1
Diagnosis and Clinical Management of
Dry Eye SyndromeCOPE Course 19153 AS
Diagnosis and Clinical Management of
Dry Eye SyndromeCOPE Course 19153 AS
COPE Course 19153-ASCOPE Course 19153-AS
Glenn S. Corbin, ODPrivate Practice, Reading, PAAdjunct Faculty, PCO at Salus University
Disclosure
I am a consultant for Alcon Laboratories, Inc. I have no financial interest in any Alcon
d t A ti f ff l b l/products. Any mention of an off-label/non-FDA approved use of any drug or product is strictly the opinion of the speaker, not of the Course Administrator.
Objectives
Discuss the prevalence as well as related structures and systems associated with dry eye
Describe the global features of dry eye Discuss current diagnostic practicesDiscuss current diagnostic practices Discuss and compare current therapeutic
management options Review results of relevant pre-clinical and
clinical trials Review pharmaceutical treatments under
investigation
The Tear Film is the Most Important Refracting Surface of the Eye
Ocular Surface Disease andAdvanced Technology
Quality of vision starts with a healthy tear film.
All of the recent advances in cataract and refractive technology are lost with even minimal compromise of the ocular surface.
Minimal Disruption of the Ocular Surface Can Severely Degrade Visual Acuity
2
Changing ParadigmsDEWS 1995
1Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eye CLAO J, 1995, 21:221-32.
Changing ParadigmsDEWS 2007
2Lemp MA, Baudouin C, Baum J, et al. The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007). Ocular Surface 2007;5:75-92.
Clinically speaking,you may be doing it wrong if you
Diagnose and treat dry eye at the routine general vision exam visit
Dont schedule an OSD assessment visit prior to treatment
Dont prescribe a specific treatment regimen and dosing schedule and just offer a grab bag approach
Dont routinely schedule a follow up visit to assess your patients progress with your treatment
Dont manage dry eye as seriously as other chronic diseases
Do your patients ever complain of Blurry vision: constant or intermittent Burning Tearing Foreign body sensation
Itching Itching Tired eyes Sore eyes Sensitive eyes Photophobia Dry eyes My eyes just dont feel right
They May Have Dry Eye
Probably the most common presentation to an eye care practice and an often missed diagnosis or mis-diagnosed ophthalmic disease
Represents an untapped opportunity to p pp pp yimprove your patients ocular and visual comfort
Represents a potential goldmine to increase practice growth and profits through medical eye care services
And now, the rest of the story.
Ocular Surface Disease is Markedly Under-Diagnosed
39.00 55.55
30
45
60
ns o
f Peo
ple
ns o
f Peo
ple
There are an There are an estimated estimated 55 55 million Americans million Americans with dry eye with dry eye disease. Most of disease. Most of them are elderly.them are elderly.
3939
1Mattson Jack Epidemiology Analysis. 20052The 2004 Gallup Study of Dry Eye Sufferers. 2004.
16.55
0
15
ECP-Diagnosed Dry
Eye
UndiagnosedDry Eye
Total Dry EyePatient
Population12
2
Mill
ion
Mill
ion
An An estimated 39 estimated 39 million dry eye million dry eye sufferers may not sufferers may not have been have been diagnosed diagnosed by an by an eye care eye care professional.professional.
3
Dry Eye Difficult disease to understand and treat
Varied causes and severities
Can be a stand-alone condition
More common in older individuals (45 years or older)More common in older individuals (45 years or older)
Affects women more commonly than men
Functional visual acuity may be significantly decreased
Quality of life impact similar to moderate-severe angina
Schiffman RM, Walt JG, Jacobsen G, Doyle, et al, Utility assessment among patients with dry eye disease. Ophthalmology, 2003;110(7): 1412-1419
Prevalence of Dry Eye Disease
Study N Age Criteria Prevalence ReferenceWisconsin 3,722 48-91 Self-reported 14.4% Moss et al,
2000
Melbourne 926 40 97 2 or more signs 7 4% McCarty et alMelbourne 926 40-97 2 or more signs 7.4% McCarty et al, 1998
Maryland 2,520 65-84 Symptoms + 1 sign 3.5% Schein et al, 1997
Womens health
39,876 49-84 (female)
Severe symptoms or clinical diagnosis
7.8% Schaumberg et al, 2003
Schaumberg et al. Am J Ophthalmol. 2003;136:318
age adjusted > 3.2m women
How Does Dry Eye Impact or Affect Patient QOL?
In a survey of 100 patients with dry eye Patients reported that they suffered from
dry eye for a median 48 months (mean 86.8dry eye for a median 48 months (mean 86.8 months, SD 103.9 months)
Most patients (75.8%) felt that their dry eye had worsened over time
Data on file, Allergan
How Does Dry EyeAffect Your Reading?
