**2. The mechanisms of ischemia in intracranial atherosclerotic disease (ICAD)**

According to Arenillas [3], our traditional understanding of ICAD is based on the detection of hemodynamically relevant intracranial arterial stenosis (ICAS). The main limitations of this classical approach are as follows:


Stroke associated with ICAD occurs in association with four mechanisms:


Thus, even mild stenosis of intracranial atherosclerotic arteries (<50%) may be clinically relevant, and high-resolution magnetic resonance imaging (HR-MRI) studies are needed to identify and determine the degree and location of stenosis in this patient group [19]. Oh Young Bang and others asserted that these mechanisms can coexist and interact in the same patient [16, 18, 20, 21].

#### **2.1 Clinical recurrence rate**

As we mentioned before, the annual recurrence rates for any ischemic stroke reported in the WASID trial were as high as 15 and 14% in the aspirin and warfarin arms, respectively [16].

It has been shown that symptomatic ICAD is particularly burdened with a high clinical recurrence rate [3]. Moreover, Famakin and coworkers reported that most subsequent strokes in patients with symptomatic ICAS occurred in the same arterial territory were nonlacunar, and nearly half of them were disabling [19]. Their results were similar to the findings in NASCET, which showed that 95% of strokes were ipsilateral in patients with 70–99% carotid stenosis, and 71% of strokes were ipsilateral in patients with 50–69% carotid stenosis [22].

It is also important to mention that Famakin and coworkers observed that patients with ICAS have a propensity for atherosclerotic stenosis at different sites within the intracranial circulation [19]. Supporting this idea, they reported that among the 27% of the strokes occurring outside the territory of the symptomatic intracranial artery, almost half (48%) could have been caused by previously asymptomatic or newly developed ICAS in a different vascular territory. However, in the same study, it was suggested that it is also possible that some of these strokes may have been caused by an embolus which partially recanalized leaving a residual stenosis [19]. Supporting this theory is data from another WASID analysis, which showed that asymptomatic ICAS that was present at study entry (coexistent with the symptomatic stenosis) was associated with a low rate of stroke (3.5% after 1 year of follow-up) [23].

Identifying whether ICAS is actually the cause of the present stroke (determining whether the stenosis is symptomatic or asymptomatic), it is however still a challenge, knowing that, according to Famakin, in up to 20% of the patients with stroke and IACS, there is another cause for its occurrence (extracranial large artery stenosis, cardiac embolism, and small artery occlusion can co-exist with ICAS) [19]. Nowadays, different noninvasive imaging techniques can provide physiological data on the mechanisms associated with ICAD-linked stroke and their forms of coexistence, including markers of anterograde and collateral flow, dynamic cerebrovascular reserve, static tissue perfusion, characteristics and morphological details of plaques with embolic potential, etc. [16, 18, 24].

All these data may improve stroke risk stratification, adding to clinical and anatomic (i.e., percent stenosis) predictors of stroke risk, developing mechanismspecific prevention and treatment strategies, and also serve in patients' selection for endovascular therapies [16, 18, 24].
