Cerebrovascular DiseaseDaniel Costello

CUH

Cerebral Vasculature

Arterial system

Venous system

Mechanisms of Vascular Disease

Arterial (high flow)

Embolic occlusion

In situ occlusion

Rupture

Dissection

Inflammation

Spasm

Venous (low flow)

Embolic occlusion

In situ occlusion

Rupture

Dissection

Inflammation

Spasm

Risk Factors - Modifiable

• Hypertension• Heart disease• Atrial fibrillation• Hypercholesterolemia• Diabetes mellitus• Carotid stenosis• Prior stroke or TIA• PFO• Elevated homocysteine,

Lp(a)• Prothrombotic

conditions• Migraine• Sleep Apnea

• Smoking• Sedentary lifestyle• Obesity• Alcohol abuse

Medical conditions Behaviors

Major Modifiable Stroke Risk Factors

10-15%2.0-3.0Hyperhomocyst(e)inemia

1-2%4.0-18.0Atrial Fibrillation

5-30%1.0-3.0Heavy alcohol use

20-40%2.7Physical Inactivity

6-40%1.0-2.0Hyperlipidemia

4-20%1.0-3.0Diabetes

20-40%1.5-2.5Smoking

25-40%3.0-5.0Hypertension

PrevalenceRelative RiskRisk factor

Stroke Epidemiology in Ireland

• Approximately 10,000 Stroke per annum in Ireland

• Stroke:TIA ratio 4:1

• 3rd commonest cause of death in Western World

• Short & long term consequences

Stroke Epidemiology in Ireland

Acute Ischaemic Stroke

Albers GW et al. Chest. 1998;119:683S-698S.Rosamond WD et al. Stroke. 1999;30:736-743.

Cardioembolic (20%)Lacunar (25%)(small vessel disease)

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

Subarachnoid Hemorrhage (30%)

Cryptogenic (30%)

Atherothrombotic CerebrovascularDisease (20%)

IntracerebralHemorrhage (70%)

Cerebrovascular Disease: Stroke Types

?

TIA: old vs new definitions

“Penumbra”=Tissue at risk

Making a diagnosis

• Sudden onset neurological deficits• Loss of consciousness uncommon• Involuntary movements uncommon• Headache common

• Investigations determine:- effect of stroke i.e. ‘brain damage’- cause of this stroke - risk of future strokes

Vascular territories (Anterior)

Vascular territories (Posterior)

Vascular territories- MCA

Vascular territories- MCA

Vascular territories- MCA

Vascular territories- ACA & PCA

Vascular territories- Posterior

Vascular territories- vertebrobasilar

Investigations

Brain imaging• CT Brain• MRI Brain ‘Stroke

protocol’ with diffusion sequences

Vessel imaging• CTA• MRA• Ultrasound carotids

•Cardiac- telemetry, Echocardiography

•Clotting

•Aorta- trans-oesophageal echocardiography

Head CT

Brain Stroke ‘window’

T1-weighted Images

Interpretation:

• Anatomic delineation

• Only a few things are bright:

– Fat

– Protein (colloid cysts, melanin, methemoglobin)

– Gadolinium

Normal SI: CSF < GM < WM

Normal SI: WM < GM < CSF

• Signal intensity generally follows water content.

• Vasogenic edema looks bright.

• Many pathologic processes result in increased water content.

Interpretation:

T2-weighted Images

“Fluid Attenuated Inversion Recovery”

• T2-weighted image in which signal from CSF has been suppressed.

• Distinguishes CSF spaces from T2-bright lesions.• Increased conspicuity of T2-bright lesions next to

CSF.• CSF signal will not suppress if:

– SAH– Protein (as in infection/inflammation)– Hyperoxygenation– Propofol– Prior gadolinium

FLAIR Images

Normal SI: CSF < WM < GM

Interpretation:

Gradient Echo images

“Susceptibility” images

Normal SI: WM < GM < CSF

• T2 weighted image.

