Review Article

Journal of Cerebral Blood Flow &

Metabolism
0(00) 1–18
New developments in clinical ischemic ! Author(s) 2017
Reprints and permissions:
stroke prevention and treatment and sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0271678X17694046
their imaging implications journals.sagepub.com/home/jcbfm

Jeremy J Heit and Max Wintermark

Abstract
Acute ischemic stroke results from blockage of a cerebral artery or impaired cerebral blood flow due to cervical or
intracranial arterial stenosis. Ischemic stroke prevention seeks to minimize the risk of developing impaired cerebral
perfusion by controlling vascular and cardiac disease risk factors. Similarly, ischemic stroke treatment aims to restore
cerebral blood flow through recanalization of an occluded artery or dilation of a severely narrowed artery that supplies
cerebral tissue. Stroke prevention and treatment are increasingly informed by imaging studies, and neurovascular and
cerebral perfusion imaging has become essential in in guiding ischemic stroke prevention and treatment. Here we review
the latest advances in ischemic stroke prevention and treatment with an emphasis on the neuroimaging principles
emphasized in recent randomized trials. Future research directions that should be explored in ischemic stroke preven-
tion and treatment are also discussed.

Keywords
Core infarction, ischemic stroke, stroke prevention, mechanical thrombectomy, imaging
Received 3 November 2016; Revised 21 December 2016; Accepted 23 January 2017

mechanical thrombectomy for the treatment of ische-

Introduction
Ischemic stroke is the leading cause of disability and the
fifth leading cause of death in the United States. 1
Ischemic stroke is caused by embolic or thromboembolic
occlusion of a cerebral artery, which results in reduced
cerebral blood flow (CBF) to the brain. This impaired
CBF results in brain ischemia, which is separated into
two distinct components: (1) the irreversibly damaged
‘‘core’’ infarction and (2) the ischemic, but viable, sur-
rounding tissue that is called the ‘‘penumbra.’’ 2,3 The
goal of all ischemic stroke treatments is restoration of
CBF to the penumbra, as penumbra reperfusion minim-
izes the final size of core infarction and results in
improved patient outcomes.2,4,5
The past several years have seen significant advance-
ments in both ischemic stroke prevention and treat-
ment. There have been significant changes in medical
stroke prevention due to cardiac arrhythmias and intra-
cranial atherosclerosis in recent years, and more
stepwise advancements in stroke prevention due to cer-
vical atherosclerotic disease. Furthermore, the recent
publication of five randomized trials4–8 that demon-
strate an overwhelming benefit of endovascular
mic stroke compared to medical management is the
most significant advance in ischemic stroke therapy
since the approval of intravenous tissue plasminogen-
activator (tPA) in 1995.9
Here we review the latest advances in ischemic stroke
prevention and treatment with an emphasis on recent
randomized trials and neuroimaging principles. We aim
to provide an update on the treatment of ischemic
stroke to the imaging community and to emphasize the
important advances in imaging as they pertain to stroke
prevention and treatment. First, recent advances in
clinical ischemic stroke prevention are discussed with
an emphasis on cardioembolic, cervical carotid artery
atherosclerosis, and intracranial atherosclerosis.
Next, cervical and intracranial atherosclerotic plaque
Department of Radiology, Neuroimaging and Neurointervention
Division, Stanford University Hospital, Stanford, CA, USA
Corresponding author:
Max Wintermark, Department of Radiology, Neuroimaging and
Neurointervention Division, Stanford University Hospital, 300 Pasteur
Drive, S0047, Stanford, CA 94305, USA.
Email: mwinterm@stanford.edu
2 Journal of Cerebral Blood Flow & Metabolism
and vessel wall imaging advances that may identify
patients at increased risk of an ischemic stroke risk
are discussed. Third, recent advances in ischemic
stroke treatment are discussed with an emphasis on
endovascular therapy. Fourth, we consider neuroima-
ging techniques for endovascular stroke therapy with
an emphasis on the variety of approaches in practice
and on neuroimaging biomarkers that predict patient
outcome. Lastly, the success of the recent ischemic
stroke trials has raised many questions with respect to
the neuroimaging evaluation of ischemic stroke
patients, and we also discuss future research directions
that should be explored to define the optimal imaging
evaluation of these patients.
Ischemic stroke prevention clinical
and imaging advances
Ischemic stroke is most commonly caused by athero-
sclerotic disease or cardiac arrhythmias, such as atrial
fibrillation, and stroke risk reduction focuses on the
medical control of these diseases.10 The most common
medical comorbidities that increase the risk of ischemic
stroke include hypertension, diabetes mellitus, hyperlip-
idemia, and smoking.10–17 Effective ischemic stroke pre-
vention requires aggressive blood pressure control
(target systolic blood pressure less than 140 mm Hg
and diastolic blood pressure less than 90 mm Hg),
hyperlipidemia reduction with exercise, diet, and
statin medications (target low-density lipoprotein
levels < 100 mg/dl), and smoking cessation.10 To date,
aggressive glycemic control in patients with diabetes
mellitus has not been shown to result in a reduced
risk of ischemic stroke.18 However, most stroke neur-
ologists suggest a hemoglobin A1C of < 6.5% as an
appropriate therapeutic target.10
In the past several years, there have been advance-
ments in the prevention of ischemic stroke due to
cardioembolic, cervical carotid atherosclerotic disease,
and intracranial atherosclerotic disease (ICAD). These
clinical advances and emerging neuroimaging tech-
niques to predict the risk of stroke due to cervical or
ICAD are briefly reviewed below.
Cardioembolic stroke risk reduction
Patients with non-valvular atrial fibrillation are at an
increased risk of ischemic stroke secondary to cardiac
thromboembolism,19 and the majority of these patients
should be anticoagulated to minimize their stroke
risk.10,20–25 For many years, most patients were antic-
oagulated with warfarin. Warfarin is an effective anti-
coagulant that targets vitamin K-dependent enzymes in
the coagulation cascade, but it interacts with various
foods and many medications and requires frequent
international normalized ratio blood tests to ensure
adequate anticoagulation.
More recently, non-vitamin K antagonist oral
anticoagulant (NOAC) medications have become the
preferred anticoagulant in the prevention of ischemic
stroke secondary to atrial fibrillation. Dabigatran, riv-
aroxaban, apixaban, and edoxaban are all NOACs that
result in non-inferior (rivaroxaban and edoxaban) or
reduced (edoxaban and dabigatran) rates of ischemic
stroke compared to warfarin.26–30 These medications
also have a similar (rivaroxaban) or reduced (dabiga-
tran, rivaroxaban, edoxaban) frequency of bleeding
complications compared to warfarin.26–30 NOACs
also have the advantage of not requiring routine
blood tests to ensure adequate anticoagulation. Thus,
NOACs represent an important iterative advancement
in the non-invasive prevention of ischemic stroke in
patients with atrial fibrillation. Future studies and
patient registries will be important to determine the
long-term safety of the NOAC medications.
Cervical carotid artery atherosclerosis risk reduction
Atherosclerotic disease affecting the common carotid
artery and cervical internal carotid artery is responsible
for 25% of ischemic strokes in the United States. 31
Atherosclerotic plaque may reduce CBF as the arterial
lumen is reduced in caliber by the plaque, and this
impaired CBF may manifest as a transient ischemic
attack (TIA) or ischemic stroke. Alternatively, athero-
sclerotic plaque rupture exposures the sub-endothelial
cholesterol-rich plaque to the bloodstream, which may
cause thrombotic or thromboembolic occlusion of the
cervical internal carotid artery or intracranial
circulation.31
All patients with a TIA or ischemic stroke undergo
imaging evaluation of the cervical common and internal
carotid arteries to evaluate for a significant stenosis due
to atherosclerotic plaque. Carotid ultrasound is the
most common imaging modality used to evaluate the
cervical arteries, and computed tomographic angiog-
raphy (CTA) or magnetic resonance angiography
(MRA) are also frequently performed (Figure 1).
Patients with ischemic symptoms referable to a
common or internal carotid artery stenosis that meas-
ures 50–99% compared to the normal adjacent vessel
caliber benefit from treatment by carotid endarterec-
tomy (CEA)32–34 or carotid artery stenting (CAS)
(Figure 1).35,36 Both CEA and CAS improve the caliber
of the treated cervical carotid artery and lead to a
reduced risk of subsequent stroke. Importantly, the
long-term results of the Carotid Revascularization
Endarterectomy versus Stenting Trial (CREST) were
published in 2016. The CREST study randomized
2502 patients with symptomatic carotid artery stenosis
Heit and Wintermark 3

(a) (b)

(c) (d)

(e) (f)

Figure 1. Acute ischemic stroke secondary to a critical cervical internal carotid artery stenosis. A DWI image demonstrates a small
area of cerebral infarction in the subcortical white matter of the right temporal lobe (a, arrow). Cervical artery vascular imaging using
carotid color Doppler ultrasound (b) and CTA (c) after presentation identified a critical cervical right internal carotid artery stenosis
(b and c, arrows). The patient underwent treatment by placement of a carotid artery stent. A pre-stent digital subtraction angiogram
in the lateral projection shows a severe cervical right internal carotid artery stenosis that measures 1 mm in diameter (d, arrow). This
lesion was treated by uneventful placement of a carotid artery stent (e, arrow), and a post-stent digital subtraction angiogram in the
lateral projection demonstrates a significant improvement in the caliber of internal carotid artery (f, arrow).

