in vivo detection of deep retinal

6/9/2014

1

In‐vivo detectionofdeepretinalneuronallayerchangesfollowing

acuteopticneuritis

OmarAl‐Louzi,MD;PavanBhargava,MD;ScottNewsome,DO;PeterCalabresi,MD;ShivSaidha,MD

DepartmentofNeuroimmunologyandNeuroinfectiousdisordersJohnsHopkinsUniversity

May31,2014

Disclosures

• Dr.Al‐Louzi reportsnodisclosures.

• Dr.Bhargavareportsnodisclosures.

• Dr.NewsomehasreceivedconsultationfeesfromBiogen‐IdecandGenzymeaswellasresearchsupportfromBiogen‐IdecandNovartis.

• Dr.Calabresi hasreceivedcompensationforconsultingandservingonscientificadvisoryboardsfrom:Vaccinex,Vertex,Prothena,andAbbvie; andhasreceivedresearchfundingforimagingresearchfromNIHR01NS082347,NMSS,RacetoEraseMS,andNovartis;andforunrelatedresearchprojectsfromBiogen‐IDECandMedImmune.

• Dr.SaidhareceivesfundingsupportfromtheRacetoEraseMS,andhasreceivedconsultingfeesfromMedicalLogix forthedevelopmentofCMEprogramsinneurology,consultingfeesfromAxonAdvisorsLLC,EducationalGrantSupportfromNovartis&Teva Neurosciences,andspeakinghonorariafromtheNationalAssociationofManagedCarePhysicians.

6/9/2014

2

Multiplesclerosis(MS)

• MSisanimmune‐mediateddemyelinatingdisorderoftheCentralNervousSystem(CNS)withbothinflammatoryanddegenerativecomponents.

• MScommonlyinvolvestheopticnerves;acuteopticneuritis(AON)isthepresentingfeaturein~20%ofpatients,while50%experienceitatsomepointduringthecourseoftheirdisease1.

• AutopsystudiesdemonstratethatopticnervepathologyispresentinthemajorityofMSpatientsevenintheabsenceofovertclinicalinvolvement2.

1. Balcer,L.J.OpticNeuritis.NEngl JMed 354, 1273–1280(2006)2. Toussaint,D.,Périer,O.,Verstappen,A.&Bervoets. J.Clin.Neuroophthalmol. 3, 211–20(1983).

Retinalhistology

Microscopiccross‐sectionalviewthroughtheopticnerveincludingtheretinallayershttp://hubel.med.harvard.edu

OPTICNERVE

RetinalNerveFiberLayer

OPTICDISC

GanglionCellLayer

6/9/2014

3

Opticalcoherencetomography(OCT)

• OCTisatechniquethatemployslowcoherenceinterferometryofnear‐infraredlight.

• Itisusedtogeneratein‐vivo high‐resolution(<5µm),cross‐sectionalimagesoftheretina.

• Becauseofthedepth‐resolvingcapacityofOCT,itenablesvisualizationofretinaltissuestructuressimilartotissuesectionsunderamicroscope.

EvidencethatretinalneuronallossoccursinMS

• Retrogradeneurodegenerationisthoughttoculminateindropoutofretinalganglioncells.

• Ourgrouphaspreviouslyshownusingmacularsegmentationthatthinningofthecompositeganglioncell+innerplexiform(GCIP)layersoccursfollowingAON1.

• However,comprehensivelongitudinalin‐vivo assessmentofdeepretinalneuronallayersfollowingONremainslargelyunexplored.

1. Syc,S.B.etal..Brain 135, 521–33(2012).

Ganglioncelldropout(79%ofMSpatienteyeballs)

Innernuclearlayerneurondropout(40%ofMSpatienteyeballs)

Greenetal.Brain2010;133:1591‐601

6/9/2014

4

Objectives

• TodeterminewhetherobjectivechangesinINLandONLthicknessesoccurfollowingAON.

• Toexplorewhetherthesechangesmaybetemporallyrelatedtothicknesschangesofthecompositeganglioncell+innerplexiformlayerthickness(GCIP).

Methods‐ Participants

• 34patientsdiagnosedwithacuteunilateraldemyelinatingON.

• Baselineevaluationwasperformedwithameandelayof14daysfromonset(SD8.8,range:1‐33days).

• Acomparisoncohortof34MSpatients,whodidnotdevelopAON,werematched1:1basedonage,sex,anddurationofOCTfollow‐up.

6/9/2014

5

Demographicandclinicalcharacteristics

Abbreviations:AON=Acuteopticneuritis;MS=multiplesclerosis;CIS=clinicallyisolatedsyndrome;RRMS=relapsing‐remittingmultiplesclerosis;SPMS=secondaryprogressivemultiplesclerosis;IQR=inter‐quartilerange.

