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4/4/12 DR. BLOOMENSTEIN’S DISCLOSURE • Presenter is on speakers panel of Alcon, Allergan, Abbott, Bausch & Lomb, Inspire, STAAR Surgical, Odyssey DIFFERENTIATING THE STAIN: WHAT DOES IT ALL MEAN? • President of the Optometric Council on Refractive Technology (OCRT) • Presenter has NO financial interest in any products mentioned Marc R. Bloomenstein OD, FAAO Scottsdale, Arizona • Except he does have stock in a certain coffee company... REFRESHER: THE CORNEAL EPITHELIUM • The cornea is exposed to the environment on its outer surface, and is epithelial in nature Mucin Layer Epithelium • The outermost part of the cornea is a stratified squamous layer, the corneal epithelium Bowman’s Membrane • The corneal epithelium is covered by a layer of mucin • The corneal epithelium is continuous at its margins with the conjunctiva of the eyelids and the eyeball Stroma REFRESHER: THE CONJUNCTIVAL EPITHELIUM • The conjunctiva houses goblet cells responsible for mucus production • Highly vascularized • Even in healthy individuals, mononuclear cells are resident in the conjunctival stroma Goblet Cells Epithelium Stroma USE OF VITAL STAINS IN PRACTICE USE OF VITAL STAINS IN PRACTICE (CONT’D) Determine the fit of contact lenses Visualize tear film components or lack of Localization of corneal foreign bodies Enhancement of palpebral conjunctival pathology To detect ocular abnormalities, such as dry-eye, corneal damage, and inflammatory conditions (ie, corneal infiltrates) ◦ Depending on the eye care practitioner, this may be performed as part of an annual check-up or only when a patient presents with a problem or both Vital stains are often used to determine the live/dead cell ratio in a cell population Vital stains most commonly used for ocular use ◦ Sodium fluorescein ◦ Lissamine green ◦ Rose bengal 1 4/4/12 WHAT WE LEARNED IN SCHOOL: LISSAMINE GREEN WHAT WE LEARNED IN SCHOOL: ROSE BENGAL • Stains degenerate cells, dead cells, and mucous fibrils in the same manner as rose bengal • Derivative of sodium fluorescein (NaFL) • Believed to stain dead or degenerated cells and mucous strands • The nucleus is generally stained more intensely that the cytoplasm • Best used to examine the conjunctiva • Suitable for vital staining of the cornea and conjunctiva Norn MS. Acta Ophthalmol (Copenh). 1973;51:483. Norn MS. Acta Ophthalmol (Copenh). 1972;113(Suppl):20 FLUORESCEIN CORNEAL STAINING LISSAMINE GREEN STAINING Exposure zone staining with limbal sparing Exposure zone staining with limbal staining Intense diffuse staining of exposure zone, limbal staining • Degree of severity increases from left to right 10 Images from Dry Eye and Ocular Surface Disorders, 2004 Synthetic organic compound Widely used as a fluorescent tracer Self-quenching at high concentrations Fluorescent intensity is highly pH dependent How it interacts with cornea is largely unknown Optimum viewing time is 3-5mns after application Absorbs light with a maximum absorbance wavelength (λ) of ≈490 nm, resulting in the emission of light (or fluorescence) at a maximum absorbance λ≈530 nm Although visible to the naked eye, this emitted λ can be enhanced when viewed through a cobalt filter of a slit lamp biomicroscope o Visual intensity is enhanced when • Lissamine green detects dead or degenerated conjunctival cells FLUORESCEIN MOLECULE the signal is viewed with an additional yellow filter, such as the Kodak Wratten 12 11 WHAT WE LEARNED IN SCHOOL: FLUORESCEIN CORNEAL STAINING • Taught in 1st year that the fluorescence observed with NaFL represents dead or damaged cells • The three potential mechanisms of corneal staining (CS) with NaFL that are most commonly described are:1 • Surface pooling • Uptake by cells • Ingress around cells • However, no one actually knows WHAT fluorescein is binding to in or on cells! 