MEDICAL ED NG UC UI AT A CONTINUING TIN IO CON N MEDICAL EDUCATION PUBLICATION CME

ISSUE 14 Diagnosing Dry Eye

ERIC D. DONNENFELD, MD Dry eye a ects 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.

Th e exact prevalence of dry eye is diffi cult 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 oft en poorly con- cordant 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 FIGURE 1 Lid margin with inspissated meibomian glands and pasty as common risk factors, including advanced age, increase.2,3 secretions indicative of MGD. Sometimes even higher estimates are cited, as dry eye symp- toms are oft en camoufl aged by other ocular surface condi- tions such as allergic , surgery, and contact CATEGORIES AND MECHANISMS discomfort; in addition, many patients—up to 60% of those Dry eye is generally divided into two main categories based with objective evidence of dry eye—are pre-symptomatic.3 on the underlying cause: aqueous defi cient and evaporative.4 Th e landmark 2007 International Dry Eye Workshop Aqueous defi ciency describes inadequate tear production by (DEWS) report off ered the fi rst thorough expert review around the lacrimal glands. In contrast, evaporative dry eye relates to dry eye, including a defi nition and characterization of two impaired production of the lipid component of the tear fi lm, broad forms—aqueous defi ciency and evaporative—with an essential for lubricating the ocular surface and keeping the emphasis on aqueous defi ciency.4 aqueous layer from evaporating.3 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 See INSIDE for: specifi c illumination around evaporative dry eye.5 Th e s e w o k- r Ocular Surface Disease among Patients: shops, along with ongoing eff orts in basic science and clinical A Review research, off er guidance to eye care providers in recognition, by Richard A. Lewis, MD diagnosis, and management of the condition.

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Supported byTopics an unrestricted in OCULAR educational ANTIINFLAMMATORIES grant from Shire. 1 Evaporative and mixed forms of TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 14 dry eyes are more prevalent than the STATEMENT OF NEED Internet connection required: Cable modem, DSL, or better. pure aqueous-deficient form.6 This The control of ocular is a critical aspect of DATE OF ORIGINAL RELEASE September 2016. Approved medical and surgical ophthalmic practice. Despite their side for a period of 12 months. article is focused on clinical fi ndings eff ects, antiinfl ammatory drugs are used to treat a very wide ACCREDITATION STATEMENT This activity has been planned and diagnosis of evaporative dry eye range of conditions throughout the eye, from ocular surface and implemented in accordance with the Essential Areas and disease and to posterior segment Policies of the Accreditation Council for Continuing Medical caused by meibomian gland disease; conditions. Use of antiinfl ammatory agents is also critical in Education (ACCME) through the joint sponsorship of the ocular surgery, contributing greatly to patient comfort and University of Florida College of Medicine and Candeo Clinical/ disease management will be covered in positive outcomes. Science Communications, LLC. The University of Florida a subsequent article. The ocular antiinflammatory landscape is changing as College of Medicine is accredited by the ACCME to provide research reveals more about the role of infl ammation in a continuing medical education for physicians. Evaporative dry eye is almost always range of ocular conditions and as new antiinflammatory CREDIT DESIGNATION STATEMENT The University of Florida 1,2 agents enter the market. Twenty years ago, for example, College of Medicine designates this educational activity for due to chronic disease of the meibomian the idea of using a topical corticosteroid to treat dry eye and/ a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians glands, oft en referred to as meibomian or allergic conjunctivitis was viewed with alarm; today, it is should only claim credit commensurate with the extent of accepted practice. their participation in the activity. gland disease or dysfunction (MGD). Although corticosteroids and nonsteroidal antiinfl ammatory FACULTY AND DISCLOSURE STATEMENTS drugs (NSAIDs) have been the mainstays of the