33.3354045
ient
s
AlotSomewhatA Little
44.4
Data on file, Allergan
13.18.1
05
1015202530
Perc
enta
ge o
f Pat Not at All
Computer Use 32.3 26.3 11.1 8.1 0.0
ADL 47.5 35.4 13.1 3.0 1.0
Never
Signs vs. Symptoms one study found that 3 patients with moderate to severe
symptoms had NO surface staining another study found lack-luster repeatability in most dry eye
measurements (corneal staining and MGD scores)This study found that low (< 10mm) Schirmer scores (more advanced disease) showed better repeatability and TBUT repeatability was substantialp y
both investigator groups found high repeatability of subjective reporting of symptomsAdditionally, these investigators found that patients typically perceive their dry eye to be worse than what the doctor perceives (4x more likely)
one study reports dry eye patients have more psychological problems and disturbances, such as emotional instability and depression
Aqueous DeficiencyNeurologicalPemphigoid
L p s
Underlying Causes of Dry Eye Disease
Lipid Deficiency Mucin Deficiency
SjogrensInflammation
Ocular Surface Disease
LupusStevens-Johnson
CombinationDeficiencies
4
Influential Factors of Dry Eye
Adverse Conditions
Arid Conditions(e.g. Midwest)
Windy Environments(e.g. air conditioning,
forced heat)
Pollutants(e.g. exhaust, smoke, smog)
Influential Factors of Dry Eye
Adverse Conditions
Visual Tasking (e.g. PC use)
Systemic Medications (e.g. anti-histamines)
Foods / Drink (e.g. alcohol)
Influential Factors of Dry Eye
Age Gender Osteoporosis Gout Ocular surgery Contact lens wear Nutritional problems Rh t id th iti
LASIK surgery Cosmetic surgery Exposure keratitis Entropion Ectropion Symblepharon Lid notches L hth l
Temperature Humidity Air movement Allergies Reading/CRT Watching movies Sleep Ill i ti Rheumatoid arthritis
Thyroid disease Time of day
Lagophthalmos Incomplete blinking Dellen formation Conjunctivochalasis
Illumination Medications Topical medication
preservatives
Prause JU, Norn M. Relation Between Blink Frequency and Break-Up Time. Acta Ophthalmol. 1983 61: 108-116.Cho P, Cheung P, Leung K, Ma V, Lee V. Effect of Reading on Non-Invasive Tear Break-Up Time and Inter-Blink Interval. Clin. Exp. Optom. 1997 80: 62-8.Tsubota K, Seiichiro H, Okusawa Y, Egami F, Ohtsuki T, Nakamori K. Quantitative Videographic Analysis of Blinking in Normal Subjects and Patients with Dry Eye. Arch. Ophthalmol. 1996 114(6): 715-720.Nally L, Ousler GW, Abelson MB. Ocular discomfort and tear film break-up time in dry eye patients: a correlation. IOVS 2000 41(4): 1436. Collins M, Seeto R, Campbell L, Ross M. Blinking and Corneal Sensitivity. Acta Ophthalmologica 1989 67(5): 525-531.Abelson MB, Holly FJ. A tentative mechanism for inferior punctate keratopathy. Am. J. Ophthalmol. 1977 83: 866-869.Doane MG. Dynamics of the Human Blink. Ber. Disch. Ophthalmol. Ges. 1980 77: 13-17.Kaneko K, Sakamoto K. Spontaneous Blinks as a Criterion of Visual Fatigue During Prolonged Work on Visual Display Terminals. Perceptual and Motor Skills 2001 92(1): 234-250.
-Adrenergic-blocking, Anti-anginals and Anti-hypertensives(e.g. Atenolol, Metoprolol)
Alkylating Immunosuppressives(e.g. Busulfan, Cyclophosphamide)
Influential Factors of Dry Eye Common Classes of Drying Systemic Medications
Tricyclic Anti-depressants(e.g. Amitriptyline, Doxepin)
Oral Anti-histamines(e.g. Loratadine, Clemastine, Hydroxyzine)
Cyclophosphamide)
Diuretics(e.g. Triamterene, Hydrodiuril)
Estrogen
Drying Systemic MedsClinical Study Protocol
To investigate the ocular drying effect of a commonly prescribed oral antihistamine (loratadine/Claritin) in normal subjects when exposed to a controlled adverse
Study Rationale
subjects when exposed to a controlled adverse environment (CAE) for 45 minutes
To examine a possible dose effect between QD and BID treatment with loratadine, 10 mg.
Welch, Ousler, Abelson. Ocular drying associated with oral antihistamines (Loratadine) in the normalpopulation. Cornea 2000 19: (Suppl): S135.
Keratitis Conjunctival Staining
2.3
3.0
2
2.5
3
3.5
4
itis
(0 -
4)
3.9
2.422.5
3
3.5
4
al S
tain
ing
(0 -
4)
Drying Systemic MedsClinical Study RESULTS
QD = 81% increase (1 unit)BID = 130% increase (1.7 units)
QD = 71% increase (1 unit)BID = 175% increase (2.5 units)
1.3
0
0.5
1
1.5
Untreated QD; 4 Days BID; 4 Days
Ker
at
1.4
0
0.5
1
1.5
Untreated QD; 4 Days BID; 4 Days
Con
junc
tiva
5
TFBUT Ocular Discomfort
3 2
5.4
3
4
5
6
me
(sec
.)
2
3
4
Ocula
r D
iscom
fort
(0 -
4)
UntreatedClaritin (QD 4 days)
Drying Systemic MedsClinical Study RESULTS
QD = 41% decrease (2.2 sec)BID = 67% decrease (3.6 sec)
QD and BID increased at all but one time point (10 min. QD)
1.8
3.2
0
1
2
Untreated QD; 4 Days BID; 4 Days
Tim
0
1
0 5 10 15 30 45
CAE Exposure Time (min.)
Claritin (QD, 4 days)Claritin (BID, 4 days)
Drying Systemic Meds: Clinical StudyDrying Systemic Meds: Clinical StudyTear Flow and Volume ResultsTear Flow and Volume Results
It has been shown that loratadine 10 mg causes clinically meaningful damage to the ocular surface due to its anti-muscarinic action (M3)1
Both tear flow and volume are decreased as a result of 4-day dosing with loratadine, as measured by fluorophotometry
1 Welch, Ousler, Abelson. Ocular drying associated with oral antihistamines (Loratadine) in the normalpopulation. Cornea 2000 19: (Suppl): S135.
Benzalkonium ChloridePreservative Effect
Short term effects* Can accelerate break up of the tear film Can cause transient corneal epitheliopathy
Long term effects* Effects are dose-dependent and can range
from apoptosis to necrosis Local inflammation causes changes that
can mimic the signs & symptoms of dry eye
*Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther. 2001;18:205-215.
When May BAK Use Be Most Problematic?
G th A t N iA i0.0001% BAK 0.050.1% BAK0.01% BAK Growth Arrest NecrosisApoptosis
1. Noecker R. Rev Ophthalmol. 2001(6).
Concentration and Duration determine the Dose
Is Long Term BAK Use a Big Deal? The Single Most Critical Advance in
The Treatment of Dry Eye Came With The Elimination of Preservatives, Such as BAK From OTC Lubricants1
BAK is Largely Responsible for The Ocular Toxicities and Inflammation Associated With The Chronic Use of Many Ophthalmic Solutions2
1. Pflugfelder SC, et al. Management and therapy of dry eye disease: Report of the management and therapy subcommittee of the international dry eye workshop (2007). The Ocular Surface. 2007;5:163-178.
