Multiple Multiple SclerosisSclerosis

Prepared by:Prepared by:

Dr. Sarwer Jamal BajalanDr. Sarwer Jamal BajalanM.B.Ch.B, F.I.B.M.S(Neurology)M.B.Ch.B, F.I.B.M.S(Neurology)

Multiple SclerosisMultiple Sclerosis

I.I. DefinitionDefinition

II.II. EpidemiologyEpidemiology

III.III. PathogenesisPathogenesis

IV.IV. Clinical featuresClinical features

V.V. Diagnostic Criteria & Diagnostic Criteria & EvaluationEvaluation

VI.VI. Differential Diagnosis Differential Diagnosis

VII.VII. Management Management

Definition of Multiple Definition of Multiple SclerosisSclerosis An inflammatory demyelinating An inflammatory demyelinating

disease of the CNS where there disease of the CNS where there is:is:– Dissemination in spaceDissemination in space– Dissemination in timeDissemination in time– No alternative neurologic diseaseNo alternative neurologic disease

MS is a clinical diagnosisMS is a clinical diagnosis

An immune-mediated [autoimmunity], An immune-mediated [autoimmunity], with secondary, significant axonal loss with secondary, significant axonal loss & cerebral atrophy& cerebral atrophy

Occurs in genetically susceptible Occurs in genetically susceptible individuals who are exposed to an individuals who are exposed to an environmental agent at a young ageenvironmental agent at a young age

Highly variable clinical courseHighly variable clinical course

EpidemiologyEpidemiology

The most common progressive neurologic disease of The most common progressive neurologic disease of young adultsyoung adults

Affects 350,000 persons in the USAAffects 350,000 persons in the USA

Most cases strike between ages 15 and 45Most cases strike between ages 15 and 45

Women outnumber men by as much as 2 to 3:1Women outnumber men by as much as 2 to 3:1

Risk Factors: Risk Factors: Female gender Female gender White raceWhite race Northern latitude (USA)Northern latitude (USA) High socioeconomic statusHigh socioeconomic status Scandinavian ancestryScandinavian ancestry

PathogenesisPathogenesis

MS involves genetic, environmental, and MS involves genetic, environmental, and immune factorsimmune factors

MS has inflammatory, demyelinating, and MS has inflammatory, demyelinating, and axonal damage componentsaxonal damage components

Pathogenesis is not clearly understoodPathogenesis is not clearly understood

Immune modulation is most successful Immune modulation is most successful therapeutic approach supporting immune therapeutic approach supporting immune role in pathogenesisrole in pathogenesis

Optic nerveMonocular visual lossScotoma

Spinal cordLimb weaknessSpasticity and hyper-reflexiaLhermitte’s signUrinary urgency and incontinence

Signs and Symptoms of MS by Lesion Location

BrainstemBrainstem Diplopia (double vision)Diplopia (double vision)

Pain (acute versus chronic)Pain (acute versus chronic)– Trigeminal neuralgia, tic-like Trigeminal neuralgia, tic-like

extremity painextremity pain

– Aching back pain, burning Aching back pain, burning sensation, leg spasmssensation, leg spasms

Numbness of face and tongueNumbness of face and tongue

Vertigo (Vertigo (sensation of moving around sensation of moving around

in spacein space))

Nystagmus (Nystagmus (involuntary eye involuntary eye

movementsmovements))

INO (INO (Inter Nuclear Inter Nuclear

OphthalmoplegiaOphthalmoplegia))

Bilateral Internuclear ophthalmoplegia (INO) - YouTube.MP4

CerebrumCerebrum– Impairment of Impairment of

concentration or concentration or memorymemory

– Hemiparesis Hemiparesis Hemisensory lossHemisensory loss

– Visual field defectVisual field defect

CerebellumCerebellum– Incoordination of limbsIncoordination of limbs– Ataxic gateAtaxic gate

Severe fatigueSevere fatigue Experienced by 75% to 95% of MS Experienced by 75% to 95% of MS

suffererssufferers

Heat sensitivityHeat sensitivity

DepressionDepression Etiology can be a: Etiology can be a:

– SymptomSymptom– Secondary complicationSecondary complication– Side effect of medications Side effect of medications

Secondary Secondary ComplicationsComplications DepressionDepression Urinary tract infectionUrinary tract infection Accelerated lumbar spondylosisAccelerated lumbar spondylosis Aspiration pneumoniaAspiration pneumonia Pulmonary thromboembolismPulmonary thromboembolism Pressure soresPressure sores Limb contractures Limb contractures Gastroparesis Gastroparesis

MS SubtypesMS Subtypes

AsymptomaticAsymptomatic SymptomaticSymptomatic

– Relapsing-remitting (85% at onset)Relapsing-remitting (85% at onset)– Primary progressive (10%)Primary progressive (10%)– Secondary Progressive (transitional Secondary Progressive (transitional

form ~50% of RR)form ~50% of RR)– Progressive Relapsing (5%)Progressive Relapsing (5%)

Multiple Sclerosis SubtypesMultiple Sclerosis Subtypes

DiagnosisDiagnosis

Clinical findingsClinical findings

– HistoryHistory– Neurologic examNeurologic exam– Clinical pictureClinical picture

