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DICAL EDU G ME CA UIN TIO TIN CON CME N A CONTINUING MEDICAL EDUCATION PUBLICATION ISSUE 14 Diagnosing Dry Eye ERIC D. DONNENFELD, MD Dry eye affects tens of millions of patients and is among the most common reasons for eye care provider visits. Knowing what to look for, how, and in whom (hint: everyone) can help stem the tide of this quiet epidemic. The exact prevalence of dry eye is difficult to ascertain, for several reasons, including the absence of a single test (or universally accepted sequence of tests) for its diagnosis, and the fact that patient-reported symptoms are often poorly concordant with objective assessments.1 Estimates based on cohort studies suggest that about 5% to 35% of adults worldwide have dry eye, a rate that is expected to rise in the upcoming decades as common risk factors, including advanced age, increase.2,3 Sometimes even higher estimates are cited, as dry eye symptoms are often camouflaged by other ocular surface conditions such as allergic conjunctivitis, surgery, and contact lens discomfort; in addition, many patients—up to 60% of those with objective evidence of dry eye—are pre-symptomatic.3 The landmark 2007 International Dry Eye Workshop (DEWS) report offered the first thorough expert review around dry eye, including a definition and characterization of two broad forms—aqueous deficiency and evaporative—with an emphasis on aqueous deficiency.4 Several years later, as it became clear that meibomian gland function was critical to ocular surface health, proceedings from the Meibomian Gland Workshop provided similarly specific illumination around evaporative dry eye.5 These workshops, along with ongoing efforts in basic science and clinical research, offer guidance to eye care providers in recognition, diagnosis, and management of the condition. FIGURE 1 Lid margin with inspissated meibomian glands and pasty secretions indicative of MGD. CATEGORIES AND MECHANISMS Dry eye is generally divided into two main categories based on the underlying cause: aqueous deficient and evaporative.4 Aqueous deficiency describes inadequate tear production by the lacrimal glands. In contrast, evaporative dry eye relates to impaired production of the lipid component of the tear film, essential for lubricating the ocular surface and keeping the aqueous layer from evaporating.3 To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ See INSIDE for: Ocular Surface Disease among Glaucoma Patients: A Review by Richard A. Lewis, MD Topics in OCULAReducational ANTIINFLAMMATORIES 1 Supported by an unrestricted grant from Shire. Evaporative and mixed forms of dry eyes are more prevalent than the pure aqueous-deficient form. 6 This article is focused on clinical findings and diagnosis of evaporative dry eye caused by meibomian gland disease; disease management will be covered in a subsequent article. Evaporative dry eye is almost always due to chronic disease of the meibomian glands, often referred to as meibomian gland disease or dysfunction (MGD). Characterized by glandular duct obstruction and diminished quality and/or quantity of sebaceous secretions, MGD prevents the ocular surface from being coated with its normal lipid layer, resulting in evaporation of aqueous tears and a hyperosmolar tear film. MGD is also associated with increased bacterial lipase activity, which break down meibum lipids into their substructures, soaps and fatty acids. A tear film containing soap and acid certainly explains the common complaints among patients with evaporative dry eye, namely tearing and burning! These processes destabilize the tear film resulting in increased evaporation, hyperosmolarity, bacterial growth on the lid margin, and increased ocular surface inflammation.5 MORBIDITY Dry eye has been associated with reduced quality of life, including negative effects on psychological, social, workrelated, and physical functioning.7,8 Difficulty with activities of everyday living—including driving, reading, working, and leisure activities—are significantly more common among patients with dry eye compared with unaffected persons.7 Dry eye may also contribute to contact lens intolerance and poor outcomes following ocular surgery.9,10 Moderate to severe dry eye can compromise vision; symptoms may include blurring, reduced contrast sensitivity, and impaired visual acuity.8,11 Pre-symptomatic and low-grade dry eye can progress and cause increased symptoms and aggravation over time. RISK FACTORS US census data project a more than 2 Topics in OCULAR ANTIINFLAMMATORIES TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 14 STATEMENT OF NEED The control of ocular inflammation is a critical aspect of medical and surgical ophthalmic practice. Despite their side effects, antiinflammatory drugs are used to treat a very wide range of conditions throughout the eye, from ocular surface disease and allergic conjunctivitis to posterior segment conditions. Use of antiinflammatory agents is also critical