INTRACRANIAL MAGNETIC RESONANCE AND VASCULAR IMAGING IN PATIENTS WITH EXTRACRANIAL CAROTID STENOSIS

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INTRACRANIAL MAGNETIC RESONANCE AND VASCULAR IMAGING IN PATIENTS WITH EXTRACRANIAL CAROTID STENOSIS

A. D. Mackinnon, A. D. Platts, and D. J. H. McCabe

Department of Radiology, St George’s Hospital (ADM); Department of Neuroradiology (ADP), and University Department of Clinical Neuro- sciences (DJHMC), Royal Free and University College Medical School, Royal Free Hospital, London, UK; Department of Neurology (DJHMC), The Adelaide and Meath Hospital, incorporating the National Children’s Hospital, Dublin, Ireland

Introduction to symptomatic and asymptomatic internal carotid artery stenosis and occlusion

The majority of transient ischemic attacks (TIAs) and ischaemic strokes are caused by thromboembolism from a stenosed large extracranial artery or occlusion of a large intracranial artery (atherothrombotic stroke), occlusion of a small intracranial artery (lacunar stroke), or embolism from the heart (cardioembolic stroke) [74]. In the remaining patients, the origin of the infarction is not established by investigation (TIA or ischaemic stroke of indeterminate aetiology), or less common causes for ischaemia or infarction are iden- tiﬁed (e.g., sickle cell disease or vasculitis).

TIA or stroke in association with extracranial internal carotid artery (ICA) stenosis is a very important cause of morbidity and mortality in adults, and in one series, 25% of patients with carotid territory ischaemic stroke had 75% stenosis or occlusion of the ipsilateral ICA [6]. However, carotid artery territory TIA or stroke can occur in association with mild (0–49%), moderate (50–69%), or severe (70–99%) extracranial ICA stenosis, or ICA occlusion. Most patients with TIA or ischaemic stroke secondary to extracranial carotid artery stenosis present with clinical features of ipsilateral middle cerebral artery (MCA) rather than anterior cerebral artery (ACA) territory ischaemia or infarction, although exceptions do occur (see later). The majority of these patients are believed to have initial atherosclerotic plaque rupture with subsequent ipsilateral distal thromboembolism of pla-

telet emboli and/or plaque fragments [24]. However, in some patients, acute thrombosis can occur on the plaque surface and cause extracranial ICA occlusion.

Carotid occlusion may be asymptomatic if there is adequate intracerebral collateral circulation, but it may cause distal haemodynamic compromise especially in the presence of severe contralateral carotid stenosis or poor collateral circulation [91], [44]. In other patients with internal carotid artery occlusion, emboli may arise (i) from the occluded internal carotid stump, (ii) from the ipsilateral common or external carotid arteries via external carotid collaterals, or (iii) by transhemispheric passage from a contralateral internal carotid stenosis via the circle of Willis [44].

Embolic and haemodynamic mechanisms may co- contribute to the pathogenesis of cerebral ischaemia or infarction in some patients with ICA stenosis or occlusion [83]. All patients with symptomatic carotid stenosis or occlusion warrant aggressive secondary prevention to reduce the risk of subsequent TIA, stroke or other vascular events.

Asymptomatic stenosis ( 50%) of the extracranial carotid artery can be incidentally detected in ap- proximately 4 to 8% of adults with non-invasive Dopp- ler ultrasound screening [18]. These patients could potentially beneﬁt from primary prevention strategies to prevent the morbidity or mortality associated with carotid territory TIA or stroke in the ﬁrst instance.

In addition to the important group of patients with extracranial ICA stenosis, up to 10% of TIAs or ischaemic strokes may be attributed to atherosclerotic stenosis of a major intracranial artery [10].

Amongst Chinese patients, non-invasive imaging

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tensiﬁcation of antithrombotic treatment in, a subgroup of carotid stenosis patients who have ongoing embolism while awaiting carotid endarterectomy or stenting.

This chapter focuses on intracerebral imaging with T1- and T2-weighted, Diffusion-Weighted and Perfusion-Weighted Magnetic Resonance Ima- ging (MRI), and intracranial vascular imaging with intra-arterial catheter angiography, CT angiography (CTA), MR angiography (MRA), and transcranial Doppler ultrasonography (TCD) in the diagnostic work-up of patients with extracranial carotid stenosis. The role of TCD in detecting intracranial atherosclerotic ICA and MCA stenosis, and in monito- ring patients with extracranial ICA stenosis will be discussed. Standard brain CT and Single-Photon Emission Computed Tomography (SPECT) imaging, T2* (gradient echo) and standard MRI of brain in patients with carotid territory haemorrhagic infarction, functional MR brain imaging, intracranial imaging of patients with carotid dissection, and Positron Emission Tomography (PET) have been dealt with in other chapters and will not be discussed further. The detailed investigation of patients with moyamoya disease is also beyond the scope of this chapter.

