Questions about Dry Eye

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1 What Is Dry Eye? Sources of Inflammation? New Understanding and Treatments Scheffer C. G. Tseng, M.D., Ph.D. Ocular Surface Center Ocular Surface Research & Education Foundation TissueTech, Inc. Questions about Dry Eye What clinical settings do we need consider dry eye? Do dry eye patients always complain irritation? Is the neurotrophic state a dry eye? How do we know dry eye is caused by aqueous tear deficiency () or lipid tear deficiency (LTD)? Does dry eye cause inflammation or vice versa? How do surgeries (e.g., LASIK) affect dry eye? Can we develop a unified understanding, differential diagnosis and approach? Key Functions of the Tear Film To see clear To ensure comfort To maintain ocular surface epithelial health with proper differentiation Serve as a smooth and clear optical surface Prevent dryness during eye opening Prevent friction during eyelid blinking Provide oxygen to corneal epithelium Provide nutrients, electrolytes, growth factors, & vitamin A Provide anti-microbials and anti-oxidants Blurry vision (fluctuating) Ocular surface irritation Surface break-down (SPK, ED, or ulcer) and Infection Incomplete Closure during Blink Leads to Exposure SPK Blink Protected Ocular Surface TBUT Unprotected Ocular Surface Blink Cycle Repeats OS Time (seconds) Dry Eye Adverse Conditions in Which the Tear Film Stability Cannot Be Sustained beyond the Inter-blink Interval Ocular Staining Discomfort 2002 ORA, Inc. 1

2 Ocular Surface Health Depends on a When Eye Is Open Compositional Factors Ocular surface epithelia s glands s glands fluids Hydrodynamic Factors A Is Maintained by A Sound Ocular Surface Defense Governed by Neuroanatomic Integration Eyelid blinking Milk out meibum lipid & help tear/lipid spread & clearance Eyelid closure Avoid exposure Reflex Tearing Is Lost in Sjögren-type Dry Eye and Its Detection Guides Punctal Occlusion Significance of Reflex Tearing Loss of reflex tearing distinguishes Sjögren syndrome-type dry eye from non-sjögren type dry eye Basic Tearing Normal Non-SS SS Reflex Tearing _ RB ± ++ Squamous Metaplasia _ ± ++ Can you cry with tears? Tsubota et al, AJO, 1991; J. Rheumatol 1996 How to Evaluate Basic and Reflex Tear and by FCT Normal with Reflex Apply a drop of 0.5% proparacaine and dry the sac in each eye Apply 5 μl 0.25% Fluoress R and allow normal blinking Perform three Schirmer tests, each for 1 min at 10 min, 20 min and 30 min Perform nasal stimulation before the 30 min test Prabhasawat & Tseng BJO 82:666, 1998 Wetting length: all > 3 mm Increased wetting length in the end Dye disappears by 15 min < 3 mm when anesthetized Increased wetting length in the end Dye disappears by 15 min 2

3 with Reflex Wetting length: < 3 mm in the beginning Dye clears: in 15 min without Reflex < 3 mm throughout Much Delayed Punctal Occlusion Consider PO if dry eye is not responsive to frequent non-preserved tear substitutes With reflex tearing, consider plugs to one punctum Without reflex tearing, consider thermal cauterization to both puncta How Can Tear Deficiency () be Differentiated from Tear Deficiency (LTD)? MG Orifice Squamous Metaplasia Kinetic Analysis of Tear Interference Images DR-1 (Kowa, Inc. Japan) Video Signal PC Monitor Normal Subject LTD without Frame Grabber Video Image Extracted to Sequential Frames Image Analysis s from Lower to Upper Horizontal Pattern Rapid s from Lower to Upper Vertical Streaking Pattern Slow Goto and Tseng, Arch Ophthalmol 2002; 121:

4 LTD without Nl Comparison in Representative Frame LTD s from Lower to Upper s from Lower to Upper Horizontal (Lower) and Vertical Vertical Streaking Pattern Streaking (Upper) Pattern Slow Slow Goto and Tseng, IOVS. 2003; 44: NL LTD Pattern Horizontal Vertical Mixed Speed Rapid Slowest Slow (sec) 0.36 ± ± ± 0.42 Thickness White-gray Dark-brown Colorful Evenness Even Less even Uneven Stability Yes No Yes Tear Evaporation Rate Correlates with Pattern of Film Differential Diagnosis Multiple regression analysis between Jeye and three indices of DR-1 showed that the pattern of lipid spread had a significant influence on Jeye. Symptoms Diurnal Variation Worst in P.M. LTD Same throughout the day r = 0.59, P = Worst Gaze Increased Blinking Up Gaze Up Gaze Rose Bengal Punctal Occlusion Exposure Zone - Liu et al, IOVS, 46: , 2005 Lee and Tseng Am J Ophthalmol, 124: , One Major Cause of MGD with LTD and Ocular Surface Inflammation is Demodex Infestation Manifestation Gao et al, Cornea, 2007 Kheirkhah et al, AJO, 143: ,

5 Manifestation Skin Manifestation Demodex has been implicated in rosacea, pityriasis folliculorum, perioral dermatitis, pustular folliculitis and basal cell carcinoma Eyelash Manifestation Cylindrical dandruff is pathognomonic for Demodex blepharitis Clean Lashes Demodex Blepharitis Coston, 1967, English, 1971, English & Nutting, 1981, Heacock,1986, Fulk & Clifford, 1990, Fulk et al, 1996, Kamoun et al. 1999, Morfin, 2003 Coston 1967; Gao et al, IOVS, 2005 Conjunctival Manifestation Corneal Manifestation Demodex blepharitis is frequently associated with conjunctival inflammation A B C Gao et al, Cornea, 2007 Kheirkhah et al, AJO, 143: , 2007 D E Kheirkhah et al, AJO, 143: , 2007 F 5

6 Survival Time of Demodex in Different Solutions Solutio n 50% BS 10% PI 75% Alc MO 4%Pilo Mix 1 Mix 2 Mix 3 Lid Scrub by TTO, but not Baby Shampoo, Stimulates Demodex to Migrate to the Skin ST (min) DN Solutio n ST (min) DN 100% Alc 3.9± % TTO 5 25% TTO 34.7± % TTO 14.8± % TTO 3.7± % CWO 4.4± % DWO 14.0±8.3 5 TTO Scrub Baby Shampoo Scrub ST: survival time recorded in minute, DN: number of demodex tested, BS: baby shampoo, MO: mineral oil, PI: povidone iodine, Alc: alcohol, Mix 1: 50% BS in water for 30 min followed by 10% PI, Mix 2: 10% SDS in water for 30 min followed by 10% PI, and Mix 3: 10% PI for 30 min followed by 75% Alc, TTO: tea tree oil. CWO: caraway oil, DWO: dill weed oil and Pilo: pilocarpine. Gao et al, Br J Ophthalmol, 89: , Gao et al, Br J Ophthalmol, Conjunctival Inflammation Is Reduced after TTO Lid Scrub Resolution of CD and Conj Inflammation after TTO Treatment Before Treatment Before After After Treatment Gao et al Cornea, 26:136, 2007 Kheirkhah et al, AJO, 143: , 2007 Improvement of Tear Film by TTO Lid Scrub Resolution of Inflammatory Corneal Lesions after TTO Treatment Before Treatment Before After After Treatment Gao et al, Cornea, 26:136, 2007 Kheirkhah et al, AJO, 143: ,

7 Demodex Count per 8 Lashes M 5 M Before 2.5 M 5 M 20/70 20/40 20/40 OD OS Blink-related Microtrauma to Ocular Surface Is Aggravated by Compositional Deficiency Lid Margin Pathology In the event of lid margin/tarsal pathologies Conjunctivalization Keratinization Significant Correlation between Lid Margin/Tarsal Pathologies and Corneal Complications Grade 1 Grade 2 Grade 3 Mild Severity of Eyelid/Tarsal Pathologies Moderate Severe gland orifice metaplasia Focal lid margin keratinization Mild Di Pascuale et al Ophthalmology, 2005 How to recognize and manage Blink-related Microtrauma caused from lid margin pathologies? Moderate gland orifice metaplasia Broad lid margin keratinization Severe Tarsal scar with keratinization, inflammation, and trichiasis 7

