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Stroke Flashcards

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1
Q

What is a stroke, and why is it considered a medical emergency?

A

A stroke is a sudden disturbance in blood supply to the brain.

It leads to a rapid loss of cerebral function.

It requires urgent treatment to prevent permanent brain damage or death.

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2
Q

What are the two main types of stroke?

A

Ischaemic stroke (≈85% of cases): Caused by blockage (e.g., clot) stopping blood flow.

Haemorrhagic stroke: Caused by bleeding in or around the brain.

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3
Q

What is a transient ischaemic attack (TIA), and why is it important?

A

A TIA is a temporary ischaemic event with stroke-like symptoms that resolve quickly.

No lasting damage, but it is a strong warning sign — high risk of full stroke in the coming weeks/months.

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4
Q

What are common symptoms of stroke?

A

Facial drooping

Inability to lift arms properly

Slurred or confused speech

Symptoms depend on the brain region affected

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5
Q

What is the most common artery involved in ischaemic stroke, and why?

A

The middle cerebral artery (MCA)

Common site due to its anatomical location

Supplies critical regions like basal ganglia and internal capsule

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6
Q

What type of stroke occurs when the lenticulostriate arteries are blocked? What symptoms are typical?

A

Lacunar stroke

Causes contralateral hemiparesis (weakness on the side opposite the stroke)

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7
Q

What is the ischaemic penumbra? Why is it clinically important?

A

The area around the stroke core with reduced blood flow but potentially salvageable tissue

Main target for timely interventions

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8
Q

What is the current standard emergency treatment for ischaemic stroke? What is its time limitation?

A

Thrombolysis using tPA (alteplase), a clot-busting agent

Must be given within 4.5 hours of symptom onset

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9
Q

Why is brain imaging critical before giving thrombolysis for stroke?

A

To distinguish between ischaemic and haemorrhagic stroke

Giving tPA in haemorrhagic stroke can cause fatal bleeding

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10
Q

What percentage of UK hospitals can provide rapid referral for suspected stroke cases?

A

Only 12% of hospitals

Highlights a major limitation in accessing timely stroke treatment

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11
Q

Why is stroke considered both an acute and chronic condition?

A

Symptoms are acute (sudden onset)

But underlying vascular damage accumulates chronically over time

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12
Q

What are the two subtypes of haemorrhagic stroke?

A

Intracerebral haemorrhage: Bleeding directly into brain tissue

Subarachnoid haemorrhage: Bleeding into the subarachnoid space

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13
Q

What is the main mechanism of neuronal death in haemorrhagic stroke?

A

Extracellular haemoglobin from lysed red blood cells causes:

Oxidative stress

Inflammation

Cell death

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14
Q

What rare stroke type was associated with early COVID-19 vaccines?

A

Cerebral venous sinus thrombosis (CVST)

Caused by platelet accumulation and clotting in venous sinuses

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15
Q

Why is subarachnoid haemorrhage particularly dangerous?

A

Blood can spread rapidly through CSF spaces

Raises intracranial pressure

Can damage critical nearby structures like the hippocampus

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16
Q

What proportion of strokes are subarachnoid haemorrhages, and who do they commonly affect?

A

About 5% of strokes

More common in younger individuals

Often fatal

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17
Q

What molecule is being studied as a potential therapy in haemorrhagic stroke?

A

Haptoglobin: A haemoglobin scavenger

May reduce oxidative damage when infused into the brain

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18
Q

What brain regions are most affected by middle cerebral artery strokes?

A

Basal ganglia: Movement regulation

Internal capsule: White matter tract carrying motor/sensory info

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19
Q

How do clinicians assess stroke symptoms to localise damage?

A

Check for contralateral weakness (hemiparesis)

Evaluate whether symptoms are focal or global

Use this to infer which artery or brain region is involved

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20
Q

What type of stroke is most common and what causes it?

A

Ischaemic stroke (85%)

Usually caused by a blood clot (thrombus) blocking an artery

Often associated with atherosclerosis in the middle cerebral artery

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21
Q

Why is the brain especially vulnerable to interruptions in blood supply?

A

It uses ~20% of the body’s energy despite being only ~2% of body weight

Depends heavily on aerobic metabolism

Requires constant oxygen and glucose supply to maintain ionic gradients (e.g. via Na⁺/K⁺ ATPase)

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22
Q

What are the immediate consequences of blocked cerebral blood flow in stroke?

A

Oxygen and glucose depletion

ATP failure

Ionic homeostasis disruption

Leads to excitotoxicity, cell swelling, and eventually cell death

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23
Q

What are the phases of injury in ischaemic stroke pathophysiology?

