UtilizationofOCTinPatientswithMultipleSclerosisHannahShinoda,ODAssistantProfessor

PacificUniversityCollegeofOptometry

Wellit’sdefinitelyanhonortobehere.I’mhappytobehereatthehomecomingCEevent.Thetopicwe’llbecoveringtodayistheUtilizationofOCTinmanagingpatientswithMultiplesclerosis.InthePacificNorthwestwe’renostrangertoMS.I’msuremanyofyouthathavefriendsorfamilymemberswhohaveitbecausebeinginthePacificNorthwestwehaveathreetimesprevalenceratecomparedtoplacesinthemoresouthernpartsof

theUnitedStates.Soifwelookatthisprevalencemaphere(Figure1),youcanseethatinthemoresouthernpartsit'salightercolormeaninglessprevalenceandaswegoupthereisagradualchangeincolorbecomingmore

redmeaningmoreprevalence.Sobeinginthemorenorthernpartsthepresenceis1in500andaswegoclosertotheequatoritcanbeaslowas1in20,000.SothissuggeststhatperhapsenvironmentplaysaroleintheetiologyofmultiplesclerosisbuttheetiologyofMSisstillisnotwellunderstood.ThetheorybehindenvironmentetiologyisthatwhenyougetclosertotheequatorthereismoresunlightandmoreVitaminD.VitaminDplaysaroleinimmunefunctionandsowedoseecorrelationswhereVitaminDandadecreasedlevelofVitaminDhaveanincreasedriskofMS.Whenwegofurthermorenorththereislesssunlight,lessVitaminD,increasedriskofMS.However,whenwelookatotherplacesintheworldwheretheyareonthesamelongitude,samedistanceawayfromtheequator,theprevalencerateisn’tcompletelythesame.Soitdoesn’tfollowthispatternelsewhereintheworld.ThereisalsothepossibilitythatgenesplayaroleintheetiologyofMS.WeknowifwehaveafamilymemberwithMSweareatanincreasedriskofdevelopingMSourselves.However,inmonozygotictwinstudiesthereisincompletepenetrancesogenesalsodon’tcompletelyexplaintheetiologyofMS.Soit’sreallynotwellunderstoodatthispoint.WedoknowthatitismorecommoninCaucasians.FemalesaremorelikelytodevelopMSthanmales.Theyareatathreetimesincreasedrisk.Theageofonsettendstobebetweentheagesof20-40yearsold.

Figure1.PrevalencemapofMSintheUnitedStates

SowhatisMS?Alotofpeopleconsideritanautoimmunedisease.Ifyou'reapuristyoumayconsideritanimmune-mediatedprocessbecauseunlikeotherautoimmunediseaseswedon’tknowthetargetantigen.Wedon’tknowwhatthetargetcellsaresensitizedtoattack.Wedoknowit’ssomeimmuneprocessthatiscausingthesechangesintheCentralNervousSystem.WeknowthatthemyelinisattackedintheCentralNervousSystemwhichincludesthespinalcord,thebrain,and,importanttous,theopticnerves(Figure2).Themyelinisthisyellowportionhereonthenerve(Figure3).Itsjobistohelpwiththeconductionofthenerveimpulse.Withmultiplesclerosisthemyelingetsattackedbutwedon’tknow

specificallywhichpart.Myelinisdamagedsothenerveimpulseisdecreasedorcompletelyblocked.Withthedecreaseinmyelinwhathappensisthatthereisfatdropletsbecausemyelinismadeoutoffat.Thiscausesthephagocytestocomeandphagocytizethefatdroplets.Theastrocytesthencomeandtheycauseglialtissuetoform.WecanactuallyvisualizetheglialtissueonMRIasitshowsup

asplagues.InMultipleSclerosiswhenthemyelinisdamageditispossibleforre-myelinationtooccur.Whenthere-myelinationoccursitdoesn’tgobacktothefullfunctionalityoftheoriginalmyelin.Themyelintendstobemorethinanddoesn’tworkaswell.ThismirrorstherelapsesandremissionsinthesymptomsofMSwherethereisadecreaseinability,followedbyaremissionwheretheabilitiescomebackbutitmaynotreachbaseline.Alsointhisprocessweknowthattheoligodendrocytesareaffected.Morerecentlywealsobecameawarethatthenerveaxonsarealsodamagedaswell,especiallywhenwelookattheplaquesinthebraintissue.Thepathogenesisfortheaxonallossisn’tcompletelyunderstoodbutitisthoughtthatthemacrophagesandTcellsthatcomeanddamagethemyelincomealsosubsequentlyaffecttheaxons.ThiscanleadtoaxonallossinMS.SothisisthecategorizationofMultiplesclerosis.ToreachthecriteriaofMSitneedstomeettwomajorthingsasabasis.Itneedstoshowthatthereisaseparationoftimeandaseparationinspace.Separationintimemeansthatyouhavetohavemorethanjustonedemyelinatingevent.Itneedstooccuratleasttwotimes.Separationinspaceitneedstooccurinmorethanjustonelocation.TherearefourareaswhereMStendstooccur,we’llgooverthatinalittlebit.Withthefirsttypehere,theclinicallyisolatedsyndrome,itisnottheclinicallydefiniteMSyetsoitdoesn’tquitefulfilltheseparationintimeandspace.Thisisthediagnosisthatis

