Distribution territories and causative mechanisms of ischemic stroke

Eur Radiol (2005) 15: 416 426 DOI 10.1007/s00330-004-2633-5 NEURO A. Rovira E. Grivé A. Rovira J. Alvarez-Sabin Distribution territories and causative mechanisms of ischemic stroke Received: 30 June 2004 Accepted: 13 December 2004 Published online: 19 January 2005 # Springer-Verlag 2005 A. Rovira (*). E. Grivé. A. Rovira. J. Alvarez-Sabin Hospital Vall d Hebron, Unidad de Resonancia Magnetica, Passeig Vall d Hebron 119-129, 08035 Barcelona, Spain e-mail: alex.rovira@idi-cat.org Abstract Ischemic stroke prognosis, risk of recurrence, clinical assessment, and treatment decisions are influenced by stroke subtype (anatomic distribution and causative mechanism of infarction). Stroke subtype diagnosis is better achieved in the early phase of acute ischemia with the use of multimodal MR imaging. The pattern of brain lesions as shown by brain MR imaging can be classified according to a modified Oxfordshire method, based on the anatomic distribution of the infarcts into six groups: (1) total anterior circulation infarcts, (2) partial anterior circulation infarcts, (3) posterior circulation infarcts, (4) watershed infarcts, (5) centrum ovale infarcts, and (6) lacunar infarcts. The subtype of stroke according to its causative mechanism is based on the TOAST method, which classifies stroke into five major etiologic groups: (1) largevessel atherosclerotic disease, (2) small-vessel atherosclerotic disease, (3) cardioembolic source, (4) other determined etiologies, and (5) undetermined or multiple possible etiologies. The different MR imaging patterns of acute ischemic brain lesions visualized using diffusionweighted imaging and the pattern of vessel involvement demonstrated with MR angiography are essential factors that can suggest the most likely causative mechanism of infarction. This information may have an impact on decisions regarding therapy and the performance of additional diagnostic tests. Keywords Diffusion. MRI. Stroke Introduction Ischemic stroke prognosis, risk of recurrence, clinical assessment, and treatment decisions are influenced by stroke subtype. Nevertheless, treatment decisions are often made before an extensive, time-consuming evaluation to identify a likely diagnosis is completed. Therefore, early classification of ischemic stroke subtype is of substantial practical clinical value. The most widely used methods for stroke subtype classification are the Oxfordshire Community Stroke Project and the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) method. In 1991 the Oxfordshire Community Stroke Project (OCSP) proposed four subgroups of cerebral infarction (Table 1) based solely on presenting signs and symptoms [1]. This method has the ability to predict the prognosis and shows good correlation with the underlying pathophysiology and imaging findings on cranial computed tomography (CT) [2]. The TOAST method is a set of guidelines developed for prospectively classifying ischemic strokes into specific subtypes, based mainly on the mechanism of infarction [3, 4]. Stroke patients are classified into five major etiologic/pathophysiologic groups (Table 2). With the widespread use of diffusion-weighted MR imaging (DWI) and MR angiography (MRA) in the acute stage of ischemic stroke, accurate early diagnosis of ischemic stroke subtype can be better achieved [5]. This information can be helpful for establishing the most likely

417 Table 1 Topographic clinical pattern of brain infarction (Oxfordshire method) 1. Lacunar infarcts (LACI) Acute stroke that includes one of the major recognized lacunar syndromes: pure motor, sensory, or sensorimotor strokes, ataxic hemiparesis, and dysarthria (clumsy hand syndrome) 2. Total anterior circulation infarcts (TACI) 3. Partial anterior circulation infarcts (PACI) 4. Posterior circulation infracts (POCI) mechanisms of ischemia and the risk of clinical progression, and for initiating the most appropriate therapy. This review article is divided into three parts. The first addresses the topographic patterns of brain infarction, the second is devoted to the mechanisms implicated in the genesis of multiple synchronous acute brain infarcts, and the third part reviews the various stroke categories on the basis of their causative mechanisms. Topographic pattern of brain infarcts Clinical syndrome in which there is ischemia in both the deep and superficial territories of the middle cerebral artery (higher cerebral dysfunction such as dysphasia, dyscalculia, visuospatial disorder; homonymous visual field defect; and ipsilateral motor and/or sensory deficit of at least two areas of the face, arm, and leg) Clinical syndrome that includes only two of the three components of the TACI syndrome, with higher cerebral dysfunction alone, or with more restricted sensorimotor deficit than those classified as LACI Clinical syndrome that includes ipsilateral cranial nerve palsy with contralateral motor and/or sensory deficit; bilateral motor and/or sensory deficit; disorder of conjugate eye movement; cerebellar dysfunction without ipsilateral long-tract deficit (i.e., ataxic hemiparesis); or isolated homonymous visual field defect Table 2 Stroke categories (TOAST method) 1 Large-vessel disease 2 Small-vessel disease 3 Cardioembolism 4 Other etiology 5 Undetermined or multiple possible etiologies The boundaries between vascular distributions are