2. Baudouin C, Riancho L. In vitro Studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost. Investigative Ophthalmology & Visual Science. 2007;48:41234128.
BAK Reduces Tear Film Break Up Time (TBUT) in 30 Healthy Volunteers
A randomized double - blind crossover study with instillation of one drop in each eye followed by a 5 day washout then the other drop instilled
TBUT (Seconds)TBUT (Seconds) CARTEOLOLCARTEOLOLWITHOUT BAKWITHOUT BAKCARTEOLOLCARTEOLOLWITH BAKWITH BAK
Baseline Baseline 9.09.0 10.4 10.4
30 minutes later30 minutes later 8.1 8.1 7.9 7.9
* Decrease in Tear Film Break Up Time at 3 hours from baseline was significantly lower in the BAK- free group than in the preserved carteolol (p=0.04)
Significantly lowered compared with baseline (p=0.001)
Baudouin C, de Lunardo C. Short term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol. 1998;82:39-42.
1 hour later1 hour later 7.3 7.3 7.4 7.4
3 hours later*3 hours later* 7.9 7.9 6.16.1
Decrease from Baseline at 3 hours -1.1 -4.3
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Tear Film Physiology
Mucin layer (hydrophilic coating) extends in a gradient throughout the aqueous Secreted by goblet cellsy g
Aqueous layer (transports principle tear components) Secreted by primary and
accessory lacrimal glands Lipid layer (limits tear
evaporation) Secreted by meibomian
glands
Normal Ocular Surface and Epithelial Glycocalyx
Lipids
Aqueous with
The glycocalyx is produced by corneal epithelial surface cells. It functions to help bind mucins and tears onto the
corneal surface.
Surface cell microvilli
Aqueous with soluble mucins
Corneal epithelial cells
Secretomotor N I l
The Healthy EyeHomeostasis
Normal tearingNormal tearingdepends on adepends on a
neuronal feedback neuronal feedback looploop
LacrimalGlands
Nerve Impulses
Tears Support and MaintainOcular Surface
Ocular SurfaceNeural Stimulation
Stern et al. Cornea. 1998:17:584
Components of Healthy Tears
A complex mixture of proteins, mucins, and electrolytes
Antimicrobial proteins:lysozyme, lactoferrinG th f t d Growth factors and suppressors of inflammation
Membrane-bound mucins 1, 4 and soluble 5AC
Electrolytes for proper osmolarity
Image from Dry Eye and Ocular Surface Disorders, 2004
Lacrimal Glands:Lacrimal Glands: Chronic IrritationChronic Irritation TT--cell activationcell activation Cytokine secretion into Cytokine secretion into
Interrupted Secretomotor Interrupted Secretomotor Nerve ImpulsesNerve Impulses
Disruption ofDisruption ofnormal neuronalnormal neuronalcontrol of tearingcontrol of tearing
Dry Eye Disease
yytearstears
Nerve ImpulsesNerve Impulses
Tears Damage Ocular SurfaceTears Damage Ocular Surface
Cytokines Cytokines Disrupt Neural ArcDisrupt Neural Arc
Stern et al. Cornea. 1998:17:584
inflammation
Dry Eye:Dysfunction of the Neural Loop?
Normal function of neural loop Should respond to restore any deficit of the tear film
Apparent dysfunction in dry eye: Decreased secretory response to stimulus Due to effects of ocular surface pathology on corneal nerves?
Increased tear osmolarity, tissue damage Or due to damage/loss of tear-secreting glands?
Stern et al, 1998
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Tears in Chronic Dry Eye (CDE)differ from Normal tears
Lesser concentrations of many proteins in CDE e.g. antimicrobial proteinsLactoferrin levels lower in dry eyepatients as compared to controls
Epidermal growth factor concentrations decreasedC t ki b l hift d Cytokine balance shifted, promotes inflammation
Soluble mucin 5AC greatly decreased Due to loss of goblet cells Impacts viscosity of tear film
Activated proteases Degrade extracellular matrix and
tight junctions Increased electrolytes
Ohashi et al. Am J Ophthalmol. 2003;136:291
Unhealthy tears in dry eye causesquamous metaplasia and loss of goblet cells.
.which decreases soluble mucins, worsening unhealthy tears
Normal conjunctival epithelium, goblet cells are violet.
Squamous metaplasia withloss of goblet cells.
Images from Dry Eye and Ocular Surface Disorders, 2004(Kunert et al, 2002; Zhao et al, 2001)
What Happens During LASIK?
Shamik Bafna and Roger F. Steinert. In Albert, Jakobiec (Eds). 2000. WB Saunders
Total number of sub-basal and superficial stromal nerves is decreased by 90% after LASIK surgery1
1. Lee et al. IOVS 2002.
Effect of Denervation
Healthy Ocular Surface
LASIK
Denervation of Ocular Surface
CornealSensitivity
Blink Rate
Aqueous(Reflex Tearing)
Inter-Blink Interval
Mucin
LipidUnhealthy Ocular Surface
Symptoms
Keratitis
ConjunctivalStaining
TFBUT
VulnerabilityMitosis
Corneal Sensitivity and Blink Rate in Normals and Dry Eye Patients
/ Min
ute
rate
Normals withNormal Corneal
Sensitivity
Dry Eye withNormal Corneal
Sensitivity
Blin
ks /
Dry Eye withLow Corneal
Sensitivity
N = 8 N = 9 N = 12
Nally, Ousler, Abelson. (Abstract). ARVO 2003
rate
LASIK Associated Dry Eye: Clinical Study
Title:
Effects of LASIK on Tear Production, Clearance and the Ocular Surface
Methods:Methods:
48 eyes underwent LASIK
Evaluations: tear fluorescein clearance, staining, tear production (Schirmers), and corneal / conj. sensitivity at baseline, 7 days and 1, 2, 6, 12 and 16 months after LASIK.
