Optical coherence tomography in MS

Dr.ShivSaidha,MBBCh,MD,MRCPIAssociateProfessorofNeurology,

JohnsHopkinsUniversitySchoolofMedicine

02/24/2017

Disclosures

•  Dr.ShivSaidhahasreceivedconsulJngfeesfromMedicalLogixforthedevelopmentofCMEprogramsinneurology,consulJngfeesfromAxonAdvisorsLLC,EducaJonalGrantSupportfromNovarJs&TevaNeurosciences,speakinghonorariafromtheNaJonalAssociaJonofManagedCarePhysicians,AdvancedStudiesinMedicineandtheFamilyMedicineFoundaJonofWestVirginia,andservedonscienJficadvisoryboardsforBiogen-Idec,NovarJs,EMDSerono,GenzymeandGenentechCorporaJon.�

•  Dr.ShivSaidhareceivesresearchfundingfromtheRacetoEraseMS&GenentechCorporaJon

Conventional MRI in MS

•  SensiJveforcapturinginflammatoryacJvity•  Goodwaytoassessinflammatoryresponsetotherapies

•  However,associaJonbetweenneworenlargingT2lesions&contrast-enhancinglesionswithdisabilityprogressionismodestKapposetal.Lancet1999

•  T2lesionquanJficaJonatbaselinehaslimitedpredicJvevalueforpredicJngdisabilityFisnikuetatal.Brain2008

Non-conventional MRI in MS

•  NumerousstudiesshowthatmeasuresofwholebrainatrophyareinverselyrelatedwithdisabilityprogressionDeStefanoetal.Brain1998,Fisheretal.Neurology2002

•  MRIsegmentaJontechniquesenablemeasurementofbrainsubstructurevolumes

•  Grayma`er(GM)degeneraJonextremelycommoninMS,beginsearly&maybemorecloselylinkedwithdisabilitythanwhitema`er(WM)degeneraJonSimonetal.MultScler2006,Calabreseetatal.J.Neurol2007,Calabreseetal.ArchNeurol2009

•  Othernon-convenJonalMRImeasuresofneurodegeneraJonincludeDTI,MTI,MRS,MWF

•  Issueswithnon-convenJonalMRI……….

OCT

•  SimilartoultrasoundbutusesnearIRlight

•  Lightsimultaneouslysenttoeye&referencemirror

•  LightpenetratesJssuelayers&sca`eredback

•  Returninglightcomparedtoreference(interferometry)allowingcomputerreconstrucJon

Why is there an interest in being able to quantify the neural components of the retina in MS?

Microscopiccross-secJonalviewthroughtheopJcnerveincludingthereJnallayersh`p://hubel.med.harvard.edu

OPTICNERVE

Re,nalNerveFiberLayer

OPTICDISC

GanglionCellLayer

•  OpJcneuropathyisvirtuallyubiquitousinMS•  OpJcnervedemyelinaJon/inflammaJon→retrogradedegeneraJon

ofopJcnerveaxons(RNFLfibers)→deathofthereJnalneuronsfromwhichthesefibersoriginate(ganglioncells)

What OCT has shown us in MS

• Re,nalnervefiberlayer(RNFL)&ganglioncell+innerplexiformlayer(GCIP)thinningreflectMSrelatedop,cnerveneurodegenera)onFrohmanetal.NatClinPractNeurol2008

• RNFL&GCIPthinningoccuraLerop,cneuri,s(ON)andaspartoftheMSdiseasecourseineyeswith&withoutahistoryofONPetzoldetal.LancetNeurol2010,Costelloetal.AnnNeurol2006,Talmanetal.AnnNeurol2010,Garcia-MarJnetal.BrJOphthalmol2011,Ratchfordetal.Neurology2013

• RNFL&GCIPthinninginMSareclinicallyrelevantandcorrelatewithvisualfunc,on,globaldisability&brainatrophyFisheretal.Ophthalmol2006,Gordon-Lipkinetal.Neurology2007,Pulickenetal.Neurology2007,Sigeretal.JNeurol2008,Villosladaetal.Neurology2008,Graziolietal.JNeurolSci2008,Dorretal.PLoSOne2011,Pfuelleretal.PLoSOne2011,Saidhaetal.ArchNeurol2012,Youngetal.EurJNeurol2013,Zimmermannetal.MultScler2013• RatesofGCIPthinningareacceleratedinMSpa,entsexhibi,ngclinicaland/orradiologicaldiseaseac,vityRatchfordetal.Neurology2013

• IncreasedINLthicknesscorrelateswithT2lesionvolumecross-sec,onallyandpredictsclinical&radiologicaldiseaseac)vitySaidhaetal.LancetNeurol2012

