Aus!der!Augenklinik!der!Medizinischen!Fakultät!Charité!!Universitätsmedizin!Berlin! !!!! DISSERTATION! !!!

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1 AusderAugenklinikderMedizinischenFakultätCharité UniversitätsmedizinBerlin DISSERTATION OpticalCoherenceTomographyBasedObservationofthe NaturalHistoryofDrusenoidLesioninEyeswith DryAgeLRelatedMacularDegeneration zurerlangungdesakademischengrades Doctormedicinae(Dr.med.) vorgelegtdermedizinischenfakultät Charité UniversitätsmedizinBerlin von YanlingOuyang auschangchuncity,jilinprovince,china DatumderPromotion:27.Feb.2015

2 TABLE&OF&CONTENTS& & &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&Page& 1.&ABSTRACT&&&&&&& 1.1&Abstract&(English)&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&3& 1.2&Abstract&(Deutsch)&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&4& 2.&Affidavit&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&5& 3.&Excerpt&of&the&Journal&Summary&List&(ISI&Web&of&Knowledge&SM)&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&6& 4.&Copy&of&publication&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&7& 5.&Curriculum&vitae&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&17& 6.&Complete&list&of&publications&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&19& 7.&Acknowledgements&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&22&

3 ABSTRACT(English) Title:'OpticalcoherencetomographybasedobservationofthenaturalhistoryofDrusenoidlesionin eyeswithdryagecrelatedmaculardegeneration.' Purpose:Tousespectraldomainopticalcoherencetomography(SDCOCT)toinvestigateriskfactors predictiveforthedevelopmentofatrophyofdrusenoidlesions(dls)(drusenanddrusenoidpigment epitheliumdetachment)ineyeswithnoncneovascularagecrelatedmaculardegeneration(nnvamd). Design:Cohortstudy. Participants:FortyConeeyesfrom29patientswithNNVAMD. Methods:PatientswithNNVAMDwhounderwentregisteredSDCOCTimagingoveraminimum periodof6monthswerereviewed.drusenoidlesionsthatwereaccompaniedbynewatrophyonset at6monthsorlastfollowcup(ful)werefurtheranalyzed.detailedlesionchangewasdescribed throughoutthestudyperiod.oddsratios(ors)andriskfornewlocalatrophyonsetwerecalculated. Main'Outcome'Measures:Drusenoidlesionfeaturesandlongitudinalchangesinfeatures,including maximumlesionheight,lesiondiameter,lesioninternalreflectivity,andpresenceandextentof overlyingintracretinalhyperreflectivefoci(hrf).subfovealchoroidalthickness(sfct)andchoroidal thickness(ct)weremeasuredbeloweachlesion. Results:Atotalof543individualDLswereidentifiedatbaseline,and28lesionsdevelopedduring followcup.themeanfollowcuptimewas21.3±8.6months(range,6c44months).some3.2%ofdls (18/571)progressedtoatrophywithin18.3±9.5months(range,5C28months)oftheinitialvisit. Drusenoidlesionswithheterogeneousinternalreflectivityweresignificantlyassociatedwithnew atrophyonsetat6months(or,5.614;95%confidenceinterval[ci],1.277c24.673)andnewatrophy onsetatful(or,7.005;95%ci,2.300c21.337).lesionswiththepresenceofhrfweresignificant predictorsofnewatrophyonsetat6months(or,30.161;95%ci,4.766c )andful(or, ;95%CI,2.513C50.019).Lesionswithabaselinemaximumheight>80µmorCT 135µm showedapositiveassociationwiththenewatrophyonsetatful(or,7.886;95%ci,2.105c andor,3.796;95%ci,1.154c12.481,respectively). Conclusions:ThepresenceofHRFoverlyingDLs,aheterogeneousinternalreflectivityofthese lesions,wasfoundconsistentlytobepredictiveoflocalatrophyonsetintheensuingmonths.these findingsprovidefurtherinsightintothenaturalhistoryofanatomicchangeoccurringinpatientswith NNVAMD. 3

