indicates

UofFluid-Ventilated,Gas-PermeableScleralLens

forManagementofSevereKeratoconjunctivitisSicca

SecondarytoChronicGraft-versus-HostDia

KikuchiTakahide,,2MichaelWu,,ter,1,3

CarinaMoravec,1BarbaraStehr,,1,3PerryRonthal,,2

s1,3

1FredHutchinsonCancerRearchCenter,2HematologyandHematopoieticCellTransplantation,CityofHope

NationalMedicalCenter,3UniversityofWashington,Seattle,Washington;4SingaporeGeneralHospital,

SingHealth,Singapore;and5HarvardMedicalSchoolandBostonFoundationforSight,Boston,Massachutts

Correspondenceandreprintrequests:s,MD,ClinicalRearchDivision,FredHutchinson

CancerRearchCenter,1100FairviewAvenueN,D5-290,Seattle,WA98109(e-mail:mflowers@).

ReceivedMarch21,2007;acceptedMay7,2007

ABSTRACT

Keratoconjunctivitissicca(KCS)occursin40%-60%ofpatientswithchronicgraft-versus-host-dia

(cGVHD)ghimmunosuppressivetherapyisthe

primarytreatmentofchronicGVHD,ocularsymptomsrequiremeasurestoimproveocularlubrication,

decreainflammation,uidcornealbandageprovidedbyafluid-

ventilated,gas-permeablesclerallens(SL)hasbeeneffectiveinmitigatingsymptomsandresurfacingcorneal

rtoutcomesin9concutive

patientsreferredforSLfittin

patientsreportedimprovementofocularsymptomsandreducedtheuoftopicallubricantsafterSLfitting

ousadvereventsorinfectionsattributabletotheSLoccurred.

ThemedianOcularSurfaceDiaIndeximprovedfrom81(75-100)to21(6-52)within2weeksafterSL

fitting,andwas12(2-53)atthetimeoflastcontact,1-23months(median,8.0)afterSLfility

relatedtoKCSresolvedin7patientsafterSLfiofSLappearstobesafeandeffectiveinpatients

withverecGVHD-relatedKCSrefractorytoconventionaltherapies.

©2007AmericanSocietyforBloodandMarrowTransplantation

KEYWORDS

Graft-versus-hostdia●Keratoconjunctivitissicca●Allogeneichematopoieticcelltransplantation

INTRODUCTION

Thetermkeratoconjunctivitissicca(KCS)denotes

inflammationcaudbydrynessoftheconjunctivaand

chronicgraft-versus-hostdia

(cGVHD)cancauacuteconjunctivalinflammation,

pudomembranousandcicatricialconjunctivitis,and

sorKCSoccursinapproximately40%-

60%ofpatientswithcGVHDafterallogeneichema-

topoieticcelltransplantation(HCT)[1-3]andmay

reprenttheonly,ormostsignificant,clinicalman-

ifestationandquelaeofcGVHDinsomepatients.

PatientswithKCSmaydevelopcornealerosions

andfilamentscausingverepainandphotophobia.

Ifinadequatelymanaged,cornealepitheliopathycan

progresstopersistentepithelialdefects,sterilecor-

nealulcers,condaryinfectiouskeratitis,andcor-

nealperforation,leadingtostromalscarringand

lossofvision[4].

Systemicimmunosuppressivetherapymaybe

neededtohaltinflammatoryprocess,andissome-

timesindicatedwhencGVHDoftheeyeisresistantto

localtherapyorassociatedwithotherorganinvolve-

ment[5].cGVHDcancauirreversibledamageto

bumandtear-producingcells,withquelaeresult-

patients,an-

cillaryandsupportivecarefortheeyeisdirectedto

improvingocularsurfacelubricationanddecreasing

infleatmentsincludeartificialtears,

BiologyofBloodandMarrowTransplantation13:1016-1021(2007)

ᮊ2007AmericanSocietyforBloodandMarrowTransplantation

1083-8791/07/1309-0001$32.00/0

doi:10.1016/.2007.05.006

1016

long-actingocularlubricants,punctalocclusionor

cauterization,ophthalmiccyclosporine[6],topical

corticosteroids,autologousrumeyedrops[7],mois-

turechambereyewear[8],andoraladministrationof

cholinergicagents[2-5].

