NeoVascular Glaucoma Ap.최진아/R2 이기일 Glaucoma Conference NeoVascular Glaucoma Ap.최진아/R2 이기일

Terminology In 1906, Coats described new vessel formation on the iris(Rubeosis iridis) in eyes with CRVO. Rubeotic glaucoma or neovascular glaucoma, which was proposed by Weiss and colleagues and is the term found most often in the current literature (cf. hemorrhagic glaucoma, congestive glaucoma, thrombotic glaucoma) Rubeosis iridis is frequently associated with a severe form of glaucoma, which has been given different names on the basis of various clinical features: hemorrhagic glaucoma, referring to the hyphema that is present in some cases; congestive glaucoma, describing the frequently acute nature of the condition; and thrombotic glaucoma, implying an underlying vascular thrombotic cause

Factors Predisposing to Rubeosis Iridis Most cases of rubeosis iridis are preceded by hypoxic disease of the retina. Diabetic retinopathy, central retinal vein occlusion, and carotid ischemic disease are the most common causes.

Factors Predisposing to Rubeosis Iridis Diabetic Retinopathy Account for 1/3 of rubeosis iridis. After ppV, rubeosis iridis ranges from 25% to 42%. whereas that for NVG ranges from 10% to 23%. Occur more often in aphakic eyes. An unrepaired retinal detachment after vitrectomy : also a risk factor for postoperative rubeosis iridis. Cataract surgery -> increased incidence of postop. rubeosis iridis and NVG

Factors Predisposing to Rubeosis Iridis Retinal Vascular Occlusive Disorders CRVO accounted for 28% of rubeosis iridis. Elevated IOP is thought to be a predisposing factor for RVOs. Optic disc cupping was reported to be a significant risk factor for RVOs in the Beaver Dam Eye Study Other risk factors : hypertension, diabetes, male, old age. CRAO is less commonly associated with rubeosis iridis. BRAO, BRVO may rarely cause rubeosis iridis.

Theories of Neovasculogenesis Retinal Hypoxia Rubeosis iridis occurs when significant capillary nonperfusion is present. Vasoinhibitory Factors The vitreous and lens are possible sources of these vasoinhibitory factors. : explain why vitrectomy or lensectomy increases the risk for rubeosis iridis in eyes with DMR. RPE cells release an inhibitor of neovascularization

Theories of Neovasculogenesis Angiogenesis Factors First hypothesized in 1948. Key angiogenic peptide, vascular endothelial growth factor (VEGF) explain how ocular neovascularization can occur remote from the site of retinal capillary nonperfusion. Under retinal ischemia, Müller cells is the primary source. Four isoforms (VEGF121, VEGF165, VEGF189, and VEGF206) Potent angiogenic stimulator, promoting proliferation, migration, proteolytic activity, and capillary tube formation.

Clinicopathologic Course ‘Prerubeosis’ Stage Diabetic Retinopathy Prevalence of rubeosis iridis : 0.25% to 20%. In PDR : ½ develops into rubeosis iridis. (rarely occur in an eye with NPDR) The risk is greatly increased when arteriolar or capillary nonperfusion is present or after vitrectomy or lensectomy. There is also a highly significant correlation with optic disc neovascularization and RRD Pupillary margin of the iris : NV is typically seen first.

Clinicopathologic Course ‘Prerubeosis’ Stage Central Retinal Vein Occlusion The incidence of rubeosis iridis and NVG significantly correlated with the extent of retinal capillary nonperfusion. (60% with retinal ischemia, 1% with good capillary perfusion). <Methods to evaluate capillary nonperfusion> FAG – most direct, not feasible when media opacity. Ophthalmoscope – complete vs incomplete occlusion. FAG of iris : abnormal leaking vessels. Laser flare-cell meter : Aqueous protein and cell concentration. RAPD Infrared pupillometry ERG : B-wave implicit time delay, reduced B/A wave amp. ratio.

Clinicopathologic Course ‘Preglaucoma’ Stage: Rubeosis Iridis Clinical Features Characterized by a normal IOP! 1. Dilated tufts of preexisting capillaries. 2. Fine, randomly oriented vessels on the surface of the iris near the pupillary margin. Gonioscopy reveals angle neovascularization. : single vascular trunks crossing the ciliary body band scleral spur and arborizing on the TM.

Clinicopathologic Course ‘Preglaucoma’ Stage: Rubeosis Iridis Histopathologic Features Begins intrastromally and develops on the surface of the iris. : dilatation of normal iris vessels. -> increased metabolism of vascular endothelial cells. -> new vessel formation. The silicone-injection studies shows that ‘new vessels’ run circumferentially in TM, with branches coursing into the fibrosed Schlemm canal and into collector channels. have thin fenestrated walls. arranged in irregular patterns. with open interendothelial cell junctions. attenuated intraendothelial cytoplasm, and pericyte.