A

Primary injury: Energy failure and ionic imbalance

Secondary injury: Excitotoxicity, spreading depolarisations, inflammation

Delayed injury: Apoptosis and tissue degradation

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24
Q

What is excitotoxicity and how does it occur in stroke?

A

Uncontrolled glutamate release due to membrane depolarisation

Activates NMDA/AMPA receptors, causing Ca²⁺ influx

Leads to oxidative stress, mitochondrial dysfunction, and neuronal death

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25
How does inflammation contribute to stroke pathology?
Blood-brain barrier becomes leaky Microglia and leukocytes infiltrate parenchyma Release cytokines and reactive oxygen species, worsening injury
26
What is the role of microglia in early versus late stroke stages?
Early: Promote damage via pro-inflammatory signalling Late: Help with clearance of dead cells and neuroprotection
26
What is the ischaemic penumbra?
Region around the stroke core with reduced perfusion Functionally silent but still viable Therapeutic target for rescuing brain tissue
27
How is the ischaemic penumbra visualised in humans?
Diffusion-weighted MRI (DWI) shows dead tissue Perfusion-weighted MRI (PWI) shows areas with reduced blood flow Mismatch between PWI and DWI indicates salvageable penumbra
28
What is the standard emergency treatment for ischaemic stroke?
Thrombolysis with alteplase (tPA) Only effective if given within 4.5 hours of symptom onset Not suitable for haemorrhagic stroke, requires prior brain imaging
29
What is the primary reason brain imaging is required before thrombolysis?
To distinguish between ischaemic and haemorrhagic stroke Thrombolysis is contraindicated in haemorrhagic stroke—it would worsen bleeding
30
What are other emergency treatments for stroke besides thrombolysis?
Antiplatelets (e.g. aspirin) Anticoagulants (e.g. heparin) Surgical interventions (e.g. clot removal, endarterectomy)
31
What are longer-term medical treatments post-stroke?
Statins to lower cholesterol Antihypertensives to manage blood pressure Aim: Reduce risk of recurrent stroke
32
What is the main treatment approach for haemorrhagic stroke?
Primarily neurosurgical May involve blood removal, clot evacuation, and repairing ruptured vessels Often requires a ‘wait and see’ approach initially
33
What clinical scale is used to assess stroke severity in hospital?
NIH Stroke Scale (NIHSS) Measures: consciousness, response to stimuli, speech, motor function, etc. Higher scores = worse outcome
34
What key trial showed effectiveness of thrombolysis and influenced guidelines?
Trial comparing tPA vs. placebo tPA group showed lower NIHSS scores (better recovery) Greatest benefit when administered within 60 minutes
35
What does the timing of thrombolysis significantly affect?
Effectiveness decreases with time post-stroke Risk ratio for benefit drops to ~1 by 3 hours Justifies 4.5-hour cut-off for administration
36
What is the single most important modifiable stroke risk factor?
High blood pressure (hypertension) Significantly increases both ischaemic and haemorrhagic stroke risk Targeted in NHS health checks and stroke prevention plans
37
What are major modifiable risk factors for stroke?
Hypertension High cholesterol Smoking Obesity Physical inactivity Atrial fibrillation
38
What are some common triggers that may precipitate a stroke?
Trauma (e.g. neck injury) Pregnancy/postpartum hormonal shifts Severe infection Substance abuse Extreme mental stress
39
What are the two main pathological changes in blood vessels that increase stroke risk?
Arteriosclerosis: stiffening of arteries Atherosclerosis: lipid and immune cell accumulation in arterial walls
40
How can atherosclerosis lead to ischaemic stroke?
Plaques rupture, exposing collagen and lipids Triggers platelet aggregation and clot formation Clot can block cerebral arteries, causing ischaemia
41
What are aneurysms and how are they related to stroke?
Weakening and ballooning of vessel walls Risk of rupture, leading to haemorrhagic stroke Often associated with chronic hypertension
42
What is the role of inflammation in atherosclerotic plaques?
Plaques attract inflammatory cells (macrophages, T cells) These cells secrete enzymes and ROS Leads to plaque instability and rupture
43
What is the typical trigger that converts chronic vessel pathology into a stroke?
Acute events like trauma, infections, hormonal changes (e.g. pregnancy), or severe stress These may activate coagulation cascades or disrupt unstable plaques
44
What is the UK’s strategy to reduce stroke burden?
Focus on awareness, prevention, rapid response, and patient involvement NHS aims to educate public and improve access to emergency care
45
What percentage of UK hospitals can rapidly refer suspected stroke cases?
