影像学指导中西医结合治疗症状性颅内动脉狭窄临床研究
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摘要
目的：
颅内动脉粥样硬化性狭窄是导致国人缺血性中风和TIA的主要原因,临床将发生过TIA和脑梗死并经过检查确定的颅内动脉粥样硬化性狭窄称之为症状性颅内动脉粥样硬化性狭窄(以下简称症状性颅内动脉狭窄),是TIA和缺血性中风复发高危因素,二级预防的重点。症状性颅内动脉狭窄发病机制与狭窄远端血流动力性障碍、狭窄部位不稳定斑块导致血栓形成或脱落、狭窄部位穿支血管闭塞有关,治疗方面包括内科治疗(西医内科治疗和中西医结合内科治疗)、外科治疗(血管内治疗和血管吻合术,前者为主)；由于临床较难正确分析症状性颅内动脉狭窄发病机制,西医内科治疗仍有较高的中风复发,血管内治疗仍有较高的围手术期并发症发生率和支架术后再狭窄率,采用何种治疗方法进行安全有效的二级预防,一直是困扰临床医生的难题,寻找合理、安全、有效的二级预防治疗方案,具有十分重要的临床意义。氙CT (Xenon-CT)是一种可以定量测定、安全可靠、成本较低的评价脑血流灌注的技术,高分辨MRI(high-resolution MRI, HR-MRI)在研判血管狭窄部位斑块特征方面有明显优势；应用Xenon-CT和HR-MRI可以了解和分析症状性颅内动脉狭窄部位斑块特征和远端血流动力学变化,结合其他影像学检查,有助于分析发病机制；广东省中医院脑病中心多年实践表明,在“中医阴阳类证”辩证论治体系指导下的中西医结合缺血性中风二级预防方案疗效确切,明显改善患者的预后,针对症状性颅内动脉狭窄,该方案显示出一定的优势。本研究旨在Xenon-CT和HR-MRI指导下,分析症状性颅内动脉狭窄发病机制,依据前瞻性设计的适应证标准,制定合理的中西医结合内科治疗方案或外科治疗方案,评估中西医结合治疗方案的安全性和有效性(降低缺血性中风复发率,降低支架术围手术期并发症率和术后再狭窄率),获得有价值的临床研究数据,为进一步深入研究获得症状性颅内动脉狭窄二级预防治疗方案的循证医学证据奠定基础。
方法：
对2010年7月至2012年2月收治的缺血性小中风、TIA和椎基底动脉供血不足的患者,首先进行常规影像学检查(CT/CTA、MRI/MRA、DSA),然后对筛选出来的20例与小中风、TIA或椎基底动脉供血不足相关的症状性颅内动脉狭窄(狭窄率≥50%)患者,进行Xenon-CT和HR-MRI检查,根据综合检查结果、前瞻性设计的适应证标准以及入组原则,将20例患者分成中西医结合强化内科治疗组(简称内科治疗组)和中西医结合强化内科治疗组+血管内治疗组(简称血管内治疗组)。中西医结合强化内科治疗方案：在强化西医内科治疗(双联抗血小板、强化降脂、积极控制危险因素)的基础上根据中医辩证原则分为阴类证和阳类证,分别予以相应的中药治疗,治疗周期为3周；血管内治疗方案：采用WINSPAN支架系统对靶血管进行血管内支架成形术。主要临床结局指标是：分别评价每组30天内再中风率和死亡率,30天后临床随访,记录每组再发缺血性中风的情况,分析每组的短期随访结果,同时对Xenon-CT和HR-MRI检查结果以及其他临床相关信息进行分析。
结果：
1.一般情况：纳入20例症状性颅内动脉狭窄患者,其中TIA患者7例,急性脑梗塞患者11例,椎基底动脉供血不足2例。男性患者14例,女性患者6例；年龄41～87岁,平均年龄64.75±8.96岁。常规影像学评价发现症状相关的前循环颅内动脉狭窄17例(其中颈内动脉颅内段狭窄3例,大脑中动脉M1段狭窄12例,大脑中动脉M2段狭窄1例,大脑前动脉A1段狭窄1例),后循环颅内动脉狭窄3例(其中椎动脉颅内段狭窄1例,基底动脉狭窄2例)。中度狭窄(50%～69%)11处,全部位于前循环；重度狭窄(≥70%)9处,其中6处位于前循环,3处位于后循环。
2.Xeon-CT和HR-MRI检查结果：17例前循环颅内动脉狭窄患者全部接受Xenon-CT检查,其中4例接受HR-MRI检查。Xenon-CT检查发现靶血管远端供血区局部血流量正常者12例,其中3例HR-MRI检查提示局部血管壁斑块异常信号；Xenon-CT检查发现靶血管远端供血区局部血流量异常者5例,其中1例HR-MRI检查提示动脉夹层。3例后循环颅内动脉狭窄接受HR-MRI检查,1例椎动脉颅内段狭窄提示局部混合性斑块形成(不稳定斑块),2例基底动脉狭窄,1例显示偏心型斑块,与穿支关系不密切,1例提示中重度阴性重塑形。对于靶血管远端供血区局部血流量异常表现情况,狭窄程度(50%～69%)和(≥70%)之间差异有统计学意义(P<0.05),显示对于中度的症状性前循环颅内动脉狭窄血流动力学障碍不是其主要的发病机制。对于是否发生TIA, Xenon-CT结果正常者和Xenon-CT结果异常者相比,差异有统计学意义(P<0.05),显示前循环TIA的发生主要与狭窄远端血流动力学障碍有关。血管内治疗组2例Xenon-CT结果异常者,分别有5处和1处分区的局部脑血流量,在血管内治疗前后差异有统计学意义(P<0.05),提示通过血管内治疗可以显著改善狭窄远端供血。应用多个独立样本T检验(Kruskal Wallis检验)比较HR-MRI对斑块特征(斑块的形态、斑块的性质、斑块与穿支的关系、斑块的重塑形、斑块强化、夹层、假性狭窄)的检出情况,显示针对斑块性质的检出与判断,磁共振尚没有良好的表现；对于斑块的形态、与穿支的关系、重塑形情况、强化、夹层、假性狭窄等的检出有良好表现。
3.分组情况以及中医辩证分型结果：14例入选内科治疗组；其中2例为靶血管远端供血区局部血流量异常者(根据标准拟入选血管内治疗组,患者本人拒绝手术而入选内科治疗组),1例为基底动脉狭窄(HR-MRI提示中重度阴性重塑形,考虑血管内治疗风险大而入选强化内科治疗组)；中医辩证分型,阴类证9例,阳类证5例；6例入选血管内治疗组,3例为大脑中动脉狭窄(Xenon-CT检查发现靶血管远端供血区局部脑血流量异常),1例为大脑中动脉狭窄(Xenon-CT检查发现远端靶血管供血区局部脑血流量正常,内科治疗期间再发同侧缺血性中风,考虑予以狭窄血管内支架成形术而入组),1例为基底动脉狭窄(HR-MRI检查提示偏心型斑块,斑块与重要穿支的关系不密切),1例为椎动脉颅内段狭窄；中医辩证分型,阴类证5例,阳类证1例。