Magnetic Resonance Imaging (MRI) techniques to establish patterns and the likely aetiology of ischaemia or infarction in patients with carotid territory TIAs or stroke

It is our practice to perform intracranial structural brain imaging in all patients with carotid stenosis, especially in those patients who are being considered for carotid endarterectomy or endovascular treatment. Cranial MRI may localise the area of cerebral ischaemia or infarction, evaluate brain structure and function, and assess perfusion characteristics and large-vessel patency in a patient with a carotid territory TIA or ischaemic stroke. A standard MRI protocol for the investigation of a patient with a carotid territory TIA or stroke may include T1- and T2- studies have suggested that intracranial stenosis may

be found in 51% of patients presenting with TIAs, [35] and a third of patients presenting with acute stroke [93]. Atherosclerotic stenosis of a major intracranial artery is also an important cause of stroke in black and Hispanic patients [10]. Cerebral ischaemia or infarction in these patients may be secondary to thrombosis, thromboembolism, or distal haemodynamic compromise, and recurrent cerebro- vascular events commonly occur despite the use of anti-thrombotic therapy [10].

Intracranial imaging can confirm or refute that the presenting symptoms and signs are secondary to carotid territory ischaemia or infarction, and may help to elucidate the aetiology and pathogenesis of the patient’s TIA or stroke. This is important because the management of these patients is influenced by the presence or absence of prior symptoms [84], [21], [28], the severity and location of the stenosis in the symptomatic subgroup [44], [10], [71], [72], and the likely aetiopathogenesis of the symptoms. For example, despite the potential benefits of carotid endarterectomy in patients with severe carotid stenosis, better risk stratification of patients is required because certain subgroups derive less benefit from surgical treatment. One needs to operate on approxima- tely 4 or 5 patients with symptomatic severe carotid stenosis within 2 weeks of symptom onset to prevent one stroke or death over the following 5 years [72].

In patients with asymptomatic 60% carotid stenosis, one needs to perform a carotid endarterectomy on 17–19 patients to prevent one stroke or death over the following 5 years [21], [28]. These data illustrate the need to enhance our understanding of the patho- genic mechanisms responsible for carotid territory TIA or stroke, and the importance of identifying individual patients with carotid stenosis or occlusion who are at highest risk of recurrent symptoms during follow-up to facilitate improvements in stroke prevention. This might allow us to target ‘lower risk’ patients with asymptomatic or symptomatic severe carotid stenosis with more intense anti-thrombotic, anti-hypertensive or lipid-lowering therapy, while re- serving surgical, endovascular or revascularisation therapy for those at ‘higher risk’. Furthermore, this information could facilitate identiﬁcation of, and in-

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weighted and Fluid-Attenuated Inversion Recovery (FLAIR) sequences, Diffusion Weighted Imaging (DWI), Perfusion Weighted Imaging (PWI) and extra- and intracranial Magnetic Resonance Angi- ography (MRA).

T1- and T2-weighted MRI in patients with carotid territory TIA or stroke

T1- and T2-weighted MRI sequences form the core of almost every clinical MRI protocol, but are not the most sensitive techniques available to identify hyperacute cerebral ischaemia or infarction. One may detect

‘absence of flow void’ in an acutely occluded intracranial artery within 2 hours (and possibly within minutes) of onset of acute carotid territory ischaemic symptoms using T1- and T2-weighted MRI; T2- weighted sequences are more sensitive than T1-MRI at detecting this subtle abnormality [16] MR imaging following administration of gadolinium may identify abnormal enhancement (abnormally high signal) within the artery feeding the area of ischaemic cortex within the first 2 hours after symptom onset, presumably secondary to sluggish flow within the partially occluded vessel [94]. These changes are more easily seen on gadolinium- enhanced T1-weighted than T2-weighted MR images [94].

When cerebral blood ﬂow falls to between 10 and 15 ml/100 g/minute, ischaemia-induced failure of the neuronal membrane sodium pump results in the intracellular accumulation of sodium and water with resultant neuronal swelling (cytotoxic oedema) [39].