Battat L, Macri A, Bursun D, Pflugfelder S. Ophthalmol 2001108:1230-1235.
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Results:
Corneal and conj. sensitivity decreased at 1 week, and 1, 12, 16 months (p < 0.007 at all visits)
Schirmers decreased from 24mm (pre op) to 18mm (1
LASIK Associated Dry Eye: RESULTSClinical Study
Schirmer s decreased from 24mm (pre-op) to 18mm (1 month post-op) (p
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Patient EducationBefore the diagnostic evaluation.
At the end of the routine exam, explain the tentative diagnosis (of a possible tear film abnormality) to your patient and that you will need to perform specific tests to confirm the diagnosis
Always explain that the testing is medical, not vision y p gcare, and is usually covered by most health insurance plans
After the diagnosis. After making the diagnosis, be specific about the
treatment that you prescribe and prognosis Follow up on the therapy that is prescribed to assess
efficacy
OCULAR SURFACE DISEASE INDEXPlease Answer The Following Questions by Checking The Box That Best Represents Your Answer
OCULAR SURFACE DISEASE INDEXPlease Answer The Following Questions by Checking The Box That Best Represents Your Answer
All of the time Most of the time Half of the time Some of the time None of the time
1 Eyes that are sensitive to light? 4 3 2 1 0
2 Eyes that feel gritty?
3 Painful or sore eyes?
4 Blurred vision?
5 Poor vision?
Have problems with your eyes limited you in performing any of the following during the last week:Have problems with your eyes limited you in performing any of the following during the last week:All of the time Most of the time Half of the time Some of the time None N/A
Have you experienced any of the following during the last week:Have you experienced any of the following during the last week:
6 Reading?
7 Driving at night?
8 Working with a computer or bank machine (ATM)?
9 Watching TV?
Have your eyes felt uncomfortable in any of the following situations during the last week:Have your eyes felt uncomfortable in any of the following situations during the last week:All of the time Most of the time Half of the time Some of the time None N/A
10 Windy conditions?
11 Placed or areas with low humidity (very dry)?
12 Areas that are air conditioned?
OSDI Severity GradingOSDI Severity Grading
Severe
0 10 20 30 40 50 60 70 80 90 100Score
0-12 23-3213-220 33-100
Total OSDI Score=(Sum of Score for All Questions Answered) X (25)
(Total # of Questions Answered)
Mild ModerateNormal SevereScore
Miller KL, Mink DR, Mathias SD, & Walt JG. Estimating the minimal clinical important difference of the Ocular Surface Disease Index: Preliminary findings [Abstract]. Abstract obtained from www.isoqol.org/2006AbstractsBook.pdf.
OSD Exam FormOSD Exam FormDate:___/___/____ Patient _________________________________________________History/CC:_______________________________________________________________________________________________________________________________________________________________________________________________________________________Risk Factors: meds ( ) systemic disease ( ) environment ( ) CL wear ( ) Other ( )Visual Acuity: cc / sc O.D. 20/ O.S. 20/
O.D. O.S. External Exam:
Rosacea Y / NComplete Blink Y / N Y / NLagophthalmus Y / N Y / NScleral Show Y / N Y / NNotches Y / N Y / NEctropion Y / N Y / NEntropion Y / N Y / N
OSD Exam FormOSD Exam Form
Biomicroscopy:
Anterior Blepharitis Y / N Y / NPosterior Blepharitis Y / N Y / NC j ti h l i Y / N Y / NConjunctivochalasis Y / N Y / NEBMD Y / N Y / NTFBUT < 5 sec / > 5 sec < 5 sec / > 5 secTear Meniscus scant / normal scant / normalDebris/Frothing Y / N Y / NLid Wiper Epitheliopathy Y / N Y / NNaFl Staining Y / N Y / NLissamine Green Y / N Y / NSchirmer I / II ____mm ____mmZone Quick ____mm ____mmExternal Photos Y / NTopography Y / N
OSD Exam FormOSD Exam Form
Diagnosis: _____________( )_______________( ) ( ) ( )
Initial Treatment:Pt. Education: Lid Hygiene:OTC meds: Rx meds:Nutritional Supplements:Punctal Occlusion: Collagen 7 Day/ 90 Day SmartPlug/Silicone RU / RL / LU / LL
Additional notes:
RTO:______________________O.D.
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Dry Eye History: Symptoms
Take a comprehensive detailed history and be sure to listen carefully t ll ti t t A kto all patient symptoms. Assess work and home environment
Be sure to differentiate refractive symptoms from possible ocular surface disease symptoms
Diagnostic Procedures
Lid Evaluation: perform a thorough external exam
Biomicroscopic Evaluation of the eyelids, puncta corneas and conjunctivaepuncta, corneas and conjunctivae lagophthalmus, notches, entropion,
ectropion, lid laxity, blink rate, incomplete blinking, conjunctivochalasis, anterior blepharitis, MGD (and associated signs), lesions, epitheliopathies (EBMD), etc.
Eyelid PathologyEyelid Pathology Diagnostic ProceduresDiagnostic Procedures
Lid EvaluationLid Evaluation: perform a thorough external : perform a thorough external examexam
BiomicroscopicBiomicroscopic EvaluationEvaluation of the eyelids, of the eyelids, punctapuncta corneas and conjunctivaecorneas and conjunctivaepunctapuncta, corneas and conjunctivae, corneas and conjunctivae lagophthalmuslagophthalmus, notches, , notches, entropionentropion, ,
ectropionectropion, lid laxity, blink rate, incomplete , lid laxity, blink rate, incomplete blinking, blinking, conjunctivochalasisconjunctivochalasis, anterior , anterior blepharitisblepharitis, MGD (and associated signs), , MGD (and associated signs), lesions, lesions, epitheliopathiesepitheliopathies (EBMD),(EBMD), etc.etc.
