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Multiple Sclerosis:Multiple Sclerosis:What the Family Physician What the Family Physician Should Know . . .Should Know . . .

Michael M.C. Yeung, MD, FRCPCMichael M.C. Yeung, MD, FRCPC

Director, MS Clinical Trials Research Director, MS Clinical Trials Research ProgramProgram

Clinical Associate ProfessorClinical Associate Professor

Department of Clinical NeurosciencesDepartment of Clinical Neurosciences

University of CalgaryUniversity of Calgary

October 2, 2014October 2, 2014

Research SupportResearch Support National Institutes of Health, MS Society of Canada, National Institutes of Health, MS Society of Canada,

BiogenIdec, Hoffman-LaRoche, Sanofi-Aventis, BiogenIdec, Hoffman-LaRoche, Sanofi-Aventis, Novartis, Elan, EMD Serono, Neuroscience Canada, Novartis, Elan, EMD Serono, Neuroscience Canada, IMPAX, Bayer, Teva Canada Innovation, Genzyme, IMPAX, Bayer, Teva Canada Innovation, Genzyme, Acorda Therapeutics, Berlex, BioMS Technology,Acorda Therapeutics, Berlex, BioMS Technology,

Protein Design Labs, Genentech, GSK, Abbott, Protein Design Labs, Genentech, GSK, Abbott, NeurocrineNeurocrine

ConsultantConsultant BiogenIdec, Novartis, EMD Serono, Bayer, Teva BiogenIdec, Novartis, EMD Serono, Bayer, Teva

Canada InnovationCanada Innovation Speakers’ BureauSpeakers’ Bureau

MS Society of Canada, BiogenIdec, Novartis, EMD MS Society of Canada, BiogenIdec, Novartis, EMD Serono, Bayer, Teva Canada InnovationSerono, Bayer, Teva Canada Innovation

HonorariaHonoraria MS Society of Canada, BiogenIdec, EMD Serono, MS Society of Canada, BiogenIdec, EMD Serono,

Bayer Teva Canada InnovationBayer Teva Canada Innovation

DisclosuresDisclosures

University of Calgary MS ClinicUniversity of Calgary MS Clinic When Should I Suspect Multiple When Should I Suspect Multiple

Sclerosis?Sclerosis? Diagnostic CriteriaDiagnostic Criteria Is it a Relapse?Is it a Relapse? Disease Modifying TreatmentsDisease Modifying Treatments Symptom ManagementSymptom Management Complementary & Alternative Complementary & Alternative

TreatmentsTreatments

ContentsContents

Established in 1978 as part of Established in 1978 as part of Canadian Network of MS ClinicsCanadian Network of MS Clinics

To provide specialized multi-disciplinary To provide specialized multi-disciplinary care and treatmentcare and treatment

To participate in clinical and To participate in clinical and investigator-driven research trialsinvestigator-driven research trials

University of Calgary University of Calgary MS ClinicMS Clinic

~6000 registered patients~6000 registered patients Foothills Medical Centre and South Health Foothills Medical Centre and South Health

CampusCampus 9 neurologists, 1 physiatrist, 2 neuro-9 neurologists, 1 physiatrist, 2 neuro-

psychiatristspsychiatrists 1 nurse practitioner, 4.5 clinic nurses, 2 1 nurse practitioner, 4.5 clinic nurses, 2

special therapies nurses, 1.5 research special therapies nurses, 1.5 research nursesnurses

3 research coordinators, 3 research 3 research coordinators, 3 research assistants, 4 health outcomes research assistants, 4 health outcomes research assistantsassistants

University of Calgary University of Calgary MS Clinic MS Clinic

OOututppatient atient TTreatment reatment iin n MuMultiple ltiple SSclerosisclerosis

OT, PT, SW, psychology, bowel & OT, PT, SW, psychology, bowel & bladder nursebladder nurse

