Stroke Flashcards
What does WHO identify stoke as?
The second most leading cause of disability and death
Stroke statistics
- 20-33% die within 1-3 months.
- In the UK almost two thirds of stroke survivors leave hospital with a disability.
- Single largest cause of adult disability. 300 000 people in England with moderate to severe disability.
- Average stay in hospital 28 days but highly variable
- 1 in 5 acute hospital beds occupied by stroke patients.
- 25% of strokes occur in people under 65.
- In England, 1/6 people will have a stroke in their lifetime.
LO
- Define what a stroke is, the risk factors and how these increase the likelihood of having a stroke.
- Identify the current therapies applicable to ischemic and/or hemorrhagic stroke
- Summaries the cellular and molecular mechanisms that cause damage following a stroke and their time course.
- Discuss potential avenues for treatments in the future.
What is a stroke?
A brain attack caused by the disturbance of the blood supply to the brain
Tell me about the stroke symptoms
There are rapidly developing clinical symptoms, focal or global, which lead to a loss of cerebral function that can only be attributed to vascular origin
Is stroke a sudden or progressive disease?
sudden event (things happen in brain prior to attack but seen suddenly)
due to blood clot or hemorrhage
a vascular event, something going wrong with blood supply
A stroke is a medical emergency, what have the NHS devised to look out for in regard to symptoms?
Large obstacle to emergency treatment:
that many people don’t know they are having a stroke and there can be a long time between stroke and getting to the hospital.
Symptoms may vary for other strokes.
- Sudden paralysis,
- Loss of vision.
key timing is 3 hours once had stroke to get medical attention
What are the major types of stoke and what are they due to?
- Ischemic (blood is not able to get to tissue, usually happens when there is a blood clot)
- Haemorrhagic
- Intracerebral haemorrhage (blood vessel is leaking into parenchyma)
- Subarachnoid haemorrhage (blood vessel leaking into subarachnoid space)
What is also relevant to stroke?
Transient ischemia attack (TIA): ischemic events.
Resolve within 24hrs. No tissue death
sometimes no treatment is required
Tell me abit of information about Haemorrhagic strokes
Extracellular haemoglobin (when RBC leak out of blood vessels and burst) induces cell death, mainly via oxidation and inflammation
haemoglobin effect on the function of neurons has little known about it. apart from oxidation and inflammation effects little is known
thought that AMPA signalling is affected but still in research (reduction in AMPA receptors)
loss of cognitive function behaviour or disfunction of motor areas could be basis of why AMPA receptors may not be functioning as well
Tell me the symptoms of cerebral venous sinus thrombosis (CVST) and is it more prevelant in females or males?
Headache
Abnormal vision
Stroke
Seizures
Females > males
What is CVST associated with?
Intracranial haemorrage i.e., Haemorrhagic stroke
veins are not muscular so rather than forming clots they keep accumulating and eventually there is a burst of sinuses which leads to cerebral haemorrhage
What is the subarachnoid space
space between meninges and brain parenchyma
subarachnoid haemorrhage can occur if blood leaks into this space
Tell me about subarachnoid haemorrhage (SAH)
Extracellular haemoglobin induces cell death, mainly via oxidation and inflammation
SAH. Mechanisms poorly understood. Highest incidence of death and disability
- Blood leaks out into the brain tissue at high pressure
- Subarachnoid blood distributes rapidly over the entire brain and penetrates easily into the deeper layers of the cortex within a few hours.
- Blood released into the subarachnoid space clots almost immediately and disappears ~3 days via clot lysis, which starts early after SAH.
Accounts for 5% of all strokes but accounts for the greatest amount of disability and death, especially in young people
What is a therapy being developed to help with SAH?
The use of Haptoglobin to scoop up free haemoglobin to try and prevent this oxidation and inflammation
Whta are the major brain structures and functional areas and what do the clinical symptoms of stroke correspond to?
the clinical symptoms of stroke correspond to the area of the brain which has been effected during the stroke
What % of stroke is Ischemic?
85%
The brain is an organ that has to be adequately perfused, what % of body weight is the brain?
roughly 2.5%
Tell me the % of energy the brain uses and the mechanism that uses the most energy
But it uses up a vast amount of energy
- 20% energy
- 15% cardiac output
Expensive to run in terms of energy (ATP)
one mechanism that uses the most energy is the sodium potassium ATPase pump
What is the middle cerebral artery?
The largets branch and the second terminal branch of the internal carotid artery
location is between the lateral sulcus between the frontal and temporal lobes and is part of the circle of Willis
most common pathologically affected blood vessel in the brain
What are the typical symptoms of MCA stroke?
arm and facial weakness, speech affected
but does all depend on location
What areas of the brain are affected by the MCA?
What is the most common form of stroke?
Lacunar stroke (Ischemic)
What arteries are affected in the Lacunar stroke?