ConjunctivochalasisConjunctivochalasis((CChCCh))
Caused by poor adhesion between Tenons capsule and the sclera
CCh
11
Two primary formsAnterior blepharitis Inflammatory condition of the exterior eyelids Often secondary to infection or associated with acne
rosacea or seborrheic dermatitis of the scalp or facial areas
Posterior blepharitis: Meibomian gland disease (MGD) Inflammation of the interior eyelids
Blepharitis A Common Ocular DisorderBlepharitis A Common Ocular Disorder
Anterior blepharitis
61
Inflammation of the interior eyelids Associated with altered composition of the
meibomian gland secretions & inflammation
Meibomian gland disease
Spectrum of Spectrum of BlepharitisBlepharitis
MixedMixedAnterior Anterior blepharitisblepharitisPosteriorPosteriorblepharitisblepharitis
Anterior BlepharitisAnterior BlepharitisAnterior BlepharitisAnterior Blepharitis
Inflammation of the outside of the eyelids Inflammation of the outside of the eyelids usually caused by bacterial infection usually caused by bacterial infection (staphylococcal) of the eyelid margin(staphylococcal) of the eyelid margin Infection normally occurs at the origins of Infection normally occurs at the origins of
the eyelashes and involves the lash the eyelashes and involves the lash follicles and the follicles and the meibomianmeibomian glandsglands
62
follicles and the follicles and the meibomianmeibomian glandsglands Signs and symptoms include:Signs and symptoms include: Morning crusting of lidsMorning crusting of lids CollarettesCollarettes -- scales that encircle lashscales that encircle lash Loss of lashesLoss of lashes Lid margin rednessLid margin redness ConjunctivalConjunctival hyperemiahyperemia
Meibomian Glands Important For Ocular Surface HealthMeibomian Glands Important For Ocular Surface Health
Enlarged sebaceous glands located posterior to eyelashes
Produce lipids and deliver them to the ocular surface where they serve as the outer layer of the tear film Stabilizes the tear film
63
Retards evaporation Helps maintain a smooth,
homogeneous refractive surface Provides a barrier to contamination
and damage to the eye
The maintenance of a free-flowing liquid lipid secretion is essential for maintaining a stable tear film
Meibomian Gland Disease EtiologyMeibomian Gland Disease Etiology
Meibomian gland disease involves a change in composition of meibomian gland secretions that leads to inflammation, irritation and an altered tear film Normal Normal meibomianmeibomian gland secretions convert from unsaturated gland secretions convert from unsaturated
lipids (that melt at body temperature) to saturated fatslipids (that melt at body temperature) to saturated fats
64
Involves degradation of triglycerides to mono- and diglycerides(solid), leading to MG obstruction Lipases appear to be involved in the degradation
The mono- and diglycerides are pro-inflammatory, leading to the inflammation and irritation associated with MGD
Posterior Blepharitis (Meibomian Gland Disease) Posterior Blepharitis (Meibomian Gland Disease)
Signs and symptoms include: Signs and symptoms include: Dilated & plugged Dilated & plugged meibomianmeibomian
gland orifices with toothpaste gland orifices with toothpaste like materiallike materialThi k d lid iThi k d lid i
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Thickened lid marginThickened lid marginFilmy vision with foam in tear Filmy vision with foam in tear
film (soaps/fatty acids)film (soaps/fatty acids)Dry eye signs and symptoms Dry eye signs and symptoms
(burning, foreign body sensation, (burning, foreign body sensation, contact lens intolerance)contact lens intolerance)
Why is it important to treat Why is it important to treat Blepharitis?Blepharitis?
Why is it important to treat Why is it important to treat Blepharitis?Blepharitis?
12
Why Is It Important to Treat Anterior Blepharitis?Why Is It Important to Treat Anterior Blepharitis?
To prevent conjunctival hyperemia (red eyes) which can be a significant problem for patients To avoid possible development of a stye or chalazion To avoid possible eyelash loss To protect patients who are undergoing ocular surgery
67
To protect patients who are undergoing ocular surgery Patients external tissues are an important source of infecting
organisms that adversely affect surgical outcomes Endophthalmitis results from patients own lid and surface flora Surgical outcome adversely affected by inflammation and
dysfunctional tears
Why Is It Important to Treat Posterior Blepharitis?Why Is It Important to Treat Posterior Blepharitis?
Posterior blepharitis is one the most common causes of the following ocular surface symptoms: burning, foreign body sensation and irritation. Potentially enhances ocular surgical outcomes Surgical outcomes may be adversely affected by inflammation
and dysfunctional tears This is particularly important in refractive surgery where achieving
68
This is particularly important in refractive surgery where achieving optimal vision requires a stable tear film
Contributes to contact lens intolerance Prevent conjunctival hyperemia (red eyes) which can be a
significant cosmetic problem for patients Avoid possible eyelash loss Minimize risk for chalazia
Meibomian Gland Meibomian Gland TransilluminationTransillumination
Normal meibomian glands Meibomian gland dysfunction:Extensive acinar dropout
Images from Dry Eye and Ocular Surface Disorders, 2004
TransilluminationTransillumination can reveal can reveal acinaracinar dropout, dropout, meibomianmeibomiancysts (cysts (chalaziachalazia) or scarring ) or scarring (Robin et al, 1985) (Robin et al, 1985)
Diagnostic Procedures NaFl dye: TBUT (tear film stability), corneal
staining (epithelial health), conj. Staining, tear meniscus, lid wiper, corneal valance
Lissamine Green or Rose Bengal gdye: conjunctival staining
Schirmer I or II test or Zone Quick (phenol red thread): tear production
Video Keratoscopy: surface regularity index (SRI)/correlates with visual fluctuation
Tear Meniscus
normal tear prism scant or thin tear prism
EBMDEBMD
13
Corneal Valance(Shahinians Sign)
It is a scalloped horizontal line of tear film thinning seen with fluorescein and cobalt filter in the upper third of the cornea.
