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Pathophysiology of Stroke

Michael Guido III, M.D. Assistant Professor SUNY Stony Brook Department of Neurology

Outline
• • • • • • Definition of stroke Epidemiology Pathophysiology common to all strokes Causes of stroke Clinical Manifestations Treatment

STROKE
• “Stroke” has 2 meanings • Traditional
– All acute events involving blood in the brain – Includes all ischemic events & all hemorrhages

• Modern
– Acute event caused by interruption of blood flow to the brain – Includes all ischemic events and those that later become red infarcts (hemorrhagic stroke)

AND – No visible infarct by CT/MRI • Equivalent to stroke – TIA’s should be thought of and treated as a stroke that just recovered quickly – These patients are at very high risk of stroke over the subsequent 30 days .TIA • Traditional – Ischemic event lasting under 24 hours • Proposed (probably more accurate) – Ischemic event lasting under 1 hour.

000 stroke survivors alive today in the US • 28% of people who suffer a stroke within a given year are under 65 .000 new or recurrent strokes per year in the United States • Every 45 seconds.1 minutes. • 283. someone in America dies of a stroke. Every 3.Epidemiology in USA • 750.000 stroke deaths in 2000 in the US (1 in 14 deaths) • 22% of men and 25% of women who have an initial stroke die within one year • 4.700. someone in America has a stroke.

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neurons will die within minutes .Brain Physiology • Neural tissue has no reserve of glucose or oxygen • Neurons are therefore dependent on a constant flow of blood to supply nutrients • In the absence of blood flow.

Definitions • CBF (Cerebral blood flow) – The volume of blood flowing into the brain tissue each minute • CPP (Cerebral perfusion pressure) – The difference between mean arterial pressure and intracerebral pressure .

Definitions • OEF (Oxygen extraction fraction) – The amount of oxygen taken from the blood into the tissue • CMRO2 (Cerebral metabolic rate of O2 ) – The amount of oxygen used by brain – Measure of health of cells – A drop in CMRO2 signifies • Reduced metabolic demand • Failure of metabolism .

the volume of fluid that flows through a vessel is proportional to its pressure • The blood vessels in the brain have the unique ability to maintain a constant blood flow despite changes in perfusion pressure .Autoregulation • According to the laws of physics.

Autoregulation • Constant flow maintained with cerebral perfusion pressure of 70-150 mmHg • When autoregulation fails. the brain can increase OEF to maintain enough tissue oxygen • Mediated by dilation and contraction of arterioles .

Autoregulation CBF Edema or hemorrhage Ischemia 0 70 CPP 150 .

Autoregulation CBF Chronic Hypertension 0 70 CPP 150 .

the brain’s OEF increases to maintain CMRO2 (misery perfusion) • If this does not suffice. there is not enough oxygen to supply metabolic demands and CMRO2 falls . autoregulation fails and flow is again dependent on pressure • Initially.Stroke • When a blood vessel becomes blocked. the perfusion pressure to the area of brain supplied by that vessel drops • If it drops below 70 mmHg.

Cerebral Blood Flow • Normal – 50-60ml/100g/min • Ischemic – 20ml/100g/min – Protein synthesis is impaired but membrane integrity preserved – Risk of apoptosis • Infarcted – <= 10ml/100g/min – Loss of structural integrity and cell death (necrosis) .

Collateral Flow Adjacent normal vessel Blocked vessel .

Collateral Flow Penumbra Ischemic Core .

Penumbra Infarction Ischemia Misery Perfusion Normal .

Penumbra Ischemic Core Penumbra Normal .

Cell Death • Necrosis – Abnormal cell death – Seen in ischemic core – Results from severe drop in blood flow – Does not require energy • Apoptosis – Programmed cell death – Seen in penumbra – Occurs when cell senses damage and commits suicide – Requires energy .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death •Lack of oxygen and glucose result in depletion of ATP •This takes 1-3 minutes .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death •Failure of energy dependent ion pumps (Na-K ATPase) .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death The neurons lose their ionic gradients and depolarize .

an excitotoxic neurotransmitter .Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Release of glutamate.

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Activation of voltage gated calcium channels NMDA. AMPA. Kainate .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death These open channels allow calcium and sodium to enter the cells .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Water follows the salts along osmotic gradients .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death The cells swells from the excess water causing the membrane to rupture .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Activation of Proteases Production of Free radicals Activation of NO synthase .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Activation of Proteases Production of Free radicals Activation of NO synthase .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Activation of Proteases Production of Free radicals Activation of NO synthase .