in ocular surgery, contributing greatly to patient comfort and positive outcomes. The ocular antiinflammatory landscape is changing as research reveals more about the role of inflammation in a range of ocular conditions and as new antiinflammatory agents enter the market.1,2 Twenty years ago, for example, the idea of using a topical corticosteroid to treat dry eye and/ or allergic conjunctivitis was viewed with alarm; today, it is accepted practice. Although corticosteroids and nonsteroidal antiinflammatory drugs (NSAIDs) have been the mainstays of the ocular antiinflammatory armamentarium, a number of new agents with novel mechanisms of action (and new ocular drug delivery systems) have come to market or are being made ready for market.3,4 As indications expand and change, and as new drugs, formulations, and delivery systems become available, clinicians require up-to-date protocols for drug selection and use. Such protocols are also needed for routine (but nevertheless offlabel) uses of corticosteroids and NSAIDs because important differences in efficacy, safety, and tolerability exist between these classes and among formulations within each of these classes.5,6 By putting the latest published evidence into the context of current clinical practice, Topics in Ocular Antiinflammatories equips ophthalmologists to maintain competencies and narrow gaps between their actual and optimal inflammation management practices, across the range of clinical situations in which current and novel ocular antiinflammatories may be used. REFERENCES 1. Song JS, Hyon JY, Lee D, et al. Current practice pattern for dry eye patients in South Korea: a multicenter study. Korean Journal of Ophthalmology. 2014;28(2):115-21. 2. Ciulla TA, Harris A, McIntyre N, Jonescu-Cuypers C. Treatment of diabetic macular edema with sustained-release glucocorticoids: intravitreal triamcinolone acetonide, dexamethasone implant, and fluocinolone acetonide implant. Expert Opin Pharmacother. 2014;15(7):953-9. 3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies for noninfectious uveitis: what may be coming to the clinics. J Ophthalmol. 2014;2014:310329. 4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, and the OPUS-1 Study Group. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology. 2014 Feb;121(2):475-83. 5. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol etabonate gel 0.5% for postoperative pain and inflammation after cataract surgery: results of a multicenter trial. Clin Ophthalmol. 2012;6:1113-24. 6. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt in clinical practice: our experience vs a meta-analysis of the literature. Clin Exp Ophthalmol. 2012;S1:003. OFF-LABEL USE STATEMENT This work may discuss off-label uses of medications. GENERAL INFORMATION This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Shire. Directions: Select one answer to each question in the exam (questions 1–10) and in the evaluation (questions 11–16). The University of Florida College of Medicine designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. There is no fee to participate in this activity. In order to receive CME credit, participants should read the report, and then take the posttest. A score of 80% is required to qualify for CME credit. Estimated time to complete the activity is 60 minutes. On completion, tear out or photocopy the answer sheet and send it to: University of Florida CME Office PO Box 100233, Gainesville, FL 32610-0233 PHONE: 352-733-0064 fax: 352-733-0007 Or you can take the test online at http://cme.ufl.edu/ed/ self-study/toai/ System requirements for this activity are: For PC users: Windows® 2000, XP, 2003 Server, or Vista; Internet Explorer® 6.0 or newer, or Mozilla® Firefox® 2.0 or newer (JavaScript™ and Java™ enabled). For Mac® users: Mac OS® X 10.4 (Tiger®) or newer; Safari™ 3.0 or newer, Mozilla® Firefox® 2.0 or newer; (JavaScript™ and Java™ enabled). Internet connection required: Cable modem, DSL, or better. DATE OF ORIGINAL RELEASE September 2016. Approved for a period of 12 months. ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Florida College of Medicine and Candeo Clinical/ Science Communications, LLC. The University of Florida College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT The University of Florida College of Medicine designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. FACULTY AND DISCLOSURE STATEMENTS Marguerite B. McDonald, MD, FACS, (Faculty Advisor) practices at Ophthalmic Consultants of Long Island, and is a clinical professor of ophthalmology at the New York University School of Medicine. She is also an adjunct clinical professor of ophthalmology at Tulane University Health Sciences Center. She’s a consultant to Allergan, Alcon, Abbott Medical Optics, Bausch + Lomb, FOCUS Laboratories, Shire, OCuSOFT, and Altaire. John D. Sheppard, MD, MMSC, (Faculty Advisor) is the president of Virginia Eye Consultants and is a professor of ophthalmology, microbiology, and molecular biology at the