Objective Monitoring Patching of Amblyopia

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Objectively monitored patching regimens fortreatment of amblyopia: randomised trial

Catherine E Stewart, David A Stephens, Alistair R Fielder, Merrick J Moseleyand ROTAS Cooperative

BMJ 2007;335;707; originally published online 13 Sep 2007;doi:10.1136/bmj.39301.460150.55

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RESEARCH

Objectivelymonitoredpatchingregimensfortreatmentofamblyopia:randomisedtrial

CatherineEStewart,departmentof

healthresearchfellow,1DavidAStephens,professorofstatistics,2AlistairRFielder,professor

ofophthalmology,1MerrickJMoseley,seniorlecturer1,fortheROTASCooperative

1DepartmentofOptometryandVisualScience,CityUniversity,LondonEC1V


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0HB

2DepartmentofMathematicsandStatistics,McGillUniversity,Montreal,QC,CanadaH3A2K6

Correspondenceto:[email protected]

doi:10.1136/bmj.39301.460150.55

ABSTRACT

ObjectivesTocomparevisualoutcomein

responsetotwoprescribedratesofocclusion(sixhoursadayand12

hoursaday).DesignUnmaskedrandomisedtrial.SettingResearchclinics


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intwoLondonhospitals.Participants97childrenwithaconfirmeddiagnosisofamblyopiaassociatedwithstrabismus,anisometropia,orboth.Interventions:18weekperiodof

wearingglasses(refractiveadaptation)followedbyocclusionprescribed(patching)forsixor12

hoursaday.MainoutcomemeasuresVisualacuitymeasuredbylogMARletterrecognition;

objectivelymonitoredrateofocclusion(hoursaday).ResultsThe


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meanageofchildrenatstudyentrywas5.6(SD1.5)years.Ninetywereeligibleforocclusionbut10droppedoutinthisphase,

leaving80childrenwhowererandomisedtoaprescribeddoserateofsix

(n=40)or12(n=40)hoursaday.Themeanchangeinvisualacuity

oftheamblyopiceyewasnotsignificantlydifferent(P=0.64)between


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thetwogroups(0.26(95%confidenceinterval

0.21to0.31)logunitsinsixhourgroup;0.24(0.19to0.29)logunits

in12hourgroup).Themeandoserates(hoursaday)actuallyreceived,

however,werealsonotsignificantlydifferent(4.2(3.7to4.7)insixhour

groupv6.2(5.1to7.3)in12hourgroup;


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P=0.06).Thevisualoutcomewassimilarforthosechildrenwhoreceivedthreetosixhoursadayormorethansixto12hours

aday,butsignificantlybetterthanthatinchildrenwhoreceivedlessthan

threehoursaday.Childrenagedunder4requiredsignificantlylessocclusionthan

olderchildren.Visualoutcomewasnotinfluencedbytypeof


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amblyopia.ConclusionsSubstantial(sixhoursaday)andmaximal(12hoursaday)prescribedocclusionresultsinsimilarvisualoutcome.Onaverage,theocclusion

dosereceivedinthemaximalgroupwasonly50%morethaninthe

substantialgroupandinbothgroupswasmuchlessthanthatprescribed.Younger

childrenrequiredtheleastocclusion.TrialsregistrationClinicalTrialsNCT00274664.


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INTRODUCTION

Thedevelopingvisualsystemishighlysensitivetovisualexperience.12Interruptionbyanyobstacle,

suchasblurredvisionor

strabismusbeforeabout7years,resultsinareductionofvisualcapacityknown

asamblyopia.13About90%ofworkinthechildrenseyeservicesisrelated

toamblyopia,4andtheconditioncarriesanincreasedlifetimerisk


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(atleastthreetimesthatofthegeneralpopulation)ofseriouslossofvisionintheothereye.5

Inanimalmodels,deficits

causedbyearlymonoculardeprivationcanbecorrectedtonormalornearnormal

levelsiftreatmentisinitiatedearlyinlife.67Thoughsuchstudieshaveincreased

ourunderstandingofthesensitivityofthedevelopingvisualsystem,


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theycannottellushowchildrenwithamblyopiawillrespond.

Treatmentofamblyopiahastwomaincomponents:refractivecorrectionbyglassesand

occlusion(bypatching)orpenalisation(bypharmacologicaloropticalmeans)oftheothereye.

