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PMCOL 412 > Stroke I & II > Flashcards

Stroke I & II Flashcards

1
Q

Stroke: definition

A

Brain damage and dysfunction that results from a

reduction in blood flow to the brain

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2
Q

Stroke vs. ischemia

A

stroke results from brain ischemia

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3
Q

Ischemia

A

reduction in blood flow to a tissue
Cerebral ischemia can lead to stroke
But stroke doesn’t equal ischemia

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4
Q

Transient ischemic attacks (TIAs)

A

resolves within 24 hours

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5
Q

Strokes effect:

___ % of deaths worldwide and ______ canadians per year

A

10%; 62,000

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6
Q

Stroke is the __ leading cause of death, and ___ leading cause of adult disability

A

3rd cause of death; 1st leading cause of disability

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7
Q

Limited treatment options due to

A

Delays with stroke recognition, diagnosis

The multifaceted pathophysiology of the ischemic cascade

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8
Q

Stroke warning signs (5)

A

Weakness, trouble speaking, vision problems, headache, dizziness

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9
Q

Signs of stroke: FAST

A

Face–is it drooping
Arms–can you raise both
Speech–is it slurred/jumbled
Time to call 911

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10
Q

Non-modifiable Risk factors for stroke

A
  • Age (most important)
  • Gender (more in men, but changes with age–older women have fewer strokes but worse outcomes)
  • Family history
  • Ethnicity (genetics and socioeconomic factors)
  • Prior stroke or Transient Ischemic attack (TIA)
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11
Q

Symptoms of stroke depend on…

A

where loss of blood flow occurs

usually unilateral–hence the unilateral weakness, drooping etc.

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12
Q

Modifiable Risk factors for stroke

A
  • High blood pressure (hypertension)
  • High blood cholesterol
  • Arthesclerosis
  • Atrial fibrillation
  • Diabetes
  • Being overweight
  • Excessive alcohol consumption
  • Physical inactivity
  • Smoking
  • Stress
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13
Q

1 Modifiable Risk factor for stroke

A

High blood pressure (hypertension)

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14
Q

How does atrial fibrillation increase stroke risk

A

poor emptying of the heart can lead to the formation of blood clots that can then be shunted throughout the body and into the brain where they can get lodged –> stroke

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15
Q

2 Types of strokes

A

Hemorrhagic stroke

Ischemic stroke

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16
Q

Hemorrhagic stroke–definition

A

stroke caused by the rupture of blood vessel in the brain

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17
Q

2 types of Hemorrhagic stroke

A 
Subarachnoid hemorrhage (SAH)
Intracerebral hemorrhage (ICH)
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18
Q

Cause of Hemorrhagic strokes

A

result from trauma, ruptured aneurysms, arteriovenous malformations

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19
Q

Stroke type by percentage

A

15% hemorrhagic; 85% ischeic

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20
Q

Subarachnoid hemorrhage (SAH)–where does it occur and what is the risk of mortality

A

Bleeding in subarachnoid space
• 40-50% early mortality
• Causes Raised intracranial pressure, Vasospasm

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21
Q

Intracerebral hemorrhage (ICH)–where and mortality

A

Vessel ruptures leaking blood into parenchyma
Causes mechanical disruption, blood toxicity
• 30-50% mortality

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22
Q

common arteries affected by ICH and why

A

Often lenticolostriate arteries

because they are small arteries coming off larger ones–> high resistance and heavy flow; more prone to breakage

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23
Q

Why does hypertension increase risk of ICH

A

hypertension weakens vessels making them more prone to rupture

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24
Q

Blood leeching into the brain–effects; factors in blood and their effects

A

Blood is toxic to brain cells
When blood leeches into the parenchyma they can release thrombin, iron which are toxic to parenchyma and worsen damage after a stroke

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25
Q

Effects of a SAH

A

causes compression of brain due to increased pressure from bleeding

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26
Q

Vasospasm

A

major complication of SAHs

Worsens stroke symptoms as it leads to global ischemia due to spasms of the vessels causing all vessels to constrict

