Dry Eye Syndrome

What is Dry Eye? Subjective Test Definition “ Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.” (NEI / Industry Workshop on Clinical Trials in Dry Eyes, 1995) Prevalence Recent figures come from largest epidemiological survey of dry eye ever (Schaumberg DA et al. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003) Studied 40,000 women to estimate prevalence of dry eye among females Conclusion: dry eye syndrome (DES) affects 3.2 million American women middle-aged and older alone. Overall prevalence likely higher. In the literature, prevalence ranges from 5-28% worldwide. DES is the most common treatable eye condition.

Paradigm Shift: Dry Eye Yesterday Limited understanding of DES Classical Tear Film Model Lipid Aqueous Mucin 3 distinct layers Palliative treatment of symptoms Dry Eye Today Current Concepts The Lacrimal Functional Unit The Inflammatory Cycle Ocular Protection Index (OPI) Hormonal influences Nutrition Updated Tear Film Model Targeted Treatment Viscosity Agents Hypotonic Agents Anti-evaporants Mucomimetics Secretagogues Anti-inflammatory Agents Immunomodulators Cytokine Inhibitors Androgens Dry Eye Hypothesis by Mathers The Lacrimal Functional Unit The Inflammatory Cycle Low-grade subclinical inflammation caused by disruption of Lacrimal Functional Unit homeostasis in DES Release of inflammatory cytokines IL-1, IL-6, TNFα Cyclical nature of inflammatory process Applications in clinical practice Ocular Protection Index (OPI) TBUT / IBI TBUT = Tear Break-up Time (sec) IBI = Inter-blink Interval (sec) >1.0 is functional, <1.0 is dysfunctional NIBUT Subjective Test used NIBUT is within 1 sec TBUT Updated Tear Film Model Bilayer: Lipid topcoat Aqueous emulsion with varying gelled concentrations of mucins (MUCs), thicker near cornea Hormonal Influences Nutrition DES Classification Simple classification Aqueous-deficient Evaporative Combination Other classification theories exist Risk Factors Age Gender Associated Systemic Diseases Sjögren’s Syndrome Acne Rosacea Arthritis Concomitant allergies Diabetes Fibromyalgia Immune disorders Leukemia Lupus Thyroid disease Viral disease (HZO) Anterior Segment Pathology Blepharitis Meibomian gland dysfunction (MGD) Lid / Blink Abnormalities Cicatricial disease Ectropion / entropion Facial nerve palsy (Bell’s) Incomplete blink / lagophthalmos Nocturnal lagophthalmos Parkinson’s Proptosis Pterygium / Pinguecula Contact Lens Wear Refractive Surgery Medications Acne medications (isoretinoin and Accutane) Anti-anxiety medications Anti-emetics Antihistamines, sedating / non-sedating Antipsychotics Birth control pills Beta-blockers Diuretics HRT OTC cold remedies Tricyclic antidepressants Foods Alcohol Artificial sweeteners Caffeine Hydrogenated and trans fats Red meat Refined sugars Vitamin A deficiency Hormonal Imbalance Menopause Pregnancy Environmental Air pollution Air travel Altitude Central heat / air Dry environment Hairdryer “Office Eye Syndrome” Pollen areas Saunas Smoking Visual tasking Windy environment

The Dry Eye Examination History / Questionnaire Classical dry eye symptom questionnaires: Key Questions in a Dry Eye History (The McMonnies Questionnaire) The Ocular Surface Disease Index (OSDI) The Dry Eye Questionnaire (DEQ) (Indiana University) The Contact Lens Dry Eye Questionnaire (CLDEQ) Symptoms more important than signs in dry eye grading Diurnal trends Correlate poorly with signs Neuro-paralytic cornea Pain thresholds Sample DES Questionnaire for Clinical Practice Adapted from McMonnies’ and Indiana University Questionnaires Schirmer / Phenol Red Thread (Zone-Quick) Assessment of lacrimal gland function / tear volume Schirmer DES: <10 mm wetting / 5 min Performed without anesthetic (NEI Dry Eye Workshop), possibly multiple times Phenol Red Thread (Zone-Quick) DES: <10 mm wetting / 15 sec Tear Lake Assessment Tear meniscus height DES: <0.3 mm tear prism height Tear lake quality Look for tear debris / frothing / filaments / oils Evaluate viscosity Topographical / wavefront surface irregularities Seen on Orbscan or wavefront analysis Mimic higher-order aberrations New topographic modeling systems for tear film stability analysis Tear Break-up Time (TBUT) Assessment of tear film stability / tear quality DES: TBUT<=10 sec Fluorescein Break-up Time (FBUT) Non-Invasive Break-up Time (NIBUT) More useful when combined with blink rate / Inter-blink Interval in OPI DET (Dry Eye Test) Laboratory Tests Limited usefulness in clinical practice Fluorescein Staining Assessment of epithelial damage Fluorescein Staining DES: >3/15 on NEI grid Test with highest sensitivity for detecting ocular surface disease Stain pattern more significant than degree Technique: Wait 1-2 min before assessment Wratten #12 yellow filter / cobalt blue NEI grids Rose Bengal / Lissamine Green Staining Assessment of dryness / mucin deficiency of ocular surface Stain pattern more significant than degree Rose Bengal 1% Lissamine Green Technique: Wait 2 - 3 min before assessment Low diffuse white illumination, gradually increased Lid Examination Assesses presence of associated lid disease Inspect lids for: Blepharitis Scaling Collarettes Lash inflammation Oily / greasy flakes Rosacea-associated telangiectasias Meibomian gland evaluation Express meibomian glands Assess gland viability Ocular Examination Assesses presence of associated ocular or systemic disease May elucidate etiology Acne Rosacea must be first rule-out Look for MGD, staphylococcal lid disease, recurrent chalazia, chronic conjunctivitis, peripheral corneal neovascularization, marginal corneal infiltrates, ulceration, episclerits, irits Examination: Lids Cornea Conjunctiva Gross Physical Examination Assesses presence of associated systemic disease Acne Rosacea Look for: subtle rosacea facies, ocular rosacea, acne Sjögren’s Triad Look for: dry eyes, dry mouth, arthritis Rheumatoid Arthritis (RA) Look for: spindling of fingers, ulnar drift, subluxation More severe than osteoarthritis

