Ischemic stroke pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

Overview

Pathophysiology

The pathophysiology of ischemic stroke may depend on the underlying cause of ischemia. Ischemic infarct may be categorized into two types depending on the area of the brain involved:

Type of ischemia Pathogenesis
Underlying cause Part of the brain involved Time of initiation of cell death Type of cell death
Focal

Thrombosis
Embolism

Focal area supplied by the occluded vessel

Acute onset (3-4 hrs)
Cell death (12 hrs)

Necrosis-central area
Apoptosis- Peripheral area

Global

Systemic hypoperfusion

Water shed area
Hippocampal pyramidal cells, cerebellar purkinjee cells, cortical laminar cells

Delayed onset (12 hrs)
Cell death (days to weeks)

Apoptosis

Hemodynamic changes in ischemic stroke

  • Hemodynamic changes in ischemic stroke results from cerebral auto regulation dysfunction as brain tissue is highly sensitive to mild changes in oxygen levels
  • Several minutes of hypoxia leads to irreversible injury
  • Cerebral auto regulation maintains the perfusion pressure in the brain between the pressure range of 60-150 mm Hg via vasoconstriction and vasodilatation.
  • Pressure changes below 60 mm Hg and more than 150 mm Hg disrupts the normal auto regulation.
  • Below 60 mm Hg, initially there is extensive vasodilatation of the affected vessels to increase blood flow to the affected area. This is mediated by increase in endothelial nitric oxide production.
  • Extensive increase in nitric oxide production due to sustained hypoxia results in massive vasodialation and formation of large amounts of nitric oxide free radicals causing damage to cellular structures.
  • Drop in blood flow rates below 30ml/100gm results in inhibition of protein synthesis and increase in anaerobic glycolysis
  • Blood flow rates below 20ml/100gm results in extensive membrane damage causing cell death.

Molecular pathophysiology of ischemic stroke

The sequence of molecular changes that may result due to ischemia include:

  • Prolonged ischemia- decrease in oxygen delivery to the cells
  • Anaerobic glycolysis with decline in ATP production
  • Increased lactic acid production
  • Increased free oxygen and nitrate radicals-cell membrane and DNA damage
  • Excitatory neurotransmitter -glutamate is increased in neuronal synapses leading to NMDA receptor activation
  • NMDA receptor activation causes opening of ion channels in the cell membrane causing K+ efflux and Na+, Ca2+ and water influx
  • Increased Ca2+ influx activates apoptotic cell death pathways
  • ATP required for final steps of apoptosis, hence massive decline in ATP results in necrosis of cells

Cellular changes in Ischemic stroke

The sequence of cellular changes during ischemic stroke results in loss of structural integrity of brain causing disruption of blood brain barrier and cerebral edema.

Genetics

The following gene loci may increase the risk for stroke:

Gross pathology

On gross pathology,

  • Central necrotic tissue is called umbra
  • Peripheral tissue which surrounds area of necrosis and can be salvaged with increased blood flow is called pneumbra

Microscopic pathology

  • Within 1-6 min of ischemia, red neurons and vacoulation results
  • If ischemia lasts > 6 min, karryorhexis and cell death occurs

Gross and microscopic changes that may occur due to ischemia with the passage of time is tabulated below:

Duration Gross pathology Microscopic pathology
Immediate

<24 hrs

No change Cellular edema
Acute

<1 week

Edema

Loss of grey and white matter junction

Red neurons

Necrosis

Neutrophilia

Subacute

1-4 weeks

Soft friable tissue

Cyst formation

Macrophages

Liquifactive necrosis

Chronic

>4 weeks

Fibrosis

Fluid filled cysts with dark grey margin

Gliosis

Necrotic tissue cleared by macrophages

Autopsy of brain showing middle cerebral artery territory
Same image; infarct area (blue shading) and midline shift


[1]

References

  1. Caplan LR (1992). "Intracerebral hemorrhage". Lancet. 339 (8794): 656–8. PMID 1347346.


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