Figure2

Figure3

giventoindividualswiththeirfirstdemyelinatingevent.Theyjusthaveonedemyelinatedevent,theyareclinicallyisolatingsyndrome,andtheyfollowthemtoseeiftheylaterdevelopclinicallydefiniteMS.Whensomeonehasaclinicallyisolatedsyndrome,typicallythereisanMRIthat’sdone.WithanMRIitgivesanideaabouttheprognosisofthepatientlaterdevelopingtheclinicallydefiniteMS.Soiftherearenolesionsthereisonlya20%chanceofconvertingtoMS.IftherearelesionsintheMRIthataretypicalofMSthereisa60-80%chance.ThewonderfulthingaboutMRIisthattherearedifferenttechniquesforviewingthelesions.WithMRI,typicallyT1andT2isdone,it’sanMRIwithcontrast.Wecanseeiflesionsareoldandwecanseeiflesionsarenew.Ifweseethereareoldlesionsandnewlesions,thatfulfillsthecriteriaofseparationintime.Ifweseethelesionsareinmorethanonelocationthatfulfillsthecriteriaofseparationinspace.SobasedoffofonesymptomaticdemyelinatingeventintheMRI,theycouldstillseeifthereareoldornewlesionsandalsoseeiftherearemultiplelocationsandthepatientcanbediagnosedwithMSfromthat.SowiththeclinicallydefiniteMS,themostcommontype,85%ofthetimethepatientsareinitiallydiagnosedwiththerelapsing-remittingtype(Figure4)Thepresentationisasitsounds,thepatienthasrelapseswheretherearediscreteperiodsofexacerbationsofsymptomswherethereisanincreaseindisabilityandthenremissionswherethesymptomsofdisabilitygobacktobaselineoronlypartially.Ifthesymptomsonlycomebackpartiallytheytendtobepermanentanditgetscarriedalong.Theimportantthingtonoteaboutthisisthatduringtheremissionperiodthereshouldbenoprogressionofdisabilityitshouldstaythesame.Onaveragewhenpatientshavemultiplesclerosistheyhaveabout1relapseevery2years.Withtherelapsing-remittingtypethemajorityofpatientsgoonto

developsecondaryprogressiveMS(Figure5).ThereasonwhyitiscalledsecondaryprogressiveMSisbecauseitissecondarytotherelapsing-remittingform.Soyoucanseetheyinitiallyhadtherelapsing-remittingformandthentheygointothepatternofprogressionthat'sthesecondaryprogressivetype.Sointhistypeyoucanseethatthereisgradualprogressionofthediseaseandtheremaybeperiodsofnochangebutthese

Figure4: http://www.nationalmssociety.org

Figure5:http://www.nationalmssociety.org

relapsesandremissionsreallydonotoccurasmuchanymore.It’sjustamatteroftimeforpatientstoconvertfromtherelapsing-remittingtypeofthesecondaryprogressive.WhenwelookatstudiesandthenationalprogressionofMSinthecourseof25years,90%ofpatientsconvertovertothesecondaryprogressivetype.ThenthelastcommontypethatwehaveistheprimaryprogressiveMS.Atthetimeofdiagnosisonly15%ofpatientshavethistype.Thistypealmostseemslikeadifferentbeastalltogetherforafewreasons.OnereasonisthatinmostpatientswithMS,therelapsing-remittingtype,theplaquestendtobeinthebrainbutfortheprimaryprogressivetypetheplaguestendtobeinthespinalcord.AndwhentherearespinalcordlesionsittendstoeffectabilityquiteabitmoresopatientsinthistypehaveanincreaseindisabilitycomparedtoothertypesofMS.Alsoit’sdifferentbecausetheageofonsetisaboutadecadelater.Theaverageageofonsetisabout40yearsoldinsteadof30yearsold.Thereisnogenderpredilectionbecauserememberwetalkedaboutfemalesaremorelikelytodevelopit.Forprimaryprogressivetypeitisequalbetweenmalesandfemales.SowhyareweconcernedwithMultipleSclerosisaseyecarepractitioners?Well,MultipleSclerosisandocularchangesareverytiedtogetherbecauseopticneuritisisthemostcommondemyelinatingeventinMS.Inthecourseofthedisease40%ofpatientswithMSwillhaveopticneuritis.Also20%ofpatientshaveopticneuritisastheirfirstdemyelinatingevent.YoumaybetheonetohelpdiagnosepatientswithMultipleSclerosisbecauseit’stheirfirstdemyelinatingevent,yousendthemofftodoanMRIandtheyfindtheirseparationintimeandspacebasedoffthescans.Youcouldbetheonetohelpdiagnosethatpatient.AlsovisualsymptomsareprevalentamongpatientswithMS.We’renotgoingintoallofthemtodaybutsomeofthemarethePulfrichphenomenon,Internuclearophthalmoplegia,someevenhaveCharlesBonnetsyndrome.Thereisdecreasedcontrastsensitivity,visualfielddefects.Aseyecarepractitionersitisimportantforustobefamiliarwithit.Whatwe’regoingtotalkaboutprimarilytodayishowtouseOCTandmanagepatientswithMS.Solet’sgobackintimealittlebitandin1974,FrisenandHoytwerethefirstindividualstonotethattherewasRNFLlossinpatientswithMS.TheinterestingthingwasthatthenotedthisRNFLlossinthemajorityofpatients,73%ofpatientshadvisibleRNFLdefects.Eveniftheywereasymptomatic,theydidn’tfeelliketherewereanyvisionchangestheystillhaveRNFLdefects.Thiswasdonethroughvendoscopy,notevenOCT.SonowadayswiththeOCTwecanquantifythatmoreandmoreaccuratelydetectchangesintheirRNFL.Theinterestingthingisthatin1974,atthattimethethoughtwasthatthecauseofdisabilityinMSwasprimarilythedemyelination.NowweknowthattheprimarycauseofdisabilityinMSis

