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
Type of ischemia	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.

Release of proteases (matrix metalloproteinases, MMP) due to cell membrane damage-ATP depletion + free radicals
MMP causes degradation of collagen and laminins in the basement membrane of the cells and blood vessels
Disruption of blood brain barrier may lead to hemorrhage
Cerebral edema due to increased Na+, Ca2+ and water influx into the cells.

Genetics

The following gene loci may increase the risk for stroke:

PITX2 and ZFHX3- atrial fibrillation and cardio embolic stroke
HDAC9- large vessel disease
ABO- ischemic 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