4.短期治疗结果：30天内,内科治疗组无再中风和死亡发生,血管内治疗组1例(基底动脉狭窄)术后即刻发生桥脑短旋支供血区的梗死,经治疗未遗留神经功能障碍,无死亡；30天后所有患者接受临床随访,随访周期3个月至14个月,平均7.4个月,其中内科治疗组发生1例同侧再次缺血性中风(为原先拟入选血管内治疗组的病例,入组后第4个月发生同侧中风),经治疗未遗留神经功能障碍,如果将2例为靶血管远端供血区局部脑血流量异常者(根据标准拟入选血管内治疗组,患者本人拒绝手术而入选内科治疗组)剔除,12例内科治疗组病例,平均7.4个月的随访周期内无1例发生同侧再次中风；血管内治疗组发生1例同侧再次缺血性中风(术后第2月),治疗后遗留轻度神经功能障碍。在主要终点事件方面(30天内再中风和死亡率以及30天后的短期随访周期内的再中风和死亡率),本研究内科治疗组低于SAMMPRIS试验内科治疗组。
结论：
1.Xenon-CT可以筛选出前循环症状性颅内动脉狭窄存在血流动力学障碍的患者,有助于选择适合的治疗方式,对治疗后局部脑血流量的测定有助于评价治疗后的血流动力学变化以及治疗效果；HR-MRI可以判断斑块的形态、斑块与穿支的关系、狭窄段血管重塑形情况,有助于术前判断血管内治疗的风险,进而选择相对安全的治疗方式；血流动力学障碍不是症状性前循环颅内动脉中度狭窄的主要发病机制；前循环症状性颅内动脉狭窄引发的TIA主要与狭窄远端血流动力学障碍有关。
2.在Xenon-CT和HR-MRI指导下,结合常规影像学检查有助于研判和查明症状性颅内动脉狭窄的发病机制,在此基础上制定的治疗方案具有较强的针对性以及较好的安全性和短期临床疗效。
3.短期结果提示,中药结合西医内科强化治疗可能促使狭窄段不稳定斑块向稳定的状态转变,有助于减少缺血性中风的发生；内科治疗组较低的同侧中风发生率可能与中药治疗稳定狭窄段斑块、抑制其血栓形成或脱落有关。
4.针对高危病例(低灌注、不稳定斑块),中西医结合强化内科治疗的最佳方案有待于进一步研究；本项研究中长期的临床疗效有待于长期随访观察或临床随机对照试验的进一步验证。
Objective
Intracranial atherosclerosis stenosis is the leading cause of ischemic stroke and TIA in our country, clinically, intracranial atherosclerotic stenosis with occurrence of TIA or cerebral infarction is defined as symptomatic intracranial arterial stenosis, which is the risk of recurrence of TIA and ischemic stroke, therefore the main point of secondary prevention. The pathogenesis of symptomatic intracranial arterial stenosis is related to distal hemodynamic disorder, thrombosis or embolus dislodgement due to unstable plaque, perforator occlusion, etc. Treatment strategies include Medical treatment (Western medicine treatment and Integrative Chinese and Western medicine treatment) and Surgical treatment (Mainly Endovascular treatment and vascular anastomosis). Western medicine treatment has a rather high recurrent stroke rate, while Endovascular treatment is facing the risk of perioperative complication and post procedure restenosis in stent. Due to the difficulties of accurate analysis of the pathogenesis of symptomatic intracranial arterial stenosis in clinical practices, the choice of a safe and effective treatment approach for secondary prevention remained controversial. Xenon computed tomography (Xenon-CT) is a quantitative determinable, safe, reliable and low cost means to evaluate cerebral perfusion, and high-resolution MRI (HR-MRI) has an advantage in analyzing the feature of plaque. With the application of the Xeon-CT and HR-MRI for symptomatic intracranial arterial stenosis, understanding and analyzing of the