SupportivecareforpatientswithverecGVHD

oftheeyecanimprovethequalityoflifeofafflicted

uidcornealbandageprovidedbya

fluid-ventilated,gas-permeablesclerallens(SL)has

beeneffectiveinmitigatingsymptomsandresurfacing

cornealerosionsinthetreatmentofKCSbecauof

otherdisorders[9,10].Wethereforeanalyzedour

experienceontheuofSLinindividualswith

cGVHD-relatedvereKCSrefractorytootherther-

rtoutcomesin9concutivepatients

referredforSLfittingastreatmentforcGVHD-

relatedvereKCSthatwasrefractorytostandard

therapies.

PATIENTSANDMETHODS

BetweenApril2004andJuly2006,9patientswere

fittedwithSLforrefractoryKCSbecauofcGVHD

followingallogeneicHCTattheFredHutchinson

-

rospectiveanalysiswasperformedinNovember2006

todescribetheoutcomeofthe9concutivepa-

tientsreferredtotheBostonFoundationforSight,a

nonprofias,thedecisionto

treatpatientsbyfittingSLwaspromptedbydebili-

tatingoculardiscomfort,visualimpairment,orkera-

topathydespitesystemicandlocaltherapiesaswellas

tusofcGVHDbefore

lensplacementwasdeterminedbypatientinterviewsand

olve-

mentofotherorgansbycGVHDatanytimebeforelens

placementandatthetimeoflensplacementwasre-

corded,aswasthedurationofeyecGVHDpriorto

fiswerereviewedforpriortopical

therapyfordryeyes,includingtheuofartificial

tears,celluloophthalmicinrts(Lacrirts),cyclo-

sporineeyedrops,doxycyclineeyedrops,punctal

plugs,autologousrumtears,andmoisturechamber

salsogatheredregardingtheuof

systemicimmunosuppressivetreatmentsandcGVHD

manifestationsbeforeandatthetimeofSLfittingand

atthetimeoflastcontact.

FittingofSLwasperformedbytheBostonFoun-

dationforSightaspreviouslydescribed[9,10].The

SL,knownastheBostonScleralLens,islathedfrom

aspecialpolymerwithanoxygenpermeabilityvalueof

128ϫ10Ϫ11cm2mLO

2

/condmLmmHganda

customization,thecurvatureofthecentralbacksur-

faceofeachlensisdesignedtomaintainshallowbut

definiteclearanceofthecorneaandlimbusafterthe

lensttles,sothatitissupportedentirelybythesclera

imallensvault

andperimeteroftheindividuallensaredetermined

byon-eyeevaluationsofdiagnosticlensandother

measurements.

TherespontotheSLwasassdbyuofthe

OcularSurfaceDiaIndex(OSDI).TheOSDIisa

12-itemquestionnairebadon3subscales:vision-

relatedfunction,ocularsymptoms,andenvironmental

triggers(Table1).Answerstoquestionsaregradedon

ascaleof0to4,where0indicatesnoneofthetime,1

indicatessomeofthetime,2indicateshalfofthetime,

3indicatesmostofthetime,and4indicatesallofthe

Ihasbeenvalidatedasareliablein-

strumentudtoasssverityofdryeyesymptoms

andvision-relatedfunctionona0-100scale,with

higherscorescorrelatingwithincreasingsymptom

verityandvision-relateddisability[11].Fromat

of12questions(Table1)administered,ascoreis

calculatedaccordingtotheformula:OSDIϭ[(sum

ofscoresforallquestionsanswered)ϫ25]/[total

numberofquestionsanswered][11].Fromthis

score,theverityofocularsurfacediaisde-

rivedaccordingtoacolorscale,asdepictedin

tion,questionnaireswereadminis-

teredretrospectivelytoinquireaboutsymptomsand

theuofartificialtears,punctalplugplacement,

uofmoisturechambereyewear,anddisability

becauofeyessymptomsbeforeandafterSL

placementand,atthetimeoflastcontact.

