医源性脑淀粉样血管病的研究进展

doi:10.11817/j.issn.1673-9248.2024.04.013

医源性脑淀粉样血管病（iCAA）是由既往医疗操作引发的脑小血管病，常表现为青年人群的自发性脑叶出血。目前临床医师对这一新兴概念尚缺乏认识，同时该病的医源性暴露途径及背后机制尚不明确。明确医源性暴露途径不仅有助于诊断，而且对散发性淀粉样血管病的发病机制将有所启迪，也可能影响脑出血患者的手术决策。因此，笔者查阅文献，追溯最早的相关病例，对不同医源性暴露途径、临床影像表现及预后进行综述，并探讨未来可能的研究方向。

关键词: 医源性脑淀粉样血管病, β淀粉样蛋白传播, 朊蛋白

Iatrogenic cerebral amyloid angiopathy (iCAA) is a small vessel disease caused by previous medical procedures, typically manifesting as spontaneous lobar hemorrhage, primarily among the middle-aged population. However, this emerging concept has not been fully recognized by most clinicians, along with the exposure sources and underlying mechanism. Clarifying these issues not only aids in diagnosis, but also provides insights into the pathogenesis of sporadic CAA. Besides, it might facilitate decision-making for those CAA-related hemorrhage patients. Therefore, we reviewed the literature, traced the earliest cases, and summarized the different exposure sources and clinical features of iCAA.

Key words: Iatrogenic cerebral amyloid angiopathy, Amyloid-β transmission, Prion

图1 医源性脑淀粉样血管病相关文献纳入及排除流程

表1 2022年Queen Square iCAA诊断标准^[9]

诊断条目	具体诊断依据
1.发病年龄	强烈建议：55岁前出现症状（即<Boston 1.5标准的诊断年龄）。注：不能仅根据年龄排除诊断，如果55岁以上的人符合其他标准（详见下文），则应考虑诊断
2.潜在接触史	强烈建议：手术或治疗过程中使用尸源性中枢神经组织（即脑、脑膜、垂体源性激素）；相关神经外科手术（即涉及脑、脊髓、后眼的手术）。注：如果有其他潜在暴露史并符合所有其他诊断标准，可考虑诊断
3.临床和影像特征与散发性CAA一致	临床表现：在发病时或病程中至少有以下一项表现。（1）ICH或蛛网膜下腔出血（单次或多发）；（2）短暂局灶性神经发作（淀粉样蛋白发作）；（3）局灶性癫痫发作（伴或不伴继发广泛性发作）；（4）非其他原因（包括急性卒中）引起的认知障碍。影像学：至少有以下一项。（1）CT影像：脑叶出血；凸面蛛网膜下腔出血；（2）MRI（血敏感序列；T2*-GRE，SWI）影像：微出血主要分布在脑叶，并远离ICH部位；磁敏感序列出现脑皮质表面铁沉积（局灶性或弥漫性）
4.有证据支持Aβ在中枢神经系统沉积	Aβ-PET阳性；相关脑脊液证据（Aβ 42、Aβ 40减少）；脑活检提示血管Aβ沉积，且没有明显炎症。注：Aβ-PET阳性不一定是血管Aβ的特异性沉积，这与所使用的示踪剂相关。建议同时参考脑脊液、脑活检结果和（或）CAA相关基因的检测（见下文）。如存在明显炎症，则诊断为CAA相关炎症或Aβ相关血管炎
5.排除中枢系统Aβ疾病的遗传因素	APP序列重复（包括21三体综合征）；APP，PSEN1，PSEN2基因突变。如果不能用其他方法证实中枢系统Aβ沉积（如脑脊液、脑活检），则应考虑对非Aβ致病的CAA突变基因（CST3、TTR、GSN、PRNP、ITM2B）进行测序
在生前诊断为很可能的iCAA，需至少满足第2、3、4和5条标准，特别是相关暴露史。如果符合标准1、2和3，则诊断为可能的iCAA

表1 2022年Queen Square iCAA诊断标准^[9]

诊断条目	具体诊断依据
1.发病年龄	强烈建议：55岁前出现症状（即<Boston 1.5标准的诊断年龄）。注：不能仅根据年龄排除诊断，如果55岁以上的人符合其他标准（详见下文），则应考虑诊断
2.潜在接触史	强烈建议：手术或治疗过程中使用尸源性中枢神经组织（即脑、脑膜、垂体源性激素）；相关神经外科手术（即涉及脑、脊髓、后眼的手术）。注：如果有其他潜在暴露史并符合所有其他诊断标准，可考虑诊断
3.临床和影像特征与散发性CAA一致	临床表现：在发病时或病程中至少有以下一项表现。（1）ICH或蛛网膜下腔出血（单次或多发）；（2）短暂局灶性神经发作（淀粉样蛋白发作）；（3）局灶性癫痫发作（伴或不伴继发广泛性发作）；（4）非其他原因（包括急性卒中）引起的认知障碍。影像学：至少有以下一项。（1）CT影像：脑叶出血；凸面蛛网膜下腔出血；（2）MRI（血敏感序列；T2*-GRE，SWI）影像：微出血主要分布在脑叶，并远离ICH部位；磁敏感序列出现脑皮质表面铁沉积（局灶性或弥漫性）
4.有证据支持Aβ在中枢神经系统沉积	Aβ-PET阳性；相关脑脊液证据（Aβ 42、Aβ 40减少）；脑活检提示血管Aβ沉积，且没有明显炎症。注：Aβ-PET阳性不一定是血管Aβ的特异性沉积，这与所使用的示踪剂相关。建议同时参考脑脊液、脑活检结果和（或）CAA相关基因的检测（见下文）。如存在明显炎症，则诊断为CAA相关炎症或Aβ相关血管炎
5.排除中枢系统Aβ疾病的遗传因素	APP序列重复（包括21三体综合征）；APP，PSEN1，PSEN2基因突变。如果不能用其他方法证实中枢系统Aβ沉积（如脑脊液、脑活检），则应考虑对非Aβ致病的CAA突变基因（CST3、TTR、GSN、PRNP、ITM2B）进行测序
在生前诊断为很可能的iCAA，需至少满足第2、3、4和5条标准，特别是相关暴露史。如果符合标准1、2和3，则诊断为可能的iCAA

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