PatientspresentingwithAONatbaseline

PatientswithMSwhodidnotdevelopAONatbaselineorduring

follow‐up

P‐value

Age,y,mean(SD) 36.4(9.4) 35.9(9.1) 0.83a

Female,n(%) 30(88) 30(88) 1.00b

Diagnosis,n(%)

CIS

RRMS

SPMS

7(20.6)

26(76.5)

1(2.9)

0(0.0)

33(97.1)

1(2.9)

0.01b

EyeswithaprevioushistoryofAON,n(%)

12(17.6) 19(27.9)0.15d

Follow‐upduration,months,median(IQR;range)

22.5(12.6‐34.2) 22.9(14.2‐36.4)0.65c

a Two‐sampleStudent’st‐test.bFisher’sexacttest.c Mann–WhitneyUtest.dChi‐squaredtest.

Retinalimaging• PatientsunderwentCirrus‐HDOCTimaging,withautomatedintra‐retinallayersegmentation,ateachstudyvisit.

• Twomacularsegmentationmethodswereusedtoobtainmeasuresofretinallayerthickness:1. Manufacturer’salgorithm

2. Graph‐based,open‐accessmethod

0.54mm

2.4mm

5mm

5mm

6/9/2014

6

Statisticalanalysis

• TimewastakenasacontinuousvariablestartingattheonsetofAONsymptoms.

• Comparisonsbetweenclinicallyaffectedandfelloweyes,atsettimeintervals,weredoneusingmixed‐effectslinearregressionaccountingforwithin‐subjectinter‐eyecorrelation.

• MultilevellinearsplinemodelswereusedtoanalyzethecourseofOCTmeasurechangesovertime.

• Breakpoints(allowingforchangesinslopetooccur)werepositioned,accordingtothebestfittothedata.

Abbreviations:GCIP=ganglioncell+innerplexiform layer;INL=innernuclearlayer;OPL=outerplexiformlayer;ONL=outernuclearlayer;PRL=photoreceptorlayer

6/9/2014

7

Table2: Estimatedratesofchangeinaverageretinallayerthicknessesinclinically‐affectedeyesafterON

OCTmeasure

Baselineto3months

3to6months 6to12months

Rateofchange

(µm/month)

P‐value

Rateofchange

(µm/month)

P‐value

Rateofchange

(µm/month)

P‐value

RNFL ‐9.85 <0.001 ‐0.91 0.713 ‐0.36 0.695

GCL+IPL

Manufacturer ‐3.68 <0.001 0.17 0.668 ‐0.16 0.281

Graph‐based ‐2.70 <0.001 0.11 0.731 ‐0.14 0.220

Abbreviations:ON=opticneuritis;GCIP=ganglioncelllayer+innerplexiformlayer;RNFL=retinalnervefiberlayer.

Table3: Estimatedratesofchangeinaverageretinallayerthicknessesinclinically‐affectedeyesafterON

OCTmeasure

Segmentationmethod

Baselineto3months

3to6months 6to12months

Rateofchange

(µm/month)

P‐value

Rateofchange

(µm/month)

P‐value

Rateofchange

(µm/month)

P‐value

INL+OPLManufacturer 0.71 <0.001 ‐0.31 0.103 0.01 0.897

Graph‐based 0.11 0.417 ‐0.26 0.061 ‐0.04 0.506

ONL+PRLManufacturer 2.18 <0.001 ‐1.34 <0.001 ‐0.17 0.095

Graph‐based 1.37 <0.001 ‐0.65 0.001 ‐0.15 0.038

Abbreviations:ON=acuteopticneuritis;INL=innernuclearlayer;OPL=outerplexiformlayer;ONL=outernuclearlayer;PRL=photoreceptorsegmentslayer.

6/9/2014

8

RelationshipbetweenGCIPlossandONLthickeningatthe4±1monthvisit

Takehomemessages• GanglioncelllayerthinningfollowingAONappearstobemostrapidintheearlymonths.

• OCTsegmentationdemonstratesatransientincreaseinONLthicknessthatappearstobeproportionaltothedegreeofGCIPlossinaffectedeyes.

• Thisraisesthepossibilityofbiologicaltrans‐synapticchangesoccurringinthedeepretinalneuronallayersandmayhelpusunderstandthecellularresponsetoinjuryinMS.

6/9/2014

9

Acknowledgements

JohnsHopkinsNeurology

• PeterA.Calabresi

• ShivSaidha

• PavanBhargava

• ScottNewsome

JohnsHopkinsElectricalandComputerEngineering

• JerryPrince

• AndrewLang

• AaronCarass

JohnsHopkinsBiostatisticsdepartment:

• Ciprian Crainiceanu

Funding:

• NIHgrant:5R01NS082347‐02

• RacetoEraseMS