The recent success of randomized controlled trials (RCTs) of endovascular revascularization treatment (ERT) for acute ischemic stroke has led us to consider ERT as a standard of care in clinical practice [1-6]. The main reasons for the success of RCTs have been 1) the development of effective and safe thrombectomy devices, 2) the appropriate selection of patients based on brain and vessel imaging, including the ischemic core/penumbra, and the status of collateral circulation, and 3) the shortened door-to-procedure time [7]. It is noteworthy that the newer thrombectomy devices, such as a stent retriever or direct aspiration system, have enabled us to achieve an improved reperfusion rate, which is strongly associated with better clinical outcomes [8]. However, these thrombectomy devises are primarily designed for recanalization of the occluded artery by removing an embolus [9-11], and recanalization may not be sufficiently achieved if a significant stenosis, related to intracranial atherosclerosis (ICAS), is present at the occlusion site [12].

While a recent French study revealed that patients with underlying ICAS accounted for 5.5% of patients who underwent ERT [13], underlying ICAS appears to be more frequent in Asian countries; a Korean study reported that around 15% of ICAS-related occlusions (ICAS-O) are found in patients with intracranial artery occlusion in anterior circulation [14]. Another Korean study demonstrated that ICAS-O was encountered in approximately 35% patients with vertebrobasilar artery occlusion [6]. Thus, the ICAS-O should not be ignored in Asian countries.

One of the biggest issues surrounding ICAS is the difficulty in differentiating ICAS-O from embolism-related occlusion (EMB-O) through baseline angiography; the presence of ICAS-O is usually identified only during the ERT procedure. Nevertheless, recent studies have identified some factors that may differentiate the two conditions. In this review, we describe the characteristics of ICAS-O, as well as the clinical and imaging findings that may help us to predict ICAS-O. We will also suggest an appropriate ERT strategy for ICAS-O based on literature review and our experiences.

With clinical and imaging factors summarized in Table 2, we can roughly predict ICAS-O before ERT procedures. ICAS-O can be further diagnosed on the basis of the emergent digital subtraction angiography (DSA) and images taken during the ERT procedure (Table 3) [6]. With DSA, rare diseases such as dissection, moyamoya disease and vasculitis should be excluded. EMB-O and ICAS-O can then be differentiated by a few passes of a mechanical thrombectomy device. Stent retrievers may be more advantageous for detecting underlying ICAS than direct clot aspiration devices, given the results of a study demonstrating that truncal-type occlusions were more closely associated with ICAS (as described under “Other findings obtained during procedure”) [19]. If a complete recanalization of the target vessel is achieved, the case can be defined as an embolic occlusion. Whereas, the presence of a residual stenosis suggests the presence of ICAS-O. ICAS-O has a strong tendency to reocclude, so repeat angiography 10-20 minutes following the thrombectomy would be reasonable. Repeat CT or MR angiography several days after ERT may show either remaining stenosis or reocclusion in ICAS-O patients, or more complete recanalization of mild remnant thrombotic stenosis in EMB-O patients, thus helping us to identify the underlying etiologies.

It has been reported that an ICAS-O is an independent predictor for poor outcomes in patients with acute vertebrobasilar occlusions and ERT [6]. This link may be attributed to the longer procedure duration and additional rescue treatment required in ICAS-O, and the neighboring perforators occlusion during ERT. In the anterior circulation, single center retrospective studies have shown that ICAS-O was associated with similar or slightly improved outcomes than EMB-O, through univariate analysis. However, this finding may be attributed to the favorable baseline characteristics, such as younger age and less severe neurologic deficits, in the ICAS-O patients [14,15].

The authors would like to suggest some ERT strategy of ICAS-O, considering it is important to reduce the time for additional rescue treatments and to prevent perforator occlusions during procedure (Figure 2). First, the removal of in situ thrombi by thrombectomy is important in ICAS-O (Figure 1). In situ thrombi can be propagated in a no-flow vessel and may further occlude perforating vessels resulting in severe neurologic deficits (Figure 2A-C). Therefore, a first-line thrombectomy using routine devices would be reasonable (Figure 2D). There are concerns regarding endothelial damage due to friction from thrombectomy devices on the atherosclerotic vascular surface [20-22]. However, stent retrievers have been generally reported to be safe, and appear to be feasible for the treatment of ICAS-O [12].

