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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

ImagingImaging ischemicischemic strokes:strokes:

CorrelatingCorrelating radiologicalradiological findingsfindings withwith thethe pathophysiologicalpathophysiological evolutionevolution ofof anan infarctinfarct

evolution evolution of of an an infarct infarct JayJay ChyungChyung,, PhD,PhD, HMSHMS IIIIII

JayJay ChyungChyung,, PhD,PhD, HMSHMS IIIIII GillianGillian Lieberman,Lieberman, MDMD

Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

PatientPatient A:A: historyhistory

91 y.o. woman

Acute onset R sided weakness and aphasia

MD September 2004 Patient Patient A: A: history history 91 y.o. woman Acute onset R sided

Jay Chyung Phd, HMS III Gillian Lieberman, MD

DDxDDx

September 2004

Stroke (Ischemic ~80% or Hemorrhagic ~20%)

September 2004 Stroke (Ischemic ~80% or Hemorrhagic ~20%) Transient ischemic attack (TIA) Seizure with post-ictal

Transient ischemic attack (TIA)

Seizure with post-ictal paralysis

Intracranial tumor (with secondary hemorrhage, seizure, or hydrocephalus)

Migraine

Metabolic encephalopathy

Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

AcuteAcute StrokeStroke ManagementManagement

Non-contrast head CT

Quickly identifies hemorrhagic strokes (fresh blood is bright on CT)

hemorrhagic strokes (fresh blood is bright on CT) Ischemic stroke Can administer tPA within 3 hrs

Ischemic stroke

Can administer tPA within 3 hrs (systemic) or 6 hrs (intra- arterial)

Identify source of ischemic stroke: Embolic, Thrombotic, Low-flow

Prevent secondary damage and expansion of infarct

Hemorrhagic stroke

DO NOT administer tPA

Mildly reduce blood pressure

Administer products to reduce interstitial fluid levels (eg. Mannitol)

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

PatientPatient A:A: NonNon--contrastcontrast CTCT

Patient Patient A: A: Non Non - - contrast contrast CT CT Findings *** No evidence

Findings

*** No evidence of hemorrhage***

Loss of gray-white matter distinction in L MCA territory Sulcal effacement Slight mass effect on
Loss of gray-white matter
distinction in L MCA
territory
Sulcal effacement
Slight mass effect on L lateral
ventricle

No midline shift

PACS, BIDMC

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

PatientPatient A:A: ProgressionProgression ofof InfarctInfarct

Findings No evidence of hemorrhagic transformation Hypodensity in region of L MCA infarct Mass effect
Findings
No evidence of
hemorrhagic
transformation
Hypodensity in region of
L MCA infarct
Mass effect on L lateral
ventricle with midline
shift
PACS, BIDMC
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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

MechanismsMechanisms ofof ischemicischemic strokestroke injuryinjury

Event in Neurons

Loss of blood supply

O 2 depletion

Glucose depletion

Conversion to anaerobic respiration

Exhaustion of cellular ATP

Time

0

10 sec 2-4 min 2-4 min 4-5 min
10 sec
2-4 min
2-4 min
4-5 min

NEURONS have very limited stores of energy in the forms of phosphocreatine and glycogen. In contrast, GLIAL cells have greater energy reserves and are less energy demanding.

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

MechanismsMechanisms ofof ischemicischemic strokestroke injuryinjury

ATP depletion Mitochondrial dysfunction Na + -K + ATPase dysfunction Loss of electrochemical gradient: Anoxic
ATP depletion
Mitochondrial
dysfunction
Na + -K + ATPase dysfunction
Loss of electrochemical gradient: Anoxic depolarization
Massive glutamate release
Ca ++ influx
Phospholipase and protease activation
Apoptosis pathway
Necrosis
Edema, FAS death ligands, cytokine release, free radical generation, acidosis

Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

EarlyEarly CTCT changeschanges fromfrom intracranialintracranial edemaedema

Loss of blood supply

intracranial intracranial edema edema Loss of blood supply ATP depletion Cell death EDEMA Edema : 0-20

ATP depletion

intracranial edema edema Loss of blood supply ATP depletion Cell death EDEMA Edema : 0-20 HU;

Cell death

edema edema Loss of blood supply ATP depletion Cell death EDEMA Edema : 0-20 HU; 1.

EDEMA

Edema: 0-20 HU;

1. Effacement of gray-white matter distinction as edema reduces the small difference in gray and white matter attenuations

the small difference in gray and white matter attenuations 2. Effacement of sulci due to swelling

2. Effacement of sulci due to swelling within limited space

3. Mass effect on ventricles due to swelling within limited space

* Earliest CT changes seen several hours to days after initial loss of blood supply depending on size of infarct and volume of edema.