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27
Q

Vasospasm after-effects

A

If they survive will show less peripheral deficits but global deficits

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28
Q

Ischemic stroke–2 types

A

Global and focal

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29
Q

Global ischemic stroke results from…

A

reduced blood flow to

the entire brain–usually due to heart-attack (less blood to get to brain)

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30
Q

Focal ischemic stroke results from…

A

an occlusion of a vessel in

the brain – typically middle cerebral artery

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31
Q

Things that can cause an occlusion of a vessel

A

Thrombus–irritation in vessel leads to clot formation

Embolus–clot forms elsewhere and travels to the area it occludes

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32
Q

Stroke symptoms depend on

A

size and location of occlusion, which depends on vasculature (which vessel is occluded and whether there is good Collateral blood supply)

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33
Q

MCA occlusions–Proximal

A

Occulsion more proximally; effects both the cortex and straitum
Leads to Hemiparalysis, aphasia

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34
Q

MCA occlusions–distal

A

occlusion more distally (further down the vessel)
leads to cortical damage (not striatal damage b/c blood can reach there before occlusion)
More focal neurological signs (affects less area than a proximal occlusion)
Blockage of M2 segment and beyond

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35
Q

Lenticulostriate arteries

A

Fragile arteries prone to rupture–especially w/ Hypertension (vessels become stiffer, more fragile)
• Lacunar infarcts, silent or variable neurological signs-harder to notice

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36
Q

Factors defining global CBF

A

CBF = cerebral blood flow

Defined by cerebral vascular resistance (CVR); blood pressure (mean arterial pressure, MAP); intracranial pressure (ICP)

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37
Q

CBF =

A

CPP/CVR

note: cpp is cerebral perfusion pressure

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38
Q

CPP =

A

MAP - ICP

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39
Q

Normal CBF perfusion rate

A

~50ml/100g/min

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40
Q

CBF <10ml/100g/min

A

Ischemia in the stroke core

Causes rapid and irreversible cell death

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41
Q

Stroke core cell death due to

A
  • loss of ion homeostasis
  • anoxic depolarization
  • necrosis
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42
Q

CBF <20ml/100g/min –

A

Ischemia in penumbra
Partial blood flow, electrically /functionally silent but alive
(at least temporarily)

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43
Q

Stroke penumbra cell death

A

• delayed cell death

Both Necrosis and apoptosis (programmed cell death)

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44
Q

CBF in SAH (explain using CBF equations)

A

Bleed cause increase in ICP (therefore CPP decreases)
Vasospasm increases CVR
Therefore CPP =MAP - ICP and CBF = CPP/CVR
CBF is decreased causing global ischemia

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45
Q

Ischemia is any CBF below

A

below normal perfusion rate

Ischemia <50ml/100g/min

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46
Q

CBF between 2-50ml/100g/min

A

Once at 70% of CBF start seeing issues

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47
Q

70% CBF causes

A

decreased protein synth (to save energy)

per–infarct depol (decreased bloodflow –> spont depol)

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48
Q

50% CBF causes

A

functional silencing as seen on SEP and EEG

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49
Q

30% CBF causes

A

anaerobic metabolism –> lactic acid production –> acidification of tissues (lacticacidosis)

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50
Q

20% CBF causes

A

ATP depletion; anoxic depol

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51
Q

Ischemic cascade

A
  • Loss of aerobic metabolism
  • Loss of ATP
  • Na/K-ATPase failure
  • Depolarization
  • Excitotoxicity
  • Increase in intracellular Na+, Ca++, Cl-
  • Cytotoxic edema
  • Protease activation
  • Free radicals
  • Lipid peroxidation
  • Mitochondrial failure (MPTP)
  • Inflammation
  • Apoptosis
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52
Q

Gradient in bloodflow around the core means

A

diff amount of bloodflow = diff consequences (different amounts of cell death)

53
Q

Apoptosis

A

safer but requires some energy
can’t occur w/o energy
Cell shrinks, chromatin condences

54
Q

Necrosis

A

cell swells and lyses
release of toxic cell insides to surrounding tissue
don’t need energy for it

55
Q

Extrinsic Apoptosis Pathway

A

TNF and Fas R bind to receptor on the cell –> Fas-associated protein with death domain (FADD) –> Death inducing signalling complex (DISC) (made up of R, FADD and caspase) –> activates caspase 3 –> breakdown of caspase substrates and DNA fragmentation

