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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 3  |  Page : 676-680

Hypodensities within Hematoma is Time-Dependent and Predicts Outcome after Spontaneous Intracerebral Hemorrhage

1 Comprehensive Stroke Care Program, Department of Neurology, Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
2 Department of Interventional Radiology, Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
3 Department of Biostatistics, Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

Date of Submission10-Aug-2019
Date of Decision14-Nov-2019
Date of Acceptance22-Jul-2020
Date of Web Publication24-Jun-2021

Correspondence Address:
Dr. P N Sylaja
Professor of Neurology, Comprehensive Stroke Care Program, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695 011, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.319222

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 » Abstract 

Background: Non-contrast CT (NCCT) brain imaging biomarkers of hematoma expansion in intracerebral hemorrhage (ICH) has gained relevance in recent times. Though intra-hematoma hypodensities (IHH) can predict hematoma expansion and outcome, it is postulated to be time-dependent.
Aim: To assess the differential prevalence of IHH in spontaneous ICH over time and assess its predictive valve in early hematoma expansion and functional outcome at 3 months.
Material and Methods: Patients with ICH within 48 h of stroke onset were included. Baseline clinical and demographic data were collected. Baseline NCCT brain was analyzed for hematoma volume, characterization of IHH, with 24-hours follow-up NCCT hematoma volume calculated for identification of hematoma expansion. Poor functional outcome was defined as mRS ≥3.
Results: Around 92 subjects were included in the study. IHH was found in 40%. Prevalence of IHH was higher in those with baseline NCCT performed within 3 h of symptom onset compared to those beyond 3 h (71% vs 29%, P = 0.002). The hematoma expansion was more common in patients with IHH compared to those without (54% vs 29%; P = 0.02). Multivariate analysis revealed the presence of IHH (rather than pattern or number) to be strongly associated with poor functional outcome at 3 months (OR 3.86; 95% CI: 1.11–13.42, P = 0.03).
Conclusion: There is a decreasing prevalence of IHH as the time from symptom onset to NCCT increases. Nevertheless, its presence is significantly associated with hematoma expansion and predicted poor short-term functional outcomes in spontaneous ICH.

Keywords: Intracerebral hemorrhage, intrahematoma hypodensities, outcome
Key Message: The prevalence of Intrahematoma Hypodensities (IHH)decreases with time in spontaneous ICH. The presence of IHH is associated with hematoma expansion and predicts poor functional outcome.

How to cite this article:
Vedartham V, Kesav P, Maniangatt S, Nagesh C, Sreedharan SE, Jayadevan E R, Sarma S, Sylaja P N. Hypodensities within Hematoma is Time-Dependent and Predicts Outcome after Spontaneous Intracerebral Hemorrhage. Neurol India 2021;69:676-80

How to cite this URL:
Vedartham V, Kesav P, Maniangatt S, Nagesh C, Sreedharan SE, Jayadevan E R, Sarma S, Sylaja P N. Hypodensities within Hematoma is Time-Dependent and Predicts Outcome after Spontaneous Intracerebral Hemorrhage. Neurol India [serial online] 2021 [cited 2021 Jul 25];69:676-80. Available from:

Primary intracerebral hemorrhage (ICH) accounts for nearly 20% of all strokes worldwide, associated with higher 30-day mortality rates and poor functional outcomes.[1] One important determinant of outcome in ICH is the presence of hematoma expansion.[2],[3],[4] Prompt recognition of those with potential for hematoma expansion has implications in treatment strategies as well as overall prognosis. Age, level of consciousness, blood pressure, blood sugar, baseline hematoma volume, location as well as the shape of hematoma, and intraventricular hemorrhage is associated with hematoma expansion.[2],[3] Though computed tomography (CT) angiography spot sign is a validated marker of hematoma expansion and post-stroke functional outcome in ICH,[5] its widespread use is limited due to the need for contrast administration and lack of widespread availability of angiography facilities. This, in turn, has paved the way for the detection of non-contrast CT (NCCT) brain biomarkers which are potentially beneficial in predicting hematoma expansion.[4],[5],[6],[7],[8],[9],[10],[11] These biomarkers in NCCT variously described as Swirl Sign (SS),[4],[5],[6] Blend Sign (BS),[7] and Black Hole Sign (BHS)[8] have been correlated with hematoma expansion,[9] but their utility in predicting functional outcomes after ICH is not well-studied. On account of the lack of standardized acceptable definition as well as variable sensitivity and specificity of the abovementioned biomarkers on NCCT, we need a more generalizable and easily reproducible parameter which could aid in the prediction of hematoma expansion as well as functional outcomes in ICH. Boulouis et al. in 2016[12] highlighted the utility of a well-defined encapsulated hypodensity within the hematoma in predicting hematoma expansion in ICH, even though its association with post-stroke functional outcomes was not explored.

