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Response by Feng et al to Letter Regarding Article, "Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Disease: Classification and Clinical Implications".

In Response: We would like to thank Kvernland et al for their interest on our recent article on classification and clinical implications of stroke mechanisms in symptomatic intracranial atherosclerosis (sICAS). In their correspondence, Kvernland et al addressed the limitation of the relatively small sample size and the small numbers of outcome events that did not allow multivariate analyses to adjust for possible confounders for independent associations between stroke mechanisms and the primary/secondary outcomes. This limitation has been discussed in the article. Because of the small sample size, we combined certain stroke mechanisms in one group and did not separate different types of border-zone infarcts in the analyses of their associations with risks of recurrent ischemic events, though we agree there might be differences in pathophysiology and prognosis of cortical versus internal borderzone infarcts. Kvernland et al also raised doubt regarding the high rate of hypoperfusion in the cohort with around half of sICAS lesions with <70% luminal stenosis, when arguing that “impaired cerebral blood flow is unlikely when the luminal stenosis is <75%.” First, the term hypoperfusion in our study indicated a probable stroke mechanism in patients with sICAS, represented by border-zone infarct(s) in the presence of intracranial atherosclerosis, rather than perfusion imaging–verified, significantly reduced cerebral blood flow. Second, according to our previous study, prolonged perfusion time without significantly reduced cerebral blood flow in the territory downstream to an intracranial atherosclerosis lesion may also lead to increased risk of cerebral infarction in the same territory, which is not uncommon in patients with <70% intracranial stenosis. We completely agree that it would be ideal to define stroke mechanisms in sICAS patients with comprehensive imaging workup, including not only perfusion imaging to detect perfusion impairment but also transcranial Doppler to detect microemboli (potential evidence for artery-to-artery embolism), and high-resolution magnetic resonance imaging or 3-dimensional rotational angiography for more accurate delineation of the characteristics of the plaques and their spatial relationships with orifices of penetrating/branch arteries. However, as mentioned in our article, it is not generalizable to apply all these advanced imaging exams in patients with sICAS in large-scale studies or in clinical practice. That was why we proposed the current criteria for classifying probable stroke mechanisms in sICAS patients based on routine brain magnetic resonance imaging and magnetic resonance/ computed tomographic angiography. Yet, we agree that the proposed classification method needs to be validated with more advanced imaging workups in larger studies before it can be used in future large-scale studies, to advance our understanding of stroke mechanisms in sICAS. Last but not least, we second that in patients with sICAS, “treatment strategies for secondary stroke prevention should ideally target the underlying mechanism.” Aggressive medical treatment may be more effective in sICAS patients with arteryto-artery embolism or parent artery atherosclerosis occluding penetrating artery as the probable stroke mechanisms, while those with hypoperfusion as the probable stroke mechanism may benefit from adjunctive endovascular treatment in addition to medical treatment. These inferences warrant further investigation, but again, a generalizable and reproducible classification system for probable stroke mechanisms in sICAS is needed before such investigations.