Fatemeh DashtiOptometrist . BSc -

MSc

Dry eye

Dry eye is a disease of the ocular surface attributable to different disturbances of the natural function and protective mechanisms of the external eye, leading to an unstable tear film during the open eye state.

Lacrimal system

Pre-corneal tear film -Superficial thin lipid layer

-Middle bulk aqueous layer

-Innermost mucous layer

Lipid layer Lipid layer is secreted by the meibomian glands &

gland of Zeiss.

Their function is: To reduce the evaporation of the aqueous layer. To increase the surface tention& asist in vertical

stability of the tear film To lubricate the eyelids.

Aqueous layer The middle layer is secreted by lacrimal gland

& has following functions: To supply atmospheric oxygen to the

avascular corneal epithelium Anti –bacterail function To reduce the irregularities of anterior corneal

surface To clean away the debris.

Mucin layer The inner layer is secreted by the conjunctiva

goblet cells,crypts of Henle & glands of Manz. It converts the corneal epithelium from hydrophobic to hydrophilic state.

Normal tear film Volume: 7-10 μl , avoid blinking 20-30 μl Thickness : 7microns Production : 1.2 μl/min (0.5-2.2) Turn over: 16% Tear evaporation (0.14 μl/min in 30% humidity) pH : 6.5-7.6 Surface tension : 40.7 dyne/cm Refractive index : 1.336 Osmolarity : 300-310 mOsm/l

Chemical properties of normal tear film 1- general tear composition

2- electrolytes

Water 98.2 g/100ml

Solids(total) 1.8 g/100ml

Ash 1.05 g/100ml

Sodium 120-170 mmol/l

Potassium 26-42 mmol/l

Calcium 0.3-2.0 mmol/l

Magnesium 0.5-1.1 mmol/l

Chloride 120-135 mmol/l

Bicarbonate 26 mmol/l

Chemical properties of normal tear film 3-Anitproteinasis

4-Nitrogenous substances

α1-Anti trypsin 0.1-3.0 mg%

α1-anti Chymotrypsin 1.4 mg%

Inter α trypsin inhibitor 0.5 mg%

α2 Macroglobulin 3-6 mg%

Total protein 0.668-0.800 g/1ooml

Albumin 0.392 g/100ml

Globulin 0.2758 g/100ml

Uric acid 0.005 g/100ml

Urea 0.04 mg/100ml

Total nitrogen 158 mg/100ml

Nonprotein nitrogen 51 mg/100ml

Chemical properties of normal tear film 5- glucose : 2.5 mg/100ml 6- sterols : Cholestrol & cholestrol esters 8-32

mg/1ooml 7-Miscellaneous

Citric acid 0.6 mg/100ml

Ascorbic acid 0.14 mg/100ml

Lysozyme 1-2 mg/ml

Amino acid 7.58 mg/100ml

Lactate 1-5mmol/l

Prostaglandin 75 pg PF/ml

Catecholamine 0.5-1.5 µg/ml

Healthy tears A complex mixture of

proteins, mucin, and electrolytes Antimicrobial proteins:

Lysozyme, lactoferrin Growth factors &

suppressors of inflammation: EGF, IL-1RA

Soluble mucin 5AC secreted by goblet cells for viscosity

Electrolytes for proper osmolarity

Tears in chronic dry eye Decrease in many proteins Decreased growth factor

concentrations Altered cytokine balance

promotes inflammation Soluble mucin 5AC greatly

decreased Due to goblet cell loss Impacts viscosity of

tear film

Proteases activated Increased electrolytes

Dry eye clasification

Tear deficient dry eye

Evaporative dry eye

Dry eye classification

Classification scheme for dry eye proposed by NEI/industry workshop

Dry eye Dry eye to afflict more than 7 million Americans

over the age of 40.

Risk factors: – Older age – Female sex – Postmenopausal status – Previous LASIK

aging The most common cause of severe dry eye is aging.

Aging is directly associated with a reduction in lipid production, resulting in evaporative dry eye.

Over time your body produces less oil- 60% less at age 65 than at age 18.

