ISCHEMIC STROKE, THROMBOLYSIS & TIA

Mark Keezer

R3 Neurology

August 26th 2009

Cigarettes and Chocolate Milk

Objectives

1. Background review of stroke

2. Approach to acute ischemic stroke 3. Thrombolysis in acute stroke4. General management of acute stroke

Craniectomy for malignant MCA BP control

5. Approach to TIA.

Synonyms Abound

Stroke is currently the most preferred term Cerebrovascular accident (CVA ) Apoplexy (Gr. Being struck down, to suffer a

seizure).

Drowning in a Sea of Strokes Dr. Charles Miller Fisher

House officers and students learn neurology “stroke by stroke”

>50% of neurological admissions

50,000 new /year in Canada

3rd most important cause of death after heart disease and cancer

Most important cause of adult disability 30% of survivors require daily assistance.

Stroke Definition

Acute Focal Neurologic syndrome Secondary to vascular pathology (ie

cerebrovascular disease)

Exclusions include local pressure effects of aneurysms, vascular headache, CNS vasculitis, elevated ICP...

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

ICH10%

SAH10%

Lacunar20% Thromboembolic

10%

Cardioembolic20%

Other 5%Other 5%

Unknown25%

Ischemic Ischemic 80%80%

Hemorrhagic Hemorrhagic 20%20%

Foulkes et al. The stroke data bank: design, methods and baseline characteristics. Stroke 1988;19:547-554.

Stroke Types

Risk Factors 1/3

Non-modifiable Age Male gender Ethnicity: African or Asian origin Family history

Stroke in first degree relative

Genetics MELAS, CADASIL Fabry’s disease Ehler’s Danlos type IV Pseudoxanthoma elasticum Dyslipidemias Vasculopathies Cardiomyopathies.

Risk Factors 2/3

Modifiable : HTN – 4 x DM – 2 x (4x with HTN) Smoking – 2 x Hyperlipidemia – 1.5 x

CAD Stroke , TIA , stenosis Drugs (cocaine, amphetamines, heroin, EtOH)

A fib – 5-6 x.

CHADS2

Gage et al. Validation of clinical classification schemes for predicting stroke. Results from the national registry of atrial fibrillation. JAMA 2001;285:2864-2870.

Risk Factors 3/3

Others: Thrombophilia

APL antibodies (lupus anticoagulant, anticardiolipin antibodies) Homocysteine

OCP.

Pathophysiology

The brain is very metabolically active tissue 15-20% of cardiac output

Normal CBF > 55ml/min/100 g CBF <23 ml/min/100 g: critical level for impairment of function CBF <10-12 ml/min/100g: infarction regardless of duration

Complete arrest of flow: 15 sec: suppression of electric activity 2-4 min: inhibition of synaptic excitability 4-6 min: inhibition of electric excitability.

Stroke Syndromes 1/2

ACA MCA (Ant choroidal, Gerstmann) PCA (Alexia without agraphia, Balint,

Dejerine-Roussy, Anton)

Lacunar (PM, PS, SM, AH, CD and 200 more).

Stroke Syndromes 2/2

Brain stem syndromes Midbrain

Weber = PCA = ipsi 3rd, contra plegia Claude = PCA = contra rubral tremor Benedikt = PCA = ipsi 3rd, contra plegia and rubral tremor

Pons Marie-Foix Syndrome = long circumferential = ipsi ataxia, contra

plegia & ST Raymond Syndrome = paramedian branches = ipsi 6th, contra plegia Millard-Gubler Syndrome (aka Foville) = paramedian branches =

ipsi 6th& 7th contra plegia Medulla

Dejerine = vertebral = ipsi 12th, contra plegia and ML Wallenberg = PICA > vertebral = ipsi 5th, 8th, 9 & 10th, Horner’s and

ataxia; contra ST + singultus.

“Code Stroke!” Now what?

ER Evaluation 1/2

Immediate response!

ABC and G (glucose)

Concise but pertinent history:

WHEN WAS THE PATIENT LAST (& DEFINITELY) SEEN NORMAL ?

Resetting the clock?

Atypical features H/A, NECK PAIN, SZ Any improvement.

Beware of Mimics!

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

ER Evaluation 2/2

Pertinent PMHx Risk factors

Dr Minuk’s “5 Horseman of the Apocalypse”

Recent MI, trauma, surgery, migraines, epilepsy or pregnancy

Pertinent Medx Anticoagulants Antiplatelets Antihypertensives Hypoglycemics / insulin.

Albrecht Dürer, Four Horsemen of the Apocalypse, 1498.

