Glaucoma is a leading cause of blindness among elderly individuals.1 Despite advances in laser and surgical treatments, topical hypotensive drops remain the cornerstone of therapy for this disease. Unfortunately, patients often require more than one medication to lower their IOP, and, over time, these medications can disrupt the tear film and adversely affect its ability to protect the ocular surface. Left untreated, a dysfunctional tear film increases the cornea's vulnerability to environmental insults that can subsequently damage epithelial cells.
Like glaucoma, dry eye syndrome and ocular surface disease are prevalent among older individuals. Because the long-term use of topical hypotensive medications can exacerbate the chronic ocular stinging, foreign body sensation, and blurry vision associated with ocular surface disease, anyone who treats patients for glaucoma should understand how commonly prescribed medications affect the ocular surface. This article reviews techniques for diagnosing ocular surface disease and describes strategies for treating this disorder in glaucoma patients.
WHAT IS OCULAR SURFACE DISEASE?
Ocular surface disease is an inclusive term describing any condition that adversely affects the stability and function of the tear film. Common causes of ocular surface disease include dry eye syndrome, blepharitis, meibomian gland dysfunction, toxicity from the preservatives used in topical medications, and any combination of these entities. Regardless of its underlying cause, ocular surface disease leads to characteristic pathologic changes in corneal epithelial cells, a decrease in the density of goblet cells, and the upregulation of inflammatory mediators.
Studies have shown that between 8% and 15% of people in the United States have symptoms of ocular surface disease.2 Although the prevalence of glaucoma is relatively low (approximately 2.5%) in this same population,3,4 studies utilizing the Ocular Surface Disease Index (OSDI) show that 40% to 59% of glaucoma patients also have ocular surface disease.5,6 Various factors contribute to the several-fold higher incidence of ocular surface disease in glaucoma patients versus the general population.
CHRONIC EXPOSURE TO PRESERVATIVES
For several years, clinicians have known that benzalkonium chloride (BAK), a preservative used in topical ophthalmic preparations, can have deleterious effects on the ocular surface. The detergent property of BAK effectively denatures the proteins and disrupts the cellular membranes of pathogens that can contaminate multidose bottles of topical glaucoma drugs. Because BAK's mechanism is indiscriminate, however, it can trigger apoptosis in human corneal and conjunctival epithelial cells, and it can cause chronic stromal inflammation. This preservative also damages microvilli on the epithelial surface and goblet cells, thus disrupting the tear film and potentially exacerbating preexisting ocular surface disease.7,8
Noecker and colleagues showed that medications containing higher concentrations of BAK (ie, dorzolamide, timolol, and latanoprost) caused more conjunctival inflammation in New Zealand white rabbits than topical agents containing lower levels of BAK (ie, bimatoprost with 0.005% BAK), drugs containing alternative preservatives (brimonidine with Purite; Alphagan P; Allergan, Inc., Irvine, CA), or unpreserved eye drops (ie, preservative-free timolol).7 In a similar animal model, Kahook and Noecker compared preservative-free artificial tears, travoprost with Sofzia (Travatan Z; Alcon Laboratories, Inc., Fort Worth, TX), and latanoprost with 0.02% BAK.8 They observed the highest rate of conjunctival inflammation in the eyes exposed to latanoprost. In addition, electron microscopy showed that latanoprost significantly damaged corneal epithelial microvilli. They did not observe similar changes in the eyes that received travoprost with Sofzia.8
Research indicates that acute and chronic exposure to BAK can cause inflammatory changes in the ocular surface and decrease tear breakup time. Horsley and Kahook found that replacing latanoprost with 0.02% BAK with travoprost with Sofzia for 8 weeks increased the mean tear breakup time of 20 consecutive patients (40 eyes) from 2.02 ±0.71 to 6.34 ±1.31 seconds (P<.001).9 The patients also reported an improvement in their dry eye symptoms on the OSDI at the end of the study (26.31 ±8.25 to 16.56 ±6.19; P<.001). Further studies are underway to determine the significance of this preliminary report.
DIAGNOSING OCULAR SURFACE DISEASE A MULTIFACTORIAL APPROACH
Currently, ophthalmologists do not have a single practical, reproducible test that can help them diagnose and stage ocular surface disease. Physicians must therefore rely on their clinical judgment and formulate treatment plans based on a combination of objective testing and their assessment of individual patients' symptoms. Clinicians and patients are often frustrated by ocular surface disease, however, because the severity of symptoms does not correlate with changes in the ocular surface. Early disease is predominated by symptoms of ocular discomfort that are accompanied by minimal physical signs. Conversely, longstanding ocular surface disease often causes neurotrophic changes on the ocular surface that are manifested as visual disturbances and increased staining versus discomfort.
SUBJECTIVE ASSESSMENTS
Questionnaires such as the OSDI are well-validated tools for detecting and staging ocular surface disease,10 especially when they are used in conjunction with clinical testing. Many physicians, however, do not incorporate questionnaires into their routine workup, and they therefore overlook a valuable opportunity to identify affected patients and initiate appropriate treatment. Technicians can administer and score the OSDI in just a few minutes and use the results to compile a precise history of the patient's ocular symptoms. The OSDI is also useful for evaluating the efficacy of various interventions, because it allows clinicians to compare a patient's baseline responses with those obtained after the initiation of treatment.