2 psychiatrists, 2 neuro-psychiatrists2 psychiatrists, 2 neuro-psychiatrists Provides access to co-ordinated rehab Provides access to co-ordinated rehab

servicesservices Entry point is MS ClinicEntry point is MS Clinic

OPTIMUS OPTIMUS

Multidisciplinary Team Approach

Diagnose and confirm MSDiagnose and confirm MS Initiate and monitor disease modifying Initiate and monitor disease modifying

therapiestherapies Give recommendations for symptom Give recommendations for symptom

managementmanagement Initiate referral to rehabilitation servicesInitiate referral to rehabilitation services Organize other community supportOrganize other community support Offer eligible patients the opportunity to Offer eligible patients the opportunity to

participate in clinical trialsparticipate in clinical trials

What the Clinic What the Clinic CanCan DoDo

Provide emergency careProvide emergency care Manage primary care needsManage primary care needs Initiate non-evidence-based treatmentsInitiate non-evidence-based treatments Manage patients without a primary care Manage patients without a primary care

providerprovider Provide services under the mandates of Provide services under the mandates of

other programsother programs

What We What We CannotCannot Do Do

What is MS?What is MS?

What is MS?What is MS?

Auto-immune disorder of CNSAuto-immune disorder of CNS InflammationInflammation Axonal degenerationAxonal degeneration

Genetic predispositionGenetic predisposition CaucasianCaucasian

Environmental triggerEnvironmental trigger Unknown Unknown

EpidemiologyEpidemiology

EpidemiologyEpidemiology

MS is the most common neurological MS is the most common neurological disorder affecting young adults in disorder affecting young adults in CanadaCanada

More common in females (2 - 3:1)More common in females (2 - 3:1) ~50,000 people with MS in Canada~50,000 people with MS in Canada Prevalence 1:500 - 1:1000Prevalence 1:500 - 1:1000 Alberta prevalence 1:300Alberta prevalence 1:300

When Should MS be in When Should MS be in the Differential the Differential Diagnosis?Diagnosis?

Common PresentationsCommon Presentations

VisualVisual Optic neuritisOptic neuritis INOINO

MotorMotor Progressive myelopathyProgressive myelopathy Incomplete transverse myelitisIncomplete transverse myelitis

SensorySensory Lhermitte’sLhermitte’s Incomplete transverse myelitisIncomplete transverse myelitis

CoordinationCoordination AtaxiaAtaxia

GaitGait

Common PresentationsCommon Presentations

Unusual PresentationsUnusual Presentations

PainPain Paroxysmal symptomsParoxysmal symptoms Migratory transient paresthesiasMigratory transient paresthesias Movement disordersMovement disorders Seizures Seizures Peripheral neuropathyPeripheral neuropathy

Unusual PresentationsUnusual Presentations

Structural lesions of brain or spinal cordStructural lesions of brain or spinal cord Cerebral vasculitisCerebral vasculitis Autoimmune diseasesAutoimmune diseases

SarcoidosisSarcoidosis LupusLupus

Metabolic diseasesMetabolic diseases Vitamin B12 deficiencyVitamin B12 deficiency

InfectionsInfections Lyme diseaseLyme disease

Differential Diagnosis Differential Diagnosis of MSof MS

Barkhof’s MRI Criteria

Gd-enhancing T2-hyperintense

Juxtacortical Periventricular

SpinalCord

Infratentorial

Differential Diagnosis Differential Diagnosis of MRI White Matter of MRI White Matter LesionsLesions

AgingAging MigrainesMigraines HypertensionHypertension TraumaTrauma Radiation therapyRadiation therapy Chronic fatigue syndromeChronic fatigue syndrome Cocaine addictionCocaine addiction CADASILCADASILDifferential Diagnosis Differential Diagnosis

of MRI White Matter of MRI White Matter LesionsLesions

CBC & differentialCBC & differential LFTs & renal functionLFTs & renal function Electrolytes, glucose, Ca, Mg, PO4Electrolytes, glucose, Ca, Mg, PO4 Vitamin D levelVitamin D level Serum protein electrophoresisSerum protein electrophoresis Vitamin B12 levelVitamin B12 level RF, ANARF, ANA VDRLVDRL MRI brain and cervical spinal cord +/- MRI brain and cervical spinal cord +/-

contrastcontrast

Work-upWork-up

Diagnostic CriteriaDiagnostic Criteria

2010 revised McDonald criteria2010 revised McDonald criteria Neurological symptoms and/or signs Neurological symptoms and/or signs

separated in time and spaceseparated in time and space MRI can help in diagnosis, but is MRI can help in diagnosis, but is notnot

THETHE diagnostic test diagnostic test

Goodin DS, et al. Neurology. 2002;58:169-178. Craig J, et al. J Neurol Neurosurg Psychiatry. 2003;74:1225-1230.

