27 Neovascular glaucoma

INTRODUCTION

Neovascular glaucoma (NVG) is classified as a secondary glaucoma. Historically, it has been referred to as hemorrhagic glaucoma, thrombotic glaucoma, congestive glaucoma, rubeotic glaucoma, and diabetic hemorrhagic glaucoma. In 1906 Coats1 described the histologic finding of new vessels on the irides of eyes with central retinal vein occlusion (CRVO). In 1928, Salus2 described similar new vessels on the irides of eyes of diabetic patients. Later, after the introduction of clinical gonioscopy, Kurz3 correlated his clinical observation of fine new vessels in the angle with the histologic finding of connective tissue along these vessels. Weiss et al.4 proposed the term “neovascular glaucoma,” because the glaucoma is due to the new vessels rather than the inconsistently present intraocular bleeding.

The formation of a fibrovascular membrane on the anterior surface of the iris (rubeosis iridis) and extending into the chamber angle leads to irreversible obliteration of the outflow system, with a corresponding rise in intraocular pressure (IOP). NVG may result in a painful blind eye. Numerous secondary ocular and systemic diseases that share one common element, retinal ischemia/hypoxia and subsequent release of an angiogenesis factor, cause NVG. This angiogenesis factor causes new blood vessel growth from preexisting vascular structures. According to the degree of progression, the treatment methods consist of panretinal photocoagulation (PRP), anterior-chamber angle photocoagulation, cryotherapy, filtering surgery, glaucoma implants, cyclophotocoagulation, beta-blockers, carbonic anhydrase inhibitors, and enucleation.5

Rubeosis iridis is one of the severest complications of the occlusive diseases of retinal vessels associated with retinal hypoxia. Neovascularization of the anterior-chamber angle then very often results in the development of the prognostically very unfavorable NVG. Data show that the most effective methods of treatment of rubeosis iridis so far are the so-called coagulation techniques – PRP or cryocoagulation. By application of these techniques, we achieve the destruction of the anatomical substrate that is responsible for the production of the vasoproliferative substance, and the result is involution of rubeosis on the iris and in the anterior-chamber angle. Medical therapy is based on the use of topical steroids and atropine, to reduce inflammation and congestion. Drugs reducing aqueous production (b-blockers, carbonic anhydrase inhibitors, α-agonists) are helpful, although ocular hypertension is often refractory. However, there has been a recent interest in the management of rubeosis iridis and NVG with pharmacologic therapy, including steroids and antiangiogenic agents.

The objective of this chapter is to describe the characteristic clinical findings of NVG as well as the current pharmacotherapy options to treat this condition.

In patients with ischemic CRVO, anterior-segment neovascularization with associated NVG develops in more than 60% of cases. This can happen within a few weeks and up to 1–2 years after the onset of CRVO. It has been reported that the fellow eye may develop retinal vein occlusion in about 7% of cases within 2 years.7 In another report, the 4-year risk of developing second venous occlusion is 2.5% in the same eye and 11.9% in the fellow eye.8

Neovascularization of the iris (NVI) in diabetes appears most often after the development of proliferative retinopathy. The onset of glaucoma after the appearance of NVI with diabetes is usually after a period of many years, as compared with only a few months with CRVO.9 The incidence of NVI in diabetic patients ranges between 1% and 17%.10 In patients with proliferative diabetic retinopathy (PDR), NVI has been reported at much higher incidence rates, ranging from 33% to 64%.11 In patients with severe PDR, NVG occurs in 5–8% of cases.12 In addition, for diabetic patients with NVG in one eye, NVG developed in the second eye in one-third of patients.13

