Multiple SclerosisMultiple SclerosisDiagnostic IssuesDiagnostic Issues

Christopher BourqueChristopher Bourque

AcknowledgementsAcknowledgements

American Academy of NeurologyAmerican Academy of Neurology Continuum seriesContinuum series

Multiple SclerosisMultiple Sclerosis Vol 10, #6, Dec. 2004Vol 10, #6, Dec. 2004

Elsevier SaundersElsevier Saunders Neurologic ClinicsNeurologic Clinics

Multiple SclerosisMultiple Sclerosis Vol 23 # 1 Feb. 2005Vol 23 # 1 Feb. 2005

MS in 1 SlideMS in 1 Slide

Manifestations due to CNS Manifestations due to CNS Slowing or failure of transmissionSlowing or failure of transmission

Inflammatory demyelinationInflammatory demyelination Axonal damageAxonal damage

Mostly damage of white matter tractsMostly damage of white matter tracts Optic neuritis, weakness, sensory loss, ataxia nystagmus, Optic neuritis, weakness, sensory loss, ataxia nystagmus,

bladder dysfunction, cognitive impairmentbladder dysfunction, cognitive impairment

Diagnosis based on clinical and laboratory Diagnosis based on clinical and laboratory evidence ofevidence of

Dissemination in timeDissemination in time Dissemination in spaceDissemination in space

Patterns of MSPatterns of MS Relapsing - remittingRelapsing - remitting

Attacks with complete/incomplete recoveryAttacks with complete/incomplete recovery Stable between attacksStable between attacks

Secondary - progressiveSecondary - progressive Initially relapsing-remittingInitially relapsing-remitting Then progression +/- attacksThen progression +/- attacks

Progressive - relapsingProgressive - relapsing Initial gradual detioriationInitial gradual detioriation Subsequent episodesSubsequent episodes

Primary progressivePrimary progressive Gradual declineGradual decline No attacksNo attacks

Schumacher Clinical CriteriaSchumacher Clinical CriteriaMS Diagnosis 1965MS Diagnosis 1965

Age (onset 10-50 years)Age (onset 10-50 years) CNS white matter diseaseCNS white matter disease Lesions disseminated in time and spaceLesions disseminated in time and space Objective abnormalities on examObjective abnormalities on exam Consistent time courseConsistent time course

Attacks lasting > 24 hrs., spaced at least 1 month Attacks lasting > 24 hrs., spaced at least 1 month apartapart

Slow or stepwise progression for > 6 monthsSlow or stepwise progression for > 6 months No better explanationNo better explanation Diagnosis by experienced clinicianDiagnosis by experienced clinician

Poser Criteria for the Poser Criteria for the Diagnosis of MS 1983Diagnosis of MS 1983

Widely used for last 20 yearsWidely used for last 20 years Definite or probableDefinite or probable Laboratory supported MSLaboratory supported MS Replaced by McDonald criteria 2001Replaced by McDonald criteria 2001

Technical advances enable quicker dx.Technical advances enable quicker dx. ControversialControversial

McDonald CriteriaMcDonald CriteriaClinical (attacks) Objective

LesionsAdditional Requirements to Make Diagnosis

2 or more 2 or more None

2 or more 1 Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS or further clinical attack involving different site

1 2 or more Dissemination in time by MRI or second clinical attack

1 monosymptomatic 1 Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS and dissemination in time by MRI or second clinical attack

0 (progression from onset)

1 Next slide

McDonald CriteriaMcDonald CriteriaClinical (attacks)

Objective Lesions

Additional Requirements to Make Diagnosis

0 (progression from onset)

1 Positive CSF and Dissemination in space by MRI evidence of 9 or more T2 brain lesionsor 2 or more cord lesions or 4-8 brain and 1 cord lesionor positive VEP with 4-8 MRI lesionsor positive VEP with less than 4 brain lesions plus 1 cord lesionandDissemination in time by MRI or continued progression for 1 year

Clinical ManifestationsClinical Manifestations DemographicDemographic

FemaleFemale Women make up to 70%-75% MS patientsWomen make up to 70%-75% MS patients

Young ageYoung age Onset before age 16: 5% of casesOnset before age 16: 5% of cases Peak onset post puberty, early 20’sPeak onset post puberty, early 20’s

Relapsing MS 28-30 yearsRelapsing MS 28-30 years

SymptomsSymptoms Recent onsetRecent onset Frequently progressiveFrequently progressive

Coming on over 1-several daysComing on over 1-several days Very acute symptoms possibleVery acute symptoms possible

