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66 Cards in this Set

  • Front
  • Back
what is multiple sclerosis?
autoimmune disease (CD4 and Th1 dysregulation) characterized by demyelination of the CNS and axonal loss
list some common facts/statements about the etiology and epidemiology.
genetics (HLA-DR2 and TCR) and environment plays a role (Demographics: further from the equator = more likely to get MS; microbial, Toxins); 200 new cases a week in the US; most common cause of non-traumatic disability in young adults; affects women more often; usual age onset 20-30s;
explain molecular mimicry.
it is where antigens evoking an immune response have similarities to the body's own proteins and cause an immune rxn; body's inability to distinguish self from non-self; some common non-self antigens (viruses and bacteria/toxins) and potential self antigens (myelin basic protein - looks like a virus - may be the problem)
name the four types of MS.
1) Benign MS; 2) Relapsing Remitting MS; 3) Secondary Progressive; 4) Primary Progressive
name the man responsible for giving us the first signs and symptoms of multiple sclerosis.
Jean-Martin Charcot
which type of MS doesn't cause cognitive problems but is mainly gait issues; it doesn't follow the typical MS spectrum.
Primary Progressive MS - typically males and mainly gait difficulties
at diagnosis most people are this type?? and develop into ___________ in 11-15 years.
at diagnosis most(85%) are relapsing remitting and develop into 58%-secondary-progressive or 42% stay relapsing remitting
what two factors will cause an MS patient to stop working?
fatigue and cognition problems
MS has been thought to be a dual phase disease. what are the stages.
inflammatory --> progressing --> to Degenerative
as an MS patient progresses from preclinical --> relapsing --> secondary progressive, how does the brain grossly change?
as the disease progresses, the ventricles enlarge and the brain atrophies
name the disability scale used to grade the MS disability.
EDSS (expanded disability status scale); 0-10; 10 is death; defined by functional, walking, and dependence; scores of 0-6 are subtle changes, once a pt is beyond a 6 the changes are very noticable
what are the 3 major groups of cells that are possibly involved in MS?
1) Tcell/Macrophage; 2) Antibody/Complement; 3) oligodendrocytes
53% of MS patients follow the pattern of having problems with which groups of cells?
tcell/macrophage and Antibody/complement are involved, but the oligodendrocytes are normal
how will MS axonal loss lesions show up on T1 MRI?
CD4 Tcells differentiate into Th1 and Th2 cells. what do Th1 and Th2 cells produce?
Th1: pro-inflammatory cytokines (IL-2, IFN, TNF) macrophage mediated; Th2: anti-inflammatory cytokines (IL-4, IL-5, IL-10, IL-13) Bcell mediated
name the newer way to measure MS functionality. it uses a 25 foot walk, a nine-hole peg test, and a PASAT (paced auditory serial addition test).
MSFC, Multiple Sclerosis Functional Composite
what are the diagnostic tools used to diagnose MS?
H&P, MRI of brain and spinal cord, CSF exam, Evoked Potentials (SSEP, VEP, BAER), and other labs
on MRI, where are the lesions?
most are typically paraventricular
is it possible to have MS and be asymptomatic but not have lesions?
not normally, axonal damage/inflammatory lesions are common to see on MRI even without symptoms; for every one relapse there are 5-10 inflammatory lesions on MRI
when ordering an MRI, what technique do you want?
3mm thick sections, no more than a 1mm skip, axial and sagittal FLAIR, wait at least 5 min between contrast and filming
name some diseases that mimic MS.
Devic's Disease (just neuromyelitis optica); sarcoidosis, Sjogren's, Behcet S, Leukodystrophies of adulthood, PML, ADEM, Lyme dz, primary CNS vasculitis, tertiary syphilis, CADASIL, antiphospholipid syndrome
define the diagnostic criteria of Devic's Dz (mimic of MS).
1) optic and transverse myelitis; 2) Two of the following: a) MRI evidence of contiguous spinal cord lesion 3 or more segments long; b) brain MR is not consistant with MS; c) NMO-IgG seropositivity (NeuroMyelitis Optica - NMO)
If a young adult patient presents with confusion, gait disturbances, seizures, headaches, with bowel/bladder problems after an acute infection, what do you think of?
