Abstract
Background and Purpose
The presence of active contrast extravasation (the spot sign) on computed tomography (CT) angiography has been recognized as a predictor of hematoma expansion in patients with intracerebral hemorrhage. We aim to systematically characterize the spot sign to identify features that are most predictive of hematoma expansion and construct a spot sign scoring system.
Methods
We retrospectively reviewed CT angiograms performed in all patients who presented to our emergency department over a 9-year period with primary intracerebral hemorrhage and had a follow-up noncontrast head CT within 48 hours of the baseline CT angiogram. Three neuroradiologists reviewed the CT angiograms and determined the presence and characteristics of spot signs according to strict radiological criteria. Baseline and follow-up intracerebral hemorrhage volumes were determined by computer-assisted volumetric analysis.
Results
We identified spot signs in 71 of 367 CT angiograms (19%), 6 of which were delayed spot signs (8%). The presence of any spot sign increased the risk of significant hematoma expansion (69%, OR=92, P<0.0001). Among the spot sign characteristics examined, the presence of ≥3 spot signs, a maximum axial dimension ≥5 mm, and maximum attenuation ≥180 Hounsfield units were independent predictors of significant hematoma expansion, and these were subsequently used to construct the spot sign score. In multivariate analysis, the spot sign score was the strongest predictor of significant hematoma expansion, independent of time from ictus to CT angiogram evaluation.
Conclusion
The spot sign score predicts significant hematoma expansion in primary intracerebral hemorrhage. If validated in other data sets, it could be used to select patients for early hemostatic therapy.
Keywords: CT angiography, emergency medicine, intracerebral hemorrhage, outcome
Nontraumatic intracerebral hemorrhage (ICH) accounts for 10% to 15% of cases of acute stroke in the United States1 and has a worse prognosis than ischemic stroke, with up to 50% 30-day mortality.2 Hematoma expansion has been shown to be an independent predictor of increased mortality and poor outcome in ICH.3 Identification of an accurate and reliable predictor of hematoma expansion in patients with ICH is important,4 because it may serve to select patients for early hemostatic therapies such as recombinant activated factor VII or intensive blood pressure reduction.3,5–8
The presence of active contrast extravasation at multide-tector computed tomography (CT) angiography (MDCTA), also known as the spot sign, is an indicator of active hemorrhage and has been associated with an increased risk of significant hematoma expansion and mortality in patients with ICH in prior studies.9–12 However, these studies have not established strict radiological criteria for the identification of a spot sign, and its positive predictive value (PPV) for significant hematoma expansion may be dependent on the time from ictus to MDCTA evaluation. Hence, the previously reported PPV of the spot sign for significant hematoma expansion has been variable, ranging from 22% to 77%.10,12 This study aims to (1) apply strict radiological criteria for the identification of the spot sign; (2) perform systematic characterization of this MDCTA finding to identify features that are most predictive of significant hematoma expansion; (3) develop a spot sign scoring system; and (4) evaluate the relationship between the spot sign's PPV and time from ictus to MDCTA evaluation.
Methods
Patient Selection
Our study was approved by the hospital's Institutional Review Board. We conducted a retrospective review of all patients who presented to our emergency department from January 1, 2000, until December 31, 2008, with (1) evidence of nontraumatic ICH on a noncontrast CT examination (NCCT) of the head; (2) evaluation with a CT angiogram (CTA) of the intracranial circulation within 24 hours of admission; and (3) a follow-up NCCT within 48 hours of the baseline CTA. Patient exclusion criteria were the presence of (1) associated subarachnoid hemorrhage in the basal cisterns or a vascular lesion as the ICH etiology identified in the CTA; (2) loss of gray-white matter differentiation in a vascular territory suggesting a pre-established acute ischemic stroke; (3) anticoagulation between the baseline CTA and follow-up NCCT; (4) administration of recombinant factor VIIa; or (5) administration of prothrombin complex concentrate. Although studies on 61 of these patients were previously published,12 all CTAs were independently reanalyzed according to the strict radiological criteria described subsequently.
Image Acquisition
NCCT and MDCTA acquisitions were performed according to standard departmental protocols on 16- or 64-section General Electric helical CT scanners (LightSpeed; GE Medical Systems, Waukesha, Wisc). NCCT examinations were performed using an axial technique with 120 to 140 kVp, 170 mA, and 5-mm slice thickness reconstruction. MDCTA was subsequently performed by scanning from the base of the C1 vertebral body to the vertex using an axial technique, 0.5 pitch, 1.25-mm collimation, 350 maximal mA, 120 kVp, 22-cm field of view, and 65 to 85 mL of iodinated contrast material administered by power injector at 4 to 5 mL per second into an antecubital vein with either a fixed 25-second delay between the onset of contrast injection and the start of scanning, or Smart-Prep, a semiautomatic contrast bolus triggering technique. The decision to perform MDCTA was at the discretion of the clinical providers.
