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Pathophysiology Final > Multiple Sclerosis > Flashcards

Multiple Sclerosis Flashcards

1
Q

true or false: MS is an autoimmune disease

A

true

  • myelin coating inside the ventricles of the brain is attacked
  • leads to pre-ventricular lesions around the ventricles of the brain
  • brain shrinks like a raisin
  • then slowly disintegrates the entire body
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2
Q

Is there a geographical influence on the diagnosis of MS?

A
  • odds to getting MS is 1:500 to 1:1000
  • yet Canada has the highest geographical prevalence of MS worldwide
  • Winnipeg and Brandon have the highest rates of prevalence within Canada
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3
Q

Contributing factors to MS

A
  • race (caucasian)
  • age (25 and 38)
  • sex: m vs f (female more likely, but if male gets it is much more debilitating-> put in wheelchair faster)
  • infection (epstein-barr, HHV6, Clamydia pneuoniae, ect)
  • injury
  • genetics
  • geography (less 15 yrs of age acquires susceptibility of the new region but over 15 will not affect-> i.e. if you come into canada before the age of 15 you take on the incidence of an average caucasian woman within Canada but after you have the inherent risk of the nationality from which you immigrated)
  • diet/sunshine (Vitamin D is an inherant deficiency in MS pts)
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4
Q

Susceptibility to MS:

sex, age, ethnicity

A
  • 3F:1M
  • age of onset= 30-40
  • high risk= N. european, US caucasians, Canadians
  • middle= australia, S. African whites, S. Europeans
  • low: african blacks, orientals
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5
Q

Genetic factors

A
  • in a 1st degree family relative of a patient with MS, absolute risk of MS is: under 5% which equals 20-40x greater risk
  • in monozygotic twins: concordance rate for MS is 31%, and in dizygotic 5% (proof genetics alone is not solely responsible for disease)
  • presence of HLA-DR2 allele increases the risk of MS
  • MS is not a hereditary disease BUT patients may have a genetic predisposition
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6
Q

why is MS not hereditary?

A

-b/c we have not characterized the exact gene responsible for passing MS through the generation

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7
Q

Theories of MS

A

1) infectious theory
- measles, mumps, rubella, EBV, HHV-6
2) molecular mimicry
- shed a protein that looks similar to the myelin in the CNS
- phagocytic cells can’t tell the difference between the foreign Ag in the body and the myelin covering the nerves, so the phagocytes attack the myelin
3) autoimmune disease

  • the sequence of aa’s produced by these might look similar to the AA that covers nerves
  • the body might have trouble differentiating between the myelin and the foreign proteins coming in
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8
Q

MS as an Autoimmune disease

A
  • injuries or tissue damage- protein from an injury could be a trigger
  • macrophages, monocytes and dendritic cells- Ag presenting cells that are filters of the blood from foreign proteins
  • the foreign proteins flow through the blood; the Ag-presenting cells act like the filter in your blood and anything not supposed to be there will get picked up
  • they then stick this forgein protein to a naive T cell (aka non-activated T-helper cell)
  • activates T cell to turn into a Th1 inflammatory cell that drives the autoimmune inflammatory responses of MS
  • CD28 CD80 = B7.1
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9
Q

MS and the imbalance of the immune system

A
  • there is an overactive proliferation of inflammatory Th1 cells (Pro-inflamm»anti-inflamm)
  • we need Th0 cells to have a balance and equally proliferate into both Th1 and Th2
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10
Q

Do MS patients ever recover from the imbalance of Th1 and Th2 cells?

A

no- there are always more Th1

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11
Q

T-Cell Balance

A
  • there is a large immune deviation favouring the inflammatory Th1 cells over the protective Th2 (Th3) therefore they cannot suppress the inflammatory Th1 effects
  • they keep producing more and more mediators of inflammation, which induces the positive feedback of proliferation to make more Th1 cells, all turning on the same mediators
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12
Q

What are the predominate activated mediators of inflammation that Th1 turns on?