to CEA or CAS, and this study demonstrated no sig-
nificant difference between CEA and CAS with respect
to periprocedural stroke, myocardial infarction, death,
post-procedure ipsilateral stroke, or long-term ipsilat-
eral stroke at up to 10 years of follow up.36 However,
a meta-analysis of randomized trials comparing CEA
and CAS showed found a higher rate of any stroke or
death in patients over 70 years who were treated with
CAS compared to CEA.37 Although CEA and CAS
may be considered equivalent therapies in the treatment
4 Journal of Cerebral Blood Flow & Metabolism
of symptomatic cervical carotid artery stenosis, CEA is
likely still superior in older patients.
Although cervical common or internal carotid artery
narrowing of 50% or greater is associated with an
increased risk of stroke, 88–90% of asymptomatic
patients with this degree of stenosis do not develop an
ischemic stroke.34,38,39 Therefore, the degree of luminal
stenosis is only one component of the atherosclerotic
plaque that determines the risk of a future ischemic
stroke, and additional studies have identified
atherosclerotic plaque composition to be important
for risk stratification.40–43 Imaging advances in cervical
atherosclerotic plaque characterization are discussed in
the ‘‘Vessel Wall Imaging in Stroke Prevention’’
Section below.
Intracranial atherosclerosis risk reduction
ICAD is an important cause of ischemic stroke, and
ICAD accounts for up to 10% of all ischemic strokes
in the USA and up to 50% of all ischemic strokes out-
side of North America.44–46 Similar to cervical athero-
sclerotic disease, ICAD may reduce CBF through
artery luminal narrowing or acute thrombotic occlusion
in the setting of a ruptured atherosclerotic plaque
(Figure 2)47–49 Similar to cervical atherosclerotic dis-
ease, reduction of stroke risk in the setting of ICAD
focuses on minimizing the risk of further arterial lumen
narrowing and preventing plaque rupture.
The medical management of ICAD requires aggres-
sive lipid lowering with atorvastatin 80 mg daily or
rosuvastatin 40 mg daily, regardless of LDL level, and
aggressive antiplatelet medical therapy to minimize the
risk of in situ atherosclerotic plaque thrombosis. 50 The
randomized trials ‘‘A Comparison of Warfarin and
Aspirin for the Prevention of Recurrent Ischemic
Stroke’’ (WARSS) and ‘‘Comparison of Warfarin and
Aspirin for Symptomatic Intracranial Arterial
Stenosis’’ (WASID) showed aspirin to be equivalent
to warfarin for prevention of ischemic stroke, cerebral
hemorrhage, or death.51,52 Patients treated with war-
farin also had a significantly higher adverse event
rate.52 The WARSS and WASID trials became the
basis for treatment of ICAD with single antiplatelet
agents, most commonly either aspirin or clopidogrel.
Subsequent studies comparing dual antiplatelet med-
ical therapy using both aspirin and clopidogrel to either
aspirin alone or clopidogrel alone did not find a benefit
of dual antiplatelet medication therapy in the preven-
tion of ischemic stroke.53,54 However, these studies
were not restricted to patients with ICAD, and the
ICAD specific ‘‘Stenting versus Aggressive Medical
Therapy for Intracranial Arterial Stenosis’’
(SAMMPRIS) trial found a lower rate of recurrent
ischemic stroke and death among ICAD patients
treated with aspirin and clopidogrel compared to his-
torical controls.55 Based upon the SAMMPRIS trial
results, most stroke neurologists and neurointerven-
tionalists consider dual antiplatelet medical therapy to
be the standard of care in the treatment of ICAD.
However, additional studies are required to define
better the most optimal medical therapy.56
More aggressive endovascular treatments for ICAD
include angioplasty and intracranial stenting. Initial
studies showed promise for these techniques in prevent-
ing ischemic strokes in patients with symptomatic
ICAD.57–62 However, the SAMMPRIS trial, which
randomized patients to either cerebral artery angio-
plasty and stenting or maximal medical therapy, was
terminated after an interim analysis demonstrated a
significantly higher rate of stroke or death in the angio-
plasty and stenting group (14.7%) compared to the
medical management group (5.8%) within 30 days of
treatment. Based upon the SAMMPRIS results, cere-
bral artery angioplasty and stenting are not recom-
mended for the treatment of ICAD. 10 Future studies
are required to determine if subsets of patients with
ICAD, such as those who develop ischemic stroke or
TIAs while on maximum medical management, benefit
from cerebral artery angioplasty or stenting.
Atherosclerotic plaque and vessel wall
imaging in stroke prevention
The advances in medical and interventional therapy for
stroke prevention in patients with cervical carotid ath-
erosclerotic disease or ICAD have been coupled with
the more recent identification of imaging biomarkers
that may more accurately predict the risk of ischemic
stroke in these populations. The degree of luminal nar-
rowing has been the mainstay of vessel imaging for over
20 years, but emerging techniques that image the com-
position, shape, and inflammatory characteristics of
atherosclerotic plaques may provide superior informa-
tion regarding the risk of a future thrombotic or
thromboembolic event due to plaque rupture. 40–43,63–65
It is not our intention to provide a complete overview
of the advances in carotid and intracranial atheroscler-
otic plaque imaging, which are well reviewed else-
where.66,67 However, we will briefly highlight the
principal advances in atherosclerotic plaque and
vessel wall imaging.
The most important imaging biomarkers of athero-
sclerotic plaque instability are: (1) intraplaque hemor-
rhage (IPH), (2) vessel wall enhancement, and (3)
plaque ulceration.68–71 MRI is the preferred imaging
modality for the assessment of carotid and intracranial
atherosclerotic plaque, as CT/CTA and CT/positron
emission tomography are less reliable in the detection
of IPH and plaque enhancement.72–74
Heit and Wintermark 5

(a) (b) (c)

(d) (e) (f)

Figure 2. Transient ischemic attacks due to a severe middle cerebral artery stenosis. A 66-year-old patient developed transient
ischemic attacks localizing the right middle cerebral artery circulation. Brain MRI demonstrated no evidence of acute or chronic
cerebral infarction (a), and MRA demonstrated a focal severe stenosis in the proximal M1 segment of the right MCA (b, c, arrows).
This stenosis was confirmed on digital subtraction angiography (d, arrow), and the appearance was consistent with ICAD. The patient
was initially treated medically, including dual anti-platelet medication initiation, but her symptoms were persistent. She underwent
endovascular treatment with cerebral artery angioplasty (e, f) given that she had failed medical management. An angioplasty balloon
was inflated across the right M1 stenosis (e, arrow). Following angioplasty, there was a marked improvement in the caliber of the right
M1 segment (f, arrow). She has had recurrent symptoms after treatment.

