Intracranial Arterial Stenosis

Review Article

Intracranial Arterial Stenosis Marta Carvalho, MD,*† Ana Oliveira, MD,*† Elsa Azevedo, MD, PhD,*†
nio J. Bastos-Leite, MD, PhD‡ and Anto

Intracranial arterial stenosis (IAS) is usually attributable to atherosclerosis and corresponds to the most common cause of stroke worldwide. 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 ancillary examinations for screening and follow-up. Computed tomography angiography 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 subtraction 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 vascular 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. Ó 2013 by National Stroke Association

Introduction 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 Hern^ani Monteiro, 4200-319 Porto, Portugal. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.06.006

Intracranial arterial stenosis (IAS) corresponds to luminal narrowing of large intracranial arteries. IAS is most often attributable to primary atherosclerosis, although embolic events can occasionally result in severe stenosis. Other causes of IAS include arterial dissection, inflammatory disorders (vasculitis), infections of the central nervous system, radiation, sickle cell disease, and moyamoya disease 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

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-11

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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 concomitantly occur in patients with stenosis in extracranial arteries, 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 atherosclerotic IAS with a particular emphasis on stenosis of the middle cerebral artery (MCA), which is the main intracranial 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 asymptomatic intracranial arterial disease in 5.9%-6.9% of subjects over the fifth decade of life.5,6 A cross-sectional study using 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 differences 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 factors may be associated with different locations of IAS.13,14 In general, potentially modifiable risk factors for intracranial atherosclerosis include hypertension, smoking, diabetes, and dyslipidemia—high total cholesterol, high low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol.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 homocysteine.4 Metabolic syndrome is also associated with IAS. It occurs in approximately 50% of the subjects with symptomatic intracranial atherosclerotic disease and is associated with substantially higher risk of major vascular events.16-18 An association between Alzheimer disease and intracranial 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 symptoms 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 asymptomatic IAS may confer risk of stroke24 because of decreased washout of small emboli25 or of potential disruption of cerebral autoregulation. In normal conditions, homeostatic mechanisms corresponding to cerebral autoregulation tend to minimize changes in cerebral blood flow (CBF) secondary to variation of the perfusion pressure. 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 inhalation), 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 impaired 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 positron 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 intracranial vertebral artery are more 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-Cr^aniennes Ath
eromateuses Symptomatiques study34 and a study by S
anchez-S
anchez

INTRACRANIAL ARTERIAL STENOSIS 35

et al, 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 evaluation of IAS, but less invasive techniques, such as TCD, MRA, and CTA became increasingly useful.

Ultrasound Techniques TCD is a noninvasive and dynamic ultrasound technique useful for fast and repeated evaluation of intracranial vessels and IAS. It has the advantage of being relatively inexpensive, but is operator dependent, requiring considerable training skills and standardized protocols 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 velocity (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 subocclusive (critical) stenoses may be actually associated with very slow flow.39 An MFV 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 Intracranial Atherosclerosis trial, a companion study to the WASID trial aiming at validating the use of TCD and MRA to diagnose intracranial atherosclerosis taking catheter DSA as the confirmation standard.41 To help avoiding false-positive results, a prestenotic to stenotic MCA velocity ratio of at least .5 was additionally proposed.40 Moreover, optimal cutoff values for PSV were found to be 140 cm/s and 180 cm/s, respectively, for a degree of luminal narrowing of 50% and 75% assessed by using MRA.42 Because there is a substantial pathophysiological variation in velocity values, especially in the acute phase, the diagnosis of stenosis in the MCA by using TCD should perhaps take into account other parameters than focal velocity increase. Therefore, a set of additional sonographic parameters to improve diagnostic accuracy has been recommended in the past few years.43 A clinical–sonographic