56
Q

Intrinsic Apoptosis Pathway

A

mitochondrial release of citochrome c –> Aparf-1 –> activate pro-caspase 9 –> caspase 9 –> activates caspase 3 –> apoptosis

57
Q

Poor outcome in SAH due to

A
  • ICP (reduces CPP and CBF)
  • Vasospasm–> tied o inflammation or blood toxicity
  • all contribute to global reductions in blood flow
58
Q

Outcome of SAH

A

50% mortality, 30% of survivors are dependent (due to cognitive decline)

59
Q

ICH Damage

A

bleeding in the brain causes mechanical damage and herniation
Hematoma expands with time –> rebleeding
Extravasation and lysis of red blood cells release thrombin and zinc (toxic to cells)

60
Q

Preventing damage due to ischemia

A

Use neuroptoection to prevent the delayed death in the penumbra

61
Q

2 main ways to prevent further damage in Punumbra

A
  • Restoration of blood flow (most effective)

- interference with ischemic cascade

62
Q

Restoring blood flow–downsides

A

takes time to recognize the issue, transport, triaging, imaging (mean time to complete CT is 4 hrs)
Damage is often already done

63
Q

Interfering with ischemic cascade

A

many targets, many agents to interfere already exist

BUT no neuroprotective strategy thus far has shown to be effective

64
Q

Restoring blood flow

A

thrombolysis (clot busting) is the main method of restoring blood flow
new focus on increasing collateral blood flow

65
Q

Action of rt-PA

A

Thrombolysis by converting plasminogen to plasmin, which degrades fibrin and degrades the clot

66
Q

Blood clots are made of

A

platelets and fibrin (generated from fibrinogen bythrombin)

67
Q

Only FDA approved clinically proven treatment for acute stroke

A

rt-PA (recombinant tissue plasminogen activator)

68
Q

Outcomes of rt-PA

A

improves outcome in some after 3 hrs (reduces damage)

significant increase in Rankin scores in patients treated w/in 4.5 hrs

69
Q

Measure of stroke outcome

A

modified Rankin scores
measure functional independence
Scores 0-2 = no disability to slight disability

70
Q

Limitations of rt-PA

A
  • If admin 4hrs post-stroke risk of hemorrhage is too high (increased mortality after 4hrs)
  • Ineffective in 60% of patients
  • Low use due to door to treatment time exceeding 4 hours
  • Proximal occlusions are too large and well formed for rt-PA to degrade
71
Q

How we use rt-PA

A

IV infusion due to short half-life (4-6 mins)

Can also do intra-arterial admin

72
Q

rt-PA revascularization rates for acute ischemic strokes for ICA, MCA and basilar occlusions AND why

A

ICA terminus–6%
MCA trunk occlusions–30%
Basilar occlusions–30%
Proximal occlusions are too large and well formed for rt-PA to degrade

73
Q

rt-PA Risks

A
  • activation of MMPS
  • BBB damage
  • hemorrhage
  • Neurotoxic interactions with NMDARs
74
Q

rt-PA derivatives

A

Tenectaplase and desmoteplase

75
Q

Tenecteplase

A

rt-PA derivative that is more fibrin-specific; has a longer half-life (allows IV bolous)

BUT phase III shows no benefit over rt-PA

76
Q

Desmoteplase

A

More specific, less neurotoxic rt-PA derivative
from saliva of vampire bat
Better than placebo, not tested against rt-PA

77
Q

Sonothrombolysis

A

using ultrasound to break clot

78
Q

Intra-aterial treatment

A

endovascular therapy/mechanical thrombectomy
use of new catheters to navigate the cerebral vasculator
ex. MR. CLEAN and ESCAPE

79
Q

Intra-arterial treatment downsides

A

require more specialized centers; less available
paradoxically even in cases with complete recanalization, outcome may be more–outcome largely tied to collateral blood flow

80
Q

Collateral therapeutics–use

A

can be used alone or in conjunction with neuro-protectives or thromblytic drugs

81
Q

Collateral therapeutics–approaches

A

increase CBF and/or dilate by altering:

  • head position
  • transient aortic occlusion
  • spenopaltine ganglion stimulation
  • volume expansion
  • external compression devices
  • pharmacological augmentation
82
Q

Concept behind Collateral therapeutics

A

Normally when MCA is working fine ACA blood won’t flow to same region but when MCA is occluded ACA blood can flow to regions of the MCA’s territory preventing ischemia
Using the non-primary vessel of an area to provide bloodflow when the primary vessel is occluded

83
Q

Pharmacological flow augmentation

A

Collateral vasodilators–NO modulation or Calcium channel blockers
Hypertensive therapy–increase global CBF
PDE inhibitors

84
Q

NO modulation

A

To increase collateral vasodilation
L-arginine (NO precurors)
Inhaled NO
NO donors–sodium nitroprusside, nitroglycerin (BUT non-selective)

85
Q

Calcium Channel blockers

A

L-Type, minodiprine, nicardipine

Used as collateral vasodilators

86
Q

Pharmacological flow augmentation via Collateral Vasodilators: Issues

A

Venous and peripheral steal

87
Q

Venous steal

A

tissue surrounding ischemic area has lower pressure than ischemic zone therefore less blood to ischemic area
Prevents blood flow to ischemic area, even when there is more blood to the brain

88
Q

Peripheral steal

A

vasodilation in periphery decreases blood flow to the head

exception: inhaled NO seems to prefer brain vessels –> less issues of peripheral steal

89
Q

Hypertensive therapy

A

increase global CBF
ex. Phenylephrine (alpha-1 adrenegeric receptor AGONIST)
Potent vasopressor, more potent in periphery than brain
BUT hypertension is a risk factor for stroke and increasing it is dangerous

90
Q

PDE (phospphodiesterase) inhibitors

A

ex. PDE3, milrinone, cilostazol
PDE3 localized in cardiac and smooth muscle
Increases cAMP causing increased contraction in cardiac mucle and increased relaxation in smooth muscle (ex. of vasculature)
Increased cardiac output and vasodilation

91
Q

Good collateral blood flow = ____ stroke

A

smaller stroke

92
Q

Why haven’t neuroprotective strategies worked so far

A

Financial motvation leads drugs with minimal evidence to move ahead when they shouldn’t
Look at the wrong thing in neuroprotective models (look at stroke size rather than rankin score–short term vs longterm outcomes)

93
Q

Difficulties with neuroprotection

A

Preclinical and clinical work isn’t aligned–outcomes, ages, endpoints, dosage, severity of stroke
Even strategies that fulfil stair criteria can fail

94
Q

STAIR (stroke therapy academic industry round table)

A

Criteria surrounding models, dosages, appropriate endpoints in the study of stroke therapies

95
Q

NXY-059

A

free-radical scaenger
preclinical studies suggested it worked
SAINTI showed improved disability but not replicated in SAINT II–showed no benefit

96
Q

Issues with NXY-059

A

may only cross the BBB in small quantities
low methodological quality–difference in preclinical and SAINT trials
preclinical evidence was’t that strong and didn’t fully meet STAIR

97
Q

Magnesium as stroke therapy

A

failed phase III

thought to reduce NMDA activation and decrease excitotoxicity

98
Q

DP-b99 as stroke therapy

A

Failed phase III

supposed to work in ion dyshomeostatsis and intra-cellular Calcium elevation

99
Q

Albumin as stroke therapy

A

Thought to protect the BBB

failed phase III

100
Q

Ebselen

A

Potential therapy–free radical scavenger

Glytathione-peroxidase like compound

101
Q

Ebselen: mechanism

A

protect against neuronal death and oxidative damage from focal ischemia
can be administered as late as 24 hours after MCAO

102
Q

Minocylcine

A

Broad-spectrum tetracycline antibiotic
mixed results in randomixed clinical trials;
may extend window for rt-PA by protecting BBB and vasculature

103
Q

Minocylcine: actions

A
  • anti-inflammatory
  • anti-apoptotic
  • MMP-inhibitor (preserves BBB)
  • neuroprotective in animal models
  • Prevents infections, hyperthermia (causes of secondary damage)
104
Q