Because T1-weighted MRI is useful for looking at normal brain anatomy, one may identify morphol- ogical swelling of the grey matter and subtle effac- ement of sulci on T1-weighted images in the acute phase after ischaemic stroke (within the ﬁrst 2-4 hours), which is presumably secondary to cytotoxic oedema [94]. Although this can occur before high signal is seen on T2-weighted images, these changes may be very subtle and may not be reliably identiﬁed, and one cannot exclude acute cerebral infarction if T1-weighted MRI of brain is normal.

If severe cerebral ischaemia persists for more than 6 hours, the integrity of the capillary endothelial

cells is compromised and intravascular ﬂuid and protein leak into the extracellular space [39]. This leads to the development of vasogenic oedema which peaks at 24 to 48 hours [39]. T2-weighted imaging may identify high signal intensity change secondary to either cytotoxic or vasogenic oedema, but is much more commonly abnormal during the phase of development of vasogenic oedema (Fig. 1). Therefore, although T2 high signal change may be seen as early as

Fig. 1. a T2-weighted axial MRI: Subtle high signal intensity changes (arrows) involving the left frontal and insular cortex, left putamen and head of the left caudate nucleus 8 hours after onset of right hemiparesis and expressive dysphasia. b T2-weighted MRI brain 4 days later in same patient showing an established left MCA territory infarct.

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pathological region of interest (Fig. 2). Noguchi et al. identiﬁed high signal changes on FLAIR MRI, consistent with acute infarction, in 6 of 7 (86%) patients who were imaged within 3 hours of onset of ischaemic stroke [65]. Although FLAIR MRI may increase the likelihood of identifying acute carotid territory infarction compared with T1- or T2- weighted MRI, high signal abnormalities also persist on FLAIR MRI after the acute phase of cerebral infarction, and do not allow one to differentiate between recent or prior infarction. Ultimately, some infarcts may also appear as low signal intensity lesions on FLAIR if cavitation of the infarct occurs and the 6 to 8 hours after the onset of ischaemic symptoms, it

is present in most, but not all, patients by 24 hours [94]. Corresponding low signal intensity change on T1-weighted MRI is rarely seen before 16 hours, and is only identiﬁed in some patients between 16 and 24 hours after onset of acute cerebral infarction, thus rendering low signal change on T1-weighted MRI a less sensitive marker of acute infarction than high signal change on T2-weighted images [94].

T1- and T2-weighted MRI can conﬁrm that the area of infarction lies within the ACA or MCA territory in a symptomatic patient with ipsilateral carotid stenosis, thus implying that the stenosis caused the symptoms. However, T1- and T2-weighted MRI cannot identify acutely ischaemic tissue that is not destined to undergone irreversible infarction, and as stated above, may not actually identify all patients with acute cerebral infarction. Furthermore, because recent and long-standing cerebral infarcts both exhibit similar high signal intensity characteristics on T2-weighted images, one may not be able to differentiate between acute and established infarction with T2-weighted MRI unless the patient has developed acute oedema in association with a recent infarct. Because a proportion of patients with carotid stenosis have clinically asymptomatic established infarction on brain MRI, and others have co-existent small vessel disease or a potential cardiac source of embolism, additional MR imaging techniques may help to clarify whether the stenosis has caused the presenting symptoms or is likely to be incidental and asymptomatic.

Fluid-Attenuated Inversion Recovery (FLAIR) MRI

More recently, FLAIR MRI has been introduced to complement conventional T2-weighted sequences.

FLAIR MRI provides a very heavily T2-weighted image of brain parenchyma and nulliﬁes the signal from cerebrospinal ﬂuid (CSF) [65]. FLAIR MRI is particularly useful in identifying periventricular and cortical infarcts which may be less obvious on conventional T2-weighted sequences because of partial volume effects and high CSF signal adjacent to the

Fig. 2. a T2-weighted Turbo Spin Echo sequence at the high convexity level demonstrating equivocal high signal intensity changes in the right MCA territory; b FLAIR image at the same level demonstrating deﬁnite high signal intensity change involving the cortex in two separate gyral regions (white arrows) (Adapted from Brant-Zawadzki et al. [19]).

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contents of the cavity approach the protein content of CSF.