Theimprovementattributabletowearingglasses(thatmostchildrenwithamblyopiarequire)takes

considerabletime,48-10aprocesswecallrefractiveadaptation.4910


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Althoughwearingglassesandpatchingmaybothimprovevision,theirindividualcontributionstooutcomearenotdifferentiatedfromeachothereitherinroutineclinical

practiceorresearchastheyareoftenprescribedtogether.Understandingofthedose-response

ofocclusionisfurtherimpededbythefailuretomonitorhowmuchof

theprescribedtreatmentachildactuallyreceives.Thetwostudies


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thathaveusedobjectivemonitoringshowedthatcomplianceisrarelytotalandthatitdiffersunpredictablyfromthatprescribed.411Compliance(concordance)withocclusioninflicts

aconsiderableburdenonthechildandfamilybecauseofarangeof

factorsincludingskinirritation,forceduseofaneyewithdegradedvision,poor

cosmesis,andlengthytreatmentperiods.

Thoughstudieshave


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providedgoodevidencethatocclusiontherapycanimprovethevisionofamblyopic

1213

eyes,resultssuggestthatmaximaldoses(12

hoursaday)arenomorebeneficialthansubstantialdoses(sixhoursa

day).Despitetheseimportantresults,manycliniciansintheUnitedStatesthinkthat

thisnewevidence14isinsufficienttoinitiateachangefrom


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traditionaltreatmentmethodsthatarebasedonbeliefs,fromyearsofexperience.15Oneobjectionraisedis

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RESEARCHRESEARCHDownloaded from bmj.com on 24 February 2009

Terminology

Refractiveadaptationphase:atimeperiodduringwhichanimprovementinvisionoftheamblyopiceyemay

occurinresponsetoopticalcorrectionalone.Sometimesreferredtoasspectacleadaptation

oropticaltreatmentofamblyopia

Occlusionphase:atimeperiodin

whichpatchingbyanopaquepatchofthefelloweye


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(betterseeingeye)wasrandomlyprescribedforsixor12hoursaday

Doserate:meannumberofhourspatched

adaywithintheocclusionphase

Total(accumulated)dose:totalnumber

ofhourspatchedwithintheocclusionphase

Timeinocclusion:number

ofdaysspentintheocclusionphase

Residual


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amblyopia:differenceinvisualacuitybetweenamblyopicandfelloweyeat

completionoftreatment

Proportionofamblyopicdeficitcorrected:VAas-VAae/VAas-VAfe,

whereVAas=visual

acuityofamblyopiceyeatbaseline;VAae=bestvisualacuity

oftheamblyopiceyeby

trialend;andVAfe=bestvisualacuity

offelloweyebytrialend

Optimumdose:


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Theminimumdoseachildrequirestoachievetheirbestvisualacuity

thatpatchinginthesetrialswasnotobjectivelymonitored.16The

researchersacknowledgedthattheycouldnotstatewithconfidencethatthechildrenin

therandomisedgroupsactuallyreceivedsignificantlydifferentamountsofocclusion.1213

Accurateknowledgeoftheamountofocclusionachildactually


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receivesisaprerequisitefordeterminingadose-responserelationandisfundamentaltoevidencebasedprescribing.Ourgroup17andanother18havedevelopedanobjective

measuringdevicetheocclusiondosemonitortodeterminetheamountofpatchingworn.Usingthis

monitorwehavepreviouslyshownapositive,almostlinear,dose-responseupto400

hours419withmostimprovementoccurringinthefirstsixweeks


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ChildrenwererecruitedfromtwoLondonhospitalsfromFebruary2002toMay2004.Includedchildrenwereaged3-8yearsandhadanisometropiaor

strabismus,orboth;asignificantdifferenceininterocularacuity(atleast0.1logMARfor

example,right6/6,left


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Beforestudyentry,allchildrenhadafullophthalmicassessmentincludingcycloplegicretinoscopyandophthalmoscopy.Thestudycomprisedthreephases:baseline,refractiveadaptation,

andocclusion.Inthebaselinephase,oneauthor(CES)enrolledparticipantsandthe

sameexaminerassessedstabilityoftheirvisualacuityonatleasttwooccasions.

Ifmeasuresdifferedbymorethan0.1logunits,further


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assessmentswereundertakenuntilmeasuresfellwithinthiscriterion.