The MS EventThe MS Event

Attack/relapse/exacerbationAttack/relapse/exacerbation Acute episode of CNS dysfunctionAcute episode of CNS dysfunction Lasting at least 24 hoursLasting at least 24 hours In absence of fever or metabolic In absence of fever or metabolic

derangementderangement All events within 30 days are unitaryAll events within 30 days are unitary

MS SymptomsMS Symptoms

Deficit reported Presenting%

During course %

Visual/oculomotorParesisParesthesiasIncoordinationGenitourinary/bowelCerebral

49424123104

1008887826339

Source: Whitaker JN, Mitchell GW 1997

Clinical ManifestationsClinical Manifestations MotorMotor

Weakness, spasticity, ataxiaWeakness, spasticity, ataxia Rarely radicularRarely radicular

lesion ant. horn, root entry zonelesion ant. horn, root entry zone painfulpainful atrophyatrophy

SomatosensorySomatosensory 1st sx. in 43% patients1st sx. in 43% patients

Includes visualIncludes visual Any anatomic distributionAny anatomic distribution Any combinationAny combination

Loss pain, temp, light touch, vbn, positionLoss pain, temp, light touch, vbn, position Positive sx. commonPositive sx. common

Paresthesiae, hyperpathia, allodynia, dysesthesiasParesthesiae, hyperpathia, allodynia, dysesthesias

Nonspecific Associated Features Nonspecific Associated Features That Suggest MSThat Suggest MS

Excessive unexplained fatigueExcessive unexplained fatigue Temperature sensitivityTemperature sensitivity

Hot, humid weatherHot, humid weather Relatively recent symptomsRelatively recent symptoms History of Lhermitte’s signHistory of Lhermitte’s sign History of bandlike sensation around the waistHistory of bandlike sensation around the waist Uhthoff’s phenomenonUhthoff’s phenomenon

eg, blurry vision with exercise or heat exposureeg, blurry vision with exercise or heat exposure

Clinical ManifestationsClinical Manifestations FatigueFatigue

One of the most important causes of disabilityOne of the most important causes of disability Several sourcesSeveral sources

Handicap fatigueHandicap fatigue Increased effort to perform routine tasksIncreased effort to perform routine tasks

Secondary fatigueSecondary fatigue Depression, sleep disturbances, medication side-Depression, sleep disturbances, medication side-

effects, other conditionseffects, other conditions Systemic fatigueSystemic fatigue

Chronic lack of energy, tirdness, malaiseChronic lack of energy, tirdness, malaise Etiology unknownEtiology unknown

Clinical ManifestationsClinical Manifestations

Cognitive DisturbancesCognitive Disturbances Common, frequently overlookedCommon, frequently overlooked

Estimated 50-75%Estimated 50-75% Most commonMost common

Impaired attention, slow info processing, short term memory Impaired attention, slow info processing, short term memory loss, reduced visuospatial skills, impaired executive functionloss, reduced visuospatial skills, impaired executive function

Impaired driving skillsImpaired driving skills Important impact QoL, ADLImportant impact QoL, ADL Can occur independentCan occur independent

of disease courseof disease course other manifestationsother manifestations

MRI in MSMRI in MS Brain lesionsBrain lesions

CharacterCharacter Large Large >> 3 mm 3 mm OvoidOvoid Oriented perpendicular to ventriclesOriented perpendicular to ventricles EnhancingEnhancing

Open-ring enhancementOpen-ring enhancement Multifocal homogeneousMultifocal homogeneous

LocationLocation Multiple white matterMultiple white matter Brainstem, infratentorialBrainstem, infratentorial JuxtacorticalJuxtacortical Corpus callosumCorpus callosum

Pointing awayPointing away Moth eatenMoth eaten Callosal atrophyCallosal atrophy

Evoked PotentialsEvoked Potentials

Visual evoked potentialsVisual evoked potentials Not auditory or somatosensoryNot auditory or somatosensory May point to subclinical involvement of optic May point to subclinical involvement of optic

nervenerve Quality control issuesQuality control issues

Principal Differential Diagnosis of Principal Differential Diagnosis of Multiple SclerosisMultiple Sclerosis

InfectionInfection Lyme, Syphilis, Progressive Multifocal Lyme, Syphilis, Progressive Multifocal

Leukoencephalopathy, HIV, HTLV-1Leukoencephalopathy, HIV, HTLV-1

InflammatoryInflammatory SLE, Sjogren syndrome, vasculitis, Sarcoidosis, Bechet’s SLE, Sjogren syndrome, vasculitis, Sarcoidosis, Bechet’s

diseasedisease

MetabolicMetabolic B12 deficiency, lysosomal disorders, adrenoleukodystrophy, B12 deficiency, lysosomal disorders, adrenoleukodystrophy,

mitochondrial disorders, other genetic diseasesmitochondrial disorders, other genetic diseases