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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 experience with these new proposals. Differences in location and number of IAS may influence the results of TCD. For example, a distal stenosis 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/M1 MFV ratio is even better for the diagnosis.45 Nevertheless, normal TCD findings do not exclude distal M1 or M2 stenoses.46 Tandem stenoses might also represent an additional sonographical challenge. TCD can be used as a noninvasive method for the assessment of vasoreactivity, measuring the effect of vasodilator stimuli on flow velocity at a given artery and providing indirect information on the state of vascular reserve 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 differentiate 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 cutoff values for PSV obtained by using TCCD. The cutoff value for PSV to detect a degree of luminal narrowing more than 50% in the MCA was found to be 220 cm/s. One study comparing TCCD with TCD for the evaluation of stenosis of the MCA showed that TCCD outperforms 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, an ultrasound modality that displays the strength of the Doppler signal, rather than the flow velocity and directional 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, threedimensional (3D) time-of-flight (TOF) is the preferred

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MRA technique for the assessment of IAS. It does not require exogenous contrast injection. Because it is a flowdependent MR sequence based on the so-called inflow effect of unsaturated spins, 3D-TOF MRA allows depiction 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 overestimated and be mistaken for occlusions (Fig 1). Alternatively, 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 overestimated on MRA. This may clarify the apparent discrepancy 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 diagnosis 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 presence of IAS, but abnormal findings still require a confirmatory 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. Although most stents are devoid of ferromagnetic properties, they still can cause artifacts on MRA.56 Therefore, this technique is not a good tool in the assessment of restenosis after stenting. Contrast-enhanced MRA and postperfusion MRA have been tried for the diagnosis of IAS,57,58 but contrastenhanced 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 consequences are acute or chronic ischemic cerebrovascular lesions in the territory of the affected vessel. Diffusionweighted imaging is very well known for increasing detectability of acute ischemic lesions. Infarcts related to IAS are usually subcortical, deep perforating artery infarcts, or internal border-zone infarcts, sometimes associated with silent cortical lesions in the same territory, the latter attributable to distal embolization.60 This pattern potentially differs from the pattern observed when there are other underlying pathophysiological mechanisms of

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stroke. For example, infarcts secondary to atherosclerotic ICA disease are usually territorial or cortical infarcts, namely involving superficial perforating arteries.61 In addition, infarcts at the striatocapsular region secondary to stenosis of the MCA may have a different pattern of topography than infarcts caused by a more proximal source of embolism (eg, from the ICA or cardiogenic).62 Alternatively, an overlap of imaging patterns may occur among MCA disease and small-vessel disease63 because of occlusion 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 associated with infarcts of deep perforating arteries, whereas severe 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 intravenous contrast bolus injection allows the determination of several parameters beyond CBF. For example, time-topeak is generally considered to be the most sensitive indicator of abnormal perfusion in the assessment of ischemic penumbra.65 Arterial spin labeling (ASL) is another functional 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 noninvasive, precluding contrast-induced nephrotoxicity or allergy to contrast material. It has the additional advantage of providing absolute quantification of CBF.66 Studies 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 blood MRA), the underlying 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 intracranial arterial wall, can be of help to distinguish atherosclerotic IAS from other less frequent underlying etiologies,68 to depict atherosclerotic lesions not detectable on 3D-TOF MRA,69 and to differentiate characteristics of atherosclerotic plaques between symptomatic and asymptomatic stenoses of the MCA.70

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Figure 1. A 37-year-old man of Portuguese origin with vascular risk factors and family history of vascular disease was admitted to a stroke unit following a transient ischemic attack. Transcranial 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 stenosis 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 hypoperfusion in the territory of both middle cerebral arteries (dark areas). Abbreviation: 3D-TOF MRA, three-dimensional time-of-flight magnetic resonance angiography.

Computed Tomography Angiography CTA is a minimally invasive imaging technique requiring exposure to ionizing radiation and intravenous injection 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 superior to TCD or TCCD for the diagnosis of distal MCA disease.46 In addition, CTA can either serve as a screening tool for the detection of IAS or increasingly as a confirmatory 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 recommended for the differentiation between atherosclerotic IAS and vasculitis.74 Other limitations of CTA include artifacts caused by mural calcifications impairing quantification of stenosis and the difficulty in evaluating restenosis after stenting.

Digital Subtraction Angiography DSA persists as the confirmation standard for the diagnosis of IAS,41 allowing to reliably measure the degree of stenosis (Fig 1).75 It is required in patients eligible for

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Figure 1.