Necrosis Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate Disruption of Cell membrane Entry of water Entry of Calcium and sodium Activation of Calcium Channels Cell Death Activation of Proteases Production of Free radicals Activation of NO synthase .

Necrosis • Process takes 6-12 hours – Process is irreversible earlier • Triggers inflammation and edema • Inflammation leads to introduction of neutrophils. lymphocytes. and monocytes into the brain • These cells release toxic cytokines and also contribute to the formation of free radicals .

Apoptosis • Cell senses prolonged ischemia – Prolonged failure to synthesize proteins • It “decides” that it is diseased and “commits suicide” to save the rest of the organism – Useful as natural limit to growth of malignancies – Also used whenever a cell has outlived its usefulness .

but at lower concentration than in necrosis • Promotes free radical production • Leads to lesser elevation of intracellular calcium .Apoptosis • Glutamate is released.

3 Forkhead family REST/NRSF Bcl-2 family • Inhibits pro-survival genes – CREB (cAMP response binding element protein) – NFKB (nuclear factor KB) .2.Apoptosis • Promotes pro-death genes – – – – Caspase 1.

Apoptosis • These pro-death proteins lead to orderly and energy dependent breakdown of mitochondria and nuclear DNA • This is a slow process and can be prevented .

so does the cerebral perfusion pressure • If this is severe enough.Global Hypoperfusion • CPP = MAP – ICP • If the MAP drops. it will cause global ischemia • Milder drops in MAP may cause preferential ischemia in territories supplied by stenotic vessels. .

air embolus • Arteriosclerosis  usually due to hypertension • Watershed infarction –  focal infarction that results from global drop in perfusion pressure • Hemorrhage  Come to my Lecture on Monday on Intracerebral Hemorrhage .bone marrow embolus.Causes of Focal Infarction • Atherosclerotic plaque  Thrombosis  Plaque itself occludes vessel  Hemorrhage into plaque • Embolism     From atherosclerotic plaque From thrombus From heart Other.

bone marrow embolus.Causes of Focal Infarction • Atherosclerotic plaque  Thrombosis  Plaque itself occludes vessel  Hemorrhage into plaque • Embolism     From atherosclerotic plaque From thrombus From heart Other. air embolus • Arteriosclerosis  usually due to hypertension • Watershed infarction –  focal infarction that results from global drop in perfusion pressure • Hemorrhage  Come to my Lecture on Monday on Intracerebral Hemorrhage .

Thrombosis • Refers to progressive decrease in diameter (stenosis) of a large to medium sized blood vessel due to plaque (atheroma) within the wall of the vessel • Most common etiology (in the elderly) is atherosclerosis – Progressive deposition of fatty material and fibrous tissue into the subintimal layer (atheroma) .

Thrombosis • Methods of expansion of atheroma – – – – Intraatheroma hemorrhage Subintimal necrosis Calcium deposition Progressive stenosis may cause infarct • Common in small vessels • Rare in large/medium vessels .

Thrombosis • Atheroma rupture – Usual final common pathway of stroke (& MI) – Platelet aggregation – Fibrin deposition • Endothelium heals  further lumen narrowing • Red cells become enmeshed – Occlude lumen – Embolize .

African-American. and Hispanic • Extracranial more common in Caucasian .Risk Factors • Modifiable – – – – – – Hypertension Diabetes Hyperlipidemia Smoking Elevated homocysteine Chronic infection/inflammation • Non-modifiable – – – – Age (increases with) Gender (male) Family history Ethnicity • Intracranial more common in Asian.Thrombosis .

usually between intima and media – Can occlude vessel or embolize – Usually seen in extracranial ICA or vertebral artery – Often traumatic but can be seen connective tissue disorders .Thrombosis – Other Causes • All of these are more common in the young • Dissection – Tearing of the vessel wall itself – Blood accumulates in the wall.

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bacterial meningitis.Thrombosis – Other Causes • Inflammatory process affects blood vessel wall – Primary angiitis restricted to CNS – Secondary to other systemic or CNS diseases • • • • PAN Temporal Arteritis Takayasu’s Arteritis Connective tissue diseases: SLE. Herpes. meningovascular syphilis. rheumatoid arthritis • CNS infection: Lyme. scleroderma. TB . Sjogren syndrome.