Eastern Virginia Medical School. He is also the research director of the ophthalmology residency program and clinical director of the Thomas R. Lee Center for Ocular Pharmacology at Eastern Virginia Medical School. Dr. Sheppard is on the advisory board for 1-800-DOCTORS, Alcon, Aldexa Pharmaceuticals, Allergan, Bausch + Lomb, Clearside, EyeGate Research, EyeRx Research, Imprimis Pharma, Inspire/Merck Pharmaceuticals, Isis Pharmaceuticals, Kala Pharmaceuticals, Lacrisciences, Lux Biosciences, Nicox, NovaBay, Novartis/Ciba Vision, OcuCure Inc., Rapid Pathogen Screening, Santen, Shire, Stemnion, Synedgen, Talia Technology, TearLab, TearScience, and Vistakon. He has received grant/clinical research support from Alcon, Aldexa Pharmaceuticals, Allergan, Bausch + Lomb, EyeGate Research, EyeRx Research, Insite, Inspire/Merck Pharmaceuticals, Isis Pharmaceuticals, Kala Pharmaceuticals, Lux Biosciences, Pfizer, Rapid Pathogen Screening, Rutech, Santen, Senju, Shire, Topcon, Vistacon, and Xoma/Servier. He is a consultant for AbbVie, Aldexa Pharmaceuticals, Allergan, Bio-Tissue, Eleven/Lexitas, Mededicus, NovaBay, Science Based Health, Stemnion, TearLab, and TearScience. Dr. Sheppard is on the speakers bureau for Abbvie, Alcon, Allergan, Bausch + Lomb, Bio-Tissue, Eleven/Lexitas, EyeGate Research, Inspire/Merck Pharmaceuticals, Isis Pharmaceuticals, Kala Pharmaceuticals, Lacrisciences, Lumenis, Mededicus, Nicox, Novartis/Ciba Vision, Omeros, Pentavision, Pfizer, Rutech, Santen, Sjo/Nicox, Talia Technology, TearLab, and TearScience. He is an investor for Rapid Pathogen Screening and has ownership of stock interest for BioLayer, Clearside, EyeGate Research, EyeRx Research, Novabay, OccuHub, OcuCure Inc., Rapid Pathogen Screening, Stemnion, Strathspey Crowne, and TearLab. He is a stock shareholder for 1-800-DOCTORS, Eyegate Research, Lacrisciences, OcuCure Inc., Shire, and TearLab. Eric Donnenfeld, MD, is a partner at Ophthalmic Consultants of Long Island and clinical professor of ophthalmology at New York University in New York, NY. Dr. Donnenfeld is a consultant for Allergan, Alcon, Bausch + Lomb, Mati Therapeutics, and Shire. He is also on the speakers’ bureau for Allergan, Alcon, Bausch + Lomb, and Shire. Richard A. Lewis, MD, is in private ophthalmology practice in Sacramento, California. Dr. Lewis is chief medical officer at Aerie and a consultant for Aerie, Allergan, Glaukos and Ivantis. He is also on the speakers’ bureau for Carl Zeiss Meditec AG. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and professional development. The information presented in this activity is not meant to serve as a guideline for patient care. Procedures, medications, and other courses of diagnosis and treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, applicable manufacturer’s product information, and comparison with recommendations of other authorities. COMMERCIAL SUPPORTERS This activity is supported by an unrestricted educational grant from Shire. To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ doubling of the population over the age of 65 years between 2014 (46 million) and 2060 (98 million).12 Advanced age is an undisputed risk factor for the development of dry eye;13 thus, unless prevention and early detection improve considerably, a corresponding rise in dry eye prevalence should be anticipated. Other dry eye correlates that have surfaced in clinical studies include female sex; poorer self-reported general health; certain systemic conditions including arthritis, allergic and autoimmune conditions, and thyroid disease untreated with hormonal therapy; and the use of certain medications including antidepressants and antihistamines.13,14 Despite increased risk, dry eye should not be considered an inevitable consequence of aging; factors within patients’ sphere of influence may play a role.3 For example, lifestyle and environmental factors—including prolonged computer use (which decreases blink rate), low humidity environments, and contact lens wear—have been associated with increased risk for the development of dry eye.3 Diets deficient in omega-3-fatty acids—found in green leafy vegetables, nuts, flaxseed oil, organ meats, and fish—may contribute to dry eye. Omega-3-fatty acid supplementation has been shown to improve the meibum fatty acid profile and increase tear breakup time.15 Smoking may be an independent contributor to dry eye, although data on the benefits of smoking cessation as it pertains to dry eye are lacking.16,17 Lastly, in patients with dry eye associated with an autoimmune disease such as Sjogren’s syndrome or rheumatoid arthritis, systemic treatments that reduce systemic inflammation will sometimes reduce ocular inflammation and dry eye as well. FIGURE 2 Tear film “soapsuds” are a sign of increased bacterial lipase acting on altered meibum associated with MGD. DIAGNOSIS Dry eye is a clinical diagnosis based upon history, physical examination, and objective assessments of tear film, ocular surface inflammation, and