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Iatrogenic glaucoma therapy failure: the adverse effects of topical antiglaucoma medication treatment outcome Expert Rev. Clin. Pharm. 2(1), 87–99 (2009)

Sophia K Mirza and Eve J Higginbotham† † Author for correspondence Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310, USA Tel.: +1 404 752 1728 Fax: +1 404 752 1594 [email protected]

Glaucoma, a group of eye diseases that share a characteristic pattern of deterioration of the optic nerve, is a leading cause of blindness internationally. The treatment options for this optic neuropathy continue to remain limited considering that patients may become refractory to either medical therapy or surgical intervention. The initial treatment of choice for most ophthalmologists is topical medical therapy. The goal of medical therapy is to reduce the intraocular pressures in an effort to either halt or slow the progressive deterioration of the optic nerve. However, topical therapy causes a spectrum of cellular responses that may lead to chronic conjunctivitis after the use of multimedication and/or long-term therapy. This chronic conjunctivitis may not only lead to intolerance to therapy, but is also attributed to a significant proportion of trabeculectomy failures due to scarring of the bleb. Since incisional surgery is a primary option for long-term management of glaucoma, particularly those patients with end-stage disease, it is important to investigate the presence of topical drug‑mediated inflammation and its effects on further surgical failure. Keywords : β-blocker • conjunctival bleb • glaucoma • prostaglandin analogue • trabeculectomy

Glaucoma is the second leading cause of blindness and the number one cause of irreversible blindness. This disease affects 4 million people in the USA, including 2 million people who do not know they have it, and 70 million people worldwide [101] . Higher prevalence rates exist with increasing age; under 50  years of age there is a rate of 0.005% while over 50 years of age there is a rate of 3.4% [1] . Population studies performed in the USA demonstrate higher prevalence rates among Hispanics and African–Americans compared with other ethnic groups. Within the Hispanic population, the fastest growing minority in the USA, patients demonsrate a 0.5% prevalence in subjects between 41 and 49 years of age and a 12.6% prevalence in those over 80  years of age [2] . Among African Americans, the prevalence for people aged 40–49 years was 1.2% while there was an alarming prevalence of 11.3% in people over 80 years of age. This was compared with 0.9% prevalence from 40–49 years and 2.1% prevalence in Caucasian subjects over the age of 80 years [3] . As the population increases in www.expert-reviews.com

10.1586/17512433.2.1.87

age, a projected 50% increase in the number of those suffering from open-angle glaucoma is expected by the year 2020 [4] . Glaucoma is more prevalent in women until the age of 65 years, beyond which the rates between males and females become even [102] . At the root of these data is the observation that most individuals who have glaucoma are unaware of the condition. A study examining a populationbased sample of Hispanic patients found that only 38% of participants knew they had glaucoma before the initiation of the study [2]; also the Los Angeles Latino Eye Study found that 75% of participants with glaucoma were previously unaware of their condition [5]. Definition of glaucoma, risk factors & benefits of treatment

What is glaucoma? Over the last three decades the definition of glaucoma has evolved from ‘a group of diseases defined by elevated intraocular pressure (IOP)’ to ‘an optic neuropathy characterized by specific indication of deterioration of the optic nerve or functional

© 2009 Expert Reviews Ltd

ISSN 1751-2433

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perimetric findings.’ IOP is considered the major controllable risk factor for developing glaucoma, as some patients present with characteristic optic-nerve and visual-field changes but have normal IOPs. The Ocular Hypertension Treatment Study (OHTS) demonstrated that treating patients who have moderately increased IOP, versus not treating these same patients, reduced their risk of developing glaucomatous optic neuropathy. Among those individuals who did not receive treatment, 9.5% developed glaucoma over 5  years compared with 4.4% who did receive treatment. An ana­lysis of those individuals who self-reported as African–American also demonstrated a benefit to treatment; among those individuals who were treated, 8.4% developed glaucoma versus 16.1% who were not treated [6] . Thus, topical treatment is effective in reducing the risk of developing glaucoma. Besides elevated IOP, the investigators of OHTS identified other risk factors for developing glaucoma: age, large cup-to-disc ratio and low central corneal thickness. Persons with glaucoma have a 50% family history of openangle glaucoma and 43% family history of ocular hypertension. Individuals with a maternal family history of glaucoma have a seven-times greater risk of developing glaucoma than on the paternal side [7] . Despite other identified risk factors, many of which are uncontrollable, the OHTS and the Early Manifest Glaucoma Treatment Study [8] confirmed the benefits of reducing IOP among individuals with ocular hypertension and glaucoma, respectively. Thus, any effective therapeutic approach to either delaying the onset of glaucoma among high-risk individuals with ocular hypertension or managing patients with glaucoma must emphasize reduction of IOP. Overview of treatment

