Ocular allergy. Anton van Biljon

Transcription

1 Ocular allergy Anton van Biljon

2 Introduction Ocular allergy may be encountered by allergists, ophthalmologists, pediatricians and primary-care doctors It is synonymous with allergic conjunctivitis It includes four major forms that differ in their clinical features, pathophysiology and response to treatment Seasonal allergic conjunctivitis (SAC) Perennial allergic conjunctivitis (PAC) Vernal keratoconjunctivitis(vkc) Atopic keratoconjunctivitis(akc) These slides also briefly discuss Giant papillary conjunctivitis (GPC) Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

3 Definition Allergic conjunctivitis: inflammation of the conjunctiva triggered by an allergic response An allergic response is an over-reaction of the body s immune system to an allergen (foreign substance) The target tissue for allergic reactions in the eye is the conjunctiva, the mucus membrane that covers most of the eye and lines the insides of the eyelids Allergic reactions in the conjunctiva resemble those in the nasal mucosa (their anatomy and physiology are similar) Main lacrimal gland Conjunctiva Accessory lacrimal gland Meibomian gland Tear film Eyelash Friedlaender. Curr Opin Allergy Clin Immunol 2011;11:

4 Definition, classification and mechanisms

5 Classification There is limited consensus on the classification of ocular allergy 1 The International Ocular Inflammation Society (IOIS) classifies allergic conjunctivitis according to clinical and immunopathologicalfeatures 2 Mediated by IgE IgE and non-ige Non-IgE Intermittent SAC Persistent PAC VKC GPC Chronic AKC GPC is sometimes omitted from classifications of ocular allergy 3 GPC is probably an irritativerather than a true allergic condition 2,4 AKC, atopic keratoconjunctivitis; GPC, giant papillary conjunctivitis; IgE, immunoglobulin E; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis 1. Del Cuvilloet al. J Investig AllergolClin Immunol2009; 19 Suppl1: Leonardi et al. Curr Opin Allergy Clin Immunol 2007;7: Calder. In: Encyclopedia of the Eye. Elsevier, 2010: Friedlaender. Curr Opin Allergy Clin Immunol 2011;11:

6 Mechanisms in ocular allergy: immediate response All four main forms of ocular allergy involve an immune reaction known as an immediate (type I) hypersensitivity response Allergen Mast cell Pro-inflammatory mediators IgE This is mediated by conjunctival mast cells, which contain granules rich in chemical mediators such as histamine IgEantibodies respond to the presence of specific allergens They trigger mast cells to release mediators into surrounding tissues via degranulation This causes effects such as Itching Increased vascular permeability Vasodilation Increased secretion of mucus IgE, immunoglobulin E Calder. In: Encyclopediaof the Eye. Elsevier, 2010:30 6.

7 Mechanisms in ocular allergy: delayed response Allergic responses that are persistent or chronic (e.g. VKC and AKC) involve mechanisms beyond the type I hypersensitivity response The increased vascular permeability allows other inflammatory cells circulating in the blood (e.g. T cells, eosinophils, neutrophils) to infiltrate tissues Inflammatory cells may become resident in tissues There may be alterations to the epithelium, tissue remodelling and collagen deposition AKC, atopic keratoconjunctivitis; VKC, vernal keratoconjunctivitis Calder. In: Encyclopediaof the Eye. Elsevier, 2010:30 6.

8 Mechanisms in ocular allergy: overview SAC and PAC are mediated predominantly by mast cells PAC involves some neutrophils/t cells, perhaps due to persistent allergendriven inflammatory response In VKC and AKC, the response is less allergen-specific, more based on enduring changes to the immune system Clinical severity SAC PAC VKC AKC histamine vasodilation histamine cytokines histamine interleukins collagen deposition histamine interleukins IFNγ cytokines cytokines mast cell neutrophil eosinophil Th2 T cell Th1 T cell fibroblast AKC, atopic keratoconjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Figure adapted from: Calder. In: Encyclopedia of the Eye. Elsevier, 2010:30 6.

9 Overview of the main ocular allergies SAC PAC VKC AKC Timing Seasonal Perennial Seasonal (perennial if severe) Age group Mostly children or young adults Perennial Adults Children Adults Prevalence Very common Common Uncommon Rare Cornea affected No No Yes Yes Sight-threatening No No Yes Yes Course Mild, non-progressive, often resolves Not serious, non-progressive Serious, usually resolveswithin 10 years with good outcomes if well managed. Can develop into AKC Serious and progressive,vision often impaired AKC, atopic keratoconjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Adapted from Calder. In: Encyclopediaof the Eye. Elsevier, 2010:30 6. and Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

10 Seasonal allergic conjunctivitis (SAC) Key features The most common of all ocular allergic diseases Personal/family history of atopyis common; frequently associated with allergic rhinitis and asthma Particularly prevalent in young adults (20 40 years), no gender predilection Symptoms occur predominantly in spring and autumn Typically symptom-free during winter months The most common triggers are Airborne pollens Grass pollen predominant in spring/early summer Other pollens (e.g. weed) predominant in late summer/autumn Airborne moulds (mostly late summer/autumn) SAC: moderate injection and papillary hypertrophy Images courtesy of Prof. Yonka A Akova Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

11 Perennial allergic conjunctivitis (PAC) Key features No age or gender predilection Compared with SAC, more strongly associated with perennial rhinitis and other allergic diseases Symptoms may persist throughout the year, though typically with exacerbations The most common triggers are indoor allergens Dust mite (in > 50% of cases) Moulds Animal epithelial allergens(desquamated scales) Occupational allergens Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

12 Seasonal/perennial allergic conjunctivitis (SAC/PAC) Signs and symptoms Hallmark key symptoms, common to both forms Itching Redness (injection) Swelling of the conjunctiva (chemosis) Lid edema Patients may also experience Tearing Mucus discharge Burning sensation Photophobia Mild conjunctivalinjection and moderate chemosis in SAC/PAC Image reproduced from La Rosa et al. ItalJ Pediatr 2013;39:18 under the terms of the Creative Commons Attribution License Leonardi et al. Clin Exp Immunol 2008;153(Suppl 1): Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

13 Vernal keratoconjunctivitis(vkc) Key features Most commonly occurs in children, particularly boys May be a female bias in incidence of new cases > 16 years old Most common in warm climates May be perennial or seasonal (exacerbations most often in summer/early autumn) Based on a delayed type hypersensitivity reaction Patients often have strong atopic history Underlying cause unknown However, predominance during high pollen season suggests that environmental antigens may have a role in triggering response Calder. In: Encyclopediaof the Eye. Elsevier, 2010:30 6. Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Leonardi et al. Clin Exp Immunol 2008;153(Suppl 1): Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

