Review Article

Intracranial Arterial Stenosis

Marta Carvalho, MD,*† Ana Oliveira, MD,*† Elsa Azevedo, MD, PhD,*†

and Ant�onio J. Bastos-Leite, MD, PhD‡

Intracranial arterial stenosis (IAS) is usually attributable to atherosclerosis and cor-

responds to themost common cause of strokeworldwide. It is very prevalent among

African, Asian, and Hispanic populations. Advancing age, systolic hypertension,

diabetes mellitus, high levels of low-density lipoprotein cholesterol, and metabolic

syndrome are some of its major risk factors. IAS may be associated with transient or

definite neurological symptoms or can be clinically asymptomatic. Transcranial

Doppler and magnetic resonance angiography are the most frequently used ancil-

lary examinations for screening and follow-up. Computed tomography angiogra-

phy can either serve as a screening tool for the detection of IAS or increasingly as

a confirmatory test approaching the diagnostic accuracy of catheter digital subtrac-

tion angiography, which is still considered the gold (confirmation) standard. The

risk of stroke in patients with asymptomatic atherosclerotic IAS is low (up to 6%

over a mean follow-up period of approximately 2 years), but the annual risk of

stroke recurrence in the presence of a symptomatic stenosis may exceed 20%

when the degree of luminal narrowing is 70% or more, recently after an ischemic

event, and in women. It is a matter of controversy whether there is a specific type

of treatment other than medical management (including aggressive control of vas-

cular risk factors and antiplatelet therapy) that may alter the high risk of stroke

recurrence among patients with symptomatic IAS. Endovascular treatment has

been thought to be helpful in patients who fail to respond to medical treatment

alone, but recent data contradict such expectation. Key Words: Atherosclerosis—

intracranial arterial stenosis—middle cerebral artery stenosis—middle cerebral

artery stroke—epidemiology—vascular risk factors—pathophysiology—

neuroimaging—management and treatment.

� 2014 by National Stroke Association

Introduction

Intracranial arterial stenosis (IAS) corresponds to lumi-

nal narrowing of large intracranial arteries. IAS is most of-

ten attributable to primary atherosclerosis, although

embolic events can occasionally result in severe stenosis.

Other causes of IAS include arterial dissection, inflamma-

torydisorders (vasculitis), infections of the central nervous

system, radiation, sickle cell disease, and moyamoya dis-

ease or moyamoya syndrome.1

IAS is the most common cause of stroke worldwide.2,3

The widespread use of noninvasive or minimally

invasive neuroimaging techniques, such as transcranial

From the *Department of Neurology, Hospital de S~ao Jo~ao, Porto,

Portugal; †Department of Clinical Neurosciences and Mental Health,

Faculty of Medicine, University of Porto, Porto, Portugal; and

‡Department of Medical Imaging, Faculty of Medicine, University

of Porto, Porto, Portugal.

Received April 23, 2013; revision received May 14, 2013; accepted

June 5, 2013.

Address correspondence to Ant�onio J. Bastos-Leite, MD, PhD,

Department of Medical Imaging, Faculty of Medicine, University of

Porto, Alameda do Professor Hernani Monteiro, 4200-319 Porto,

Portugal. E-mail: abastosleite@med.up.pt.

1052-3057/$ - see front matter

� 2014 by National Stroke Association

http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.06.006

Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 4 (April), 2014: pp 599-609 599

Doppler (TCD) and magnetic resonance angiography

(MRA) or computed tomography angiography (CTA),

has increased the detection of this type of pathology.

IAS may involve any intracranial vessel and may con-

comitantly occur inpatientswith stenosis in extracranial ar-

teries, namely in the extracranial part of the internal carotid

artery (ICA) or the vertebrobasilar system. The present

work aims at reviewing the state of the art concerning ath-

erosclerotic IAS with a particular emphasis on stenosis of

the middle cerebral artery (MCA), which is the main intra-

cranial artery perfusing the cerebral hemispheres.

Epidemiology and Risk Factors

IAS is far more prevalent in Asian and African subjects

and in subjects of Hispanic origin.4 By using TCD,

population-based studies in China revealed asymptom-

atic intracranial arterial disease in 5.9%-6.9% of subjects

over the fifth decade of life.5,6 A cross-sectional study us-

ing TCD in Hong Kong found asymptomatic IAS in 12.6%

of the included cases.7 One study using MRA in Japan

found asymptomatic IAS in 14.7% of subjects referred to

a neurology clinic because of concerns about a possible

stroke.8 IAS is more severe in black people than in other

populations. Black subjects with IAS are at higher risk

of stroke recurrence than whites.9

Although studies addressing possible gender differ-

ences provided conflicting results on the prevalence and

severity of IAS among asymptomatic subjects,5,10 women

with symptomatic IAS enrolled into the Warfarin–

Aspirin Symptomatic Intracranial Disease (WASID)

trial11 were found to have greater risk of stroke and death

than men.12

Different vascular risk factorsmaybeassociatedwithdif-

ferent locations of IAS.13,14 In general, potentially

modifiable risk factors for intracranial atherosclerosis

include hypertension, smoking, diabetes, and dyslipi-

demia—high total cholesterol, high low-density lipoprotein

cholesterol, and low high-density lipoprotein choles-

terol.5,10,15 Nonmodifiable risk factors include race, age,

certain angiotensin-converting enzyme polymorphisms,

an increased plasma endostatin/vascular endothelial

growth factor ratio, the glutathione S-transferase omega-1

gene polymorphism, and increased levels of plasma homo-

cysteine.4Metabolic syndrome is alsoassociatedwith IAS. It

occurs in approximately 50%of the subjectswith symptom-

atic intracranial atherosclerotic disease and is associated

with substantially higher risk of major vascular events.16-18

An association between Alzheimer disease and intra-

cranial atherosclerosis has been described.19,20 It is also

conceivable that IAS in itself might be a specific cause

of vascular cognitive impairment. Furthermore, there is

an increasing awareness that both cerebrovascular and

neurodegenerative pathology may concomitantly occur

very often21 and that there are common risk factors for

each of them.22

Pathophysiology and Clinical Expression

IAS may cause transient or definite neurological symp-

toms or can be clinically asymptomatic, depending on

severity of IAS, reversibility of the potentially associated

ischemia, or on the efficiency of arterial collateralization.

Possible mechanisms of cerebral infarction secondary to

IAS include hemodynamic compromise distal to the site

of stenosis, in situ thrombosis leading to complete artery

occlusion, artery-to-artery embolism, perforating local

branch occlusion, or a combination.23

Chronic cerebral hypoperfusion secondary to asymp-

tomatic IAS may confer risk of stroke24 because of

decreased washout of small emboli25 or of potential dis-

ruption of cerebral autoregulation. In normal conditions,

homeostatic mechanisms corresponding to cerebral au-

toregulation tend to minimize changes in cerebral blood

flow (CBF) secondary to variation of the perfusion pres-

sure. To maintain CBF, cerebral autoregulation mostly

relies on the capacity of the precapillary vascular wall

to contract or distend, causing changes in vessel diameter.

