THE CLASSIC STEPPED ALGORITHM
Mechanism
The only proven method of treating glaucoma is reducing IOP. All of the medications approved for glaucoma treatment in the US enhance aqueous outflow or impede its inflow and thereby decrease IOP. Similarly, all of the laser procedures we employ lower pressure, either by enhancing aqueous outflow (trabeculoplasty and iridotomy) or by reducing aqueous inflow (cyclophotodestruction). Finally, whether traditional or novel, every surgical intervention reduces IOP.
Disparate Viewpoints
The overall approach to IOP control in glaucoma is a classic stepped algorithm, but the order of the steps varies considerably among practitioners and between global regions. As noted earlier, US surgeons usually commence glaucoma treatment with medications, proceed if necessary to laser procedures, and resort to surgery if all else fails (Figure 1). By no means, however, is glaucoma treatment in this country straightforward; a recent estimate cites more than 56,000 ways of combining the various medications available, a statistic highlighting the difficulty of this step.1 In contrast, the glaucoma faculty at Moorfields Eye Hospital in London has advocated a surgery-first algorithm for several years.2,3
Figure 1. The classic stepped algorithm of glaucoma management.
How can such disparity exist? US practitioners advocate the medicine-first algorithm on the basis of maximizing patient safety and minimizing the invasiveness of treatment. Across the Atlantic, physicians defend the surgery-first algorithm based on better IOP outcomes as compared with treatment using medications or lasers and cite a belief that surgery is more effective in patients who have not undergone long-term treatment with topical medications.
Does chronic exposure to topical glaucoma medications decrease the likelihood of successful filtering surgery? A similar question remains unanswered with respect to the outcomes of argon laser trabeculoplasty and trabeculectomy. The potential mechanisms by which argon laser trabeculoplasty may affect later surgical outcomes are less obvious than with medications, because the conjunctiva is exposed to every drop of medication instilled. We need, therefore, to examine the effects of these medications on the structure of the conjunctiva.
THE TOXIC CONJUNCTIVA
Numerous studies have demonstrated that the conjunctivae of glaucoma patients on chronic medical therapy differ histologically from those of untreated glaucoma patients and persons without glaucoma. One group of investigators used light microscopy to examine the histology of the conjunctiva of glaucoma patients undergoing trabeculectomy after topical therapy for various durations of time.4 The researchers found that those who had received topical medications for 2 months or less had normal conjunctivae, whereas patients treated for greater than 12 months before surgery possessed higher numbers of subepithelial fibroblasts and inflammatory cells such as lymphocytes, mast cells, and macrophages.
A similar study5 compared conjunctival biopsies from trabeculectomy patients who had previously undergone treatment with glaucoma medications to the conjunctival biopsies of surgical patients with nonconjunctival diseases and no history of topical eye drop use. The investigators found that conjunctivae exposed to chronic glaucoma medications possessed more fibroblasts and inflammatory components when examined both by light and electron microscopy and by advanced immunohistochemical techniques to detect markers of chronic inflammation. Multiple researchers have confirmed these findings in vivo6-8 and in vitro,9 in the trabecular meshwork and in the conjunctiva.10 These changes can appear in the conjunctiva after as few as 3 months of topical therapy.11 Nevertheless, another study12 reported no difference in the numbers of inflammatory cells, goblet cells, or fibroblasts between patients treated for at least 1 year with a minimum of two different glaucoma medications (mean 46 months) versus patients with no history of topical eye drop use.
Additionally, it is important to recognize that commercially available glaucoma medications contain both active and inactive ingredients. The term inactive ingredient may be a misnomer; although these ingredients (eg, preservatives such as the ubiquitous benzalkonium chloride) may not lower IOP, they may be toxically active to the conjunctiva. Two of the investigations cited earlier comment that preservative-mediated conjunctival toxicity cannot be excluded,6,7 and one of the studies specifically looked for—and found—evidence of increased conjunctival toxicity in tissue exposed to benzalkonium chloride compared with unexposed tissue.9
THE EFFECT UPON SURGICAL OUTCOMES
The available science provides strong evidence that the conjunctiva is affected by chronic exposure to glaucoma medications and that this exposure results in increased numbers of fibroblasts and inflammatory elements, which are known to adversely affect trabeculectomy success rates (Figure 2). We must then ask (1) whether patients previously treated with chronic glaucoma medications have poorer surgical outcomes than those undergoing early surgical intervention and (2) if the British algorithm is superior to that of the US.