Diffusion Weighted Imaging (DWI)

MRI can exploit the normal random motion of water molecules in the brain to produce image contrast [39]. In a Diffusion Weighted Imaging (DWI) protocol, the spatial location of each water molecule is effectively ‘tagged’ so that any net movement of water molecules during image acquisition results in a loss of signal and darkening of the images. This ‘tag- ging’ is achieved by a pair of very strong magnetic ﬁeld gradients (diffusion gradients) which are typically added to a T2-weighted spin echo sequence [4]. These gradient pulses are designed to cancel each other out if there has been no movement of water molecules. Signal attenuation therefore occurs in normal tissues with random water motion, such as CSF; high signal change is seen on DWI in tissues that have restricted diffusion, e.g., with cytotoxic oedema associated with hyperacute cerebral ischaemia/infarction, and may also occur with subsequent vasogenic oedema in the later stages after cerebral infarction (see below).

Diffusion weighted scans are characterised by their b value (in s/mm²) which is a function of the diffusion gradient strength, its duration, and the time interval between gradients. The conspicuity of the lesion on DWI relates to this b value. Although DW images are useful, the absolute intensities may not be a direct indicator of the diffusion coefﬁcient.

Factors that affect the diffusion coefficient on DWI include the T2 signal and the b value. DWI can be influenced by the ‘T2 shine through effect’ caused by high signal intensity changes on a corresponding T2-weighted MRI. However, each DW image has a corresponding Apparent Diffusion Coefficient (ADC) map which allows one to measure the degree of signal decay (slope of decay) rather than the absolute value, thus eliminating the influence of the T2 shine through effect on the ADC map. Areas which exhibit restricted diffusion and appear bright on a DW image have a low diffusion coefficient and appear hypointense or dark on an ADC map.

DWI has been shown to detect ischaemic lesions within minutes of the ictus in experimental animals, and within 30–90 minutes of acute stroke onset in humans [82]. Therefore, DWI is more sensitive than CT or conventional MRI at detecting acute cerebral ischaemia or infarction in the ﬁrst few minutes and hours after symptom onset [64], [86], [22], [23], [5], [76], [42]. Acute ischaemic foci typically appear bright on DWI (‘light bulb’ sign) and dark on ADC maps (Fig. 3) [88]. High signal abnormalities on DWI may persist for up to 57 days (and very occasionally for up to 90 days) after ischaemic stroke, and then typically decrease in intensity [20]. Dark signal abnormality on an ADC map usually lasts for 10 days after ischaemic stroke onset, pseudonormalises, and may subsequently change to exhibit increased signal intensity [20].

However, dark signal abnormality on an ADC map may persist for up to a month in border-zone infarcts between the superﬁcial and deep perforators of the middle cerebral artery, and should not be interpreted as indicating hyper-acute infarction in a patient with severe ipsilateral ICA stenosis [34].

It was initially felt that acute DWI signal changes on MRI represented irreversibly infarcted brain tissue. However, more recent longitudinal studies have shown that brain regions with initial abnormal signal intensity on DWI may regain normal signal intensity after recanalisation of the occluded artery [43] suggesting that cerebral ischaemia may also cause DWI signal change. This is supported by the observation that 45% of patients who had a hemispheric TIA in association with severe ipsilateral carotid stenosis had abnormal signal change on DWI in one series [42].

The additional information obtained from DWI in TIA and ischaemic stroke may inﬂuence clinical management. For example, an 85 year old man with severe right extracranial ICA stenosis who experiences a non-disabling stroke causing left arm and leg weakness, who is found to have an acute ischaemic lesion on DWI consistent with right pontine lacunar infarction, may not undergo carotid endarterectomy when the clinician concludes that the stenosis is asymptomatic. On the contrary, a patient with carotid stenosis who presents with a ‘lacunar stroke syndrome’ may be

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outweigh the risks in that individual. Although one must stress that there is no evidence from randomised controlled trials that clinically asymptomatic patients with cerebral infarction on MRI beneﬁt more from carotid endarterectomy than patients without evidence of infarction on MRI, this is an issue that warrants further investigation.