Brain arterioles can dilate and increase the corresponding

blood flow in response to several stimuli (eg, hypercapnia

secondary to breath holding, acetazolamide, or CO2 inha-

lation), a process called vasoreactivity.26,27 In the presence

of severe IAS, compensatory vasomotor mechanisms

work up to their limit, leading to a maximum distension

of the vascular wall. If such a limit is exceeded, the

stenosis may become symptomatic because of a lack of

cerebral perfusion pressure, and it is expected that any

additional vasodilator stimuli will not lead to an

increase of perfusion in the corresponding vascular

territory. In other words, cerebral vasoreactivity might

become compromised in the presence of a high-grade

arterial stenosis or occlusion. Therefore, patients with im-

paired cerebral vasoreactivity and severe IAS may be at

higher risk of subsequent stroke, similar to patients with

impaired cerebral vasoreactivity in association with

asymptomatic extracranial carotid stenosis or occlusion.28

Asymptomatic stenoses might also become symptomatic,

through a hemodynamic mechanism, when a subject with

severe IAS is submitted to a long period of hypotension

(eg, after heart attack, trauma, or surgery). Computed

tomography and magnetic resonance (MR) perfusion,

single-photon emission computed tomography, and posi-

tron emission tomography studies have been used to

evaluate vasoreactivity and cerebrovascular reserve in

patients with IAS, but the ability of those examinations

to predict future stroke risk in such patients is yet to be

determined.24,29-33

Lesions involving the MCA, basilar artery, or the intra-

cranial vertebral artery aremore likely to be symptomatic,

whereas lesions occurring in the territory of anterior or

posterior cerebral arteries are often asymptomatic.13 The

Groupe d’Etude des St�enoses Intra-Craniennes Ath�eromateuses

Symptomatiques study34 and a study by S�anchez-S�anchez

M. CARVALHO ET AL.600

et al,35 have found that MCA involvement occurs in

approximately 27% of the cases with symptomatic IAS.

Clinically silent lesions can be incidentally detected on

neuroimaging examinations.

Diagnostic Work-up

Catheter digital subtraction angiography (DSA) is still

considered the gold (confirmation) standard for the eval-

uation of IAS, but less invasive techniques, such as TCD,

MRA, and CTA became increasingly useful.

Ultrasound Techniques

TCD is a noninvasive and dynamic ultrasound tech-

nique useful for fast and repeated evaluation of intracra-

nial vessels and IAS. It has the advantage of being

relatively inexpensive, but is operator dependent, requir-

ing considerable training skills and standardized proto-

cols to ensure that the results can be reproducible and

comparable. A major limitation of TCD arises when the

temporal bone window is insufficient, but this difficulty

has been partially overcome by using ultrasound contrast

agents.36-38

TCD determines flow velocity, allowing detection and

grading of stenosis according to blood flow velocity

(BFV) criteria derived from several studies that compared

TCD with MRA or DSA. These criteria are mostly based

on elevated peak systolic velocity (PSV), mean flow veloc-

ity (MFV), and the ratio between velocity in the location of

highest blood flow acceleration and velocity in the pre- or

the poststenotic segment, in the feeding vessel, or even in

the corresponding contralateral vessel. Basically, they are

based on the assumption that there is acceleration of

blood flow in the location of stenosis, though subocclu-

sive (critical) stenoses may be actually associated with

very slow flow.39

AnMFV cutoff value of 100 cm/s was found to provide

optimal accuracy for the diagnosis of stenosis of the MCA

with 50% or more of luminal narrowing,40 as confirmed

by the Stroke Outcomes and Neuroimaging of Intracra-

nial Atherosclerosis trial, a companion study to the

WASID trial aiming at validating the use of TCD and

MRA to diagnose intracranial atherosclerosis taking cath-

eter DSA as the confirmation standard.41 To help avoiding

false-positive results, a prestenotic to stenotic MCAveloc-

ity ratio of at least .5 was additionally proposed.40 More-

over, optimal cutoff values for PSV were found to be

140 cm/s and 180 cm/s, respectively, for a degree of lumi-

nal narrowing of 50% and 75% assessed by using MRA.42

Because there is a substantial pathophysiological varia-

tion in velocity values, especially in the acute phase, the di-

agnosis of stenosis in the MCA by using TCD should

perhaps take into account other parameters than focal ve-

locity increase. Therefore, a set of additional sonographic

parameters to improve diagnostic accuracy has been rec-

ommended in the past fewyears.43Aclinical–sonographic

index taking into account both the asymmetry between

middle cerebral arteries and a difference in the pulsatility

index (systolic BFV–diastolic BFV/mean BFV) has been

proposed as well.44 There is, however, limited clinical ex-

perience with these new proposals.

Differences in location and number of IAS may

influence the results of TCD. For example, a distal steno-

sis with more than 50% of luminal narrowing in the MCA

(eg, at segment M2) is more difficult to assess by TCD

than a stenosis of similar degree at segment M1. An

MFV more than 80 cm/s or an asymmetry index greater

than 30% can be used for the diagnosis of a distal stenosis,

but a TCD index more than .97 of the M2/M1MFVratio is

even better for the diagnosis.45Nevertheless, normal TCD

findings do not exclude distal M1 or M2 stenoses.46 Tan-

dem stenoses might also represent an additional sono-

graphical challenge.

TCD can be used as a noninvasive method for the as-

sessment of vasoreactivity, measuring the effect of vasodi-

lator stimuli on flow velocity at a given artery and

providing indirect information on the state of vascular re-

serve in the territory distal to an IAS.26,27

Transcranial color-coded Doppler (TCCD) sonography

represents an evolution of conventional TCD providing

higher sensitivity and specificity for the diagnosis of

steno-occlusive intracranial lesions, in particular for the

diagnosis of severe stenosis of the MCA. The major

advantage of TCCD over TCD is the ability to reliably dif-

ferentiate stenosis of the MCA trunk from stenosis of the

ICA terminal part, to ascertain the diagnosis of stenosis in

a branch of the MCA and to perform angle-corrected flow

velocity measurements.47,48 Taking catheter DSA as the

confirmation standard, Baumgartner et al37 proposed cut-

off values for PSV obtained by using TCCD. The cutoff

value for PSV to detect a degree of luminal narrowing

more than 50% in the MCAwas found to be 220 cm/s.