12 1. Morgan PB, Maldonado-Codina C. Cont Lens Ant erior Eye. 2009;32:48. 2 4/4/12 INFERIOR STAINING PATIENT CCF • Lid laxity conditions such as ectropion • Lagophthalmos • Incomplete blink • MGD/blepharitis • Exposure keratopathy • Environmental contributors • Elevated computer screen SUPERIOR STAINING • Superior Limbic Keratoconjunctivitis • Limbal stem cell deficiency 3 4/4/12 LSCD CAUSES • Chemical burns • Chronic inflammation e.g. scleritis • Abuse of contact lens wear NEW FINDINGS SUGGEST THIS MAY NOT BE ENTIRELY ACCURATE… HOW LONG DOES EPITHELIAL STAINING LAST AND HOW DO WE GET RID OF IT? NaFL enters healthy cells and result in transient “corneal staining” with an intact epithelium FL staining after impression cytology in normal patient 3 hours after impression cytology later of same eye Bakkar M, et al. Optom Vis Sci. 2010; E-abstract 100959; Thinda S, et al. Br J Ophthalmol. 2010;94:406. 4 4/4/12 ENHANCING PALPEBRAL PATHOLOGY INDENTIFYING SIGHT OF IMPACT – BB TO EYE 5 4/4/12 SOMETIMES YOU DON’T NEED FL TO TELL THE SITE OF IMPACT… DIFFERENTIAL STAINING – RB VS FL AGAIN USING RB TO DIFFERENTIATE STAINING 6 4/4/12 3 DAYS LATER – STEROID AND ANTIBIOTICS WE ARE NOT DONE YET. DO WE ALWAYS NEED TO DO A DIFFERENTIAL STAIN? CORNEAL STAINING • Thygesons • EKC • Herpetic • Zoster (pseudodendritic) • etc. DRY EYE STAINING 42 43 7 4/4/12 44 45 46 47 48 49 8 4/4/12 EPITHELIAL BASEMENT DYSTROPHY (EBMD) • Abnormal corneal epithelial regeneration and maturation • Abnormal basement membrane • Very common dystrophy • Considered age related • Prevalence increases with age • Onset is around 40-70 y.o. • Late onset supports degeneration vs. dystrophy 50 50 9 4/4/12 EBMD PHOTO COURTESY TRACY SWARTZ OD, FAAO RCE 64 65 10 4/4/12 2 DAYS LATER – LOOK AT STAINING PATTERN RCE 66 FUCH’S DYSTROPHY • Characterized • Corneal Guttata • Small refractile “drops” on corneal endothelium • Affects the “pump” action of the endothelium • Edema • Greater in the AM • Desiccates as day goes on • Long standing edema may lead to corneal scarring • RCE’s common FUCH’S DYSTROPHY • Symptoms vary with degree of guttata and compromise of the endothelial tissue • Moderate guttata • May affect visual function • May induce mild-moderate edema • Halos around lights • Hazy vision > a.m. • Severe guttata • Vision decreases • Possible bullous develops PHOTO COURTESY TRACY SWARTZ OD, FAAO FUCH’S DYSTROPHY CORNEAL DEGENERATIONS PHOTO COURTESY TRACY SWARTZ OD, FAAO 11 4/4/12 CORNEAL DEGENERATIONS DEGENERATIONS • Defined as a deterioration or change from a higher to a lower form, especially change of tissue to a lower or less functionally active • Arcus • Non-inherited • Amyloid • Unilateral or bilateral • Limbal girdle of Vogt • Asymmetric • Band keratopathy • Develop in later years • Salzman’s nodular degeneration • Variable progression • Spheroidal degeneration • Systemic disease can be associated DEGENERATIONS • Coats white Ring • Hassal-Henle bodies • Crocodile shagreen • Senile furrow • Dellen • Pingueculae • Pterygium ENHANCING CROCODILE SHAGREEN DRY EYE EVALUATION Lissamine Green 12 4/4/12 USING FL TO VISUALIZE TEAR FILM SLITLAMP EXAMINATION Fluorescein Staining Evaluation of Tear Meniscus INCOMPLETE BLINK/NOCTURNAL LAGOPHTHALMOS Rose Bengal/ Lissamine Green Staining Tear film break up viewed with fluorescein stain on a patient with dry eye 0 seconds 1 second 2 seconds 3 seconds 4 seconds 5 seconds 6 seconds 16 seconds Tear film break up is indicated by the dark areas that appear on the cornea. 