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Module 2 > Stroke > Flashcards

Stroke Flashcards

1
Q

4 types of stroke?

A

Transient cerebral ischaemia

Cerebral ischaemic stroke

Primary intracranial cerebral haemorrhage

Sub-arachnoid haemorrhage

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2
Q

3 Prophylactic measures?

A

Statins, ACE inhibitors, anti platelet, anti hypertensives.

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3
Q

What ml/100g/min blood flow is normal, olighaemi and ischaemic penumbra respectively?

A

> 50 Normal
22<50 olighaemia
<22 is ischaemic penumbra
<10 rapid cell death

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4
Q

What cellular changes occur under 20ml/100g/min?

A 
ATP Depletion 
HSP upregulation
Glucose utilisation decreased (gluconeogensis)
Oedema
Lactic acidosis
Decreased protein synthesis.
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5
Q

What are the 5 time dependent stages?

A
  1. Energy failure
  2. Excitotoxicity
  3. Induction of immediate early genes
  4. Inflammation
  5. Apoptosis
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6
Q

What changes are associated with energy failure?

A

Acidosis
Oedema (ion gradients fail, energy dependent GLU transporters inactivated.)
Oedema
Leakage of glutamate, GABA and adenosine into extracellular space.

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7
Q

What occurs as a result of excitotoxicity?

A

IOn influx thorugh AMPA and NMDA receptors.

Calcium influx activates:
Proteolytic enzymes
Phospholipase A2, Cyclo-oxygenase
XDH
Nitric oxide synthase
Mitochondrial swelling, cytochrome c release.
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8
Q

3 types of nitric oxide synthase and their functions?

A

nNOS: retrograde messenger. TOxic

eNOS: Vasodilator

iNOS: Immune mediator. Toxic.

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9
Q

Which molecules would help combat increases in free radicals?

A

Superoxide dismutase (SOD), Catalase, Ascorbic acid, Glutathione peroxidase

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10
Q

How was it proven that NMDA receptors are involved in neurotoxicity?

A
  • NMDA NR2A knockout decreases infarct size.
  • Interruption of singalling using 2B subunit antibody affecting PSD95 interaction reduces ischaemic damage.
  • NR1 antibody given after MCAO reduces infarct size.
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11
Q

Which genes are activated in the transcriptional cascade?

A

Inducible transcription factors (IEGs)
Enzymes such as COX-2, which underlie developmental and behavioural responses.
Neuroprotective proteins (HSPs)

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12
Q

Which transcription pathway is modulated by glutamate?

A

NMDA-> Ca2+ entry.
Ca2+ Calmodulin kinase IV pathway (CAMKIV)
Phosphorylation of cAMP-response element binding protein (CREB)
CREB binding protein complex activates transcription.

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13
Q

How to regulate transcription to decrease infarct size?

A

COX-2 knockout reduces infarct size. however, whilst lacking gastric toxicity of COX-1, they decrease prostacyclin (vasodilator) and lack COX-1 anti-thrombotic properties.

HSP70 & HSP27 transgenic mice reduced MCAO infarct size up to 40%.

HSPs: Ischaemic preconditioning. Mediated through NF-kB pathway. (reduced infarct size)

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14
Q

Current stroke treatment is limited as recanalisation rate can be low, there is lack of penumbra salvage and regaining of functional independence. What are current research strategies?

A

Reduce energy demands of the penumbra. (Hypothermia?)

Suspension of cell death process early on, to keep chance of spread to the penumbra low. Give tpa o increase flow.

TMS- inhibit peri infarct depolarisation

Target NMDA to inhibit them.

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15
Q

List the types of ischaemic stroke.

A

Arterial: Acute ischaemic stroke (lacunar)

Venous: CVST- Cerebral venous sinus thrombosis

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16
Q

List the types of haemorrhagic stroke.

A 
Arterial: 
AIS (acute ischaemic)
AVM (arterial venous malformation)
PICH (Primary intracerebral haemorrhage)
Anuerysm
EDH (extradural haemorrhage)

Subdural haemorrhage
CVST (cerebral venous sinus thrombosis)
Cavernoma

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17
Q

What are the factors in virchow’s triad?

A

Hypercoagulability
Stasis
Vessel wall injury

18
Q

List 3 endogenous anticoagulant molecules.

A

Protein S
Proteins C
Anti-thrombin 3.

19
Q

What are the causes of vessel wall injury?

ADVISE

A 
Atherosclerosis
Dysplasia
Vasculitis
Injury (radiation, catheter..)
Spasm (migraine)
Extra (embolism, compression)
20
Q

What are the causes of stasis?

OOORR

A 
Operation (ortho)
Obesity
Overland flights
Reduced circulating volume
Right sided heart failure
21
Q

What are the causes of hypercoagulability?

Heparinise

A 
Hereditary: (Prothrombin mutation)
Endocrine (estrogen, testosterone)
Polycythaemia
Autoimmune
Renal
Infection
Neoplasia
Injury
Smoking
Exogenous (chemotherpy, COX-2 inhibitors)
22
Q

Why are the middle cerebral arteries important in stroke?

