Neovascular glaucoma (NVG) is a potentially blinding secondary glaucoma, characterized by the development of rubeosis iridis and elevated intraocular pressure (IOP). Coats described rubeosis iridis in 1906 in a patient with central retinal vein occlusion (CRVO). It has been referred to as hemorrhagic glaucoma, thrombotic glaucoma, congestive glaucoma, rubeotic glaucoma, and diabetic hemorrhagic glaucoma. Weiss et al. proposed the term NVG as the elevated IOP was shown related to the new vessels' formation and associated connective tissue growth. NVG is a secondary ocular disorder resulting from a variety of ocular pathologies, and nearly in all cases, retinal ischemia is the underlying mechanism. The prevalence of NVG in the population is low, 0.12% in migrant Indians in Singapore and 0.01% in the Hooghly River Study (West Bengal, India). In hospital-based studies, the proportion of eyes with NVG among the secondary glaucomas was 9–17.4%. Though the overall prevalence of NVG is low, it contributes to significant visual loss and morbidity.
This review includes a comprehensive overview of the etiology, pathology, diagnosis, and management of eyes with NVG.
A large number of ocular and systemic disorders could cause NVG [Table 1]. But three quarters of times it is caused by three conditions—diabetic retinopathy (DR) (33%), ischemic CRVO (33%), and the ocular ischemic syndrome (OIS) (13%).
NVG is a complication mostly of ischemic CRVO. Up to 60% of patients with ischemic CRVO develop anterior-segment neovascularization (NV) within a few weeks to 2 years after disease onset, with an estimated incidence of 3,800 new cases per year. Eyes with nonischemic CRVO usually do not develop NV or NVG unless there is associated DR or OIS. Usually, eyes with larger areas of capillary nonperfusion (CNP), 30–75 disc areas, are at risk of developing NVG. Identifying ischemic CRVO is crucial for proper management. Hayreh had proposed two broad categories of tests to differentiate ischemic from nonischemic CRVO; these include both “Functional” tests (vision, visual filed on a Goldmann perimeter, relative afferent pupillary defect, and electroretinography), and “Morphological” tests (ophthalmoscopy and fluorescein angiography [FA]).
NVG is an advanced manifestation of DR. The incidence of new vessels of the iris (NVI) among people with diabetes ranges from 1% to 17%, occurring most often in proliferative diabetic retinopathy (PDR). The incidence of NVI in PDR was reported as high as 65% with a 33% risk of contralateral eye developing NVG in people with diabetes with NVG in one eye. NVG in DR is related to the degree of retinal ischemia.
OIS results from global reduction of blood flow to the eyeball. While it could cause both anterior and/or posterior segment ischemia, the former is mostly responsible for development of iris and angle new vessels. Severe carotid artery occlusive disease and DR are usually associated with OIS.
The pathogenesis of NVG is outlined in the flow chart [Fig. 1]. The primary event is a condition leading to retinal hypoxia and ischemia which disrupts the balance between pro- and anti-angiogenic factors and thereby stimulates angiogenesis. Common angiogenic factors are vascular endothelial growth factors (VEGFs), hepatocyte growth factor, insulin-like growth factor, tumor necrosis factor, and inflammatory cytokines (especially IL-6). Common antiangiogenic factors are pigment epithelium-derived factor, transforming growth factor-beta (TGF-β), thrombospondin, and somatostatin. VEGF, produced by a variety of cells in the retina (Muller cells, retinal pigment epithelium, pericytes, and ganglion cells) as well as the nonpigmented ciliary epithelium, is the major inciting factor implicated in the disease process. VEGF is a vaso-permeability factor and a strong endothelial cell mitogen. It induces endothelial cell migration by expression of α/β integrins. In addition to cell migration, VEGF increases the leucocyte adhesion at the endothelium resulting in breakdown of blood–retinal barrier. TGF-β stimulates the formation of the fibrovascular membrane and fibroblast proliferation. The secondary event is the growth of new leaky vessels in the anterior chamber obstructing the trabecular meshwork. This leads to a rise in IOP and can rapidly progress to glaucomatous optic neuropathy with irreversible blindness, if not managed on time. It is also postulated that oxygen from the aqueous humor diffuses posteriorly to the hypoxic retina, thereby causing iris hypoxia. Consequently, the nonpigmented ciliary epithelium becomes an important site of VEGF synthesis. This could explain the high risk of rubeosis in cases of NVG after surgeries like vitrectomy and lens extraction, in which the oxygen can easily reach the ischemic retina through diffusion and lead to rapid and severe iris hypoxia.
