Download MS Overview

“Multiple Sclerosis Overview”
January 17, 2008
Khurram Bashir, MD, MPH
Associate Professor of Neurology
Director, Multiple Sclerosis Center
Optic Neuritis
MS History – Saint Lidwina (1421)
1794-1848 » Sir Augustus d'Esté
Grand-son of George III
The Regent did not
approve of the marriage
of his son, Prince
Augustus Frederick, to
Lady Augusta Murray,
and had the marriage
annulled
Although later given a
knighthood, Augustus
was made illegitimate
1868 » First detailed clinicopathological
description of MS
Charcot became the Professor of Neurology at the
University of Paris and is often referred to as the
"Father of Modern Neurology".
Multiple Sclerosis
Immune-mediated, demyelinating
disease of the central nervous system
white matter characterized by
neurologic dysfunction separated in
time and space
Multiple Sclerosis
Immune-mediated and
neurodegenerative, demyelinating with
axonal loss disease of the central
nervous system white and gray matter
characterized by neurologic dysfunction
separated in time and space
CHALLENGES FOR THE
HEALTHCARE PROVIDER
• Difficult diagnosis
• No single specific test
• No two cases of MS are alike
• No proven cause
• No known cure
• MS is unpredictable
• Partially effect treatments
Epidemiology of Multiple Sclerosis
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Age:
F:M ratio:
Race:
Incidence
• Worldwide
• US
Clusters/”Epidemics”:
Effect of migration:
20-40 yrs (mean 30 yrs)
1.5-2.0 : 1
W > B > Other racial groups
2.5 million
365,000 – 400,000
Faroe Islands, Iceland
Exposure at < 15 yrs of
age is important
Epidemiology of Multiple Sclerosis

Geographical
Association:
Increases with increasing
and decreasing latitude
Epidemiology of Multiple Sclerosis

Duration of disease
> 30 years

Severely disabled
30% (w/o Rx)

Unemployed
70%

Average care cost
$30,000/year

US economy cost
$9.6 billion/year
(1998 $)
(1998 $)
Pathophysiology of Multiple Sclerosis
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Genetic Factors
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Polygenic
Monozygotic twin concordance rate of ~2530% compared to dizygotic twin concordance
rate of ~4-5%
MS is more common in Caucasians
Minor influence of HLA (on chromosome 6) in
familial cases and Caucasian patients with RR
MS
Several areas of interest - 17q11, 6p21, 5q11,
17q22, 16p13, 3p21, 12p13, and 6qtel.
Pathophysiology of Multiple Sclerosis
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Environmental Factors
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Infectious ?
Toxins ?
Unknown
No increased risk of MS in adoptees
No increased risk in spouses
Pathophysiology of Multiple Sclerosis
Genetic predisposition
Infectious agent?
Abnormal immunologic response
Environmental factors
MS
Noseworthy J., Progress in determining the causes and treatment of multiple sclerosis.
Nature. June 1999: A40-A47.
Activation of Immune System in MS
Inflammation and the CNS in MS
Axonal Damage and Lesion Formation
in MS
Multiple Sclerosis – Gross Pathology
Multiple Sclerosis Pathology
Inflammation
Demyelination
Axonal Loss
Remyelinating Oligodendrocyte
Multiple Sclerosis : Severe Myelin,
Axonal, and Neuronal Loss
Normal White Matter
Plaque
Lymphocytes
Neurons
Myelin
Axons
Astrocytes
Adapted with kind permission from Dr. W. Brück.
Macrophages
Gray Matter Lesion Patterns
Patients often experience neurologic symptoms
that do not correlate with white matter pathology
Affects subcortical and
white matter and cortex
Restricted to the
cortex, small in size,
circular intracortical
lesions, often centered
on vessels
Peterson JW et al. Neurol Clin. 2005;23:107-129.
Extend from the pial
surface into the cortex,
often involve multiple gyri
Symptoms at Onset of MS
Symptom
Percentage of
Patients
Sensory symptoms in arms/legs
33
Unilateral vision loss
16
Polysymptomatic onset
14
Slowly progressive motor deficit
9
Acute motor deficit
5
Diplopia
Other
7
16
Paty. In: Multiple sclerosis, diagnosis, medical management, and rehabilitation. 2000.
MS: Common Symptoms
Symptom
Bladder symptoms
Fatigue
Prevalence, %
97.1
89.8
Spasticity
70.2
Sexual dysfunction
Pain
Cognitive dysfunction
Bowel dysfunction
Depression
64.2
61.9
61.9
47.8
41.6
Goodin et al. Mult Scler. 1999;5:78-88.
Forms of MS
Relapses
Time
Relapsingremitting
55%
Increasing disability
Increasing disability
Relapses with Disability
Time
Increasing disability
Increasing Disability
Secondary
progressive
30%
Some of the available therapies can slow disability progression
in relapsing forms of MS.
Disability Progression
No Distinct Relapses
Time
Primary
progressive
5%-10%
SPECTRUM OF MS DISEASE ACTIVITY
Genetic Susceptibility
Environmental Factors
Immune System Activation in the CNS
Demyelination ± Axonal Loss
Multiple Sclerosis
Benign RR SP Transitional PP PR Malignant
Minimal Disability
Severe Disability
Laboratory and Imaging Studies
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MRI
Brain
Spinal cord
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CSF
Evoked Potential Studies
Visual
Brainstem auditory
Somatosensory
Multiple Sclerosis: Cranial MRI
T1
“black hole”
Gd
enhancement
Brain atrophy
T2 lesion
Spinal cord lesion
Multiple Sclerosis : Serial MRI Findings
Visual Evoked Potentials
Common CSF Abnormalities
MS Profile
MBP
IgG Index
IgG Synthesis Rate
OCB
Elevated
Elevated
Elevated
Present
Revised MacDonald Diagnostic Criteria
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Relapse Definition
• Neurological disturbance consistent with MS
• Subjective report or objective observation
• 24 hour duration, minimum
• Excludes psudorelapses, single paroxysmal
episodes
• At least 30 days between onset of event 1
and event 2
Revised MacDonald Diagnostic Criteria
Clinical Presentation
1