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000/dL) Anti-phospholipid antibody syndrome Lupus anticoagulant Sickle Cell Disease Antithrombin III Protein C/S Mutation in genes for Factor V or II . cocaine.000.Thrombosis – Other Causes • Drugs – Amphetamines. heroin – Combination of vasoconstriction and vasculitis • Hypercoagulable states – – – – – – – – – Disorders of the blood that predispose to clotting Polycythemia vera Thrombocytosis (platelet ct > 1.

Clinical Presentation • Thrombosis can cause strokes by lack of blood flow due to progressive stenosis (Can also cause embolism (artery to artery) • Symptoms vary based on location of infarct .

Progressive Stenosis • More likely to be preceded by TIA’s than embolic • Symptoms are acute in onset but may worsen over brief period • Tend to be smaller than embolic infarcts • Symptoms tend to vary with blood pressure .

Internal Carotid Artery Disease of the Internal Carotid Artery (ICA) can cause stroke via 2 mechanisms – Thrombosis / Hypoperfusion – Embolism – We are focusing on Thrombosis right now .

Internal Carotid Artery • Patients with ICA disease frequently have TIA’s prior to actual infarct • Hemodynamic – Stereotyped symptoms – Varies with blood pressure – Preferentially affects border zones • (We’ll come back to this when we get to Watershed Infarcts) .

air embolus • Arteriosclerosis  usually due to hypertension • Watershed infarction –  focal infarction that results from global drop in perfusion pressure • Hemorrhage  Come to my Lecture on Monday on Intracerebral Hemorrhage .Causes of Focal Infarction • Atherosclerotic plaque  Thrombosis  Plaque itself occludes vessel  Hemorrhage into plaque • Embolism     From atherosclerotic plaque From thrombus From heart Other.bone marrow embolus.

Embolism • Occlusion of a cerebral blood vessel by a small piece of blood clot. spleen. air. kidneys . fat. tumor. or clump of bacteria • Emboli may partially or totally occlude a cerebral vessel • Emboli to brain are frequently multiple • Can be associated with infarcts in lungs.

dissection Cardiac – Atrial Fibrillation. dissection Vertebral Artery – plaque.Embolic Sources • • • • Carotid Artery – plaque. dissection Aorta – plaque. PFO – Paradoxical Embolus .

Cardiac Sources of Emboli • Valvular vegetations or calcifications • Cardiomyopathy • MI – Acute • Especially anterior wall • Tumor (myxoma) • Patent foramen ovale(PFO) & atrial septal aneurysm(ASA) – Paradoxical embolism – Thrombus within ASA – Chronic • Ventricular aneurysm • Focal hypokinesis • Arrhythmias – Sick sinus syndrome – Atrial fibrillation .

or main trunk or branch of the PCA .Cardiac Sources of Emboli • 15-20% of all ischemic strokes • (23-36% in patients < 45 years old) • Cerebral circulation absorbs 10-15% of cardiac output • Most common sites for lodgment of cardiac emboli – main trunk and branches of MCA • 10% of cerebral emboli enter the vertebro-basilar circulation – lodge mainly at the top of the basilar.

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active person • Deficits depend on location of embolism • Headache • Diminished level of consciousness at onset • Rapid improvement • History of systemic emboli • Predisposing heart condition • Involvement of larger vascular area .Clinical Features • Abrupt onset of maximum defect in an awake.

Middle Cerebral Artery Infarct & Dense MCA Sign .

receptive. expressive.Middle Cerebral Artery • • • • Contralateral gaze palsy Contralateral hemiplegia (arm+face>leg) Contralateral hemisensory loss Aphasia (dominant side only (D)) – Can be global. or transcortical depending on which branches involved .

Anterior Cerebral Artery • Contralateral hemiplegia (leg>arm+face) • Abulia • Depression .

Anterior Cerebral Artery .

Anterior Cerebral Artery From Dr Seidman’s talk .

Posterior Cerebral Artery • • • • • • • Contralateral homonymous hemianopsia Contralateral hemisensory loss Neglect Prosopagnosia (N) Alexia without agraphia (D) Anomic or transcortical sensory aphasia (D) Almost always embolic .

Posterior Cerebral Artery .

Posterior Cerebral Artery Alexia Without Agraphia .