Peripapillary nerve fiber layer

Fovea

ILM RNFLGCL

IPLINL OPL

ONL

RPE

ELM

OS/IS

ISOS

Macular OCT Segmentation

ILM:InnerlimiJngmembraneRPE:ReJnalpigmentepitheliumRNFL:ReJnalnervefiberlayerIPL:InnerplexiformlayerOPL:OuterplexiformlayerGCL:GanglioncelllayerINL:InnernuclearlayerONL:OuternuclearlayerIS:InnerphotoreceptorsOS:Outerphotoreceptors

Saidhaetal.MultScler2011Saidhaetal.Brain2011Sycetal.Brain2011Saidhaetal.JAMANeurol2012Saidhaetal.LancetNeurol2012Saidhaetal.AnnNeurol2015

MacularcubescanacquiredwithCirrusHD-OCT(CarlZeissMeditecInc,Dublin,CA)

Longitudinal study of OCT & MRI in MS •  6-monthlyspectral-domainOCT(includingautomatedintra-reJnal

segmentaJon)•  Baseline&annual3TbrainMRI(includingsubstructurevolumetrics)•  PaJentswithocularrelapses(opJcneuriJs)duringthestudyexcluded•  Individual-specificratesofchangeinreJnalandbrainmeasureswerecorrelated,

adjusJngforage,sex,diseaseduraJon&ONhistory.

Saidhaetal.AnnNeurol2015

Relationships between rates of change in OCT & MRI measures over study duration

MRI-derivedbrain

compartmentvolumerateof

change

OCT-derivedreJnallayerthicknessrateofchange§

RNFL GCIP INL ONL

CorJcalGM 0.207* 0.371*¶ 0.092 -0.028CerebralWM 0.144 0.285* 0.036 -0.066Thalamus 0.273* 0.379*¶ 0.228* -0.242*Caudate 0.438*¶ 0.155 -0.015 -0.144Putamen 0.146 0.147 0.186 -0.228*Brainstem 0.329*¶ 0.210* -0.019 -0.094Lesions** 0.014 -0.128 -0.120 0.169

CVF 0.291* 0.449*¶ 0.085 -0.068‡ParJalcorrelaJoncoefficientswereadjustedforage,gender,MSsubtype,diseaseduraJonandhistoryofON.§Theaveragerateofchangeforbotheyeswasusedtocomputethesubject-specificrateofchangeinreJnallayerthickness.*Indicatesanunadjustedp-value<0.05.¶Indicatesap-value<0.05aserBonferroniadjustmentformulJplecomparisons.

AlloftheaboveresultswereverifiedbytwoaddiJonalstaJsJcaltechniques,includingempiricalBayespredicJonsfrommixed-effectslinearregressionmodelsandSIMEX.**RRMS:GCIP(r=-0·30;p=0·01),INL(r=-0.28,p=0.04)

GCIP – CVF relationship over time

Saidhaetal.AnnNeurol2015

MSsubtype ONmodel§ Cor,calGM

CerebralWM CVF

Total

Model1:n=107

Model2:n=95

Model3:n=59

Model1

Model2

Model3

0.361

0.416

0.500

0.275

0.267

0.433

0.437

0.492

0.614

RRMS

Model1:n=71

Model2:n=61

Model3:n=32

Model1

Model2

Model3

0.312

0.431

0.575

0.201

0.211

0.334

0.328

0.450

0.602

ProgressiveMS

Model1:n=36

Model2:n=34

Model3:n=27

Model1

Model2

Model3

0.528

0.546

0.535

0.619

0.583

0.637

0.673

0.670

0.677

GCIP – MRI relationships by subtype & ON history

§Allmodelswereadjustedforbaselineage,gender,anddiseaseduraJon.Model1usestheaverageoftheratesofreJnallayerthicknesschangefrombotheyes,regardlessofONhistory,butisaddiJonallyadjustedforapasthistoryofON.Model2excludeseyeswithapasthistoryofONfromthecalculaJonoftherateofchangeofreJnallayerthickness.Model3excludessubjectswithaprevioushistoryofONineithereye.