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 replacement 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 WASID trial undergoing 4-vessel DSA and 27.3% of those with baseline MRA were found to have at least 1 concomitant 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 benign 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

(Continued)

Symptomatic Intracranial Arterial Stenosis The natural history of symptomatic IAS without treatment is mostly unknown as the information regarding evolution of symptomatic IAS derives from studies designed 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 precipitate symptoms.83,84 The 2-year rate of ischemic stroke in the WASID trial was 19.7% for patients treated with aspirin.11 The Groupe d’Etude des St
enoses Intra-Cr^aniennes Ath
eromateuses Symptomatiques study showed a 2-year recurrence 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

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used in patients with symptomatic stenosis of the MCA. The recommended levels of low-density lipoprotein cholesterol 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 anticoagulation 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 aspirin.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 advantageous.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 procedures 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 stenoses (with $50% of luminal narrowing) in such patients99,100 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 enrollment, 2. Any stroke or death within 30 days after an endovascular procedure of the qualifying lesion during follow-up, or 3. Stroke in the territory of the symptomatic intracranial artery beyond 30 days after enrollment. The inclusion of patients for the SAMMPRIS trial has been prematurely stopped in April 2011, after randomiza-

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tion of 451 (59% of the planned 764) patients at 50 participating sites, because 14.7% of the patients belonging to the angioplasty and stenting plus aggressive medical therapy 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 the patients receiving aggressive medical therapy alone.102 Rates of stroke in the territory of the stenotic artery seem to be similar in both groups beyond 30 days of enrollment, although additional 2-year followup 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 substantially 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 enrollment 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 modification program.101 Such achievement with aggressive medical therapy alone in SAMMPRIS limits the odds of endovascular procedures 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 treatments for patients with symptomatic IAS.105 Actually, endovascular procedures may possibly improve, and new devices or techniques might be developed in the future aimed at being beneficial for patients refractory to medical treatment alone, especially in patients with symptomatic IAS secondary to hemodynamic compromise distal to the site of stenosis. Alternatively, angioplasty alone instead of angioplasty and stent placement can be an acceptable 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 endovascular procedures are likely to be (or not) beneficial should include the assessment of differences in the periprocedural 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 anticipated to be 0% in the WASID trial11 and seemed to occur in only 1 patient belonging to the endovascular

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arm of the SAMMPRIS trial. In addition, efforts at reducing periprocedural complications from angioplasty and stenting for IAS must focus on reducing the risk of regional perforator infarctions, delayed intracerebral (reperfusion) hemorrhage, and subarachnoid hemorrhage because of wire perforation.106 Finally, direct or indirect extracranial–intracranial bypass 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 diagnostic work-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 factors and antiplatelet therapy that may alter the high risk of stroke recurrence among patients with symptomatic IAS. However, completely noninvasive, advanced neuroimaging modalities, still not regularly implemented in clinical practice, may possibly become useful in the near future to improve risk stratification and treatment choice. For example, HR-MRI may be useful to identify plaque features that can lead to a better selection of patients either for medical treatment alone or for adjunctive endovascular procedures.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 atherosclerosis. Chichester, UK: Wiley-Blackwell, 2008. 2. De Silva DA, Woon FP, Lee MP, et al. South Asian patients with ischemic stroke: intracranial large arteries are the predominant site of disease. Stroke 2007; 38:2592-2594. 3. Gorelick PB, Wong KS, Bae HJ, et al. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008; 39:2396-2399. 4. Suri MF, Johnston SC. Epidemiology of intracranial stenosis. J Neuroimaging 2009;19(Suppl 1):11S-16S. 5. Huang HW, Guo MH, Lin RJ, et al. Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi County, Guangdong. Cerebrovasc Dis 2007;24:111-115. 6. Wong KS, Huang YN, Yang HB, et al. A door-to-door survey of intracranial atherosclerosis in Liangbei County, China. Neurology 2007;68:2031-2034.

