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Performance of blend sign in predicting hematoma expansion in intracerebral hemorrhage: A meta-analysis
Accepted Manuscript Title: Performance of blend sign in predicting hematoma expansion in intracerebral hemorrhage: a meta-analysis Authors: Zhiyuan Yu, Jun Zheng, Rui Guo, Lu Ma, Mou Li, Xiaoze Wang, Sen Lin, Hao Li, Chao You PII: DOI: Reference:
S0303-8467(17)30279-2 https://doi.org/10.1016/j.clineuro.2017.10.017 CLINEU 4802
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
23-8-2017 26-9-2017 19-10-2017
Please cite this article as: Yu Zhiyuan, Zheng Jun, Guo Rui, Ma Lu, Li Mou, Wang Xiaoze, Lin Sen, Li Hao, You Chao.Performance of blend sign in predicting hematoma expansion in intracerebral hemorrhage: a meta-analysis.Clinical Neurology and Neurosurgery https://doi.org/10.1016/j.clineuro.2017.10.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Performance of blend sign in predicting hematoma expansion in intracerebral hemorrhage: a meta-analysis
Zhiyuan Yu1, a; Jun Zheng1, a; Rui Guo1, a; Lu Ma1; Mou Li2; Xiaoze Wang2; Sen Lin1; Hao Li1; Chao You1*
1
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
2
Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
a
Zhiyuan Yu, Jun Zheng and Rui Guo contributed equally to this work
*
Corresponding author:
Chao You Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China Email: [email protected] Tel: +86-028-85422490 Fax: +86-028-85422490
Highlights
This study assessed the performance of blend sign in predicting hematoma expansion
Pooled sensitivity and specificity of blend sign were calculated
SROC plot was conducted to evaluate the predictive accuracy
Abstract Objectives: Hematoma expansion is independently associated with poor outcome in intracerebral hemorrhage (ICH). Blend sign is a simple predictor for hematoma expansion on non-contrast computed tomography. However, its accuracy for predicting hematoma expansion is inconsistent in previous
studies. This meta-analysis is aimed to systematically assess the performance of blend sign in predicting hematoma expansion in ICH. Material and methods: A systematic literature search was conducted. Original studies about predictive accuracy of blend sign for hematoma expansion in ICH were included. Pooled sensitivity, specificity, positive and negative likelihood ratios were calculated. Summary receiver operating characteristics curve was constructed. Publication bias was assessed by Deeks’ funnel plot asymmetry test. Results: A total of 5 studies with 2248 patients were included in this meta-analysis. The pooled sensitivity, specificity, positive and negative likelihood ratios of blend sign for predicting hematoma expansion were 0.28, 0.92, 3.4 and 0.78, respectively. The area under the curve (AUC) was 0.85. No significant publication bias was found. Conclusion: This meta-analysis demonstrates that blend sign is a useful predictor with high specificity for hematoma expansion in ICH. Further studies with larger sample size are still necessary to verify the accuracy of blend sign for predicting hematoma expansion.
Keywords: Blend sign; Hematoma expansion; Intracerebral hemorrhage; Meta-analysis; Non-contrast computed tomography; Predictor
1.
Introduction
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high rates of morality and dependence.[1, 2] Although several studies have been conducted in the past decades, the optimal treatment for ICH patients is still controversial.[3, 4] Approximately 16-38% ICH patients suffer hematoma expansion.[5] Hematoma expansion is not only an independent predictor for poor outcome, but also a potential therapeutic target in ICH.[6] Thus, it is important to identify predictors for hematoma expansion. The spot sign, defined as enhanced foci within hematoma on computed tomographic angiography (CTA), has been demonstrated as a good predictor for hematoma expansion with good interobserver reliability.[7] Leakage sign, which is also based on CTA and defined as more than 10% increase in Hounsfield units in hematoma in delayed phase, is also a sensitive indicator for predicting hematoma expansion and can be consistently identified by different reviewers.[8] However, CTA is not available to all ICH patients in many developing countries and it is still necessary to identify reliable
predictors on non-contrast computed tomography. Recent studies have suggested several novel predictors on non-contrast computed tomography (NCCT) for hematoma expansion with good interobserver reliability, such as blend sign, black hole sign (defined as hypoattenuating region within hyperattenuating hematoma), hypodensities and heterogenous density.[9-12] Especially, blend sign is defined as blending regions of high and low density with clear boundary within the hematoma, which is easily recognizable.[9] (Fig 1) Several previous studies have reported the role of blend sign in predicting hematoma expansion, but the accuracy of blend sign for predicting hematoma expansion varies in different studies.[9, 13, 14] This meta-analysis was performed to systematically assess the performance of blend sign in predicting hematoma expansion in ICH.
2.
Material and methods
2.1 Search strategy This study was performed following Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines.[15] Systematic literature search was conducted on July 30, 2017 in the following databases: PubMed, Embase, CNKI, VIP and Wanfang. The following search strategy was used: (“intracerebral hemorrhage” OR “intracranial hemorrhage” OR “cerebral hemorrhage” OR “brain hemorrhage” OR “ICH”) AND (“blend sign” OR “noncontrast CT” OR “nonenhanced CT” OR “NCCT”) AND (“hematoma growth” OR “hematoma expansion” OR “hematoma enlargement”). References of related studies were also checked for potential eligible studies. There was no language restriction in this literature search.
