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

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

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

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

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

CBF & Ischemic Thresholds Normal CBF 50-60 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

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?)

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

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

Timing of Neuronal Death Coagulation necrosis Apoptosis

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

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

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

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

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

Embolism

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.”

Watershed Infarcts Resulting From Hemodynamic Crisis (Hypotensive Stroke)

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.

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.”

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