Figure6:http://www.nationalmssociety.org

actuallyduetoaxonalloss.Soaseyecarepractitionerswecanprovideveryvaluableinformationwiththatfortworeasons.Theopticnerveistheonlypartofthecentralnervoussystemthatwecanseeinvivo.Thesecondreasonisthateverywhereelseinthecentralnervoussystemalltheaxonsaremyelinated.WithRNFLitisunmyelinatedsowhateverwearequantifying,whateverwearemeasuring,it’snotconfoundedbythemyelinandthemyelinlosssowecanmoredirectlymeasuretheaxonalloss.Soit’simportantforustobefamiliarwiththenaturalprogressionofopticatrophyfromopticneuritis.ThisisaprospectivestudydonebyCostello.Shelookedatpatientsthathadacuteopticneuritisandshefollowedthemtoseehowlongitwouldtakeforopticatrophytodevelop.Sothedefinitionofchangeinherstudywasthebaselinewastheothereye.Sooneeyehadtheopticneuritisandtheothereyedidnot.Thedefinitionofchangewaswhentherewasasignificantdifferencebetweenthetwoeyeswithaconfidenceintervalwith95%.Shefoundthatduringthefirst3monthstherewasoverallnochangeintheRNFLthickness.Duringmonths3-6waswhentherewasthemostchangewithanaverageof19micronsofatrophydeveloped.After6monthsnofurthersignificantatrophywasdetected.Theearliestchangeshenotedwasactuallyatthe2monthmarkandthelatestchangeshesawwas2yearsaftertheopticneuritisevent.Overall,mostofthechangeoccursduringthat3-6months.Sofromthisweknowthatthe3-6monthwindowisthebesttimetoreallyassesshowmuchchangeisreallygoingtooccurwithopticatrophy.ShealsofoundthattheamountofatrophythatdevelopedformtheopticneuritiseventwasnotpredictiveofwhetherornotthepatientwoulddevelopMS.Theareathatwasthefirsttoshowatrophywasthetemporalarea.Thetemporalrimisgoingtobethemostsensitiveintermsoffirstshowingtheopticatrophysigns.FromanotherstudyweseethatonaveragethepatientsRNFLisabout105microns.Ifthereisahistoryofopticneuritiswealsosawthereisabouta20microndecrease.EvenwithpatientswithmultiplesclerosisthatdonothaveahistoryofopticneuritisthereisstillabitofthinningintheRNFLthicknesscomparedtothenormal,96versus105.Soyoudon’thavetohaveahistoryofopticneuritistoshowthinningofRNFL.Justhavingmultiplesclerosisisenoughtoshowsomechange.Sohowdoesthatapplytoclinic?Well,thehopeisthatwecanlookatthepatientsRNFLthicknessandbeabletodeterminewhattheirvisualfunctionis.Weknowthatwithpatientswithmultiplesclerosistheyoftencomeinwithvisualsignsandsymptomsandwewanttoseeifourobjectivedatamatcheswiththeirsubjectivefindings.SovisualacuitywasinvestigatedandfromwhatwetalkedaboutweknowthatinopticneuritiswedefinitelyhaveadecreaseinRNFL,anaverageofabout20microns.Wealsoknowfromtheopticneuritistreatmenttrial,afteropticneuritis,whatwasthebaselinevisualacuityforthemajorityofpatients?Theytypicallywentbackto20/20,themajorityofthem,ifwearelookingatfullcontrastvisualacuity.SoweknowthatthecorrelationbetweenfullcontrastvisualacuityandRNFLisnotgoingtocorrelateverywellthere(Figure7).Thereisjustaverymildcorrelation

betweenRNFLandfullcontrastvisualacuity.Thisstudyfoundthatthereissomecorrelationbutasyoucanseefromthischartherethecorrelationisnotverystrong.Therelationshipwasnotfoundinallstudies.Soinsteadtheylookedatlowcontrastvisualacuity.

Withlowcontrastvisualacuityitwasalotmoresensitive.Thismeansthatwhenyouhavepatientsthathaveahistoryofopticneuritisthatcomeinandsaythattheirvisionisn’tasgoodasitusedtobeandtheythinksomethinghaschanged.IfyoubringupafullcontrastvisualacuitySnellencharttheyaregoingtosee20/20.You’regoingtosaywellyou’rethesameasbaseline,Idon’tknowwhattotellyou.Butifwewanttomoresensitivefordetectingchangeweshouldbelookingatlowcontrastletteracuities.SothisstudylookedattheSloan1.25%contrast,theSloan2.5%contrastandthePolli-Robsonchart.OverhereIhaveaSloan1.25%(Figure8)andtheylookatcontrolpatients,patientswithMSandopticneuritis,andpatientswithMSandwithoutopticneuritis.Theycountedhowmanyletterstheywereabletosee.Fromthistopparthere,overalltheywereabletoreadthesamenumberoflettersforthefullcontrastacuitychartinallgroups.Thebiggestdifferencethatwecansee,themostsensitive,isactuallyusingthis1.25%contrastletteracuitychart.Sowhenwehavepatientsthatcomeinsayingthattheyhavesomechangesintheirvisionthisisgoingtobethemostsensitiveforquantifyingtheirsubjectivevisualdecrease.Withthatwecanbettermonitorforthechanges.Soinretrospectitwouldhavebeengreatifintheopticneuritistreatmenttrialtheyusedthischartinsteadofthefullcontrast.Fromthisstudytheypredictedthattherewasa1linedecreasein