Histologically, vascular proliferation occurs with endothelial budding at the capillary level from minor and major arterial circle. These endothelial buds progress to glomerulus-like vascular tufts and new vessels that are mainly located near or on the iris surface and are composed of endothelial cells without a muscular layer and with little adventitial tissue [Fig. 2]. They arise from any place in the iris including root of iris and major arterial circle and are mostly located over the surface of the iris but can also be found in the stroma. The endothelial cells of the new vessels lack tight junctions and have fenestrated walls, which leads to leakage of proteins and cells into the aqueous. The fibrovascular membrane in NVI also contains proliferating myofibroblasts with smooth muscle differentiation. This clinically transparent and contractile membrane causes flattening and effacement of iris surface.
The main reason for visual loss with high IOP in NVG is ischemia of the optic nerve head and/or retina. Perfusion pressure (mean blood pressure—IOP) and ocular blood flow (perfusion pressure/vascular resistance) play important roles in this cascade of events. Blood flow is reduced significantly in an event of high IOP and low blood pressure; this causes greater damage to the optic nerve head and retina. Hence, it is suggested to take care not to lower the systemic arterial blood pressure while lowering the IOP, crucial for treatment of NVG.
NVG typically presents with a chronically red, painful eye that often has significant vision loss. It could be asymptomatic in the early stages, if IOP rise is gradual and the corneal endothelial count is good, especially in young individuals.
The first sign of iris NV is leakage of intravenously injected sodium fluorescein from vessels at the pupillary margin. The leakage can be detected even when the iris is apparently normal on slit-lamp examination. The following features are clinically seen:
- Visible neovascularization of the iris (NVI) and neovascularization of angle (NVA). Only rarely will NVA develop without NVI. NVI usually begins at pupillary margin but can also begin at the edges of a YAG iridotomy
- Elevated IOP (often exceeding 50 mmHg) with or without corneal edema
- Gonioscopically, NVA with partial or complete closure of the angle
- Fundoscopically, features of ophthalmic disorders, such as DR, retinal vessel occlusion, or OIS.
Two consistent signs are the NVI and NVA. NVI, on slit-lamp examination, presents as thin, tortuous vessels, randomly oriented on the surface of the iris, near the pupillary margin, and is more obvious in light-colored iris. These newly formed blood vessels must be differentiated from the normal radial vessels from the ciliary trunk and the radial iris vessels from the circular ciliary band. The aberrant normal vessels are radial, often arising from the iris root, and may be visible until mid-periphery and disappear into the iris stroma. At an early stage, the abnormal iris new vessels may be fine or these may appear as small tufts of blood vessels at the pupillary ruff, which can be easily missed unless specifically looked for. Leakage of vessels at pupillary margin after an intravenous injection of 5–10% sodium fluorescein occurs before clinically evident NVI (prerubeotic stage). Sometimes these iris new vessels may be extensive, flat, arborizing, and present all over the iris surface with grooves/tracks typically seen in OIS [Fig. 3]. In advanced cases, there would be ectropion uveae at pupillary margin with attenuation of normal iris pattern due to growth of fibrovascular membrane.
NVA is a gonioscopic finding. They appear as thin vessels crossing the scleral spur, branching, and arborizing over the trabecular meshwork [Fig. 3]. Sometimes these vessels may initially grow in the angle prior to appearance of pupillary margin NV and therefore gonioscopy is essential to recognize this important clinical finding. They should be differentiated from occasional prominent vessels in the angle which may have a radial orientation or may be looped and visible close to the iris root, which arise from major arterial circle.
The clinical stages of NVG and classification of NVI and NVA are shown in Tables 2 and 3. NVG can be divided into a prerubeotic stage where new vessels are not clinically visible but may be documented on anterior segment angiography and three clinical stages—the rubeosis iridis, secondary open-angle glaucoma, and secondary angle-closure glaucoma. Fig. 4 shows the clinical stages of NVG.
