Stroke Flashcards
What is a stroke?
Brain damage and dysfunction that results from reduction in blood flow to the brain
- Stroke results from brain ischemia
What are treatment options for stroke?
- Few treatment options, only one clinically proven strategy
- Restore BF
- Because delays with stroke recognition/diagnosis
- Ischemic cascade - multifaceted pathophysiology
Strokes can be classified as ____ or ______
Strokes can be classified as hemorrhagic or ischemic
What is a hemorrhagic stroke?
What are two subtypes?
Hemorrhagic stroke - rupture of blood vessel in the brain (brain bleed)
- Subarachnoid hemorrhage (SAH)
- Bleeding in subarachnoid space
- 40-50% early mortality
- Raised intracranial pressure, vasospasm
- Intracerebral hemorrhage (ICH)
- Vessel ruptures leaking blood into parenchyma
- Mechanical disruption, blood toxicity
- Often lenticolostriate arteries
- More common with hypertension, diabetes
- 30-50% mortality
What is an ischemic stroke?
What are two types?
Ischemic strokes are caused by blockage rather than rupture, though rupture may happen later
- Global ischemic stroke
- Reduced BF to entire brain
- Heart attack
- Focal ischemic stroke
- occlusion of vessel in the brain - typically Middle Cerebral Artery
- Thrombus - blood clot in brain
- Embolus - came from another area & lodges in brain
- Thromboembolus most common (clots in heart travel to brain)
- occlusion of vessel in the brain - typically Middle Cerebral Artery
Stroke symptoms depend on _____ and ______ which depends on vasculature
- ______ vessel
- _______ blood supply
Stroke symptoms depend on size and location which depends on vasculature
- Occluded vessel
- Collateral blood supply
Middle Cerebral Artery Occlusions:
- Proximal (M1) occlusion
- ____ and ____ damage
- Symptoms:
- Severity
Middle Cerebral Artery Occlusions:
- Proximal (M1) occlusion
- cortical and striatal damage
- Symptoms: hemiparalysis (whole body) ; Aphasia
- Severity: Severe
- poor outcome
- M1 is early in MCA and thus supplies many regions
Middle Cerebral Artery Occlusions:
- Distal (M2) occlusions
- Damage
- Symptoms
- Severity
Distal M2 occlusions
- Cortical damage
- More focal neurological signs
- Severity depends on location of clot - more distal = less severe
Middle Cerebral Artery Occlusions
- Lenticulostriate arteries
- Lenticulostriate arteries
- Fragile arteries prone to rupture in response to hypertension
- Lacunar infarcts, silent or variable neurological signs
- often small ruptures of these vessels are asymptomatic
What is the result of ischemia is <10mL/100g/min (20%)?
- Rapid and irreversible cell death
- Anoxic depolarization → necrotic cell death
- Lose of ion homeostasis = anoxic depolarization
What is the result of ischemia <20mL/100g/min (20-40%)?
- Cells functionally silent but still allive
- Stroke “penumbra” - partial blood flow, electrically silent but alive
- Delayed cell death through apoptosis
What happens after severe ischemia (<20%) in core?
Anoxic Depolarization (Panx) → Necrosis → inflammation, local energy
13 Steps to the ischemic cascade:
- Loss of aerobic metabolism
- Neurons deprived of oxygen and glucose
- Loss of ATP, Acidosis
- Na/K-ATPase failure - excess of extracellular K+
- Depolarization (glutamate release)
- Excitotoxicity (more glutamate causing further depolarization)
- Increase in intracellular [Na] [Ca] [Cl] (2nd messenger systems; NMDA/AMPA/IP3)
- Cytotoxic edema - osmotic lysis
- Protease, kinase, lipase activation
- Increase free radicals
- Lipid peroxidation
- Mitochondrial failure (MPTP)
- Immune cell infiltration and inflammation
- damage to BBB
- Apoptosis
_______ maintain partial blood flow
Pial collaterals maintain partial blood flow
What are the pial collaterals?
- Collateral circulation
- Connected between distal segments that nourish
- Commonly between M1 segment and anterior cerebral artery
- Healthy collaterals increase Stroke outcome because retrograde BF into ischemic area
Describe the extrinsic pathway of apoptosis
- TNF and FasR
- Fas-associated protein with Death Domain (FADD)
- Death inducing signaling complex (DISC=R, FADD, Caspase 8)
- Disc joins with FADD
- Effector caspases → activate capsase 3
- Caspase cascade → apoptosis
What is the intrinsic method of apoptosis
- Mitochondrial release of Cytochrome-c
- Mitochondrial stress from ROS → pore in mitochondria → release of many things notably Cyto-C (apoptisome)
What are two possible secondary effects causing damage after stroke?
