimize the potential injury caused by traditional trabeculectomy. However, no study reported about the posterior segment insertion of this device. This article reports an alternative surgical technique and outcomes of pars plana insertion of glaucoma shunt in a patient with refractory NVG. DIAGNOSES: This research was a retrospective study of a patient with refractory NVG and in whom trabeculectomy with EX-PRESS implantation was performed. However, bleb failure developed three times in four years. INTERVENTIONS: In this patient, the previous EX-PRESS shunt was retrieved and reinserted into the posterior segment through the pars plana 3.5 mm behind the limbus. OUTCOMES: The post-operation intraocular pressure was stable for more than eight months after surgery without any surgical intervention or antiglaucoma medication use. No discomfort nor major complication was observed after this operation. LESSONS: Pars plana insertion of glaucoma shunt may provide an alternative to treat refractory NVG in patients who had received pars plana vitrectomy.

Management of neovascular glaucoma with intravitreal ranibizumab, panretinal photocoagulation, and subsequent 5-fluorouracil augmented trabeculectomy: A case report.

RATIONALE: Neovascular glaucoma (NVG) is one of the most refractory types of glaucoma caused by high ischemic retinal disorders, resulting in severe visual loss. Intravitreal injections of ranibizumab have been reported to have anatomical and functional success in treating NVG. PATIENT CONCERNS-DIAGNOSES-INTERVENTIONS: We report a case with neovascular glaucoma due to central retinal vein occlusion who received combination therapy with intravitreal ranibizumab (IVR) injection, panretinal photocoagulation (PRP) and subsequent 5-fluorouracil (5-FU) augmented trabeculectomy. OUTCOMES: One week after IVR injection, the intraocular pressure (IOP) had partially decreased to 33 mmHg, and there was a complete regression of neovascularization of the iris (NVI) and the angle (NVA). PRP was feasible after IVR due to improvement of corneal edema which made an adequate view of the posterior pole of fundus. The surgery of trabeculectomy with 5-FU was performed 2 weeks after IVR to control the IOP. The intraoperative and postoperative courses were uneventful without any adverse complication. Post trabeculectomy, his vision remained stable and the IOP was in the range of 4-15 mmHg without topical antiglaucoma medications. A functioning bleb was maintained and there was no recurrence of NVI and NVA during the complete follow-up period of 6 months. LESSONS: Combined treatment of IVR, PRP, and subsequent 5-FU augmented trabeculectomy is demonstrated to be a possible new paradigm for the management of advanced NVG with angle closure and intractable elevation of IOP.

[Effect of Intravitreal Bevacizumab Injection on Iris and Iridocorneal Angle Neovascularization in Neovascular Glaucoma].

Neovascular glaucoma is a serious complication associated with retinal ischemic changes, which increase the production of vascular endothelial growth factor. Vascular endothelial growth factor has been implicated as a key molecule in the development of newly formed vessels and neovascular glaucoma. Intravitreal injection of bevacizumab, a full-length humanized anti-vascular endothelial growth factor monoclonal antibody, leads to a dramatic regression of the new iris and iridocorneal angle vessels on slitlamp examination. However, anterior segment angiography reveals that bevacizumab does not cause a regression of the neovascular vessels themselves but reduces vascular permeability while newly formed vessels are still present in the iris and iridocorneal angle. This review focuses on the pathology and diagnosis of neovascula glaucoma and the effect of intravitreal bevacizumab on the iris and iridocorneal angle neovascularization.

Advanced exudative retinopathy with neovascular glaucoma as the clinical presentation of diabetes mellitus and severe combined hyperlipidemia: a case report.

