DEMYELINATING DISEASE MULTIPLE SCLEROSIS ELLEN MARDER MD PHD

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DEMYELINATING DISEASE MULTIPLE SCLEROSIS ELLEN MARDER MD PHD, 8/4/2005

DEMYELINATING DISEASE MULTIPLE SCLEROSIS ELLEN MARDER MD PHD, 8/4/2005

MYELIN • PROTEOLIPID INSULATION OF AXONS • ENHANCES NERVE SIGNAL TRANSMISSION • SUPPORTS AXON

MYELIN • PROTEOLIPID INSULATION OF AXONS • ENHANCES NERVE SIGNAL TRANSMISSION • SUPPORTS AXON FUNCTION • OLIGODENDROCYTES FORM CNS MYELIN • SCHWANN CELLS FORM PNS MYELIN

DEMYELINATION DESTRUCTION OF MYELIN ETIOLOGIES Infection: Progressive multifocal leukoencephalopathy (PML) Postinfectious: Guillain Barre Syndrome

DEMYELINATION DESTRUCTION OF MYELIN ETIOLOGIES Infection: Progressive multifocal leukoencephalopathy (PML) Postinfectious: Guillain Barre Syndrome (AIDP) Autoimmune: Multiple sclerosis Genetic/metabolic: Adrenoleukodystrophy

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

DEMYELINATING DISEASES • CENTRAL NERVOUS SYSTEM: Multiple sclerosis, progressive multifocal leukoencephalopathy, acute disemminated encephalomyelitis, adrenoleukodystrophy • PERIPHERAL NERVOUS SYSTEM: Guillain Barre Syndrome(AIDP), chronic inflammatory demyelinating polyneuropathy(CIDP)

ACUTE V CHRONIC • ACUTE or SUBACUTE: ADEM, GBS, PML • CHRONIC: MS, CIDP,

ACUTE V CHRONIC • ACUTE or SUBACUTE: ADEM, GBS, PML • CHRONIC: MS, CIDP, ALD, MLD

RESULTS OF DEMYELINATION • CONDUCTION BLOCK • AXONAL DEATH

RESULTS OF DEMYELINATION • CONDUCTION BLOCK • AXONAL DEATH

MULTIPLE SCLEROSIS • Chronic central nervous system demyelinating disease • 85% relapsing - remitting

MULTIPLE SCLEROSIS • Chronic central nervous system demyelinating disease • 85% relapsing - remitting • Most common cause of nontraumatic disability in young adults • Prevalence in the US – 400, 000 • Reduction in life expectancy <5 -7 years

INTERNAL MEDICINE AND MULTIPLE SCLEROSIS (MS) INVOLVEMENT AT EVERY STAGE • Recognition: first clinical

INTERNAL MEDICINE AND MULTIPLE SCLEROSIS (MS) INVOLVEMENT AT EVERY STAGE • Recognition: first clinical episode • Referral: for diagnosis and treatment • Return or continuing care: for health maintainence and treatment of the complications of chronic disease

WHAT IS MS? • MS is an autoimmune disease caused by myelin-reactive T cells

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

IMMUNOLOGY-MS

IMMUNOLOGY-MS

PATHOPHYSIOLOGY OF MS • Focal areas of myelin destruction associated with inflammatory infiltrates (Tcells,

PATHOPHYSIOLOGY OF MS • Focal areas of myelin destruction associated with inflammatory infiltrates (Tcells, macrophages) around periventricular venules • Axonal loss – even in early stages • Eventual scarring and more axonal loss • Brain atrophy

MULTIPLE SCLEROSIS GROSS PATHOLOGY

MULTIPLE SCLEROSIS GROSS PATHOLOGY

MRI in MS

MRI in MS

EARLY AXONAL INJURY Damage to myelin and axons occurs early Trapp BD, et al.

EARLY AXONAL INJURY Damage to myelin and axons occurs early Trapp BD, et al. NEJM 1998; 338: 278 -285.

