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Multiple Sclerosis 2


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What is MS?
a prototypical demyelinating disease
What are the features of MS?
2.demylinating disease with axonal component
3.affects the CNS
4.affects primarily white matter
5.hallmark is dissemination in space and time
How do you diagnose MS?
its difficult; there is no single test to rule out or confirm MS; MRIs and CSF tests are supportive but not definitive
Is MS the same in all patients?
No, no two cases are alike because it affects different areas of the CNS at different times
Is there a cause or a cure for MS?
none proven
What is the course of MS like?
unpredictable and individual to each patient in both symptoms and progression
Are MS treatments effective?
only partially
Who does MS commonly affect?
women between the ages of 20-40 (primarily Caucasians of northern european or scandinavian descent)
What causes MS?
don't really know, a combination of genetics and environment
What is the life expectancy of someone with MS?
normal (the same as an age-matched control)
What are some consequences of untreated MS?
becoming wheelchair bound, vision loss, bowel or bladder dysfunction
What is the genetic component of MS?
a complex of genes that predisposes a person to MS
What are some environmental agents proposed to cause MS?
viruses (CMG, Epstein-Barr), bacteria, toxins (lead, copper)
What is the difference between dysmyelinating and demyelinating diseases?
dys:abnormal or defective myelin formation
de: damage to myelin previously normally formed
What is the trimolecular complex that is formed?
the infectious agent, taken up by APC, presented to naive T-cells
What is molecular mimicry?
a naive T cell that is activated agaisnt an infectious agent then identifies a similar epitope on an internal protein and attacks that internal protein
What is attacked in MS?
boty the myelin and the myelin producing oligodendrocytes
The attacking of myelin and oligodendrocytes is thought to be due to...
a complex interaction of immune system components such as macrophages, T-cells, and various cytokines
The immune response in MS is initiated __________ the CNS.
Explain what happens after a molecular mimic to myelin is detected.
T cells activated
release cytokines into blood
activate B cells and other T cells
cytokines cause endothelial cells lining bv to express adhesion molecules
activated T cells bind to these adhesion molecules and walk through the BBB into the CNS
in the CNS T cells continue to release pro-inflamm cytokines
other immune cells including B cells and macrophages enter CNS through BBB
these cells attack myelin
What is thought to cause the symptoms of MS?
problems of nerve conduction due to axonal demyelination and disruption
What can happen afer inflammation?
some ion channels repopulate the axons and some remyelination occurs
What leads to plaques?
gliosis, proliferation of glial cells to fill in the damaged areas
What does the standard MS plaque look like?
it shows a gradient of pathological changes- the center of the plaque represents older damage where axons are demyelinated and damaged, near the border the # of macrophages increases and there is ongoing demyelination/remyelination
How could you create an environment that is favorable to remyelination?
inhibit gliosis (don't know how to do this yet)
What was the most promising substance in inhibiting gliosis?
IVIG, intravenous immunolgobulin (not good in clincal trials)
What can plasmaphaeresis be used for? What is it not good for?
to help in acute demyelinating relapses and when someone has a severe relapse that doesn't respond to steroids;
not effective in preventing disability long-term
What is the pathological hallmark of MS?
plaques (MS means multiple scars)
What are the 3 main pathological processes seen in MS?
1st: inflammation
2nd: demyelination
3rd: axonal loss
Is MS purely a demyelinating disease?
No, it can affect gray matter too
Recent studies have suggested that MS lesions tend to:
1.extend from the subcortical white matter to the cortical grey matter
2.exist purely in the grey matter
3.large areas of demyelination that extend into the grey matter
What is the damage to grey matter responsible for?
cognitive difficulties
What is the most common symptom of MS?
numbness that begins in the arm or leg and gradually spreads to waist or neck levels
What are some symptoms of MS?
visual loss,
bladder problems,
sexual dysfunction,
cognitive dysfunction
What is the second most common symptom of MS?
visual loss
What causes visual loss?
optic neuritis
Specifically, how does vision loss present?
partial or complete visual loss
development of scotomas
changes in color vision
pain with extraocular movements
What is the most common pattern of MS? What percentage does this pattern occur in?
