““Multiple Sclerosis Overview”Multiple Sclerosis Overview”January 17, 2008January 17, 2008

Khurram Bashir, MD, MPHAssociate Professor of NeurologyDirector, Multiple Sclerosis Center

Optic NeuritisOptic Neuritis

MS History – Saint Lidwina (1421)MS History – Saint Lidwina (1421)

1794-1848 » Sir Augustus d'Esté

Grand-son of George III

The Regent did not approve of the marriage of his son, Prince Augustus Frederick, to Lady Augusta Murray, and had the marriage annulled

Although later given a knighthood, Augustus was made illegitimate

1868 1868 » First First detailed clinicopathological description of MS

Charcot became the Professor of Neurology at the University of Paris and is often referred to as the "Father of Modern Neurology".

Multiple SclerosisMultiple Sclerosis

Immune-mediated, demyelinating Immune-mediated, demyelinating disease of thedisease of the central nervous system central nervous system white matter white matter characterized bycharacterized by neurologic dysfunction neurologic dysfunction separated in separated in time and spacetime and space

Multiple SclerosisMultiple Sclerosis

Immune-mediated Immune-mediated and and neurodegenerativeneurodegenerative, demyelinating , demyelinating with with axonal lossaxonal loss disease of thedisease of the central central nervous system white nervous system white and grayand gray matter matter characterized bycharacterized by neurologic dysfunction neurologic dysfunction separated in time and spaceseparated in time and space

CHALLENGES FOR THE CHALLENGES FOR THE HEALTHCARE PROVIDERHEALTHCARE PROVIDER

• Difficult diagnosis

• No single specific test

• No two cases of MS are alike

• No proven cause

• No known cure

• MS is unpredictable

• Partially effect treatments

Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis

Age:Age: 20-40 yrs (mean 30 yrs)20-40 yrs (mean 30 yrs) F:M ratio:F:M ratio: 1.5-2.0 : 11.5-2.0 : 1 Race:Race: W > B > Other racial groupsW > B > Other racial groups IncidenceIncidence

• WorldwideWorldwide 2.5 million2.5 million• USUS 365,000 – 400,000365,000 – 400,000

Clusters/”Epidemics”:Clusters/”Epidemics”: Faroe Islands, IcelandFaroe Islands, Iceland Effect of migration:Effect of migration: Exposure at < 15 yrs of Exposure at < 15 yrs of

age is importantage is important

Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis Geographical Geographical Increases with increasing Increases with increasing

Association:Association: and decreasing latitudeand decreasing latitude

Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis

Duration of diseaseDuration of disease > 30 years> 30 years

Severely disabledSeverely disabled 30% (w/o Rx)30% (w/o Rx)

UnemployedUnemployed 70%70%

Average care costAverage care cost $30,000/year $30,000/year (1998 $)(1998 $)

US economy cost US economy cost $9.6 billion/year$9.6 billion/year (1998 $)(1998 $)

Pathophysiology of Multiple SclerosisPathophysiology of Multiple Sclerosis

Genetic FactorsGenetic Factors PolygenicPolygenic Monozygotic twin concordance rate of ~25-Monozygotic twin concordance rate of ~25-

30% compared to dizygotic twin concordance 30% compared to dizygotic twin concordance rate of ~4-5%rate of ~4-5%

MS is more common in CaucasiansMS is more common in Caucasians Minor influence of HLA Minor influence of HLA (on chromosome 6) (on chromosome 6) in in

familial cases and Caucasian patients with RR familial cases and Caucasian patients with RR MSMS

Several areas of interest - Several areas of interest - 17q11, 17q11, 6p216p21, 5q11, , 5q11, 17q22, 16p13, 3p21, 12p13, and 6qtel. 17q22, 16p13, 3p21, 12p13, and 6qtel.

Pathophysiology of Multiple SclerosisPathophysiology of Multiple Sclerosis

Environmental FactorsEnvironmental Factors Infectious ?Infectious ? Toxins ?Toxins ? UnknownUnknown

No increased risk of MS in adopteesNo increased risk of MS in adoptees No increased risk in spousesNo increased risk in spouses

Abnormal immunologic response

Genetic predisposition

Infectious agent?

Pathophysiology of Multiple SclerosisPathophysiology of Multiple Sclerosis

MS

Environmental factors

Noseworthy J., Progress in determining the causes and treatment of multiple sclerosis. Nature. June 1999: A40-A47.