Clinicopathologic Course ‘Open-Angle Glaucoma’ Stage Clinical Features Incidence of NVG in diabetic patients with rubeosis iridis ranges from 13% to 41%. Incidence is higher in CRVO & occurs 8-15 wks after CRVO -> “90-day glaucoma” Rubeosis iridis : more florid AC : Inflammatory reaction, sometimes with hyphema Elevated IOP with intense NV(angle : open)

Clinicopathologic Course ‘Open-Angle Glaucoma’ Stage Histopathologic Features Hallmark : fibrovascular membrane that covers the anterior chamber angle and anterior surface of the iris and may even extend onto the posterior iris. Obstruction of the TM by the fibrovascular membrane, with variable contribution from the inflammation and Hemorrhage.

Clinicopathologic Course ‘Angle-Closure Glaucoma’ Stage Clinical Features The stroma of the iris has become flattened, with a smooth, glistening appearance. Ectropion uvea is frequently present, and the iris is often dilated and pulled anteriorly from the lens. The contracture leads to formation of peripheral anterior synechia, with eventual total synechial closure of the angle. Typically severe and usually requires surgical intervention.

Clinicopathologic Course ‘Angle-Closure Glaucoma’ Stage Histopathologic Features Peripheral anterior synechiae and flattening of the anterior iris surface by a confluent fibrovascular membrane. Overlying the new vessels is a superficial layer of myofibroblasts(i.e., fibroblastic cells with smooth-muscle differentiation). -> tissue contraction

Clinicopathologic stages of NVG

Differential Diagnosis In the open-angle stage, Angle closure glaucoma(no angle NVs) Glaucoma associated with anterior uveitis.(dilated iris vv.) Cf.) Fuchs heterochromic iridocyclitis also have angle NVs In the angle-closure stage, DDx. with causes of iris distortion and PAS Ex.) iridocorneal endothelial syndrome

Management Panretinal Photocoagulation Ablation of the peripheral retina with laser (usually argon) Photocoagulation : the first line of Tx. for most cases of NVG The machanism may be related to decreasing the retinal oxygen demand This may reduce the stimulus for release of an angiogenesis factor or may reduce the hypoxia in the anterior ocular segment.

Management Panretinal Photocoagulation Prophylactic Therapy For CRVO : better to follow patients closely and intervene promptly with PRP at the early signs of Rubeosis. For DMR : vitrectomy or lensectomy, peripupillary fluorescein leakage, may be indications for Prophylactic Tx. Treatment of Glaucoma May reverse IOP elevation in the open-angle glaucoma stage and in some early angle closure NVG(less then 270˚ synechia) For DMR : intraop. PRP c ppV > preop. PRP followed by ppV

Management Panretinal Cryotherapy Anti-VEGF Agents Useful when cloudy media preclude PRP -> Transscleral panretinal cryotherapy, often combined with Cyclocryotherapy. Anti-VEGF Agents 1.25 mg bevacizumab in the vitreous cavity or AC The effect lasts for weeks Important to proceed with PRP as soon as practical to prevent recurrence.

Management Medical Management of Glaucoma and Inflammation The mainstay : carbonic anhydrase inhibitors topical ß-blockers, a2- agonists (drugs that reduce aqueous production) PG analogues : rarely effective because access to the uveoscleral route is generally compromised. Miotics & PGs -> exacerbation of inflammation! IVTA : reduced retinal NVs in rabbit eyes. Atropine : helpful for relief of pain in far-advanced cases.

Management Glaucoma Surgical Procedures Cyclodestructive Procedures Cyclocryotherapy Transscleral Nd:YAG cyclophotocoagulation Diode laser cyclophotocoagulation(less inflammation, lower IOP) Filtering Surgery Combined PRP, anti-VEGF treatment reduce NV sufficiently to perform a standard filtering operation, such as trabeculectomy. Use of 5-FU, MMC may improve success rate. Younger age, prev. vitrectomy : poor Px. Factors Modified trabeculectomy with intraocular bipolar cautery of pph. iris and ciliary processes and creation of a small iridectomy

Management Glaucoma Surgical Procedures Glaucoma Drainage-Device Surgery Encouraging results with tubes or valves into the AC and through the pars plana (when combined with a vitrectomy) in NVG. Adjunctive bevacizumab may improve the success rate. Other Surgical Procedures Endoscopic cyclophotocoagulation Silicone oil injection during revision of vitrectomy Intravitreal injection of crystalline triamcinolone acetonide Exposure to 100% oxygen under hyperbaric conditions

Key points NVG is a common and serious complication of several retinal disorders, especially DMR, CRVO, and ocular ischemia, as well as certain other ocular and extraocular conditions. The pathophysiology of NVG involves abnormally high levels of VEGF within the eye and growth of a fibrovascular membrane on the iris surface and in the AC angle, which initially obstructs aqueous outflow in an open-angle glaucoma and then contracts to produce an angle-closure form of glaucoma. The most effective long-term treatment of neovascularization of the iris or NVG is PRP in the early stages to reduce the stimulus for anterior segment NVs. Intravitreal or intracameral injection of anti-VEGF agents cause regression of anterior segment neovascularization and can thus be a very useful short-term adjunct.

Reference) Shields Textbook of Glaucoma, 6th Edition