4 ABSTRAKT(Deutsch) Titel:SD2OCTbasierteBeschreibungdesnatürlichenVerlaufesvonDrusenbeitrockener altersbedingtermakuladegeneration. Hintergrund:Zielwares,dieSD2OCTdazuzuverwenden,prädiktiveRisikofaktorenfürdenÜbergang vondrusenzuatrophiezonenbeiaugenmittrockeneraltersbedingtermakuladegeneration(amd) zuuntersuchen. Design:Kohortenstudie. Probanden:EinundvierzigAugenvon29PatientenmittrockenerAMD. Methoden:WiruntersuchtenretrospektivPatientenmittrockenerAMD,dieübermindestens6 MonatemittelsregistrierterSD2OCT2Scansbeobachtetwurden.DrusenimOCT,diesichnach6oder mehrmonatenzuatrophiezonenentwickelten,wurdeneingehenduntersucht.hierfürwurden ParameterwiemaximaleHöhe,Drusendurchmesser,interneReflektivität,DickederChorioideaund intraretinalehyperreflektivefoci(hrf)ausgewertet.oddsratios(or)undkonfidenzintervalle(ki)für dasrisikoeineratrophieentwicklungwurdenerrechnet Hauptuntersuchungsmerkmale:MerkmaledrusenoiderPigmentepithelabhebungen(DPE)und longitudinaleveränderungendiesermerkmale,eingeschlossenmaximalerdpe2höhe,dpe2 Durchmesser,interneDPE2ReflektivitätunddasVorhandenseinbzw.dasAusmaßüberderDPE liegenderhyperreflektiverfoci(hrf).diesubfovealechorioideadicke(sfct)sowiediechoroidale DickeunterhalbderDPE(CT)wurdenebenfallsgemessen. Ergebnisse:Insgesamtkonnten543individuelleDPEzumStartzeitpunktidenitifiziertwerden,28 neuedpeentwickeltensichimverlaufderstudie.diemittlerebeobachtungszeitwar21.3±8.6 Monate(Bereich,6244Monate).Bei3.2ProzentderDPE(18/571)bildetesicheineAtrophiezone innerhalbvon18.3±9.5monaten(bereich,5228monate)nachbeginnderbeobachtungaus.dpemit heterogenerinternerreflektivitätwarensignifikanthäufigermitneueratrophienach6monaten (OR,5.614;95%Konfidenzintervall[CI], )undneuerAtrophiezumletzten Beobachtungszeitpunkt(FUL)(OR,7.005;95%CI, )assoziiert.DPEmitHRFwaren signifikanteprädiktorenfürneueatrophienach6monaten(or,30.161;95%ci, )und zumful(or,11.211;95%ci, ).läsionenmiteinermaximalenhöhe>80µmoderct 135µmzuBeginnderBeobachtungwarenebenfallspositivmitdemAuftretenneuerAtrophie assoziiert(or,7.886;95%ci, undor,3.796;95%ci, ). Zusammenfassung:DasVorhandenseinvonHRFübereinerDPE,sowieeineheterogeneinterne ReflektivitätderDPEwarensignifikantmitderlokalenEntwicklungvonAtrophieinnerhalbder folgendenmonateassoziiert.dieseergebnisseerweiternunserverständisdermorphologischen VeränderungenimnatürlichenVerlaufdertrockenenAMD. 4

5 Optical Coherence Tomography Based Observation of the Natural History of Drusenoid LesioninEyeswithDryAgeARelatedMacularDegeneration Affidavit( I, Yanling, Ouyang certify under penalty of perjury by my own signature that I have submittedthethesisonthetopic"opticalcoherencetomographybasedobservationofthe NaturalHistoryofDrusenoidLesioninEyeswithDryAgeARelatedMacularDegeneration".I wrote this thesis independently and without assistance from third parties, I used no other aidsthanthelistedsourcesandresources. Allpointsbasedliterallyorinspiritonpublicationsorpresentationsofotherauthorsare,as such, in proper citations (see "uniform requirements for manuscripts (URM)" the ICMJE indicated. The section on methodology (in particular practical work, laboratory requirements, statistical processing) and results (in particular images, graphics andtables)correspondstotheurm(s.o)andareansweredbyme.mycontributioninthe selected publication for this dissertation corresponds to those that are specified in the followingjointdeclarationwiththeresponsiblepersonandsupervisor. The importance of this affidavit and the criminal consequences of a false affidavit(section 156,161 of the Criminal Code) are known to me and I understand the rights and responsibilitiesstatedtherein. Date16.Aug.2014 Signature Detailed(Declaration(of(Contribution( Publication:YanlingOuyang,FlorianM.Heussen,AmirhosseinHariri,PearseA.Keane, SrinivasR.Sadda.Optical(coherence(tomography(based(observation(of(the(natural(history( of(drusenoid(lesion(in(eyes(with(dry(age;related(macular(degeneration.(ophthalmology) Dec;120(12): Epub 2013 Jul 4. Contributionindetail: Yanling Ouyang has conducted the experiment, collected and analysed/interpreted the data, wrote the article and proofed/revised the article. Amirhossein Hariri has provided part of the materials. Pearse A. Keane has revised the article. Florian M. Heussen and Srinivas R. Sadda have together designed the experiment, supervised theexperiment,andproofed/revisedthearticle. Signature,dateandstampofthesupervisingUniversityteacher Signatureofthedoctoralcandidate 5

