TheThe DiagnosisDiagnosis OfOf MultipleMultiple SclerosisSclerosis

DRDR SAHERSAHER HASHEMHASHEM PROFPROF OFOF NEUROLOGYNEUROLOGY CAIROCAIRO UNIVERSITYUNIVERSITY  ThereThere isis nono pathpath gnomonicgnomonic oror perfectperfect laboratorylaboratory testtest whichwhich maymay bebe usedused inin isolationisolation toto reliablyreliably diagnosediagnose MS.MS.  TheThe keykey toto correctcorrect diagnosisdiagnosis isis typicalitytypicality  TheThe duckduck testtest isis importantimportant ,, (( isis thisthis aa duck,duck, itit lookslooks likelike aa duck,duck, walkwalk likelike andand quacksquacks likelike aa duck,duck, thenthen itit isis probablyprobably aa duck.duck. duck, and QuestionQuestion OneOne

 WhatWhat isis thethe mostmost commoncommon mistakemistake duringduring MSMS diagnosis?diagnosis?  TheThe mostmost commoncommon mistakemistake duringduring MSMS diagnosisdiagnosis isis aa falsefalse positivepositive attributionattribution thatthat isis makingmaking aa diagnosisdiagnosis ofof MSMS inin patientspatients whowho dondon ’’tt havehave MS.OftenMS.Often thisthis errorerror isis thethe resultresult ofof uncriticaluncritical oror causalcausal reliancereliance onon MRIMRI withoutwithout appropriateappropriate clinicalclinical correlationcorrelation  6262 patientspatients assessedassessed byby generalgeneral neurologistsneurologists andand reassessedreassessed byby otherother generalgeneral neurologistsneurologists usingusing McMc DonaldDonald ’’ss criteriacriteria andand foundfound 51%51% ofof MSMS patientspatients werewere notnot confirmed.confirmed.

McMc HughHugh etet alal MultipleMultiple sclerosissclerosis 2008,14:812008,14:81 --8585 TimeTime fromfrom initialinitial symptomsymptom toto MSMS diagnosisdiagnosis  InitialInitial symptomsymptom TimeTime toto MSMS diagnosisdiagnosis  19801980 --19841984 77 yy  19851985 -- 19891989 5.35.3 yy  19901990 -- 19941994 3.73.7 yy  19951995 -- 19991999 1.8y1.8y  >> 20002000 0.63y0.63y  MarieMarie etet alal NeurologyNeurology 2005,65;10662005,65;1066 --10701070 QuestionQuestion 22

 WhatWhat isis thethe definitiondefinition andand goldgold standardsstandards inin thethe diagnosisdiagnosis ofof MS.?MS.? 11-- EvidenceEvidence ofof disseminationdissemination inin spacespace (( multifocality).multifocality). 22-- EvidenceEvidence ofof disseminationdissemination inin timetime (( recurrentrecurrent attacksattacks oror steadysteady progression)progression) 33-- NoNo betterbetter explanationexplanation toto accountaccount forfor signssigns andand symptoms.symptoms.  ClinicallyClinically isolatedisolated syndromessyndromes areare notnot MS.MS.  ThisThis couldcould bebe opticoptic neuritis,,orneuritis,myelitis,or brainbrain stemstem dysfunctiondysfunction CISCIS isis notnot MSMS .this.this isis veryvery analogousanalogous toto firstfirst attackattack ofof .convulsions.  CISCIS maymay oror maymay notnot evolveevolve toto MS.thisMS.this dependsdepends onon followfollow upup usingusing McMc Donald'sDonald's criteriacriteria (( paraclinicalparaclinical MRIMRI evidence).evidence).  ACISACIS == AtypicalAtypical clinicallyclinically isolatedisolated syndromesyndrome LikeLike parasthesiasparasthesias oror clumsiness.clumsiness.