Figure7: OpticNeuritisStudyGroup(2004):Visualfunctionmorethan10yearsafteropticneuritis:experienceoftheopticneuritistreatmenttrial.AMJOphthalmol137:77-83�TripSA,JonesSJ,AltmannDR,Garway-HeathDF<ThompsonAJ,PlantGT&MillerDH(2005):Retinalnervefiberlayeraxonallossandvisualdysfunctioninopticneuritis.AnnNeurol58:383-391

Figure8

Figure9: Fisher JB, Markowitz CE, Galetta Sl et al. (2006): Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 113:808-817

visualacuitywhichcorrespondedwitha4microndecreaseinRNFL.SoifyouhaveapatientwithanRNFLonanOCTislow,youcancorrespondittotheir1.25%Sloanacuitychartvisualacuity.ItwasalsofoundthattheRNFLcorrespondedwithvisualfields.Asyouknow,withglaucomaouropticnervesarebuiltwithalotofsparecapacity.SoyoucanloosequiteabitofRNFLbeforefindinganyvisualfielddefects.Samethingforpatientswithmultiplesclerosis.YoucouldloosequiteabitofRNFLbeforeseeinganyvisualfielddefects.Thecutoffpointforwhenvisualfielddefectsstartedshowingupwasatthis75micronpoint.ThisstudywasalsodonebyCostelloandherewecanseewhentheirRNFLwasquitefullnochangeinthemeandeviationofthevisualfield(Figure10).Thereisthinning,thinning,stillnochangebutrightwhentheyreachthe75micronpointthenwecanstarttoseeadecreaseinthemeandeviationonthefield.Sowhenyouhaveapatientwithmultiplesclerosisandyou’relookingattheirOCT.Onceyoureachbelow75youmightexpecttoseesomevisualfielddefects.ThiswasdonewiththeHumphrey30-2fullthresholdfield.Thatwasthetypeofstrategythattheyused.NewerdirectionsinOCTisactuallylookingontheganglioncelllayerbecauseit’simportanttorememberthatfortheRNFLtheaxonsaretheganglioncells.Soifwe’reseeingeffectsthereweshouldalsobeseeingsomechangesoftheganglioncells.WiththeganglioncellsforOCTanalysisforsomeinstrumentsyouhavethemmeasuringtheGCPI,whichistheganglioncellinterpluxiformlayer,asyourganglioncellcomplex,that’swhat’sdonewithCirrus.SomeinstrumentsliketheSpectralysmeasuretheganglioncelllayer.We’lloftenbereferringtotheminterchangeably.WithopticneuritisespeciallyifitistheanteriortypeasyoucanseehereweinitiallyhavethickeningofRNFL.SowhenwehavethickeningoftheRNFLfromanterioracuteopticneuritiswearenotabletodetecttheatrophyuntilthat3-6monthwindow.Soittakesquiteabitlongerforustoknowhowmuchatrophydevelopshere.However,whenwe’relookingattheganglioncellinterpluxifromlayer,it’snotconfoundedbytheRNFLedemafromtheinflammation.Here(Figure11)wecanseethatintheanterioroptic

Figure10:CostelloF,HodgeW,LorelloGR,KorolukJ,PanYI,FreedmanMS,ZackonDH&KardonRH(2006):QuantifyingaxonallossafteropticneuritiswithopticalcoherencetomographyAnnNeurol59:963-969.

Figure11: Rebolleda,Gema,etal.“OCT:NewPerspectivesinNeuro-Ophthalmology.”SaudiJournalofOphthalmology,vol.29,no.1,2015,pp.9–25.,doi:10.1016/j.sjopt.2014.09.016.

neuritistheganglioncellinterpluxiformlayerisunchanged.Wecandetectthinningoftheganglioncellinterpluxiformlayerasearlyastwoweeksaftertheonsetwhenthenervestilllooksedemidus.WhereasifwewereonlytorelyonRNFLwewouldhavetowait2weeks,6weeksuntilweseesomechangeandthen3monthsuntilweseeevenfurtherchange.Sowhenwe’relookingforatrophyfromopticneuritisitsimportanttoalsodotheganglioncellinterpluxiformlayerbecausethatisgoingtobealotmoresensitive,andalotmorefasteratpickingitup.

