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Pathophys, Exam 3: Multiple Sclerosis

Terms in this set (61)

MS can occur at any age but when is diagnosis most commonly made?
3rd or 4th decade of life
True or false: MS is always diagnosed between the ages of 20-50
false (dx can occur at any age)
In terms of gender, who is more likely to get MS?
women > men (2-3:1)
Men are more likely to get MS than women, but what is unique to men?
men more likely to be dx later in life and more often the progressive disease
What is the etiology of MS?
unknown; could be environmental - viruses (EBV); bacteria (measles); genetic (159 genetic variations have been identified that increase risk)
What is EBV? How does it relate to MS?
Epstein-Barr virus, causes mono; at higher risk for developing MS
What are the 5 risk factors for MS?
environment; geography (above 37th parallel; 15 years of age); genetics/ethnicity (caucasians, scandinavians more likely); vitamin D deficiency; smoking
What is actually a NEGATIVE risk factor for MS? (hint: virus)
cytomegalovirus (CMV)
Geography can be a risk factor for MS, how?
live above 37th parallel; 15 years of age; note -- if you lived above until you were say 17, and then moved below, you would still have the SAME risk as if you lived above (formative years are important)
What is general risk % for MS? If you have a first degree relative? If you have an identical twin?
0.1%; first degree relative 1-5%; identical twin 25%
Vitamin D deficiency increases your risk for Ms but what else does it do?
decreased time between first attack with MRI findings (CIS) and 2nd exacerbation/attack/relapse
What is the most common pathophysiological MS theory?
autoimmune degenerative - three components: inflammation, demyelination/remyelination; permanent axonal damage
Permanent axonal damage is a component of the autoimmune/neurodegenerative theory of MS. What does it refer to?
long term disability; black holes on MRI
In the autoimmune/neurodegenerative theory of MS, which came first - inflammation or demyelination/remyelination?
we don't know
What are the two types of T-cells and what do they do? (not looking for CD4 and CD8)
-T-helper cells: receive sensory input from sensor cells that lead to destruction of foreign cells