- Cortical Spinal Tract degeneration
- descending peripheral spinal tract damage
- Diaschisis
- Brain dysfunction distal to but connected with area of infarction
- Cortical stroke causing crossed damage in cerebellum
What are two main ways that damage due to ischemia might be lessened
- Cell death in the core is immediate, but delayed death in penumbra offers hope for neuroprotection
- Restore blood flow
- Timing
- Interfere with ischemic cascade
- Restore blood flow
What is thrombolysis?
- Clot busting with rt-PA which cleaves fibrin (component of blood clots)
- Goal is to restore blood flow
What is endovascular therapy
- mechanical device inserted into clot
- intra-arterial therapy
- New catheters can navigate into cerebral vasculature
- Local thrombolytic delivery and or mechanical thrombectomy
- May be effective up to 24 hours after stroke (only in proximal stroke - can’t get catheter to distal)
Blood clots are made up primarily of ____ and ______
Thrombolysis with _______works by cleaving fibrin
____ is only FDA approved clinically proven tx of acute stroke
Blood clots are made up primarily of fibrin (generated from fibrinogen by thrombin) and platelets
Thrombolysis with recombinant tissue plasminogen activator (rt-PA) works by cleaving fibrin
rt-PA is only FDA approved clinically proven tx of acute stroke
After how long is rt-PA no longer effective?
After 4.5hours post onset
What are collateral therapeutics?
8 Approaches?
- Because collaterals predict infarct growth and response to therapy question arose whether we can improve collaterals to improve outcome
- Approaches
- increase collateral blood flow and/or dilate
- Head position
- Transient aortic occlusion
- Sphenopalatine ganglion stimulation
- Volume expansion
- External compression devices
- pharmacological augmentation
- remote ischemia
How is Pharmacological flow augmentation used to improve collateral blood flow? (2)
- Nitric oxide dependent vasodilators
- Ach
- Bradykinin
- Substance P
- Adenosine
- Increase Ca++
- Activates c-Nos which converts L-arg to NO
- (↑c-Nos → ↑NO)
- Nitric oxide modulation
- L-arginine - NO precursor
-
Inhaled NO → potent vasodilations → some evidence for neuroprotection
- targets ischemic vessels rather than whole body
- NO donors → potent but non-selective
- may drop BP unless given in carotid
- Glycerin trinitrate
Inhaled _____ to increase CBF during stroke (cerebral blood flow)
Inhaled NO to increase CBF during stroke (cerebral blood flow)
- dilation of veins and arteries in the brain with NO → ↓BP → significant neural protection in mice
What is Remote Ischemic Perconditioning?
- Target organ ischemic for period of time → protective signals to heart and brain
- Increase CBF
- Activation of RISK (pAkt)
- Activation of mitochondrial K+/ATP
- Inhibition of mitochondrial permeability pore
What were five proposed molecules for neuroprotection. Why did they fail?
- Glutamate antagonists
- Glutamate release inhibitors
- Free radical scavengers
- Ca++ chelators
- GABA agonists
Fail because poor alignment btwn clinical data
What are Pannexins?
- hemi-channels
- Open on cell membrane and allow cations in → anoxic depolarization → activate cell death cascades
Metabotropic coupling of NMDA receptors to ________ via _____ leads to cell death cascade
Metabotropic coupling of NMDA receptors to pannexin-1 via Src family kinases leads to cell death cascade
What happens if you block the interaction of NMDA with Src (via T-cell permeable Tat peptide Panx308)
- Blocks anoxic depolarization
- Prevents panx1 opening and reduces damage and disability due to stroke
What is the theory behind blocking NMDAR associated protein PSD-95?
Is it effective?
- PSD-95 binds NMDA receptors and nNOS at excitatory synapses
- inhibiting PSD-95 (with NA-1) prevents formation of NMDA-receptor/PSD-95/nNOS complex and generation of NO
- Physiological NMDA functions are not affected
- Effective
- PSD-95 inhibitors reduce infact in rodent models and exerts neuroprotective properties in gyrencephalic non-human primates
- Protective after small strokes
What is NA-1 and Recanalization?
- Combined endovascular therapy with NA-1
- Moderate-good collaterals
- NA-1 prior to EVT within 12 hours
- Suggests benefit in patients who didn’t recieve tPA
