The Relationship of Diabetic Retinopathy and Glaucoma

11.1Interaction of Diabetes and Glaucoma

Diabetes, diabetic retinopathy, and their various treatments can each influence a patient’s risk of developing not only neovascular glaucoma, but open angle, narrow angle, and secondary glaucoma as well. After reviewing the connections between these types of glaucoma and diabetes, the pathogenesis and management of neovascular glaucoma will be discussed in detail.

Quigley et al. estimated that there are more than 60 million people with glaucoma worldwide.1 While 171 million people had diabetes in 2004, by 2030 this number is expected to more than double.2 How many of these diabetics also have glaucoma, and whether having diabetes increases the risk of developing glaucoma, remains unresolved. Bonovas performed a meta-analysis of studies that attempted to determine whether diabetes is a risk factor for open angle glaucoma and found that patients with diabetes were at increased risk of developing glaucoma.3 Other studies have determined that the presence of type 2 diabetes and the duration of disease were each independently associated with a higher risk of having open angle glaucoma.4 And in another recent study higher hemoglobin A1c levels were correlated with higher intraocular pressures.5

The mechanism by which diabetes may increase the risk of glaucoma remains speculative. Nakamura

D.J. Browning (*)

Charlotte Eye Ear Nose & Throat Associates, Charlotte, NC 28210, USA

e-mail: dbrowning@ceenta.com

postulated that diabetes may not only increase the incidence of elevated intraocular pressure and the risk of vascular compromise but also impair neuronal and glial metabolism and promote apoptosis.6 Corneal elasticity may also be abnormal in diabetics, causing falsely elevated intraocular pressure measurements.7

But while many studies have found an association between diabetes and open angle glaucoma5,8–21 others do not confirm this finding.22–29 Pache and

Flammer30 reviewed the literature and concluded that evidence does not yet exist to be able to claim conclusively that diabetes is a risk factor for the development of open angle glaucoma. In fact, the Ocular Hypertension Treatment Study31 actually found diabetes to be protective and to reduce the likelihood of having glaucoma. Quigley has hypothesized that locally elevated VEGF concentrations in diabetic retinas may provide a neuroprotective environment for retinal ganglion cells, possibly explaining the paradoxical results. But since this is still the only study to have found diabetes to be advantageous in this way, the authors postulated that they may have been misled by having enrolled an unrepresentative group of diabetic patients, since only those without diabetic retinopathy were included.

Diabetes may also be directly implicated in the pathogenesis of some cases of narrow angle glaucoma. Rapid correction of hyperglycemia has been associated with the onset of acute angle closure glaucoma.32–34 In Singapore, diabetes was found to be associated with the risk of developing narrow angle glaucoma, which is the variety most commonly found in this predominantly Asian population.35 In this population of Singapore residents of Chinese ancestry, diabetics had shallower anterior

chambers and thicker lenses than an ageand gender-matched group of nondiabetics, even

though axial length, refractive error, and vitreous chamber depth did not differ.36 Wiemer et al.37,38

also found increased lens thickness in a northern European population, but only in patients with type 1 diabetes, and the amount of thickening was also correlated with the duration of disease.

In addition, certain treatments of diabetic retinopathy and its complications may predispose to narrowing of the anterior chamber angles in ways unrelated to the specifics of the underlying disease. Panretinal photocoagulation and scleral buckling can both lead to transient choroidal thickening and forward rotation of the ciliary body with secondary narrowing of the anterior chamber angle. Silicone oil and intraocular gas can also push the iris forward and obstruct aqueous outflow.

Most well known, however, is the ability of steroids, by any route, to provoke elevated intraocular pressure. In general, diabetics are at higher risk than nondiabetics to develop a steroid response.39 Intravitreal injection of triamcinolone, which places a long-term depot of the drug into the eye, has recently become a frequent cause of elevated intraocular pressure. The incidence of intraocular pres-

sure rise after intravitreal triamcinolone (IVT) injection ranges from 30 to 68%,40–44 with the ele-

vation beginning between 7 and 60 days after injec-

tion. The risk is higher in younger patients, in males, and in those with a fluocinolone implant.45–47 Most

of these pressure spikes are clinically insignificant and self-limited, but in some cases glaucoma medications need to be started, and in others glaucoma filtration surgery or other interventions may be indicated.

When glaucoma medicine fails to control the

intraocular pressure spike following IVT both argon laser trabeculoplasty48,49 and selective laser

trabeculoplasty can be effective.50,51 Another novel approach is the anterior subtenons injection of anecortave acetate. Robin reported that four eyes of three patients with elevated IOP due to IVT responded to a single injection of anecortave acetate, with IOP falling within a month by an average of 48%, the effect lasting 6 months.52 Further inves-

tigations of this approach to nonsteroid-related open angle glaucoma are also ongoing.53,54

Not only does diabetes influence the development of glaucoma, but intraocular pressure has a relationship to the development of diabetic retinopathy. Eyes with proliferative retinopathy on average have lower intraocular pressures than eyes with nonproliferative retinopathy.55 High intraocular pressures can be protective with respect to the development of diabetic retinopathy, and many years ago the purposeful induction of a steroid response was seriously discussed as a possible treatment approach for diabetic retinopathy.56 Conversely, low intraocular pressures are associated with worse diabetic macular edema as a logical consequence of Starling’s law (see Chapter 7).57 For unknown reason, diabetic patients who are steroid responders have slower rates of progression of diabetic retinopathy despite absence of differences in baseline intraocular pressures. That is, factors associated with the steroid response other than increased intraocular pressure may confer this relative resistance to diabetic retinopathy progression.58

11.2Iris and Angle Neovascularization Pathoanatomy and Pathophysiology

The most clinically significant and vision-threatening link between diabetes and glaucoma is the propensity of diabetes to lead to neovascular glaucoma. The remainder of this chapter will review the anatomy, pathogenesis, and management of this challenging disorder.