UNLABELLED: A 50-year-old man presented with bilateralprogressive visual loss for 5 months. Visual acuity was reduced to countingfingers in the right eye and light perception in the left. Although neovascularizations were detected in the angles of the eyes, neovascular glaucoma and rubeosis iridis were demonstrated only in the left. Fundus examination showed bilateral advanced exudative retinopathy in both eyes. Severe attenuated retinal arteries and enlarged cupping with disc pallor were observed in the left eye. Generalized eruptive xanthomas were found on the back and extremities. Extreme dyslipidemia (serum cholesterol 1311 mg/dl and triglycerides 6356 mg/dl) and diabetes mellitus (fasting plasma glucose 325 mg/dl and HbA1 c 12.1%) were first diagnosed. The serum lipid profiles and glucose levels were dramatically decreased within a month after treatment with subcutaneous insulin injections and oral hypolipidemic agents; notwithstanding, his vision was not significantly improved, even after treatment with intravitreal anti-VEGF injection, intravitreal steroid injection and panretinal photocoagulation. CONCLUSION: The principle causes of advanced exudative retinopathy are severe breakdown of the blood-retinal barrier due to diabetes mellitus and altered retinal pigment epithelium lipid metabolism. In ourpatient, central retinal vascular occlusion was also the suspected cause ofneovascular glaucoma.

[Neovascular glaucoma treatment in 2012: role of anti-VEGF agents]. / Traitement du glaucome néovasculaire en 2012 : apport des anti-VEGF.

Neovascular glaucoma is a serious pathology with a variety of causes. It results from the secretion by hypoxic retinal tissue of growth factors, including vascular endothelial growth factor (VEGF). Anterior segment involvement begins in the iris, followed by the development of a fibrovascular membrane in the angle, with resultant goniosynechiae. Treatment of the underlying disease consists most often of panretinal photocoagulation. As for the secondary sequelae, current treatment consists of intravitreal injection of anti-VEGF agents. The most utilized agent is bevacizumab or Avastin, off-label. Avastin is effective against neovascularization and ocular hypertension, especially in the early stages. It also represents an adjunct to filtering surgery. It appears to be very well tolerated.

Clinical outcomes and changes in aqueous vascular endothelial growth factor levels after intravitreal bevacizumab for iris neovascularization and neovascular glaucoma: a retrospective two-dose comparative study.

PURPOSE: To evaluate the clinical outcomes and biologic effects on the aqueous humor concentrations of vascular endothelial growth factor (VEGF) in patients with neovascular glaucoma (NVG) treated with intravitreal bevacizumab (IVB). METHODS: Twenty-nine consecutive patients (35 eyes) treated with 1.0- or 0.1-mg injections of IVB for NVG between January and December 2009 were enrolled in this retrospective, interventional pilot study. The visual prognosis and changes in intraocular pressure (IOP) were followed for >6 months after the initial injection. Aqueous humor samples were obtained at the initial IVB injection from all study eyes and 1 week after the first injection in eyes undergoing a second intervention to measure the VEGF concentration. RESULTS: The VEGF concentrations in the 35 eyes significantly correlated (r=0.535, P<0.001) with the pretreatment IOP. The mean reductions of the VEGF levels 1 week after IVB did not differ significantly between the 1.0- and 0.1-mg groups (P=0.738). Despite more repeated injections in the 0.1-mg group and additional medical or surgical interventions in both groups, both dosages inhibited the neovascular activity. The ability to control the IOP after IVB did not differ significantly between groups at 1 week (P=0.625) and 6 months (P>0.99). Visual improvements also did not differ significantly between groups during the 6-month follow-up (P=0.437). CONCLUSIONS: Aqueous humor levels of VEGF were significantly correlated with the IOP. Low-dose (0.1 mg) IVB was as effective as the currently used higher dose (1.0 mg) for treating NVG within at least 6 months after the initial injection.

[Results in neovascular glaucoma treatment]. / Rezultate terapeutice in glaucomul neovascular.

This report presents the results of a study on 34 patients with neovascular glaucoma. We analyse the difficulties and the results of the management of this severe form of glaucoma.

Intravitreal bevacizumab treatment for neovascular glaucoma: histopathological analysis of trabeculectomy specimens.

BACKGROUND: Neovascular glaucoma (NVG) is a serious complication for patients with proliferative diabetic retinopathy (PDR). Bevacizumab is a full-length humanized monoclonal antibody that binds all isoforms of vascular endothelial growth factor (VEGF). Recently, encouraging results regarding the off-label use of intravitreal bevacizumab (IVB) for the treatment of NVG have been reported. We evaluated the histology of bevacizumab-treated trabeculectomy specimens to clarify IVB's biological effects on angle neovascularization. METHODS: We retrospectively reviewed the charts of a consecutive series of 15 eyes of 13 patients who underwent trabeculectomy to treat NVG caused by PDR. In ten eyes of eight patients, 1.25 mg bevacizumab was injected intravitreally via the pars plana. Using light or electron microscopy, the surgically excised trabecular tissue was compared to that without IVB. RESULTS: Light microscopy revealed decreased edema, fibrin deposition, inflammation and vascular congestion in the trabecular meshwork in specimens with IVB compared to those without IVB. Electron microscopy revealed endothelial cell degeneration in the bevacizumab-treated specimens. CONCLUSIONS: The biological effects on angle neovascularization after IVB may involve reduced vascular permeability, decreased inflammatory reaction, loss of vascular function, and endothelial cell degeneration.