Treatment Mild DES Occasional symptoms Minimal staining Lubricating therapy as needed Artificial tears TID-QID Low to moderate viscosity agents Active Lid Disease Treat active lid disease first Blepharitis / Meibomian Gland Dysfunction (MGD) Lid hygiene / hot compresses / antibiotic ointment Preservative-free artificial tears if DES present Anti-evaporants (Refresh Endura) Nutritional supplements Omega-3 fish oil / flaxseed oil Oral management with tetracyclines if non-responsive Anti-inflammatory activity, rearrange fatty acids in meibomian glands, improving lipid function Oral doxycycline, 100 mg BID x 6 weeks, then taper to QD x few mos Contraindicated in pregnancy / nursing; phototoxicity, gastritis side effects Ocular Rosacea / Acne Rosacea: Patient education: avoid sun, spicy foods, alcohol If limited improvement on above regimen Reduce to periostat (anti-gingivitis) 20 mg BID or QD Metronidazole cream once stable Diet / Water Intake Tear dysfunction caused by excess dietary fats, cholesterol, salt, sucrose, protein, alcohol Fluids / water Consume half one’s body weight in oz water/day, ex 50 oz/100 lbs, not with meals Water-containing fruits and vegetables Omega-3 fatty acids Anti-inflammatory properties, may improve tear lipid layer Cold-water fish, ex. salmon, cod, sardines, herring, eel, trout Flaxseed oil Similar benefits to fish oils, may be substituted Flaxseed meal added to food / cereals Nutritional supplements Research in this area is limited Always check with Primary Care Physician first Omega-3 fish oil pills, 1000mg TID with food, contraindicated in pts on blood thinners Flaxseed oil 1000 mg BID TheraTears Nutrition (Advanced Vision Research) claims to suppress meibomitis, improve lipid layer, stimulate tear secretion, contains omega-3 supplement, enriched flaxseed oil and Vitamin E Hydrate Essential (Cynacon/Ocusoft) conatins flaxseed oil, evening primrose oil and bilberry extract Vitamin A 10,000 IU in beta-carotene form, regulates proliferation / differentiation epithelial and goblet cells Vitamin E 400 IU, protect fish oil fatty acids from oxidative damage in body, can have negative effect on cholesterol-lowering agents Avoidance Alcohol Caffeine Common food allergens / processed foods ex. milk, pasteurized dairy products, corn, wheat, refined sugars, red meat Benefits reported after 30 days’ use Environmental Modification “Office Eye Syndrome” Increasing in prevalence Poor blink Eyestrain / fatigue Low humidity Poor ventilation Humidifier Blinking exercises Recommended for DES caused by visual tasking, incomplete blink, lagophthalmos Limited Patient compliance Avoidance Dry environments Nature’s Tears Moisturizing Mist, facial spray made of tissue-culture grade, pH-correct water, claims to replenish tear film Dust Smoke / smoking Ventilation Turn AC / fans / vents away from face Wind Modify Contact Lens Care Symptoms worse at end of day Material modification Switch to non-ionic, low water, higher center thickness materials Silicone hydrogels Non-ionic lenses Daily disposable lenses Gas-permeable (GP) Solution modification New solutions eliminate or contain milder preservatives and / or contain wetting agents and lubricant additives to provide longer, more comfortable wear For severe DES preservative-free agents are indicated Rewetting agents New agents decoat the contact lens during wear, add to tear viscosity Lifestyle modification Decreasing wear time Midday soaks Therapeutic lenses in DES Custom large-diameter hydrogels (up to 22 mm diameter) Custom high Dk GP scleral shell (15-24 mm diameter) Medication Review / Modification Lubricating Therapy Mainstay of DES treatment Low-viscosity, unit-dose Low-viscosity, multi-dose Moderate viscosity High-viscosity Gels Ointments Current concepts: Preservative-free / disappearing / “gentle” preservatives Muco-adhesive and viscosity agents Electrolyte and hypotonic agents Ointments supplanted by gels Punctal Occlusion Indications Failure / noncompliance with maximal lubricating