Timing of Occurrence Is the Most Important Characteristic of Spot Sign

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1 Timing of Occurrence Is the Most Important Characteristic of Spot Sign Binli Wang, MM*; Shenqiang Yan, MD*; Mengjun Xu, MD; Sheng Zhang, PhD; Keqin Liu, MD; Haitao Hu, MD; Magdy Selim, MD, PhD; Min Lou, MD, PhD Background and Purpose Most previous studies have used single-phase computed tomographic angiography to detect the spot sign, a marker for hematoma expansion (HE) in spontaneous intracerebral hemorrhage. We investigated whether defining the spot sign based on timing on perfusion computed tomography (CTP) would improve its specificity for predicting HE. Methods We prospectively enrolled supratentorial spontaneous intracerebral hemorrhage patients who underwent CTP within 6 hours of onset. Logistic regression was performed to assess the risk factors for HE and poor outcome. Predictive performance of individual CTP spot sign characteristics were examined with receiver operating characteristic analysis. Results Sixty-two men and 21 women with spontaneous intracerebral hemorrhage were included in this analysis. Spot sign was detected in 46% (38/83) of patients. Receiver operating characteristic analysis indicated that the timing of spot sign occurrence on CTP had the greatest area under receiver operating characteristic curve for HE (0.794; 95% confidence interval, ; P=0.007); the cutoff time was seconds. On multivariable analysis, the presence of early-occurring spot sign (ie, spot sign before seconds) was an independent predictor not only of HE (odds ratio=28.835; 95% confidence interval, ; P<0.001), but also of mortality at 3 months (odds ratio =22.377; 95% confidence interval, ; P=0.016). Moreover, the predictive performance showed that the redefined early-occurring spot sign maintained a higher specificity for HE compared with spot sign (91% versus 74%). Conclusions Redefining the spot sign based on timing of contrast leakage on CTP to determine early-occurring spot sign improves the specificity for predicting HE and 3-month mortality. The use of early-occurring spot sign could improve the selection of ICH patients for potential hemostatic therapy. (Stroke. 2016;47: DOI: / STROKEAHA ) Key Words: cerebral hemorrhage hematoma outcome assessment perfusion imaging stroke Spontaneous intracerebral hemorrhage (SICH) accounts for 10% to 30% of all strokes worldwide and is much more likely to result in death or severe neurological deficits than either ischemic stroke or subarachnoid hemorrhage. 1,2 Glasgow coma scale score, baseline hematoma volume, age, the presence of intraventricular hemorrhage, and hematoma expansion (HE) are all independent predictors of poor outcomes in patients with SICH. Of these, HE is the only potentially modifiable factor. 3 6 In the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, 7 the use of hemostatic therapy to attenuate HE did not translate into improved outcomes, partly because patients who were destined to have HE were not specifically targeted which may have diluted any treatment effect. The spot sign, described as a tiny enhancing foci of contrast leakage within hematoma on computed tomography (CT) scan, has been validated as a surrogate marker for HE and poor clinical outcome Previous studies revealed that 22% to 77% of ICH patients with a spot sign at presentation would undergo HE based on varied definitions of spot sign and HE Most of these studies used single-phase CT angiography (CTA) to detect the spot sign. More recent studies have shown that the use of perfusion CT (CTP) improves the detection rate of the spot sign As the process of ongoing bleeding is dynamic, CTP allows to dynamically track the spot sign on the same slice in