Vertebral Artery • Rarely causes hypoperfusion stroke unless there is a problem with the other VA • Posterior inferior cerebellar artery – Vertigo – Nausea/emesis – Gait ataxia • Lateral medullary artery – Wallenberg syndrome • • • • • • Ipsilateral limb ataxia Ipsilateral Horner’s syndrome Contralateral hemisensory loss Vertigo Dysphagia Hoarse voice .

Basilar Artery – – – – – – – Brainstem signs Cranial neuropathies Ataxia Cerebellar signs Nausea. emesis Change in level of consciousness Crossed signs .

Causes of Focal Infarction • Atherosclerotic plaque  Thrombosis  Plaque itself occludes vessel  Hemorrhage into plaque • Embolism     From atherosclerotic plaque From thrombus From heart Other.bone marrow embolus. air embolus • Arteriosclerosis  usually due to hypertension • Watershed infarction –  focal infarction that results from global drop in perfusion pressure • Hemorrhage  Come to my Lecture on Monday on Intracerebral Hemorrhage .

g.a. ”small vessel disease” • Process whereby you develop thrombosis of small vessels (e. thalamic perforators) – Analogous to atherosclerosis of large/medium arteries • Primary process is lipohyalinosis • More to come in ICH lecture on Monday .k.Arteriosclerosis • a.

Perforators • Small vessel disease leads to lacunar strokes • Can worsen over 1-2 days (stuttering lacune) • Pure motor – Internal capsule. pons • Pure sensory – Thalamus • Clumsy hand dysarthria – Pons • Ataxic hemiparesis – Internal capsule .

bone marrow embolus.Causes of Focal Infarction • Atherosclerotic plaque  Thrombosis  Plaque itself occludes vessel  Hemorrhage into plaque • Embolism     From atherosclerotic plaque From thrombus From heart Other. air embolus • Arteriosclerosis  usually due to hypertension • Watershed infarction –  focal infarction that results from global drop in perfusion pressure • Hemorrhage  Come to my Lecture on Monday on Intracerebral Hemorrhage .

Border Zone • Areas of anastomosis between the most distal branches of major cerebral vessels • Areas get poor supply from both arteries • Most susceptible to hypoperfusion .

Border Zone .

Border Zone = Watershed Infarct • Symptoms/Signs mimic the nearby territories • Anterior Border Zone – – – – Between MCA and ACA Contralateral weakness May see (motor) aphasia May see neglect • Posterior Border Zone – – – – – Between MCA and PCA Contralateral homonymous hemianopsia May see (sensory) aphasia Mood disturbance (non-dominant) May see Anosognosia or neglect .

Special Kinds of Strokes • Venous • Spinal .

Are all strokes due to arterial obstruction? .

• The deep system drains the deep white matter. and diencephalon and drains into the Galenic system.Anatomy • Cerebral veins contain ~70% of the total cerebral blood volume. basal ganglia. • Can be divided into a superficial and deep system.Venous Infarcts . . • Highly variable. • The superficial system drains the outer 2 cm of brain and drains into the sinuses.

thus increasing arterial flow and pressure to maintain CBF. leading to ischemia. • Only when the autoregulation limit is exceeded will the CPP and CBF drop. • As the venous pressure rises.Pathophysiology of Venous Thrombosis • Cerebral blood flow depends upon the difference in the arterial and venous pressures. . Autoregulation will cause arterial dilation. perfusion pressure drops.

due to tumor).Pathophysiology of Venous Thrombosis • The outcome of venous occlusion depends on the availability of pre-existing channels. and the creation of new collateral channels. • Neo-vascularization cannot occur unless the occlusion develops slowly (i.e. the extent of propagation of clot. .

Pathophysiology of Venous Thrombosis • Normally present anastomotic channels are sufficient to prevent infarction unless also occluded by propagating clot. .

Case 24 year-old woman on birth control pills has progressively worsening severe headache. On exam. . She becomes lethargic and then develops diplopia. As you are writing up your consult note she has a seizure. She has bilateral 6th nerve palsies (more on this in Dr Harth’s Oncology lecture). she is sleepy and slightly confused.

Sagittal Sinus Thrombosis .

Pathology of Venous Infarct
• When infarction does occur, it is frequently associated with petechial and gross hemorrhages in the parenchyma as well as perivenous subarachnoid and subdural hemorrhage. • Pathology shows neuronal loss. Oligodendrocytes show cytoplasmic swelling. Venules show congestion with numerous hemorrhages and hypertrophy of the endothelial cells. • Surrounding regions also show neuronal loss associated with microglial and astrocytic proliferation.