Image Analysis
The NCCT examinations were reviewed by 3 experienced neuroradiologists to determine the ICH location (lobar, deep gray matter, or infratentorial), presence of associated intraventricular hemorrhage (IVH), and presence of calcifications within or adjacent to the ICH. Subsequently, the 1.25-mm axial CTA source images were independently reviewed in “spot windows” (width 200, level 110) by the same 3 neuroradiologists to determine the presence of active contrast extravasation, the spot sign, according to the following strict radiological criteria: (1) ≥1 focus of contrast pooling within the ICH; (2) with an attenuation ≥120 Hounsfield units (HU); (3) discontinuous from normal or abnormal vasculature adjacent to the ICH; and (4) of any size and morphology.
The number of spot signs, maximum dimension in a single axial CTA source image, morphology (round, curvilinear, irregular), location within the hematoma (central or peripheral), maximum absolute attenuation, and maximum relative attenuation compared with the ipsilateral distal supraclinoid internal carotid artery (or distal basilar artery in cases of infratentorial ICH) were recorded. In CTAs with >1 spot sign, the characterization was performed on the largest spot sign identified. If a delayed CTA acquisition was obtained, it was reviewed by the same 3 neuroradiologists, blinded to the first-pass CTA, to determine the presence and characteristics of spot signs according to the same radiological criteria. Differences in reader interpretation for the presence and/or characteristics of spot signs were adjudicated by consensus.
Determination of the initial and follow-up ICH and IVH volumes was performed independently and blinded to the CTA categorization with Analyze 9.0 software (Mayo Clinic, Rochester, Minn) by thresholding with manual hematoma outline adjustment in the baseline and first follow-up NCCT examinations. Significant hematoma expansion was defined as an increase in ICH volume of >6 mL or >30% from the baseline ICH volume.10
Medical Record Review
Medical records were reviewed for time of ictus, patient age, gender, admission mean arterial blood pressure, International Normalized Ratio (INR), blood glucose level, history of hypertension, antiplatelet therapy, and surgical intervention. In addition, the administration of fresh-frozen plasma, vitamin K, and platelet transfusions on admission was also recorded. A known time of ictus was only recorded if the onset of symptoms was either witnessed or self-reported by the patient within a 15-minute margin of error as documented in the Neurology Emergency Department consultation notes. For all other patients, including those patients who awoke with neurological symptoms, a known time of ictus was not recorded.
Statistical Analysis
Statistical analysis was performed using the SAS 9.1 software package (SAS Institute Inc, Cary, NC). We performed receiver operating characteristic analysis for each spot sign characteristic to determine thresholds that maximized the area under the curve for the prediction of significant hematoma expansion. Subsequently, we conducted a stepwise multivariate logistic regression analysis to determine which spot sign characteristics were independent predictors of significant hematoma expansion, which were used to construct a spot sign scoring system.
In addition, we constructed a multivariate logistic regression model to determine the correlation of the NCCT and clinical variables with the presence of a spot sign and significant hematoma expansion. Subsequently, the regression analysis for the prediction of significant hematoma expansion was repeated including as an additional variable, first the presence of any spot sign and then the spot sign score. Interobserver agreement for the identification of any spot sign as well as the calculation of the spot sign score was determined with the kappa statistic. A P value ≤0.05 was considered statistically significant.
Results
From January 1, 2000, until December 31, 2008, a total of 818 patients presented to our emergency department with nontraumatic ICH on a NCCT examination and were evaluated with MDCTA of the intracranial circulation within 24 hours of admission. Four hundred fifty-one patients were excluded from the study (55.1%): 251 due to lack of a follow-up NCCT within 48 hours of the baseline CTA, 152 due to the presence of associated subarachnoid hemorrhage within the basal cisterns or a vascular lesion as the ICH etiology, 19 due to incomplete admission clinical data, 15 due to loss of gray–white matter differentiation in a vascular territory, 11 due to immediate anticoagulation treatment for dural venous sinus thrombosis, 2 due to administration of recombinant factor VIIa, and one due to administration of gadolinium contrast material for the CTA. No patient received prothrombin complex concentrate.