BRAIN ATROPHY

BRAIN ATROPHY

DIAGNOSIS - TRADITIONAL • The demonstration of abnormal physical SIGNS indicating the presence of

DIAGNOSIS - TRADITIONAL • The demonstration of abnormal physical SIGNS indicating the presence of lesions at TWO SEPARATE sites in the CNS, in an individual with a history of at least two episodes of neurological disturbance of the kind seen in MS, and there is no better explanation for the clinical picture. • THESE CRITERIA CAN BE FULFILLED BY CLINICAL ASSESSMENT ALONE

LABORATORY ASSISTED DIAGNOSIS MS lesions in various stages can now be seen on MRI

LABORATORY ASSISTED DIAGNOSIS MS lesions in various stages can now be seen on MRI Cerebrospinal fluid analysis can identify immunoglobulin synthesis Evoked potentials can demonstrate clinically and even MRI silent lesions

NEW DIAGNOSTIC CRITERIA (Mac. Donald Criteria*) • Allows separation in space criterion to be

NEW DIAGNOSTIC CRITERIA (Mac. Donald Criteria*) • Allows separation in space criterion to be met by MRI lesions or evoked potential abnormalities (e. g. visual evoked response or VER) • Allows new MRI lesions or contrast enhancing lesions to substitute for a second physical sign or clinical attack Mc. Donald Ann Neurol 2001; 50: 121

DIAGNOSIS – HOW EARLY? CHAMPS STUDY* • First isolated, well defined neurologic event: optic

DIAGNOSIS – HOW EARLY? CHAMPS STUDY* • First isolated, well defined neurologic event: optic nerve, spinal cord, brain stem or cerebellum, clinically documented • At least 2 (>3 mm) MRI lesions characteristic of MS • 50% chance of another attack in 3 years • 35% chance of second attack if treated with weekly interferon beta-1 a Jacobs NEJM 2000; 343: 898

MRI - DISEASE SURROGATE? • Easily accomplished • Objective • Readily measurable – volume

MRI - DISEASE SURROGATE? • Easily accomplished • Objective • Readily measurable – volume and number of lesions, enhancement of lesions, brain atrophy • Weak correlation with disability

IS IT MS? • Women 2 x> men • Peak incidence 3 rd and

IS IT MS? • Women 2 x> men • Peak incidence 3 rd and 4 th decade • Highest incidence in Caucasians • Increased incidence with distance from equator • Family history: 50% concordance in identical twins and 5% increased incidence among first degree relatives

MS: PRESENTATION • Visual: loss, dim, blurred (49%) • Oculomotor: impaired eye movements, nystagmus(42%)

MS: PRESENTATION • Visual: loss, dim, blurred (49%) • Oculomotor: impaired eye movements, nystagmus(42%) • Paresis: unilateral, mono-, paraparesis(42%) • Incoordination: extremity, gait, tremor(23%) • GU/bowel: incontinence, retention(10%) • Cerebral: cognitive impairment(4%)

CLINICAL COURSE RELAPSES • 58% Have one relapse in first 2 years • 21%

CLINICAL COURSE RELAPSES • 58% Have one relapse in first 2 years • 21% Have two relapses “ • 9% Have 3 or more attacks • 80% Have full recovery • There is a correlation between relapses in the first two years and the time to significant disability* Weinshenker Brain 1989; 112: 1419

CLINICAL COURSE • 10 -15% “Benign” disease – patients fully • • • functional

CLINICAL COURSE • 10 -15% “Benign” disease – patients fully • • • functional at 15 years after disease onset Less than 10% have “malignant” disease – rapid progression to significant disability or death in a short time Over 50% accumulate neurologic deficits over time, that affect gait, coordination, vision, and cognitive function. Once accumulation starts, time to significant disability is predictable – 4 -6 years* Confavreaux NEJM 2000; 343: 1430

CLINICAL COURSE CHRONIC DEFICITS* • 100% Develop problems with vision • 88% Develop problems

CLINICAL COURSE CHRONIC DEFICITS* • 100% Develop problems with vision • 88% Develop problems with weakness – usually paraparesis • 82% Develop some form of incoordination • 63% Have problems with bladder and/or bowels • 39% (conservative estimate) have cognitive impairment Whitaker Multiple Sclerosis 1997: 3 -19