ocular Marguerite B. McDonald, MD, FACS, (Faculty Advisor) Characterized by glandular duct ob- antiinfl ammatory armamentarium, a number of new agents practices at Ophthalmic Consultants of Long Island, and is a with novel mechanisms of action (and new ocular drug struction and diminished quality and/or clinical professor of ophthalmology at the New York University delivery systems) have come to market or are being made School of Medicine. She is also an adjunct clinical professor of quantity of sebaceous secretions, MGD ready for market.3,4 ophthalmology at Tulane University Health Sciences Center. prevents the ocular surface from being As indications expand and change, and as new drugs, She’s a consultant to Allergan, Alcon, Abbott Medical Optics, formulations, and delivery systems become available, clinicians Bausch + Lomb, FOCUS Laboratories, Shire, OCuSOFT, and coated with its normal lipid layer, result- require up-to-date protocols for drug selection and use. Such Altaire. protocols are also needed for routine (but nevertheless off - John D. Sheppard, MD, MMSC, (Faculty Advisor) is the ing in evaporation of aqueous tears and label) uses of corticosteroids and NSAIDs because important president of Virginia Eye Consultants and is a professor of diff erences in effi cacy, safety, and tolerability exist between a hyperosmolar tear fi lm. MGD is also ophthalmology, microbiology, and molecular biology at these classes and among formulations within each of these the Eastern Virginia Medical School. He is also the research associated with increased bacterial li- classes.5,6 director of the ophthalmology residency program and pase activity, which break down meibum By putting the latest published evidence into the context of clinical director of the Thomas R. Lee Center for Ocular current clinical practice, Topics in Ocular Antiinfl ammatories Pharmacology at Eastern Virginia Medical School. Dr. Sheppard lipids into their substructures, soaps and equips ophthalmologists to maintain competencies and is on the advisory board for 1-800-DOCTORS, Alcon, Aldexa fatty acids. A tear fi lm containing soap narrow gaps between their actual and optimal infl ammation Pharmaceuticals, Allergan, Bausch + Lomb, Clearside, EyeGate management practices, across the range of clinical situations Research, EyeRx Research, Imprimis Pharma, Inspire/Merck and acid certainly explains the com- in which current and novel ocular antiinfl ammatories may Pharmaceuticals, Isis Pharmaceuticals, Kala Pharmaceuticals, be used. Lacrisciences, Lux Biosciences, Nicox, NovaBay, Novartis/Ciba mon complaints among patients with REFERENCES Vision, OcuCure Inc., Rapid Pathogen Screening, Santen, Shire, evaporative dry eye, namely tearing and 1. Song JS, Hyon JY, Lee D, et al. Current practice pattern for Stemnion, Synedgen, Talia Technology, TearLab, TearScience, dry eye patients in South Korea: a multicenter study. Korean and Vistakon. He has received grant/clinical research support burning! Th ese processes destabilize the Journal of Ophthalmology. 2014;28(2):115-21. from Alcon, Aldexa Pharmaceuticals, Allergan, Bausch + tear fi lm resulting in increased evapora- 2. Ciulla TA, Harris A, McIntyre N, Jonescu-Cuypers C. Lomb, EyeGate Research, EyeRx Research, Insite, Inspire/Merck Treatment of diabetic macular with sustained-release Pharmaceuticals, Isis Pharmaceuticals, Kala Pharmaceuticals, tion, hyperosmolarity, bacterial growth glucocorticoids: intravitreal triamcinolone acetonide, Lux Biosciences, Pfi zer, Rapid Pathogen Screening, Rutech, dexamethasone implant, and fluocinolone acetonide Santen, Senju, Shire, Topcon, Vistacon, and Xoma/Servier. He on the lid margin, and increased ocular implant. Expert Opin Pharmacother. 2014;15(7):953-9. is a consultant for AbbVie, Aldexa Pharmaceuticals, Allergan, 5 Bio-Tissue, Eleven/Lexitas, Mededicus, NovaBay, Science Based 3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies for surface infl ammation. Health, Stemnion, TearLab, and TearScience. Dr. Sheppard is noninfectious : what may be coming to the clinics. J on the speakers bureau for Abbvie, Alcon, Allergan, Bausch Ophthalmol. 