A total of 367 patients met our study's inclusion criteria with a mean age of 66 years (median, 68 years; range, 6 to 94 years). Mean time from emergency department admission to MDCTA evaluation was 2.4 hours (median, 1.25 hours; range, 0.25 to 24 hours). Mean time to first follow-up NCCT was 14.1 hours after the baseline CTA (median, 12 hours; range, 1 to 48 hours). Two hundred two patients had a known time of ictus (55%; mean time from ictus to MDCTA evaluation, 7.4 hours; median, 5.5 hours; range, 0.75 to 37.75 hours). Delayed CTA images were acquired in 75 patients (20.4%; mean delay time, 174 seconds after the first-pass CTA; median, 113 seconds; range, 17 to 689 seconds). Mean initial ICH volume was 28.8 mL (median, 19.8 mL; range, 0.2 to 169 mL), and mean initial IVH volume was 10.9 mL (median, 4.1 mL; range, 0.1 to 116 mL). Sixty-eight patients received fresh-frozen plasma (18.5%), 62 patients received vitamin K (16.9%), and 24 patients received platelet transfusions (6.5%) on admission.
Clinical and NCCT Predictors of a Spot Sign and Significant Hematoma Expansion in Primary ICH
Table 1 provides a summary of the clinical and NCCT predictors of a spot sign and significant hematoma expansion. We identified at least one spot sign in 65 of the 367 first-pass CTAs (17.7%) and in 24 of the 75 delayed CTA acquisitions (32%). In 18 cases, spot signs were present in both the first-pass and delayed CTA acquisitions, and in 6 cases, spot signs were present in the delayed CTA acquisition only. There were no cases in which a spot sign was identified in the first-pass CTA but not in the delayed acquisition. Overall, we identified at least one spot sign in 71 CTAs (19.3%).
Table 1. Clinical and NCCT Predictors of a Spot Sign and Significant Hematoma Expansion in Primary ICH.
| Spot Sign Frequency, n (%) | P Value | Hematoma Expansion,* n (%) | P Value | |
|---|---|---|---|---|
| All patients, n=367 (100) | 71 (19) | N/A | 56 (15) | N/A |
| Gender | 0.14 | 0.5 | ||
| Males, n=214 (58) | 47 (22) | 35 (16) | ||
| Females, n=153 (42) | 24 (16) | 21 (14) | ||
| Age, years | 0.058 | 0.2 | ||
| 6–45, n=37 (10) | 2 (5) | 2 (5) | ||
| 46–70, n=164 (45) | 37 (23) | 27 (16) | ||
| 71–94, n=166 (45) | 32 (19) | 27 (16) | ||
| Time from ictus to CTA, h | <0.0001† | <0.0001† | ||
| ≤3, n=43 (12) | 26 (60) | 24 (56) | ||
| >3–≤6, n=68 (18) | 12 (18) | 8 (12) | ||
| >6, n=91 (25) | 9 (10) | 6 (7) | ||
| Unknown, n=165 (45) | 24 (15) | 18 (11) | ||
| Admission MABP, mm Hg | 0.002† | 0.05 | ||
| ≤100, n=147 (40) | 20 (14) | 15 (10) | ||
| 101–120, n=116 (32) | 19 (16) | 19 (16) | ||
| >120, n=104 (28) | 32 (31) | 22 (21) | ||
| Admission INR | <0.0001† | 0.0024† | ||
| <1.5, n=303 (83) | 49 (16) | 39 (13) | ||
| 1.5–2.5, n=41 (11) | 8 (20) | 8 (20) | ||
| >2.5, n=23 (6) | 14 (61) | 9 (39) | ||
| History of hypertension | 0.0115 | 0.04 | ||
| Yes, n=237 (65) | 55 (23) | 43 (18) | ||
| No, n=130 (35) | 16 (12) | 13(10) | ||
| Antiplatelet therapy | 0.03 | 0.0037 | ||
| Yes, n=116 (32) | 30 (26) | 27 (23) | ||
| No, n=251 (68) | 41 (16) | 29 (12) | ||
| IC and antiplatelet therapy | 0.004 | 0.0035 | ||
| Yes, n=19 (5) | 9(47) | 8(42) | ||
| No, n=348 (95) | 62 (18) | 48 (14) | ||
| Blood glucose ≥170 mg/dL | 0.013 | 0.005 | ||
| Yes, n=79 (22) | 23 (29) | 20 (25) | ||
| No, n=288 (78) | 48 (17) | 36 (13) | ||
| ICH location | 0.15 | 0.4 | ||
| Lobar, n=196 (53) | 37 (19) | 30 (15) | ||
| Deep gray, n=142 (39) | 32 (23) | 24 (17) | ||
| Infra, n=29 (8) | 2(7) | 2(7) | ||
| Initial ICH volume, mL | <0.0001† | <0.0001† | ||
| 0.2–29.9, n=237 (65) | 29 (12) | 21 (9) | ||
| 30–59.9, n=81 (22) | 20 (25) | 18 (22) | ||
| ≥60, n=49 (13) | 22 (45) | 17 (35) | ||
| Initial IVH volume, mL | <0.0001† | 0.03 | ||
| 0, n=204 (55) | 27 (13) | 24 (12) | ||
| 0.1–4.9, n=88 (24) | 18 (20) | 14 (16) | ||
| 5–14.9, n=39 (11) | 9 (23) | 7 (18) | ||
| ≥15, n=36 (10) | 17 (47) | 11 (31) | ||
| Surgical evacuation | 0.6 | 0.56 | ||
| Yes, n=25 (7) | 6 (24) | 5 (20) | ||
| No, n=342 (93) | 65 (19) | 51 (15) |
Hematoma expansion defined as >30% or >6 mL increase from the initial ICH volume.
