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Management of Multiple Sclerosis,Part 1 of 2: Differential Diagnosis–

A Consensus Approach

Supported by an unrestricted educationalgrant from Pfizer Inc.

Guest Host

Aaron Miller, MDProfessor of NeurologyMedical Director, Corinne Goldsmith DickinsonCenter for Multiple SclerosisMount Sinai School of MedicineNew York, NY

Aaron Miller, MDDisclosures

Grants/Research Support: Acorda Therapeutics;Genentech, Inc.; Genzyme Corporation; NovartisPharmaceuticals Corporation; Sanofi-aventis; TevaPharmaceuticals

Consultant: Acorda Therapeutics; Biogen Idec; DaiichiSankyo; EMD Serono, Inc.; GlaxoSmithKline; Merk Serono;Novartis Pharmaceuticals Corporation; Ono PharmaceuticalCo., Ltd; Sanofi-aventis; Teva Pharmaceuticals

Speakers Bureau: Biogen Idec; EMD Serono, Inc.; PfizerInc.; Teva Pharmaceuticals

Guest Host


Featured Author

Fred D. Lublin, MDSaunders Family Professor of NeurologyDirector, The Corinne Goldsmith DickinsonCenter for Multiple SclerosisMount Sinai School of MedicineNew York, NY

Fred D. Lublin, MDDisclosures

Research/Grants: Acorda Therapeutics; Biogen Idec;Genentech, Inc.; Genzyme Corporation; NovartisPharmaceuticals Corporation; Sanofi-aventis; Teva Neuroscience,Inc.

Consultant/Advisory Boards: Acorda Therapeutics; ActelionPharmaceuticals Ltd; Allozyne, Inc.; Bayer HealthCarePharmaceuticals; Biogen Idec; BioMS Medical Corp.; EMDSerono, Inc.; Genentech, Inc.; Genmab; Medicinova, Inc.;Novartis Pharmaceuticals Corporation; Pfizer Inc.; QuestcorPharmaceuticals, Inc.; Sanofi-aventis; Teva Neuroscience, Inc.

Speakers Bureau: EMD Serono, Inc.; Pfizer Inc.; TevaNeuroscience, Inc.

Stock: Cognition Pharmaceuticals, Inc.

Dr. Lublin has disclosed that he may discuss unapproved agentsthat are in the MS developmental pipeline without anyrecommendation on their use.

Disclosures of facultyfinancial relationships

and biographical profilescan be found at

neuroscienceCME.com/426

The faculty have beeninformed of their

responsibility to discloseto the audience if they will

be discussing off-labelor investigational uses(any use not approvedby the FDA) of products

or devices.

Miller DH, Weinshenker BG, Filippi M, et al.Differential diagnosis of suspected multiplesclerosis: a consensus approach. Mult Scler

2008;14:1157-1174.

Learning Objective

Utilize consensus-basedguidelines in determining amore accurate differential

diagnosis of MS

To receive CE credits for thisactivity, participants mustcomplete the post-test and

evaluation online atneuroscienceCME.com/test

Guest Host


Featured Author


Miller DH, Weinshenker BG, Filippi M, et al.Differential diagnosis of suspected multiplesclerosis: a consensus approach. Mult Scler

2008;14:1157-1174.

Featured Author


Background2001—International panel convened to developguidelines for diagnosing multiple sclerosis (MS)

All modern diagnostic criteria for MS had includedthe caveat ”that there be no better diagnosis”

Diagnostic criteria for MS designed to provide clinicaland paraclinical guidelines for making the diagnosis

Criteria did not distinguish MS from other diseasesthat could mimic it

2007—Second panel convened to developguidelines for the differential diagnosis of MS

Alternative Diagnosis, (i.e. not inflammatorydemyelinating diseases (IDD))

Clinically Isolating Syndrome (CIS)

Differentiating MS from other idiopathicinflammatory demyelinating diseases (IIDD)

Miller DH, et al. Mult Scler 2008:1157–1174.

Objectives

The panel focused on three areas:

Exclusion of MS mimics

Diagnosis of common CIS

Differentiating between MS and non-MS idiopathicinflammatory demyelinating disease

Panel Guidelines

Diagnostic algorithms for MS differential diagnosis

Differential diagnosis of patients presenting withdemyelinating:

Optic neuritis

Brain stem syndrome

Spinal cord syndrome


Red Flags

Table of 79 “Red Flags”—clinical and MRI

Major red flags—carry more weight;scored highest for concern

Examples:Bone Lesions histiocytosisLung involvement sarcoidosis

Intermediate red flags—scored in betweenmajor and minor

Minor red flags—less consensus forimportance


Red Flags

Help to exclude nondemyelinatingsyndromes

Classic IIDD or alternative diagnosis

IIDDMS

Classical neuromyelitis optica (NMO)

Acute disseminated encephalomyelitis (ADEM)

Less well classified IIDD, (i.e., Bellows orMarburg)