feature of plaque in site and distal hemodynamic changes should be achieved, combined with other imaging findings, could allow to analyze the pathogenesis of symptomatic intracranial arterial stenosis. On the other hand, the many years of practice of encephalopathy center of Guangdong Provincial Hospital has shown that Integrative Chinese and Western medicine treatment is safe and effective as a secondary prevention strategy of ischemic stroke, and can significantly improve prognosis, especially for patients with symptomatic intracranial arterial stenosis. This study was designed to analysis the pathogenesis of symptomatic intracranial arterial stenosis under the guidance of the Xenon-CT and the HR-MRI, and to evaluate the safeness and effectiveness of Integrative Chinese and Western medicine treatment.
Methods
20patients with symptomatic intracranial arterial stenosis patients (administrated from January2010to February2012), with stenosis rate greater than or equal to50%, were engaged with Xenon-CT and HR-MRI examination. Based on the test result, the patients were divided into Integrative Medical Treatment group and Endovascular Treatment group. Patients within Integrative Medical Treatment group were given Traditional Chinese Medicine besides western medicine treatment (double antiplatelet regimen, intensive hypolipemic treatment and active controll of risk factors), treatment period lasted for3weeks, while patients within Endovascular treatment group underwent intravascular stenting of target vessel with WINSPAN stent system. Then analysis the recurrent stroke rate and mortality rate and mordality rate within30days and beyond30days during follow-up period.
Result
1. Of20patients with symptomatic intracranial arterial stenosis,7cases presented with TIA,11cases with acute infraction and2cases with Vertebrobasilar insufficiency. Number of male and female patient is14and6separately, age ranging from41-87, with an average of64.75±8.96. of17cases located in the anterior circulation,3cases was located at Intracranial internal carotid artery,12cases Ml section of MCA,1case M2section of MCA and1case A1section of ACA. And the other3cases located in the posterior circulation,1case was located at intracranial segment of vertebral artery,2cases basilar artery. Amoung them, there are11cases with moderate stenosis (stenosis rate up to50～69%), all located in the anterior circulation, and9cases with severe stenosis (stenosis rate up to more than70%),6located in the anterior circulation, the other3located in the posterior circulation.