14 Vernal keratoconjunctivitis(vkc) Signs and symptoms Bilateral, though ocular signs may be very asymmetrical Itching, redness and swelling Additional symptoms may include Conjunctival papillae Discharge Photophobia (may be intense) Corneal involvement Can affect vision Shield ulcer in VKC Image courtesy of Prof. Yonka A Akova ~6% patients left with visual impairment owing to corneal damage, rarely cataract or glaucoma Bonini et al. Eye 2004;18: Calder. In: Encyclopediaof the Eye. Elsevier, 2010:30 6. Friedlaender. Curr Opin Allergy Clin Immunol 2011;11:

15 Vernal keratoconjunctivitis (VKC) Signs and symptoms (cont.) Three forms defined (according to conjunctival involvement) Palpebral/tarsal: giant, cobblestone-like papillae on superior tarsal conjunctiva Limbal: thick, gelatinous papillae at the limbus, commonly associated with multiple white spots (Horner-Trantas dots) Mixed: shows features of both palpebral and limbal forms Giant hypertrophic papillae in VKC Limbal VKC Images courtesy of Prof. Yonka A Akova Leonardi et al. Clin Exp Immunol 2008;153(Suppl 1): Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

16 Atopic keratoconjunctivitis(akc) Key features A severe, chronic inflammatory disease Persistent and may be progressive Based on a delayed type hypersensitivityreaction Most commonly develops in adults aged years, particularly males Personal and family history of atopic disease in 95% of cases Particularly closely associated with atopic dermatitis/childhood eczema Atopic lid disease and limbal hypertrophy in AKC Images courtesy of Prof. Yonka A Akova Calder. In: Encyclopediaof the Eye. Elsevier, 2010:30 6. Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

17 Atopic keratoconjunctivitis(akc) Signs and symptoms Bilateral disorder Can have serious effect on visual acuity Lid signs Conjunctiva signs Cornea signs Severe eczema Papillary hypertrophy Corneal erosions Blepharoconjunctivitis Giant papilla Filamentary keratitis Excessive tearing Sheet scarring Corneal thinning Maceration of eyelid skin Trantas dots Vascularization Limbal hypertrophy/inflammation Perforation Calder. In: Encyclopedia of the Eye. Elsevier, 2010:30 6. Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Guglielmettiet al. CurrOpinAllergy ClinImmunol2010;10: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

18 Giant papillary conjunctivitis (GPC) Bilateral but asymmetrical Characterized by papillae in superior palpebral conjunctiva Often described as an irritative rather than an allergic condition Signs suggestive of an immune-mediated inflammatory disorder However, stimuli are inert substances, not allergens Most commonly results from prolonged mechanical irritation by Contact lenses Ocular prostheses Exposed sutures following ocular surgery Image courtesy of Prof. Yonka A Akova Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

19 Patient impact of allergic conjunctivitis Quality of life may be disrupted by itching, sensations of ocular dryness, vision fatigue and reading difficulties 1 A study in a Spanish setting 2 identified significant impairments using the Visual Functioning Questionnaire 25 (VFQ-25) on the domains of Overall vision Distance vision Ocular pain Mental health Role limitations Dependency A 2002 study in the UK estimated an annual cost per patient of Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2): Smith et al. Ophthalmic Epidemiol 2005;12: Pitt et al. Ophthalmic Epidemiol 2004;11:17 33.

20 Diagnosis

21 Diagnosis Diagnosis is primarily based on clinical presentation A thorough examination of the eyes is required Further investigations are not always required, although may be used to support the diagnosis Skin testing (scratch test or intradermal injection of allergen) In vitro tests for IgE antibodies Total IgE levels in tears Conjunctival smear (for presence of eosinophils, mast cells or basophils) IgE, immunoglobulin E Friedlaender. Curr Opin Allergy Clin Immunol 2011;11:

22 Differential diagnosis: non-allergic disorders Non-allergic ocular disorders must be excluded Conjunctival infections Viral Bacterial Fungal Parasitic Autoimmune disorders Scleritis Uveitis Non-specific causes Irritant conjunctivitis Blepharitis (inflammation of the eyelid) Dry eye disease Rosacea Foreign body in the eye Moloney& McCluskey. Med Today 2007;8: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

23 Differential diagnosis: key questions Where is the itching localized? Itching may be a feature of other conditions such as contact dermatitis, atopic eczema or psoriasis, but this itching is focused on the eyelids rather than the conjunctiva Is there personal/family history of allergy? Adult onset without prior history of allergy is rare, although it can occur in a particularly severe allergy season or if an individual is exposed to new allergens (e.g. due to relocation) Are we in the allergy season? Is there exposure to perennial allergens? Do symptoms abate away from home or the workplace, for example? Friedlaender. Curr Opin Allergy Clin Immunol 2011;11:

24 Treatment

25 Treatment: overview by symptom severity Mild symptoms Allergen avoidance Artificial tears Cold compresses Oral antihistamines Mild-to-moderate symptoms Antihistamine eye drops* Mast cell stabilizers Severe symptoms Corticosteroids (topical/systemic) Immunotherapy * Sometimes combined with vasoconstrictors Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Kari & Saari. J Asthma Allergy 2010;3:

26 Treatment: non-pharmacological If symptoms are mild, patients may not require treatment The most important non-pharmacological approach is allergen avoidance Eye lubricants (artificial tears) may reduce accessibility of the eye to allergens or simply wash out allergens Cold compresses/bathing the eyes with cold water may relieve symptoms Patients should avoid rubbing eyes Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

27 Treatment: antihistamines Act via antagonism of H 1 receptors, thus reducing histamine-induced symptoms Topical ocular or oral administration Some topical antihistamines have dual action, e.g. stabilization of mast cells, inhibition of leukotrienes Oral administration may alleviate symptoms of associated rhinitis Unlike first-generation drugs, second-generation systemic antihistamines are not associated with sedative and anticholinergic effects (e.g. dry mouth) Used extensively for treatment of SAC and PAC Of limited value for VKC or AKC Topical drugs may ease symptoms of GPC AKC, atopic keratoconjunctivitis; GPC, giant papillary conjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Del Cuvillo et al. J Investig Allergol Clin Immunol 2009;19(Suppl. 1):11 8. Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

28 Treatment: mast cell stabilizers Prevent release of mediators (e.g. histamine) by inhibiting mast cell degranulation Topical ocular administration Generally have a good safety profile Effective and well tolerated for SAC, PAC, VKC and AKC May help to ease symptoms of GPC Some have antihistamine activity AKC, atopic keratoconjunctivitis; GPC, giant papillary conjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Moloney& McCluskey. Med Today 2007;8: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

29 Treatment: drugs with dual action Some drugs have both antihistamine and mast cell stabilizing action Topical ocular administration Selective H 1 antagonists with mast cell stabilizing activity are now the mainstays of treatment for most ocular allergic diseases Can be used year-round in patients with PAC/AKC, may be discontinued over autumn/winter in patients with SAC/VKC AKC, atopic keratoconjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Moloney& McCluskey. Med Today 2007;8:16 21.