Criteria for defining NMO

Criteria for diagnosing ADMEM


Clinically Isolated Syndrome(CIS)

Term has no pathologic specificity

Monofocal—involvement of one areaof the nervous system

Multifocal—involvement of multipleareas of the nervous system

Considered the fist episode of aninflammatory demyelinating event

Exception: CIS type 5—initial event ispicked up on an MRI


Methods

Table of 79 red flags rated independently on scaleof 1-5

1-2: Minor3: Intermediate4-5: Major

MajorTotal score of 24 or greater, no more than one individualwith a score of 3

MinorTotal score of 12 or less, no more than one individualwith a score of 3

IntermediateTotal score between 13-23, more than one individualwith a score of 3Indicated a lack of consensus among the raters


Minor Red Flags

Minor red flags = think about thediagnostic issue

Caveat—“no better diagnosis”Are you missing something?

Make sure you have supportingevidence to confirm diagnosis andexclude minor confounding factors

Red flags may not alter diagnosisof MS


Types of CIS

5 different types of CIS

Type 1 CIS: clinically monofocal, at least oneasymptomatic MRI lesion

Type 2 CIS: clinically multifocal, at least oneasymptomatic MRI lesion

Type 3 CIS: clinically monofocal, MRI may appearnormal; no asymptomatic MRI lesions

Type 4 CIS: clinically multifocal, MRI may appearnormal; no asymptomatic MRI lesions

Type 5 CIS: no clinical presentation to suggestdemyelinating disease, but MRI is suggestive


Monofocal vs. Multifocal CIS

Difference between monofocal CIS with oneor more abnormalities on MRI vs.monofocal CIS with no changes on MRI?

MRI useful in guiding diagnostic andprognostic process of CISChanges on the MRI consistent with IDDmore likely to have another attack thanthose who have normal MRIsMultifocal CIS – raises different issues withdifferential diagnosis, (i.e. isolated opticneuritis with no changes vs. optic neuritisand corticospinal track dysfunction andmany lesions on the MRI)

IDD = inflammatory demyelinating disease


Type 5 CIS

MRI shows changes in brain that looktypical for MS, but no clinicalsymptoms

CIS is really MRI isolated

Need more research to determinediagnosis and prognosis


Classical MS vs. Other EntitiesImportance of Nomenclature

Prognostic implications

Potential therapeutic implications

Example 1: Distinguishing between ADEM vs. firstattack of MS

ADEM occurs more commonly in childrenConsiderable overlap between ADEM and MS at time offirst attackIf ADEM—no ongoing therapyIf MS—treatment for MS at that time reduces risk offurther exacerbations

Example 2: Classical NMOSome similar syndromes within the spectrum that mimicsNMOOverlaps considerably with MS


Criteria for Diagnosis of NMO

Major criteria

Episode of optic neuritisIn one or both eyes

Episode of transverse myelitisClinically complete or incompleteRadiologic evidence of an extensive spinal cordlesion—extending over 3 or more spinalsegments

No evidence for other systemic diseasesSarcoidosisVasculitisClinically manifest collagen vascular disorders,(i.e., systemic lupus erythematosus or Sjogren'sdisease)



Minor criteria

Most recent brain MRI should benormal or show abnormalities thatdon’t fit McDonald diagnostic criteriafor MS

McDonald diagnostic criteria for MS:Integrate data MRIFocus on early diagnosis of patientspresenting with CIS suggestive of MS(e.g., unilateral optic neuritis,internuclear ophthalmoplegia, partialmyelopathy)



Minor criteria

Could be nonspecific brain abnormalities

Lesions in the dorsal medulla noted ashypothalamic lesions

Linear periventricular corpus callosumsignal abnormalities

Not ovoid lesionsNot extending into the parancema of thecerebral hemisphere in a Dawson’s finger-likeconfiguration

Positive test for serum or spinal fluid forthe NMO-IGG aquaporin 4 antibodies


Presentation of Myelopathic SyndromeMS vs. Non-MS Diagnosis

In MS myelopathy comes on in sub-acutefashion

Hours to daysProgressive MS—weeks, months, or yearsPartial myelopathy—not truly transverseAcute exacerbation—reasonable degree of recoveryLongitudinal extent in MS less than 3 vertebralsegments

In other conditions, (i.e., spinal cord infarct)Deficit is more rapidMore vascular patternIn compressive lesions of the spinal cord—sloweronsetIn NMO—damage to spinal cord more extensive andless likely to recover



Conclusions

“Red Flags” help clinicians to develop adifferential diagnosis of MS and other IIDDs

Help to exclude non-IIDDs

CIS can either be monofocal or multifocalor seen on MRI only

MS must be distinguished from other IIDDsNMO

ADEM

Through the use of differential features andrelative red flags, the diagnosis of MS or itsmimics is made easier for the practicingclinician

Additional Resources

VisitVisitneuroscienceCME.com/MSneuroscienceCME.com/MSfor clinical information andfor clinical information and

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