every phase of imaging acquisition. However, it is not enough to only focus on improving the detection rate of the spot sign. A recent study using first-pass and delayed CTA found that increased detection rate of the spot sign did not increase its positive predictive value for HE. 11 Therefore, we undertook the current study to explore the relationship between the presenting characteristic of the spot Received January 7, 2016; final revision received February 23, 2016; accepted March 1, From the Department of Neurology, the 2nd Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China (B.W., S.Y., M.X., S.Z., H.H., M.L.); Department of Neurology, Hangzhou First People s Hospital, Hangzhou, China (K.L.); and Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (M.S.). *B. Wang and Dr Yan contributed equally. Guest Editor for this article was Giuseppe Lanzino, MD. Corresponding to Min Lou, MD, PhD, Department of Neurology, the 2nd Affiliated Hospital of Zhejiang University, School of Medicine, No 88 Jiefang Rd, Hangzhou, China. loumingxc@vip.sina.com 2016 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 1234 Stroke May 2016 sign on CTP (such as number, timing of occurrence, and maximum density) and the risk of HE and clinical outcomes after SICH. Our aim was to improve the definition of the spot sign to increase both its detection rate and predictive value. Materials and Methods Patient Cohort We retrospectively reviewed our prospectively collected database for consecutive patients with SICH who were admitted between June 2014 and August Patients aged 18 years who had a supratentorial SICH and underwent a noncontrast head CT (NCCT) followed by CTP acquisition within 6 h of onset and a follow-up NCCT at 24 hours were included. Exclusion criteria were (1) secondary ICH, including trauma, underlying aneurysm, or vascular malformation, hemorrhagic venous infarct, or hemorrhagic transformation of ischemic stroke; (2) infratentorial ICH; and (3) poor image quality (one patient was excluded because of severe head movement artifact and another because of incomplete consecutive acquisition). Patients who died before a follow-up CT was performed at 24 hour were excluded from the HE analysis, but included in the outcome analysis. Patients who underwent surgical evacuation of the hematoma were excluded from the outcome analysis; those who underwent evacuation before follow-up CT were also excluded from HE analysis. Clinical Data Baseline clinical variables were recorded in an ICH database, including patient demographics, medical history, medications, onset to imaging time, baseline National Institute of Health Stroke Scale (NIHSS), and laboratory results. Neurological outcomes including NIHSS at 24 hours, mortality in hospital, and modified Rankin Scale, including death at 3-month follow-up, were collected from the medical records. Imaging Protocol CTP was performed on a dual-source 64-slice CT scanner (SOMATOM Definition Flash; Siemens Healthcare Sector, Forchheim, Germany), including NCCT scan (120 kv, 320 ma, contiguous 5 mm axial slices) and whole-brain volume perfusion computed tomography (100 mm in the z-axis, 4 seconds delay after start of contrast medium injection, 74.5 seconds total imaging duration, 80 kv, 120 ma, slice thickness 1.5 mm, collimation mm). Volume perfusion computed tomography consisted of 26 consecutive spiral acquisitions of the brain. All 26 scans were divided into 4 parts: (1) 2 scans with 3-second cycle time; (2) 15 scans with 1.5-seconds cycle time; (3) 4 scans with 3-seconds cycle time; and (4) 5 scans with 6-seconds cycle time. Axial slice coverage was 150 mm. A 60-mL bolus of contrast medium (Iopamidol; Braccosine, Shanghai, China) with a single injection was used at a flow rate of 6 ml/s, followed by a 20 ml saline chaser at 6 ml/s. The effective dose (calculated by multiplying dose-length products with published conversion factors) was 5.94 msv for volume perfusion computed tomography acquisition and 1.82 msv for NCCT acquisition. As described by Frolich et al, baseline 4D CTA images were reconstructed in axial, coronal, and sagittal with 20-mm-thick slabs. 