meibomian gland morphology and function. Patients with dry eye present with a range of symptoms that may fluctuate from day to day. Common complaints include ocular surface irritation, visual fluctuation, reflex tearing, or difficulty with prolonged visual tasks such as CORE CONCEPTS ✦ Dry eye is due to aqueous deficiency, MGD, or both; MGD and mixed forms are most prevalent. ✦ MGD is characterized by gland plugging, reduced quality and quantity of meibum, hyperosmolar and unstable tear film, bacterial overgrowth, and ocular surface inflammation. ✦ Dietary fatty acid intake, reduced blink rate associated with computer use, and environmental factors may all contribute to dry eye. ✦ Dry eye may cause mild, moderate, or severe symptoms including irritation and visual change. ✦ Patients may have reduced quality of life and difficulty with daily tasks. ✦ Patients may have no symptoms but have objective evidence of dry eye. ✦ Dry eye symptom questionnaires and point of service tests improve the chance of detecting dry eye. computer use or driving. Patients often ascribe the symptoms they are experiencing to something other than dry eye. One sensitive and efficient means for improving dry eye diagnosis is to screen all patients with a brief questionnaire that can be completed in the waiting room. A written symptom screen is more efficient (and possibly more precise) than inquiring in an interview. In my practice, every patient who comes to the office is asked to fill out a modified Ocular Surface Disease Index (OSDI) questionnaire before I see them; three or more positive answers raise concern for dry eye and, via the protocol we use, empower my technician to order more definitive testing including tear osmolarity, matrix metalloproteinase-9 (MMP9), and sometimes meibomian gland imaging. Rapid point-of-care determination of tear osmolarity and ocular surface inflammation biomarker MMP9 greatly enhances the chance of detecting dry eye and increase efficiency in the office.18,19 A thorough external examination starts with the skin, looking for evidence of systemic or local risk factors such as psoriasis, rosacea, or other dermatologic conditions. The lid margins should be examined for erythema and blood vessel dilation that can accompany acute inflammatory MGD and telangiectasia, which is present in chronic MGD. The meibomian gland orifices should be examined for plugging and inspissation of secretions and expressed to evaluate the consistency of secretions; olive oil-looking secretions indicate normal function, whereas thick toothpaste-like secretions indicate MGD (Figure 1). This is a technique that has fallen off somewhat in clinical practice, which is unfortunate, as it is a quick, immediate way to get actionable information about meibomian gland health. The presence of a chalazion, or plugged meibomian gland, is a red flag for more widespread MGD. My practice is to then examine the tear film, looking at To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 3 meniscus height, lid apposition, and evidence of any debris. I look carefully for a “soapsuds” appearance in the tear film, a sign of increased lipase activity associated with MGD (Figure 2). In addition, I often perform a test of tear fi lm breakup time to assess tear film stability. Lissamine green staining is useful to assess the extent of ocular surface damage and to rule out disorders that can mimic dry eye such as entropion, ectropion, floppy eye syndrome, and conjunctival chalasis. With the exception of assessing aqueous deficiency dry eye severity, I generally do not rely on Schirmer testing. The questionnaire, exam, and selected tests can be administered in surprisingly little time, leaving me plenty of time to discuss therapy with patients who have positive results. CONCLUSION Dry eye, especially due to meibomian gland disease, is very common and likely affects more of our patients than those who carry the diagnosis. Developing an in-office protocol for diagnosing dry eye, including a screening process for all patients, will lead to better care for patients and improved outcomes following ocular surgery. Eric Donnenfeld, MD, is a partner at Ophthalmic Consultants of Long Island and clinical professor of ophthalmology at New York University in New York, NY. Dr. Donnenfeld is a consultant for Allergan, Alcon, Bausch + Lomb, Mati Therapeutics, and Shire. He is also on the speakers’ bureau for Allergan, Alcon, Bausch + Lomb, and Shire. Medical writer Noelle Lake, MD, assisted in the preparation of this manuscript. REFERENCES 1. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea. 2004;23:762-70. 2. The epidemiology of dry eye disease: report of the Epidemiology Subcom- 4 Topics in OCULAR ANTIINFLAMMATORIES mittee of the International Dry Eye WorkShop. Ocul Surf. 2007;5:93-107. 3. Bron AJ, Tomlinson A, Foulks GN, et al. Rethinking Dry Eye Disease: A Perspective on Clinical Implications. Ocul Surf. 2014;12(2S):S1-31. 4. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92. 5. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland dysfunction: executive summary. Invest Ophthalmol Vis Sci. 2011;52:1922-9. 6. Lemp MA, Crews LA, Bron AJ, et al. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: A retrospective study. Cornea. 2012;31(5):472-8. 7. Miljanovic B, Dana R, Sullivan DA, et al. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol. 2007;143:409-15. 8. Uchino M, Schaumberg DA. Dry eye disease: impact on quality of life and vision. Curr Ophthalmol Rep. 2013;1:51-7. 9. Li XM, Hu L, Hu J, et al. Investigation of dry eye disease and analysis of the pathogenic factors in patients after cataract surgery. Cornea. 2007;26(9 Suppl 1):S16-20. 10. Konomi K, Chen LL, Tarko RS, et al. Preoperative characteristics and a potential mechanism of chronic dry eye after LASIK. Invest Ophthalmol Vis Sci. 2008;49:168-74. 11. Montés-Micó R. Role of the tear film in the optical quality of the human eye. J Cataract Refract Surg. 2007;33:1631-5. 12. 2014 National Population Projections: Publications. http://www.census. gov/population/projections/data/national/2014/publications.html. Accessed April 7, 2016. 13. Moss SE, Klein R, Klein BE. Long-term incidence of dry eye in an older population. Optom Vis Sci. 2008;85:668-74. 14. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol. 2014;157:799-806. 15. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-56. 16. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol. 2000;118:1264-8. 17. Klein BE, Klein R. Lifestyle exposures and eye diseases in adults. Am J Ophthalmol. 2007;144:961-9. 18. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol. 2011;151(5):792-8. 19. Sambursky R, Davitt WF 3rd, Latkany R, et al. Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA Ophthalmol. 2013;131(1):24-8. To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ Ocular Surface Disease among Glaucoma Patients: A Review RICHARD A. LEWIS, MD Chronic topical hypotensive exposure can exacerbate ocular surface disease. Detecting and addressing ocular surface issues in glaucoma patients is one important way that eye care providers can enhance their care as they simultaneously work to maintain IOP. The state of the ocular surface has always taken a back seat to the chief consideration in the management of glaucoma: maintaining good health of the optic nerve and preserving vision. However, ocular surface disease is not trivial; it has been implicated in reducing quality of life, contact lens tolerability, and ocular surgical outcomes.1-4 Importantly, ocular surface disorders can have a deleterious impact on visual function and acuity.2,5 Ocular surface disease is widespread in the glaucoma population, and while awareness is increasing, it is almost certainly underdiagnosed. Among medically treated glaucoma patients, one study showed that 80% also had meibomian gland disease.6 Other estimates show ocular surface disease prevalence of between 40% to 85%—many cases of which are severe—within the glaucoma population.7 Advancing age predisposes to both conditions; in addition, long-term topical medications may induce ocular surface changes via inflammatory, allergic, and/or toxic mechanisms.8 MEDICATIONS The glaucoma population—indeed, any group of patients dependent on chronic application of topical ocular medication—is at risk for medication-induced ocular surface damage. The extent of medication exposure (eg, number of therapies, number of drops, and treatment duration) has been shown to correlate with the effect on the ocular surface.9,10 In a prospective controlled trial, greater exposure to topical medications for lowering intraocular pressure (IOP), quantified as number of drops per week multiplied by treatment years, was associated with significantly worse ocular surface disease compared with lesser exposed glaucoma patients.9 In a separate study, patients on multiple topical anti-glaucoma medications had more severe ocular surface symptoms compared with patients on monotherapy.10 The most commonly cited cytotoxic agent in ocular medication is benzalkonium chloride (BAK), a quaternary ammonium compound that serves as a preservative and antibacterial agent in many ophthalmic preparations.11 In vitro studies show that BAK contributes to corneal and conjunctival cell apoptosis and ocular surface inflammation in a dosedependent fashion.8 Animal studies reveal that BAK induces CORE CONCEPTS ✦ Ocular surface disruption is common among glaucoma patients; it may stem from age-related ocular surface disorders or chronic medication use. ✦ Most glaucoma eye drops, especially ones containing BAK, can cause minor disruptions in the ocular surface and exacerbate dry eye signs and symptoms. ✦ Treating pre-existing dry eye and other ocular surface conditions may help improve tolerability and prevent noncompliance. corneal neurotoxicity, inflammation, and reduced aqueous tear production.12 And clinical studies reveal that dry eye signs and symptoms improve when patients are switched from