One study comparing TCCD with TCD for the evalua-

tion of stenosis of the MCA showed that TCCD outper-

forms TCD when luminal narrowing is less than 50%,

whereas no significant difference in diagnostic accuracy

between both methods was found for the diagnosis of

stenosis with more than 50% of luminal narrowing.49

Intensity-dependent color-coded Doppler or power

Doppler, anultrasoundmodality that displays the strength

of the Doppler signal, rather than the flow velocity and di-

rectional information,50 can also be used to complement

TCCD and increase the detection of high-grade stenoses.38

Finally, by detecting microembolic signals, both TCD

and TCCD may allow to identify intracranial sources of

emboli and differentiate these from extracranial sources

(eg, cardiac).51,52

MR Techniques

Among several MR sequences available, three-

dimensional (3D) time-of-flight (TOF) is the preferred

INTRACRANIAL ARTERIAL STENOSIS 601

MRA technique for the assessment of IAS. It does not re-

quire exogenous contrast injection. Because it is a flow-

dependent MR sequence based on the so-called inflow

effect of unsaturated spins, 3D-TOF MRA allows depic-

tion of the arterial lumen, but very slow flow cannot be

detected because of saturation effects.53 Therefore, critical

stenoses associated with very slow flow can be overesti-

mated and be mistaken for occlusions (Fig 1). Alterna-

tively, a very rapid acceleration of flow causing

turbulence distal to the location of stenosis may cancel

out the angiographic effect and overestimate the length

and degree of a given IAS.53 In fact, high-grade stenoses

associated with very rapid blood flow can be overesti-

mated on MRA. This may clarify the apparent discrep-

ancy between the aforementioned cutoff values for PSV

to detect a degree of luminal narrowing 50% or more in

the MCA by using ultrasound techniques as the PSV

value of 140 cm/s proposed by Gao et al42 was obtained

taking MRA as the reference for measuring the degree

of stenosis, though the PSV value of 220 cm/s proposed

by Baumgartner et al37 relied on DSA as the confirmation

standard. Nonetheless, it is also possible that a significant

proportion of stenoses can be underestimated on MRA.54

According to the results of the Stroke Outcomes and

Neuroimaging of Intracranial Atherosclerosis trial, both

TCD and MRA have a negative predictive value of 91%

but a positive predictive value of only 59% for the diagno-

sis of IAS with 50%-99% of luminal narrowing. Although

this might not reflect more recent technical developments

leading to improvement of MRA imaging quality, those

figures indicate that MRA can reliably exclude the pres-

ence of IAS, but abnormal findings still require a confir-

matory test, such as CTA or DSA.41,55

One of the major limitations of MRA is the follow-up of

patients previously treated with intracranial stents.

Althoughmost stents are devoid of ferromagnetic proper-

ties, they still can cause artifacts on MRA.56 Therefore,

this technique is not a good tool in the assessment of reste-

nosis after stenting.

Contrast-enhanced MRA and postperfusion MRA have

been tried for the diagnosis of IAS,57,58 but contrast-

enhanced MRA is perhaps more often used in clinical

practice for the assessment of extracranial carotid stenosis.

Other conventional and advanced MR sequences are

helpful to evaluate consequences of IAS and some were

confirmed at postmortem.59 The most relevant conse-

quences are acute or chronic ischemic cerebrovascular

lesions in the territory of the affected vessel. Diffusion-

weighted imaging is very well known for increasing

detectability of acute ischemic lesions. Infarcts related to

IAS are usually subcortical, deep perforating artery in-

farcts, or internal border-zone infarcts, sometimes associ-

ated with silent cortical lesions in the same territory, the

latter attributable to distal embolization.60 This pattern po-

tentially differs from the pattern observed when there are

other underlying pathophysiological mechanisms of

stroke. For example, infarcts secondary to atherosclerotic

ICA disease are usually territorial or cortical infarcts,

namely involving superficial perforating arteries.61 In ad-

dition, infarcts at the striatocapsular region secondary to

stenosis of theMCAmay have a different pattern of topog-

raphy than infarcts caused by a more proximal source of

embolism (eg, from the ICA or cardiogenic).62 Alterna-

tively, an overlap of imaging patterns may occur among

MCA disease and small-vessel disease63 because of occlu-

sion of deep perforating arteries arising from the stenotic

segment, but the location of stenosis may still determine

the location of a subcortical infarct—proximal stenoses at

segment M1 are usually associated with infarcts involving

the internal capsule, whereas distal stenoses may generate

subcortical infarcts in the upper part of the pyramidal tract

(eg, at the corona radiata).64 Furthermore, the severity of

disease might also influence infarct location. Actually,

mild to moderate stenoses of the MCA are usually associ-

ated with infarcts of deep perforating arteries, whereas se-

vere stenoses or occlusions of the MCA are more often

associated with internal border-zone or even corticopial

infarcts.60,61

Perfusion-weighted imaging (PWI) is an advanced

magnetic resonance imaging (MRI) technique enabling

to assess hemodynamic parameters at the microvascular

level. Dynamic susceptibility contrast PWI using intrave-

nous contrast bolus injection allows the determination of

several parameters beyond CBF. For example, time-to-

peak is generally considered to be the most sensitive indi-

cator of abnormal perfusion in the assessment of ischemic

penumbra.65 Arterial spin labeling (ASL) is another func-

tional MRI technique that represents an alternative to

dynamic susceptibility contrast PWI for the evaluation

of CBF (Fig 1). By using water as a diffusible tracer, ASL

does not require either ionizing radiation or an exogenous

contrast bolus injection. It is, therefore, completely nonin-

vasive, precluding contrast-induced nephrotoxicity or

allergy to contrast material. It has the additional advan-

tage of providing absolute quantification of CBF.66 Stud-

ies using PWI in patients with IAS are scarce, especially

studies using ASL.67

Further advanced neuroimaging modalities still not

regularly implemented in clinical practice may become

more useful in the future for the assessment of the degree

of luminal narrowing (eg, black bloodMRA), the underly-

ing pathophysiology of IAS (eg, high-resolution magnetic

resonance imaging [HR-MRI]), or for the assessment of

the corresponding cerebrovascular repercussions (eg,

susceptibility-weighted imaging). In particular, HR-MRI,

an advanced MRI modality enabling to depict the intra-

cranial arterial wall, can be of help to distinguish athero-

sclerotic IAS from other less frequent underlying

etiologies,68 to depict atherosclerotic lesions not detect-

able on 3D-TOF MRA,69 and to differentiate characteris-

tics of atherosclerotic plaques between symptomatic and

asymptomatic stenoses of the MCA.70

M. CARVALHO ET AL.602

Computed Tomography Angiography

CTA is a minimally invasive imaging technique requir-

ing exposure to ionizing radiation and intravenous injec-

tion of contrast for the visualization of the arterial lumen.

CTA enables higher acquisition speed and less distortion

by motion artifacts than MRA, providing similar or

higher accuracy for the diagnosis of IAS,71,72 except

perhaps at the region of the skull base.72 CTA is also supe-

rior to TCD or TCCD for the diagnosis of distal MCA dis-

ease.46 In addition, CTA can either serve as a screening

tool for the detection of IAS or increasingly as a confirma-

tory test approaching the diagnostic accuracy of DSA.73

CTA is not appropriate for the study of arteries with

a diameter smaller than .7 mm and, therefore, not recom-

mended for the differentiation between atherosclerotic

IAS and vasculitis.74 Other limitations of CTA include

artifacts caused by mural calcifications impairing quanti-

fication of stenosis and the difficulty in evaluating reste-

nosis after stenting.