Childrenwhorequiredcorrectionwithglasses(measureablerefractiveerror,definedpreviously9)orwho

hadalreadybeenwearingglassesforlessthan18weeksenteredtherefractive

adaptationphase.Theywereinstructedtowearglassesallthetimeandscheduled

toreturnforassessmentofvisioneverysixweeksfrom


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week0(onsetofwearingglasses)until18weeksofrefractiveadaptationhadbeencompleted:aperiodthatwehavepreviouslyestablishedwouldallow

forallmeasurableimprovementattributabletowearingglassestohaveoccurred.9Oncompletion

ofrefractiveadaptation,childrenwhostillmetthestudysoperationaldefinitionofamblyopia

(seebelow)enteredtheocclusionphase.Thosechildrenwhodid


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notrequirecorrectionwithglassesorwhohadpreviouslywornglassesfor18weeksorlongerentereddirectlyintotheocclusionphase.CESallocated

childrentoprescribeddoseratesofeither12hoursaday(maximal)or

sixhoursaday(substantial)usingarandomnumbergeneratorinthestatistical

packageR(www.r-project.org/),stratified,butnotblocked,bytype


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ofamblyopiaandimplementedbymeansofaconcealedtypedallocationlist.Neitherinvestigatornortheparentsweremaskedtogroupallocation.

Theocclusiondosemonitor21recordedepisodesofocclusiontothenearestminute.The

monitorconsistsofaneyepatchwithtwoelectrodesattachedtoitsundersurface

connectedbyaplasticencapsulatedwireleadtoadata


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loggerpoweredbybattery.22Visualfunctionwasrecordedeverytwoweeks,atwhichtimewealsoauditedtheocclusiondosereceivedbetweenvisits.The

occlusionphasecontinueduntilvisualacuityceasedtoimproveasevidencedbyeithertwo

inflexionsofchangeinacuity(forexample,improve/decline/improve/decline)orthreeconsecutivemeasurements

ofacuitynotdifferingbyplusorminus


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0.02logunits.22Oncompletionoftheocclusionphase,childrenreturnedtostandardclinicalcare.Outcomemeasures

Ourprimaryoutcomemeasurewas

logMARvisualacuity.22Toencompassthereadingabilityandagespanofthe

children,weusedthreelogMARvisualacuitycharts:ETDRS(PrecisionVision,IL,USA),

crowded,anduncrowded(Keeler,Windsor).Weusedstandardprotocolsfor


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visualacuitytesting,scoredbyletter.Thetypeofchartusedforeachchilddidnotchangeduringthecourseofthestudy.

Weexpressedvisualoutcomeinthreeways:firstly,bycalculatingthechange

invisualacuityoftheamblyopiceye;secondly,bycalculatingtheamountof

residualamblyopia(acuitydifferencebetweentheamblyopicandfelloweye


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atoutcome);and,thirdly,bycalculatingtheproportionofthevisualdeficitcorrected(proportionalimprovement).20Theboxgivesdetailsofrelevantterminology.

Statisticalanalysis

WeusedWilcoxonsignedrankanalysistotestfor

significantdifferencesinoutcomeanddosebetweenthegroupsandKruskal-Wallisoneway

analysisof

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varianceonrankstotestforsignificantdifferencesinoutcomeforparticipantsbyobjectivelymonitoreddoserate.Thestatisticalpower

oftheanalyses(basedontheoutcomeofapreviouslyreportedstudy4)ranged

from0.6to0.9todetecta0.20differenceinlogMARvaluesbetween

groups(forrangesofn=17-41),witha=0.01.

RESULTS


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Ninetysevenchildrenwithameanageof5.6(SD1.5)yearsenteredthestudy.Fortytwohadamblyopiaassociatedwithanisometropia

(meanage6.3(SD1.4)years),21hadstrabismus(4.7(SD1.3)years),

and34hadmixedanisometropiaandstrabismus(5.3(SD1.5)years).Ninetythree

childrenhadmeasurablerefractiveerror,althoughninehadundergonefull


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refractiveadaptationbeforestudyentryandprogresseddirectlyfrombaselinetotheocclusionphase,leaving84(89%)childrenwhounderwentrefractiveadaptation(fig1).

Noadverseeventsoccurred.

Refractiveadaptationphase

Theprimary

purposeofthisphasewastoensurethatfullrefractiveadaptationwascomplete

before

Entered study and met inclusion criteria (n=122)Consented to study (n=121)Consent refused (n=1)BaselineRefractive adaptationOcclusionEntered study (n=97)Occlusion required (n=90)Randomised for occlusion (n=80)


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Continued until gains in visual acuityceased to be statistically verifiableDid not attend (n=24)No measurablerefractive error (n=4)Measurablerefractive error (n=93)Amblyopic (n=77)No longer amblyopic (n=7)12 hour group (n=40)6 hour group (n=40)Completed (n=40)Completed (n=40)Refractive adaptationcomplete before studyentry (>18 weeks) (n=9)Refractive adaptation (n=84):Full in study (n=44)Some before study (n=40)Left study (n=10):Did not attend (n=6)Did not wear occlusion monitor (n=4)Table1|Baselinecharacteristics

ofchildrenaccordingtotwoprescribedocclusion

Prescribedocclusion(hours/day)