SurfaceDiaIndex©Questionnaire

Haveyouexperiencedanyofthefollowingduringthelastweek?

atarensitivetolight?

atfeelgritty?

lorsoreeyes?

dvision?

sion?

Haveproblemswithyoureyeslimitedyouinperforminganyof

thefollowingduringthelastweek?

g?

gatnight?

gwithacomputerorbankmachine(ATM)?

ngTV?

Haveyoureyesfeltuncomfortableinanyofthefollowing

situationsduringthelastweek?

onditions?

orareaswithlowhumidity(verydry)?

hatareairconditioned?

Answerstoquestionsaregradedonascaleof0to4,where0

indicatesnoneofthetime;1,someofthetime;2,halfofthe

time;3,mostofthetime;and4,total

scoresforanswers1to5(A),answers6to9(B),andanswers10

to12(C)areaddedtogether(AϩBϩC)toobtainD(sumof

scoresforallquestionsanswered).(E)isthetotalnumberof

questionsanswered(excludingquestionsansweredN/A).

ReproducedwithpermissionfromAllergan®.

ChronicGraft-versus-HostDiaoftheEyes1017

RESULTS

PatientdemographicsaresummarizedinTable2.

DiagnosattimeofHCTwereacuteorchronic

leukemia(nϭ5),myelodysplasticsyndrome(nϭ2),

aplasticanemia(nϭ1)andmultiplemyeloma(nϭ1).

MedianpatientageatthetimeofSLfittingwas56

(range:25-64)ientshadpriorcGVHD

involvingmultiplesitesthatrequiredsystematicim-

munosuppressivetherapyincludingcorticosteroids

tientswerereceivingcorti-

costeroidsand3patientswerereceivingcyclosporine

atthetimeofSLfiientshadalsore-

ceivedtreatmentwithazathioprine,6patientsre-

ceivedmycophenolatemofetil,and2patientshad

beentreatedwithPUVAtherapybeforeSLfitting

(Table2).ThemostcommoncGVHDsitesother

thaneyesatthetimeofSLfittingwere6mucosal

surfaces(oralandvagina),liver(nϭ3),skin(nϭ2),

followedbygut(nϭ1)andlungs(nϭ1).Atthetime

ofSLfitting,7patientswerereceivingsystemicim-

munosuppressivemedicationsand2patientshaddis-

continuedadministrationofallsystemicimmunosup-

pressivemedicationsafternonocularmanifestationsof

atientshadnoactive

manifestationofcGVHDotherthanKCSatthetime

ofSLfitting.

uoftheSLledtoimprovementinocularsymptoms

ousadvereventsorinfections

9patientsud

topicallubricantsfrequentlyduringthedaybefore

fittingtheSL(baline).Inallpatients,thefrequency

oftopicallubricantuwasreducedafterSLfittingto

twicedailyorless(nϭ3),2to6timesdaily(nϭ4),

orbya50%reductionfrombaline(nϭ2).Pre-

scriptionmoisturechambereyewearwasneededin3

patientsbeforeSLandnolongerrequiredin2ofthe

9patientssubjectivelyas-

sdthemlvestohavedisabilitybeforefittingthe

SL,and6patientswerenolongerdisabledafterlens

ienthadsignificantdifficultyin-

rtingtheSL,evenwithassistance(Patient3).

TherespontotheSLwasassdbypatient-

reportedoculardisability,uofancillaryeyecare,

inTable3,the

medianOSDIavailableimprovedfrom81(75-100)to

21(6-52)within2weeksofSLfittingandwas12

(2-53)atthetimeoflastcontact,1-23months(me-

dian,8.0)afterSLfitting.

