Original Contribution Island Sign An Imaging Predictor for Early Hematoma Expansion and Poor Outcome in Patients With Intracerebral Hemorrhage Qi Li, MD, PhD*; Qing-Jun Liu, MD*; Wen-Song Yang, MD; Xing-Chen Wang, MD; Li-Bo Zhao, MD; Xin Xiong, MD; Rui Li, MD; Du Cao, MD; Dan Zhu, MD; Xiao Wei, MA; Peng Xie, MD
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Background and Purpose—The aim of the study was to investigate the usefulness of the computed tomography (CT) island sign for predicting early hematoma growth and poor functional outcome. Methods—We included patients with spontaneous intracerebral hemorrhage (ICH) who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016. Two readers independently assessed the presence of the island sign on the admission noncontrast CT scan. Multivariable logistic regression analysis was used to analyze the association between the presence of the island sign on noncontrast admission CT and early hematoma growth and functional outcome. Results—A total of 252 patients who met the inclusion criteria were analyzed. Among them, 41 (16.3%) patients had the island sign on baseline noncontrast CT scans. In addition, the island sign was observed in 38 of 85 patients (44.7%) with hematoma growth. Multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and the presence of the island sign on baseline CT scan independently predicted early hematoma growth. The sensitivity of the island sign for predicting hematoma expansion was 44.7%, specificity 98.2%, positive predictive value 92.7%, and negative predictive value 77.7%. After adjusting for the patients’ age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, presence of subarachnoid hemorrhage, admission systolic blood pressure, baseline ICH volume, and infratentorial location, the presence of the island sign (odds ratio, 3.51; 95% confidence interval, 1.26–9.81; P=0.017) remained an independent predictor of poor outcome in patients with ICH. Conclusions—The island sign is a reliable CT imaging marker that independently predicts hematoma expansion and poor outcome in patients with ICH. The noncontrast CT island sign may serve as a potential marker for therapeutic intervention. (Stroke. 2017;48:00-00. DOI: 10.1161/STROKEAHA.117.017985.) Key Words: computed tomography ◼ hematoma growth ◼ intracerebral hemorrhage ◼ predictors ◼ stroke
I
ntracerebral hemorrhage (ICH) is the least treatable form of stroke that accounts for ≈10% to 30% of all strokes worldwide.1 The 1-month mortality rate ranges from 30% to 50%, and half of the deaths occur within 48 hours after the onset of symptoms.2–5 Early hematoma growth occurs in approximately one third of ICH patients who present within a few hours and is an independent predictor of a poor functional outcome and increased mortality in patients with ICH.6–8 Recent studies suggest that ICH is a dynamic event, and early identification of patients at risk for further hematoma expansion is important in terms of therapeutic intervention.9,10
The computed tomography (CT) angiography (CTA) spot sign is a reliable predictor of hematoma expansion.11–16 However, it requires early CTA examination, which is not readily available in many institutions.16 Therefore, identification of novel imaging markers based on noncontrast CT (NCCT) is crucial for triaging patients for future therapeutic interventions. In a recent review, Boulouis et al17 proposed that NCCT biomarkers may have the potential to become an easy-to-use and readily available tool to stratify the risk of hematoma growth in patients with ICH. Several NCCT imaging predictors, including the blend sign, CT hypodensities, the black hole sign,
Received May 18, 2017; final revision received August 9, 2017; accepted August 30, 2017. From the Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, China (Q.L., W.-S.Y., X.-C.W., X.X., R.L., D.C., D.Z., P.X.); Department of Neurology, Yongchuan Hospital of Chongqing Medical University, China (Q.-J.L., W.-S.Y., L.-B.Z.); Department of Neurology, Chongqing Traditional Chinese Medicine Hospital, China (X.X.); and Department of Medical Technology, Chongqing Medical and Pharmaceutical College, China (X.W.). *Drs Qi Li and Liu contributed equally. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 117.017985/-/DC1. Correspondence to Qi Li, MD, PhD, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. E-mail [email protected] or Xiao Wei, MA, Department of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China, E-mail [email protected] or Peng Xie, MD, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China, E-mail [email protected] © 2017 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.117.017985
1
2 Stroke November 2017 swirl sign, and the irregularity of hematoma have been associated with early hematoma expansion in patients with ICH.18–20 However, most imaging markers focus on heterogeneity of hematoma. In previous reports, several authors categorized the shape of hematoma into round and irregular. However, the classification is subjective, and we found that only the most irregularly shaped hematoma accurately predicts hematoma expansion. Here, we proposed a CT-based imaging predictor of hematoma growth called the island sign to describe extreme margin irregularities. The aim of our study was to investigate the value of the island sign for predicting early hematoma growth and functional outcome in patients with ICH.
