多模态影像学预测脑梗死后出血性转化的研究进展
Research Progress of Multi-Modal Imaging in Predicting Hemorrhagic Transformation af-ter Ischemic Stroke
DOI: 10.12677/ACM.2022.1281140, PDF, HTML, XML, 下载: 52  浏览: 71 
作者: 李宝娜:青海大学研究生院,青海 西宁;张庆欣*:青海省人民医院,青海 西宁
关键词: 多模态影像脑卒中出血性转化预测因素Multi-Modal Image Stroke Hemorrhagic Transformation Predictors
摘要: 脑梗死后出血性转化是与急性缺血性卒中相关的最常见的不良事件之一,影响到治疗方案和临床预后评价。本文总结了不同的影像学方法和影像学生物标志物,包括计算机断层扫描、磁共振成像、血管造影成像等方法在预测HT方面的作用,同时也包括不同的影像学生物标志物指标,如早期缺血改变、大的缺血病灶体积、严重的血流受限情况、血脑屏障破坏、不良的侧支循环形成和血流速度高等都与HT风险相关。
Abstract: Hemorrhagic transformation is one of the most common adverse events associated with acute is-chemic stroke, which affects treatment and clinical prognosis. This paper summarizes the role of different imaging methods and imaging biomarkers, including computed tomography, magnetic resonance imaging and angiography in predicting HT, as well as different imaging biomarker indi-cators. For example, early ischemic changes, large ischemic lesion volume, severe blood flow re-striction, destruction of blood-brain barrier, poor collateral circulation formation and high blood flow velocity are all associated with the risk of HT.
文章引用:李宝娜, 张庆欣. 多模态影像学预测脑梗死后出血性转化的研究进展[J]. 临床医学进展, 2022, 12(8): 7911-7918. https://doi.org/10.12677/ACM.2022.1281140

1. 引言

脑梗死后出血性转化(Hemorrhagic transformation, HT)是急性缺血性卒中(Acute Ischemic Stroke, AIS)的常见并发症,常由再灌注治疗引起,早期预测HT可避免临床恶化,并制定最佳治疗方案,并且延长再灌注治疗时间窗口,要求更准确地预测HT倾向,所以,采用多模态影像学技术可以进行更加个性化和精确的HT预测,是未来的发展目标。

HT根据出血方式分为出血性脑梗死(hemorrhagic infarction, HI)和脑实质血肿(parenchymatous hematoma, PH),目前最常用的分型是欧洲急性卒中研究II (European Cooperative Acute Stroke Study II, ECASS-II) [1],其将HT细分为4型,不同的出血方式对功能影响不同,其中PH2型与预后关系最为密切。根据ECASS III标准 [2],结合临床症状,症状性颅内出血(symptomatic intracranial hemorrhage, sICH)是指脑内出血与美国国立卫生研究院卒中量表(national institute of health stroke scale, NIHSS)评分增加 ≥ 4分相关,或导致死亡。目前对HT机制的研究多归因于缺血程度而非低灌注程度,即使半影区/低灌注病变的体积在临床结果中起作用,但无论何种类型的再灌注治疗,它与AIS患者的HT关系有限,大量相关的影像学标志物已被证明能充分代表卒中病灶的缺血程度,因此有助于对HT风险的预测。

2. HT的危险因素

研究表明HT与脑缺血引发细胞、代谢和炎症反应,导致血脑屏障(blood brain barrier, BBB)的破坏和脑血管的自调节能力受损,使其在缺血组织再灌注时易发生血管外渗有关 [3]。诸多临床因素与HT风险增加相关[4],如高龄、高血压病史、房颤、心源性卒中、高NIHSS、高血糖、低脂蛋白(总胆固醇和低密度脂蛋白)、球蛋白水平升高、蛋白尿、血小板计数降低等与HT有关,其中,NIHSS评分可评估患者神经功能损伤程度,评分越高代表患者大脑遭受不可逆性神经功能损伤越重,因此更易发生HT [4];高血糖可加重动脉壁的缺氧和营养不良,使动脉壁容易变性和坏死,诱发HT [4];心房颤动是引发心源性栓塞型脑梗死的主要因素,在缺血性卒中患者中,房颤的存在与严重的低灌注量有关,导致了梗死面积的扩大,最终梗死体积的增加,更频繁的严重HT,更差的卒中结局 [5]。另外,延迟再灌注,重组组织型纤溶酶原激活剂(recombinant tissue type plasminogen activator, rt-PA)静脉溶栓,同时使用抗血栓药物或抗凝剂,纤溶剂和血管内治疗均为HT的相关危险因素 [3]。

3. CT扫描

3.1. 非造影剂CT (The Non-Contrast Computed Tomography, NCCT)