15 The follow-up head NCCT was obtained within 24 hours of the CTP examination. Assessment of CTP Spot Sign Two experienced neurologists blinded to the patients clinical data jointly reviewed and reconstructed all admission CTP images by using commercial software (MIStar; Apollo Medical Imaging Technology, Melbourne, VIC, Australia). Spot sign was visualized on spot windows (width, 200; level, 110) on CTP. 9 The CTP spot sign was defined according to the following criteria: (1) 1 focus (attenuation 120 HU) of any size and morphology within the ICH, (2) not visualized at the corresponding location on NCCT images, (3) discontinuous from normal or abnormal vasculature adjacent to the ICH, and (4) can be visualized in the follow-up continuous imaging of the same slice after presence. 10,12 14 Discrepancies were resolved by consensus. Timing of occurrence (time from the start of CTP scanning to first detection of spot sign), total number of spots, maximum spot attenuation (maximum attenuation among all phases where spot sign was present), axial dimensions (largest spot size in the axial CTP source image) were recorded by locating the specific slices and frame. In CTPs with >1 spot sign, the characterization was performed on the earliest spot sign identified. Assessment of Radiographic and Clinical Outcome Hematoma volumes were calculated on the initial and follow-up NCCT by planimetric method. Briefly, regions of interest were manually drawn by tracing the perimeters of the hematoma in each slice throughout the hemorrhagic lesion. The traced regions of interest in the contiguous voxels were then summed automatically after adjusting for the slice thickness to yield a hematoma volume (MIStar). 16 Intraventricular hemorrhage volume was not included in the volume analysis, but recorded by using Modified Graeb score. 17 Absolute ICH growth (follow-up volume baseline volume) and relative ICH growth [(follow-up volume baseline volume)/baseline volume)] were calculated, respectively. HE was defined as an absolute ICH growth 6 ml or relative growth 33%. 10 Poor outcome included early neurological worsening (defined as worsening of 4 points in the NIHSS score at 24 hours compared with baseline) and mortality. 10 Statistical Analysis Results were delineated as the mean±sd or interquartile rangefor quantitative variables and as proportions for categorical variables. Inter-rater and intrarater reliability for hematoma volumes and detection of spot sign were assessed by the intraclass correlation coefficients and the kappa statistic. Continuous data were assessed by using 2-tailed t test or Mann Whitney U test. Categorical data were assessed by using the Fisher exact test. The Spearman correlation coefficient was used to determine the correlation between timing of spot sign occurrence and ICH volume growth (absolute and relative). Variables with a P<0.05 in univariate regression analyses were included in the multivariate logistic regression models. Baseline NIHSS score, glucose level, previous use of antiplatelet and baseline hematoma volume, which were thought to be potential factors associated with HE, were forced into the model. 