NeoplasticNeoplastic CNS lymphomaCNS lymphoma

Spine diseaseSpine disease Vascular malformations, degenerative spine diseaseVascular malformations, degenerative spine disease

Cerebrospinal FluidCerebrospinal Fluid Useful, not diagnosticUseful, not diagnostic

Other conditionsOther conditions Chronic CNS infections, viral syndromes, neuropathiesChronic CNS infections, viral syndromes, neuropathies

Immunoglobulin abnormalitiesImmunoglobulin abnormalities Production of immunoglobulinProduction of immunoglobulin

By plasma or B cells in CNSBy plasma or B cells in CNS Oligoclonal bands of immunoglobulin (IgG) (OCB)Oligoclonal bands of immunoglobulin (IgG) (OCB)

In CSF, not serumIn CSF, not serum Isoelectric focusing techniqueIsoelectric focusing technique

Elevated IgG indexElevated IgG index Ratio of IgG/protein in serum and CSFRatio of IgG/protein in serum and CSF index = index = (csf IgG/csf albumin)(csf IgG/csf albumin)

(serum IgG/serum (serum IgG/serum albumin)albumin)

Cerebrospinal FluidCerebrospinal Fluid First event - chance of progression to MSFirst event - chance of progression to MS

In 3 yearsIn 3 years OCB +ve: 25%OCB +ve: 25% OCB -ve: 9%OCB -ve: 9%

CIS:clinically isolated syndromeCIS:clinically isolated syndrome 62.5% cases +ve OCB62.5% cases +ve OCB

Clinically definite MSClinically definite MS 90% +OCB90% +OCB

MRI in MSMRI in MS Spinal cord lesionsSpinal cord lesions

CharacterCharacter Asymptomatic lesionsAsymptomatic lesions Focal T2/proton density hyperintense lesionsFocal T2/proton density hyperintense lesions Diffuse proton density abnormalitiesDiffuse proton density abnormalities AtrophyAtrophy Asymmetric involvementAsymmetric involvement

Multiple scattered lesionsMultiple scattered lesions Edema with acute plaquesEdema with acute plaques

Often enhancingOften enhancing

LocationLocation Cervical and thoracicCervical and thoracic

Especially midcervicalEspecially midcervical PeripheralPeripheral Less than 2 vertebral segmentsLess than 2 vertebral segments Less than 50% cross-sectional areaLess than 50% cross-sectional area Lateral, dorsal cordLateral, dorsal cord

Paroxysmal Symptoms in MSParoxysmal Symptoms in MS

Trigeminal neuralgia (and others)Trigeminal neuralgia (and others) Tonic “seizures”Tonic “seizures” Paroxysmal dysarthriaParoxysmal dysarthria Hemifacial spasmHemifacial spasm Paroxysmal itchingParoxysmal itching Abrupt loss of muscle toneAbrupt loss of muscle tone Paroxysmal aphasiaParoxysmal aphasia Paroxysmal kinesogenic choreoathetosisParoxysmal kinesogenic choreoathetosis Lhermitte’s signLhermitte’s sign

MS SymptomsMS Symptoms

Deficit reported Presenting%

During course %

Visual/oculomotorParesisParesthesiasIncoordinationGenitourinary/bowelCerebral

49424123104

1008887826339

Source: Whitaker JN, Mitchell GW 1997

Clinical ManifestationsClinical Manifestations

Visual symptoms, afferentVisual symptoms, afferent Almost any pattern, related to locationAlmost any pattern, related to location Optic neuritisOptic neuritis

Central scotomaCentral scotoma Mild: color desaturationMild: color desaturation Severe: blindnessSevere: blindness

Vast majority have excellent return by 6 monthsVast majority have excellent return by 6 months Frequent painFrequent pain

Worse on eye movementWorse on eye movement

Optic NeuritisOptic NeuritisRisk of Subsequent MSRisk of Subsequent MS

Higher RiskHigher Risk Young adult (26-40 years)Young adult (26-40 years) Venous sheathingVenous sheathing Recurrent optic neuritisRecurrent optic neuritis Female sexFemale sex History of minor neurologic symptomsHistory of minor neurologic symptoms Brain MRI lesionsBrain MRI lesions CSF oligoclonal bands or intrathecal IgG productionCSF oligoclonal bands or intrathecal IgG production