由于脑部NCCT仍然是AIS患者的首选检查。可通过早期细微征象来预测HT,包括豆状核和岛叶分界消失,高密度脑动脉征(hyperdense middle cerebral artery sign, HMCAS)有研究表明 [6] HMCAS能独立预测溶栓治疗后的HT。亦有研究表明HMCAS的出现与侧支循环间的联系 [7],HMCAS与软脑膜侧支循环不良、卒中严重程度和急性卒中时神经预后不良有关 [8]。早期CT低密度面积 < 1/3 (OR 3.17, 95% CI 1.42至7.04)和面积 > 1/3大脑中动脉区域(OR 9.38, 95% CI 3.68至23.90)是rt-PA静脉溶栓(intravenous thrombolysis, IVT)治疗后sICH的独立预测因素 [9]。在一项对118名接受IVT治疗的患者的研究中 [10],缺血区NCCT低密度的程度取决于低密度是否轻微(1级),类似于对侧白质的低密度(2级),或小于对侧脑白质(3级),NCCT低密度与PH (AUC 0.69; 95% CI 0.61~0.77)显著相关。ASPECTS评分(Alberta Stroke Program Early CT Score)是一种评估大脑中动脉供血区早期缺血性改变的半定量评分系统,将大脑中动脉供血区分为2个层面,10个区域,即核团层面(尾状核头、豆状核、内囊后肢和岛叶、M1、M2、M3)及核团以上层面(M4、M5、M6),区域都为1分,评分时从10分中减去相应的区域数目,可准确、快速地获得病灶大小的信息 [11],被广泛用于评估血管再通治疗适应证及预测患者预后,ASPECTS评分 < 7分的患者通常病情重、预后差,血管再通治疗后更易发生HT [12]。

另外,介入治疗后CT平扫的造影剂外渗情况可进一步判断缺血性卒中患者发生HT的风险,在一项研究中 [13],大血管闭塞患者机械取栓后即刻平扫CT上出现高密度征,即基底节内非点状脑内高密度灶(直径 ≥ 1 cm)内最大CT密度为 > 90 HU,可预测24小时内实质出血的发生,有助于介入治疗后24小时内的处理,高密度征是一种易于获得和可靠的基于NCCT的影像标志物,可能有助于识别取栓后PH风险较高的患者,并易于临床应用。

3.2. 双能CT (Dual-Energy Computed Tomography, DECT)

Jang [14] 等发现AIS血管内治疗后颅内碘对比剂外渗区域存在出血风险,且病灶密度越高出血几率越大。相对传统CT,DECT重组获得的碘图可以直接测量碘对比剂外渗区域的碘浓度,对碘外渗程度进行量化。在本研究中,病灶的最大碘浓度以2.7 mg I/ml为阈值预测发生HT的敏感度为73.7%,特异度92.5%,提示机械取栓术后颅内高碘浓度区域其BBB破坏及血管内皮细胞损伤较为严重,存在HT的可能性较低碘浓度区域大,DECT不仅可以早期准确诊断AIS机械取栓术后是否合并颅内出血,而且对预测HT有一定的价值。

3.3. CT血管造影术(Computed Tomography Angiography, CTA)

CT血管造影可以通过对侧支循环的评估从而预测HT发生的可能性,良好的侧支循环往往提示患者具有较低HT风险和良好的预后 [15]。患者治疗前的CTA图像更容易获取,所以应用CTA评价梗死区域侧支循环情况在急性脑梗死患者治疗选择上具有较大的临床应用价值,但是CTA图像受到扫描时间点影响,可能会低估或高估侧支循环情况,多时相CTA可进行更加有效评估脑侧枝循环状态,对于缺血性卒中IVT治疗后血管未再通者,HT风险与脑梗死核心密切相关 [15],而血管再通者HT风险与侧支循环不良密切相关,侧支循环良好、中等及不良组HT的发生率分别为7.4%、14.8%及34.1% [8]。通过计算患者在西尔维安裂隙内的侧支血管的最大脑血流(the maximum cerebral blood flow of collateral vessels, cCBFmax),评估西尔维安裂隙内的血管充盈状况,评估侧支循环,较高的cCBFmax是较低的HT风险的独立预测因素 [16]。

3.4. 计算机断层扫描灌注(Computed Tomography Perfusion, CTP)

