Glaucomas: Glaucoma and the Cornea

Core Messages

››Intraocular pressure measurements are affected by corneal hydration.

››Corneal edema can result from high intraocular pressure, topical medications, laser and incisional glaucoma surgery.

››Corneas with tenuous endothelial function and density are most at risk for decompensation following interventions for glaucoma.

››Certain corneal diseases can lead to glaucoma.

47.1  How Do Glaucoma and IOP

Affect the Cornea?

From the glaucoma specialist’s standpoint, the cornea has generated a great deal of interest since the Ocular Hypertension Treatment Study (OHTS) highlighted the importance of central corneal thickness as a risk factor for glaucoma development. The cornea has always been important though, because a compact and transparent cornea is necessary for a clear view of the optic nerve, for good visual acuity to perform visual fields, and for accurate measurements of intraocular pressure. The effects of glaucoma and glaucoma treatment on the corneal endothelium are of particular concern, as a compromised endothelium poses a great risk for corneal decompensation.

J. A. Giaconi

Jules Stein Eye Institute, David Geffen School of Medicine, 100 Stein Plaza, Los Angeles, CA 90095, USA

e-mail: giaconi@jsei.ucla.edu

The cornea is essentially a sandwich of stroma in between the epithelium and the endothelium. Glaucoma and glaucoma treatment can affect the health and structure of these outer layers (how they do this will be answered over the series of proceeding questions), which in turn can lead to stromal edema. Stromal edema can result in the false underestimation of the intraocular pressure [1, 2]. Although an edematous cornea is thick, its viscoelastic properties are changed compared to a normally hydrated cornea. The rule of thumb that thick corneas overestimate IOP does not apply in the case of thick, edematous corneas.

Corneal edema can be the result of insults or abuse at various levels. The stroma makes up over 90% of the cornea’s structure and has a natural tendency to swell because its glycosoaminoglycan and protein content draws fluid into itself [3]. First, it is important to understand what forces work together to keep the cornea clear. Tight junctions between epithelial cells prevent tears from entering the stroma. In the endothelial cell layer, leaky junctions allow aqueous humor to seep into the stroma to provide nutrition, but simultaneously these cells are actively drawing fluid out via an active pump mechanism. In addition, IOP produces an outward compressive force that helps keep the stromal layers compact. In part, corneas become edematous during hypotony because this compressive effect of IOP is lost. On the other hand, in cases of acutely elevated IOP, micro cystic epithelial edema results when high IOP drives fluid across the loose endothelial junctions. Eventually, stromal edema accumulates as end­ othelial cell function begins to fail. The endothelium is extremely important in maintaining corneal clarity. The average adult’s cornea has an endothelial cell density (ECD) of 1,500–2,000 cells/mm2. A clear corneal stroma can be maintained until a threshold of approximately 500 cells/mm2 is reached.

The relationship between IOP and corneal endothelial cell loss is not fully understood. In acute angleclosure attacks with very high IOP, the average loss of endothelial cells is 23–35.1%, with losses as high as 68% reported. Cell loss correlates with the duration of IOP elevation in acute angle-closure, with significant losses beginning at 72 h duration [4–6]. With chronic and moderately elevated IOP, what happens to the endothelium is less clear. In an elegant and in depth study where ocular hypertension was induced by laser in one eye of monkeys, ECD was lower in the hypertensive eye (33% loss) compared to the control eye after 2.5 years. The average IOP was double that seen in the control eyes (ranging from 25 to 59 mmHg). The ECD decrease correlated with duration of IOP elevation but not to the height of the IOP response [7]. In two clinical studies, ECD was measured in glaucoma patients and controls (controls were cataract patients). ECD was lower in glaucoma patients vs. controls, in primary angle-closure glaucoma vs. primary open-angle glaucoma, and in those patients on 3–4 topical medications vs. those on 1–2 medications. The ECD count correlated with IOP level; however, if the few patients with extremely low ECD (i.e., those status post acute angle-closure attacks) were removed from the analysis, the correlation was no longer significant [8, 9].

With the common clinical scenario of chronic openangle glaucoma and IOP in the mid to high 20s range, there may be some statistically significant loss of endothelial cells, but it does not appear to be clinically significant. In cases of acute angle-closure glaucoma lasting 72 h or more, very high losses of ECD may be sustained that can prove clinically significant, particularly in eyes that go on to have further endothelial cell insults such as intraocular surgery.