BAK-preserved medications to BAK-free formulations.13 BAK may be a contributing factor to conjunctival allergy, dry eye disease, and failure of glaucoma surgery in patients on longterm topical ocular therapy. Preservative-free anti-glaucoma medications are available; however lack of coverage by insurance providers makes them more expensive for patients and thus infrequently prescribed. Patients who can afford the additional, out of pocket expense may find BAK-free therapies less irritating to the ocular surface. Ocular surface related side effects vary within each class of agent, which may relate to the active molecule, the type and concentration of preservative, or due to any component of the medication vehicle. A study compared the effect of four commercially available prostaglandin analog (PGA) agents—bimatoprost, tafluprost, travoprost, and latanoprost—on normal human conjunctival cell culture in vitro and found that all four induced some level of concentration-dependent cytotoxicity, with preservative-free tafluprost inducing the least damage.14 Among BAK-containing PGA agents, latanoprost was the least cytotoxic. The ocular surface may also be susceptible to the active ingredient of antihypotensive agents, many of which are vasodilatory.7,15 To a varying degree, PGAs cause conjunctival hyperemia as a side effect in some patients; similarly, alpha agonists can cause rebound conjunctival redness following an initial blanching phase.15,16 Redness and other ocular surface manifestations have a negative influence on quality of life and can interfere with medication adherence. The long-term effect on the tear film and ocular surface is unknown.8 COMPLIANCE Ocular surface conditions present in a variety of ways, including ocular irritation, redness, discharge, visual To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 5 complaints, and related behaviors such as repeatedly rubbing the eye. Symptoms may start within the first few days of taking a new therapy or present after months to years on the same therapy. In some patients, ocular surface symptoms play a role in medication nonadherence, a multifactorial and vexing problem within the glaucoma population.17 Research has shown that only 33% to 39% of patients persist in taking ocular hypotensive medication as prescribed by 12 months after initiation.18 It not hard to imagine how a patient with daily medication-related symptoms such as stinging or burning— or other disincentive such as cost, denial, difficulty instilling drops, or erroneous belief in the inevitability of blindness— might struggle with adherence to a treatment prescribed in perpetuity for a symptomless disease. Although no studies have proven that decreased hypotensive medication adherence leads to vision loss, one would logically assume that patients who discontinue treatment can expect outcomes similar to untreated patients. MANAGEMENT Maintaining ocular surface health should be part and parcel of glaucoma management for the reasons mentioned: ocular comfort and quality of life, surface-related visual clarity, and optimal anti-glaucoma medication adherence and success. In addition to routine IOP-related testing and management, every clinic visit for patients with glaucoma should include a thorough physical examination of the ocular surface and questions about ocular surface symptoms and medication tolerance. It is also useful to inquire to the patient, family, or caregiver about medication adherence; suboptimal adherence, if uncovered, may be a tip off for tolerability issues related to the ocular surface. Patients with signs or symptoms of ocular surface disease should be assessed for treatable underlying disorders whether related or unrelated to glaucoma management. In particular, look carefully for evidence of blepharitis and dry eye disease which are common comorbidities among older patients. Also consider less common culprits such as seasonal and perennial allergies and exposure to products such as makeup that may contact the eye. As discussed, consider the possibility of medication-induced ocular surface disruption. For treatment, choose the simplest, most definitive method that targets the underlying cause or causes. Blepharitis treatment is dictated by the subtype and should always include lid hygiene. Also, patients should be advised to avoid rubbing eyes, as fingers can be a source of infection. Patients with blepharitis who wear eye makeup may need to temporarily stop or at least replace any products which might have become contaminated. Dry eye disease must also be treated according to its particular type. It may respond to topical moisturizers or anti-inflammatory medication; punctal plugs may be preferable when administering drops is problematic.19 There is some data to support prescribing oral omega-3-fatty acid supplementation (with flaxseed or fish oil) to reduce ocular 6 Topics in OCULAR ANTIINFLAMMATORIES surface inflammation in patients with meibomian gland disease and/or blepharitis.20 