RISK FACTORS

The most frequent cause is retinal ischemia resulting either from vascular occlusion or from diabetic alterations. Therefore, some of the risk factors that lead to ischemia in retinal vascular occlusions or in diabetic retinopathy (DR) are common to NVG. An increased risk of CRVO was found in patients with systemic hypertension, diabetes mellitus, and open-angle glaucoma; the risk of CRVO was decreased for patients with increasing levels of physical activity and increasing levels of alcohol consumption. For women, the risk decreased with the use of postmenopausal estrogen and increased with a higher erythrocyte sedimentation rate. The following conditions all showed a significant association with ischemic cases only: cardiovascular disease, electrocardiographic abnormalities, albumin:globulin ratio, history of treatment for diabetes mellitus, and blood glucose level. Both systolic and diastolic blood pressure showed significant associations with both types of CRVO, but the odds ratio is greater for ischemic CRVO. Overall, a stronger cardiovascular risk profile was shown for the ischemic type of CRVO.

The greatest visual threat to patients having both glaucoma and diabetes is the development of NVG. Over 60 years ago, it was hypothesized that ischemic retinal tissue released a diffusable angiogenic substance that stimulated neovascularization.14 However, only recently was vascular endothelial growth factor (VEGF) found to be an agent that satisfies this description.15 It has been discovered that significantly higher VEGF levels occur in the ocular fluids of patients with PDR when compared with patients without that disorder. Extremely elevated levels of VEGF were found in the ocular fluids of patients with NVG.

DISEASE PREVALENCE AND INFLUENCE

The prevalence of NVG is estimated to affect about 75 000–113 000 persons in the European Union. In the USA the incidence of NVG is rare. However, the treatment and maintaining visual acuity in patients with NVG are difficult. NVG is more prevalent in elderly patients.6

ETIOLOGY/PATHOGENESIS

In 1948, Michaelson14 proposed that “there exists in the retina a factor or factors affecting the budding of new vessels.” Ashton16 and others later expanded the model to suggest that hypoxia of the retina was the

• 27 chapterGlaucoma Neovascular

Figure 27.1  Neovascularization of the iris (NVI) appears to progress sequentially from the pupil to the periphery.

primary stimulus of retinal production of angiogenic factors. Leung et al.17 identified and purified a heparin-binding VEGF from media conditioned by bovine pituitary follicular or folliculostellate cells. VEGF is a potent mitogen for vascular endothelial cells isolated from both small and large vessels, but does not affect the growth of BHK-21 fibroblasts, lens epithelial cells, corneal endothelial cells, keratinocytes, or adrenal cortex cells. The presence of VEGF in high concentrations in the medium conditioned by folliculostellate cells suggested that VEGF is a secreted molecule and that it may be a soluble mediator of endothelial cell growth and angiogenesis. Current reports support that VEGF and its receptors serve an important role in various steps of intraocular angiogenesis by virtue of its ability to be induced by hypoxia and its diffusible nature. However, angiogenesis is a multistep process in which many growth factors and cytokines are involved and have essential roles.18 Besides VEGF, other molecules that have been demonstrated to be correlated with the development of NVG include basic fibroblast growth factor,19 platelet-derived growth factor, insulin-like growth factor-1,20 and interferon-α.21

The neovascular process begins as endothelial budding from capillaries of the minor arterial circle at the pupil. Clinically, this NVI appears to progress sequentially from the pupil to the periphery (Figure 27.1). However, histologically, once the process starts at the papillary margin, new endothelial buds may appear from vessels anywhere in the iris, including the major arterial circle in the iris root. These endothelial buds progress to become glomerulus-like vascular tufts. These new vessels are composed of endothelial cells without a muscular layer or much adventitia and supportive tissue. They have a tendency to be thinwalled and to be located toward the surface of the iris, but can be anywhere within the stroma of the iris.9

The fibrous component of the fibrovascular membrane in NVG consists of proliferating myofibroblasts, which are fibroblasts with smoothmuscle differentiation. The fibrous portion of the membrane is clinically transparent but produces a flattening of the iris surface architecture. The contractile smooth-muscle components explain the effacement of the iris surface, the development of ectropion uveae, formation of peripheral anterior synechiae (PAS), and ultimately, synechial angle closure.22

All conditions associated with diffuse hypoxia of the posterior segment, retinal detachment, and some intraocular tumors may cause NVG. Currently, probably one-third of cases of NVG are attributable to CRVO, one-third to DR, and one-third to other causes, with carotid artery occlusive disease (CAOD) being prominent.