Gray matter: ~46 HU;

White matter: ~40 HU

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

ProgressionProgression ofof anan ischemicischemic infarctinfarct

Loss of blood supply

an ischemic ischemic infarct infarct Loss of blood supply ATP depletion Cell death EDEMA CYTOKINES FAS

ATP depletion

ischemic infarct infarct Loss of blood supply ATP depletion Cell death EDEMA CYTOKINES FAS DEATH LIGANDS

Cell death

infarct Loss of blood supply ATP depletion Cell death EDEMA CYTOKINES FAS DEATH LIGANDS FREE RADICAL

EDEMA

CYTOKINES

FAS DEATH LIGANDS

FREE RADICAL DAMAGE

ACIDOSIS

FAS DEATH LIGANDS FREE RADICAL DAMAGE ACIDOSIS CELL DEATH Increase in infarct size over time is

CELL DEATH

Increase in infarct size over time is possible

Ischemic Penumbra - the region surrounding the infarcted tissue is subjected to numerous stresses:

the infarcted tissue is subjected to numerous stresses: • Decreased perfusion Abnormal cerebrovascular pressure

Decreased perfusion

Abnormal cerebrovascular pressure autoregulation

Compression by neighboring edema

Active inflammation

Free radical damage from infarcted region and neutrophils, astrocytes, microglia

Induction of apoptosis by FAS death ligands

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

PtPt B:B: ProgressionProgression ofof anan ischemicischemic infarctinfarct

Time = 3.25 hr Late CT changes: 30 hr 8 days
Time = 3.25 hr
Late CT changes:
30 hr
8 days

Increased infarction area, mass effect on ventricle, loss of sulci, hypodensity in infarcted tissue

* Hypodensity due to replacement of tissue by fluid

[Figure from Pantano et al. 1999. Stroke 30:502-507]

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

HemorrhagicHemorrhagic transformationtransformation ofof ischemicischemic strokestroke

Loss of blood supply

of of ischemic ischemic stroke stroke Loss of blood supply ATP depletion Cell death FREE RADICAL

ATP depletion

ischemic stroke stroke Loss of blood supply ATP depletion Cell death FREE RADICAL DAMAGE: METABOLIC BYPRODUCTS

Cell death

stroke stroke Loss of blood supply ATP depletion Cell death FREE RADICAL DAMAGE: METABOLIC BYPRODUCTS NEUTROPHILS

FREE RADICAL DAMAGE:

METABOLIC

BYPRODUCTS

NEUTROPHILS

O 2

DAMAGE: METABOLIC BYPRODUCTS NEUTROPHILS O 2 HEMORRHAGE Hemorrhagic transformation of ischemic stroke

HEMORRHAGE

Hemorrhagic transformation of ischemic stroke results from reperfusion injury.

- -
-
-

Reperfusion injury: Restoration of blood flow through a previously occluded intracranial vessel that results in vessel wall destruction and hemorrhage.

Spontaneous or tPA-induced clot lysis

O 2 combines with toxic metabolites to generate superoxide O 2

Invading neutrophils convert O 2 to O 2

Blood-brain barrier destruction from free radical damage to

endothelial cells AND ischemic endothelial cell death (3-4 hrs)

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

PatientPatient C:C: HemorrhagicHemorrhagic transformationtransformation ofof anan ischemicischemic strokestroke

of of an an ischemic ischemic stroke stroke 13 [Figure from http://www.strokecenter.org/educati
13
13

[Figure from http://www.strokecenter.org/education/ais_pathogenesis/16_hemorrhagic_conversion.htm]

Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

tPAtPA--inducedinduced hemorrhagichemorrhagic transformation:transformation: potentialpotential treatmenttreatment

1. tPA treatment for ischemic stoke often leads to secondary hemorrhagic transformation due to reperfusion injury

hemorrhagic transformation due to reperfusion injury 2. Current models state that reperfusion injury occurs in

2. Current models state that reperfusion injury occurs in large part from free radical damage following clot-lysis

3. Therefore, delivery of tPA WITH anti-oxidants should reduce the probability of hemorrhagic transformations

Animals models support co-administration of tPA with anti-oxidants in the prevention of secondary hemorrhagic transformation

Lapchak and Zivin. 2003. STROKE 34(8):2013-8

Lapchak et al. 2001. STROKE 32(1):147-153

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

IschemicIschemic strokes:strokes: imagingimaging withwith MRIMRI DiffusionDiffusion--WeightedWeighted ImagingImaging (DWI)(DWI)

Loss of blood supply

Weighted Imaging Imaging (DWI) (DWI) Loss of blood supply ATP depletion Massive depolarization ↑ intracellular ions

ATP depletion

Imaging (DWI) (DWI) Loss of blood supply ATP depletion Massive depolarization ↑ intracellular ions INTRACELLULAR

Massive depolarization

Loss of blood supply ATP depletion Massive depolarization ↑ intracellular ions INTRACELLULAR EDEMA Cell death

intracellular ions

ATP depletion Massive depolarization ↑ intracellular ions INTRACELLULAR EDEMA Cell death EXTRACELLULAR EDEMA DWI

INTRACELLULAR

EDEMA

depolarization ↑ intracellular ions INTRACELLULAR EDEMA Cell death EXTRACELLULAR EDEMA DWI signal intensity is