Digital Subtraction Angiography

DSA persists as the confirmation standard for the diag-

nosis of IAS,41 allowing to reliably measure the degree of

stenosis (Fig 1).75 It is required in patients eligible for

Figure 1. A 37-year-old man of Portuguese or-

igin with vascular risk factors and family history

of vascular disease was admitted to a stroke unit

following a transient ischemic attack. Transcra-

nial Doppler showed evidence of occlusion of

both middle cerebral arteries. 3D-TOF MRA did

not depict the corresponding arterial lumina

(top left). Coronal T2-weighted (top right), axial

T2*-weighted (middle left), and diffusion

weighted (middle right) images did not show

any cerebrovascular lesions. Catheter digital

subtraction angiography (bottom row) shows

a high-grade stenosis in the terminal part of the

right internal carotid artery, and a critical steno-

sis in the right middle cerebral artery (bottom

left), as well as occlusion of the left middle cerebral

artery at segment M1 (bottom right). (B) Arterial

spin labeling images show clear evidence of hypo-

perfusion in the territory of both middle cerebral

arteries (dark areas). Abbreviation: 3D-TOF

MRA, three-dimensional time-of-flight magnetic

resonance angiography.

INTRACRANIAL ARTERIAL STENOSIS 603

angioplasty or stenting. Nonetheless, it does not qualify

as a screening tool because it is an invasive technique

not always available.

In the case of a critical IAS, it has been claimed that the

distal vessel may be poorly filled or difficult to visualize

on DSA and be mistaken for an occlusion. In addition,

DSA may not be superior to CTA for the evaluation of

steno-occlusive disease in the posterior circulation when

slow flow is present,71 but there is still not sufficient

body of evidence to generally advocate the possible re-

placement of DSA by CTA as the confirmation standard.

Major drawbacks of DSA include costs and some risks.

Costs are, in part, attributable to the need of at least 1-day

hospital admission. Stroke associated with permanent

disability occurs in just .14% of the cases76 but is the

most feared risk. Other risks include peripheral vascular

complications.

Natural History

Atherosclerotic IAS may progress or stabilize, and it

may occasionally regress.77,78 The risk of stroke in

patients with asymptomatic atherosclerotic IAS is low,

but there is substantial risk of stroke recurrence in the

presence of a symptomatic stenosis.

Asymptomatic Intracranial Arterial Stenosis

Approximately 19% of patients enrolled into the WA-

SID trial undergoing 4-vessel DSA and 27.3% of those

with baseline MRAwere found to have at least 1 concom-

itant asymptomatic IAS. On the basis of MRA, the risk of

stroke secondary to such asymptomatic stenoses was

found to be low (5.9%) over a mean follow-up period of

approximately 2 years.79 Likewise, TCD studies have

shown that asymptomatic stenosis of the MCA has a be-

nign long-term prognosis80,81 perhaps because chronic

asymptomatic atherosclerotic plaques in such a location

are often fibrocalcific and, therefore, not usually prone

to correspond to an embolic focus as supported by 1

Doppler study using detection of microembolic signals.82

Symptomatic Intracranial Arterial Stenosis

The natural history of symptomatic IAS without treat-

ment is mostly unknown as the information regarding

evolution of symptomatic IAS derives from studies de-

signed to measure treatment effects.83

The annual risk of stroke recurrence in the territory of

a stenotic artery among patients with symptomatic IAS

undergoing medical treatment is high and may exceed

20% when the degree of luminal narrowing is 70% or

more, recently after an ischemic event, and in women.

In addition, patients may be at increased risk when there

is a history of stroke or when hemodynamic triggers pre-

cipitate symptoms.83,84 The 2-year rate of ischemic stroke

in the WASID trial was 19.7% for patients treated with as-

pirin.11 The Groupe d’Etude des St�enoses Intra-Craniennes

Ath�eromateuses Symptomatiques study showed a 2-year re-

currence rate of 38.2% for ischemic events in the territory

of a stenotic artery.34 Other studies showed annual rates

of ipsilateral stroke recurrence of 9.1%78,85 and an

overall stroke risk of 12.5% per year in patients with

symptomatic stenosis of the MCA.85

Management and Treatment

General guidelines for primary prevention of stroke

should also apply to IAS, in particular those concerning

control of vascular risk factors.86,87 During the acute

phase of stroke caused by atherosclerotic stenosis of the

MCA, management also follows general guidelines,

including control of blood pressure and the use of aspirin.

Secondary Prevention

Secondary prevention should always include aggressive

control of vascular risk factors and antiplatelet therapy.88

Aggressive control of vascular risk factors is essential.

Blood pressure control is mandatory, given that high

blood pressure (systolic blood pressure $ 140 mm Hg)

significantly increases the risk of ischemic stroke in the

territory of a stenotic artery.89 Statins should also be

Figure 1. (Continued)

M. CARVALHO ET AL.604

used in patients with symptomatic stenosis of the MCA.

The recommended levels of low-density lipoprotein cho-

lesterol should be less than 70 mg/dL.90-92 Additional

modifiable risk factors should also be controlled,

according to general guidelines for secondary

prevention of stroke.86,93

Although aspirin may be as effective as warfarin in

stroke prevention, antiplatelet therapy is preferred to an-

ticoagulation because it is safer. In fact, patients treated

with warfarin were found to have higher rates of major

hemorrhage and death than patients treated with aspi-

rin.11 Even patients suffering from severe IAS or having

stroke recurrence despite previous use of antiplatelet

therapy were not found to benefit from anticoagulation.94

Several combinations of different antiplatelet agents

have been tried in IAS. The combination of aspirin and

clopidogrel was found to be more effective than aspirin

alone in reducing microembolic signals in patients with

IAS (relative risk reduction of approximately 40%).95

The combination of aspirin and cilostazol is also advanta-

geous.96 Both these combinations seem to be equally

effective with respect to preventing progression of IAS

and the occurrence of further ischemic cardiovascular

events or new lesions on brain MRI.97

Despite optimal medical treatment, there are patients

who fail to respond.98 Several types of endovascular pro-

cedures have been proposed for patients refractory to

medical treatment. In particular, angioplasty and stent

placement using the self-expanding nitinol Wingspan

stent have been tested for the treatment of high-grade ste-

noses (with $50% of luminal narrowing) in such pa-

tients99,100 and were also expected to be useful in the

case of recently symptomatic stenoses. However, data

from the Stenting and Aggressive Medical Management

for Preventing Recurrent Stroke in Intracranial Stenosis

(SAMMPRIS) trial, a prospective randomized study that

started in the United States in 2008 to determine

whether angioplasty and stenting plus aggressive

medical therapy is superior to aggressive medical

therapy alone for the prevention of stroke recurrence in

patients with IAS with 70% or more of luminal

narrowing (and transient ischemic attack or no

disabling stroke within 30 days before enrollment),101

suggest that medical therapy alone is far more beneficial.