Intraplaque hemorrhage imaging. IPH is present in one-
third of atherosclerotic plaques with a luminal stenosis
of at least 50%.64,75 Histologic analysis of cervical
carotid artery atherosclerotic plaque demon- strates
regions of hemorrhage within the plaque, which occur
secondary to transient endothelial break- down
overlying the plaque or hemorrhage due to vasa
vasorum breakdown adjacent to the plaque. 76 These
hemorrhagic foci are hypothesized to perpetu- ate
ongoing plaque growth and further instabil- ity.64,76,77
Consistent with this idea, the presence of IPH strongly
correlates with an increased risk of plaque progression
and stroke in patients without symptoms irrespective of
the degree of associated arterial stenosis.41,64,78
Furthermore, retrospective stu- dies demonstrate that
IPH absence confers a 90– 100% negative predictive
value of a subsequent ische- mic stroke.40,41,64,78 Larger
prospective studies are needed to validate IPH as a
biomarker of stroke risk, but this biomarker holds
promise in the evalu- ation of patients at risk of
ischemic stroke.
MRI identifies IPH by imaging methemoglobin
within the plaque as a region of T1 shortening (T1
hyperintense signal abnormality). Most protocols use
T1-weighted two-dimensional spin echo sequences or
three-dimensional magnetization prepared gradient
echo sequences to image IPH.41,64,68,78,79 Volumetric
3D acquisitions and the use of fat suppression tech-
niques may further increase the conspicuity of these
lesions in the vessel wall.66
Vessel wall and plaque enhancement. Atherosclerotic
plaque inflammation results in plaque instability and
a higher risk of atherosclerotic plaque rupture and
ischemic stroke.80,81 The mechanism by which plaque
inflammation results in plaque instability remains
incompletely understood, but it is thought to result in
cytokine signaling that promotes macrophage recruit-
ment, endothelial and fibrous cap breakdown, and
plaque rupture.82 Carotid plaque enhancement reflects
this atherosclerotic plaque inflammation, and this
enhancement has been used as a marker of increased
6 Journal of Cerebral Blood Flow & Metabolism
ischemic stroke risk.83–87 Similar to IPH, plaque
enhancement is associated with an increased risk of
ischemic stroke regardless of the degree of associated
vessel stenosis.85,86
Plaque enhancement is measured by dynamic
contrast enhanced MRI following intravenous
gadolinium-based contrast agent injection.69,83–85 Post-
contrast T1-weighted images are typically acquired in
the axial plane so as to be perpendicular to the course
of the cervical common and internal car- otid arteries.
Fat-saturation techniques can help to increase the
conspicuity of the plaque enhancement.69
Plaque ulceration imaging. Rupture of an atherosclerotic
plaque occurs when there is a sudden exposure of the
highly thrombogenic lipid core to the blood traversing
the arterial lumen. Plaque rupture then results in plate-
let adhesion and formation of a thrombus at the lipid–
blood interface, and this thrombus may result in an
ischemic stroke. Therefore, high-risk atherosclerotic
plaques are those with a high likelihood of exposure
of the lipid-rich core to arterial blood flow.
The lipid-rich core of an atherosclerotic plaque is
separated from the endothelial lumen by a fibrous
cap. Discontinuity in this fibrous cap represents
plaque ulceration, which has been correlated with an
increased risk of ischemic stroke. 71,88 On MRI, this
fibrous cap appears as a discrete structure between
the vessel lumen and the underlying plaque, and this
cap is hypointense on conventional MRA images.
Plaque ulceration is best demonstrated on contrast
enhanced MRA as a focal disruption in the hypointense
cap with T1 shortening.89 Future prospective studies
are required to validate fibrous cap ulceration as a
marker of increased stroke risk.
Intracranial artery wall and atherosclerotic plaque
imaging. Similar to cervical artery atherosclerotic pla-
ques, atherosclerotic plaques in the intracranial circu-
lation and are at risk of in situ thrombosis and
thromboembolism that may result in ischemic stroke.
Cerebral artery IPH and wall enhancement have been
linked to a higher risk of ischemic stroke in the vascular
territory of the affected vessel,90–92 but the smaller size
of the cerebral arteries introduces challenges in the ima-
ging of these high-risk plaques. To our knowledge,
cerebral artery plaque ulceration imaging has not yet
been described.
Atherosclerotic plaques commonly involve the
middle cerebral artery (MCA), the intracranial verte-
bral arteries, and basilar artery. Interestingly, MCA
atherosclerotic plaques typically localize asymmetric-
ally to one wall of the cerebral artery, 93 and symptom-
atic plaques are more commonly located on the
superior and posterior wall of the MCA. These findings
suggest that symptomatic plaques are more closely
associated with the origins of the lenticulostriate perfor-
ating arteries, which may become occluded. 94 Most
ischemic strokes affect the MCA vascular bed, and
MCA IPH is present in up to 20% of patients with
ischemic stroke due to ICAD. 95,96 These data suggest
that cerebral vessel wall imaging to identify IPH may be
valuable in the evaluation of ischemic stroke patients,
especially those who otherwise have cryptogenic ische-
mic strokes.
Plaque enhancement is seen in 70% of patients with
symptoms referable to the enhancing plaque, but
whereas only 8% of asymptomatic plaques demon-
strate enhancement (Figure 3).97 In support of these
findings, a recent meta-analysis found enhancement of
cerebral artery plaque to be highly associated with
ischemic infarction within the territory of the enhancing
vessel with an odds ratio of 10.8. 92 Future prospective
studies are needed to validate these findings and deter-
mine the relative risk of cerebral vessel wall enhance-
ment in predicting ischemic stroke risk.
Future directions in atherosclerotic plaque and vessel wall
imaging. Cervical and intracranial atherosclerotic
plaque and vessel wall imaging hold great promise in
the evaluation and risk stratification of patients with
acute ischemic stroke. The preliminary studies summar-
ized above should be validated with larger prospective
trials. If IPH, vessel wall enhancement, and plaque
ulceration are validated as risk markers for stroke, it
will be of interest to determine whether these findings
may be successfully used as imaging surrogates in med-
ical or interventional studies in the emerging era of
personalized medicine. Furthermore, we envision how
individual patients’ plaque imaging evaluation may
lead to change in medical management to reduce the
risk of ischemic stroke.
Ischemic stroke treatment advances
There have been significant advances in endovascular
stroke treatment by mechanical thrombectomy over the
past several years, although these advances were pre-
ceded by significant setbacks in earlier trials. In 2013,
the Interventional Management of Stroke III (IMS-
III), Mechanical Retrieval and Recanalization of
Stroke Clots Using Embolectomy (MR RESCUE),
and Local Versus Systemic Thrombolysis for Acute
Ischemic Stroke (SYNTHESIS) trials were published,
and these trials all found no benefit of endovascular
stroke therapy compared to medical management in
the treatment of acute ischemic stroke.98–100 These
data generated much discouragement in the stroke
neurology and neurointerventional community, and
many of these physicians struggled to understand
Heit and Wintermark 7

(a) (b) (c)

(d) (e) (f)

Figure 3. Vessel wall enhancement in a patient with intracranial atherosclerotic disease. A middle aged patient presented with
recurrent transient ischemic attacks localizing to the right MCA circulation. An MRI FLAIR image demonstrated evidence of prior
cerebral infarction (a, arrow), and MRA identified a severe stenosis in the M1 segment of the right MCA (b, c, arrows). The right M1
stenosis was felt to be most consistent with ICAD, and the patient underwent further evaluation with vessel wall imaging (d–f). A
coronal T2-weigthed image demonstrates the right M1 stenosis (d, arrow). Post-contrast black-blood vessel wall imaging demon-
strates mild enhancement of the arterial wall localizing to the region of stenosis, which is shown in the coronal (e, arrow) and sagittal
(f, arrow) planes. The inset images (e, f) highlight this enhancement (e, f, arrowheads).

these trial results when they had so often seen superior
outcomes with endovascular stroke therapy in their
own practices.
Critical analyses of IMS-III, MR RESCUE, and
SYNTHESIS identified several design limitations of
these trials that principally included: (1) a lack of vas-
cular imaging prior to randomization and (2) a paucity
of third generation stent retriever devices used for
mechanical thrombectomy in the endovascular arms
of the studies.2,101 For example, patients in the IMS-
III were randomized without performing a CTA or
MRA in all patients, and 19% of patients in the endo-
vascular arm did not receive endovascular treatment
because no target arterial blockage was identified. 99,101
Stent retrievers result in significantly higher rates of
revascularization compared to older generation
devices,102,103 but stent retrievers were used in only
1% of the IMS-II, 13% of the SYNTHESIS, and 0%
of the MR RESCUE endovascular arms.98–100 These,
and other, design limitations likely accounted for the
failure of these trials to show a benefit of endovascular
stroke therapy compared to medical management.
Fortunately, the disappointment of 2013 was
reversed in 2015 with the unprecedented publication
of five randomized trials that showed an overwhelming
benefit of endovascular stroke therapy using mechan-
ical thrombectomy compared to medical management
following more stringent neuroimaging inclusion
criteria. These trials are the: (1) Multicenter
Randomized Clinical Trial of Endovascular
Treatment for Acute Ischemic Stroke (MR CLEAN),
(2) Endovascular Treatment for Small Core and
Anterior Circulation Proximal Occlusion with
Emphasis on Minimizing CT to Recanalization Times
(ESCAPE), (3) Randomized Trial of Revascularization
with Solitaire FR Device versus Best Medical Therapy
in the Treatment of Acute Stroke Due to Anterior
Circulation Large Vessel Occlusion Presenting within
Eight Hours of Symptom Onset (REVASCAT), (4)
Extending the Time for Thrombolysis in Emergency
Neurological Deficits – Intra-Arterial (EXTEND-IA),
and (5) Solitaire with the Intention for Thrombectomy
as Primary Endovascular Treatment (SWIFT PRIME).4–
8
The designs and outcomes of these trials
8 Journal of Cerebral Blood Flow & Metabolism

Table 1. Clinical and imaging selection and outcomes in recent randomized endovascular stroke trials.

MR CLEAN REVASCAT ESCAPE SWIFT PRIME EXTEND -IA

Time since 0–6 h 0–8 h 0–12 h 0–6 h 0–6 h

symptom onset
Dominant NCCT NCCT NCCT NCCT NCCT
imaging selection CTA CTA CTA CTA CTA
PCT (RAPID) PCT (RAPID)
Vessel occlusions ICA, M1, M2, ICA, M1 ICA, M1, All M2s ICA, M1 ICA, M1, M2
included A1, A2
Core Infarction None ASPECTS > 6 ASPECTS > 5 <50 ml (PCT) <70 ml (PCT)
Assessment
Collateral imaging None None Vessels within > 50% of None None
assessment ischemic territory by
CTA or Multiphase CTA
Penumbra None None None Tmax > 6 (PCT) Tmax > 6 (PCT)
imaging
assessment
Endovascular mRS c 2 33% 44% 53% 60% 71%
Medical 19% 28% 29% 36% 40%
mRS c 2

