Multiple Sclerosis 2
Terms
undefined, object
copy deck
- What is MS?
- a prototypical demyelinating disease
- What are the features of MS?
-
1.immune-mediated
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.
- outside
- 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?
-
itching,
pain,
numbness,
visual loss,
bladder problems,
fatigue,
spasticity,
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
80% - What are the four patterns of MS?
-
1.relapsing remitting MS
2.secondary progressive MS
3.primary progressive MS
4.progressive relapsing MS - What is the second most common type of MS?
-
secondary progressive MS
50% - Approximately __% of patients with untreated RR MS will develop ____________ within __ years.
-
50%
secondary progressive MS
10 - What % of patients have primary progressive MS?
- 10%
- 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?
-
MRI
Visual evoked potentials
CSF - What do you look for to diagnose MS on an MRI?
-
T2 lesions (scars that appear white)
active lesions
atrophy
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;
100ms - 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?
- none...you 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?
-
women
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?
-
Betaseron;
1993 - 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.
- True
- What is a chemotherapy drug given intravenously?
- Novantrone
- 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