3335 Ischemic Stroke CHAPTER 427

A B

C D

FIGURE 426-13 Magnetic resonance imaging (MRI) of acute stroke. A. MRI

diffusion-weighted image (DWI) of an 82-year-old woman 2.5 h after onset of

right-sided weakness and aphasia reveals restricted diffusion within the left basal

ganglia and internal capsule (colored regions). B. Perfusion defect within the left

hemisphere (colored signal) imaged after administration of an IV bolus of gadolinium

contrast. The discrepancy between the region of poor perfusion shown in B and

the diffusion deficit shown in A is called diffusion-perfusion mismatch and provides

an estimate of the ischemic penumbra. Without specific therapy, the region of

infarction will expand into much or all the perfusion deficit. C. Cerebral angiogram of

the left internal carotid artery in this patient before (left) and after (right) successful

endovascular embolectomy. The occlusion is within the carotid terminus. D. Fluidattenuated inversion recovery image obtained 3 days later showing a region of

infarction (coded as white) that corresponds to the initial DWI image in A, but not

the entire area at risk shown in B, suggesting that successful embolectomy saved

a large region of brain tissue from infarction. (Used with permission from Gregory

Albers, MD, Stanford University.)

stenotic lesions in the large intracranial arteries because such lesions

increase systolic flow velocity. TCD can also detect microemboli from

otherwise asymptomatic carotid plaques. In many cases, MR angiography combined with carotid and transcranial ultrasound studies

eliminates the need for conventional x-ray angiography in evaluating

vascular stenosis. Alternatively, CTA of the entire head and neck can

be performed during the initial imaging of acute stroke. Because this

images the entire arterial system relevant to stroke, with the exception

of the heart, much of the clinician’s stroke workup can be completed

with this single imaging study.

Perfusion Techniques Both xenon techniques (principally xenon

-CT) and positron emission tomography (PET) can quantify cerebral

blood flow. These tools are generally used for research (Chap. 423)

but can be useful for determining the significance of arterial stenosis

and planning for revascularization surgery. Single-photon emission

computed tomography (SPECT) and MR perfusion techniques report

relative cerebral blood flow. As noted above, CT imaging is used as the

initial imaging modality for acute stroke, and some centers combine

both CTA and CT perfusion imaging together with the noncontrast

CT scan. CT perfusion imaging increases the sensitivity for detecting

ischemia and can measure the ischemic penumbra (Fig. 426-12). Alternatively, MR perfusion can be combined with MR diffusion imaging

to identify the ischemic penumbra as the mismatch between these two

imaging sequences (Fig. 426-13).

■ FURTHER READING

Benjamin EJ et al: Heart disease and stroke statistics-2019 update: A

report from the American Heart Association. Circulation 139:e56,

2019.

Blumenfeld H: Neuroanatomy Through Clinical Cases, 2nd ed.

Oxford, UK, Oxford University Press, 2010.

Tamutzer AA et al: ED misdiagnosis of cerebrovascular events in the era

of modern neuroimaging: A meta-analysis. Neurology 88:1468, 2017.

The clinical diagnosis of stroke is discussed in Chap. 426. Once this

diagnosis is made and either a noncontrast computed tomography

(CT) scan or magnetic resonance imaging (MRI) scan has been performed, rapid reversal of ischemia is paramount. This chapter will

focus on the stroke treatment timeline and subsequent secondary

stroke prevention.

■ PATHOPHYSIOLOGY OF ISCHEMIC STROKE

Acute occlusion of an intracranial vessel causes reduction in blood

flow to the brain region it supplies. The magnitude of flow reduction

is a function of collateral blood flow, and this depends on individual

vascular anatomy (which may be altered by disease), the site of occlusion,

and systemic blood pressure. A decrease in cerebral blood flow to zero

causes death of brain tissue within 4–10 min; values <16–18 mL/100 g tissue per minute cause infarction within an hour; and values <20 mL/100 g

tissue per minute cause ischemia without infarction unless prolonged

for several hours or days. If blood flow is restored to ischemic tissue

before significant infarction develops, the patient may experience only

transient symptoms, and the clinical syndrome is called a transient

ischemic attack (TIA). Another important concept is the ischemic

penumbra, defined as the ischemic but reversibly dysfunctional tissue

surrounding a core area of infarction. The penumbra can be imaged by

perfusion imaging using MRI or CT (see below and Figs. 426-12 and

426-13). The ischemic penumbra will eventually progress to infarction

if no change in flow occurs, and hence, saving the ischemic penumbra

is the goal of revascularization therapies.