Only 12% have rapid referral capacity And only 50% can provide brain scans within 3 hours of arrival
46
How does the structure of the brain contribute to stroke outcomes?
Dense neural networks depend on constant perfusion Specific areas like the internal capsule and basal ganglia are highly vulnerable Symptoms reflect the damaged vascular territory
47
What is the ischaemic penumbra?
Area of reduced perfusion around the infarct core Neurones are electrically silent but potentially salvageable Key target for therapeutic intervention
48
What determines whether penumbra tissue survives?
Speed of reperfusion (e.g. via thrombolysis) Balance between injury signals (e.g. ROS, calcium overload) and repair mechanisms If untreated, penumbra tissue progresses to infarction
49
What imaging techniques are used to identify the ischaemic penumbra in stroke patients?
Diffusion Weighted Imaging (DWI): shows areas with restricted water diffusion = infarct core Perfusion Weighted Imaging (PWI): shows areas with reduced blood flow Mismatch between DWI and PWI = identifies penumbra
50
What do DWI and PWI mismatches reveal about stroke progression?
DWI shows irreversibly damaged tissue PWI shows at-risk but salvageable tissue Over time, penumbra can become infarct if not rescued
51
What is the MCAO model and how is it used in stroke research?
Middle Cerebral Artery Occlusion (MCAO) in rodents Mimics ischaemic stroke by temporarily clamping the MCA Used to study tissue damage, ATP levels, and treatment efficacy
52
What happens to ATP levels in MCAO animal models after reperfusion?
Initial ATP recovery upon reperfusion But infarcted tissue shows progressive decline in ATP Indicates delayed cell death despite restored blood flow
53
How is protein synthesis affected after a stroke?
Suppressed in the penumbra Correlates with regions at risk of delayed neuronal death Recovery of synthesis may signal tissue survival
54
What experimental methods simulate ischaemia in cultured neurons?
Oxygen and Glucose Deprivation (OGD) Addition of cyanide to block mitochondrial respiration Mimics ATP depletion and depolarisation
55
What role does glutamate play in ischaemic neuronal death?
Excess glutamate release due to depolarisation Causes overactivation of NMDA and AMPA receptors Leads to calcium overload, ROS generation, and cell death
56
: What experimental evidence shows the role of glutamate in excitotoxicity?
Blocking NMDA and AMPA receptors prevents cell death in early OGD Demonstrates glutamate-mediated calcium influx as a key death trigger
57
How do glutamate transporters malfunction during ischaemia?
Normally remove glutamate from synapses During ischaemia, gradients reverse → transporters export glutamate Exacerbates excitotoxicity
58
What is the effect of nitric oxide synthase (nNOS) activation after NMDA receptor stimulation?
Produces nitric oxide, which combines with superoxide to form peroxynitrite Peroxynitrite causes mitochondrial damage, protein oxidation, and neuronal death
59
What is the role of PSD-95 in stroke-related excitotoxicity?
PSD-95 scaffolds NMDA receptors and nNOS Brings them into proximity → facilitates nitric oxide production Enables formation of a toxic complex after NMDA activation
60
How did antisense oligonucleotides targeting PSD-95 affect neuronal survival?
Reduced PSD-95 expression in cultured neurons Disrupted NMDA–nNOS interaction Led to 50% reduction in NMDA-induced neuronal death
61
What is the peptide NA-1 (nerinetide) and its mechanism of action?
Synthetic peptide mimicking NMDA receptor tail Competes for PSD-95 binding → dislodges NMDA–PSD-95–nNOS complex Reduces NO production and protects neurons
62
What animal models were used to validate NA-1 before clinical trials?
MCAO model in mice showed reduced infarct size Primate studies confirmed reduced damage and improved function Supported progression to human trials
63
What was the outcome of NA-1 trials in non-human primates?
Lower perfusion deficits post-stroke Improved neurological scores compared to placebo Showed neuroprotection without affecting blood flow
64
What were the findings of the first clinical trial for NA-1 (nerinetide)?
Compared NA-1 vs placebo in acute ischaemic stroke 10% more patients achieved functional independence NA-1 was safe, even when stroke type was not pre-established
65
Why is NA-1 potentially suitable for pre-hospital use?
Can be administered without imaging Safe in both ischaemic and haemorrhagic stroke Potential for ambulance-based treatment
66
What unexpected issue arose when NA-1 was combined with tPA?
tPA (clot-busting agent) broke down NA-1 Reduced NA-1 efficacy in combination Highlighted need to administer separately
67
What makes NA-1 a promising stroke therapy despite early limitations?