Lenticulostriate arteries
What does Lacunar stroke lead to?
leads to contralateral hemiparesis (weakness on one side of the body, opposite side of the body to where the clot is)
As it passes the lateral fissure, Lenticulostriate arteries
Basal ganglia: important in motor control
What can brain stem stroke affect?
Fiber tracts (e.g., spinothalamic tract)
Nuclei (of cranial nerves)
Physiological functions (consciousness and arousal)
Summaries the cause of brain stem stroke and the clinical features
Occlusion (blockage or closing of blood vessels) of a vessel in the posterior circulation
Clinical features may include
- Tracts: motor/sensory disturbance, ataxia, Horner’s syndrome
- Nuclei: cranial nerve dysfunction
- Physiological centres: decrease in consciousness
What are important brainstem stroke syndomes?
Medulla: Wallenberg’s syndrome
Midbrain: weber’s syndrome
Pons: locked-in syndrome
Whats the evolution of stroke from minutes –> hours –> days –> weeks…
What are the current treatments of Ischemic and Haemorrhagic strokes?
Thrombolysis “clot busting” <4.5 hours, 8% eligibility, tPA (alteplase) (treatment for ischemic stroke)
- time is the main reason why the eligibility is low. Must be given under 4.5 hours
- can’t give someone clot busting agent prior to finding out if ischemic. as if it was a haemorrhagic stroke and they have this agent it will kill them. so, to find this out must gain images to see, which is where the time goes
Antiplatelets (chronic treatment)
Anticoagulants (more chronic treatment)
Carotid endarterectomies remove fatty deposits from artery (more ischemic)
Statins (more prevention act my modulating blood pressure so not an immediate fix)
Antihypertensives (more prevention)
Neurosurgery: remove blood, repair burst blood vessels (treatment for haemorrhagic stroke or the wait and see approach. the latter is preferred as neurosurgery is very invasive)
How is the clinical outcome of stroke measured?
National institutes of Health stroke scale (NIHSS)
What has a clinical trial shown about the treatment time for the preferred outcome of stroke?
What are the modifiable risk factors for stroke in ischemic stroke?
- Hypertension
- Elevated total cholesterol level
- Smoking
- Physical inactivity
- Obesity
- Asymptomatic carotid stenosis
- Alcohol consumption
- Arterial fibrillation
What are the non-modifiable risk factors for ischemic stroke?
- Older age
- Race (Hispanic, black)
- Maternal history of stroke
- Sex (males)
- Diabetes*
How do risk factors increase the propensity to stroke?
- Structure and function of blood vessels
- Interface with circulating blood
How does stroke affect the structure and function of blood vessels?
- Atherosclerosis
- Stiffening of arteries
- Narrowing thickening and tortuosity of arterioles and capillaries
How does a stroke interface with circulating blood?
Reduction/ alteration of cerebral blood flow (CBF)
Whats an Atheroma?
An accumulation of intracellular and extracellular lipid in the inner layer of large and medium sized arteries
Whats Artherosclerosis?
Atherosclerosis is a subtype of arteriosclerosis.
Other types include the thickening of the walls of arteries and arterioles usually e.g., as a result of hypertension or diabetes.
Whats an Aneurysm?
An aneurysm is a bulge in a blood vessel caused by a weakness in the blood vessel wall, usually where it branches.
Atheromas contain cells whose functions critically influence atherogenesis. Tell me these cells and examples
Intrinsic Vascular Wall Cells:
Endothelium Smooth Muscle Cells
Inflammatory Cells:
Macrophages, T Lymphocytes, Mast Cells.
Cascade – lesion development.
Stroke triggers can be identified in some patients. Give some examples of some triggers
Neck trauma; can lead to dissection of vertebral or carotid arteries
Pregnancy/ postpartum
Systemic infections
Use of drugs
Mental stress
The NHS have devised a ten-point plan of action for strokes…
- Awareness
- Preventing stroke
- Patient involvement
- Acting on the warnings: TIAs are a clear warning sign that a further stroke may occur. The time window for action is very short – in about half of cases this is a matter of days (1 in 5 patients who had a TIA are at risk of having a full stroke within 4 weeks)
- Stroke as a medical emergency
- Stroke unit quality: multidisciplinary team.
- Rehabilitation and community support
- Participation
- Workforce
- Service improvement
20% risk of a full stroke within the first four weeks after a TIA
12% of hospitals with rapid referral of those with suspected stroke
<50% per cent of hospitals with acute stroke units have access to brain scanning within 3 hours of admission to hospital.
What cell types does stroke involve?
All cell types of the brian
Whats normal aerobic metabolism and how is this affected by stroke?
There is also a malfunction of the ATP dependent process in stroke, tell me about this
Tell me about inflammation with stroke
Ischemia evokes a robust inflammatory response (hours –> days. Highly stereotyped:
Inflammatory markers used to determine the approximate age of cerebrovascular lesions).