Laboratory Laboratory evaluations evaluations

– Magnetic resonance Magnetic resonance imaging (MRI)imaging (MRI)

– Evoked potentialsEvoked potentials– Cerebrospinal fluid Cerebrospinal fluid

(CSF) analysis(CSF) analysis

McDonald Diagnostic Criteria-McDonald Diagnostic Criteria-11[Relapsing Remiting MS][Relapsing Remiting MS]

Lesions disseminated in time(DIT) and space(DIS)

Time: More than one attack separated by at least one month

Space: CNS involvement of more than one area

Exclusion of other possible causes

McDonald Diagnostic Criteria - 2McDonald Diagnostic Criteria - 2 [[Primary Progressive MS]Primary Progressive MS]

Insidious course with steady Insidious course with steady progression of clinical deficits with progression of clinical deficits with paraclinicalparaclinical evidence of: evidence of:

– DISDIS by MRI in combination with VER & by MRI in combination with VER & positive CSFpositive CSF

– DIT DIT by MRI or continued progression for 1 by MRI or continued progression for 1 yryr

Imaging & Lab Work-up for Imaging & Lab Work-up for MSMS(Modified from Fleming J, MS & Its Masquerades, AAN-2003)(Modified from Fleming J, MS & Its Masquerades, AAN-2003)

Brain MRI with GdBrain MRI with Gd Evoked Responses [VER(VEP), BAER, SSER]Evoked Responses [VER(VEP), BAER, SSER] CBC, Chem 7, Liver enz, UACBC, Chem 7, Liver enz, UA Lyme serology (based on exposure history)Lyme serology (based on exposure history) ANA, VDRL, ESRANA, VDRL, ESR B12B12 T3, T4, TSHT3, T4, TSH HIVHIV CSF (based on clinical and MRI)CSF (based on clinical and MRI) C & T Spine MRI (if Brain MRI nl or indicated clinically)C & T Spine MRI (if Brain MRI nl or indicated clinically) CXR CXR

MRI: FLAIR & T1 with MRI: FLAIR & T1 with GadoliniumGadolinium

MRI: T1 MRI: T1 ““Black HolesBlack Holes””

MRI: Sagittal ViewsMRI: Sagittal Views

MRI: Spinal ImagingMRI: Spinal Imaging

MRIMRI: T2, T2, FLAIR, T1-Gd: T2, T2, FLAIR, T1-Gd

Visual Evoked PotentialsVisual Evoked Potentials

CSF StudiesCSF Studies Glucose:Glucose: NormalNormal

Protein:Protein: Normal to Mild ElevationNormal to Mild Elevation

WBC:WBC: Normal to Mild Mononuclear Normal to Mild Mononuclear PleocytosisPleocytosis

Intrathecal Antibody Production:Intrathecal Antibody Production:

Increased Increased IgG Synthesis RateIgG Synthesis Rate,,

Oligoclonal BandsOligoclonal Bands

Oligoclonal BandsOligoclonal Bands

Differential Diagnosis of Differential Diagnosis of MSMS

MANGEMENT OFMANGEMENT OF

MULTIPLE SCLEROSISMULTIPLE SCLEROSIS

Treatment GoalsTreatment Goals

Reduce (control) relapsesReduce (control) relapses

Delay disease progression & Delay disease progression & disability disability

Alleviate symptomsAlleviate symptoms

CorticosteroidsCorticosteroids

Symptomatic management for acute relapses Symptomatic management for acute relapses

Used in moderate-to-severe exacerbations Used in moderate-to-severe exacerbations

IV methylprednisolone 500-1000 mg/day for 3-5 days IV methylprednisolone 500-1000 mg/day for 3-5 days followed by oral prednisone (followed by oral prednisone (optionaloptional))

Hasten clinical recoveryHasten clinical recovery

Delay recurrence of neurologic eventsDelay recurrence of neurologic events

Does not alter the course of MSDoes not alter the course of MS

Disease Modifying AgentsDisease Modifying Agents

(Parentral(Parentral)) BetaseronBetaseron (interferon (interferon -1b)-1b) AvonexAvonex (interferon (interferon -1a)-1a) RebifRebif (interferon (interferon -1a)-1a) CopaxoneCopaxone (glatiramer acetate) (glatiramer acetate)

NovantroneNovantrone (mitoxantrone) (mitoxantrone) 12 mg/m2 as short IV infusion12 mg/m2 as short IV infusion Cumulative lifetime dose Cumulative lifetime dose 140 mg/m2 140 mg/m2

TysabriTysabri (Natalizumab) (Natalizumab) 300mg IV infusion over 1hr q 4 wks300mg IV infusion over 1hr q 4 wks

Disease Modifying AgentsDisease Modifying Agents(Oral)(Oral)

Gilenya (Fingolimod)Gilenya (Fingolimod) available since 2011available since 2011 0.5 mg/day0.5 mg/day S/E:S/E: Transitory slow heart rate Transitory slow heart rate macular edemamacular edema Herpes infection: 2 patients have died from itHerpes infection: 2 patients have died from it