determined by anatomic variations and by hemodynamic conditions that govern flow in leptomeningeal anastomoses connecting the different arterial territories [6]. Despite this variability, brain imaging can accurately locate an ischemic stroke lesion in a specific vascular distribution in the majority of cases [7 10]. Arterial cerebral circulation can be divided into two systems: (1) the leptomeningeal (also known as superficial or pial) artery system; and (2) the perforating (or deep perforating) artery system (Table 3). Leptomeningeal artery system The leptomeningeal arteries comprise the terminal branches of the cerebral and cerebellar arteries, which penetrate the cortex and subjacent white matter. Infarcts within the territories irrigated by these arteries are often described as territorial infarcts. Territorial anterior infarcts Territorial anterior infarcts, mostly related to the middle cerebral artery (MCA) territory, can be divided into large and limited types. Large infarcts, defined as those covering at least two of the three MCA territories (deep, superficial anterior, and superficial posterior), show a high frequency of clinical deterioration, a minimum chance of good outcome, and a high mortality rate. Large MCA infarctions are associated with cardioembolism, internal carotid artery (ICA) occlusion, and ICA dissection. In patients with large infarcts without ICA occlusion, the frequency of cardioembolic Table 3 Topographic radiologic pattern of brain infarction Leptomeningeal artery system Deep perforator artery system Territorial anterior circulation infarcts Large Malignant Limited Territorial posterior circulation infarcts Large territorial Small or end zone infarcts Brainstem infarcts Centrum ovale infarcts Large Small Watershed infarcts Internal Cortical anterior Cortical posterior Lacunar infarcts

418 disease is clearly higher than in large infarcts with ICA occlusion or limited infarcts without ICA occlusion [11]. Malignant MCA infarction refers to life-threatening (80% associated mortality), complete or almost complete MCA infarction. This type of infarction occurs in up to 10% of all stroke patients. The main cause of death is severe post-ischemic brain edema leading to raised intracranial pressure. The clinical course is uniform, with clinical deterioration developing within the first 2 to 3 days after stroke. DWI in the early phase of large territorial anterior infarction is an accurate method for predicting malignant MCA infarction (lesion volume >145 cm 3 )[12] in patients with persistent arterial occlusion and signs of total anterior circulation infarction. Early detection may be important since treatment for these large infarcts, such as hypothermia and/or hemicraniectomy can significantly reduce mortality [13]. Limited infarcts, covering only one of the three MCA territories, show a very low frequency of clinical deterioration. The mechanism of infarction in these cases is either cardioembolism or large-artery atherosclerosis in equal numbers. The lower incidence of cardioembolism in limited MCA infarcts as compared to large infarcts can be explained by the fact that cardiac thrombi are generally larger than thrombi of the large vessels [2] (Fig. 1). Territorial posterior infarcts With the use of MR imaging, posterior circulation infarcts can be diagnosed and their topography delineated with high sensitivity. Infarcts are recognized in the territory of the posterior inferior (PICA), anterior inferior (AICA), and superior (SCA) cerebellar arteries and their branches, and in the territory of the posterior cerebral arteries (PCA) [8]. Large-vessel atherosclerosis of the extracranial and intracranial vertebrobasilar arteries, has been demonstrated angiographically in more than two thirds of patients with cerebellar infarction, and in situ branch artery disease in almost one fifth of these patients. Proximal disease of the vertebral artery is the most common feature in large-artery disease, leading to PICA, SCA, and PCA infarcts. The vessels most frequently affected by intraarterial embolism are the intracranial vertebral artery (leading to PICA infarcts) and the distal basilar artery (leading to SCA and PCA infarcts). Thrombus originating from proximal vertebral artery disease never occludes the intracranial vertebral artery, but it can affect the PICA, AICA, and SCA. Therefore, vascular imaging in patients with atherothrombotic cerebellar infarcts must assess the proximal vertebral artery (V1) [14]. Clinical deterioration in posterior circulation infarcts is associated with severe brain atrophy (suggesting longstanding hypoperfusion), and significant stenosis in the vertebrobasilar arteries. This feature implies that large-vessel disease plays an important role in clinical worsening in posterior circulation infarcts [2]. Small cerebellar infarcts (<2 cm) are frequently recognized with MR imaging. These small infarcts were thought to affect the boundary zone between various territories (nonterritorial infarcts), but in fact, they seem to be very small territorial infarcts resulting from involvement of small distal arteries. Therefore, small cerebellar infarcts correspond to end zone infarcts, with embolic or local arterial disease as the mechanism of infarction in the majority of cases; a low-flow hemodynamic state is the likely cause of infarction in only a minority of patients. Territorial and nonterritorial (small) cerebellar infarcts are essentially the same, and it is likely that their extent and location simply depend on the size of the embolus causing the infarct [15, 16]. Brainstem infarcts may be related to large-vessel disease (stenosis or occlusion) affecting the vertebral and basilar arteries or their main branches. In this situation, brain MR usually shows additional infarcts involving the territories irrigated by the cerebellar and posterior cerebral arteries. Fig. 1 Diffusion-weighted MR imaging in anterior choroidal artery (AChA) infarcts. Right acute lacunar infarct limited to the AChA territory with no significant stenosis in an ipsilateral large artery, probably related to small-vessel disease (A). Acute right AChA territory infarct associated with other ipsilateral internal carotid artery infarcts due to internal carotid artery dissection (arrow) (B). Centrum ovale infarcts The centrum ovale is the central white matter of the cerebral hemispheres, including the most superficial part of the corona radiata and the long associated fasciculi. The cen-

419 trum ovale is supplied by long (2 to 5 cm) noninterdigitating medullary arteries that perforate it and course toward the upper part of the lateral ventricles. At the deeper part of the corona radiata the medullary branches tend to form an area of junction with the deep perforating branches of the MCA and the AChA. Centrum ovale infarcts are those limited to the territory of the medullary branches without accompanying involvement of the cortex or deep perforator territory [17]. Centrum ovale infarcts can be large and small. Large centrum ovale infarcts (>1.5 cm) affect more than one medullary branch. A hemodynamic mechanism related to severe ipsilateral internal carotid or MCA disease may be the leading cause. In this situation, the infarct affects the area of the internal border zone, between the deep perforators and superficial medullary territories of the MCA (internal border zone infarcts). However artery-to-artery embolism and cardioembolism cannot be ruled out in some patients. Small centrum ovale infarcts (<1.5 cm) involve only one medullary branch. Small infarcts were thought to be related to small-vessel disease involving the medullary branches, in a manner similar to lacunar infarction. In fact, the neurologic picture of small infarct of the centrum ovale is consistent with a so-called lacunar syndrome, although the motor or sensory distribution pattern is less often complete (face, arm, and leg) than partial. However, recent studies have shown that in a significant percentage of patients, small centrum ovale infarcts are associated with largevessel and heart disease, and should be distinguished from the more common lacunar infarcts [18]. Identification of subsidiary small acute infarcts in addition to an acute small infarct in the centrum ovale on DWI suggests an embolic mechanism [17]. Watershed infarcts Watershed infarcts (WIs) are ischemic lesions that occur at the junction between two or three arterial territories and account for approximately 10% of ischemic strokes. The pathogenesis of WIs is controversial. It may involve various mechanisms such as systemic hypotension, severe arterial stenosis or ICA occlusion, microemboli, or a combination of these. Watershed infarcts account for 72% of delayed strokes in patients with ICA occlusion, but are rarely the initial manifestation of ICA occlusion (5%) [19]. Recent data indicate that WIs are often explained by a combination of two inter-related processes: hypoperfusion and embolization. In fact, severe ICA occlusive disease and cardiac surgery cause both embolization and decreased brain perfusion. This decreased perfusion might alter blood flow currents, encouraging microemboli to reach recipient blood vessels with the least effective blood flow. Moreover, microemboli that reach a border zone area with decreased blood flow are difficult to wash out [20]. Two types of vascular border zone areas exist within the cerebral hemispheres: the cortical and the internal. Cortical border zone areas are located between the cortical supply of the ACA and MCA (anterior cortical border zone), and between the MCA and PCA (posterior cortical border zone). Internal border zone areas are located between the ACA (anterior cerebral artery), MCA, and PCA, and the area supplied by the Heubner, lenticulostriate, and ACh arteries (Fig. 2). Purely anterior cortical WIs are very rare, as in most cases they are associated with internal border zone infarcts. Posterior cortical WIs are frequently difficult to differentiate from limited territorial infarcts affecting the posterior division of the MCA. Embolism, not distal field perfusion failure, is the predominant stroke mechanism in this type of WI. Internal border zone infarcts, commonly associated with severe ICA stenosis, are larger than lacunar infarcts within the vascular territory of the deep perforators. In some cases it is difficult to distinguish internal border zone infarcts from centrum ovale infarcts within the territory irrigated by the medullary branches of the MCA. The presence of two or more lesions, appearing as a chain of round infarcts along the internal vascular border zone, suggests an internal bor- Fig. 2 Watershed infarcts. Diffusion-weighted MR images showing the classical pattern of anterior cortical (A), posterior cortical (B) and internal (C) watershed infarcts.