are summarized in Table 1. Neurointerventional stroke
therapy has rapidly become the standard of care for
patients with occlusion of the major intracranial
arteries (Figure 4), but many questions remain regard-
ing the best imaging triage of endovascular stroke can-
didates. We now review the neuroimaging evaluation of
endovascular stroke candidates with an emphasis on
the results of these five trials.
Neuroimaging selection of endovascular stroke
candidates
The neuroimaging evaluation of acute ischemic stroke
patients has several goals that include establishing the
ischemic stroke diagnosis, excluding stroke mimics,
identifying contraindications to intravenous or intra-
arterial thrombolysis, and identifying patients who
may benefit from endovascular treatment. 2 Patients
most likely to benefit from endovascular stroke treat-
ment are those with a relatively small volume of core
infarction, a large vessel occlusion (cervical or intracra-
nial internal carotid artery, M1 or M2 segment of the
MCA), and salvageable brain tissue.2,104 The five ran-
domized trials all addressed these three factors, but
there was variation in the imaging techniques used in
the neuroimaging evaluation.4–8 These three principal
components of acute ischemic stroke imaging are now
discussed further.
Ischemic core imaging. The ischemic core, which we define
as irreversibly infarcted brain tissue, should be measured
or estimated in all acute ischemic stroke patients to guide
subsequent treatment. Diffusion-weighted imaging
(DWI) that demonstrates restricted diffusion in brain
tissue remains the gold-standard for core infarction iden-
tification (Figure 5) However, not every patient can
undergo MRI, and not every stroke center has unre-
stricted access to MRI. In fact, very few patients
among the five randomized trials underwent pre-endo-
vascular treatment evaluation by MRI.4–8,105 These limi-
tations of MRI have led to the widespread adoption of
CT-based techniques to assess the core infarction.
The simplest CT measure of core infarction is a volu-
metric estimation of abnormal hypodensity. Most cen-
ters currently use the more quantitative 10-point
Alberta Stroke Program Early CT Score (ASPECTS)
as an estimate of the size of core infarction on non-
contrast head CT.106 The ESCAPE, REVASCAT,
and SWIFT PRIME trials required an ASPECTS of
6-10 for inclusion, and patients with ASPECTS of 0-5
excluded under the assumption that endovascular treat-
ment would offer no benefit in the setting of a large
volume of core infarction and that treatment of these
patients would lead to an increased risk of reperfusion
hemorrhage.4,7,8 By contrast, the MR CLEAN trial did
not require any estimation of the core infarct size, and a
non-contrast head CT was only used to exclude intra-
cranial hemorrhage.6 A recent subgroup analysis of the
MR CLEAN trial determined patient outcomes as a
function of pre-treatment ASPECTS, which were
grouped into large infarction (ASPECTS 0–4), moder-
ate infarction (ASPECTS 5–7), and small infarction
Heit and Wintermark 9

(a) (b) (c) 12

10

(d) (e)

(f) (g) (h) 12

10

Figure 4. Endovascular stroke therapy in a patient with acute ischemic stroke due to occlusion of the M1 segment of the left middle
cerebral artery. An elderly patient with an acute ischemic stroke due to occlusion of the M1 segment of the left MCA. (a–c) MRI
obtained prior to endovascular treatment shows a small core infarction on DWI (A, arrow), occlusion of the M1 segment of the left
MCA on a MRA maximum intensity projection image (b, arrow), and a large penumbra on the PMRI Tmax map (c, white outline). (d, e)
The patient underwent endovascular stroke therapy, and a digital subtraction angiogram prior to treatment demonstrates occlusion of
the M1 segment of the left MCA (d, arrow), which was completely recanalized after mechanical thrombectomy (e). An MRI obtained
on the day after endovascular treatment shows an unchanged region of core infarction on DWI (f, arrow), complete recanalization of
the left MCA (g, arrowhead), and normalization of cerebral perfusion on the PMRI Tmax map (h, white outline).

(ASPECTS 8–10).107 This study found no significant
difference in outcome or adverse events among these
groups, which suggests that patients with ASPECTS
less than six may be considered for treatment.107
Core infarction may also be estimated by perfusion
CT (PCT) as a significant reduction in either CBF or
cerebral blood volume (CBV) relative to the contralat-
eral normal hemisphere (Figure 5).104,108 The
EXTEND-IA and SWIFT PRIME trials both esti-
mated the core infarction as a 70% reduction in CBF
relative to the normal cerebral hemisphere, and the
volume of core infarction was processed using commer-
cially available automated software.4,5 Patients with a
core infarction greater than 50 ml (SWIFT PRIME) 4 or
70 ml (EXTEND-IA)5 were excluded from treatment.
These results demonstrate that the size of core
infarction is an important consideration in the selection
of endovascular treatment candidates, but much uncer-
tainty exists as to the most optimal imaging method to
estimate the ischemic core size. Furthermore, whether
10 Journal of Cerebral Blood Flow & Metabolism

(a) (b)

(c) (d)

(e) (f)

Figure 5. CT-, PCT-, and MRI-based measures of core infarction in a patient with an acute ischemic stroke. Non-contrast head CT
images from a patient with an acute ischemic stroke due to occlusion of the M1 segment of the left MCA (a, b). These images
demonstrate hypodensity of the left lentiform nucleus (a, arrow; b, arrowhead), left insular ribbon (a, arrowhead), and the left caudate
head (b, arrow). No abnormal hypodensity was identified in the cortical regions, and this patient was assigned a favorable ASPECTS of
7. By contrast, PCT images (c, d) estimated a much larger area of core infarction in this patient. CBF imaging (c) showed a large region
of decreased blood flow within the left MCA territory (C, arrow), and CBV imaging showed a slightly less large region of decreased
cerebral blood volume (d, arrow). The patient underwent successful revascularization, and DWI obtained after treatment (e, f)
demonstrated a core infarction (e, f, arrows) that corresponded to the core infarction estimated by the CBV and CBF PCT images.

patients with core infarctions larger than 70 ml (espe- determinant of patient outcome.109–111 The finding that
cially in non-dominant hemispheres) may benefit from patients with low ASPECTS still benefit from endovas-
treatment remains uncertain. Some studies have found cular treatment107 and the increasingly observed phe-
that the size of presenting core infarction is a strong nomenon of reversal of diffusion restriction after
Heit and Wintermark
endovascular therapy112 underscores the need for add-
itional research into how the core infarction influences
patient outcome after endovascular treatment.
Vascular imaging to localize vessel occlusion. The use of non-
invasive vascular imaging to identify the presence of a
large vessel occlusion is critical in the appropriate selec-
tion of patients for endovascular stroke treatment. The
five recent endovascular stroke trials all used CT or
MR angiography to localize the level of vascular occlu-
sion prior to randomization to endovascular or medical
treatment.4–8 The ESCAPE, REVASCAT, and SWIFT
PRIME trials were the most restrictive in their selection
criteria, and these trials required occlusion of the inter-
nal carotid artery or M1 segment of the MCA for con-
sideration of treatment.4,7,8 By contrast, the EXTEND-
IA and MR CLEAN trials allowed for more distal
occlusion of the M2 segment of the MCA. 5,6 Anterior
cerebral artery occlusion was also allowed in the MR
CLEAN trial, but only three patients with anterior
cerebral artery occlusions were included in this trial.6
The use of vascular imaging in the evaluation of
stroke patients who are being considered for endovas-
cular treatment ensures that only patients with a target
for treatment undergo triage to the neuroendovascular
suite.2,104 The IMS-III trial did not use vascular ima-
ging prior to triage for endovascular therapy, and, as
described previously, 19% of patients undergoing
endovascular therapy did not have a vascular occlusion
that could be intervened upon. 99 Given the significant
resources required for endovascular stroke therapy,
appropriate patient triage with vascular imaging is
likely to be very cost effective.
Salvageable brain tissue and penumbral imaging. A funda-
mental goal of endovascular stroke therapy is to limit
the size of cerebral infarction through the timely reca-
nalization of the occluded vessel. The patient most
likely to benefit from endovascular recanalization is
one with a small volume of core infarction and a
large volume of brain tissue at risk of infarction if
CBF is not restored in a timely manner (the so called
‘‘target mismatch’’) (Figure 6).2,104,113
There remains significant variation and controversy
surrounding the best method by which the volume of
salvageable tissue should be estimated. There are some
who argue that time is of the essence in acute ischemic
stroke, and that additional imaging designed to charac-
terize the salvageable brain tissue (‘‘penumbra’’) results
in unnecessary delays to treatment. This philosophy fits
within the imaging selection criteria of the MR CLEAN
and REVASCAT trials in which only a non-contrast
head CT or CTA were required before consideration
of treatment.6,8 In this imaging selection model, the
size of the penumbra is estimated as a mismatch
11
between the estimated core of infarction on the non-
contrast head CT and the clinical stroke severity, which
is most often measured by the National Institutes of
Health Stroke Scale (NIHSS) score. Patients without
a large core infarction who have a high NIHSS must
have salvageable tissue and should be considered for
endovascular stroke treatment. This strategy was effect-
ive in MR CLEAN and REVASCAT, and it resulted in
a good clinical outcome in 33% (MR CLEAN) and
44% (REVASCAT) of patients who underwent endo-
vascular therapy compared with only 19% (MR
CLEAN) and 28% (REVASCAT) of patients in the
medical management arms.6,8
By contrast, others have argued for a more stringent
neuroimaging inclusion criteria prior to consideration
for endovascular treatment. The two techniques most
commonly performed for additional evaluation of
endovascular stroke candidates include (1) collateral
imaging using multiphase CTA, PCT, or PMRI and
(2) penumbral imaging using PCT or perfusion MRI
(PMRI) techniques. Robust collateral vessels allow
for increased blood flow to ischemic brain tissue,
which limits the size of the core infarction and main-
tains the viability of the penumbra. The ESCAPE trial
included patients with moderate-to-good collaterals,
which were assessed by CTA or multiphase CTA. 7 In
ESCAPE, a good clinical outcome was achieved in 53%
of the endovascular arm compared to 29% of the med-
ical management arm,7 and a higher rate of good out-
comes in the endovascular arm were achieved
compared to the MR CLEAN and REVASCAT
trials.6,8 These data suggest a benefit of collateral ima-
ging in selecting patients for endovascular therapy.
The SWIFT PRIME and EXTEND-IA trials per-
formed PCT or PMRI and quantified the ischemic pen-
umbra as the volume of tissue with a time-to-maximum
delay of greater than six seconds using the automated
RAPID software.4,5,114 The use of penumbral imaging
in these trials resulted in a good clinical outcome in
60% (SWIFT PRIME) and 71% (EXTEND-IA) of
patients who underwent endovascular therapy com-
pared with only 35% (SWIFT PRIME) and 40%
(EXTEND-IA) of patients in the medical management
arms.4,5 Thus, the results of SWIFT PRIME and
EXTEND-IA also suggest that a more rigorous neuroi-
maging selection leads to better outcomes when
patients undergo endovascular stroke treatment.
The results of the recent five randomized stroke trials
underscore both the importance of neuroimaging in
selecting patients for treatment and the need for
ongoing research to determine the most optimal ima-
ging algorithms for patient triage and to eliminate futile
procedures. Patients being considered for endovascular
therapy at minimum require an assessment of the size
of core infarction and non-invasive vascular imaging to
12 Journal of Cerebral Blood Flow & Metabolism