Observed in EBMD patients due to minute epithelial Observed in EBMD patients due to minute epithelial irregularities produced by the cysts and excess basement membrane material increasing the rate of contamination of the mucin layer.
Tear Film Break-up Time (TFBUT) Tear film instability is the hallmark of dry eye
Correlates significantly with aqueous and evaporative tear deficiency(Pflugfelder et al, 1998)
TBUT measures tear film quality - Ability to resist thin spots Fluorescein dye introduced from strip or micropipette TBUT = time from completed blink to 1st dry spot (3 repetitions)
Proper patient instruction on procedure. 3 Blinks, look straight ahead. Repeat 3X.
Local alterations of the corneal surface can cause persistent break-up spots
Less is Better Micro-quantities of fluorescein (5l)
yield more precise, reliable TFBUT measurements
Newer Reference Values (n = 200+)
Newer TFBUT Reference ValuesNewer TFBUT Reference Values
Correlating Ocular Discomfort and TFBUT
- In 100s patients, over 70%report ocular awarenessfollowed by discomfort within1 second of TFBUT = NITFBUT Newer Reference Values (n 200 )
Normal > 5 seconds (mean = 7.1 sec)
Dry Eye < 5 seconds (mean = 3.2 sec)
Reference: Lacrimal Gland, Tear Film, and Dry Eye Syndromes 3Edited by D. Sullivan et al., Kluwer Academic/Plenum Publisher 2002
Blink TFBUT BlinkTear ProtectedOcular Surface
UnprotectedOcular Surface
Cycle Repeats
0 1 2 3 4 5 6 7
Time (seconds)
StainingOcularDiscomfortConsequences of an
Unprotected Ocular Surface
TFBUT Patterns:Aqueous Tear Deficiency
Localized circulartear break-up
Diffuse circulartear break-up
Images from Dry Eye and Ocular Surface Disorders, 2004
TFBUT Patterns:Meibomian Gland Disease
Inferior streaktear break-up
Broad streaktear break-up
Images from Dry Eye and Ocular Surface Disorders, 2004
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Consequence of Dry Eye = Staining
Damaged corneal cells show up as dry spots during corneal staining
Damaged corneal epithelial cell
(loss of microvilli and glycocalyx)
NaFl Staining in Dry Eye
Lid pattern staining Diffuse staining Meibomian glanddiseaseAqueous tear deficiency
Images from Dry Eye and Ocular Surface Disorders, 2004
Why is SPK Often Missed?Without Yellow Wratten Filter
Photo courtesy University of Iowa Health Care, January, Photo courtesy University of Iowa Health Care, January, 20052005
With Wratten Filter
Photo courtesy University of Iowa Health Care, January, 2005
Tiffen/Wratten Filter
Adorama42 West 18th StreetNew York, NY 10011800-223-2500
SKU # TF55Y12Tiffen 55mm round/Yellow #12
Rose Bengal Conjunctival Staining in Dry Eye
Classical exposure zone staining
D bl t i l Double triangle pattern characteristic of dry eye
Rose bengal is irritating
Image from Dry Eye and Ocular Surface Disorders, 2004
15
Lissamine Green Stainingin Dry Eye
Lissamine green detects dead or degenerated conjunctival cells Degree of severity increases from left to right pictured above
Exposure zone staining with limbal sparing
Exposure zone staining with limbal staining
Intense diffuse staining of exposure zone,
limbal staining
Images from Dry Eye and Ocular Surface Disorders, 2004
Delayed clearance correlates well with other measures of dry eye (Afonso et al, 1999; Pflugfelder et al, 1998) Rate of clearance should relate to tear production
5 L of 2% fluorescein instilled; wait 15 min
Tear Turnover in Dry Eye:Fluorescein Clearance
Delayed clearance
Match color of lateral inferior tear meniscus to standard scale
3 is the threshold between normal and symptomatic patients (Afonso et al, 1999)
Other reading methods Insert Schirmer strip, compare to standard colors Fluorometer measures tear concentration directly
Rapid clearance
Image from Dry Eye and Ocular Surface Disorders, 2004
Impression CytologyTemporal Bulbar Conjunctiva
Normal: Epithelial pattern is regularGoblet cells stain violet
Dry eye: Squamous metaplasiaGoblet cells absent
Detects squamous metaplasia and loss of goblet cells associated with dry eye (Pflugfelder et al, 1990) Goblet cells essential for secretion of soluble mucins into the tear film
An important research toolCytology membrane pressed against conjunctival surface and removedthen stained with periodic acid-Schiff (PAS) or antibodies
Images from Dry Eye and Ocular Surface Disorders, 2004
Lubricity: an Overlooked Factor in Ocular Health and Comfort
Lubricity is the inverse of the coefficient of friction Two tissues with high lubricity slide smoothly along
one another Lubricity is extremely important in maintaining lid and
ocular health and patient comfortocular health and patient comfortLu
bric
ityLu
bric
ity FrictionFriction
Resistance
Resistance
What is the Lid Wiper?
The lid wiper is that portion of the marginal conjunctiva of the upper
eyelid that wipes the ocular surface during blinking.
The epithelial health of the lid wiper can be determined with a simple graded staining test similar to that used in analyzing the bulbar conjunctiva
Korb, DR, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005 Jan; 31(1):2-8.
Lid Wiper EpitheliopathyLid Wiper Epitheliopathy Characterized by presence of damaged epithelial cells
on lid wiper portion of marginal conjunctivaNaFl, LG or RB can be used to dye the lid wiper Staining graded on scale of 0 to 3, where 0 = no
staining, 3 = heavy staining
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.
12
16
Evaluation of the Lubricity of Marketed Dry Eye Products
Performed by Drs. Robert Baier and Ann Meyer, University of Buffalo
Pre-clinical model based on the measurement of friction of tissue on tissue
Measures the coefficient of friction of lubricants on human tissue from stabilized umbilical cord vein graft
Coefficient of Friction/ Comparison of Marketed Ocular Lubricants
*****
##
*p
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How does lacrimal gland disease increase tear osmolarity?