420 der zone infarct. Lesions in the internal border zone are mainly attributed to the effect of hemodynamic impairment caused by severe stenosis or occlusion of the ICA or MCA. Nevertheless, some studies have suggested an embolic mechanism for both cortical watershed and internal border zone infarcts [21]. Watershed infarcts involving more than one of the border zone areas in a single hemisphere are mostly related to severe ICA stenosis or occlusion. Bilateral watershed infarcts are typically related to a profound global reduction in perfusion pressure (hypoxia, hypovolemia) or to diffuse cerebral vessel disease (sickle-cell disease). The perforating (or deep perforating) artery system The perforating arteries arise from the arterial circle of Willis, the AChA, and the basilar artery, perforating the brain parenchyma as direct penetrators and supplying the diencephalon (thalamus, hypothalamus, subthalamus, and epithalamus), basal ganglia, internal capsule, and brainstem [10]. Lacunar infarcts The strict pathologic definition of a lacunar infarction (LI) is a small (<1.5 cm in diameter), fluid-filled cavity representing the healed stage of a small deep infarct, which was likely due to occlusion of a single penetrator artery arising from the large arteries of the circle of Willis or from the basilar artery. The most frequently affected perforating arteries include the lenticulostriate, the thalamoperforate and the perforators arising from the AChA. Thus, LI can be located deep within the cerebral hemispheric white matter, the upper two thirds of the basal ganglia, the internal capsule, the thalamus or the paramedian and lateral regions of the brainstem. Brainstem LI are mainly found in the paramedian region of the pons, which is supplied by long arterioles (midline and anteromedial perforators) arising from the basilar artery. The medulla and midbrain are supplied by short arterioles, which are less vulnerable to aging and hypertension, and as a consequence LI are very uncommon in these locations. The maximum size of 15 mm is probably true for LI in the chronic stage. In fact, most of them have a diameter <10 mm, but this dimension does not apply in the acute phase, when cellular swelling and extracellular edema can produce LI larger than 15 mm in diameter. Most first-ever symptomatic LI are located in the area supplied by the AChA [9, 22], while multiple, asymptomatic LI are mainly located within the territory irrigated by perforating arteries arising from the MCA or ACA. Most LI are asymptomatic. Symptoms are related to size (most lesions less than 200 μm in diameter are silent) and location (LI in the posterior limb of the internal capsule or in the pontine base are usually symptomatic, whereas lesions in the basal ganglia tend to be silent). Although most lacunar strokes appear to be a consequence of small-vessel disease (atherosclerosis or lipohyalinosis) [23], many of the other potential causes of small-vessel occlusion rarely cause LI, such as infective or immune vasculitis, artery-to-artery or cardiogenic embolism, arterial dissection, and in situ thrombosis due to a variety of hypercoagulable states [24]. This non smallvessel disease mechanism of LI is supported by the not infrequent association of acute LI and superficial infarcts. As a consequence, vascular imaging of the cervical and intracranial arteries and a focussed search for a cardiac source of the embolism is needed in first-ever lacunar strokes. The detection of subsidiary infarctions in patients presenting with a classic lacunar syndrome and often diagnosed with intrinsic small-vessel disease (with a high probability of excellent recovery, recommendation of antiplatelet agents for secondary prevention, and low priority placed on extensive cardiac or arterial testing for other causes of stroke), should prompt the physician to search for an underlying embolic source and tailor a secondary stroke prevention strategy to treat the underlying cause. Embolic infarcts can present as a clinically well-defined lacunar syndrome. However, the concept of embolic LI is dubious for two main reasons: the low likelihood of an embolus entering a vascular territory that receives such a small proportion of cerebral blood flow, and the sharp angle of the penetrating vessels arising from the parent vessel, which makes it more likely for an embolus to be directed toward the leptomeningeal arteries. However, as compared to a leptomeningeal territory, the lack of collateral flow pathways in the deep perforating artery territories may make them more susceptible to infarction on entry of a very small embolus. In fact, it has been suggested that a massive shower of emboli such as that occurring during cardiac and aortic operations, in cholesterol embolization from ulcerated atheroma, and in paradoxical fat or air embolism can produce LI. Acute multiple brain infarction Synchronous acute multiple brain infarcts (AMBIs) can have various mechanisms of origin, which are suggested by their topographic pattern. With the use of DWI, the different types of AMBI can be easily identified [25, 26]: (1) Internal watershed infarcts: multiple rosary-like infarcts within border zone areas. Unilateral watershed infarcts are usually related to ICA disease, whereas bilateral ones are typically related to a profound overall reduction in perfusion pressure or to diffuse cerebral vascular disease. (2) Multiple small cortical or subcortical infarcts within the same arterial territory. This type of AMBI is attri-