8 History 48 y/o F developed SJS/TEN after taking Lamictal in Dec 2000, and complained of waking up with lids stuck together, constant eye irritation and photophobia despite artificial tears every 15 min and 4 PO with cauterization. Intolerable to Boston Scleral Lens OD OS OD Before After Synthetic Meibum ) Examination VA: OD: 20/20-3, OS: 20/30+1 TBUT:: 0 sec, OU Lid Margin: MGD with orifice metaplasia, focal keratinization Vertical Streaking Pattern Disappearance of Vertical Pattern with Granules Severity of Eyelid/Tarsal Pathologies Stevens Johnson Syndrome Mild Moderate Severe gland orifice metaplasia Focal lid margin keratinization Mild PO and Serum Drops What is the next step? When to consider contact lens/scleral lens and mucous membrane graft? Moderate gland orifice metaplasia Broad lid margin keratinization Severe Tarsal scar with keratinization, inflammation, and trichiasis MMG Oral Mucosal Membrane Graft Neurotrophic Keratopathy Is the Worst Form of Dry Eye; Punctal Occlusion Is the First Treatment Primary Secondary Factors Making Neurotrophic Keratopathy Worse Corneal Sensitivity Chronic CL wear, LASIK Lid and Lash Sensitivity Chronic blepharitis with lash loss Conjunctival Sensitivity Atopy, Allergy, Floppy lids, Conjunctivochalasis Nasal Sensitivity Chronic nasal allergy Ocular Sensitivity is the summation of Cornea Lid Margin/ Lashes Conjunctiva Nasal Mucosa (Anterior) Solomon et al, Comp Ophthalmol Update,

9 How to Distinguish the Primary vs. Secondary Neurotrophic Effect Differential Use Fluorescein and Rose Bengal Primary Effect Intrinsic Epithelial Degeneration Due to deprivation of neurotrophic factors (neurotrophins) Secondary Effect Unstable Tear Film (Dry Eye) Fluorescein Disrupted Cell-cell Junctions Rose Bengal Insufficient Preocular Protection Due to interruption of neural reflexes mediated by Medicamentosa (Toxic) Squamous metaplasia KCS, SLK Use Rose Bengal staining pattern to differentiate the secondary from the primary effect Use Fluorescein Test to verify the presence of the secondary effect Conjunctivalized cornea Dysplasia CIN Viral epitheliopathy HSV, HZO Hydroxy-xanthine Dyes Solomon et al, Comp Ophthalmol Update, 2000 Feenstra & Tseng, Arch Ophthalmol, 1992; Ophthalmology, 1992 Primary Neurotrophic Effect PJ ( ) 56M H/O HSV OS x 15 years with intermittent flare up, each treated with Acyclovir and 0.1% PF Secondary Neurotrophic Effect Presented with corneal perforation, LP, and flat A/C Failed to be glued Received emergency PKP Postop day 1: No ED Postop Day 1: No ED Postop day 7: ED FCT Is this serious? What to do? Perform Differential Dye Staining Punctal Occlusion 9

10 1 wk after PO 5 years after PO Managements of Persistent Corneal Epithelial Defects/Ulcers Non-limbal Deficient (Neurotrophic) Punctal Occlusion Autologous Serum Drops Bandage Contact Lens (high DK) AM as temporary graft (Prokera) (superficial) AM as permanent graft (one or multiple layers) (deep) Tarsorrhaphy Limbal Deficient Partial AMT Total Limbal SC Transplantation Major Dysfunctional Elements Loss of reflex tearing in Severe Dry Eye Punctal Occlusion, Autologous Serum Neurotrophic Keratopathy is the worst form of dry eye Punctal Occlusion, AS, CL, Tarsorrhaphy Blink-mediated microtrauma due to cicatrix when there are abnormalities in lid margins, lashes, and meibomian gland orifices CL/Plastic Correction/Fornix Reconstruction Subclinical Delayed Tear Is Common and May Be Pathogenic? suppression Prabhasawat & Tseng BJO 82:666, 1998 Pathophysiology of DTC Prabhasawat & Tseng BJO 82:666, 1998 Differential Diagnosis Old Decreased Floppy Age Female Ocular Sensitivity lids CCh Allergy Atopy Ineffective or Decreased Blinking Mucosal Inflammation & Edema Hydrodynamic Inflammatory Rosacea MGD Floppy lids Decreased DTC Inflammatory stimuli Medication Toxicity Compositional Ocular Irritation Medicamentosa Drug-induced OCP Steroid-induced HT Symptoms Diurnal Variation Worst Gaze Increased Blinking Rose Bengal Punctal Occlusion Worst in P.M. Up Gaze Exposure Zone DTC Worst in AM The same sleep side -or NE Worsened Prabhasawat & Tseng BJO 82:666,