RRMS

Progressive

Julia Button, Omar Al-Louzi, Andrew Lang, Pavan Bhargava, Scott D. Newsome, Teresa Frohman, Laura J. Balcer, Elliot M. Frohman, Jerry Prince,

Peter A. Calabresi, Shiv Saidha

Bu`onetal.Neurology2017

Bu`onetal.Neurology2017

Clinical and baseline demographic characteristics

Treatmentgroup GA IFNSC IFNIM NAT HC pvalue

Numberofpa,ents(eyes) 48(95) 35(69) 28(53) 46(91) 47(92) --

Age;mean,years(SD)41.6(9.6)

40.5(11.1)

45.0(9.0)

39.4(10.6)

39.0(10.1)

0.101a

Females;n(%) 39(81) 30(86) 21(75) 34(74) 30(64) 0.174b

Race;n(%)

CaucasianAfricanAmericanHispanicAsian-PacificIslanderUnknown

40(83)5(10)1(2)1(2)1(2)

26(74)6(17)0(0)2(6)1(3)

23(82)2(7)2(7)0(0)1(4)

40(87)4(9)1(2)0(0)1(2)

37(79)5(11)1(2)1(2)3(6)

0.845c

Follow-updura,on;mean,years(SD)

3.2(1.3) 3.0(1.5) 2.9(1.5) 3.0(1.4) 3.4(1.6) 0.141a

Op,cneuri,shistory;n(%) 25(52) 17(49) 14(52) 24(52) -- 0.988bDisease-dura,on;mean,years(SD)

8.4(6.4) 8.8(6.8) 9.8(7.2) 8.8(5.5) -- 0.738a

Gap,me;mean,years(SD) 3.0(2.9) 2.2(1.9) 5.1(3.9) 1.3(0.8) -- <0.001a

FirstDMT;n(%) 36(77) 17(49) 19(76) 2(4) -- <0.001cRelapseduringfollow-up;n(%) 9(19) 9(26) 3(11) 4(9) -- 0.176c

a:ComputedwithKruskal-Wallisequality-of-populaJonranktest;b:ComputedwithChisquare(χ2)test;c:ComputedwithFischer’sexacttest

Differences in rates of retinal atrophy by DMTs

Averagerates(µm/year)of

re,nallayerlossover,meby

DMTs

p-valueofpair-wisecomparisonbetweenDMTs

NAT IFNIM GA IFNSC NATvs

GA

NATvs

IFNSC

NATvs

IFNIM

IFNIMvs

GA

IFNIMvs

IFNSC

GAvs

IFNsc

GCIP -0.17 -0.28 -0.31 -0.54 0.035 <0.001 0.157 0.750 0.002 0.001

INL -0.06 -0.08 -0.09 -0.20 0.450 0.001 0.671 0.848 0.023 0.011

ONL +0.02 -0.20 -0.16 -0.36 0.014 <0.001 0.013 0.644 0.102 0.014

AMT -0.08 -0.60 -0.55 -1.14 0.019 <0.001 0.030 0.813 0.036 0.006ReJnallayerthicknesschangeswereanalyzedusingmixed-effectslinearregressionadjusJngforageatbaseline,diseaseduraJonatbaseline,sex,gapJme,relapseduringfollow-upandbaselinethicknessofthereJnallayerofinterest.

IFNSC has a faster rate of atrophy during first year of treatment

Dataplo`edrepresentstheGCIPthicknessforeacheyeofpaJentswhostartedIFNSCwithagapJmelessthanoneyear.

Rates of GCIP loss over time in treated RRMS patients compared to HC cohort.

GCIPthicknesschangeswereanalyzedusingmixed-effectslinearregressionadjusJngforageatbaselineandsexaccounJngforwithin-subjectinter-eyecorrelaJonsandthebaselinethicknessof

thereJnallayerofinterest

CohortRateofGCIP

loss

RateofGCIPlosscomparedtoHC(p-

value)

HC 0.14 ---

GA 0.30 -0.16(0.010)

IFNSC 0.54 -0.40(<0.001)

IFNIM 0.28 -0.14(0.080)

NAT 0.16 -0.02(0.720)

Bu`onetal.Neurology2017

Anterior Visual Pathway Measures are Associated with Cognition in Multiple Sclerosis

James Nguyen, Alissa Rothman, Anna Whetstone, Stephanie Mazurek, Jannelle Aquino, Laura J. Balcer, Elliot M. Frohman, Ciprian Crainiceanu,

Meghan Beier, Scott Newsome, Peter Calabresi, Shiv Saidha

Nguyenetal.

Neuropsychological tests and fatigue & depression surveys administered

Measure DomainMSFC

Workingmemory,complexconcentraJon,informaJonprocessingspeedlowerextremityandfinemotorskills

SDMT

InformaJonprocessingspeed,visualscanning,workingmemory

BVMT-RTotalRecall VisuallearningBVMT-RDelayedRecall VisualdelayedfreerecallJLO VisuospaJalfuncJoningCOWAT Phonemicfluency,execuJvefuncJoning

