dry eye: a multifactorial disease

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Dry EyeDry Eye

A Multifactorial DiseaseA Multifactorial Disease

dr samarth mishradr samarth mishra

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Prevalence of Dry Eye Prevalence of Dry Eye DiseaseDisease

• 60 million affected worldwide.60 million affected worldwide.• 1 to 2 million suffer from severe, chronic symptoms.1 to 2 million suffer from severe, chronic symptoms.• 7 to 10 million Americans have some form of dry 7 to 10 million Americans have some form of dry

eye needing artificial tears. eye needing artificial tears. • 33 million adults may be undiagnosed.33 million adults may be undiagnosed.• Sjögren’s - associated dry effects 1% to 2% of the Sjögren’s - associated dry effects 1% to 2% of the

population.population.

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Prevalence of Dry Eye Prevalence of Dry Eye DiseaseDisease•Average age of a dry eye patient Average age of a dry eye patient

is 54; most are women.is 54; most are women.•Dry Eye Syndrome affects 75% Dry Eye Syndrome affects 75%

of people over age 65.of people over age 65.•Common reason for Common reason for

ophthalmologist visits.ophthalmologist visits.

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Prevalence of Dry Eye Disease in Prevalence of Dry Eye Disease in IndiaIndia

Study N Age Creteria Prevalence ReferenceWisconsin 3,722 48-91 Self-reported 14.4% Moss SE et al. Arch

Ophthalmol. 2000;118(9):1264-1268.

Shihpai (Taiwan)

2,038 >65 One of 6 symptoms 33.7% Lin PY et al. Ophthalmology. 2003;110(6):1096-1101.

Maryland 2,520 65-84 Symptoms + 1 sign 3.5% Schein OD et al. Am. J. Ophthalmol. 1997;124(6):723-728.

Women’s Health Study

39,876 49-84 (female)

Severe symptoms or clinical diagnosis

7.8% Schaumberg DA et al. Am. J. Ophthalmol. 2003;136(2):318-326.

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Contd..Contd..Study N Age Creteria Prevalence Reference

Dry Eye Prevalence (India)

500 >20 Symptoms + Tests 18.4% Sahai A et al Indian J Ophthalmol 2005;53:87-91

Dry Eye Study (Thailand)

550 >550 Symptoms 34% Lekhanont et al cornea2006;25:1162-67

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‘‘Dry eye is a disorder of the tear film due to tear Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation, which causes deficiency or excessive tear evaporation, which causes damage to the interpalpebral ocular surface and is damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.’associated with symptoms of ocular discomfort.’

Global Definition of Dry Eye

Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995 Oct;21(4):221-32. 66

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DEWS Dry Eye Definition (2007)

‘Dry Eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface.

It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.’

The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007 Apr;5(2):75-92. 77

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Classification SystemsClassification Systems

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Behrens A, Doyle JJ, Stern L, Chuck RS, McDonnell PJ, Azar DT, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006Sep;25(8):900-7.

Delphi Panel Report − Dysfunctional TearSyndrome Classification

Panel Delphi Panel Approach to Dry Eye DiseaseYear 2006

Key highlights A new term proposed for Dry Eye disease: Dysfunctional Tear Syndrome (DTS)

Treatment recommendations based primarily on patient symptoms and signs

Basis of classification Primary – symptoms and signs Secondary – staining and other diagnostic tests

Major categories With lid margin disease Without lid margin disease Altered tear distribution and clearance

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The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007 Apr;5(2):75-92.

DEWS: Dry Eye Classification

Panel Definition and Classification Subcommittee of DEWSYear 2007

Key highlights Classification is more comprehensive, as it includes various tests in addition to symptoms and signs

Adopted and modified the Delphi Panel Dry Eye severity grading

Basis of classification

Symptoms and signs Staining Tear Film BreakUp Time (TFBUT) Schirmer’s test values Lid/meibomian gland disease

Major categories

Aetiopathogenic Causative mechanisms Severity

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DEWS: Classification

DEWS Dry Eye classification

Aetiopathogenic

Tear hyperosmolar

ityTear film instability

Level 4Level 3Level 2Level 1

Causative mechanisms

Severity of disease

Details on next slide


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DEWS: Subset 1 − Aetiopathogenic Classification