11 Unilateral DTC Bilateral DTC Normal Swollen Puncta Wetting length: > 3mm throughout Dye never clears, but dilutes with time (Partial Block) > 3 mm throughout Dye never clears, and nearly not diluted (Complete Block) 53 F with rosacea and allergy developed chronic red eye with irritation and tearing Failed to respond to all conventional medications including tears, steroids, & Abc Bulbar conjunctival injection: Inferior worse than superior Tarsal Papillary Rx: Inferior worse than superior Before After Dryness and Redness (OU) for 2 yrs % improvement Redness and tearing (OD>OS) for 2 wk s Asymptomatic FK506 oint: helped a lot 11

12 Dry Eye Can Be Caused by Poor or Incomplete of Tear Film Due to Surface Changes Meller & Tseng, Surv Ophthalmol 43:225, 1998 Literature Review Key Features of Conjunctivochalasis Mid-aged or elderly patients often overlooked and trivialized, and mixed (confused) with dry eye. CCh is the main diagnosis when dry eye cannot be managed by PO and Restasis. Can be worsened by surgeries for cataracts (retrobulbar or peribulbar anesthesia), or tightening lids by blepharoplasty. Benign subconjunctival hemorrhage is caused by CCh Superior limbic keratoconjunctivitis (SLK) is a focal form of CCh involving superior bulbar conjunctiva 75 y/o M complained of Intermittent Tearing OS after CE Surgery OD: CE/IOL (Apr 06); OS: CE/IOL (Mar 06), IOL Reposition (May 06), IOL Exchange (Sep 06) OD Conjunctivochalasis Inferior Redundant Bulbar Conjunctiva Severity Pathogenesis Symptoms Severe Exposure Pain, Ulcer Subconjunctival hemorrhage OS Moderate Delayed Tear Tearing Mild Unstable Tear film Dry eye Meller & Tseng, Surv Ophthalmol 43:225, 1998 Literature Review Differential Diagnosis Exposure Zone Symptoms Chalasis LTD Diurnal Variation Worst in P.M. Same throughout the day Same throughout the day Worst Gaze Increased Blinking Rose Bengal Punctal Occlusion Up Gaze Exposure Zone Down Gaze Worsened Non- Exposure Zone Worsened Up Gaze - CCh Detected by Roes Bengal Di Pascuale et al Br J Ophthalmol, 2004 Non- Exposure Zone 12

13 Normal Detected by Fluorescein CCh with Dry Eye Di Pascuale et al Br J Ophthalmol, 2004 Di Pascuale et al Br J Ophthalmol, 2004 Normal Mild CCh Mistaken for Blepharitis Mistaken for Conjunctivitis Moderate CCh Severe CCh Conjunctivochalasis Vigorous Blinking under Slit Lamp Tenting by 0.12 Forceps After AMT Press Finger to the Lid against the Globe 13

