DEMYELINATING DISEASEDEMYELINATING DISEASEMULTIPLE SCLEROSISMULTIPLE SCLEROSIS

ELLEN MARDER MDELLEN MARDER MD

PHD, 8/4/2005PHD, 8/4/2005

MYELIN MYELIN

• PROTEOLIPID INSULATION OF AXONSPROTEOLIPID INSULATION OF AXONS

• ENHANCES NERVE SIGNAL ENHANCES NERVE SIGNAL TRANSMISSIONTRANSMISSION

• SUPPORTS AXON FUNCTIONSUPPORTS AXON FUNCTION

• OLIGODENDROCYTES FORM CNS OLIGODENDROCYTES FORM CNS MYELINMYELIN

• SCHWANN CELLS FORM PNS MYELINSCHWANN CELLS FORM PNS MYELIN

DEMYELINATIONDEMYELINATION

DESTRUCTION OF MYELIN DESTRUCTION OF MYELIN ETIOLOGIESETIOLOGIES

Infection: Progressive multifocal leuko-Infection: Progressive multifocal leuko- encephalopathy (PML)encephalopathy (PML)Postinfectious:Guillain Barre Syndrome Postinfectious:Guillain Barre Syndrome

(AIDP)(AIDP)Autoimmune: Multiple sclerosis Autoimmune: Multiple sclerosis Genetic/metabolic: AdrenoleukodystrophyGenetic/metabolic: Adrenoleukodystrophy

DEMYELINATING DISEASESDEMYELINATING DISEASES

• CENTRAL NERVOUS SYSTEM: Multiple CENTRAL NERVOUS SYSTEM: Multiple sclerosis, progressive multifocal sclerosis, progressive multifocal leukoencephalopathy, acute leukoencephalopathy, acute disemminated encephalomyelitis, disemminated encephalomyelitis, adrenoleukodystrophyadrenoleukodystrophy

• PERIPHERAL NERVOUS SYSTEM: Guillain PERIPHERAL NERVOUS SYSTEM: Guillain Barre Syndrome(AIDP), chronic Barre Syndrome(AIDP), chronic inflammatory demyelinating inflammatory demyelinating polyneuropathy(CIDP)polyneuropathy(CIDP)

ACUTE V CHRONICACUTE V CHRONIC

• ACUTE or SUBACUTE: ADEM, GBS, ACUTE or SUBACUTE: ADEM, GBS, PMLPML

• CHRONIC: MS, CIDP, ALD, MLDCHRONIC: MS, CIDP, ALD, MLD

RESULTS OF DEMYELINATIONRESULTS OF DEMYELINATION

• CONDUCTION BLOCKCONDUCTION BLOCK

• AXONAL DEATHAXONAL DEATH

MULTIPLE SCLEROSISMULTIPLE SCLEROSIS

• Chronic central nervous system Chronic central nervous system demyelinating diseasedemyelinating disease

• 85% relapsing - remitting85% relapsing - remitting

• Most common cause of nontraumatic Most common cause of nontraumatic disability in young adultsdisability in young adults

• Prevalence in the US – 400, 000Prevalence in the US – 400, 000

• Reduction in life expectancy <5-7 Reduction in life expectancy <5-7 yearsyears

INTERNAL MEDICINE AND INTERNAL MEDICINE AND MULTIPLE SCLEROSIS (MS)MULTIPLE SCLEROSIS (MS)

INVOLVEMENT AT EVERY STAGEINVOLVEMENT AT EVERY STAGE

• Recognition: first clinical episodeRecognition: first clinical episode

• Referral: for diagnosis and treatmentReferral: for diagnosis and treatment

• Return or continuing care: for health Return or continuing care: for health maintainence and treatment of the maintainence and treatment of the complications of chronic disease complications of chronic disease

WHAT IS MS?WHAT IS MS?

• MS is an autoimmune disease caused by MS is an autoimmune disease caused by myelin-reactive T cells in the peripheral myelin-reactive T cells in the peripheral circulation that become activated by a circulation that become activated by a trigger (?viral or bacterial), invade the trigger (?viral or bacterial), invade the central nervous system and cause central nervous system and cause destruction of myelin and axons directly destruction of myelin and axons directly and by initiating the release of various and by initiating the release of various inflammatory mediators. There is often inflammatory mediators. There is often ineffective or no repair of damage.ineffective or no repair of damage.