18 Receiver operating characteristic curve analysis was taken to identify the predictive performance of characteristics of spot sign for HE. All statistical analyses were performed using SPSS, Version 19.0 (IBM, Armonk, New York). A P value <0.05 was considered statistically significant. Results A total of 83 patients met the eligibility criteria for this study. The mean age was 65.49±15.20 years; 21 patients (25.3%) were women; and median baseline NIHSS score was 12 (7 15). Spot sign was detected in 46% (38/83) of patients. The location of ICH was lobar in 10/83 (12%) and deep in 73/83 (88%). Eleven patients (6 with positive spot sign) did not undergo follow-up NCCT within 24 hours; therefore, only the remaining 72 patients (83 11) were included in the analysis of HE. The excluded patients had higher systolic blood pressure (208±39 mm Hg versus 176±39 mm Hg; P=0.016), higher diastolic blood pressure (123±27 mm Hg versus 100±22 mm Hg; P=0.002), greater median baseline hematoma volume (52.30 ml versus ml; P=0.029), and higher median NIHSS score (21 versus 11; P=0.004) compared with the remaining patients. Twelve patients (including one with follow-up CT, 7 patients with positive spot sign) underwent surgical hematoma evacuation, and the remaining 71 (83 12) patients were included for the analysis of outcome. Inter-rater and intrarater

3 Wang et al Timing of Occurrence of Spot Sign 1235 Table 1. Baseline Characteristics Entire Cohort Spot Sign Positive Spot Sign Negative P Value No of subjects, n Age, mean (SD), y 65.5± ± ± Male, n (%) 62 (75%) 26 (68%) 36 (80%) Past medical history Hypertension, n (%) 45 (54.0%) 20 (52.6%) 25 (55.6%) Antiplatelet use, n (%) 7 (8.4%) 6 (15.8%) 1 (2.2%) Clinical variables Platelets, mean (SD), 10 9 /L 177.5± ± ± Glucose, mean (SD), mmol/l 7.45± ± ± SBP, mean (SD), mm Hg 181±40 190±38 173± DBP, mean (SD), mm Hg 103±24 108±26 98± INR, mean (SD) 1.01± ± ± APTT, mean (SD), s 31.9± ± ± NIHSS, median (IQR) 12 (7 15) 12 (10 17) 10 (5 14) Radiological data OIT, mean (SD), min 182±78 180±80 194± Baseline hematoma volume, median (IQR), ml ( ) 22.9 ( ) 13.1 ( ) Presence of IVH, n (%) 23 (27.7%) 14 (36.8%) 9 (20.0%) APTT indicates activated partial thromboplastin time; DBP, diastolic blood pressure; INR, international normalized ratio; IQR, interquartile range; IVH, intraventricular hemorrhage; NIHSS, National Institute of Health Stroke Scale; OIT, onset to imaging time; SBP, systolic blood pressure; and SD, standard deviation. kappa value for detection of the spot sign were 0.89 and 1.00; and inter-rater and intrarater intraclass correlation coefficients for hematoma volumes were 0.99 and All CTP acquisitions achieved full hematoma coverage. As summarized in Tables 1 and 2, patients with positive spot sign had higher median baseline ICH volume (22.9 ml versus 13.1 ml; P=0.037), greater median volume of Table 2. Radiographic and Clinical Outcomes hematoma growth (5.60 ml versus 0.06 ml; P=0.043), and higher median modified Rankin Scale score (4 versus 3; P=0.004) and mortality rate (32% versus 8%; P=0.012) at 3 months, compared with patients without spot sign. Hematoma expansion, using different definitions, was significantly more frequent in the spot sign positive group than in the spot sign negative group (all P<0.05). Entire Cohort Spot Sign Positive Spot Sign Negative P Value Radiographic outcomes No of subjects, n Absolute ICH growth, median 0.86 ( 1.06 to 6.32) 5.90 ( ) 0.05 ( 1.60 to 1.24) (IQR), ml Relative ICH growth, median (IQR), % 9.12 ( 6.58 to 47.62) ( ) 1.02 ( to 14.19) ICH growth >6 ml, n (%) 19 (26%) 16 (50%) 3 (8%) <0.001 ICH growth >33%, n (%) 22 (30%) 18 (56%) 4 (10%) <0.001 ICH growth >6 ml or 33%, n (%) 25 (34%) 20 (63%) 5 (13%) <0.001 Clinical outcomes No of subjects, n mrs at 3 mo, median (IQR) 3 (1 4) 4 (2 6) 3 (1 4) Mortality at 3 mo, n (%) 13 (18%) 10 (32%) 3 (8%) ICH indicates intracerebral hemorrhage; IQR, interquartile range; and mrs, modified Rankin Scale.