For some patients, switching anti-glaucoma medication may help; for example, a patient with redness and irritation on brimonidine may benefit from switching to a PGA. Some patients benefit from laser trabeculoplasty or glaucoma surgery to reduce or eliminate topical medication dependency. Patients with cataract, glaucoma, and medication-related ocular surface disease may make excellent candidates for a combination cataract surgery/minimally invasive glaucoma surgery (MIGS) which can reduce dependence on ocular hypotensive medication.21 Clearing up the ocular surface preoperatively using antiinflammatory medication is important for accurate preoperative calculations and best postoperative visual outcomes.22 In the future, improved MIGS methods and delivery of anti-glaucoma medication via intracameral injection (or other sustained delivery system that bypasses the ocular surface) could be instrumental in reducing ocular surface stress and adherence issues that accompany today’s daily drop regimens. CONCLUSION Ocular surface disease is multifactorial and variable in its presentation in glaucoma patients. Physicians must remember to keep the front of the eye in mind though their focus is on the back. Richard A. Lewis, MD, is in private ophthalmology practice in Sacramento, California. Dr. Lewis is chief medical officer at Aerie and a consultant for Aerie, Allergan, Glaukos and Ivantis. He is also on the speakers’ bureau for Carl Zeiss Meditec AG. Medical writer Noelle Lake, MD, assisted in the preparation of this manuscript. REFERENCES 1. Miljanovic B, Dana R, Sullivan DA, et al. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol. 2007;143:409-15. 2. Uchino M, Schaumberg DA. Dry eye disease: impact on quality of life and vision. Curr Ophthalmol Rep. 2013;1:51-7. 3. Li XM, Hu L, Hu J, Wang W. Investigation of dry eye disease and analysis of the pathogenic factors in patients after cataract surgery. Cornea. 2007;26(9 Suppl 1):S16-20. 4. Konomi K, Chen LL, Tarko RS, et al. Preoperative characteristics and a potential mechanism of chronic dry eye after LASIK. Invest Ophthalmol Vis Sci. 2008;49:168-74. 5. Montés-Micó R. Role of the tear film in the optical quality of the human eye. J Cataract Refract Surg. 2007;33:1631-5. 6. Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, et al. Meibomian Gland Dysfunction in Patients Receiving Long-Term Glaucoma Medications. Cornea. 2016 Apr 6. Epub ahead of print. 7. Bron AJ, Tomlinson A, Foulks GN, et al. Rethinking dry eye disease: A perspective on clinical implications. Ocul Surf. 2014;12(2S):S1-31. 8. Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312-34. 9. Saade CE, Lari HB, Berezina TL, et al. Topical glaucoma therapy and ocular surface disease: a prospective, controlled cohort study. Can J Ophthalmol. 2015;50:132-6. 10. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressurelowering medications. Cornea. 2010;29:618-21. 11. Yee RW, Norcom EG, Zhao XC. Comparison of the relative toxicity of To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ travoprost 0.004% without benzalkonium chloride and latanoprost 0.005% in an immortalized human cornea epithelial cell culture system. Adv Ther. 2006;23:511-9. 12. Sarkar J, Chaudhary S, Namavari A, et al. Corneal neurotoxicity due to topical benzalkonium chloride. Invest Ophthalmol Vis Sci. 2012;53:1792-802. 13. Horsely MB, Kahook MY. Effects of prostaglandin analog therapy on the ocular surface of glaucoma patients. Clin Ophthalmol. 2009:3;291-5. 14. Pérez-Roca F, Rodrigo-Morales E, Garzón I, et al. Effects of four formulations of prostaglandin analogs on eye surface cells: a comparative study. PLoS One. 2015;10:e0129419. 15. Stewart WC, Kolker AE, Stewart JA, et al. Conjunctival hyperemia in healthy subjects after short-term dosing with latanoprost, bimatoprost, and travoprost. Am J Ophthalmol. 2003;135:314-20. 16. Honrubia F, García-Sánchez J, Polo V, et al. Conjunctival hyperaemia with the use of latanoprost versus other prostaglandin analogues in patients with ocular hypertension or glaucoma: a meta-analysis of randomised clinical trials. Br J Ophthalmol. 2009;93:316-21. 17. Reardon G, Kotak S, Schwartz GF. Objective assessment of compliance and persistence among patients treated for glaucoma and ocular hypertension: a systematic review. Patient Prefer Adherence. 2011;5:441-63. 18. Schwartz GF, Quigley HA. Adherence and persistence with glaucoma therapy. Surv Ophthalmol. 2008;53 Suppl1:S57-68. 19. Ervin AM, Wojciechowski R, Schein O. Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev. 2010;(9):CD006775. 20. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-56. 21. Brandão LM, Grieshaber MC. Update on Minimally Invasive Glaucoma Surgery (MIGS) and New Implants. J Ophthalmol. 2013;2013:705915. 