7. Wong KS, Ng PW, Tang A, et al. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 2007;68:2035-2038. 8. Uehara T, Tabuchi M, Mori E. Frequency and clinical correlates of occlusive lesions of cerebral arteries in Japanese patients without stroke. Evaluation by MR angiography. Cerebrovasc Dis 1998;8:267-272. 9. Waddy SP, Cotsonis G, Lynn MJ, et al. Racial differences in vascular risk factors and outcomes of patients with intracranial atherosclerotic arterial stenosis. Stroke 2009;40:719-725. 10. Bae HJ, Lee J, Park JM, et al. Risk factors of intracranial cerebral atherosclerosis among asymptomatics. Cerebrovasc Dis 2007;24:355-360. 11. 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. 12. Williams JE, Chimowitz MI, Cotsonis GA, et al. Gender differences in outcomes among patients with symptomatic intracranial arterial stenosis. Stroke 2007; 38:2055-2062. 13. Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996;27:1974-1980. 14. Turan TN, Makki AA, Tsappidi S, et al. Risk factors associated with severity and location of intracranial arterial stenosis. Stroke 2010;41:1636-1640. 15. Uehara T, Tabuchi M, Mori E. Risk factors for occlusive lesions 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 metabolic syndrome with intracranial atherosclerotic stroke. Neurology 2005;65:296-298. 17. Ovbiagele B, Saver JL, Lynn MJ, et al. Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 2006;66:1344-1349. 18. Park JH, Kwon HM, Roh JK. Metabolic syndrome is more associated with intracranial atherosclerosis than extracranial atherosclerosis. Eur J Neurol 2007;14:379-386. 19. Honig LS, Kukull W, Mayeux R. Atherosclerosis and AD: analysis of data from the US National Alzheimer’s Coordinating Center. Neurology 2005;64:494-500. 20. Beach TG, Wilson JR, Sue LI, et al. Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol 2007;113:13-21. 21. Bastos-Leite AJ, van der Flier WM, van Straaten EC, et al. The contribution of medial temporal lobe atrophy and vascular pathology to cognitive impairment in vascular dementia. Stroke 2007;38:3182-3185. 22. Barkhof F, Fox NC, Bastos-Leite AJ, et al. Neuroimaging in dementia. Berlin, Germany: Springer, 2011. 23. Wong KS, Gao S, Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002;52:74-81. 24. Taylor RA, Kasner SE. Natural history of asymptomatic intracranial 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 cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke 1992;23:668-673.

INTRACRANIAL ARTERIAL STENOSIS 27. Muller M, Voges M, Piepgras U, et al. Assessment of cerebral vasomotor reactivity by transcranial Doppler ultrasound and breath-holding. A comparison with acetazolamide as vasodilatory stimulus. Stroke 1995; 26:96-100. 28. Markus H, Cullinane M. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001; 124:457-467. 29. Chen A, Shyr MH, Chen TY, et al. Dynamic CT perfusion imaging with acetazolamide challenge for evaluation of patients with unilateral cerebrovascular steno-occlusive disease. Am J Neuroradiol 2006;27:1876-1881. 30. Grubb RL Jr, Derdeyn CP, Fritsch SM, et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998;280:1055-1060. 31. Ma J, Mehrkens JH, Holtmannspoetter M, et al. Perfusion MRI before and after acetazolamide administration for assessment of cerebrovascular reserve capacity in patients 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. Evidence of misery perfusion and risk for recurrent stroke in major cerebral arterial occlusive diseases from PET. J Neurol Neurosurg Psychiatry 1996;61:18-25. 33. Yamauchi H, Fukuyama H, Nagahama Y, et al. Significance of increased oxygen extraction fraction in fiveyear prognosis of major cerebral arterial occlusive diseases. J Nucl Med 1999;40:1992-1998. 34. Mazighi M, Tanasescu R, Ducrocq X, et al. Prospective study of symptomatic atherothrombotic intracranial stenoses: 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 in a series of 134 patients in Spain. Rev Neurol 2004; 39:305-311. 36. Baumgartner RW, Arnold M, Gonner F, et al. Contrastenhanced transcranial color-coded duplex sonography in ischemic cerebrovascular disease. Stroke 1997; 28:2473-2478. 37. Baumgartner RW, Mattle HP, Schroth G. Assessment of $50% and ,50% intracranial stenoses by transcranial color-coded duplex sonography. Stroke 1999;30:87-92. 38. Griewing B, Schminke U, Motsch L, et al. Transcranial duplex sonography of middle cerebral artery stenosis: a comparison of colour-coding techniques—frequencyor power-based Doppler and contrast enhancement. Neuroradiology 1998;40:490-495. 39. Sharma VK, Tsivgoulis G, Lao AY, et al. Noninvasive detection of diffuse intracranial disease. Stroke 2007; 38:3175-3181. 40. Felberg RA, Christou I, Demchuk AM, et al. Screening for intracranial stenosis with transcranial Doppler: the accuracy of mean flow velocity thresholds. J Neuroimaging 2002;12:9-14. 41. Feldmann E, Wilterdink JL, Kosinski A, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 2007;68:2099-2106. 42. Gao S, Lam WW, Chan YL, et al. Optimal values of flow velocity on transcranial Doppler in grading middle cerebral artery stenosis in comparison with magnetic resonance angiography. J Neuroimaging 2002;12:213-218. 43. Hao Q, Gao S, Leung TW, et al. Pilot study of new diagnostic criteria for middle cerebral artery stenosis by transcranial Doppler. J Neuroimaging 2010;20:122-129.