2.2 Study Selection The inclusion criteria in this study were: 1) original studies of adult patients with intracerebral hemorrhage diagnosed by computed tomography (CT) scan; 2) clear time of initial and follow-up CT scans; 3) clear definition of blend sign and hematoma expansion; 4) blend sign was used to predict hematoma expansion; 5) sufficient data for true positive, false positive, true negative and false negative numbers. The exclusion criteria were: 1) review, case report or case series; 2) secondary intracerebral hemorrhage caused by aneurysm, arteriovenous malformation, moyamoya disease or tumor; 3) unknown time of CT scans; 4) blend sign or hematoma expansion was not defined; 5) insufficient data for true positive, false positive, true negative and false negative numbers. If studies had duplicated data, the study
with more sample size was included. Two reviewers (Z.Y. & J.Z.) screened the studies independently. If any disagreement occurred, it would be solved by consensus with the third reviewer (L.M.).
2.3 Data extraction Based on a predesigned data extraction table, two reviewers independently extracted the following information: first author, publication year, area, sample size, percentage of male, definition of hematoma expansion, time form onset to initial CT scan, time from initial CT scan to follow-up CT scan, blinded assessment, true positive, false positive, true negative and false negative numbers.
2.4 Quality evaluation The quality of all included studies was independently evaluated by two reviewers with Quality Assessment of Diagnostic Accuracy Studies (QUADAS).[16] Any disagreement was solved by discussion with the third reviewer.
2.5 Statistical analysis Stata 14.0 (Stata Corporation, College Station, Texas) was used for all statistical analyses in this metaanalysis. Pooled values of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and their 95% confidence intervals (CI) were calculated using bivariate generalized linear mixed model.[17] Heterogeneity was assessed by Chi-square and Cochran-Q test. If I2 >50%, substantial heterogeneity was considered.[18] Summary receiver operator characteristics (SROC) curve was conducted to assess the accuracy of blend sign for predicting hematoma expansion. [19] Based on sample size, study design and blinded assessment, meta-regression was performed to evaluate potential factors for heterogeneity. Deeks’ funnel plot asymmetry test was used to assess publication bias among included studies and significant publication bias was considered If P <0.05.
3.
Results
3.1 Study Selection A total of 139 records were identified in 5 databases and 56 were excluded due to duplication. After screening titles and abstracts, 74 studies were excluded. Full texts of 9 studies were reviewed, in which 3 were not about blend sign and another did not have clear time of initial CT scan. Finally, 5 studies [9,
11, 13, 14, 20] were included in this meta-analysis. (Fig 2)
3.2 Characteristics of included studies Table 1 shows characteristics of 5 included studies. A total of 2248 patients were enrolled in 5 included studies. The sample size ranged from 63 to 1029. The definitions of hematoma expansion were slightly different in these studies. The time from onset to baseline CT ranged from 2 to 6 hours. The interval between baseline CT and follow-up CT ranged from 6 to 48 hours. Blinded assessment was used in 4 studies. Table 2 shows the results of quality evaluation of 5 included studies.
3.3 Pooled predictive accuracy In 5 included studies, the pooled sensitivity and specificity were 0.28 (0.16-0.46) and 0.92 (0.88-0.95), respectively. Substantial heterogeneity was found among 5 included studies (Sensitivity: I 2=91.84%; Specificity: I2=94.69%) (Fig 3) The pooled positive and negative likelihood ratios were 3.4 (1.6-7.4) and 0.78 (0.62-0.98), respectively. SROC curve showed pooled area under the curve (AUC) was 0.85 (0.820.88). (Fig 4)
3.4 Subgroup analysis and meta-regression Subgroup analysis and meta-regression were performed based on sample size, study design and blinded assessment. Table 3 shows the results of subgroup analysis and meta-regression. Sample size and study design were found to influence specificity significantly.
3.5 Publication bias No significant publication bias was identified in the Deeks’ funnel plot asymmetry test (P=0.06). Fig 5 shows the funnel plot.
4.