The treatment of glaucoma usually begins with topical medical therapy; however, later incisional surgery might be necessary for those individuals who may not respond initially to noninvasive modes of treatment. Topical medical therapy has changed over the years, as older drugs and their adverse side-effect profiles have given way to newer topical medications and comparatively fewer side effects. For decades, physicians were limited to parasympathomimetics, adrenergic agonists and oral carbonic anhydrase inhibitors. Parasympathomimetic drops were previously a staple of medical therapy of glaucoma for over 100 years but were associated with miosis, cataracts and reduction of peripheral vision, a consequence of glaucoma itself. Adrenergic agonists may be associated with conjunctival hyperemia, thus negatively impacting patient tolerance. Oral carbonic anhydrase inhibitors also significantly reduce IOP by decreasing aqueous production; however, systemic adverse effects, such as hyperkalemia, renal calculi, parasthesias, diarrhea, weight loss and loss of libido, limit their long-term use in some patients. Towards the end of the 20th century, the choices for medical therapeutic intervention increased and in general, potential side effects decreased. In the 1970s, β-blockers, a class of medication that also reduce aqueous production, became available. This class is contraindicated in those patients with either chronic obstructive pulmonary disease or heart failure. Topical carbonic anhydrase 88

inhibitors became available in the 1990s, a more tolerable option compared with the oral agents. Most recently, prostaglandin analogues have been used as the initial medical therapy of choice for open-angle glaucoma. These drugs work by increasing the egress of aqueous humor using the uveoscleral pathway and have been shown to cause transient hyperemia and very few systemic adverse effects. Ultimately, for those patients who are refractory to medical therapy, either nonincisional or incisional surgery may be necessary to either slow or halt disease progression. Surgical options in the management arsenal

Surgery is conventionally considered when progression of the disease has made medical treatment refractory to lowering pressures and preventing further optic neuropathy. Several surgical options are now available for advanced glaucoma. Laser therapies with either argon laser trabeculoplasty or selective laser trabeculoplasty have provided other tools for ophthalmologists. However, they have only been found to be a temporary control measure; the effect of these procedures wears off over time in a significant proportion of patients. Filtering surgery or more specifically, trabeculectomy, remains the primary surgical option. Adjunctive use of antifibrotic agents, such as mitomycin C and 5-fluorouracil has been shown to increase the success of filtration surgery in those patients who are at risk for failure. Nonpenetrating filtering procedures, such as viscocanulostomy and canaloplasty, trabeculotomy and glaucoma filtration devices, have been shown to be associated with fewer complications than trabeculectomy, but the long-term success of these procedures is unknown. Other surgical techniques include endocyclophotocoagulation and transscleral cylodiathermy (in which the portions of the ciliary body are destroyed) are additional options. However, the magnitude of the reduction in IOP is unpredictable. Thus, despite the advent of newer techniques, trabeculectomy remains the primary option for those patients with progressive glaucoma. Current management protocols

The question of whether or not medical therapy should precede surgical therapy for the majority of patients with glaucoma has been debated for decades. Previous data indicated that filtering surgery enables better pressure management, visual field preservation, and comparable visual acuity between surgery and medication. Other reasons supporting initial surgery include better quality of life and decreased medication costs [9] . For mild open-angle glaucoma, either medication or surgery maintain a similar risk of glaucoma progression; however, in severe open-angle glaucoma, surgery was shown to reduce progression better than medical therapy, specifically pilocarpine [10] . The Collaborative Initial Glaucoma Treatment Study, a more recent study, also examined the question of management. This randomized, controlled clinical trial compared two arms of treatment. The first arm was initial medical therapy followed by laser trabeculoplasty and trabeculectomy, if progression continues. The second arm was a surgical arm in which trabeculectomy was the first intervention followed Expert Rev. Clin. Pharmacol. 2(1), (2009)

Iatrogenic glaucoma therapy failure

by trabeculoplasty and then medical therapy, if progression continues. Interim results comparing the two treatment groups were reported after 5  years of follow-up and indicated that the surgical cohort exhibited a 2–3 mmHg reduction in IOP, but sustained a greater visual field loss and decrease in visual acuity, as well as more cataract surgeries. Thus, their current recommendation is to maintain the current standard of initial medical therapy, leaving surgery as an option when medical therapy is no longer beneficial [11]. In addition to these findings, it is also evident that medications tend to be more accessible than surgery. Both the literature and clinical experience support the central role of topical medical therapy in the treatment of either high-risk patients with ocular hypertension or those patients who have been diagnosed with glaucoma. Effects of topical medications

Considering that antiglaucoma medications continue to be firstline therapy, it is likely that most individuals with glaucoma will be treated for long periods of time. Thus, it is important to evaluate the effects these topical antiglaucoma medications may have on both external and internal structures of the eye and the impact these drugs may ultimately have on subsequent filtration surgery. Several studies have linked topical antiglaucoma medications to poor surgical outcomes. Longstaff et al. demonstrated that the only noteworthy risk factor for failure of IOP management postoperatively was the chronic use of topical antiglaucoma medications; however, no single medication was identified in this study [12] . Another study observed that medication used prior to surgery for longer periods of time (1 year vs 2 weeks of treatment prior to trabeculectomy) was associated with higher rates of surgical failure, while also indicating that the most important risk factor was the number of medications used before surgery. This same study also demonstrated a greater frequency of failure when sympathomimetics were used as opposed to β-blockers alone  [13] . A similar trend associating presurgical sympathomimetics, among other risk factors, was found a year later in 1991 [14] . In this case–control study, however, the duration of treatment was not strictly documented. Other studies indicate that the greatest influences are the duration of treatment along with combination therapy [15] . Questions regarding whether the duration of treatment versus the number of medications used has the most detrimental effects on trabeculectomy procedures are still largely unanswered. Cytologic studies examining the conjunctiva of patients exhibited a much higher degree of subclinical inflammation when taking either a β-blocker alone, or a β-blocker combined with a miotic, or these two medications combined with a sympathomimetic. When patients were taking these medications for longer than 3  years, they exhibited a much higher degree of subclinical inflammation. The inflammation was characterized by an increase in macrophages and lymphocytes in the epithelium and substantia propria. The effect was the same for the briefly treated (