Stroke I & II Flashcards
Stroke: definition
Brain damage and dysfunction that results from a
reduction in blood flow to the brain
Stroke vs. ischemia
stroke results from brain ischemia
Ischemia
reduction in blood flow to a tissue
Cerebral ischemia can lead to stroke
But stroke doesn’t equal ischemia
Transient ischemic attacks (TIAs)
resolves within 24 hours
Strokes effect:
___ % of deaths worldwide and ______ canadians per year
10%; 62,000
Stroke is the __ leading cause of death, and ___ leading cause of adult disability
3rd cause of death; 1st leading cause of disability
Limited treatment options due to
Delays with stroke recognition, diagnosis
The multifaceted pathophysiology of the ischemic cascade
Stroke warning signs (5)
Weakness, trouble speaking, vision problems, headache, dizziness
Signs of stroke: FAST
Face–is it drooping
Arms–can you raise both
Speech–is it slurred/jumbled
Time to call 911
Non-modifiable Risk factors for stroke
- 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)
Symptoms of stroke depend on…
where loss of blood flow occurs
usually unilateral–hence the unilateral weakness, drooping etc.
Modifiable Risk factors for stroke
- High blood pressure (hypertension)
- High blood cholesterol
- Arthesclerosis
- Atrial fibrillation
- Diabetes
- Being overweight
- Excessive alcohol consumption
- Physical inactivity
- Smoking
- Stress
1 Modifiable Risk factor for stroke
High blood pressure (hypertension)
How does atrial fibrillation increase stroke risk
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
2 Types of strokes
Hemorrhagic stroke
Ischemic stroke
Hemorrhagic stroke–definition
stroke caused by the rupture of blood vessel in the brain
2 types of Hemorrhagic stroke
Subarachnoid hemorrhage (SAH) Intracerebral hemorrhage (ICH)
Cause of Hemorrhagic strokes
result from trauma, ruptured aneurysms, arteriovenous malformations
Stroke type by percentage
15% hemorrhagic; 85% ischeic
Subarachnoid hemorrhage (SAH)–where does it occur and what is the risk of mortality
Bleeding in subarachnoid space
• 40-50% early mortality
• Causes Raised intracranial pressure, Vasospasm
Intracerebral hemorrhage (ICH)–where and mortality
Vessel ruptures leaking blood into parenchyma
Causes mechanical disruption, blood toxicity
• 30-50% mortality
common arteries affected by ICH and why
Often lenticolostriate arteries
because they are small arteries coming off larger ones–> high resistance and heavy flow; more prone to breakage
Why does hypertension increase risk of ICH
hypertension weakens vessels making them more prone to rupture
Blood leeching into the brain–effects; factors in blood and their effects
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
Effects of a SAH
causes compression of brain due to increased pressure from bleeding
Vasospasm
major complication of SAHs
Worsens stroke symptoms as it leads to global ischemia due to spasms of the vessels causing all vessels to constrict
Vasospasm after-effects
If they survive will show less peripheral deficits but global deficits
Ischemic stroke–2 types
Global and focal
Global ischemic stroke results from…
reduced blood flow to
the entire brain–usually due to heart-attack (less blood to get to brain)
Focal ischemic stroke results from…
an occlusion of a vessel in
the brain – typically middle cerebral artery
Things that can cause an occlusion of a vessel
Thrombus–irritation in vessel leads to clot formation
Embolus–clot forms elsewhere and travels to the area it occludes
Stroke symptoms depend on
size and location of occlusion, which depends on vasculature (which vessel is occluded and whether there is good Collateral blood supply)
MCA occlusions–Proximal
Occulsion more proximally; effects both the cortex and straitum
Leads to Hemiparalysis, aphasia
MCA occlusions–distal
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
Lenticulostriate arteries
Fragile arteries prone to rupture–especially w/ Hypertension (vessels become stiffer, more fragile)
• Lacunar infarcts, silent or variable neurological signs-harder to notice
Factors defining global CBF
CBF = cerebral blood flow
Defined by cerebral vascular resistance (CVR); blood pressure (mean arterial pressure, MAP); intracranial pressure (ICP)
CBF =
CPP/CVR
note: cpp is cerebral perfusion pressure
CPP =
MAP - ICP
Normal CBF perfusion rate
~50ml/100g/min
CBF <10ml/100g/min
Ischemia in the stroke core
Causes rapid and irreversible cell death
Stroke core cell death due to
- loss of ion homeostasis
- anoxic depolarization
- necrosis
CBF <20ml/100g/min –
Ischemia in penumbra
Partial blood flow, electrically /functionally silent but alive
(at least temporarily)
Stroke penumbra cell death
• delayed cell death
Both Necrosis and apoptosis (programmed cell death)
CBF in SAH (explain using CBF equations)
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
Ischemia is any CBF below
