tgs referat

7/25/2019 Tgs Referat

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KHURANA , 2007The dry eye per se is not a disease entity, but a symptom complex occurring as a

seuelae to de!iciency or abnormalities o! the tear !ilm"Etiology

1. Aqueous tear deficiency. #t is also $no%n as keratoconjunctivitis sicca. #t is

seen in conditions li$e congenital alacrimia, paralytic hyposecretion, primary and

secondary &'ogren(s syndrome, Riley )ay syndrome and idiopathic

hyposecretion"

2. Mucin deficiency dry eye. #t occurs %hen goblet cells are damaged, as in

hypo*itaminosis A +xerophthalmia and con'uncti*al scarring diseases such as

&te*ens-.ohnson syndrome, trachoma, chemical burns, radiations and ocular

pemphigoid"

3. Lipid deficiency and abnormalities. /ipid de!iciency is extremely rare" #t has

only been described in some cases o! congenital anhydrotic ectodermal dysplasia

along %ith absence o! meibomian glands" Ho%e*er, lipid abnormalities are uite

common in patients %ith chronic blepharitis and

chronic meibomitis"

4. Impaired eyelid function. #t is seen in patients %ith ell(s palsy, exposure

$eratitis, dellen, symblepharon, pterygium, nocturnal lagophthalmos

and ectropion"

5. Epitheliopathies. 1%ing to the intimate relationship bet%een the corneal

sur!ace and tear !ilm, alterations in corneal epithelium a!!ect the stability

o! tear !ilm"

Clinical features

Symptoms suggesti*e o! dry eye include irritation, !oreign body +sandy sensation,

!eeling o! dryness, itching, non-speci!ic ocular discom!ort and chronically sore

eyes not responding to a *ariety o! drops instilled earlier"

Signs o! dry eye include presence o! stringy mucus and particulate matter in the

tear !ilm, lustureless ocular sur!ace, con'uncti*al xerosis, reduced or absent

marginal tear strip and corneal changes in the !orm o! punctate epithelial erosions

and !ilaments"

Tear film tests


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These include tear !ilm brea$-up time +UT, &chirmer- # test, *ital staining %ith

Rose engal, tear le*els o! con'uncti*al impression cytology" 1ut o! these UT,

&chirmer-# test and Rose engal staining are most important and %hen any t%o o!

these are positi*e, diagnosis o! dry eye syndrome is con!irmed"

1. Tear film break-up !"T#. #t is the inter*al bet%een a complete blin$ and

appearance o! !irst randomly distributed dry spot on the cornea" #t is noted a!ter

instilling a drop o! !luorescein and examining in a cobalt-blue light o! a slit-lamp"

UT is an indicator o! adeuacy o! mucin component o! tears" #ts normal

*alues range !rom 34 to 54 seconds" 6alues less than 30 seconds imply an unstable

tear !ilm"

2.Schirmer-I test" #t measures total tear secretions" #t is per!ormed %ith the helpo! a 4 54 mm strip o! 8hatman-93 !ilter paper %hich is !olded 4 mm !rom one

end and $ept in the lo%er !ornix at the 'unction o! lateral one-third and medial

t%o-thirds" The patient is as$ed to loo$ up and not to blin$ or close the eyes A!ter

4 minutes %etting o! the !ilter paper strip !rom the bent end is measured" Normal

*alues o! &chirmer-# test are more than 34 mm" 6alues o! 4-30 mm are suggesti*e

o! moderate to mild $eratocon'uncti*itis sicca +K:& and less than 4 mm o!

se*ere K:&"3.$ose !engal staining. #t is a *ery use!ul test !or detecting e*en mild cases o!

K:&" )epending upon the se*erity o! K:& three staining patterns A, and

: ha*e been described ;:( pattern represents mild or early cases %ith !ine

punctate stains in the interpalpebral area< ;( the moderate cases %ith extensi*e

staining< and ;A( the se*ere cases %ith con!luent staining o! con'uncti*a and

cornea"

TreatmentAt present, there is no cure !or dry eye" The !ollo%ing treatment modalities ha*e

been tried %ith *ariable results

1.Supplementation %ith tear substitutes. Arti!icial tears remains the mainstay in

the treatment o! dry eye" These are a*ailable as drops, ointments and slo%release

inserts" =ostly a*ailable arti!icial tear drops contain either cellulose deri*ati*es

+e"g", 0"24 to 0"7> methyl cellulose and 0"5> hypromellose or poly*inyl alcohol

+3"9>"


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2. Topical cyclosporine +0"04>, 0"3> is reported to be *ery e!!ecti*e drug !or

dry eye in many recent studies" #t helps by reducing the cell-mediated

in!lammation o! the lacrimal tissue"

3. Mucolytics, such as 4 percent acetylcystine used 9 times a day help by

dispersing the mucus threads and decreasing tear *iscosity"

4. Topical retinoids ha*e recently been reported to be use!ul in re*ersing the

cellular changes +suamous metaplasia occurring in the con'uncti*a o! dry eye

patients"

5. &reser'ation of e(isting tears by reducing e'aporation and decreasing

drainage.

Evaporation can be reduced by decreasing room temperature, use o! moistchambers and protecti*e glasses"

Punctal occlusion to decrease drainage can be carried out by collagen implants,

cynoacrylate tissue adhesi*es, electrocauterisation, argon laser occlusion and

surgical occlusion to decrease the drainage o! tears in patients %ith *ery se*ere

dry eye"


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Dry Eye Syndrome

=ohammad-Ali .a*adi, =) and &epehr ?ei@i, =)

1phthalmic Research :enter, &hahid eheshti Uni*ersity o! =edical &ciences,

Tehran, #ran

:orrespondence to =ohammad-Ali .a*adi, =)" ro!essor o! 1phthalmology,

1phthalmic Research :enter, B25 aidar!ard &t", oostan C &t", asdaran, Tehran

3DDDD, #ran< Tel ECF 23 224F 4C42, ?ax ECF 23 224C 0D07< e-

mail moc"oohayGida*a'am"

. 1phthalmic 6is Res" .ul 2033< D+5 3C2I3CF

httpJJ%%%"ncbi"nlm"nih"go*JpmcJarticlesJ=:550D309J

INTRD!CTIN

)ry eye is a disorder o! the tear !ilm %hich occurs due to tear de!iciency or

excessi*e tear e*aporation< it causes damage to the interpalpebral ocular sur!aceand is associated %ith a *ariety o! symptoms re!lecting ocular discom!ort"3)ry

eye syndrome, also $no%n as $eratocon'uncti*itis sicca +K:&, is a common

condition reported by patients %ho see$ ophthalmologic care and is characteri@ed

by in!lammation o! the ocular sur!ace and lacrimal glands"

)ry eye symptoms may be a mani!estation o! a systemic disease, there!ore timely

detection may lead to recognition o! a li!eIthreatening condition" Additionally,

patients %ith dry eye are prone to potentially blinding in!ections, such as bacterial

$eratitis2and also at an increased ris$ o! complications !ollo%ing common

procedures such as laser re!racti*e surgery"

Kno%ledge o! the pathophysiology o! dry eye has recently been impro*ed and the

condition is no% understood to be a multi!actorial disease, characteri@ed by

in!lammation o! the ocular sur!ace and reduction in tear production"5This

a%areness has led to the de*elopment o! highly e!!ecti*e therapies"
http://www.ncbi.nlm.nih.gov/pubmed/?term=Javadi%20MA%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Feizi%20S%5Bauth%5Dmailto:dev@nullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/#b1-jovr-6-3-192http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/#b2-jovr-6-3-192http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/#b3-jovr-6-3-192http://www.ncbi.nlm.nih.gov/pubmed/?term=Feizi%20S%5Bauth%5Dmailto:dev@nullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/#b1-jovr-6-3-192http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/#b2-jovr-6-3-192http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/#b3-jovr-6-3-192http://www.ncbi.nlm.nih.gov/pubmed/?term=Javadi%20MA%5Bauth%5D