Aubagio (Terflunamide)Aubagio (Terflunamide) 30% reduction in relapse frequency30% reduction in relapse frequency S/E: diarrhea, nausea, hair loss and abnormal S/E: diarrhea, nausea, hair loss and abnormal

hepatic biochemistryhepatic biochemistry

FumarateFumarate used in Germany for 10 years to treat psoriasis used in Germany for 10 years to treat psoriasis

(Fumaderm)(Fumaderm)

Laquinimod Laquinimod One dose: 0.6 mg/dayOne dose: 0.6 mg/day Modest effect: 25% reduction in relapse frequencyModest effect: 25% reduction in relapse frequency

Interferon BetaInterferon BetaMechanism of ActionMechanism of Action

Reduce the production of the Reduce the production of the TNFaTNFa (tumor necrosis factor (tumor necrosis factor alpha) and T-cells, known to induce damage to myelinalpha) and T-cells, known to induce damage to myelin

Reduce inflammation by:Reduce inflammation by:– Switching Switching cytokinecytokine production from type 1 ( production from type 1 (pro-inflammatorypro-inflammatory) )

to type 2 (to type 2 (anti-inflammatoryanti-inflammatory) cells ) cells

– Increasing levels of interleuken 10 (Increasing levels of interleuken 10 (IL-10IL-10))

Decrease antigen presentation, to reduce the attack on myelinDecrease antigen presentation, to reduce the attack on myelin

Reduce the ability of immune cells to cross the blood-brain Reduce the ability of immune cells to cross the blood-brain barrier, by affecting barrier, by affecting adhesion molecules, chemokines, and adhesion molecules, chemokines, and proteasesproteases

Betaseron (interferon beta-Betaseron (interferon beta-1b)1b)(Betaferon)(Betaferon) Indication:Indication: Relapsing forms of MS Relapsing forms of MS

Dose:Dose: 8 million IU (250 8 million IU (250 mcgmcg) SC every other ) SC every other dayday

Reduces rate of clinical relapseReduces rate of clinical relapse Reduces the development of Reduces the development of

new lesionsnew lesions Delays the increase in the Delays the increase in the

volume of lesionsvolume of lesions

Immunomodulating AgentsImmunomodulating Agents

Type Recombinant Recombinant RecombinantPolypeptide

protein protein protein mixture

Use Slow Reduce ReduceReduce

accumulation frequency frequencyfrequency

of disability of relapses of relapses of relapses

Injection IM SC SCSC

Administration Weekly 3 /week Every other day Daily

Dosage 30 g 22 g 0.25 mg (8 MIU) 20 mg

44 g

IFN -1a(Avonex®)

IFN -1a(Rebif®)

IFN -1b(Betaseron

®)

Glatiramer Acetate

(Copaxone®)

IFNs

Symptomatic TreatmentsSymptomatic Treatments

Problem Management

Spasticity Remove irritating factors, Physical therapy, baclofen, diazepam, dantrolene

Paroxysmal phenomena carbamazepine, gabapentin, phenytoin

Fatigue Energy conservation, amantidine ,Modafinil ,Dalfampridine (Ampyra)

Depression Anti-depressants

Sexual dysfunction Behavioral therapy, Viagra(sildenafil), Muse(alprostadil)

Urinary dysfunction Tolterodine(Detrol), Oxybutynin(Ditropan), Bethanicol, Botox

PrognosisPrognosis

FavorableFavorable

Low attack rateLow attack rate Long interval to 2nd attackLong interval to 2nd attack Complete recovery from 1st attackComplete recovery from 1st attack Younger age at onsetYounger age at onset Female sexFemale sex Low disability at 2 and 5 yearsLow disability at 2 and 5 years

yearsO

2

4

6

8

201000

Multiple sclerosis- Disease progression (EDSS) -

What’s NewWhat’s New??

The Therapy The Therapy Pyramid in 2013Pyramid in 2013

ReferencesReferences

1. Multiple Sclerosis: Making the Diagnosis 1. Multiple Sclerosis: Making the Diagnosis M. Wallin, MD, MPH M. Wallin, MD, MPH Neurology Service VAMC, Washington, DCNeurology Service VAMC, Washington, DC

2. 2. Wallin M, et al Baker Clin Neurol CD-2003Wallin M, et al Baker Clin Neurol CD-2003

3. 3. David H. Snyder, M.D.: Multiple Sclerosis: Clinical Aspects David H. Snyder, M.D.: Multiple Sclerosis: Clinical Aspects 2005 2005 dsnyder@nynapc.com 212.794.2281212.794.2281

4. Multiple Sclerosis: Janet Toth, MS, RPh Branch Manager, 4. Multiple Sclerosis: Janet Toth, MS, RPh Branch Manager, Specialty Pharmacy July 15, 2006Specialty Pharmacy July 15, 2006

5. Harrison’ principles of internal medicine; MS5. Harrison’ principles of internal medicine; MS

6. Continuum multiple sclerosis. 20116. Continuum multiple sclerosis. 2011

7. 7. Clinical Neurology, Michael J. Aminoff, etal

8. Neurology 8. Neurology

9. NEJM9. NEJM