2014;2014:310329. + Lomb, Bio-Tissue, Eleven/Lexitas, EyeGate Research, MORBIDITY 4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, and the Inspire/Merck Pharmaceuticals, Isis Pharmaceuticals, Kala OPUS-1 Study Group. Lifi tegrast ophthalmic solution 5.0% Pharmaceuticals, Lacrisciences, Lumenis, Mededicus, Nicox, Dry eye has been associated with re- for treatment of dry : results of the OPUS-1 phase Novartis/Ciba Vision, Omeros, Pentavision, Pfizer, Rutech, duced quality of life, including negative 3 study. Ophthalmology. 2014 Feb;121(2):475-83. Santen, Sjo/Nicox, Talia Technology, TearLab, and TearScience. 5. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol He is an investor for Rapid Pathogen Screening and has eff ects on psychological, social, work- etabonate gel 0.5% for postoperative and infl ammation ownership of stock interest for BioLayer, Clearside, EyeGate 7,8 after surgery: results of a multicenter trial. Clin Research, EyeRx Research, Novabay, OccuHub, OcuCure Inc., related, and physical functioning. Ophthalmol. 2012;6:1113-24. Rapid Pathogen Screening, Stemnion, Strathspey Crowne, and Difficulty with activities of everyday 6. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt in TearLab. He is a stock shareholder for 1-800-DOCTORS, Eyegate clinical practice: our experience vs a meta-analysis of the Research, Lacrisciences, OcuCure Inc., Shire, and TearLab. living—including driving, reading, literature. Clin Exp Ophthalmol. 2012;S1:003. Eric Donnenfeld, MD, is a partner at Ophthalmic Consultants working, and leisure activities—are OFF-LABEL USE STATEMENT This work may discuss off -label of Long Island and clinical professor of ophthalmology at New uses of medications. York University in New York, NY. Dr. Donnenfeld is a consultant significantly more common among GENERAL INFORMATION This CME activity is sponsored by for Allergan, Alcon, Bausch + Lomb, Mati Therapeutics, and the University of Florida College of Medicine and is supported Shire. He is also on the speakers’ bureau for Allergan, Alcon, patients with dry eye compared with by an unrestricted educational grant from Shire. Bausch + Lomb, and Shire. 7 unaff ected persons. Directions: Select one answer to each question in the exam Richard A. Lewis, MD, is in private ophthalmology practice Dry eye may also contribute to con- (questions 1–10) and in the evaluation (questions 11–16). in Sacramento, California. Dr. Lewis is chief medical offi cer at The University of Florida College of Medicine designates this Aerie and a consultant for Aerie, Allergan, Glaukos and Ivantis. tact lens intolerance and poor outcomes activity for a maximum of 1.0 AMA PRA Category 1 Credit™. He is also on the speakers’ bureau for Carl Zeiss Meditec AG. 9,10 There is no fee to participate in this activity. In order to DISCLAIMER Participants have an implied responsibility following ocular surgery. Moderate to receive CME credit, participants should read the report, and to use the newly acquired information to enhance patient severe dry eye can compromise vision; then take the posttest. A score of 80% is required to qualify outcomes and professional development. The information for CME credit. Estimated time to complete the activity is 60 presented in this activity is not meant to serve as a guideline symptoms may include blurring, re- minutes. On completion, tear out or photocopy the answer for patient care. Procedures, medications, and other courses duced contrast sensitivity, and impaired sheet and send it to: of diagnosis and treatment discussed or suggested in this University of Florida CME Offi ce activity should not be used by clinicians without evaluation 8,11 visual acuity. Pre-symptomatic and PO Box 100233, Gainesville, FL 32610-0233 of their patients’ conditions and possible contraindications or PHONE: 352-733-0064 fax: 352-733-0007 dangers in use, applicable manufacturer’s product information, and comparison with recommendations of other authorities. low-grade dry eye can progress and Or you can take the test online at http://cme.ufl .edu/ed/ self-study/toai/ COMMERCIAL SUPPORTERS This activity is supported by an cause increased symptoms and aggrava- unrestricted educational grant from Shire. System requirements for this activity are: For PC users: tion over time. 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®) RISK FACTORS or newer; Safari™ 3.0 or newer, Mozilla® Firefox® 2.0 or newer; US census data project a more than (JavaScript™ and Java™ enabled).