DKEFSSorJngProblemsolving,cogniJveflexibility,execuJvefuncJoning

BDI Self-reporteddepressivesymptoms

MFIS

Self-reportedimpactoffaJgueonphysicalcogniJve,andpsychosocialfuncJon

Relationships in RRMS Scores AnteriorVisualPathwayMeasures

AverageGCIPThickness 100%-VA 2.5%-LA 1.25%-LA

p-value R2 p-value R2 p-value R2 p-value R2MSFC(n=95)a 0.616 0.114 0.511 0.114 0.048 0.056 0.107 0.052OralSDMT(n=76)b 0.47 0.237 0.689 0.287 0.055 0.118 0.002 0.161BVMT-RTotalRecall(n=71)c 0.978 0.244 0.025 0.348 0.092 0.125 0.001 0.205BVMT-RDelayedRecall(n=71)c 0.206 0.259 0.364 0.318 0.361 0.098 0.024 0.149JLO(n=30)a 0.277 0.232 0.097 0.387 0.47 0.306 0.166 0.209DKEFS(n=28)a 0.386 0.217 0.964 0.449 0.004 0.617 0.02 0.572COWAT(n=45)b 0.706 0.154 0.689 0.249 0.027 0.368 0.139 0.201BDI(n=39)d 0.446 0.149 0.325 0.372 0.015 0.480 0.12 0.295MFIS(n=68)d 0.06 0.187 0.016 0.262 0.305 0.037 0.811 0.021

p-values and coefficients of determination were adjusted for: a age, sex, disease duration, years of education, and ON history b sex, disease duration, and ON history c sex, disease duration, years of education, and ON history d age, sex, disease duration, and ON history 1 Snijders/Bosker Level 1 R2-values were also derived from the mixed regression model

Pa3entswithpRNFL≤87μm(Cirrus)-88μm(Spectralis)hadincreasedriskofdisabilityworseningover5-yearsfollow-up

Riskx2

Riskx4

1 3

3 5pRNFL≤87-88μmpRNFL87-88μmto98μmpRNFL>98μm

MarJnez-Lapiscinaetal.LancetNeurol2016

Re,nalmeasuresatbaselinehavevalueforpredic,ngdisabilityinMSat10years

4060

8010

012

014

0

Aver

age

RN

FL

0 2 4 6 8 10EDSS5.

56

6.5

77.

5

Aver

age

TMV

0 2 4 6 8 10EDSS

CourtesyofAlissaRothmanandPeterCalabresi

Ongoing Projects ElucidaJonanddeterminaJonoftherelevanceoftrans-synapJcdegeneraJoninMS

Al-Louzietal,INPRESS,MSJ

A model for hemi-macular GCIP representation cortically

IndividualGCIPtrajectories(adjustedforage,sex&hxofAON)

RegressedGCIPslopesonindividualgenevariantsusingSequenceKernelAssociaJonTest(SKAT)tocalculategenebased-p-values

AppliedHotNet2algorithmtoextractnovelsubnetworks(bymappinggenep-valuestoareferenceprotein-proteininteracJonmatrix)

Genewithverylowp-value

Largestconsensussubnetworkhighlyenrichedinearlycomplementpathway

Singlegene-basedp-value

KateFitzgerald

LongitudinalOCTxGWASRevealsNovelGeneNetworkPathway

C1RC1S

C2

C3

C3AR1

CFB

CR2

ITGAX CFHR5

OLFM4

Ongoing Projects •  VasculatureinMS•  TSDin-vivoinMS•  EvoluJonofINLandONLchangesinMS•  InvesJgaJonoftherapeuJceffectsinRRMS&PMS•  LongitudinalrelaJonshipsbetweenAVPmeasures&neuropsychologicalfuncJoninMS

•  UseofOCTinMSprecisionmedicine•  EffectsoflifestylefactorsinMS•  OCTopJmizaJon•  NovelOCT&otherreJnalimagingtechniques

JohnsHopkinsNeurology:PeterCalabresiOmarAl-LouziJuliaBu`onJimmyNguyenAlissaRothmanPavanBhargavaSco`NewsomeJohnsHopkinsOphthalmology:SarahSolomonJohnsHopkinsElectricalEngineering:JerryPrinceAaronCarassJohnsHopkinsRadiology:PetervanZijlDzungPhamJohnsHopkinsBiostaJsJcs:CiprianCrainiceanuNINDS:DanielReich

Collaborators NYU:LauraBalcerRachelNolanUTSouthwesternNeurology:ElliotFrohmanCharité-UniversitätsmedizinBerlin:FriedemannPaulAlexanderBrandtInsJtutBiomedicalResearchAugustPiSunyer(IDIBAPS):PabloVillosladaElenaHMar,nez-Lapiscina

FundingRacetoEraseMSGenentechCorporaJonNaJonalInsJtuteofHealth(5R01NS082347-02)NaJonalMulJpleSclerosisSociety(TR3760-A3

&RG4212-A-4)NaJonalEyeInsJtute(R01EY014933&R01EY

019473)BraxtonDebbieAngelaDillon&Skip(DADS)

DonorAdvisorFund