Summary for the Clinician

››IOP compresses the corneal stroma to help keep it compact; with hypotony this compressive effect is lost, contributing to corneal swelling.

››Corneal edema leads to false underestimations of actual IOP.

››Acute angle-closure attacks lasting ³72 h can lead to large losses of endothelial cells.

››Chronically elevated IOP may lead to a decrease in ECD, but this does not appear to be clinically significant for most patients.

47.2  What Effect Do Topical

Medications Have on the Corneal

Endothelium and Epithelium?

Endothelial toxicity is always feared with application of a new compound to the eye. Multiple clinical trials have shown that there is no clinically significant decline in ECD with the use of different topical glaucoma medications. The longest follow-up shows no effect over a 6-year period [10–12]. Carbonic anhydrase inhibitors (CAI) specifically raised concerns, given a number of reports that showed corneal decompensation and increased central corneal thickness after topical CAI use [13–17]. Carbonic anhydrase (CA) isoenzymes are found in the ciliary epithelium and corneal endothelium. The isoenzyme CA II plays a major role in keeping the cornea in a relatively steady state of dehydration [18]. If CA II is inhibited, and dorzolamide is a major inhibitor, the cornea may swell and lose transparency. As it turns out, CAIs mainly pose a risk of decompensation in corneas with borderline endothelial function/density. In healthy corneas, these medications can be used safely [10, 12].

In recent years, the effect of preservatives on the ocular surface has become a popular topic of discussion. Preservatives are necessary to prevent microbial contamination of bottles, but they can have inflammatory, toxic, and allergic side effects. Benzalkonium chloride (BAK) is the single most commonly used ocular preservative today. In vitro studies on immortalized human cornea cells show that medication with BAK has a significant kill effect on these cells compared to non-BAK medication [19]. Studies on rabbits show that BAK causes desquamation of superficial epithelial layers [20]. These effects are thought to affect the tolerability of topical drops. Two large European studies examined ocular signs and symptoms in thousands of patients using preserved and nonpreserved glaucoma medications. They found that the use of nonpreserved drops was associated with about half as many complaints of dry eye symptoms, pain on instillation, foreign body sensation and burning, as well as fewer objective ocular signs than the use of preserved drops [21,  22]. Other preservatives found in commercially available glaucoma medications include benzododecinium bromide, Purite (a stabilized oxychloro complex), and SofZia, a proprietary ionic buffer system that upon contact with the eye falls apart into nontoxic component parts (boric acid, propylene glycol, sorbitol, and

zinc chloride). BAK and other older preservatives have been found to enhance ocular penetration of IOPlowering medications by disrupting epithelial permeability [23]. A concern with formulations using BAK alternatives is whether they will penetrate the ocular surface sufficiently and have equal efficacy to the original formulations – something manufacturers have had to demonstrate for approval in the U.S. market. Preser­ vatives may also have negative toxic and inflammatory effects on the conjunctiva, which theoretically may affect the future success of filtering surgery [24–26]. Increased expression of inflammatory markers and de­­ creased mucin production with the use of BAK has been reported [21].

Another possible side effect of topical medications is subclinical neurotrophic keratopathy. The cornea is a highly innervated tissue. This innervation serves multiple purposes in the cornea’s defense. It is responsible for the aversion response, trophic effects that maintain a normally functioning cornea, and the neural feedback loop that is important in regulating the tear film [27]. A study published in 2006 examined the effects of chronic topical glaucoma medication use in a small cohort of 26 OHTS patients. Using confocal microscopy, the authors of this study found the subbasal nerve plexus was decreased in patients taking chronic topical therapy compared to those in the observation group, and they questioned whether topical medications were causing a subclinical neurotrophic keratitis [10]. If this study can be replicated this may be an important finding. Decreased sensation, as seen in penetrating keratoplasty patients where corneal nerves are severed, can lead to epithelial dysfunction via increased permeability, decreased cell migration, and decreased cell mitosis [27]. This may explain surface changes often seen with chronic topical medication use, such as tear film disturbances and punctate epithelial erosions (Fig. 47.1).

Summary for the Clinician

››Commonly used topical glaucoma medications do not appear to be toxic to healthy endothelial cells with clinical use.

››Carbonic anhydrase inhibitors do inhibit end­ othelial cell carbonic anhydrase, and in corneas with compromised endothelium this may lead to decompensation.

››Benzalkonium chloride is the most common ocular preservative and is toxic to corneal epithelium, which can lead to ocular surface signs and symptoms.