The incidence of severe dry eyes over the age of 65 is around 75%.

Most susceptible group to dry eye Post menopausal women Patient of 50 yrs plus group Patient on diuretics , beta blockers , psychotropics & oral

acne medication Rheumatoid arthritis patient People exposed to heat and dust Patient with blepharitis (MGD) Environmental Stresses

Contact Lens Wear Wind Air Pollution– Low Humidity: Heating/Air Cond.Low Humidity: Heating/Air Cond.– Lack of SleepLack of Sleep– Use of Computer TerminalsUse of Computer Terminals

Medications That May Contribute to Dry Eye Disease

Systemic Topical

Antihypertensives Antiandrogens Anticholinergics Antidepressants Cardiac Antiarrhythmic

Drugs Parkinson’s Disease

Agents Antihistamines

o Preservatives in tears

EnvironmentEnvironmentMedicationsMedicationsContact LensContact LensSurgerySurgery

Rheumatoid ArthritisRheumatoid ArthritisLupusLupusSjögren’sSjögren’sGraft vs HostGraft vs Host

PostmenopausePostmenopauseMeibomian Meibomian Gland DiseaseGland Disease

Symptoms of Ocular Surface DiseaseSymptoms of Ocular Surface Disease

InflammationInflammation

TearTearDeficiency/Deficiency/InstabilityInstability

IrritationIrritation

Current Triggers of Dry Eye Disease

Common symptomso – ocular discomforto – irritation such as scratchiness, grittiness, foreign

body sensation, burning, blurring, and itching

Correlations between symptoms, clinical signs, and diagnostic test results are variable

symptoms

Dry eyeOur understanding of dry eye has evolved from

considering:

Tear volume insufficiency

to

Tear film instability with underlying

inflammation due to altered tear composition

Propose mechanism of ocular surface inflammation in dry eye

Dry eye : HistoryExacerbation by certain activities (reading or

watching TV, or environment (low humidity or

smoky)

patients With dry eye tend to get worse at night ,

while patients with predominantly MGD are worse

in the morning

Symptomatic response to artificial tears support the

diagnosis of dry eye

Dry eye : historyPast ocular history :

contact lens, allergy, herpes infection, corneal

surgery, topical medications

Past medical history :

autoimmune disease, diabetes, neurological disease

Medications:

Complete list of the patient’s medications

Dry eye diagnostic tests

Type of evaluation Test

Tear secretion Schirmer I,John”s test, cotton thred test, Dye clearance test, Fluorophotometery

Tear stability Invasive BUT- NoninvasiveBUT

Tear film integrityEpithelial integrity

Rose bengal staining

Physical feature Osmolality , PH, Ferning evaporation rate

Chemistry Electrolytes, Protein(lysozyme, lactoferin)

Histology Imperssion cytology, lacrimal gland biopsy, minor salivary gland biopsy

Entery level tests for dry eye

Tear break – up time (TBUT)

Fluorescein clearance test

Tear film osmolarity

Tear break up- time test

Tear break up- time test Indicate of tear film insatiability in all different

causes of dry eye With fluorescein (invasive) –reflex tearing Non invasive (toposcope)

Values of < 10s are considered abnormal

Values of 5-9s are borderline dry eye

Values of < 5s are clearly indicative of

dry eye

NITBUT

NITBUT

Fluorescein clearance test (FCT) Delayed clearance of tears from the eye is thought to

be a contributing factor in pathogenisis of dry eye

Tear turn over is important for:

removing inflammatory cytokines

providing fresh supply of growth factors

Delay tear clearance strongly correlates with ocular irritation symptoms independent of aqueous tear production

Fluorescein clearance test (FCT)Standardized amount of fluorescein is placed in cojunctival

sac and tear turn over rate is determined by persistent of fluorescein in tears at specific timepoints later

To detect amount of residual fluorescein is using Schirmer

strip to collect fluorescein –stained tears.

