Treatment Guidelines

Treatment Guidelines for Management of Dry Eye: Role and Relevance of Formulations

Goals of management – Establish the diagnosis of dry eye, differentiating it from other causes of irritation and redness, – Identify the causes of dry eye, – Establish appropriate therapy, – Relieve discomfort, – Prevent complications, such as loss of visual function, infection, and structural damage, – Educate and involve the patient in the management of this disease. 13th October 2006

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Treatment – Principles 1. Hydrating and Lubricating the ocular surface 2. Suppressing the inflammatory response of the ocular surface

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Cycle of Inflammation Cyclosporin Corticosteroids Tetracyclines Serum/Plasma

Artificial Tears Punctal Occulusion Secretogogues

Irritation

Inflammation

Tear deficiency/ instability Artificial Tears Punctal Occulusion Serum/ Plasma Tetracyclin Secretogogues

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Therapy Involves 1. Eliminating Exacerbating Factors 2. Support of Functional unit 3. Hydrating, stabilizing and lubricating Therapy 4. Secretogogues 5. Punctal Occlusion 6. Anti-Inflammatory Therapy 7. Use of contact Lens 13th October 2006

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Eliminating Exacerbating Factors

• The factors that decrease tear production or increase tear evaporation such as use of systemic anticholinergic medications and desiccating environmental stresses should be minimized or eliminated

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Support of Functional unit • Aimed at normalizing tear secretion by secretory glands and promoting normal growth and differentiation of the ocular surface epithelia. Androgen receptors are present in tear secreting glands , meibomian glands, corneal and conjunctival epithelia and accessory lacrimal glands. Andrgens appear to attenuate autoimmune reaction. Clinical trials of topical administration of androgen for therapy of dry eye are currently in progress. 13th October 2006

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Support of Functional unit • Hormone replacement therapy in postmenopausal women is associated with increased prevalence of dry eye symptoms • Testosteron, 120 mg/day for two months results in improvement in Schirmer test value and reduction in ocular surface Rose Bengal staining. 13th October 2006

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Support of Functional unit • Autologous Serum – It contains several growth factors that are present in tears including Vitamin A , epidermal growth factor, TGF beta and fibronectin. It contains potential inhibitors of inflammatory cytokines (e.g. IL-1) and Matrix metalloproteinase.

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Autologous Serum • Use of diluted serum 1:3 with normal saline resulted in significant improvement in symptoms of ocular irritation and decrease in ocular surface Rose Bengal staining, ocular surface fluorescein staining and increase the expression of MUC 1 mucin by conjunctival epithelium. In addition it may provide anti-inflammatory effect by inhibiting inflammatory cascades. • (Fox RI et al, Arthritis Rheum 1984 and Tsubota K, et al , BJO 1999) 13th October 2006

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Autologous Serum • In contrast others have observed no difference between serum and control of dry eye. (Tananuva TN and coworkers , Arch of Ophthalmology 1988)

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Hydrating, Stabilizing, and Lubricating Therapies • There is reduced tear volume, elevated tear osmolality , increased tear electrolytes and decreased tear film stability in cases of aqueous tear deficiency. These alterations can be treated with artificial tear, secretogogues and punctal occlusions

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Artificial Tear Polymers Polymer Properties ----------------------------------------------------------Cellulose esters Viscoelastic (hypermellose, hydroxyethylcellulose, Methycellulose, Carboxymethylcellulose) 13th October 2006

polysacchrides increase the viscocity of tears increase in viscocity when concentration is moderately increased

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Polymer Properties ----------------------------------------------------------Polyvinyl alcohol Low Viscocity , optimal wetting characteristics at 1.4% Povidone Superior wetting when (polyvinyl pyprolidone) co-formulated with polyvinyl alcohol 13th October 2006

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Polymer Properties ----------------------------------------------------------Carbomers High molecular weight polymers (polyacrylic acid) of acrylic acid: high viscocity when eye is static, thinning during blinking or eye movement, maximizes thickness of tear film while minimizing drag; longer retention time than polyvinyl alcohol