Less frequent causes of NVG include the following: branch retinal vein occlusion, central retinal artery occlusion (CRAO), intraocular tumor, chronic retinal detachment, secondary to intraocular lens (uve- itis–glaucoma–hyphema (UGH) syndrome), chronic or severe ocular inflammation, endophthalmitis, sickle-cell retinopathy, retinopathy of

prematurity, radiation retinopathy, Eales’ disease, Coats’ disease, carotid cavernous fistula, ocular ischemic syndrome/carotid insufficiency, Takayasu’s disease, giant-cell arteritis, and trauma.

CENTRAL RETINAL VEIN OCCLUSION

Numerous studies have reported that approximately 25% of CRVOs show over 10 disc areas of retinal capillary nonperfusion on fluorescein angiography (defined ischemic) and 75% are nonischemic (Figure 27.2). The natural history of untreated CRVO is that essentially none of the nonischemic eyes progress to NVG, whereas 18–60% of eyes in the ischemic group do.23 NVG had been thought to appear 2–3 months after the CRVO (hence the term “90-day glaucoma”). However, NVG can occur anywhere from 2 weeks to 2 years after the initial occlusion. Nevertheless, in over 80% of cases, NVI and NVG appear within the first 6 months after CRVO. A fluorescein angiogram is imperative in the diagnosis, and ultimately the treatment, of CRVO. Clinically, it is sometimes impossible to determinate the degree of capillary nonperfusion because retinal hemorrhages block visualization of these areas. The nonischemic type can convert to the ischemic type. The CRVO study showed a 16% conversion rate within 4 months of the occlusion. This has led to the recommendation that the follow-up of nonischemic type should be within 2 months of presentation.24

The bilateral occurrence of CRVO has been reported to be around 15%. The CRVO study found 9% of eyes with CRVO had a vascular occlusion, including central retinal artery and branch or central vein occlusion, in the fellow eye.24

DIABETIC RETINOPATHY

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

In adults from about age 20 to 60 years, it is the leading cause of new blindness and one of the major causes of NVG. Most blindness in diabetic patients is due to PDR and only 5% is due to NVG. The overall prevalence of NVG in diabetes mellitus is about 2%, but increases to over 21% in PDR, where the frequency of iris neovascularization is 65%. It is now well accepted that NVI is associated with retinal hypoxia and proliferative retinopathy (Figure 27.3).

The crucial risk factor for the development of DR is the duration of diabetes. Several studies have shown that tight glycemic control (glycohaemoglobin < 7.5%) can delay the onset of the microvascular complications and therefore also NVG.

DIABETIC NEOVASCULAR GLAUCOMA

If a diabetic patient develops NVG in one eye, the disease tends to affect the fellow eye if prophylactic treatment is not provided. Bilateral NVI or NVG in adults is almost exclusively due to DR. The time interval between the onset of NVI and NVG in untreated cases varies from 1 month to over 3 years. Furthermore, it is unpredictable as to which untreated eyes with NVI ultimately progress to NVG. In eyes with early changes (microaneurysms and hemorrhages), 45% were found to return to retinopathy-free status at least once during regular annual ophthalmic examinations, and NVI can undergo spontaneous regression in over 26% of cases.25

Capillary dropout and retinal hypoxia make the eye with DR vulnerable to further insult. Surgical procedures such as cataract extraction may aggravate DR and precipitate NVG. All procedures that interrupt the integrity of the anterior hyaloid or posterior capsule constitute a risk, since these structures probably act as a barrier against the diffusion of angiogenic factors. Therefore, before surgery, the fundus should be carefully evaluated, performing PRP if necessary. Close postoperative control must be scheduled and first or further PRP carried out if NVI appears.

Pharmacotherapy to Amenable Diseases Retinal • 3 section