-Cytotoxic T-cells: responsible for cell-mediated immunity via direct destruction of foreign cells
What are the antigen-presenting cells?
macrophages (phagocytic; have antigens present on cell membrane); monocytes become macrophages
What is the role of B-cells?
transformed into plasma cells that secrete antibodies that directly or indirectly lead to destruction of foreign cells
What are complement?
group of inactive plasma proteins that when sequentially activated lead to destruction of foreign cells by attacking their plasma membrane
What are oligodendrocytes?
myelin-forming cells of the CNS (called schwann cells in the rest of the body)
What is myelin?
lipid layer that surrounds nerves at regular intervals along the axon (providing efficient signal conduction)
What are the types of T-cells (not looking for T-helper vs cytotoxic)? What do they do?
CD4 and CD8 - have different types of these:
-T-helper cells type 1 and 17: pro-inflammatory
-T-helper cells type 2 and T-regulatory cells: anti-inflammatory
-T-helper cell type 17 and T-regulatory cells exhibit plasticity - can convert to different T-helper cells
What is the pathophysiology of MS?
-Some sort of trigger auto-activates T-cells
-Activated T-cells express alpha-4 integrin on their cell surface; also secrete MMP
-Alpha-4 integrin binds VCAM receptors on the BBB; MMP results in dysregulation of the BBB allowing cell entry into the CNS
-in the CNS pro-inflammatory cytokines (TNF-alpha, INF-gamma, OP) are secreted causing inflammation and further T-cell entry into the CNS
-T-cells in the CNS interact with microglia, astrocytes, and macrophages to produce reactive oxygen species and nitric oxide causing CNS damage
-B-cells also enter the CNS and produce myelin-specific antibodies that form membrane attack complexes with complement, causing cell lysis
What is alpha-4 integrin?
also known as very late antigen 4 (VLA-4); adhesion molecules expressed on T-cell surface; bind to vascular cell adhesion molecule (VCAM) receptors on the BBB
What is MMP?
matrix metalloproteinases; secreted by T-cells; allows further entry of T-cells and other cells into the CNS
What are pro-inflammatory cytokines?
secreted by T-cells; could be interleukins, tumor necrosis factor alpha (TNF-alpha), interferon-gamma (INF-gamma), osteopontin (OP); cause inflammation and further T-cell entry into the CNS
What are myelin-specific antibodies?
produced by B-cells; form membrane attack complexes with complement, causing cell lysis
What is presentation of MS? What are often the first symptoms?
presentation is variable, no MS patient presents the same way, dx of exclusion; presentation is based on where lesion occurs; could have paresthesias, visual changes (optic neuritis); gait issues/falls; fatigue; weakness; impaired coordination; cognitive changes; first symptoms are often paresthesias and optic neuritis
What is optic neuritis?
unilateral vision loss with painful movement
What do we want to consider when we take patient history for MS dx?
birthplace; family history; travel; past medical history
What kind of lab tests can we perform when we are trying to dx MS?
complete blood count (CBC); complete metabolic panel (CMP); vitamin B12 (vit B12 def = neuropathy)
What do we check for in the neurological exam of MS dx?
motor function/balance/coordination assessment (gait and balance difficulty, dysdiadochokinesia; weakness; foot drop); sensory exam; reflex assessment; evaluation of cranial nerves (abnormalities due to optic neuritis, CN 2, or using fundoscope; nystagmus, CN 3, 4, 6)
How often do we perform neurological exams with MS?
baseline; repeat yearly or as clinically indicated
What is dysdiadochokinesia (DDK)?
difficulty with rapid alternating movements
What is nystagmus?
inability to steady the eye
How often do we perform cognitive assessments in MS? What is an important consideration when choosing a test? Which test is used often because it doesn't take long?
baseline, repeat yearly or as clinically indicated; pick a test and stick with it so you can see changes in the assessment; SDMT is used often
What tests (non-imaging) do we perform for MS dx?
evoked potential; lumbar puncture
What is the evoked potential test for MS?
identify areas of demyelination that are not resulting symptoms; slowed visual, brain stem, and somatosensory conductions; not as sensitive or specific as MRI or CSF
What is the lumbar puncture test for MS?
-especially done in PPMS
-CNS synthesis of IgG increased, serum levels normal -- looking for oligoclonal bands (OCBs) found in 90-95% of patients BUT can be indicative of other diseases too
-myelin basic protein (MBP) present immediately after exacerbation because of breakdown of myelin BUT can be present in other disease too
-increased CSF protein; approx 25%, if greater than 25% not indicative of MS
In general, when/why would we be performing evoked potential or lumbar puncture tests in MS dx?
if we still have a mixed picture; won't be a gold standard or provide a dx
What is the gold standard for MS dx?
MRI with or without contrast; looking for enhancing lesion, non-enhancing lesion, black holes
What is another name for enhancing lesion? What is the difference between an enhancing and non-enhancing?
Gadolinium enhanced lesions = new; non-enhancing = not new
What do black holes indicate in an MRI?
permanent axonal damage - nothing there
How often do we perform MRIs?
baseline and at least yearly; depends on exacerbation frequency and med therapy - some meds can increase degenerative effects of certain viruses on the brain
What is the McDonald criteria for MS dx?
-must show lesions disseminated in time (DIT) and space (DIS)

-DIT demonstrated by either:
-new and old lesions at the same time
-baseline MRI we can compare to a follow-up indicating we have a new lesion

-DIS demonstrated by one or more lesions in 2 of 4 areas indicative of MS: periventricular, juxtacortical, infratentorial, spinal cord
Where are juxtacortical lesions? Periventricular? Infratentorial?
-juxtacortical = along cortex
-periventricular = around ventricles
-infratentorial = inbetween cerebellum and cerebrum
What are the 5 clinical presentations of MS and what additional data would be needed for MS dx with each one?
-clinical pres: two or more attacks AND objective clinical evidence of 2 or more lesions or 1 lesion with reasonable evidence of a prior attack -----> NO additional data needed

-clinical pres: two or more attacks AND objective clinical evidence of 1 lesion -----> need DIS or await further clinical attack implicating diff site

-clinical pres: one attack AND objective clinical evidence of 2 or more lesions -----> need DIT or await a second clinical attack