13 4/4/12 POTENTIAL SEVERE CONSEQUENCES OF UNTREATED DRY EYE DISEASE Sterile Melting BLEPHARITIS Is the most common and arguably the most important diagnosis presenting to the ophthalmologist Anterior Inflammation mainly centered around the eyelash and follicles Blepharitis Bacterial Keratitis SIGNS AND SYMPTOMS Morning crusting Recurrent hordeola Loss of lashes Conjunctival hyperemia Foreign body sensation Inflammation that involves the meibomian gland orifices Collarretes (scales that encircle lash) Posterior Staph immune disease • Phlyctenula • Pannus • Catarrhal infiltrates • etc Lid Wiper Epitheliopathy • Characterized by presence of damaged epithelial cells on lid wiper portion of marginal conjunctiva • Fluorescein or rose bengal can be used to dye the lid wiper • Staining graded on scale of 0 to 3: 0 = no staining, 3 = heavy staining 2 1 FLUORESCEIN TEAR CLEARANCE • Meant to differentiate the inflammatory dry eye • Reduced clearance leads to stasis, which allows inflammatory mediators to remain in contact with ocular tissue • Tseng, Pflugfelder 1. Korb DR, Herman JP, Greiner JV, et. al: Lid Wiper epitheliopathy and dry eye symptoms. Eye & Contact Lens 31(1): 2-8, 2005. 2. Korb DR, Herman JP, Greiner JV, et. al: Lid Wiper epitheliopathy and dry eye symptoms in contact lens wearers. CLAO J 28: 211-216, 2002. 14 4/4/12 CONTACT LENS/SOLUTION STAINING GRIDS PRESERVATIVES IN MPS ARE TAKEN UP AND THEN RELEASED BY SOFT CONTACT LENSES • All preservatives are taken up by all soft contact lenses during the soak1-5 • Amount absorbed and rate of absorption depends on lens material and preservative • After application, the lens releases the preservative into the tear film2 • The release rate depends on preservative and lens material combination2,4 • The tears slowly dissipate the preservatives 1. Data on File. CFR-6091/CFR-6047. Bausch & Lomb, Inc. 2008. 2. Powell CH, et al. Cont Lens Anterior Eye. 2010;33:9. 3. Sentell KB, Beaullieu E. Invest Ophthalmol Vis Sci. 2004;45:E-Abstract 1573. 4. Willcox MD, et al. Optom Vis Sci. 2010 Sep 2. [Epub ahead of print]. 5. Dassanayake N, et al. Invest Ophthalmol Vis Sci. 2005;46:E-abstract 915. 15 4/4/12 THE MPS PRESERVATIVE PHMB DOES NOT DAMAGE CORNEAL CELL MEMBRANES MPS PRESERVATIVES AND TRANSIENT HYPERFLUORESCENCE WITH NAFL ® At the cornea, preservatives may interact with the cell membrane • The commonly used preservative PHMB (ie, renu) binds to mucin… • PHMB may be binding to other components of the ocular surface… ® In the presence of PHMB, the corneal cell membrane is not affected PHMB Cell Membrane • PHMB may be interacting with NaFL… PHMB (polyhexamethylene biguanide) is a preservative in COMPLETE® Easy Rub®*, Boston Simplus® Multi-Action**, Biotrue™**, Renu® family**, AQuify®†, MeniCare Plus, Sauflon All in One Lite, SOLO-care Aqua™‡ THE PRESERVATIVE PHMB HAS AN EXTREMELY STRONG AFFINITY FOR NAFL ® NaFL adheres to MPS PHMB on the eye ® NaFL has a strong affinity for PHMB, which is up to 50-times greater than that for PQ-1 Fluorescein FluoresceinPHMB Complex PHMB Fluorescein Trademark of *AMO, **B+L, †Novartis, ‡CIBA Vision. 