Focal cerebral infarction occurs via two distinct pathways

(Fig. 427-1): (1) a necrotic pathway in which cellular cytoskeletal

breakdown is rapid, due principally to energy failure of the cell; and

(2) an apoptotic pathway in which cells become programmed to die.

Ischemia produces necrosis by starving neurons of glucose and oxygen,

which in turn results in failure of mitochondria to produce ATP. Without ATP, membrane ion pumps stop functioning and neurons depolarize, allowing intracellular calcium to rise. Cellular depolarization also

causes glutamate release from synaptic terminals; excess extracellular

glutamate produces neurotoxicity by activating postsynaptic glutamate

receptors that increase neuronal calcium influx. Ischemia also injures

or destroys axons, dendrites, and glia within brain tissue. Free radicals

are produced by degradation of membrane lipids and mitochondrial

dysfunction. Free radicals cause catalytic destruction of membranes and

likely damage other vital functions of cells. Lesser degrees of ischemia, as

are seen within the ischemic penumbra, favor apoptotic cellular death,

causing cells to die days to weeks later. Fever dramatically worsens brain

injury during ischemia, as does hyperglycemia (glucose >11.1 mmol/L

[200 mg/dL]), so it is reasonable to suppress fever and prevent hyperglycemia as much as possible. The value of induced mild hypothermia to

improve stroke outcomes is the subject of continuing clinical research.

TREATMENT

Acute Ischemic Stroke (Fig. 427-2)

After the clinical diagnosis of stroke is made (Chap. 426), an orderly

process of evaluation and treatment should follow. The first goal

427 Ischemic Stroke

Wade S. Smith, S. Claiborne Johnston,

J. Claude Hemphill, III

3336 PART 13 Neurologic Disorders

Glutamate

receptors

Energy failure

Proteolysis

Cell Death

Ca2+/Na+ influx

Ischemia Reperfusion

PARP

Arterial Occlusion

Glutamate

release

Thrombolysis

Thrombectomy

Mitochondrial

damage

Free radical

formation

Inflammatory

response

Arachidonic acid

production

Membrane and

cytoskeletal breakdown

Apoptosis

Phospholipase

iNOS

Leukocyte

adhesion

Lipolysis

FIGURE 427-1 Major steps in the cascade of cerebral ischemia. See text for details. iNOS, inducible nitric oxide synthase; PARP, poly-A ribose polymerase.

Suspected acute

stroke

Prehospital call

ahead

Code stroke

activation

Onset <6 h Onset 6–24 h

CT no

hemorrhage

IV PA eligible? Favorable

perfusion? Give IV PA

No

Yes

Yes

No

Yes No

ICA/M1-2 or BA

occlusion? Thrombectomy Inpatient

management Perform CTA

CT no

hemorrhage

CTA/CTP

FIGURE 427-2 Management of acute stroke (pathway followed by the authors). For suspected stroke identified by prehospital professionals, we encourage calling ahead to

the destination hospital. This allows early “stroke code” activation to prepare for an emergent computed tomography (CT) on arrival. For patients with onset <6 h from last

time seen normal, we expedite a noncontrast head CT scan, and if free of hemorrhage and the patient is IV plasminogen activator (PA) eligible, this is administered in the

CT scanner. (For IV tissue PA [tPA], the bolus is given and infusion initiated; for tenecteplase, the full dose is given as a bolus). Then CT angiography (CTA) from left atrium to

skull vertex is performed to identify an eligible target lesion for thrombectomy. For a patient presenting in the 6- to 24-h time window, PA is not considered, and the decision

to perform thrombectomy is based on perfusion imaging.

Priorities of Acute Stroke Consultation: Once stroke is suspected, the first priorities are to assess airway and blood pressure, followed by establishing the time last seen

normal. Patients with disabling neurologic deficits (particularly with National Institutes of Health Stroke Scale >5) may be eligible for thrombolytic or endovascular therapy.

Based on the onset time, we follow the protocol shown in the figure. Following acute treatments, if any, we proceed with establishing the cause of the ischemic stroke. If

atrial fibrillation is established or newly discovered, we favor use of apixaban 5 mg twice daily (or a reduced dose of 2.5 mg twice daily for impaired glomerular filtration

rate) lifelong. If atrial fibrillation is not detected, we obtain a transthoracic echocardiogram to assess left atrial size and/or any valvular lesions. With large left atria and

a clear embolic stroke, we favor use of an oral anticoagulant while obtaining ambulatory 30-day electrocardiogram monitoring. If we identify significant internal carotid

stenosis, we refer for carotid endarterectomy during the same hospitalization regardless of infarct size. For all else, we use the dual antiplatelet agents aspirin (81 mg) and