ADEM Acute Disseminated Encephalomyelitis: will reveal an abnormal brain/cord MRI with multiple enhancing lesions; CSF: increase protein, pleocytosis, and no Oligoclonal bands; usually monophasic
this MS mimicing dz is a reactivation of JC virus commonly presented in immunocompromised patients. also, what MS drug may cause this to occur?
PML - progressive multifocal leukoencephalopathy; the MS drug of last resort is Natalizumab
even if a patient is labeled CIS (clinically isolated syndrome) it may be important to start therapy (controversial) since axonal loss may occur early. if a patient has CIS with optic neuritis, what puts that patient at increased and/or decreased risk?
INCREASED RISK of developing MS: young adult, female, unilateral, pain, normal disc, brain lesions, abnormal CSF (OCBs, increased leukocytes, protein, myelin basic protein, normal glucose); DECREASED RISK: children, male, bilateral, painless, severe disc edema, normal brain MRI, Normal CSF
what are the increased and decreased risk factors of developing MS after an episode of Transverse myelitis?
INCREASED: incomplete TM, asymmetric sx, abnormal brain MRI, OCB in CSF, no CSF pleocytosis, smaller cord lesion, no edema; DECREASED RISK: complete TM, symmetric sx, normal brain MRI, no OCB in CSF, CSF pleocytosis, multi-segments, and edema
name the two criteria methods used to diagnose MS after CIS.
1) Poser Criteria: need evidence of 2 separate attacks (1st is the CIS, 2nd is confirming); 2) McDonald Criteria: since MRI can be abnormal and pt asymptomatic, this criteria uses MRI as the defining 2nd event
What is found in the CSF of an MS patient that is sensitive and specific?
OCB (oligoclonal bands)
there are 3 ways to medically manage MS, name them.
1) treat the relapses, 2) manage the symptoms, 3) alter the course of MS
common causes for an MS exacerbation or flare up are:
new illness, fever
name the common steroid treatments for MS relapses.
Solumedrol (methylprednisolone); oral prednison; ACTH
management of MS patients should include treating the symptoms, name common ones.
pain (present in 70%), spasticity (tizanidine), bladder/bowel problems, mood, cognitive dysfxn, fatigue (improve quality of life!)
what is the most common symptom in MS?
Fatigue is seen in 90% of pts; listed as disabling in 50% (lassitude is the term used to define tiredness not related to activity); fatigue is heat sensitive and occurs in specific muscle groups after use
name the phenomenon where symptoms show up after an increase in body temperature.
Uthoff's Phenomenon
what do activated t-cells express to cross the BBB? what happens if the naive t-cell finds an antigen that it is specific for?
activated t-cells express VLA-4 and are able to cross the BBB because the endothelial cells express VCAM-1 and ICAM; if these activated tcells encounter the antigen to which they are specific, they will form effector cells and either secrete pro-inflammatory cytokines (CD4) or kill myelin (cytotoxic CD8)
what types of cells vary in early vs late lesions?
early lesions have predominately tcells especially CD4 cells (inflammation); chronic lesions: macrophages and microglial predominate with loss of oligodendrocytes and axons (CD8 predominate in chronic)
the gene with the strongest link to MS is what?
the MHC, particularly the HLA-DR2 (class II HLA are expressed on antigen presenting cells, dendritic cells, activated macrophages, Bcells) - class II allow CD4 cells to attach
what do CD4 cells predominately secrete?
cytokines: gamma IFN, TNF, and IL-2 (promote mononuclear infiltrate, recruite cytotoxic Tcells, macrophages, adn NK cells into the area)
what do the anti-myelin CD8 cells do?
attach to class I antigens of oligodendrocytes and cause damage
what is the role of glial cells?
normally glial cells are the macrophages of the nervous system; microglial cells present antigens to t-cells; activated glial cells proliferate and express MHC I and II, co-stimulatory molecules for CD8 and CD4 activation.
explain the role of astrocytes in MS.
normally astrocytes maintain the BBB. In MS they are induced to proliferate because of the damage, this causes an astrocyte scar to form, this is a typical lesion in an MS patient. both astrocytes and oligodendrocytes can be induced by cytokines to express MHC II antigens and participate in antigen presention to CD4 cells
CD4 secrete IFN, TNK, IL-2. what do they do to myelin?