InPatient1,SLfittingcoincidedwithreinstitu-

tionofsystemicimmunosuppressivetreatment,and

-

thoughtheOSDIdecreadpromptlyafterSLfitting,

systemictreatmentcouldhavecontributedtotheres-

t2,whohadhealing

ofapersistentcornealepithelialdefectafterSLfitting

(Figure2),resumedtherapywithprednisoneandta-

crolimusformanagementofothermanifestationsof

cGVHDat9monthsafterSLfit3was

theonlypatientamongthe9whohadsignificant

difficultyinrtingtheSL,

patienthadsignificantinitialimprovementwithreg-

ularuoftheSL,butatprentwearstheSLonly

twicemonthlyfornomorethan4hoursbecau

mucousdebrisaccumulatesontheoutsidesurfaceof

thelensandinterfereswithvisionduringlongerperiods

ts4,5and8hadsignificantimprovement

inocularsymptomsandalsoreportedasignificantre-

ductionintheuoftopicallubricantstoonceortwice

dailyafterSLfits6and7haddebriscollec-

tiononthelensthathasrequiredremovalandcleaning

t9,despiteimprovementinocular

symptoms,remaineddisabledwithimpairmentinhis

abilitytoreadanddriveatnight.

DISCUSSION

Ourresultsdocumenttheresponofchronic

ocularGVHD-associatedKCStoSLfi

oftenaccompaniedbycGVHDactivityinotheror-

gans,butmayalsoreprenttheonlymanifestationof

cGVHD[1].Themyriadanddebilitatingsymptoms

ofKCSincludeburning,irritation,pain,foreignbody

nsation,blurredvision,-

mentmeasuresthatcancontrolKCSormitigateits

symptomsarethereforeimportantinrestoringthe

qualityoflifeofindividualsafterHCT.

SupportivecareforthetreatmentofcGVHDof

theeyehasbeenrecentlysummarizedintheNational

InstitutesofHealthConnsusDevelopmentProject

onCriteriaforClinicalTrialsinChronicGraft-

versus-HostDia[4],andinvolveslubrication,con-

hesumofscoresforall

questionsanswered(D)andthenumberofquestionsanswered(E),

thecorrespondingscoreforthepatientisthenderivedfromthe

Icharthasacolorschemeforcomputationofthe

ucedwithpermission

fromAllergan®.

deetal.1018

tDemographics

Cas

Characteristics123456789

DiagnosisAplasticAnemiaCML—CPCML—BCMDS/RACMMLCML—BCCLLMMAML

AgeatSLfitting(years)392556645643595258

ChronicGVHD

InitialontafterHCT

(months)

377127261226

Involvedorgansotherthan

eyes

Skin,liver,

mouth,gut

Skin,liver,

mouth

Skin,liver,

mouth,vagina

Skin,liver,lung,

gut,mouth

Skin,liver,lungSkin,gutmouthMouth,joints,

vagina

Skin,

mouth

Skin,

mouth

Totalduration(months)246426936

TotalDurationofeye

cGVHD(months)

228426936

DurationofeyecGVHD

beforeSLfitting(months)

1927136

InvolvedOrgansattimeof

SLfitting

Liver,mouth,GI

tract

NoneSkin,liver,

mouth,vagina

NoneNoneSkin,eyesMouth,eyesMouth,

eyes

Eyes,lungs

PriorTherapiesforcGVHDPDN,CSP,TAC,

PUVA,AZA

PDN,CSP,TAC,

MMF

PDN,CSP,TAC,

MMF

PDN,CSP,

MMF

PDN,CSP,TAC,

AZA,PUVA

PDN,CSP,MMFPDN,CSP,

MMF

PDN,CSP,

TAC

PDN,CSP,

MMF

PriorTopicaltherapyfordry

eyes

ArtificialTears(AT)YesYesYesYesYesYesYesYesYes

SlowreleaAT(Lacrirts)NoYesYesNoNoNoNoNoNo

CyclosporineeyedropsYesYesYesYesNoYesYesYesYes

CorticosteroidsNoNoNoNoYesNoNoNoYes

PunctalplugsYesYesYesYesYesYesYesYesYes

AutologousrumtearsYesNoNoNoNoNoNoNoNo

MoisturechambereyewearYesNoYesYesNoNoNoNoNo

Systemicimmunosuppressive

treatmentattimeofSL

fitting

PDN,TACNonePDN,MMFNonePDNPDN,CSP,MMF,

RAPA

CSPTACCSP,MMF

CMLindicateschronicmyelogenousleukemia;CP,chronicpha;BC,blastcrisis;MDS,myelodysplasticsyndrome;RA,refractoryanemia;CMML,chronicmyelomonocyticleukemia;CLL,chronic

lymphocyticleukemia;MM,multiplemyeloma;AML,acutemyelogenousleukemia;SL,sclerallens;PDN,prednisolone;CSP,cyclosporine;TAC,tacrolimus;AZA,azathioprine;MMF,

mycophenolatemofetil;cGVHD,chronicgraft-versus-hostdia;GI,gastrointestinal.