MS: Clinical SubtypesMS: Clinical Subtypes

Four established clinical courses differ by the time Four established clinical courses differ by the time course of relapse and progressioncourse of relapse and progression

Relapsing-Remitting MS (RRMS) Relapsing-Remitting MS (RRMS) Secondary Progressive MS (SPMS)Secondary Progressive MS (SPMS) Primary Progressive MS (PPMS)Primary Progressive MS (PPMS) Progressive Relapsing MS (PRMS)Progressive Relapsing MS (PRMS)

Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

No disease progression between relapses

Acute relapses with full recovery Acute relapses with sequelae and residual deficit upon recovery

Incr

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Time Time

Relapsing-Remitting MSRelapsing-Remitting MS

Patients with an initial RRMS course convert to SPMS, which is characterized by continuous progression

Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

Without relapses With relapses

Time Time

Incr

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Secondary Progressive Secondary Progressive MSMS

PPMS is characterized by progression of disability from onset

Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

Without plateaus or remissions With occasional plateaus and temporary minor improvements

Time Time

Incr

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isab

ility

Incr

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Primary Progressive MSPrimary Progressive MS

PRMS is characterized by disease progression from onset withthe occurrence of clear acute relapses

Full recovery following relapse with progression between relapses

Without full recovery following relapse with progression between relapses

Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

Time Time

Incr

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ngD

isab

ility

Incr

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Progressive Relapsing Progressive Relapsing MSMS

Clinical Subtypes (at Clinical Subtypes (at Presentation)Presentation)

Jacobs LD, et al. Jacobs LD, et al. Mult Scler.Mult Scler. 1999;5:369-376. 1999;5:369-376.

About 80%–85% of all MS patients initially have RRMS;About 80%–85% of all MS patients initially have RRMS;most will convert to SPMS in 6-10 yearsmost will convert to SPMS in 6-10 years

(N = 3019)

Education and supportEducation and support Optimize overall wellnessOptimize overall wellness Relapse identification and treatmentRelapse identification and treatment Symptom managementSymptom management Disease modifying therapiesDisease modifying therapies

MS TreatmentMS Treatment

WellnessWellness

Healthy and balanced dietHealthy and balanced diet Regular exerciseRegular exercise Smoking cessationSmoking cessation Avoid excessive caffeine & alcoholAvoid excessive caffeine & alcohol Routine screening medical exams and Routine screening medical exams and

attention to other medical conditionsattention to other medical conditions Recognition and treatment of depressionRecognition and treatment of depression Manage stressManage stress Vitamin D3 4000 IU/dayVitamin D3 4000 IU/day Vaccinations (avoid live attenuated Vaccinations (avoid live attenuated

vaccines)vaccines)

WellnessWellness

Vitamin DVitamin DAdapted from Hollis et al., CMAJ 2006

Vitamin DVitamin DAdapted from Mora et al., Nature Reviews immunology 2009

Relapse vs Pseudo-Relapse vs Pseudo-relapse vs Fluctuationrelapse vs Fluctuation

30-yr-old woman with RRMS for 3 years, 30-yr-old woman with RRMS for 3 years, on a DMT, calls the Clinic. Over the last on a DMT, calls the Clinic. Over the last 3 days, she has noted pain in the L eye 3 days, she has noted pain in the L eye with some visual blurring, worse at the with some visual blurring, worse at the end of day. Colours seem less bright. end of day. Colours seem less bright. Her last relapse (Lhermitte’s with Her last relapse (Lhermitte’s with numbness of her R arm) was ~2 years numbness of her R arm) was ~2 years ago prior to starting her DMT.ago prior to starting her DMT.

What would you do?What would you do?

Case Mrs. RRCase Mrs. RR

““a focal disturbance of function, affecting a focal disturbance of function, affecting a white matter tract, lasting for more than a white matter tract, lasting for more than 24 hours. Typically, tends to progress 24 hours. Typically, tends to progress over a period of a few days, reaching a over a period of a few days, reaching a maximum in less than 1 week and then maximum in less than 1 week and then slowly resolving.”slowly resolving.” SchumacherSchumacher

““occurrence of a symptom or symptoms of occurrence of a symptom or symptoms of neurological dysfunction, in the absence of neurological dysfunction, in the absence of fever, with or without objective fever, with or without objective confirmation, lasting more than 24 hours.”confirmation, lasting more than 24 hours.” Clinical trialsClinical trials

What is a relapse?What is a relapse?