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E"IDE#I$%&

Approximately 3 out o! 7 indi*iduals aged D4 to F9 years reports symptoms o! dry

eye o!ten or all o! the time"

9

=oss et al

4

reported the pre*alence o! dry eye to be39"9> in 5,722 sub'ects aged 9F to C3 years and noted that the pre*alence o! the

condition doubled a!ter the age o! 4C" &chein et al 9, in contrast, !ound no

correlation bet%een dry eye and age or sex, %hile other researchers ha*e reported

such associations to exist" A study on C2D sub'ects aged 90 years and older, !ound

a higher pre*alence o! dry eye in %omen %ho %ere also more li$ely to ha*e a dry

eye-related diagnosis or procedure"DAccording to another study, %omen

experienced a sharp increase in the pre*alence o! dry eye earlier than men, around

the age o! 94, roughly at the onset o! menopause"7

pidemiological studies on dry eye syndrome suggest *ast di!!erences in

pre*alence" The di!!iculty in determining the extent o! the disease stemmed in part

!rom limited understanding o! the pathophysiology o! dry eye" As such,

de!initions o! dry eye syndrome di!!ered !rom one study to another, ma$ing

results di!!icult to compare"FThis is !urther complicated by the lac$ o! a

standardi@ed clinical testing protocol to diagnose the condition"

C$INIC'$ T&"ES

The precorneal tear !ilm is an essential component o! the ocular sur!ace and can

be subdi*ided into an anterior lipid layer, a middle aueous layer and an

innermost mucin layer" These layers are produced by the meibomian glands, the

lacrimal gland and goblet cells o! the con'uncti*a, respecti*ely"2The tear !ilm

lubricates the eye, maintains nutrition and oxygenation o! ocular structures, acts as

a re!racti*e component and helps remo*e debris !rom the ocular sur!ace" #n terms

o! tear production, dry eye can be di*ided into tear de!icient and e*aporati*e

types"5Tear de!iciency dry eye can !urther be subdi*ided into non-&'ogren

syndrome and &'ogren syndrome, %hich is an autoimmune disease associated %ith

lacrimal and sali*ary gland lymphocytic in!iltration" *aporati*e dry eye can be

di*ided into meibomian gland disease +=L) and exposure-related dry eye" 9,4#n
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yet another group o! patients, mucin de!iciency due to &te*ens-.ohnson syndrome

or ocular cicatricial pemphigoid is the underlying mechanism o! dry eye"F

ETI$%&

)ry eye syndrome is associated %ith a long list o! causes %hich can be di*ided

into primary and secondary" )ry eye may de*elop secondary to in!lammatory

disease +e"g" *ascular, allergic, en*ironmental conditions +e"g" allergens, cigarette

smo$e, dry climate, hormonal imbalance +e"g" perimenopausal %omen and

patients under hormone replacement therapy, and contact lens %ear" &ystemic

disorders, such as diabetes mellitus, thyroid disease, rheumatoid arthritis and

systemic lupus erythematosus can also lead to dry eye" #n addition, neurotrophic

de!iciency, pre*ious eye surgery +such as corneal transplantation, extracapsular

cataract procedures and re!racti*e surgery, or long-term use o! medications %hich

create hypersensiti*ity or toxicity in the eye can predispose to dry eye" =any

systemic medications, such as diuretics, antihistamines, antidepressants,

psychotropics, cholesterol lo%ering agents, beta-bloc$ers and oral contracepti*es

may also be associated %ith dry eye"C,30

ostmenopausal %omen may be the largest at ris$ group< this is due to a decrease

in hormonal le*els leading to loss o! anti-in!lammatory protection and decreased

lacrimal secretion"C

"'T(%ENESIS

&tudies per!ormed on the proteomic pro!ile o! the ocular sur!ace comparing dry

%ith normal eyes using en@yme-lin$ed immunosorbent assay +/#&A has

re*ealed a decrease in lacto!errin and epidermal gro%th !actor in dry eyes" A

protein !ound in acinar cells o! the lacrimal gland, AM-4, %as sho%n to be

increased in the &'ogren type o! dry eye syndrome, indicating possible lea$age o!

such proteins into the tear !ilm due to lymphocytic in!iltration o! the lacrimal

gland"C&olomon et al30!ound an increase in in!lammatory cyto$ines interleu$in 3

+#/-3 alpha and #/-3 beta in both =L) and &'ogren syndrome, indicating

increased protease acti*ity on the ocular sur!ace, mainly in the con'uncti*al

epithelium" Apart !rom #/-3, #/-D %as also increased in &'ogren
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syndrome,33 indicating an in!lammatory process in this subgroup o! dry eye"

Another study in*estigating sialic acid, a component o! mucin in tears, !ound a

lo%er le*el in dry eye patients compared to controls, indicating a change in

uantity and uality o! tear !ilm glycoproteins in dry eye disease" 32The change in

tear protein pro!ile in dry eye syndrome, especially in &'ogren disease, has shed

light on mechanisms o! dry eye"

C$INIC'$ S"T#S

&ymptoms associated %ith dry eye may include ocular burning, !oreign body

sensation, stinging sensation, pain, photophobia and blurred *ision"CI32

)R*!"

As dry eye syndrome may be associated %ith a *ariety o! causes, it is important to

per!orm a comprehensi*e e*aluation be!ore proceeding to treatment" A care!ul

history should be obtained %ith particular attention to diabetes, thyroid disease,

connecti*e tissue disorders and contact lens %ear" re*ious ocular procedures,

such as laser re!racti*e surgery are also important in determining the cause o! dry

eye syndrome" =any medications can a!!ect tear secretion and it is important tore*ie% the patient(s drug history" A care!ul clinical examination should include slit

lamp biomicroscopy to determine ocular sur!ace status and diagnose associated

meibomian gland dys!unction, blepharitis or meibomian seborrhoea" xamination

o! the tarsus and !ornices !or scars and symblepharon is important to exclude pre-

existing &te*ens-.ohnson syndrome, other ocular sur!ace in!lammatory disease or

pre*ious in!ections" A care!ul loo$ at the con'uncti*a and cornea %ould be help!ul

to assess the se*erity o! dry eye< an increase in staining is obser*ed in more se*erecases" 1ccasionally, corneal !ilaments and edema may be obser*ed in extremely

dry eyes" #t is important to be thorough in the examination to !ind other areas o!

in*ol*ement" :ertain systemic causes o! dry eye, such as rheumatoid arthritis and

systemic lupus erythematosus not only in*ol*e the ocular sur!ace but also cause

in!lammation o! the episclera or sclera, and occasionally the posterior segment"

DI'%NSTIC CRITERI'
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1hashi et alCsuggested that a combination o! +3 dry eye symptoms, +2

suggesti*e !indings on &chirmer + 4 mm %etting a!ter 4 minutes and !luorescein

clearance tests, and +5 !luorescein and Rose engal staining +O 5E %ould *eri!y

clinical dry eye" 1ther authors ha*e de*ised di!!erent diagnostic criteria and there

is no consensus in this regard"35I34To !urther complicate the issue, symptoms and

signs do not al%ays correlate %ell %ith each other in many patients"39

To con!irm a diagnosis o! dry eye, certain tests are reuired in the clinical setting"

Tear !ilm stability can be assessed %ith the !luorescein tear brea$-up time test

+TUT" This measures the inter*al in seconds bet%een a complete blin$ and the

!irst appearance o! a dry spot or discontinuity in the precorneal !ilm" atients %ith

TUT less than 5 seconds are classi!ied %ith clinical dry eye" #! there is aueous

de!iciency, the tear meniscus %ill appear to be thin, less than 3 mm in height"

Another clinical method !or assessing the se*erity o! dry eye is ocular sur!ace dye

staining" ?luorescein and Rose engal stains can be used as diagnostic dyes"

?luorescein staining occurs %hen the epithelial barrier is disrupted and ser*es as a

good test !or e*aluation o! dry eye" Rose engal stains de*itali@ed epithelial cells

on the con'uncti*a and ser*es a similar purpose" Ho%e*er, Rose engal causes

transient irritation a!ter instillation and may be less com!ortable" atients %ith dry

eye syndrome can sho% signs o! punctate epitheliopathy and e*en corneal

abrasions"