Fluorophotometer: quantify amount of fluorescein persisting in eye

– Minimally stimulated tear samples collected

– using micro tube from Inferior tear meniscus 15 minute

after 5μl of 2% fluorescein

Fluorescein clearance test (FCT)

Tear film osmolarity In dry eye tear film is in a hyperosmolar state:

Decrease productionDecrease production

Decrease volumeDecrease volume

Decrease lipidDecrease lipid

Decrease stabilityDecrease stability

Increase evaporationIncrease evaporation

Tear film osmolarity

Lacrimal gland disease

Decreased corneal sensation

Increased palpebral fissure

Meibomian gland dysfunction

Decreasde sensation

Increased evaporation

Increased tear osmolarity

Tear film osmolarity Values higher than 312 mOsol / Liter are diagnostic

of dry eye:

– 90% sensitivity

– 95% specificity

A commercial osmometer specifically designed to test nanometer volume of tear is now in use but is not widespread due to cost consideration

Normal osmolarity : 300-310 mosm/l

Tear film osmolarity

Condition Expected range of value

Normal < 312 mosm/l

Borderline dry eye 312- 323 mosm/l

Moderate/severe dry eye > 323 mosm/l

Secondary tests to determine the specific causes of the dry eye Schirmer test Diagnostic dye staining Nasolacrimal reflex Serum auto antibodies Meibomian gland evaluation Impression cytology Conjunctiva and cornea sensation Tear protein analysis

Schirmer test

Schirmer test The most commonly used technique for assessment

of tear secretion described in 1903 (aqueous production)

In patients with dry eye there is not a strong correlation between the level of aqueous tear production and the severity of dry eye

Schirmer test The Schirmer strip is placed over the lateral third

of the lower lid If using an anesthetic , adequate time should be

given after the drop to minimize reflex tearing from the burning sensation due to drop.

Schirmer I (without anesthesia ) : basic and reflex secretion

Schirmer II (with anesthesia ): basic secretion

A cut of 10 mm to indicate aqueous tear deficiency

Schirmer I test in 5 mm of wetting after 5 min

– very specificity (90%)

– 25% sensitive for diagnosis dry eye

Schirmer test

<5mm wetting in 5 min is sign of clinical dry eye 5-10mm wetting suggests borderline dry eye >10mm wetting represents normal secretion

Phenol red test

Diagnosting dye stainings The installation of dyes is a common method to

detect ocular surface epithelial pathology

associated by dry eye:

– Fluorescein sodium

– Rose bengal

– lissamine green

Diagnosting dye staining Fluorescein is the most commonly used :

– stains the cornea more than conjunctiva

– significantly greater amount of staining in Sjogren’s aqueous tear deficiency

Diagnosting dye staining Rose bengal unlike fluorescein which stains tissue

by penetrating into intercellular spaces stains:

– devitalized epithelial cell

– healthy epithelial cells when they are not protected by a healthy layer of mucin.

Rose bengal staining In interpretation of rose bengal staining in dry eye is

based on two factors :(Van Bijsterveld score)

– intensity and location

– scale of 0 – 3 in 3 area Conjunctiva usually stains more intensity than the

cornea

The intensity of rose bengal staining correlates well with the degree of aqueous tear deficiency

Diagnosting dye staining Lissamine green B similarly stains with rose

bengal:

– produces much less irritation

– staining pattern to be identical to rose bengal

– When score >5 indicated diagnosis of Sjogren’s syndrome

Diagnosting dye staining

Rose bengal staining Inferior epitheliopathy

Nasolacrimal reflex Can be elicited by stimulating the nasal mucosa

under the middle turbinate with a cotton – tipped applicator:

– increase tearing dramatically in non-Sjogren’s syndrome

– no increase in Sjogren’s syndrome

Serum auto antibodies Its criteria used to diagnosis of Sjogren’s syndrome Presence one or more these auto antibodies:

– ANA (titer≥ 1:160)

– RF (titer≥ 1:160)

– anti – Ro (ss-A) or anti – La (ss-B) presence of anti – M3 muscarian cholinergic

receptor anti body in a high percentage of Sjogren’s syndrome

Meibomian gland evaluation Diagnosis is made by following pathologic signs:

– ductal orifice metaplasia (white shafts of keratin in the orifices)

– increase turbidity and viscosity of the expressed secretions

– reduced expressibility of secretion

– morphologic abnormality of the gland acine and ductules

Meibomian gland evaluation-NORMAL

Meibomian gland evaluation-MGD

Impression cytology In advanced dry eye the epithelium undergoes pathology

changes: – squamous metaplasia – decreased density of goblet cells

a small piece of nitrocellulose membrane applied against the conjunctival surface

Methods to grade the extent and severity of squamous metaplasia based on :

-Loss of goblet cells -Enlargement and increase cytoplasmic / nuclear ratio -Keratinization

Overall impression cytology is a highly sensitive method

Conjunctiva and cornea sensation Decreased corneal sensation can be both the cause and

the effect of dry eye

Sensory denervation may lead to dry eye by : -Decreasing the afferent signal that drive aqueous tear

secretion -Reducing the blink rate (leading to ocular surface

desiccation) -Altering growth and differentiation of ocular surface

epithelium through diminished trophic influence of trigeminal nerve

-Auto immune sensory neuropathy and sensory neural degeneration due to inflammation or chronic over stimulation

Corneal esthesiometry

Tear proteins analysis Lysozyme accounts for 20-40% of total tear protein:

– its measurement is based on the enzyme ability to lyse a suspension of the bacterium , micrococcus lysodeikticus

– Tear lysozyme level are decreased in ATD

– more sensitive test than either the Schirmer test or rose bengal staining

– main disadvantage is lack of specifity

– false positive in HSV keratitis , bacterial conjunctivitis , smog irritation and malnutrition

Tear protein analysis

Lactoferrin is normally produced by the lacrimal gland and used as a relative indicator of lacrimal gland function, measured by lacto card.

Epithermal growth factor to be lower in tears with Sjogren’s syndrome and there is inverse correlation with severity of dry eye.

VALUES IN NORMAL TEAR AND DRY EYE

INTERFEROMETRY OF THE LIPID LAYER

Tearscope –plus lipid layer thickness(LLT)

Tearscope –plus lipid layer thickness(LLT) Five main categories of normal lipid appearance are

graded in order of increasing thickness and visibility: Open meshwork Tight meshwork Waves Amorphous Colors The abnormal appearances of tle lipid layer are: Globular Abnormal colors Lipid break-up

Tearscope –plus lipid layer thickness(LLT)

Waves Colors

CRYSTALLIZATION : FERNING TEST Tear film composition affects the way in which a

coolected sample dries on a glass slide. This test is based on mucus ferning patterns that have been used in cervical smear testing. Tears are collected with a glass capillary & placed on a glass slide & left to dry at room temperature. The sample is then observed in white light or by polarized microscopy & classified in to 4 grades according its appearance following crystallization.

The tears of dry eye patient exibit less ferning than those of normal patients.

Test may reflect the quality of tear protein profile.

Ferning test

Levels of severity of dry eye disease

Treatment

treatment Dry eye /ocular surface disorder is :progressive , life-long ,inflammatory , symptomatic disease. Treatment must aim for :*explanation of disease & psychotherapy*prevention of aggregative factors.*treatment of the cause (inflammation).*stimulation of tear secretion .*Replacement of tear .*Maintenance of tear .*treatment of ocular surface disorders. present treatments are only palliative , Although Dry

eye isn’t curable, But new trials are against the causes.

prevention of aggregative factors A: medications ( Atropines ,anti- histaminic, , Beta-

blockers , contra- septives ,diuretics, Retinoid , chemotherapy , - anti-glaucoma, preservatives)

B: environment (low humidity – dust –smoke – allergens-cosmetics)(≠ air conditioners - +humidifiers )

C: long periods of near work (computer -…) – overnight jobs

D: viral inf. , allergy . E : pregnancy – Hormone replace therapy F: C.L. G: some ocular surgeries (refractive surgery –

blepharoplasty keratoplasty - ECCE )

Dry Eye : lubricants:Replacement of tear Artificial tear (drops -gel – pomade –spray –inserts-

…) Indications of use :

A) symptomatic relief of dry eye.