9 44. Jung KH, Lee YS. Clinical-sonographic index (CSI): a novel transcranial Doppler diagnostic model for middle cerebral artery stenosis. J Neuroimaging 2008; 18:256-261. 45. Ahn SW, Park SS, Lee YS. Novel parameter for the diagnosis of distal middle cerebral artery stenosis with transcranial Doppler sonography. J Clin Ultrasound 2010; 38:420-425. 46. Suwanwela NC, Phanthumchinda K, Suwanwela N. Transcranial Doppler sonography and CT angiography in patients with atherothrombotic middle cerebral artery stroke. Am J Neuroradiol 2002;23:1352-1355. 47. Klotzsch C, Popescu O, Sliwka U, et al. Detection of stenoses in the anterior circulation using frequency-based transcranial color-coded sonography. Ultrasound Med Biol 2000;26:579-584. 48. Krejza J, Mariak Z, Babikian VL. Importance of angle correction in the measurement of blood flow velocity with transcranial Doppler sonography. Am J Neuroradiol 2001;22:1743-1747. 49. Swiercz M, Swiat M, Pawlak M, et al. Narrowing of the middle cerebral artery: artificial intelligence methods and comparison of transcranial color coded duplex sonography with conventional TCD. Ultrasound Med Biol 2010;36:17-28. 50. Martinoli C, Derchi LE, Rizzatto G, et al. Power Doppler sonography: general principles, clinical applications, and future prospects. Eur Radiol 1998;8: 1224-1235. 51. Nabavi DG, Georgiadis D, Mumme T, et al. Detection of microembolic signals in patients with middle cerebral artery stenosis by means of a bigate probe. A pilot study. Stroke 1996;27:1347-1349. 52. Wong KS, Gao S, Lam WW, et al. A pilot study of microembolic signals in patients with middle cerebral artery stenosis. J Neuroimaging 2001;11:137-140. 53. Edelman RR, Mattle HP, Atkinson DJ, et al. MR angiography. Am J Roentgenol 1990;154:937-946. 54. Korogi Y, Takahashi M, Mabuchi N, et al. Intracranial vascular stenosis and occlusion: diagnostic accuracy of three-dimensional, Fourier transform, time-of-flight MR angiography. Radiology 1994;193:187-193. 55. Hirai T, Korogi Y, Ono K, et al. Prospective evaluation of suspected stenoocclusive disease of the intracranial artery: combined MR angiography and CT angiography compared with digital subtraction angiography. Am J Neuroradiol 2002;23:93-101. 56. Bartels LW, Smits HF, Bakker CJ, et al. MR imaging of vascular stents: effects of susceptibility, flow, and radiofrequency eddy currents. J Vasc Interv Radiol 2001; 12:365-371. 57. Pedraza S, Silva Y, Mendez J, et al. Comparison of preperfusion and postperfusion magnetic resonance angiography in acute stroke. Stroke 2004;35:2105-2110. 58. Yang JJ, Hill MD, Morrish WF, et al. Comparison of preand postcontrast 3D time-of-flight MR angiography for the evaluation of distal intracranial branch occlusions in acute ischemic stroke. Am J Neuroradiol 2002; 23:557-567. 59. Chen XY, Lam WW, Ng HK, et al. Diagnostic accuracy of MRI for middle cerebral artery stenosis: a postmortem study. J Neuroimaging 2006;16:318-322. 60. Lee DK, Kim JS, Kwon SU, et al. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: early diffusion-weighted imaging study. Stroke 2005;36:2583-2588.