Rabbit rubeosis iridis induced by intravitreal latex-derived angiogenic fraction.

PURPOSE: To describe the presence of iris neovascularization in a rabbit-model of retinal neovascularization induced by the intravitreal injection of latex-derived angiogenic fraction microspheres (LAF). MATERIALS AND METHODS: Eight New Zealand rabbits received one intravitreal injection of PLGA (L-lactide-co-glycolide) microspheres with 50 ug of LAF in the right eye (Group A). Microspheres without the LAF (0.1 ml) were injected in controls (Group B; n = 8). Follow-up with clinical evaluation and iris fluorescein angiography was performed after 4 weeks when eyes were processed for light microscopy. RESULTS: All eyes from Group A showed significant vascular dilation, conjunctival hyperemia and neovascularization on the iris surface, after LAF injection. No vascular changes were observed in Group B. CONCLUSIONS: The intravitreal injection of microspheres containing the LAF can induce rubeosis iridis in rabbits and could be used as a simple experimental model for iris neovascularization.

Neovascular glaucoma after stereotactic radiotherapy for juxtapapillary choroidal melanoma: histopathologic and dosimetric findings.

PURPOSE: Enucleation after stereotactic radiotherapy (SRT) for juxtapapillary choroidal melanoma may be required because of tumor progression (TP) or the development of intractable radiation-induced neovascular glaucoma (NVG). We compare pathologic changes and dosimetric findings in those eyes enucleated secondary to NVG as opposed to TP to better understand potential mechanisms. METHODS AND MATERIALS: Patients with juxtapapillary choroidal melanoma treated with SRT (70 Gy in 5 fractions, alternate days over a total of 10 days) at the Princess Margaret Hospital, Toronto, Ontario, Canada, who underwent enucleation between 1998 and 2006 were selected. We correlated dosimetric data based on the patient's original SRT treatment plan with histopathologic findings in the retina, optic nerve head, and anterior chamber. A dedicated ocular pathologist reviewed each case in a blinded fashion. RESULTS: Ten eyes in ten patients were enucleated after SRT. Six were enucleated secondary to NVG and four secondary to because of TP. Aggressive tumor features such as invasion of the sclera and epithelioid cell type were observed predominantly in the TP group. Retinal damage was more predominant in the NVG group, as were findings of radiation-related retinal vascular changes of fibrinoid necrosis and hyalinization. No conclusive radiation-related effects were found in the anterior chamber. The maximum point dose and dose to 0.1 cc were lower for the anterior chamber as compared with the dose to the tumor, retina, and optic nerve head. The mean 0.1-cc doses to the retina were 69.4 Gy and 73.5 Gy and to the anterior chamber were 4.9 Gy and 17.3 Gy for the NVG group and tumor progression group, respectively. CONCLUSIONS: Our findings suggest that NVG is due to radiation damage to the posterior chamber of the eye rather than primary radiation damage to the anterior segment.

Evaluation of cytotoxicity of bevacizumab on VEGF-enriched corneal endothelial cells.