421 buted to fragmentation of an embolus near its origin or located within a major proximal intracranial artery. Most of these infarcts are found within one cerebral hemisphere in the anterior circulation. (3) Multiple small infarcts attributable to multiple arteryto-artery thromboembolic material (located in one or more major arterial territories, depending on the arterial anatomy). Sometimes these infarcts are located in two hemispheres and in both the anterior and posterior circulation. Acute multiple brain infarcts exclusively affecting the posterior circulation are, in most cases, related to large-artery atherosclerosis. The anatomic variations that may explain AMBI include (1) posterior communicating artery (PCoA) originating from the ICA (fetal-type PCA), which explains the simultaneous infarcts in the anterior and posterior cerebral artery territory (25% of cerebral hemispheres); (2) PCoA patency (67% of anatomic dissections), explaining multiple infarcts in both the anterior and posterior circulation; and (3) AMBI in the territories of both ACAs when a single artery supplies the two medial aspects of the hemispheres, occurring in 18% of the normal population. (4) Multiple infarcts located in one or more major arterial territories of the anterior and/or posterior circulation produced from embolic sources proximal to the cervical arteries (heart or aortic arch), not attributable to anatomic variations of the cervicocranial arterial vessels. The pattern of multiple, small and large bihemispheric AMBIs is especially frequent in nonbacterial thrombotic endocarditis (marantic endocarditis). (5) Multiple simultaneous deep perforators. Most of these cases are related to bilateral, simultaneous small-artery occlusion. Cardioembolism can be the mechanism of infarcts in groups 2, 3, and 4, although it is much more frequent in group 4. Nevertheless, bilateral carotid stenosis or occlusion can also be associated with acute infarcts in both cerebral hemispheres. The main causes of AMBI in one hemisphere in the anterior circulation are MCA and ICA disease (75%). Although the factors that determine contemporary infarcts in small-vessel occlusion or severe bilateral largevessel disease are unknown (groups 3 and 5), it is believed that erytrocytosis (elevated primary or secondary hematocrit) and increased serum fibrinogen, may be important contributory factors [25]. In fact, these factors are significantly associated with bilateral cerebral infarction in patients with large-artery atherosclerosis or small-artery occlusion. Other possible explanations for AMBI located in different vascular territories include bilateral or unilateral watershed infarctions, or diffuse thrombotic or inflammatory processes, such as thrombotic thrombocytopenic purpura, granulomatous angiitis, and anticardiolipin syndrome, which lead to multiple small-vessel occlusions within a short period of time. Stroke categories The subtype of stroke according to its causative mechanism (TOAST) is based on risk factor profiles, clinical features, and the results of diagnostic tests [3, 4]. The TOAST algorithm classifies patients with ischemic stroke into five major etiologic and pathophysiologic groups: large-vessel atherosclerotic disease, small-vessel atherosclerotic disease, cardioembolism, other etiologies, and undetermined or multiple possible etiologies. Examining responses to acute treatment in each one of these subgroups of stroke mechanisms is clinically important; therefore, highly accurate early stroke subtyping is needed. The sensitivity and positive predictive value of the initial TOAST diagnosis of large- and small-vessel disease improves considerably with the combined use of DWI and MRA techniques [5]. Large-vessel atherosclerotic disease Large-vessel atherosclerosis represents about 13% of all patients with a first-ever stroke. Cortical or cerebellar lesions and brainstem or subcortical hemispheric infarcts greater than 1.5 cm in diameter on brain imaging are considered to be potential large-artery disease strokes. Supportive evidence by vascular imaging of more than 50% stenosis in an appropriate intracranial or extracranial artery (presumably due to atherosclerosis) is needed. Embolic (artery-to-artery) and hemodynamic mechanisms are the cause of stroke in these patients. The coexistence of both mechanisms has been postulated. Five patterns of ischemic lesions can be differentiated in patients with acute stroke and large-vessel disease [27, 28] (Fig. 3). Cortical territorial infarction Cortical territorial infarcts are ischemic lesions involving the cerebral cortex and subcortical structures in one or more major cerebral artery territories. Almost half of the patients with ICA occlusion have territorial infarction. However about 20% of strokes in the territory of a highgrade symptomatic ICA are cardioembolic or lacunar. This pattern can be subclassified into three forms: (1) limited MCA infarction in occlusions of a distal MCA branch or the proximal MCA, associated with effective collateral circulation; (2) large MCA infarction, frequently related to large emboli that proximally occlude the MCA in the absence of an efficient collateral system, or to occlusions of the distal ICA with a partially effective collateral

422 Fig. 3 Different patterns of cortical territorial infarcts within the internal carotid artery (ICA) territory demonstrated with diffusion-weighted MR imaging and MR angiography. A Limited left middle cerebral artery (MCA) infarction due to occlusion of the proximal MCA. B Complete right ICA infarction due to occlusion of the ICA. C Large left MCA infarction due to occlusion of the MCA. D Subcortical right MCA infarction due to MCA occlusion with small fragmented subcortical and cortical subsidiary infarcts. E Fragmented right cortical MCA infarction due to severe MCA stenosis (arrow). F Small fragmented right infarctions in the left MCA territory due to severe stenosis at the origin of the right ICA.