Activation of Immune System in MSActivation of Immune System in MS

Inflammation and the CNS in MSInflammation and the CNS in MS

Axonal Damage and Lesion Formation Axonal Damage and Lesion Formation in MSin MS

Multiple Sclerosis – Gross PathologyMultiple Sclerosis – Gross Pathology

Multiple Sclerosis PathologyMultiple Sclerosis Pathology

Demyelination

Inflammation

Axonal Loss

Remyelinating OligodendrocyteRemyelinating Oligodendrocyte

Adapted with kind permission from Dr. W. Brück.

Multiple Sclerosis : Severe Myelin, Multiple Sclerosis : Severe Myelin, Axonal, and Neuronal LossAxonal, and Neuronal Loss

Normal White Matter Plaque

Myelin

Axons

Astrocytes

NeuronsLymphocytes

Macrophages

Peterson JW et al. Neurol Clin. 2005;23:107-129.

Affects subcortical and white matter and cortex

Restricted to the cortex, small in size, circular intracortical lesions, often centered on vessels

Extend from the pial surface into the cortex, often involve multiple gyri

Patients often experience neurologic symptoms that do not correlate with white matter pathology

Gray Matter Lesion PatternsGray Matter Lesion Patterns

Symptoms at Onset of MSSymptoms at Onset of MS

SymptomSymptom Percentage of Percentage of PatientsPatients

Sensory symptoms in arms/legsSensory symptoms in arms/legs 3333

Unilateral vision lossUnilateral vision loss 1616

Polysymptomatic onsetPolysymptomatic onset 1414

Slowly progressive motor deficitSlowly progressive motor deficit 99

Acute motor deficitAcute motor deficit 5 5

DiplopiaDiplopia 77

OtherOther 1616

Paty. In: Multiple sclerosis, diagnosis, medical management, and rehabilitation. 2000.

MS: Common SymptomsMS: Common Symptoms

Symptom Symptom Prevalence, %Prevalence, %

Bladder symptomsBladder symptoms 97.197.1

FatigueFatigue 89.889.8

SpasticitySpasticity 70.270.2

Sexual dysfunctionSexual dysfunction 64.264.2

PainPain 61.961.9

Cognitive dysfunctionCognitive dysfunction 61.961.9

Bowel dysfunctionBowel dysfunction 47.847.8

DepressionDepression 41.641.6

Goodin et al. Mult Scler. 1999;5:78-88.

Forms of MSForms of MS

Relapses

Incr

easi

ng

dis

abili

ty

Time

Relapsing-remitting

55%

Relapses with Disability

Some of the available therapies can slow disability progression in relapsing forms of MS.

TimeIncr

easi

ng

dis

abili

ty

Primaryprogressive

5%-10%

Disability ProgressionNo Distinct Relapses

Incr

easi

ng

dis

abili

tyTime

Secondaryprogressive

30%

Increasing Disability

SPECTRUM OF MS DISEASE ACTIVITYSPECTRUM OF MS DISEASE ACTIVITY

Genetic SusceptibilityGenetic Susceptibility Environmental FactorsEnvironmental Factors

Immune System Activation in the CNSImmune System Activation in the CNS

Demyelination ± Axonal LossDemyelination ± Axonal Loss

Multiple SclerosisMultiple Sclerosis

Benign RR SP Transitional PP PR MalignantBenign RR SP Transitional PP PR Malignant

Minimal DisabilityMinimal Disability Severe DisabilitySevere Disability

Laboratory and Imaging StudiesLaboratory and Imaging Studies

MRIMRI BrainBrain Spinal cordSpinal cord

CSFCSF Evoked Potential StudiesEvoked Potential Studies

VisualVisual Brainstem auditoryBrainstem auditory SomatosensorySomatosensory

Multiple Sclerosis: Cranial MRIMultiple Sclerosis: Cranial MRI

Gdenhancement

T2 lesion

T1 “black hole”

Brain atrophy

Spinal cord lesion

Multiple Sclerosis : Serial MRI FindingsMultiple Sclerosis : Serial MRI Findings

Visual Evoked PotentialsVisual Evoked Potentials

Common CSF AbnormalitiesCommon CSF Abnormalities

MS ProfileMS ProfileMBPMBP ElevatedElevated

IgG IndexIgG Index ElevatedElevated

IgG Synthesis RateIgG Synthesis Rate ElevatedElevated

OCBOCB PresentPresent

Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic Criteria

Relapse DefinitionRelapse Definition• Neurological disturbance consistent with MSNeurological disturbance consistent with MS• Subjective report or objective observationSubjective report or objective observation• 24 hour duration, minimum24 hour duration, minimum• Excludes psudorelapses, single paroxysmal Excludes psudorelapses, single paroxysmal

episodesepisodes• At least 30 days between onset of event 1 and At least 30 days between onset of event 1 and

event 2event 2

Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic CriteriaClinical PresentationClinical Presentation Additional data needed for MS diagnosisAdditional data needed for MS diagnosis

