CWS is a rare clinical syndrome that has not been extensively studied. Previous studies have shown that the incidence of CWS in TIA patients was 1.5–4.5% [1,2,3]. In the present study, patients with recurrent lacunar syndromes up to 48 h from the first episode were included. The percentage in AIS/TIA was 1.71%, which appears to be consistent with that in previous studies.
CWS has been characterized by the abrupt onset of symptoms, and the duration of each episode varies. One study revealed that the mean duration of each episode was 6.1 min [1]. In the present study, for patients with recurrent TIA presentations within several hours from the first episode, the symptoms completely improved within 2–50 min, and the mean duration of each episode was 24 min. CWS has generally manifested as a repetitive lacunar syndrome, although some authors have reported that CWS might be associated with other symptoms, such as sensory dullness and ophthalmoplegia [15]. The most frequent symptom was MLS. In a previous study, Donnan et al. recruited 50 patients with CWS, and the percentage of MLS was 50% [1]. In another study, Camps-Renom et al. reported that MLS accounted for 61.9% of 42 CWS cases [16]. In the present study, 32 patients mainly manifested with pure motor syndrome, while 24 patients manifested with sensory motor syndrome, and the frequency of pure motor syndrome/sensory motor syndrome was 77.78%. This present finding was consistent with a recent study [17].
CWS has a high risk of developing ischemic stroke with a permanent deficit. The 7-day stroke risk following CWS can reach as high as 60, 71.2% patients had acute ischemic lesions with the routine use of MRI [2]. The most frequent location was in the internal capsule (50%), some studies have revealed that ischemic lesions can occur at other locations [16, 18]. In our study, 58 (80.56%) patients had an acute infarction on DWI, the most frequent location was in the internal capsule, which occurred in 41 (70.69%) patients, while the other locations were in the thalamus, midbrain, pons and striatum, the results were consistent with that in previous studies [16, 18].
The exact pathophysiological mechanism of CWS remains unclear. Studies have confirmed that hypertension, diabetes, dyslipidemia, smoking and other common stroke risk factors are correlated to CWS, which might suggest that atherosclerosis may be involved in the pathogenesis of CWS [1, 19,20,21]. Some authors have speculated that CWS was most likely to be ischemia due to in situ small-penetrating vessel disease, while some authors have considered that intermittent hemodynamic changes secondary to structural arterial changes or hypertension might be the most likely mechanism of CWS [1, 22]. In the present study, the cranial CTA revealed that vascular stenosis or dissection was not found in patients, while echocardiography did not reveal any cardiac sources. Therefore, we suspect that the pathogenesis of CWS may be correlated to the arteriosclerosis of small-penetrating vessels. However, the mechanism of the symptom fluctuations remains unclear.
There has been some debate on the most effective treatment in the acute phase of CWS. Regardless of the various available treatments being used, it remains unclear whether these treatments alter the natural course of the syndrome. Intravenous thrombolysis, double antiplatelet therapy, single antiplatelet therapy, anticoagulants, and vasopressors have been used to treat patients with CWS [1, 4, 5, 7, 9,10,11,12,13, 23,24,25,26,27,28,29]. However, it remains uncertain whether any of these therapies can change the progression of the syndrome. There was no strong evidence for the efficacy of anticoagulant therapy in the acute phase of CWS. Furthermore, a case series suggested that double antiplatelet therapy (aspirin with the addition of clopidogrel) might be beneficial, which might be similar to the effect observed in acute coronary syndromes [7, 28, 29]. In a case series that includes two patients with CWS, it was reported that following the start of double antiplatelets, there was no progression of symptoms [8]. A retrospective study revealed that double antiplatelet therapy could decrease clinical fluctuations and improve functional outcome [30]. However, there were also reports that double antiplatelet therapy cannot prevent infarction. In a recent study, 17 patients with stuttering lacunar syndrome (SLS) were treated with double antiplatelet therapy. A loading dose of 300 mg of clopidogrel was administered along with aspirin in all cases, and the symptoms improved in 11 patients. Hence, the authors reported that double antiplatelet therapy appears to be effective for the acute treatment of SLS [17]. In the present study, 25 patients suffered from infarction, even though they received double antiplatelet therapy, while 12 patients treated with single antiplatelet therapy had infarction, and 2 patients treated with single antiplatelet therapy had recurrent ischemic stroke within 3 months. The result showed that double antiplatelet therapy may be more effective than aspirin or clopidogrel alone, as a secondary prevention strategy in CWS.
There is little evidence on whether thrombolysis is beneficial for CWS. Some studies have shown that for CWS patients treated with thrombolysis, the symptoms completely disappeared. Hence, some scholars have considered that rt-PA could be effective [31, 32]. However, a previous study revealed that there was no significant benefit in functional outcomes in nine patients who received intravenous thrombolysis, when compared to nine patients who did not received thrombolysis [3]. In a recent study, it was revealed that intravenous thrombolysis could stop stuttering in patients with SLS. Therefore, the author considered that thrombolysis should be the therapeutic choice when patients with SLS present within the therapeutic time window with disabling symptoms [17]. In the present study, 27 patients were treated with intravenous rt-PA and 45 patients were treated with no rt-PA, the difference in therapeutic effects among the rt-PA, single and double antiplatelet groups was not statistically significant (Table 3). This might be correlated to the small sample size of the study. In the future, multicenter clinical randomized controlled trials should be conducted to explore the effect of thrombolytic therapy in CWS.
Finally, one of the aims of the present study was to analyze the prognosis between the rt-PA and no rt-PA groups. In the present study, a favorable outcome was observed in 61 (84.72%) patients after 3 months. Among these patients, 23 patients (23/27,85.19%) were from the rt-PA group and 38 (38/45,84.44%) patients were from the no rt-PA group. There was no difference in functional outcome at 3 months between the rt-PA and no rt-PA groups. In general, intravenous thrombolysis is safe for CWS patients, and no bleeding complications have been reported. Therefore, intravenous thrombolysis is an alternative treatment for CWS within 4.5 h after the onset of symptoms. Due to the small number of patients, the effect of rt-PA in CWS must be further confirmed in clinical studies.
Some limitations of the present study merit consideration. The present study updates some information about CWS. Since the present study was a multicenter and retrospective study, CWS is a rare clinical disease, and the number of included patients was small, these may have affected the results of the present study. A total of seven patients were followed up by face-to-face interview. The recollection of these patients on the functional outcome after 3 months of onset might lead to some recollection bias. In the future, there may be a need to further expand the number of patients and further explore the mechanism of CWS, in order to find the best treatment.