ticagrelor (180-mg load, followed by 90 mg twice daily) daily for 30 days then discontinue ticagrelor and continue aspirin at 81 mg daily. We prefer ticagrelor to clopidogrel,

which is also proven in these settings, because it is not affected by common polymorphisms of CYP2C19 that limit efficacy of clopidogrel in significant proportions of

patients, particularly those of Asian descent. If the CTA revealed significant intracranial atherosclerosis or other precranial vessel stenosis within the vascular territory of

the infarct (lumen caliber reduced by >50%) we continue dual antiplatelet agents for at least 3 months, then convert to a single agent. Unless contraindicated, all patients

receive atorvastatin 80 mg, with goal low-density lipoprotein level of <70 mg/dL unless the stroke has a nonatherothrombotic cause. Patients who are statin intolerant can

receive PSK9 inhibitors. Blood pressure control should target systolic blood pressure <120 mmHg long term, but we allow permissive hypertension for the first few weeks

to help with collateral flow to the brain. BA, basilar artery; CTP, computed tomography perfusion; ICA, internal carotid artery; IV, intravenous; M1, middle cerebral artery first

division; M2, middle cerebral artery second division; PA, plasminogen activator.

3337 Ischemic Stroke CHAPTER 427

is to prevent or reverse brain injury. Attend to the patient’s airway, breathing, and circulation (ABCs), and treat hypoglycemia

or hyperglycemia if identified by finger stick testing. Perform an

emergency noncontrast head CT scan to differentiate between

ischemic stroke and hemorrhagic stroke (Chap. 428); there are no

reliable clinical findings that conclusively separate ischemia from

hemorrhage, although a more depressed level of consciousness,

higher initial blood pressure, or worsening of symptoms after

onset favor hemorrhage, and a deficit that is maximal at onset, or

remits, suggests ischemia. Treatments designed to reverse or lessen

the amount of tissue infarction and improve clinical outcome fall

within six categories: (1) medical support, (2) IV thrombolysis,

(3) endovascular revascularization, (4) antithrombotic treatment,

(5) neuroprotection, and (6) stroke centers and rehabilitation.

MEDICAL SUPPORT

When ischemic stroke occurs, the immediate goal is to optimize

cerebral perfusion in the surrounding ischemic penumbra. Attention is also directed toward preventing the common complications

of bedridden patients—infections (pneumonia, urinary, and skin)

and deep-venous thrombosis (DVT) with pulmonary embolism.

Subcutaneous heparin (unfractionated and low-molecular-weight)

is safe and can be used concomitantly. Use of pneumatic compression stockings is of proven benefit in reducing risk of DVT and is a

safe alternative to heparin.

Because collateral blood flow within the ischemic brain may

be blood pressure dependent, there is controversy about whether

blood pressure should be lowered acutely. Blood pressure should

be reduced if it exceeds 220/120 mmHg, if there is malignant

hypertension (Chap. 277) or concomitant myocardial ischemia,

or if blood pressure is >185/110 mmHg and thrombolytic therapy

is anticipated. When faced with the competing demands of myocardium and brain, lowering the heart rate with a β1

-adrenergic

blocker (such as esmolol) can be a first step to decrease cardiac

work and maintain blood pressure. Routine lowering of blood

pressure below the limits listed above has the potential to worsen

outcomes. Fever is detrimental and should be treated with antipyretics and surface cooling. Serum glucose should be monitored and

kept <10.0 mmol/L (180 mg/dL), and above at least 3.3 mmol/L

(60 mg/dL); a more intensive glucose control strategy does not

improve outcome.

Between 5 and 10% of patients develop enough cerebral edema

to cause obtundation and brain herniation. Edema peaks on the

second or third day but can cause mass effect for ~10 days. The

larger the infarct, the greater the likelihood that clinically significant edema will develop. Water restriction and IV mannitol may

be used to raise the serum osmolarity, but hypovolemia should be

avoided because this may contribute to hypotension and worsening

infarction. Combined analysis of three randomized European trials

of hemicraniectomy (craniotomy and temporary removal of part of

the skull) shows that hemicraniectomy reduces mortality by 50%,

and the clinical outcomes of survivors are significantly improved.

Older patients (age >60 years) benefit less but still significantly. The

size of the diffusion-weighted imaging volume of brain infarction

during the acute stroke is a predictor of future deterioration requiring hemicraniectomy.