6 Excerpt(of(the(Journal(Summary(List(ISIWebofKnowledgeSM) 6

7 4.Copyofthepublication: Ouyang(Y,HeussenFM,HaririA,KeanePA,SaddaSR. Opticalcoherencetomographybasedobservationofthenaturalhistoryofdrusenoidlesion ineyeswithdryagearelatedmaculardegeneration.ophthalmology.2013dec;120(12):2656a

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17 5.Curriculum(vitae: For(data(protection(reasons,(my(resume(is(not(published(in(the(electronic(version(of(my( thesis.( 17

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19 LISTofPUBLICATIONS OriginalPublications 1. OuyangY,ShaoQ,ScharfD,JoussenAM,HeussenFM.RetinalVesselDiameter MeasurementsbySpectralDomainOpticalCoherenceTomography.Graefe sarchive forclinicalandexperimentalophthalmology.accepted. 2. McDonnellEC,HeussenFM,RuizOGarciaH,OuyangY,NaralaR,WalshAC,SaddaSR. EffectofantiOVEGFtreatmentonchoroidalthicknessovertimeinpatientswith neovascularageorelatedmaculardegeneration.eurjophthalmol.[epubaheadof print] 3. OuyangY,ShaoQ,ScharfD,JoussenAM,HeussenFM.EasyMethodtoDifferentiate RetinalArteriesfromVeinsbySpectralDomainOpticalCoherenceTomography: Retrospective,ObservationalCaseSeries.BMCOphthalmology.2014May15;14: OuyangY,PleyerU,ShaoQ,KeanePA,StübigerN,JoussenAM,SaddaSR,HeussenFM, EvaluationofCystoidChangePhenotypesinOcularToxoplasmosisusingOptical CoherenceTomography.PLOSOne.2014Feb5;9(2):e HeussenFM,ShaoQ,OuyangY,JoussenAM,MüllerB.Clinicaloutcomesafter switchingtreatmentfromintravitrealranibizumabtoafliberceptinneovascularageo relatedmaculardegeneration.graefe sarchiveforclinicalandexperimental ophthalmology.2014jun;252(6):909o OuyangY,HeussenFM,KeanePA,SaddaSR,WalshAC.ComparisonofNonOMydriatic FundusPhotographyandThreeDimensionalOpticalCoherenceTomographyfor DetectionofRetinalIrregularities.Investigativeophthalmology&visualscience.2013 Aug21;54(8):5694O OuyangY,HeussenFM,HaririA,KeanePA,SaddaSR.OpticalCoherenceTomography BasedObservationofNaturalHistoryofDrusenoidLesioninEyeswithDryAgeORelated MacularDegeneration.Ophthalmology.2013Dec;120(12):2656O OuyangY,WalshAC,KeanePA,etal.DifferentPhenotypesoftheAppearanceofthe OuterPlexiformLayeronOpticalCoherenceTomography.Graefe sarchiveforclinical andexperimentalophthalmology.2013oct;251(10):2311o7. 9. OuyangY,HeussenFM,KeanePA,etal.EvaluationoftheAxialLocationofCystoid SpacesinRetinalVeinOcclusionUsingOpticalCoherenceTomography.Retina (Philadelphia,Pa).2013May;33(5):1011O OuyangY,HeussenFM,KeanePA,etal.Juxtapapillarypigmentepitheliumdetachment observedinasymptomaticparticipantsusingopticalcoherencetomography. Investigativeophthalmology&visualscience2013;54(2): HuZ,WuX,OuyangY,OuyangY,etal.SemiOautomatedSegmentationoftheChoroid inspectralodomainopticalcoherencetomographyvolumescans.investigative ophthalmology&visualscience.2013mar7;54(3):1722o OuyangY,HeussenFM,KeanePA,etal.Theretinaldiseasescreeningstudy: prospectivecomparisonofnonmydriaticfundusphotographyandopticalcoherence tomographyfordetectionofretinalirregularities.investigativeophthalmology& visualscience.2013;54(2): TanCS,OuyangY,RuizH,SaddaSR.Diurnalvariationofchoroidalthicknessinnormal, healthysubjectsmeasuredbyspectraldomainopticalcoherencetomography. Investigativeophthalmology&visualscience.2012;53:

20 14. KeanePA,HeussenFM,OuyangY,etal.Assessmentofdifferentialpharmacodynamic effectsusingopticalcoherencetomographyinneovascularageorelatedmacular degeneration.investigativeophthalmology&visualscience.2012;53: OuyangY,ZhangY,XuG,etal.Opticalcoherencetomographyfeaturesofbest vitelliformmaculardystrophyatdifferentstages.chinesejournalofocularfundus Diseases2012;28(4): (Chinese) 16. PappuruRR,BricenoC,OuyangY,etal.ClinicalsignificanceofBOscanaveragingwith SDOOCT.Ophthalmicsurgery,lasers&imaging :theofficialjournaloftheinternational SocietyforImagingintheEye.2012;43: HeussenFM,OuyangY,McDonnellEC,etal.Comparisonofmanuallycorrectedretinal thicknessmeasurementsfrommultiplespectralodomainopticalcoherencetomography instruments.thebritishjournalofophthalmology.2012;96: HeussenFM,OuyangY,SaddaSR,WalshAC.Simpleestimationofclinicallyrelevant lesionvolumesusingspectraldomainoopticalcoherencetomographyinneovascular ageorelatedmaculardegeneration.investigativeophthalmology&visualscience. 2011;52: OuyangY,HeussenFM,MokwaN,etal.Spatialdistributionofposteriorpolechoroidal thicknessbyspectraldomainopticalcoherencetomography.investigative ophthalmology&visualscience.2011;52: PappuruRR,OuyangY,NittalaMG,etal.Relationshipbetweenouterretinalthickness substructuresandvisualacuityineyeswithdryageorelatedmaculardegeneration. Investigativeophthalmology&visualscience.2011;52: SaddaSR,KeanePA,OuyangY,etal.Impactofscanningdensityonmeasurements fromspectraldomainopticalcoherencetomography.investigativeophthalmology& visualscience.2010;51: KeanePA,PatelPJ,OuyangY,etal.Effectsofretinalmorphologyoncontrast sensitivityandreadingabilityinneovascularageorelatedmaculardegeneration. Investigativeophthalmology&visualscience.2010;51: KeanePA,AghaianE,OuyangY,etal.Acuteseverevisualdecreaseafterphotodynamic therapywithverteporfin:spectralodomainoctfeatures.ophthalmicsurgery,lasers& imaging:theofficialjournaloftheinternationalsocietyforimagingintheeye. 2010;41Suppl:S OuyangY,KeanePA,SaddaSR,WalshAC.Detectionofcystoidmacularedemawith threeodimensionalopticalcoherencetomographyversusfluoresceinangiography. Investigativeophthalmology&visualscience.2010;51: AlasilT,KeanePA,UpdikeJF,DustinL,OuyangY,etal.Relationshipbetweenoptical coherencetomographyretinalparametersandvisualacuityindiabeticmacular edema.ophthalmology.2010;117: OuyangY,ZhangY,XuG,etal.ClinicalmanifestationsandgeneanalysisinoneChinese familywithbestvitelliformmaculardystrophy.zhonghuayankezazhi.chinese journalofophthalmology.2008;44:321 6.(Chinese) 27. OuyangY,ZhangY,XuG,etal.ClinicalfeaturesofBestvitelliformmaculardystrophy. Zhonghuayankezazhi.Chinesejournalofophthalmology.2007;43: (Chinese) Reviewpapers 1.HeußenFM,OuyangY,JoussenAM.Retinalangiomatousproliferations.Klinische MonatsblätterfürAugenheilkunde.2012;229:877 81(review).(German) 2.OuyangY,ZhangY.Bestvitelliformmaculardystrophy.InternationalReviewof Ophthalmology.2007;31: (review)(Chinese) 20

21 3.OuyangY,ZhangY,WangW.ApplicationofBevacizumab(avastin)inOphthalmology. ChineseJournalofOphthalmologyandOtorhinolaryngology.2007;7: (review) (Chinese) 4.OuyangY,ZhangY,ZhangC.Ocularcicatricialpemphigoid.InternationalReviewof Ophthalmology.2007;31: (review)(Chinese) Casereport 1.OuyangY,ZhangY.Acasereportofsyphiliticopticneuritis.ChineseJournalofOcular FundusDiseases.2007;23: (casereport)(Chinese) 21

22 ACKNOWLEGEMENTS Prof.SrinivasR.Sadda,andDr.med.FlorianM.Heussendeservemygreatthanks forexcellentsupervision.thankyou IthankDr.AmirhosseinHariri,forgladlyhelpingmetocollectclinicaldataduring thecourseofthestudy. IthankDr.PearseA.Keane,forcriticalEnglishrevisionforthemanuscript. IalsothankProf.AntoniaM.Joussenforthehelpfuldiscussionofandstatistical suggestionsforthefinalmanuscript. 22