CWS was a rare clinical syndrome, which had not been extensively studied. In previous studies showed that the incidence of CWS in TIAs patients was only 1.5% to 4.5% [1-3]. In different studies, the time lapse used to define what was considered CWS was highly variable. In our study, we included patients with recurrent lacunar syndromes up to 48h from the first episode. The incidence in AIS/TIAs was 1.71%, which appears to be consistent with previous studies.
CWS was characterized by an abrupt onset of symptoms, the duration of each episodes was variable, one study showed that the mean duration of each episode was 6.1 minutes . In this study, patients with recurrent TIA presentations within several hours from the first episode, symptoms completely improved within 2-50 minutes, the mean duration of CWS was 24 minutes. CWS was generally manifested as repetitive lacunar syndrome, although some authors had reported that CWS might be associated with other symptoms, such as sensory dullness and ophthalmoplegia . The most frequent symptom was MLS. In the past study, Donnan et al.recruited 50 patients with CWS, the percentage of MLS was 50% , and Camps-Renom et al. reported that MLS accounted for 61.9% of 42 CWS . In our study, 32 patients were mainly manifested as pure motor hemiparesis, and 24 patients were manifested as sensory motor hemiparesis, the incidence of pure motor hemiparesis/sensory motor hemiparesis was 77.78%, our finding was consistent with a recent study .
CWS had a high risk of developing ischemic stroke with a permanent deficit, 7-day stroke risk following CWS was as high as 60%, this rate rises to 71·2% with routine use of MRI . In our study, 58(80.56%) patients had an acute infarction on DWI, the result was consistent with previous studies. The most frequent location was internal capsule (50%) [16,18]. With the wide use of MRI, some studies showed that ischemic lesion could occur at other location. In our study, that area of 41(70.69%) patients's infarction was the internal capsule, other area of infarction was in the thalamus, midbrain, pons, striatum. Therefore, the applicability of the term "Capsular warning syndrome " was inadequate, "Vascular warning syndrome" or "Stroke warning syndrome" might be more appropriate
Studies had confirmed that hypertension, diabetes, dyslipidemia, smoking and other common stroke risk factors were related to CWS, which might suggest that atherosclerosis was involved in the pathogenesis of CWS. However, the exact pathophysiological mechanism of CWS was not clear. Some authors had speculated that CWS was most likely to be ischemia due to in situ small-penetrating vessel disease, and some authors believed that intermittent hemodynamic changes secondary to structural arterial changes or hypertension might be the most likely mechanism of CWS[1,19]. In our study, cranial CTA showed that vascular stenosis or dissection was not found in patients, echocardiography did not showed any cardiac sources, therefore, we further confirmed that the pathogenesis of CWS was related to arteriosclerosis of small-penetrating vessel, but the mechanism of symptoms fluctuate remains unclear.
There was some debate about the most effective treatment in the acute phase of CWS. Despite various treatments being available and used, it was unclear whether these treatments alter the natural course of the syndrome. Intravenous thrombolysis, double antiplatelet therapy, single antiplatelet therapy, anticoagulants, vasopressors had been used to treat patients with CWS[1,4,5,7,9-13,20-28], it remains uncertain whether any of these therapies were able to change the progression of the syndrome. There was no strong evidence for the efficacy of anticoagulant therapy in the acute phase of CWS. There had been case series suggesting that double antiplatelets (aspirin add clopidogrel) might be beneficial, similar to the effect seen in acute coronary syndromes [7,27,28]. In a case series including two patients with CWS, it was reported that following the start of double antiplatelets, there was no progression of symptoms. However, there were also reports that double antiplatelets could not prevent infarction. In a recent study, 17 patients with stuttering lacunar syndrome(SLS) were treated with double antiplatelets, a loading dose of 300mg of clopidogrel was administered along with aspirin in all cases, symptoms improved in 11 patients, so the authors suggested that double antiplatelets appeared effective for the acute treatment of SLS. In our study, 25 patients suffered from infarction despite receiving double antiplatelets therapy. Therefore, the effectiveness of double antiplatelet therapy on CWS needs to be confirmed by randomized controlled trials.
There was little evidence about whether thrombolysis was beneficial in CWS. In some studies showed that CWS patients were treated with thrombolysis, the symptoms completely disappeared, so some scholars considered that rt-PA could be effective[29,30]. However, a recent study showed no significant benefit in functional outcomes in 9 patients receiving intravenous thrombolysis compared with 9 patients not receiving thrombolysis . In our study, 27 patients were treated with intravenous rt-PA. 45 patients were treated with no rt-PA. Age, NIHSS and mean number of episodes were lower in r-tPA group than no r-tPA group, the difference might be related to our sample size, the number of patients in the r-tPA group was small, the patients who received r-PA were younger, and had mild symptoms, but there were no statistical difference in two groups (P>0.05) Although the difference in therapeutic effects between rt-PA, single and double antiplatelet groups was not significant, patients who receive rt-PA seemed to have more frequent complete recovery and fewer new episodes after treatment(Table 3). In this setting, rt-PA should be the therapeutic choice when patients with CWS present within the therapeutic time window with disabling symptoms.
Finally, one of the aims of our study was to analyze the prognosis of patients with CWS. In our study, a favorable outcome was observed in 61 (84.72%) patients at 3-month, 23 patients (23/27,85.19%) in rt-PA group and in 38 (38/45,84.44%) patients in no rt-PA group. There was no difference in functional outcome at 3 months between the two groups. In general, intravenous thrombolysis was safe for CWS patients, and no bleeding complications had been reported. Due to the small number of patients, the effect of rt-PA in CWS must be further confirmed in clinical studies.
Some limitations of this study merit consideration. This study updated and added some new information about CWS, although our study was a multicenter retrospective study, as CWS was a rare clinical disease and the number of patients included was small, which may affect the results of the study. We may need to further expand the number of patients and further explore the relationship between CWS and hemodynamic changes to find the best treatment for CWS.