Relapsing Remitting MS
What are the four patterns of MS?
1.relapsing remitting MS
2.secondary progressive MS
3.primary progressive MS relapsing MS
What is the second most common type of MS?
secondary progressive MS
Approximately __% of patients with untreated RR MS will develop ____________ within __ years.
secondary progressive MS
What % of patients have primary progressive MS?
Which type of MS is more common in men?
primary progressive MS
Patients who have progressive relapsing MS start out with ________ MS
primary progressive
What are the 4 variations in the course of MS
mild MS
relapsing MS
progressive MS
malignant MS
What is Marburg's variant of MS? How long do these patients live?
a malignant subtype of MS in which patients develop diffuse areas of demyelination
die within 6-12 months despite therapy
What are the 3 diagnostic tests for MS?
Visual evoked potentials
What do you look for to diagnose MS on an MRI?
T2 lesions (scars that appear white)
active lesions
T1 black holes (axonal loss)
lesions in th spinal cord
Why is the MRI helpful?
you can follow it over time
What is visual evoked potentials? What is the average response time in normal person?
you stimulate the eyes with a checkerboard pattern and the impulses are measured over the occipital area where the visual center is;
What proteins are you looking for in CSF?
MBP (myelin basic protein)
quantitative indicators of IgG abnormalities
oligoclonal bands
A patient presents with optic neuritis and transverse myelitis, what diagnostic tests should you order to confirm MS? can diagnose because the symptoms disseminate in space
What is the caveat to diagnosing MS?
rule out other potential etiologies
What occurs in the typical course of MS?
relapses become less frequent
disability increases
MRI burden of disease increases
patient develops atrophy
increase in NAA
What is NAA?
N-Acetyl Aspartate;
a marker of axonal loss
Which patients typically have a better prognosis?
younger patients
patients with RR MS
patients with fewer relapses
patietns with less disability early on
patients with a low burden of disease (volume of brain affected) on MRI
What is the standard treatment for relapse?
IV methylprednisolone (solmedrol) for 3-5 days followed by oral predinsone for 2-4 weeks
What is the main goal of treatment?
treat the underlying disease
What was the first approved treatment for MS? when?
What type of MS are most drugs indicated for?
RR MS (because it is most common)
How do you treat MS?
with interferons or non-interferon agents
What are the interferons used and what is the method of delivery?
Betaseron (subcutaneous injection)
Interferon Beta-1A (intramuscular injection)
Rebif (subcutaneous interferon beta-1A)
What are some non-interferon agents and what is their method of delivery?
copaxone (subcutaneous)
Natalizumab (intravenously)
T/F: All interferon therapies have been proven effective in patients with secondary progressive MS with superimposed relapses.
What is a chemotherapy drug given intravenously?
What are the 3 proposed mechanisms of interferon?
1.interfere with actions of T-cells (instead of becoming TH1 they become TH2)
2.act on metalloproteinases (MMPs) helping to prevent the entry of T-cells into the CNS
3.stabilize the BBB preventing T cell entry
What is copaxone? How does it act?
a syntehetic complex polymer of amino acids that is taken by subcutaneous injection once a day, an auto-peptide ligand;
by changing TH1 to TH2 and by producing glatiramer acetate specific cells
What do glatiramer acetate specific cells do?
go into the CNS and cause bystander supression adn produce cytokines and chemokines that would reduce the inflammatory response
Where does Copaxone work?
in periphery and CNS
What is the drug that has been taken off the market? How does it work?
Natalizumab; a monoclonal antibody that acts by blocking VLA4 and thus preventing T-cells from getting into the CNS
What is novantrone used for? Why?
progressive MS because it acts on bascially all steps of the immune response
What are some issues of treatment?
-interferons produce neutralizing antibodies
-drugs have side effects
-setting realistic expectations
-managing breakthrough diseas
What are some side effects of MS treatment drugs?
flu-like symptoms, injection site problems and necrosis, liver abnormalities, blood count abnormalities
What are some other demyelinating diseases?
Acute disseminated encephalomyelitis
Devic's disease (neuromyelitis optica)
Balo's concentric sclerosis
Marburg variant

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