30 Treatment: vasoconstrictors Topical ocular administration Act via stimulation of α-adrenoceptors, reducing conjunctival hyperemia (no direct effect on immune response itself) Duration of effect limited to ~4 h Potential side effects include Follicular conjunctivitis Eczematous blepharoconjunctivitis Drug-induced conjunctivitis secondary to rebound hyperemia Not often used, except when combined with topical antihistamines These combinations are particularly useful for reducing redness Adverse reactions are rare with the combination products Friedlaender. Curr Opin Allergy Clin Immunol 2011;11: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

31 Treatment: corticosteroids Potent anti-inflammatory action, via inhibition of phospholipasea 2, cytokine production and inflammatory cell migration Topical administration, either ocular or nasal In severe cases, may be administered systemically or via subconjunctival injection Rarely used for SAC or PAC; an important treatment option for VKC and AKC Side effects are common and may threaten vision, e.g. glaucoma, cataract or ocular infection Should only be given in the short term, and by an ophthalmologist Frequent eye examinations required to monitor intraocular pressure and cataract formation AKC, atopic keratoconjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Moloney& McCluskey. Med Today 2007;8: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

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33 Treatment: NSAIDs Act by blocking cyclo-oxygenasepathway, thus reducing prostaglandin and thromboxane synthesis Topical ocular administration May reduce itching and hyperemia Clinical effect can vary Symptoms may worsen on occasion May promote superficial keratitis(particularly in patients with AKC) AKC, atopic keratoconjunctivitis; NSAID, non-steroidal anti-inflammatory drug Moloney& McCluskey. Med Today 2007;8: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

34 Treatment: immunotherapy Allergen-specific immunotherapy involves administration of increasing doses of allergen with the aim of achieving hyposensitization Appropriate only in cases of severe allergy May be subcutaneous or sublingual Sublingual administration may be associated with fewer side effects Enduring effect (~10 years) Kari & Saari. J Asthma Allergy 2010;3: Sánchez et al. J Investig Allergol Clin Immunol 2011;21(Suppl. 2):1 19.

35 Treatment: other immunomodulation approaches Anti-IgEtreatment Used in severe allergic asthma May be a therapeutic option for severe allergic conjunctivitis, e.g. AKC Calcineurin inhibitors Calcineurin is involved in the activation of T cells Inhibitors can induce local immunosuppression Used for atopic dermatological conditions Efficacious in reducing ocular allergic inflammation AKC, atopic keratoconjunctivitis; IgE, immunoglobulin E Kari & Saari. J Asthma Allergy 2010:

36 Referral Referral to an ophthalmologist is advisable if Diagnosis is uncertain Symptoms are sufficiently severe to require topical corticosteroids Investigations suggest a possible diagnosis of VKC, AKC or GPC Referral to an allergist may be required for Allergen identification Management of severe cases of SAC or PAC Consideration of immunotherapy AKC, atopic keratoconjunctivitis; GPC, giant papillary conjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis Moloney& McCluskey. Med Today 2007;8:16 21.

37 Case history

38 Case history: presentation and investigation Patient is a 22-year-old woman presenting with itching and redness in both eyes Consultation Symptoms are not seasonal, but do worsen periodically Itching localized to eye itself rather than eyelids Reports perennial rhinitis and history of childhood atopic dermatitis Has not noticed impairments to vision Examination No conjunctival papillae No evidence of corneal involvement Investigations Positive skin tests for reaction to dust mite and animal dander

39 Case history: diagnosis and management Diagnosis of perennial allergic conjunctivitis, with sensitivity to dust mites and animal dander Management Recommendations for allergen avoidance Symptom relief via cold compress, and avoid rubbing eyes Initial trial of second-generation oral antihistamine treatment generally effective However, did not achieve adequate response during exacerbations Short-term use of topical ocular antihistamine + mast cell stabilizer provided effective symptom relief during exacerbations

40 Summary Diagnosis of ocular allergy is based primarily on clinical presentation The most common forms are SAC and PAC Triggered by specific allergens, differ in their seasonality Hallmark symptoms are itching, redness and swelling Non-progressive and rarely serious, but can significantly affect quality of life and productivity AKC and VKC are chronic allergic disorders Symptoms more extensive, often with corneal involvement Vision may be affected, with possibility of sequelae, e.g. cataracts Symptoms often managed effectively by allergen avoidance and use of antihistamines/mast cell stabilizers More potent treatments such as corticosteroids and immunotherapy reserved for severe cases AKC, atopic keratoconjunctivitis; PAC, perennial allergic conjunctivitis; SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis

41 DRY EYE DISEASE

42 Introduction Dry eye disease (DED) is a common but frequently overlooked clinical condition The term can have varying meanings and may refer to 1 Specific symptoms Signs Syndromes Various diseases The term dry eye is synonymous with Keratoconjunctivitis sicca 2 Lacrimal keratoconjunctivitis 2 1. Murube et al. Eur J Ophthalmol 2005;15: Smith et al. Cornea 2008;27:

43 Key landmarks in the understanding of DED Year Development 1995 First systemic effort to define and classify DED: the National Eye Institute/Industry (NEI/Industry) Dry Eye Workshop classifications Proposal that cytokine/receptor-mediated inflammation is common to all ocular surface disorders, includingdry eye disease Triple classification of DED proposed Recommendationof the Delphi approach to treatment International Dry Eye Workshop (DEWS) report 5 1. Lemp et al. CLAO J 1995;21: Stern et al. Cornea 1998;17: Murube et al. Eur J Ophthalmol 2005;15: Behrens et al. Cornea 2006;25: International Dry Eye Workshop. Ocul Surf 2007;5:

44 Expert panels on dry eye disease Since 1995, four major expert panels have attempted to provide simple, structured solutions for understanding and managing DED NEI/Industry workshop 1 International Society of Dacryologyand Dry Eye 2 Delphi panel 3 DEWS panel members Classification based upon diagnostic tests members Classification based upon signs and symptoms tests members Classification based upon signs, symptoms and staining tests members Classification based upon signs, symptoms, staining, tear film breakup time, MGD MGD, meibomian gland dysfunction 1. Lemp et al. CLAO J 1995;21: Murube et al. Eur J Ophthalmol 2005;15: Behrens et al. Cornea 2006;25: International Dry Eye Workshop. Ocul Surf 2007;5:

45 Definition

46 Evolving definitions of dry eye disease A number of panels and workshops have attempted to define DED Year Panel Definition Key points 1995 NEI/Industry Dry Eye Workshop Dry eye is a disorder of the tear film due to tear deficiency or excessive evaporation, which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort. 1 Symptoms Interpalpebral surface damage Tear instability Tear hyperosmolarity 2006 Delphi Panel Proposed the term Dysfunctional Tear Syndrome (DTS) to describe patients with normal tear volume but abnormal tear film composition DEWS Panel Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. 3 Treatment recommendations based on patient signs and symptoms Multifactorial disease Potential damage to ocular surface Each cause of dry eye may act through a common pathway 1. Lemp et al. CLAO J 1995;21: Behrens et al. Cornea 2006;25: International Dry Eye Workshop. Ocul Surf 2007;5:

47 NEI/Industry workshop: limitations of global definition This was the first attempt at a global definition forded that included all major classes and subclasses However, it had limitations Ocular surface damage is not always present, even with positive signs and symptoms 1 Ocular damage is not always interpalpebral 1 Symptoms of ocular discomfort are not always present 1 Inflammatory mechanisms were not incorporated 2 Did not accommodate the overlap of aqueous deficiency and evaporation that is often observed 2 Visual function was not considered 3 1. Lemp et al. CLAO J 1995;21: Behrens et al. Cornea 2006;25: International Dry Eye Workshop. Ocul Surf 2007;5:

48 Dry eye workshop (DEWS): definition of dry eye Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface Key components of the definition Multifactorial disease Predominantly a disease of tears and ocular surface Associated with altered function of tear film and ocular surface inflammation Potential for impairment of the ocular surface Non-specific symptoms of discomfort, visual disturbance and tear film instability International Dry Eye Workshop. Ocul Surf 2007;5:

49 DEWS: goals and outcomes Published in 2007 with support from the Tear Film and the Ocular Surface Society (TFOS) The panel of 70 international experts compiled an evidence-based review of DED over a period of 3 years Goals included Develop an up-to-date definition of dry eye Classify dry eye based on etiology, mechanisms and stage of disease Outcomes included Reviewed and modified the NEI/Industry workshop definition, incorporating new insights into Tear hyperosmolarity Ocular surface inflammation Effects of dry eye on visual function International Dry Eye Workshop. Ocul Surf 2007;5:

50 Classification

51 Summary of the classification of DED from each panel Dry eye has been classified by each of the 4 major workshops The classifications have become increasingly more comprehensive, incorporating the latest learning and developments NEI/Industry 1 Triple 2 Delphi 3 DEWS 4 Tear-deficient dry eye Evaporative dry eye Severity grading (3 grades*) (4 levels) (4 levels) Etiopathogenic classification * Two additional grades: Grade 1-minus and Grade 3-plus 1. Lemp et al. CLAO J 1995;21: Murube et al. Eur J Ophthalmol 2005;15: Behrens et al. Cornea 2006;25: International Dry Eye Workshop. Ocul Surf 2007;5:

52 DEWS: dry eye classification Panel Year 2007 Definition and Classification Subcommittee of DEWS Key highlights Classification is more comprehensive, as it includes various tests in addition to symptoms and signs Adopted and modified the Delphi Panel Dry Eye severity grading Basis of classification Major categories Symptoms and signs Staining Tear film break-up time (TBUT) Schirmer test values Lid/meibomian gland disease Etiopathogenic Causative mechanisms Severity International Dry Eye Workshop. Ocul Surf 2007;5:

53 DEWS: classification The DEWS classification has three major categories DEWS Dry Eye classification Etiopathogenic Causative mechanisms Severity of disease Tear hyperosmolarity Tear film instability Level 1 Level 2 Level 3 Level 4 International Dry Eye Workshop. Ocul Surf 2007;5:

54 DEWS: etiological classification Etiopathogenic classification Aqueous deficient Evaporative Sjögrensyndrome dry eye Non-Sjögren dry eye Intrinsic Extrinsic Primary Secondary Meibomiangland dysfunction Vitamin A deficiency Lacrimal deficiency Lacrimal gland duct obstruction Disorder of lid aperture Topical drugs preservatives Primary Secondary Low blink rate Contact lens wear Reflex block Systemic drugs Drug action accutane Ocular surface disease, for example: allergy International Dry Eye Workshop. Ocul Surf 2007;5:

55 Aqueous deficient DED - Sjögren syndrome Etiopathogenic classification Sjögrensyndrome dry eye Primary Secondary Aqueous deficient Autoimmune condition affecting the salivary and lacrimal glands Epithelial cell death Hyposecretion of tears/saliva Primary Aqueous-deficient dry eye PLUS Dry mouth Auto-antibodies Reduced salivary secretion +ve minor salivary gland biopsy Secondary Primary PLUS Autoimmune connective disease (e.g. rheumatoid arthritis, systemic lupus erythematosus) International Dry Eye Workshop. Ocul Surf 2007;5:

56 Meibomian glands Located in the eyelids Secrete lipids into the tear film, reducing evaporation Dysfunction is generally either obstruction or reduced meibum production Results in evaporative DED Etiopathogenic classification Meibomian gland dysfunction Evaporative International Dry Eye Workshop. Ocul Surf 2007;5:

57 Meibomian gland dysfunction (MGD) MGD Hypersecretory meibomian seborrhoea Hyposecretory meibomian sicca Obstructive simple Obstructive cicatricial (duct orifices are drawn into the lid) Reduced number of glands Congenital deficiency Acquired MGD Gland replacement Distichiasis Distichiasis lymphedema syndrome Metaplasia International Dry Eye Workshop. Ocul Surf 2007;5:

58 Lipid-deficient DED is common Patients (%) Distribution of aqueous-deficient and evaporative dry eye in clinic-based assessments 1,2 58 Tong et al. (n = 200) Lemp et al. (n = 224) Evaporative Aqueous Mixed Neither 8 Evaporative dry eye is more common than pure aqueous deficiency, but the two often occur together 1. Tong et al. IOVS 2010;51: Lemp et al. Cornea 2012;31:472 8.