6(n=40)12(n=40)

Mean(SD)baselinevisualacuity0.45(0.30)

0.44(0.30)Typeofamblyopia:Anisometropia1420Strabismus12


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7Mixed1413Mean(SD)age(years)5.4(1.7)5.6(1.4)

occlusioncommenced.Themean(SD)visualacuityofamblyopiceyes

improvedfrom0.55(0.28)to0.38

(0.34)logMAR;ameanimprovement

of0.17(95%confidenceinterval0.12to0.22).In40childrenwhohad

undergonepartialrefractiveadaptationbeforestudyentry(withamean


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(SD)numberofweekswearingglasses14(3)),themeanchangeinacuitywas0.11(0.05to0.17).Thechangeinacuityinthe

44childrenwhounderwentfullrefractiveadaptationmonitoredinourstudywassignificantly

greater(P=0.03)(mean0.22(0.16to0.28)logMARunits).Duringrefractiveadaptation,visual

acuityinsevenchildrenimprovedtoanextentthatthey


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werenolongereligibletoentertheocclusionphase,withmeanlogMARvisualacuity0.00(-0.07to0.07)intheamblyopiceyeand-0.04

(-0.10to0.02)inthefelloweye.

Occlusionphase

Though90childrenwereeligibleforocclusion,10leftthestudy.The80

remainingwererandomisedtoaprescribedocclusiondoserateof


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six(n=40;age5.4,SD1.7)or12hoursaday(n=40;age5.6,SD1.4)(table1).Inthesixhourgroup,the

mean(SD)visualacuityintheamblyopiceyeimprovedfrom0.45(0.30)to

0.19(0.19)logMAR,achangeof0.26(95%confidenceinterval0.21to0.31)

logunits.Inthe12hourgroup,themean(SD)


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improvementwasfrom0.44

(0.30)to0.20(0.24)logMAR,achangeof0.24(0.19to0.29)logunits(table2).Therewas

nosignificantdifferencebetweenthetwogroupsforanyoutcomemeasure(visualacuity

atstartandend,magnitudeofchangeinacuity,amountofresidualamblyopia,

orproportionoftheamblyopiadeficitcorrected)(table2).The


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meandoserates(hoursaday)actuallyreceivedwerenotsignificantlydifferent(4.2(3.7to4.7)inthesixhourgroupv6.2(5.1

to7.3)inthe12hourgroup;P=0.06)(fig2).Correspondingly,therewas

nodifferenceinthetotal(accumulated)dosereceivedbychildrenineitherof

thetwogroups(P=0.03)(fig3).Onlynine(23%)and


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three(7%)childreninthetwogroups,respectively,achievedanaverageconcordancewithin10%oftheirprescribeddoserate.Concordancewas

Fig

1|Recruitmentandretentionofparticipantsduringthree3.6timesmorevariable

inthe12hourgroupthaninstudyphasesthesixhourgroup.

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Table2|Mean(95%confidenceinterval)visualoutcomeaccordingtoprescribeddoseofocclusion(sixor12hoursaday)and

actualdosereceived*

ChangeinvisualProportionofdeficitCumulativedoseDoserate

(hours/TimetobestvisualacuitycorrectedResidualamblyopia(hours)day)acuity(days)

Prescribedocclusiondose(hours/day)

6(n=39)0.26


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(0.21to0.31)0.67(0.57to0.77)0.17(0.11to0.23)225(183to267)4.2(3.7to4.7)59(49to69)

12(n=41)0.24(0.18to0.30)0.61(0.50to0.72)0.22(0.15

to0.29)307(240to384)6.2(5.1to7.3)54(44to

64)

Difference0.02(0.0to0.04)0.06(0.03


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to0.09)0.05(0.03to0.07)82(63to101)2.0(1.7to2.3)05(1.8to8.8)

Pvalue0.640.34

0.250.300.06

Receivedocclusiondose(hours/day)

=3(n=21)0.18

(0.11to0.25)0.33(0.16to0.50)0.31(0.25to0.37)87(51

to123)1.6(1.3to1.9)70(51to89)


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>3-6(n=32)0.25(0.18to0.32)0.77(0.67to0.87)0.10(0.06to0.14)255(213to297)4.3(4.0to4.6)

66(55to77)

Difference0.07(0.06to0.12)0.44(0.39

to0.49)0.21(0.19to0.23)168(153to181)2.7(2.6to

2.8)4(-2to10)

Pvalue0.040.004


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value0.130.080.11


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Also,themeandoserateofocclusiondidnotdiffersignificantlywithtypeofamblyopia,evenwhenwestratifiedbyprescribeddoserate(P=0.05).