Second, stabilization of ICAS endothelium seems to be important. Inflammatory responses occur in the stenotic or ruptured atherosclerotic plaque lesions, which have been well described in vulnerable coronary and carotid plaques [23,24]. This irritable endothelial status may cause re-occlusion of the recanalized vessels (Figure 2E) [12,25,26]. Procoagulant activity may increase in stroke patients who are given intravenous tissue plasminogen activator [27]. Therefore, antiplatelet treatment may be more useful in patients with irritable and vulnerable vascular lesions than fibrinolytics, such as tissue plasminogen activator or urokinase [25]. Local infusion of an antiplatelet agent, tirofiban, to the in situ thrombotic occlusive lesion was shown to be safe, to reduce re-occlusion events, and to improve reperfusion rates (Figure 2F) [26]. Glycoprotein IIb/IIIa inhibition blocks fibrinogen molecules, which form bridges between adjacent platelets, providing an effective antiplatelet function [28]. Abciximab, the glycoprotein IIb/IIIa inhibitor, has an irreversible action on platelets, whilst other inhibitors, such as tirofiban and eptifibatide, have a reversible action and may reduce periprocedural hemorrhagic complications [28]. A recent open-label non-randomized study found that hemorrhagic complications did not increase in acute stroke patients who undertook 3 days of intravenous tirofiban infusion immediately following intravenous tissue plasminogen activator, compared to patients who were given intravenous tissue plasminogen activator only [29]. The use of glycoprotein IIb/IIIa inhibitors appears to be potential safe and effective treatment, although further randomized clinical trials are needed to confirm their efficacy.

Third, angioplasty using balloons and/or stenting should be selectively considered as the next line of treatment. However, it is possible that branch perforators can be occluded during angioplasty/stenting via a so-called “snowplow” effect, similar to a snowplow truck that itself compresses snow and blocks a sinkhole while removing snow. In fact, a randomized controlled ICAS study (SAMMPRIS) found that percutaneous stenting/angioplasty used in combination with the best medical treatment shows poorer outcomes than when the best medical treatment alone [30]. In this study, among the 19 patients with periprocedural ischemic complications, 12 patients had perforator occlusions and 2 patients had mixed perforator and embolic occlusions [31]. In addition, the interventional treatment for occlusions in the basilar artery had an odds ratio of 6.2 for periprocedural ischemic events when compared to occlusions of other vessels [31]. Despite the concerns of branch occlusion, emergent angioplasty, with or without stenting in the hyperacute period of intracranial large artery occlusion, has been shown to be feasible and have favorable outcomes [32]. In intractable intracranial occlusions treated with detachable stent retrievers, permanent stenting by detaching the just-used stent retriever improves reperfusion rates and clinical outcomes [33]. To achieve these better outcomes, clinicians should determine whether important branches are located near the ICAS lesion (Figure 2G). If important branches are located near the remnant ICAS site and are predicted to be prone to occlusion during angioplasty/stenting, it would be better not to perform the treatment. In addition, clinicians should keep in mind that antiplatelet pretreatment prior to stenting is related to less recoil and in situ thrombotic complications, as well as better outcomes in early percutaneous coronary intervention treatments for coronary artery obstructive disease [34]. In reality, however, antiplatelet pretreatment is difficult to administer to patients preparing for an emergent ERT. In addition, hemorrhagic transformations from large cerebral infarctions can inhibit further antiplatelet treatment. In this situation, in situ thrombosis is especially likely in patients with intracranial stenting in the hyperacute period. Therefore, intracranial stenting as a rescue method during the hyperacute period should be considered last and only in selected patients with relatively small infarct volumes, which are less associated with hemorrhagic transformation, and those who have not been treated with intravenous fibrinolytic agents prior to stenting. These conditions allow for continued antiplatelet administration, which is required to maintain intracranial stenting. Cerebral infarcts due to hemodynamic impairments are better candidates for intracranial stenting than those due to branch atheromatous diseases and thromboembolic occlusions, which may underlie ICAS [35].

Postprocedural medical treatment management by attending physicians is also of substantial importance. The current best medical treatments, which are based on strong antiplatelet and intensive statin administration for ICAS, appear to lead to stenosis regression more often than expected, even without intervention. Around 80% of patients with ICAS have regression of the stenosis within 1 year of occlusion [36]. Therefore, dual antiplatelet and intensive statin treatment are necessary to prevent remnant ICAS stenosis after finishing ERT. However, the above treatments should be applied cautiously during the immediate postprocedural period, especially when ERT follows intravenous fibrinolytic treatment. Intravenous maintenance with a reversible antiplatelet agent, such as tirofiban, may be a good treatment option, although more evidence regarding its safety and efficacy is required.