Neuroprotective effects independent of reperfusion Works in the penumbra, targeting cell survival pathways Could increase treatment window beyond tPA's 4.5 hours
68
What does the NA-1 development story illustrate about translational neuroscience?
Shows progression from basic research → animal studies → clinical trials Demonstrates how understanding molecular mechanisms informs therapy Highlights challenges and opportunities in drug development for stroke
69
What clinical trial design was used to test tPA efficacy?
Randomised controlled trial comparing tPA vs placebo Patients assessed using NIHSS scores Showed more low scores (better outcomes) in tPA group
70
How did researchers determine the 4.5-hour window for tPA?
Used risk ratio analysis based on time since stroke Found significant benefit within 3–4.5 hours Beyond 4.5 hours, benefit sharply declined
71
What is the biggest modifiable risk factor for stroke?
High blood pressure (hypertension) Increases mechanical stress on blood vessels Raises risk of both ischaemic and haemorrhagic stroke
72
How does atherosclerosis contribute to stroke risk?
Causes arterial stiffening and plaque formation Reduces cerebral blood flow Increases risk of clot formation or vessel rupture
72
What are common non-modifiable stroke risk factors?
Age – risk increases with age Genetics or family history Sex (men higher risk), and ethnicity in some populations
73
What events can trigger a stroke in susceptible individuals?
Trauma (e.g. neck injury) Hormonal changes (e.g. pregnancy, postpartum) Infections, drug use, or severe mental stress
74
What is the earliest molecular consequence of ischaemia in neurones?
ATP depletion due to impaired mitochondrial respiration Failure of sodium-potassium ATPase Loss of ionic gradients Membrane depolarisation Initiation of calcium influx
75
What is excitotoxicity, and how does it contribute to ischaemic damage?
Caused by excessive glutamate release and receptor activation Leads to sustained calcium influx Activates proteases and ROS generation Damages membranes, proteins, DNA, and mitochondria Results in irreversible neuronal injury
76
How does glutamate contribute to neuronal death during stroke?
Massive, unregulated glutamate release into the synapse Glutamate transporters reverse, releasing glutamate instead of reuptake Overactivation of NMDA and AMPA receptors Sustained depolarisation and calcium overload Triggers downstream toxic cascades
77
How do NMDA receptors link to nitric oxide production during stroke?
NMDA receptor activation allows Ca²⁺ influx Calcium activates neuronal nitric oxide synthase (nNOS) nNOS is physically tethered to NMDA receptors via PSD-95 Generates excessive nitric oxide → forms peroxynitrite Leads to oxidative and mitochondrial damage
78
What role does PSD-95 play in stroke-induced neuronal toxicity?
Acts as a scaffold linking NMDA receptors to nNOS Facilitates excessive nitric oxide production at the synapse Disruption of PSD-95 interaction reduces NO toxicity Targeting PSD-95–nNOS interaction is a therapeutic strategy
79
How did researchers test the toxicity of NMDA–nNOS–PSD-95 signalling in vitro?
Cultured neurones were exposed to NMDA or oxygen-glucose deprivation (OGD) Blocking NMDA receptors or calcium influx reduced cell death Knockdown of PSD-95 or inhibition of nNOS provided neuroprotection Demonstrated the triad’s critical role in excitotoxic death
80
What is NA-1, and how does it protect against stroke damage?
A synthetic peptide mimicking the NMDA receptor’s C-terminal Binds PSD-95, preventing its interaction with NMDA receptors and nNOS Blocks nitric oxide production without inhibiting normal NMDA signalling Shown to reduce infarct size and improve outcomes in preclinical models
81
What preclinical evidence supported testing NA-1 in humans?
In primate models of middle cerebral artery occlusion NA-1 treatment reduced infarct volume and improved neurological scores Showed effective neuroprotection without toxicity Outperformed placebo in controlled experiments
82
What were the results of the first clinical trial using NA-1 (nerinetide)?
10% more patients reached functional independence vs placebo Showed significant benefit when not combined with alteplase (TPA) When co-administered with TPA, NA-1 was degraded → reduced efficacy Trial highlighted its safety and potential standalone benefit
82
83
Why is NA-1 a promising stroke therapy compared to thrombolytics?
Can be given without needing to distinguish stroke subtype (ischemic vs haemorrhagic) Avoids risk of worsening haemorrhagic strokes Effective beyond the tight 4.5-hour window of TPA Targets neuronal survival pathways, not just clot removal
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