Wealsoanalysedthedatabyobjectivelymonitoreddoserate(that

is,receivedratherthanprescribed).Childrenwerecategorisedintothreegroupsaccordingto

thedoseratereceivedinhoursaday:


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=3-6(n=32),and=6-12(n=27).Wefoundasignificantdifferenceinvisualoutcomebetweenchildrenwhoreceivedlessthanthreehoursadaycompared

withthoseintheothertwogroups,withnodifferencebetweenthelatter

(table2).Therewasasignificant

trendforimprovedvisualoutcome

(greaterchangeinvisualacuityandproportionalimprovement,lessresidual


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amblyopia)withincreasingdoseratesuptofourhoursaday(figs4).

Durationofocclusiontherapy

Themeantime

toachievebestvisualacuitywasnineweeks(SD5,range2-26weeks).

Only12children(eightinthesixhourgroup;fourinthe12

hourgroup)requiredmorethan14weeksofocclusion.The


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meantimetoachievebestvisualacuitydidnotdiffersignificantlybetweentheprescribedgroups(10weeks(SD6,range2-26)inthe

sixhourgroupveightweeks(SD5,range1-18)inthe12

hourgroup).Mostoftheimprovementoccurredinthefirstsix

Dose rate (hours/day)

15

129

MedianMeanTotal dose (hours)


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6 hour group 12 hour group

1200

900

600

MedianMean6300

3

0

6 hour group 12 hour group

0

Fig|3

Totaldoseofocclusionactuallyreceivedinchildren

Fig2|Achieved

doserateinchildrenallocatedtosixor12allocatedtosixor

12hoursofocclusionaday.Verticallines


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hoursofocclusionaday.Verticallinesindicateinterquartileindicateinterquartilerange.Toenhanceclarity,dotshave

range.Toenhanceclarity,dots

havebeenjitteredhorizontallybeenjitteredhorizontally

page4of7



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Allocated to 6 hours of occlusion a dayTable3|Meandoserateandconcordancewithprescribedregimenwithage(years)andtypeof

Allocated to 12 hours of occlusion a dayamblyopia

1.2

Mean(95%CI)Pvalue

1.0

Doserate(hours/day):

Proportion of deficit corrected

0 2 4 6 810

0.8

0.6

0.4

0.2

0


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47(30to64)>6years58(46to70)Doserate(hours/day):Anisometropia5.19(4.19to6.19)0.48Strabismus5.79(4.39to7.19)

Mixed4.56(3.46to5.66)

-0.2

Dose rate (hours/day)

weeks(53%

bytwoweeks,68%byfourweeks,78%bysixweeks,85%by

eightweeks).

Factorsaffectingoutcomeasafunction


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ofdoserate

Theproportionofthedeficitcorrectedandresidualamblyopiawerenotsignificantlydifferent(P=0.46andP=0.42,respectively)foreach

typeofamblyopia.Themean(95%confidenceinterval)proportionsofdeficitcorrectedwere

0.60(0.48to0.72)foranisometropia,0.67(0.54to0.80)formixed,and

0.67(0.52to0.82)forstrabismus.Themeanresidualamblyopia


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atlowdoserates(0-3hoursaday)withmarginalbutnotsignificant(P=0.54)additionalgainsfordosesoverthreehoursaday(table

4).Incontrast,childrenaged4-6andover6yearsshowedsignificantdifferences

(P=0.03andP


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tosixandsixto12hoursa

Fig4|Doserateandproportionofdeficitcorrectedaccordingtoprescribedregimen.Fitted

linesaredefaultLOWESS(locallyweightedsmoothed)lineofbestfit

6,

thoseagedover6neededtoachieveadoserateoverthreehours

aday.