2 Topics in OCULAR ANTIINFLAMMATORIES 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 CORE CONCEPTS 13 undisputed risk factor for the development of dry eye; thus, ✦ Dry eye is due to aqueous defi ciency, MGD, or both; MGD unless prevention and early detection improve considerably, a and mixed forms are most prevalent. corresponding rise in dry eye prevalence should be anticipated. ✦ MGD is characterized by gland plugging, reduced quality Other dry eye correlates that have surfaced in clinical and quantity of meibum, hyperosmolar and unstable studies include female sex; poorer self-reported general health; tear fi lm, bacterial overgrowth, and ocular surface certain systemic conditions including arthritis, allergic and infl ammation. autoimmune conditions, and thyroid disease untreated with ✦ Dietary fatty acid intake, reduced blink rate associated hormonal therapy; and the use of certain medications includ- 13,14 with computer use, and environmental factors may all ing antidepressants and antihistamines. contribute to dry eye. Despite increased risk, dry eye should not be considered an inevitable consequence of aging; factors within patients’ ✦ Dry eye may cause mild, moderate, or severe symptoms including irritation and visual change. sphere of infl uence may play a role.3 For example, lifestyle and environmental factors—including prolonged computer ✦ Patients may have reduced quality of life and diffi culty use (which decreases blink rate), low humidity environments, with daily tasks. and contact lens wear—have been associated with increased ✦ Patients may have no symptoms but have objective risk for the development of dry eye.3 evidence of dry eye. Diets defi cient in omega-3-fatty acids—found in green ✦ Dry eye symptom questionnaires and point of service leafy vegetables, nuts, fl axseed oil, organ meats, and fi sh—may tests improve the chance of detecting dry eye. contribute to dry eye. Omega-3-fatty acid supplementation has been shown to improve the meibum fatty acid profi le and increase tear breakup time.15 computer use or driving. Patients oft en ascribe the symptoms Smoking may be an independent contributor to dry eye, they are experiencing to something other than dry eye. although data on the benefi ts of smoking cessation as it per- One sensitive and effi cient means for improving dry eye tains to dry eye are lacking.16,17 diagnosis is to screen all patients with a brief questionnaire Lastly, in patients with dry eye associated with an auto- that can be completed in the waiting room. A written symp- immune disease such as Sjogren’s syndrome or rheumatoid tom screen is more effi cient (and possibly more precise) than arthritis, systemic treatments that reduce systemic infl am- inquiring in an interview. In my practice, every patient who mation will sometimes reduce ocular infl ammation and dry comes to the offi ce is asked to fi ll out a modifi ed Ocular Surface eye as well. 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 defi nitive testing including tear osmolarity, matrix metal- loproteinase-9 (MMP9), and sometimes meibomian gland imaging. Rapid point-of-care determination of tear osmolarity and ocular surface infl ammation biomarker MMP9 greatly enhances the chance of detecting dry eye and increase ef- fi ciency in the offi ce.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. Th e lid margins should be examined for erythema and blood vessel dilation that can accompany acute infl ammatory MGD and telangiectasia, which is present in chronic MGD. FIGURE 2 Tear fi lm “soapsuds” are a sign of increased bacterial lipase Th e meibomian gland orifi ces should be examined for acting on altered meibum associated with MGD. plugging and inspissation of secretions and expressed to evaluate the consistency of secretions; olive oil-looking secre- DIAGNOSIS tions indicate normal function, whereas thick toothpaste-like Dry eye is a clinical diagnosis based upon history, physical secretions indicate MGD (Figure 1). Th is is a technique that has examination, and objective assessments of tear fi lm, ocular fallen off somewhat in clinical practice, which is unfortunate, surface infl ammation, and meibomian gland morphology as it is a quick, immediate way to get actionable information and function. Patients with dry eye present with a range of about meibomian gland health. Th e presence of a , symptoms that may fl uctuate from day to day. Common or plugged meibomian gland, is a red fl ag for more widespread complaints include ocular surface irritation, visual fl uctuation, MGD. refl ex tearing, or diffi culty with prolonged visual tasks such as My practice is to then examine the tear fi lm, 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. mittee of the International Dry Eye WorkShop. Ocul Surf. 2007;5:93-107. I look carefully for a “soapsuds” appearance in the tear fi lm, 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. a sign of increased lipase activity associated with MGD 4. e defi nition and classifi cation of dry eye disease: report of the Defi nition (Figure 2). In addition, I oft en perform a test of tear fi lm and Classifi cation Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92. breakup time to assess tear fi lm stability. 