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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)
TIA
Traditional
Ischemic event lasting under 24 hours
Equivalent to stroke
TIAs 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
Epidemiology in USA
750,000 new or recurrent strokes per year in the United States Every 45 seconds, someone in America has a stroke. Every 3.1 minutes, someone in America dies of a stroke. 283,000 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 4,700,000 stroke survivors alive today in the US 28% of people who suffer a stroke within a given year are under 65
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, neurons will die within minutes
Definitions
CBF (Cerebral blood flow)
The volume of blood flowing into the brain tissue each minute
Definitions
OEF (Oxygen extraction fraction)
The amount of oxygen taken from the blood into the tissue
Autoregulation
According to the laws of physics, 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
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
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, autoregulation fails and flow is again dependent on pressure Initially, the brains OEF increases to maintain CMRO2 (misery perfusion) If this does not suffice, there is not enough oxygen to supply metabolic demands and CMRO2 falls
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
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
Entry of water
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
Entry of water
Cell Death
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
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
Entry of water
Cell Death
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
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
Entry of water
Cell Death
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Activation of Proteases
Activation of NO synthase
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Activation of Proteases
Activation of NO synthase
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Activation of Proteases
Activation of NO synthase
Necrosis
Exhaustion of ATP Failure of Ion pumps Depolarization Release of Glutamate
Entry of water
Cell Death
Activation of Proteases
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
Apoptosis
Glutamate is released, but at lower concentration than in necrosis Promotes free radical production Leads to lesser elevation of intracellular calcium
Apoptosis
Promotes pro-death genes
Caspase 1,2,3 Forkhead family REST/NRSF Bcl-2 family
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
Global Hypoperfusion
CPP = MAP ICP If the MAP drops, so does the cerebral perfusion pressure If this is severe enough, it will cause global ischemia Milder drops in MAP may cause preferential ischemia in territories supplied by stenotic vessels.
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
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
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
Non-modifiable
Age (increases with) Gender (male) Family history Ethnicity
Intracranial more common in Asian, African-American, and Hispanic Extracranial more common in Caucasian
Hypercoagulable states
Disorders of the blood that predispose to clotting Polycythemia vera Thrombocytosis (platelet ct > 1,000,000/dL) Anti-phospholipid antibody syndrome Lupus anticoagulant Sickle Cell Disease Antithrombin III Protein C/S Mutation in genes for Factor V or II
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 TIAs 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
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
Embolism
Occlusion of a cerebral blood vessel by a small piece of blood clot, tumor, fat, air, 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, spleen, kidneys
Embolic Sources
Carotid Artery plaque, dissection Vertebral Artery plaque, dissection Aorta plaque, dissection Cardiac Atrial Fibrillation, PFO
Paradoxical Embolus
Chronic
Ventricular aneurysm Focal hypokinesis
Arrhythmias
Sick sinus syndrome Atrial fibrillation
Clinical Features
Abrupt onset of maximum defect in an awake, 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
&
Vertebral Artery
Rarely causes hypoperfusion stroke unless there is a problem with the other VA Posterior inferior cerebellar artery
Vertigo Nausea/emesis Gait ataxia
Basilar Artery
Brainstem signs Cranial neuropathies Ataxia Cerebellar signs Nausea, emesis Change in level of consciousness Crossed signs
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
Arteriosclerosis
a.k.a. small vessel disease Process whereby you develop thrombosis of small vessels (e.g. thalamic perforators)
Analogous to atherosclerosis of large/medium arteries
Perforators
Small vessel disease leads to lacunar strokes Can worsen over 1-2 days (stuttering lacune) Pure motor
Internal capsule, pons
Pure sensory
Thalamus
Ataxic hemiparesis
Internal capsule
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
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
Case
24 year-old woman on birth control pills has progressively worsening severe headache. She becomes lethargic and then develops diplopia. On exam, she is sleepy and slightly confused. She has bilateral 6th nerve palsies (more on this in Dr Harths Oncology lecture). As you are writing up your consult note she has a seizure.
Clinical Features
Headache
Diffuse, worse on recumbency, present on awakening
Papilledema
Increased pressure on the eye, may lead to blindness
Case
69 year-old-man who awoke following an abdominal aortic aneurysm repair unable to move his lower extremities. On exam, there is significant weakness of both legs. He is not able to perceive light touch or pinprick on his legs, but he is able to feel a vibrating tuning fork on his legs.
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
Sensory
Loss of sensation, sparing vibration and position sense, below the level of the lesion
Bladder dysfunction
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
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
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
Temperature
Metabolic demand varies proportionally with temperature Drowning victims Induction of hypothermia is under investigation
Already shown to be useful in cardiac arrest
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%
Treatment - Chronic
Depends on underlying etiology Most commonly antiplatelet agents [e.g. aspirin, Plavix (clopidogrel), Aggrenox (dipyridamole)] Interferes with platelet aggregation in the event of endothelial rupture over an atheroma Reduces growth of atheroma and likelihood of embolism
Treatment - Chronic
Anticoagulants (Coumadin)
Used in the presence of some hypercoagulable states and atrial fibrillation
The End