SomeSome suggestedsuggested thethe useuse ofof earlyearly treatmenttreatment inin MSMS andand somesome typestypes ofof CISCIS FrahmanFrahman etet alal ArchArch .neurol..neurol. 20062006 ;; 614614 --618618 Question 3

 What are the Mc Donald's criteria ?  The first or ground floor ,without which the structure can ’t exist, is the clinical assessment (history,neurologic examination the goal of which is:  1-DIS (dissemination in space)  2-DIT ( dissemination in time )  3-NBE ( no better explanation )  Schmacher et al Ann NY acad sci 1965 , 12:522 -568  Poser et al ,Neurosurg,2004; 106 : 147 -158.  Mc Donalds et al, Ann Neurolog , 2001 ,50: 121 -127  Definition of MS attack according to Mc Donald's 2001:  1-Clinical event of type seen in MS.  2-Event lasts at least 24 hours.  3-Objective findings must be present.  4-The event shouldn ’t be pseudo attack (temporary worsening due to fever or infection)  5-The onset should be at least 40 days after onset of previous attack.  6- Single eg muscle is not countable, but multiple paroxysmal events occurring over a period of 24 hours .  AA patientpatient whowho presentedpresented withwith ONON ,experience,experience aa secondsecond attackattack oneone monthmonth later(DIT)later(DIT) withwith bilateralbilateral INOINO (DIS)(DIS) andand therethere areare nono atypicalatypical features(NBE)features(NBE)  Revised (2005) Mc Donalds criteria for (DIS) and (DIT)  A-DIS at least 3 of the following must be present 1 - At least one gadolinium enhancing lesion or nine T 2 hyperintense lesions. 2 -At least one infratentorial lesion 3-At least one juxta cotical 4 - At least 3 periventricular.  NB one spinal lesion may be used to fulfill criteria 1+2.Spinal lesions at least 3 mm in size ,less than 2 vertebral segments occupying only part of the cross section of .CSF oligoclonal bands and 2 typical MRI lesions can establish the diagnosis of MS DITDIT  TheThe presencepresence ofof newnew lesionlesion (gadolinium(gadolinium enhanced)enhanced) notnot correspondingcorresponding toto sitesite implicatedimplicated withwith initialinitial eventevent ifif thethe scanscan donedone 33 monthsmonths afterafter thethe event.event. MRIMRI LesionsLesions similarsimilar toto MS.MS.

 11--SLESLE 22 -- SJOGRENSJOGREN SS  33-- SARCOIDOSISSARCOIDOSIS 44 --ADEMADEM  55-- ANTIPHOSPHOLIPIDANTIPHOSPHOLIPID ANTIBODYANTIBODY SYNDSYND  66-- LEBERLEBER OPTICOPTIC ATROPHYATROPHY  77--CADASILCADASIL 88 --SUSACSUSAC SYNDROMESYNDROME

99 --USHERUSHER SYNDROMESYNDROME 1010 --VITVIT EE DEFICIENCYDEFICIENCY 1111 --LYMPHOMALYMPHOMA SUSACSUSAC SYNDROMESYNDROME

Was first described in 1975 sufferers often experience personality changes and bizarre and develop paranoid behavior. Speech can be affected and many experience severe and . Some hearing and visual loss which might correct itself in a matter of 5 years. Diagnosis MRI multifocal supratentorial lesions most lesions are small ones 3 -7 mm which might affect grey matter and show meningeal enhancement which never found in MS NOR ADEM. Pathogenesis vasculitis,hypercoagulable,or viral infection .treatment hyperbaric o2 ,ivig,iv steroids usherusher syndromesyndrome

 IsIs aa leadingleading causecause ionion isis ofof deafdeaf blindnessblindness isis anan autosomalautosomal recessiverecessive conditioncondition .the.the visionvision isis describeddescribed asas doughnutdoughnut vilevile visionvision wherewhere centralcentral andand peripheralperipheral visionsvisions areare sparedspared whilewhile impairedimpaired inin anan annulusannulus aroundaround centralcentral vision.vision. ThreeThree typestypes werewere describeddescribed 1&21&2 areare bornborn withwith diseasedisease whilewhile 33 acquiredacquired lossloss ofof visionvision andand hearing.hearing. TreatmentTreatment genegene therapy.therapy. QuestionQuestion 44