Lower RiskLower Risk Age < 10Age < 10 Macular star/exudatesMacular star/exudates Retinal or disc hemorrhageRetinal or disc hemorrhage Severe disc edemaSevere disc edema No brain MRI lesionsNo brain MRI lesions Normal CSFNormal CSF

Clinical ManifestationsClinical Manifestations

Visual symptoms, efferentVisual symptoms, efferent Any eye movement abnormalityAny eye movement abnormality INOINO

Internuclear ophthalmoplegiaInternuclear ophthalmoplegia Adductor weaknessAdductor weakness Abduction nystagmusAbduction nystagmus In young adult strongly suggests MSIn young adult strongly suggests MS

NystagmusNystagmus Many typesMany types

Clinical ManifestationsClinical Manifestations

Other Brain Stem StructuresOther Brain Stem Structures Facial weaknessFacial weakness VertigoVertigo Loss of hearing, tasteLoss of hearing, taste Dysarthria, dysphagiaDysarthria, dysphagia

Bulbar musclesBulbar muscles Weakness, ataxia, spasticityWeakness, ataxia, spasticity

Clinical ManifestationsClinical Manifestations

Psychiatric DisturbancesPsychiatric Disturbances DepressionDepression

Also up to 75% of patientsAlso up to 75% of patients Major depression less frequentMajor depression less frequent Suicide: 15% of adult MS deathsSuicide: 15% of adult MS deaths

Risk factorsRisk factors Living aloneLiving alone FH mental illnessFH mental illness Reporting social isolationReporting social isolation PH major depression, anxiety, alcohol abusePH major depression, anxiety, alcohol abuse

Emotional incontinenceEmotional incontinence Frontal lobe involvementFrontal lobe involvement

Clinical ManifestationsClinical Manifestations Bladder dysfunction; the importance of urodynamic studiesBladder dysfunction; the importance of urodynamic studies

Failure to store: detruser hyperactivityFailure to store: detruser hyperactivity Urgency, frequency, nocturiaUrgency, frequency, nocturia

Failure to emptyFailure to empty Detruser-sphincter dyssynergiaDetruser-sphincter dyssynergia Poor detruser contractionPoor detruser contraction

Hesitancy, increased residual vol., retentionHesitancy, increased residual vol., retention

BothBoth Combined Combined

detruser hyperactivitydetruser hyperactivity detruser-sphincter dyssynergiadetruser-sphincter dyssynergia

IncontinenceIncontinence Detruser hyperactivity orDetruser hyperactivity or OverflowOverflow Symptoms may not be accurate indicator of urodynamic pathologySymptoms may not be accurate indicator of urodynamic pathology

Clinical ManifestationsClinical Manifestations Bowel dysfunctionBowel dysfunction

ConstipationConstipation Can be aggrevated by Can be aggrevated by

fluid restrictionfluid restriction Anticholinergic medicationsAnticholinergic medications

Urgency and incontinenceUrgency and incontinence

Sexual dysfunctionSexual dysfunction Erectile dysfunctionErectile dysfunction Women: loss of libido, anorgasmiaWomen: loss of libido, anorgasmia Both sexesBoth sexes

Loss of perineal sensationLoss of perineal sensation Neuropathic painNeuropathic pain SpasticitySpasticity IncontinenceIncontinence Depression, fatigueDepression, fatigue

Pain Syndromes in MSPain Syndromes in MS Primary painPrimary pain

NeuralgicNeuralgic Trigeminal neuralgiaTrigeminal neuralgia Other neuralgiasOther neuralgias

Dysesthetic painDysesthetic pain Most often burning (legs)Most often burning (legs) Other dysesthesiasOther dysesthesias

Radicular painRadicular pain Tonic seizuresTonic seizures SpasticitySpasticity

Flexor spasmsFlexor spasms Extensor spasmsExtensor spasms

Secondary painSecondary pain Low back painLow back pain Osteoporosis with fracturesOsteoporosis with fractures

Neurologic Syndromes Likely for MS Neurologic Syndromes Likely for MS

Optic neuritisOptic neuritis Unilateral eye involvementUnilateral eye involvement Retrobulbar rather than papillitisRetrobulbar rather than papillitis Eye painEye pain Partial vision loss, with at least some recoveryPartial vision loss, with at least some recovery No retinal exudates, disc hemorrhages, macular starNo retinal exudates, disc hemorrhages, macular star

10 years follow-up: 38% develop MS10 years follow-up: 38% develop MS MRI other lesions: risk 56%MRI other lesions: risk 56% MRI normal: risk 22%MRI normal: risk 22%