A

IL-12
IFN-gamma
TNF-alpha

(others: IL-2, IL-6)

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13
Q

What are the mediators activated by Th2 cells (and are therefore lacking)

A

IL-4
IL-10
TGF-beta

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14
Q

Generic overview steps of MS Immunology

A

1) activation
2) adhesion
3) invasion
4) reactivation
- > -> tissue damage in the CNS

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15
Q

How does the familiarization of that foreign protein cause myelin to be attacked?

A
  • mediators of inflammation induce and feedback of proliferation to make more Th1 cells for that specific protein
  • Th1 cells now recognize that one foreign protein that is similar to the myelin -> myelin is attacked
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16
Q

where does up-regulation of adhesion molecules occur?

A
  • in molecules on the endothelial surface of the blood brain barrier
  • this is caused by the mediators of inflammation
  • the blood brain barrier then becomes sticky like velcro to the Th1 cells
  • the Th1 cells keep sticking to the BBB and keep churning more inflammatory and adhesion mediators
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17
Q

What other up-regulation occurs at the BBB?

A
  • up-regulation of the metaloproteases
  • they loosen the integrity of the BBB of the endothelial cells that allows the T cells to pass through the BBB and into the CNS and therefore also into the cerebral spinal fluid
  • this generates the white spots of damage that we see in an MRI
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18
Q

Do Th1 cells cause direct myelin damage?

A

no- because they are an immune cell

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19
Q

How do the Th1 cells end up causing their damage to the myelin?

A
  • Th1 cells start becoming reactivated ALL over again INSIDE THE BBB on the CNS side
  • inflammatory mediators of the reactivated Th1 cells activates the productions of the ABs and the other phagocytic cells (i.e. macrophages, plasma cells, etc)
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20
Q

true or false: the mediators of inflammation released by the Th1 cells are only released in the CNS

A

true- since they are only within the CNS they start to eat away at the myelin that coats the brain

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21
Q

What mediators are re-activated within the CNS?

A

cytotoxic t-cells, macrophages, large granular lymphocytes neutrophils, b-lymphocytes (which release antibodies)
(the macrophages themselves can also proliferate into large granular lymphocytes and neutrophils)

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22
Q

What are the antigen-presenting cells?

A

macrophages, monocytes, dendritic cells

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23
Q

how do the macrophages contribute to MS?

A
  • they eat up the myelin

- also activate the B lymphocytes that turn into inflammatory antibodies

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24
Q

How do B-lymphocytes contribute to MS?

A
  • produce AB’s

- phagocytic function

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25
Q

true or false: here are normally antibodies in the CSF

A

false- normally none, but an MS patient would show ABs

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26
Q

What is a consequence of having ABs in the CNS?

A

-means they have a full blown immune response to myelin

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27
Q

What makes the myelin in the CNS?

A

-oligodendrocytes

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28
Q

true or false: can the oligodendrocytes regenerate

A

false

  • in the PNS the Schwann cells produce the myelin and they can regenerate
  • but the oligodendrocytes CANNOT regenerate
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29
Q

What are the ABs that are found in the CNS in MS?

A

IgG

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30
Q

true or false: MS is a white matter disease

A

true

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31
Q

what happens to the propagation of electrical nerve signals in MS?

A
  • the electrical signal dissipates out of the holes where the myelin has been eaten away (leaves an exposed de-myelinated axon)
  • this prevents a full signal
32
Q

what happens to the axons eventually?

A

-the nerve cell will eventually die b/c the whole axon coated with myelin gets eaten away

33
Q

what cognitive nerve damage is usually lost during MS?

A

-usually short term memory is lost and the long term memory stays

34
Q

Physically disability of MS

A
  • median time to requiring can/crutch= 15 years

- median time to wheelchair confinement= 25 years

35
Q

is it better to develop the disease earlier or later on in life?

A

later
-if you are 20 y/o at diagnosis, you will be more affected later on in life than a 45 y/o (the older you are the less it will affect you before you die)

36
Q

What are the current opinions regarding treatment effects?

A
  • the theoretical model states early treatment is critical

- early treatment has the greatest potential impact on both pathological and clinical course

37
Q

What happens if there is no treatment?