Discussion
To the best of our knowledge, this is the first meta-analysis evaluating the accuracy of blend sign in predicting hematoma expansion in ICH. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of blend sign for predicting hematoma expansion were 0.28 (0.16-0.46), 0.92 (0.88-0.95), 3.4 (1.6-7.4) and 0.78 (0.62-0.98), respectively. The pooled AUC was 0.85 (0.82-0.88). The
result of this study suggests blend sign is a useful predictor for hematoma expansion in ICH, especially with high specificity. Blend sign was first reported by Li et al. and considered to represent bleeding with different ages. [9] In their study, the sensitivity and specificity of blend sign for predicting hematoma expansion were 0.39 and 0.96, respectively.[9] Zheng et al.’s study suggested the sensitivity and specificity of blend sign for hematoma expansion were 0.43 and 0.89, respectively.[13] However, in Boulouis et al.’s study, although the specificity of blend sign for hematoma expansion prediction was 0.87, the sensitivity was only 0.15. [11] Morotti et al. analyzed the association between blend sign and hematoma expansion in Antihypertensive Treatment of Acute Cerebral Hemorrhage II Study, in which the sensitivity and specificity of blend sign for predicting hematoma expansion were 0.13 and 0.93, respectively.[14] In this meta-analysis, the pooled sensitivity and specificity of blend sign for predicting hematoma expansion were 0.28 and 0.92, respectively. These results suggest blend sign has high specificity for predicting hematoma expansion, but its sensitivity is low. In recent years, several different neuroimaging predictors for hematoma expansion have been reported. CTA spot sign has been suggested as a reliable indicator for predicting hematoma expansion in several different studies.[21-23] Previous studies have also demonstrated CTA spot sign is a better predictor for hematoma expansion compared with some NCCT predictors.[13, 24] However, considering CTA is not available to all ICH patients in many developing countries, indicators on NCCT are still important. Barras et al.’s study has shown that density heterogeneity is an independent predictor for hematoma expansion.[12] Li et al. has reported black hole sign as another hematoma expansion predictor on NCCT.[10] Boulouis et al.’s study also suggested that hypodensities on NCCT could predict hematoma expansion in ICH.[11] Rodriguez-Luna
et al. suggested ultraearly hematoma growth was a promising
predictor for hematoma expansion.[25] To optimally utilize these NCCT predictors, their accuracy for predicting hematoma expansion should be carefully evaluated. In this meta-analysis, we have confirmed blend sign is a useful predictor for hematoma expansion with high specificity. However, considering its low sensitivity, further studies are still needed to identify more sensitive predictors on NCCT. Besides predicting hematoma expansion, several other studies have been performed to investigate the other roles of blend sign in ICH. Blend sign was found to be a predictor for secondary neurological deterioration after ICH.[26] Wu et al. reported blend sign was related to rebleeding in ICH patients receiving minimally invasive surgery.[27] Recently, Li et al. reported blend sign could predict poor 90-
day functional outcome independently.[28] Blend sign seems to be related to worse prognosis and more aggressive treatment may be reasonable for these patients. However, Morotti et al.’s study did not find patients with blend sign could benefit from intensive blood pressure reduction.[14] The optimal treatment for patients with blend sign is still controversial. Our study shows blend sign has a high specificity for predicting hematoma expansion. Thus, further studies on hematoma expansion prevention may use blend sign to screen potentially eligible patients. There are several limitations in this study. First, only 5 studies met the criteria and were included in this meta-analysis. Second, high heterogeneity was found between these studies. The high heterogeneity could be caused by many factors, such as study design, sample size, population, definition of hematoma expansion, time from onset to baseline CT, interval between baseline CT and follow-up CT, and blinded assessment. Among these 5 included studies, four studies[9, 11, 13, 20] were retrospective and only Morotti’s study[14] was prospective. The prospective study could provide more reliable results than the retrospective ones and the different study designs could lead to heterogeneity between these studies. These studies also had different sample sizes. Two studies (Boulouis et al.[11] & Morotti et al.[14]) had large sample sizes, but the other 3 studies (Li et al.[9], Zheng et al.[13] & Zhou et al.[20]) have relatively small sample sizes, which could influence the stability of results in these studies. These studies also had different populations. Three studies (Li et al.[9], Zheng et al.[13] & Zhou et al.[20]) were performed in China, Boulouis et al.’s study[11] included patients in USA and Morotti et al.’s study[14] was an international study. This difference in population could also potentially contribute to heterogeneity in this meta-analysis. The definitions for hematoma expansion were also slightly different in these 5 studies. Hematoma expansion was defined as >33% or >12.5ml increase of hematoma volume in 3 studies (Li et al.[9], Zheng et al.[13] & Zhou et al.[20]). However, >33% or >6 ml increase of hematoma volume was considered as hematoma expansion in Boulouis et al.’s study.[11] In Morotti et al.’s study, >33% increase of hematoma volume was regarded as hematoma expansion.[14] The different definitions for hematoma expansion could cause heterogeneity between these studies. These studies also had different onset-toinitial CT time (ranging from 2h to 6h) and follow-up time (ranging from 6h to 48h). which could influence the identification of hematoma expansion and cause data heterogeneity among these studies. Blinded assessment could also influence the heterogeneity. Blinded assessment was not used in Zhou et al.’s study[20], which brought potential heterogeneity. The other four studies[9, 11, 13, 14] adopted blinded assessment, but the κ values for interobserver reliability were different in these studies, ranging
from 0.67 to 0.96. Although all these studies could be considered to have good interobserver reliability based on their κ values, this difference could still cause heterogeneity potentially. However, due to the limited number of studies and the variety of data, subgroup analysis and meta-regression were only conducted based on study design, sample size and blinded assessment, which suggested study design and sample size could cause the heterogeneity. Thus, the conclusions from this meta-analysis should be considered carefully when used in clinical practice. Moreover, although no obvious publication bias was found, potential publication bias could not be completed avoided. Further studies with large sample size are still necessary to determine the accuracy of blend sign for predicting hematoma expansion in ICH. In conclusion, this meta-analysis demonstrates that blend sign is a useful predictor with high specificity for hematoma expansion in ICH. Further studies with larger sample size are still necessary to verify the accuracy of blend sign for predicting hematoma expansion.
Funding: This work was supported by Support Project Funding of Department of Science and Technology of Sichuan Province [grant number 2015SZ0051]
Conflicts of interest: None.
Acknowledgement: We thank our colleague, Dr. Chuan Wang, for reviewing the statistical analysis in this study.