IMMUNOLOGY-MSIMMUNOLOGY-MS

PATHOPHYSIOLOGY OF MSPATHOPHYSIOLOGY OF MS

• Focal areas of myelin destruction Focal areas of myelin destruction associated with inflammatory associated with inflammatory infiltrates (T-cells, macrophages) infiltrates (T-cells, macrophages) around periventricular venulesaround periventricular venules

• Axonal loss – even in early stages Axonal loss – even in early stages

• Eventual scarring and more axonal Eventual scarring and more axonal lossloss

• Brain atrophyBrain atrophy

MULTIPLE SCLEROSISMULTIPLE SCLEROSISGROSS PATHOLOGYGROSS PATHOLOGY

MRI in MSMRI in MS

EARLY AXONAL INJURYEARLY AXONAL INJURY

Damage to myelin Damage to myelin and axons occurs and axons occurs earlyearly

Trapp BD,et al.NEJMTrapp BD,et al.NEJM

1998;338:278-285.1998;338:278-285.

BRAIN ATROPHY BRAIN ATROPHY

DIAGNOSIS - TRADITIONALDIAGNOSIS - TRADITIONAL

• The demonstration of abnormal physical The demonstration of abnormal physical SIGNS indicating the presence of lesions SIGNS indicating the presence of lesions at TWO SEPARATE sites in the CNS, in an at TWO SEPARATE sites in the CNS, in an individual with a history of at least two individual with a history of at least two episodes of neurological disturbance of episodes of neurological disturbance of the kind seen in MS, and there is no the kind seen in MS, and there is no better explanation for the clinical better explanation for the clinical picture.picture.

• THESE CRITERIA CAN BE FULFILLED BY THESE CRITERIA CAN BE FULFILLED BY CLINICAL ASSESSMENT ALONECLINICAL ASSESSMENT ALONE

LABORATORY ASSISTED LABORATORY ASSISTED DIAGNOSISDIAGNOSIS

MS lesions in various stages can now MS lesions in various stages can now be seen on MRI be seen on MRI

Cerebrospinal fluid analysis can Cerebrospinal fluid analysis can identify immunoglobulin synthesisidentify immunoglobulin synthesis

Evoked potentials can demonstrate Evoked potentials can demonstrate clinically and even MRI silent lesionsclinically and even MRI silent lesions

NEW DIAGNOSTIC CRITERIANEW DIAGNOSTIC CRITERIA(MacDonald Criteria*)(MacDonald Criteria*)

• Allows separation in space criterion to be Allows separation in space criterion to be met by MRI lesions or evoked potential met by MRI lesions or evoked potential abnormalities (e.g. visual evoked abnormalities (e.g. visual evoked response or VER)response or VER)

• Allows new MRI lesions or contrast Allows new MRI lesions or contrast enhancing lesions to substitute for a enhancing lesions to substitute for a second physical sign or clinical attacksecond physical sign or clinical attack

McDonald Ann Neurol 2001;50:121McDonald Ann Neurol 2001;50:121

DIAGNOSIS – HOW EARLY?DIAGNOSIS – HOW EARLY?CHAMPS STUDY*CHAMPS STUDY*

• First isolated, well defined neurologic First isolated, well defined neurologic event: optic nerve,spinal cord,brain stem event: optic nerve,spinal cord,brain stem or cerebellum, clinically documentedor cerebellum, clinically documented

• At least 2 (>3mm) MRI lesions At least 2 (>3mm) MRI lesions characteristic of MScharacteristic of MS

• 50% chance of another attack in 3 years50% chance of another attack in 3 years• 35% chance of second attack if treated 35% chance of second attack if treated

with weekly interferon beta-1awith weekly interferon beta-1a Jacobs NEJM 2000; 343:898Jacobs NEJM 2000; 343:898

MRI - DISEASE SURROGATE?MRI - DISEASE SURROGATE?

• Easily accomplishedEasily accomplished

• ObjectiveObjective

• Readily measurable – volume and Readily measurable – volume and number of lesions, enhancement of number of lesions, enhancement of lesions, brain atrophylesions, brain atrophy

• Weak correlation with disabilityWeak correlation with disability

IS IT MS?IS IT MS?