PURPOSE: To evaluate the cytotoxicity of varying doses of Bevacizumab on corneal endothelial cells in the presence of a range of concentrations of vascular endothelial growth factor (VEGF). Bevacizumab, a drug widely used in the treatment of neovascular glaucoma neutralizes all isoforms of VEGF and ameliorates neovascularization after intracameral administration. However, the safety of intracameral administration of Bevacizumab and dose-dependent toxicity on corneal endothelial cells has not been established. METHODS: Bovine corneal endothelial (BCE) cells were treated with VEGF (50 ng/ml) and/or Bevacizumab (0.1-2 mg/ml) for 72 h. Cell proliferation was measured with the water soluble tetrazolium salts (WST-1) assay. Morphological changes were recorded by bright-field microscopy of cells. Cytotoxicity in response to Bevacizumab was evaluated by trypan blue exclusion, as well as annexin V/propidium iodide (PI) staining. RESULTS: Bevacizumab was not cytotoxic at the concentrations tested and the percentage of Bevacizumab-treated cells staining positively for both PI and Annexin V was less than 1%. The anti-proliferative effects of Bevacizumab on BCE cells were dose-dependent; a dose of 1.5 mg/ml or 2 mg/ml produced a 33% (p=0.005) or 47% (p=0.001) decrease in cell proliferation compared to controls. Similar results were obtained in cells treated with a combination of Bevacizumab and VEGF. VEGF (50 ng/ml) had no significant effect on cell proliferation compared to controls. Morphology of cells was unchanged after treatment with Bevacizumab and/or VEGF compared to controls. CONCLUSIONS: Bevacizumab was safe and not toxic to BCE cells at concentrations commonly used in clinical practice.

Langerhans cell histiocytosis of the uvea with neovascular glaucoma: diagnosis by fine-needle aspiration biopsy and management with intraocular bevacizumab and brachytherapy.

A 6-year-old boy with known multisystem Langerhans cell histiocytosis developed photophobia, conjunctival injection, iris neovascularization, and an iridociliochoroidal mass. Fine-needle aspiration biopsy revealed mononucleated and multinucleate histiocytes that demonstrated positive immunostaining for CD68 and S100 consistent with Langerhans cell histiocytosis. Management with intracameral bevacizumab (1.25 mg/0.05 mL) resolved the iris neovascularization, and plaque radiotherapy (brachytherapy) resolved the mass rapidly and completely, preserving the patient's visual acuity and preventing glaucoma during the 10-month follow-up.

Combined diode laser cyclophotocoagulation and intravitreal bevacizumab (Avastin) in neovascular glaucoma.

BACKGROUND: Intravitreal injection of bevacizumab (Avastin) in eyes with neovascular glaucoma (NVG) has recently been shown to induce rapid regression of anterior segment neovascularization and has promise as adjunct treatment to diode laser cyclophotocoagulation (CPC) to control intraocular pressure (IOP). This study presents the outcome of concomitant treatment with CPC and intravitreal bevacizumab in painful poor visual potential eyes in a case series of consecutively diagnosed NVG. METHODS: Twelve patients (14 eyes) were treated with CPC and concurrent intravitreal bevacizumab 0.05 mL (1.25 mg) and study end-points were IOP lowering, regression of anterior segment neovascularization and resolution of pain. RESULTS: The mean preoperative IOP was 42.1 11.4 and was lowered to 16.6 7.1 mmHg at 1-month postoperatively. Anterior segment neovascularization regressed dramatically within 1 week of intravitreal bevacizumab in 12 eyes. Thirteen eyes reported persistent relief of ocular pain at 6 months following treatment. CONCLUSIONS: Combined intravitreal bevacizumab and CPC treatment for NVG provides rapid control of anterior segment neovascularization and may lead to improved symptomatic relief and IOP control.

Histopathology of neovascular tissue from eyes with proliferative diabetic retinopathy after intravitreal bevacizumab injection.

PURPOSE: To examine the histopathologic effect of a single intravitreal injection of bevacizumab on newly formed vessels in eyes with proliferative diabetic retinopathy (PDR). DESIGN: Interventional case series and laboratory investigation. METHODS: Two days after intravitreal injection of bevacizumab (1.25 mg/eye), pars plana vitrectomy or trabeculectomy was performed for the treatment of PDR or neovascular glaucoma (NVG) associated with PDR. Ten surgically removed preretinal proliferative tissues and 6 deep scleral flaps containing trabecular meshwork were fixed in 2% glutaraldehyde or 4% paraformaldehyde and were subjected to transmission electron microscopic analysis, immunohistochemical analysis, and terminal deoxyuridiine triphosphate (dUTP) nick-end labeling staining. Two surgically removed preretinal proliferative tissues and 2 deep scleral flaps from patients with PDR and NVG, but without preoperative intravitreal injection of bevacizumab (IVB), served as controls. RESULTS: In control tissues, vascular endothelial cells possessed many fenestrations and were accompanied by pericytes. Apoptotic vascular endothelial cells frequently were observed in tissue after intravitreal injection of bevacizumab, whereas they were not observed in control tissues. Additionally, no apparent fenestration was observed in newly formed vessels from either proliferative tissue or trabecular meshwork after intravitreal injection of bevacizumab. In both PDR and NVG tissues after intravitreal injection of bevacizumab, overexpression of smooth muscle actin was observed in newly formed vessels, suggesting that the treatment may have increased pericytes on the vasculature as compared with control tissue. CONCLUSIONS: Intravitreal injection of bevacizumab may induce changes in immature, newly formed vessels of PDR or NVG tissue, leading to endothelial apoptosis with vascular regression, while inducing normalization of premature vessels by increasing pericyte coverage and reducing vessel fenestration.