10 61. Lee PH, Oh SH, Bang OY, et al. Infarct patterns in atherosclerotic middle cerebral artery versus internal carotid artery disease. Neurology 2004;62:1291-1296. 62. Lee KB, Oh HG, Roh H, et al. Can we discriminate stroke mechanisms by analyzing the infarct patterns in the striatocapsular region? Eur Neurol 2008;60:79-84. 63. Cho AH, Kang DW, Kwon SU, et al. Is 15 mm size criterion for lacunar infarction still valid? A study on strictly subcortical middle cerebral artery territory infarction using diffusion-weighted MRI. Cerebrovasc Dis 2007;23:14-19. 64. Cho KH, Kang DW, Kwon SU, et al. Location of single subcortical infarction due to middle cerebral artery atherosclerosis: proximal versus distal arterial stenosis. J Neurol Neurosurg Psychiatry 2009;80:48-52. 65. Kidwell CS, Alger JR, Saver JL. Evolving paradigms in neuroimaging of the ischemic penumbra. Stroke 2004; 35:2662-2665. 66. Williams DS, Detre JA, Leigh JS, et al. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A 1992;89:212-216. 67. Wu B, Wang X, Guo J, et al. Collateral circulation imaging: 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 magnetic resonance imaging reveals hidden etiologies of symptomatic vertebral arterial lesions. J Stroke Cerebrovasc Dis 2013. pii: S1052-3057(13)00064-5. http://dx.doi. org/10.1016/j.jstrokecerebrovasdis.2013.02.021. [Epub ahead of print]. 69. Li ML, Xu WH, Song L, et al. Atherosclerosis of middle cerebral artery: evaluation with high-resolution MR imaging at 3T. Atherosclerosis 2009;204:447-452. 70. Chung GH, Kwak HS, Hwang SB, et al. High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis. Eur J Radiol 2012;81:4069-4074. 71. Bash S, Villablanca JP, Jahan R, et al. Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. Am J Neuroradiol 2005;26:1012-1021. 72. Skutta B, Furst G, Eilers J, et al. Intracranial stenoocclusive disease: double-detector helical CT angiography versus digital subtraction angiography. Am J Neuroradiol 1999;20:791-799. 73. Nguyen-Huynh MN, Wintermark M, English J, et al. How accurate is CT angiography in evaluating intracranial atherosclerotic disease? Stroke 2008;39:1184-1188. 74. Villablanca JP, Rodriguez FJ, Stockman T, et al. MDCTangiography for detection and quantification of small intracranial arteries: comparison with conventional catheter angiography. Am J Roentgenol 2007;188:593-602. 75. Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. Am J Neuroradiol 2000;21:643-646. 76. Kaufmann TJ, Huston J III, Mandrekar JN, et al. Complications of diagnostic cerebral angiography: evaluation of 19,826 consecutive patients. Radiology 2007;243:812-819. 77. Akins PT, Pilgram TK, Cross DT III, et al. Natural history of stenosis from intracranial atherosclerosis by serial angiography. Stroke 1998;29:433-438. 78. Arenillas JF, Molina CA, Montaner J, et al. Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: a long-term follow-up transcranial Doppler ultrasound study. Stroke 2001;32:2898-2904. 79. Nahab F, Cotsonis G, Lynn M, et al. Prevalence and prognosis of coexistent asymptomatic intracranial stenosis. Stroke 2008;39:1039-1041.