Sjögren Syndrome Dry Eye

Non-Sjögren Dry Eye

Primary Secondary

Lacrimal gland duct

obstruction

Reflex sensory block

Reflex motor block

Lacrimal deficiency

Reflex hyposecretion

Intrinsic

Vitamin A deficiency

Topical drugspreservatives

Contact lens wear

Ocular surface disease, for example: allergy

Meibomian gland

dysfunction

Disorder of lid aperture

Low blink rate

Drug action accutane

Aetiopathogenic Classification

EvaporativeAqueous deficient

Extrinsic

Primary Secondary


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Dry Eye Severity Level 1 Level 2 Level 3 Level 4*Discomfort, severityand frequency

Mild and/or episodic;occurs underenvironmental stress

Moderate episodic orchronic, stress or nostress

Severe frequent orconstant withoutstress

Severe and/ordisabling and constant

Visual symptoms None or episodic mildfatigue

Annoying and/oractivity-limitingepisodic

Annoying, chronicand/or constant,limiting activity

Constant and/orpossibly disabling

Conjunctival injection None to mild None to mild + /− + /++Conjunctival staining None to mild Variable Moderate to marked MarkedCorneal staining (severity/location)

None to mild Variable Marked central Severe punctateerosions

Corneal/tear signs None to mild Mild debris,decreased meniscus

Filamentary keratitis,mucous clumping,increased tear debris

Filamentary keratitis,mucous clumping,increased tear debris, ulceration

Lid/meibomian glands MGD variably present

MGD variably present Frequent Trichiasis, keratinisation,symblepharonTFBUT (sec) Variable ≤10 ≤5 Immediate

Schirmer’s score (mm/5 min)

Variable ≤10 ≤5 ≤2*Must have signs and symptoms; MGD: Meibomian Gland Dysfunction; TFBUT: Tear Film BreakUp Time

DEWS: Subset 3 − Dry Eye Severity Grading System

The basic scheme of the Delphi Panel report was adopted and modified to produce the third component of the recommendation

The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007 Apr;5(2):75-92.1313

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Dry Eye Is a Continuum of Dry Eye Is a Continuum of DiseaseDisease

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LacrimalLacrimalGlandsGlands

Secretomotor Secretomotor Nerve ImpulsesNerve Impulses

Tears Support and MaintainTears Support and MaintainOcular SurfaceOcular Surface

Ocular SurfaceOcular SurfaceNeural StimulationNeural Stimulation

The Healthy EyeThe Healthy Eye

Stern et al, Cornea. 1998:17:584

Normal tearingNormal tearingdepends on adepends on a

neuronal feedback loopneuronal feedback loop

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Lacrimal Glands:Lacrimal Glands:• Neurogenic Neurogenic

InflammationInflammation• T-cell ActivationT-cell Activation• Cytokine Secretion into Cytokine Secretion into

TearsTears

Interrupted Secretomotor Interrupted Secretomotor Nerve ImpulsesNerve Impulses

Tears Inflame Ocular SurfaceTears Inflame Ocular Surface

Cytokines Cytokines Disrupt Neural ArcDisrupt Neural Arc

Inflammation disruptsInflammation disruptsnormal neuronalnormal neuronal

control of tearing.control of tearing.

Stern et al, Cornea. 1998:17:584

Dry Eye Disease: An Immune-Dry Eye Disease: An Immune-Mediated Inflammatory Mediated Inflammatory DisorderDisorder

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Multiple Factors in Dry EyeMultiple Factors in Dry Eye• Transient discomfortTransient discomfort• May be stimulated by environmental May be stimulated by environmental

conditionsconditions11

• Inflammation and ocular surface damageInflammation and ocular surface damage• Altered tear film compositionAltered tear film composition22

•Few other conditions like Ocular allergy, &Few other conditions like Ocular allergy, & Allergic Allergic

Conjunctivitis, Blepharitis, Contact lens usage etc.Conjunctivitis, Blepharitis, Contact lens usage etc. 1de Paiva and Pflugfelder. In: Dry Eye and Ocular Surface Disorders. 2004;