59 DED has multiple risk factors Mostly consistent Medications Antihistamines Nutritional deficiency Vitamin A Omega-3 and -6 fatty acids Older age Female sex Hormone deficiency Estrogen Androgen Refractive surgery Hepatitis C Radiation therapy Suggestive Medications Antidepressants Serotonin inhibitors Diuretics Beta-blockers Diabetes mellitus HIV Asian ethnicity Chemotherapy Keratoplasty Low humidity environments Unclear Medications Anticholinergics Anxiolytics Antipsychotics Alcohol Menopause Hispanic ethnicity Smoking Alcohol Botulinum toxins Pregnancy Gout Acne International Dry Eye Workshop. Ocul Surf 2007;5:

60 DEWS: severity grading system Dry eye severity Level 1 Level 2 Level 3 Level 4* Discomfort, severity and frequency Conjunctival staining Mild and/or episodic; occurs under environmental stress Moderate episodic or chronic, stress or no stress Severe frequent or constant without stress None to mild Variable Moderate to marked Severe and/or disabling and constant Marked Corneal staining None to mild Variable Marked central Severe punctate erosions TBUT (s) Variable 10 5 Immediate Schirmerscore (mm/5 min) *Requires both signs and symptoms Variable International Dry Eye Workshop. Ocul Surf 2007;5:

61 Burden of disease

62 DED is a globally prevalent disorder Study N Age(years) Prevalence (%) USA Salisbury Eye Study Beaver Dam Women s Health Study 36, Physicians Health Studies I and II 25,655 50, 55 Australia Blue Mountains Melbourne Visual Impairment Project Asia Shihpai Sumatra Adapted from DEWS Epidemiology. OculSurf 2007;5:

63 Varied prevalence of DED across Europe Study N Age(years) Prevalence (%) UK Spain Denmark Italy Variation is likely a result of differing age, ethnicity, diagnostic criteria and definition of DED Reported DED prevalence worldwide ranges from 5.5% to 57.1% 1. Young et al. Contact Lens Anterior Eye 2011;34: Visoet al. Ophthalmic Epidemiol2009;16 (abs). 3. Bjerrum. ActaOphthalmol Scand1997;75 (abs) 4. Versura et al. Ophthalmic Res 2001;33:221 7 (abs).

64 Patient impact DED can have a considerable impact on Visual function Daily activities Social and physical functioning Productivity at work Quality of life Pflugfelder et al. Am J Manag Care 2008;14:S102 6.

65 Economic impacts Cost drivers Direct Indirect Intangible Medical Non-medical Doctor visits Medications Eye wear Humidifiers Surgical costs Patient transportation Lost work time Lost productivity Changes in type of work Reduced quality of life Lost leisure time Impaired social, emotional and physical functioning Pflugfelder et al. Am J Manag Care 2008;14:S102 6.

66 Diagnosis

67 Key mechanisms of dry eye disease Goblet cell loss Lipid changes Tear film instability MGD Flora changes Eyelid Esterase/lipase release inflammation Toxins Cytokine release MMP activation Hyperosmolarity Inflammation Cell damage Nerve stimulation Apoptosis Adapted from Baudouin et al. J Fr Ophthalmol 2007;30:

68 Evaporation of the aqueous layer may lead to hyperosmolarity Evaporation Evaporation Lipid layer Compatible solutes Aqueous layer Water Hyperosmolarity Mucin layer Water Conjunctival cells Apoptosis Image is for illustrative purposes only.

69 Core mechanisms: tear film instability Tear film instability Tear film instability is frequently the initiating event 1 However, the most common cause of evaporative dry eye is a deficient tear film lipid layer due to MGD 1 The normal tear film lipid layer reduces water evaporation by about 90 95% 2 DED can be present with a normal quantity of tears 1. International Dry Eye Workshop. Ocul Surf 2007;5: Bron et al. Ocul Surf 2009;7:78 92.

70 Core mechanisms: tear hyperosmolarity Hyperosmolarity Tear hyperosmolarity considered main cause of damage to ocular surface Aqueous-deficiency Lipid-deficiency Normal evaporation rate Reduced water secretion rate Loss of goblet cells Altered mucin production Apoptosis Activates a cascade of pro-inflammatory products Increased evaporation rate Normal water secretion rate Classify your patients as lipid and/or aqueous deficiency, as it has consequences for their management Bron et al. Ocul Surf 2009;7:78 92.

71 Cellular response to hyperosmolarity Hyperosmolarity Normal cell Dehydrated cell Restored cell volume Exposure to hypertonic environment Regulatory volume increase Water loss Uptake of inorganic solutes Cell damage and death Decreased cell function, stress activation Image is for illustrative purposes only. Adapted from Strange et al. Adv Physiol Educ 2004;28:155 9.

72 Core mechanisms: apoptosis Apoptosis Epithelial damage by apoptosis can lead to a loss of goblet cells and disturbance of mucin expression 1 Epithelial injury stimulates corneal nerve endings, causing 1 Discomfort Increased blinking Compensatory reflex lacrimal tear secretion Damage to the corneal epithelia can affect visual function of dry eye patients 2 None Mild Severe Fluorescein staining at the central zone in the cornea, indicating epithelial damage 2 1. Bron et al. Ocul Surf 2009;7: Kaido et al. Invest Ophthalmol Vis Sci 2011;52:

73 Core mechanism: inflammation Inflammation Inflammation has two major consequences in dry eye disease 1 Tissue destruction Neurosecretoryblock mediated by inflammatory cytokines It is thought that chronic neural damage eventually leads to 1 Loss of sensory Decreased Reduced reflex drive to the corneal Altered tear tear secretion levels of the neuromodulators lacrimal glandcgrp, NPY and sensitivity NGF in DED correlate with clinical severity 2 CGRP, calcitonin gene-related peptide; NPY, neuropeptide Y; NGF, growth factor (NGF) 1. Bron et al. Ocul Surf 2009;7: Lambiase et al. Arch Ophthalmol 2011;129:981 6

74 Key mechanisms of dry eye disease Tear film instability Tear hyperosmolarity Apoptosis Inflammation Goblet cell loss Cytokine release MMP activation Lipid changes Eyelid inflammation Tear film instability MGD Flora changes Esterase/ lipase release Toxins Hyperosmolarity Inflammation Cell damage Nerve stimulation Apoptosis Adapted from Baudouin et al. J Fr Ophthalmol 2007;30:

75 Importance of diagnostic tests The key objective of diagnostic tests are To diagnose DED in clinical practice To follow up the natural history of DED A number of options are available Practical in an out-patient setting Requiring specialized clinics Grading staining Schirmer tests Tear film break-up time (TBUT) Meibomium gland expression Evaporimetry Interferometry Fluorimetry Non-invasive TBUT Novel tests in development Optical coherence tomography (OCT) Tear osmometer Computerized videotopography

76 Key challenges in diagnosis Considerable variation in signs and symptoms 1 Variability in disease terminology e.g. lacrimal keratoconjunctivitis, DTS, keratoconjunctivitis sicca 1 No definitive diagnostic test 1 No consensus on which test combinations to use 2 Lack of correlation between signs, symptoms and diagnostic test results 2 Little reproducibility of the clinical tests Natural variability of disease process Relative corneal anaesthesia with ageing and worsening of disease Subjective natures of the symptoms Variability in pain thresholds and responses to questions 1. Smith et al. Cornea 2008;27: International Dry Eye Workshop. Ocul Surf 2007;5:

77 DEWS recommended a number of examinations to be carried out in sequence It is often impractical to apply all the tests available for the diagnosis of DED in day-to-day clinical practice DEWS recommended a sequence based upon Test invasiveness Facilities available in each center An initial assessment can be carried out in primary care Evaluation of symptoms (e.g. duration, changes with season or ventilation) Medical history (e.g. menopause, ocular surgery, medications) Physical examination (conjunctival hyperemia, discharge) Specialist tests require an ophthalmologist with a slit lamp Fluorescein staining TBUT Grading of staining International Dry Eye Workshop. Ocul Surf 2007;5:

78 DEWS recommendations for the sequence of tests Clinical history Questionnaire Symptoms Fluorescein TBUT Tear stability Grading staining Ocular surface damage Tear secretion Schirmertests I and II Reflex tear secretion Lid and meibomian morphology Signs of meibomian gland dysfunction International Dry Eye Workshop. Ocul Surf 2007;5:

79 Clinical picture Objective clinical tests (most require a slit lamp) Symptoms (can be assessed in primary care) Reduced tear breakup time Altered tear quantity (measured by Schirmer) Altered or abnormal tear film stability (measured by TBUT) Ocular surface damage Itching, sandy gritty feeling Burning Dryness Sensitivity to bright light/sunshine Irritation and foreign-body sensation Pain Blurred vision Contact lens intolerance OSDI (ocular surface disease index) Nichols et al. Ocul Surf 2006;4:

80 Clinical history A careful clinical history is important Particularly relevant to differential diagnosis Allergy Infection Medication side effects Timing of dry eye symptoms may suggest aetiology Use of a questionnaireis often helpful in eliciting symptoms and judging their severity

81 Commonly used symptom questionnaires A number of questionnaires have been developed for use in DED, ranging from diagnosis alone to identifying precipitating factors and impact on the quality of life Questionnaire No. of questions Women s Health Study (WHS) 3 International Sjögren Classification 3 Schein s 6 McMonnies 12 Ocular Surface Disease Index (OSDI) 12 CANDEES 13 Dry Eye Questionnaire (DEQ) 21 IDEEL (3 modules and 6 scales) 57 International Dry Eye Workshop. Ocul Surf 2007;5:

82 OSDI: commonly used questionnaire Often used as a measure in randomized controlled trials 12 questions are graded 0 4 (none of the time to all of the time) OSDI score = Σ(scores of questions answered) 100 Σ(total number of questions answered) 4 The higher the score, the more severe the disease A validated and reliable instrument for measuring DED Accessed June 2013.

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84 Initial examination (without slit lamp) Skin texture Lid anatomy Eyelash appearance Check corneal sensation Signs of rosacea (nose in men, cheeks in women) Lagophthalmos when blinking Look for hyperaemia and discharge Blink pattern OCEAN panel expert opinion. Image is for illustrative purposes only.

85 Slit-lamp examination (before fluorescein) Tear meniscus Anterior blepharitis Signs of chronic inflammation (e.g. follicules, papillae) Tear film debris Filaments Symblephara Conjunctivochalasis OCEAN panel expert opinion. Image is for illustrative purposes only.

86 Examinations: tear film break-up time (TBUT) Methodology for determining tear film stability through assessment of the time required for tear film break-up and the appearance of dry spots on the corneal surface after blinking Slit lamp with cobalt blue light to intensify observation of the tear film Spontaneous break up of the tear film normally takes > 10 s Results are very variable, as measurements are performed in different ways by practitioners 0s 8s Time lapse fluorescein stain of TBUT 4s 12s International Dry Eye Workshop. Ocul Surf 2007;5:

87 Fluorescein TBUT test procedure Instil 1 5 μl of non-preserved, 2% fluorescein onto the bulbar conjunctiva using a dye-impregnated strip Patient should blink naturally several times without squeezing, to distribute the fluorescein Within s of instillation, patient should stare straight ahead without blinking, until told otherwise Set slit-lamp magnification at 10 Keep background illumination intensity constant Record time between last complete blink and first appearance of the growing micelle International Dry Eye Workshop. Ocul Surf 2007;5:

88 Clinical diagnosis of MGD Suggestive Confirmatory Low TBUT Meibography transillumination or infrared photography Meibumexpression quality and quantity graded Irregular lid morphology Meibometry measures the amount of lipid in the lower lid reservoir Tomlinson et al. Invest Ophthalmol Vis Sci 2011;52:

89 Examinations: ocular surface staining Stain Fluorescein (corneal staining) Rose bengal Lissamine green Mechanism of staining Detects corneal epithelium damage by staining damaged epithelial cells green (a healthy eye should not take up the stain) Fluorescein can also be used to measure TBUT Defines areas of conjunctival damage at the cellular level Stains cells not protected by a normal mucin layer Generally less used than lissamine green, as poorly tolerated Defines areas of conjunctival damage at the cellular level Stains dead or degenerated cells Less irritating than rose bengal All three are available as impregnated strips for convenience Savini et al. Clin Ophthalmol 2008;2:31 55.

90 Ocular surface damage: staining Corneal staining Fluorescein Conjunctival staining Lissamine green Rose bengal Mild Moderate Severe Images courtesy of ORION expert panel.