• Women 2x> menWomen 2x> men

• Peak incidence 3Peak incidence 3rdrd and 4 and 4thth decade decade

• Highest incidence in CaucasiansHighest incidence in Caucasians

• Increased incidence with distance from equatorIncreased incidence with distance from equator

• Family history: 50% concordance in identical Family history: 50% concordance in identical twins and 5% increased incidence among first twins and 5% increased incidence among first degree relativesdegree relatives

MS: PRESENTATIONMS: PRESENTATION

• Visual: loss, dim, blurred (49%)Visual: loss, dim, blurred (49%)

• Oculomotor: impaired eye movements, Oculomotor: impaired eye movements, nystagmus(42%)nystagmus(42%)

• Paresis:unilateral,mono-,paraparesis(42%)Paresis:unilateral,mono-,paraparesis(42%)

• Incoordination:extremity,gait,tremor(23%)Incoordination:extremity,gait,tremor(23%)

• GU/bowel: incontinence, retention(10%)GU/bowel: incontinence, retention(10%)

• Cerebral: cognitive impairment(4%)Cerebral: cognitive impairment(4%)

CLINICAL COURSECLINICAL COURSERELAPSESRELAPSES

• 58% Have one relapse in first 2 years58% Have one relapse in first 2 years

• 21% Have two relapses “21% Have two relapses “

• 9% Have 3 or more attacks9% Have 3 or more attacks

• 80% Have full recovery80% Have full recovery

• There is a correlation between relapses There is a correlation between relapses in the first two years and the time to in the first two years and the time to significant disability*significant disability*

Weinshenker Brain 1989;112:1419Weinshenker Brain 1989;112:1419

CLINICAL COURSECLINICAL COURSE

• 10-15% “Benign” disease – patients fully 10-15% “Benign” disease – patients fully functional at 15 years after disease onsetfunctional at 15 years after disease onset

• Less than 10% have “malignant” disease – Less than 10% have “malignant” disease – rapid progression to significant disability or rapid progression to significant disability or death in a short timedeath in a short time

• Over 50% accumulate neurologic deficits Over 50% accumulate neurologic deficits over time, that affect gait, coordination, over time, that affect gait, coordination, vision, and cognitive function. vision, and cognitive function.

• Once accumulation starts, time to significant Once accumulation starts, time to significant disability is predictable – 4-6 years*disability is predictable – 4-6 years*

Confavreaux NEJM Confavreaux NEJM 2000;343:14302000;343:1430

CLINICAL COURSE CLINICAL COURSE CHRONIC DEFICITS*CHRONIC DEFICITS*

• 100% Develop problems with vision100% Develop problems with vision• 88% Develop problems with weakness – 88% Develop problems with weakness –

usually paraparesisusually paraparesis• 82% Develop some form of incoordination82% Develop some form of incoordination• 63% Have problems with bladder and/or 63% Have problems with bladder and/or

bowelsbowels• 39% (conservative estimate) have 39% (conservative estimate) have

cognitive impairmentcognitive impairment Whitaker Multiple Sclerosis 1997: 3-19Whitaker Multiple Sclerosis 1997: 3-19

TREATMENTTREATMENT

• EXACERBATIONSEXACERBATIONS

• RELAPSING AND REMITTING DISEASERELAPSING AND REMITTING DISEASE

• REFRACTORY RELAPSING REMITTING REFRACTORY RELAPSING REMITTING DISEASEDISEASE

• CHRONIC PROGRESSIVE DISEASECHRONIC PROGRESSIVE DISEASE

TREATMENT OF TREATMENT OF EXACERBATIONSEXACERBATIONS

• Methylprednisolone 500-1000mg qd x 5 +/- oral Methylprednisolone 500-1000mg qd x 5 +/- oral taper taper (Durelli Neurology 1986;36: 238)(Durelli Neurology 1986;36: 238)

• Oral high dose steroidsOral high dose steroids(Morrow Neurology2004;63:1079)(Morrow Neurology2004;63:1079)

• Plasma exchangePlasma exchange(WeinshenkerAnn Neurol 1999;46:878)(WeinshenkerAnn Neurol 1999;46:878)

• Intravenous immunoglobulin Intravenous immunoglobulin (AchironNeurology 1998;50:398)(AchironNeurology 1998;50:398)

DISEASE MODULATING AGENTSDISEASE MODULATING AGENTS

• All demonstrate reduction of clinical All demonstrate reduction of clinical relapses (30%) and new MRI lesions in 3 relapses (30%) and new MRI lesions in 3 year double blind, placebo-controlled year double blind, placebo-controlled studies. They are FDA approvedstudies. They are FDA approved