Φ

Vitals (including glucose) Dr Côté checks the BP in both arms Pulse(s)

Cardiac murmurs or carotid bruits.

NINDS Stroke Scale

NINDS Stroke Scale

Requisite Initial Interventions Would this pt benefit from IV NS?

Dr Wein doesn’t hesitate to give 120cc/hr

Consider a NS Bolus if hypotensive

Maintain fiO2 ≥92%.

Requisite Initial Investigations CBC

INR

SMA7 (incl glucose)

EKG, troponin +/- CXR (very modest value and can the pt afford

the delay?)

Selected patients: toxicology, b-HCG.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Neuro-imaging in Acute Stroke

Immediate Goal

Exclude hemorrhageExclude mass lesions

Assess location & degree of brain injury

+/- CTA protocol to identify occluded vessel.

First Step

CT scan: Non-contrast Goal is door-to-CT in 25 mins

Subtle signs (82% of large vessel occlusions within 6 hrs) Loss of gray-white matter differentiation Sulcal effacement Obscuration of basal ganglia, insula MCA sign (M1 branch), dot sign (M2/M3 branch) Parenchymal hypodensity.

ASPECTS: Alberta Stroke Programme Early CT Score

Quantitative alternative to 1/3 MCA exclusion criterion for rt-PA (greater sensitivity and specificity for poor outcome) Normal: 10 points; -1 point for each area of hypoattenuation or focal

swelling

Increased disability ≤ 7.

Barber et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000;355:1670-1674.

Thrombolysis!

Indications for rt-PA

Intravenous may be given within 4.5 hours of symptom onset

Intra-arterial may be given within 6 hours under the care of a stroke neurologist

Intra-arterial may be given within 24 hours (or more?) for catastrophic posterior fossa event

AHA guidelines Do not wait for platelets or INR unless you suspect a

possible bleeding diathesis.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

AHA Guideline Criteria 1/2

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

AHA Guideline Criteria 2/2

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

1/3 of MCA rule

Von Kummer et al. Acute stroke: usefullness of early CT findings before thrombolytic therapy. Radiology 1997;205:327-333.

ASPECTS: Alberta Stroke Programme Early CT Score

Quantitative alternative to 1/3 MCA exclusion criterion for rt-PA (greater sensitivity and specificity for poor outcome) Normal: 10 points; -1 point for each area of hypoattenuation or focal

swelling

Increased disability ≤ 7.

Barber et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000;355:1670-1674.

Barber et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. The Lancet 2000;355:1670-1674.

ASPECTS: Alberta Stroke Programme Early CT Score

Increased death & disability if ASPECTS ≤ 7 Increased death & disability if initial NIHSS >15.

NINDS rt-PA Stroke Study Group Randomized, double-blind, placebo controlled

trial

Included only patients within 3h

Permuted block randomization Half within 90 minutes Half between 90-180 minutes

Strict exclusion criteria No stroke severity criteria No ischemic size criteria No myocardial infarction criteria.

NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587.

2 parts Part 1: early improvement

291 pts randomized to rt-PA or placebo Looked at NIHSS improvement ≥4 pts at 24h

Part 2 : delayed improvement 333 pts randomized to rt-PA or placebo Primary outcome: pts with minimal or no

deficits at 3 months 95 or 100 on Barthel index ≤1 on NIHSS ≤ 1 on mRS 1 on Glasgow outcome scale.

NINDS rt-PA Stroke Study Group

NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587.

12% absolute risk reduction at 3 monthsNNT = 8

NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587.

NINDS rt-PA Stroke Study Group

5.9% absolute risk increase at 36 hoursNNH = 17

NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587.

NINDS rt-PA Stroke Study Group

For every 4 pts with improved outcome at 3 months 2 pts will suffer

symptomatic HT within 36 hrs 1 of whom will die

A trend towards decreased mortality among treatment group.

NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587.

rt-PA Arithmetic

Cochrane Review

Wardlaw et al. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD000213. DOI: 10.1002/14651858.CD000213

rt-PA versus control; Outcome = death or dependency at the end of follow up; patients randomised within 3 hours of stroke.

European Cooperative Acute Stroke Study (ECASS) III

Randomized, double-blind, placebo controlled trial

rt-PA from 3 to 4.5 hrs

Primary outcome was mRS at 3 months Favourable outcome ≤1

Exclusion criteria included: Severe stroke (NIHSS ≥25 or ≥1/3 MCA territory) Combination of previous stroke and diabetes

mellitus.

Hacke et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. NEJM 2008;359:1317-1329.

