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

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

DEMYELINATION DESTRUCTION OF MYELIN ETIOLOGIES Infection: Progressive multifocal leuko- encephalopathy (PML) encephalopathy (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, adrenoleukodystrophy CENTRAL NERVOUS SYSTEM: Multiple sclerosis, progressive multifocal leukoencephalopathy, acute disemminated encephalomyelitis, adrenoleukodystrophy PERIPHERAL NERVOUS SYSTEM: Guillain Barre Syndrome(AIDP), chronic inflammatory demyelinating polyneuropathy(CIDP) PERIPHERAL NERVOUS SYSTEM: Guillain Barre Syndrome(AIDP), chronic inflammatory demyelinating polyneuropathy(CIDP)

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

RESULTS OF DEMYELINATION CONDUCTION BLOCK CONDUCTION BLOCK AXONAL DEATH AXONAL DEATH

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

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

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

MULTIPLE SCLEROSIS GROSS PATHOLOGY

MRI in MS

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

BRAIN ATROPHY

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. 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 THESE CRITERIA CAN BE FULFILLED BY CLINICAL ASSESSMENT ALONE

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

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

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

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

MS: PRESENTATION Visual: loss, dim, blurred (49%) Visual: loss, dim, blurred (49%) Oculomotor: impaired eye movements, nystagmus(42%) Oculomotor: impaired eye movements, 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 COURSE RELAPSES 58% Have one relapse in first 2 years 58% Have one relapse in first 2 years 21% Have two relapses “ 21% Have two relapses “ 9% Have 3 or more attacks 9% Have 3 or more attacks 80% Have full recovery 80% Have full recovery There is a correlation between relapses in the first two years and the time to significant disability* There is a correlation between relapses in the first two years and the time to significant disability* Weinshenker Brain 1989;112:1419 Weinshenker Brain 1989;112:1419

CLINICAL COURSE 10-15% “Benign” disease – patients fully functional at 15 years after disease onset 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 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. 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* Once accumulation starts, time to significant disability is predictable – 4-6 years* Confavreaux NEJM 2000;343:1430 Confavreaux NEJM 2000;343:1430

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

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

TREATMENT OF EXACERBATIONS Methylprednisolone mg qd x 5 +/- oral taper (Durelli Neurology 1986;36: 238) Methylprednisolone mg qd x 5 +/- oral taper (Durelli Neurology 1986;36: 238) Oral high dose steroids (Morrow Neurology2004;63:1079) Oral high dose steroids (Morrow Neurology2004;63:1079) Plasma exchange (WeinshenkerAnn Neurol 1999;46:878) Plasma exchange (WeinshenkerAnn Neurol 1999;46:878) Intravenous immunoglobulin (AchironNeurology 1998;50:398) Intravenous immunoglobulin (AchironNeurology 1998;50:398)

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

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

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

GLATIRAMER ACETATE (COPAXONE) Random copolymer of amino acids alanine, lysine, glutamic acid, tyrosine Random copolymer of amino acids alanine, lysine, glutamic acid, tyrosine Interferes with antigen presentation and T-cell activation Interferes with antigen presentation and T-cell activation Drives T-cell population to Th2 type - suppression Drives T-cell population to Th2 type - suppression

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

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

MITOXANTRONE (NOVANTRONE*) FDA approved FDA approved Inhibits DNA synthesis Inhibits DNA synthesis Infusions well tolerated Infusions well tolerated Side effects: cardiomyopathy, leukemia Side effects: cardiomyopathy, leukemia Infusions every 3 months 12mg/m2; total 82 mg Infusions every 3 months 12mg/m2; total 82 mg Millefiorini J Neuro 1997;244:153l Millefiorini J Neuro 1997;244:153l

CONCLUSION MS is a chronic immunologic disease caused by peripheral T-cell activation in a susceptible host 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 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 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 and drug testing 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 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 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 affects long-term outcome but despite that there is a general feeling that early treatment will be beneficial in the long run. 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.