Methods Patients Downloaded from http://stroke.ahajournals.org/ by guest on October 10, 2017
The Ethics Committee of The First Affiliated Hospital of Chongqing Medical University approved this prospective study. Consecutive adult patients (>18 years) with spontaneous ICH who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016 were screened for inclusion into this study. A follow-up CT scan was performed within 30 hours after the initial CT scan. Patients who were operated on before the follow-up CT scan were excluded from the study. Also excluded were patients whose ICH was secondary to arteriovenous malformation, head trauma, cerebral aneurysm, brain tumor, and hemorrhagic transformation of a brain infarction. Anticoagulant-associated ICH patients were also excluded. The time to baseline and follow-up CT scans and baseline clinical variables were recorded for each participant. The functional outcome was assessed using the modified Rankin Scale at 90 days. Patients
with a modified Rankin Scale score ≥3 were considered to have a poor outcome according to previous definitions.8,9
Imaging Analysis The admission and follow-up CT scans were performed using standard clinical protocols. The images were acquired through the picture archiving and communication system and saved as DICOM format (Digital Imaging and Communications in Medicine) for further review. For this study, we defined hematoma growth as a 33% increase in hematoma volume or >6 mL at the time of the follow-up CT scan according to previous definitions.14,21 The island sign was defined as (1) ≥3 scattered small hematomas all separate from the main hematoma (Figure 1A through 1C) or (2) ≥4 small hematomas some or all of which may connect with the main hematoma (Figure 1D). The scattered small hematomas (separate islands) could be round or oval and are separate from the main hematoma. The small hematomas that connect with the main hematoma (connected islands) should be bubble-like or sprout-like but not lobulated. The detailed methodology for identifying the island sign and its mimics is shown in Figures 2 and 3. Two experienced readers who were blinded to the clinical profiles of the patients independently reviewed all images to assess the presence or absence of the CT island sign. Discrepancies regarding the presence of the CT island sign were settled by consensus.
Statistical Analysis All statistical analyses were performed using an SPSS software package (Version 19.0; IBM Corporation, Armonk, NY). Discrete variables were presented as percentage (%). Continuous data are expressed either as medians and interquartile ranges or mean±standard deviation (SD). The demographic, clinical, and radiological characteristics were compared between patients with the island sign and those without it using Fisher exact test, student’s t test, or the Mann–Whitney
Figure 1. Illustration of island sign. Axial noncontrast computed tomography (CT) images of 4 patients with CT island sign. A, CT island sign in a patient with basal ganglia hemorrhage. Note the there are 3 small scattered little hematomas (arrows), each separate from the main hematoma. B, Putaminal intracerebral hemorrhage with 3 small separate hematomas (arrowheads). Note that there are hypointense areas between the 3 small hematomas and the main hematoma. C, Lobar hematoma with 4 scattered separate hematomas (arrowheads). D, Large basal ganglia hemorrhage with intraventricular extension. The hematoma consists of 4 bubble-like or sprout-like small hematomas (arrowheads) that connect with the main hematoma and one separate small hematoma (arrow).
Li et al Island Sign to Predict Early Hematoma Expansion 3
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Figure 2. Methodology for distinguishing the island sign and its mimics. A, True computed tomography (CT) island sign in a patient with putaminal hemorrhage. Note the 3 scattered small hematomas (arrows), each separate from the main hematoma. The main hematoma comprises 4 lobes. B, Irregularly shaped putaminal hematoma. The hematoma is lobulated (arrowheads), with the lobules not considered islands. Note that the tiny intracerebral hemorrhage spot (arrow) is not considered a separate hematoma. C, Putaminal hemorrhage with 2 scattered small hematomas (arrows). Note that the irregular margin (arrowheads) of the main hematoma is not considered islands. D, A basal ganglia hematoma with 2 lobules (arrowheads). The small lobules of the main hematoma are not considered islands.
