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PRESENTATION TITLE
Subtitle & Date
Boston Medical Center is the primary teaching affiliate
of the Boston University School of Medicine.
Boston Medical Center is the primary teaching affiliate
of the Boston University School of Medicine.
3
4/2/2016
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– Second bullet
• Third bullet
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MULTIPLE SCLEROSIS
CLINICAL UPDATE
James A.D. Otis, M.D.
Associate Professor of Neurology
Boston University School of Medicine
Boston Medical Center is the primary teaching affiliate
of the Boston University School of Medicine.
OVERVIEW
• An autoimmune disease of the central nervous system
producing lesions separated in space and time. Although
mostly demyelinating, there is axonal damage
• Exact etiology unknown
EPIDEMIOLOGY
• Affect between 250,000-350,000 patients in U.S.
• 100/100,000 prevalence in northern states, 20/100,000 in
southern states
• Most common in northern Europe, almost unknown in
southeast Asia
• Migration from high to low incidence area reduces risk after
15 years
BIOLOGICAL BASIS
•A multiple sclerosis plaque is formed after activated peripheral T cells adhere to CNS
postcapillary venules.
•The T cells pass through the endothelial cells and migrate into periventricular
parenchyma.
•The inflammation is associated with destruction of the inner myelin lamellae and
dysfunction of oligodendroglia (and likely with diffuse effects such as fatigue).
•The inflammation resolves in 2 to 6 weeks, presumably suppressed by endogenous
CNS and immune mechanisms, such as IL-4, IL-10, transforming growth factor-beta,
prostaglandin E, a rise in cortisol, and apoptosis of invading cells.
• Astrocyte hypertrophy and gliosis follow.
BIOLOGICAL BASIS
•In active multiple sclerosis, lymphocytes express excessive levels of activation
proteins (HLA-DR, CD71) and co-stimulatory molecules (CD80, B7-1)
•Inflammatory cytokines (eg, IL-2, IL-15, interferon-gamma) and cytokinesecreting cells are seen in the serum at low, but higher than normal, levels IL-1,
tumor necrosis factor-alpha, IL-6, and IL-15 are present in the CSF. Messenger
ribonucleic acid for inflammatory cytokines is elevated in white blood cells
•These Th1-like cytokines and monokines amplify immune responses.
•. During attacks concanavalin A-induced suppressor cell function drops.
Interleukin-12 production increases, likely inducing interferon-gamma. Indeed,
interferon-gamma "therapy" triggers attacks of multiple sclerosis reactions
•Many of these changes could lead to delayed-type hypersensitivity or Th1-type
immune.
PATHOLOGY
• Areas of demyelination with occasional axonal loss.
Periventricular white matter and other subcortical white matter
most common as well as spinal cord pathways
• Inflammatory cells often found near new areas of
demyelination
CLINICAL COURSE
• Primary progressive
• Relapsing-remitting
• Secondarily progressive
DIAGNOSIS
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•
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•
High index of suspicion
MRI
Evoked potentials
Lumbar puncture
– Myelin basic protein
– Oligoclonal bands
– IgG synthesis index
• McDonald Criteria
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–
–
–
Complex
Currently being revised
Require 2 lesions separated in space and time
LPs recommended only to rule out other diagnoses
DIFFERENTIAL DIAGNOSIS
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•
•
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Encephalomyelitis
Infection
Vasculitis/angiitis
Behcet’s disease
Sarcoidosis
Adrenoleukodystrophy
Other dysmyelinating diseases
DIAGNOSTIC EVALUATION
• Examination
• MRI with contrast
• CSF with IgG synthesis index and oligoclonal bands and
myelin basic protein
• Evoked potentials to find occult lesions
OLIGOCLONAL BANDS
• Oligoclonal bands in
CSF phoresis
MRI
• Typical white matter
plaque in acute MS
with diffuse
enhancement
MRI
• T1 (A) and T2 (B)
images of cervical
cord showing
multiple plaques
MRI
• MRI showing typical
periventricular
demyelination
CLINICAL SYMPTOMS
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Fatigue (most common)
Visual loss secondary to optic nerve demyelination
Weakness
Ataxia
Bladder/bowel dysfunction
Paresthesias
Cranial nerve abnormalities
OPTIC NEURITIS
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Retro-orbital pain
Visual loss
Decreased acuity
Normal fundus in acute
stage in 60%
• Optic pallor and atrophy
in chronic state
• Visual evoked
potentials show delay in
cortical response on the
side affected
MANAGEMENT
• Primary prophylaxis
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Beta interferon (Betaseron, Avonex, Rebif)
Glatiramate acetate (Copaxone)
Natalizumab (Tysabri)
Fingolimod
Fumarate
Teriflunomide
• Acute exacerbations treated with Solumedrol 1gm qd for 5-10
days
• Some evidence to support plasma exchange
DOES PROPHYLAXIS WORK ?
• There is a reduction of 30-35% in the relapse rate with all
treatments
• There is clear decrease in MRI plaque burden over a 5 year
period
• Time to loss of independent mobility is increased
• Caution must be used when using natalizumab and new oral
agents because of risk of PML
• Tests for JC virus now commercially available and safe
• Recent European study calls into question the relation between
exacerbations and progression
SYMPTOMATIC TREATMENT
• Treat infections
– UTI most common
• Treat spasticity with lioresal or tinazidine
• Treat fatigue with amantadine, modafinil or methylphenidate
• Monitor liver enzymes and CBC while on prophylactic agents
ADVANCED TREATMENT
• Many patients progress through prophylaxis
• For these, additional treatments are used to prevent further
deterioration
• These include methotrexate, azathioprine and monthly doses
of solumedrol
• There is some evidence that IV IgG is also helpful