1. Pathophysiology of Stroke Sid M
Pathophysiology of Stroke Sid M. Shah, MD Assistant Residency Director Assistant Clinical Professor Department of Emergency Medicine Michigan State University East Lansing, MI 54 1 54

2. Pathogenesis of Stroke: Ischemia & Hemorrhage
Ischemia: lack of circulating blood deprives the neurons of oxygen and nourishment
Hemorrhage: Extravascular release of blood causes damage by cutting off connecting pathways, resulting in local or generalized pressure injury
In an ischemic stroke lack of circulating blood ….
And in a hemorrhagic stroke extravasculaar release of blood

3. Acute Ischemic Injury
The occlusion of a large vessel (such as MCA) is rarely complete and cerebral blood flow (CBF) depends on the degree of obstruction, and collateral circulation
Many factors influence progression and extent of ischemic injury

4. Conditions influencing progression and extent of ischemic injury
Rate & duration of the ischemic event
Collateral circulation in the involved area of the brain
Systemic circulation & arterial blood pressure
Coagulation abnormalities
Temperature
Glucose

5. Pathophysiology at Macro Tissue Level
Cerebral Blood Flow (CBF)
Ischemic Thresholds
Ischemic Penumbra and Window of Opportunity

6. CBF & Ischemic Thresholds
Normal CBF cc/100 g/minute
Varies in different regions of the brain
CBF 20-30cc/100g/min Loss of electrical activity
CBF 10 cc/100g/minNeuronal death

7. Ischemic Penumbra & Window Of Opportunity
Ischemic zone that surrounds a central core of infarction with CBF of 25% to 50% of normal and loss of auto regulation
Viability of brain tissue is preserved if perfusion is restored within a critical time period (2 to 4 hours?)

8. Microcellular Mechanisms of Neuronal Injury
Development of microcirculatory disturbances
Formation of micro thrombi
Accumulation of noxious metabolites
Interaction of endothelial cells with PMN leukocytes & platelets
PMNs trigger neuronal necrosis

9. Microcellular Mechanisms of Neuronal Injury: Excitotoxicity
Ischemia depletes neuronal energy stores causing energy dependent membrane ion pumps to fail
This results in increased extracellular glutamate concentration
Release of excitotoxic Glutamate & Aspartate open up calcium channels resulting in influx of calcium, sodium and chloride and out flux of potassium causing irreversible neuronal damage

10. Timing of Neuronal Death
Coagulation necrosis
Apoptosis

11. Coagulation Necrosis
A process of cell death that evolves over 6 hours to 12 hours
Necrotic death is attributed to effects of physical, chemical and osmotic damage to the plasma membrane
Morphology of dying cells is distinct from that of cells dying from apoptosis

12. Apoptosis
“Programmed cell death” triggered by ischemia, evolves over 2 hours
Ischemia activates latent “suicide” proteins that triggers an autolytic process mediated by DNA cleavage

13. Major Categories of Ischemic Stroke
Thrombosis
Embolism
Global-Ischemic or Hypotensive Stroke

14. Thrombotic Stroke
Atherosclerosis: the commonest pathology of vascular obstruction leading to thrombosis
Other pathological causes:
Fibro muscular dysplasia
Arteritis (Giant Cell & Takayasu)
Dissection of vessel wall and hemorrhage into atheromatous plaque
Hypercoaguability

15. Embolic Stroke Two most common sources of emboli:
Left sided cardiac chambers
Artery to artery stroke: as in detachment of a thrombus from ICA at the site of a plaque
Many embolic strokes become “hemorrhagic”
Generally “smaller” strokes than thrombotic strokes

16. Embolism

17. Ischemic Stroke Due To Hemodynamic Crisis: “Hypotensive Stroke”
Any event causing abrupt drop in blood pressure results in critical compromise of CBF (cerebral blood flow) and hence cerebral perfusion.
Sites affected by critically low CBF are located at the end of an arterial territory. Hence the term “watershed or boundary zone infarct.”

18. Watershed Infarcts Resulting From Hemodynamic Crisis (Hypotensive Stroke)

19. Selective Vulnerability of Neurons to Global Ischemia
Hippocampus: pyramidal cell layer
Cerebral cortex: Purkinje cell layer
Cerebellar cortex
The increased vulnerability of these neurons is due to the abundance of neurotransmitter glutamate in these neurons
Some neurons are more susceptible to ischemia than others. The more common ones are listed here. The pyramidal cell layer of hippocampus and the purkinje cell layer or the cerebral cortex are most vulnerable to lack of oxygen. This is believed to be due to the fact that these neurons are rich in neurotransmitter glutamate
Now I will review what happens when CBF is restored as it occurs either spontaneously or thru interventional therapy.

20. Complications Of Restoration of Blood Flow: Hemorrhage and Edema
Arterial occlusion causes ischemia to capillaries, arterioles and vascular walls in addition to the deleterious effects on neurons
Hemorrhage (red infarcts) result when the fragile “ischemic” or “injured” vessels rupture after sudden restoration of blood flow
Vasogenic edema can also occur following a massive stroke or sudden restoration of blood flow to an ischemic area
Arterial occlusion causes ischemia to capillaries, arterioles and vascular walls in addition to the deleterious effects on neurons
Hemorrhage called (red infarcts) result when the fragile “ischemic” or “injured” vessels rupture after sudden restoration of blood flow
Vasogenic edema can also occur following a massive stroke or sudden restoration of blood flow to an ischemic area
The pathophysiological basis of evolution of reperfusion hemorrhage is important to understand.
The initial obstruction occurs usually at a bifurcation. The occlusion may obstruct one or both of the branches, producing ischemia of the distal tissue. When the occluding embolus is either lyses spontaneously or breaks up and migrates distally, CBF is now restored to the “injured or ischemic” arterioles. This can result in a hemorrhagic (red infarct) in what had previously been a blood less field.The area of brain which continues to be poorly perfused ends up as “Anemic infarction.”

22. Factors Associated With Red Infarcts (Hemorrhagic Transformation)
Size of the infarct - bigger infarcts have a higher chance of becoming hemorrhagic
Richness of collateral circulation
Use of anti-coagulants
Treatment with thrombolytic agents