Primary end points in the SAMMPRIS trial were101:

1. Any stroke or death within 30 days after enroll-

ment,

2. Any stroke or death within 30 days after an endo-

vascular procedure of the qualifying lesion during

follow-up, or

3. Stroke in the territory of the symptomatic intracra-

nial artery beyond 30 days after enrollment.

The inclusion of patients for the SAMMPRIS trial has

been prematurely stopped in April 2011, after randomiza-

tion of 451 (59% of the planned 764) patients at 50 partici-

pating sites, because 14.7% of the patients belonging to

the angioplasty and stenting plus aggressivemedical ther-

apy arm of the study were found to experience stroke or

died within the first 30 days of enrollment, in comparison

with only 5.8%of thepatients receiving aggressivemedical

therapy alone.102 Rates of stroke in the territory of the ste-

notic artery seem to be similar in both groups beyond

30 days of enrollment, although additional 2-year follow-

up results will be essential for further interpretation.103

The 30-day rate of stroke or death in the aggressive

medical therapy arm of the SAMMPRIS trial was substan-

tially lower than both the estimated and the recurrence

rates of stroke formerly found in studies on symptomatic

IAS (eg, the WASID trial). One major explanation for this

is the maximized efficiency of the aggressive medical

treatment used in SAMMPRIS, which comprised aspirin

325 mg/d (for the entire duration of follow-up) and

clopidogrel 75 mg/d (for 90 days after enrollment).

Clopidogrel could be continued beyond 90 days after en-

rollment under recommendation by a cardiologist. There

was also an intensive risk factor management targeting

systolic blood pressure less than 140 mm Hg (,130 mm

Hg in diabetic patients) by using 1 medication from

each major class of antihypertensive agents. In addition,

the patients received rosuvastatin and a lifestyle modifi-

cation program.101

Such achievement with aggressive medical therapy

alone in SAMMPRIS limits the odds of endovascular pro-

cedures to provide additional clinical benefit in patients

with symptomatic IAS,104 but there are potential subsets

of patients in whom angioplasty and/or stent placement

still might be the best therapeutic approach. Therefore,

the promising results of the SAMMPRIS trial should not

undermine the development of new and effective treat-

ments for patients with symptomatic IAS.105 Actually, en-

dovascular procedures may possibly improve, and new

devices or techniques might be developed in the future

aimed at being beneficial for patients refractory to medi-

cal treatment alone, especially in patients with symptom-

atic IAS secondary to hemodynamic compromise distal to

the site of stenosis. Alternatively, angioplasty alone in-

stead of angioplasty and stent placement can be an ac-

ceptable option less prone to originate periprocedural

complications, but this should be properly evaluated in

future randomized clinical trials.103,105

Strategies to further realize to what extent endovascu-

lar procedures are likely to be (or not) beneficial should

include the assessment of differences in the periproce-

dural complication rate when treating lesions occurring

in the posterior versus the anterior cerebral circulation,

imaging characteristics of atherosclerotic plaques leading

to IAS, and the assessment of angiographic risk of stroke

before any endovascular procedure, which has been an-

ticipated to be 0% in the WASID trial11 and seemed to

occur in only 1 patient belonging to the endovascular

INTRACRANIAL ARTERIAL STENOSIS 605

arm of the SAMMPRIS trial.106 In addition, efforts at re-

ducing periprocedural complications from angioplasty

and stenting for IAS must focus on reducing the risk of

regional perforator infarctions, delayed intracerebral (re-

perfusion) hemorrhage, and subarachnoid hemorrhage

because of wire perforation.106

Finally, direct or indirect extracranial–intracranial by-

pass surgery between the superficial temporal artery

and the MCA is currently an option mostly restricted to

moyamoya.107,108 It was also proposed for the treatment

of symptomatic atherosclerotic occlusion of the ICA but

represents a very invasive option that fails to provide

clear benefits in reducing stroke recurrence.109

Conclusion

Atherosclerotic IAS is a major cause of stroke. A refined

diagnosticwork-up, including conventional neuroimaging

examinations, is essential to identify IAS. Although there

are several therapeutic options available, it is currently

a matter of controversy whether there is a specific type of

treatment other than aggressive control of vascular risk fac-

tors and antiplatelet therapy that may alter the high risk of

stroke recurrence among patients with symptomatic IAS.

However, completely noninvasive, advanced neuroimag-

ing modalities, still not regularly implemented in clinical

practice, may possibly become useful in the near future to

improve risk stratification and treatment choice. For exam-

ple, HR-MRImay be useful to identify plaque features that

can lead to a better selection of patients either for medical

treatment alone or for adjunctive endovascular proce-

dures.110 ASL is a very promising technique to identify

hemodynamic compromise distal to the site of stenosis.

Acknowledgment: The authors are indebted to S�ergio

Ferreira for the assistance with the layout of the illustration.

References

1. Kim JS, Caplan LR, Wong KSL. Intracranial atheroscle-rosis. Chichester, UK: Wiley-Blackwell, 2008.

2. De Silva DA, Woon FP, Lee MP, et al. South Asianpatients with ischemic stroke: intracranial large arteriesare the predominant site of disease. Stroke 2007;38:2592-2594.

3. Gorelick PB, Wong KS, Bae HJ, et al. Large artery intra-cranial occlusive disease: a large worldwide burdenbut a relatively neglected frontier. Stroke 2008;39:2396-2399.

4. Suri MF, Johnston SC. Epidemiology of intracranialstenosis. J Neuroimaging 2009;19(Suppl 1):11S-16S.

5. Huang HW, Guo MH, Lin RJ, et al. Prevalence and riskfactors of middle cerebral artery stenosis in asymptom-atic residents in Rongqi County, Guangdong. Cerebro-vasc Dis 2007;24:111-115.

6. Wong KS, Huang YN, Yang HB, et al. A door-to-doorsurvey of intracranial atherosclerosis in LiangbeiCounty, China. Neurology 2007;68:2031-2034.

7. Wong KS, Ng PW, Tang A, et al. Prevalence of asymp-tomatic intracranial atherosclerosis in high-riskpatients. Neurology 2007;68:2035-2038.

8. Uehara T, Tabuchi M, Mori E. Frequency and clinicalcorrelates of occlusive lesions of cerebral arteries inJapanese patients without stroke. Evaluation byMR an-giography. Cerebrovasc Dis 1998;8:267-272.

9. Waddy SP, Cotsonis G, Lynn MJ, et al. Racial differ-ences in vascular risk factors and outcomes of patientswith intracranial atherosclerotic arterial stenosis.Stroke 2009;40:719-725.

10. Bae HJ, Lee J, Park JM, et al. Risk factors of intracranialcerebral atherosclerosis among asymptomatics. Cere-brovasc Dis 2007;24:355-360.

11. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Com-parisonofwarfarin andaspirin for symptomatic intracra-nial arterial stenosis. N Engl J Med 2005;352:1305-1316.