With decreased tear secretion, tear t d Th t iturnover decreases. The tears remain on the eye longer giving evaporation more time to act.
As tear volume declines, but surface area remains constant, evaporation has a greater effect on tear osmolarity.
Differential DiagnosisDifferential DiagnosisDifferential Diagnosis Differential Diagnosis
Differential Diagnoses:other external diseases
Allergic Conjunctivitis Bacterial Conjunctivitis Blepharitis
Contact lens related (mechanical conjunctivitis)
Ocular Rosaceap Viral Conjunctivitis Chlamydia Pemphigoid
Medicamentosa(OTC abuse)
Contact Lens Contact Lens RelatedRelated
Dry Eye IssuesDry Eye Issues
Contact Lenses 101
H2O2O H2O
More hydrophobic less wetting More hydrophilic more wetting
Advancing Contact Angle Receding Contact Angle
Water Model
Contact Lens Care Products, Lens Comfort & the Ocular Surface
Some lens care products produce significant corneal staining.*
Different lens care products possess different wetting capabilities and aredifferent wetting capabilities and are not equally biocompatible with all lens materials.
Studies demonstrate that staining and comfort correlate.
*L. Jones, N. Macdougall, L. Sorbara Asymptomatic Corneal Staining Associated with the Use of Balafilcon Silicone-Hydrogel Contact Lenses Disinfected with a Polyaminopropyl Biguanide-Preserved Care Regimen. Optometry & Visual Science, (2002) 79 (12);753-761
*Young G, Pritchard N, Hunt C, Coleman S. Subjective and Objective Measures of Corneal Staining Related to Multipurpose Care Systems. Contact Lens & Anterior Eye 26 (2003) 3-9
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Therapeutic Approaches Therapeutic Approaches Therapeutic Approaches Therapeutic Approaches p ppp ppp ppp pp
Managing the OSD/Dry Eye Patient
Schedule an OSD evaluation (follow previously discussed history and di ti t ti )diagnostic testing)
Utilize an OSD exam form Code Level 3 E/M or Intermediate
Ophthalmologic Exam (99203/99213/92002/92012)
Delphi Panel 2003 17 international representatives from the U.S. and
Europe Convened in Baltimore to define DTS and develop a
clinically practical scheme for diagnosing and treating dry eye
DEWS 2007 Sponsored by the NEI, published a compendium as a
follow-up to the Delphi Panel findings based on an EBM review of the literature
Beta Panel 2008 ASCRS group recommendations (included loteprednol
and Restasis or Azasite with lid scrubs)
Delphi Panel Consensus for Dry Eye Management
SEVERITY SIGNS AND SYMPTOMS RECOMMENDED TREATMENT
1 Mild to moderate symptoms; no signsMild to moderate conjunctival signs
Patient counseling, preserved tears, environmental management, use of hypoallergenic products, water intake.
2 Moderate to severe symptomsTear film signs
Unpreserved tears, gels, ointments, cyclosporine A, secretagogues, topical
Mild corneal punctate stainingCorneal stainingVisual signs
steroids, nutritional support (flax-seed oil).
3 Severe SymptomsMarked corneal punctate stainingCentral corneal stainingFilamentary keratitis
Tetracyclines, PUNCTAL PLUGS
4 Severe symptomsSevere corneal staining, erosionsConjunctival scarring
Systemic anti-inflammatory therapy, oral cyclosporine, moisture goggles, acetylcysteine, punctal cautery, surgery
Behrens A, et al. (Dysfunctional Tear Film Study Group). Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006 Sep;25(8):900-7.
TREAT
Therapeutic Approaches Stabilize the tear film
(subjective)
Increase lubricity -decrease coefficient of friction TREAT
SUBJECTIVELY
Manage a patients dry eye based on
the medication and dosing that best
fits their particular form of the condition.
Increase aqueous production
Decrease inflammation
Create a more normal tear film environment for epithelial healing
Dry Eye Management
Patient Education Lid Hygiene (treat underlying cause) OTC Therapy
/ O Punctal/Lacrimal Occlusion Nutrition Rx treatment Moisture goggles Surgery
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Patient EducationBefore the diagnostic evaluation.
At the end of the routine exam, explain the tentative diagnosis (of a possible tear film abnormality) to your patient and that you will need to perform specific tests to confirm the diagnosis
Always explain that the testing is medical, not vision y p gcare, and is usually covered by most health insurance plans
After the diagnosis. After making the diagnosis, be specific about the
treatment that you prescribe and prognosis Follow up on the therapy that is prescribed to assess
efficacy
Patient EducationDiscuss/Modify
Influential Factors Environment: humidifier Medications (query OTC use) Fluid consumptionFluid consumption Blink rate Visual tasking: Computer monitor
location (height)
Dry Eye Management
Patient Education Lid Hygiene (treat underlying
cause)OTC Therapy OTC Therapy
Punctal/Lacrimal Occlusion Nutrition Rx treatment Moisture goggles Surgery
Lid HygieneMost important to treat the underlying cause(s) of dry eye (Anterior/Posterior Blepharitis)
Warm Compresses Lid Massage (MG expression in - office) Lid Scrubs (pre-moistened pads or Sterilid) Antibiotic or A-S Ointment or Antibiotic-Steroid gtts for
staphylococcus bacteria/inflammation (Azasite, Erythromycin, Bacitracin, Ciloxan, Tobradex, Zylet)
Oral Tetracycline drugs: Doxycycline 50 mg BID, then 20mg Omega-3 intake Rx pad (pre-printed) with specific instructions Schedule a follow up visit to assess progress and efficacy of
treatment plan (92012/99212)
AzaSite(azithromycin ophthalmic solution) 1%1
AzaSite is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following microorganisms: CDC coryneform group G*, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and StreptococcusStreptococcus mitis group, and Streptococcus pneumoniae.