Another important clinical test is the &chirmer test %hich measures aueous tear

production" This test is easy to per!orm in clinical settings but may be sub'ect to

errors" &trips o! !ilter paper, called &chirmer strips, are placed on the lo%er lid

inside the tarsal con'uncti*a" The patient is allo%ed to blin$ normally and the tear

strip is scored according to the degree it %ets in 4 minutes" There are t%o %ays to

per!orm this test +a %ithout topical anesthesia +&chirmer test # %hich e*aluates

the ability o! the ocular sur!ace to respond to sur!ace stimulation< and +b under

topical anesthesia +&chirmer test ## %hich e*aluates basal tear secretion" atients

%ith tear soa$ing less than 30 mm are considered to ha*e clinical dry eye and eyes

%ith less than 4 mm %etting are diagnosed as se*erely dry" Ho%e*er, it is
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important to note that &chirmer tests are sub'ect to en*ironmental and physiologic

changes %ith *arying results o*er time"

#'N'%E#ENT

=anagement o! dry eye depends on the cause and se*erity o! the condition"

Arti!icial tears are used to replenish the de!icient aueous layer o! the tear !ilm

and to dilute in!lammatory cyto$ines" Arti!icial tears are a*ailable in di!!erent

*iscosities and preser*ed or non-preser*ed preparations" #! the tear de!iciency is

se*ere, more *iscous agents such as gels or ointments can be used to maintain

longer protection" &ince K:&, including &'ogren syndrome, is associated %ith

in!lammation, the use o! topical steroids or non-steroidal anti-in!lammatory

medications is sometimes help!ul" Topical antibiotics may be necessary i! the dry

eye syndrome is associated %ith corneal complications" =eibomian gland disease

%arrants prescription o! eyelid hygiene and %arm lid compresses, together %ith

topical or e*en systemic antibiotics such as doxycycline"35,39

?or more se*ere disease, topical immunomodulating agents, such as cyclosporine-

A drops, may become necessary" &tudies ha*e demonstrated an impro*ement in

signs and symptoms o! dry eye, together %ith reduction in con'uncti*al T-cell

in!iltration and tear cyto$ine le*els !ollo%ing the use o! cyclosporine-A drops"34,3D

#n *ery se*ere cases, !reuent topical lubricants may not su!!ice" &tudies ha*e

loo$ed into the use o! autologous serum as topical eye drops !or se*erely dry eyes

%ith impro*ement reported a!ter prolonged treatment regimens ranging !rom 9 to

D %ee$s" Lro%th !actors pro*ided by autologous serum are important !or

epithelial healing" Autologous serum can be prepared by centri!uging *enous

blood and diluting it %ith balanced salt solution to 20>"37

andage contact lenses are sometimes use!ul in dry eyes to minimi@e the extent o!

exposure $eratopathy" &e*ere dry eye disease %ith corneal complications may

%arrant surgical inter*ention such as punctal occlusion" /acrimal puncta can be

plugged temporarily %ith absorbable collagen plugs or !or a longer period o! time

%ith non-absorbable plugs %hich need to be remo*ed i! problems arise"

ermanent punctal occlusion can also be per!ormed to pre*ent tears !rom draining
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through the drainage system" ?or patients %ith dry eye secondary to connecti*e

tissue disease, it is important to collaborate %ith internists and optimi@e treatment

!or the systemic disorders" #n *ery se*ere dry eye secondary to ocular sur!ace

disease +such as chemical in'ury, &te*ens-.ohnson syndrome, or ocular cicatricial

pemphigoid, amniotic membrane transplantation, tarsorrhaphy, $eratoplasty,

limbal stem cell transplantation, or e*en ocular prostheses, such as rigid scleral

contact lenses, may become necessary !or restoration o! *ision"3F

'nti+Inflammatory T,era-y

e!ore recent !indings re!ramed our understanding o! dry eye, treatment %as

limited to the use o! arti!icial tears, ointments, and non-pharmacologic therapies,

such as punctal occlusion, en*ironmental control, moisture-retaining eye%ear, and

surgery" ach had limited e!!icacy and !e% resulted in long-lasting impro*ement

in patients( uality o! li!e" Today, dry eye can be treated success!ully %ith anti-

in!lammatory agents, the most bene!icial o! %hich is topical cyclosporine" :linical

e*idence indicates that anti-in!lammatory therapy inhibits the production o!

in!lammatory mediators and reduces the signs and symptoms o! K:&"

Corticosteroids

:orticosteroids are potent anti-in!lammatory agents routinely used to control

in!lammation in *arious organs" :orticosteroids ha*e multiple mechanisms o!

action" They %or$ through traditional glucocorticoid receptor mediated path%ays

%hich directly regulate gene expression and also by non-receptor path%ays that

inter!ere %ith transcriptional regulators o! pro-in!lammatory genes" Among their

multiple biological acti*ities, corticosteroids inhibit the production o!in!lammatory cyto$ines and chemo$ines, decrease the synthesis o! matrix

metalloproteinases and lipid mediators o! in!lammation +e"g" prostaglandins,

reduce the expression o! cell adhesion molecules +e"g" intercellular adhesion

molecule 3, and stimulate lymphocyte apoptosis"3CI23&teroids ha*e been reported

to decrease the production o! a number o! in!lammatory cyto$ines, including #/-3,

#/-D, #/-F, tumor necrosis !actor-alpha +TN?-P, and granulocyte macrophage

colony-stimulating !actor +L=-:&?, and matrix metalloproteinase C +==-C by
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the corneal epithelium"22:orticosteroids ha*e been success!ully used !or treatment

o! corneal epithelial disease due to dry eye in se*eral clinical studies"25I24

Cyclos-orine

:yclosporine A +:sA is a lipophilic cyclic undecapeptide isolated !rom the

!ungusHypocladium inflatum gams"2D#t %as !irst introduced !or clinical use as an

immune-suppressant drug !or pre*ention o! organ transplant re'ection in 3CF5"

The immuno modulatory e!!ect o! this agent has been pro*en to be bene!icial !or

treatment o! a broad range o! disorders such as psoriasis, rheumatoid arthritis and

ulcerati*e colitis %hich ha*e an underlying in!lammatory basis" 1ne o! its

mechanisms o! action is inhibition o! calcineurin, a serineJthreonine phosphatase,%ith subseuent reduction in the expression o! certain genes in*ol*ed in T-cell

acti*ation such as #/-2, #/-9, #/-32"

The potential o! :sA !or treating dry eye disease has been demonstrated in se*eral

randomi@ed double-mas$ed clinical trials"27I2C

Tetracyclines and t,eir Deriaties

The tetracyclines ha*e anti-in!lammatory, as %ell as antibacterial, properties thatmay ma$e them use!ul !or management o! chronic in!lammatory diseases" These

agents decrease the acti*ity o! collagenase, phospholipase A2, and se*eral matrix

metalloproteinases" They also decrease the production o! #/-3P and TN?-P in a

%ide range o! tissues, including the corneal epithelium"50I52At high

concentrations, tetracyclines inhibit staphylococcal exotoxin-induced cyto$ines

and chemo$ines"55,59Tetracyclines are also $no%n to inhibit matrix

metalloproteinase expression, suggesting a rationale !or their use in ocularrosacea"54They can also inhibit angiogenesis, %hich may de*elop in rosacea"

)oxycycline %as disco*ered in the early 3CD0s" #t is a semisynthetic long-acting

tetracycline deri*ati*e %hich inhibits bacterial ribosomes in a %ide *ariety o!

