Dry Eye: Pathophysiology , Diagnosis and Management

1. Dry Eye: Pathophysiology, Diagnosis and Management Optometry 8370 Winter 2008

2. The Problem • 25% of patients over 65 have dry eye; (The cause in 33% of these patients is directly related to use of systemic medications) • The population of those over 65 will be increasing for many years to come • You will need to properly recognize and manage dry eye in this large part of your patient base to be successful in practice • Many doctors don’t do a good enough job of managing dry eye….

3. The Ocular Surface: A Functional Unit • Components: • Tear film • Epithelia of cornea, conjunctiva & limbus • Conjunctival goblet cells • Muco-epidermal junction of the lid, and lid as a whole • Meibomian glands • Lacrimal glands • Components are in anatomic continuity and share feedback mechanisms, resulting in simultaneous reactions to a single stimulus

4. The Ocular Surface: A Functional Unit • For example, a minor wound to the cornea would cause: • Reflex increase in tear flow • Change in content of tear fluid • Increased epithelial movement to the corneal surface • Increased limbal mitosis • Conjunctival capillary dilation • Increased vessel permeability

5. The Ocular Surface: A Functional Unit • The ocular surface is the interface between the eye and the outer world • Must guarantee the quality of the refractive surface to insure sharpest vision • Must be able to react quickly to resist injury • Ocular surface as a whole, and its individual components, are in a highly dynamic state, in response to: Blinking Foreign bodies Air currents Attack by microorganisms Low humidity Environmental toxins Any other insult to ocular surface homeostasis

6. The Ocular Surface: A Functional Unit • Traffic of information between different structures is regulated by: • Sensory (trigeminal) and motor (facial) nervous connections • Tear fluid • Blood (including lymphocytes) • Cytokines • Systemic hormones • Lid movement • If homeostasis is disrupted by pathogenic events, a vicious cycle of events will lead to the development of disease

7. The Vicious Cycle

8. The Ocular Surface: A Functional Unit • Tear film is by far the most dynamic structure in the functional unit • Should be considered a type of extracellular matrix (provides nutrients and communication pathway, distributes regulatory factors, and provides pathway for cells to reach the epithelium) • Tear film/Air interface is the strongest diopter of the eye’s optical system (nearly 45D) • A small change in tear film stability or volume can result in significantly reduced vision

9. The Ocular Surface: A Functional Unit • Tear film: • Linked to epithelial cell surface by the: • Glycocalyx (delicate mucinous material produced by the surface cells of the epithelium) • Products of the sub-surface vesicles of the conjunctival epithelium • Poorly adheres to ocular surface epithelia when epithelial cells are damaged, or are immature • Important part of the ocular surface reflex loop

10. Regulation of Tears via Reflex loop

11. The Ocular Surface: A Functional Unit • Regulation of tear production: • Stimulation of nerves at the ocular surface (or nasal mucosa) send impulses to the brain via CN5 • Reflex response generated by nerves passing to lacrimal glands • Chronic afferent stimulation and increased lacrimal secretion results from excessive evaporation, low humidity, or contact lens wear • Blinking causes spreading of the tear fluid on the ocular surface to form the complex tear film • Tear film architecture, previously disturbed by evaporation and environmental contamination during the interblink period, is regularly reconstructed

12. The Ocular Surface: A Functional Unit • Tear film composition: • Defining exact composition at any point in time is impossible, due to its highly dynamic nature • Includes: • Water • Enzymes • Proteins • Immunoglobulins • Lipids • Various metabolites • Exfoliated epithelial and polymorphonuclear cells

13. Classic Model Current Model Components of Tear Film

14. Mucin Layer • Produced by conjunctival goblet cells, and corneal and conjunctival epithelial cells • Corneal and conjunctival cells produce the mucin-like glycoprotein (“transmembrane mucin”) that forms the glycocalyx • Glycocalyx promotes tear film spreading and proper ocular surface wetting • Prevents adhesion of foreign debris, cells, or pathogens to the ocular surface • Mucin of the glycocalyx renders the entire ocular surface hydrophilic and allows for the even spread of aqueous over the eye

15. Mucin Layer Breakdown • Goblet cell deficiency is found in most forms of dry eye • Certain disorders may cause goblet cell loss: • Vitamin A deficiency (Vitamin A critical to goblet cell maintenance and ocular surface mucin) • Cicatrizing conjunctival disorders • Stevens-Johnson syndrome • Trachoma • Pemphigoid • Chemical burns • Topical medications • Preservatives

16. Aqueous Layer • Produced by the main and accessory lacrimal glands due to hormonal, sympathetic, and parasymp. stimuli • Responsible for creating the proper environment for the epithelial cells • Carries essential nutrients and oxygen to the cornea • Allows cell movement over the cellular surface • Washes away epithelial debris, toxic elements and foreign bodies • Changes in composition (which may occur rapidly) can influence the health, proliferation, maturation, and movement of surface epithelial cells • Contains growth factors (from lacrimal gland)which are thought to play a significant role in corneal physiology

17. Aqueous Layer Breakdown • Most common cause of dry eye • Usually caused by decreased lacrimal secretion, but increased tear evaporation may also be involved • Changes in aqueous layer composition are associated with ocular surface damage: • Increased electrolyte concentration • Loss of growth factors • Presence of pro-inflammatory cytokines combined with slow tear turnover