A

-the degree of disability that occurs without treatment progresses quickly

38
Q

What happens if there is early intervention

A
  • right at diagnosis- the neurological disability is minimal
  • the earlier the treatment, the greater the prognosis
  • this may prolong serious outcomes
  • later intervention will still prolong a person’s life and lessen their disability, but not as much as early treatment
39
Q

What are some clinical diagnostic tools to examine cerebro-spinal fluid?

A
  • oligoclonal IgG bands (in >95% patients with clinically definite MS (CDMS))
  • severe headaches post-CSF sample
40
Q

The MRI as a diagnostic tool

A
  • secondary indicator of disease progression

- measure brain atrophy and brain size; measure size, number, and location of lesions

41
Q

true or false: there is a direct correlation between a SPECIFIC LESION of a neutron in the brain and a SPECIFIC FUNCTION

A

false

42
Q

Can you have a lot of lesions and still be healthy?

A

yes

BUT ONE lesion by chance could be the trigger

43
Q

true or false: there is a direct correlation between NUMBER of lesions and PROGRESSION of disease

A

false

HOWEVER- the more lesions that you have, the more chance you will have one that causes severe effects

44
Q

What can the measure of brain atrophy and brain size show?

A

-severity, number of relapses, and time

45
Q

What can the measure of size, location and number of lesions indicate?

A

-they are all indicators of disease progression

46
Q

What happens to the ventricles in the brain as the disease progresses

A

they start to deteriorate

47
Q

SLIDE 21 IS THE MOST IMPORTANT SLIDE- MS: pathological vs. clinical course of disease

A

aka GO LOOK AT IT AND STUDY IT

48
Q

clinical threshold

A
  • this is where the symptoms start to be seen-
  • early on, we may go back under this threshold (and not see symptoms), but eventually we will get to a point where we never go back under (b/c demyelination has been occurring the whole time)
49
Q

First clinical attack

A
  • when the first symptom is seen
  • the demyelination made the clinical threshold be met for a short period of time, but then they stop experiencing those
  • this is often a clinically isolated event (1 attack where symptoms are felt and then not experienced again)
50
Q

demyelination process during the course of the disease

A
  • w demyelination may occur so that a clinical attack occurs, but symptoms may be sporadic
  • while the patient may not be experiencing symptoms at all times, the demyelination is still proceeding
  • as the disease progresses, and demyelination worsens, the attacks above the clinical threshold become shorter apart
51
Q

What happens early on before we even touch the clinical threshold

A
  • activation of Th1 cells due to foreign antigen
  • recruiting more and more- through the pathophysiology we learned- into BBB- all of a sudden there will be a symptom
  • if you drop below that clinical threshold you may feel fine but you are most likely not fine
52
Q

After first clinical attack

A

-body tries to recover- no symptoms
-years might go by and more symptoms could occur again (i.e. a second bout of immune cells)
-keep building until the next attack
-2 attacks anytime in life could confirm MS
(aka clinically isolated syndrome)

53
Q

Diagnosis of MS

A
  • each attack has to be >24 hours
  • separated by a second attack that is a minimum of 30 days apart from each other
  • ie foot drag one week, next week optic neuritis does NO = 2 attacks -> if the optic neuritis was 30 days later it would be a second attack
54
Q

progression of disease (and attacks)

A
  • as the disease progresses the attacks become shorter in duration apart- more accelerated attacks hitting different parts of the body
  • MS moves into RRMS (constantly relapsing and remitting)
55
Q

Above clinical threshold

A
  • eventually might stay above threshold and that means that the symptoms will always be constant
  • we are now onto secondary progressive MS (some are primary- i.e. males)
56
Q

true or false: steroids can help to alter the course of MS

A

false

-steroids can only suppress the disease, not alter its course/severity

57
Q

What could happen with axonal loss (or at least eventually)

A
  • likely in a wheelchair

- death could occur

58
Q

What are the symptoms induced by MS

A

-fatigue and weakness
-bladder control
-neuropathic pain
-cognitive defects
-optic neuritis
-sexually dysfunction
-ataxia
-depression
(these are listed in highest to lowest ranging from 90% to 50%)

59
Q

Why does a patient with MS feel fatigued and weak

A
  • hole in axon- electricity runs out of holes
  • body has to work harder to get an output
  • therefore more energy is being used
60
Q