micro-organisms" #n subantimicrobial doses it is also e!!ecti*e as primary

treatment !or rosacea and sterile corneal ulceration" 5D,57re*ious studies using

experimental dry eye models demonstrated that doxycycline %as e!!icacious in

decreasing gelatinolytic acti*ity in the ocular sur!ace epithelia, as %ell as
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decreasing le*els o! ==-C mRNA transcripts, and pre*enting experimental dry

eye-induced increase in #/-3 and TN?-P"5F)oxycycline also impro*es corneal

sur!ace regularity and barrier !unction"5C

Essential /atty 'cids

ssential !atty acids are necessary !or health" They cannot be synthesi@ed by

*ertebrates and must be obtained !rom dietary sources" Among the essential !atty

acids are the 3F carbon omega-D and omega-5 !atty acids" #n a typical %estern

diet, omega-D !atty acids are consumed 20 to 24 times more than omega-5 !atty

acids" 1mega-D !atty acids are precursors o! arachidonic acid and certain pro-

in!lammatory lipid mediators such as prostaglandin 2and leu$otriene 9" #ncontrast, certain omega-5 !atty acids, such as eicosapentaenoic acid !ound in !ish

oil, inhibit synthesis o! these lipid mediators and also bloc$ the production o! #/-3

and TN?-P"90,93A bene!icial clinical e!!ect !rom !ish oil omega-5 !atty acids on

rheumatoid arthritis has been obser*ed in se*eral double-mas$ed placebo-

controlled clinical trials"92,95#n a prospecti*e placebo-controlled clinical trial,

linoleic acid and gamma-linoleic acid administered orally t%ice a day led to

signi!icant impro*ement in ocular irritation symptoms, and a reduction in ocularsur!ace lissamine green staining con'uncti*al H/A-)R reacti*ity"99#n an animal

model o! induced dry eye, topical treatment %ith alpha-linolenic acid signi!icantly

decreased corneal !luorescein staining as compared to both *ehicle and untreated

controls, decreased :)33b+E cells and reduced the expression o! corneal #/-3P

and TN?-P, and con'uncti*al TN?-P"94

CNC$!SINS

)ry eye syndrome consists o! a %ide spectrum o! disorders %ith di!!erent causes"

:linicians should be a%are o! the extent o! dry eye symptoms" A thorough history

and in*estigation is necessary to identi!y the cause o! dry eye" Use!ul clinical tests

!or assessing the se*erity o! the condition include &chirmer, !luorescein dye, and

tear brea$ up time tests" =anagement depends on an accurate diagnosis and the

se*erity o! the condition" Treatments that replenish de!icient tears include arti!icial

tears, gels and ointments in mild to moderate disease" 1ther treatment modalities
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such as topical steroids, immunomodulating drugs, antibiotics, bandage contact

lenses, autologous serum and amniotic membrane transplantation may be used in

more se*ere cases" #n se*erely dry eyes, surgical inter*ention such as punctal

occlusion can be employed to minimi@e tear drainage" :ertain con'uncti*al and lid

operations can also be per!ormed to treat speci!ic causes"


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)RQ Q &QN)R1=Author : &tephen ?oster, =), ?A:&, ?A:R, ??A1, ?AR61

httpJJemedicine"medscape"comJarticleJ3230937-clinical

0acground

)ry eye syndrome +)&, also $no%n as $eratocon'uncti*itis sicca +K:& or

$eratitis sicca, is a multi!actorial disease o! the tears and the ocular sur!ace that

results in discom!ort, *isual disturbance, and tear !ilm instability %ith potential

damage to the ocular sur!ace"3S #t is accompanied by increased osmolarity o! the

tear !ilm and in!lammation o! the ocular sur!ace" =ultiple causes can produce

either inadeuate tear production or abnormal tear !ilm constitution, resulting in

excessi*ely !ast e*aporation or premature destruction o! the tear !ilm"

)& may be subdi*ided into 2 main types as !ollo%s

)& associated %ith &'gren syndrome+&&

)& unassociated %ith && +non-&& K:&

atients %ith aueous tear de!iciency +AT) ha*e && i! they ha*e associated

xerostomia or connecti*e tissue disease +:T)" atients %ith primary && ha*e

e*idence o! a systemic autoimmune disease, as mani!ested by the presence o!

serum autoantibodies and se*ere AT) and ocular sur!ace disease" These patients,

%ho are mostly %omen, do not ha*e a separate, identi!iable :T)" &ubsets o!

patients %ith primary && lac$ e*idence o! systemic immune dys!unction, but they

ha*e similar clinical ocular presentation"

&econdary && is de!ined as )& that is associated %ith a diagnosable :T), %hich

is most commonly rheumatoid arthritis +RA but could also be systemic lupus

erythematosus +&/ or systemic sclerosis"

Non-&& )& is mostly !ound in postmenopausal %omen, %omen %ho are

pregnant, %omen %ho are ta$ing oral contracepti*es, or %omen %ho are on

hormone replacement therapy +especially estrogen-only pills" The common

denominator is a decrease in androgens, either !rom reduced o*arian !unction +in
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postmenopausal %omen or !rom increased le*els o! the sex hormoneIbinding

globulin +in %omen %ho are pregnant or are ta$ing birth control pills"

Androgens are belie*ed to be trophic !or the lacrimal and meibomian glands" Theyalso exert potent anti-in!lammatory acti*ity through the production o!

trans!orming gro%th !actor beta +TL?-, suppressing lymphocytic in!iltration"

)& is essentially a clinical diagnosis, made by combining in!ormation obtained

!rom the history and !rom the physical examination and per!orming 3 or more

tests to lend some ob'ecti*ity to the diagnosis" No single test is su!!iciently

speci!ic to permit an absolute diagnosis o! )&"

arly detection and aggressi*e treatment o! )& may help pre*ent corneal ulcers

and scarring" Treatment depends on the le*el o! se*erity and may include

medications, eye protection de*ices, and surgical inter*entions" The !reuency o!

!ollo%-up care depends on the se*erity o! the signs and symptoms" n*ironment-

related issues that may exacerbate the )& should be discussed< alternati*es may

be needed"

AnatomyThe tear !ilm co*ers the normal ocular sur!ace" #t is generally considered to

comprise the !ollo%ing 5 intert%ined layers

A super!icial thin lipid layer +0"33 Vm I This layer is produced by the

meibomian glands, and its principal !unction is to retard tear e*aporation and to

assist in uni!orm tear spreading7S

A middle thic$ aueous layer +7 Vm I This layer is produced by the main

lacrimal glands +re!lex tearing, as %ell as by the accessory lacrimal glands o!

Krause and 8ol!ring +basic tearing

An innermost hydrophilic mucin layer +0"02-0"04 Vm I This layer is

produced by both the con'uncti*a goblet cells and the ocular sur!ace epithelium

and associates itsel! %ith the ocular sur!ace *ia its loose attachments to the

glycocalyx o! the microplicae o! the epithelium< it is the hydrophilic uality o!

the mucin that allo%s the aueous layer to spread o*er the corneal epithelium


16/44

The lipid layer acts as a sur!actant, constitutes an aueous barrier +retarding

e*aporation o! the underlying aueous layer, and pro*ides a smooth optical

sur!ace" #t may also act as a barrier against !oreign particles, and it may possess

some antimicrobial properties"

ecause the meibomian glands are holocrine in nature, the secretions contain both

polar lipids +aueous-lipid inter!ace and nonpolar lipids +air-tear inter!ace, as

%ell as proteinaceous material" All o! these are held together by ionic bonds,

hydrogen bonds, and *an der 8aals !orces" The secretions are sub'ect to neuronal

+parasympathetic, sympathetic, and sensory sources, hormonal +androgen and

estrogen receptors, and *ascular regulation" *aporati*e loss is predominantly

due to meibomian gland dys!unction +=L)"

The aueous component includes about D0 di!!erent proteins, electrolytes, and

%ater" /yso@yme, the most abundant +20-90> o! total protein and most al$aline

o! the tear proteins, is a glycolytic en@yme capable o! brea$ing do%n bacterial cell

%alls" /acto!errin has antibacterial and antioxidant !unctions, and epidermal

gro%th !actor +L? helps maintain the normal ocular sur!ace and promote

corneal %ound healing" 1ther components include albumin, trans!errin,immunoglobulin A +#gA, immunoglobulin = +#g=, and immunoglobulin L

+#gL"

