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)

TIA
Traditional
Ischemic event lasting under 24 hours

Proposed (probably more accurate)

Ischemic event lasting under 1 hour, AND No visible infarct by CT/MRI

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

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

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

Chronic Hypertension 0 70 CPP 150

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

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

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, 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

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

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

Inhibits pro-survival genes

CREB (cAMP response binding element protein) NFKB (nuclear factor KB)

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.

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

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

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

Thrombosis - 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, African-American, and Hispanic Extracranial more common in Caucasian

Thrombosis Other Causes

All of these are more common in the young Dissection
Tearing of the vessel wall itself Blood accumulates in the wall, 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

Inflammatory process affects blood vessel wall
Primary angiitis restricted to CNS Secondary to other systemic or CNS diseases
PAN Temporal Arteritis Takayasus Arteritis Connective tissue diseases: SLE, scleroderma, Sjogren syndrome, rheumatoid arthritis CNS infection: Lyme, bacterial meningitis, meningovascular syphilis, Herpes, TB

Thrombosis Other Causes

Drugs
Amphetamines, cocaine, heroin Combination of vasoconstriction and vasculitis

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

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 TIAs prior to actual infarct Hemodynamic
Stereotyped symptoms Varies with blood pressure Preferentially affects border zones
(Well come back to this when we get to Watershed Infarcts)

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

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

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

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, or main trunk or branch of the PCA

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

Middle Cerebral Artery Infarct

&

Dense MCA Sign

Middle Cerebral Artery

Contralateral gaze palsy Contralateral hemiplegia (arm+face>leg) Contralateral hemisensory loss Aphasia (dominant side only (D))
Can be global, expressive, receptive, 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 Seidmans 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 Horners 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

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

Primary process is lipohyalinosis More to come in ICH lecture on Monday

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

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

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?

Venous Infarcts - Anatomy

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

Pathophysiology of Venous Thrombosis

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

Pathophysiology of Venous Thrombosis

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

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. 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.

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

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

Spinal Stroke - Clinical

Motor
Cervical quadriplegia Thoracic paraplegia

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

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 - 4.5 hours

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

Reduction of Metabolic Stress

The necrosis pathway begins with depletion of ATP If we reduce the usage of ATP, we can delay the onset of necrosis

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

At least, we must aggressively treat fever

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

Control of risk factors

Treat diabetes, hypertension, hyperlipidemia Stop smoking

The End