11 ≥ ≥ 2 relapses;2 relapses; Objective clinical evidence Objective clinical evidence of ≥ 2 lesionsof ≥ 2 lesions

NoneNone

22 ≥ ≥ 2 relapses2 relapses Objective clinical evidence Objective clinical evidence of 1 lesionsof 1 lesions

Dissemination in space, demonstrated Dissemination in space, demonstrated by:by:

- MRI, - MRI, OROR

- ≥ 2 MRI lesions + positive CSF, - ≥ 2 MRI lesions + positive CSF, OROR

- 2- 2ndnd clinical relapse disseminated in clinical relapse disseminated in spacespace

33 1 relaspe1 relaspe Objective clinical evidence Objective clinical evidence of ≥ 2 lesionsof ≥ 2 lesions

Dissemination in time, demonstrated Dissemination in time, demonstrated by:by:

- MRI, - MRI, OROR

- 2- 2ndnd clinical relapse clinical relapse

Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic CriteriaClinical PresentationClinical Presentation Additional data needed for MS diagnosisAdditional data needed for MS diagnosis

44 1 relapse1 relapse Objective clinical evidence of 1 Objective clinical evidence of 1 lesionlesion

Dissemination in space, demonstrated by:Dissemination in space, demonstrated by:

- MRI, - MRI, OROR

- ≥ 2 MRI lesions + positive CSF, - ≥ 2 MRI lesions + positive CSF,

ANDAND Dissemination in time, demonstrated by:Dissemination in time, demonstrated by:

- MRI, - MRI, OROR

- 2- 2ndnd clinical relapse clinical relapse

55 Insidious neurological Insidious neurological progression suggestive of MSprogression suggestive of MS

1 year of disease progression 1 year of disease progression (retrospectively or prospectively determined)(retrospectively or prospectively determined)

ANDAND 2 out of 3 of the following:2 out of 3 of the following:

- Positive bran MRI (9 T2 lesions - Positive bran MRI (9 T2 lesions OROR ≥ 4 T2 ≥ 4 T2 MRI lesions and positive VEPMRI lesions and positive VEP

- Positive spinal cord MRI (≥ 2 T2 lesions)- Positive spinal cord MRI (≥ 2 T2 lesions)

- Positive CSF- Positive CSF

Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic Criteria

CaveatCaveat• No Better ExplanationNo Better Explanation

• Need to rule out other potential etiologies that Need to rule out other potential etiologies that might explain clinical or imaging might explain clinical or imaging abnormalitiesabnormalities

Clinical Stages in Relapsing MSClinical Stages in Relapsing MS

Gd + lesions Clinical Relapse

T2W lesion burdenAccumulateddisability

Pre-Symptomatic

Early RR MS Late RR MSSP MS

BPF

WM NAA

Multiple Sclerosis TreatmentMultiple Sclerosis Treatment

Treatment of Relapse (“Exacerbation”)Treatment of Relapse (“Exacerbation”) Treatment of Underlying DiseaseTreatment of Underlying Disease Treatment of SymptomsTreatment of Symptoms Psychosocial SupportPsychosocial Support Patient EducationPatient Education

Acute RelapseAcute Relapse

Pre-Symptomatic

Early RR MS Late RR MSSP MS

Treatment of an Acute RelapseTreatment of an Acute Relapse

Standard Treatment(s):Standard Treatment(s):

• IV MethylprednisoloneIV Methylprednisolone• Oral PrednisoneOral Prednisone• ACTH injectionsACTH injections• Therapeutic Plasma Exchange Therapeutic Plasma Exchange (for steroid (for steroid

unresponsive severe demylinating relapses)unresponsive severe demylinating relapses)

Relapsing MSRelapsing MS

Pre-Symptomatic

Early RR MS Late RR MSSP MS

Treatment for Relapsing MSTreatment for Relapsing MS

Interferon AgentsInterferon Agents• IFN IFN -1b (Betaseron)-1b (Betaseron)• IFN IFN -1a intramuscular (Avonex)-1a intramuscular (Avonex)• IFN IFN -1a subcutaneous (Rebif)-1a subcutaneous (Rebif)