Clinical Features of Cerebral Venous Thrombosis
• Prior to CT and MR, when Dx was by autopsy only, CVT was described as a syndrome of alternating deficits, seizures, and coma. • Now that non-fatal cases are diagnosed, we realized that the clinical presentation is highly variable. • Mode of onset:
– Acute (less than 2 days) – 30%. – Subacute (2 days – 1 month) – 50%. – Chronic (over 1 month) – 20%.

Clinical Features
• Headache
– Diffuse, worse on recumbency, present on awakening

• Papilledema
– Increased pressure on the eye, may lead to blindness

• Seizures • Loss of consciousness • Stroke/focal deficits

Clinical Features of Cerebral Venous Thrombosis • Rarer complaints include: – – – – – – Multiple cranial nerve palsies Cerebellar signs Nystagmus Hearing loss Bilateral or alternating signs Thunderclap headache .

but he is able to feel a vibrating tuning fork on his legs. there is significant weakness of both legs. .Case 69 year-old-man who awoke following an abdominal aortic aneurysm repair unable to move his lower extremities. He is not able to perceive light touch or pinprick on his legs. On exam.

Spinal Stroke • Anatomy – The spinal cord is supplied by a single anterior spinal artery and paired posterior spinal arteries – The posterior arteries supply the dorsal columns only – Cervical • All arise from the vertebral arteries .

Spinal Stroke • Thoracic – Posterior arteries arise from aorta at each level – There is a single branch off the aorta (artery of Adamkiewicz) which supplies the anterior segments – Etiology • • • • Dissection Atherosclerosis Complication of surgery Rarely vasculitis or embolic .

Clinical • Motor – Cervical – quadriplegia – Thoracic – paraplegia • Sensory – Loss of sensation. below the level of the lesion • Bladder dysfunction . sparing vibration and position sense.Spinal Stroke .

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Treatment of Stroke • Acute – Minimize damage from the current event • Chronic – Reduce risk of future events .

Treatment .Acute • Promotion of blood flow • Interference with cellular mechanisms of necrosis and apoptosis • Reduction of metabolic stress .

Blood Flow • Restoration of flow through blocked artery • Increase cerebral perfusion pressure .

5 hours .Restoration of Blood Flow • Recombinant tissue plasminogen activator – – – – Attempts to dissolve the clot Only FDA approved treatment for acute stroke Carries high risk of hemorrhage Must be administered in first 3 .4.

Restoration of Blood Flow • Intra-arterial treatment – Perform cerebral angiogram to locate clot – Infuse small doses of tPA directly into the clot – Mechanically remove the clot .

Interference • Can we intervene to prevent the cascade of necrosis and apoptosis? • Neuroprotectants • Dozens of compounds have been tried • All have failed .

Aspirin • Acts to reduce thrombosis • Also reduces inflammation • Has been proven to slightly reduce mortality from acute strokes • Should be given to all patients within the first 24-48 hours .

we can delay the onset of necrosis .Reduction of Metabolic Stress • The necrosis pathway begins with depletion of ATP • If we reduce the usage of ATP.

Glucose • Reduced blood glucose causes “starvation” of neurons • Elevated blood glucose in the setting of ischemia lead to lactic acid production by glial cells • Lactic acid is toxic to ischemic cells and promotes necrosis • Glucose should be maintained in narrow range .

we must aggressively treat fever .Temperature • Metabolic demand varies proportionally with temperature • Drowning victims • Induction of hypothermia is under investigation – Already shown to be useful in cardiac arrest • At least.

Oxygen • There needs to be enough oxygen in the blood to support metabolism • Excess oxygen has not been shown to be helpful • Use oxygen as needed to keep oxygen saturation >= 95% .

Chronic • Depends on underlying etiology • Most commonly – antiplatelet agents [e. aspirin. Aggrenox (dipyridamole)] • Interferes with platelet aggregation in the event of endothelial rupture over an atheroma • Reduces growth of atheroma and likelihood of embolism .Treatment .g. Plavix (clopidogrel).

hypertension.Chronic • Anticoagulants (Coumadin) – Used in the presence of some hypercoagulable states and atrial fibrillation • Control of risk factors – Treat diabetes.Treatment . hyperlipidemia – Stop smoking .

The End .