Also,whenwearecomparingtheganglioncellinterpluxiformlayerwithRNFLwealsoknowthereismuchstrongercorrelationcoefficients.Juststandingbackandlookingatthischart(Figure12)herewe’relookingatthecorrelationwithRNFLfindingsandvisualacuityandtheganglioncellinterpluxiformlayerandvisualacuity.We’relookingatthevisualacuitythroughthe2.5%contrastchartandtheSloan1.25%contrastchart.Youcanseejustlookingatthedottedpointsnexttothislinethatthe

dotsaremuchmoretightaroundthelinearregressionlinehereintheganglioncellinterpluxiformlayerforbothchartscomparedtotheRNFL.Sothecorrelationwithvisualacuityandtheganglioncellinterpluxiformlayerismuchstrongeraswell.Soit’sanimportantdatapointtohave.AlsoweknowjustfromlookingatnormativedatabasesthatjustwithagewehavejustgradualthinningoftheRNFL.NotduetopathologybutthereisalittlebitofRNFLthinningthatoccursjustwithtime.Samethingwiththeganglioncellinterpluxiformlayer,notduetopathologybutjustduetoagewehavegradualthinningoftheganglioncellinterpluxiformlayerthatoccurswithtime.WhenwecomparethatwithpatientswithMultipleSclerosisthathavenothadahistoryofopticneuritisweseethatsamechangeoccurringbutatamuchfasterrate.Whenwelookoverhere(Figure13)forthenormalchangeit’sabout.19-.52micronsperyearbutwithMultipleSclerosispatientstherateisaboutthreetimesfasterforRNFLthinning.SamethingwithGCIPwhenwecomparetothenorms,forMultipleSclerosistherateisaboutthreetimesfasterthancomparedtonorms.SowecanexpecttoseesomethinninginboththosereadingsforpatientswithMSevenwithoutahistoryofopticneuritis.Again,theareathatismostsensitivetothatchangeisthetemporalsideoftheopticnerve.

Figure12:Saidha,Shiv,etal.“VisualDysfunctioninMultipleSclerosisCorrelatesBetterwithOpticalCoherenceTomographyDerivedEstimatesofMacularGanglionCellLayerThicknessthanPeripapillary

RetinalNerveFiberLayerThickness.”MultipleSclerosisJournal,vol.17,no.12,2011,pp.1449–1463.,doi:10.1177/1352458511418630.�S.D.Walter,H.Ishikawa,K.M.Galetta,R.E.Sakai,D.J.Feller,S.B.Henderson,etal.GanglioncelllossinrelationtovisualdisabilityinmultiplesclerosisOphthalmology,119(2012),pp.1250-1257

ThisisanotheruseforassessingpatientswithMultipleSclerosis.Herewecanseeinthismacularscan(Figure14)thatwehavesmallmicrocysticedemaplaces.Whatlayerwouldyousaythatis?Internuclearlayer,therearesomesmallmicrocysticspacesintheinternuclearlayer.Thisisoftenfound1-2%ofthetimeinpatientsusingFingolimod.FingolimodistheonlyFDAapproveddiseasemodifyingdrugforpatientswithMultipleSclerosiswheretheyactuallytakeitorally.OtherMultipleSclerosisdiseasemodifyingagentsaretakenparentally.Sothiscanbefoundwithinfourmonthsofinitiatingtreatment.WherewithFingolimodweseethesesmallmicrocysticspaceshereandit’sreallynotunderstoodwhythathappensbutitseemstobedosedependent.Whereifyouhaveahigherdoseyouhaveahigherlikelihoodofdevelopingthosesmallmicrocysticspaces.OnanothernoteaninterestingthingisthattheyfoundinasmallsubsetofpatientswithMStheyhavethesesmallmicrocysticchangeshereintheINLwithoutahistoryofFingolimodandwithoutanyknownofcause.InthatsmallsubsetofpatientswithMSthey’reactuallyfoundtohaveworsedisabilitycomparedtoothers.SothisisanimportantscantodoonallpatientswithMSbecauseiftheyaren’ttakingFingolimod,thereisnootherknowncauseandweseethesesmallmicrocysticchangesitcangiveusanideaoftheirprognosisofdisabilityinthefuture.WithGCIPanalysiswearemeasuringtheganglioncellinterpluxiformlayersoit’sgoingtobeinnertotheinternuclearlayer.Sowhenwe’remeasuringtheGCIPit’snotaffectedbythisedemathatisseenhere.Evenwhenyou’refollowingpatientsandtheyhavethisedema,youcanstillassessiftherearechangesintheGCIPbecauseit’sinnertotheareasofedemaasyoucanseeheretherearestillnotedareasofthinning.

Figure13: Narayanan,Divya,etal.“TrackingChangesoverTimeinRetinalNerveFiberLayerandGanglionCell-InnerPlexiformLayerThicknessinMultipleSclerosis.”MultipleSclerosisJournal,vol.20,no.10,2014,pp.1331–1341.,doi:10.1177/1352458514523498.

C.Fjeldstad,M.Bemben,G.Pardo.Reducedretinalnervefiberlayerandmacularthicknessinpatientswithmultiplesclerosiswithnohistoryofopticneuritisidentifiedbytheuseofspectraldomainhigh-definitionopticalcoherencetomography.JClinNeurosci,18(2011),pp.1469-1472

Figure14:Rebolleda,Gema,etal.“OCT:NewPerspectivesinNeuro-Ophthalmology.”SaudiJournalofOphthalmology,vol.29,no.1,2015,pp.9–25.,doi:10.1016/j.sjopt.2014.09.016.