Slit-lamp biomicroscopy and gonioscopy are the essential tools to screen for NVI. Gonioscopy is a dynamic examination and is easily performed at the slit lamp but has a learning curve. Very fine NVI could be missed in both slit-lamp examination and gonioscopy. In these early stages, FA is more useful to detect rubeosis iridis. Fundus fluorescein angiography (FFA) is the current gold standard to detect areas of CNP and retinal new vessels elsewhere (NVE) or on the disc (NVD). Ultrawide-field FFA helps to visualize a larger retinal area, up to 200°. Iris FA shows leakage from these new vessels. Anterior segment indocyanine green angiography has the advantage of displaying the vasculature in more detail. Dye-based angiography is good but cannot be used in people allergic to these dyes. The most recent technique to assess retinal ischemia and neovascularization is the optical coherence tomography angiography (OCTA). This imaging technique is based on motion contrast. It is noninvasive and can be performed in eyes without dilatation. The OCTA in comparison to FFA can delineate the extent and depth of NV. Also, OCTA can be an excellent follow-up tool to document regression of NV [Fig. 5]. Commercial availability of wide field OCTA imaging has enabled larger area (12 mm × 12 mm) of retinal scanning [Fig. 5]. OCTA has also been used to image the iris vasculature and detect NVI.
Many studies have reported the ability of OCTA to detect NV and were comparable to FA. A dye-based angiography is superior to OCTA when one needs to study the dye leakage pattern. The sensitivity and specificity of OCTA vis-à-vis FA and different modalities of OCTA in detecting new vessels have been reported. OCTA was 79% sensitive and 96% specific compared to FA, wide-field OCTA was 100% sensitive and 97% specific compared to ultrawide field FA, and wide-eld OCTA imaging at baseline and 3 months after panretinal photocoagulation (PRP) was comparable with ultrawide field FA. OCTA could be useful to monitor the activity of neovascular complexes after panretinal photocoagulation providing better assessment of treatment response and guide additional treatment with retinal laser and/or intravitreal anti-VEGF injections. OCTA could allow a fast and noninvasive screening tool of patients with NVG and patients at risk of NV. However, certain technological issues like motion artifacts, image registration for follow-up imaging, as well as a quantitative and objective evaluation method for retinal and iris NV have to be addressed before it can be recommended for routine clinical practice.
Ultrasonography B scan (USG-B scan) helps to exclude rare and unexplained causes of NVG like the long-standing retinal detachment or intraocular tumors. In young patients with NVG, ultrasound biomicroscopy helps to rule out ciliary body tumors.
The basic checklist of systemic investigations in these patients is shown in Table 4. Certain special tests may not be recommended for all patients.
The differential diagnosis of NVG takes into consideration various etiologies, which can predispose to NVG, as well as ocular conditions that may have similar clinical presentation [Table 6]. It is important to note that the underlying mechanism for various ocular conditions may be multifactorial and concurrent.
Acute angle-closure glaucoma mimics NVG most closely. The patient presents with an acutely painful eye, with decreased vision, increased IOP, and dilation of circumciliary blood vessels. In the former, engorged iris vessels may be mistaken for rubeosis iridis, or the assessment of iris vessels may not be possible due to associated corneal edema. The examination of the fellow eye, with occludable or closed angles, is often the only differentiating feature, in eyes where posterior segment assessment is not possible. If the posterior segment can be visualized, the presence (usually measured by FFA) of retinal hypoxia helps in diagnosing NVG.
OIS resulting from carotid artery obstructive disease is the third most common cause of NVG. These patients may have normal or even low IOP despite established NVG. There may be a history of ocular pain, amaurosis fugax, and metamorphopsia.
Engorged vessels in patients with anterior uveitis, especially after surgery, and/or hypotony, may also be confused with NVG. A therapeutic trial of topical corticosteroids decreases this dilation of vessels, whereas NV of the iris does not regress.
Anterior segment NV along with elevated IOP may also be seen in anterior segment dysgenesis (especially essential iris atrophy), Fuchs' heterochromic iridocyclitis, and pseudoexfoliation syndrome.
A good clinical examination helps. The prominent iris vessels are radial, lie within the iris stroma, and never traverse the scleral spur. New vessels, on the other hand, are haphazard, superficial, and often cross the scleral spur, causing a zippering of the anterior chamber angle.