2Pflugfelder et al. In: Dry Eye and Ocular Surface Disorders. 2004.1717

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ConjunctivitisConjunctivitis• InflammationInflammation• ErythemaErythema• Several causes:Several causes:

– Bacterial Bacterial – ViralViral– AllergicAllergic– ChemicalChemical

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ConjunctivitisConjunctivitis

Christopher Baudouin Survey of Ophthalmol 2001;45(2):S211-S220

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Chronic cicatrizing Chronic cicatrizing conjunctivitisconjunctivitis• Stevens-Johnson syndrome (SJS)Stevens-Johnson syndrome (SJS)• Toxic epidermal necrolysis (TEN)Toxic epidermal necrolysis (TEN)• TrachomaTrachoma• Epidemic keratoconjunctivitis (EKC)Epidemic keratoconjunctivitis (EKC)• Atopic keratoconjunctivitisAtopic keratoconjunctivitis• Sjogren’s syndromeSjogren’s syndrome• Progressive systemic sclerosisProgressive systemic sclerosis• SarcoidosisSarcoidosis

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Chronic Ocular AllergyChronic Ocular Allergy

• Dry eye is commonly associated with chronic Dry eye is commonly associated with chronic allergic conjunctivitis. allergic conjunctivitis.

• An allergic history has been reported by 36% of An allergic history has been reported by 36% of dry eye patients.dry eye patients.

• Chronic allergy results in loss of goblet cells, Chronic allergy results in loss of goblet cells, destabilization of the tear film & damage to destabilization of the tear film & damage to ocular surface.ocular surface.

• VKC is associated with 38% incidence of dry eye.VKC is associated with 38% incidence of dry eye.

Surv Oph 2001, 45(2), S211-202121

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AllergyAllergy36% of dry eye patients have a history 36% of dry eye patients have a history

of allergyof allergy

Stimulation of the local immune system

Destabilization of tear film

Increased rate of tear evaporationJ.M. Albietz Clin Exp Optom.2001;84(1):4-18Christopher Baudouin Survey of Ophthalmol 2001;45(2):S211-S220

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Dry Eyes and BlepharitisDry Eyes and Blepharitis• Very common in older patientsVery common in older patients• Chronic remitting problemChronic remitting problem• Not usually serious but constant Not usually serious but constant

nuisancenuisance• Patient EducationPatient Education

– LifestyleLifestyle– Regular hygiene/instillation of drops/gelsRegular hygiene/instillation of drops/gels– Realistic expectations of treatment!Realistic expectations of treatment!

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BlepharitisBlepharitis

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Blepharitis is an extremely frequent Blepharitis is an extremely frequent cause of Dry Eyecause of Dry Eye

Loss of meibomian gland function

Impairment in the lipid phase of tear film

Increased rate of tear evaporation

Destabilization of tear film

Deficient mucin secretion

Loss of goblet cells

Christopher Baudouin Survey of Ophthalmol 2001;45(2):S211-S220

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Lid anatomyLid anatomyMeibomian/tarsal glandsGlands of Zeiss and Moll

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Blepharitis-SymptomsBlepharitis-Symptoms• Sore burning itching irritation of lidsSore burning itching irritation of lids• Grittiness and wateringGrittiness and watering• Mild stickiness particularly on wakingMild stickiness particularly on waking• Red lid marginsRed lid margins• Dry eyesDry eyes

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Contact Lens usage and Dry eyeA survey of 310 practitioners found that:

-18% to 30% of CL patients had dry eye problems

-12 to 21% had reduced wearing time due to

dryness

-6% to 9% discontinued wear due to dryness

(Orsborn & Zantos, CL Spectrum, 1989)

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29DRYNESS SYMPTOMS WITH CONTACT LENS WEAR

A survey of 214 hydrogel patients found:

21% of males and 26% of females had reducedwearing time due to dryness symptoms.