Non-Interferon AgentsNon-Interferon Agents• Synthetic Polymer Synthetic Polymer

Glatiramer acetate (Copaxone)Glatiramer acetate (Copaxone)

• Selective Adhesion Molecule (SAM) InhibitorSelective Adhesion Molecule (SAM) Inhibitor Natilzumab (Tysabri)Natilzumab (Tysabri)

SP MSSP MS

Pre-Symptomatic

Early RR MS Late RR MSSP MS

Treatment for SP MSTreatment for SP MS

Interferon AgentsInterferon Agents• IFN IFN -1b (Betaseron)*-1b (Betaseron)*• IFN IFN -1a (Avonex, Rebif)**-1a (Avonex, Rebif)**• Natalizumab (Tysabri)**Natalizumab (Tysabri)**

Non-Interferon AgentsNon-Interferon Agents• Anthracenedione DerivativeAnthracenedione Derivative

Mitoxantrone (Novantrone)***Mitoxantrone (Novantrone)***

* Approved therapy for SP MS in Europe and Canada* Approved therapy for SP MS in Europe and Canada* And ** Appropriate for use in relapsing SP MS* And ** Appropriate for use in relapsing SP MS

*** Only FDA-approved therapy for SP MS in the US*** Only FDA-approved therapy for SP MS in the US

Goals of Treatment of MSGoals of Treatment of MS

Therapeutic Effects of Current Therapies:Therapeutic Effects of Current Therapies:

• Reduction inReduction in

Relapse rateRelapse rate Progression of disabilityProgression of disability MRI MRI

• Total burden of diseaseTotal burden of disease• Gad enhancing lesions on MRIGad enhancing lesions on MRI• Brain atrophyBrain atrophy

PP MSPP MS

Treatment for PP MSTreatment for PP MS

Currently no treatments proven to slow or Currently no treatments proven to slow or stop progression of diseasestop progression of disease

Management focused on:Management focused on:• Treating symptomsTreating symptoms• Maximizing functionMaximizing function• Improving quality of lifeImproving quality of life

MS symptom and side effect management

SYMPTOMS PHARMACOLOGIC TREATMENT OPTIONSSpasticity Baclofen, Diazepam, Gabapentin, Tizanidine, Dantrium

Urinary Dysfunction Propantheline Bromide, Oxybutynin,

Hyoscyamine Sulfate, Tolterodine Tartrate

Fatigue Amantadine, Pemoline, Fluoxetine,

Methylphenidate, Modafinil

Depression SSRIs:Fluoxetine, Sertraline

Tricyclics: Amitriptyline, Nortriptyline, Desipramine

Venlafaxine

Pain Anticonvulsants: Carbamazepine, DPH, Gabapentin

Antidepressants: Amitriptyline, Nortriptyline,

Desipramine, Venlafaxine

Sexual Dysfunction Sildenafil, Vardenafil, Tidalafil

Ataxia Ondansetron, Clonazepam, Propranolol, Levetiracetam

Aug2000

Other Demyelinating DiseasesOther Demyelinating Diseases

Acute Disseminated EncephalomyelitisAcute Disseminated Encephalomyelitis Hyper-acute, severe, monophasic, multifocal, Hyper-acute, severe, monophasic, multifocal,

paraifectious/paravaccination, demylinating paraifectious/paravaccination, demylinating Devic’s Diseases (Neuromyelitis Optica, NMO)Devic’s Diseases (Neuromyelitis Optica, NMO)

Severe, necrotizing, relapsing/rapidly progressive, Severe, necrotizing, relapsing/rapidly progressive, demyelinating, associated with NMO IgG, involving optic demyelinating, associated with NMO IgG, involving optic nerves and spinal cordnerves and spinal cord

Balo’s Concentric SclerosisBalo’s Concentric Sclerosis MS variant, acute, large, demyelinating lesions, with MS variant, acute, large, demyelinating lesions, with

concentric rings of demyelination and remyelination concentric rings of demyelination and remyelination Marburg VariantMarburg Variant

MS variant, severe, rapidly progressive, involves large MS variant, severe, rapidly progressive, involves large area of CNS white matter, death usually within monthsarea of CNS white matter, death usually within months

Questions ?Questions ?