2.17cases with intracranial arterial stenosis in the anterior circulation received Xenon-CT examination, and4of17cases received HR-MRI examination. Xenon-CT showed normal regional cerebral blood flow in12cases, and abnormal plaque signal of vessel wall was detected via HR-MRI in3cases. Xeon-CT showed showed a decrease of CBF in related brain area in5cases, and HR-MRI showed arterial dissection in1case of5cases. The other3cases with intracranial arterial stenosis in the posterior circulation received HR-MRI examination, which showed mixed plaque (unstable plaque) in the patient with intracranial segment of vertebral stenosis, and of the other2cases of basilar artery stenosis, eccentic plaque formation (not in close relation with perforating branches) was seen in one case, and severe negative reconstruction of vessel wall in the other case. There is a significant difference of CBF value between moderate and severe stenosis of target vessel (P<0.05), which demonstrated that for patients with moderate stenosis, hemodynamic dysfunction is not the primary pathogenesis. There is also a significant difference of TIA attack incidence between patients with normal and abnormal Xenon-CT result (P<0.05), which demonstrated that the incidence of TIA in the anterior circulation is related to distal hemodynamic disorder.2cases from Endovascular treatment group showed significant increase of CBF after operation compared to that before operation (P<0.05), and this result allow to support the theory that endovascular treatment can improve distal blood supply. Kruskal Wallis test showed that HR-MRI has a favorable outcome of reliability in detecting morphology of plaque, relationship of plaque with perforators, reconstruction, enhancement, dissection and pseudostenosis, while not reliable in analysis about characteristic of plaque.
3.14cases were selected for the Integrative Medical treatment group, among them2cases with a decrease in CBF in related brain area shown by Xenon-CT (originally included into the Endovascular treatment group, but transfered into Integrative Medical treatment group due to declination to operation), and1case of basilar stenosis (HR-MRI showed severe negative reconstruction) was included into Integrative Medical treatment group due to the consideration on high operative risk.9cases of them were regarded as the "Yin" kind of Traditional Chinese Medicine, while the other5the "Yan" kind.6cases were selected for Endovascular treatment group, and of6cases3cases of MCA stenosis with a decrease in CBF in related brain area shown by Xenon-CT,1 case of MCA stenosis with normal CBF in related brain area shown by Xenon-CT (underwent recurrent ipsilateral ischemic stroke while receiving standard western medicine treatment), and1case of basilar artery stenosis (HR-MRI show eccentric plaque formation, not in close relation with perforating branches) and1case of vertebral artery stenosis.5cases of them were regarded as the "Yin" kind of Traditional Chinese Medicine, while the other1the "Yan" kind.
4. Within30days, no cases of recurrent stroke and death in the Integrative Medical treatment group, and infarction of pons occurred in1case(basilar artery stenosis) from the endovascular treatment group postopratively without neurological dysfunction after treatment. During the Follow-up period ranges from3months to10months with an average of6.5months,1case from the Integrative Medical treatment group suffered from ipsilateral ischemic stroke (4month after discharge)without neurological dysfunction after treatment, and1case from the Endovascular treatment group suffered from ipsilateral stroke(2months after operation)with mild neurological dysfunction after treatment. If to exclude the2cases with decrease in CBF in related brain area (originally included into the Endovascular treatment group, but transfered into Integrative Medical treatment group due to declination to operation), among the12cases from Integrative Medical treatment group, within the follow-up period of an average of7.4months, none of ipsilateral recurrent stroke took place, comparing with1case from Endovascular treatment group suffered from ipsilateral recurrent stroke (2months after operation) with mild neurological dysfunction after treatment. In the term of End Event (recurrent stroke rate and morality and modality within30days and beyond30days), the result of Integrative Medical treatment group in our study was lower than the medical treatment group in SAMMPRIS study.
Conclusion
1. Xenon-CT can filter out hemodynamic disorder in the patients with sympomatic intracranial arterial stenosis of anterior circulation, and to determinate the appropriate treatment and evaluate hemodynamic changes after treatment and effectiveness of endovascular treatment. HR-MRI can detect morphology of plaque, relation of plaque with perforators, reconstruction, which allow to evaluate the risk of endovascular treatment. Hemodynamic disorder is not the primary pathogenesis of moderate symptomatic intracranial arterial stenosis of the anterior circulation. TIA caused by symptomatic intracranial arterial stenosis in the anterior circulation is related to distal hemodynamic disorder.
2. Xenon-CT and HR-MRI combined with conventional imaging had significant direction in formulating a individual and safe treatment strategy with desirable short term efficacy.
3. Analysis of short term result suggest that Integrated Chinese and Western Medicine treatment might promote conversion of the unstable plague into stable plaque, so as to reduce the rate of recurrent ischemic stroke. The low ipsilateral recurrent ischemic stroke rate from the Integrated Chinese and Western Medicine group might be related to the stabilization of plaque and inhibition to thrombosis, thrombus dislodgement, which suggest that Tradition Chinese Medicine might play a positive role in this process.
4. Further research is needed to determine the efficacy of Integrative Chinese and Western Medicine treatment on high risk patients (complicated with hypoperfusion and unstable plaque). The medium and long term efficacy of this study still needs further validation from long term follow-ups or clinical randomized controlled trials.