DISCUSSION

Substantial(sixhours


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aday)andmaximal(12hoursaday)prescribedocclusionregimensprovideequivalentvisualoutcomeforthetreatmentofunilateralamblyopiainchildrenaged

3-8.Thesefindingsagreewiththosefromapreviousstudy.13Byobjectivelymonitoring

occlusionweshowedthatthemaximalgroupreceivedonlyabout50%moreocclusion

aday,despitebeingprescribedtwicetherateinthe


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substantialgroup.Furthermore,analysisofdose-responseshowedthattheaverageamountofocclusionreceivedineachgroupwassufficienttoachievebestoutcome.Researchers

havepreviouslyraisedthepossibilitythatsimilaroutcomesseenwithdifferentprescribedocclusion

ratescouldbebecausesimilarrateswereactuallyreceived,butthestudydid

notincludeanyobjectivemonitoring.13

Optimumdoserate


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Wecarriedoutexploratoryanalysesontheeffectofreceiveddoserateandondoserateandage.Therelationbetweendose

ratesandoutcomeshowedthat


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uptothree

hoursadayhadlittledeficitcorrected.Togainequiva

lentproportionalimprovementinchildrenagedunder

Table4|Proportionofdeficitcorrected(meansand95%confidence

intervals)groupedbyageat

startofocclusionanddoserate

received

0.8

0.6

0.4

0.2


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0

Age(years)=3hours/day(n=22)>3-6hours/day(n=32)>6-12hours/day(n=27)Pvalue

-0.2

6

(n=17)0.17(-0.1to0.44)0.83(0.61to1.05)0.67


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(0.45to0.89)


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=6and>6years.

lineofbestfit

BMJ|ONLINEFIRST|bmj.compage5of7


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outcomewassimilarinchildrenreceivingbetweenfourand12hoursaday.Weobservedalinearrelationbetweenimproved

outcomeandincreaseddoseratefordoseratesuptofourhoursa

day(fig4),andouranalysissuggeststhatachievinganinitialdoserate

ofthreetofourhoursadayshouldbea


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clinicalpriority.Theresponsedependsonage,however,sothatforthoseunder4yearsthiscouldbereduced.Higherdoseratesachievethe

bestoutcomemorerapidlybutatariskofaccumulatingexcessivenon-therapeutichours

ofpatching.Thus,patchingforallwakinghoursisalmostcertainlyexcessive.

Weconsiderthattheobservedeffectofdoseprescribed


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(thatis,intheintentiontotreatanalysis)wasnotcompromisedbypotentialconfoundingofothervariables(forexample,typeofamblyopia,ageof

child,visualacuityatstartofstudy).Theimperfectadherencetoassignedtreatment,

however,impliesthatanobservationalanalysisthatinspectstheeffectofdosereceived

maybesubjecttoconfounding.Acarefullyconstructedmultipleregression


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analysisofcausalinferencemethodswouldthereforeberequiredtoanalysethedataondosereceived.19

Concordance

Eyepatchingcan

causeconsiderabledistressforboththechildandfamily.2324Fullconcordancewith

prescribeddoseratesisrare;childreninourstudyreceivedonaverage66%

and50%oftheirprescribedocclusionofsixand12


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hoursaday,respectively.Thissuggeststhattheseprescribedregimensimposedaconsiderableburdenonourparticipantsandwouldbeexpectedtodoso

inroutinelytreatedpatients.Weobservedaplateauofimprovementinoutcomeat

aboutfourhoursaday.Prescriptionsofocclusionshouldtakethisintoaccount,

minimisingtheamountsnecessaryforbestexpectedoutcome.


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Theconventionalclinicalapproachinachildwhosevisiondoesnotimprovewithparttimeocclusiontherapyistoprescribeamoreintenseregimen,16

thusincreasingtheburdenoftreatmentonthechildandfamily.4192324Knowledgeof

concordancewithtreatmentpermitsdetailedevaluationoftreatmentstrategy.Forexample,ifcompliance

waslowinitiallythenthiscouldbethereasonfor


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pooroutcome,inwhichcaseeducation25ordifferentpatchingstrategiesmayfacilitatebestoutcome.Ifconcordancewashigh,however,additionalocclusionwillprobablynot

bebeneficial.

Objectivemonitoringofocclusion

Ourstudyhighlights

thebenefitsofobjectivemonitoringofocclusionwithinroutineclinicalpractice.Firstly,clinicians

nolongerhavetorelyonsubjectiveandqualitativefeedback


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fromchildrenandparentsastotheamountofpatchingachieved.Secondly,theavailabilityofanobjectivequantitativerecordoftheocclusiondoseand

doserateallowsthecliniciantotailoradviceandprescriptiontoanindividual

patient.Inpracticalterms,thiswillreducethenumberofpatchinghoursprescribed

andclinicvisitsrequired.Thisshouldresult

page


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inanimprovementincosteffectivenessandpotentiallyabetterexperienceforthechildandhisorherfamily.