4 1236 Stroke May 2016 Table 3. Multivariate Logistic Regression Analysis of Hematoma Expansion Odds Ratio 95% CI P Value Glucose, mmol/l APTT, s NIHSS Baseline hematoma volume, ml Presence of spot sign <0.001 Antiplatelet use APTT indicates activated partial thromboplastin time; and NIHSS, National Institute of Health Stroke Scale. Analysis of Risk Factors for HE and Mortality We compared the baseline characteristics between patients with and without HE and found that the rate of spot sign was higher in HE patients than in those without HE (62.5% versus 12.5%; P<0.001). With multivariate analysis (Table 3), the presence of spot sign was still independently associated with HE (odds ratio=13.507; 95% confidence interval [CI], ; P<0.001) after adjustment for activated partial thromboplastin time, glucose, NIHSS, baseline hematoma volume, and antiplatelet use. We also compared the relationships between baseline characteristics and mortality at 3 months and found that there was a trend for an association between the presence of spot sign and 3-month mortality (32% versus 8%, odds ratio=5.649; 95% CI, ; P=0.063) after multivariate analysis. Spot Sign Characteristics and Predictive Performance of Early-Occurred Spot Sign Spot sign was detected much earlier in patients with HE than in those without HE (18.75 s versus s; P=0.007). The timing of spot sign occurrence was significantly correlated with both absolute (r= 0.549; P=0.001) and relative ICH volume growth (r= 0.507; P=0.004). There was no association between the spot sign number, maximum axial dimension, or maximum density and HE (all P>0.05). Among all of the characteristics of spot sign listed in Table 4, the timing of occurrence had the greatest area under receiver operating characteristic curve (0.781; 95% CI, ; P=0.014). Early-occurring spot sign (EOSS), that is, spot sign detected before seconds, had sensitivity of 0.67 and specificity of On multivariable analysis, EOSS was an independent predictor of HE (odds ratio=28.835; 95% CI, ; P<0.001) and 3-month mortality (odds ratio=22.377; 95% CI, ; P=0.016). The predictive performance of the spot sign and EOSS is shown in Table 5 and Figure. EOSS maintained a higher specificity for HE compared with spot sign (91% versus 74%). Discussion In this cohort of SICH patients, spot sign on CTP was associated with HE. Furthermore, we found that the timing of spot sign occurrence was the most important characteristic of spot sign for predicting HE. The predictive ability of HE was highest for spot sign that was detected before seconds (EOSS). EOSS was also an independent predictor of 3-month mortality. In our study, the median time from symptom onset to CTP was 180 ( ) minutes. The overall prevalence rate of spot sign in our cohort was 46%; 66% of which were EOSS. This is higher than most previous reported rates (18% to 50%). 8 14,19 In the predicting hematoma growth and outcome in interracial hemorrhage using contrast bolus CT (PREDICT) study, the largest prospective study using CTA to detect the spot sign, the median time from symptom onset to CTA was 159 (32 475) minutes, and 30% of patients were spotsign positive. 10 The higher detection rate of spot sign in our study is attributed to the use of CTP technique because unlike CTA, CTP provides an observation of the contrast leakage and dynamic change of spot sign throughout the whole process of scanning. However, recent studies using CTP imaging acquisition also reported that inadequate spatial coverage of hematoma was an important limitation, leading to increased misclassification of CTP spot sign, even with a high detection rate of spot sign. 12,14 To avoid these limitations, we used whole brain CTP and thin slices to visualize the entire hematoma and minimize misclassification of the spot sign. This suggests that the use of thin-slices whole-brain CTP could improve our ability to detect spot sign positive patients. We also found that the predictive ability of CTP spot sign varied according to its timing of occurrence. 19 Based on our results, EOSS before seconds was accurate in predicting HE. The positive predictive value of EOSS for HE (PPV=0.82) in our study was much higher than previously reported values (PPV= ). 10,11 One possible explanation is that more delayed spots were captured and analyzed on CTA, even though they may not have been related to the development of HE, which is consistent with the finding that delayed detection increased sensitivity but not specificity in post hoc analysis of PREDICT study. 11,20,21 A recent study found that CTA spot sign was associated with more intraoperative bleeding, more postoperative rebleeding, and larger residual ICH volumes, indicating Table 4. Spot Sign Characteristics by HE HE (n=20) No HE (n=11) AUC (95% CI) P Value Number 1 ( ) 1 ( ) ( ) Maximum density, HU 240 ( ) 210 ( ) ( ) Maximum axial dimension, mm 3.0 ( ) 2.5 ( ) ( ) Timing of occurrence, s ( ) ( ) ( ) AUC indicates area under receiver operating characteristic curve; HE, hematoma expansion, defined as an absolute ICH growth 6 ml or relative growth 33%.

