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11/4 Multiple Sclerosis
Neuro
36
Medical
11/07/2011

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Term
multiple sclerosis

clinical hallmark
Definition
*multiple lesions separated in space and time*

multifocal, subacute process --> inflammatory

MS affects the spinal cord as a focal process
Term
MS symptoms

areas affected
Definition
typical lesion sites:

spinal cord - 50%

optic nerve - 25%

brainstem/cerebellum - 20%
Term
MS symptoms

spinal cord
Definition
numbness
paraesthesias (Lhermitte's)
pain
weakness
stiffness
clumsiness
bladder/bowel disturbance
impotence
Term
Lhermitte's
Definition
paresthesia as a sense of electric shock precipitated by flexion at the neck

not a symptom to be ignored!
Term
MS symptoms

optic nerve
Definition
blurred vision

loss of vision

eye pain
Term
MS symptoms

brainstem/cerebellum
Definition
diplopia
dysarthria
dysphagia
clumsiness
vertigo
numbness
weakness
Term
clinical course of MS
Definition
relapsing remitting

secondary progressive

primary progressive

progressive relapsing
Term
clinical course

relapsing-remitting
Definition
at onset, 85% of MS cases are relapsing remitting (with half of these evolving to secondary progressive after 10 years)

clearly defined attacks (relapses), with no disease progression during the periods between the attacks

patients typically recover from the attacks (but not always), and the recovery may be partial or complete
Term
clinical course

primary-progressive
Definition
continued disease progression from onset

may have occasional plateaus or temporary periods of minor improvement

(10% of cases at onset)
Term
clinical course

secondary-progressive
Definition
initial relapsing-remitting course, followed by continues progression

may be occasional plateaus, superimposed relapses, or temporary periods of minor improvement
Term
clinical course

progressive-relapsing
Definition
continued progression from onset, but with clear superimposed relapses followed by partial or full recovery

continuing progression during the periods between relapses

(5% of cases at onset)
Term
gross pathology of MS
Definition
demyelinating plaques = pathologic hallmark

affects white matter of the brain - see gray in the middle of white area, indicates demyelination

plaques of MS like to form near the ventricles

plaque = well-demarcated areas of discoloration that can occur anywhere in the white matter, but especially in the regions near the ventricles and cerebral aqueduct
Term
microscopic pathology of MS
Definition
plaques appear as perivascular collections of macrophages and lymphocytes (CD4+ T cells)

reduction in number of axons, but axons themselves preserved, just demyelinated

preservation of neurons - neuron cell bodies remain intact

*demyelination
*inflammation
Term
pathophysiology of MS
Definition
demyelination

axonal damage

lesions/inflammatory changes
Term
pathophysiology

demyelination
Definition
primary damage to oligodendrocytes causes slowed/interrupted nerve conduction

impaired function from decreased Na channels in previously myelinated axons

(axon remains intact, function can be restored as Na channels redistribute or axon gets remyelinated)
Term
pathophysiology

axonal damage
Definition
axonal transection is a consistent feature of MS lesions

number of transected axons correlates to degree of inflammation

lower axon density
Term
pathophysiology

inflammation - theories
Definition
T-cells may be sensitized to one or more components of myelin and trigger an immune cascade

may be a generalized problem with immune system regulation that affects primarily CNS neurons and oligodendrocytes

may be a primary pathologic process in oligodendrocytes, neurons, myelin, or axons, and the immune activation is just a response to this underlying pathology
Term
pathogenesis of MS
Definition
circulating CD4+ Tcells activated in periphery and adhere to postcapillary venules in the brain and spinal cord

pass through endothelial cells and migrate to perivascular brain parenchyma, with monocytes

adhesion molecules on Tcells and endothelial cells important

now in the CNS, Tcells restimulated by microglial cells

cause direct and indirect damage to oligodendrocytes, myelin sheath, axons

upregulation of cytokines (interleukins, gamma interferon, TNF_alpha, TGF-beta)
Term
environmental factors
Definition
exposure to large amounts of sunlight correlated with reduced risk

increased prevalence with increased distance from the equator ("hygiene hypothesis")

seems that environmental exposure early in life can affect subsequent risk of developing the disease

suggestive associations with mini-epidemics
Term
genetic factors
Definition
no single Mendenlin locus

MZ twin concordance rate = 30% (200 times background rate)