18. Aqueous Layer Breakdown • Causes: • Sjogren’s syndrome • Senile hyposecretion • Lacrimal gland excision • Sarcoidosis or lymphoma causing immune lacrimal gland damage • Sensory or motor reflex loss • Scarring conditions of the conjunctiva • Contact lens wear • Others

19. Lipid Layer • Formed by the meibomian glands • Principal function to prevent tear evaporation and to enhance tear film stability • Presence of a smooth lipid layer is important to quality optics of the tear film/corneal interface • Blink reflex important in the release of meibomian gland secretions • Rapid, forceful blinking (e.g. foreign body) increases lipid layer thickness • By contrast, computer users with decreased blink rate and dry eyes have a corresponding decreased lipid layer thickness

20. Lipid Layer Breakdown • Usually caused by meibomian gland obstruction (either spontaneously or in association with skin disease) with resulting increased evaporation • Associated conditions: • Atopic keratoconjunctivitis • Blepharitis • Generalized sebaceous gland dysfunction (e.g. acne rosacea and seborrheic blepharitis) • Several airborne polluting agents (e.g. turpentine) • Androgen hormone deficiency (menopause)

21. Other Dry Eye Etiologies • Collagen vascular disease • RA (lymphocytic infiltration of lacrimal gland) • Scleroderma (70% of patients have dry eye) • SLE (positive ANA) • Sjogren’s syndrome (chronic autoimmune disease, affecting major exocrine glands; conjunctiva infiltrated by inflammatory cells) • Allergy (due to continual activation of the local immune system) • Systemic Meds: thiazide diuretics, tricyclic and tetracyclic antidepressants, beta-blockers, anticholinergics, benzodiazapines, anti-Parkinson’s drugs, antihistimines, and antihypertensives, among others

22. The Role of Tear Film Osmolarity • When lacrimal gland secretion does not keep pace with tear film evaporation, tear film osmolarity increases • Research indicates that increased tear osmolarity (causing higher tear film concentrations of inflammatory mediators) promotes conjunctival inflammation

23. Summary • Aqueous Deficiency Dry Eye: • Tear fluid hyposecretion > altered tear film stability > increased evaporation > hyperosmolarity > inflammation > epithelial damage > decreased tear film stability • Evaporative Dry Eye: • Increased evaporation > inadequate tear production > hyperosmolarity > inflammation > ocular surface damage > altered tear film distribution > increased evaporation

24. The Vicious Cycle

25. Dry Eye Diagnosis • History & questionnaire are most important! • Comprehensive slit lamp exam • TBUT • Corneal & conjunctival staining • Tear meniscus • Schirmer’s and other “measures” of basal tearing • Impression cytology • Elicit type of dry eye: aqueous deficiency vs. evaporative deficiency vs. combined mechanism

26. Dry Eye Management • Artificial tears • Best to prescribe, not recommend; all drops are not = • Preservative-free if more often that qid (Toxic effects of common preservatives are real, and will often make patients more symptomatic!) • Consider GenTeal and Refresh drops and gels • Ointments, patching, moisture chambers, and tarsorrhaphy work well for severe cases • Punctal occlusion (collagen, silicone, thermal cautery) • Restasis • Omega 3s • Steroids

27. Dry Eye Management • Proper hydration is often overlooked; therefore suggest adequate water consumption over the course of the day • Steroids (Alrex or Lotemax) bid x 2 weeks • Conjunctival T-cells and other inflammatory mediators suppressed? • Off-label use • One study: 83% of Sjogrens patients showed improvement in symptoms with 2 weeks of use • Long-term use risky?

28. LASIK & Dry Eye • Severing of corneal nerves (efferent pathway) causes dry eye due to effect on reflex arc (corneal efferent nerves supply the ocular surface with neurotrophic growth factors) • 95% have normal corneal sensitivity by 6 months post-op • Nasal hinges cause less incidence of dry eye than superior hinges; corneal nerves probably regenerate from the deeper cornea (vs. limbus) • Prescribing Celluvisc 4-6x/day for one week, then tapering, has been shown to cause a 50% increase in conjunctival goblet cells and significantly reduced dry eye symptoms

29. Miscellaneous Dry Eye Topics

30. DEWS • Tear Film & Ocular Surface Society (see link) • Peer-reviewed review of current state of knowledge in dry eye diagnosis and management

31. Cytokines • Pro-inflammatory cytokines on the ocular surface play a large role in dry eye pathophysiology, including amplification of the dry eye feedback cycle • Cause decreased goblet cell density, permanent stem cell damage and apoptosis • Therefore, to Tx effectively the clinician must break the cycle

32. Approaches to Therapy • Increase ‘lubricity’ (decrease coefficient of friction) • Increase aqueous function • Decrease inflammation • Others in the pipeline… Secretagogues, mucomimetics, hormonal tx, nutritional supplements, anti-inflammatories, anti-evaporatives, improved polymers, more…

33. Categories of Artificial Tears • Cellulose derivative products (carboxymethylcellulose or hypromellose) • Glycerin products • Lipid based emulsions (Endura, Soothe) • Polyethylene glycol/propylene glycol (Systane)

34. Other Topics • ‘Lid Wiper Epitheliopathy’ • 70/30 rule • Androgen targets • Lissamine green • NEI staining grids

35. Dry eyes suck.