therapy Non-responsive Patients with low tear volume, Schirmer <5 mm Contraindications Inflammatory dry eye, ex Sjogren’s Younger Patients with Schirmer >10 mm New Products Cauterization Indicated for Schirmer <3mm Heat / Electrocautery or argon laser ablation Cautions Patient awareness Dislodging Continued supplementation with prior treatments necessary Collagen plug trial Informed consent Moisture Chambers Enclose eye to prevent evaporative tear loss Reduce wind current / increase humidity at eye level Modify Patient’s own eyewear or use wraparound shields Surgery Tarsorraphy Ectropion / Entropion Repair Modern Therapy Viscosity Agents Systane (Alcon) Useful in moderate-severe DES with surface damage BID dosage HP Guar, polypropylene glycol, polyethylene glycol 400, borate, essential ions: K, Ca, Mg, Na 3 mechanisms of action: Ocular shield / bandage effect HP guar combines with glycolcalyx slowing TBUT, creates microenvironment for corneal / conjunctival epithelial cell repair Viscosity increases from bottle to eye, with pH change Longer dwell time, 30-75 min Essential ions for healing Dosing QHS makes a.m. dryness less severe 51% reduction in corneal staining from baseline in clinical trials Hypotonic Agents TheraTears (Advanced Vision Research) Useful in moderate-severe DES with surface damage Hypotonic formulation containing K decreases tear film osmolarity, restores homeostasis, improves epithelial cell health Anti-Evaporants Refresh Endura (Allergan) Useful in lipid-anomalous DES Castor-oil emulsion (was vehicle in Restasis trials) Polar oils increase lipid stability, prevent evaporation of aqueous layer beneath Claims to enhance all 3 tear film layers Mucomimetics Milcin (Vista Scientific) Currently under investigation Agent becomes incorporated into mucin layer and mimics its function Secretagogues Mucin Secretagogues Stimulate mucin production by mucosal surfaces Goal is to increase mucin production by ocular surface and decrease ocular surface damage 15 (S) – HETE (hydroxy-eicosatetraenoic acid) (Alcon) INS365 / diquafosol tetrasodium (Inspire Pharmaceuticals / Allergan) Tear Secretagogues Salagen (MGI /Global Pharmaceutics) Others Anti-Inflammatory Agents Useful in severe DES for short-term aggressive inflammation control Site-specific Steroids Alrex (loteprednol 0.2%, Bausch & Lomb) Lotemax (loteprednol 0.5%, Bausch & Lomb) Vexol (rimexolone 1%, Alcon) rimexolone 0.1% in development for DES QID x 1 mo, BID x 1 mo, repeat Q4-6 mos PRN Safety Profile Excellent but monitor IOP / cataract formation <1% IOP rise vs >7% for ketone steroids Immunomodulators Restasis Ophtahalmic Emulsion (Allergan) Useful in long-term management of inflammatory DES BID dosage Cyclosporine A (CsA) 0.05% in castor oil vehicle Mechanism of action: Inhibits activation of inflammatory T-lymphocytes, stimulating lacrimal gland tear production 3-4 months to achieve clinically significant effect, 6 months for full therapeutic potential 59% Patients achieved improvement from baseline Schirmer scores at 6 months FK-506 / Tacrolimus (Sucampo Pharmaceuticals Inc) Potent immnosuppressive, in clinical trials Cytokine Inhibitors Under investigation Androgens Androgen receptors in lacrimal and meibomian glands Regulate lacrimal secretory function and meibomian gland oils Testosterone creams In development Applied to eyelid skin for pulsed delivery Androgen supplements Under investigation Patient Education Chronic nature of DES Prescribing treatments improves compliance Exit form Follow-up RTC 1 month to monitor: Compliance Preservative toxicity / medicamentosa Treatment efficacy Re-appoint and follow-up Chronic nature of disease Provide encouragement

Clinical Pearls Diagnosis: proper staining techniques Treatment: Treat signs OR symptoms and treat aggressively Look for / treat active lid disease first Re-appoint / follow-up Patient empathy

Conclusion DES is complex disease entity Understanding of DES evolving Controversies Entering era of potentially curative treatments