*Efficacy for this organism was studied in fewer than 10 infections
1. AzaSite [package insert] Durham, NC: Inspire Pharmaceuticals, Inc. 2007.
Anti-Inflammatory Activity of A ith i & A Sit Azithromycin & AzaSite
20
Anti-inflammatory Properties of Azithromycin
Azithromycin has been shown to have significant anti-inflammatory effects as demonstrated by reductions in:1,2,3
inflammatory cell infiltration
edema
mucus hypersecretionmucus hypersecretion
expression of pro-inflammatory cytokines
The anti-inflammatory activity is much higher in cells exposed to bacterial products than in normal cells4
1. Amsden GW. J Antimicrob Chemother. 2005; 55:10-212. Ianaro A, et al. J Pharmacol Exp Ther. 2000; 292(1):156-1633. Shinkai M, et al. Paediatr Respir Rev. 2005;: 6; 227-2354. Glaudue R, et al. Antimicrob Agents Chemother. 1989; 277 - 282
Impact of MMP-9 on Corneal Tissue1
Matrix metalloproteinases (MMPs) coordinate multiple processes in normal, damaged, and diseased corneas.
In normal corneas, MMP-9 is expressed in the epithelium and affects epithelial regeneration and integrity of the basement membrane
Over-expression of MMP-9 involves degradation of epithelial basement membrane and contributes to failure of re-epithelialization following injury
1. Jacot J, et al. Poster Presented at ARVO. Ft. Lauderdale, FL 2008
Suppression of MMP-9 in HCEC by AzaSite
Primary human corneal epithelial cells secrete abundant pro-MMP-91
AzaSite reduced activity of MMP-9 by 33% and MMP-2 by 41% in ocular tissue1
1. Jacot J, et al. Poster Presented at ARVO. Ft. Lauderdale, FL 2008
AzaSite Anti-Inflammatory Conclusions
The macrolide and tetracycline classes of antibiotics have well documented anti-inflammatory effects1,2
Azithromycin specifically has well documented anti-inflammatory effects3,4documented anti inflammatory effects
AzaSite has shown the ability to inhibit production of MMP-9 in ocular tissue5
1. Dougherty JM, et al. The Role of Tetracycline in Chronic Blepharitis. Invest Opthal. Vis Sci. 1991; 32: 2970 2975 2. Pflugfelder SC. Anti-inflammatory Therapy of Dry Eye. The Ocular Surface. 2002; 1: 31-363. Amsden GW. J Antimicrob Chemother. 2005; 55:10-214. Ianaro A, et al. J Pharmacol Exp Ther. 2000; 292(1):156-1635. Jacot J, et al. Poster Presented at ARVO. Ft. Lauderdale, FL 2008
Rapidly improves patient comfort & reduces lid margin and conjunctival hyperemia
Significant anti-inflammatory activity w/o side effects of steroids
AzaSite is disease modifying therapy for Blepharitis
119
steroids
Penetrates conjunctiva, cornea and eyelid tissue to achieve effective and sustained levels
Broad spectrum anti-microbial activity
Unique ability to quickly improve meibomian gland secretions
Clinical trials evaluating efficacy of AzaSite for blepharitisClinical trials evaluating efficacy of AzaSite for blepharitis
2 week trial in patients with moderate/severe meibomian gland disease (posterior blepharitis)1 AzaSite provides significant improvement in comfort and reduces lid margin
hyperemia
4 week trial in patients with moderate/severe anterior and posterior (mixed) blepharitis2
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(mixed) blepharitis AzaSite provides significant improvement in comfort and reduces lid margin
and conjunctival hyperemia
4 weeks trial in patients with moderate/severe meibomian gland disease (posterior blepharitis)3 AzaSite rapidly improves patient comfort within one week of beginning therapy
1 Luchs J, Adv Ther, Sept 25 (9):858-870, 20082 Data on file. Inspire Pharmaceuticals, Inc., Study 041-104; accepted for presentation at ASCRS/ARVO 20093 Data on file. Inspire Pharmaceuticals, Inc., Study 041-105; accepted for presentation at ASCRS 2009
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Two week Trial in Posterior Blepharitis: Patient-Rated Efficacy1Two week Trial in Posterior Blepharitis: Patient-Rated Efficacy1
Global Assessment Global Assessment of Efficacy*of Efficacy*
AzaSiteAzaSite in Combination in Combination with Warm Compresseswith Warm Compresses Warm Compresses AloneWarm Compresses Alone
Excellent 25% 0%
Good 50% 18%
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Fair 13% 73%
Poor 13% 9%
Deterioration 0% 0%
75% of patients in the AzaSite group rated the efficacy as excellent or good compared to 18% in the WC alone group (p = 0.024) (n=19)
* per-protocol population
1 Luchs J, Adv Ther, Sept 25 (9):858-870, 2008
Two week Trial in Posterior Blepharitis: Investigator Assessment of Lid Margin HyperemiaTwo week Trial in Posterior Blepharitis: Investigator Assessment of Lid Margin Hyperemia
2
3
4WCAzaSite + WC
p < 0.001
Mea
n Sc
ore
122
69% improvement in mean from baseline w/ AzaSite vs. 10% w/ WC alone (n=21)
(0) Normal: no redness (3) Severe: increased vascularity of the eyelid margin(1) Mild: slightly dilated blood vessels (4) Very severe: clearly increased vascularity of the eyelid margin(2) Moderate: more apparent dilation of blood vessels
0
1
Baseline After 2 Weeksof Treatment
M
Luchs J, Adv Ther, Sept 25 (9):858-870, 2008
Four Week Trial in Anterior/Posterior Blepharitis1Four Week Trial in Anterior/Posterior Blepharitis1
AzaSiteAzaSiteVisit 1Visit 1
(Baseline)(Baseline)Visit 2*Visit 2*
(After 4 wks (After 4 wks dosing)dosing)
Visit 3*Visit 3*(2 wks after (2 wks after
dosing stopped)dosing stopped)
Visit 4*Visit 4*(4 wks after (4 wks after
dosing stopped)dosing stopped)Eyelid Margin Hyperemia 2.0 1.3
p
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