• Substances that exhibit susceptibility effect will look dark and “bloom:”– Deoxyhemoglobin– Intracellular methemoglobin– Hemosiderin– Calcium (sometimes)– Air– Metal (aneurysm clips,

earrings, braces, etc).

Interpretation:

Normal SI:

Diffusion-Weighted Images (DWI)

Normal SI: CSF < WM < GM

• T2-weighted image, in which substances look brighter if water diffusion is restricted.

• In acute stroke, water diffusion is restricted, so tissue looks bright.

Interpretation:

Vessel imaging

• Ultrasound

• CT angiography

• MR angiography

• Conventional catheter angiography

Magnetic Resonance Angiography (MRA)

• Moving blood looks bright.• All other substances dark.• No contrast necessary (but

we use gadolinium for better neck MRA images).

• Less spatial resolution than CTA, more motion-sensitive.

Interpretation:

Treatment of Acute Ischaemic Stroke

• Rapid assessment- NIHSS• Consider tPA (IV or IA)• Anti-coagulation• Anti-platelet agent• Blood pressure, glucose monitoring, fever control• Surgery• Early evaluation- fasting glucose & lipids, brain &

vessel imaging, screen for Atrial Fibrillation, TTE +- TOE

• Rehabilitation- SALT, PT, OT

ECASS III: tPA 3-4.5 hrs

ECASS III Outcomes

• 821- 418 to alteplase group and 403 to placebo.• Median NIHSS lower in tPA group (9 vs 10, p=.03)

and fewer patients with prior stroke (7.7% vs. 14.1%; p= 0.03)

• The median OTT time was 3 hours 59 minutes. • More patients had a favorable outcome with

alteplase (52.4% vs. 45.2%; odds ratio, 1.34; 95% CI 1.02 to 1.76; P = 0.04).

• In the global endpoint, the outcome was also improved with alteplase (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05).

• An adjusted analysis accounting for predictors of poor outcome showed a more favorable (odds ratio, 1.42; 95% CI, 1.02 to 1.98; P = 0.04)

ECASS III Safety

• The incidence of intracranial hemorrhage was higher with alteplase than with placebo for any ICH, (27.0% vs. 17.6%; P = 0.001) or for symptomatic ICH (2.4% vs. 0.2%; P = 0.008). Mortality did not differ (7.7% and 8.4%; P = 0.68).

• There was no significant difference in the rate of other serious adverse events.

Meta-Analysis of the major IV tPA trials shows clear benefit up to 3 hrs and beyond

Lancet 2004; 363: 768–74

NINDS 12% ECASS3 7%

Comparison of EfficacyTrials Pts Rx To Prevent CEA (NASCET) 6 1 major stroke

Pro-UK 7 1 major stroke

tPA NINDS 8 1 major stroke

tPA ECASS314 1 major stroke

Stroke Unit^ 18 1 major stroke/death

CEA (ACAS) 15-20 1 stroke

OAT AFIB 20 1 stroke /yr

tPA AMI* 26 1 death from MI

NASCET (n=659), NINDS (n=624) ^ BMJ 1997; 314:1151-9. *Lancet 1994;343:311-22

Courtesy Dr. Huang-Hellinger

Carotid and Vertebral Artery Dissection

• 2% of all ischemic strokes• 25% of stroke in young• Incidence 2.6 per 100,000

(carotid) and 1.0 per 100,000 (vertebral)

• Peaks in the 5th decade• Intracranial dissections are

rare, occur at younger agesIntimal tear sub intimal or sub adventitial hematoma (arterial occlusion, ‘pseudo’ aneurysm)From Schievink WI, NEJM 2001

Dissection: management

Management is controversial, no RCT

• Medical– Short term anticoagulation with heparin / warfarin

followed by long term anti-platelet agents– CTA, MRA, Carotid duplex useful for follow-up