• INTERFERONSINTERFERONSBeta interferon-1a: Avonex, Beta interferon-1a: Avonex,

RebifRebif Beta interferon-1b: BetaseronBeta interferon-1b: Betaseron• GLATIRAMER ACETATE: CopaxoneGLATIRAMER ACETATE: Copaxone Galetta.Archives of Int Med. 2002;162:2161Galetta.Archives of Int Med. 2002;162:2161

INTERFERONSINTERFERONS

• Part of the innate immune systemPart of the innate immune system

• Up-regulates immunosuppressionUp-regulates immunosuppression

• Blocks entry of activated T-cells into Blocks entry of activated T-cells into the CNSthe CNS

INTERFERONSINTERFERONS

• Injected IM weekly, SC tiw or qodInjected IM weekly, SC tiw or qod

• Injections side reactionsInjections side reactions

• Common side effects: flu-like Common side effects: flu-like syndrome with headache, fever, syndrome with headache, fever, myalgiasmyalgias

• Hepatic enzyme elevations, bone Hepatic enzyme elevations, bone marrow suppresionmarrow suppresion

• Antibody formation affects efficacyAntibody formation affects efficacy

GLATIRAMER ACETATEGLATIRAMER ACETATE(COPAXONE)(COPAXONE)

• Random copolymer of amino acids Random copolymer of amino acids alanine, lysine, glutamic acid, alanine, lysine, glutamic acid, tyrosinetyrosine

• Interferes with antigen presentation Interferes with antigen presentation and T-cell activationand T-cell activation

• Drives T-cell population to Th2 type - Drives T-cell population to Th2 type - suppressionsuppression

GLATIRAMER ACETATEGLATIRAMER ACETATE

• Daily subcutaneous injectionDaily subcutaneous injection

• Injection site reactions: erythema, Injection site reactions: erythema, lipodystrophylipodystrophy

• Idiosyncratic reactions: chest Idiosyncratic reactions: chest tightness, shortness of breath, tightness, shortness of breath, usually single episodeusually single episode

REFRACTORY R-R MSREFRACTORY R-R MSADD-ON THERAPYADD-ON THERAPY

• High dose methylprednisolone pulse High dose methylprednisolone pulse therapytherapy

• IVIGIVIG

• Plasma exchangePlasma exchange

• ImmunosuppressivesImmunosuppressives-mitoxantrone-mitoxantrone

-cyclophosphamide-cyclophosphamide

-azathioprine-azathioprine

-methotrexate-methotrexate

MITOXANTRONE MITOXANTRONE (NOVANTRONE*)(NOVANTRONE*)

• FDA approvedFDA approved

• Inhibits DNA synthesisInhibits DNA synthesis

• Infusions well toleratedInfusions well tolerated

• Side effects: cardiomyopathy, leukemiaSide effects: cardiomyopathy, leukemia

• Infusions every 3 months 12mg/m2; total Infusions every 3 months 12mg/m2; total 82 mg82 mg

Millefiorini J Neuro 1997;244:153lMillefiorini J Neuro 1997;244:153l

CONCLUSIONCONCLUSION

• MS is a chronic immunologic disease MS is a chronic immunologic disease caused by peripheral T-cell activation caused by peripheral T-cell activation in a susceptible hostin a susceptible host

• The clinical course is variable but it The clinical course is variable but it results in significant disability for the results in significant disability for the majoritymajority

• MS patients should be treated at the MS patients should be treated at the time of diagnosis because those at time of diagnosis because those at risk cannot be identifiedrisk cannot be identified

CONCLUSIONCONCLUSION

• MRI is now used as a surrogate for MRI is now used as a surrogate for disease activity for treatment and disease activity for treatment and drug testingdrug testing

• There is no long term data on the There is no long term data on the value of MRI as a surrogate markervalue of MRI as a surrogate marker

• Suppression of clinical and MRI Suppression of clinical and MRI evidence of disease activity are now evidence of disease activity are now treatment goalstreatment goals

CONCLUSIONCONCLUSION

There is no evidence that suppression There is no evidence that suppression of disease activity clinically or on MRI of disease activity clinically or on MRI affects long-term outcome but affects long-term outcome but despite that there is a general feeling despite that there is a general feeling that early treatment will be beneficial that early treatment will be beneficial in the long run.in the long run.