Special vigilance is warranted for patients with cerebellar infarction. These strokes may mimic labyrinthitis because of prominent

vertigo and vomiting; the presence of head or neck pain should alert

the physician to consider cerebellar stroke due to vertebral artery

dissection. Even small amounts of cerebellar edema can acutely

increase intracranial pressure (ICP) by obstructing cerebrospinal

fluid (CSF) flow leading to hydrocephalus or by directly compressing the brainstem. The resulting brainstem compression can manifest as coma and respiratory arrest and require emergency surgical

decompression. Suboccipital decompression is recommended in

patients with cerebellar infarcts who demonstrate neurologic deterioration and should be performed before significant brainstem

compression occurs.

INTRAVENOUS THROMBOLYSIS

The National Institute of Neurological Disorders and Stroke

(NINDS) Recombinant Tissue Plasminogen Activator (rtPA) Stroke

Study showed a clear benefit for IV rtPA in selected patients with

acute stroke. The NINDS study used IV rtPA (0.9 mg/kg to a

90-mg maximum; 10% as a bolus, then the remainder over 60 min)

versus placebo in ischemic stroke within 3 h of onset. One-half of

the patients were treated within 90 min. Symptomatic intracranial

hemorrhage occurred in 6.4% of patients on rtPA and 0.6% on

placebo. In the rtPA group, there was a significant 12% absolute

increase in the number of patients with only minimal disability

(32% on placebo and 44% on rtPA) and a nonsignificant 4% reduction in mortality (21% on placebo and 17% on rtPA). Thus, despite

an increased incidence of symptomatic intracranial hemorrhage,

treatment with IV rtPA within 3 h of the onset of ischemic stroke

improved clinical outcome.

Three subsequent trials of IV rtPA did not confirm this benefit,

perhaps because of the dose of rtPA used, the timing of its delivery,

and small sample size. When data from all randomized IV rtPA

trials were combined, however, efficacy was confirmed in the <3-h

time window, and efficacy likely extended to 4.5 h and possibly to

6 h. Based on these combined results, the European Cooperative

Acute Stroke Study (ECASS) III explored the safety and efficacy

of rtPA in the 3- to 4.5-h time window. Unlike the NINDS study,

patients aged >80 years and diabetic patients with a previous stroke

were excluded. In this 821-patient randomized study, efficacy was

again confirmed, although the treatment effect was less robust than

in the 0- to 3-h time window. In the rtPA group, 52.4% of patients

achieved a good outcome at 90 days, compared to 45.2% of the

placebo group (odds ratio [OR] 1.34, p = .04). The symptomatic

intracranial hemorrhage rate was 2.4% in the rtPA group and 0.2%

in the placebo group (p = .008).

Based on these data, rtPA is approved in the 3- to 4.5-h window

in Europe and Canada but is still only approved for 0–3 h in the

United States. A dose of 0.6 mg/kg is typically used in Japan and

other Asian countries based on observation of >600 patients given

this lower dose and observing similar outcomes to historical controls and a lower rate of intracranial hemorrhage. This dose also

mitigates concerns that patients of Asian descent have a higher

propensity to bleed from most antithrombotic and thrombolytic

medications. Use of IV rtPA is a central component of primary

stroke centers (see below). It represents the first treatment proven

to improve clinical outcomes in ischemic stroke and is cost-effective

and cost-saving. The time of stroke onset is defined as the time the

patient’s symptoms were witnessed to begin or the time the patient

was last seen as normal. Patients who awaken with stroke have the

onset defined as when they went to bed. Advanced neuroimaging

techniques (see Chap. 426) may help to select patients beyond the

4.5-h window who will benefit from thrombolysis. Two trials using

MRI selection beyond 4.5 h have shown clinical benefit from IV

rtPA. Patients with minor stroke (nondisabling deficit and National

Institutes of Health Stroke Scale [NIHSS] 0–5) appear to respond to

acute aspirin as well as IV rtPA. Table 427-1 summarizes eligibility

criteria and instructions for administration of IV rtPA.

The plasminogen activator tenecteplase (0.25 mg/kg IV bolus

over 5 s), although not directly tested against IV rtPA, is being used

by some centers because it is given without need for a 1-h infusion.

This may improve the efficiency of transferring patients from primary to comprehensive stroke centers for thrombectomy because

the IV infusion required for IV rtPA is not required for tenecteplase,

thus obviating need for critical care transport. Several trials using

tenecteplase prior to endovascular therapy have found it to be safe.

ENDOVASCULAR REVASCULARIZATION

Ischemic stroke from large-vessel intracranial occlusion results in

high rates of mortality and morbidity. Occlusions in such large

vessels (middle cerebral artery [MCA], intracranial internal carotid

artery, and the basilar artery) generally involve a large clot volume

and often fail to open with IV rtPA alone.