Althoughtreatmentforamblyopiaisthoughttobemoresuccessfulat

earlierstagesofvisualdevelopment,26theevidenceisunconvincingandcontradictory.26-32Wehave

providedfurtherevidencethatagecaninfluenceeffectiveness.Itseems


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thatpatchingdoserateisthepredictivefactorofwhetherolderchildren(over6years)canbetreatedsuccessfully.Thusthechildunder4

yearsrespondsbothmorerapidlyandwithlessocclusionthantheolderchild,

butthefinallevelofattainmentforallagesbetween3and8

yearsisthesame.Thedataprovidefurtherevidenceof


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thetimingandplasticitywithinthesensitiveperiodforvisualrecovery.Towardstheendofthevisualsensitiveperiod,however,itseemsthatthe

deficitbecomesmoreresistantandlessplastic,requiringmoreocclusiontoachievethe

sameoutcome.

Wedidnotintendtoprovidespecificevidencebased

guidelinesforthetreatmentofamblyopiaasthiswouldrequire


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furtheraccumulationofevidence(suchasontheinfluenceoftheseverityofamblyopia).Ourresults,however,suggestthatatypicalamblyopicchild(in

thisstudyachildwithameanacuityof0.45logMARafterrefractive

adaptationwhoimprovedby0.26logMARasaresultofocclusion)wouldrequire

anaccumulationintheregionof180-270receivedhoursof


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patchingatanaveragedoserateoffourhoursaday(table2andfigure4).

Dose-responseanalysisofamblyopiatherapyis

anovelapproachthatcanelucidatethekineticsofthesensitiveperiodin

humans.Byfinetuningtherapeuticstrategiesitwillbepossibletofacilitateevidence

basedtreatmentplansspecificforeachchild.Thiswillreduce


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theburdenofamblyopiatreatmentforthechildandfamilyand,ultimately,forhealthserviceproviders.

Wethankallthechildrenand

parentswhotookpartinthestudyandthemembersoftheROTAS

Cooperative(TriciaRice,RowenaMcNamara,AvrilCharnock,ClareBaldwin,NaheemAbbas).

Contributors:Allauthorscontributedtothedesign.CESwasresponsible


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forthedaytodaymanagementofthestudy.ARFandCESwereresponsiblefortheclinicalexaminationofparticipants.CESandDASanalysed

thedata.CESdraftedthemanuscript,whichwasrevisedbyallauthors.ARF

isguarantor.Funding:ROTASwasfundedbyaprojectgrantfromFightfor

Sight,UK.Noneoftheauthorswereemployees,trustees,or


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adviserstoFightforSightduringtheperiodthefundingapplicationwasunderconsideration.Competinginterests:Nonedeclared.Ethicalapproval:HillingdonandStMarys

HospitalsLondonNHSTrustslocalresearchethicscommittees.Provenanceandpeerreview:Non-commissioned;

externallypeerreviewed.

1HubelDH,WieselTN.Theperiodof

susceptibilitytothephysiological

effectsofunilateraleye


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closureinkittens.JPhysiol

1970;206:419-36.2DawNW.Criticalperiodsinthevisualsystem.In:HopkinsB,

JohnsonSP,

eds.Neurobiologyofinfantvision.Westport,CT:

Praeger,2003:43-103.3BlakemoreC,

GareyL,Vital-DurandF.Thephysiologicaleffectsof

monoculardeprivationand

theirreversalinthemonkeyscortex.J

Physiol1978;283:223-62.


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4StewartCE,MoseleyMJ,StephensDA,FielderAR,theMOTAS

cooperative.Thetreatmentdose-responseinamblyopiatherapy:

resultsfrom

themonitoredocclusiontreatmentofamblyopiastudy

(MOTAS)InvestOphthalmolVis

Sci2004;45:3048-54.

5RahiJ,LoganS,TimmsC,Russell-EggittI,

TaylorD.Risk,causesandoutcomesofvisualimpairmentafter


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lossofvisioninthenon-



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WHATISALREADYKNOWNONTHISTOPIC

Occlusiontherapy(patching)isthemaintreatmentforamblyopiaItis

anunpleasantprocedureandcompliancewithtreatmentisoftenpoorGiventheinability

torecordobjectivelytheamountofocclusionachildactuallyreceives,

manypractitionersprescribelargedoses,abovesixhoursaday


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RS,SmithEL,CrawfordMLJ,vonNoordenGK.Theeffectsofreversemonoculardeprivationinmonkeys.I.Psychophysicalexperiments.ExpBrainRes1989;74:327-37.

7LeVayS,WieselTN,HubelDH.Thedevelopmentofoculardominance

columnsinnormalandvisuallydeprivedmonkeys.JCompNeurol1980;191:1-51.