91 Ocular surface damage: grading of staining Characteristic Description Usefulness Description Conduct of test To estimate surface damage Surface damage to the exposed eye is assessed by staining. It is graded against standard chart Dye is instilled in the eye White light is used to assess the amount of staining Staining is marked on a series of panels Score: 0 5 for each panel Maximum score: 15 Bron et al. Cornea 2003;22:

92 Examinations: Schirmer test The Schirmer test evaluates aqueous tear production by the lacrimal gland by measuring the wetting of a strip of filter paper over a period of 5 min 5 mm of wetting is regarded as an abnormal response The Schirmer II variant is performed with anesthesia, and the nasal mucosa are stimulated to generate reflex tears The Schirmer II test is rarely performed Savini et al. Clin Ophthalmol 2008;2: International Dry Eye Workshop. Ocul Surf 2007;5:

93 Summary of further diagnostic tests Diagnostic test Description Meibomiangland expression Applying gentle pressure to release oils from meibomian glands Measures the quality and quantity of meibomianoil 1 Lid parallel conjunctival folds (LIPCOF) Intensity of LIPCOF Scale from 0 (none) to 3 (severe) 2 Non-invasive tear breakup test (NIBUT) Videokeratography drops are not required for visualisation 3 Lipid layer thickness measurement (LLT) Lipid-layer interferometer Colours in optical interference patterns correspond to LLT 4 Evaporimetry Measures tear evaporation rate 3 Tear meniscus measurement Height, curve and area of upper and lower eyelid tear menisci 5 1. Foulks et al. Ocul Surf 2003;1: Szalaiet al. Cornea 2012;31: International Dry Eye Workshop. Ocul Surf 2007;5: Korb et al. Optom Vis Sci 2005;82: Saviniet al. ClinOphthalmol2008;2:31 55.

94 Emerging and complementary technologies A number of diagnostic tests are emerging that promise to advance investigation and monitoring of DED Devices to measure osmolarity would allow a quantitative measurement of disease severity Osmometers such as TearLab and Lacripen are non-invasive devices developed for use in everyday clinical practice Techniques that capture images of the ocular surface can potentially provide new information on dynamic changes of corneal topography and tear film behaviour Techniques include confocal microscopy, OCT, high-speed videotopography and meniscometry Sampling cells or mucin from the ocular surface by impression cytology allows an immediate snapshot of the area, although the technique is invasive Lemp et al. Am J Ophthalmol 2011;151: International Dry Eye Workshop. Ocul Surf 2007;5:

95 Phenol red thread test A variant of the Schirmer test using cotton thread treated with phenol red 1 Placed in the eye for 15 s, the thread turns from yellow to red where wetted 1 < 10 mm indicates dry eye mm is considered marginal 2 Phenol red thread Image is for illustrative purposes only. 1.Savini. ClinOphthalmol2008;2: Saleh et al. Eye 2006;20:

96 Tear osmolarity testing Tear hyperosmolarity is thought to be the central cause of damage in dry eye disease 1 The TearLab Collects ~50 nlof tear fluid directly from the eye with minimal invasiveness 2 Produces an accurate osmolarity figure in < 2 min 2 Variability in measurements can be addressed by measuring both eyes and taking the higher value 1. International Dry Eye Workshop. Ocul Surf 2007;5: Lemp et al. Am J Ophthalmol 2011;151:792 8.

97 Tear film stability analysers Several approaches have been tried to estimate TBUT non-invasively Corneal topography Wavefront aberrometry Laser scanning microscopy 1 Corneal topography is currently available in commercial systems 1,2 Validated normal values and diagnostic cut-offs are lacking 1 Non-invasive TBUT measurement 1. Saviniet al. ClinOphthalmol2008;2: Koury. Advanced Ocular Care 2011;May/June:36 7.

98 Tear meniscus measurements A slit lamp with a micrometer cannot always identify the meniscus 1 Optical coherence tomography (OCT) 2 is generally available only at large centres Corneal topographs can also be used for this purpose 3 Validated normal values and diagnostic cut-offs are lacking 1 1. Saviniet al. ClinOphthalmol2008;2: Ibrahim et al. Ophthalmology 2010;117: Koury. Advanced Ocular Care 2011;May/June:36 7.

99 Meibography Imagesthe evertedeyelid using infrared microscopy, laser confocal microscopy or OCT Quick and non-invasive Assesses gross and microscopic structure of the meibomian glands Meiboscoreis a single measure of meibomian gland function that correlates with Lid margin abnormality Meibum scores OCT, optical coherence tomography Wise et al. Saudi J Ophthalmol 2012;26:

100 Matrix metalloproteinase-9 testing Tear film in dry eye disease contains inflammatory markers, including matrix metalloproteinase-9 (MMP-9) 1 Testing for MMP-9 is quick and straightforward, using commercially available kits MMP-9 correlates well with many other tests for dry eye disease, including OSDI questionnaire, staining, Schirmer test and measures of MGD 1 1. Messmer et al. Presented at SOE 2013, abstract FP-OCS-062.

101 How key concerns relate to tests Inflammation Apoptosis (cell damage) Tear film instability Hyperosmolarity Tear volume Slit-lamp examination (hyperaemia, lid margins) Ocular surface staining Ocular surface staining Tear film break-up time Meibomian gland morphology Meibomian gland expression Schirmer test Emerging and complementary technologies MMP-9 testing Impression cytology Non-invasive TBUT analysis Meibography TearLab* Phenol red thread test Tear meniscus measurement *For measuring tear film hyperosmolarity

102 DED differential diagnostic tree Chronic, bilateral, minimal hyperemiaand discharge, age 50 years, female, worse in cold/hot climates Predominantly in the morning, especially in winter Evaporative DED more likely Primary care doctor Symptoms Predominantly in the evening, gritty, burning, dryness Aqueous deficient DED more likely Acute, unilateral, hyperemiaand discharge, concomitant dryness of mouth, age 50 years Unlikely to be DED, refer to relevant specialist Petriček. Int Ophthamol 2008;28(Suppl.):18 31.

103 Differential diagnosis: alternatives to dry eye disease Acute infectious disease: viral, bacterial or chlamydial 1,2 Rapid onset, pronounced hyperaemia 2 Allergic disease Itching and swelling 2 Superior limbic keratoconjunctivitis 1 Alternative diagnoses do not rule out dry eye disease multiple ocular surface disorders frequently coexist 1. Kanski& Bowling. Clinical Ophthalmology, 7th edn. Elsevier, Berta et al. IntOphthalmol2008;(suppl.)1 64.