12. Williams JE, Chimowitz MI, Cotsonis GA, et al. Genderdifferences in outcomes among patients with symptom-atic intracranial arterial stenosis. Stroke 2007;38:2055-2062.

13. Wityk RJ, Lehman D, Klag M, et al. Race and sex differ-ences in the distribution of cerebral atherosclerosis.Stroke 1996;27:1974-1980.

14. Turan TN, Makki AA, Tsappidi S, et al. Risk factorsassociated with severity and location of intracranialarterial stenosis. Stroke 2010;41:1636-1640.

15. Uehara T, Tabuchi M, Mori E. Risk factors for occlusivelesions of intracranial arteries in stroke-free Japanese.Eur J Neurol 2005;12:218-222.

16. Bang OY, Kim JW, Lee JH, et al. Association of the met-abolic syndromewith intracranial atherosclerotic stroke.Neurology 2005;65:296-298.

17. Ovbiagele B, Saver JL, Lynn MJ, et al. Impact of meta-bolic syndrome on prognosis of symptomatic intracra-nial atherostenosis. Neurology 2006;66:1344-1349.

18. Park JH,KwonHM,Roh JK.Metabolic syndrome ismoreassociated with intracranial atherosclerosis than extra-cranial atherosclerosis. Eur J Neurol 2007;14:379-386.

19. Honig LS, Kukull W, Mayeux R. Atherosclerosis andAD: analysis of data from the US National Alzheimer’sCoordinating Center. Neurology 2005;64:494-500.

20. Beach TG,Wilson JR, Sue LI, et al. Circle ofWillis athero-sclerosis: association with Alzheimer’s disease, neuriticplaques and neurofibrillary tangles. Acta Neuropathol2007;113:13-21.

21. Bastos-Leite AJ, van der Flier WM, van Straaten EC,et al. The contribution of medial temporal lobe atrophyand vascular pathology to cognitive impairment in vas-cular dementia. Stroke 2007;38:3182-3185.

22. Barkhof F, Fox NC, Bastos-Leite AJ, et al. Neuroimagingin dementia. Berlin, Germany: Springer, 2011.

23. Wong KS, Gao S, Chan YL, et al. Mechanisms of acutecerebral infarctions in patients with middle cerebralartery stenosis: a diffusion-weighted imaging and mi-croemboli monitoring study. Ann Neurol 2002;52:74-81.

24. Taylor RA, Kasner SE. Natural history of asymptomaticintracranial arterial stenosis. J Neuroimaging 2009;19(Suppl 1):17S-19S.

25. Caplan LR, Hennerici M. Impaired clearance of emboli(washout) is an important link between hypoperfusion,embolism, and ischemic stroke. Arch Neurol 1998;55:1475-1482.

26. Markus HS, Harrison MJ. Estimation of cerebrovascularreactivity using transcranial Doppler, including the useof breath-holding as the vasodilatory stimulus. Stroke1992;23:668-673.

M. CARVALHO ET AL.606

27. Muller M, Voges M, Piepgras U, et al. Assessment ofcerebral vasomotor reactivity by transcranial Dopplerultrasound and breath-holding. A comparison with ac-etazolamide as vasodilatory stimulus. Stroke 1995;26:96-100.

28. Markus H, Cullinane M. Severely impaired cerebrovas-cular reactivity predicts stroke and TIA risk in patientswith carotid artery stenosis and occlusion. Brain 2001;124:457-467.

29. Chen A, ShyrMH, Chen TY, et al. Dynamic CT perfusionimaging with acetazolamide challenge for evaluation ofpatients with unilateral cerebrovascular steno-occlusivedisease. Am J Neuroradiol 2006;27:1876-1881.

30. Grubb RL Jr, Derdeyn CP, Fritsch SM, et al. Importanceof hemodynamic factors in the prognosis of symptom-atic carotid occlusion. JAMA 1998;280:1055-1060.

31. Ma J, Mehrkens JH, Holtmannspoetter M, et al. Perfu-sion MRI before and after acetazolamide administrationfor assessment of cerebrovascular reserve capacity inpatients with symptomatic internal carotid artery(ICA) occlusion: comparison with 99mTc-ECD SPECT.Neuroradiology 2007;49:317-326.

32. Yamauchi H, Fukuyama H, Nagahama Y, et al. Evidenceof misery perfusion and risk for recurrent stroke inmajor cerebral arterial occlusive diseases from PET. JNeurol Neurosurg Psychiatry 1996;61:18-25.

33. Yamauchi H, Fukuyama H, Nagahama Y, et al. Signifi-cance of increased oxygen extraction fraction in five-year prognosis of major cerebral arterial occlusivediseases. J Nucl Med 1999;40:1992-1998.

34. Mazighi M, Tanasescu R, Ducrocq X, et al. Prospectivestudy of symptomatic atherothrombotic intracranial ste-noses: the GESICA study. Neurology 2006;66:1187-1191.

35. S�anchez-S�anchez C, Egido JA, Gonzalez-Gutierrez JL,et al. Stroke and intracranial stenosis: clinical profile ina series of 134 patients in Spain. Rev Neurol 2004;39:305-311.

36. Baumgartner RW, Arnold M, Gonner F, et al. Contrast-enhanced transcranial color-coded duplex sonographyin ischemic cerebrovascular disease. Stroke 1997;28:2473-2478.

37. Baumgartner RW, Mattle HP, Schroth G. Assessment of$50% and ,50% intracranial stenoses by transcranialcolor-coded duplex sonography. Stroke 1999;30:87-92.

38. Griewing B, Schminke U, Motsch L, et al. Transcranialduplex sonography of middle cerebral artery stenosis:a comparison of colour-coding techniques—frequency-or power-based Doppler and contrast enhancement.Neuroradiology 1998;40:490-495.

39. Sharma VK, Tsivgoulis G, Lao AY, et al. Noninvasive de-tection of diffuse intracranial disease. Stroke 2007;38:3175-3181.

40. Felberg RA, Christou I, Demchuk AM, et al. Screeningfor intracranial stenosis with transcranial Doppler: theaccuracy of mean flow velocity thresholds. J Neuroi-maging 2002;12:9-14.

41. Feldmann E, Wilterdink JL, Kosinski A, et al. The StrokeOutcomes and Neuroimaging of Intracranial Athero-sclerosis (SONIA) trial. Neurology 2007;68:2099-2106.

42. Gao S, Lam WW, Chan YL, et al. Optimal values of flowvelocity on transcranial Doppler in grading middle cere-bral artery stenosis in comparison with magnetic reso-nance angiography. J Neuroimaging 2002;12:213-218.

43. Hao Q, Gao S, Leung TW, et al. Pilot study of new diag-nostic criteria for middle cerebral artery stenosis bytranscranial Doppler. J Neuroimaging 2010;20:122-129.

44. Jung KH, Lee YS. Clinical-sonographic index (CSI):a novel transcranial Doppler diagnostic model for mid-dle cerebral artery stenosis. J Neuroimaging 2008;18:256-261.