Independent predictor in multivariate logistic regression analysis (P≤0.05). The multivariate logistic regression analysis for hematoma expansion excludes the presence of a spot sign and includes the administration of FFP, vitamin K, and platelet transfusions on admission.
MABP indicates mean arterial blood pressure; IC, impaired coagulation (defined as INR ≥1.5); Infra, infratentorial; N/A, not applicable; FFP, fresh-frozen plasma.
Accuracy of the Spot Sign for the Prediction of Significant Hematoma Expansion in Primary ICH
The presence of any spot sign at MDCTA markedly increased the risk of significant hematoma expansion (PPV 69%; OR=92 [95% CI, 37 to 227], P<0.0001; Table 2). Spot signs were more predictive of significant hematoma expansion in patients who underwent MDCTA evaluation within 3 hours of ictus (PPV 85%, 92% sensitivity, OR=41 [95% CI, 6.7 to 255], P<0.0001). Overall, interobserver agreement for the identification of any spot sign was almost perfect with κ statistics ranging from 0.88 to 0.93 among the 3 readers (95% CI, 0.84 to 0.97). There was greater agreement in the delayed scans (κ statistics ranging from 0.94 to 0.97 [95% CI, 0.9 to 1.0]) than in the first-pass CTAs (κ statistics ranging from 0.86 to 0.92 [95% CI, 0.76 to 1.0]), although this difference was not statistically significant.
Table 2. Accuracy of the Spot Sign for the Prediction of Significant Hematoma Expansion in Primary ICH.
| Accuracy Parameter | Hematoma Expansion* (95% CI) |
|---|---|
| Sensitivity | 88 (75–94) |
| Specificity | 93 (89–95) |
| Positive predictive value | 69 (57–79) |
| Negative predictive value | 98 (95–99) |
| Positive likelihood ratio | 12.4 (8.2–18.7) |
| Negative likelihood ratio | 0.13 (0.07–0.27) |
| Accuracy | 92 |
Hematoma expansion defined as >30% or >6 mL increase from the initial ICH volume.
There was a significantly higher frequency of spot signs in the 75 delayed CTA acquisitions (32%) compared with the 367 first-pass CTAs (17.7%, P=0.005, Pearson χ2 test). Indeed, 6 of the 71 spot signs were seen in the delayed CTA acquisition only (8.5%). These “delayed” spot signs were equally predictive of significant hematoma expansion (PPV 67%).
All of the 7 false-negative CTAs for significant hematoma expansion had supratentorial ICH (7 lobar, one deep gray), none had delayed CTA images acquired, the mean initial ICH volume was 53 mL (median, 73.3 mL; range, 1.5 to 95.7 mL), and the mean time from ictus to MDCTA evaluation was 3.9 hours (median, 3.75 hours; range, 2.5 to 6.25 hours).
Spot Sign Characterization
The results of the receiver operating characteristic analysis for the different spot sign characteristics are summarized in Table 3. For the purpose of this analysis, we used the spot sign characteristics in the first CTA acquisition in which a spot sign was identified. Stepwise multivariate logistic regression analysis showed that the presence of ≥3 spot signs (P=0.004), a maximum spot sign dimension in a single axial CTA source image ≥5 mm (P=0.03), and a maximum attenuation of the largest spot sign ≥180 HU (P=0.03) were independent predictors of significant hematoma expansion.