颅内动脉粥样硬化性狭窄是导致国人缺血性中风和TIA的主要原因,临床将发生过TIA和脑梗死并经过检查确定的颅内动脉粥样硬化性狭窄称之为症状性颅内动脉粥样硬化性狭窄(以下简称症状性颅内动脉狭窄),是TIA和缺血性中风复发高危因素,二级预防的重点。症状性颅内动脉狭窄发病机制与狭窄远端血流动力性障碍、狭窄部位不稳定斑块导致血栓形成或脱落、狭窄部位穿支血管闭塞有关,治疗方面包括内科治疗(西医内科治疗和中西医结合内科治疗)、外科治疗(血管内治疗和血管吻合术,前者为主)；由于临床较难正确分析症状性颅内动脉狭窄发病机制,西医内科治疗仍有较高的中风复发,血管内治疗仍有较高的围手术期并发症发生率和支架术后再狭窄率,采用何种治疗方法进行安全有效的二级预防,一直是困扰临床医生的难题,寻找合理、安全、有效的二级预防治疗方案,具有十分重要的临床意义。氙CT (Xenon-CT)是一种可以定量测定、安全可靠、成本较低的评价脑血流灌注的技术,高分辨MRI(high-resolution MRI, HR-MRI)在研判血管狭窄部位斑块特征方面有明显优势；应用Xenon-CT和HR-MRI可以了解和分析症状性颅内动脉狭窄部位斑块特征和远端血流动力学变化,结合其他影像学检查,有助于分析发病机制；广东省中医院脑病中心多年实践表明,在“中医阴阳类证”辩证论治体系指导下的中西医结合缺血性中风二级预防方案疗效确切,明显改善患者的预后,针对症状性颅内动脉狭窄,该方案显示出一定的优势。本研究旨在Xenon-CT和HR-MRI指导下,分析症状性颅内动脉狭窄发病机制,依据前瞻性设计的适应证标准,制定合理的中西医结合内科治疗方案或外科治疗方案,评估中西医结合治疗方案的安全性和有效性(降低缺血性中风复发率,降低支架术围手术期并发症率和术后再狭窄率),获得有价值的临床研究数据,为进一步深入研究获得症状性颅内动脉狭窄二级预防治疗方案的循证医学证据奠定基础。
方法：
对2010年7月至2012年2月收治的缺血性小中风、TIA和椎基底动脉供血不足的患者,首先进行常规影像学检查(CT/CTA、MRI/MRA、DSA),然后对筛选出来的20例与小中风、TIA或椎基底动脉供血不足相关的症状性颅内动脉狭窄(狭窄率≥50%)患者,进行Xenon-CT和HR-MRI检查,根据综合检查结果、前瞻性设计的适应证标准以及入组原则,将20例患者分成中西医结合强化内科治疗组(简称内科治疗组)和中西医结合强化内科治疗组+血管内治疗组(简称血管内治疗组)。中西医结合强化内科治疗方案：在强化西医内科治疗(双联抗血小板、强化降脂、积极控制危险因素)的基础上根据中医辩证原则分为阴类证和阳类证,分别予以相应的中药治疗,治疗周期为3周；血管内治疗方案：采用WINSPAN支架系统对靶血管进行血管内支架成形术。主要临床结局指标是：分别评价每组30天内再中风率和死亡率,30天后临床随访,记录每组再发缺血性中风的情况,分析每组的短期随访结果,同时对Xenon-CT和HR-MRI检查结果以及其他临床相关信息进行分析。
结果：
1.一般情况：纳入20例症状性颅内动脉狭窄患者,其中TIA患者7例,急性脑梗塞患者11例,椎基底动脉供血不足2例。男性患者14例,女性患者6例；年龄41～87岁,平均年龄64.75±8.96岁。常规影像学评价发现症状相关的前循环颅内动脉狭窄17例(其中颈内动脉颅内段狭窄3例,大脑中动脉M1段狭窄12例,大脑中动脉M2段狭窄1例,大脑前动脉A1段狭窄1例),后循环颅内动脉狭窄3例(其中椎动脉颅内段狭窄1例,基底动脉狭窄2例)。中度狭窄(50%～69%)11处,全部位于前循环；重度狭窄(≥70%)9处,其中6处位于前循环,3处位于后循环。
2.Xeon-CT和HR-MRI检查结果：17例前循环颅内动脉狭窄患者全部接受Xenon-CT检查,其中4例接受HR-MRI检查。Xenon-CT检查发现靶血管远端供血区局部血流量正常者12例,其中3例HR-MRI检查提示局部血管壁斑块异常信号；Xenon-CT检查发现靶血管远端供血区局部血流量异常者5例,其中1例HR-MRI检查提示动脉夹层。3例后循环颅内动脉狭窄接受HR-MRI检查,1例椎动脉颅内段狭窄提示局部混合性斑块形成(不稳定斑块),2例基底动脉狭窄,1例显示偏心型斑块,与穿支关系不密切,1例提示中重度阴性重塑形。对于靶血管远端供血区局部血流量异常表现情况,狭窄程度(50%～69%)和(≥70%)之间差异有统计学意义(P<0.05),显示对于中度的症状性前循环颅内动脉狭窄血流动力学障碍不是其主要的发病机制。对于是否发生TIA, Xenon-CT结果正常者和Xenon-CT结果异常者相比,差异有统计学意义(P<0.05),显示前循环TIA的发生主要与狭窄远端血流动力学障碍有关。血管内治疗组2例Xenon-CT结果异常者,分别有5处和1处分区的局部脑血流量,在血管内治疗前后差异有统计学意义(P<0.05),提示通过血管内治疗可以显著改善狭窄远端供血。应用多个独立样本T检验(Kruskal Wallis检验)比较HR-MRI对斑块特征(斑块的形态、斑块的性质、斑块与穿支的关系、斑块的重塑形、斑块强化、夹层、假性狭窄)的检出情况,显示针对斑块性质的检出与判断,磁共振尚没有良好的表现；对于斑块的形态、与穿支的关系、重塑形情况、强化、夹层、假性狭窄等的检出有良好表现。
3.分组情况以及中医辩证分型结果：14例入选内科治疗组；其中2例为靶血管远端供血区局部血流量异常者(根据标准拟入选血管内治疗组,患者本人拒绝手术而入选内科治疗组),1例为基底动脉狭窄(HR-MRI提示中重度阴性重塑形,考虑血管内治疗风险大而入选强化内科治疗组)；中医辩证分型,阴类证9例,阳类证5例；6例入选血管内治疗组,3例为大脑中动脉狭窄(Xenon-CT检查发现靶血管远端供血区局部脑血流量异常),1例为大脑中动脉狭窄(Xenon-CT检查发现远端靶血管供血区局部脑血流量正常,内科治疗期间再发同侧缺血性中风,考虑予以狭窄血管内支架成形术而入组),1例为基底动脉狭窄(HR-MRI检查提示偏心型斑块,斑块与重要穿支的关系不密切),1例为椎动脉颅内段狭窄；中医辩证分型,阴类证5例,阳类证1例。