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mortality in patients with primary intracerebral hemorrhage, Journal of Korean Neurosurgical Society 56(4) (2014) 303-9. [23] F.Z. Du, R. Jiang, M. Gu, C. He, J. Guan, The accuracy of spot sign in predicting hematoma expansion after intracerebral hemorrhage: a systematic review and meta-analysis, PloS one 9(12) (2014) e115777. [24] Z. Yu, J. Zheng, L. Ma, R. Guo, M. Li, X. Wang, S. Lin, H. Li, C. You, The predictive accuracy of the black hole sign and the spot sign for hematoma expansion in patients with spontaneous intracerebral hemorrhage, Neurological Sciences 38(9) (2017) 1591-1597. [25] D. Rodriguez-Luna, P. Coscojuela, M. Rubiera, M.D. Hill, D. Dowlatshahi, R.I. Aviv, Y. Silva, I. Dzialowski, C. Lum, A. Czlonkowska, J.M. Boulanger, C.S. Kase, G. Gubitz, R. Bhatia, V. Padma, J. Roy, A. Tomasello, A.M. Demchuk, C.A. Molina, Ultraearly hematoma growth in active intracerebral hemorrhage, Neurology 87(4) (2016) 357-64. [26] P.B. Sporns, M. Schwake, R. Schmidt, A. Kemmling, J. Minnerup, W. Schwindt, C. Cnyrim, T. Zoubi, W. Heindel, T. Niederstadt, U. Hanning, Computed Tomographic Blend Sign Is Associated With Computed Tomographic Angiography Spot Sign and Predicts Secondary Neurological Deterioration After Intracerebral Hemorrhage, Stroke 48(1) (2017) 131-135. [27] G. Wu, Z. Shen, L. Wang, S. Sun, J. Luo, Y. Mao, Post-operative re-bleeding in patients with hypertensive ICH is closely associated with the CT blend sign, BMC neurology 17(1) (2017) 131. [28] Q. Li, W.S. Yang, X.C. Wang, D. Cao, D. Zhu, F.J. Lv, Y. Liu, L. Yuan, G. Zhang, X. Xiong, R. Li, Y.X. Hu, X.Y. Qin, P. Xie, Blend sign predicts poor outcome in patients with intracerebral hemorrhage, PloS one 12(8) (2017) e0183082.
Figure Legends:
Fig 1: Illustration of blend sign in intracerebral hemorrhage: (a) blend sign (+); (b) blend sign (-)
Fig 2: Literature search and study selection
Fig 3: Pooled sensitivity and specificity of blend sign for predicting hematoma expansion
Fig 4: Summary receiver operating characteristics curve of blend sign for predicting hematoma expansion
Fig 5: Publication bias
Table 1: Characteristics of included studies Sample
Male,
size
%
Retrospective
172
USA
Retrospective
2017
International
Zheng
2017
Zhou
2017
Study
Year
Area
Study design
Li
2015
China
Boulouis
2016
Morotti
Interval between
Blinded
CT scans
assessment
24 h
Yes
48 h
Yes
4.5 h
24 h
Yes
>33% or >12.5 mL
6h
24 h
Yes
>33% or >12.5 mL
2h
6h
N/A
HE definition
Onset-to-initial CT time
68.0%
>33% or >12.5 mL
6h
1029
45.1%
>6 mL or >33%
Prospective
869
61.9%
>33%
China
Retrospective
115
73.0%
China
Retrospective
63
61.9%
HE= Hematoma expansion; CT= Computed tomography; N/A= Not available.
Development cohort: Median 4.9 h; Replication cohort: Median 3.2 h
Table 2: Quality evaluation using QUADAS (Quality Assessment of Diagnostic Accuracy Studies) Study
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Li (2015)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Boulouis (2016)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Morotti (2017)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Zheng (2017)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Zhou (2017)
Y
Y
Y
N/A
Y
Y
Y
N
Y
Y
Y
Y
Y
U
Y, satisfied; N, not satisfied; N/A, not applicable; U, unclear. QUADAS criteria: 1. Was the spectrum of patients representative of the patients who will receive the test in practice? 2. Were selection criteria clearly described? 3. Is the reference standard likely to correctly classify the target condition? 4. Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? 5. Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis? 6. Did patients receive the same reference standard regardless of the index test result? 7. Was the reference standard independent of the index test (i.e., the index test did not form part of the reference standard)? 8. Was the execution of the index test described in sufficient detail to permit replication of the test? 9. Was the execution of the reference standard described in sufficient detail to permit its replication? 10. Were the index test results interpreted without knowledge of the results of the reference standard? 11. Were the reference standard results interpreted without knowledge of the results of the index test 12. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 13. Were uninterpretable/intermediate test results reported? 14. Were withdrawals from the study explained? Table 3: Subgroup analysis and meta-regression of 5 included studies Parameter
n
Sensitivity(95%CI)
Sample size
P
Specificity(95%CI)
0.44
<0.01
≥200
2
0.14 (0.10-0.17)
0.90 (0.86-0.94)
<200
3
0.43 (0.34-0.53)
0.93 (0.89-0.97)
Study design
0.05
<0.01
Retrospective
4
0.33 (0.18-0.49)
0.91 (0.87-0.95)
Prospective
1
0.13 (-0.01-0.27)
0.93 (0.89-0.97)
Blinded assessment
0.15
0.19
Yes
4
0.24 (0.12-0.36)
0.91 (0.88-0.95)
Unclear
1
0.56 (0.18-0.94)
0.94 (0.85-1.00)
n= Number of studies; CI= Confidence interval
P
S0303-8467(17)30279-2 https://doi.org/10.1016/j.clineuro.2017.10.017 CLINEU 4802
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
23-8-2017 26-9-2017 19-10-2017
