Pathophysiology of StrokePathophysiology of Stroke

Sid M. Shah, MDSid M. Shah, MD

Assistant Residency DirectorAssistant Residency DirectorAssistant Clinical ProfessorAssistant Clinical Professor

Department of Emergency MedicineDepartment of Emergency MedicineMichigan State UniversityMichigan State University

East Lansing, MIEast Lansing, MI

Sid Shah, MD

Pathogenesis of Stroke:Pathogenesis of Stroke:Ischemia & HemorrhageIschemia & 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

Sid Shah, MD

Acute Ischemic InjuryAcute 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

Sid Shah, MD

Conditions influencing progression Conditions influencing progression and extent of ischemic injuryand 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

Sid Shah, MD

Pathophysiology Pathophysiology at Macro Tissue Levelat Macro Tissue Level

• Cerebral Blood Flow (CBF)– Ischemic Thresholds

• Ischemic Penumbra and Window of Opportunity

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CBF & Ischemic ThresholdsCBF & 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/minNeuronal death

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Ischemic Penumbra Ischemic Penumbra & Window Of Opportunity& 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?)

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Microcellular Mechanisms Microcellular Mechanisms of Neuronal Injuryof 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

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Microcellular Mechanisms of Microcellular Mechanisms of Neuronal Injury: Excitotoxicity 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

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Timing of Neuronal DeathTiming of Neuronal Death

• Coagulation necrosis

• Apoptosis

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Coagulation NecrosisCoagulation 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

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ApoptosisApoptosis

• “Programmed cell death” triggered by ischemia, evolves over 2 hours

• Ischemia activates latent “suicide” proteins that triggers an autolytic process mediated by DNA cleavage

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Major Categories Major Categories of Ischemic Strokeof Ischemic Stroke

• Thrombosis

• Embolism

• Global-Ischemic or Hypotensive Stroke

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Thrombotic StrokeThrombotic 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

Sid Shah, MD

Embolic StrokeEmbolic 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

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EmbolismEmbolism

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Ischemic Stroke Due To Hemodynamic Ischemic Stroke Due To Hemodynamic Crisis: “Hypotensive Stroke”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.”

Sid Shah, MD

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

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Selective Vulnerability of Selective Vulnerability of Neurons to Global IschemiaNeurons 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

Sid Shah, MD

Complications Of Restoration of Complications Of Restoration of Blood Flow: Hemorrhage and EdemaBlood 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

Sid Shah, MD

Sid Shah, MD

Factors Associated With Red Infarcts Factors Associated With Red Infarcts (Hemorrhagic Transformation)(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