 WhatWhat areare thethe bestbest clinicalclinical keyskeys forfor MSMS diagnosis?diagnosis?  AA-- TypicalTypical timetime coursecourse ofof anan attackattack ofof MS.UsuallyMS.Usually thethe attackattack takestakes aa gradualgradual progressiveprogressive coursecourse withwith peakpeak atat 33 --44 weeksweeks withwith gradualgradual declinedecline andand recoveryrecovery atat 66 weekweek differingdiffering fromfrom epilepsyepilepsy andand migrainemigraine attacksattacks whichwhich resolvesresolves inin 2424 hours.hours.  BB--TypicalTypical historyhistory  UsingUsing schumacherschumacher criteriacriteria 19651965 involvinginvolving DIT,DIS,andDIT,DIS,and NBE.NBE.  CC-- RedRed flagsflags  ThisThis meansmeans negativenegative criteriacriteria diagnosingdiagnosing NOTNOT MS.MS.  11-- NeurologicalNeurological redred flags.flags.  22-- GeneticGenetic redred flags.flags.  33-- PsychiatricPsychiatric redred flags.flags.  44-- MRIMRI redred flags.flags. 11-- NeurologicalNeurological redred flags.flags.

 Absence of eye signs like ON ,or INO  Absence of clinical remission.  Absence of sensory finding or bladder disturbance.  Localized in one brain region.  Absence of typical CSF changes

 Rudik RA; et al Arch 1989;53:1698 -1704. 22--GeneticGenetic redred flags.flags.

 FamilyFamily historyhistory ofof MSMS (( firstfirst degreedegree relative)relative)  EarlyEarly ageage ofof onsetonset (( lessless thanthan 1515 yearsyears old)old)

NatawiczNatawicz andand Bejjani,Am.j.Bejjani,Am.j. GeneticsGenetics ,1994;46,1994;46 149149 --169169 33-- PsychiatricPsychiatric redred flags.flags.

 MarkedMarked disproportiondisproportion ofof psychiatricpsychiatric symptomssymptoms relativerelative toto objectiveobjective neurologicalneurological signs.signs.  PriorPrior historyhistory ofof majormajor psychiatricpsychiatric illnessillness

 ParlsonParlson GWGW ,south,south medmed JJ 1969;891969;89 ;301;301 --304304 44-- MRIMRI redred flagsflags

------MRI finding ------Think over ------Brain Symmetrical lesions ------ ADEM,or adult Absent activity on ------> ADEM or chronic Serial scans Infarcts ------ SLE,lacunes Predominant juxta ------> small vessel disease. Cortical lesions Normal brain MRI in spite ------ Neuromyelitis optica Severe cord and optic lesions  SpinalSpinal MRIMRI ------ ThinkThink overover  MoreMore thanthan 33 segmentssegments ------ NMO,SS,ADEM,NMO,SS,ADEM,  TSTS myelitismyelitis  DiffuseDiffuse posteriorposterior columncolumn ----  vitvit BB 1212 def,def,  acquiredacquired cucu defdef  MeningealMeningeal enhancementenhancement -- SusacSusac syndromesyndrome  primaryprimary CNSCNS angitisangitis  Behcet,Lymes,sarcoidBehcet,Lymes,sarcoid QuestionQuestion 55