The secretion o! the lacrimal gland is controlled by a neural re!lex arc, %ith

a!!erent ner*es +trigeminal sensory !ibers in the cornea and the con'uncti*a

passing to the pons +superior sali*ary nucleus, !rom %hich e!!erent !ibers pass in

the ner*us intermedius to the pterygopalatine ganglion and postganglionic

sympathetic and parasympathetic ner*es terminating in the lacrimal glands"

The glycocalyx o! the corneal epithelium contains the transmembrane mucins

+glycosylated glycoproteins present in the glycocalyx =U:3, =U:9, and

=U:3D" These membrane mucins interact %ith soluble, secreted, gel-!orming

mucins produced by the goblet cells +=U:4A: and also %ith others, such as

=U:2" The lacrimal gland also secretes =U:7 into the tear !ilm"


17/44

These soluble mucins mo*e about !reely in the tear !ilm +a process !acilitated by

blin$ing and electrostatic repulsion !rom the negati*ely charged transmembrane

mucins, !unctioning as cleanup proteins +pic$ing up dirt, debris, and pathogens,

holding !luids because o! their hydrophilic nature, and harboring de!ense

molecules produced by the lacrimal gland"

Transmembrane mucins pre*ent pathogen adherence +and entrance and pro*ide a

smooth lubricating sur!ace, allo%ing lid epithelia to glide o*er corneal epithelia

%ith minimal !riction during blin$ing and other eye mo*ements" #t has been

suggested that the mucins are mixed throughout the aueous layer o! tears +o%ing

to their hydrophilic nature and, being soluble, mo*e !reely %ithin this layer"

Pathophysiology

A genetic predisposition in &&-associated )& exists, as is e*idenced by the high

pre*alence o! human leu$ocyte antigen F +H/A-F haplotype in these patients"

This condition leads to a chronic in!lammatory state, %ith the production o!

autoantibodies, including antinuclear antibody +ANA, rheumatoid !actor +R?,!odrin +a cytos$eletal protein, the muscarinic =5 receptor, or &&-speci!ic

antibodies +eg, anti-R1 &&-AS and anti-/A &&-S< in!lammatory cyto$ine

release< and !ocal lymphocytic in!iltration +ie, mainly :)9ET cells but also

cells o! the lacrimal and sali*ary gland, %ith glandular degeneration and

induction o! apoptosis in the con'uncti*a and lacrimal glands"

This results in dys!unction o! the lacrimal gland %ith reduced tear production, as

%ell as loss o! response to ner*e stimulation and less re!lex tearing" Acti*e T

lymphocytic in!iltrate in the con'uncti*a also has been reported in non-&& )&"

Sex hormone defciency

oth androgen and estrogen receptors are located in the lacrimal and meibomian

glands" && is more common in postmenopausal %omen" At menopause, a decrease

in circulating sex hormones occurs, possibly a!!ecting the !unctional and secretory


18/44

aspect o! the lacrimal gland" #nitial interest in this area centered on e*aluating

estrogen or progesterone de!iciency to explain the lin$ bet%een )& and

menopause< subseuent research has tended to !ocus more on androgens

+speci!ically, testosterone or metabolites o! androgens"

#n =L), androgen de!iciency results in loss o! the lipid layerWspeci!ically, loss

o! triglycerides, cholesterol, monounsaturated essential !atty acids +eg, oleic acid,

and polar lipids +eg, phosphatidylethanolamine and sphingomyelin" /oss o! polar

lipids +present at the aueous-tear inter!ace exacerbates e*aporati*e tear loss, and

loss o! unsaturated !atty acids raises the melting point o! meibomian gland

secretions +meibum, leading to thic$er, more *iscous secretions that obstructductules and cause stagnation o! secretions"

atients on antiandrogenic therapy !or prostate disease also ha*e increased

*iscosity o! meibum, decreased tear brea$up time +TUT, and increased tear !ilm

debris, all o! %hich are indicati*e o! a de!icient or abnormal tear !ilm"

Proinammatory activity

6arious proin!lammatory cyto$ines that may cause cellular destruction, including

interleu$in +#/I3, #/-D, #/-F, TL?-, tumor necrosis !actor alpha +TN?-P, and

RANT&, are altered in patients %ith )&" #/-3 and TN?-P, %hich are present

in the tears o! patients %ith )&, cause the release o! opioids that bind to opioid

receptors on neural membranes and inhibit neurotransmitter release through

production o! nuclear !actor $appa-light-chain-enhancer o! acti*ated cells +N?-

X"

#/-2 also binds to the delta opioid receptor and inhibits cA= production and

neuronal !unction" This loss o! neuronal !unction diminishes normal neuronal

tone, leading to sensory isolation o! the lacrimal gland and e*entual atrophy"

roin!lammatory neurotransmitters, such as substance and calcitonin geneI

related peptide +:LR, are released, and these substances recruit and acti*ate

local lymphocytes" &tudies suggest that dry eye se*erity is directly correlated %ith


19/44

ner*e gro%th !actor +NL? le*els and in*ersely correlated %ith :LR and

neuropeptide Q +NQ tear le*els"

NL? tear le*els point to a direct relation %ith con'uncti*al hyperemia and!luorescein staining results, suggesting that tear le*els o! NL? are more closely

connected to corneal epithelial damage, perhaps as a re!lection o! attempted

compensatory repair responses, and that the decreased tear le*els o! NQ and

:LR in dry eye disease are lin$ed to impaired lacrimal !unction" FS #n one study,

ele*ated NL? tear le*els %ere decreased by gi*ing 0"3> prednisolone"CS

&ubstance also acts *ia the nuclear !actor o! acti*ated T cells +N?-AT and N?-

X signaling path%ay leading to expression o! intercellular adhesion molecule 3

+#:A=-3 and *ascular cell adhesion molecule-3 +6:A=-3, adhesion molecules

that promote lymphocyte homing and chemotaxis to sites o! in!lammation"

:yclosporine is a neuro$inin +NKI3 and NK-2 receptor inhibitor that can

do%nregulate these signaling molecules and is a no*el addition to the therapeutic

armamentarium !or dry eye, being used to treat both aueous tear de!iciency and

=L)" #t has been sho%n to impro*e the goblet cell counts and to reduce thenumbers o! in!lammatory cells and cyto$ines in the con'uncti*a"

These cyto$ines, in addition to inhibiting neural !unction, may also con*ert

androgens into estrogens, resulting in =L)" An increased rate o! apoptosis is also

seen in con'uncti*al and lacrimal acinar cells, perhaps due to the cyto$ine

cascade" le*ated le*els o! tissue-degrading en@ymes called matrix

metalloproteinases +==s are also present in the epithelial cells"

Mucin defciency

=ucin-synthesi@ing genes representing both transmembrane mucins and goblet

cellIsecreted soluble mucins, ha*e been isolated and designatedMUC1

MUC1!.Their roles in hydration and stabili@ation o! the tear !ilm are being

in*estigated in patients %ith K:&" articularly signi!icant isMUC"#C, %hich is

expressed by strati!ied suamous cells o! the con'uncti*a and %hose product is the


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predominant component o! the mucous layer o! tears" A de!ect in this and other

mucin genes may be a !actor in the de*elopment o! )&"

esides )&, other conditions may e*entually lead to loss o! goblet cells,including ocular cicatricial pemphigoid, &te*ens-.ohnson syndrome, and *itamin

A de!iciency, %hich lead to drying or $eratini@ation o! the ocular epithelium" oth

classes o! mucins are decreased in these diseases, and on a molecular le*el, mucin

gene expression, translation, and posttranslational processing are altered"

=ucin de!iciency leads to poor %etting o! the corneal sur!ace %ith subseuent

desiccation and epithelial damage, e*en in the presence o! adeuate aueous tear

production"

Reduced tear protein production

Normal production o! tear proteins, such as lyso@yme, lacto!errin, lipocalin, and

phospholipase A2, is decreased in )&"