TNF and gamma IFN damage myelin
what tolerance mechanism may be dysfunctional in MS?
central tolerance may be dysfxnal. normally, central tolerance prevents t-cells from having specificity to self
name some commonly suggested microorganism/viruses that may play a role in MS.
EBV, HHV-6, retroviruses, chlamydia pneuoniae
how infectious agents cause MS is uncertain, but ____________ is the most commonly offered explanation.
molecular mimicry (it is where antigens evoking an immune response have similarities to the body's own proteins and cause an immune rxn)
normally, there are __________________ protecting the integrity of the BBB.
tight junctions
overall, if you had a choice of what type of t-cell (Th1 or Th2) you could put into the CNS of a MS pt, which would it be and why?
since MS has inflammatory component, you would want to add or stimulate the activation of Th2 cells since they release anti-inflammatory cytokines like IL-10
what is the microglia's role in lesion formation and lesion repair?
formation: secretes inflammatory mediators and presents antigens to CD4 cells; REPAIR: secretes growth factors that promote remyelination
what is the endothelial's role in lesion formation and lesion repair?
formation of lesion: recruit mononuclear cells, antigen presentation; REPAIR: maintain BBB
what is the macrophage's role in lesion formation and lesion repair?
formation: secretion of cytokines and mediators which degrade myelin; antigen presentation to CD4 cells; REPAIR: secrete anti-inflammatory cytokines IL10, TGFb
once in the brain, t cells secrete _________ that assist in their migration and degrade type 4 collagen, thereby causing damage to the BBB; it also induces proteolysis of myelin sheath.
MMP-9: matrix metalloproteases
name the three main categories of treatment meds for MS patients.
1) IMMUNOMODULATORS: BETA-IFNs: avonex, betaseron, rebif; glatiramer acetate; natalizumab; 2) CORTICOSTEROIDS: methylpredisolone; 3) IMMUNOSUPPRESSORS: mitoxantrone, cyclophasphamide, azathioprine, methotrexate
What is glatiramer acetate and its MOA?
immunomodulator; copolymer of 4 amino acids; similar in structure to myelin basic protein; suggested to secrete anti-inflammatory cytokines (IL-4, IL-10, TGF-b) by TH2 t-cells
corticosteroids are manily used to treat what in MS?
significant relapses; symptomatic management; inhibit pro-inflammatory cytokines
the immunomodulators (beta-IFN) are usually indicated to do what in MS?
to lower the number of relapses and stop progression; the reduce the activation of Tcells
what is the proposed role in the immunomodulator, natalizumab and what may it cause that would most likely be lethal?
natalizumab is the drug of last resort for MS patients; most likely it works as an antibody to the alpha 4 subunit of the VLA-4 on activated T-cells (that bind to VCAM on endothelial cells)
define primary progressive MS.
progressive deterioration without relapses and remissions, there are occasional plateus and temporary minor improvements; mainly have gait problems
define progressive-relapsing (PRMS).
rare, progressive from onset with acute relapses that may or may not result in complete recovery
Name the immunomodulators used to treat MS.
Betaseron, Avonex, Rebif, glatiramer acetate
name the immunosuppressors used to treat MS.
explain the MOA of interferon beta.
reduce production of TNFa, T-cells; reduce inflammation by switching to more TH2 cells and increasing levels of IL-10; decrease antigen presentation, reduce ability of cells to cross the BBB
what are the indications of using Avonex, Rebif ( both interferon B-1a) and Betaseron (interferon beta-1b) on MS pts?
use in relapsing forms, one IM shot weekly for Avonex and 3 subc shots for Rebif and subc every other day in Betaseron; reduces relapse rate and development of new lesions
List some common side-effects of interferons.
flu-like symptoms, chills, fever, muscle aches, asthenia, possible injection site rxn
name the immunomodulator that is not an interferon.
glatiramer acetate (less s/e than interferons but may cause chest pains)
name the anitneoplastics/immunosuppresants indications and Side-effects?
mitoxantrone: reduction of relapse rate and clinical disability; mainly used for progressive MS; IV infusion every 3months; S/E: bone marrow suppression, cardiac tox, teratogenic effects,
what is the astrocyte's role in lesion formation and lesion repair?
formation: secretes inflammatory mediators and presents antigens to CD4 cells; REPAIR: secretes growth factors that promote remyelination