Cell death

↑ intracellular ions INTRACELLULAR EDEMA Cell death EXTRACELLULAR EDEMA DWI signal intensity is related to the

EXTRACELLULAR

EDEMA

DWI signal intensity is related to the apparent diffusion coefficient (ADC) of water molecules (independent of the amount of water)

ADC(water) decreases by ~50% within 5-10 min of ischemic stroke due to intracellular edema and also possibly decreased temperature– recall that ATP is depleted from neurons within 4-5 min.

recall that ATP is depleted from neurons within 4-5 min. *** DWI changes can be seen

*** DWI changes can be seen within minutes of an ischemic stroke.

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

PtPt D:D: ImagingImaging ischemicischemic strokesstrokes withwith MRIMRI DiffusionDiffusion--WeightedWeighted ImagingImaging (DWI)(DWI)

- - Weighted Weighted Imaging Imaging (DWI) (DWI) Left inferior temperal/occipital lobe ischemic infarct
- - Weighted Weighted Imaging Imaging (DWI) (DWI) Left inferior temperal/occipital lobe ischemic infarct

Left inferior temperal/occipital lobe ischemic infarct

- Weighted Weighted Imaging Imaging (DWI) (DWI) Left inferior temperal/occipital lobe ischemic infarct PACS, BIDMC 16

PACS, BIDMC

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

SummarySummary slideslide

Loss of blood supply

2004 Summary Summary slide slide Loss of blood supply ATP depletion Cell Death DWI: increased signal

ATP depletion

Summary slide slide Loss of blood supply ATP depletion Cell Death DWI: increased signal intensity (5-10

Cell Death

slide slide Loss of blood supply ATP depletion Cell Death DWI: increased signal intensity (5-10 min
DWI: increased signal intensity (5-10 min post-ischemic injury) Early CT changes: GW & sulcal effacement,
DWI:
increased signal intensity
(5-10 min post-ischemic injury)
Early CT changes:
GW & sulcal effacement,
mass effect (hrs to days)
Reperfusion injury
effacement, mass effect (hrs to days) Reperfusion injury Hemorrhagic transformation 17 Edema, cytokine release,
effacement, mass effect (hrs to days) Reperfusion injury Hemorrhagic transformation 17 Edema, cytokine release,

Hemorrhagic

transformation

17

to days) Reperfusion injury Hemorrhagic transformation 17 Edema, cytokine release, free radical damage, FAS death

Edema, cytokine release, free radical damage, FAS death ligands

cytokine release, free radical damage, FAS death ligands Cell Death Bright lesion on CT Late CT
cytokine release, free radical damage, FAS death ligands Cell Death Bright lesion on CT Late CT

Cell Death

Bright lesion on CT

Late CT changes:

Hypodensity, mass effect, possibly enlarged infarct region

Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

ReferencesReferences

Easton JB et al. “Cerebrovascular diseases,” Chapter 366 in Harrison’s Principles of Internal Medicine 1998, 14 th Edition: 2325-2348.

Ishikawa M et al. “Platelet-leukocyte-endothelial cell interactions after middle cerebral artery occlusion and reperfusion.” J Cereb Blood Flow Metab. (2004) 24(8):907-15.

Lapchak PA et al. “Pharmacological effects of the spin trap agents N-t-butyl-phenylnitrone (PBN) and 2,2,6, 6- tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator.” Stroke (2001) 32(1):147-153.

plas minogen activator.” Stroke (2001) 32(1):147-153. Lapchak PA and Zivin JA. “Ebselen, a seleno-organic

Lapchak PA and Zivin JA. “Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits:

synergism with low-dose tissue plasminogen activator.” Stroke (2003) 34(8):2013-8.

Onteniente B et al. “Molecular pathways in cerebral ischemia.” Mol Neurobiol. (2001) 27(1):33-72.

Pantana P et al. “Delayed increase in infarct volume after cerebral ischemia: Correlations with thrombotic treatment and clinical outcomes.” Stroke (1998) 30:502-507.

Sen S. “Magnetic resonance imaging in acute stroke.” eMedicine: http://www.emedicine.com/neuro/topic431.htm

(2004).

Wang X and Lo EH. “Triggers and mediators of hemorrhagic transformation in cerebral ischemia. Mol Neurobiol. (2003) 28(3):229-44.

Welch KMA et al. “Magnetic resonance assessment of acute and chronic stroke.” Prog. in Cardiovasc. Dis. (2000) 43(2): 113-134.

http://www.strokecenter.org/education/ais_pathogenesis/16_hemorrhagic_conversion.htm

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Jay Chyung Phd, HMS III Gillian Lieberman, MD

September 2004

AcknowledgementsAcknowledgements

Dan Cornfeld, MD Larry Barbaras Gillian Lieberman, MD Pamela Lepkowski

2004 Acknowledgements Acknowledgements Dan Cornfeld, MD Larry Barbaras Gillian Lieberman, MD Pamela Lepkowski 19