423 system; and (3) complete infarcts involving two major ICA cerebral artery territories in distal occlusions of the ICA without an effective collateral system. Subcortical infarction Subcortical infarcts are ischemic lesions in the territory of the deep perforating branches arising from the distal ICA or MCA trunk in proximal occlusions of the MCA or ICA in the presence of patent collaterals. Additional fragmented small cortical or subcortical infarctions can be also identified. Cortical territorial infarction with fragmentation Large ischemic cortical lesions with additional smaller cortical or subcortical lesions due to partial fragmentation of an embolus fall into the category of cortical infarction with fragmentation. Fragmented infarction Fragmented infarcts are defined as several small, disseminated lesions sprinkled randomly in the cortical ICA regions due to multiple emboli or the break-up of an embolus. Fragmented infarctions are more common in moderate ICA stenosis or in fragmentation of a lodged embolus. In the latter case, there is often no evidence of stenosis or occlusion in the intracranial arteries (resolved embolism). Watershed infarction The pathogenesis of watershed infarctions is controversial. The leading mechanism is believed to be critical ICA stenosis or occlusion, which may or may not be associated with transient hypoperfusion. In fact, 75% of patients with WI have high-grade ICA stenosis or occlusion associated with hemodynamically significant heart disease, increased hematocrit, or acute hypotension. Conversely, 50% of patients with high-grade or subtotal ICA stenosis have watershed infarcts. Atherosclerotic disease of the MCA may also cause watershed infarcts. For this reason, in addition to the extracranial vessel, cerebrovascular investigation in these patients should include the large intracranial vessels. Small-vessel disease (small-artery occlusion) Small-vessel disease is the cause of about 25% of all firstever strokes. The most frequent pathologic events related to small-vessel disease are atherosclerosis and lipohyalinosis limited to the small penetrator vessels [23]. Chronic hypertension seems to be the main etiology of these pathologic events, but a variety of other conditions such as aging, hypoperfusion, generalized atherosclerosis, diabetes, and orthostatic hypotension can contribute to the brain microcirculation compromise. In fact, in a significant proportion of patients, small-vessel disease is identified in normotensive, nonelderly, nondiabetic individuals. Atherosclerosis Atherosclerosis of the small penetrator vessels or microatheromatosis is the leading cause of small-artery disease. Atheroma plaques are localized in the proximal perforating arteries (microatheroma), in the origin of the penetrator artery (junctional atheroma), or in the parent artery on the circle of Willis (mural atheroma). Mural atheroma is particularly frequent in the basilar artery, producing infarcts limited to its pontine perforating branches. The atheroma plaques result in occlusion of the proximal segment of the large penetrating arteries (300 900 μm) and usually lead to single, large, frequently symptomatic LI [29]. This type of small-vessel disease, which is not so strongly related to hypertension, seems to predominantly involve the penetrator vessels arising from the anterior choroidal artery. Radiologic studies in patients with a firstever lacunar stroke of this type commonly show no additional asymptomatic infarcts or leukoaraiosis (Fig. 4a). Lipohyalinosis Lipohyalinosis, a vascular disease associated with longlasting, severe hypertension, is the second small-vessel lesion of relevance in lacunar infarction. It is a destructive lesion of the small penetrating arteries (<200 μm) that leads to small LI, which are commonly asymptomatic and located predominantly in the striatocapsule and thalamus. Leukoaraiosis and old asymptomatic LI are commonly seen on brain imaging in these patients (Fig. 4b). The mechanism of infarction seems to be related to occlusive thrombosis (perhaps exacerbated by a hypercoagulable state) or to non-occlusive poststenotic hypoperfusion. Patients with this type of small-vessel disease have a better outcome and a smaller prevalence of large-vessel cerebral disease and coronary disease than patients with the atherosclerotic type. Cardioembolism Cardiogenic embolism is responsible for about 15 27% of all first-ever strokes. The incidence is higher in patients under 45 years old, primarily because of the lower incidence of atherosclerotic disease in this age group. About 16% of ischemic strokes are associated with atrial fibril-