(Orsborn & Robboy, J Brit CL J. 1989)

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32DRYNESS SYMPTOMS WITH CONTACT LENS WEAR

Numerous factors effect the dehydration of hydrogel lenses:

Water content: higher water lenses lose more water

Thickness: Thin lenses dehydrate more

Humidity: Lenses dehydrate more in low humidity environments

Temperature: less water at higher temperatures.-less water in lens on eye than in solution

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Computer vision syndromeComputer vision syndrome• Excessive use of visual display units Excessive use of visual display units • Insufficient tear flowInsufficient tear flow• Glare and reflection on monitorGlare and reflection on monitor• Need for glassesNeed for glasses• SymptomsSymptoms

– eyestrain/fatigueeyestrain/fatigue– itching/burningitching/burning– photophobiaphotophobia– blurred visionblurred vision– irritation and heaviness of lidsirritation and heaviness of lids

www.allaboutvision.com

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WHAT IS CVS ?WHAT IS CVS ?

Computer Vision Syndrome affects 60% of computer usersComputer Vision Syndrome affects 60% of computer users

Causes Symptoms• Low Blink Rate Narrowing eye lid-

slits• Screen Flicker Eye irritation/pain• Incorrect viewing Angles Redness - Burning

Headaches3434

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STARTING AT MONITORSSTARTING AT MONITORS

REDUCED RATE OF BLINKINGREDUCED RATE OF BLINKING

FASTER TEAR FILM EVAPORATIONFASTER TEAR FILM EVAPORATION

DEPRIVATION OF LUBRICATIONDEPRIVATION OF LUBRICATION

& NOURISHMENT& NOURISHMENT

CVSCONSULT YOURDOCTOR TODAY,TO FIND RELIEF

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BLINKING TIME PER MINUTEBLINKING TIME PER MINUTE

Average:22 times perminute

While reading:10 times perminute

While looking atcomputer/TV screen:7 times perminute

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WHO IS AT RISK?WHO IS AT RISK?

• Computer users - programmers,Computer users - programmers,data entry operatorsdata entry operators

• Additionally, those in air-conditioned officesAdditionally, those in air-conditioned offices

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WHAT IS THE SOLUTION?WHAT IS THE SOLUTION?

• Regular use of tear substitutes / ocular Regular use of tear substitutes / ocular

lubricantslubricants

• Acts like real tears to soothe and relieve Acts like real tears to soothe and relieve

ocular discomfortocular discomfort

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Diagnosing Dry Eye Diagnosing Dry Eye DiseaseDisease

1Nichols et al. Cornea. 2000.3939

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Lemp, 1995; Marsh et al, 1999Lemp, 1995; Marsh et al, 1999

SlitlampSlitlamp

FluoresceinFluoresceinDye StainDye Stain

MildMild SevereSevere

Clinical Presentation Can Vary in Clinical Presentation Can Vary in SeveritySeverity

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Schirmer TestSchirmer TestWithout Without

AnesthesiaAnesthesia• Measures reflex Measures reflex

tear secretion.tear secretion.

With AnesthesiaWith Anesthesia• Eliminates Eliminates

stimulated tearing.stimulated tearing.

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Sterile Melting Bacterial Keratitis

Potential Severe Potential Severe Consequences of Untreated Consequences of Untreated Dry Eye DiseaseDry Eye Disease

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43Left Untreated, Chronic Dry EyeLeft Untreated, Chronic Dry EyeMay Become a Progressive May Become a Progressive DisorderDisorder

• Patients suffering from dry eye disease Patients suffering from dry eye disease may move between severity levels and may move between severity levels and can become worse, if untreatedcan become worse, if untreated11

– Disease management options can be Disease management options can be adjusted for individual patients depending adjusted for individual patients depending on disease severityon disease severity

1Nelson et al. Adv Ther. 2000.4343

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Treatment Options for DE Treatment Options for DE conditionsconditions

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Dry Eye TreatmentDry Eye Treatment

Tear-SubstitutesTear-Substitutes

Punctal Punctal OcclusionOcclusionMoist-chamber gogglesMoist-chamber goggles

Immuno Suppressants – CyclosporineImmuno Suppressants – Cyclosporine

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DEWS Review: Available Treatment Options

Treatment Option Group/subgroup

Tear supplementation Lubricants

Tear retention Punctal occlusion Moisture chamber spectacles Contact lenses

Tear stimulation Secretagogues

Biological tear substitutes Serum Salivary gland autotransplantation

Anti-inflammatory therapy Cyclosporine Corticosteroids Tetracyclines

Essential fatty acids Omega-3 fatty acids

Environmental strategies Avoid low humidity and air conditioning drafts Video display terminal should be lowered below eye level

Management and therapy of dry eye disease: report of the management and therapy subcommittee of the international dry eye workshop (2007). Ocul Surf 2007 Apr;5(2):163-78.