Table 3. Spot Sign Characterization.
| Maximal Operating Point for Spot Sign Characteristic* | Hematoma Expansion† | AUC/P Value |
|---|---|---|
| No. of spot signs ≥3, n=26 | 0.76/<0.0001‡ | |
| Sensitivity/specificity | 51/96 | |
| PPV | 96 | |
| Maximum axial dimension ≥5 mm, n=34 | 0.83/<0.0001‡ | |
| Sensitivity/specificity | 63/86 | |
| PPV | 91 | |
| Maximum attenuation ≥180 HU, n=45 | 0.77/<0.0001‡ | |
| Sensitivity/specificity | 78/68 | |
| PPV | 84 | |
| Curvilinear/irregular morphology, n=50 | 0.71/0.0006 | |
| Sensitivity/specificity | 84/59 | |
| PPV | 82 | |
| Relative attenuation ≥50%,§ n=54 | 0.70/0.002 | |
| Sensitivity/specificity | 90/50 | |
| PPV | 80 | |
| Central location, n=17 | 0.61/0.12 | |
| Sensitivity/specificity | 31/91 | |
| PPV | 88 |
For the purpose of this analysis, the spot sign characterization was performed in the first CTA acquisition in which a spot sign was identified. For CTAs with >1 spot sign, the maximum axial dimension, attenuation, morphology and location apply to the largest spot sign identified.
Hematoma expansion defined as >30% or >6 mL increase from the initial ICH volume.
Independent predictor in multivariate logistic regression analysis (P≤0.05).
Relative to the distal supraclinoid ICA ipsilateral to the ICH (for infratentorial ICH, the calculation was made relative to the distal basilar artery).
AUC indicates area under the curve after receiver operating characteristic analysis; ICA, internal carotid artery.
The Spot Sign Score
We devised a practical spot sign scoring system based on the spot sign characteristics that were independent predictors of significant hematoma expansion (Table 4). Table 5 provides a summary of the predictive value of the spot sign score for significant hematoma expansion in primary ICH. Overall, there was almost perfect interobserver agreement for the calculation of the spot sign score with κ statistics ranging from 0.89 to 0.93 among the 3 readers (95% CI, 0.85 to 0.97). However, there was greater agreement in the delayed scans (κ statistics 0.98 among the 3 readers [95% CI, 0.96 to 1.0]) than in the first-pass CTAs (κ statistics ranging from 0.85 to 0.92 [95% CI, 0.81 to 0.96]).
Table 4. Calculation of the Spot Sign Score.
| Spot Sign Characteristic* | Points |
|---|---|
| No. of spot signs | |
| 1–2 | 1 |
| ≥3 | 2 |
| Maximum axial dimension | |
| 1–4 mm | 0 |
| ≥5 mm | 1 |
| Maximum attenuation | |
| 120–179 HU | 0 |
| ≥180 HU | 1 |
The spot sign characterization is performed in the first CTA acquisition in which a spot sign is identified. For CTAs with >1 spot sign, the maximum dimension in a single axial CTA source image and maximum attenuation of the largest spot sign is determined. The spot sign score is obtained by adding the total no. of points for the CTA.
Table 5. Predictive Value of the Spot Sign Score in Primary ICH.
| Spot Sign Score* | Risk of Hematoma Expansion,† % | Mean/Median ICH Expansion, mL‡ (Range) | Mean/Median ICH Expansion, %‡ (Range) | Mean/Median IVH Expansion, mL‡ (Range) | Mean Time to Follow-up, hours‡ (Range) |
|---|---|---|---|---|---|
| 0 (n=296) | 2 | 11/10 (2–19) | 39/25 (10–140) | 0/0 (0–1) | 12 (2–23) |
| 1 (n=18) | 33 | 9/8 (3–22) | 21/23 (5–38) | 1/0 (0–4) | 11 (4–27) |
| 2(n=18) | 50 | 9/8 (3–18) | 39/29 (16–128) | 1/0 (0–4) | 12 (3–43) |
| 3(n=18) | 94 | 21/15 (5–80) | 68/38 (10–448) | 5/0 (0–48) | 7 (2–13) |
| 4(n=17) | 100 | 36/31 (6–136) | 72/55 (13–293) | 12/4 (0–76) | 5 (1–8) |
| AUC (95% CI) | 0.93 (0.89–0.95) | ||||
| P | <0.0001 |
A score of zero indicates that no spot sign is identified in the CTA.
Hematoma expansion defined as >30% or >6 mL increase from the initial ICH volume.
The reported mean, median, and range for ICH and IVH expansion as well as the mean and range for time to first follow-up NCCT applies to those patients with hematoma expansion as defined.
AUC indicates area under the curve after receiver operating characteristic analysis.
Among patients who had significant hematoma expansion, there was a significant difference between the mean time from the baseline CTA to the first follow-up NCCT for those patients with spot sign scores of 0 to 2 (11.3 hours; median, 8.5 hours; 95% CI, 7.2 to 15.4 hours) and those patients with scores of 3 and 4 (5.9 hours; median, 5.5 hours; 95% CI, 4.9 to 6.9 hours; P=0.01, Mann–Whitney test).