Hacke et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. NEJM 2008;359:1317-1329.

7.2% absolute risk reduction at 3 monthsNNT = 14

European Cooperative Acute Stroke Study (ECASS) III

Hacke et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. NEJM 2008;359:1317-1329.

4.4% absolute risk increase at 3 monthsNNH = 23

European Cooperative Acute Stroke Study (ECASS) III

Time is Brain!

Saver JL. Time is brain – quantified. Stroke 2006;37:263-266.

“Remember that time is money.” Benjamin Franklin, Advice to a Young Tradesman (1748)

Time is Brain!

The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. The Lancet 2004;363:768-774.

Intra-arterial vs. Intravenous PROACT II (JAMA 1999)

Pro-urokinase in MCA occlusion @ < 6hrs 180 patients (121 tx; 59 placebo) ARR 15% but a further 8% with ICH at 24hrs

Intra-arterial may result in greater rates of recanalization (66%!?) Intravenous remains favoured due to

potential delays in delivery.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Consider Intra-arterial if…

Severe neurological deficits (NIHSS ≥10) Presentation between 3 and 6 hours Recent major surgery Occlusion of major cervical or intracranial

vessels

Presence of hyper-dense artery sign?

If considering, give bridging rt-PA IV dose while waiting.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Angioplasty and Stenting

Possible acute uses (in conjunction with thrombolysis) ICA occlusion Vertebrobasilar occlusion

Anecdotally, >24hrs post onset!

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Outside the Window(s)?!

Nothing to do?

Don’t be sad. Or angry at someone...

There are still ways to help your patient.

Early Stroke Management

Maintain adequate tissue oxygenation, ≥92 % Common: pneumonia, severe dysphagia,

atelectasis NPO Elevate HOB? Robinul, atropine 1% eye drops po?

Cardiac monitoring MI and arrhythmia frequent after stroke, most

often a. fib Arrhythmia associated with insular strokes (right

>>left) 24 hour monitoring recommended.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Early Stroke Management

Avoid hyperthermia Treat fever and infections No evidence for cooling and potential risks of

hypotension, cardiac arrhythmia and pneumonia

Glucose Treat hyperglycemia aggressively, frequent

testing, scales and Insulin

DVT prophylaxis Frequent complication 5000 U bid or LMWH, safe with ASA.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Early Stroke Management

Seizures: 5-8 % after stroke, prophylaxis not

recommended

Incontinence not uncommon in acute stroke Limit use of Foleys to avoid urosepsis

Decubitus ulcers in 15% of pts Think of it Positioning, dressings, adequate nutrition.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

BP and Long Term Outcome

Leonardi-Bee et al. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002; 33: 1315-1320.

BP and Short Term Outcome

50

60

70

80

90

100

110

<70 (n=9)

70-89(n=49)

90-109(n=132)

110-129(n=122)

130-149(n=34)

>150(n=12)

Baseline MAP (mmHg)

Poo

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utco

me

at D

ay 1

0 (%

)

Keezer et al. Blood pressure and antihypertensive therapy as predictors of early outcome in acute ischemic stroke. Cerebrovascular Diseases 2008;25:202-208.

Acute Hypertension Management Blood pressure monitoring

Lower and higher BP associated with ↑ infarct volume at 7 days

AHA guidelines Lower only if > 220/120 mmHg

or 185/110 for rt-PA Labetalol 10-20 mg IV q 10-20 min (or

nitroprusside infusion) Goal is 15-25% reduction within first 24hrs Otherwise, hold all antihypertensives for first

24 hours!

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.

Acute Hypertension Management No conclusive data, only expert opinion

1. Hold all antihypertensives Follow the guidelines

2. Continue all antihypertensives If the brain wants hypertension (and the heart

can handle it), it will happen

3. Continue some of them Avoid holding those that will give rebound

hypertension or tachycardia.

Controlling Hypertension and Hypotension immediately Post-Stroke (CHHIPS) Lisinopril 5mg po or labetalol 50mg po Repeat BP at 4 and 8 hrs

If BP has not decreased 15mmHg or to 145-155mmHg, then repeat medx.

Potter et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double blind pilot study. The Lancet Neurology 2008;8:48-56.

Potter et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double blind pilot study. The Lancet Neurology 2008;8:48-56.

Controlling Hypertension and Hypotension immediately Post-Stroke (CHHIPS)

Acute Hypertension Management I’ve been known to use hydralazine or

clonidine if SBP >>200 mmHg (not expert opinion )

But remember, impaired auto-regulation is relative If I’ve been walking around for 5 yrs with a BP

210/140, be careful about dropping it too much Maybe I’ll extend my infarct if you drop me to a

~measly 170/100 Use the AHA 15% rule!

