DEMYELINATING DISEASE MULTIPLE SCLEROSIS

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DEMYELINATING DISEASEMULTIPLE SCLEROSIS

• ELLEN MARDER MD
• PHD, 8/4/2005

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MYELIN

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

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DEMYELINATION

• DESTRUCTION OF MYELIN
• ETIOLOGIES
• Infection Progressive multifocal leuko-
• encephalopathy (PML)
• PostinfectiousGuillain Barre Syndrome (AIDP)
• Autoimmune Multiple sclerosis
• Genetic/metabolic Adrenoleukodystrophy

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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)

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ACUTE V CHRONIC

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

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RESULTS OF DEMYELINATION

• CONDUCTION BLOCK
• AXONAL DEATH

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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 lt5-7 years

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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

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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.

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IMMUNOLOGY-MS
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PATHOPHYSIOLOGY OF MS

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

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MULTIPLE SCLEROSISGROSS PATHOLOGY
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MRI in MS
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EARLY AXONAL INJURY
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BRAIN ATROPHY
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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

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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

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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 new MRI lesions or contrast enhancing
  lesions to substitute for a second physical sign
  or clinical attack
• McDonald Ann
  Neurol 200150121

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DIAGNOSIS HOW EARLY?CHAMPS STUDY

• First isolated, well defined neurologic event
  optic nerve,spinal cord,brain stem or cerebellum,
  clinically documented
• At least 2 (gt3mm) MRI lesions characteristic of
  MS
• 50 chance of another attack in 3 years
• 35 chance of second attack if treated with
  weekly interferon beta-1a
• Jacobs
  NEJM 2000 343898

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MRI - DISEASE SURROGATE?

• Easily accomplished
• Objective
• Readily measurable volume and number of
  lesions, enhancement of lesions, brain atrophy
• Weak correlation with disability

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IS IT MS?

• Women 2xgt men
• Peak incidence 3rd and 4th 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

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MS PRESENTATION

• Visual loss, dim, blurred (49)
• Oculomotor impaired eye movements,
  nystagmus(42)
• Paresisunilateral,mono-,paraparesis(42)
• Incoordinationextremity,gait,tremor(23)
• GU/bowel incontinence, retention(10)
• Cerebral cognitive impairment(4)

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CLINICAL COURSERELAPSES

• 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 19891121419

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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 20003431430

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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

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TREATMENT

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

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TREATMENT OF EXACERBATIONS

• Methylprednisolone 500-1000mg qd x 5 /- oral
  taper (Durelli Neurology 198636 238)
• Oral high dose steroids(Morrow Neurology20046310
  79)
• Plasma exchange(WeinshenkerAnn Neurol
  199946878)
• Intravenous immunoglobulin (AchironNeurology
  199850398)

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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-1a Avonex, Rebif
• Beta interferon-1b Betaseron
• GLATIRAMER ACETATE Copaxone
• 
  Galetta.Archives of Int Med. 20021622161

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INTERFERONS

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

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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

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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 Th2 type -
  suppression

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GLATIRAMER ACETATE

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

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REFRACTORY R-R MSADD-ON THERAPY

• High dose methylprednisolone pulse therapy
• IVIG
• Plasma exchange
• Immunosuppressives
• -mitoxantrone
• -cyclophosphamide
• -azathioprine
• -methotrexate

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MITOXANTRONE (NOVANTRONE)

• FDA approved
• Inhibits DNA synthesis
• Infusions well tolerated
• Side effects cardiomyopathy, leukemia
• Infusions every 3 months 12mg/m2 total 82 mg
• Millefiorini J
  Neuro 1997244153l

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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

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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

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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.