The mean and median spot sign scores for patients with spot signs in our population were 2.5 and 2, respectively. In the 47 patients with spot signs and a known time of ictus, there was a significant difference between the mean spot sign score for patients imaged ≤3 hours from ictus (mean score 3.1), >3 to ≤6 hours from ictus (mean score, 2.3; P=0.05, Mann–Whitney test), and >6 hours from ictus (mean score, 1.4; P<0.01, Mann–Whitney test). The mean score for the 24 patients with spot signs and an unknown time of ictus was 2.3.
There was no significant difference in the scores of the 65 spot signs identified in the first-pass CTA acquisition (mean score, 2.5) compared with the 6 spot signs identified in the delayed CTA acquisition only (mean score, 1.8; P=0.15, Mann–Whitney test). In the 18 patients with spot signs identified in both the first-pass and delayed CTA acquisitions, there was no significant difference in the scores in the delayed CTA acquisition (mean score, 3.3) compared with the first-pass acquisition (mean score, 2.9; P=0.32, Mann-Whitney test). The Figure illustrates a spot sign with a score of 4. Supplemental Figure I, available online at http://stroke.ahajournals.org, illustrates a “delayed” spot sign with a score of 2. Supplemental Figure II illustrates a spot sign with a score of 3.
Figure.
A 67-year-old man on warfarin therapy for atrial fibrillation and daily aspirin intake presents with syncope and increasing unresponsiveness (admission INR, 2.7). A, NCCT demonstrates a right thalamic ICH (24 mL) with associated IVH (6 mL). B, Axial CTA source image in spot windows demonstrates 3 foci of contrast pooling within the ICH with an attenuation ≥120 HU (arrowheads), consistent with spot signs (a total of 5 spot signs were identified). The largest spot sign measures 10 mm in maximum axial dimension and has an attenuation of 225 HU (spot sign score, 4). C, Delayed CTA acquisition 48 seconds after the first-pass CTA shows that the spot signs increased in volume and changed in morphology (arrowheads). D, NCCT 8 hours after the baseline CTA demonstrates marked interval expansion of both the ICH (94 mL) and IVH (82 mL). The patient died shortly after the follow-up NCCT.
Effect of the Spot Sign Score on the Statistical Model for the Prediction of Significant Hematoma Expansion in Primary ICH
When the presence of a spot sign was entered into the multivariate logistic regression model as a binary variable (in addition to the variables provided in Table 1 as well as the administration of fresh-frozen plasma, vitamin K, and platelet transfusions), the presence of a spot sign (P<0.0001), the time from ictus to MDCTA evaluation (P=0.037), and the admission blood glucose level (P=0.039) became the independent predictors of significant hematoma expansion. However, when the spot sign score was entered into the multivariate logistic regression model, the spot sign score became the only independent predictor of significant hematoma expansion (P<0.0001) independent of time from ictus to MDCTA evaluation, admission INR, mean arterial blood pressure, blood glucose level as well as initial ICH volume and controlling for the administration of fresh-frozen plasma, vitamin K, and platelet transfusions.
Discussion
Strict radiological criteria for the identification of the MDCTA spot sign can be applied reliably with high accuracy for the prediction of significant hematoma expansion in patients with primary ICH (92%). Our accuracy results are similar to those reported in patients imaged within 3 hours of ictus (90%)10 and higher than in a previously reported subset of our patient population that used a less strict spot sign definition (56%).12 Adhering to these strict radiological criteria while evaluating CTAs for the presence of a spot sign is important, because this determination could play a central role in future clinical studies that may rely on the MDCTA “spot sign status” for the selection of patients to receive early hemostatic therapy.
Systematic characterization of the MDCTA spot sign has identified objective and easily determined features that, when used to construct a simple scoring system, becomes the strongest predictor of significant hematoma expansion, independent of time from ictus to MDCTA evaluation, admission INR, mean arterial blood pressure, blood glucose level, and initial ICH volume. The spot sign score also explains the relationship between the spot sign's PPV and the time from ictus to MDCTA evaluation; as time from ictus to imaging increases, there is a significant decrease in both the overall frequency of spot signs and in the mean spot sign score. The lower spot sign scores, in turn, indicate a lower PPV for significant hematoma expansion. Furthermore, in patients who develop significant hematoma expansion, the spot sign score also serves to predict the extent of both ICH and IVH expansion.