Acute Hypotension Management Rare Correct hypovolemia Correct any cardiac arrythmia (ie fast a.

fib)

Dopamine is proposed by the AHA Little if any data to support their use CHHIPS attempted to look at phenylephrine

but suffered from inadequate recruitment Phenylephrine has been favoured because of

little cerebral vasoconstriction.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.Mistri et al. Pressor therapy in acute ischemic stroke. Systematic review. Stroke 2006;37:1565-1571.

Anticoagulation

International Stroke Trial 19,435 pts

ASA (300mg qd) + ufH (5000 or 12,500 U bid) ASA alone ufH alone Neither

Death at 14 days, death or dependency at 6 months

Heparin led to fewer recurrent strokes at 14 days (2.9% vs 3.8%) Offset by an increase in ICH (1.2% vs 0.4%) No significant difference in death or non-fatal recurrent

stroke (11.7% vs 12.0%)

AHA does not recommend its use, even in the setting of worsening stroke.

IST Collaborative Group. The IST: a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischemic stroke. The Lancet 1997;349:1569-1581.

Antiplatelets

Effect of early ASA not proven with IST

IST combined with Chinese Acute Stroke Trial (CAST) ASA during first 14 days post-stroke produced

10 fewer deaths or recurrent strokes per 1000 pts 4 more ICH, transfused or fatal extra-cranial bleeds per

1000 pts

No data for early clopidogrel or dipyridamole/ASA

Currently, none are recommended within first 24 hours.

Adams et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the AHA/ASA stroke council… Stroke 2007;38:1655-1711.IST Collaborative Group. The IST: a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischemic stroke. The Lancet 1997;349:1569-1581.

Decompressive Craniectomy +/- Mannitol

HAMLET, DECIMAL, DESTINY

Hofmeijer et al. Surgical decompression for space-occupying cerebral infarction (the hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial [HAMLET]): a multicentre, open, randomised trial. The Lancet Neurology 2009;8:326-333.

48hrs

Decompressive Craniectomy +/- Mannitol

Hofmeijer et al. Surgical decompression for space-occupying cerebral infarction (the hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial [HAMLET]): a multicentre, open, randomised trial. The Lancet Neurology 2009;8:326-333.

Transient Ischemic Attack

TIA

Classic definition Focal neurological deficits lasting < 24 hours

New AHA definition: “Transient episode of neurological dysfunction

caused by focal brain, spinal cord, or retinal ischemia, without acute infarction”

Most last <1 or 2 hours (if not 5 to 20 mins)

It is a stroke that did not finish, yet!

Easton et al. Definition and evaluation of transient ischemic attack. A scientific statement for healthcare professionals from the AHA/ASA stroke council… Stroke 2009;40:2276-2293.

Imaging positive TIA

Easton et al. Definition and evaluation of transient ischemic attack. A scientific statement for healthcare professionals from the AHA/ASA stroke council… Stroke 2009;40:2276-2293.

Gladstone et al. Management and outcomes of transient ischemic attacks in Ontario. CMAJ 2004;170:1099-1104.

TIA Prognosis

High risk TIA – ABCD2 score Age > 60 yrs = 1 pt BP >140/90 = 1 pt Clinical

Weakness (2 pts) Speech without weakness (1 pt) Other (0 pts)

Duration >60 min (2pts), 10-59 1 (pt) <10 (0 pts)

Diabetes = 1 pt.

Johnston et al. Validation and refinement of scores to predict very early stroke risk after transient ischemic attack. The Lancet 2007;369:283-292.

High risk TIA – ABCD2 score

Johnston et al. Validation and refinement of scores to predict very early stroke risk after transient ischemic attack. The Lancet 2007;369:283-292.

48hr risk of stroke High risk = score 6-

7 = 8.1% risk Mod risk = score 4-

5 = 4.1% risk Low risk = score 0-3

= 1.0% risk

Evaluation & Management

Current AHA guidelines If ABCD2 ≥3 then admit for monitoring

In case of urgent need for thrombolysis More rapid investigations

Otherwise evaluation and management similar to that of stroke.

Easton et al. Definition and evaluation of transient ischemic attack. A scientific statement for healthcare professionals from the AHA/ASA stroke council… Stroke 2009;40:2276-2293.

On the shoulders of giants:Mathias Ziller, Mike Sidel, Alexandre Poppe, Adel Al-Hazzani.

Poses

Thank you