Neovascular Glaucoma Current Concepts and Management
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THERAPEUTICS UPDATE Neovascular Glaucoma Current concepts and management. BY JAMES C. TSAI, MD, AND M. BRUCE SHIELDS, MD eovascular glaucoma (NVG) is a devastating is the most extensively studied of the pro-angiogenic ocular disease, often seen as an end-stage factors in the pathogenesis of NVG.5,6 Müller cells are complication of retinal ischemia. Its patho- thought to represent a significant source of VEGF N genesis is associated with neovascularization under the conditions of retinal hypoxia. Elevated lev- of the iris (NVI) and of the anterior chamber angle els of VEGF have been identified in the aqueous (NVA), with resultant proliferation of fibrovascular tissue humor of patients with NVG.7 Experimental studies in in the anterior chamber. The fibrovascular membrane eventually obstructs the trabecular meshwork and con- A tracts to produce progressive angle closure with broad peripheral anterior synechiae. The IOP may become sig- nificantly elevated and difficult to control, resulting in advanced glaucomatous optic neuropathy and irre- versible visual loss.1 The most common conditions associated with NVG are proliferative diabetic retinopathy (PDR), central reti- nal vein occlusion (CRVO), and ocular ischemic syn- drome.1,2 The list of associated ocular diseases is exten- B sive, however, and the majority (up to 97%) are associ- ated with an underlying process of retinal ischemia and hypoxia.1 This article focuses on the current under- standing of NVG, its diagnosis, and its treatment as well as future therapies. MOLECULAR CONCEPTS Retinal ischemia is one of the most significant etiolog- C ic factors in the formation of NVI and NVA. The result- ing hypoxia causes the release of factors that both pro- mote and inhibit the growth of new vessels.3 Moreover, vascular endothelial cells play a crucial role in the entire process of angiogenesis. In response to tissue hypoxia, these endothelial cells secrete diffusible, pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, tumor necrosis factor-alpha, insulin-like growth factors, interleukin-6, Figure 1. The clinicopathologic stages of neovascular glauco- and platelet-derived growth factor.4 This process stimu- ma are preglaucoma (A), open-angle glaucoma (B), and lates a cascade leading to the activation, proliferation, angle-closure glaucoma (C). (Adapted and reprinted with per- and migration of endothelial cells with the formation of mission from Allingham RR, Damji K, Freedman S, et al. new, leaky, fragile blood vessels. Shields’Textbook of Glaucoma. 5th ed. Lippincott Williams & Comprising four homodimeric polypeptides, VEGF Wilkins: Philadelphia; 2005: 331.) 36 IGLAUCOMA TODAYIMAY/JUNE 2006 THERAPEUTICS UPDATE Neovascularization of angle/iris No useful vision Useful vision Pain No Pain Cause of NVA/NVI Monitor Normal IOP High IOP Retinal ischemia Inflammation Anti-inflammatory Steroids, Medical Normal IOP High IOP cycloplegia glaucoma Rx, Rx steroids, cycloplegia Media Media not Media Media not clear clear clear clear Normal IOP High IOP Pain No pain PRP Monitor, PRP Diode Continue Rx vitrectomy/ retinopexy, Cyclodestruction, Continue Rx Monitor endolaser retinal retrobulbar alcohol, cryablation, enucleation vitrectomy/ endolaser • Medical glaucoma Rx • Glaucoma surgery: - Trabeculectomy with antimetabolite - Aqueous tube shunt - Diode laser cyclophotocoagulation Figure 2. This treatment algorithm for NVG uses the following abbreviations: NVA/NVI, neovacularization of the angle/iris; PRP, panretinal photocoagulation; and Rx, therapy. (Adapted and reprinted with permission from Tsai JC, Forbes M. Medical Management of Glaucoma. 2nd ed. Professional Communications: Caddo, OK; 2004: 224-225.) nonhuman primates have also shown that intravitreal factor-alpha, interleukin-6, and platelet-derived injections of human recombinant VEGF are sufficient growth factor. to produce noninflammatory NVI, ectropion uveae, The formation of new vessels in the eye is affected to a and NVG.8 large extent by the homeostatic balance between VEGF Therapy targeted for VEGF is complex, owing to the and other pro-angiogenic factors and the anti-angiogenic diversity of endothelial cells, which includes variation factor, pigment-epithelium-derived factor (PEDF).9,10 in tissue expression of the gene encoding VEGF and PEDF is a naturally occurring and extremely potent in- the complexity of the VEGF family isoforms and recep- hibitor of angiogenesis that not only targets new vessel tors. Furthermore, VEGF therapy alone would likely growth but also has powerful neuroprotective activities. not be sufficient to fully counteract the angiogenesis Studies have shown increased levels of VEGF and de- process due to the