4.短期治疗结果：30天内,内科治疗组无再中风和死亡发生,血管内治疗组1例(基底动脉狭窄)术后即刻发生桥脑短旋支供血区的梗死,经治疗未遗留神经功能障碍,无死亡；30天后所有患者接受临床随访,随访周期3个月至14个月,平均7.4个月,其中内科治疗组发生1例同侧再次缺血性中风(为原先拟入选血管内治疗组的病例,入组后第4个月发生同侧中风),经治疗未遗留神经功能障碍,如果将2例为靶血管远端供血区局部脑血流量异常者(根据标准拟入选血管内治疗组,患者本人拒绝手术而入选内科治疗组)剔除,12例内科治疗组病例,平均7.4个月的随访周期内无1例发生同侧再次中风；血管内治疗组发生1例同侧再次缺血性中风(术后第2月),治疗后遗留轻度神经功能障碍。在主要终点事件方面(30天内再中风和死亡率以及30天后的短期随访周期内的再中风和死亡率),本研究内科治疗组低于SAMMPRIS试验内科治疗组。
结论：
1.Xenon-CT可以筛选出前循环症状性颅内动脉狭窄存在血流动力学障碍的患者,有助于选择适合的治疗方式,对治疗后局部脑血流量的测定有助于评价治疗后的血流动力学变化以及治疗效果；HR-MRI可以判断斑块的形态、斑块与穿支的关系、狭窄段血管重塑形情况,有助于术前判断血管内治疗的风险,进而选择相对安全的治疗方式；血流动力学障碍不是症状性前循环颅内动脉中度狭窄的主要发病机制；前循环症状性颅内动脉狭窄引发的TIA主要与狭窄远端血流动力学障碍有关。
2.在Xenon-CT和HR-MRI指导下,结合常规影像学检查有助于研判和查明症状性颅内动脉狭窄的发病机制,在此基础上制定的治疗方案具有较强的针对性以及较好的安全性和短期临床疗效。
3.短期结果提示,中药结合西医内科强化治疗可能促使狭窄段不稳定斑块向稳定的状态转变,有助于减少缺血性中风的发生；内科治疗组较低的同侧中风发生率可能与中药治疗稳定狭窄段斑块、抑制其血栓形成或脱落有关。
4.针对高危病例(低灌注、不稳定斑块),中西医结合强化内科治疗的最佳方案有待于进一步研究；本项研究中长期的临床疗效有待于长期随访观察或临床随机对照试验的进一步验证。
Objective
Intracranial atherosclerosis stenosis is the leading cause of ischemic stroke and TIA in our country, clinically, intracranial atherosclerotic stenosis with occurrence of TIA or cerebral infarction is defined as symptomatic intracranial arterial stenosis, which is the risk of recurrence of TIA and ischemic stroke, therefore the main point of secondary prevention. The pathogenesis of symptomatic intracranial arterial stenosis is related to distal hemodynamic disorder, thrombosis or embolus dislodgement due to unstable plaque, perforator occlusion, etc. Treatment strategies include Medical treatment (Western medicine treatment and Integrative Chinese and Western medicine treatment) and Surgical treatment (Mainly Endovascular treatment and vascular anastomosis). Western medicine treatment has a rather high recurrent stroke rate, while Endovascular treatment is facing the risk of perioperative complication and post procedure restenosis in stent. Due to the difficulties of accurate analysis of the pathogenesis of symptomatic intracranial arterial stenosis in clinical practices, the choice of a safe and effective treatment approach for secondary prevention remained controversial. Xenon computed tomography (Xenon-CT) is a quantitative determinable, safe, reliable and low cost means to evaluate cerebral perfusion, and high-resolution MRI (HR-MRI) has an advantage in analyzing the feature of plaque. With the application of the Xeon-CT and HR-MRI for symptomatic intracranial arterial stenosis, understanding and analyzing of the feature of plaque in site and