Please cite this article as: Yu Zhiyuan, Zheng Jun, Guo Rui, Ma Lu, Li Mou, Wang Xiaoze, Lin Sen, Li Hao, You Chao.Performance of blend sign in predicting hematoma expansion in intracerebral hemorrhage: a meta-analysis.Clinical Neurology and Neurosurgery https://doi.org/10.1016/j.clineuro.2017.10.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Performance of blend sign in predicting hematoma expansion in intracerebral hemorrhage: a meta-analysis
Zhiyuan Yu1, a; Jun Zheng1, a; Rui Guo1, a; Lu Ma1; Mou Li2; Xiaoze Wang2; Sen Lin1; Hao Li1; Chao You1*
1
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
2
Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
a
Zhiyuan Yu, Jun Zheng and Rui Guo contributed equally to this work
*
Corresponding author:
Chao You Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China Email: [email protected] Tel: +86-028-85422490 Fax: +86-028-85422490
Highlights
This study assessed the performance of blend sign in predicting hematoma expansion
Pooled sensitivity and specificity of blend sign were calculated
SROC plot was conducted to evaluate the predictive accuracy
Abstract Objectives: Hematoma expansion is independently associated with poor outcome in intracerebral hemorrhage (ICH). Blend sign is a simple predictor for hematoma expansion on non-contrast computed tomography. However, its accuracy for predicting hematoma expansion is inconsistent in previous
studies. This meta-analysis is aimed to systematically assess the performance of blend sign in predicting hematoma expansion in ICH. Material and methods: A systematic literature search was conducted. Original studies about predictive accuracy of blend sign for hematoma expansion in ICH were included. Pooled sensitivity, specificity, positive and negative likelihood ratios were calculated. Summary receiver operating characteristics curve was constructed. Publication bias was assessed by Deeks’ funnel plot asymmetry test. Results: A total of 5 studies with 2248 patients were included in this meta-analysis. The pooled sensitivity, specificity, positive and negative likelihood ratios of blend sign for predicting hematoma expansion were 0.28, 0.92, 3.4 and 0.78, respectively. The area under the curve (AUC) was 0.85. No significant publication bias was found. Conclusion: This meta-analysis demonstrates that blend sign is a useful predictor with high specificity for hematoma expansion in ICH. Further studies with larger sample size are still necessary to verify the accuracy of blend sign for predicting hematoma expansion.
Keywords: Blend sign; Hematoma expansion; Intracerebral hemorrhage; Meta-analysis; Non-contrast computed tomography; Predictor
1.
Introduction
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high rates of morality and dependence.[1, 2] Although several studies have been conducted in the past decades, the optimal treatment for ICH patients is still controversial.[3, 4] Approximately 16-38% ICH patients suffer hematoma expansion.[5] Hematoma expansion is not only an independent predictor for poor outcome, but also a potential therapeutic target in ICH.[6] Thus, it is important to identify predictors for hematoma expansion. The spot sign, defined as enhanced foci within hematoma on computed tomographic angiography (CTA), has been demonstrated as a good predictor for hematoma expansion with good interobserver reliability.[7] Leakage sign, which is also based on CTA and defined as more than 10% increase in Hounsfield units in hematoma in delayed phase, is also a sensitive indicator for predicting hematoma expansion and can be consistently identified by different reviewers.[8] However, CTA is not available to all ICH patients in many developing countries and it is still necessary to identify reliable
predictors on non-contrast computed tomography. Recent studies have suggested several novel predictors on non-contrast computed tomography (NCCT) for hematoma expansion with good interobserver reliability, such as blend sign, black hole sign (defined as hypoattenuating region within hyperattenuating hematoma), hypodensities and heterogenous density.[9-12] Especially, blend sign is defined as blending regions of high and low density with clear boundary within the hematoma, which is easily recognizable.[9] (Fig 1) Several previous studies have reported the role of blend sign in predicting hematoma expansion, but the accuracy of blend sign for predicting hematoma expansion varies in different studies.[9, 13, 14] This meta-analysis was performed to systematically assess the performance of blend sign in predicting hematoma expansion in ICH.
2.
Material and methods
2.1 Search strategy This study was performed following Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines.[15] Systematic literature search was conducted on July 30, 2017 in the following databases: PubMed, Embase, CNKI, VIP and Wanfang. The following search strategy was used: (“intracerebral hemorrhage” OR “intracranial hemorrhage” OR “cerebral hemorrhage” OR “brain hemorrhage” OR “ICH”) AND (“blend sign” OR “noncontrast CT” OR “nonenhanced CT” OR “NCCT”) AND (“hematoma growth” OR “hematoma expansion” OR “hematoma enlargement”). References of related studies were also checked for potential eligible studies. There was no language restriction in this literature search.