104 Treatment

105 Challenges in the management of DED DED requires careful management as it is chronic and long-term Treatment has two goals To alleviate symptoms and enhance the patient s quality of life To prevent the development of possible complications such as infection, corneal scarring or perforation The Delphi and DEWS panels both suggested stepwise treatment algorithms Delphi treatment recommendations were developed from a consensus of expert advice DEWS treatment recommendations were developed from a review of available literature and a modification of the Delphi approach based on severity Petriček. Int Ophthamol 2008;28(Suppl.): International Dry Eye Workshop. Ocul Surf 2007;5:

106 DEWS review: available treatment options Treatment option Tear supplementation Tear retention Tear stimulation Biological tear substitutes Group/subgroup Lubricants, e.g. artificial tears Punctal occlusion Moisture chamber spectacles Contact lenses, e.g. silicone hydrogel, daily disposable Secretagogues Anti-inflammatory therapy Cyclosporine-A Corticosteroids Tetracyclines Essential fatty acids Environmental strategies Autologous serum Salivary gland autotransplantation Omega-3 fatty acids Avoid low humidity and air conditioning drafts Lower video display terminal below eye level International Dry Eye Workshop. Ocul Surf 2007;5:

107 DEWS recommendations for clinical approach Diagnosis of dry eye Primary care doctor Level 1 Level 2 Level 3 Level 4 Follow Level 1 treatment algorithm Follow Level 2 treatment algorithm Follow Level 3 treatment algorithm Follow Level 4 treatment algorithm If Level 1 treatments are inadequate, add: If Level 2 treatments are inadequate, add: If Level 3 treatments are inadequate, add: International Dry Eye Workshop. Ocul Surf 2007;5:

108 DEWS: treatment algorithm based on disease severity Environmental/dietary modification Level 1 treatment options Eliminate inappropriate medications Artificial tear substitutes Eye lid therapy Anti-inflammatory drugs Level 2 treatment options Tetracylines Punctal plugs Secretagogues Moisture chamber spectacles Level 3 treatment options Serum Contact lenses Permanent punctual occlusion Systemic anti-inflammatory drugs Level 4 treatment options Surgery (lid surgery, mucous membrane, salivary gland and amniotic membrane transplantation, keratoplasty) International Dry Eye Workshop. Ocul Surf 2007;5:

109 Lubricants: artificial tear substitutes General characteristics 1 Active ingredient is polymeric base or viscosity agent Balanced to mimic the electrolytes, osmolarity and ph of normal tears 2 Increase the tear volume 2 Some artificial tears incorporate compatible solutes ( osmoprotectants ) such as erythritoland l-carnitine 1 Distribute between the tears and intracellular fluids to protect against cellular damage from hyperosmolarity 1 Provide a strategy to reduce the production of inflammatory mediators and proteases by those corneal epithelial cells exposed to elevated osmolarity in the extracellular environment 3 Normal healthy tears 1. International Dry Eye Workshop. Ocul Surf 2007;5: Pflugfelderet al. Asian J Ophthalmol2005;7(Suppl.): Corrales et al. Cornea 2008;27:574 9.

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111 Tear retention agents Punctal occlusion Retards tear clearance Useful for treatment of aqueous deficient DED Two types of punctal plugs: absorbable and non-absorbable Moisture chamber spectacles Moisture-conserving spectacles Limited evidence to support efficacy Gas-permeable contact lenses Hydrates and protects corneal surface in severe DED Some improvements reported Increased but small risk of corneal infection and vascularisation International Dry Eye Workshop. Ocul Surf 2007;5:

112 Anti-inflammatory treatments Topical cyclosporine-a Significant improvements in subjective and objective scores 1 Efficacy is well documented 1 FDA-approved specifically for DED 2 Topical corticosteroids Effective in DED but only for short-term use 2 Prolonged use may give rise to infection, glaucoma and cataracts 2 Oral tetracyclines Antibacterial, anti-inflammatory and antiangiogenic 1 Useful for rosacea and posterior blepharitis 1 Potential hazard of long-term use 1 1. International Dry Eye Workshop. Ocul Surf 2007;5: Lemp. Am J Manag Care 2008;14:S

113 Other therapeutic options Tear stimulation secretagogues May stimulate aqueous secretion and mucous secretion Can be topical or oral Biological tear substitutes Serum or saliva (naturally occurring) Concerns include compositional differences, sterility and stability Essential fatty acids Omega-3 fatty acids Inhibit inflammatory mediators Environmental strategies Avoid factors that decrease tear production or increase tear evaporation Humidification in dry climates and at high altitudes International Dry Eye Workshop. Ocul Surf 2007;5:

114 MGD-specific treatment options Treatment option Application of heat to lid, massage and cleaning of lid Topical medication Systemic medication Adjunctive treatment Description Warm compress applied to lid Massage upper and lower lids Clean with wet cotton bud Antibiotic ointments, short-term steroid treatment Antibiotics e.g. tetracycline for infection and inflammation Lipid-supplemented artificial tears Geerling et al. Invest Ophthalmol Vis Sci 2011;52:

115 Case history 1: presentation and investigation Patient is a 57-year-old woman presenting with burning pain and gritty sensation in both eyes Consultation Symptoms are intermittent, but have worsened in recent years Symptoms are worse in the winter, particularly in windy weather, and in areas with low humidity Has to turn off air conditioning when driving Vision sometimes becomes blurred when watching TV or reading Postmenopausal Not taking any medications Physical examination Moderate conjunctival hyperaemia Very little discharge

116 Case history 1: diagnosis and management Diagnosis: DED, severity level 1 Management Recommended to take an artificial tear (preferably one with osmoprotectants), which will aid lubrication and alleviate symptoms Recommended to avoid dry and high-ventilation environments Recommendation of forceful intentional blinking during computer work or while reading and watching TV Referral to an ophthalmologist should be considered, as the patient may develop secondary complications The ophthalmologist will examine the ocular surface to ascertain the extent of epithelial damage Short-term use of anti-inflammatory agents may be considered

117 Case history 2: presentation Female patient aged 67 years Type 2 diabetes History of dry eye symptoms for 20 years Ocular irritation in left eye since cataract surgery 1 year earlier Visual acuity 20/20 in both eyes Normal IOP Normal lid morphology No evidence of meibomian gland problems

118 Case history 2: test results and diagnosis Significantly decreased corneal sensation Tear break-up time 8 s in right eye, 2 s in left eye Extensive fluorescein staining on cornea and conjunctiva of left eye only Schirmer s test with anaesthesia Right eye 7 mm in 5 min Left eye 5 mm in 5 min Diagnosis: bilateral dry eye disease with neurotrophic keratopathy in the left eye only