ChronicGraft-versus-Host

Dia

of

the

Eyes

1019

trolofevaporation,controlofdrainage,anddecreas-

ingocularsurfaceinfllubricationin

vereKCSmaybeachievedbytheuofartificial

tears,viscousointment,muscarinicreceptoragonists,

estocontrol

evaporationincludetheuofmoisturechambereye

wear,tarsorrhaphy,andtheuoflidcareandwarm

compresstomaximizeoutputofthemeibomian

glandsthatproducetheouteroillayerofthetearfilm.

Punctalocclusionusingsiliconeplugsorthermalcau-

terizationmaybenecessarytominimizefluidloss

surfaceinflammationmay

bereducedduringsystemicimmunosuppressivetreat-

ment,judiciousuoftopicalsteroids,cyclosporine

eyedrops,autologousrumeyedrops,and,interest-

ingly,theingestionofflverecas,

transplantationofautologouslimbalepithelialcells

mayprovidebenefit[12].TheuofSLhelpsto

controlevaporationbyactingasagas-permeablepro-

protectionagainstevaporationandthemechanical

traumaoftheeyelidsallowscornealdefectstoregen-

erateintheprenceofadequategaousperfusion.

AllpatientsfittedwithSLforvereKCSbecau

ofcGVHDreportedasignificantreductionintopical

lubricantucomparedtobaline,mostlikelyasa

resultofdecreadevaporationandtheprotective

remarkablewascornealhealingnoticedaarlyas6

symptomaticandclinicallyvisibleimprovementwas

eninallpatients.

Quantifiableindices,uofOSDIscores,avali-

datedtoolforpatientlf-reportingofdryeyes[8],

alsoshowedconsistentimprovement,althoughretro-

spectiveuofOSDImaylimitthevalidityofthis

eless,patientscanreport

accuratelysymptomstheyexperiencedbeforeSL

wear,becautheyexperiencethesamesymptomsif

uldbe

udinprospectivestudiesofpatientswithKCS

tion,abalineasssment

fluoresceindyeisudtodelineatepunctatekeratopathy,corneal

abrasions,andulcerations.a,Thecorneaofpatient2beforeinitial

tographshowninbwastakenafterwearing

thelensfor6hoursandimmediatelyafterlensremoval.

RespontoScleralLens(SL)Fitting

Cas

Characteristics123456789

OcularSurfaceDiaIndex*

BeforefittingSL1817577

First2weeksafterfittingSL2152

Atlastcontact82553124621252

Uofprescription-type

moisturechambereye

wear

BeforefittingSLYesNoYesYesNoNoNoNoNo

First2weeksafterfittingSLNoNoYesNoNoNoNoNoNo

AtlastcontactNoNoYesNoNoNoNoNoNo

Subjectiveasssmentof

disability

BeforefittingSLYesYesYesYesYesYesYesYesYes

First2weeksafterfittingSLNoNoYesNoYesNoNoNoYes

AtlastcontactNoNoYesNoYesNoNoNoYes

SystemicImmunosuppressive

medicationsatlastcontactNonePDN,TACUnchangedNoneUnchangedUnchangedUnchangedUnchangedUnchanged

LastcontactafterSLfitting

(months)44

*ScoringsystemshowninFigure1.

deetal.1020

ofocularsurfacedia,whichwasunavailableinour

ries,reprentsanobjectivemeasureofKCSver-

itythatcouldbeudinfutureprospectivestudiesof

ocularGVHD.