TREATMENT • EXACERBATIONS • RELAPSING AND REMITTING DISEASE • REFRACTORY RELAPSING REMITTING DISEASE •

TREATMENT • EXACERBATIONS • RELAPSING AND REMITTING DISEASE • REFRACTORY RELAPSING REMITTING DISEASE • CHRONIC PROGRESSIVE DISEASE

TREATMENT OF EXACERBATIONS • Methylprednisolone 500 -1000 mg qd x 5 +/- oral taper

TREATMENT OF EXACERBATIONS • Methylprednisolone 500 -1000 mg qd x 5 +/- oral taper (Durelli Neurology 1986; 36: 238) • Oral high dose steroids(Morrow Neurology 2004; 63: 1079) • Plasma exchange(Weinshenker. Ann Neurol 1999; 46: 878) • Intravenous immunoglobulin (Achiron. Neurology 1998; 50: 398)

DISEASE MODULATING AGENTS • All demonstrate reduction of clinical relapses • • (30%) and

DISEASE MODULATING AGENTS • All demonstrate reduction of clinical relapses • • (30%) and new MRI lesions in 3 year double blind, placebo-controlled studies. They are FDA approved INTERFERONS Beta interferon-1 a: Avonex, Rebif Beta interferon-1 b: Betaseron GLATIRAMER ACETATE: Copaxone Galetta. Archives of Int Med. 2002; 162: 2161

INTERFERONS • Part of the innate immune system • Up-regulates immunosuppression • Blocks entry

INTERFERONS • Part of the innate immune system • Up-regulates immunosuppression • Blocks entry of activated T-cells into the CNS

INTERFERONS • Injected IM weekly, SC tiw or qod • Injections side reactions •

INTERFERONS • Injected IM weekly, SC tiw or qod • Injections side reactions • Common side effects: flu-like syndrome with headache, fever, myalgias • Hepatic enzyme elevations, bone marrow suppresion • Antibody formation affects efficacy

GLATIRAMER ACETATE (COPAXONE) • Random copolymer of amino acids alanine, lysine, glutamic acid, tyrosine

GLATIRAMER ACETATE (COPAXONE) • Random copolymer of amino acids alanine, lysine, glutamic acid, tyrosine • Interferes with antigen presentation and T -cell activation • Drives T-cell population to Th 2 type suppression

GLATIRAMER ACETATE • Daily subcutaneous injection • Injection site reactions: erythema, lipodystrophy • Idiosyncratic

GLATIRAMER ACETATE • Daily subcutaneous injection • Injection site reactions: erythema, lipodystrophy • Idiosyncratic reactions: chest tightness, shortness of breath, usually single episode

REFRACTORY R-R MS ADD-ON THERAPY • High dose methylprednisolone pulse therapy • IVIG •

REFRACTORY R-R MS ADD-ON THERAPY • High dose methylprednisolone pulse therapy • IVIG • Plasma exchange • Immunosuppressives -mitoxantrone -cyclophosphamide -azathioprine -methotrexate

MITOXANTRONE (NOVANTRONE*) • FDA approved • Inhibits DNA synthesis • Infusions well tolerated •

MITOXANTRONE (NOVANTRONE*) • FDA approved • Inhibits DNA synthesis • Infusions well tolerated • Side effects: cardiomyopathy, leukemia • Infusions every 3 months 12 mg/m 2; total 82 mg Millefiorini J Neuro 1997; 244: 153 l

CONCLUSION • MS is a chronic immunologic disease caused by peripheral T-cell activation in

CONCLUSION • MS is a chronic immunologic disease caused by peripheral T-cell activation in a susceptible host • The clinical course is variable but it results in significant disability for the majority • MS patients should be treated at the time of diagnosis because those at risk cannot be identified

CONCLUSION • MRI is now used as a surrogate for disease activity for treatment

CONCLUSION • MRI is now used as a surrogate for disease activity for treatment and drug testing • There is no long term data on the value of MRI as a surrogate marker • Suppression of clinical and MRI evidence of disease activity are now treatment goals

CONCLUSION There is no evidence that suppression of disease activity clinically or on MRI

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