CaseStudy:Let’stalkaboutacase.SothisisapatientthatIhadduringmyresidencyanditkindofsparkedmyinterestinMultipleSclerosis.Sosheisa30yearoldAfricanAmericanfemaleandthereasonshewascominginwasfora6monthfollowup.ShewashereforaDFE,IOPcheck,andpupils.Shewasalsofollowedasaglaucomasuspectasa30yearold.HerpersonalocularhistorywasarecurrenthistoryofopticneuritisandsecondarytoMultipleSclerosis.She’dhave3episodesofopticneuritisintherightand3inthelefteye.Shealsohadahistoryofchronicallergicconjunctivitis.LookingatherpersonalmedicalhistoryshehasrelapsingremittingtypesofMS,themorecommontype.ShehasalsohadahistoryofHerpesZoster,SyndromeofInappropriateAntidiureticHormoneSecretion,Migraines,MajorDepressiveDisorder,Obesity.ButmorerecentlysomeabnormalweightlossshewastakingTopamaxandTopamaxcancausesomeweightloss.Shewasalsohavingsomeweightlossfromfinancialissuesandarecentviralbronchitis.ShealsohasNeurogenicbladder,hypertonicbladder,Menorrhagia,Anemia,Dysmenorrhea,BreastMass,AbnormalPapsmear,Allergicrhinitis,Viralbronchitis,andVitaminDdeficiency.Soprettytypicalpatientthatyou’dseeataVA.Thisisherlistofmedications-ArtificialTears,VitaminD,CitalopramHydrobromideformood,DimethylFumarate,IronTablets,OxybuyninChloride,Propanolol,Sumatriptan,Docusate,ointmentfordryskin,andLidocaine/Prilocainecream.Socominginhervisualacuitiesthatwemeasuredwhere20/20inbotheyes.Thoughshesubjectivelyreportedsomechangesinherrighteyeanditsoundedlikeadecreaseincontrast.IfIcouldgointimemyonethingthatIwouldaddtothetestwouldbetohavethatSloan1.25%contrastchartbecauseIbetthatIwouldn’thavegotten20/20onthatrighteyeifIhadthat.Sopupilswereequal,roundandreactivetolightbutshehada2+APD.ForherEOMsshereportedthattherewassomeeyepainonmovementfortherighteye.Furtheraskingquestionsaboutthateyepainitsoundsliketheeyepainhasbeenlongstandingfor2yearsbutithasbeenmorenoticeableinthelast3monthsandherlastopticneuritisepisodeintherighteyewasjust7monthsago.ShehadnoINO,nonystagmus,nodiplopia.FortheRedCapDesaturationTestshemeasuring7/10forcolordesaturationintherighteyeand10/10inthelefteye.HRRshowedmildred-greencolordefects,normalinthelefteye.FDTnodefects,thatwasjusttheFDTscreener.IOPswere10and11.Anteriorsegmentwasunremarkableexceptsmallcornealscarthatwasnotonthevisualaxis.

Lookingatheropticnerveshere(Figure15)whatdoyouthink?Whatdoyouthinkaboutthecuptodiscratio?Alittlebitlargerontherighteye.Sofromlookingatit,itlookedlikeabouta.065andthelefteyewethinkalittlebitsmallersowemeasureda0.4.Anythingelseyounoticeabouttheopticnervethatseemsabnormal?Yeah,yougotit,sopallor.Sotherighteyelookslikethereissomepallorespeciallyonthattemporalrim,maybeevengoingintothatsuperiortemporalarea.ShealsohadahistoryofthatAPD.Solookingherehowmanyofyouwouldconsiderheraglaucomasuspect?Theinterestingthingisweknowthatthereisopticatrophythatoccursfromopticneuritissoweareexpectingtoseeincreasedcuppingifwe’vehadmoreopticneuritisintherighteyethanthelefteye.Sowedoseethatcuppingevidenthere.SotherewasastudythatwasdoneandtheylookedatpatientswithMSandtheyfoundthatin25%ofpatientswithMStheyhadacuptodiscasymmetryof0.2ormore.Soit’saglaucomamasqueraderthatisimportanttokeepinthebackofourmindiftheyhaveahistoryofmultiplesclerosis.Soit’smorelikelyduetoMSbutaswedowithallourglaucomapatients,wejustmonitorandlooktoseewhattheprogressiongoingtobelike.ThisisRNFLOCTwithaSpectralys(Figure16)andintherighteyewehadnotedthetemporalpallorextendingsuperiortemporallythatwecouldseeimagedhereaswell.Theglobalfortherighteyeis69andforthelefteyewehave100.

Figure15

Figure16

Sowiththerighteyewegotaglobalof69.Doyouguysknowwhatthatcutoffwasforvisualdefects?75,wehavesomevisualfielddefectshere.ThisiswiththeHumphrey24-2SITAStandard.Thereliabilityindiceswereprettygood.Wedoseesomeeyemovementshereontherighteye.Itrequiressomerepeatingbutwecan

seethatthereissomecorrespondinginferiornasaldefectsontherighteye.Intermsofvisualfielddefectsformultiplesclerosisitcanfollowanypattern.Lefteyehereisprettyunremarkable.ThisistheganglioncellcomplexfortheSpectralys(Figure18).FortheSpectralystheylookforinter-eyedifferencesandintra-eyesymmetry.Fortheinter-eyesymmetrynormallythetotalvaluesbetweentherighteyeandlefteyeshouldbewithin5.Thetotalvaluesbetweentheintra-eyewhichisbetweenthesuperiorandinferiorshouldbewithin8.That’swhatnormalwouldbe.SoforourpatientwithMSherewecanseethatfortherighteyeit’sdefinitelylessthan5.Wehave268versus281andthatalsocorrespondsverywellwithourRNFLOCT.Wecanalsoseethatfortheintra-eyewhereitshouldbelessthan8thelefteyefallswithinnormsbuttherighteyeisdefinitelygreaterthan8.263versus274.ThatisalsoabnormalandcorrespondswellwithourRNFLOCT.OurpatienthadanMRIdone7monthsagowhenshehadherlastepisodeofopticneuritissoletstakealookatherMRIscans.Beforewedothatlet’sgooverthesectionsrealquick(Figure19).Soforthefirstoneforourredplanewithhavecoronalsoundinglikethewordcrownandcrownsbackinthedaywerewornmore