Stimulated glia and blood vessels then communicate through complex signaling.
Innate and adaptive immune systems participate.
Early vascular, perivascular, and parenchymal events triggered by ischemia and reperfusion
ischemic stretches blood vessels and causes stress
platelets present P-selectin –> lead to aggregation and occlusion?
opening of BBB due to increase in ROS and decrease in NO
causes histamines to enter and macrophages to go into brain parenchyma to release substances which are pro-inflammatory
microglia and astrocytes in brain are activated
can occur within minutes to hours
Cell death and activation of pattern, recognition receptors set the stage of adaptive immunity
injured neurons send signals to immune cells e.g., ATP, UTP, HMGB1 etc. which are danger signalling molecules
these go to microglia or macrophages to trigger activation of TF such like NFkB
which produce a generation of inflammatory signalling molecules like IL-… and TNF
this goes on to form tissue damage and further ROS
leads to tissue damage and matrix degradation
pro-inflammatory signalling
Resolution of inflammation and tissue repair
produce neuroprotective signalling when a dying cell is noticed
read paper on ‘The immunology of stroke: from mechanism to translation’
animals had better outcome if microglia was not there during initial signalling of stoke
What are the peripheral immunological changes after stroke?
Blood, bone marrow, spleen, and other lymphoid organs.
White blood cell count and expression of cytokines and inflammatory markers UP within hours after ischemia, then DOWN within 1 or 2 days
–> Marked immuno-depression
A major determinant of stroke morbidity and mortality
Respiratory and urinary tract infections
Ischemic brain via autonomic nervous system produces immunosuppression
What is the ischemic penumbra?
an area of reduced perfusion sufficient to cause potentially reversible clinical deficits but insufficient to cause disrupted ionic homeostasis
Tell me about the Ischemic penumbra and Ischemic core and how this can be affected the longer the stroke is left untreated
Ischemic core (area of brain that has no oxygen and dies)
- Irreversibly damaged tissues
- <20% baseline blood flow levels
- depleted ATP stores
- Failure energy metabolism
Ischemic penumbra
- (perinfarct zone)
- Depressed tissue perfusion
- Basal ATP levels and oxygen metabolism
- Normal ions gradients
- Electrical silence
- Suppressed protein synthesis
What imaging techniques are used to identify the area of penumbra?
MRI (DWI and PWI)
Acute Ischemic Stroke
1. Diffusion-weighted imaging (DWI):
Detects areas of restricted diffusion of water. Bright-up in acute ischemic stroke
2. Perfusion-weighted imaging (PWI):
Detects abnormal blood flow
compare DWI and PWI to find area of penumbra
3. Diffusion-perfusion mismatch:
Area of penumbra?
How does the brain go from being salvagable to becoming infarct if treatment is not quick enough?
What is used to study stroke?
Patients (post-mortem, clinical trials)
Animal models (eg. Medial Cerebral Artery Occlusion)
In vitro studies (eg. Oxygen Glucose Deprivation)
Reversal of focal ischemia in animal model (rat)
How have scientists stimulated Ischaemia…?
What have these experiments shown?
Simulated ischaemia (no oxygen, no glucose, cyanide (interferes with ATP)) in neurons
causes a sharp increase in glutamate receptor activation and anoxic depolarization (AD).
Major glial glutamate transporter GLT-1,
KO animals clearly have a slower take-up of glutamate, but the simulated ischemia response is the same in WT and KO animals.
glutamate receptors involved in loss of function as shown in voltage clamp and current clamp experiments above
Under ischemic conditions, disruptions to Na+ and K+ and pH gradients cause what?
Transporters to function in reverse, leading to elevated extracellular glutamate concentrations
Possible involvement of NMDARs, TRPM2 and TRPM7 channels in anoxic neuronal death
Nitric oxide
Multifunctoional biological messenger
Molecular mechanisms of stroke
Nitric oxide, Reactive oxygen species
Endothelial NO
- Vasoregulatory effects
- Antiaggregant
- Antiproliferative
- Anti-cell adhesion
NO Loss leads to vasoconstriction
Negative impact on vascular flow
- –> Platelet aggregation
- –> Leukocyte adhesion to endothelial cells
- –> Smooth muscle proliferation
- –> Key steps to vascular inflammation
Specific coupling of NMDA receptor activation to nitric oxide Neurotoxicity by PSD-95 protein
Strategy of perturbing protein-protein interactions involving the postsynaptic scaffolding protein PSD-95.
Treatment of stroke with PSD-95 inhibitor in the primate brain
What was a stroke that was developed for both Ishemic and Haemorrhagic strokes?
Drug relevant for ischaemic and haemorrhagic stroke: neuroprotectant stroke drug N1-A drug. as won’t need imaging to find out which stroke can be given in ambulance which helps save time
