Examination of carotid endarterectomy specimens revealed that plaque inflammation, ulceration, erosion and hemorrhages were more common in symptomatic than asymptomatic patients [40–42]. Rupture of this unstable plaque promotes thrombus formation [43, 44], that may be broken up by blood flow and migrate through the bloodstream to occlude distant arteries, resulting in clinical symptoms (artery-to-artery embolism). The plaques can be identified in vivo by CTA, MRA, or conventional angiography (Fig. 8.3). On duplex scans, vulnerable plaques appear as echolucent and heterogeneous, with occasional evidence of intraplaque hemorrhage [45]. MES detected by TCD is also helpful in predicting future embolic stroke [46]. Artery-to-artery embolism is the predominant stroke mechanism in patients with ECAS, and one of the important stroke mechanisms in patients with ICAS (i.e., proximal MCA to distal MCA) [47] (Fig. 8.4).

DWI is useful in assessing the embolic mechanism of stroke, in that it can reliably detect small, scattered, cortical infarcts in the territory of the diseased artery. In many patients, DWI-identified lesions are also located in border zone areas, suggesting that embolism often develops in combination with hypoperfusion. Underlying perfusion deficits may contribute to artery-to-artery embolism by promoting a thrombotic condition and by the impaired clearance of migrated emboli [48].

Although less frequent than in anterior circulation stroke, artery-to-artery embolism also occurs in the posterior fossa. Significant atherothrombosis in the proximal vertebral artery often induces embolization, occluding distal arteries such as the PCA, superior cerebellar artery, posterior inferior cerebellar artery and the tip of the basilar artery [49]. Stenoses in the distal vertebral and basilar arteries may also produce embolism, although they more often cause brainstem infarction by way of branch occlusion [50, 51]. As in the anterior circulation, embolisms seem to occur more frequently in the setting of posterior fossa hypoperfusion caused by bilateral vertebral artery disease or hypoplasia.

Embolisms may develop in more proximal arteries such as the common carotid artery, subclavian arteries, ascending aorta and aortic arch. Transesophageal echocardiography is required to detect plaques in the aorta. Case control studies showed that thick (≥4 mm), mobile atherosclerotic plaques in the aorta are prone to develop recurrent strokes [52], although this argument has not been unanimously agreed [53, 54].

Extensive thrombus formation in areas of atherosclerotic plaque can ultimately occlude the vessel. In patients with ECAS, the clinical consequences of arterial occlusion are not so grave because of the ample collateral circulations in the circle of Willis. Therefore, total arterial occlusion may remain asymptomatic or produce minor hemodynamic TIAs or strokes. In rare patients with insufficient collaterals or those with previous contralateral ICA occlusion, ICA occlusion may result in devastating infarcts involving whole ICA (MCA and ACA, plus PCA in the presence of fetal circulation) territories [55].

In contrast to ECAS, insitu thrombotic occlusion in patients with ICAS more often produces significant cerebral infarction as the collateral circulation is less sufficient. The resultant infarcts are usually larger than those caused by branch occlusion. However, unlike cardiogenic embolism, in situ thrombotic occlusion rarely produces sudden, whole territory infarction because of the relatively well developed collateral circulation in patients with a chronic atherosclerotic process [56]. In patients with in situ thrombotic occlusion, the initial infarct size frequently grows in following hours or days, accompanied by progressive neurological worsening (Fig. 8.6). Thus, the ultimate size of the infarct varies according to the status of the collateral circulation, the speed of arterial occlusion and hemodynamic stability after the occurrence of stroke. With sufficient collaterals, total thrombotic intracranial occlusion may remain asymptomatic or result in only minor stroke or TIA.

Branch or perforator occlusion is a stroke mechanism unique to patients with ICAS. Atherosclerotic plaques in the intracranial artery can occlude the orifice of the perforators, causing infarcts limited to the subcortical (Fig. 8.5) or brainstem areas [57] (Fig. 8.7). Pathological studies [58, 59] have shown that the pathologic substrates occluding the branching vessel are microdissection, plaque hemorrhage, and platelet-fibrin materials. Branch occlusion is an important, yet so-far neglected mechanism of LAD [57, 60]. It is one of the major mechanisms of brainstem stroke [50, 51, 61, 62]. Branch occlusion is currently easily recognized by imaging methodologies such as MRA and CTA [63–66]. Compared with arterial lesions producing embolism or hemodynamic impairment, branch occlusion is related to milder atherosclerosis [67].

The infarcts associated with branch occlusion do not differ fundamentally from “lacunar infarcts” caused by lipohyalinotic small artery disease (SAD), although their pathologic nature is different. The subcortical infarcts caused by branch occlusion tend to extend to the basal surface (Figs. 8.5 and 8.7), whereas a lacune caused by lipohyalinosis usually produces an island of ischemic tissues within the parenchyma (Fig. 8.8). Although both conditions equally produce lacunar syndromes clinically, the former is more often associated with atherosclerosis in other vascular beds [68], and an unstable and adverse clinical course than the latter [51, 69, 70].

Progressive narrowing of the atherosclerotic vessel leads to hypoperfusion distal to the site of stenosis. Generally, the degree of hypoperfusion depends on the severity of vascular stenosis/occlusion, and there is a correlation between the occurrence of ischemic stroke and the severity of occlusive disease [71, 72]. However, the ischemic event is also influenced by the status of collateral flow, from arteries at the circle of Willis, external carotid artery system and cervicothyroid arteries, etc.

In patients with severe vascular stenosis/occlusion and insufficient collaterals, hemodynamic TIAs can occur. Typically, symptoms such as hemiparesis, aphasia, monocular blindness, limb shaking (in anterior circulation disease) or dizziness, diplopia, and visual disturbances (in posterior circulation disease) occur briefly and stereotypically in patients who are dehydrated or fatigued or at the time they suddenly stand up. Revascularization therapies, such as angioplasty/stenting or bypass surgery, may rapidly relieve these symptoms (Fig. 8.2). When stroke develops, the symptoms may fluctuate widely according to the degree of hydration, blood pressure and the position of the patient’s head. With a continued perfusion defect, the symptoms may worsen gradually.

In the anterior circulation, infarcts caused by hemodynamic impairment usually develop in superficial (anterior cerebral artery-MCA, MCA-PCA) and/or internal borderzone areas (areas between superficial MCA pial penetrators and lenticulostriate arteries), the latter being more specifically associated with hemodynamic impairment than the former. Hypoperfusion as a pathogenic mechanism can therefore be recognized by DWI lesion patterns, the degree of vascular stenosis, the status of collateral vessels, perfusion imaging findings and appropriate clinical histories. In the posterior circulation, hemodynamic TIAs and strokes occur following severe steno-occlusive lesions occurring in both vertebral arteries or the basilar artery. Here, DWI patterns of hemodynamic infarction have not been clearly established.

Although hypoperfusion is an important stroke mechanism, strokes caused by hemodynamic failure alone are uncommon in clinical practice. More often, hypoperfusion plays an additive role in the development of stroke, together with other major stroke mechanisms. As discussed earlier, the co-occurrence of hypoperfusion and embolism in patients with severe steno-occlusive vascular diseases is common, due in part to both mechanisms being related to complicated atherosclerotic plaques protruding into the lumen, and in part to ineffective wash out of emboli in hypoperfused areas [48].