CLINICAL TESTING
In 2007, the International Dry Eye Workshop published its guidelines for diagnosing and treating ocular surface disease. In addition to identifying critical clinical tests, this report recommended that physicians adhere to the following sequence when objectively assessing patients for ocular surface disease:
- Measure tear breakup time with fluorescein.
- Perform vital staining with lissamine green or rose bengal.
- Evaluate the production of tears with Schirmer testing.
- Assess the morphology of the eyelids and meibomian glands.
- Test the function of the meibomian glands.
Performing these tests out of order may affect their integrity and provide inaccurate information.11
Each of the steps just described provides specific information about dry eye. Testing tear breakup time with fluorescein is a sensitive and practical method for assessing the stability of the tear film. This approach reportedly has a high specificity and 85% accuracy for measuring tear breakup time.11 During fluorescein testing, a physician or technician places a small amount of dye in the fornix of the patient's eye and monitors the tear film for breakthroughs (Figure 1). A normal tear film typically takes 10 seconds or longer to break up.
Vital staining with lissamine green and rose bengal helps clinicians identify devitalized epithelial cells that are not protected by mucin and glycocalyx. In contrast, fluorescein highlights cells in the basement membrane in eyes with advanced ocular surface disease, thus indicating areas that have been denuded of epithelial cells (Figure 2).
Schirmer testing that produces less than 5 mm of wetting at 5 minutes is very specific (80% to 100%) but has a low sensitivity (10% to 25%) for aqueous tear deficiency.11 Finally, inspecting the meibomian gland for inspissations and turbid secretion is a good way to determine if the patient's ocular surface disease includes a component of evaporative tear loss.
Many emerging technologies such as functional wavefront imaging, optical coherence tomography, confocal microscopy, and osmolarity measuring systems show promise for improving the diagnosis of ocular surface disease. Until these new diagnostic tests become the standard of care, however, physicians should continue to follow the recommendations issued by the Dry Eye Workshop.
COMMON TECHNIQUES FOR TREATING OCULAR SURFACE DISEASE
The chronic, remitting nature of ocular surface disease poses significant challenges to treatment. Clinicians have attempted to overcome various obstacles by adopting a stepped approach to therapy.
First-line therapy for mild ocular surface disease usually includes over-the-counter lubricating eye drops. The greatest advance in the treatment of dry eye can perhaps be attributed to the Dry Eye Workshop Study, which recommended that manufacturers eliminate BAK from lubricating eye drops. These ophthalmic solutions are now preserved with nondetergent agents, or they are available in preservative-free formulations.
Moderate dry eye that does not respond to environmental control and requires frequent dosing with unpreserved eye drops is often treated with cyclosporine ophthalmic emulsion 0.05% (Restasis; Allergan, Inc., Irvine, CA). Studies have shown that cyclosporine improves the signs and symptoms of ocular surface disease, decreases inflammatory mediators, and increases the density of goblet cells.12 Physicians often implant punctal plugs in patients whose ocular surface disease is related to aqueous tear deficiency if they do not respond to cyclosporine alone. Approximately 74% to 86% of patients who receive this combined treatment report an improvement in their dry eye symptoms.11
Blepharitis is another condition that contributes to evaporative tear loss in patients with ocular surface disease. A regimen of lid hygiene that includes warm compresses (to soften secretions) and scrubbing with gentle cleansers often improves symptoms. If these measures do not provide satisfactory relief, patients may benefit from the antibacterial and anti-inflammatory properties of tetracycline derivatives.
Given the mounting evidence of the deleterious effects of BAK on the ocular surface, physicians should take steps to limit glaucoma patients' exposure to this detergent preservative. Currently available drugs that contain alternative preservatives or are preservative free include travoprost with Sofzia, brimonidine with Purite, and unpreserved unit-dose timolol.
CONCLUSION
Ocular surface disease is a serious and debilitating pathology that is prevalent among elderly individuals. This condition appears to be exacerbated by the use of topical ophthalmic medications preserved with BAK. Together, these factors increase the risk that elderly glaucoma patients will develop ocular surface disease.
Physicians can prevent or minimize ocular surface disease among their glaucoma patients by paying proper attention to the disease's clinical signs and symptoms. They can also improve patients' comfort and produce better therapeutic outcomes with prompt intervention. Often, minimizing or eliminating patients' exposure to extrinsic factors such as caustic preservatives may reduce the incidence and severity of ocular surface disease among those who use glaucoma medications.
Malik Y. Kahook, MD, is Assistant Professor of Ophthalmology and Director of Clinical Research in the Department of Ophthalmology at the University of Colorado Denver. He is a consultant to, has received grant/research support from, and is on the speakers' bureau of Alcon Laboratories, Inc., and he has consulted to and received research support from Allergan Inc. Dr. Kahook may be reached at (720) 848-2500; malik.kahook@uchsc.edu.
Clark L. Springs, MD, is Assistant Professor of Ophthalmology at the Indiana University of School of Medicine in Indianapolis. He has received grant/research support from and is on the speakers' bureau of Alcon Laboratories, Inc. Dr. Springs may be reached at (317) 278-5100: csprings@iupui.edu.