contribution of dozens of other creased levels of PEDF in the vitreous humor of patients factors in the angiogenesis cascade.9 These other pro- with PDR. Observations of reduced PEDF levels in the vit- angiogenic factors include insulin-like growth factors I reous of patients with active diabetic retinopathy, com- and II, insulin-like growth factor binding proteins 2 pared with inactive retinopathy, further support the the- and 3, basic fibroblast growth factor, tumor necrosis ory of a VEGF-PEDF homeostatic equilibrium.11,12 MAY/JUNE 2006 IGLAUCOMA TODAYI 37 THERAPEUTICS UPDATE CLINICAL DIAGNOSIS nostic recommendations include a high index of suspi- In patients with associated ocular conditions who are cion and complete ocular examination such as undilated at high risk of developing NVG, clinicians should per- slit-lamp biomicroscopy, gonioscopy, and dilated fun- form a comprehensive ocular evaluation with particular duscopic examination. Level A therapeutic recommen- attention to the pupillary margin of the iris. In patients dations include treating the underlying disease process with CRVO, studies have shown that a relative afferent with adequate panretinal photocoagulation (PRP), if reti- pupillary defect indicates an increased risk of developing nal ischemia is present, and the initial medical control of rubeosis iridis.13 the IOP and inflammation. Level B recommendations An undilated slit-lamp examination and gonioscopy include glaucoma surgery to lower the IOP when med- are essential to the detection of NVI and NVA, respec- ical therapy and PRP are unsuccessful. tively. Although NVI usually precedes NVA, new vessels may occasionally be found in the angle without evidence THE TREATMENT OF of iris neovascularization at the slit lamp.14 The Central NEOVASCULARIZATION Vein Occlusion Study (CVOS) revealed that approxi- In the majority of patients with NVG secondary to mately 10% of eyes with nonischemic CRVO and 6% of PDR, wherein retinal ischemia is the underlying etiology, eyes with ischemic CRVO developed NVA without signs the ablation of the peripheral retina is first-line therapy of iris neovasularization.15 The importance of careful to counter the angiogenic cascade. In most instances, gonioscopy cannot be overstated in these patients. PRP with the argon laser is the treatment of choice.17,18 Other diagnostic techniques for predicting the risk of The importance of adequate PRP treatment must be developing rubeosis iridis in patients with CRVO in- emphasized. One study reported that 1,200 to 1,600 clude fluorescein angiography and electroretinography. laser spots produced a regression of rubeosis in 70.4% of Although there is limited prognostic value in using reti- diabetic patients, whereas 400 to 650 spots produced nal angiography, iris angiography may reveal early, sub- regression in only 37.5%.18 tle NVI. In a study of 200 randomly selected fluorescein Although the efficacy of prophylactic PRP in prevent- angiograms of the iris, rubeosis iridis was detected in ing NVG is well documented in patients with diabetic 97.2% with a false-positive rate of 1%.16 Moreover, in retinopathy, a 10-year prospective study of eyes with approximately one-third of the eyes, the iris angiogra- CRVO undergoing PRP revealed no significant difference phy test allowed the detection of rubeosis prior to its in the incidence of subsequent NVG compared to eyes becoming clinically evident on slit-lamp biomicroscopy. without PRP.19 In the CVOS, prophylactic PRP in pa- tients with ischemic CRVO but without manifest rubeo- CLINICAL MANAGEMENT sis iridis did not completely prevent the development of Despite advances in the medical and surgical manage- NVI/NVA. The prompt regression of the anterior seg- ment of glaucoma, the visual prognosis for patients with ment neovascularization was more likely when PRP was NVG remains poor. Visual outcomes will only be im- performed after early signs of rubeosis iridis became proved with the early detection of NVI/NVA and the manifest.20 The CVOS investigators also recommended prompt initiation of therapy that specifically targets the performing PRP promptly when 2 clock hours of NVI underlying disease process. The clinicopathologic course and/or any NVA is observed. Thus, for patients with of NVG can be conceptualized as proceeding from an CRVO, the preferred practice is to follow them fre- initial preglaucoma stage (ie, existing rubeosis iridis) quently with undilated slit-lamp examination and goni- through an intermediate stage of open-angle glaucoma oscopy and to institute PRP upon the earliest signs of to the advanced angle-closure stage (Figure 1). In the anterior segment neovascularization. intermediate stage, gonioscopy shows an open anterior PRP should be administrated prophylactically when chamber angle, but histologic