DWI allows us to identify patterns of infarction in the acute stage after TIA or stroke, and can improve our understanding of the likely aetiopathogenesis of ischaemia or infarction in patients with extracranial carotid stenosis. Szabo et al. have utilised data from previous studies to describe 5 main patterns of infarction in patients with ischaemic stroke distal to an ipsilateral extracranial ICA stenosis or occlusion (Fig. 4) [83]:

(i) “Territorial infarction” involves the cerebral cortex and subcortical structures within the MCA, ACA or both vascular territories [83]. MCA infarcts may be considered to be “partial” if a distal MCA found to have a large subcortical infarct on DWI that

could not be attributed to small vessel occlusion, thus allowing the clinician to conclude that the stenosis is

“symptomatic” and warrants intervention [76]. Fur- thermore, some patients with severe carotid stenosis may have an alternative source of embolism; the find- ing of recent bilateral MCA and vertebrobasilar territory lesions on DWI would prompt a more intensive search for a cardio-embolic source of embolism that might require treatment with anticoagulation. An- other important group of patients that might benefit from the information obtained from DWI are those with “clinically asymptomatic” severe extracranial ICA stenosis who have never had prior symptoms of TIA or stroke. The identification of recent ipsilateral MCA territory infarction on DWI in a “clinically asymptomatic” patient suggests that the stenosis has been “radio- logically symptomatic” and may encourage the clinician to recommend carotid endarterectomy for stroke prevention if the potential benefits of treatment

Fig. 3. a DWI in a patient with an acute right MCA territory infarct showing bright signal abnormality (‘light bulb sign’) in the right corona radiata (arrow); b Corresponding ADC map showing dark signal abnormality in the same region (arrowhead).

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Fig. 4. Different patterns of infarction that one may see in patients with extracranial ICA stenosis (reproduced from [83]).

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branch is occluded, and “large” if there is proximal occlusion at the level of the MCA bifurcation or tri- furcation without an efﬁcient collateral system (Fig. 5) [83]. “Complete” ACA and MCA territory infarction may occur in patients with embolisation and occlusion of the distal intracranial ICA [83].

(ii) “Subcortical infarction” involves the terri- tory supplied by deep perforating branches origina- ting from the distal intracranial ICA or the MCA trunk in the presence of adequate collateral supply to the cortex [83]. For example, embolic occlusion of the MCA trunk in the presence of patent super- ficial collaterals may cause a large striatocapsular infarct [83].

(iii) “Territorial infarction with fragmentation”

represents a large territorial infarct with additional smaller lesions in either cortical or subcortical regions, presumably due to partial fragmentation of an embolus to the MCA [83].

(iv) Small “disseminated lesions” may be ran- domly distributed in the MCA territory and mainly involve the cortex [83]. This pattern of infarction may be secondary to fragmentation of a single MCA embolus, or may occur if multiple smaller emboli occlude smaller branches of the MCA [83].

(v) “Border-zone infarction” may also occur at the junction between two or more adjacent non-anas- tomosing arterial systems in patients with extracranial carotid stenosis [83], [61]. Two different patterns of border-zone infarction are recognised:

(a) “Cortical (external) border-zone infarcts”

involve the cortical boundary zones that lie in the vascular territory supplied by the distal arterial

Fig. 5. Different patterns of infarction on MRI brain in two patients with extracranial internal carotid artery occlusion: a Axial T2- weighted MRI showing a right MCA territorial infarct with sparing of the right ACA territory. It is assumed that the right ACA territory has been spared because of collateral blood supply from the left carotid circulation via the anterior communicating artery; b Axial FLAIR MRI showing infarction in the border-zone between the MCA and the ACA territories, with relative preservation of parts of the fronto-parietal cortex; it is also possible that the patient had multiple emboli from the ICA stump to the MCA at the time of the occlusion. The relative sparing of the cortex suggests that the patient had a well developed superﬁcial collateral supply e.g. from branches of the right external carotid artery.

branches of both the ACA and the MCA, the MCA and the posterior cerebral artery (PCA), or in the triple border-zone between the ACA, the MCA and the PCA; [61]. (b) “Internal border-zone infarcts”

involve the white matter that lies in the vascular

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territory between the arterial supply of the superﬁ- cial arterial perforators (medullary perforating arteries) and the deep perforating arteries (lenticulostriate arteries) of the MCA [89], or in the centrum semi- ovale in the territory between the superﬁcial arterial perforators of the MCA and ACA [61].