Figure17

Figure18

likeheadbandssoifyoucanimagineaheadbandgoingthroughyourheadthat’swhatthecoronalsectionlookslike.NextwehavethesagittalandthewayIremembersagittalisthatifyouwereevertohaveyourheadslicedinonedirection,Ithinkgoingstraightdownthemiddlewouldbethesaddestsothat’sthesagittalplane.Itworksforme.Thentransversegoesfromthefrontoftheheadtothebackofthehead.

SoletstakealookatherMRIscans(Figure20).Herewehaveacoronalsection.Weseethenasalsinuseshere,theextraocularmusclesaround.Whatcanyounoticethat’sdifferentorseemsabnormal?Whatabouttherightsidedoesn’tlookliketheleft?Youcanseealittleareathat’shyperreflectivehere.That’sshowingtheacuteopticneuritisthere.Theopticnerveisprevalenttherearetherightside.Thisiswithcontrastbytheyway.Whenlookingatthescansit’sasthoughthepatientisfacingyousothisisthepatient’sleftsideandpatient’srighteye.Soherewecanseethattheopticneuritisispresent.Thenoverhereonthescanontheleftsidethisisatransversescanwiththescangoingfromthefronttotheback.Wedon’tseeanymassesortumors.

Figure19

Figure20

Overherewehaveasagittalscanandagainsagittalbeingtheverysadslicegoingstraightthroughtheface(Figure21)Wecanseeherethefrontofthefaceandhere’s

thebackandwecanseeontheventriclesherethesewhitelittleplaques.SoareaswhereplaquestendtooccurinpatientswithmultiplesclerosisImentionedearlierwere4places.It’sthespinalcord,paraventricular,sorightnexttotheventriclesasyoucanseehere,juxtacortical,soifwelookrighthere,rightnexttothecortexwecanseeanother

whiteplaque,andthelastplaceisinfratentorial.Sothetentoriumisthislinethatseparatesthecerebrumfromthecerebellumandthebrainstemsoit’sinareasthatarebelowthat.Sofromourpatientwecanseethattherearetheseperpendicularwhiteplaquesaroundtheventricles.InpatientswithmoreadvancedMultipleSclerosisyouactuallyseequiteafewwhitelineslikethat.TheyactuallyhaveanamecalledDawsonsfingersbecausetheylooklikefingers.Herewehaveanothertransversesection(Figure22)andit’skindofhardtoimagineherebutthiswouldbetheinfratentorialbecausethisisthebrainstemandonthepatientsleftsidewecanseethatthere’salittlewhiteplaqueattheleftbrainstemwhichisprettytypicalofMSaswell.Soforourassessmentandplan,thepatienthadahistoryofrecurrentopticneuritissecondarytotheRelapsingRemittingtypeofMultipleSclerosis.Wecommunicatedwiththeneurologistconcerningthelongstandingeyepainwiththeboutofincreasedeyepaininthelast3months.ThepatientwastocontinueonhercurrentspectaclecorrectionandwasreferredbacktoOphthalmologyforfollowupcare.