/ipocalins +pre*iously $no%n as tear-speci!ic prealbumin, %hich are present in

the mucous layer, are inducible lipid-binding proteins produced by the lacrimal

glands" They lo%er the sur!ace tension o! normal tears, %hich pro*ides stability to

the tear !ilm and also explains the increase in sur!ace tension seen in )&

characteri@ed by lacrimal gland de!iciency" /ipocalin de!iciency can lead to

precipitation in the tear !ilm, !orming the characteristic mucous strands seen in

patients %ith dry eye symptoms"

tiology

The #nternational )ry ye 8or$&hop +)8& de*eloped a 5-part classi!ication o!

dry eye based on etiology, mechanisms, and disease stage" 3S This classi!ication

system distinguishes 2 main categories +or causes o! dry eye states, as !ollo%s

An aueous de!iciency state

An e*aporati*e state
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Aueous tear de!iciency +AT) is the most common cause o! dry eye, and it is due

to insu!!icient tear production" :auses o! de!icient aueous production include the

!ollo%ing

&& dry eye +primary and secondary

/acrimal gland de!iciency

/acrimal gland duct obstruction

Re!lex hyposecretion

&ystemic drugs

:auses o! e*aporati*e loss include the !ollo%ing

=L)

)isorders o! lid aperture

/o% blin$ rate

)rug action +eg, isotretinoin

6itamin A de!iciency

Topical drugs and preser*ati*es

:ontact lens %ear

1cular sur!ace disease +eg, allergy

Etiology deficient aueous -roduction

:auses o! de!icient aueous production can be !urther classi!ied as related or

unrelated to &&"

$on%j&gren syndrome

rimary lacrimal gland de!iciencies that may impair aueous production include

the !ollo%ing

#diopathic

Age-related dry eye

:ongenital alacrima +eg, Riley-)ay syndrome

?amilial dysautonomia


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&econdary lacrimal gland de!iciencies that may impair aueous production

include the !ollo%ing

/acrimal gland in!iltration &arcoidosis

/ymphoma

A#)&

Lra!t *s host disease

Amyloidosis

Hemochromatosis

/acrimal gland in!ectious diseases

H#6 di!!use in!iltrati*e lymphadenopathy syndrome

Trachoma

&ystemic *itamin A de!iciency +xerophthalmia I =alnutrition, !at-!ree

diets, intestinal malabsorption !rom in!lammatory bo%el disease, bo%el

resection, or chronic alcoholism

/acrimal gland ablation /acrimal gland dener*ation

/acrimal obstructi*e diseases that may impair aueous production include the

!ollo%ing

Trachoma

1cular cicatricial pemphigoid

rythema multi!orme and &te*ens-.ohnson syndrome

:hemical and thermal burns

ndocrine imbalance

ostirradiation !ibrosis

=edications that may impair aueous production include the !ollo%ing

Antihistamines

eta bloc$ers


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henothia@ines

Atropine

1ral contracepti*es

Anxiolytics

Antipar$insonian agents

)iuretics

Anticholinergics

Antiarrhythmics

Topical preser*ati*es in eye drops

Topical anesthetics

#sotretinoin

The !ollo%ing conditions may lead to re!lex hyposecretion

Neurotrophic $eratitis I :ranial ner*e +:N 6Jganglion

sectionJin'ectionJcompression

:orneal surgery - /imbal incision +eg, extracapsular cataract extraction,

$eratoplasty, and re!racti*e surgery #n!ecti*e - Herpes simplex $eratitis and herpes @oster ophthalmicus

Topical agents - Topical anesthesia

&ystemic medications I eta bloc$ers and atropineli$e drugs

:hronic contact lens %ear

)iabetes

Aging

Trichloroethylene toxicity

:N 6## damage

=ultiple neuromatosis

%j&gren syndrome

rimary && has no associated :T)" &econdary && may be associated %ith any o!

the !ollo%ing :T)s


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RA

&/

rogressi*e systemic sclerosis +scleroderma

rimary biliary cirrhosis

#nterstitial nephritis

olymyositis and dermatomyositis

olyarteritis nodosa

Hashimoto thyroiditis

/ymphocytic interstitial pneumonitis

#diopathic thrombocytopenic purpura

Hypergammaglobulinemia

8aldenstrom macroglobulinemia

8egener granulomatosis

Etiology ea-oratie loss

:auses o! e*aporati*e loss can be !urther classi!ied as intrinsic or extrinsic"

'ntrinsic causes

=eibomian gland disease may in*ol*e a reduced number o! !unctioning glands, as

in congenital de!iciency or acuired =L), or replacement, as in distichiasis,

lymphedema-distichiasis syndrome, or metaplasia" =L) may be di*ided into 5

subtypes as !ollo%s

Hypersecretory - =eibomian seborrhea

Hyposecretory - Retinoid therapy

1bstructi*e I This may be simple, primary or secondary to local disease

+eg, anterior blepharitis, systemic disease +eg, acne rosacea, seborrheic

dermatitis, atopy, ichthyosis, or psoriasis, syndromes +eg, anhidrotic ectodermal

dysplasia, ectrodactyly syndrome, or Turner syndrome, or systemic toxicity +eg,

35-cisretinoic acid or polychlorinated biphenyls< or it may be cicatricial,

primary or secondary to local disease +eg, chemical burns, trachoma,


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pemphigoid, erythema multi!orme, acne rosacea, *ernal $eratocon'uncti*itis

6K:S, or atopic $eratocon'uncti*itis AK:S

*aporati*e loss may result !rom a lo% blin$ rate caused by the !ollo%ing

hysiologic phenomenon, such as may occur during per!ormance o! tas$s

that reuire concentration +eg, %or$ing at a computer or a microscope

xtrapyramidal disorder, such as ar$inson disease +decreasing

dopaminergic neuron pool

*aporati*e loss may result !rom the !ollo%ing disorders o! eyelid aperture and

eyelid-globe congruity

xposure +eg, craniostenosis, proptosis, exophthalmos, and high myopia

/id palsy

ctropion

/id coloboma

#n addition, the actions o! drugs such as isotretinoin may lead to e*aporati*e loss"

E(trinsic causes

6itamin A de!iciency may cause dry eye as a conseuence o! the !ollo%ing

)e*elopment disorder o! goblet cells

/acrimal acinar damage

1ther extrinsic causes are as !ollo%s

Topical drugs and preser*ati*es +sur!ace epithelial cell damage

:ontact lens %ear

1cular sur!ace disease +eg, allergy

#ec,anisms

A classi!ication o! dry eye on the basis o! mechanisms includes tear

hyperosmolarity and tear-!ilm instability"

Seerity


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?or classi!ication o! )& on the basis o! se*erity, the )elphi anel Report %as

adopted and modi!ied as a third component o! the )8& +see the Table belo%" 3,

30S

Table" )ry ye &e*erity le*els+1pen Table in a ne% %indo%

ariale

Dry Eye Seerity leel

1 2 3

4 6must ,ae

signs and

sym-toms7

)iscom!ort+se*erity and

!reuency

=ild, episodic to 50> o! the study population depending on the criteria usedto de!ine the condition and the di!!erences in the de!inition o! the study population4,7I33S" roblems encountered in the exact estimation o! pre*alence may rely on%hether the data came !rom general population sur*eys or physician assessments"Among patients diagnosed by physicians, estimated pre*alence may *arydepending on the diagnostic criteria used and the clinicians( sub'ecti*eassessments 32S"

#n addition to age, the ris$ !actors !or de*elopment o! dry eye include race orethnicity< greater incidence is seen in patients o! :hinese, Hispanic, Asian, andaci!ic #slands descent and !emale sex +%omen report dry eye t%ice as o!ten asmen" 8omen are particularly susceptible to dry eye symptoms, especially thoserecei*ing estrogen replacement therapy 7S" The pre*alence o! dry eye is higher inthe presence o! ocular conditions such as blepharitis, meibomian glanddys!unction, and con'uncti*al disease< in the presence o! systemic conditionsincluding arthritis, osteoporosis, gout, and thyroid disorders< and a!ter corneal,retinal, or ocular oncologic surgery 32, 35S"