Attheprenttime,fittingofthefluid-ventilated

gas-permeableSLisavailableonlyattheBoston

FoundationforSight,anonprofi

processofcustom-fittingthisdeviceiscostlyand

time-consuming,makingitsulimitedtopatients

whoareverelydisabledbyeyesymptomsthathave

rmore,cor-

nealendothelialdysfunction,ifprent,canprovoke

,theuofthedeviceiscon-

traindicatedintheprenceofpriorcornealedema

and,intheabnceofvisibleedema,anevaluationof

respontotemporaryplacementofadiagnosticgas-

,somepatientswith

considerablebuildupofeyedebrismayexperience

difficultywithextendeduoftheSL.

Inthisstudy,SLplacementallowedforimprove-

mentsinthequalityoflifeandresumptionofnormal

lifeactivitiesinnearlyallindividualssufferingfrom

ludethatSL

canbeasafeandeffectivetreatmentforpatientssuf-

feringfromverecGVHD-relatedKCSthatisre-

edaccessibilityof

SLdevicewouldbenecessarytoofferthistherapyto

morepatientsinneed.

ACKNOWLEDGMENTS

WethankJudyCampbell,RN,andColleen

McKinnon,RN,andtheLong-TermFollow-Upstaffat

theFredHutchinsonCancerRearchCenterandthe

SeattleCancerCareAllianceandatCityofHopefor

theirexcellentcareprovidedtoourpatientsandfam-

ratefultoourpatientswhoparticipated

edthe

study,analyzedtheresults,andwrotethepaper.T.K.,

C.M.,butedininterviewingthepa-

tientsandincollectingthedata.P.R.fittedalltheSL

ofthepatientsinthisstudyandcontributedinthe

finalanalysisandinterpretationofthedata.P.M.P.,

W.Y.K.H.,P.A.C.,P.J.M.,butedin

thefi

workwassupportedinpartbygrantsCA018029from

theNIH,Bethesda,MD.

REFERENCES

endorffB,elAzaziM,syndromein

long-termfollow-upofbonemarrowtransplantedpatients.

BoneMarrowTransplant.1989;4:675-678.

liA,DuellT,WeissM,-ontkeratoconjunc-

tivitissiccasyndromeafterbonemarrowtransplantation:inci-

anGrouporBloodandMarrow

Transplantation(EBMT)

MarrowTransplant.1996;17:1105-1111.

sMED,ParkerPM,JohnstonLJ,isonof

chronicgraft-versus-hostdiaaftertransplantationofpe-

ripheralbloodstemcellsversusbonemarrowinallogeneic

recipients:.

2002;100:415-419.

lD,CarpenterPA,CutlerC,arytherapyand

supportivecareofchronicgraft-versus-hostdia:National

InstitutesofHealthConnsusDevelopmentProjectonCrite-

riaforClinicalTrialsinChronicGraft-versus-HostDia:V.

Ancillarytherapyandsupportivecareworkinggroupreport.

BiolBloodMarrowTransplant.2006;12:375-396.

,OkamotoS,KuwanaM,sfultreatmentof

dryeyeintwopatientswithchronicgraft-versus-hostdia

withsystemicadministrationofFK506andcorticosteroid.

Cornea.2001;20:430-434.

,TesavibulN,YeeR,oftopicalcyclo-

rrow

Transplant.1998;22:147-151.

,OkamotoS,MoriT,gousrumeye

dropsforthetreatmentofveredryeyeinpatientswith

rrowTransplant.

2003;31:579-583.

,SimkoM,roducemoisturecham-

omAssoc.1994;

65:517-522.

OD,RonthalP,-permeablescleral

thalmol.1990;

109:318-322.

halP,-ventilated,gas-permeablescleral

contactlensisaneffectiveoptionformanagingvereocular

surfacediaandmanycornealdisordersthatwouldother-

tactLens.2005;

31:130-134.

manRM,ChristiansonMD,JacobnG,ility

hthal-

mol.2000;118:615-621.

,LiLM,tructionofdamagedcorneas

JMed.2000;343:86-93.

ChronicGraft-versus-HostDiaoftheEyes1021