1、隐源性卒中（Cryptogenic Strokes）2022-5-28北美和欧洲研究北美和欧洲研究2022-5-28332022-5-28CSCS定义的演变定义的演变1988年，Mohr在新英格兰医学杂志最先提出CS这一概念，并将其定义为“缺乏已知危险因素的卒中”。Mohr JPN Ensl J Med，1988，318(18)：1197-11981989年，Sacco等注意到40的脑梗死患者经过积极排查后仍不能明确其原因，将这类脑梗死称为CS。Saeco RL，et al.Ann Neurol，1989，25(4)：382-3901993年，Adams等进一步将原因不明型的缺血性卒中分为3种
2、情况：未接受全面评价者；发现两种或多种可能的病因，但不能明确哪种病因是脑梗死的实际原因此种情况被称为两种或多种病因亚型（(two or more causes，TMC)；经过积极排查后仍找不到原因的缺血性卒中。(TOAST criteria）Adams HP Jr，et al.Stroke，1993，24(1)：35-412022-5-28CSCS定义的演变定义的演变2009年，Timsit和Breuilly等明确将CS定义为，尽管经过积极排查，仍有部分脑梗死缺乏可以解释其发生的原因，称之为隐源性脑梗死。Timsit S，Breuilly CPresse Med，2009，38(12)：183
3、218422014年，Hart 等建议用ESUS（Embolic strokes of undetermined source）Hart RG,et al. Lancet Neurol 2014; 13: 429382022-5-28Potential sources of thromboembolism underlying ESUSMinor-risk potential cardioembolic sources*（50%）Mitral valve（二尖瓣） Myxomatous valvulopathy with prolapse（伴脱垂的粘液瘤样心瓣膜病） Mitral annula
4、r calcifi cation（二尖瓣环形钙化）Aortic valve(主动脉瓣）主动脉瓣） Aortic valve stenosis（主动脉瓣狭窄） Calcifi c aortic valve（主动脉瓣钙化）Non-atrial fibrillation atrial dysrhythmias and stasis Atrial asystole and sick-sinus syndrome（房性停博和病窦综合征） Atrial high-rate episodes Atrial appendage stasis with reduced fl ow velocities or s
5、pontaneous echodensitiesAtrial structural abnormalities（房间隔异常）（房间隔异常） Atrial septal aneurysm（房中隔动脉瘤） Chiari networkLeft ventricle（左心室）（左心室） Moderate systolic or diastolic dysfunction (global or regional)（中度收缩期或舒张期功能障碍） Ventricular non-compaction Endomyocardial fibrosis（心内膜心肌纤维化）2022-5-287Potential s
6、ources of thromboembolism underlying ESUSCovert paroxysmal atrial fibrillation（隐匿性阵发性房颤）（隐匿性阵发性房颤）（1020%）Cancer-associated Covert non-bacterial thrombotic endocarditis Tumour emboli from occult cancerArteriogenic emboli（15%）（动脉源性栓塞）（动脉源性栓塞） Aortic arch atherosclerotic plaques Cerebral artery non-ste
7、notic plaques with ulcerationParadoxical embolism（反常栓塞）（反常栓塞） Patent foramen ovale（卵园孔未闭）（25%） Atrial septal defect（房间隔缺损） Pulmonary arteriovenous fistula（肺动静脉动瘘）*Minor-risk sources are more often incidentally present than is the stroke cause when identified in an individual stroke patient, are asso
8、ciated with a low or uncertain rate of initial stroke, and consequently cause-effect relation and management implications are usually unclear.2022-5-28Criteria for diagnosis of ESUD Stroke detected by CT or MRI that is not lacunar Absence of extracranial or intracranial atherosclerosis causing 50% l
9、uminal stenosis in arteries supplying the area of ischaemia No major-risk cardioembolic source of embolismNo other specific cause of stroke identifi ed (eg, arteritis, dissection, migraine/vasospasm, drug misuse)2022-5-28Proposed diagnostic assessment for ESUDBrain CT or MRI12-lead ECGPrecordial ech
10、ocardiography(transoesophageal echocardiography)Cardiac monitoring for 24 h with automated rhythm detection Imaging of both the extracranial and intracranial arteries supplying the area of brain ischaemia (catheter, MR, or CT angiography, or cervical duplex plus transcranial doppler ultrasonography)
11、2022-5-28Stroke recurrence ratesThe reported rate of recurrent stroke varies widely, of 36% per year varying criteria for diagnosis non-standardised antithrombotic treatment varying prognostic factors(particularly mean patient age)Young patients (average age mid-40s) with PFO :12% per year when give
12、n asprin.older patients with PFO: 14% per year in one report2022-5-2811Antithrombotic therapy for secondary stroke prevention in ESUSThe only randomised assessment of anticoagulation in cryptogenic stroke is the subgroup analysis of the Warfarin-Aspirin Recurrent Stroke Study (WARSS) done between 19