≥ 2 relapses;
 Objective clinical evidence
of ≥ 2 lesions
2
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3
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≥ 2 relapses
 Objective clinical evidence
of 1 lesions
1 relaspe
 Objective clinical evidence
of ≥ 2 lesions
Additional data needed for MS diagnosis

None
Dissemination in space, demonstrated
by:
- MRI, OR
- ≥ 2 MRI lesions + positive CSF, OR
- 2nd clinical relapse disseminated in
space
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Dissemination in time, demonstrated
by:
- MRI, OR
- 2nd clinical relapse
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Revised MacDonald Diagnostic Criteria
Clinical Presentation
4
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1 relapse
 Objective clinical evidence of 1
lesion
5
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Insidious neurological
progression suggestive of MS
Additional data needed for MS diagnosis
Dissemination in space, demonstrated by:
- MRI, OR
- ≥ 2 MRI lesions + positive CSF,
AND
 Dissemination in time, demonstrated by:
- MRI, OR
- 2nd clinical relapse

1 year of disease progression
(retrospectively or prospectively determined)
AND
 2 out of 3 of the following:
- Positive bran MRI (9 T2 lesions OR ≥ 4 T2
MRI lesions and positive VEP
- Positive spinal cord MRI (≥ 2 T2 lesions)
- Positive CSF
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Revised MacDonald Diagnostic Criteria
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Caveat
• No Better Explanation
• Need to rule out other potential etiologies that
might explain clinical or imaging
abnormalities
Clinical Stages in Relapsing MS
PreSympto
matic
Early RR MS
Gd + lesions
T2W lesion burden
Late RR MS
Clinical Relapse
Accumulated
disability
SP MS
BPF
WM NAA
Multiple Sclerosis Treatment
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Treatment of Relapse (“Exacerbation”)
Treatment of Underlying Disease
Treatment of Symptoms
Psychosocial Support
Patient Education
Acute Relapse
PreSympto
matic
Early RR MS
Late RR MS
SP MS
Treatment of an Acute Relapse

Standard Treatment(s):
• IV Methylprednisolone
• Oral Prednisone
• ACTH injections
• Therapeutic Plasma Exchange
(for steroid
unresponsive severe demylinating relapses)
Relapsing MS
PreSympto
matic
Early RR MS
Late RR MS
SP MS
Treatment for Relapsing MS
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Interferon Agents
• IFN -1b (Betaseron)
• IFN -1a intramuscular (Avonex)
• IFN -1a subcutaneous (Rebif)
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Non-Interferon Agents
• Synthetic Polymer
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Glatiramer acetate (Copaxone)
• Selective Adhesion Molecule (SAM) Inhibitor
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Natilzumab (Tysabri)
SP MS
PreSympto
matic
Early RR MS
Late RR MS
SP MS
Treatment for SP MS
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Interferon Agents
• IFN -1b (Betaseron)*
• IFN -1a (Avonex, Rebif)**
• Natalizumab (Tysabri)**
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Non-Interferon Agents
• Anthracenedione Derivative
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Mitoxantrone (Novantrone)***
* Approved therapy for SP MS in Europe and Canada
* And ** Appropriate for use in relapsing SP MS
*** Only FDA-approved therapy for SP MS in the US
Goals of Treatment of MS
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Therapeutic Effects of Current Therapies:
• Reduction in
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Relapse rate
Progression of disability
MRI
• Total burden of disease
• Gad enhancing lesions on MRI
• Brain atrophy
PP MS
Treatment for PP MS
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Currently no treatments proven to slow or
stop progression of disease
Management focused on:
• Treating symptoms
• Maximizing function
• Improving quality of life
MS symptom and side effect management
SYMPTOMS
PHARMACOLOGIC TREATMENT OPTIONS
Spasticity
Baclofen, Diazepam, Gabapentin, Tizanidine, Dantrium
Urinary Dysfunction
Propantheline Bromide, Oxybutynin,
Hyoscyamine Sulfate, Tolterodine Tartrate
Fatigue
Amantadine, Pemoline, Fluoxetine,
Methylphenidate, Modafinil
Depression
SSRIs:Fluoxetine, Sertraline
Tricyclics: Amitriptyline, Nortriptyline, Desipramine
Venlafaxine
Pain
Anticonvulsants: Carbamazepine, DPH, Gabapentin
Antidepressants: Amitriptyline, Nortriptyline,
Desipramine, Venlafaxine
Sexual Dysfunction
Sildenafil, Vardenafil, Tidalafil
Ataxia
Ondansetron, Clonazepam, Propranolol, Levetiracetam
Aug2000
Other Demyelinating Diseases
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Acute Disseminated Encephalomyelitis
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Devic’s Diseases (Neuromyelitis Optica, NMO)
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Severe, necrotizing, relapsing/rapidly progressive,
demyelinating, associated with NMO IgG, involving optic
nerves and spinal cord
Balo’s Concentric Sclerosis
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Hyper-acute, severe, monophasic, multifocal,
paraifectious/paravaccination, demylinating
MS variant, acute, large, demyelinating lesions, with
concentric rings of demyelination and remyelination
Marburg Variant
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MS variant, severe, rapidly progressive, involves large
area of CNS white matter, death usually within months
Questions ?