424 Table 4 Sources of risk for cardioembolism Higher risk sources for cardioembolism Lower risk sources for cardioembolism Atrial fibrillation Mural thrombus associated with acute myocardial infarction Prosthetic heart valve Dilated cardiomyopathy Bacterial endocarditis Rheumatic mitral stenosis Ascending aorta atheroma ( 4mmin size) Intracardiac thrombus Spontaneous left atrial echo contrast Left ventricular aneurysm or large area of dyskinesia Nonbacterial (marantic) endocarditis Sick sinus syndrome Calcified aortic stenosis Patent foramen ovale or atrial septal defect Atrial septal aneurysm Mitral annulus calcification Ventricular septal defect Mitral valve prolapse Fig. 4 Acute LI (Fast-Flair and diffusion-weighted MR images). A Acute left internal capsule (territory of the anterior choroidal artery) infarct with no additional infarcts or leukoaraiosis, probably related to microatherosclerosis. B Acute left thalamic lacunar infarct associated with small chronic LI and dilated Virchow-Robin spaces, suggesting small-vessel atherosclerotic disease due to lipohyalinosis. lation, and 10% are probably due to embolism from an atrial appendage thrombus, with the remainder caused by other stroke mechanisms [30]. Cerebral infarction in atrial fibrillation tends to be large and severely disabling [31]. A possible or probable diagnosis of cardioembolic stroke requires the identification of at least one cardiac source for an embolus (high-risk or medium-risk sources) (Table 4). Evidence of a previous transient ischemic attack or stroke in more than one vascular territory or systemic embolism supports a clinical diagnosis of cardiogenic stroke. On brain imaging, large cortical territorial infarction should suggest a cardioembolic mechanism, particularly if it is not associated with ICA occlusion. The median volume of infarcts caused by cardiogenic embolism is more than twice the median volume of infarcts caused by artery-toartery embolism [31]. Although it has been suggested that simultaneous acute infarction indicates a cardioembolic mechanism, in the majority of cases they are not caused by a proximal embolism from the heart or aortic arch, but instead by arteryto-artery embolism or fragmentation of a proximal artery embolus. Other etiologies Only 2% of all patients with a first-ever stroke fall into the other etiology category. The lesion can have any size or location. To classify a stroke under this category, cardiac sources of embolism and large-artery atherosclerosis should be excluded. These unusual mechanisms of stroke include nonatherosclerotic, nonhypertensive vascular diseases (Moya-Moya disease, craniocervical arterial dissection, and primary and systemic vasculitis), migraine, hypercoagulable states, hematologic disorders, stroke after catheter angiography, and sporadic or genetically determined small-vessel occlusion such as cerebral autosomal dominant arteriopathy (CADASIL) and Fabry s disease. These rare forms of small-vessel occlusion cannot be differentiated radiologically from the classical atherosclerotic and hypertensive forms of small-vessel disease. Undetermined etiology or multiple possible etiologies Strokes classified as having undetermined or multiple possible etiologies must possess one of the following conditions: (1) No cause found despite extensive assessment. (2) Most likely cause could not be determined because more than one plausible cause was found (e.g., atrial fibrillation or lacunar infarct associated with >50% symptomatic large vessel stenosis).

425 This type of stroke represents about 35% of all patients with a first-ever stroke. However, this percentage can vary considerably, since in some cases an extensive diagnostic evaluation is performed (ECG, Duplex, MRI/MRA, transcraneal Doppler ultrasound, transesophageal echocardiography, laboratory tests for coagulation factors, proteins C and S, antithrombin III, and various autoantibodies), whereas in others the evaluation is cursory. Conclusion The goal of imaging in the acute phase of ischemic stroke is to identify the location and extension of the relevant lesion and the presence of significant arterial stenosis or occlusion. Multimodal MR imaging facilitates the achievement of these diagnostic goals, improving the accuracy of early ischemic stroke subtype identification. The various MRI patterns of acute brain ischemia (topography, size, and multiplicity) visualized using DWI, the pattern of vessel involvement demonstrated with MR angiography, and the presence of previous ischemic lesions detected with conventional MRI, are essential factors that can suggest the most likely mechanisms of origin. This information may have an impact on decisions regarding therapy and the performance of additional diagnostic tests. References 1. Bamford J, Sandercock P, Dennis M et al (1991) Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337:1521 1526 2. Tei H, Uchiyama S, Ohara K, Kobayashi M, Uchiyama Y, Fukuzawa M (2000) Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project. Stroke 31:2049 2054 3. Adams HP, Bendixen BH, Kappelle LJ et al (1993) Classification of subtype of acute ischemic stroke: definitions for use in a Multicenter Clinical Trial. Stroke 24:35 41 4. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU (2001) Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a populationbased study. Stroke 32:2735 2740 5. Lee LJ, Kidwell CS, Alger J et al (2000) Impact on stroke subtype diagnosis of early diffusion-weighted magnetic resonance imaging and magnetic resonance angiography. Stroke 31:1081 1089 6. van der Zwan A, Hillen B, Tulleken CA, Dujovny M, Dragovic L (1992) Variability of the territories of the major cerebral arteries. J Neurosurg 77:927 940 7. Tatu L, Moulin T, Bogousslavsky J, Duvernoy H (1998) Arterial territories of the human brain: cerebral hemispheres. Neurology 50:1699 1708 8. Tatu L, Moulin T, Bogousslavsky J, Duvernoy H (1996) Arterial territories of human brain: brainstem and cerebellum. Neurology 47:1125 1135 9. Hupperts RM, Lodder J, Heuts-van Raak EP, Kessels F (1994) Infarcts in the anterior choroidal artery territory: anatomical distribution, clinical syndromes, presumed pathogenesis and early outcome. Brain 117:825 834 10. Takahashi S, Suzuki M, Matsumoto K, Ishii K, Higano S, Fukasawa H, Sakamoto K (1994) Extent and location of cerebral infarcts on multiplanar MR images: correlation with distribution of perforating arteries on cerebral angiograms and on cadaveric microangiograms. Am J Roentgenol 163:1215 1222 11. Heinsius T, Bogousslavsky J, Van Melle G (1998) Large infarcts in the middle cerebral artery territory: etiology and outcome patterns. Neurology 50:341 350 12. Oppenheim C, Samson Y, Manai R, Lalam T, Vandamme X, Crozier S, Srour A, Cornu P, Dormont D, Rancurel G, Marsault C (2000) Prediction of malignant middle cerebral artery infarction by diffusion-weighted imaging. Stroke 31:2175 2181 13. Georgiadis D, Schwarz S, Aschoff A, Schwab S (2002) Hemicraniectomy and moderate hypothermia in patients with severe ischemic stroke. Stroke 33:1584 1588 14. Min WK, Kim YS, Kim JY, Park SP, Suh CK (1999) Atherothrombotic cerebellar infarction: vascular lesion MRI correlation of 31 cases. Stroke 30:2376 2381 15. Amarenco P, Kase CS, Rosengart A, Pessin MS, Bousser MG, Caplan LR (1993) Very small (border zone) cerebellar infarcts: distribution, causes, mechanisms and clinical features. Brain 116:161 186 16. Amarenco P, Levy C, Cohen A, Touboul PJ, Roullet E, Bousser MG (1994) Causes and mechanisms of territorial and nonterritorial cerebellar infarcts in 115 consecutive patients. Stroke 25:105 112 17. Bogousslavsky J, Regli F (1992) Centrum ovale infarcts: subcortical infarction in the superficial territory of the middle cerebral artery. Neurology 42:1992 1998 18. Yonemura K, Kimura K, Minematsu K, Uchino M, Yamaguchi T (2002) Small centrum ovale infarcts on diffusionweighted magnetic resonance imaging. Stroke 33:1541 1544 19. Bogousslavsky J, Regli F (1986) Borderzone infarctions distal to internal carotid artery occlusion: prognostic implications. Ann Neurol 20:346 350 20. Belden JR, Caplan LR, Pessin MS, Kwan E (1999) Mechanisms and clinical features of posterior border-zone infarcts. Neurology 53:1312 1318 21. Del Sette M, Eliasziw M, Streifler JY, Hachinski VC, Fox AJ, Barnett HJ (2000) Internal borderzone infarction: a marker for severe stenosis in patients with symptomatic internal carotid artery disease. For the North American Symptomatic Carotid Endarterectomy (NASCET) Group. Stroke 3:631 636

426 22. Boiten J, Lodder J, Kessels F (1993) Two clinically distinct lacunar infarct entities? A hypothesis. Stroke 24:652 656 23. de Jong G, Kessels F, Lodder J (2002) Two types of lacunar infarcts: further arguments from a study on prognosis. Stroke 33:2072 2076 24. Lodder J, Bamford JM, Sandercock PA, Jones LN, Warlow CP (1990) Are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke 21:375 381 25. Roh JK, Kang DW, Lee SH, Yoon BW, Chang KH (2000) Significance of acute multiple brain infarction on diffusionweighted imaging. Stroke 31:688 694 26. Baird AE, Lovblad KO, Schlaug G, Edelman RR, Warach S (2000) Multiple acute stroke syndrome: marker of embolic disease? Neurology 54:674 678 27. Min WK, Park KK, Kim YS, Park HC, Kim JY, Park SP, Suh CK (2000) Atherothrombotic middle cerebral artery territory infarction: topographic diversity with common occurrence of concomitant small cortical and subcortical infarcts. Stroke 31:2055 2061 28. Szabo K, Kern R, Gass A, Hirsch J, Hennerici M (2001) Acute stroke patterns in patients with internal carotid artery disease: a diffusion-weighted magnetic resonance imaging study. Stroke 32:1323 1329 29. Arauz A, Murillo L, Cantu C, Barinagarrementeria F, Higuera J (2003) Prospective study of single and multiple lacunar infarcts using magnetic resonance imaging: risk factors, recurrence, and outcome in 175 consecutive cases. Stroke 34:2453 2458 30. Hart RG, Halperin JL (2001) Atrial fibrillation and stroke: concepts and controversies. Stroke 32:803 808 31. Timsit SG, Sacco RL, Mohr JP, Foulkes MA, Tatemichi TK, Wolf PA, Price TR, Hier DB (1993) Brain infarction severity differs according to cardiac or arterial embolic source. Neurology 43:728 733