U test as appropriate. Multivariate logistic regression analysis was performed to determine the independent association of the CT island sign, significant hematoma growth, and functional outcome. Multivariate logistic regression analysis was performed using variables that were significantly associated with poor outcome on univariate analysis. Variables known to be associated with poor outcome based on multiple external data sets were also included in the multivariate model. The interobserver agreement for identifying the island sign was determined using kappa values, which were categorized as follows: κ=0.01 to 0.20, 0.21 to 0.4, 0.41 to 0.6, 0.61 to 0.8, and 0.81 to 0.99 indicated, respectively, slight, fair, moderate, substantial, and excellent agreement between observers. A value of P
Downloaded from http://stroke.ahajournals.org/ by guest on October 10, 2017
Background and Purpose—The aim of the study was to investigate the usefulness of the computed tomography (CT) island sign for predicting early hematoma growth and poor functional outcome. Methods—We included patients with spontaneous intracerebral hemorrhage (ICH) who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016. Two readers independently assessed the presence of the island sign on the admission noncontrast CT scan. Multivariable logistic regression analysis was used to analyze the association between the presence of the island sign on noncontrast admission CT and early hematoma growth and functional outcome. Results—A total of 252 patients who met the inclusion criteria were analyzed. Among them, 41 (16.3%) patients had the island sign on baseline noncontrast CT scans. In addition, the island sign was observed in 38 of 85 patients (44.7%) with hematoma growth. Multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and the presence of the island sign on baseline CT scan independently predicted early hematoma growth. The sensitivity of the island sign for predicting hematoma expansion was 44.7%, specificity 98.2%, positive predictive value 92.7%, and negative predictive value 77.7%. After adjusting for the patients’ age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, presence of subarachnoid hemorrhage, admission systolic blood pressure, baseline ICH volume, and infratentorial location, the presence of the island sign (odds ratio, 3.51; 95% confidence interval, 1.26–9.81; P=0.017) remained an independent predictor of poor outcome in patients with ICH. Conclusions—The island sign is a reliable CT imaging marker that independently predicts hematoma expansion and poor outcome in patients with ICH. The noncontrast CT island sign may serve as a potential marker for therapeutic intervention. (Stroke. 2017;48:00-00. DOI: 10.1161/STROKEAHA.117.017985.) Key Words: computed tomography ◼ hematoma growth ◼ intracerebral hemorrhage ◼ predictors ◼ stroke
I
ntracerebral hemorrhage (ICH) is the least treatable form of stroke that accounts for ≈10% to 30% of all strokes worldwide.1 The 1-month mortality rate ranges from 30% to 50%, and half of the deaths occur within 48 hours after the onset of symptoms.2–5 Early hematoma growth occurs in approximately one third of ICH patients who present within a few hours and is an independent predictor of a poor functional outcome and increased mortality in patients with ICH.6–8 Recent studies suggest that ICH is a dynamic event, and early identification of patients at risk for further hematoma expansion is important in terms of therapeutic intervention.9,10
The computed tomography (CT) angiography (CTA) spot sign is a reliable predictor of hematoma expansion.11–16 However, it requires early CTA examination, which is not readily available in many institutions.16 Therefore, identification of novel imaging markers based on noncontrast CT (NCCT) is crucial for triaging patients for future therapeutic interventions. In a recent review, Boulouis et al17 proposed that NCCT biomarkers may have the potential to become an easy-to-use and readily available tool to stratify the risk of hematoma growth in patients with ICH. Several NCCT imaging predictors, including the blend sign, CT hypodensities, the black hole sign,
Received May 18, 2017; final revision received August 9, 2017; accepted August 30, 2017. From the Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, China (Q.L., W.-S.Y., X.-C.W., X.X., R.L., D.C., D.Z., P.X.); Department of Neurology, Yongchuan Hospital of Chongqing Medical University, China (Q.-J.L., W.-S.Y., L.-B.Z.); Department of Neurology, Chongqing Traditional Chinese Medicine Hospital, China (X.X.); and Department of Medical Technology, Chongqing Medical and Pharmaceutical College, China (X.W.). *Drs Qi Li and Liu contributed equally. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 117.017985/-/DC1. Correspondence to Qi Li, MD, PhD, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. E-mail [email protected] or Xiao Wei, MA, Department of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China, E-mail [email protected] or Peng Xie, MD, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China, E-mail [email protected] © 2017 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.117.017985
1
2 Stroke November 2017 swirl sign, and the irregularity of hematoma have been associated with early hematoma expansion in patients with ICH.18–20 However, most imaging markers focus on heterogeneity of hematoma. In previous reports, several authors categorized the shape of hematoma into round and irregular. However, the classification is subjective, and we found that only the most irregularly shaped hematoma accurately predicts hematoma expansion. Here, we proposed a CT-based imaging predictor of hematoma growth called the island sign to describe extreme margin irregularities. The aim of our study was to investigate the value of the island sign for predicting early hematoma growth and functional outcome in patients with ICH.