5% for siblings and DZ twins

1st degree relatives have 25x higher risk of MS than general population

association with certain HLA types, IL-2 receptor alpha, IL-7RA genes
Term
diagnosis
Definition
CLINICAL diagnosis based on multiple lesions separated in sapce AND time (without other risk factors; ie Lupus can mimic)

when necessary, supplementary tests may be ordered
Term
diagnosis

supplementary tests
Definition
brain MRI

spinal cord MRI

LP (CSF testing)

evoked potentials
Term
supplemental diagnostic tests

brain MRI
Definition
may show additional lesions that night not be presenting at the time

not 100% sensitive or specific

MRI scan can only be interpreted reliably in the context of history and examination
Term
supplemental diagnostic tests

MRI spinal cord
Definition
white matter lesions in the spinal cord are rarely insignificant
Term
supplemental diagnostic tests

CSF testing via LP
Definition
oligoclonal bands: CSF marker of IgG production; from electrophoretic analysis of CSF

increased IgG index: presence of IgG antibodies in CSF as measured by a specific ratio

[IgGCSF/albuminCSF] / [IgGserum/albuminserum]
Term
supplemental diagnostic tests

evoked potentials
Definition
useful when the physical exam does not provide compelling evidence for more than one CNS lesion

measures of the speed with which sensory information reaches the brain (which is dependent on the function of myelinated pathways)

EEG recordings time-locked to different repeat stimuli: visual, auditory, somatosensory; averaged over multiple stimuli and compared to control or analogous waveform in same pt on opposite side

abnormal function of the sensory pathway results in a prolonged latency of the signal - may provide evidence of a clinical lesion not apparent on the neurologic exam
Term
"diagnosis" of a single episode
Definition
by definition, a single episode is NOT MS
-very likely to be MS if: typical syndrome, diffuse MRI changes

differential:
-ADEM
-NMO
Term
acute disseminated encephalomyelitis
ADEM
Definition
condition that is difficult to distinguish from MS

multifocal

begins abruptly and progresses over hours

often associated fever, HA, neck stiff, decreased consciousness

typically a history of antecedent infection (sometimes vaccine)
Term
neuromyelitis optics (Devic's syndrome)
NMO
Definition
some patients develop optic neuritis and transverse myelitis separately or simultaneously but then never develop any other MS lesions

associated with a specific auto-antibody to aquaporin 4

spinal cord MRIsshow demyelinating lesions extending over more spinal segments that in a typical MS lesion (brain MRI's usually normal)
Term
MS management

disease modifying agents
Definition
6 medications approved for use in MS:

3 are different preps of interferon beta (2 of 1a, 1 of 1b) - AVONEX, REBIF, BETASERON

1 polypeptide synthetic analogue of myelin basic protein - GLATIRAMER

1 monoclonal antibody against a Tcell adhesion molecule - NATALIZUMAB

1 chemotherapeutic agent - MITOXANTRONE
Term
MS management

interferons
Definition
AVONEX (1a) - low dose, IM 1/week
REBIF (1a) - high dose, subq 3/week
BETASERON (1b) - high dose, subq every other day

different preparations of interferon-beta

reduce frequency of relapses in patients with relapsing-remitting MS and reduce progression of MRI abnormalities in clincial disability

dose effect

patients may form neutralizing antibodies after dose

flu-like symptoms with each dose
Term
MS management

glatiramer acetate
Definition
polypeptide devleoped as a synthetic analogue of myelin basic protein

reduce relapse frequency in relapsing-remitting disease

may slow progression of disability

daily subq
Term
MS management

natalizumab
Definition
monoclonal antibody against the Tcell adhesion molecule, alpha4 integrin

reduces frequency of relapse and degree of clinical progression in patients with relapsing-remitting disesase

risk of PML (fatal viral infection) in 1/1000

only when other treatments have failed

IV 1/month
Term
MS management

mitoxantrone
Definition
chemotherapeutic agent

reduce relapse frequency and rate of disease progression in relapsing-remitting AND secondary-progressive MS

cardiac toxicity limits treatment duration to 3 years

IV every 3 months
Term
principles of management
Definition
hard to know benefit of treatment on an individual basis

relapsing-remitted patients encouraged to start glatiramer or interferon as early as possible (poss in clinically isolated syndromes too)

decision of specific drug based on side effects, convenience of administration, cost
Term
MS management

role of steroids
Definition
glucocorticoids appear to accelerate the recovery from an acute MS replase

no consistent evidence for long-term benefit

should be considered for relapses that result in considerable discomfort or dysfunction (but not used too frequently because of high incidence of side affects