below normal perfusion rate
Ischemia <50ml/100g/min
CBF between 2-50ml/100g/min
Once at 70% of CBF start seeing issues
70% CBF causes
decreased protein synth (to save energy)
per–infarct depol (decreased bloodflow –> spont depol)
50% CBF causes
functional silencing as seen on SEP and EEG
30% CBF causes
anaerobic metabolism –> lactic acid production –> acidification of tissues (lacticacidosis)
20% CBF causes
ATP depletion; anoxic depol
Ischemic cascade
- 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
Gradient in bloodflow around the core means
diff amount of bloodflow = diff consequences (different amounts of cell death)
Apoptosis
safer but requires some energy
can’t occur w/o energy
Cell shrinks, chromatin condences
Necrosis
cell swells and lyses
release of toxic cell insides to surrounding tissue
don’t need energy for it
Extrinsic Apoptosis Pathway
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
Intrinsic Apoptosis Pathway
mitochondrial release of citochrome c –> Aparf-1 –> activate pro-caspase 9 –> caspase 9 –> activates caspase 3 –> apoptosis
Poor outcome in SAH due to
- ICP (reduces CPP and CBF)
- Vasospasm–> tied o inflammation or blood toxicity
- all contribute to global reductions in blood flow
Outcome of SAH
50% mortality, 30% of survivors are dependent (due to cognitive decline)
ICH Damage
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)
Preventing damage due to ischemia
Use neuroptoection to prevent the delayed death in the penumbra
2 main ways to prevent further damage in Punumbra
- Restoration of blood flow (most effective)
- interference with ischemic cascade
Restoring blood flow–downsides
takes time to recognize the issue, transport, triaging, imaging (mean time to complete CT is 4 hrs)
Damage is often already done
Interfering with ischemic cascade
many targets, many agents to interfere already exist
BUT no neuroprotective strategy thus far has shown to be effective
Restoring blood flow
thrombolysis (clot busting) is the main method of restoring blood flow
new focus on increasing collateral blood flow
Action of rt-PA
Thrombolysis by converting plasminogen to plasmin, which degrades fibrin and degrades the clot
Blood clots are made of
platelets and fibrin (generated from fibrinogen bythrombin)
Only FDA approved clinically proven treatment for acute stroke
rt-PA (recombinant tissue plasminogen activator)
Outcomes of rt-PA
improves outcome in some after 3 hrs (reduces damage)
significant increase in Rankin scores in patients treated w/in 4.5 hrs
Measure of stroke outcome
modified Rankin scores
measure functional independence
Scores 0-2 = no disability to slight disability
Limitations of rt-PA
- 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
How we use rt-PA
IV infusion due to short half-life (4-6 mins)
Can also do intra-arterial admin
rt-PA revascularization rates for acute ischemic strokes for ICA, MCA and basilar occlusions AND why
ICA terminus–6%
MCA trunk occlusions–30%
Basilar occlusions–30%
Proximal occlusions are too large and well formed for rt-PA to degrade
rt-PA Risks
- activation of MMPS
- BBB damage
- hemorrhage
- Neurotoxic interactions with NMDARs
rt-PA derivatives
Tenectaplase and desmoteplase
Tenecteplase
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
Desmoteplase
More specific, less neurotoxic rt-PA derivative
from saliva of vampire bat
Better than placebo, not tested against rt-PA
Sonothrombolysis
using ultrasound to break clot
Intra-aterial treatment
endovascular therapy/mechanical thrombectomy
use of new catheters to navigate the cerebral vasculator
ex. MR. CLEAN and ESCAPE
Intra-arterial treatment downsides
require more specialized centers; less available
paradoxically even in cases with complete recanalization, outcome may be more–outcome largely tied to collateral blood flow
Collateral therapeutics–use
can be used alone or in conjunction with neuro-protectives or thromblytic drugs
Collateral therapeutics–approaches
increase CBF and/or dilate by altering:
- head position
- transient aortic occlusion
- spenopaltine ganglion stimulation
- volume expansion
- external compression devices
- pharmacological augmentation
Concept behind Collateral therapeutics
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
Pharmacological flow augmentation
Collateral vasodilators–NO modulation or Calcium channel blockers
Hypertensive therapy–increase global CBF
PDE inhibitors
NO modulation
To increase collateral vasodilation
L-arginine (NO precurors)
Inhaled NO
NO donors–sodium nitroprusside, nitroglycerin (BUT non-selective)
Calcium Channel blockers
L-Type, minodiprine, nicardipine
Used as collateral vasodilators
Pharmacological flow augmentation via Collateral Vasodilators: Issues
Venous and peripheral steal
Venous steal
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
Peripheral steal
vasodilation in periphery decreases blood flow to the head