Why does a patient with MS have troubles with bladder control

A
  • electrical circuit- we have inhibitory and excitatory stimuli that tell us when we need to pee
  • if the nerve got damage that regulates this there might be over excitation of the bladder, or they could suffer from urinary retention (can’t pee)
  • an MS patient is more likely to die from UTIs etc (common 2nd result of MS)
61
Q

why does a patient with MS experience neuropathic pain

A

b/c the nerves are being damaged

62
Q

why does a patient with MS experience cognitive defects

A

killing of nerve cells prevents memory, ect

63
Q

why does a patient with MS experience optic neuritis

A

there is often damage to the optic nerve (the myelin coating) which then affects vision

64
Q

Why does a patient with MS experience ataxia

A
  • this is a loss of body movement
  • patient has difficult time walking (drunk-like) b/c the cerebellum gets attacked by MS
  • leads to balance issues
65
Q

Why does a patient with MS experience depression

A

all these different symptoms lead to depression b/c of what they do and you also can’t do much w/o feeing symptoms

66
Q

what are the various clinical types of MS

A

1) relapsing-remitting MS
2) primary progressive MS
3) secondary progressive MS
4) progressive relapsing MS

67
Q

relapsing-remitting MS

A

McDonald Clinical Criteria:

  • clinical attack(s) +/- MRI must show dissemination in time and space
  • 2 clinical attacks where each attack lasted greater than 24 hours
  • dissemination in time (at least 30 days apart)
  • does not require a + MRI (b/c MRI is a secondary diagnoses of disease progression)
68
Q

primary progressive MS

A

-most males do to this route after RRMS

69
Q

secondary progressive MS

A
  • most females develop from RRMS to this; 80% of all RRMS develop into this AFTER RRMS
  • always recover… but eventually there is one that we never recover from
70
Q

Progressive relapsing MS

A
  • one domain of the body is still relapsing and remitting, while another domain is progressing and not remitting
  • this is likely a final stage before it starts to get ugly
71
Q

MRI Criteria: RRMS

Definitive Diagnosis

A
  • 1+ Gad+ or 9 peri-ventricular lesions
  • 1+ infratentorial lesion
  • 1+ juxtacortical lesion
  • 1+ spinal cord lesion
  • pt must have 3 out of 4 criteria for MRi to fulfill dissemination in space criteria OR MRI criteria depicting dissemination in time plus 1 clinical attack
72
Q

dissemination

A

the act of spreading something, especially information, widely; circulation.

73
Q

Clinically Isolated Syndrome (CIS)

A

-1 attack that lasted greater than 24 hours EVEN with a +/-ve MRI that doesn’t fulfill McDonald criteria in regard to dissemination in time and/or space
-NO definitive diagnosis of MS
(although if the MRI is indeed positive there is an 80% chance of them eventually developing MS)

74
Q

RRMS: MB/AB IMA drug coverage

A

(interferon- beta 1a and 1b and glatiramer acetate)

  • need 2 attacks where each attack lasts greater than 24 hours and is separated in space by at least 30 days with a positive MRI that meets McDonald criteria within the past 2 years
  • the attacks must be within 2 years for the province to cover, EVEN IF you are diagnosed with MS)
  • therefore if we treat these people earlier we could prevent the longer term health care expenses
75
Q

besides the major health costs, what is the negative consequence of the insurance coverage policy in place right now

A

-this restriction of drug coverage only makes progression of the disease worse (as people may not get all the therapy that they need)

76
Q

Immunomodulatory (IMA) Therapy for RRMS

A

-interferon beta 1a 30ug IM once weekly
-interferon beta 1b 8 M.U. sc EOD
0interferon beta 1a 44ug sc tiw
-glatiramer acetate 20mg sc qd
-these drugs are immunomodulatry agents
THESE DRUGS REDUCE THE IMMUNE RESPONSE BY SUPPRESSING Th1 INFLAMMATORY PRODUCTION
AND TRY TO MAKE THE T-CELL BALANCE ACTUALLY EQUAL AGAIN (inflammatory-> protective)

Pathophysiology Final (10 decks)

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