 IsIs thethe populationpopulation suspectedsuspected toto havehave MSMS areare homogenoushomogenous ??  InIn factfact thethe populationpopulation suspectedsuspected toto havehave MSMS constituteconstitute aa heterogeneousheterogeneous groupsgroups manymany ofof themthem willwill ultimatelyultimately bebe foundfound toto havehave MS,andMS,and somesome ofof whomwhom maymay havehave otherother neurologicalneurological diseasesdiseases whichwhich mimicmimic MS.MS. StratificationStratification ofof MSMS suspectedsuspected intointo subgroupssubgroups onon basisbasis ofof typicality.typicality.  GroupGroup 1:1: findingfinding typicaltypical ofof MS.MS. MSMS isis likelylikely aa diagnosis.diagnosis.  GroupGroup 2:2: atypicalatypical withwith normalnormal finding'sfinding's isis veryvery unusualunusual  GroupGroup 3:3: atypicalatypical withwith minimalminimal definitedefinite findingsfindings ,MS,MS isis possiblepossible  GroupGroup 4:4: atypicalatypical withwith majormajor unusualunusual findings,findings, widewide DDDD ExampleExample ofof groupgroup 11

 FemaleFemale 1818 y,presentedy,presented withwith rtrt eyeeye painpain andand blurringblurring ofof visionvision sheshe waswas diagnoseddiagnosed asas ONON andand treatedtreated withwith steroidssteroids andand recoveredrecovered partiallypartially inin ononee month.Twomonth.Two yy laterlater (DIT)(DIT) sheshe developeddeveloped overover aa periodperiod ofof weekweek RTRT ULUL parasthesiaparasthesia andand weaknessweakness withwith spontaneousspontaneous resolutionresolution overover aa monthmonth (DIS)(DIS) onon /ex/ex severesevere opticoptic atrophy,atrophy, briskbrisk DTRDTR RTRT sideside withwith bilateralbilateral subtlesubtle .MRIataxia.MRI numerousnumerous TT 22 periventricularperiventricular hyperintesties(NBE)hyperintesties(NBE) .Disease.Disease modifyingmodifying therapytherapy waswas initiatedinitiated (DMT)(DMT) inin thethe formform ofof interferons.interferons. ExampleExample ofof groupgroup 22

 Female 28 y she underwent hysterectomy for cervical dysplasia 2 days later she developed weakness and shooting in her LLs. Work up was negative and she recovered completely in 6 weeks with physiotherapy. Succeeding 5 y she continued to experience transient non specific pains, mental stress,,cramps,tingling in non anatomical patterns. Her past medical history was notable for depression and fibromyalgia and bimonthly severe occipital which was not associated with nausea or vomiting or scintillating scotomata .Assessment by her primary neurologist revealed NAD all investigations were negative apart from some white spots (punctuate) in the left cerebrum. ExampleExample ofof groupgroup 33

 (possible or probable MS) a male 27 y ,noted electric like shocks on neck flexion, these symptoms recurred for 2 months and stopped but recurred again at the age of 33y(DIT).His past medical history showed transient left arm at age of 30y with notably no specific diagnosis. Significantly ,his family history revealed documented MS in older sister and perhaps in mother. Comment essentially this gentleman presents with recurrent lehermitte sign and strong FH. Over the course of one decade he had no major progression this remained possible due to lack of (DIS) and lack of objective neurological signs. Finally at age of 37yhe developed sub acute sensory loss in LLs and csf was +ve and MRI was classic of MS he received pulsed steroids with good response and he started DMT ExampleExample groupgroup 44

 AtypicalAtypical patientpatient presentspresents withwith majormajor butbut unusualunusual findingfinding herehere otherother neurologicalneurological diseasedisease isis possible.possible. QuestionQuestion 66