Interobserver agreement for the identification and scoring of spot signs was almost perfect. However, as previously reported by Gazzola et al,13 before making the diagnosis of a spot sign, (1) review of the NCCT is important to exclude a pre-existing calcification that may “mimic” a spot sign in the CTA source images; and (2) careful inspection of the CTA source images is imperative to ensure discontinuity of the spot sign from the vasculature adjacent to the ICH to exclude the presence of an aneurysm or arteriovenous malformation/fistula. An additional spot sign “mimic” to be cognizant of is the normal choroidal enhancement, particularly in ICHs that are either in close proximity to the ventricular surface or associated with IVH.
The frequency of spot signs in the delayed CTA acquisitions was higher than in the first-pass CTAs, although not all patients in our study had delayed images acquired. Indeed, 8.5% of spot signs in our study were identified in the delayed CTA acquisitions only, and none of the false-negative CTAs in our patient population had delayed images acquired. Thus, performing delayed CTA acquisitions 2 to 3 minutes after contrast injection either in all patients with ICH or in patients without a spot sign in the first-pass CTA may identify additional “delayed” spot signs and possibly increase this sign's sensitivity for the prediction of significant hematoma expansion. However, future studies are needed to examine this matter more thoroughly.
This study's limitations are its retrospective design, the lack of data on desmopressin administration, the fact that the spot sign scoring system has not been validated in an independent data set, and the lack of delayed CTA acquisitions in all patients. The latter has likely led to an underestimation of the frequency of spot signs in our study group and the spot sign's sensitivity for the prediction of significant hematoma expansion.
Conclusion
By applying strict radiological criteria for the identification of the MDCTA spot sign and systematically characterizing this finding in a large patient population, we have been able to construct a practical, accurate, and reliable scoring system. The spot sign score is an important predictor of significant hematoma expansion in primary ICH, independent of time from ictus to MDCTA evaluation, admission INR, mean arterial blood pressure, blood glucose level, and initial ICH volume. If validated in other data sets, this simple scoring system could be used to select patients for early hemostatic therapy.
Supplementary Material
Figure I. A 77-year-old man with a history of hypertension, warfarin therapy for atrial fibrillation, and daily aspirin intake presented with a left-sided headache and right-sided visual field deficit (admission INR, 3.7). A, NCCT demonstrates a left occipital ICH (15 mL). B, Axial source image of the delayed CTA acquisition performed 95 seconds after the first-pass CTA in spot windows demonstrates one focus of contrast pooling within the ICH with a maximum axial dimension of 8 mm and an attenuation of 130 HU (arrowhead) consistent with a spot sign (spot sign score, 2). No spot sign was identified in the first-pass CTA. C, NCCT 11 hours after the baseline CTA demonstrates interval enlargement of the ICH (20 mL). The patient was discharged home.
Figure II. A 79-year-old man with a history of hypertension, warfarin therapy for atrial fibrillation, and daily aspirin intake presented with worsening right-sided weakness and aphasia (admission INR, 2.1). A, NCCT demonstrates a left parietal ICH (18 mL). B, Axial CTA source image in spot windows demonstrates several foci of contrast pooling within the ICH with an attenuation ≥120 HU (arrowheads) consistent with spot signs (a total of 8 spot signs were identified). C, Axial CTA source image in spot windows demonstrates the largest spot sign with a maximum axial dimension of 2 mm and a maximum attenuation of 184 HU (arrowhead; spot sign score, 3). D, NCCT 7 hours after the baseline CTA demonstrates marked interval expansion of the ICH (98 mL) as well as interval development of IVH (2.5 mL). The patient died shortly after the follow-up NCCT.
Acknowledgments
We thank Elkan Halpern, PhD, for his contribution in the statistical analysis and Eleni K. Balasalle, BA, for her contribution in the artwork for this article.
Source of Funding: Supported, in part, by the American Heart Association Grant-in-Aid 0755984T.
Footnotes
Disclosures: J.R. is the recipient of the American Heart Association Grant-in-Aid 0755984T. M.H.L. is part of the medical advisory board and has received lecture honoraria from General Electric Healthcare.