exception: inhaled NO seems to prefer brain vessels –> less issues of peripheral steal
Hypertensive therapy
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
PDE (phospphodiesterase) inhibitors
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
Good collateral blood flow = ____ stroke
smaller stroke
Why haven’t neuroprotective strategies worked so far
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)
Difficulties with neuroprotection
Preclinical and clinical work isn’t aligned–outcomes, ages, endpoints, dosage, severity of stroke
Even strategies that fulfil stair criteria can fail
STAIR (stroke therapy academic industry round table)
Criteria surrounding models, dosages, appropriate endpoints in the study of stroke therapies
NXY-059
free-radical scaenger
preclinical studies suggested it worked
SAINTI showed improved disability but not replicated in SAINT II–showed no benefit
Issues with NXY-059
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
Magnesium as stroke therapy
failed phase III
thought to reduce NMDA activation and decrease excitotoxicity
DP-b99 as stroke therapy
Failed phase III
supposed to work in ion dyshomeostatsis and intra-cellular Calcium elevation
Albumin as stroke therapy
Thought to protect the BBB
failed phase III
Ebselen
Potential therapy–free radical scavenger
Glytathione-peroxidase like compound
Ebselen: mechanism
protect against neuronal death and oxidative damage from focal ischemia
can be administered as late as 24 hours after MCAO
Minocylcine
Broad-spectrum tetracycline antibiotic
mixed results in randomixed clinical trials;
may extend window for rt-PA by protecting BBB and vasculature
Minocylcine: actions
- anti-inflammatory
- anti-apoptotic
- MMP-inhibitor (preserves BBB)
- neuroprotective in animal models
- Prevents infections, hyperthermia (causes of secondary damage)
Anti–inflammatories for stroke
Minocycline
Fingolimod
Natalizumab
Fingolimod
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
Natalizumab
Humanized CD49d antibody that blocks alpha4-integrin
reduces leukocyte invasion into brain post-stroke
Fingolimod and natizumab can be combined with…
rt-PA
Statins as stroke therapy (ex. lovastatin)
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
NA-1 -mechanism
potential therapy that works via inhibition of the NMDAR signalling (do not block NMDARs)–inhibits interaction of PSD-95 w/ the NMDARs
NA-1 efficacy
reduces infarct in rodents, neuroprotective in primates and after small stroke sin humans
ESCAPE NA-1 trial
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
IL-1 antagonism
IL_1 = inflammatory cytosine release during ischemia
IL-1ra is a naturally occurring competitive antagonist
Reverses immune suppression associated with stroke
IL-1 antag efficacy
38% reduction in infarct voume
IV admin w/in 6hrs is safe and well tolerated
Hypothermia as a stroke therapy may
- prevent formation of free radicals
- show cellular metabolism
- reduce BBB disruption
- reduce glut release
- reduce inflammation
- diminish PKC activity
Inducing hypothermia: support
affects many mechanisms in ischemic cascade–lots of pre-clincal support
issues with feasibility–hard to cool and rewarm
Inducing hypothermia in humans: complications
shivering, pneumonia, infections, hypotension, cardiac arrhythmia, hemorrhage, increased intracranial pressure during rewarming
Potential Therapies for SAH
- prevent rebleeding
- reduce ICP
- Reduce vasospasm
- reduce inflammation
focus primarily on ICP and vasospam
SAH therapy: prevent rebleeding
~20%
surgical intervention, clip ruptured aneurysms
SAH therapy: Reduce ICP
Lower pressure in head
elevate bed
IV mannitol and other osmotic agents
use diuretics
SAH therapy: reduce vasospasm
monitor blood volume (hypovolemia can trigger it)
Use L-type channel blocker (nimodipine)
PDE III inhibitors (milrinone, cilostrazol)
Ryanodine receptor inhibitor (dantrolene)
L-type channel blocker (nimodipine) for SAH
impairs vascular tone, can be neuroprotective
PDE III inhibitors (milrinone, cilostrazol) for SAH
vasodilator, inotropic (increases heart contractility)
Ryanodine receptor inhibitor (dantrolene) for SAH
reduces intracellular calcium release
SAH therapy: Reduce inflammation
methylpredinisone (synthetic corticosteroud)
Etanercept (TNF-alpha antagonist, inflammatory and vascular effects)
Potential therapies for ICH
Reducing hematoma
reducing hematoma expansion
Prevnting secondary damage due to blood toxicity
ICH therapy: reducing hematoma
Craniotomy or minimally invasive aspiration
ICH therapy: reducing hematoma expansion
Hemostatic therapy (activated coagulation factor VIIa & prothrmic complex concentration prevents rebleeding ) Blood pressure management (reduce pressure on vessles--reduce to <130 mmHg)
ICH therapy: preventing secondary damage due to blood toxicity
hypothermia, minocycline, albumin Iron chelators (ex. DFO)