5. Nichols KK, Foulks GN, Bron AJ, et al. e international workshop on Lissamine green staining is useful to assess the extent of meibomian gland dysfunction: executive summary. Invest Ophthalmol Vis ocular surface damage and to rule out disorders that can mimic Sci. 2011;52:1922-9. 6. Lemp MA, Crews LA, Bron AJ, et al. Distribution of aqueous-defi cient and dry eye such as , , fl oppy eye syndrome, evaporative dry eye in a clinic-based patient cohort: A retrospective study. and conjunctival chalasis. With the exception of assessing . 2012;31(5):472-8. aqueous defi ciency dry eye severity, I generally do not rely on 7. Miljanovic B, Dana R, Sullivan DA, et al. Impact of on vision-related quality of life. Am J Ophthalmol. 2007;143:409-15. Schirmer testing. 8. Uchino M, Schaumberg DA. Dry eye disease: impact on quality of life and Th e questionnaire, exam, and selected tests can be admin- vision. Curr Ophthalmol Rep. 2013;1:51-7. istered in surprisingly little time, leaving me plenty of time to 9. Li XM, Hu L, Hu J, et al. Investigation of dry eye disease and analysis of the pathogenic factors in patients after . Cornea. 2007;26(9 Suppl discuss therapy with patients who have positive results. 1):S16-20. 10. Konomi K, Chen LL, Tarko RS, et al. Preoperative characteristics and a CONCLUSION potential mechanism of chronic dry eye after LASIK. Invest Ophthalmol Vis Sci. 2008;49:168-74. Dry eye, especially due to meibomian gland disease, is very 11. Montés-Micó R. Role of the tear fi lm in the optical quality of the human eye. common and likely aff ects more of our patients than those J Cataract Refract Surg. 2007;33:1631-5. who carry the diagnosis. Developing an in-offi ce protocol 12. 2014 National Population Projections: Publications. http://www.census. gov/population/projections/data/national/2014/publications.html. Accessed for diagnosing dry eye, including a screening process for all April 7, 2016. patients, will lead to better care for patients and improved 13. Moss SE, Klein R, Klein BE. Long-term incidence of dry eye in an older outcomes following ocular surgery. population. Optom Vis Sci. 2008;85:668-74. 14. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam off spring study: prevalence, risk factors, and health-related quality of life. Am Eric Donnenfeld, MD, is a partner at Ophthalmic Consultants of Long Island J Ophthalmol. 2014;157:799-806. and clinical professor of ophthalmology at New York University in New York, 15. Macsai MS. e role of omega-3 dietary supplementation in and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. NY. Dr. Donnenfeld is a consultant for Allergan, Alcon, Bausch + Lomb, Mati 2008;106:336-56. erapeutics, and Shire. He is also on the speakers’ bureau for Allergan, Alcon, 16. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syn- Bausch + Lomb, and Shire. Medical writer Noelle Lake, MD, assisted in the drome. Arch Ophthalmol. 2000;118:1264-8. 17. Klein BE, Klein R. Lifestyle exposures and eye diseases in adults. preparation of this manuscript. Am J Ophthalmol. 2007;144:961-9. 18. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and REFERENCES management of dry eye disease. Am J Ophthalmol. 2011;151(5):792-8. 1. Nichols KK, Nichols JJ, Mitchell GL. e lack of association between signs 19. Sambursky R, Davitt WF 3rd, Latkany R, et al. Sensitivity and specifi city and symptoms in patients with dry eye disease. Cornea. 2004;23:762-70. of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing 2. e epidemiology of dry eye disease: report of the Epidemiology Subcom- infl ammation related to dry eye. JAMA Ophthalmol. 2013;131(1):24-8.

4 Topics in OCULAR ANTIINFLAMMATORIES 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 CORE CONCEPTS hypotensive exposure can exacerbate ocular surface disease. Detecting and addressing ocular surface issues ✦ Ocular surface disruption is common among glaucoma patients; it may stem from age-related ocular surface in glaucoma patients is one important way that eye care disorders or chronic medication use. providers can enhance their care as they simultaneously ✦ Most glaucoma eye drops, especially ones containing work to maintain IOP. BAK, can cause minor disruptions in the ocular surface and exacerbate dry eye signs and symptoms. Th e state of the ocular surface has always taken a back seat ✦ Treating pre-existing dry eye and other ocular surface to the chief consideration in the management of glaucoma: conditions may help improve tolerability and prevent maintaining good health of the and preserving noncompliance. vision. However, ocular surface disease is not trivial; it has been implicated in reducing quality of life, contact lens toler- ability, and ocular surgical outcomes.1-4 Importantly, ocular corneal neurotoxicity, infl ammation, and reduced aqueous surface disorders can have a deleterious impact on visual tear production.12 And clinical studies reveal that dry eye function and acuity.2,5 signs and symptoms improve when patients are switched from Ocular surface disease is