2.2 Study Selection The inclusion criteria in this study were: 1) original studies of adult patients with intracerebral hemorrhage diagnosed by computed tomography (CT) scan; 2) clear time of initial and follow-up CT scans; 3) clear definition of blend sign and hematoma expansion; 4) blend sign was used to predict hematoma expansion; 5) sufficient data for true positive, false positive, true negative and false negative numbers. The exclusion criteria were: 1) review, case report or case series; 2) secondary intracerebral hemorrhage caused by aneurysm, arteriovenous malformation, moyamoya disease or tumor; 3) unknown time of CT scans; 4) blend sign or hematoma expansion was not defined; 5) insufficient data for true positive, false positive, true negative and false negative numbers. If studies had duplicated data, the study
with more sample size was included. Two reviewers (Z.Y. & J.Z.) screened the studies independently. If any disagreement occurred, it would be solved by consensus with the third reviewer (L.M.).
2.3 Data extraction Based on a predesigned data extraction table, two reviewers independently extracted the following information: first author, publication year, area, sample size, percentage of male, definition of hematoma expansion, time form onset to initial CT scan, time from initial CT scan to follow-up CT scan, blinded assessment, true positive, false positive, true negative and false negative numbers.
2.4 Quality evaluation The quality of all included studies was independently evaluated by two reviewers with Quality Assessment of Diagnostic Accuracy Studies (QUADAS).[16] Any disagreement was solved by discussion with the third reviewer.
2.5 Statistical analysis Stata 14.0 (Stata Corporation, College Station, Texas) was used for all statistical analyses in this metaanalysis. Pooled values of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and their 95% confidence intervals (CI) were calculated using bivariate generalized linear mixed model.[17] Heterogeneity was assessed by Chi-square and Cochran-Q test. If I2 >50%, substantial heterogeneity was considered.[18] Summary receiver operator characteristics (SROC) curve was conducted to assess the accuracy of blend sign for predicting hematoma expansion. [19] Based on sample size, study design and blinded assessment, meta-regression was performed to evaluate potential factors for heterogeneity. Deeks’ funnel plot asymmetry test was used to assess publication bias among included studies and significant publication bias was considered If P <0.05.
3.
Results
3.1 Study Selection A total of 139 records were identified in 5 databases and 56 were excluded due to duplication. After screening titles and abstracts, 74 studies were excluded. Full texts of 9 studies were reviewed, in which 3 were not about blend sign and another did not have clear time of initial CT scan. Finally, 5 studies [9,
11, 13, 14, 20] were included in this meta-analysis. (Fig 2)
3.2 Characteristics of included studies Table 1 shows characteristics of 5 included studies. A total of 2248 patients were enrolled in 5 included studies. The sample size ranged from 63 to 1029. The definitions of hematoma expansion were slightly different in these studies. The time from onset to baseline CT ranged from 2 to 6 hours. The interval between baseline CT and follow-up CT ranged from 6 to 48 hours. Blinded assessment was used in 4 studies. Table 2 shows the results of quality evaluation of 5 included studies.
3.3 Pooled predictive accuracy In 5 included studies, the pooled sensitivity and specificity were 0.28 (0.16-0.46) and 0.92 (0.88-0.95), respectively. Substantial heterogeneity was found among 5 included studies (Sensitivity: I 2=91.84%; Specificity: I2=94.69%) (Fig 3) The pooled positive and negative likelihood ratios were 3.4 (1.6-7.4) and 0.78 (0.62-0.98), respectively. SROC curve showed pooled area under the curve (AUC) was 0.85 (0.820.88). (Fig 4)
3.4 Subgroup analysis and meta-regression Subgroup analysis and meta-regression were performed based on sample size, study design and blinded assessment. Table 3 shows the results of subgroup analysis and meta-regression. Sample size and study design were found to influence specificity significantly.
3.5 Publication bias No significant publication bias was identified in the Deeks’ funnel plot asymmetry test (P=0.06). Fig 5 shows the funnel plot.
4.