Recurrence of old symptomsRecurrence of old symptoms Short durationShort duration Accompanying metabolic or toxic changeAccompanying metabolic or toxic change Disappearance of symptoms and signs Disappearance of symptoms and signs

when aggravating metabolic change has when aggravating metabolic change has been correctedbeen corrected

What is a pseudo-What is a pseudo-relapse?relapse?

Changing neurological function Changing neurological function throughout day.throughout day.

What are fluctuations?What are fluctuations?

Lhermitte’s phenomenon/symptomLhermitte’s phenomenon/symptom Uhthoff’s phenomenon/symptomUhthoff’s phenomenon/symptom Multiple tonic spasms over 24 hoursMultiple tonic spasms over 24 hours Trigeminal neuralgiaTrigeminal neuralgia Dragging foot after shopping for 20 Dragging foot after shopping for 20

minutes; better after having coffee and minutes; better after having coffee and éclairéclair

Increased leg weakness with recent Increased leg weakness with recent URTIURTI

Numbness to waist lasting 3 weeksNumbness to waist lasting 3 weeks

Relapse/pseudo-relapse/Relapse/pseudo-relapse/fluctuation?fluctuation?

To Treat or Not to To Treat or Not to Treat?Treat?

InterferonsInterferons Betaseron®Betaseron® Extavia®Extavia® Rebif®Rebif® Avonex®Avonex®

Glatiramer acetate Glatiramer acetate (Copaxone®)(Copaxone®) Natalizumab Natalizumab (Tysabri®)(Tysabri®) Fingolimod Fingolimod (Gilenya®)(Gilenya®) Dimethyl fumarate Dimethyl fumarate (Tecfidera®)(Tecfidera®) Teriflunomide (Aubagio®)Teriflunomide (Aubagio®) Alemtuzumab (Lemtrada®)Alemtuzumab (Lemtrada®)

Disease Modifying Disease Modifying TherapiesTherapies

Seems to protect from relapses (2Seems to protect from relapses (2ndnd & 3 & 3rdrd trimester); likely related to hormone trimester); likely related to hormone levelslevels Fertility treatments may increase risk of Fertility treatments may increase risk of

relapserelapse Increased relapse rate during 1Increased relapse rate during 1stst

trimester post-partumtrimester post-partum First-line injectable DMTs (GA, IFN-β) First-line injectable DMTs (GA, IFN-β)

considered safe in breast-feedingconsidered safe in breast-feeding

PregnancyPregnancy

Symptom ManagementSymptom Management

Sources of SymptomsSymptoms vary widely in incidence

and severity

Sensory symptoms,Lhermitte’sPainProprioception

Optic neuritis

DiplopiaVertigoDysarthriaINO

Tremor,Ataxia

Cognitive loss

Emotional disinhibition

Bladder dysfunction

SymptomsSymptoms

SpasticitySpasticity Tremor & ataxiaTremor & ataxia FatigueFatigue Sensory symptomsSensory symptoms Bowel and bladderBowel and bladder Sexual dysfunctionSexual dysfunction Cognitive impairmentCognitive impairment

Complementary & Complementary & Alternative TreatmentsAlternative Treatments

CAM WebsitesCAM Websites

Neurologycare.netNeurologycare.net Naturaldatabase.comNaturaldatabase.com

There is no specific diagnostic test There is no specific diagnostic test (imaging, blood, CSF) for MS(imaging, blood, CSF) for MS

There is a differential diagnosis for white There is a differential diagnosis for white matter lesions on MRImatter lesions on MRI

Neurological symptoms in MS patients Neurological symptoms in MS patients are not always related to MS activityare not always related to MS activity

MS patients can develop other diseases MS patients can develop other diseases that may impact their MS symptomsthat may impact their MS symptoms

Take HomeTake Home

Exacerbations do not necessarily require Exacerbations do not necessarily require treatment with corticosteroidstreatment with corticosteroids

There is NO role for low dose There is NO role for low dose corticosteroids in the treatment of MS corticosteroids in the treatment of MS relapsesrelapses

Treatment of symptoms will improve Treatment of symptoms will improve quality of lifequality of life

Take HomeTake Home

Thank you!Thank you!