Ischemic stroke is the primary clinical manifestation of VBD; others included hemorrhage, SAH, compression of a cranial nerve, hydrocephalus et al. [16]. In this stroke registry-based study, 19.1% of VBD patients suffered a IS recurrence during a maximum 30-month follow-up. It seemed that stroke patients with VBD might have a higher recurrence risk than the general population, for example, Flemming et al. selected 159 VBD cases from the radiological database which included not only stroke patients, after an average of 3.8-years follow-up, 44 patients occurred cerebral infarction or TIA. The 1, 5, and 10-year risk of an ischemic stroke was 6.1%, 17.3%, and 25.4% [2]. Passero et al. performed a clinical and imaging follow-up study and found that 75 (48%) of the 156 VBD patients had a stroke after an average of 11.7 years follow-up [1]. Besides, it seemed that the mortality (3.5%) in our study is lower than the previous study [17], this may be due to the relatively short follow-up time and exclusion of patients who died within seven days because their diagnoses of stroke recurrence were mostly undetermined. Also, patients with none MRI were excluded; many of them were under unstable condition. These may lead to the underestimate of mortality. However, our report seemed similar with a previous study, which performed an average of 3.4 years follow-up of first ischemic stroke patients with IADE and found a high stroke recurrence (58%) but low mortality (17%) [3].
Although VBD patients have a high stroke-recurrence rate, studies about the predictive factors of recurrence were limited. This study evaluated variables potentially associated with stroke recurrence in VBD patients and found that extremely dolichoectasia such as basilar artery diameter ≥ 5.3 mm (90th percentile) was independently associated with IS recurrence. The higher IS recurrence among patients with extremely enlarged or kinking elongated arteries may be related to the multiple mechanisms that could lead to stroke occurrence [3], including local thrombosis, embolism, penetrating artery occlusion induced by compression or stretching of deep branches (Fig. 2) of the basilar artery. Interestingly, Pico et al. found that the BA diameter was also associated with a 5-year risk of death in stroke patients, the adjusted hazard ratio of stroke mortality was 1.23 (95% CI, 1.07-1.41) with per 1-mm increase in BA diameter [8].
In another hand, we found another intracranial arterial geometry abnormality, the diffuse intracranial dolichoectasia, was correlated with IS recurrence. Patients with anterior circulation dolichoectasia have been reported in previous studies [1, 12]; however, the IS recurrence of patients with diffuse intracranial dolichoectasia was seldom mentioned [12]. Diffuse intracranial dolichoectasia patients suffered more IS recurrence mainly because it may be the severe form of arterial dolichoectasia. Brinjikji, W. et al. suggested that diffuse intracranial dolichoectasia is a systemic arteriopathy affecting multiple vascular beds, which may be different from a single intracranial artery dolichoectasia [12]. However, in this study, we could not uniquely say patients with diffuse dolichoectasia are different with the rest of patients with VBD alone, as we did not screen if any patients in this study have diseases that may often coexist with systemic vascular expansion, such as connective tissue disease, autosomal dominant polycystic kidney disease, or infection in this study.
This study found that previous ischemic heart disease was the independent predictors for IS recurrence in VBD patients. Interestingly, a previous study suggested that IADE patients were eligible to have a previous myocardial infarction [18], and the coronary artery ectasia was also correlated with ischemic heart disease [19]. Concomitant coronary and basilar artery ectasia in stroke patients may suggest common pathogenesis [20]. However, in multivariable analysis, we did not find the statistical difference of vascular risk factors such as age, hypertension, diabetes mellitus, hyperlipidemia, smoking between the recurrence and none-recurrence group. It may vary due to the small number of recurrent patients in our study. Also, the negative findings of between-group differences refers to vascular risk factors might suggest the different pathogenesis between IADE and ICAS, as the characters above were widely accepted as risk factors for atherosclerosis vascular disease.