Discussion
To the best of our knowledge, this is the first meta-analysis evaluating the accuracy of blend sign in predicting hematoma expansion in ICH. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of blend sign for predicting hematoma expansion were 0.28 (0.16-0.46), 0.92 (0.88-0.95), 3.4 (1.6-7.4) and 0.78 (0.62-0.98), respectively. The pooled AUC was 0.85 (0.82-0.88). The
result of this study suggests blend sign is a useful predictor for hematoma expansion in ICH, especially with high specificity. Blend sign was first reported by Li et al. and considered to represent bleeding with different ages. [9] In their study, the sensitivity and specificity of blend sign for predicting hematoma expansion were 0.39 and 0.96, respectively.[9] Zheng et al.’s study suggested the sensitivity and specificity of blend sign for hematoma expansion were 0.43 and 0.89, respectively.[13] However, in Boulouis et al.’s study, although the specificity of blend sign for hematoma expansion prediction was 0.87, the sensitivity was only 0.15. [11] Morotti et al. analyzed the association between blend sign and hematoma expansion in Antihypertensive Treatment of Acute Cerebral Hemorrhage II Study, in which the sensitivity and specificity of blend sign for predicting hematoma expansion were 0.13 and 0.93, respectively.[14] In this meta-analysis, the pooled sensitivity and specificity of blend sign for predicting hematoma expansion were 0.28 and 0.92, respectively. These results suggest blend sign has high specificity for predicting hematoma expansion, but its sensitivity is low. In recent years, several different neuroimaging predictors for hematoma expansion have been reported. CTA spot sign has been suggested as a reliable indicator for predicting hematoma expansion in several different studies.[21-23] Previous studies have also demonstrated CTA spot sign is a better predictor for hematoma expansion compared with some NCCT predictors.[13, 24] However, considering CTA is not available to all ICH patients in many developing countries, indicators on NCCT are still important. Barras et al.’s study has shown that density heterogeneity is an independent predictor for hematoma expansion.[12] Li et al. has reported black hole sign as another hematoma expansion predictor on NCCT.[10] Boulouis et al.’s study also suggested that hypodensities on NCCT could predict hematoma expansion in ICH.[11] Rodriguez-Luna
et al. suggested ultraearly hematoma growth was a promising
predictor for hematoma expansion.[25] To optimally utilize these NCCT predictors, their accuracy for predicting hematoma expansion should be carefully evaluated. In this meta-analysis, we have confirmed blend sign is a useful predictor for hematoma expansion with high specificity. However, considering its low sensitivity, further studies are still needed to identify more sensitive predictors on NCCT. Besides predicting hematoma expansion, several other studies have been performed to investigate the other roles of blend sign in ICH. Blend sign was found to be a predictor for secondary neurological deterioration after ICH.[26] Wu et al. reported blend sign was related to rebleeding in ICH patients receiving minimally invasive surgery.[27] Recently, Li et al. reported blend sign could predict poor 90-
day functional outcome independently.[28] Blend sign seems to be related to worse prognosis and more aggressive treatment may be reasonable for these patients. However, Morotti et al.’s study did not find patients with blend sign could benefit from intensive blood pressure reduction.[14] The optimal treatment for patients with blend sign is still controversial. Our study shows blend sign has a high specificity for predicting hematoma expansion. Thus, further studies on hematoma expansion prevention may use blend sign to screen potentially eligible patients. There are several limitations in this study. First, only 5 studies met the criteria and were included in this meta-analysis. Second, high heterogeneity was found between these studies. The high heterogeneity could be caused by many factors, such as study design, sample size, population, definition of hematoma expansion, time from onset to baseline CT, interval between baseline CT and follow-up CT, and blinded assessment. Among these 5 included studies, four studies[9, 11, 13, 20] were retrospective and only Morotti’s study[14] was prospective. The prospective study could provide more reliable results than the retrospective ones and the different study designs could lead to heterogeneity between these studies. These studies also had different sample sizes. Two studies (Boulouis et al.[11] & Morotti et al.[14]) had large sample sizes, but the other 3 studies (Li et al.[9], Zheng et al.[13] & Zhou et al.[20]) have relatively small sample sizes, which could influence the stability of results in these studies. These studies also had different populations. Three studies (Li et al.[9], Zheng et al.[13] & Zhou et al.[20]) were performed in China, Boulouis et al.’s study[11] included patients in USA and Morotti et al.’s study[14] was an international study. This difference in population could also potentially contribute to heterogeneity in this meta-analysis. The definitions for hematoma expansion were also slightly different in these 5 studies. Hematoma expansion was defined as >33% or >12.5ml increase of hematoma volume in 3 studies (Li et al.[9], Zheng et al.[13] & Zhou et al.[20]). However, >33% or >6 ml increase of hematoma volume was considered as hematoma expansion in Boulouis et al.’s study.[11] In Morotti et al.’s study, >33% increase of hematoma volume was regarded as hematoma expansion.[14] The different definitions for hematoma expansion could cause heterogeneity between these studies. These studies also had different onset-toinitial CT time (ranging from 2h to 6h) and follow-up time (ranging from 6h to 48h). which could influence the identification of hematoma expansion and cause data heterogeneity among these studies. Blinded assessment could also influence the heterogeneity. Blinded assessment was not used in Zhou et al.’s study[20], which brought potential heterogeneity. The other four studies[9, 11, 13, 14] adopted blinded assessment, but the κ values for interobserver reliability were different in these studies, ranging
from 0.67 to 0.96. Although all these studies could be considered to have good interobserver reliability based on their κ values, this difference could still cause heterogeneity potentially. However, due to the limited number of studies and the variety of data, subgroup analysis and meta-regression were only conducted based on study design, sample size and blinded assessment, which suggested study design and sample size could cause the heterogeneity. Thus, the conclusions from this meta-analysis should be considered carefully when used in clinical practice. Moreover, although no obvious publication bias was found, potential publication bias could not be completed avoided. Further studies with large sample size are still necessary to determine the accuracy of blend sign for predicting hematoma expansion in ICH. In conclusion, this meta-analysis demonstrates that blend sign is a useful predictor with high specificity for hematoma expansion in ICH. Further studies with larger sample size are still necessary to verify the accuracy of blend sign for predicting hematoma expansion.
Funding: This work was supported by Support Project Funding of Department of Science and Technology of Sichuan Province [grant number 2015SZ0051]
Conflicts of interest: None.
Acknowledgement: We thank our colleague, Dr. Chuan Wang, for reviewing the statistical analysis in this study.