B) symptomatic relief of irritants (wind – sun -….)

C) symptomatic relief of exposure .

D) refreshment of contact lenses & prosthesis.

E) as basis for preparing topical medications . ( e.g. ; fort antibiotic drop)

Artificial Tear Eye drops Solvent water Active ingredient water soluble polymers Viscosity polymers concentration Preservatives prevention of contamination balanced tonicity Inorganic electrolytes NaCl&KCL equivalent to 0.9%

NaCl P.H buffers Anti-oxidants Sometimes Vit. A Lipids phospholipids

Artificial Tear Eye dropsActive ingredient ( water soluble polymers)

provides viscosity & tear film stability Hyaloronic acid Cellulose & methylcellulose & their derivatives: hydroxypropyl Cellulose hydroxyethyl Cellulose hydroxypropyl methylcellulose (HPMC) 0.2% & 0.3% & 0.5% carboxymethylcellulose 0.25% & 0.5% & 1% Carmelosa (low viscosity) Polyvinyl alcohol 1.4% Povidine 0.6% Glycerin 0.3% & 1% dextran 70 propylene glycol (PG) polyEthyleneGlycol (PEG 400) polycarophil hydroxypropyl Agar (Systane R)

Artificial Tear Eye drops Mechanisms of effect : classical view of the tear film : a 10-micron film of aqueous

tears, sandwiched between thin layers of lipid and mucous.mucous promoting tear adherence. lipid preventing evaporation & This it has been challenged recently that :

1) the tear film may be considerably thicker than 10 microns ,&2) dissolved mucus and protein may form a structured aqueous

gel that adheres to the epithelium and covers its irregularities, thus providing a high-quality optical surface

Artificial tear provides a viscous layer which : Stabilize & thicken pre-corneal tear film . prolongs tear film B.U.T. keeps ocular surface wet & lubricated . helps to repair ocular surface damage keeps ocular surface smooth(improves decreased vision &

aberrations)

Artificial Tear Eye drops

Due to temporary effect of these drugs,

Consider for other long term therapeutic options

Artificial Tear Eye drops Preservatives : Benzalkanium chloride (0.01% for eye-drops , 0/02% for C.L.

solutions & 1% as disinfectant ) Chlorbutanol . Chlorhexidine (0.002- 0.005%) Thimerosal & mercuric oxides (0.002- 0.005% ) EDTA . Methylparaben . Propylparaben . Polyquad ( SPK) Purite . Potasium sorbate . Sodium perborate (air touch changes to H2O2,then H2O &

O2) Sorbic acid (less toxic)

Ocular complications of Preservatives pigmentation: (mercury deposits in lids –conj. – cornea

& lens ) Irritation: (redness – photophobia – lacrimation –burning

-….) dermatitis & urticaria & eczema – blepharitis – allergic: papillary & follicular conjunctivitis –pseudo

membrane pemphigoid – symblepharon- SPK – corneal edema – panus –corneal opacity – adherence to CL. & CL. intolerance – ocular surface mal-function & inflammation

Toxic: Epith. Cell exfoliation . SPK

Due to side effects of preservatives , now preservative – free artificial tears are made , but most of them are in unit dose form (chance of contamination),Also they are expensive.

Preservative – free artificial tears

Artificial Tear Eye drops Dosage & frequency of use :

As frequent as needed

Q 15min ~ occasionally if necessary

Some believe & advise for a scheduled regimen : (e.g. Q 6h )

Artificial Tear Eye drops Storage : Keep out of the reach of children. Don’t keep outdated medicine . keep away from direct light & air ( air-tight bottles) keep between 8` ~ 35` (room temperature) (no need for refrigerator ) [Store away from heat

(>40`)] care for bottle head contamination ( ≠ hand touch )

(close immediately after use ) after opening ,use in a maximum period of 15 -30

days !