% Etiology

The health o! the ocular sur!ace is maintained by e!!icient production, secretion,and elimination o! a physiologically stable tear !ilm" The tear !ilm hastraditionally been considered to consist o! three distinct layers a thin outer lipidlayer that is secreted by the meibomian glands, an inner layer o! mucous secreted

by goblet cells o! the con'uncti*a, and a complex middle aueous layer secretedby the main lacrimal and accessory gland that contains a %ide array o! dissol*edsubstances" A ne%er concept describes the tear !ilm as a dynamic mucinous gel

that decreases in density to%ard the outer layer" The tear !ilm maintains thestructure and !unctioning o! the cornea under normal physiological conditions inindi*iduals %ith normal ocular anatomy" The tear !ilm maintains an opticallyuni!orm sur!ace, lubricates and nourishes eye tissue, %ashes out cellular debrisand !oreign bodies, and also protects !rom bacterial in!ections 39I3DS"

#n!lammation is a central !eature o! ocular sur!ace disease" An associationbet%een ocular symptoms and acti*ation o! T lymphocytes has been established inpatients %ith &'gren(s syndrome 5S" Today it is understood that a localautoimmune occurrence could appear irrespecti*e o! systemic autoimmune

disease" :on'uncti*al in!lammation is mani!ested by in!iltration o! in!lammatory
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cells and upregulated expression o! immune mar$ers" Hyperosmolar stress hasproin!lammatory e!!ect" A better understanding o! the immunopathologicalmechanisms o! ocular sur!ace disorders etiology corresponds %ith modi!ication o!applied therapy 34, 3DS"

& Ris' (actors

As pre*iously noted, ris$ !actors !or dry eye include !emale sex, older age,postmenopausal estrogen therapy, computer use, contact lens %ear, a diet lo% inomega-5 essential !atty acids or a high ratio o! omega-D to omega-5 !atty acids,re!racti*e surgery, *itamin A de!iciency, radiation therapy, bone marro%transplantation, hepatitis :, and certain classes o! systemic and ocularmedications, including antihistamines" 6itamin A de!iciency is a %ell-recogni@ed

ris$ !actor !or dry eye, and the etiology includes inadeuate inta$e due to alcohol-related nutritional de!iciency, stomach surgery, malabsorption, eating disorders,and a *egan diet"

1ther ris$ !actors include diabetes mellitus, human immunode!iciency *irus, H#6and human T cell lymphotropic *irus-3 in!ection, connecti*e tissue diseases,systemic cancer chemotherapy, and medications such as isotretinoin,antidepressants, anxiolytics, beta-bloc$ers, and diuretics" Ho%e*er, acomprehensi*e study o! these !actors is still lac$ing" :on!licting results ha*e beenreported on the association bet%een dry eye and some !actors, including alcohol,

cigarette smo$ing, ca!!eine, acne, and menopausal status" /i$e%ise, *ery !e%reports exist on the ris$ o! dry eye %ith use o! oral contracepti*es and duringpregnancy 4,C,30,37I3CS"

) Symptoms

#t is o!ten incorrectly assumed that symptoms o! dry eye are the main !eature o!this disease, %hereas un!ortunately they do not al%ays correspond %ith diagnostictest results except in se*ere cases" The symptoms that patients describe are thesame ocular sensations !elt in other ocular sur!ace disorders, namely, reports o! a

gritty, sandy !oreign body sensation and *isual disturbances" 6isual complaints arehighly pre*alent among dry eye patients usually described as blurry *ision thatclears temporarily upon blin$ing DS" These transient changes, resulting !romdisrupted tear !ilm in the central cornea, can be pro!ound %ith mar$ed drops incontrast sensiti*ity and *isual acuity thereby a!!ecting %or$place producti*ity and*ision-related uality o! li!e D, 3CS"

* Diagnostic Procedures

The diagnosis o! ocular sur!ace disease is based on the patient(s symptoms and

medical history %hich should include uestions about topical and systemic
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medications used and possible exposure to aggra*ating !actors" :urrentlya*ailable diagnostic tests and external examinations are also indispensable !ore*ery practitioner in order to reach the decision on the most suitable treatment 3S"&ymptom uestionnaires allo% !or rapid and e!!icient collection o! rele*ant

in!ormation and can !acilitate diagnosis o! ocular sur!ace disorders"Muestionnaires and dry eye index scores can be use!ul to detect the presence o!dry eye and to e*aluate the e!!ect o! therapeutic treatment" &e*eral uestionnairesare a*ailable, %ith the most common being the 1cular &ur!ace )isease #ndex+1&)# 20S" Ho%e*er, there is still no standardi@ed dry eye disease uestionnairethat is uni*ersally accepted" A!ter patient(s medical history is obtained anduestionnaires administered, clinical examination o! the anterior segment andob'ecti*e tests are necessary to con!irm the diagnosis o! dry eye 2,23S"

8.1. 9ectie Testing

1b'ecti*e tests !or dry eye can be di*ided into tests that examine the tears andthose that examine the integrity o! the ocular sur!ace" The !ormer can !urther besubdi*ided into tests that in*estigate the uantity, uality, or !unctional propertieso! tears"

8.2. Tear :uality

&ome authors consider that the determination o! tear osmolarity is signi!icant indry eye diagnosis< ho%e*er, it reuires expert technical support, and its use has to

date been con!ined to speciali@ed laboratories 22S" The appearance o! ne% morea!!ordable osmometers has expanded their use in e*eryday practice 25S" The mostcommon test !or determining tear !ilm uality in use today is the tear brea$up time+TUT %hich is described later in this paper"

8.3. Tear :uantity

The most %idely used techniue to e*aluate tear uantity is the &chirmer test 3,per!ormed %ithout anesthesia" #n this test, a mm strip o! !ilter paper that is bent 4mm !rom the end is placed under the lo%er eyelid on the temporal side" The strip

is $ept in place !or 4 minutes and then the length o! the moistened strip ismeasured" A result yielding less than 4 mm sho%s aueous tear de!iciency"#nsertion o! the strip !or 4 minutes may cause discom!ort %ith re!lex tearssecretion" There!ore, as an alternati*e, some practitioners $eep the paper in place!or 2 minutes or apply a topical anesthetic prior to placing the strip +&chirmer ##39,29S" Another nonin*asi*e method used is the tear meniscus heightmeasurement on the lo%er eyelid, %hereby a height lo%er than 0"2 mm isassociated %ith tear de!iciency 24S"
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8.4. Stains and Dyes of t,e cular Surface

?luorescein is use!ul in assessing dry eye %here its application can determine theintegrity o! the corneal and con'uncti*al epithelium" The normal epithelium does

not stain< ho%e*er, %hen the mucous layer is absent, the dye penetrates and stainsthe epithelium" *aluation a!ter 2 minutes is recommended since prematureexamination o! the sur!ace may underestimate the degree o! damage 2,39S"/issamine green is another dye used to e*aluate the anterior segment and is usedto stain dead or degenerated cells and produces less irritation compared %ith rose

bengal dye" Lrading ocular sur!ace staining a!ter application o! *ital dyes is acentral component o! dry eye diagnosis 2DS" ?luorescein is also used !or classictear !ilm stability tests" ?luorescein is applied into the lo%er !ornix, and the

patient is !irst as$ed to blin$ se*eral times and then to a*oid blin$ing" A broad slit-lamp beam %ith cobalt blue !ilter is used to scan the tear !ilm" The presence o!

blac$ spots or lines indicates the appearance o! dry spots in the tear !ilm 27S" Tear!ilm brea$up time +TUT is the inter*al bet%een the blin$ and the appearance o!the !irst randomly distributed dry spot" A TUT o! less than 30 seconds isconsidered abnormal 39, 27S"

8.5. 'dditional Tests

atients %ith $eratocon'uncti*itis sicca o!ten ha*e a decreased eyelid blin$ rate asresult o! diminished corneal sensiti*ity due to ocular sur!ace in!lammation"Ho%e*er, reduced corneal sensation is also obser*ed a!ter re!racti*e surgery as