1. Bright FV, et al. Poster presented at: The 6th Biennial Scientific Symposium of the Contact Lens Association of Ophthalmologists Education & Research Foundation; September 23-25, 2010; Las Vegas, Nevada, USA. ALDOX CONCENTRATION AT PEAK RELEASE IS ~20X GREATER VS PHMB PEAK RELEASE CONCENTRATION • Aldox concentration1 at peak time is ~20x greater in comparison to PHMB peak concentration (ppm)1,2 0.5 • Aldox concentration peaks: within 30 min1 • PHMB concentration peaks: within 2 hours1,2 • Every preservative is taken up and released by lenses: Cell Membrane Concentration (ug/uL) Muya L, et al. Invest Ophthalmol Vis Sci. 2008;49:E-Abstract 4869; Bright FV, et al. Poster presented at: The 6th Biennial Scientific Symposium of the Contact Lens Association of Ophthalmologists Education & Research Foundation; September 23-25, 2010; Las Vegas, Nevada, USA. PQ-1 (polyquaternium-1/POLYQUAD®) is a preservative in COMPLETE® RevitaLens OcuTec™*, Biotrue™**, OPTI-FREE® Express®†, and OPTI-FREE® RepleniSH®† PHMB RELEASE FROM SILICONE HYDROGEL LENS* GREATEST BETWEEN INSERTION AND TWO HOURS System PHMB (B&L) PHMB (Powell) Aldox (Powell) 0.3 Peak Maxima (h) 0.74 0.71 0.24 0.2 0.1 0.0 0 • Detection is based on: Trademark of *AMO, **B+L, †Alcon. Bright FV, et al. Poster presented at: The 6th Biennial Scientific Symposium of the Contact Lens Association of Ophthalmologists Education & Research Foundation; September 23-25, 2010; Las Vegas, Nevada, USA. PHMB w/ Balafilcon A (B&L) PHMB w/ Balafilcon A (Powell) Aldox w/ Balafilcon A (Powell) 0.4 2 4 6 8 10 12 14 Time (h) • Time of observation • Fluorescent probe used 1. Powell CH, et al. Cont Lens Anterior Eye. 2010;33:9. 2. Data on File. Bausch & Lomb, Inc. 2010. ASSESSING FLUORESCEIN: PRESERVATIVE AGENT ASSOCIATION 0.014 Fluorescence greatest + ≈2 hrs 0.01 PHMB release 0.008 0.006 0.004 0.002 0 0 2 4 6 8 10 12 14 Time (hrs) Does not consider tear exchange rate which would reduce absolute values but not profile shape *SiHy lens is PureVision (balafilcon A). Data on File. Bausch & Lomb, Inc. 2010. Steady-State Fluorescence Anisotropy PHMB Concentration (µg/µl) 0.012 0.04 Strong association 0.03 Modest association 0.02 0.01 0.00 Weak/No association 0 2000 4000 6000 8000 10000 Preservative Agent 16 4/4/12 THE BINDING OF PHMB AND NAFL RESULTS IN A BENIGN, TRANSIENT FLUORESCENCE1 ® The signal intensity with PHMB solutions:1,2 Peaks at 2 hours Dissipates within 6-8 hours indicating no ocular surface damaged occurred Insertion 2 hours THIS PRESERVATIVE-ASSOCIATED TRANSIENT HYPERFLUORESCENCE OR PATH IS DIFFERENT THAN CLINICALLY RELEVANT STAINING ® The science suggests this visual signal is not representative of pathological or true corneal staining1-5 6 hours Fluorescence at 2 hrs Pathological Staining The punctate appearance of the signal results from many PHMB molecules aggregating and binding with NaFL3 1. Bright FV, et al. Poster presented at: The 6th Biennial Scientific Symposium of the Contact Lens Association of Ophthalmologists Education & Research Foundation; September 23-25, 2010; Las Vegas, Nevada, USA. 2. Garofalo RJ, et al. Eye Contact Lens. 2005;31:166. 3. Alila S, et al. Langmuir. 2005;21:8106. 1. Garofalo RJ, et al. Eye Contact Lens. 2005;31:166. 2. Jones L, et al. Optom Vis Sci. 2002;79:753. 3. Ward KW. Optom Vis Sci. 2008;85:8. 