Anti–inflammatories for stroke

A

Minocycline
Fingolimod
Natalizumab

105
Q

Fingolimod

A

inhibitory of sphingosine-1 phosphate receptors –> limits infiltraition of lymphocyte into brain and local activation of microglia and macrophages (anti-inflam)
pre-clinical shows reduced infarct size

106
Q

Natalizumab

A

Humanized CD49d antibody that blocks alpha4-integrin

reduces leukocyte invasion into brain post-stroke

107
Q

Fingolimod and natizumab can be combined with…

A

rt-PA

108
Q

Statins as stroke therapy (ex. lovastatin)

A

lower cholesterol and reduce heart disease
also importer blood flow (increases NO)
Anti-inflammatory
antioxidant
(alters many regions of ischemic cascade)
promising in preclinical and clinical studies

109
Q

NA-1 -mechanism

A

potential therapy that works via inhibition of the NMDAR signalling (do not block NMDARs)–inhibits interaction of PSD-95 w/ the NMDARs

110
Q

NA-1 efficacy

A

reduces infarct in rodents, neuroprotective in primates and after small stroke sin humans

111
Q

ESCAPE NA-1 trial

A

Phase III trial combining endovascular therapy with NA-1
Safe But missed primary efficacy endpoint
Beneficial in those who didn’t have rt-PA treatment

112
Q

IL-1 antagonism

A

IL_1 = inflammatory cytosine release during ischemia
IL-1ra is a naturally occurring competitive antagonist
Reverses immune suppression associated with stroke

113
Q

IL-1 antag efficacy

A

38% reduction in infarct voume

IV admin w/in 6hrs is safe and well tolerated

114
Q

Hypothermia as a stroke therapy may

A
  • prevent formation of free radicals
  • show cellular metabolism
  • reduce BBB disruption
  • reduce glut release
  • reduce inflammation
  • diminish PKC activity
115
Q

Inducing hypothermia: support

A

affects many mechanisms in ischemic cascade–lots of pre-clincal support
issues with feasibility–hard to cool and rewarm

116
Q

Inducing hypothermia in humans: complications

A

shivering, pneumonia, infections, hypotension, cardiac arrhythmia, hemorrhage, increased intracranial pressure during rewarming

117
Q

Potential Therapies for SAH

A
  • prevent rebleeding
  • reduce ICP
  • Reduce vasospasm
  • reduce inflammation
    focus primarily on ICP and vasospam
118
Q

SAH therapy: prevent rebleeding

A

~20%

surgical intervention, clip ruptured aneurysms

119
Q

SAH therapy: Reduce ICP

A

Lower pressure in head
elevate bed
IV mannitol and other osmotic agents
use diuretics

120
Q

SAH therapy: reduce vasospasm

A

monitor blood volume (hypovolemia can trigger it)
Use L-type channel blocker (nimodipine)
PDE III inhibitors (milrinone, cilostrazol)
Ryanodine receptor inhibitor (dantrolene)

121
Q

L-type channel blocker (nimodipine) for SAH

A

impairs vascular tone, can be neuroprotective

122
Q

PDE III inhibitors (milrinone, cilostrazol) for SAH

A

vasodilator, inotropic (increases heart contractility)

123
Q

Ryanodine receptor inhibitor (dantrolene) for SAH

A

reduces intracellular calcium release

124
Q

SAH therapy: Reduce inflammation

A

methylpredinisone (synthetic corticosteroud)

Etanercept (TNF-alpha antagonist, inflammatory and vascular effects)

125
Q

Potential therapies for ICH

A

Reducing hematoma
reducing hematoma expansion
Prevnting secondary damage due to blood toxicity

126
Q

ICH therapy: reducing hematoma

A

Craniotomy or minimally invasive aspiration

127
Q

ICH therapy: reducing hematoma expansion

A 
Hemostatic therapy (activated coagulation factor VIIa &amp; prothrmic complex concentration prevents rebleeding )
Blood pressure management (reduce pressure on vessles--reduce to <130 mmHg)
128
Q

ICH therapy: preventing secondary damage due to blood toxicity

A 
hypothermia, minocycline, albumin
Iron chelators (ex. DFO)

PMCOL 412 (35 decks)

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