Methods Patients Downloaded from http://stroke.ahajournals.org/ by guest on October 10, 2017
The Ethics Committee of The First Affiliated Hospital of Chongqing Medical University approved this prospective study. Consecutive adult patients (>18 years) with spontaneous ICH who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016 were screened for inclusion into this study. A follow-up CT scan was performed within 30 hours after the initial CT scan. Patients who were operated on before the follow-up CT scan were excluded from the study. Also excluded were patients whose ICH was secondary to arteriovenous malformation, head trauma, cerebral aneurysm, brain tumor, and hemorrhagic transformation of a brain infarction. Anticoagulant-associated ICH patients were also excluded. The time to baseline and follow-up CT scans and baseline clinical variables were recorded for each participant. The functional outcome was assessed using the modified Rankin Scale at 90 days. Patients
with a modified Rankin Scale score ≥3 were considered to have a poor outcome according to previous definitions.8,9
Imaging Analysis The admission and follow-up CT scans were performed using standard clinical protocols. The images were acquired through the picture archiving and communication system and saved as DICOM format (Digital Imaging and Communications in Medicine) for further review. For this study, we defined hematoma growth as a 33% increase in hematoma volume or >6 mL at the time of the follow-up CT scan according to previous definitions.14,21 The island sign was defined as (1) ≥3 scattered small hematomas all separate from the main hematoma (Figure 1A through 1C) or (2) ≥4 small hematomas some or all of which may connect with the main hematoma (Figure 1D). The scattered small hematomas (separate islands) could be round or oval and are separate from the main hematoma. The small hematomas that connect with the main hematoma (connected islands) should be bubble-like or sprout-like but not lobulated. The detailed methodology for identifying the island sign and its mimics is shown in Figures 2 and 3. Two experienced readers who were blinded to the clinical profiles of the patients independently reviewed all images to assess the presence or absence of the CT island sign. Discrepancies regarding the presence of the CT island sign were settled by consensus.
Statistical Analysis All statistical analyses were performed using an SPSS software package (Version 19.0; IBM Corporation, Armonk, NY). Discrete variables were presented as percentage (%). Continuous data are expressed either as medians and interquartile ranges or mean±standard deviation (SD). The demographic, clinical, and radiological characteristics were compared between patients with the island sign and those without it using Fisher exact test, student’s t test, or the Mann–Whitney
Figure 1. Illustration of island sign. Axial noncontrast computed tomography (CT) images of 4 patients with CT island sign. A, CT island sign in a patient with basal ganglia hemorrhage. Note the there are 3 small scattered little hematomas (arrows), each separate from the main hematoma. B, Putaminal intracerebral hemorrhage with 3 small separate hematomas (arrowheads). Note that there are hypointense areas between the 3 small hematomas and the main hematoma. C, Lobar hematoma with 4 scattered separate hematomas (arrowheads). D, Large basal ganglia hemorrhage with intraventricular extension. The hematoma consists of 4 bubble-like or sprout-like small hematomas (arrowheads) that connect with the main hematoma and one separate small hematoma (arrow).
Li et al Island Sign to Predict Early Hematoma Expansion 3
Downloaded from http://stroke.ahajournals.org/ by guest on October 10, 2017
Figure 2. Methodology for distinguishing the island sign and its mimics. A, True computed tomography (CT) island sign in a patient with putaminal hemorrhage. Note the 3 scattered small hematomas (arrows), each separate from the main hematoma. The main hematoma comprises 4 lobes. B, Irregularly shaped putaminal hematoma. The hematoma is lobulated (arrowheads), with the lobules not considered islands. Note that the tiny intracerebral hemorrhage spot (arrow) is not considered a separate hematoma. C, Putaminal hemorrhage with 2 scattered small hematomas (arrows). Note that the irregular margin (arrowheads) of the main hematoma is not considered islands. D, A basal ganglia hematoma with 2 lobules (arrowheads). The small lobules of the main hematoma are not considered islands.
U test as appropriate. Multivariate logistic regression analysis was performed to determine the independent association of the CT island sign, significant hematoma growth, and functional outcome. Multivariate logistic regression analysis was performed using variables that were significantly associated with poor outcome on univariate analysis. Variables known to be associated with poor outcome based on multiple external data sets were also included in the multivariate model. The interobserver agreement for identifying the island sign was determined using kappa values, which were categorized as follows: κ=0.01 to 0.20, 0.21 to 0.4, 0.41 to 0.6, 0.61 to 0.8, and 0.81 to 0.99 indicated, respectively, slight, fair, moderate, substantial, and excellent agreement between observers. A value of P