››Chronic topical medication use may possibly affect corneal innervation, which may explain ocular surface side effects.

47.3What Effect Does Laser Glaucoma Surgery Have on the Cornea?

Laser iridotomy and trabeculoplasty are generally considered to be treatment options with a relatively low risk of adverse effects in comparison to incisional surgery. Reports of corneal decompensation after variable amounts of elapsed time (immediate to 16 years later) have been reported following laser iridotomy, particularly argon iridotomy [28–31]. A report from Japan cites 39 eyes that developed argon laser iridotomyinduced bullous keratopathy requiring penetrating keratoplasty [32]. Over half the eyes (59%) had received a prophylactic iridotomy without ever having suffered an acute angle-closure attack (remember that acute angleclosure can dramatically decrease the baseline endothelial cell count – see Sect. 47.1). Of note, nearly a quarter of patients in this report had preexisting corneal guttata,

although a history of other intraocular procedures was not reported. A case series from Singapore similarly describes 14 eyes with inferior corneal edema leading to generalized decompensation following peripheral laser iridotomy [33]. It must be noted that these alarming cases represent a rare long-term complication. The authors estimated that these 14 eyes comprised 0.33% of all laser iridotomies performed over the 12-year review period.

It has been hypothesized that aqueous humor dynamics are altered by an iridotomy. Using a rabbit model, it has been shown that upon pupillary constriction a jet of aqueous fluid is forced through an iridotomy and is directed toward the endothelium. This jet of fluid may mechanically damage the endothelium [34]. In a human study using specular microscopy, Nd:YAG laser was shown to induce corneal endothelial damage in nearly all iridotomies, although damage was usually confined to the immediate area of laser treatment. Differences in surface area damaged may be due to differences in the iris/cornea distance and laser energy used [35]. With laser trabeculoplasty no significant damage to the corneal endothelium has been found [36, 37].

Summary for the Clinician

››Laser iridotomy can cause localized loss of endothelial cells. There are reports of delayed corneal decompensation following argon laser iridotomy, although they are rare.

››Laser trabeculoplasty poses no known danger to the endothelium.

47.4  What Effect Does Incisional

Glaucoma Surgery Have on

the Cornea?

The most devastating effect of incisional glaucoma surgery on the cornea is a flat chamber postoperatively. If central cornea to lens touch occurs, over 50% of the endothelial cells can be lost. In shallow chambers where only the peripheral cornea is in contact with the iris, ECD decreases have been reported to be 8.1 ± 15.4%. In cases where there is no chamber shallowing, average losses after surgery are 1.6 ± 19.1% [38, 39].

To keep everything in perspective, average ECD losses after phacoemulsification are reported to be 8–10% at 1 year [40, 41].

47.4.1  Antimetabolite Use

and the Cornea

The use of adjunctive antimetabolite with trabeculectomy has been examined as a possible source of corneal toxicity. Mitomycin-C is generally considered safe to the cornea in its current clinical uses – for example, LASIK surgeons apply it directly to the stroma in doses of 0.02% to prevent corneal haze and no clinical reports of damage to the endothelium in normal human corneas have been reported to date [42]. However, directly applied to endothelial cells there is a dose-dependent toxic effect [43]. 5-Fluorouracil is especially toxic to epithelium, as it inhibits cells with rapid turnover. Punctate epitheliopathy and epithelial defects have been reported. Subtle changes in the endothelium seen on confocal microscopy are also reported [44]. Studies of both antimetabolites have measured low concentrations in the aqueous humor after external application [45, 46]. Given that these agents are capable of subclinical toxicity within the anterior chamber at currently used concentrations, theoretically, there may be a risk of decompensation in eyes with unhealthy endothelium at baseline. There do exist case reports of corneal decompensation after mitomycin-C trabeculectomy in patients with corneal guttata [47].

47.4.2  Glaucoma Drainage Devices

and the Cornea

There is a significant body of literature on tube shunts and corneal decompensation, although most of this literature concentrates on corneal grafts. Corneal grafts with glaucoma drainage devices in place have a survival rate as low as 25.8% at 2 years [48]. Corneal grafts are more tenuous to begin with than a normal cornea, as many grafts have a high rate of endothelial cell loss in the first five postoperative years [49]. In the past, tube shunts were reserved for eyes with refractory glaucomas whose corneas may have already withstood many intraocular insults, placing them in a precarious