widespread in the glaucoma BAK-preserved medications to BAK-free formulations.13 BAK population, and while awareness is increasing, it is almost may be a contributing factor to conjunctival allergy, dry eye certainly underdiagnosed. Among medically treated glaucoma disease, and failure of glaucoma surgery in patients on long- patients, one study showed that 80% also had meibomian term topical ocular therapy. Preservative-free anti-glaucoma gland disease.6 Other estimates show ocular surface disease medications are available; however lack of coverage by insur- prevalence of between 40% to 85%—many cases of which are ance providers makes them more expensive for patients and severe—within the glaucoma population.7 Advancing age thus infrequently prescribed. Patients who can aff ord the ad- predisposes to both conditions; in addition, long-term topical ditional, out of pocket expense may fi nd BAK-free therapies medications may induce ocular surface changes via infl am- less irritating to the ocular surface. matory, allergic, and/or toxic mechanisms.8 Ocular surface related side eff ects vary within each class of agent, which may relate to the active molecule, the type and MEDICATIONS concentration of preservative, or due to any component of the Th e glaucoma population—indeed, any group of patients medication vehicle. A study compared the eff ect of four com- dependent on chronic application of topical ocular medica- mercially available analog (PGA) agents—bi- tion—is at risk for medication-induced ocular surface damage. matoprost, tafl uprost, travoprost, and latanoprost—on normal Th e extent of medication exposure (eg, number of therapies, human conjunctival cell culture in vitro and found that all four number of drops, and treatment duration) has been shown to induced some level of concentration-dependent cytotoxicity, correlate with the eff ect on the ocular surface.9,10 In a prospec- with preservative-free tafl uprost inducing the least damage.14 tive controlled trial, greater exposure to topical medications Among BAK-containing PGA agents, latanoprost was the for lowering intraocular pressure (IOP), quantifi ed as number least cytotoxic. of drops per week multiplied by treatment years, was associ- Th e ocular surface may also be susceptible to the active ated with signifi cantly worse ocular surface disease compared ingredient of antihypotensive agents, many of which are va- with lesser exposed glaucoma patients.9 In a separate study, sodilatory.7,15 To a varying degree, PGAs cause conjunctival patients on multiple topical anti-glaucoma medications had hyperemia as a side eff ect in some patients; similarly, alpha more severe ocular surface symptoms compared with patients agonists can cause rebound conjunctival redness following an on monotherapy.10 initial blanching phase.15,16 Redness and other ocular surface The most commonly cited cytotoxic agent in ocular manifestations have a negative infl uence on quality of life and medication is benzalkonium chloride (BAK), a quaternary can interfere with medication adherence. Th e long-term eff ect ammonium compound that serves as a preservative and anti- on the tear fi lm and ocular surface is unknown.8 bacterial agent in many ophthalmic preparations.11 In vitro studies show that BAK contributes to corneal and conjunctival COMPLIANCE cell apoptosis and ocular surface infl ammation in a dose- Ocular surface conditions present in a variety of ways, dependent fashion.8 Animal studies reveal that BAK induces 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 rub- surface infl ammation in patients with meibomian gland dis- bing the eye. Symptoms may start within the fi rst few days of ease and/or blepharitis.20 taking a new therapy or present aft er months to years on the For some patients, switching anti-glaucoma medication same therapy. may help; for example, a patient with redness and irritation In some patients, ocular surface symptoms play a role in on brimonidine may benefi t from switching to a PGA. Some medication nonadherence, a multifactorial and vexing prob- patients benefi t from laser trabeculoplasty or glaucoma sur- lem within the glaucoma population.17 Research has shown gery to reduce or eliminate topical medication dependency. that only 33% to 39% of patients persist in taking ocular Patients with cataract, glaucoma, and medication-related hypotensive medication as prescribed by 12 months aft er ocular surface disease may make excellent candidates for a initiation.18 It not hard to imagine how a patient with daily combination cataract surgery/minimally invasive glaucoma medication-related symptoms such as stinging or burning— surgery (MIGS) which can reduce dependence on ocular or other disincentive such as cost, denial, diffi culty instilling hypotensive medication.21 Clearing up the ocular surface pre- drops, or erroneous belief in the inevitability of blindness— operatively using antiinfl ammatory medication is important might struggle with adherence to a treatment prescribed in for accurate preoperative calculations and best postoperative perpetuity for a symptomless disease. Although no studies