Treatment of NVG
- Treatment of retinal ischemia, in order to reduce the stimulus for NV:
- Intravitreal anti-VEGF agents to suppress iris and angle NV
- Panretinal photocoagulation
- Treatment of underlying systemic disease, if any, in order to improve retinal blood flow
- Control of IOP
- Control of inflammation
The management protocol is shown in Fig. 6. PRP is the current treatment of choice wherever retinal ischemia is the cause of NVG. The photocoagulation parameters in NVG are 1200–1600 burns, approximately 500 μm spot size and one spot apart. Ideally, it is completed in 1–3 sessions, over a period of 5–7 days. PRP is indicated not only in initial rubeosis but also in late stages of NVG with goniosynechiae. The treatment paradigm is changing with the introduction of anti-VEGF agents. The broad treatment guidelines of glaucoma are shown in Table 5. It is an incremetal increase from PRP only in preglaucoma stage to combination of anti-VEGF injections, antiglaucoma medications, and glaucoma filtration surgery based on the disease progression and angle configuration.
When adequate PRP is not possible due to a poor view of the fundus, retinal ablation can be augmented with anterior retinal cryotherapy (ARC). ARC can be combined with intravitreal anti-VEGF injection; and in extreme cases, vitrectomy could be combined with intravitreal anti-VEGF injection, PRP, and endocyclo-photocoagulation. NVG with the primary pathology of PDR was reported to be less aggressive than ischemic CRVO.
Antiglaucoma medications include carbonic anhydrase inhibitors (oral and topical), beta-blockers, and alpha-2 agonists, which lower aqueous production. Prostaglandin analogs may aggravate inflammation but are effective and are used only when IOP is not controlled with other medications. Miotics should be avoided because they may increase the inflammation and worsen synechial angle closure. Supportive measures like topical steroids and cycloplegics help in treating inflammation in these eyes.
VEGF inhibitors are effective but provide temporary means of reducing NVI and NVA leading to lowering of IOP. Anti-VEGF agents induce a rapid involution of NVI confirmed with iris FA and allow time for the onset of action of PRP.
Surgical management of NVG is challenging mainly due to increased risk for failure. The main indications of surgery in NVG are insufficient IOP control despite maximum medical therapy and extensive peripheral anterior synechiae formation that occludes the angle and impedes aqueous outflow. Prior measures to reduce inflammation and activity of neovascularization help improve the surgical outcome. Common surgical modalities include trabeculectomy, glaucoma drainage devices (GDDs), and cyclodestructive procedures.
Traditional trabeculectomy has a high failure rate attributed to severe inflammation and hyphema. Success of trabeculectomy has improved with use of antimetabolites (mitomycin C/5-fluorouracil), prior good PRP, prior ARC, and intravitreal anti-VEGF injection alone or with vitrectomy [Fig. 7]. The success rates of trabeculectomy with mitomycin C vary from 62.6% to 81.2% at 1 year and reduce to 51.3% at 5 years. Preoperative intravireal bevacizumab (IVB) has shown to decrease postoperative hyphema and improve success of trabeculectomy with mitomycin C. The possible causes of failure of trabeculectomy in NVG have been investigated. Takihara et al. found age ≤50 years (P = 0.0007) and history of previous vitrectomy (P = 0.02) to be significant independent risk factors for failure on multivariate analysis. Studies have also reported lower preoperative IOP and previous cataract surgery to be significant risk factors for persistent hypotony or failure.
Glaucoma drainage devices
The glaucoma drainage devices (GDDs) include valved/flow restrictive implants (Ahmed glaucoma valve [AGV]) and nonvalved implants (Bearveldt, Molteno, and AADI). In eyes with NVG, valved implants are preferred to help with immediate IOP reduction with lesser possibilities of hypotony. Care should be taken to prevent intraoperative and postoperative hypotony and damage to the iris. Success rates of GDD in NVG are lower compared to other indications. The success rate did not improve with prior PRP or concurrent use of anti-VEGF therapy. Reduction of IOP is not much different with Ahmed glaucoma valve and Baerveldt shunt implant. The 5-year results of the Ahmed versus Baerveldt study were similar on a multivariate analysis (P = 0.20). GDD surgery combined with vitrectomy could bring additional benefit.