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Lubricant ComponentsLubricant Components• Match characteristics of normal tearMatch characteristics of normal tear• Lubricants contain:Lubricants contain:

– polymers which affect viscosity/surface tensionpolymers which affect viscosity/surface tension– buffers which affect pHbuffers which affect pH– salts which affect tonicitysalts which affect tonicity– preservativepreservative

• Preservatives can reduce tear film stabilityPreservatives can reduce tear film stability• Preservative-free products preferredPreservative-free products preferred

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Ideal lubricantIdeal lubricant• The ideal ocular lubricant should:The ideal ocular lubricant should:

– create a stable tear filmcreate a stable tear film– be comfortablebe comfortable– be sterilebe sterile– be free from adverse effectsbe free from adverse effects– be non-toxicbe non-toxic– have a pH of 7.0-7.4have a pH of 7.0-7.4– have a long retention timehave a long retention time– not impair ocular tissue regenerationnot impair ocular tissue regeneration

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Lubricant propertiesLubricant properties• Key physical properties of a lubricant are:Key physical properties of a lubricant are:

– Surface tension - as close to normal tears as Surface tension - as close to normal tears as possible (46 dynes/cm2)possible (46 dynes/cm2)

– pH - around 7.4pH - around 7.4– Tonicity/ Osmolarity - hypo, hyper or isotonic Tonicity/ Osmolarity - hypo, hyper or isotonic

(as required)(as required)– Viscosity - not so high as to blur vision or cause Viscosity - not so high as to blur vision or cause

crustingcrusting

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PolymersPolymers• Long chain moleculesLong chain molecules• Can increase viscosity of tear filmCan increase viscosity of tear film• Viscosity increases ocular retention and Viscosity increases ocular retention and

increases tear B.U.T.increases tear B.U.T.• Can affect surface tension of TFCan affect surface tension of TF• Prolong ocular retention by retarding Prolong ocular retention by retarding

evaporationevaporation• Increased B.U.T. reduces dry spots and Increased B.U.T. reduces dry spots and

associated discomfortassociated discomfort

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PolymersPolymers• Mimic role of mucinMimic role of mucin

– are surfactants that reduce surface tension of aqueous layerare surfactants that reduce surface tension of aqueous layer– some polymers adhere to ocular surfacesome polymers adhere to ocular surface– make corneal surface hydrophilicmake corneal surface hydrophilic– help spread tearshelp spread tears

• Key considerations - the impact of lubricant Key considerations - the impact of lubricant components on lipid layercomponents on lipid layer

• Can stabilise or destabilise lipid layerCan stabilise or destabilise lipid layer• Destabilised lipid layer increases evap’nDestabilised lipid layer increases evap’n• Some can slow epithelium regeneration time (eg: Some can slow epithelium regeneration time (eg:

saline, methylcellulose 0.5%)saline, methylcellulose 0.5%)

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Polyvinyl AlcoholPolyvinyl Alcohol• Synthetic alcoholSynthetic alcohol• Commonly used in eye dropsCommonly used in eye drops• Excellent surface contact timeExcellent surface contact time• 1.4% PVA has same surface tension as tears - 1.4% PVA has same surface tension as tears -

optimises wettingoptimises wetting• 3.0% has longer retention time but higher 3.0% has longer retention time but higher

viscosity can blur vision (more severe OSD cases)viscosity can blur vision (more severe OSD cases)• Does not destabilise lipid layerDoes not destabilise lipid layer• Does not retard epithelium regenerationDoes not retard epithelium regeneration

