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Transcript
DEMYELINATING DISEASE
MULTIPLE SCLEROSIS
ELLEN MARDER MD
PHD, 8/4/2005
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
(AIDP)
Autoimmune: Multiple sclerosis
Genetic/metabolic: Adrenoleukodystrophy
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, ALD, MLD
RESULTS OF DEMYELINATION
• CONDUCTION BLOCK
• AXONAL DEATH
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 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 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 (Tcells, macrophages) around periventricular
venules
• Axonal loss – even in early stages
• Eventual scarring and more axonal loss
• 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;338:278-285.
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.
• 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 new MRI lesions or contrast
enhancing lesions to substitute for a
second physical sign or clinical attack
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
• At least 2 (>3mm) 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;
343:898
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 2x> 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
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% 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 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 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
• CHRONIC PROGRESSIVE DISEASE
TREATMENT OF EXACERBATIONS
• Methylprednisolone 500-1000mg qd x 5 +/- oral
taper
(Durelli Neurology 1986;36: 238)
• Oral high dose steroids(Morrow Neurology2004;63:1079)
• Plasma exchange(WeinshenkerAnn Neurol 1999;46:878)
• 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
INTERFERONS
Beta interferon-1a: Avonex, Rebif
Beta interferon-1b: Betaseron
GLATIRAMER ACETATE: Copaxone
Galetta.Archives of Int Med. 2002;162:2161
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
• 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
• Interferes with antigen presentation and
T-cell activation
• Drives T-cell population to Th2 type suppression
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
• Plasma exchange
• Immunosuppressives
-mitoxantrone
-cyclophosphamide
-azathioprine
-methotrexate
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 1997;244:153l
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 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 affects
long-term outcome but despite that there
is a general feeling that early treatment
will be beneficial in the long run.