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Polymer Properties ----------------------------------------------------------Hyluronic acid, Glycosaminoglycan chondroitin sulfate dissacharide biopolymer exhibiting nonNewtonian properties and longer retention times 13th October 2006 Dr Sanjay Shrivastava 16

Tolerance – merit wise 1. Carboxymethylcellulose (CMC-U), 2. Unpreserved, polyvinyl alcohol-based product (PVA-U), 3. Hydroxypropylmethylcellulose formulation (HPMC-P) that contains edetate disodium (EDTA). 4. Preserved formulation (PVA-P), using polyvinyl alcohol as the polymer and containing EDTA and benzalkonium chloride (BAK), 13th October 2006

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• Frequent instillation of artificial tears with reduced tears turnover makes patients of aqueous tear deficiency susceptible to ocular surface epithelial toxicity from preservatives particularly Benzalkonium chloride. Preservative free lubricants allows patients to use these artificial tear preparations as frequently as necessary without toxicity. Such preparations should be considered in patients who requires drugs for more than 4 times. 13th October 2006

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• More recent addition is the use of disappearing preservatives such as Sodium Perborate and Purite ™. These preservatives decompose into water, oxygen or sodium upon contact with tears film or with light. • Lubricating ointments are useful for bedtime application , they contain oily substances such as Lanolin, Petrolatum. • Lipid emulsions may have promising role, further studies are needed to determine its role in management of KCS. 13th October 2006

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Secretogogues • Stimulates endogenous tear production. They are: a. Oral Pilocarpine (SALAGEN tablets) 5 mgm four times (side effects- excessive sweating, nausea and intestinal cramping) b. Cevilemine (Evoxac tablets) 90 mg/d and is tolerated at doses up to 180 mg/d. These agents (Cholinergic agonist) are found to improve irritation and tear production. 13th October 2006

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Secretogogues • Currently P2Y2 receptor agonist Diuridine Tetraphosphate is under phase III clinical trial of FDA. Preliminary results have shown increase in Schirmer test score, decrease fluorescein stain and improve the worst irritation symptoms (Tauber J , Invest Ophthalmol Vis Sci 2003) . Stimulation of P2Y2 receptors induce secretion of mucin by conjunctival cells. 13th October 2006

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Punctal Occlusion • •

Semitransparent silicon Themolabile polymers Punctal Plugs/ Canalicular implant (gelatin plugs / rods)

(http://www.agingeye.net/dryeyes/plugsetc.php #) c. Thermocautery d. Radiofrequency needle e. Suture f. Argon Laser 13th October 2006 Dr Sanjay Shrivastava 22

Surgical Treatment

• •

To decrease the exposure and evaporative loss of tears, side panels and moist inserts on eyeglasses may be tried OR surgical methods: Tarsorrhaphy: Lateral and /or median Type A Botulinum toxin into the LPS muscle induces a temporary (6-8 weeks) complete ptosis of the upper eyelid.

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3. Salivery Gland Transplantationa. Parotid duct transposed and redirected to drain into inferior fornix. b. Transplantation of minor salivery glands into inferior tarsal or fornicial conjunctiva c. Transplantation of a portion of submandibular gland with its duct into temporal fossa, duct is transplanted in superior temporal fornix. 13th October 2006

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Anti-inflammatory Therapy This therapy targets one or more components of the inflammatory response to dry eye . Anti-inflammatory therapy may be considered for patients with stagnated and unstable tear film who continue to have symptoms or have corneal disease on aqueous enhancement therapies.

