Diabetes and Glaucoma

Neovascular Glaucoma

“If an adult presents with bilateral rubeosis iridis, diabetes mellitus should be considered the most likely cause.” This statement was made by glaucoma surgeons Higginbotham and Yang.¹ Thus, the clinician must have a high index of suspicion for diabetic patients with severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy (PDR). Ischemia is thought to play an important role in this disease. The bilaterality of the rubeosis iridis suggests a systemic disease.

Historically, in the medical literature, neovascular glaucoma is associated most strongly with retinal venous obstructive diseases (36.1%), diabetic retinopathy (32.2%), and carotid obstructive disease (12.9%). Other less common causes are central retinal artery obstruction (3.8%), combined retinal arterial and venous obstruction (3.8%), and rhegmatogenous retinal detachment (1.5%). The rest of the 3.5% is comprised of vitreous wick syndrome, radiation retinopathy, syphilitic vasculitis, nonrhegmatogenous retinal detachment associated with malignant melanoma and angiomatosis retinae, squamous cell carcinoma of the conjunctiva, and carotid sinus fistula.²

Gartner and Henkind³ elucidated the causes of neovascularization of the iris and that neovascular glaucoma causes 20% of all eye enucleations (Table 13-1).

However, when one looks at the causes of neovascularization of the iris and neovascular glaucoma, central retinal vein occlusion usually is associated with a systemic vascular disorder such as hypertension or diabetes. In that context, diabetes plays a large role in the incidence of neovascular glaucoma.

In one study by Klein et al.,⁴ a cohort of people with diabetes self-reported glaucoma. Data were taken from an 11-county area of southern Wisconsin. Two thousand three hundred and sixty-six diabetics were part of the evaluation over a 10-year period. The authors found that the 10-year incidence of glaucoma was 3.7% in the younger onset people. It was 6.9% in the older onset people not using insulin and 11.8% in the older onset people using insulin. Univariate analyses showed that in the younger onset people, there was a greater body mass index. In the older age group of noninsulin users, there was a longer duration of diabetes, history of cataract surgery, and increased severity of diabetic retinopathy at baseline.

Older onset diabetics who were using insulin had longer duration of diabetes, higher intraocular pressure (IOP), history of cataract surgery at baseline, and an increased risk of glaucoma.⁴ In multivariate analyses, only age was significantly related to increased incidence of glaucoma in younger onset people. Age, IOP, and insulin use were significantly associated with increased risk in the older onset group.⁴

The incidence of neovascular glaucoma and vitreous hemorrhage after cataract surgery in diabetic patients has been studied by Aiello et al.⁵ in 154 patients. After intracapsular cataract extraction in patients with active PDR, the incidence was 40% for the development of rubeosis iridis/neovascular glaucoma.⁵ In patients with active PDR, there was a 20% incidence of vitreous hemorrhage. However, in eyes with no diabetic retinopathy or background diabetic retinopathy, the incidence was 6.5% for the development of vitreous hemorrhage. In eyes without regard to preoperative diabetic retinopathy, the incidence of rubeosis iridis/neovascular glaucoma was 7.8%.⁵ From the glaucoma surgeon’s perspective, the teaching was that 20% of the eyes enucleated were due to neovascular glaucoma.³ Of eyes not enucleated, after cyclocryotherapy, more than half suffered severe vision loss.³

Sivak-Callcott et al.⁶ performed a meta-analysis of the literature from 1966 to the present. The current literature reaffirms the need for a full ocular examination when there is a high index of suspicion, undilated gonioscopy and pupil examination. The recommendations for treatment include treatment of the underlying disease, complete panretinal photocoagulation (PRP) in retinal ischemia is a factor. Medical control of the elevated IOP and medical treatment of the accompanying inflammation are needed. If medical treatment is inadequate for the control of the IOP, then glaucoma surgery is necessary. While the ideal glaucoma surgery is still controversial, trabeculectomy with antimetabolite therapy, aqueous shunt implants, diode laser cyclophotocoagulation, or cycloablation with cryopexy are the preferred treatment modalities.⁶