A

Middle cerebral artery occlusion is common, as the striatum and the basal ganglia areas it supplies are not as protected as the frontal and temporal lobes. 2/3 of ischaemic strokes.

THERE IS NO COLLATERAL SUPPLY TO THE AREA.

23
Q

What clinical presentation is seen with middle cerebral, anterior cerebral and posterior cerebral infarcts respectively?

A

Anterior: Leg weakness one side. (supplies leg on homonculus)

Middle: Hemiplegia

Posterior: Homonymous hemianopia.

24
Q

What is the watershed zone?

A

This is the area directly in the middle of two arteries. E.g internal carotid splits into middle and anterior cerebral arteries. Watershed is in between these areas and is not perfused.

25
Q

3 pathophysiological causes of vessel occlusion?

A

Thromboembolism: Thrombus forms on plaque, occludes downstream vessel.

Hypoperfusion: Drop in BP- watershed zone most affected.

Lacunar: Small infarct in small vessels.

26
Q

List 4 imaging modalities.

A

Carotid dopplers
Angiogram
Bubble echocardiogram
24 Hour ECG

27
Q

What are the two mainstay methods for recanalisation?

A
  1. IVT (tPA)

2. Mechanical thrombectomy

28
Q

Asides from time, what is another challenge?

A

Efficacy of recanalisation. I.V rtPA has a 46.2% recanalisation rate.

29
Q

What are some alternative recanalisation approaches?

A 
Ultrasound EKOS
Shock wave vacuum- angiojet
Retrieval devices
Laser devices
Stent retrievers.
30
Q

Which strokes require ICU or surgery?

A

Basilar artery thrombosis: Atherothrombotic occlusion of basilar artery. Sudden symptom onset, brain stem signs, loss of consciousness. Severe morbidity- early recanalisation vital.

Space occupying middle cerebral artery infarcts: Craniectomy is a method to address this.

31
Q

What are the management options for intracranial haemorrhage?

A
  1. Haemostatic therapy:
    Recombinant factor VIIa (to activate coagulation cascade), Tranexamic acid.
  2. Minimise risk of patients taking oral anticoagulants.
  3. Anti-hypertensive therapy
  4. Surgery
32
Q

What is the most important primary outcome measure?

A

Modified ranking scale.
0=No symptoms
1= Independent, can perform usual activities.
2=Slight disability, still independent.
3= requires help, able to walk without assistance
4=Needs help to mobilise and attend to bodily needs
5=Bedbound, incontinent, constant care needed
6=Dead

33
Q

What are the main causes of intracranial haemorrhage?

A

Arteriolopathy (70%) and Cerebral amyloid angiopathy (20%)

34
Q

Describe the FAST and INTERACT-2 trials.

A

FAST: Volume reduction in bleeding with Factor VIIa treatment, but no mortality decrease.

INTERACT-2: Intense blood pressure lowering did not reduce risk of death or severe disability. Study was unblinded however, and intracranial pressure/cerebral perfusion data were not recorded.

35
Q

What insights do we gain through stroke animal models?

A
  1. Pathophysiology
  2. Brain imaging
  3. Drug development
36
Q

Describe methods of stroke induction in animal models.

A

Intraluminal filament: MCAo

  • Implant occludes MCA, blood flow detected w/laser
  • Infarct size controlled with duration of implant inside
  • Easy, reperfusion but high mortality, short observation period.

Surgical MCAo

  • Transient: Clip/ligation, Permanent: Coagulation, ligation
  • Low mortality, long observation possible, but skull opened, does not model recanalisation.

Embolic stroke

  • Inject thrombi, laser doppler flowmetry for blood flow
  • -No craniectomy, allows thrombosis analysis, but low rate of successful MCAo, no control over lodgement site.

Photothrombosis
-Rose bengal injected, laser can cause infarcts.
-Lesions induced chemotactically
-Precise infraction location, minimal mortality
but direct effects on brain function, expensive/difficult.

37
Q

What are the reasons for a translational roadblock for animal models?

A

In the lab, young and healthy animals are used.
No clinically relevant time point of treatment, & physiological parameters not controlled.

Clinical studies:
Adequate drug levels not reached, high dose in animal, low dose in human
Time window different in animals vs human
Insufficient statistical power to prove efficacy

38
Q

What are the 2 methods of haemorrhage modelling?

A

Injecting blood

Collagenase- breaks down basal lamina.

39
Q

What are the hallmarks of stroke induced immunosuppression?

A
  1. Lymphocytopenia

2. Reduced responsiveness of monocytes

40
Q

What goes on in the biphasic modulation of the immune system?

A

Early, massive activation of peripheral immune cells:
IL-6, IFNf, MCP-1. Splenocytes: TNFa, IFNy, IL-6 & IL-10

There is then downregulation.
Splenic & Thymic atrophy
Decreased splenocyte proliferation
Decreased proinflammatory cytokines.

Infarct size is major determinator of extent of immune depression.

41
Q

What are anti-inflammatory therapeutic strategies?

A 
Anti CD49 (blocks leukocyte adhesion)
Inhibit T cell effector mechanisms- block modulators of CD4 &amp; CD8.

Module 2 (7 decks)

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