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Figure 6. CT and MRI examples of the target mismatch in acute ischemic stroke. Three different patients presenting with acute
ischemic stroke and target mismatch neuroimaging profiles. Patient 1 (a–c). Non-contrast head CT demonstrates a small core
infarction in a hypodense right lentiform nucleus (a, arrow). PCT demonstrates a prolonged time-to-maximum (Tmax) within the right
MCA territory (b, arrow). Maximum projection images from CTA demonstrate occlusion of the M1 segment of the right MCA (c,
arrow). Patient 2 (d–f). PCT head demonstrates a small core infarction in the right corona radiata as an area of markedly reduced CBF
(d, arrow) and a prolonged Tmax within the right MCA territory (e, arrow). Maximum projection images from CTA demonstrate
occlusion of the M1 segment of the right MCA (f, arrow). Patient 3 (g–i). DWI identifies a small core infarction in the left lentiform
nucleus (g, arrow). There is prolonged Tmax within the left MCA territory on PMRI (h, arrow). Maximum projection images from
MRA demonstrate occlusion of the M1 segment of the left MCA (i, arrow).

confirm the presence of a large vessel occlusion.
Additional imaging designed to understand better the
patient’s cerebral perfusion using collateral or penum-
bral imaging may offer additional benefit in selecting
patients who are most likely to benefit from endovas-
cular stroke therapy. Among the recent trials, there was
a trend toward better outcomes in studies with more
rigorous neuroimaging selection for enrollment,
although other confounding variables might also
explain this difference. Future studies should seek to
determine the best neuroimaging algorithm for the
selection of endovascular stroke candidates. These stu-
dies would be bolstered by studies designed to estimate
the cost-effectiveness of collateral and penumbral ima-
ging based upon the recent trial results.
Neuroimaging prediction of outcome after ischemic
stroke. The importance of non-invasive brain imaging
Heit and Wintermark
is not restricted to the acute evaluation of patients with
ischemic stroke. Imaging studies obtained both before
and after ischemic stroke treatment provide prognostic
information and the likelihood of achieving a good
clinical outcome. As the number of patients undergoing
endovascular stroke treatment increases, we anticipate
an increased role of neuroimaging in the prediction of
patient outcome. Here we briefly review emerging areas
of stroke outcomes imaging research.
The size of cerebral infarction has long been known
to predict patient outcome, and patients with large
cerebral infarctions have a worse prognosis, which
may be measured at presentation or within days of
presentation.109,115–117 More recent studies focusing
on structural imaging after ischemic stroke have
found that the location of infarction is important in
predicting patient outcome. Patients with infarction
involving eloquent tissue (motor and language regions
in particular) are more likely to have a poorer clinical
outcome than those with infarctions involving less elo-
quent tissue.118 Similarly, preservation of the corticosp-
inal tract has been shown to be an important predictor
of motor function recovery.119
Diffusion-tensor imaging (DTI) continues to evolve
as a prognostic tool for recovery after an ischemic
stroke. DTI measures fractional anisotropy in the
major neuronal tracts of the brain, and it may charac-
terize disruption of these tracts following ischemic
stroke. Injury to the corticospinal tract from direct
ischemia or due to Wallerian degeneration correlates
with poor recovery of motor function when measured
by DTI weeks to months after presentation. 119–123
Interestingly, similar injury to the corticospinal tract
on DTI in the acute setting does not predict motor
outcome, which suggests some recovery of the corti-
cospinal tract is possible.124 Similar to the corticospinal
tract, decreased fractional anisotropy in the superior
longitudinal and arcuate fasciculi correlates with lan-
guage deficits following ischemic stroke.125 Large pro-
spective studies validating neuronal tract and
connectivity network disruption as predictors of patient
outcome are needed.
The functional connectivity between neural net-
works may also be assessed by resting-state func-
tional-MRI (rs-fMRI). This technique measures
changes in regional CBF using blood oxygen level
dependent (BOLD) imaging, and it may be used to
demonstrate activation of compensatory networks
after ischemic stroke.126 rs-fMRI shows promise as
prognostic tool after ischemic stroke, but additional
studies are needed to understand the significance and
prognostic importance of changes in neural networks.
It will also be of interest to learn whether changes in
resting-state functional networks may reveal activation
of inhibitory pathways that may impair recovery after
13
stroke.127 The identification and understanding of such
inhibitory pathways would represent additional targets
for therapies designed to improve patient recovery after
stroke.128,129
We expect that these and other neuroimaging tech-
niques will become more established predictors of out-
come after ischemic stroke.56 Prospective and
randomized trials are needed to validate these techniques
for prognostication. Additionally, validation of imaging
biomarkers that predict outcome after stroke may also
be used as surrogate endpoints for trials designed to test
new therapeutic approaches, which has the potential to
make clinical trials more efficient and require less lengthy
and expensive patient follow up.
Future directions in ischemic stroke treatment. The recent
endovascular stroke trials have led to a rapid change
in ischemic stroke treatment in a short period of time,
and the results of these trials have generated many
important questions that require additional study.
Future studies to compare and refine imaging selection
algorithms for endovascular stroke treatment are
needed. The stroke healthcare provider and research
community must continue to discuss and debate the
practical, and cost-effectiveness of various acute ische-
mic stroke imaging protocols, which has important
implications for patients and the increasingly expensive
USA healthcare system.
The recent endovascular stroke trials showed an
overwhelming benefit of treatment for patients present-
ing within 6 h of symptom onset. The REVASCAT and
ESCAPE trials also enrolled patients presenting up to 8
and 12 h after onset, respectively, but these studies were
not powered to determine endovascular treatment
effectiveness in these later time windows. 7,8 Therefore,
it remains uncertain whether patients presenting in later
time windows may also benefit from endovascular
treatment. The Endovascular Therapy Following
Imaging Evaluation for Ischemic Stroke 3 (DEFUSE
3) and the Trevo and Medical Management Versus
Medical Management Alone in Wake Up and Late
Presenting Strokes (DAWN) trials are two randomized
trials investigating this question. Both trials are rando-
mizing patients to endovascular stroke therapy versus
medical management 6 to 16 h (DEFUSE 3) or 6 to 24 h
(DAWN) after symptom onset, and both trials are
using vascular imaging and PCT or PMRI with a
target mismatch profile for patient inclusion.
Similarly, the randomized WAKE-UP trial is asking
whether patients with an unknown time of symptom
onset benefit from intravenous thrombolysis. 130
Patients eligible for enrollment in the WAKE-UP trial
have an MRI that demonstrates a core infarction to
fluid attenuation inversion recovery (FLAIR) signal
mismatch, and patients with this profile are randomized
14
to intravenous thrombolysis with tPA compared to
placebo.130
The results of these trials will be of significant inter-
est given the potential to extend significantly the treat-
ment window for patients with ischemic stroke.
Additional studies have correlated PCT and clinical
data in an effort to characterize better the penumbra
in late time windows.131 Thus, the ongoing randomized
stroke trials and efforts to combine imaging and clinical
data are testing a personalized medicine approach for
ischemic stroke treatment triage by using physiologic
PMRI or PCT imaging in their inclusion criteria, and
it will be of interest to see if this imaging approach is