• Endovascular– Balloon occlusion or stenting considered if

recurrent symptoms occur despite medical treatment

– Coiling of a ‘pseudo’aneurysm

• Surgical– Bypass, Surgery for pseudoaneurysm

Secondary Preventionof Ischemic Stroke

– Carotid endarterectomy: >50% stenosis

– Anticoagulation therapy: Cardioembolic stroke

– Antiplatelet therapy: Most common therapy

Antiplatelet Agentsfor Stroke Prevention

– Aspirin

– Ticlopidine

– Clopidogrel

– Dipyridamole

PatientPatient Relative RiskRelative Risk OddsOddsPopulationPopulation TherapyTherapy Reduction (%)Reduction (%) Reduction Reduction (%)(%)

Efficacy of Antiplatelet Agentsfor Prevention of Stroke, MI,

or Vascular Death

All VascularAll Vascular All antiplateletAll antiplatelet 2222 2727DiseasesDiseases regimensregimens

Stroke/TIAStroke/TIA All antiplateletAll antiplatelet 1717 2222regimensregimens

Stroke/TIAStroke/TIA AspirinAspirin 1313 1616

Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996.Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996.

Risk ReductionsRisk Reductions

Efficacy of Antiplatelet Agents vs Placebo for Prevention of Stroke, MI, or Vascular Death in Stroke/TIA Patients

Aspirin (all doses)Aspirin (all doses) 1010 1313

TiclopidineTiclopidine 11 2323

Dipyridamole + ASADipyridamole + ASA 44 3030

All Antiplatelet AgentsAll Antiplatelet Agents 1818 1717

Relative RiskRelative Risk Antiplatelet Agent Antiplatelet Agent No. of Studies No. of Studies Reduction (%)Reduction (%)

Source: Algra and Van Gijn 1996; Gent et al.Source: Algra and Van Gijn 1996; Gent et al.1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.

• Double-blind, randomized, multicenter trial

• Warfarin (INR 1.4-2.8) vs Aspirin (325 mg/day)

• Primary Endpoint: Recurrent Ischemic Stroke or Death

• Eligible: Ischemic Stroke (Non-cardioembolic,

Non-operable Atherosclerotic) within prior 30 days

• Sample size: 30% risk reduction (n=2206)

• Secondary Endpoints: TIA, MI

• Adverse Experience: Hemorrhage

Stroke Subtypes in WARSS

Aspirin Warfarin N (%) N(%)

Cryptogenic embolic 281(25.5) 295 (26.7)

Large Artery 144 (13.1) 115 (10.4)

Lacunar 612 (55.5) 625 (56.7)

Other 66 (6.0) 68 (6.2)

Carotid Endarterectomy Trials

• NASCET I (70-99%)• Medical 26%• Surgical 9% (5.8% risk of stroke or death within 30 days)

• NASCET II (50-69%)• Medical 22.2%• Surgical 15.7% ( 6.7% risk of stroke or death within 30 days)

• ACAS (>60%)• Medical 11%• Sugical 5.1% (2.3% risk of stroke or death within 30 days)

WASID Wafarin v.s. Aspirin for Symptomatic Intracranial Arterial

Stenosis

• Randomized, double-blind, placebo-controlled, multicenter trial

• 569 patients with TIA or stroke attributable to 50-99% stenosis of MCA, ICA or V-B system

• Randomized to – Warfarin with target INR 2.0-3.0– ASA 650 mg bid

• Primary endpoint: IS, ICH, death from vascular cause

Chimowitz et al. N Engl J Med. 2005;352:1305-16.

Adapted from Goldstein, et al. Circulation 2001;103:163-182.

68% (warfarin)21% (aspirin)

Atrial fibrillation

20-30% with statins in patients with known coronary heart disease

Hyperlipidemia

44% reduction in hypertensive diabetics with tight blood pressure control

Diabetes

50% within 1 year, baseline after 5 years

Smoking

30% - 40%Hypertension

Potential Benefit with Treatment Factor

Potential Stroke Risk Reduction for Individuals -- AHA

Guidelines

CVST

CVST

Topics not covered

• Vascular Malformations• Extraparenchymal haemorrhage

- Subarachnoid Haemorrhage- Subdural haemorrhage- Extradural haemorrhage

• Inflammation (vasculitis)• Arterial spasm• Strokes in young patients• Rehabilitation after acute stroke