Figure21

Figure22

SothenewdirectionforusingOCTinrelationshiptoMSistotrytoprovideahelpful,usefulpieceofinformationwheretheOCTwouldsomehowshowssomeinformationabouttheMRI.RightnowthegoldstandardfortakingcareofpatientsandmonitoringforchangeinpatientswithMSisMRI.MRIisprettyexpensive,sometimestherearesomeissuesofavailabilitybutMRIiscurrentlythegoldstandard.Ifyouwerejusttokindoftracttheprogressionofthediseaseoffthepatient’ssymptoms,patient’ssymptomsarenotassensitivebecausewhenwelookatnewlesionsonMRIversuspatient’sreportsofnewsymptomstheMRIis5-10timesmoresensitive.Sothat’swherewearerightnowbutthehopeisthatOCTwouldmaybeprovidesomeinformationaboutcerebralchangesthatcouldbehelpfulfortrackingpatientsprogression,responsetomedications,andsoforth.Thedatathatwehaverightnow,thecorrelationisnotverystrongbutwecanseesomemildcorrelationsaswe’reheadedtowardthatdirectionandaswe’refindingoutnewthings.Thereasonwhythecorrelationwillneverbevery,verystrongisbecausewe’reonlyseeingasmallpartofthecentralnervoussystem.We’reonlyabletomeasuretheRNFL,we’reonlyabletomeasuretheaxons.WhereaswithchangesthatareoccurringinthebrainforMultipleSclerosisyouarenotonlyhavingaxonalloss,you’realsohavingdemyelination,you’realsohavewaterchangesandsynapsechangestoo.Soit’snotreflectedinjustthesmallpieceofinformationthatwe’regetting.Thisisthemoderatecorrelationthatwe’reabletoseerightnow.Thereneedstobemorestudiesonthis.Lookingatthebrain,they’vecreatedabrainparenchymalfractionwhereit’ssimplythefractionofgraymatterpluswhitematterovergraymatterpluswhitematterpluscerebralspinalfluid.Herewecanseethatwiththebrainparenchymalfractionbeinghigher,0.79,theRNFLismoreintactbutaswe’regoingthiswaywecanseethatthereisRNFLthinningandthebrainparenchymalfractionisalsodecreasing.Soit’ssuggestingthatasthebrainparenchymalfractionisdecreasingthere’smorecorticalatrophythatweshouldalsoseetheRNFLreflectingthatchangeaswell.Thisisfoundinpatientswithoutahistoryofopticneuritisbecauseifyouhaveahistoryofopticneuritisyou’rehavinganareathat’sjustafocalacutedemyelination.You’regoingtohaveaxonallossandthat’saconfoundingfactors.Soit’sonlyinpatientsthathavenothadahistoryofopticneuritiswherethispatternisseenmore.Youcanalsoappreciatethedecreaseinthebrainparenchymalfractionbytheenlargementoftheventriclesthat’sseeninpatientswithMS.They’vealsofoundthatwhenlookingatRNFLcorrelationstobrainchangesthattheganglioncellinterpluxiformlayerisactuallybetterintermsofindicatingbrainatrophy.Thetheoriesofwhythatisarebecausethere’sbetterreproducibilitywithGCIP.AlsowithdamagetotheRNFLthereisastrogliosiswhichcanaddtothevolumeofwhatyou’remeasuring.AlsowiththeRNFLthereissomeedemathatoccursfrominflammationandtheGCIPisnotaffectedbythatarea.They’vealsofoundthattheGCIPrelatestoMSrelapsessoagainthecorrelationisnotverystrong,it’smoderateandthereneedstobemoredataonthis.Theyfoundthatastheganglioncellinterpluxiformlayeristhinningitcorrelatestonewlesions,acutelesionsthatarefoundonT1MRIscansandalsolesionsfoundonT2which

tendstobemorepermanent.Itcorrespondswithdisabilityprogression.Fromtheirstudytheyfoundthatlossof1micronofGCIPinpatient’seyeswithoutopticneuritiswaspredictiveof0.4%corticalvolumeloss.Corticalvolumelossisprettysynonymouswiththebrainparenchymalfraction.Also,theyfoundthattheRNFLcorrespondssomewhattoalsothepotentialthatthepatientisgoingtohaveincreaseddisabilityandfordisabilityforpatientswithmultiplesclerosisit’sthismeasuredonthisexpandeddisabilitystatusscalewhichgoesfrom1to10(Figure23).OnemeaningnodisabilityfromMSandasthenumbersprogressitlookslikethepatientabilitytoambulateandlateronthepatientscognitiveabilitiesandthen10isdeathfromMS.TheyfoundthatRNFLispredictiveofworseningdisability.Whenwe’relookingatthishereifthepatientshadRNFLvaluelessthan87micronsthereisanincreasedriskofthedisabilityworsening.HerewecanlookattheRNFLthat’slowestinthered.HereintheblueandpurpleintermediateandhighestRNFL.WecanseethatthechancesofdisabilityworseningwithpatientswithlowestRNFL.SothereseemstobesomecorrelationtheretoowhereperhapswecanrelaythisinformationtothepatientsneurologistastheyaretrackingprogressioninpatientswithMS.SowhatarethebenefitsofusingOCTinmanagingpatientswithMS?Well,asyouareallfamiliarOCTisreadilyaccessibleforpatients.Theacquisitionisveryquick.It’smuchcheapercomparedtoMRI.Also,we’reabletocorrelatestructuretovisualfunctionintermsofvisualfieldandlowcontrastvisualacuity.Inthefuturewe’rehopingtocorrelatethestructureofRNFLandtheganglioncellinterpluxiformlayerwithchangesthatareoccurringinthebrainandalsothepatientsphysicalability.ThetakehomepointsistouseRNFLandmacularOCTaspotentialmarkersforchangesinMS.RememberthatevenwithoutahistoryofopticneuritispatientswillshowchangesinthinninginboththemacularscanandtheRNFLscancomparedtocontrolgroups.OCTfindingscorrelatewithdiseaseprogressioninMS.SothepointtoconsideristoperformRNFLandmacularOCTregularlyinpatientswithMStohelpmonitorchangesinrelapses.

Figure23

Questions?Q:Whatisconsideredregularly?HowregularlyshouldwebepreformingOCTandmacularscans?A:Atthispoint,thereisn’tastandardbutwearecomparingittootherpatients,likeglaucomasuspectswedoitatleastonceayear.SoIwouldrecommenddoingitatleastonceayearbutifyouhavesomeonewhoisshowingthattheyareprimaryprogressivetypeandthey’reshowingdisabilitymuchfasterthantherelapsingremittingtypemaybeevery6months.Q:WhatportionofMSpatientsdonotgetopticneuritis?A:60%Q:Howdoyoubillforthis?A:Idon’tknow,doesanyonehaveananswerforthat?YouuseanMSdiagnosisandbillforyourOCTs