distal hemodynamic changes should be achieved, combined with other imaging findings, could allow to analyze the pathogenesis of symptomatic intracranial arterial stenosis. On the other hand, the many years of practice of encephalopathy center of Guangdong Provincial Hospital has shown that Integrative Chinese and Western medicine treatment is safe and effective as a secondary prevention strategy of ischemic stroke, and can significantly improve prognosis, especially for patients with symptomatic intracranial arterial stenosis. This study was designed to analysis the pathogenesis of symptomatic intracranial arterial stenosis under the guidance of the Xenon-CT and the HR-MRI, and to evaluate the safeness and effectiveness of Integrative Chinese and Western medicine treatment.
Methods
20patients with symptomatic intracranial arterial stenosis patients (administrated from January2010to February2012), with stenosis rate greater than or equal to50%, were engaged with Xenon-CT and HR-MRI examination. Based on the test result, the patients were divided into Integrative Medical Treatment group and Endovascular Treatment group. Patients within Integrative Medical Treatment group were given Traditional Chinese Medicine besides western medicine treatment (double antiplatelet regimen, intensive hypolipemic treatment and active controll of risk factors), treatment period lasted for3weeks, while patients within Endovascular treatment group underwent intravascular stenting of target vessel with WINSPAN stent system. Then analysis the recurrent stroke rate and mortality rate and mordality rate within30days and beyond30days during follow-up period.
Result
1. Of20patients with symptomatic intracranial arterial stenosis,7cases presented with TIA,11cases with acute infraction and2cases with Vertebrobasilar insufficiency. Number of male and female patient is14and6separately, age ranging from41-87, with an average of64.75±8.96. of17cases located in the anterior circulation,3cases was located at Intracranial internal carotid artery,12cases Ml section of MCA,1case M2section of MCA and1case A1section of ACA. And the other3cases located in the posterior circulation,1case was located at intracranial segment of vertebral artery,2cases basilar artery. Amoung them, there are11cases with moderate stenosis (stenosis rate up to50～69%), all located in the anterior circulation, and9cases with severe stenosis (stenosis rate up to more than70%),6located in the anterior circulation, the other3located in the posterior circulation.