Figure 2. Conjunctival changes associated with chronic topical glaucoma therapy.
The Moorfields group13 undertook a retrospective study over a decade ago that compared the outcomes of trabeculectomy in two groups: those with little or no prior exposure to topical medication (less than 2 weeks) and those with at least 1 year of exposure to topical agents. They found a statistically better success rate among the minimally exposed group. In contrast, a retrospective US study14 determined that there was no correlation between surgical outcomes and a prior history of topical glaucoma medications. The investigators examined fellow-eye pairs. Although the second eye to undergo surgery experienced approximately 1.8 years of additional medical therapy before surgical intervention, they found no between-eye differences in surgical outcomes, a result supporting the theory that medications do not adversely affect surgical outcomes.
Undaunted, the Moorfields group subsequently conducted a prospective study of 124 patients undergoing trabeculectomy and explored the relationship between the length of presurgical topical glaucoma therapy, conjunctival changes, and surgical outcomes.15,16 The investigators divided patients into four groups. Group A had received topical glaucoma therapy for less than 2 weeks prior to surgery; group B had received chronic therapy with beta-blockers only; group C had received chronic beta-blocker and miotic therapy; and group D had undergone chronic therapy with beta-blockers, miotics, and sympathomimetic agents.
The researchers reported normal conjunctivae in groups A and B, as well as equally high surgical success rates (in the 90% range). In group C and even more so in group D, however, they found abnormal conjunctivae with reduced goblet cell numbers and increased amounts of fibroblasts, macrophages, lymphocytes, and mast cells. They also reported that the surgical success rates were statistically lower in groups C and D, 72% and 45%, respectively. These findings do not necessarily mean that beta-blockers do not harm the conjunctiva; the progressively worse outcomes associated with using greater numbers of medications, however, may suggest that the exposure to cumulative doses of preservative are at least partially to blame for conjunctival toxicity and poor surgical outcomes.
CLINICAL RELEVANCE
What do these study findings mean for our patients? The truth is that we do not know conclusively whether or not prior medical therapy adversely affects eventual surgical outcomes. Although it certainly would be helpful, we have essentially no data on the effects on conjunctival health of presently popular glaucoma medications. Most of the medications commonly used today only became available during the last 5 years, so we have limited information about their long-term safety.
Clinicians who wish to minimize conjunctival toxicity and improve the health of their patients' conjunctivae prior to surgery should note a study17 demonstrating that ceasing all topical glaucoma medications and commencing treatment with topical steroids 1 month before glaucoma surgery can reduce the amount of toxic conjunctival changes. Investigators showed that 1% fluoromethalone q.i.d. for 1 month significantly reduced the number of fibroblasts and inflammatory elements in chronically treated conjunctivae.
A CAUTIONARY NOTE
In an editorial several years ago,18 Harry Quigley, MD, of Baltimore used epidemiological data to suggest that the surgery-first model might backfire if applied widely. According to his calculations, if every glaucoma patient underwent trabeculectomy as a first-line treatment, the number of eyes blinded from surgical complications would rival the number of people blinded by glaucoma itself.
Tony Realini, MD, is Associate Professor of Ophthalmology at West Virginia University Eye Institute in Morgantown, West Virginia. Dr. Realini participates in the Speakers' Bureaus for Merck & Co., Inc., Alcon Laboratories, Inc., Allergan, Inc., Pfizer Inc., and Novartis Ophthalmics. Dr. Realini may be reached at (304) 598-6925; hypotony@yahoo.com.
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