In China, ICAS is the most common vascular lesions in patients suffered cerebral vascular disease, and the stroke recurrence is higher in patients with serve stenosis [21]. However, the relationship between large arterial atherosclerosis and dolichoectasia has always been debated. This study found that VBD patients had a frequent incidence of ICAS, and this proportion was higher in recurrent cases; however, we did not find its association with IS recurrence in multivariate analysis. IADE may differ with ICAS; autopsy study found that IADE is associated with rarefaction of elastic tissue of the tunica media with the degeneration of the internal elastic laminin [20, 22], while atherosclerosis always has a pathological change of plaque with a lipid core and the fibrous cap [23]. Also, hemodynamic abnormalities such as the wall shear stress, noticeable eddy currents in dolichoectasia vertebrobasilar artery were reported, and notably, without apparent arterial stenosis [24]. Interestingly, the ischemic lesions in the BA branches-supplied territories often exit at the contralateral side of the laterality of the BA [25], as is shown in Fig. 2. These findings suggested that the hemodynamic abnormality may promote the development of ischemic vascular events without atherosclerosis but due to stretching of the small branch vessels.
IADE and ICAS often coexisted in the large cranial arteries [1]. It implies that these two large artery abnormalities may share some common pathogenic factors. For example, Matrix metalloproteinases (MMPs) was related to IADE as it could degrade various extracellular proteins including collagen, elastin, or proteoglycans that located in the tunica media [26]. Also, MMPs degrade the extracellular matrix and then causes vascular remodeling, finally leads to atherosclerosis [27]. And the high turbulent shear stresses and the region of flow separation and stagnation (especially in patients under long term hemodynamic changes such as hypertension) all give rise to the risk of thrombosis, and then caused the occlusion of the perforating artery [23] or the distal embolism. However, it is also possible that IADE is merely a hint for severe atherosclerosis.
The widely accepted consensus of the second prevention for IS recurrence in VBD patients is absent. The safety and effectiveness of antiplatelet or anticoagulant therapy in VBD patients has not yet been assessed [23]. Our study did not find the differences in treatment between groups referring to the IS recurrence, such as antiplatelet, anticoagulant, or statin. However, previous small sample (13 patients) study suggested anticoagulant therapy because they observed a more favorable outcome in this group than that using antiplatelet treatment [28], but other study cautioned that using antiplatelet or anticoagulant agents may increase the incidence of intracranial bleeding in VBD patients [29]. It seemed reasonable to give antithrombotic therapy conservatively in patients with a basilar artery diameter larger than 10 mm, in consideration of the high risk of rupture [23]. A favorable outcome was reported in patients with subarachnoid hemorrhage caused by posterior circulation fusiform aneurysms by using surgery or endovascular procedure [30]. However, randomized clinical trials are needed to access the safety and efficacy of these approaches.
Our research has some limitations. First, this is a retrospective and hospital-based study, it was limited with case selection or referral bias, so the predictors of stroke recurrence in our study may not be an accurate reflection of the general population. Second, we did not include suspectable TIA patients or patients with negative CT/MRI findings as the recurrent cases, because it is difficult giving the definite diagnosis based on the retrospective medical records, as the mimic neurological deficits might be caused by epilepsy, peripheral vertigo, or syncope. Therefore, this may underestimate the true IS recurrence. Third, we did not use the high-resolution MRI analyzing the vascular wall or the plaque stability as previous studies [31], as the negative arterial remolding may underestimate arterial diameter [32]. However, this is a stroke registry-based study; patients were included prospectively and consecutively. Also, this is relatively a large cohort; it provided some assistance in predicting IS recurrence in VBD patients and had a likely warning effect on some unique VBD patients such as combined with diffuse intracranial dolichoectasia. This study may be helpful to guide medical therapy and may improve the counseling of patients with VBD. The large sample of prospective studies, use high-resolution MRI or fluid dynamics, or randomized clinical trials aimed to access the effective treatment of VBD, needs further developed.