Gel tears Less greasy than pomades

Emollients : simple Eye pomades Base : Lanolin , Petrolatum , mineral oil , Also

electrolytes ,usually no preservatives . They form an oily layer on ocular surface Which

disseminates by blinking . They remain longer than drops . They are used for : Sever dry eye Exposure keratopathy Night time use in dry eye Use 0.25 -0.50 inch /fornix . It causes slight irritation & temporary blurred vision . Don`t use it with C.L. & Don`t Use pomades before eye

drops .

Emollients : simple Eye pomades

slow release lubricants : [Lacrisert] each rod contains 5mg hydroxypropyl cellulose (It is

preservative free ) It imbibes water , swells ,dissolves. effect begins after 1 h & remains for 14–24 h {So 1

insert / morning is enough for 1 day} It is inserted in lower fornix .[ education is

necessary (either by doctor or written directory of drug package)]

Disadvantages : More expensive .(~ 55 US$ / box = 1US $ / day) Manual dexterity is needed . Sometimes blurred vision due to thick tear film (use

BSS or physiologic serum) Dislocation into palpebral fissure & irritation (even

loss) Complications as: eye redness or discomfort ;

watering of eyes .photophobia; matting or stickiness of eyelashes; swelling of eyelids.

artificial tear spray

Less chance of contamination .

Tears Again Liposome spray (10cc) ($15) ( occusoft)

Natures Tears Eye Mist (10cc) ($7) (all scripts)

Dry Eye : stimulation of tear secretion Secretagugoes (cholinergic agonists & Muscarinic )

purinergic receptor (p2y2) agonist [Diquafosal (Inspire)]

stimulates mucin &tear secretion of Goblet cells. Oral Pilocarpine (Salagan) (effective for dry mouth

not dry eye- 5mg tab x 4-6/day) IBMX (isobutyl-methyl xanthin) Eledoisin (endekapeptides)

Dry Eye : treatment of the cause A) MGD – allergy B) Lagophthalmos & exposure C) ocular surface disorders,

proptosis ,retraction ,Ectropion ,trichiasis ,pterigium. D) inflammation :

systemic treatment of rheumatoid & other causes of Sjogren’s synd, topical anti- inflammatory drugs :

recent clinical trials demonstrated effectiveness of topical Cyclosporin A 0.05%

Dry Eye : surgical treatment Usually when medications doesn’t alleviate

symptoms.

Prevention of tear drainage (surgical Punctal occlusion)

Prevention of tear evaporation (Tarsorhaphy & cantorhaphy)

Transplantation of secretory glands

Dry Eye : maintenance of tear Temporary (absorbable collagen inj. & plugs –

Gelatin ) ( N-buthyl cyanoacrylate up to 2.5 w) Reversible (Silicon – acrylamide & smart plug) Permanent (thermal & electro-cautery –laser )

( conj. Graft) Usually at first ,temporary collagen plugs of only

lower punctom;If suitable then permanent plugs. If there is reflex tearing ,only lower punctom,

otherwise both punctoms. If still inadequate ,then cantorhaphy.

collagen discs & plugs

Silicon plugs

Complications: Irritation ( erosions -GPC –allergic dermatitis – symblepharon -..) Pyogenic granoloma Adherence of bacteria to plug & infection Extrusion Migration into canaliculs (canaliculitis – dacryocystitis)

Smart plugs (thermo-sensitive acrylic) Best performance under :Slit lamp examination (Magnification & illumination)

Cold light

Topical anesthesia

Needs a punctom dilator & forceps

Permanent Punctal occlusion In mild cases can cause epiphorea , in sever

KCS has no effect (there is no tear )

so it’s contra-indicated if :

Schirmer >10mm

Normal cornea

Temporary conditions

Tarsorhaphy & cantorhaphy Usually when corneal abnormality

Transplantation of secretory glands

Dry eye treatment recommendations by severity level

Dry eye treatment recommendations by severity level

Dry eye treatment recommendations by severity level

Dry eye treatment recommendations by severity level

Never walk on the traveled path, because it only leads you where the others have been.

Graham Bell