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 categorised 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 autoregulation dysfunction as brain tissue is highly sensitive to mild changes in oxygen levels
Several minutes of hypoxia leads to irreversible injury
Cerebral autoregulation maintains the perfusion pressure in the brain between the pressure range of 60-150 mmHg via vasoconstriction and vasodilation.
Pressure changes below 60 mmHg and more than 150 mm Hg disrupts the normal autoregulation.
Below 60 mm Hg, initially there is extensive vasodilation of the affected vessels to increase blood flow to the affected area which may later result in inhibition of protein synthesis and increase in anaerobic glycolysis if blood flow rate drops down below 30ml/100g.
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 neurotransmittor -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

Disruption of blood brain barrier

Release of proteases (matrix metalloproteinases, MMP) due to cell membrane damage-ATP depletion + free radicals
MMP causes degradation of collagens 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, Ca and water influx into the cells.

Genetics

The following gene loci may increase the risk for stroke:

PITX2 and ZFHX3- atrial fibrillation and cardioembolic 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