5 Wang et al Timing of Occurrence of Spot Sign 1237 Table 5. Predictive Performance of Spot Sign and EOSS Sensitivity Specificity PPV NPV Accuracy Odds Ratio (95% CI; P Value) Hematoma expansion Spot sign ( ; <0.001) EOSS ( ; <0.001) Mortality Spot sign ( ; 0.063) EOSS ( ; 0.016) CI indicates confidence interval; EOSS, early occurred spot sign; NPV, negative predictive value; and PPV, positive predictive value. that spot sign may be a surrogate of continuous bleeding. 22 In our study, we found increased contrast concentration with time on the postcontrast CT, which also suggests an active extravasation and a reverse correlation between timing of CTP spot sign occurrence and ICH volume growth. This suggests that the extravasated contrast gradually accumulated before spot sign could be detected and that the timing of occurrence of CTP spot sign may reflect the speed and volume of ongoing bleeding in hematoma. Our study also demonstrates that EOSS also predicts 3-month mortality with a relatively high specificity. The EOSS maintained a higher specificity compared with CTP spot sign (91% versus 74%). In the context of previous findings that multiphase acquisition including both arterial- and venousweighted images could increase the detection rate, although only early-phase acquisition was associated with greater absolute HE, 12,20 our definition of spot sign based on the timing of its detection on CTP to identify EOSS, together with the improved detection rate of CTP spot sign, would improve current ability to stratify ICH patients at increased risk for HE. Our study has some limitations. First, it was performed in a single center with a relatively small sample size. The characterization of the spot sign was based on the CTP parameters in our center, including the rate of contrast bolus injection and the contrast dose. This requires further external validation in future studies. Moreover, it is important to point out that the predictive value of EOSS does not reflect the performance of spot sign on single phase CTA, considering the dynamic observation of EOSS based on CTP. Second, we cannot exclude selection bias because of the retrospective nature of our study. Third, the spot sign positive patients in our study had a high rate of surgical evacuation of the hematoma, which may lead us to underestimate the spot sign s positive predictive value for mortality. In conclusion, we demonstrate improved detection rate and sensitivity for predicting HE and mortality with CTP spot sign. We also redefined the spot sign based on timing of contrast leakage on CTP and found that EOSS (before seconds) improves the specificity of the spot sign for predicting HE and mortality after SICH. These results suggest that the use of CTP to identify spot sign and EOSS after SICH could improve the selection of ICH patients for potential hemostatic therapy. Our findings require further prospective validation in a larger cohort of SICH patients. Sources of Funding This work was supported by the Science Technology Department of Zhejiang Province (2013C and 2014C33186), the National Natural Science Foundation of China ( ), and the National Institute of Neurological Disorders and Stroke (NINDS) (U01 NS074425). Figure. A, perfusion computed tomography (CTP) demonstrates no spot sign before s, and a 2-mm spot sign is then detected at 35.1 s (red arrow). B, Hematoma volume are comparable on baseline noncontrast CT (NCCT) and 24 h follow-up NCCT. C, 5-mm spot sign is detected at 15.8 s and then enlarged (red arrow). D, Hematoma volume on 24 h follow-up NCCT is significantly larger than that on the baseline NCCT.

6 1238 Stroke May 2016 Disclosures Dr Selim is partly supported by the NINDS (U01 NS074425). The other authors report no conflicts. References 1. Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997;28: Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8: doi: /S (09) Tuhrim S, Dambrosia JM, Price TR, Mohr JP, Wolf PA, Hier DB, et al. Intracerebral hemorrhage: external validation and extension of a model for prediction of 30-day survival. Ann Neurol. 1991;29: doi: /ana Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993;24: Hemphill JC III, Bonovich DC, Besmertis L, Manley GT, Johnston SC. 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