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Cyclosporin A Is reported to be effective in dry eye and keratoconjunctivitis sicca. It prevents the activation of transcription factors that are necessary for T cell activation and the production of IL 2 Cyclosporin A act by inhibiting epithelial apoptosis and T cell activation. The density of goblet cells on ocular surface also increases. Used as 0.05% drops twice daily. It significantly decrease conjunctival Rose Bengal Staining, SPK and Ocular irritation symptoms 13th October 2006

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Corticosteroids Corticosteroids have been reported to improve both symptoms and signs of dry eye. Irritative symptoms and corneal fluorescein staining improves. Occasionally severe cases of Sjogren’s syndrome improve with alternate day oral Prednisolon (40 mgm) therapy. Improvement in Schirmer test , decrease in Rose Bengal Staining and elevation of tear lysozyme enzyme level is observed. 13th October 2006

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Tetracycline Tetracycline or Doxycycline are effective for treating ocular surface inflammatory diseases. They inhibit the production and activity of inflammatory cytokines and other inflammatory reaction modulators. Doxycycline is particularly effective in treating dry eye associated with meibomian gland disease. 13th October 2006

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Recommendations for use of Antiinflammatory therapy of Dry Eye Constant ocular irritation from tear film instability that is not relieved by artificial tears and patients who develops corneal epithelial disease from dry eye, are the situations where anti-inflammatory therapy is indicated. CsA is started , if patient does not respond then add topical steroids and oral tetracycline, topical steroids are best used in short pulses 1-4 weeks, then frequency is decreased to once or twice or replaced with Loteprednol or Fluoromethalone 13th October 2006

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Autologous Serum

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Essential Fatty Acids • Recent research has shown that oral therapy with polyunsaturated fatty acids reduces ocular surface inflammation and improves dry eye symptoms (Cornea 2003;22:97-101). In this study patients received tablets containing 28.5 mg linoleic (omega-6 fatty acid) and 15 mg gamma-linolenic acid (omega-3 fatty acid) twice daily for 45 days. Both of these are polyunsaturated fats. Use of these agents shows improvement in ocular irritation symptoms, decrease ocular surface Lissamine staining 13th October 2006

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Use of Contact Lens Soft bandage contact lens (DK Silicon or Hydrogel) and Gas permeable scleral hard lens have shown improvement in patients with KCS with epitheliopathy or recurrent filamentary keratitis. CL are indicated in few selected cases.

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COUNSELING/REFERRAL

• The most important aspects of caring for patients with dry eye are to educate them about the chronic nature of the disease process and to provide specific instructions for therapeutic regimens.

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Summary

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Cycle of Inflammation Cyclosporin Corticosteroids Tetracyclines Serum/Plasma

Artificial Tears Punctal Occulusion

Secretogogue s

Irritation

Inflammation

Tear deficiency/ instability Artificial Tears Punctal Occulusion Serum/ Plasma Tetracyclin Secretogogues

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Summary 1. Multipronged approach 2. Systemic and environmental stresses should be minimized 3. Artificial Tears 4. Systemic cholinergic agonists 5. Preservation of natural tears and punctal occlusion 6. Cyclosporin A 7. Topical Steroids 8. Environmental correction / Counseling 13th October 2006

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References 1. Ali R. Djalilian, Pedram Hamrah, Stephen C Plugfilder. Dry Eye, p 521-541, in Cornea- fundamentals, Diagnosis and Management – Vol- 1 , Krachmer, Mannis, Holland, Elsevier Mosby- 2005. 2. Stephen C Pflugfelder and Abraham Soloman, Dry EyeP 49-57, in Ocular Surface Diseases, Medical and Surgical Management, Edward J Holland and Mark J Mannis, Springer 2002 3. Stephen C Pflugfelder and Michael E Stern. Therapy of Lacrimal Keratoconjunctivitis. In Dry Eye and Ocular Surface Disorders ed by Stephen C Pflugfelder, Roger W. Beuerman, Michael E Stern, p 309-325, Marcel Dekker, Inc ,2005 13th October 2006

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References … Contd. • Ocular Surface Disease Index questionnaire is available on site www.agape1.com/Questionnaires/Ocular%20S urface%20Disease.pdf • Dry Eye Syndrome Preferred Practice Pattern™

http://www.aao.org/education/library/ppp/dryeye_new • Artificial Tears http://www.agingeye.net/dryeyes/dryeyesdrugtre 13th October 2006 Dr Sanjay Shrivastava 38 atment.php

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• Thanks you

Thank you 13th October 2006

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