CTP可以通过对脑血流量(cerebral blood flow, CBF)、脑血容量(cerebral blood volume, CBV)和平均通过时间(mean transit time, MTT)的定量评估来区分潜在可挽救的“半影区”和不可逆受损的脑组织“梗死核心”。 [17] Yassi及其同事研究了预测急性缺血性卒中PH的最佳CTP参数,在多变量逻辑回归模型中,血流达峰时间(time to maximum, Tmax) > 14 s和溶栓治疗都能独立预测PH值(P < 0.05),作者得出结论,Tmax > 14 s与PH关系最密切。在最近的一项meta分析中 [18],作者调查了CT灌注对急性缺血性卒中HT预测的诊断性能,其结果指出,从CT灌注得出的高BBB通透性和低灌注状态与HT有关,反应血脑屏障渗透性(blood-brain barrier permeability, BBBP)的两种最常见的方法是渗透性相关系数Ktrans和渗透性表面面积PS,其中Ktrans/PS升高代表BBB的破坏,由入院CTP得出的Ktrans/PS预测HT的敏感性为78%,特异性为76%。

4. MRI成像技术

MRI成像能够提供更加全面和更具代表性的各种参数来反映AIS后的缺血程度,并提供更多HT相关的影像标志物,从而指导临床医生应用这些方法对患者进行治疗前的综合评估,降低急性脑梗死血管内治疗后HT的发生率并减轻HT带来的不良结果。

4.1. 扩散加权成像(Diffusion Weighted Imaging, DWI)

DWI可以通过评估梗死范围大小来预测HT风险,DWI测得的核心梗死灶体积大小可以有效预测HT。此外,磁共振血脑屏障通透性参数恢复百分比能够有效反映BBB的损伤程度,从而评估急性缺血性卒中发生HT的风险。Campbell等 [19] 通过DWI序列分别对以0%、2.5%、5%和10%为阈值标准确定的极低脑血容量(very low cerebral blood volume, VLCBV)体积进行测量,表明以2.5%为阈值确定的VLCBV体积 > 2 mL患者在rt-PA溶栓治疗后发生HT的风险增加。由于预测HT的最佳MRI参数仍未达成共识,因此有必要进行更大规模和更全面的研究。一项对944名接受IVT治疗的患者研究表明 [20],MRI对sICH最可靠的预测因素是DWI序列显示的异常体积,同一项研究的结论是 [20],DWI异常体积为4 ml可以预测sICH,敏感性和特异性分别为78%和58%,超过其他MRI成像标记物,如FLAIR血管高信号和梗死灶内平均表观弥散系数(apparent diffusion coefficient, ADC),然而,4 ml的临界值远小于大血管闭塞的AIS患者的梗死灶,DWI病变体积仅反映了梗死灶的大小,而不是确切的缺血程度,这使得这一结果不太适用。另有研究 [21] 表明,相对ADC值(ADC ratio值) < 0.65也是预测HT的有效指标。DWI-ASPECTS评分是以CT的ASPECTS评分为基础在DWI图像上建立的评分方法,有研究发现 [22],当DWI-ASPECTS ≤ 5分可能是一个好的预测HT风险的阈值,测量DWI梗死体积更为精确,但需要有后处理测量工具,应用DWI-ASPECTS评分相对方便快捷。

4.2. T2液体衰减反转恢复序列(Fluid Attenuated Inversion Recovery, T2-FLAIR)

早期T2-FLAIR上的高信号可用于预测血管内治疗后HT的发生 [23]。已有研究表明,FLAIR高信号在3~6小时内预测PH的敏感性和特异性仅为40%和64% [24]。另外,在急性脑小血管病(cerebral small vessel disease, CSVD)的FLAIR高信号与白质高信号(white matter hyperintensity, WMH)很难区分。Sung-Ho Ahn等 [23] 在卒中急性期患者中发现,早期FLAIR改变与再灌注治疗后发生HT的风险相关,具有高度匹配的位置关系,尤其是MCA M1~M2段供血区的皮层–皮层下区域存在FLAIR早期高信号者,同部位HT发生率更高,可达68.8%。因此,鉴别FLAIR改变可能是评估接受再灌注治疗的患者继发HT可能性的有用工具。

4.3. 磁共振灌注成像(Perfusion-Weighted Imaging, PWI)

PWI能够提供更加全面反映灌注程度的参数来评价AIS后的缺血程度,而且在HT方面也发挥重要作用 [25]。有研究表明 [19] 极低脑血容量VLCBV2.5 (异常灌注区域较健侧下降大于2.5%的区域) > 2 mL和Tmax > 14 s被认为是再灌注治疗前对HT预测最可靠的指标。将灌注与其他预测方法联合应用,其预测能力可以进一步提升,在Campbell等 [19] 的研究中通过将VLCBV与DWI梗死体积相联合,明显提高HT的预测能力。另一项使用ASL和单光子发射计算机断层扫描(SPECT/CT)评估HT与再灌注后高灌注之间关系的研究中 [26] 发现,局部高灌注(同侧与对侧之比 > 1.5)与再灌注后HT有关(OR = 9.3; 95% CI, 1.4~64.0),动脉自旋标记(arterial spin labeling, ASL)再灌注后的过度灌注可作为HT的可靠标志物。Mishra等 [27] 研究了AIS患者在血管内介入治疗后VLCBV灌注参数对PH的预测作用,该研究结果显示预测PH的最佳阈值为rCBV < 0.42 (曲线下面积为0.77),在此阈值下,当VLCBV病变体积 ≥ 3.55 ml,对于PH预测的灵敏度为94%,特异度为63%,与没有VLCBV的患者比较,存在VLCBV的患者有更高的NIHSS评分。