 WhatWhat areare thethe MSMS variants?variants?  11-- NeuromyelitisNeuromyelitis opticaoptica NMONMO  22-- TumefactiveTumefactive MSMS (( tumortumor likelike course)course)  33-- FulminateFulminate acuteacute MSMS (Marburg)(Marburg)  44-- BaloBalo concentricconcentric sclerosis.sclerosis.  55-- MyelinoclasticMyelinoclastic diffusediffuse sclerosis(Schildersclerosis(Schilder disease)disease)  NMONMO isis consideredconsidered whenwhen patientpatient presentspresents acutelyacutely withwith severesevere bilateralbilateral opticoptic ONON forfor thethe firstfirst timetime oorr presentingpresenting withwith unusuallyunusually severesevere myelitis,MRImyelitis,MRI headhead minimalminimal atypicalatypical changes,changes, spinalspinal MRIMRI showsshows longitudinallongitudinal moremore thanthan 33 segmentssegments extensiveextensive lesion.lesion. andand CSFCSF showsshows +ve+ve monoclonalmonoclonal bandsbands inin 25%25% andand +ve+ve autoantibodyautoantibody NMONMO igGigG withwith sensitivitysensitivity ofof 73%73% andand 90%90% specificityspecificity andand isis directeddirected againstagainst aquaporinaquaporin waterwater channelschannels presentpresent onon astrocyticastrocytic footfoot process.process. CSFCSF alsoalso showsshows granulocyticgranulocytic increaseincrease ratherrather thanthan lymphocyticlymphocytic increase.Itincrease.It hashas badbad responseresponse toto DMT.DMT. QuestionQuestion 77

 WhatWhat isis thethe rolerole ofof lablab inin MS?MS?  11-- ScreeniningScreenining teststests likelike MRI,cbc,ANA,vitMRI,cbc,ANA,vit bb 12,RPR12,RPR (rapid(rapid plasmaplasma reaginreagin forfor syphilis)syphilis)  22-- CSFCSF forfor oligoclonaloligoclonal bands.igGbands.igG indexindex andand synthesissynthesis ,VER,SS,VER,SS --A,SSA,SS -- B,SER,ANCA,anticardiolipin,lymeB,SER,ANCA,anticardiolipin,lyme serology,thyroidserology,thyroid function,serumfunction,serum antibodiesantibodies inNMO,seruminNMO,serum coppercopper incaseincase ofof unexplainedunexplained ,serummyelopathy,serum longlong chainchain fattyfatty acids,DNA,foracids,DNA,for cadasil,arylcadasil,aryl sulphatasesulphatase andand ACEACE forfor sarcoidosis.sarcoidosis. AccuracyAccuracy ofof MRIMRI

 ApplicationApplication ofof MRIMRI accordingaccording McMc Donald'sDonald's criteriacriteria hashas yieldedyielded highhigh sensitivitysensitivity ofof 75%75% andand specificityspecificity ofof 85%85% forfor predictionprediction ofof CDMSCDMS duringduring approximatelyapproximately 22 yearsyears ofof observationobservation forfor patientspatients withwith CISCIS .. ANNANN (2003)(2003) publishedpublished guidelinesguidelines forfor thethe useuse ofof MRIMRI inin diagnosisdiagnosis ofof MS.MS. SayingSaying thatthat 33 characteristiccharacteristic whitewhite mattermatter lesionslesions areare moremore sensitivesensitive predictorpredictor ofof CDMSCDMS inin CISCIS patientspatients thanthan complexcomplex McMc Donald'sDonald's criteria.criteria. QuestionQuestion 88

 WhatWhat areare majormajor pitfallspitfalls inin MSMS diagnosis?diagnosis? 11-- AtypicalAtypical MSMS :: ThisThis isis CDMSCDMS withwith somesome unusualunusual featuresfeatures likelike aa-- AcuteAcute attacksattacks withwith abruptabrupt onset.onset. bb-- FixedFixed relationshiprelationship toto mensesmenses cc-- LateLate onsetonset dd-- ProminentProminent cognitive,cognitive, oror psychiatricpsychiatric symptomssymptoms earlyearly inin diseasedisease  22-- InconvenientInconvenient MS.MS. WhereWhere MSMS patientpatient hashas onlyonly oneone inconvenientinconvenient lablab testtest e.g.e.g. veryvery highhigh ANAANA inin thethe absenceabsence ofof rheumatologicrheumatologic disease,disease, oror CSFCSF withwith markedmarked pleocytosis.pleocytosis. 33-- PartialPartial MS.MS. TheseThese casescases representrepresent intermediateintermediate betweenbetween CISCIS andand CDMS.CDMS. THANKTHANK YOUYOU