Supplementary Material for: Spot Signs in Intracerebral Hemorrhage: Useful for Identifying Patients at Risk for Hematoma Enlargement?

<b><i>Background:</i></b> Prognostic signs for the identification of patients with acute spontaneous intracerebral hemorrhage (SICH) prone to hematoma expansion are limited. Contrast extravasation (spot signs, SpS) on computed tomographic angiography (CTA) may be a promising method to predict hematoma expansion in acute SICH. However, prospective data on the predictive value of the SpS on hematoma expansion and clinical outcome are still limited. We aimed to investigate associations between the presence of SpS, hematoma expansion, and clinical outcome in acute SICH. <b><i>Methods:</i></b> A prospective observational study was performed between 08/2008 and 08/2011. Patients with SICH presenting within 6 h of symptom onset were included. Patients with secondary hematomas, purely intraventricular hematomas, incomplete CT evaluation, hematoma evacuation prior to follow-up brain imaging, and incomplete follow-up data and those who refused to give consent for data analysis were excluded. CT and CTA brain imaging were carried out in all patients at baseline. After 24 h, follow-up brain imaging was performed. Hematoma location, hematoma volume, and substantial hematoma expansion were documented. CTA images were evaluated by two investigators for the presence of SpS. In all positive SpS cases, images were additionally reviewed by a third rater to achieve consensus for interpretating contrast extravasation. Clinical outcome was measured by the modified Rankin Scale (mRS) at discharge and at 3 months. <b><i>Results:</i></b> In total, 101 patients [median age 73 years (interquartile range 60-79); male 61.4%] were included in the analysis. Median time from onset to CTA was 128 min (interquartile range 90-209 min); median initial National Institute of Health Stroke Scale score was 16 (8-21). SpS were detected in 27 patients (26.7%). Cohen's kappa for the presence of SpS was 0.606, indicating moderate agreement. SpS patients had significantly higher initial hematoma volumes than patients without SpS (36.0 vs. 14.39 ml, p = 0.005). Hematoma expansion was significantly more frequent in SpS patients (59.3 vs. 21.6%, p &lt; 0.001) and associated with the presence of SpS in the univariate analysis (OR 5.273; 95% CI 2.047-13.584, p = 0.001) and in multivariable analysis adjusted for the initial hematoma volume (OR 4.678, 95% CI 1.781-12.288, p = 0.002). Sensitivity of SpS to predict hematoma expansion was 0.5, specificity was 0.84. The positive likelihood ratio for SpS to predict hematoma expansion was 3.136 (95% CI 1.649-5.967), the negative likelihood ratio was 0.595 (95% CI 0.414-0.854). No difference in 3-month clinical outcome was observed between patients with and without SpS (median mRS score 4 and 4, p = 0.457). <b><i>Conclusions:</i></b> The clinical value of SpS needs to be further explored. Future studies should particularly focus on structured training procedures to identify SpS and measure the time needed to precisely assess the presence of SpS and on the prevalence of SpS in consecutive intracerebral hemorrhage populations.

**背景：** 目前用于识别易发生血肿扩大的急性自发性脑内出血（spontaneous intracerebral hemorrhage, SICH）患者的预后指征十分有限。计算机断层血管造影（computed tomographic angiography, CTA）上的对比剂外渗（亦称斑点征，spot signs, SpS）或可作为预测急性SICH患者血肿扩大的潜在手段。然而，目前关于SpS对血肿扩大及临床结局预测价值的前瞻性研究数据仍较为匮乏。本研究旨在探讨急性SICH患者中SpS的存在与否与血肿扩大及临床结局之间的关联。
**方法：** 本研究为一项前瞻性观察性研究，纳入周期为2008年8月至2011年8月。纳入标准为发病6小时内就诊的SICH患者。排除标准包括：继发性血肿患者、单纯脑室内血肿患者、CT评估不完整者、随访颅脑影像前已行血肿清除术者、随访数据不完整者，以及拒绝同意参与数据分析的患者。所有患者均在基线时接受颅脑CT及CTA检查，并于发病24小时后行随访颅脑影像检查。记录血肿位置、血肿体积及显著血肿扩大情况。由两名研究者评估CTA图像是否存在SpS；对于SpS阳性的病例，另由第三名评估者复阅图像以达成对比剂外渗判读的共识。于出院时及发病3个月时采用改良Rankin量表（modified Rankin Scale, mRS）评估临床结局。
**结果：** 本研究共纳入101例患者，年龄中位数为73岁（四分位间距60~79岁），男性占比61.4%。从发病至行CTA检查的时间中位数为128分钟（四分位间距90~209分钟）；基线美国国立卫生研究院卒中量表（National Institute of Health Stroke Scale, NIHSS）评分中位数为16（8~21）。27例患者（26.7%）检出SpS。SpS判读的科恩kappa值（Cohen's kappa）为0.606，提示一致性中等。SpS阳性患者的基线血肿体积显著高于SpS阴性患者（36.0 ml vs. 14.39 ml，p=0.005）。SpS阳性患者的血肿扩大发生率显著更高（59.3% vs. 21.6%，p<0.001）；单因素分析显示，SpS的存在与血肿扩大显著相关（优势比（odds ratio, OR）=5.273，95%置信区间（confidence interval, CI）：2.047~13.584，p=0.001）；在校正基线血肿体积的多因素分析中，该关联仍具有统计学意义（OR=4.678，95%CI：1.781~12.288，p=0.002）。SpS预测血肿扩大的灵敏度为0.5，特异度为0.84。SpS预测血肿扩大的阳性似然比为3.136（95%CI：1.649~5.967），阴性似然比为0.595（95%CI：0.414~0.854）。SpS阳性与阴性患者的3个月临床结局无显著差异（mRS评分中位数均为4，p=0.457）。
**结论：** SpS的临床应用价值仍有待进一步探索。未来的研究应重点关注SpS识别的标准化培训流程、精准评估SpS所需的耗时，以及连续纳入的脑内出血人群中SpS的患病率。