14 Algorithms of Treating Ocular Irritation Eliminate intrinsic irritation especially if associated with DTC LASIK-induced Dry Eye Exists, and Is Caused by Disruption of Compositional Reflex Leading to both and LTD, and Disruption of Hydrodynamic Reflex Leading to Decreased Blinking and Delayed Tear Intrinsic Irritation (inflammatory, infectious, allergic, toxic) DTC aggravating protecting Treat LTD after Ocular Irritation LASIK Older Age LTD Dry Eye Unstable Tear Film (/LTD Deficiency) Perform PO if there is no intrinsic irritation by creating DTC AMT for CCh Unstable Tear Film (Mechanical Deficiency) LINE Decreased Floppy Lids Di Pascuale et al, JCRS. 31:1741, Delayed Tear Persistent LASIK-induced Dry Eye PS PC Tarsal plate with meibomian gland Pretarsal orbicularis Pars ciliaris Pars fascicularis Pars subtarsalis Lipham et al. A Histologic Analysis and Three-Dimensional Reconstruction of the Muscle of Riolan. Ophth Plas and Recon Surg 2002;18:93-98 Visit 0 POHx, Symptoms TBUT, FCT Kinetic Analysis Interference Images Visit 1 Symptom improvement (20-50%) TBUT, FCT Visit 2 Symptom improvement (30-40%) FCT, TBUT Ocular Surface Disease Index Kinetic Analysis Interference Images Visit 3 More wetness (52%) TBUT Ocular Surface Disease Index Kinetic Analysis Interference Images Non-preserved 0.2% Dexamethasone For 2 wks Punctal Occlusion For 2 wks Eye Warming Device Eyefeel for 4 wks Final Follow Up DTC LTD 30 eyes (88%) DTC LTD 16 eyes (47%) DTC DTC Di Pascuale et al, JCRS. 31:1741, eyes/17 patients LTD 22 eyes (100%) LTD 20 eyes Results 17 patients (9 M, 8 F), 46.3 ± 11 (25-61) years old LASIK for myopia (32 eyes) and hyperopia (2 eyes) All except 1 patient were free of symptoms before LASIK All complained of dryness persistent for 41 ± 19.3 months (1-6 years) after LASIK LASIK complications (26%): Enhancement (8 eyes), Microstriae (1 eyes), Epithelial in growth (1 eye) Floppy eyelids in 24/34 eyes (71%), contributing to delayed tear clearance (DTC) Despite PO performed in 9 of 16 eyes with before the study, was still present (47%). Even after additional PO, TBUT remained < 5 sec. Before PO After PO Treatments for LTD Warm Compress (Eyefeel - FDA approved Disposable Device) manufactured by Kao, Inc. (Japan) Mechanical expression of meibomian glands Endura Refresh (Allergan) Synthetic Meibum s- under development by Dr. Tseng High DK Contact Lens Di Pascuale et al Ophthalmology 111: ,

15 OSDI Results (after Eye Warming with Eyefeel from Kao, Inc.) Before EW 60.6 ± 10.6 After EW 25.8 ± 18.5 P=0.007 A B After PF Dexamethasone DTC After PO 49 F Myopic LASIK March, 2002 Dryness, sandy sensation. Worse in morning, reading, watching TV OSDI score: 60.4 After PF Dexamethasone After PO TBUT TI Pattern 2.6 ± 3.9 Vertical (n=10) 7.9 ± 3.6 P=0.004 Horizontal (n=7) C D Time (sec) 1.3 ± ± 0.4 P=0.001 Di Pascuale et al, JCRS. 31:1741, After Eye Warming LTD After dexamethasone and PO 50% symptom improvement After Eye Warming 100% symptom improvement OSDI score: 16.6 After Eye Warming Surgical Treatments of Dry Eye Punctal Occlusion Removal of Conjunctivochalasis with AMT Plastic Correction of Lid Margin Pathologies Prevention of Cicatrix Formation by AMT Fornix Reconstruction with MMC and AMT Opening of Conjunctival Cyst Removal of Cicatrix Obliterating Excretory Ducts Conclusion Ocular surface health depends on a stable tear film on the open-eye state. Dry eye occurs whenever there is dysfunction of any element(s) governing ocular surface defense, which is controlled by neuroanatomic integration. Besides compositional deficiency, dry eye can also occur when there is hydrodynamic deficiency in the eyelid blink/closure leading to tear spread and clearance. Diagnostic work up is aimed at identifying all dysfunctional elements. Effective treatment plans can be formulated based on an algorithm to restore dysfunctional elements in a stepwise manner. Restoration of ocular surface defense with a stable tear film is a prerequisite for successful ocular surface reconstruction. 15

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