One might expect the ﬁrst four patterns of ischaemia or infarction to occur predominantly in carotid stenosis patients with embolic occlusion of the intracranial ICA or MCA, and border-zone infarction to occur in patients with severe extracranial ICA stenosis with haemodynamic compromise secondary to poor collateral supply. However, because the size and location of the border-zones vary enor- mously between carotid stenosis patients, and even within individuals who develop increasingly severe carotid stenosis over time, it is difﬁcult to be certain whether the cause of the ischaemic lesion on MR imaging is secondary to thromboembolic occlusion,

‘low ﬂow’ with haemodynamic compromise, or a combination of both mechanisms [90]. A detailed history may provide some clues as to whether a carotid territory TIA is likely to secondary to thromboembolism or haemodynamic compromise. Hae- modynamic TIAs are typically described as evolving over minutes (embolic TIAs are typically maximal within seconds of symptom onset), and may be associated with course jerking of the arm and/or leg contralateral to the stenosis in association with limb weakness or numbness. In patients with ‘low ﬂow retinopathy’ distal to a unilateral severe extracranial ICA stenosis, monocular ‘visual whiteout’ may develop after exposure to bright sunlight and resolve over seconds to minutes when the patient leaves the bright surroundings. A haemodynamic mechanism is also more likely if TIA symptoms occur after standing or sitting up suddenly, after intake of anti- hypertensive medication, or if the symptoms only occur in very hot weather, after a hot bath or heavy meal [90]. One must accept that a patient with e.g.

intracranial MCA branch stenosis who has an embolism to the MCA trunk from an extracranial ICA stenosis may present with a TIA that evolves in a manner that suggests ‘haemodynamic’ ischaemia.

It is also important to remember that because the lenticulostriate arteries arise from the MCA, occlusion

of one of these ‘end arteries’ by an embolus from an extracranial ICA stenosis can also cause a clinical ‘lacunar syndrome’ with associated ‘lacunar infarction’ on brain imaging [37]. Therefore, screening for carotid stenosis in a patient with an anterior circulation lacunar TIA or stroke can be justiﬁed, although the pick- up rate is likely to be lower than in patients with clas- sical large artery atherothrombotic TIA or stroke.

The following section reviews the imaging modalities that may improve our understanding of the potential mechanism(s) that may cause these different patterns of infarction in patients with extracranial ICA stenosis, and which may in turn inform clinical management decisions in this patient population.

Magnetic resonance Perfusion-Weighted Imaging (PWI)

Perfusion-Weighted Imaging (PWI) is an additional MRI technique that can provide some information about cerebral blood volume and blood flow [5] by ex- ploiting magnetic susceptibility effects within the brain [39]. PWI involves rapidly injecting an intravenous bolus of gadolinium diethylenetriamine penta- acetic acid [70], which causes a transient reduction in signal within the cerebral blood vessels and brain parenchyma on T2*-weighted imaging [39]. Multi-slice images of the whole brain are typically acquired every 1 to 2 seconds, and sequential changes in signal intensity can be used to produce pixel-based colour maps, and to calculate a number of indices including the mean transit time of the bolus thorough the brain (MTT), the relative cerebral blood volume (rCBV) and the relative cerebral blood flow (rCBF) [39]. The relative cerebral blood flow is calculated by dividing the relative cerebral blood volume by the mean transit time (rCBF rCBV/MTT). Prolongation of the mean transit time of the injected bolus is the earliest and most consistent sign of impaired cerebral perfusion [39]. When the MTT increases, autoregulatory mechanisms are activated which promote vasodilation and recruitment of collateral vessels, thus increasing cerebral blood volume and maintaining cerebral blood flow at a relatively constant level [39]. Thus, the response to impaired perfusion and prolongation of the

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tients with acute carotid territory TIA or stroke? In- travenous recombinant tissue plasminogen activator has been shown to improve the likelihood of a favour- able outcome during follow-up if administered within 180 minutes of acute stroke onset, and may be of beneﬁt in patients treated up to 270 minutes after symptom onset [27]. Ongoing studies, e.g. the Echo- planar Imaging Thrombolysis Evaluation Trial, are investigating the usefulness of combined DWI-PWI studies in selecting patients who may beneﬁt from

‘delayed thrombolytic therapy’ if they seek medical at- tention outside of the usual three hour time period following stroke onset. Preliminary results from the Desmoteplase in Acute Ischemic Stroke trial suggest that DWI-PWI mismatch data may be used to select patients who may benefit from treatment with novel thrombolytic agents between 3 and 9 hours after acute ischaemic stroke onset, but larger trials are required to confirm these initial results [26]. Con- versely, it may also be sensible to avoid thrombolytic therapy in patients with acute DWI lesions who have no residual perfusion deficit on PWI, because it is likely that these patients have already spontaneously recanalised the temporarily occluded feeding artery and may not derive any further benefit from thrombolysis. Furthermore, future PWI studies may facilitate identification of patients with acute MCA infarction who are likely to develop a malignant MCA syndrome secondary to more extensive MCA ischaemia than is predicted by DWI alone. If the results of ongoing trials, such as the Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY) trial are encouraging, the use of PWI in this setting deserves further study.