4.4. 增强磁共振成像

造影剂给药后T1WI增强序列可能是评估HT风险的另一个重要工具,Warach等 [28] 报道144例rt-PA治疗的AIS患者,发现其中47例(33%)显示急性再灌注高信号征(hyperintense acute reperfusion marker, HARM),HARM与HT、预后不良相关,其原因可能是HARM阳性者BBB破坏导致对比剂渗漏至蛛网膜或软脑膜区有关。亦有研究者 [29] 尝试应用增强MRI显示闭塞MCA,并研究其对HT的预测价值,结果发现闭塞的MCA在增强上呈高信号,且管径较对侧明显增粗,该影像学特征预测HT的特异性高达100%,敏感性为54.5%。一项关于动态对比剂增强磁共振血管成像(Dynamic contrast material-enhanced magnetic resonance angiography, DCE-MRA)研究 [30],它可以对AIS患者同时评价侧支和通透性成像来预测PH2,在症状发作后8小时内,由于单侧颈内动脉闭塞或大脑中动脉M1段引起的AIS患者PH2的预测因素是非常差的侧支灌注状态(MAC 0),在MAC 0患者中,Kep图像上的通透性信号又与PH2独立相关(P = 0.009),Kep通透性成像预测PH2的特异性为93.8% (95% CI: 69.8, 99.8)。

4.5. T2*加权梯度回波序列(T2*-Weighed Gradient-Recalled Echo, GRE)和磁敏感加权成像(Susceptibility Weighted Imaging, SWI)

在GRE或SWI序列上显示脑微出血(cerebral microbleeds, CMBs)为小的、圆形的、均匀的低信号病变,一些探讨缺血性卒中患者中CMBs与rt-PA治疗后HT风险之间关系的研究表明可能存在联系 [31],在美国心脏协会/美国卒中协会最新的急性缺血性卒中指南中,将CMBs > 10个视为唯一溶栓相对禁忌症的影像标志物 [32],因为这会导致与HT (特别是PH和sICH)相关的风险增加。此外,静脉内脱氧血红蛋白的增加可导致T2*加权或SWI成像中出现“毛刷征”,表现为髓静脉增大,这代表严重的缺血,可作为大血管闭塞患者HT的预测指标。梗死区内部或周围的异常静脉扩张和增加,与缺氧的严重程度和侧支血管的建立相对应 [33]。

5. 数字减影血管造影术(Digital Subtraction Angiography, DSA)

DSA是一种有创伤性的检查,可清楚的显示动脉管腔狭窄、闭塞、侧支循环建立情况等以及预测HT。在最近的一项研究中 [34],作者指出DSA可以预测HT,他前瞻性地分析了35名因心肌梗塞导致的AIS患者,缺血性病变由DWI进行评分,血流灌注状态是用ASL评估,早期静脉充盈是通过DSA评估的,结果显示,再灌注治疗后,35名患者中有22名(66%)观察到早期静脉填充。早期静脉充盈与DWI-ASPECTS (6.2 vs 8.8, P = 0.0003)、过度灌注(17 vs 1, P < 0.001)、HT (17 vs 1, P = 0.005)之间存在显著的相关性。这项综合研究显示,再灌注治疗后的早期静脉充盈与术后过度灌注有关。早期静脉充盈可能是高灌注过程的一个标志,导致出血和不利预后。检测早期静脉充盈可能是DSA上的一个重要发现,以便随后加强围手术期管理。

综上所述,大量的影像标志物已被证明能够充分反映卒中病变的缺血程度,因此它们可以有力地预测HT的风险。目前用于预测HT发生风险的影像学方法很多,上述各种影像学方法都表现出一定的预测能力,但是基于HT发生的病理基础的影像学评估方法可能有更好的预测能力,特别是灌注成像。除此之外,我们提出在这些方式中组合HT的放射学生物标志物可能比单一生物标志物提供更敏感和预测的HT风险值。使用简单、稳健的影像指标结合卒中发病时间预测HT的个体化和精确化仍是未来的发展目标。

NOTES

*通讯作者。

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