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Polyvinyl AlcoholPolyvinyl Alcohol• PVA advantages:-PVA advantages:-• 1.4% ST is 46 dynes/cm2 - same as tears1.4% ST is 46 dynes/cm2 - same as tears• water-dragging ability leads to thicker tear water-dragging ability leads to thicker tear

film than HPMCfilm than HPMC• promotes corneal health (does not slow promotes corneal health (does not slow

regeneration as does MC and saline)regeneration as does MC and saline)• 1.4% does not blur vision1.4% does not blur vision• does not destabilise tear film (unlike does not destabilise tear film (unlike

polysorbate)polysorbate)

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Methylcellulose Methylcellulose • Non-irritating synthetic compoundsNon-irritating synthetic compounds• Excellent surface contact timesExcellent surface contact times• Suitable for more advances OSDSuitable for more advances OSD• Most useful in treatment of aqueous and lipid Most useful in treatment of aqueous and lipid

deficienciesdeficiencies• The higher viscosity can produce some blurring The higher viscosity can produce some blurring

of vision and crusting on lids and lashesof vision and crusting on lids and lashes• Methylcellulose has been shown to slow Methylcellulose has been shown to slow

corneal regenerationcorneal regeneration

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CarboxymethylcelluloseCarboxymethylcellulose• Also known as carmellose sodiumAlso known as carmellose sodium• From group of synthetic cellulosesFrom group of synthetic celluloses

– carboxymethylcellulosecarboxymethylcellulose– methylcellulosemethylcellulose– hydroxypropylmethylcellulosehydroxypropylmethylcellulose

• Excellent surface contact timesExcellent surface contact times• Carmellose also has negative chargeCarmellose also has negative charge

– promotes adhesion to cornea and prolongs promotes adhesion to cornea and prolongs lubrication and comfortlubrication and comfort

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Cyclosporine Ophthalmic Cyclosporine Ophthalmic Emulsion 0.05%Emulsion 0.05%

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What Is RestasisWhat Is Restasis®®??• Ophthalmic Cyclosporine 0.05% emulsion• Cyclosporine: Immunomodulator • Cyclosporine inhibits T-cell activation thus

restoring natural tear production• Restasis® ophthalmic emulsion increases

tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with Keratoconjunctivitis Sicca (KCS)

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How Does RestasisHow Does Restasis®® Work? Work? (Cyclosporine 0.05% Ophthalmic Emulsion)(Cyclosporine 0.05% Ophthalmic Emulsion)

• Restasis® is believed to inhibit T-cell activation(Kunert et al, Arch Ophthalmol. 2000;118:1489)

– Activated T-cells produce cytokines that may result in•Recruitment of additional T cells (Stern et al, IOVS.

2002;43:2609)

•Increased cytokine production (Pflugfelder et al, Curr Eye Res. 1999;19:201)

•Neural signal to lacrimal gland that disrupts production of natural tears

– Leads to a decrease in quality and quantity of tears– Tissue damage in lacrimal glands and ocular surface

(Yeh et al, IOVS. 2003;44:124)

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Cyclosporine Is EffectivelyCyclosporine Is EffectivelyDelivered to Target TissueDelivered to Target Tissue

•Cyclosporine 0.05% ophthalmic emulsion– Instilled BID in rabbits

•Cyclosporine in surface tissues– Cornea—1550 ng/g- half life 40 hours– Conjunctiva—713 ng/g– Lacrimal gland—12 ng/g

• Intraocular cyclosporine– Aqueous humor—1.4 ng/mL– Retina—0.7 ng/g

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Pre CsA Post CsA

CD3

Dry Eye Dog Conjunctiva

62Omega 3 Fatty AcidsOmega 3 Fatty Acids

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Improvement in Meibum Scores with ω-3 Fatty Acids

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ω-3 fatty acids aid in clearing and thinning of meibomian gland secretions.

ω-3 fatty acids alter fatty acid saturation in meibum gland.

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Effect Of ω-3 Fatty Acids on the Dry Eye Network

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Lubricants:-Eye dropsLubricants:-Eye dropsEye DropsEye Drops• Most widely used lubricant modalityMost widely used lubricant modality• Used in the first instance by most Used in the first instance by most

Px’s suffering with OSDPx’s suffering with OSD• Available in unit or multi-dose Available in unit or multi-dose

formatsformats

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Thank You.Thank You.

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dry eye: a multifactorial disease

Health & Medicine