validated in these later time windows.
Conclusions
The endovascular stroke trials of 2015 have led to a sea
change in the treatment of patients with acute ischemic
stroke in a very short period of time. Modern endovas-
cular stroke therapy coupled with the recent advances
in stroke prevention and stroke imaging advances
promises to continue to decrease the morbidity, mor-
tality, and frequency of ischemic stroke. Ongoing and
future studies will optimize the imaging selection of
stroke patients for endovascular therapy and possibly
extend the time window for treatment based upon a
personalized medicine imaging approach.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
References
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease
and stroke statistics – 2015 update: A report from the
American Heart Association. Circulation 2015; 131: e29–
e322.
2. Heit JJ and Wintermark M. Imaging selection for reperfu-
sion therapy in acute ischemic stroke. Curr Treat Options
Neurol 2015; 17: 332.
3. Hossmann KA. Viability thresholds and the penumbra of
focal ischemia. Ann Neurol 1994; 36: 557–565.
4. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever
thrombectomy after intravenous t-PA vs. t-PA alone in
stroke. N Engl J Med 2015; 372: 2285–2295.
5. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular
therapy for ischemic stroke with perfusion-imaging selec-
tion. N Engl J Med 2015; 372: 1009–1018.
Journal of Cerebral Blood Flow & Metabolism
6. Berkhemer OA, Fransen PS, Beumer D, et al. A rando-
mized trial of intraarterial treatment for acute ischemic
stroke. N Engl J Med 2015; 372: 11–20.
7. Goyal M, Demchuk AM, Menon BK, et al. Randomized
assessment of rapid endovascular treatment of ischemic
stroke. N Engl J Med 2015; 372: 1019–1030.
8. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy
within 8 hours after symptom onset in ischemic stroke. N
Engl J Med 2015; 372: 2296–2306.
9. Tissue plasminogen activator for acute ischemic stroke.
The national institute of neurological disorders and
stroke rt-PA stroke study group. N Engl J Med 1995;
333: 1581–1587.
10. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines
for the prevention of stroke in patients with stroke and
transient ischemic attack: A guideline for healthcare pro-
fessionals from the American Heart Association/
American Stroke Association. Stroke 2014; 45: 2160–
2236.
11. Rapsomaniki E, Timmis A, George J, et al. Blood pres-
sure and incidence of twelve cardiovascular diseases:
Lifetime risks, healthy life-years lost, and age-specific
associations in 1.25 million people. Lancet 2014; 383:
1899–1911.
12. Lewington S, Clarke R, Qizilbash N, et al. Age-specific
relevance of usual blood pressure to vascular mortality: A
meta-analysis of individual data for one million adults in
61 prospective studies. Lancet 2002; 360: 1903–1913.
13. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking
cessation and decreased risk of stroke in women.
JAMA 1993; 269: 232–236.
14. Wilson PW, Hoeg JM, D’Agostino RB, et al. Cumulative
effects of high cholesterol levels, high blood pressure, and
cigarette smoking on carotid stenosis. N Engl J Med
1997; 337: 516–522.
15. Luitse MJ, Biessels GJ, Rutten GE, et al. Diabetes,
hyperglycaemia, and acute ischaemic stroke. Lancet
Neurol 2012; 11: 261–271.
16. Kurth T, Everett BM, Buring JE, et al. Lipid levels and
the risk of ischemic stroke in women. Neurology 2007; 68:
556–562.
17. Yaghi S and Elkind MS. Lipids and cerebrovascular dis-
ease: Research and practice. Stroke 2015; 46: 3322–3328.
18. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of inten-
sive control of glucose on cardiovascular outcomes and
death in patients with diabetes mellitus: A meta-analysis
of randomised controlled trials. Lancet 2009; 373: 1765–
1772.
19. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk
for development of atrial fibrillation: The Framingham
heart study. Circulation 2004; 110: 1042–1046.
20. The effect of low-dose warfarin on the risk of stroke in
patients with nonrheumatic atrial fibrillation. The Boston
area anticoagulation trial for atrial fibrillation investiga-
tors. N Engl J Med 1990; 323: 1505–1511.
21. Petersen P, Boysen G, Godtfredsen J, et al. Placebo-con-
trolled, randomised trial of warfarin and aspirin for pre-
vention of thromboembolic complications in chronic
atrial fibrillation. The Copenhagen AFASAK study.
Lancet 1989; 1: 175–179.
Heit and Wintermark
22. Stroke Prevention in Atrial Fibrillation Study. Final
results. Circulation 1991; 84: 527–539.
23. Warfarin versus aspirin for prevention of thromboembol-
ism in atrial fibrillation: Stroke Prevention in Atrial
Fibrillation II Study. Lancet 1994; 343: 687–691.
24. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin
in the prevention of stroke associated with nonrheumatic
atrial fibrillation. Veterans affairs stroke prevention in
nonrheumatic atrial fibrillation investigators. N Engl J
Med 1992; 327: 1406–1412.
25. Connolly SJ, Laupacis A, Gent M, et al. Canadian atrial
fibrillation anticoagulation (CAFA) study. J Am Coll
Cardiol 1991; 18: 349–355.
26. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran
versus warfarin in patients with atrial fibrillation. N Engl
J Med 2009; 361: 1139–1151.
27. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban
versus warfarin in nonvalvular atrial fibrillation. N Engl
J Med 2011; 365: 883–891.
28. Granger CB, Alexander JH, McMurray JJ, et al.
Apixaban versus warfarin in patients with atrial fibrilla-
tion. N Engl J Med 2011; 365: 981–992.
29. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban
versus warfarin in patients with atrial fibrillation. N Engl
J Med 2013; 369: 2093–2104.
30. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison
of the efficacy and safety of new oral anticoagulants with
warfarin in patients with atrial fibrillation: A meta-ana-
lysis of randomised trials. Lancet 2014; 383: 955–962.
31. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive
summary: Heart disease and stroke statistics – 2010
update: A report from the American Heart Association.
Circulation 2010; 121: 948–954.
32. North American Symptomatic Carotid Endarterectomy
Trial C. Beneficial effect of carotid endarterectomy in
symptomatic patients with high-grade carotid stenosis.
N Engl J Med 1991; 325: 445–453.
33. MRC European Carotid Surgery Trial: Interim results
for symptomatic patients with severe (70–99%) or with
mild (0-29%) carotid stenosis. European Carotid Surgery
Trialists’ Collaborative Group. Lancet 1991; 337: 1235–
1243.
34. Randomised trial of endarterectomy for recently symp-
tomatic carotid stenosis: Final results of the MRC
European Carotid Surgery Trial (ECST). Lancet 1998;
351: 1379–1387.
35. Brott TG, Hobson RW 2nd, Howard G, et al. Stenting
versus endarterectomy for treatment of carotid-artery
stenosis. N Engl J Med 2010; 363, 2nd ed11–23.
36. Brott TG, Howard G, Roubin GS, et al. Long-term
results of stenting versus endarterectomy for carotid-
artery stenosis. N Engl J Med 2016; 374: 1021–1031.
37. Carotid Stenting Trialists C, Bonati LH, Dobson J, et al.
Short-term outcome after stenting versus endarterectomy
for symptomatic carotid stenosis: A preplanned meta-
analysis of individual patient data. Lancet 2010; 376:
1062–1073.
38. The CASANOVA Study Group. Carotid surgery versus
medical therapy in asymptomatic carotid stenosis. Stroke
1991; 22: 1229–1235.
15
39. Executive committee for the asymptomatic carotid ath-
erosclerosis study. Endarterectomy for asymptomatic
carotid artery stenosis. JAMA 1995; 273: 1421–1428.
40. Altaf N, Beech A, Goode SD, et al. Carotid intraplaque
hemorrhage detected by magnetic resonance imaging pre-
dicts embolization during carotid endarterectomy. J Vasc
Surg 2007; 46: 31–36.
41. Altaf N, MacSweeney ST, Gladman J, et al. Carotid
intraplaque hemorrhage predicts recurrent symptoms in
patients with high-grade carotid stenosis. Stroke 2007; 38:
1633–1635.
42. Spagnoli LG, Mauriello A, Sangiorgi G, et al.
Extracranial thrombotically active carotid plaque as a
risk factor for ischemic stroke. JAMA 2004; 292: 1845–
1852.
43. Saam T, Cai J, Ma L, et al. Comparison of symptomatic
and asymptomatic atherosclerotic carotid plaque features
with in vivo MR imaging. Radiology 2006; 240: 464–472.