visual outcomes.22 In the future, improved MIGS methods have proven that decreased hypotensive medication adherence and delivery of anti-glaucoma medication via intracameral leads to vision loss, one would logically assume that patients injection (or other sustained delivery system that bypasses who discontinue treatment can expect outcomes similar to the ocular surface) could be instrumental in reducing ocular untreated patients. surface stress and adherence issues that accompany today’s daily drop regimens. MANAGEMENT Maintaining ocular surface health should be part and CONCLUSION parcel of glaucoma management for the reasons mentioned: Ocular surface disease is multifactorial and variable in its ocular comfort and quality of life, surface-related visual clarity, presentation in glaucoma patients. Physicians must remember and optimal anti-glaucoma medication adherence and success. to keep the front of the eye in mind though their focus is on In addition to routine IOP-related testing and management, the back. 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 Richard A. Lewis, MD, is in private ophthalmology practice in Sacramento, tolerance. It is also useful to inquire to the patient, family, or California. Dr. Lewis is chief medical offi cer at Aerie and a consultant for Aerie, caregiver about medication adherence; suboptimal adherence, Allergan, Glaukos and Ivantis. He is also on the speakers’ bureau for Carl Zeiss if uncovered, may be a tip off for tolerability issues related to Meditec AG. Medical writer Noelle Lake, MD, assisted in the preparation of the ocular surface. this manuscript. Patients with signs or symptoms of ocular surface disease should be assessed for treatable underlying disorders whether REFERENCES related or unrelated to glaucoma management. In particular, 1. Miljanovic B, Dana R, Sullivan DA, et al. Impact of dry eye syndrome on look carefully for evidence of blepharitis and dry eye disease vision-related quality of life. Am J Ophthalmol. 2007;143:409-15. which are common comorbidities among older patients. Also 2. Uchino M, Schaumberg DA. Dry eye disease: impact on quality of life and vision. Curr Ophthalmol Rep. 2013;1:51-7. consider less common culprits such as seasonal and peren- 3. Li XM, Hu L, Hu J, Wang W. Investigation of dry eye disease and analysis nial allergies and exposure to products such as makeup that of the pathogenic factors in patients after cataract surgery. Cornea. 2007;26(9 may contact the eye. As discussed, consider the possibility of Suppl 1):S16-20. 4. Konomi K, Chen LL, Tarko RS, et al. Preoperative characteristics and a medication-induced ocular surface disruption. potential mechanism of chronic dry eye after LASIK. Invest Ophthalmol Vis For treatment, choose the simplest, most defi nitive method Sci. 2008;49:168-74. that targets the underlying cause or causes. Blepharitis treat- 5. Montés-Micó R. Role of the tear fi lm in the optical quality of the human eye. J Cataract Refract Surg. 2007;33:1631-5. ment is dictated by the subtype and should always include lid 6. Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, et al. Meibomian Gland hygiene. Also, patients should be advised to avoid rubbing Dysfunction in Patients Receiving Long-Term Glaucoma Medications. eyes, as fi ngers can be a source of infection. Patients with Cornea. 2016 Apr 6. Epub ahead of print. 7. Bron AJ, Tomlinson A, Foulks GN, et al. Rethinking dry eye disease: A blepharitis who wear eye makeup may need to temporarily perspective on clinical implications. Ocul Surf. 2014;12(2S):S1-31. stop or at least replace any products which might have become 8. Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: the good, contaminated. Dry eye disease must also be treated accord- 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 ing to its particular type. It may respond to topical moistur- surface disease: a prospective, controlled cohort study. Can J Ophthalmol. izers or anti-infl ammatory medication; punctal plugs may be 2015;50:132-6. preferable when administering drops is problematic.19 Th e r e 10. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure- is some data to support prescribing oral omega-3-fatty acid lowering medications. Cornea. 2010;29:618-21. supplementation (with fl axseed or fi sh oil) to reduce ocular 11. Yee RW, Norcom EG, Zhao XC. Comparison of the relative toxicity of