Contributor Information
Josser E. Delgado Almandoz, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Albert J. Yoo, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Michael J. Stone, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Pamela W. Schaefer, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Joshua N. Goldstein, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Jonathan Rosand, Department of Neurology and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Alexandra Oleinik, Department of Neurology, Department of Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Michael H. Lev, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
R. Gilberto Gonzalez, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Javier M. Romero, Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
References
- 1.Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–1460. doi: 10.1056/NEJM200105103441907. [DOI] [PubMed] [Google Scholar]
- 2.Broderick JP, Brott T, Tomsick T, Huster G, Miller R. The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med. 1992;326:733–736. doi: 10.1056/NEJM199203123261103. [DOI] [PubMed] [Google Scholar]
- 3.Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, Begtrup K, Steiner T Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175–1181. doi: 10.1212/01.wnl.0000208408.98482.99. [DOI] [PubMed] [Google Scholar]
- 4.Becker KJ, Tirschwell DL. Intraparenchymal hemorrhage, bleeding, hemostasis, and the utility of CT angiography. Int J Stroke. 2008;3:11–13. doi: 10.1111/j.1747-4949.2008.00179.x. [DOI] [PubMed] [Google Scholar]
- 5.Mayer SA, Brun NC, Broderick J, Davis S, Diringer MN, Skilnock BE, Steiner T Europe/AustralAsia NovoSeven ICH Trial Investigators. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke. 2005;36:74–79. doi: 10.1161/01.STR.0000149628.80251.b8. [DOI] [PubMed] [Google Scholar]
- 6.Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777–785. doi: 10.1056/NEJMoa042991. [DOI] [PubMed] [Google Scholar]
- 7.Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T Factor Seven for Acute Hemorrhagic Stroke (FAST) Trial Investigators. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127–2137. [Google Scholar]
- 8.Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, Heeley E, Skulina C, Parsons MW, Kim JS, Tao QL, Li YC, Jiang JD, Tai LW, Zhang JL, Xu E, Cheng Y, Heritier S, Morgenstern LB, Chalmers J INTERACT Investigators. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7:391–399. doi: 10.1016/S1474-4422(08)70069-3. [DOI] [PubMed] [Google Scholar]
- 9.Becker KJ, Baxter AB, Bybee HM, Tirschwell DL, Abouelsaad T, Cohen WA. Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage. Stroke. 1999;30:2025–2032. doi: 10.1161/01.str.30.10.2025. [DOI] [PubMed] [Google Scholar]
- 10.Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G, Symons SP. CT angiography ‘spot sign’ predicts hematoma expansion in acute intracerebral hemorrhage. Stroke. 2007;38:1257–1262. doi: 10.1161/01.STR.0000259633.59404.f3. [DOI] [PubMed] [Google Scholar]
- 11.Kim J, Smith A, Hemphill JC, III, Smith WS, Lu Y, Dillon WP, Wintermark M. Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage. AJNR Am J Neuroradiol. 2008;29:520–525. doi: 10.3174/ajnr.A0859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Goldstein JN, Fazen LE, Snider R, Schwab K, Greenberg SM, Smith EE, Lev MH, Rosand J. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology. 2007;68:889–894. doi: 10.1212/01.wnl.0000257087.22852.21. [DOI] [PubMed] [Google Scholar]
- 13.Gazzola S, Aviv RI, Gladstone DJ, Mallia G, Li V, Fox AJ, Symons SP. Vascular and nonvascular mimics of the CT angiography ‘spot sign’ in patients with secondary intracerebral hemorrhage. Stroke. 2008;39:1177–1183. doi: 10.1161/STROKEAHA.107.499442. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure I. A 77-year-old man with a history of hypertension, warfarin therapy for atrial fibrillation, and daily aspirin intake presented with a left-sided headache and right-sided visual field deficit (admission INR, 3.7). A, NCCT demonstrates a left occipital ICH (15 mL). B, Axial source image of the delayed CTA acquisition performed 95 seconds after the first-pass CTA in spot windows demonstrates one focus of contrast pooling within the ICH with a maximum axial dimension of 8 mm and an attenuation of 130 HU (arrowhead) consistent with a spot sign (spot sign score, 2). No spot sign was identified in the first-pass CTA. C, NCCT 11 hours after the baseline CTA demonstrates interval enlargement of the ICH (20 mL). The patient was discharged home.
Figure II. A 79-year-old man with a history of hypertension, warfarin therapy for atrial fibrillation, and daily aspirin intake presented with worsening right-sided weakness and aphasia (admission INR, 2.1). A, NCCT demonstrates a left parietal ICH (18 mL). B, Axial CTA source image in spot windows demonstrates several foci of contrast pooling within the ICH with an attenuation ≥120 HU (arrowheads) consistent with spot signs (a total of 8 spot signs were identified). C, Axial CTA source image in spot windows demonstrates the largest spot sign with a maximum axial dimension of 2 mm and a maximum attenuation of 184 HU (arrowhead; spot sign score, 3). D, NCCT 7 hours after the baseline CTA demonstrates marked interval expansion of the ICH (98 mL) as well as interval development of IVH (2.5 mL). The patient died shortly after the follow-up NCCT.