M. CARVALHO ET AL. 80. Kremer C, Schaettin T, Georgiadis D, et al. Prognosis of asymptomatic stenosis of the middle cerebral artery. J Neurol Neurosurg Psychiatry 2004;75:1300-1303. 81. Ni J, Yao M, Gao S, et al. Stroke risk and prognostic factors of asymptomatic middle cerebral artery atherosclerotic stenosis. J Neurol Sci 2011;301:63-65. 82. Segura T, Serena J, Castellanos M, et al. Embolism in acute middle cerebral artery stenosis. Neurology 2001; 56:497-501. 83. Kasner SE. Natural history of symptomatic intracranial arterial stenosis. J Neuroimaging 2009;19(Suppl 1):20S-21S. 84. Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006;113:555-563. 85. Kern R, Steinke W, Daffertshofer M, et al. Stroke recurrences in patients with symptomatic vs asymptomatic middle cerebral artery disease. Neurology 2005;65:859-864. 86. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25:457-507. 87. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2011;42:517-584. 88. Turan TN, Derdeyn CP, Fiorella D, et al. Treatment of atherosclerotic intracranial arterial stenosis. Stroke 2009;40:2257-2261. 89. Turan TN, Cotsonis G, Lynn MJ, et al. Relationship between blood pressure and stroke recurrence in patients with intracranial arterial stenosis. Circulation 2007; 115:2969-2975. 90. Chaturvedi S, Turan TN, Lynn MJ, et al. Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology 2007;69:2063-2068. 91. Prabhakaran S, Romano JG. Current diagnosis and management of symptomatic intracranial atherosclerotic disease. Curr Opin Neurol 2012;25:18-26. 92. Vergouwen MD, de Haan RJ, Vermeulen M, et al. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008;39:497-502. 93. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:227-276. 94. Kasner SE, Lynn MJ, Chimowitz MI, et al. Warfarin vs aspirin for symptomatic intracranial stenosis: subgroup analyses from WASID. Neurology 2006;67:1275-1278. 95. Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (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 the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke 2005;36:782-786. 97. Kwon SU, Hong KS, Kang DW, et al. Efficacy and safety of combination antiplatelet therapies in patients with symptomatic intracranial atherosclerotic stenosis. Stroke 2011;42:2883-2890. 98. Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000;55:490-497.

INTRACRANIAL ARTERIAL STENOSIS 99. Bose A, Hartmann M, Henkes H, et al. A novel, selfexpanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses: the Wingspan study. Stroke 2007;38:1531-1537. 100. Henkes H, Miloslavski E, Lowens S, et al. Treatment of intracranial atherosclerotic stenoses with balloon dilatation and self-expanding stent deployment (WingSpan). Neuroradiology 2005;47:222-228. 101. Chimowitz MI, Lynn MJ, Turan TN, et al. Design of the stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis trial. J Stroke Cerebrovasc Dis 2011;20:357-368. 102. 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. 103. Jiang WJ, Yu W. Stenting versus medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:2140-2141. author reply 2141. 104. Chaudhry SA, Watanabe M, Qureshi AI. The new standard for performance of intracranial angioplasty and stent placement after Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial. Am J Neuroradiol 2011;32:E214.

11 105. Qureshi AI, Al-Senani FM, Husain S, et al. Intracranial angioplasty and stent placement after stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) trial: present state and future considerations. J Neuroimaging 2012;22:1-13. 106. Derdeyn CP, Fiorella D, Lynn MJ, et al. Mechanisms of stroke after intracranial angioplasty and stenting in the SAMMPRIS trial. Neurosurgery 2013;72:777-795. 107. Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol 2008; 7:1056-1066. 108. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med 2009;360:1226-1237. 109. Powers WJ, Clarke WR, Grubb RL, et al. Extracranialintracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA 2011; 306:1983-1992. 110. Fiorella D, Derdeyn CP, Lynn MJ, et al. Detailed analysis of periprocedural strokes in patients undergoing intracranial stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS). Stroke 2012;43:2682-2688.