The normal iris and angle structures are shown in Fig. 11.1. The iris has zones denoted as the pupillary margin, the collarette, the ciliary zone, and the iris root. The iris vascular endothelium is nonfenestrated with tight junctions, which comprise part of the blood–aqueous barrier. Fluorescein does not typically leak across the endothelium of iris

vessels, but often does in the elderly, in pseudoexfoliation, and in inflamed eyes.59,60

The innermost angle structure is the trabecular meshwork, which bridges between the peripheral cornea (Schwalbe’s line) and the scleral spur. Aqueous percolates through the meshwork as it leaves the anterior chamber, and then reaches Schlemm’s canal, a circumferential channel that rests against

the sclera. Aqueous leaves this canal through collector channels that carry it back into the bloodstream via aqueous veins, with a smaller amount leaving by a transconjunctival route. Aqueous also leaves the eye by a nontrabecular outflow pathway, primarily through the iris and the portion of the ciliary body that faces the anterior chamber.

Neovascularization occurring anterior to the retina in diabetic retinopathy arises secondary to retinal ischemia, which preferentially involves the midperipheral and peripheral retina in diabetic reti- nopathy.61–63 Several varieties of the condition exist including entry site neovascularization after pars plana vitrectomy, anterior hyaloidal fibrovascular proliferation, cyclitic membrane formation, iris neovascularization (NVI), and anterior chamber angle neovascularization (NVA).64 Retinal ischemia induces production of vascular endothelial

growth factor (VEGF) in the retina and ciliary body, which diffuses into the vitreous gel and ultimately into the aqueous humor.65 Other growth factors may also be involved.66 Bathing the anterior and posterior surfaces of the iris and the anterior chamber angle, VEGF induces neovascularization in all these tissues with secondary scarring, synechiae formation, hemorrhage, obstruction of aqueous outflow, elevated intraocular pressure, and

eventually ciliary body detachment and hypotony with phthisis bulbi.67–69 Antibodies to VEGF can

block this cascade of events in animal models and in clinical reports.70–72

The single most important factor in anterior segment neovascularization in association with diabetic retinopathy is the concentration of vascular endothelial growth factor (VEGF) in the aqueous humor.73 Vitreous levels of VEGF are significantly

correlated with the severity of diabetic retinopathy, and it is thought that the aqueous humor VEGF originates from the retina and the ciliary body,

diffuses into the vitreous, and thence into the aqueous humor.63–67

Eyes with NVI are frequently observed to have dilated retinal vessels traversing zones of nonperfused retina ending in broom-like expanses of new vessels feeding a ridge of neovascularization just posterior to the ora serrata.63 These findings have been described best by intraoperative fluorescein angiography employing an ophthalmic endoscope, and the descriptions and photographs resemble findings in retinopathy of prematurity.63

Neovascularization of the iris is associated with a myofibroblastic membrane on the iris surface that effaces iris surface crypts and contraction furrows and produces the tractional forces leading to ectropion uvea and angle synechia.74 The new vessels lie beneath this myofibroblastic membrane (Figs. 11.2 and 11.3).67 Although the new vessels predominantly grow on the anterior iris surface, cases have been reported in which

they grow on the posterior surface and on the surface of the ciliary body.75,76 They also can

grow over the pupil and adhere to the lens (seclusio pupillae).74 Untreated cases of NVI often progress to hyphema.74

The pathophysiology of anterior segment neovascularization explains how treatment has beneficial effects. The photoreceptor–retinal pigment epithelial complex consumes two-thirds of the oxygen used by the retina. Laser photocoagulation

Fig. 11.2 A myofibroblastic membrane (black arrow) is present on the iris surface with subjacent iris new vessels. Ectropion uvea is indicated by the open arrow. Reprinted with permission from Roth and Brown172

Fig. 11.3 Anterior synechia secondary to neovascularization of the iris causing effacement of the anterior chamber angle. Reprinted with permission from Roth and Brown172

selectively destroys the retinal pigment epithelium and photoreceptor layers, thus decreasing oxygen consumption of the outer retina and allowing more choroidal oxygen to diffuse to the remaining, viable inner retina.77 This downregulates the production of VEGF and leads to regression of anterior segment neovascularization.78

11.3 Epidemiology

Presence of NVI and NVA in a diabetic patient is a sign of advanced diabetic retinopathy, and often is also a sign that diabetes treatment has not been adequate. Using the slit lamp examination for diagnosis, Ohrt79 found no case of NVI without diabetic retinopathy, and 64% of cases of PDR had NVI. Using fluorescein gonioangiography, Ohnishi et al.80 found NVA in 24% of eyes with NPDR and 73% of eyes with PDR. Consecutive series of eyes undergoing vitrectomy surgery for

complications of diabetic retinopathy report preoperative NVI in 4–27% of eyes.81,82 In a clinical

series of eyes examined with iris fluorangiography and having varying degrees of retinopathy, the prevalence of NVI when severe NPDR and PDR were present was 44 and 66%, respectively.83 No patients with less advanced retinopathy than severe NPDR had NVI.83 In an unselected series of patients with untreated diabetic retinopathy from the 1950s, NVI was present in 6.8% of patients.79 A similar series from 1980 was a lower