13、93 and 2000.2206 patients, 30 and 85 years with recent (30 days) ischaemic stroke who were randomly assigned to aspirin 325 mg per day or adjusted-dose warfarin (target internationalnormalised ratio INR 14282022-5-28the primary outcome of ischaemic stroke or death : 150% warfarin versus 165% aspirin
14、 over 2 years.the 2 year rate of recurrent ischaemic stroke or death was 12% with warfarin versus 18% with aspirin (HR 066, 95% CI 0412).WARSS subgroup support the notion that anticoagulation2022-5-28The oral factor Xa inhibitors apixaban and rivaroxaban, and the oral direct thrombin inhibitor dabig
15、atran, are at least as efficacious as warfarin for prevention of stroke in patients with atrial fibrillation, and have significantly lower rates of intracranial bleeding.No randomised trials have tested anticoagulants in patients with cryptogenic strokes associated with PFO.Little is known about the
16、 relative efficacy of anticoagulant versus antiplatelet therapy for secondary stroke prevention for arteriogenic embolism to the brain, but available data support greater efficacy of anticoagulants. 2022-5-28Guideline recommendations for secondary preventionrecommend antiplatelet therapy 2008 Americ
17、an College of Chest Physicians guideline 2008 American Heart Association guideline do not comment specifi cally on cryptogenic stroke, but recommend antiplatelet therapy for patients with non-cardioembolic ischaemic stroke. The European Stroke Organisation guideline the 2011American Heart Associatio
18、n revised guideline the 2012 American College of Chest Physicians guideline the 2010 Canadian Best Practice Recommendations for Stroke Care2022-5-28CSCS诊断思路诊断思路强调：费用一疗效比适当、常见病的不漏诊和可治性疾病的确诊。临床上应该重点考虑以下4种疾病： 卵圆孔未闭(patent foramen oval，PF0) 动脉夹层 主动脉粥样硬化斑块形成 Fabry病2022-5-2816卵圆孔未闭卵圆孔未闭PFO是目前最受到关注的CS的病因，4
19、3.9% Handke M, et al. N Engl J Med 2007;357:2262-2268诊断：TEE和TCD的发泡试验，这2种检查的敏感度和特异度都在90以上。对于55岁以下的CS患者TCD或者TEE检查是必要的项目。大的PF0或合并房间隔动脉瘤的PF0，推荐介入（Amplatzer occluder device）或手术治疗，降低卒中的复发。2022-5-28PFO和通过PFO的深静脉血栓导致了导致了4.5%-5%卒中发生卒中发生 2022-5-2818卵园孔未闭的筛查卵园孔未闭的筛查TCDTCD2022-5-28PFO诊断方法比较2014国际卒中大会（ISC）2022-5
20、-28Magnetic resonance imaging scan showing multiple small ischemic Magnetic resonance imaging scan showing multiple small ischemic lesions on FLAIR sequence.lesions on FLAIR sequence.2022-5-28动脉夹层动脉夹层青年卒中，动脉夹层是重点考虑的诊断外伤、颈部按摩或过伸动作，迅速的转头，剧烈的Valsalva动作都可以引起颅内、外血管的夹层出现。典型的病史，结合动脉影像的线样征、火焰征、波纹征、双腔征、活瓣征、半
21、月征，可以对患者作出诊断。一些没有明确病史的患者，也可以根据影像学检查结果直接作出高度怀疑的诊断。治疗一般以抗凝为主，也可以抗血小板治疗2022-5-28主动脉粥样硬化斑块形成主动脉粥样硬化斑块形成对于55岁以上的患者，优先考虑的诊断一些患者经过仔细检查也没有发现颅内、外血管和心脏的病变，并且排除了腔隙性脑梗死的可能，要进行TEE检查和CTA检查 对于升主动脉内膜中膜厚度超过4 mm的患者，其卒中的发生率很高 发现低回声、有溃疡或出血的斑块，其造成卒中的可能性更大。治疗ASA2022-5-28如何提高主动脉弓病变检出率？J Neurol Neurosurg Psychiatry 2010;81
22、:1306e1311TEETEE2022-5-2824CE-CTA84岁老年男性，主动脉弓多层螺旋CT (矢状位重建) 箭头所指为5mm厚主动脉弓处动脉粥样硬化斑块，伴有钙化以及低密度成分2022-5-28TEE与多层螺旋CT（MSCT）从急性缺血性卒中前瞻性研究的150例患者中选择30例病因不明的患者TEE共检测出8位患者 (29.6%) 存在主动脉弓斑块，而多层螺旋CT共检测出12位患者 (40%)存在主动脉弓斑块在检测主动脉弓斑块的大小和性质方面，多层螺旋多层螺旋CT比比TEE更敏感更敏感 Journal of Vascular and Interventional Neurology
23、2011;4(1):5-92022-5-28主动脉弓斑块与脑卒中复发和死亡风险516 例缺血性卒中患运用TEE评估斑块厚度及形态：斑块溃疡：血管腔面存在不连续压痕的斑块，其基底宽度和最大深度2毫米复杂性斑块：存在溃疡和/或可移动的斑块终点事件为2年随访时间内发生复发性卒中以及死亡事件Circulation. 2009;119:2376-23822022-5-28主动脉弓斑块与脑卒中复发和死亡风险Circulation. 2009;119:2376-23822022-5-28FabryFabry病病不明原因的青年人卒中，尤其是伴有肾功能损害者，要考虑Fabry病Fabry病认为是x染色体隐性遗传的鞘糖酯代谢障碍性疾病，但目前证实女性同样也可以发病Fabry病的常见表现是后循环卒中，前循环也可以出现散在的小血管阻塞样病灶提示症状包括肢端烧灼样疼痛、多汗、血管角质瘤、蛋白尿、心肌病、心律失常，胃肠功能紊乱的证据等影像学表现上，Fabry病可以出现双侧丘脑枕的T1高信号，部分患者有动脉扩张。最终确诊需要靠病理和基因学诊断Fabry病属于可治性疾病，但费用昂贵，需要终生服用。2022-5-28小结小结CI是一个复杂的疾病群通过一切最敏感的检查手段来查找患者的卒中病因，不轻易作出隐源性卒中的诊断可试用抗凝治疗2022-5-28Thanks!