Comparison of trabeculectomy and GDD in eyes with NVG
In a retrospective study, Shen et al. reported similar success rate for trabeculectomy with MMC and AGV over 2 years (trabeculectomy 55%, AGV 60%, P = 0.474). In a prospective study, higher success was seen in eyes with intravitreal ranibizumab (IVR) followed by trabeculectomy than AGV (significantly lower IOP in IVR at 1 month (P = 0.02) but not at 6 months; complete + qualified success 94.5% and 68.4%, respectively; P = 0.32). Wang et al. recorded greater reduction of IOP with AGV over trabeculectomy in eyes with NVG and vitreous hemorrhage (VH) (performed after pars plana vitrectomy for VH) (P = 0.01 at 12 months); but the difference in absolute success probabilities was not significantly different with AGV or trabeculectomy at 12 months: 71.3% and 46.7%, P = 0.11.
The outcome is not much different between trabeculectomy with MMC and AGV when retinal ischemia is adequately addressed preoperatively. Usually, GDD is reserved for eyes with persistent new vessels, or in those where other filtering surgeries are not feasible [Fig. 8].
Cyclophotocoagulation (CPC) using diode laser is a cycloablative procedure to decrease aqueous production and reduce IOP in eye with NVG. Complications following CPC include hyphema, chronic iritis, corneal edema, and phthisis bulbi. CPC is usually reserved for eyes with poor visual potential or as a temporizing measure in eyes with high IOP where the media are not clear enough to perform PRP or in those instances where other filtering surgeries are not feasible.
CPC could also be combined with anterior retinal cryopexy in eyes with persistent NV and uncontrolled IOP. Micropulse diode CPC is another modality, but the ability to control IOP is not much different than diode CPC. Endocyclophotocoagulation with pars plana vitrectomy and PRP are reported to have better capability to reduce the elevated IOP.
The treatment of NVG secondary to OIS should be multidisciplinary approach by involving a cardiologist and/or vascular surgeon for carotid arteries imaging and carotid endarterectomy if indicated.
Complications after glaucoma surgery in eyes with neovascular glaucoma
In view of complex pathology in NVG, ongoing inflammation and new vessels in the eye, and surgical interventions like trabeculectomy and GDD are associated with various complications. Most common complication is hyphema that ranges from 4% to 85% [Fig. 9]. The incidence of hyphema can be reduced by cauterizing iris before iridectomy, preoperative IVB to reduce NVI, and avoiding intraoperative and postoperative hypotony. Other complications include anterior chamber shallowing up to 30%, and serous choroidal detachment up to 20%. Late complications like bleb leak with mitomycin C trabeculectomy have been reported in up to 13% eyes. Two serious complications in these eyes are persistent hypotony reported up to 16.7% and suprachoroidal hemorrhage up to 5% of eyes.
GDD in NVG has good IOP control; however, long-term complications can be serious. Microangiopathy and ischemia predispose eyes with GDD to complications like conjunctival erosion and tube exposure in up to 12.5% eyes. Contraction of fibrovascular membrane results in tube occlusion and tube corneal touch may present in 3% to 14% eyes.
NVG carries a guarded prognosis. Prognosis is predominantly dependent on two factors: prevention and treatment of NVG early in its course and the underlying disease process. Intensity and frequency of follow-up depend on the etiology of NVG and the clinical course. In subjects with ischemic CRVO, it calls for a 2–4 weekly review with a detailed evaluation including undilated gonioscopy to detect early angle new vessels that could occur in 6–12% of eyes with CRVO without NVI.
NVG is a potentially blinding disease and is an ophthalmic emergency. Early diagnosis and multidisciplinary systematic approach would be needed to salvage useful vision in these eyes. Timely and appropriate treatment of underlying cause of ischemia and controlling the IOP are the keys to successful management of this condition. Diabetes is an important cause of NVG. With global increase in diabetes mellitus, an increase in NVG secondary to DR is expected. Hence, prompt detection and adequate treatment of PDR would help decrease the occurrence of this blinding disease.
Financial support and sponsorship
The study was supported by the Hyderabad Eye Research Foundation.
Conflicts of interest
There are no conflicts of interest.
The authors thank Dr. Talvir Sidhu for photographs of angle and iris new vessels and Dr. Dilip Mishra for the histopathology images.
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