45. Ahn SW, Park SS, Lee YS. Novel parameter for the diag-nosis of distal middle cerebral artery stenosis with trans-cranial Doppler sonography. J Clin Ultrasound 2010;38:420-425.

46. Suwanwela NC, Phanthumchinda K, Suwanwela N.Transcranial Doppler sonography and CT angiographyin patients with atherothrombotic middle cerebral arterystroke. Am J Neuroradiol 2002;23:1352-1355.

47. Klotzsch C, Popescu O, Sliwka U, et al. Detection of ste-noses in the anterior circulation using frequency-basedtranscranial color-coded sonography. Ultrasound MedBiol 2000;26:579-584.

48. Krejza J, Mariak Z, Babikian VL. Importance of anglecorrection in the measurement of blood flow velocitywith transcranial Doppler sonography. Am J Neurora-diol 2001;22:1743-1747.

49. Swiercz M, Swiat M, Pawlak M, et al. Narrowing of themiddle cerebral artery: artificial intelligence methodsand comparison of transcranial color coded duplexsonography with conventional TCD. Ultrasound MedBiol 2010;36:17-28.

50. Martinoli C, Derchi LE, Rizzatto G, et al. PowerDoppler sonography: general principles, clinical appli-cations, and future prospects. Eur Radiol 1998;8:1224-1235.

51. Nabavi DG, Georgiadis D, Mumme T, et al. Detection ofmicroembolic signals in patients with middle cerebralartery stenosis by means of a bigate probe. A pilot study.Stroke 1996;27:1347-1349.

52. Wong KS, Gao S, LamWW, et al. A pilot study of micro-embolic signals in patients with middle cerebral arterystenosis. J Neuroimaging 2001;11:137-140.

53. Edelman RR, Mattle HP, Atkinson DJ, et al. MR angiog-raphy. Am J Roentgenol 1990;154:937-946.

54. Korogi Y, Takahashi M, Mabuchi N, et al. Intracranialvascular stenosis and occlusion: diagnostic accuracy ofthree-dimensional, Fourier transform, time-of-flightMR angiography. Radiology 1994;193:187-193.

55. Hirai T, Korogi Y, Ono K, et al. Prospective evaluation ofsuspected stenoocclusive disease of the intracranialartery: combined MR angiography and CT angiographycompared with digital subtraction angiography. Am JNeuroradiol 2002;23:93-101.

56. Bartels LW, Smits HF, Bakker CJ, et al. MR imaging ofvascular stents: effects of susceptibility, flow, and radio-frequency eddy currents. J Vasc Interv Radiol 2001;12:365-371.

57. Pedraza S, Silva Y, Mendez J, et al. Comparison of pre-perfusion and postperfusion magnetic resonance angi-ography in acute stroke. Stroke 2004;35:2105-2110.

58. Yang JJ, Hill MD, Morrish WF, et al. Comparison of pre-and postcontrast 3D time-of-flight MR angiography forthe evaluation of distal intracranial branch occlusionsin acute ischemic stroke. Am J Neuroradiol 2002;23:557-567.

59. Chen XY, LamWW,NgHK, et al. Diagnostic accuracy ofMRI for middle cerebral artery stenosis: a postmortemstudy. J Neuroimaging 2006;16:318-322.

60. Lee DK, Kim JS, Kwon SU, et al. Lesion patterns andstroke mechanism in atherosclerotic middle cerebralartery disease: early diffusion-weighted imaging study.Stroke 2005;36:2583-2588.

INTRACRANIAL ARTERIAL STENOSIS 607

61. Lee PH, Oh SH, Bang OY, et al. Infarct patterns in athero-sclerotic middle cerebral artery versus internal carotidartery disease. Neurology 2004;62:1291-1296.

62. Lee KB, OhHG, RohH, et al. Canwe discriminate strokemechanisms by analyzing the infarct patterns in thestriatocapsular region? Eur Neurol 2008;60:79-84.

63. ChoAH,KangDW,KwonSU, et al. Is 15mmsize criterionfor lacunar infarction still valid? A study on strictly sub-cortical middle cerebral artery territory infarction usingdiffusion-weighted MRI. Cerebrovasc Dis 2007;23:14-19.

64. Cho KH, Kang DW, Kwon SU, et al. Location of singlesubcortical infarction due to middle cerebral arteryatherosclerosis: proximal versus distal arterial stenosis.J Neurol Neurosurg Psychiatry 2009;80:48-52.

65. Kidwell CS, Alger JR, Saver JL. Evolving paradigms inneuroimaging of the ischemic penumbra. Stroke 2004;35:2662-2665.

66. Williams DS, Detre JA, Leigh JS, et al. Magnetic reso-nance imaging of perfusion using spin inversion of arte-rial water. Proc Natl Acad Sci U S A 1992;89:212-216.

67. Wu B, Wang X, Guo J, et al. Collateral circulation imag-ing: MR perfusion territory arterial spin-labeling at 3T.Am J Neuroradiol 2008;29:1855-1860.

68. Chung JW, Kim BJ, Choi BS, et al. High-resolution mag-netic resonance imaging reveals hidden etiologies ofsymptomatic vertebral arterial lesions. J Stroke Cerebro-vasc Dis 2013. pii: S1052-3057(13)00064-5. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.02.021. [Epubahead of print].

69. Li ML, Xu WH, Song L, et al. Atherosclerosis of middlecerebral artery: evaluation with high-resolution MRimaging at 3T. Atherosclerosis 2009;204:447-452.

70. Chung GH, Kwak HS, Hwang SB, et al. High resolutionMR imaging in patients with symptomatic middle cere-bral artery stenosis. Eur J Radiol 2012;81:4069-4074.

71. Bash S, Villablanca JP, Jahan R, et al. Intracranial vascu-lar stenosis and occlusive disease: evaluation with CTangiography, MR angiography, and digital subtractionangiography. Am J Neuroradiol 2005;26:1012-1021.

72. Skutta B, Furst G, Eilers J, et al. Intracranial stenoocclu-sive disease: double-detector helical CT angiographyversus digital subtraction angiography. Am J Neurora-diol 1999;20:791-799.

73. Nguyen-Huynh MN, Wintermark M, English J, et al.How accurate is CT angiography in evaluating intracra-nial atherosclerotic disease? Stroke 2008;39:1184-1188.

74. Villablanca JP, Rodriguez FJ, Stockman T, et al.MDCTan-giography for detection and quantification of small intra-cranial arteries: comparison with conventional catheterangiography. Am J Roentgenol 2007;188:593-602.

75. Samuels OB, Joseph GJ, Lynn MJ, et al. A standardizedmethod for measuring intracranial arterial stenosis.Am J Neuroradiol 2000;21:643-646.

76. Kaufmann TJ, Huston J III, Mandrekar JN, et al. Compli-cations of diagnostic cerebral angiography: evaluation of19,826 consecutive patients. Radiology 2007;243:812-819.