%ith normal aging 2FS" The ocular protection index +1# %as designed in anattempt to pro*ide a combined measurement o! tear !ilm instability and theinterblin$ inter*al +##" #t is calculated by di*iding the number o! eyelid blin$s in3 minute by D0 %hereby the normal ## is bet%een 30 and 32 seconds" )i*idingthe TUT *alue by the ##, the 1# *alue is obtained" 1# *alues less than 3suggest that the tear !ilm destabili@es bet%een blin$s %hilst 1# *alues o! 3 orhigher seem to correlate %ith patient symptoms 2CS" Additional use!ul testsinclude con'uncti*al impression cytology +to e*aluate the goblet cells, brushcytology +to analy@e the possible in!lammation o! the ocular sur!ace, andmeasuring the uantities o! lyso@yme and lacto!errin in the tears" )ecreases in theconcentration o! these t%o ma'or lacrimal proteins secreted by the lacrimal glandsin tear !ilm indicate lacrimal gland dys!unction 50S"

8.;. Emerging Tec,nologies

Ne%er research attempts to detect and de*elop ne% diagnostic technologies that%ill sho% promise !or ad*ancing our ability to in*estigate, monitor, and diagnosedry eye disease in the !uture" There is particular interest in nonin*asi*e orminimally in*asi*e technologies, namely, *arious instruments that can detectoptical changes in tear !ilm consistency %ithout touching the eye that could beadapted !or e*eryday clinical use" Research is continuously stri*ing to de*elop
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and impro*e technologies that allo% changes in tears at the ocular sur!ace to bedetected %hile causing the least disturbance to tear !ilm dynamics during sampling53S"

+ #omplications o ,ntreated Dry Eye

&ince tears protect the ocular sur!ace !rom in!ection in se*ere cases o! untreateddry eye syndrome, the associated in!lammation can damage the con'uncti*a andthe cornea %ith an increased ris$ o! eye in!ection" ?ortunately, most cases o! dryeye related con'uncti*itis are mild and do not need speci!ic treatment" #!in!lammation ho%e*er becomes se*ere and chronic, timely and appropriatetherapy must be applied prior to damages o! the corneal sur!ace %hich leads toirreparable ulceration or scarring" These complications can produce more se*ere

symptoms such as extreme sensiti*ity to light, pain, red eyes, and loss o! *ision39,52S"

- Treatment

The prime goal o! treatment o! the ocular sur!ace disorders includes relie! o!symptoms, impro*ement o! *isual acuity and uality o! li!e, restoration o! ocularsur!ace and tear !ilm, and correction o! underlying de!ects" Treatment optionscomprise o! hygiene and li!e style changes, arti!icial or autologous serum tear use,and anti-in!lammatory drug therapy, as %ell as physical and surgical procedures to

increase tear retention" Treatment should be ad'usted to incorporate the patient(sresponse and must maintain a balance bet%een e!!icacy, sa!ety, and patientcon*enience 39S"

The simplest and most e!!ecti*e %ay to relie*e symptoms o! dry eye is a li!estylechange" atients should be ad*ised to a*oid long exposure to computers, T6, andreading %hich is associated %ith a reduced blin$ rate and thus increasede*aporation" The use o! arti!icial tears and short brea$s during these acti*ities arerecommended" Humidi!ication o! air in the home and %or$ place could alsoalle*iate undesirable e!!ects" A*oidance o! hot, %indy, lo%-humidity, and high-

altitude en*ironments as %ell as smog and smo$e is also ad*isable 39,55S"

yelid hygiene, %arm compresses, and topical antibiotics %hen needed areessential !or chronic blepharitis and meibomian gland dys!unction treatment%hich can be associated %ith tear dys!unction" These measures reduce bacterialinduced changes in the lipid component o! the tear !ilm, %hich in turn reducese*aporati*e tear loss 55S"

#t has been sho%n that a higher dietary inta$e o! omega-5 !atty acids %ith lo%erdietary ratio o! omega-D to omega-5 !atty acids as %ell as use o! supplements
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containing linoleic and gamma-linoleic acid decreases the ris$ associated %ith dryeye symptoms 59,54S"

Tear supplements pro*ide only temporary relie! o! dry eye symptoms and usually

contain preser*ati*es %hich can irritate the eye and additionally exacerbatesymptoms" Thus patients reuiring tear supplements more than 9 times a dayshould be prescribed preser*ati*e-!ree products" Arti!icial tears cannot replace thecyto$ines and gro%th !actors %hich are comprised in normal tears and produced

by normal-!unctioning lacrimal glands and thus do not ha*e direct anti-in!lammatory e!!ect 39, 55S"

Keeping in mind that in!lammation is a $ey component o! the pathogenesis o! dryeye, the e!!icacy o! some anti-in!lammatory agents !or dry eye disease treatmenthas been in*estigated" This !orm o! therapy may be used !or patients %ho ha*e

corneal disease and ha*e persistent symptoms despite extensi*e use o! arti!icialtears" The most %idely used anti-in!lammatory agents are topical corticosteroids,tetracyclines, cyclosporine A, and in some cases in patient %ith &'gren(ssyndrome pilocarpine" e!ore using this medication possible side e!!ects should

be assessed %ith respect to their potential bene!it 39,34,55S"

Autologous serum tears is the !luid component o! !ull blood that remains a!terclotting and contains !ibronectin, *itamin A, cyto$ines, gro%th !actors, and anti-in!lammatory substances" Ko'ima et al" obser*ed the bene!it o! 20> autologousserum solution sho%ing symptom relie!, impro*ement o! TUT test, and rose-

bengal staining score in patients %ith dry eye disease" #t should ho%e*er be notedthat this $ind o! treatment should be reser*ed !or management o! se*ere casesonly 5DS" Kinoshita et al" in their randomi@ed, multicenter phase 5 study sho%edthat administration o! 2> rebamipide %as e!!ecti*e in impro*ing both theob'ecti*e signs and sub'ecti*e symptoms o! dry eye 57S" Those !indings, inaddition to the %ell-tolerated pro!ile o! 2> rebamipide, clearly sho%ed that it isalso an e!!ecti*e therapeutic method !or dry eye"

unctual plugs relie*e dry eye symptoms in patients %ith &'gren(s syndrome,!ilamentary $eratitis, chronic &te*ens-.ohnson syndrome, trachoma, neurotrophicand diabetic $eratopathy, $eratitis sicca, and in patients %ith dry eye a!terre!racti*e surgery" 1bstruction or in!lammations o! the lacrimal canaliculi or ductsas %ell as acti*e blepharitis is a contraindication !or their application" ermanentsurgical punctual occlusion is an alternati*e to use o! punctal plugs 5FS"

=oisture-retaining eye %ear protects the eyes !rom en*ironmental drying andincreases periocular humidity 5CS" Hydrophilic bandage contact lenses may beconsidered !or corneal sur!ace protection or pain relie! or as an aid to cornealreepitheli@ation" The lenses act as a reser*oir !or sustained hydration, ser*e as a

barrier that protects the traumati@ed cornea, and pro*ide splitting e!!ect !orcorneal healing 90S"
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&urgical procedures suitable !or treatment o! se*ere dry eye include lid procedures+permanent punctal closure usually %ith cautery and tarsorrhaphy andcon'uncti*al procedures +con'uncti*al transplantation, amniotic membranetransplant, !ree con'uncti*al gra!t, and stem cell replacement"

To surmise, the recommendations o! the )ry ye 8or$shop based on diseasese*erity consist o! !our le*els o! treatment 39, 55S"

/e*el 3 +dry sensation, burning" ducation and en*ironmentalJdietarymodi!ications< elimination o! o!!ending systemic medications< use o! preser*edarti!icial tear substitutes, gels, and ointments< and eyelid therapy"

/e*el 2 +itching, pain, photophobia" Use o! nonpreser*ed arti!icial tearsubstitutes< anti-in!lammatory agents +topical corticosteroids, topical cyclosporine

A, topical or systemic omega-5 !atty acids< tetracyclines +!or meibomianitis orrosacea< punctal plugs +a!ter the in!lammation has been brought under control

tgs referat

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