In a diabetic patient who presents with unilateral rubeosis iridis, loss of vision, and central retinal vein occlusion, the IOP will be low, and the patient will be in the fifth decade slightly younger than a nondiabetic patient with a CRVO.² The patient will most likely have an ischemic CRVO. Forty percent of the patients in this group develop neovascular glaucoma within 7 months, and 50% develop neovascular glaucoma after 3 years.⁷

In cases of marked asymmetry of diabetic retinopathy and unilateral rubeosis iridis, where upon PRP does not eliminate anterior segment neovascularization, think about carotid occlusive disease. Carotid artery obstruction produces bilateral rubeosis iridis only in 8% of the cases.⁸ IOP can be normal despite 360 degrees of peripheral anterior synechiae (PAS). In fact, only one third of the patients have elevated IOP with PAS.⁹ These diabetic patients with carotid artery disease may present with a painful red eye, periorbital pain, engorged episcleral and conjunctival vessels, a cloudy cornea, ischemic uveitis with cells and flare in the anterior chamber, rubeoisis iridis, venous stasis retinopathy, and a decreased central retinal arterial pressure as measured by ophthalmodynamometry. Cataracts are seen as a late finding. When there is severe eye and periorbital pain, send the patient for an emergency sedimentation rate to evaluate for temporal arteritis. In cases with severe pain, the majority of patients may have normal IOP or low IOP because of hypoperfusion of the ciliary body and thus a decreased rate of aqueous production.⁸

Once carotid occlusive disease is suspected, fluorescein angiography will show delayed filling of the arteriovenous phase, areas of choroidal hypoperfusion, or areas of capillary nonperfusion. Systemic workup would involve carotid artery ultrasonography; magnetic resonance angiography of the carotid artery, echocardiography of the heart, Holter monitoring can be performed.

The presence of any neovascularization is an indication for PRP. The PRP will cause a regression of the iris neovascularization. This can be done in patients who are awaiting surgical treatment of their carotid occlusive disease.

The postoperative IOP should be followed closely because glaucoma can develop after reperfusion of the ischemic ciliary body. It is important to control IOP in order to prevent further optic nerve damage. Medical therapy, trabeculectomy, and cyclocryotherapy have been ineffective, and some glaucoma surgeons recommend the use of a seton implant such as a Molteno implant or other implants. Anticoagulation with aspirin is suggested as well, while awaiting the definitive procedure of carotid artery surgery.

Pathophysiology

The common factor of neovascular glaucoma and diabetes is retinal ischemia. Vasoproliferative factors such as VEGF are thought to play a role in rubeosis iridis. There are some case reports on the use of intravitreal bevacizumab (Avastin) for the treatment of neovascular glaucoma among glaucoma surgeons.^10,11

Neovascularization of the iris begins as endothelial budding from capillaries or venules in the iris. New vessels form at the pupillary zone or iris periphery where there are many capillaries. However, new vessels can arise in the iris stroma as well. The new vessels tend to grow in the anterior surface of the iris and are thin walled. These new vessels leak fluorescein because their endothelium has gaps and fenestrations as recorded in electron microscopy studies.¹²

Accompanying the new vessels is the proliferation of myofibroblasts, resulting in the formation of a fibrovascular membrane.¹³ The myofibroblasts contract, causing the fibrovascular membrane to shrink, flatten the iris, and lose their surface architecture. As the membrane shrinks, the posterior pigment layer of the iris may be pulled anteriorly onto the anterior iris surface, creating ectropion uveae. If the sphincter muscle becomes distorted, the condition is called ectropion of the sphincter muscle. In late iris neovascularization, the progressive fibrosis causes loss of the dilator muscle function and partial atrophy of the sphincter muscle. This explains the fixed dilated pupil and unresponsive iris seen in advanced cases of neovascular glaucoma.

As iris neovascularization moves to the angle, the fibroavascular membrane adheres to the cornea, iris, and causes PAS. Furthermore, if the fibrovascular membrane progresses further, secondary angle closure can occur.

Diagnosis

The key in the diagnosis of neovascularization of the iris is a high index of suspicion and early diagnosis. The diagnosis of neovascular glaucoma begins with the slit lamp examination, under high magnification (Fig. 13-1). Look for the new iris vessels at the papillary margin, the usual site of origin. This is especially difficult in darkly pigmented irides.

FIGURE 13-1. Iris neovascularization.

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