-clinical pres: one attack AND objective clinical evidence of 1 lesion (clinically isolated syndrome, CIS) -----> need DIS and DIT

-clinical pres: insidious neurologic progression suggestive of primary progressive MS (PPMS) -----> need one year of disease progression and DIS, demonstrated by 2 or more of the following: DIS demonstrated by one or more lesions in MS characteristic regions OR evidence for DIS in spinal cord based one 2 or more lesions there OR positive CSF (evidence of oligoclonal bands and/or elevated IgG)
What is CIS? Can we tx it?
clinically isolated syndrome; we can treat someone with CIS because it is indicative they will probably develop clinically definitive MS
How do we phenotype MS?
step 1 - define course:
-clinically isolated syndrome (CIS)
-radiographically isolated syndrome (RIS)
-relapsing remitting (RRMS)
-secondary progressive (SPMS)
-primary progressive (PPMS)

step 2 - define modifiers (active or progressing)
-assessment of activity - yearly but may be extended if stable, PPMS ---> not active, active (CIS active = RRMS; PPMS active = PRMS), activity indeterminate (no assess made recently)
-assessment of progression - yearly ---> not progressing or progressing
What is RIS?
radiographically isolated syndrome; NOT a dx - we have an MRI with feature indicative of MS but can't make a dx; follow pt closely; pts who had an MRI for a diff reason and we happened to see it
What MS course was removed and why?
PRMS (progressive relapsing) because we look at modifiers
What is RRMS?
relapsing remitting MS; episodes of acute worsening with some recovery and no progression inb/t exacerbations; most common (85%); exacerbation freq decreases w/time; recovery of function good but declines as exacerbations increase; patient normal and then acute exacerbation, patient gets better and close to baseline but then sudden exacerbation again -- nothing happening inb/t exacerbations
What is SPMS?
secondary progressive MS; people with RRMS move to more progressive disorder --> SPMS; must have had RRMS to have SPMS; most patients will go to this but it is decreasing (50% within 10 years, 90% within 25 years); steady progression of the disease; fewer new lesions, more TI holes and atrophy = disability accumulates; progression the whole time
What is PPMS?
primary progressive MS; progressive worsening of disease - constant progression; not as many patients; 10-15%; later onset; men = women; looks at lot like SPMS; must meet McDonald Criteria: one year of disease progression plus 2 of 3 of the following:
-evidence for DIS in brain
-evidence for DIS in spinal cord
-positive CSF (oligoclonal bands and/or IgG elevation)
What is the expanded disability status scale (EDSS)?
quantifies impairment associated with MS; comes down a lot to mobility; must confirm at 3-6 months because it could be permanent disability or acute exxacerbation; 0 is normal, 10 is death due to MS; considers 8 functional systems - pyramidal (vol movements); cerebellar (muscle activity, equilibrium); brain stem; sensory; bowel and bladder; visual; cerebral; other
What is good prognosis for MS?
< 40 at onset; female; first symptoms optic neuritis/sensory issues; low exacerbation freq; RRMS; single lesion location/low lesion load/low rate of black holes
What is bad prognosis for MS?
> 40 at onset; male; first symptoms motor or cerebellar; high exacerbation freq; PPMS; multiple lesion locations/high lesion load/high rate of black holes
What are tx goals for MS?
decrease attack/exacerbation rate; decrease annualized relapse rate (ARR); slow disease progression (disability, MRI findings, cognition); prevent/limit ADRs; effectively manage symptoms
What is tx for acute exacerbations of MS?
steroids, IV or PO
Currently there is no tx approved for what type of MS? Hence, hesitancy when labeling a patient as this because of insurance and drug coverage.
PPMS
What kinds of symptoms do we try to manage in MS? Can manage with pharmacological and non-pharm therapy.
fatigue; bladder dysfunction; cognitive dysfunction; bowel dysfunction (usually constipation); depression; spasticity; tremors; ambulation/gait issues; sensory impairment/neuropathic pain; musculoskeletal pain
What is monitoring/follow-up for MS?
neurologist visit at least every 6 mo-1 yr; MRI every year or based on need - based on neurologist, MS phenotype, med therapy; neurological exam; EDSS; health maintenance - whole patient needs to be looked at, they are a patient to start with not just an MS patient
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