4. Andrasko GJ, Ryen KA. Rev Cornea Contact Lenses. March 2007:36. 5. Carnt N, et al. Optom Vis Sci. 2007;84:309. PRESERVATIVE-ASSOCIATED TRANSIENT HYPERFLUORESCENCE OR PATH IS DIFFERENT THAN CORNEAL STAINING (PATHOLOGICAL) Corneal Staining PATH • • • Etiology likely due to benign preservative interactions1 Generally Surface asymptomatic2-4 phenomenon3,4 commonly)3-5 • Punctate (most • Resolution - within a few hrs* 2,4,6 • Onset – within a few hrs* 2,6,7 • Not associated with future complications4,8 • Etiology due to epithelial damage9 • Commonly symptomatic4,10 • Depth varies9 • Macropunctate to coalesced9 • Resolution – dependent on epithelial turnover rate; commonly several days11 • May or may not be associated with future complications12,13 *Post-lens insertion. 1. Bright FV, et al. Poster presented at: The 6th Biennial Scientific Symposium of the Contact Lens Association of Ophthalmologists Education & Research Foundation; September 23-25, 2010; Las Vegas, Nevada, USA. 2. Garofalo RJ, et al. Eye Contact Lens. 2005;31:166. 3. Jones L, et al. Optom Vis Sci. 2002;79:753. 4. Ward KW. Optom Vis Sci. 2008;85:8. 5. Andrasko GJ, Ryen KA. Rev Cornea Contact Lenses. March 2007:36. 6. Kislan T. Optometry. 2008;79:Poster 69. 7. Bandamwar KL, et al. Cont Lens Anterior Eye. 2010;33:199. 8. FDA Ophthalmic Devices Panel meeting, June 10, 2008. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfAdvisory/details. cfm? mtg5699. 9. Snyder C. Clin Refract Optom. 2005;16:1. 10. Sweeney DF, et al. Cornea. 2003;22:435. 11. Korb DR, Korb JM. J Am Optom Assoc. 1970;41:233. 12. Barr JT, et al. Cornea. 2006;25:16. 13. Sweeney DF, et al. Poster presented at: The 31st Annual Meeting of the British Contact Lens Association; May 29-June 1, 2008; Birmingham, UK. “Superficial corneal staining as captured during uneventful clinical visits…is not associated with an eventual infiltrative response”1 – L. Szczotka-Flynn EVEN IN EXTENDED WEAR – WHICH CARRIES THE HIGHEST RISK FOR COMPLICATIONS – ASYMPTOMATIC “REAL” CORNEAL STAINING IS NOT ASSOCIATED WITH CORNEAL INFLAMMATION “supported by Fleiszig et al… who have shown in animal models that the superficial epithelium can be severely abraded in the presence of virulent strains of Pseudomonas species with no increased susceptibility to infection.” Image reproduced from Lee EJ, Evans DJ, Fleiszig SM. Invest Ophthalmol Vis Sci 2003;44:5220–7. 1. Szczotka-Flynn L, et al. Invest Ophthalmol Vis Sci. 2010 Jun 10. [Epub ahead of print]. 2. Evans DJ, Fleiszig SM. Invest Ophthalmol Vis Sci 2003;44:5220. 17 4/4/12 SO WHAT DOES THIS MEAN? CLINICAL LESSONS: VITAL STAINS • In the absence of symptoms, results from the use of vital stains, in particular NaFL, may be misleading…especially in MPS users • In the presence of acute signs and symptoms: • NaFL should be used to assess the cornea • Either lissamine green/rose bengal best to examine the conjunctiva • For persistent symptoms, such as discomfort, scratchiness, tearing, look to the conjunctiva with lissamine green/rose bengal for dry eye! • Put vital stains in the context • In the absence of symptoms, results may be misleading as PATH ≠ Pathology • In the presence of persistent low grade symptoms: Don’t forget the conjunctiva! Use lissamine green or rose bengal in diagnosis • When using any corneal stain: Don't paint the cornea, less is more • You can always add more, but too much dye can obstruct the view of subtle staining patterns THANK YOU 18