8

PediatricEyeDiseaseInvestigatorGroup.Treatmentofanisometropicamblyopiain


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childrenwithrefractivecorrection.Ophthalmology2006;113:895-903.

9MoseleyMJ,NeufieldM,McCarryB,CharnockA,McNamaraR,RiceT.Remediationofrefractive

amblyopiabyopticalcorrectionalone.OphthalmicPhysiolOpt2002;22:296-9.

10Stewart

CE,MoseleyMJ,StephensDA,FielderAR,onbehalfoftheMOTAScooperative.

Refractiveadaptationinamblyopia:quantificationofeffectandimplicationsfor


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practice.BrJOphthalmol2004;88:1552-6.

11AwanM,ProudlockFA,GottlobI.Arandomizedcontrolledtrialofunilateralstrabismicandmixedamblyopia

usingocclusiondosemonitorstorecordcompliance.InvestOphthalmolVisSci2005;46:1435-9.

12PediatricEyeDiseaseInvestigatorGroup.Arandomizedtrialofpatchingregimens

fortreatmentofmoderateamblyopiainchildren.ArchOphthalmol2003;121:603-11.


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13PediatricEyeDiseaseInvestigatorGroup.Arandomizedtrialofprescribedpatchingregimensfortreatmentofsevereamblyopiainchildren.Ophthalmology2003;110:2075-87.

14VonNoordenGK,CamposEC.Patchingregimens.Ophthalmology2004;111:1063.

15Wygnanski-JaffeT.Theeffectonpediatricophthalmologistsoftherandomizedtrial

ofpatchingregimensfortreatmentofmoderateamblyopia.JAAPOS


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2005;9:208-11.

16KushnerBJ.Patchingregimensforamblyopia.Ophthalmology2004;112:736.

17FielderAR,AuldR,IrwinM,CockerKD,Jones

HS,MoseleyMJ.Compliancemonitoringinamblyopiatherapy.Lancet1994;343:547.

18

LoudonSE,PollingJR,SimonszHJ.Apreliminaryreportabouttherelationbetween

visualacuityincreaseandcomplianceinpatchingtherapyforamblyopia.


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Strabismus2002;10:79-82.

19StewartCE,StephensDA,FielderAR,MoseleyMJ,MOTASCooperative.Modellingdose-responseinamblyopia:towardachild-specifictreatment

plan.InvestOphthalmolVisSci2007;48:2589-94.

20StewartCE,MoseleyMJ,

FielderAR.DefiningandmeasuringtreatmentoutcomeforunilateralamblyopiaBrJOphthalmol

2003;87:1229-31.

21FielderAR,IrwinM,AuldR,CockerKD,JonesHS,MoseleyMJ.Compliancemonitoringinamblyopia


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therapy:objectivemonitoringofocclusion.BrJOphthalmol1995;79:585-9.

22StewartCE,FielderAR,StephensDA,MoseleyMJ.Designofthemonitored

occlusiontreatmentofamblyopiastudy(MOTAS).BrJOphthalmol2002;86:915-9.

23

HrisosS,ClarkeMP,WrightCM.Theemotionalimpactofamblyopiatreatmentin

preschoolchildren.Ophthalmology2004;111:1550-6.

24SearleA,Norman


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ofthefixingeye.TransOphthalmolSocAust1965;24:39-46.

27HiscoxFN,StrongN,ThompsonJR,MinshullC,WoodruffG.Occlusionfor

amblyopia:acomprehensivesurveyofoutcome.Eye1992;6:300-4.

28LeaHSJ,

RubensteinJLMP.Thesensitiveperiodforanisometropicamblyopia.Eye1989;3:783-90.

29

KutschkePJ,ScottWE,KeechRV.Anisometropicamblyopia.Ophthalmology1991;98:259-63.


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30CobbCJ,RussellK,CoxA,MacEwanCJ.Factorsinfluencingvisualoutcomeinanisometropicamblyopes.BrJOphthalmol2002;86:1278-81.

31FlynnJT,WoodruffG,ThompsonJR,HiscoxF,FeverW,ShiftmanJ.

Thetherapyofamblyopia:ananalysiscomparingtheresultsofamblyopiatherapyutilizing

twopooledsets.TransAmOphthalmolSoc1999;97:373-90.


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32FultonAB,MayerDL.Esotropicchildrenwithamblyopia:effectsofpatchingonacuity.GraefesArchClinExpOphthalmol1988;226:309-12.

Accepted:16

July2007

BMJ|ONLINEFIRST|bmj.compage7of

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Objective Monitoring Patching of Amblyopia

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