77. Akins PT, Pilgram TK, Cross DT III, et al. Natural historyof stenosis from intracranial atherosclerosis by serialangiography. Stroke 1998;29:433-438.

78. Arenillas JF, Molina CA, Montaner J, et al. Progressionand clinical recurrence of symptomatic middle cerebralartery stenosis: a long-term follow-up transcranialDoppler ultrasound study. Stroke 2001;32:2898-2904.

79. Nahab F, Cotsonis G, Lynn M, et al. Prevalence andprognosis of coexistent asymptomatic intracranial ste-nosis. Stroke 2008;39:1039-1041.

80. Kremer C, Schaettin T, Georgiadis D, et al. Prognosis ofasymptomatic stenosis of the middle cerebral artery. JNeurol Neurosurg Psychiatry 2004;75:1300-1303.

81. Ni J, Yao M, Gao S, et al. Stroke risk and prognostic fac-tors of asymptomatic middle cerebral artery atheroscle-rotic stenosis. J Neurol Sci 2011;301:63-65.

82. Segura T, Serena J, Castellanos M, et al. Embolism inacute middle cerebral artery stenosis. Neurology 2001;56:497-501.

83. Kasner SE.Natural historyof symptomatic intracranial ar-terial stenosis. J Neuroimaging 2009;19(Suppl 1):20S-21S.

84. Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors ofischemic stroke in the territory of a symptomatic intra-cranial arterial stenosis. Circulation 2006;113:555-563.

85. Kern R, Steinke W, Daffertshofer M, et al. Stroke recur-rences in patients with symptomatic vs asymptomaticmiddlecerebral arterydisease.Neurology2005;65:859-864.

86. Guidelines for management of ischaemic stroke andtransient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507.

87. GoldsteinLB, BushnellCD,AdamsRJ, et al. Guidelines fortheprimarypreventionofstroke: aguideline forhealthcareprofessionals from the American Heart Association/American Stroke Association. Stroke 2011;42:517-584.

88. Turan TN, Derdeyn CP, Fiorella D, et al. Treatment ofatherosclerotic intracranial arterial stenosis. Stroke2009;40:2257-2261.

89. Turan TN, Cotsonis G, Lynn MJ, et al. Relationship be-tween blood pressure and stroke recurrence in patientswith intracranial arterial stenosis. Circulation 2007;115:2969-2975.

90. Chaturvedi S, Turan TN, Lynn MJ, et al. Risk factor sta-tus and vascular events in patients with symptomaticintracranial stenosis. Neurology 2007;69:2063-2068.

91. Prabhakaran S, Romano JG. Current diagnosis andman-agement of symptomatic intracranial atheroscleroticdisease. Curr Opin Neurol 2012;25:18-26.

92. Vergouwen MD, de Haan RJ, Vermeulen M, et al. Statintreatment and the occurrence of hemorrhagic stroke inpatients with a history of cerebrovascular disease.Stroke 2008;39:497-502.

93. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for theprevention of stroke in patients with stroke or transientischemic attack: a guideline for healthcare professionalsfrom the American Heart Association/American StrokeAssociation. Stroke 2011;42:227-276.

94. Kasner SE, Lynn MJ, Chimowitz MI, et al. Warfarin vsaspirin for symptomatic intracranial stenosis: subgroupanalyses from WASID. Neurology 2006;67:1275-1278.

95. Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirinversus aspirin alone for reducing embolisation in pa-tients with acute symptomatic cerebral or carotid arterystenosis (CLAIR study): a randomised, open-label,blinded-endpoint trial. Lancet Neurol 2010;9:489-497.

96. Kwon SU, Cho YJ, Koo JS, et al. Cilostazol prevents theprogression of the symptomatic intracranial arterial ste-nosis: the multicenter double-blind placebo-controlledtrial of cilostazol in symptomatic intracranial arterialstenosis. Stroke 2005;36:782-786.

97. Kwon SU, Hong KS, Kang DW, et al. Efficacy and safetyof combination antiplatelet therapies in patients withsymptomatic intracranial atherosclerotic stenosis. Stroke2011;42:2883-2890.

98. Thijs VN, Albers GW. Symptomatic intracranial athero-sclerosis: outcome of patients who fail antithrombotictherapy. Neurology 2000;55:490-497.

M. CARVALHO ET AL.608

99. Bose A, Hartmann M, Henkes H, et al. A novel, self-expanding, nitinol stent in medically refractory intracra-nial atherosclerotic stenoses: the Wingspan study. Stroke2007;38:1531-1537.

100. Henkes H, Miloslavski E, Lowens S, et al. Treatment ofintracranial atherosclerotic stenoses with balloon dilata-tion and self-expanding stent deployment (WingSpan).Neuroradiology 2005;47:222-228.

101. Chimowitz MI, Lynn MJ, Turan TN, et al. Design of thestenting and aggressive medical management for pre-venting recurrent stroke in intracranial stenosis trial. JStroke Cerebrovasc Dis 2011;20:357-368.

102. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stentingversus aggressive medical therapy for intracranial arte-rial stenosis. N Engl J Med 2011;365:993-1003.

103. Jiang WJ, Yu W. Stenting versus medical therapy for in-tracranial arterial stenosis. N Engl J Med 2011;365:2140-2141. author reply 2141.

104. Chaudhry SA, Watanabe M, Qureshi AI. The new stan-dard for performance of intracranial angioplasty andstent placement after Stenting versus Aggressive Medi-cal Therapy for Intracranial Arterial Stenosis (SAMMP-RIS) trial. Am J Neuroradiol 2011;32:E214.

105. Qureshi AI, Al-Senani FM, Husain S, et al. Intracranial an-gioplastyandstentplacement after stentingandaggressivemedical management for preventing recurrent stroke inintracranial stenosis (SAMMPRIS) trial: present state andfuture considerations. J Neuroimaging 2012;22:1-13.

106. Derdeyn CP, Fiorella D, Lynn MJ, et al. Mechanisms ofstroke after intracranial angioplasty and stenting in theSAMMPRIS trial. Neurosurgery 2013;72:777-795.

107. Kuroda S, Houkin K. Moyamoya disease: current con-cepts and future perspectives. Lancet Neurol 2008;7:1056-1066.

108. Scott RM, Smith ER. Moyamoya disease and moyamoyasyndrome. N Engl J Med 2009;360:1226-1237.

109. Powers WJ, Clarke WR, Grubb RL, et al. Extracranial-intracranial bypass surgery for stroke prevention inhemodynamic cerebral ischemia: the Carotid OcclusionSurgery Study randomized trial. JAMA 2011;306:1983-1992.

110. Fiorella D, Derdeyn CP, Lynn MJ, et al. Detailed analysisof periprocedural strokes in patients undergoing intra-cranial stenting in Stenting and Aggressive MedicalManagement for Preventing Recurrent Stroke in Intra-cranial Stenosis (SAMMPRIS). Stroke 2012;43:2682-2688.

INTRACRANIAL ARTERIAL STENOSIS 609