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mortality in patients with primary intracerebral hemorrhage, Journal of Korean Neurosurgical Society 56(4) (2014) 303-9. [23] F.Z. Du, R. Jiang, M. Gu, C. He, J. Guan, The accuracy of spot sign in predicting hematoma expansion after intracerebral hemorrhage: a systematic review and meta-analysis, PloS one 9(12) (2014) e115777. [24] Z. Yu, J. Zheng, L. Ma, R. Guo, M. Li, X. Wang, S. Lin, H. Li, C. You, The predictive accuracy of the black hole sign and the spot sign for hematoma expansion in patients with spontaneous intracerebral hemorrhage, Neurological Sciences 38(9) (2017) 1591-1597. [25] D. Rodriguez-Luna, P. Coscojuela, M. Rubiera, M.D. Hill, D. Dowlatshahi, R.I. Aviv, Y. Silva, I. Dzialowski, C. Lum, A. Czlonkowska, J.M. Boulanger, C.S. Kase, G. Gubitz, R. Bhatia, V. Padma, J. Roy, A. Tomasello, A.M. Demchuk, C.A. Molina, Ultraearly hematoma growth in active intracerebral hemorrhage, Neurology 87(4) (2016) 357-64. [26] P.B. Sporns, M. Schwake, R. Schmidt, A. Kemmling, J. Minnerup, W. Schwindt, C. Cnyrim, T. Zoubi, W. Heindel, T. Niederstadt, U. Hanning, Computed Tomographic Blend Sign Is Associated With Computed Tomographic Angiography Spot Sign and Predicts Secondary Neurological Deterioration After Intracerebral Hemorrhage, Stroke 48(1) (2017) 131-135. [27] G. Wu, Z. Shen, L. Wang, S. Sun, J. Luo, Y. Mao, Post-operative re-bleeding in patients with hypertensive ICH is closely associated with the CT blend sign, BMC neurology 17(1) (2017) 131. [28] Q. Li, W.S. Yang, X.C. Wang, D. Cao, D. Zhu, F.J. Lv, Y. Liu, L. Yuan, G. Zhang, X. Xiong, R. Li, Y.X. Hu, X.Y. Qin, P. Xie, Blend sign predicts poor outcome in patients with intracerebral hemorrhage, PloS one 12(8) (2017) e0183082.
Figure Legends:
Fig 1: Illustration of blend sign in intracerebral hemorrhage: (a) blend sign (+); (b) blend sign (-)
Fig 2: Literature search and study selection
Fig 3: Pooled sensitivity and specificity of blend sign for predicting hematoma expansion
Fig 4: Summary receiver operating characteristics curve of blend sign for predicting hematoma expansion
Fig 5: Publication bias
Table 1: Characteristics of included studies Sample
Male,
size
%
Retrospective
172
USA
Retrospective
2017
International
Zheng
2017
Zhou
2017
Study
Year
Area
Study design
Li
2015
China
Boulouis
2016
Morotti
Interval between
Blinded
CT scans
assessment
24 h
Yes
48 h
Yes
4.5 h
24 h
Yes
>33% or >12.5 mL
6h
24 h
Yes
>33% or >12.5 mL
2h
6h
N/A
HE definition
Onset-to-initial CT time
68.0%
>33% or >12.5 mL
6h
1029
45.1%
>6 mL or >33%
Prospective
869
61.9%
>33%
China
Retrospective
115
73.0%
China
Retrospective
63
61.9%
HE= Hematoma expansion; CT= Computed tomography; N/A= Not available.
Development cohort: Median 4.9 h; Replication cohort: Median 3.2 h
Table 2: Quality evaluation using QUADAS (Quality Assessment of Diagnostic Accuracy Studies) Study
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Li (2015)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Boulouis (2016)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Morotti (2017)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Zheng (2017)
Y
Y
Y
N/A
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Zhou (2017)
Y
Y
Y
N/A
Y
Y
Y
N
Y
Y
Y
Y
Y
U
Y, satisfied; N, not satisfied; N/A, not applicable; U, unclear. QUADAS criteria: 1. Was the spectrum of patients representative of the patients who will receive the test in practice? 2. Were selection criteria clearly described? 3. Is the reference standard likely to correctly classify the target condition? 4. Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? 5. Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis? 6. Did patients receive the same reference standard regardless of the index test result? 7. Was the reference standard independent of the index test (i.e., the index test did not form part of the reference standard)? 8. Was the execution of the index test described in sufficient detail to permit replication of the test? 9. Was the execution of the reference standard described in sufficient detail to permit its replication? 10. Were the index test results interpreted without knowledge of the results of the reference standard? 11. Were the reference standard results interpreted without knowledge of the results of the index test 12. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 13. Were uninterpretable/intermediate test results reported? 14. Were withdrawals from the study explained? Table 3: Subgroup analysis and meta-regression of 5 included studies Parameter
n
Sensitivity(95%CI)
Sample size
P
Specificity(95%CI)
0.44
<0.01
≥200
2
0.14 (0.10-0.17)
0.90 (0.86-0.94)
<200
3
0.43 (0.34-0.53)
0.93 (0.89-0.97)
Study design
0.05
<0.01
Retrospective
4
0.33 (0.18-0.49)
0.91 (0.87-0.95)
Prospective
1
0.13 (-0.01-0.27)
0.93 (0.89-0.97)
Blinded assessment
0.15
0.19
Yes
4
0.24 (0.12-0.36)
0.91 (0.88-0.95)
Unclear
1
0.56 (0.18-0.94)
0.94 (0.85-1.00)
n= Number of studies; CI= Confidence interval
P