Intracranial vascular imaging with catheter angiography, CTA, and MRA in patients with extracranial carotid stenosis

Most clinicians request colour Doppler ultrasound imaging to initially establish the diagnosis of extracranial proximal ICA and carotid bifurcation stenosis. Colour Doppler ultrasound has a relatively MTT provides some information about the brain’s au-

toregulatory capacity and collateral reserve.

PWI has the potential to play a role in evaluating patients with extracranial ICA stenosis. However, it must be appreciated that PWI is semi-quantitative and cannot provide absolute values, but comparison of blood flow between the two hemispheres may provide information about the relative reduction in blood flow in the affected hemisphere [39]. In the presence of impaired perfusion distal to a severe unilateral ICA stenosis, relative cerebral blood volume in the affected hemisphere may be normal or increased if collateral supply is adequate, but may be decreased if collateral blood supply is insufficient and if maximum vasodila- tory capacity has been exceeded [39]. This may allow one to speculate that recurrent stereotyped MCA territory TIAs in a patient with severe ipsilateral ICA stenosis are haemodynamic in origin if other non-invasive imaging modalities fail to provide evidence of embolism to the ipsilateral MCA (see section on TCD below). It follows that the data obtained from PWI may be less informative in patients with bilateral severe ICA stenosis who have impaired perfusion in the MCA or ACA territories on both sides. However, in some patients with bilateral ICA occlusion with collateral supply to the anterior circulation from extracranial collaterals, PWI may show impaired perfusion in the region of the cortical border-zones on both sides [39].

In acute carotid territory TIA or ischaemic stroke, perfusion of the affected brain region is impaired and can be detected with PWI. Initially, because DWI lesions were considered to represent areas of irreversible infarction, and because the perfusion defect was often larger than the lesion seen on DWI, it was assumed that the difference between the two defects, the “MR diffusion-perfusion mismatch zone”, represented an area of ischaemic brain that had not yet undergone irreversible infarction (the ischaemic penumbra) [75].

Because more recent data have shown that DWI lesions may reverse following recanalisation of the feeding artery [43], the MR diffusion-perfusion mismatch model may overestimate the amount of irreversibly infarcted core tissue, thus underestimating the extent of the ischaemic penumbra.

How could these MR imaging studies provide useful information that could improve the care of pa-

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high sensitivity and speciﬁcity in identifying severe extracranial ICA stenosis [62], [59], and the combination of Doppler ultrasound with other non-invasive imaging studies (e.g., extracranial MRA or CTA) improves the likelihood of ‘accurately’ identifying a severe ICA stenosis that might warrant intervention [66]. Because of the safety of non-invasive imaging techniques, many patients with proximal extracranial ICA stenosis do not have their stenosis severity measured with the “gold standard”

technique of catheter angiography, and routine imaging of the intracranial circulation is not performed in many centres as part of the work-up of patients with carotid stenosis. Although standard cross-sec- tional CT and MRI images provide some information about the patency of the intracranial vessels, de- dicated intracranial vascular imaging protocols are required to delineate the intracranial vessels in de- tail.

The potential beneﬁts of intracranial imaging in patients with extracranial carotid stenosis include identiﬁcation of:

– ‘Tandem arterial stenosis’ in the extracranial and intracranial ICA (Fig. 6)

– Intracranial atherosclerosis of the MCA, ACA, PCA, and their branches

– The response to intravenous or intra-arterial thrombolytic therapy

– The extent of the intracranial collateral arterial supply and

– Other pathological processes, including vasculitis or dissection, that may occasionally co-exist in patients with atherosclerosis.

Clinical examples of patients who could beneﬁt from intracranial vascular imaging

Because colour Doppler ultrasound cannot visualise the distal extracranial ICA far above the angle of the mandible, one should suspect distal ‘tandem’ carotid stenosis in a patient with ‘high-resistance ﬂow’ on Doppler waveform analysis of the proximal ICA, and distal extracranial and intracranial vascular imaging should be performed [73]. Intracranial vascular imag-

ing should also be considered in patients at higher risk of having intracranial stenosis; e.g., the occur- rence of ‘haemodynamic’ carotid territory TIAs in an Asian or black patient who only has moderate extracranial ICA stenosis warrants a search for co-existent intracranial stenosis that could be contributing to the symptoms. Intracranial vascular imaging may