20 years follow-up: 70% develop MS20 years follow-up: 70% develop MS

Neurologic Syndromes Likely for MSNeurologic Syndromes Likely for MS

Transverse MyelitisTransverse Myelitis IncompleteIncomplete Sensory > motorSensory > motor AssociatedAssociated

Lhermitte’s signLhermitte’s sign Bandlike abdominal or chest pressure Bandlike abdominal or chest pressure

Internuclear OphthalmoplegiaInternuclear Ophthalmoplegia Trigeminal NeuralgiaTrigeminal Neuralgia Hemifacial SpasmHemifacial Spasm

Neurologic Syndromes Likely for MSNeurologic Syndromes Likely for MS

Paroxysmal symptomsParoxysmal symptoms Last seconds to minutesLast seconds to minutes Occur multiple times dailyOccur multiple times daily

Tonic spasmsTonic spasms Dysarthria, ataxiaDysarthria, ataxia Hemiparesis, hypesthesiaHemiparesis, hypesthesia

Polysymptomatic Syndrome Without Mental Polysymptomatic Syndrome Without Mental Status ChangesStatus Changes

Clues to a Misdiagnosis; MSClues to a Misdiagnosis; MS

HistoricalHistorical No disseminationNo dissemination Onset < 10 yrs. or > 55 yrs.Onset < 10 yrs. or > 55 yrs. Genetic red flagsGenetic red flags

+ve FH+ve FH However about 20% of MS patients have FHHowever about 20% of MS patients have FH

Early-age onsetEarly-age onset Unexplained non-CNS diseaseUnexplained non-CNS disease

Progressive course starting before age 35Progressive course starting before age 35 Localized diseaseLocalized disease

Clues to a Misdiagnosis; MSClues to a Misdiagnosis; MS ExaminationExamination

Prominent Prominent fever, headache, uveitis, painfever, headache, uveitis, pain

Abrupt Abrupt hemiparesis, hearing losshemiparesis, hearing loss

NoNo optic nerve/ocular involvementoptic nerve/ocular involvement bowel/bladder involvementbowel/bladder involvement

Progressive myelopathyProgressive myelopathy Without bowel/bladder involvementWithout bowel/bladder involvement

Impaired level of consciousnessImpaired level of consciousness Nonscotomatous visual field defectsNonscotomatous visual field defects Grey matter featuresGrey matter features

Early dementia, aphasiaEarly dementia, aphasia FasciculationsFasciculations Extrapyramidal featuresExtrapyramidal features

Clues to a Misdiagnosis; MSClues to a Misdiagnosis; MS MRIMRI

BrainBrain NormalNormal Small lesions < 3 mm.Small lesions < 3 mm. Subcortical location (internal capsule)Subcortical location (internal capsule) Prominent infratentorial involvementProminent infratentorial involvement Prominent grey matter involvement (basal Prominent grey matter involvement (basal

ganglia)ganglia) Symmetric, confluent hemispheric white matter Symmetric, confluent hemispheric white matter

involvementinvolvement HydrocephalusHydrocephalus Severe cerebellar/brain stem atrophySevere cerebellar/brain stem atrophy No callosal/periventricular lesionsNo callosal/periventricular lesions

Clues to a Misdiagnosis; MSClues to a Misdiagnosis; MS MRIMRI

Spinal cordSpinal cord Large lesion, multiple segments (>2)Large lesion, multiple segments (>2) Severe swellingSevere swelling Full thickness lesionsFull thickness lesions Leptomenengial enhancementLeptomenengial enhancement T1 hypointense lesionsT1 hypointense lesions

Clues to a Misdiagnosis; MSClues to a Misdiagnosis; MS CSFCSF

NormalNormal Disappearance of oligoclonal bandsDisappearance of oligoclonal bands

Normalization of IgG indexNormalization of IgG index

Cell count > 50 wbc/cubic mm.Cell count > 50 wbc/cubic mm. Protein > 100 mg/dlProtein > 100 mg/dl

MS Diagnosis; 1 Final SlideMS Diagnosis; 1 Final Slide

Manifestations due to CNS Manifestations due to CNS Slowing or failure of transmissionSlowing or failure of transmission Mostly damage of white matter tractsMostly damage of white matter tracts Recent appreciation of axonal/grey matter involvementRecent appreciation of axonal/grey matter involvement

Diagnosis based on clinical and laboratory evidence ofDiagnosis based on clinical and laboratory evidence of Dissemination in timeDissemination in time Dissemination in spaceDissemination in space Recent appreciation of role of MRI in assisting diagnosisRecent appreciation of role of MRI in assisting diagnosis

In-office pattern recognitionIn-office pattern recognition Appropriate demographicAppropriate demographic Appropriate clinical eventAppropriate clinical event