22. Kim P, Plugfelder S, Slomovic AR. Top 5 pearls to consider when implanting advanced-technology IOLs in patients with ocular surface disease. Int Ophthalmol Clin. 2012;52:51-8. To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 7 EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 14 This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted educational grant from Shire. Directions: Select the one best answer to each question in the exam (Questions 1–10) and in the evaluation (Questions 11–16) below by circling one letter for each answer. Participants must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University of Florida College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. There is no fee to participate in this activity. You can take the test online at http://cme.ufl.edu/ed/self-study/toai/. 1. Which of the following procedures can reduce the need for ocular hypotensive medication? A. MIGS with phacoemulsification B. MIGS without phacoemulsification C. Both A and B D. Neither A nor B 2. Pathognomonic signs of MGD include which of the following? A. “Soap suds” appearance to the tear film B. Chalazion C. Conjunctival chalasis D. Both A and B 3. Which of the following is NOT a component of meibomian gland disease pathophysiology? A. Ocular surface inflammation B. Hypoosmolarity C. Bacterial growth on lid margins D. Altered meibum 4. Managing ocular surface disease in glaucoma patients may improve: A. Quality of life B. Anti-glaucoma medication adherence C. Surgical outcomes D. All of the above 5. Which of the following has NOT been shown to correlate with degree of ocular surface disease in glaucoma patients? A. Number of topical medications B. Intensity of treatment (drops per week times years of treatment) C. Weeks of therapy missed D. None of the above 6. Which of the following forms of dry eye is caused by inadequate tear production? A. Meibomian gland disease B. Evaporative C. Aqueous deficiency D. None of the above EXAMINATION ANSWER SHEET 8. Which of the following would likely NOT benefit patients with ocular surface disease related to antiglaucoma medication? A. Sustained anti-glaucoma drug delivery via punctal plug B. Sustained anti-glaucoma drug delivery via intracameral injection C. Improved MIGS procedures D. All of the above 9. Which of the following is NOT a risk factor for the development of dry eye? A. Advanced age B. Autoimmune disease C. Antidepressant use D. Male sex EVALUATION: 1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding 11. Extent to which the activity met the identified Objective 1: 1 2 3 4 5 Objective 2: 1 2 3 4 5 Objective 3: 1 2 3 4 5 Objective 4: 1 2 3 4 5 1.A B C D 6.A B C D 12. Rate the overall effectiveness of how the activity: Related to my practice: 1 2 3 4 5 Will influence how I practice: 1 2 3 4 5 Will help me improve patient care: 1 2 3 4 5 Stimulated my intellectual curiosity: 1 2 3 4 5 Overall quality of material: 1 2 3 4 5 Overall met my expectations: 1 2 3 4 5 Avoided commercial bias/influence: 12345 2.A B C D 7.A B C D 13. Will the information presented cause you to make any changes in your practice? Yes No 3.A B C D 8.A B C D 14. If yes, please describe: __________________________ 4.A B C D 9.A B C D 5.A B C D 10.A B C D 15. How committed are you to making these changes? 12345 ANSWERS: Topics in OCULAR ANTIINFLAMMATORIES 10. Ocular surface disruption among patients taking topical hypotensive medication may: A. Be caused by exposure to the preservative B. Be caused by exposure to the active moiety C. Occur within any time frame D. All of the above TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 14 This CME activity is jointly sponsored by the University of Florida and Candeo Clinical/Science Communications, LLC, and supported by an unrestricted educational grant from Shire. Mail to: University of Florida CME Office, PO Box 100233, Gainesville, FL 32610-0233. DIRECTIONS: Select the one best answer for each question in the exam above (Questions 1–10). Participants must score at least 80% on the questions and complete the entire Evaluation (Questions 11–16) to receive CME credit. CME exam expires August 31, 2017. 8 7. Which of the following is a common presenting complaint among patients with dry eye? A. Burning B. Blurry vision C. No symptoms D. All of the above are common dry eye presentations ________________________________________________ 16.Are future activities on this topic important to you? Yes No If you wish to receive credit for this activity, please fill in the following information. Retain a copyfor your records. PLEASE PRINT CLEARLY ________________________________________________________________ FIRST NAME LAST NAME DEGREE ________________________________________________________________ ORGANIZATION/INSTITUTE ________________________________________________________________ CITY STATE ZIP ________________________________________________________________ ADDRESS LINE 1 ________________________________________________________________ ADDRESS LINE 2 ________________________________________________________________ PHONE FAX ________________________________________________________________ E-MAIL ADDRESS To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/