6 Topics in OCULAR ANTIINFLAMMATORIES 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% trials. Br J Ophthalmol. 2009;93:316-21. in an immortalized human cornea epithelial cell culture system. A d v e r . 17. Reardon G, Kotak S, Schwartz GF. Objective assessment of compliance and 2006;23:511-9. persistence among patients treated for glaucoma and : a 12. Sarkar J, Chaudhary S, Namavari A, et al. Corneal neurotoxicity due to topical systematic review. Patient Prefer Adherence. 2011;5:441-63. benzalkonium chloride. Invest Ophthalmol Vis Sci. 2012;53:1792-802. 18. Schwartz GF, Quigley HA. Adherence and persistence with glaucoma 13. Horsely MB, Kahook MY. Eff ects of prostaglandin analog therapy on the therapy. Surv Ophthalmol. 2008;53 Suppl1:S57-68. ocular surface of glaucoma patients. Clin Ophthalmol. 2009:3;291-5. 19. Ervin AM, Wojciechowski R, Schein O. Punctal occlusion for dry eye syn- 14. Pérez-Roca F, Rodrigo-Morales E, Garzón I, et al. Eff ects of four formulations drome. Cochrane Database Syst Rev. 2010;(9):CD006775. of prostaglandin analogs on eye surface cells: a comparative study. PLoS One. 20. Macsai MS. e role of omega-3 dietary supplementation in blepharitis and 2015;10:e0129419. meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 15. Stewart WC, Kolker AE, Stewart JA, et al. Conjunctival hyperemia in 2008;106:336-56. healthy subjects after short-term dosing with latanoprost, bimatoprost, and 21. Brandão LM, Grieshaber MC. Update on Minimally Invasive Glaucoma travoprost. Am J Ophthalmol. 2003;135:314-20. Surgery (MIGS) and New Implants. J Ophthalmol. 2013;2013:705915. 16. Honrubia F, García-Sánchez J, Polo V, et al. Conjunctival hyperaemia with 22. Kim P, Plugfelder S, Slomovic AR. Top 5 pearls to consider when implant- the use of latanoprost versus other prostaglandin analogues in patients with ing advanced-technology IOLs in patients with ocular surface disease. Int ocular hypertension or glaucoma: a meta-analysis of randomised clinical 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 4. Managing ocular surface 7. Which of the following procedures can reduce the disease in glaucoma patients is a common presenting need for ocular hypotensive may improve: complaint among patients medication? A. Quality of life with dry eye? A. MIGS with B. Anti-glaucoma A. Burning phacoemulsification medication adherence B. Blurry vision B. MIGS without C. Surgical outcomes C. No symptoms phacoemulsification D. All of the above D. All of the above are C. Both A and B common dry eye D. Neither A nor B 5. Which of the following presentations has NOT been shown to 2. Pathognomonic signs of correlate with degree of 8. Which of the following MGD include which of the ocular surface disease in would likely NOT benefit following? glaucoma patients? patients with ocular surface A. “Soap suds” appearance A. Number of topical disease related to anti- to the tear film medications glaucoma medication? B. Chalazion B. Intensity of treatment A. Sustained anti-glaucoma C. Conjunctival chalasis (drops per week times drug delivery via punctal 10. Ocular surface disruption plug among patients taking D. Both A and B years of treatment) C. Weeks of therapy missed B. Sustained anti-glaucoma topical hypotensive medication may: D. None of the above drug delivery via 3. Which of the following intracameral injection A. Be caused by exposure to is NOT a component of C. Improved MIGS the preservative meibomian gland disease 6. Which of the following procedures B. Be caused by exposure to pathophysiology? forms of dry eye is caused by D. All of the above the active moiety A. Ocular surface inadequate tear production? C. Occur within any time inflammation A. Meibomian gland disease frame B. Hypoosmolarity B. Evaporative 9. Which of the following is NOT a risk factor for the D. All of the above C. Bacterial growth on lid C. Aqueous deficiency development of dry eye? margins D. None of the above A. Advanced age D. Altered meibum B. Autoimmune disease C. Antidepressant use D. Male sex

EXAMINATION ANSWER SHEET TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 14

This CME activity is jointly sponsored by the University EVALUATION: If you wish to receive credit for this activity, please fill in the of Florida and Candeo Clinical/Science Communications, 1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding following information. Retain a copy­ for your records. LLC, and supported by an unrestricted educational grant 11. Extent to which the activity met the identified PLEASE PRINT CLEARLY from Shire. Mail to: University of Florida CME Office, PO Objective 1: 1 2 3 4 5 Objective 2: 1 2 3 4 5 Box 100233, Gainesville, FL 32610-0233. DIRECTIONS: ______Objective 3: 1 2 3 4 5 FIRST NAME LAST NAME DEGREE Select the one best answer for each question in the Objective 4: 1 2 3 4 5 exam above (Questions 1–10). Participants must score 12. Rate the overall effectiveness of how the activity: ______at least 80% on the questions and complete the entire Related to my practice: 1 2 3 4 5 ORGANIZATION/INSTITUTE Evaluation (Questions 11–16) to receive CME credit. Will influence how I practice: 1 2 3 4 5 CME exam expires August 31, 2017. Will help me improve patient care: 1 2 3 4 5 ______Stimulated my intellectual curiosity: 1 2 3 4 5 ADDRESS LINE 1 Overall quality of material: 1 2 3 4 5 ANSWERS: Overall met my expectations: 1 2 3 4 5 ______1. A B C D 6. A B C D Avoided commercial bias/influence: 1 2 3 4 5 ADDRESS LINE 2 13. Will the information presented cause you to make any ______2. A B C D 7. A B C D changes in your practice? Yes No CITY STATE ZIP 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 15. How committed are you to making these changes? PHONE FAX 1 2 3 4 5 5. A B C D 10. A B C D 16. Are future activities on this topic important to you? ______Yes No E-MAIL ADDRESS 8 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/