In vivo corneal endothelial safety of intracameral bevacizumab and effect in neovascular glaucoma combined with Ahmed valve implantation.

PURPOSE: To evaluate the corneal toxicity of intracameral bevacizumab in rabbit eyes and also the effects of intracameral bevacizumab in neovascular glaucoma patients combined with Ahmed glaucoma valve implantation. MATERIALS AND METHODS: Intracameral bevacizumab (1.25 mg/0.05 mL) was injected into 5 eyes of 5 New Zealand white rabbits. A balanced salt solution (0.05 mL) was injected intracamerally in another 5 rabbits as a control. The corneal thickness, endothelial cell counts, and intraocular pressure were measured before and at 1, 2, and 4 weeks after the intracameral injection of bevacizumab and a balanced salt solution. Scanning electron microscopic examinations were performed at 1 and 4 weeks after injection. In the clinical cases, 6 patients who received an intracameral injection of bevacizumab (1.25 mg) and Ahmed glaucoma valve implantation were enrolled. The visual acuity, intraocular pressure, and regression of iris rubeosis by iris fluorescein angiography were recorded before and at 1 week, 1 month, and 2 months after the intracameral bevacizumab injection and Ahmed glaucoma valve implantation. RESULTS: No morphologic and functional changes in the corneal endothelial cells were observed in the rabbit eyes after the intracameral bevacizumab and balanced salt solution injections. Iris rubeosis regression was observed in all eyes within 1 week after the injection. The visual acuity remained stable or improved, and the intraocular pressure was controlled in all eyes throughout the follow-up period. There were no ocular and systemic complications associated with the combined procedure. CONCLUSIONS: An intracameral injection of bevacizumab may be a safe alternative treatment for iris rubeosis in neovascular glaucoma when combined with Ahmed glaucoma valve implantation.

Intracameral bevacizumab (Avastin) for neovascular glaucoma: a pilot study in 6 patients.

PURPOSE: To describe the use of intracameral bevacizumab (ICB) Avastin in neovascular glaucoma (NVG) as the first maneuver before pan retinal photocoagulation and/or filtering surgery. METHODS: Between June 2006 and May 2007, 6 consecutive patients with NVG underwent intracameral injection of bevacizumab (1.25 mg/0.05 mL) as the initial treatment of NVG. Pre-ICB and post-ICB anterior segment photography, iris fluoresceingraphy when possible, gonioscopy with peripheral anterior synechiae (PAS), neovascular membrane (NVM) extension grading, as well as intraocular pressure (IOP) changes during treatment were recorded. All patients were followed for at least 7 months. RESULTS: ICB resulted in a marked regression of anterior segment neovascularization with IOP control without filtering surgery in 2 cases. When PAS extended <330 degrees without previous glaucoma, no filtering surgery was needed to control IOP<18 mm Hg. Iris neovascularization extension had no prognostic value in terms of IOP control. After vascular regression following the administration of ICB, filtering surgery with drainage implants or trabeculectomy were performed when needed with no added difficulties owing to the underlying NVG. No macroscopic signs of corneal toxicity were detected, even when ICB injection had to be repeated. In this case, the time elapsed for the neovascular membrane to reappear at the anterior segment was 3 months. CONCLUSION: ICB resulted in a rapid regression of the iris and angle neovascularization, which permitted to halt the progression of PAS process. This pilot study shows that intracameral injection of bevacizumab may be a helpful adjunct for the surgical treatment of NVG.