44. Sacco RL, Kargman DE, Gu Q, et al. Race-ethnicity and
determinants of intracranial atherosclerotic cerebral
infarction. The Northern Manhattan Stroke Study.
Stroke 1995; 26: 14–20.
45. Gorelick PB, Wong KS, Bae HJ, et al. Large artery intra-
cranial occlusive disease: A large worldwide burden but a
relatively neglected frontier. Stroke 2008; 39: 2396–2399.
46. Wong LK. Global burden of intracranial atherosclerosis.
Int J Stroke 2006; 1: 158–159.
47. Qureshi AI and Caplan LR. Intracranial atherosclerosis.
Lancet 2014; 383: 984–998.
48. Holmstedt CA, Turan TN and Chimowitz MI.
Atherosclerotic intracranial arterial stenosis: Risk fac-
tors, diagnosis, and treatment. Lancet Neurol 2013; 12:
1106–1114.
49. Bang OY. Intracranial atherosclerosis: Current under-
standing and perspectives. J Stroke 2014; 16: 27–35.
50. Stone NJ, Robinson JG, Lichtenstein AH, et al.
Treatment of blood cholesterol to reduce atherosclerotic
cardiovascular disease risk in adults: Synopsis of the 2013
American College of Cardiology/American Heart
Association cholesterol guideline. Ann Intern Med 2014;
160: 339–343.
51. Mohr JP, Thompson JL, Lazar RM, et al. A comparison
of warfarin and aspirin for the prevention of recurrent
ischemic stroke. N Engl J Med 2001; 345: 1444–1451.
52. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al.
Comparison of warfarin and aspirin for symptomatic
intracranial arterial stenosis. N Engl J Med 2005; 352:
1305–1316.
53. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin
and clopidogrel compared with clopidogrel alone after
recent ischaemic stroke or transient ischaemic attack in
high-risk patients (MATCH): Randomised, double-blind,
placebo-controlled trial. Lancet 2004; 364: 331–337.
54. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and
aspirin versus aspirin alone for the prevention of athero-
thrombotic events. N Engl J Med 2006; 354: 1706–1717.
55. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting
versus aggressive medical therapy for intracranial arterial
stenosis. N Engl J Med 2011; 365: 993–1003.
16
56. Zhang Q, Wang C, Zheng M, et al. Aspirin plus clopido-
grel as secondary prevention after stroke or transient
ischemic attack: A systematic review and meta-analysis.
Cerebrovasc Dis 2015; 39: 13–22.
57. Higashida RT, Tsai FY, Halbach VV, et al. Transluminal
angioplasty for atherosclerotic disease of the vertebral
and basilar arteries. J Neurosurg 1993; 78: 192–198.
58. Clark WM, Barnwell SL, Nesbit G, et al. Safety and effi-
cacy of percutaneous transluminal angioplasty for intra-
cranial atherosclerotic stenosis. Stroke 1995; 26: 1200–
1204.
59. Connors JJ 3rd and Wojak JC. Percutaneous translum-
inal angioplasty for intracranial atherosclerotic lesions:
Evolution of technique and short-term results.
J Neurosurg 1999; 91: 415–423.
60. Marks MP, Marcellus M, Norbash AM, et al. Outcome
of angioplasty for atherosclerotic intracranial stenosis.
Stroke 1999; 30: 1065–1069.
61. Gress DR, Smith WS, Dowd CF, et al. Angioplasty for
intracranial symptomatic vertebrobasilar ischemia.
Neurosurgery 2002; 51: 23–27; discussion 27–29.
62. Gupta R, Schumacher HC, Mangla S, et al. Urgent endo-
vascular revascularization for symptomatic intracranial
atherosclerotic stenosis. Neurology 2003; 61: 1729–1735.
63. Chu B, Ferguson MS, Chen H, et al. Magnetic [corrected]
resonance imaging [corrected] features of the disruption-
prone and the disrupted carotid plaque. JACC
Cardiovasc Imaging 2009; 2: 883–896.
64. Singh N, Moody AR, Gladstone DJ, et al. Moderate
carotid artery stenosis: MR imaging-depicted intraplaque
hemorrhage predicts risk of cerebrovascular ischemic
events in asymptomatic men. Radiology 2009; 252: 502–
508.
65. Fleg JL, Stone GW, Fayad ZA, et al. Detection of high-
risk atherosclerotic plaque: Report of the NHLBI
Working Group on current status and future directions.
JACC Cardiovasc Imaging 2012; 5: 941–955.
66. Brinjikji W, Huston J 3rd, Rabinstein AA, et al.
Contemporary carotid imaging: From degree of stenosis
to plaque vulnerability. J Neurosurg 2016; 124: 27–42.
67. Choi YJ, Jung SC and Lee DH. Vessel wall imaging of
the intracranial and cervical carotid arteries. J Stroke
2015; 17: 238–255.
68. Bitar R, Moody AR, Leung G, et al. In vivo 3D high-
spatial-resolution MR imaging of intraplaque hemor-
rhage. Radiology 2008; 249: 259–267.
69. Oppenheim C, Naggara O, Touze E, et al. High-resolu-
tion MR imaging of the cervical arterial wall: What the
radiologist needs to know. Radiographics 2009; 29:
1413–1431.
70. Lusby RJ, Ferrell LD, Ehrenfeld WK, et al. Carotid
plaque hemorrhage. Its role in production of cerebral
ischemia. Arch Surg 1982; 117: 1479–1488.
71. Gupta A, Baradaran H, Schweitzer AD, et al. Carotid
plaque MRI and stroke risk: A systematic review and
meta-analysis. Stroke 2013; 44: 3071–3077.
72. JM UK-I, Fox AJ, Aviv RI, et al. Characterization of
carotid plaque hemorrhage: A CT angiography and MR
intraplaque hemorrhage study. Stroke 2010; 41: 1623–
1629.
Journal of Cerebral Blood Flow & Metabolism
73. van Gils MJ, Vukadinovic D, van Dijk AC, et al. Carotid
atherosclerotic plaque progression and change in plaque
composition over time: A 5-year follow-up study using
serial CT angiography. AJNR. Am J Neuroradiol 2012;
33: 1267–1273.
74. Anzidei M, Napoli A, Geiger D, et al. Preliminary experi-
ence with MRA in evaluating the degree of carotid sten-
osis and plaque morphology using high-resolution
sequences after gadofosveset trisodium (Vasovist) admin-
istration: Comparison with CTA and DSA. Radiol Med
2010; 115: 634–647.
75. Lovett JK, Gallagher PJ, Hands LJ, et al. Histological
correlates of carotid plaque surface morphology on
lumen contrast imaging. Circulation 2004; 110: 2190–
2197.
76. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque
ruptures and sudden coronary death: Evidence that sub-
clinical rupture has a role in plaque progression.
Circulation 2001; 103: 934–940.
77. Saam T, Hatsukami TS, Takaya N, et al. The vulnerable,
or high-risk, atherosclerotic plaque: Noninvasive MR
imaging for characterization and assessment. Radiology
2007; 244: 64–77.
78. Treiman GS, McNally JS, Kim SE, et al. Correlation of
carotid intraplaque hemorrhage and stroke using 1.5 T
and 3 T MRI. Magn Reson Insights 2015; 8(Suppl 1): 1–8.
79. Ota H, Yarnykh VL, Ferguson MS, et al. Carotid intra-
plaque hemorrhage imaging at 3.0-T MR imaging:
Comparison of the diagnostic performance of three T1-
weighted sequences. Radiology 2010; 254: 551–563.
80. Ross R. Atherosclerosis – an inflammatory disease. N
Engl J Med 1999; 340: 115–126.
81. Marnane M, Merwick A, Sheehan OC, et al. Carotid
plaque inflammation on 18F-fluorodeoxyglucose posi-
tron emission tomography predicts early stroke recur-
rence. Ann Neurol 2012; 71: 709–718.
82. Tousoulis D, Oikonomou E, Economou EK, et al.
Inflammatory cytokines in atherosclerosis: Current thera-
peutic approaches. Eur Heart J 2016; 37: 1723–1732.
83. Gaens ME, Backes WH, Rozel S, et al. Dynamic con-
trast-enhanced MR imaging of carotid atherosclerotic
plaque: Model selection, reproducibility, and validation.
Radiology 2013; 266: 271–279.
84. Kerwin WS, Oikawa M, Yuan C, et al. MR imaging of
adventitial vasa vasorum in carotid atherosclerosis. Magn
Reson Med 2008; 59: 507–514.
85. Millon A, Boussel L, Brevet M, et al. Clinical and histo-
logical significance of gadolinium enhancement in carotid
atherosclerotic plaque. Stroke 2012; 43: 3023–3038.
86. Qiao Y, Etesami M, Astor BC, et al. Carotid plaque
neovascularization and hemorrhage detected by MR ima-
ging are associated with recent cerebrovascular ischemic
events. Am J Neuroradiol 2012; 33: 755–60.
87. Wasserman BA, Smith WI, Trout HH 3rd, et al. Carotid
artery atherosclerosis: In vivo morphologic characteriza-
tion with gadolinium-enhanced double-oblique MR ima-
ging initial results. Radiology 2002; 223: 566–573.
88. Homburg PJ, Rozie S, van Gils MJ, et al. Atherosclerotic
plaque ulceration in the symptomatic internal carotid
Heit and Wintermark
artery is associated with nonlacunar ischemic stroke.
Stroke 2010; 41: 1151–1156.
89. Etesami M, Hoi Y, Steinman DA, et al. Comparison of
carotid plaque ulcer detection using contrast-enhanced
and time-of-flight MRA techniques. Am J Neuroradiol
2013; 34: 177–184.
90. Yu JH, Kwak HS, Chung GH, et al. Association of