Fig. 6. a Intra-arterial digital subtraction angiogram with selective ICA injection showing 80% stenosis of the origin of the extracranial internal carotid artery according to NASCET criteria (long black arrow). There is severe stenosis and trickle ﬂow in the proximal external carotid artery (short black arrow), and there is a tandem stenosis of the proximal cavernous segment of the in- tracranial ICA (white arrow); b Intracranial time of ﬂight MRA also showing the stenosis of the intracranial cavernous ICA.

a

b

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giography significantly influenced the risk of subsequent stroke only in patients with 85–99% extracranial ICA stenosis who were treated with best medical therapy alone; intracranial stenosis did not significantly impact on stroke risk in patients with

50%, 50 to 69%, or 70 to 84% stenosis [41]. The three-year risk of ipsilateral stroke distal to an 85–

99% extracranial ICA stenosis was significantly higher in those with versus those without intracrani- al atherosclerosis (45.7% vs. 25.3%, relative risk 1.8 [95% confidence interval 1.1–3.2]) [41]. In the same study, the three-year risk of ipsilateral stroke in surgically treated patients with 85–99% extracranial ICA stenosis was similar in those with and those without intracranial atherosclerosis (8.6% vs. 10%, relative risk 0.9, [95% confidence interval 0.2–3.0]).

These data can be of use when counselling this subgroup of patients before carotid endarterectomy. Pa- tients who have combined very severe extracranial and intracranial atherosclerosis have a very high risk of stroke if they are treated with best medical therapy alone, but the presence of intracranial stenosis does not appear to increase the hazard associated with surgery if they proceed to carotid endarterectomy.

A further study revealed that the presence of intracranial collateral supply to the symptomatic hemisphere in medically treated patients with symptomatic 70–99% extracranial ICA stenosis reduced the two-year absolute risk of ipsilateral hemispheric stroke by 16.5% (11.3 vs. 27.8%, p 0.005) and the risk of ipsilateral hemispheric TIA by 17% (19.1 vs.

36.1%, p 0.008) compared with patients who did not have collaterals [30]. Surgically treated patients with symptomatic 70–99% extracranial ICA stenosis who had collateral supply to the affected hemisphere had a lower peri-operative stroke risk in the 30 days after surgery compared with those patients without collaterals (1.1 vs. 4.9%) [30]. However, the pres- ence of collaterals did not provide signiﬁcant added protection against TIA or stroke in these surgically treated patients during prolonged follow-up at 2 years [30]. The beneﬁcial effect of collateral supply was not evident in either the medically or surgically treated patient with near occlusion of the ICA.

These data may also be useful in risk stratifying pa- provide useful clinical information in a patient with

mild carotid stenosis who is found to have proximal MCA occlusion on intracranial MRA 4 hours after stroke onset, because this patient may then be considered for intra-arterial thrombolysis. The degree of recanalisation of the occluded vessel can be re-assess- ed at a later date with non-invasive MRA. A patient with severe bilateral ICA stenosis who has recurrent posterior circulation ischaemic symptoms, but no evidence of proximal vertebral stenosis, would beneﬁt from intracranial imaging to look for evidence of ba- silar artery stenosis and to assess intracranial collateral supply to the posterior and anterior circulation.

If one encounters a patient with severe extracranial ICA stenosis who has multifocal bilateral ischaemic and haemorrhagic lesions on CT or MRI brain, intracranial catheter angiography may show features suggestive of vasculitis, and the stenosis may then be considered to be asymptomatic.

How might intracranial vascular imaging inﬂuence clinical management?

The information obtained from intracranial vascular imaging can inﬂuence clinical decision making in patients with carotid stenosis. In patients with carotid territory TIAs or stroke in association with tandem arterial stenosis affecting the extracranial and intracranial ICA, many clinicians would advise treatment of the extracranial stenosis ﬁrst with either carotid endarterectomy or endovascular therapy.

If TIAs or stroke recur in the absence of extracranial ICA restenosis, especially if one can detect emboli in the ipsilateral MCA on transcranial Doppler imaging and no other cause for the symptoms is identi- ﬁed, then one may conclude that the intracranial stenosis is causing the recurrent symptoms. This could lead to further intensiﬁcation of best medical therapy or perhaps endovascular intervention, although it must be stressed that no randomised studies comparing these interventions have been pub- lished to date.

In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the presence of intracranial atherosclerotic disease on catheter an-

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