2.17cases with intracranial arterial stenosis in the anterior circulation received Xenon-CT examination, and4of17cases received HR-MRI examination. Xenon-CT showed normal regional cerebral blood flow in12cases, and abnormal plaque signal of vessel wall was detected via HR-MRI in3cases. Xeon-CT showed showed a decrease of CBF in related brain area in5cases, and HR-MRI showed arterial dissection in1case of5cases. The other3cases with intracranial arterial stenosis in the posterior circulation received HR-MRI examination, which showed mixed plaque (unstable plaque) in the patient with intracranial segment of vertebral stenosis, and of the other2cases of basilar artery stenosis, eccentic plaque formation (not in close relation with perforating branches) was seen in one case, and severe negative reconstruction of vessel wall in the other case. There is a significant difference of CBF value between moderate and severe stenosis of target vessel (P<0.05), which demonstrated that for patients with moderate stenosis, hemodynamic dysfunction is not the primary pathogenesis. There is also a significant difference of TIA attack incidence between patients with normal and abnormal Xenon-CT result (P<0.05), which demonstrated that the incidence of TIA in the anterior circulation is related to distal hemodynamic disorder.2cases from Endovascular treatment group showed significant increase of CBF after operation compared to that before operation (P<0.05), and this result allow to support the theory that endovascular treatment can improve distal blood supply. Kruskal Wallis test showed that HR-MRI has a favorable outcome of reliability in detecting morphology of plaque, relationship of plaque with perforators, reconstruction, enhancement, dissection and pseudostenosis, while not reliable in analysis about characteristic of plaque.
3.14cases were selected for the Integrative Medical treatment group, among them2cases with a decrease in CBF in related brain area shown by Xenon-CT (originally included into the Endovascular treatment group, but transfered into Integrative Medical treatment group due to declination to operation), and1case of basilar stenosis (HR-MRI showed severe negative reconstruction) was included into Integrative Medical treatment group due to the consideration on high operative risk.9cases of them were regarded as the "Yin" kind of Traditional Chinese Medicine, while the other5the "Yan" kind.6cases were selected for Endovascular treatment group, and of6cases3cases of MCA stenosis with a decrease in CBF in related brain area shown by Xenon-CT,1 case of MCA stenosis with normal CBF in related brain area shown by Xenon-CT (underwent recurrent ipsilateral ischemic stroke while receiving standard western medicine treatment), and1case of basilar artery stenosis (HR-MRI show eccentric plaque formation, not in close relation with perforating branches) and1case of vertebral artery stenosis.5cases of them were regarded as the "Yin" kind of Traditional Chinese Medicine, while the other1the "Yan" kind.
4. Within30days, no cases of recurrent stroke and death in the Integrative Medical treatment group, and infarction of pons occurred in1case(basilar artery stenosis) from the endovascular treatment group postopratively without neurological dysfunction after treatment. During the Follow-up period ranges from3months to10months with an average of6.5months,1case from the Integrative Medical treatment group suffered from ipsilateral ischemic stroke (4month after discharge)without neurological dysfunction after treatment, and1case from the Endovascular treatment group suffered from ipsilateral stroke(2months after operation)with mild neurological dysfunction after treatment. If to exclude the2cases with decrease in CBF in related brain area (originally included into the Endovascular treatment group, but transfered into Integrative Medical treatment group due to declination to operation), among the12cases from Integrative Medical treatment group, within the follow-up period of an average of7.4months, none of ipsilateral recurrent stroke took place, comparing with1case from Endovascular treatment group suffered from ipsilateral recurrent stroke (2months after operation) with mild neurological dysfunction after treatment. In the term of End Event (recurrent stroke rate and morality and modality within30days and beyond30days), the result of Integrative Medical treatment group in our study was lower than the medical treatment group in SAMMPRIS study.
Conclusion
1. Xenon-CT can filter out hemodynamic disorder in the patients with sympomatic intracranial arterial stenosis of anterior circulation, and to determinate the appropriate treatment and evaluate hemodynamic changes after treatment and effectiveness of endovascular treatment. HR-MRI can detect morphology of plaque, relation of plaque with perforators, reconstruction, which allow to evaluate the risk of endovascular treatment. Hemodynamic disorder is not the primary pathogenesis of moderate symptomatic intracranial arterial stenosis of the anterior circulation. TIA caused by symptomatic intracranial arterial stenosis in the anterior circulation is related to distal hemodynamic disorder.
2. Xenon-CT and HR-MRI combined with conventional imaging had significant direction in formulating a individual and safe treatment strategy with desirable short term efficacy.
3. Analysis of short term result suggest that Integrated Chinese and Western Medicine treatment might promote conversion of the unstable plague into stable plaque, so as to reduce the rate of recurrent ischemic stroke. The low ipsilateral recurrent ischemic stroke rate from the Integrated Chinese and Western Medicine group might be related to the stabilization of plaque and inhibition to thrombosis, thrombus dislodgement, which suggest that Tradition Chinese Medicine might play a positive role in this process.
4. Further research is needed to determine the efficacy of Integrative Chinese and Western Medicine treatment on high risk patients (complicated with hypoperfusion and unstable plaque). The medium and long term efficacy of this study still needs further validation from long term follow-ups or clinical randomized controlled trials.
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