intraplaque hemorrhage and acute infarction in patients
with basilar artery plaque. Stroke 2015; 46: 2768–2772.
91. Turan TN, Bonilha L, Morgan PS, et al. Intraplaque
hemorrhage in symptomatic intracranial atherosclerotic
disease. J Neuroimaging 2011; 21: e159–e161.
92. Gupta A, Baradaran H, Al-Dasuqi K, et al. Gadolinium
enhancement in intracranial atherosclerotic plaque and
ischemic stroke: A systematic review and meta-analysis.
J Am Heart Assoc 2016; 5: e1–e14.
93. Swartz RH, Bhuta SS, Farb RI, et al. Intracranial arter-
ial wall imaging using high-resolution 3-tesla contrast-
enhanced MRI. Neurology 2009; 72: 627–634.
94. Xu WH, Li ML, Gao S, et al. Plaque distribution of
stenotic middle cerebral artery and its clinical relevance.
Stroke 2011; 42: 2957–2959.
95. Chen XY, Wong KS, Lam WW, et al. Middle cerebral
artery atherosclerosis: Histological comparison between
plaques associated with and not associated with infarct
in a postmortem study. Cerebrovasc Dis 2008; 25: 74–80.
96. Xu WH, Li ML, Gao S, Ni J, et al. Middle cerebral
artery intraplaque hemorrhage: Prevalence and clinical
relevance. Ann Neurol 2012; 71: 195–198.
97. Vakil P, Vranic J, Hurley MC, et al. T1 gadolinium
enhancement of intracranial atherosclerotic plaques
associated with symptomatic ischemic presentations.
Am J Neuroradiol 2013; 34: 2252–2258.
98. Kidwell CS, Jahan R, Gornbein J, et al. A trial of ima-
ging selection and endovascular treatment for ischemic
stroke. N Engl J Med 2013; 368: 914–923.
99. Broderick JP, Palesch YY, Demchuk AM, et al.
Endovascular therapy after intravenous t-PA versus t-
PA alone for stroke. N Engl J Med 2013; 368: 893–903.
100. Ciccone A, Valvassori L, Nichelatti M, et al.
Endovascular treatment for acute ischemic stroke. N
Engl J Med 2013; 368: 2433–2434.
101. Qureshi AI, Abd-Allah F, Aleu A, et al. Endovascular
treatment for acute ischemic stroke patients:
Implications and interpretation of IMS III, MR
RESCUE, and SYNTHESIS EXPANSION trials: A
report from the Working Group of International
Congress of Interventional Neurology. J Vasc Interv
Neurol 2014; 7: 56–75.
102. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restor-
ation device versus the Merci Retriever in patients with
acute ischaemic stroke (SWIFT): A randomised, paral-
lel-group, non-inferiority trial. Lancet 2012; 380: 1241–
1249.
103. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus
Merci retrievers for thrombectomy revascularisation of
large vessel occlusions in acute ischaemic stroke
(TREVO 2): A randomised trial. Lancet 2012; 380:
1231–1240.
17
104. Warach SJ, Luby M, Albers GW, et al. Acute stroke
imaging research roadmap III imaging selection and
outcomes in acute stroke reperfusion clinical trials:
Consensus Recommendations and further research prio-
rities. Stroke 2016; 47: 1389–1398.
105. Lovblad KO and Pereira VM. MRI of acute stroke:
What went wrong? Am J Neuroradiol 2015; 36: 1996–
1997.
106. Pexman JH, Barber PA, Hill MD, et al. Use of the
alberta stroke program early CT score (ASPECTS) for
assessing CT scans in patients with acute stroke. Am J
Neuroradiol 2001; 22: 1534–1542.
107. Yoo AJ, Berkhemer OA, Fransen PS, et al. Effect of
baseline Alberta Stroke Program Early CT Score on
safety and efficacy of intra-arterial treatment: A sub-
group analysis of a randomised phase 3 trial (MR
CLEAN). Lancet Neurol 2016; 15: 685–694.
108. Heit JJ and Wintermark M. Perfusion computed tom-
ography for the evaluation of acute ischemic stroke:
Strengths and pitfalls. Stroke 2016; 47: 1153–1158.
109. Thijs VN, Lansberg MG, Beaulieu C, et al. Is early
ischemic lesion volume on diffusion-weighted imaging
an independent predictor of stroke outcome? A multi-
variable analysis. Stroke 2000; 31: 2597–2602.
110. Yoo AJ, Chaudhry ZA, Nogueira RG, et al. Infarct
volume is a pivotal biomarker after intra-arterial
stroke therapy. Stroke 2012; 43: 1323–1330.
111. Leslie-Mazwi TM, Hirsch JA, Falcone GJ, et al.
Endovascular stroke treatment outcomes after patient
selection based on magnetic resonance imaging and clin-
ical criteria. JAMA Neurol 2016; 73: 43–49.
112. Inoue M, Mlynash M, Christensen S, et al. Early diffu-
sion-weighted imaging reversal after endovascular reper-
fusion is typically transient in patients imaged 3 to 6
hours after onset. Stroke 2014; 45: 1024–1028.
113. Lansberg MG, Straka M, Kemp S, et al. MRI profile
and response to endovascular reperfusion after stroke
(DEFUSE 2): A prospective cohort study. Lancet
Neurol 2012; 11: 860–867.
114. Lansberg MG, Lee J, Christensen S, et al. RAPID auto-
mated patient selection for reperfusion therapy: A
pooled analysis of the Echoplanar Imaging
Thrombolytic Evaluation Trial (EPITHET) and the
Diffusion and Perfusion Imaging Evaluation for
Understanding Stroke Evolution (DEFUSE) Study.
Stroke 2011; 42: 1608–1614.
115. Lovblad KO, Baird AE, Schlaug G, et al. Ischemic
lesion volumes in acute stroke by diffusion-weighted
magnetic resonance imaging correlate with clinical out-
come. Ann Neurol 1997; 42: 164–170.
116. Vogt G, Laage R, Shuaib A, et al. Initial lesion volume
is an independent predictor of clinical stroke outcome at
day 90: An analysis of the Virtual International Stroke
Trials Archive (VISTA) database. Stroke 2012; 43:
1266–1272.
117. Alexander LD, Pettersen JA, Hopyan JJ, et al. Long-
term prediction of functional outcome after stroke using
the Alberta Stroke Program Early Computed
Tomography Score in the subacute stage. J Stroke
Cerebrovasc Dis 2012; 21: 737–744.
18
118. Phan TG, Chen J, Donnan G, et al. Development of a
new tool to correlate stroke outcome with infarct top-
ography: A proof-of-concept study. Neuroimage 2010;
49: 127–133.
119. Lindenberg R, Renga V, Zhu LL, et al. Structural integ-
rity of corticospinal motor fibers predicts motor impair-
ment in chronic stroke. Neurology 2010; 74: 280–287.
120. Puig J, Pedraza S, Blasco G, et al. Wallerian degener-
ation in the corticospinal tract evaluated by diffusion
tensor imaging correlates with motor deficit 30 days
after middle cerebral artery ischemic stroke. Am J
Neuroradiol 2010; 31: 1324–1330.
121. Watanabe T, Honda Y, Fujii Y, et al. Three-dimen-
sional anisotropy contrast magnetic resonance axono-
graphy to predict the prognosis for motor function in
patients suffering from stroke. J Neurosurg 2001; 94:
955–960.
122. Radlinska B, Ghinani S, Leppert IR, et al. Diffusion
tensor imaging, permanent pyramidal tract damage,
and outcome in subcortical stroke. Neurology 2010; 75:
1048–1054.
123. Wen H, Alshikho MJ, Wang Y, et al. Correlation of
fractional anisotropy with motor recovery in patients
with stroke after postacute rehabilitation. Arch Phys
Med Rehabil 2016; 97: 1487–1495.
124. Doughty C, Wang J, Feng W, et al. Detection and pre-
dictive value of fractional anisotropy changes of the
corticospinal tract in the acute phase of a stroke.
Stroke 2016; 47: 1520–1526.
Journal of Cerebral Blood Flow & Metabolism
125. Breier JI, Hasan KM, Zhang W, et al. Language dys-
function after stroke and damage to white matter tracts
evaluated using diffusion tensor imaging. Am J
Neuroradiol 2008; 29: 483–487.
126. Rossini PM, Calautti C, Pauri F, et al. Post-stroke plas-
tic reorganisation in the adult brain. Lancet Neurol
2003; 2: 493–502.
127. Murase N, Duque J, Mazzocchio R, et al. Influence of
interhemispheric interactions on motor function in
chronic stroke. Ann Neurol 2004; 55: 400–409.
128. Hsu WY, Cheng CH, Liao KK, et al. Effects of repeti-
tive transcranial magnetic stimulation on motor func-
tions in patients with stroke: A meta-analysis. Stroke
2012; 43: 1849–1857.
129. Du J, Tian L, Liu W, et al. Effects of repetitive tran-
scranial magnetic stimulation on motor recovery and
motor cortex excitability in patients with stroke: A ran-
domized controlled trial. Eur J Neurol 2016; 23: 1666–
1672.
130. Thomalla G, Fiebach JB, Ostergaard L, et al. A multi-
center, randomized, double-blind, placebo-controlled
trial to test efficacy and safety of magnetic resonance
imaging-based thrombolysis in wake-up stroke (WAKE-
UP). Int J Stroke 2014; 9: 829–836.
131. Kemmling A, Flottmann F, Forkert ND, et al.
Multivariate dynamic prediction of ischemic infarction
and tissue salvage as a function of time and degree of
recanalization. J Cereb Blood Flow Metab 2015; 35:
1397–1405.