The concept of “Time is Brain” holds good in case of spontaneous ICH as well, on account of the time-bound nature of hematoma expansion, with the majority occurring within 6 h of the index event.[3],[5] This has, in turn, contributed to incorporation of time from symptom onset to performance of baseline NCCT as one of the integral components of hematoma expansion risk prediction scores in ICH such as BAT (Blend sign, Any hypodensity, Time from onset to NCCT) score[13] and BRAIN (Baseline ICH volume, Recurrent ICH, Anticoagulation with warfarin at onset, Intraventricular extension, Number of hours to baseline CT from symptom onset) score[14] with the premonition of shorter onset to scan times related to higher chances of hematoma expansion. However, there is a paucity of information regarding the distribution of intra-hematoma hypodensities (IHH) with the time of performing baseline NCCT from symptom onset. Hence, we analyzed the prevalence of IHH on baseline NCCT over time and assessed its utility in predicting early hematoma expansion as well as short-term functional outcomes after spontaneous ICH.

 » Material and Methods Top

The study included patients with spontaneous ICH admitted to a comprehensive stroke care center between January 2010 and November 2016, within 48 h of stroke onset, with the availability of baseline and follow-up NCCT head at 24 h following admission. Those with secondary causes of ICH and with premorbid modified Rankin Scale score (mRS)>2 were excluded from the study. The demographic and clinical variables which included the level of consciousness, blood pressure at the baseline, stroke severity using the National Institute of Health Stroke Scale (NIHSS) score, and relevant hematological parameters were collected. NCCT at baseline and 24-hours follow-up were reviewed by neuroradiologists who were blinded for clinical details and the following radiological parameters were analyzed: a) presence of well-defined hypodensity within hematoma, its number, and pattern b) hematoma volume (baseline and follow-up) as assessed by ABC/2 method[15] c) location of the bleed d) the presence of an intraventricular extension of hemorrhage and e) presence of midline shift. A well-defined hypodensity (also referred in the text as IHH) is described as an enclosed area of iso or hypoattenuation within the hyperdense hematoma spanning across at least two contiguous 5 mm axial CT slices, with the exclusion of those confined to the margin of the hematoma as well as those communicating with the surrounding brain parenchyma. The NCCTs done within and after 3 h of symptom onset were compared for the prevalence of IHH. Patterns of hypodensities were classified into linear, curvilinear, globular, slit-like, irregular, or mixed type [Figure 1]. The presence of hematoma expansion was defined as an increase in hematoma volume on 24-hour follow-up NCCT by >33% or 6 mL from the baseline scan. Functional outcome at 90 days was assessed by a mRS either during a clinic visit, telephonic interview, or review of electronic medical records, with excellent outcome defined as mRS <3. Data regarding in-hospital mortality was obtained as a secondary outcome. The study was approved by the institutional ethics committee. The IEC number is 974. The date of receiving the IEC approval was 14th October 2016.
Figure 1: NCCT brain representing various patterns of hypodensity within the hematoma: (a) Globular, (b) Linear, (c) Slit-like, (d) Irregular, (e) Curvilinear

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Statistical analysis

For univariate analysis, Student's t-tests were used for continuous variables; Pearson χ2 tests and Fisher's exact tests being used for categorical variables. For ordinal variables, extended Mantel-Heanzel χ2 test for assessing a linear trend was used. Multivariable logistic regression analysis was done to assess if the presence of IHH was an independent predictor of hematoma expansion and functional outcome at 3 months. P < 0.05 was considered statistically significant. All statistical analyses was performed using Statistical Package for the Social Sciences (SPSS) 22.0 software.

 » Results Top

Out of the 120 patients screened for the study, 92 subjects met the inclusion and exclusion criteria while 28 were excluded from the study, due to the nonavailability of images (n = 16) and presentation after 48 h of onset (n = 12). Males constituted 76% of the study population. The mean age (SD) of the study population was 57.93 (12.02) years. The baseline demographic characteristic of the study population is depicted in [Table 1].
Table 1: Baseline demographic variables of the study population

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Around 40% (37 of 92 subjects) of the study population had at least one well-defined hypodensity within the hematoma on NCCT. In those subjects with baseline hematoma volume <30 mL, the prevalence of IHH was 43% (16 of 62 patients) as against 57% (21 of 30 subjects) in those with hematoma volume of 30 mL or more (P < 0.001). The IHH was more likely to be present if the symptom onset to baseline NCCT brain time was shorter than 3 h (71% vs 29%, P = 0.002). Patients with IHH showed significant hematoma expansion compared to those without (54% vs 29%; P = 0.02) [Figure 2]. Around 89% (32 of 37 patients) with IHH had a poor 90 days functional outcome with mRS ≥3 compared to 56% (31 of 55 patients) without (P = 0.03), which did not differ in those with single (92%; 12 of 13 patients) or multiple hypodensities (87%; 20 of 23 patients) [P = 0.34]. In our study, further analysis of the patterns of IHH (linear, curvilinear, globular, slit-like, irregular, mixed), as well as its correlation with other variables, could not be done on account of small sample size. No statistically significant association was noted between the presence of IHH and clinical variables such as systemic hypertension, diabetes mellitus, dyslipidemia, history of smoking, alcohol consumption, current use of antiplatelets, baseline blood sugar, Glasgow coma scale, and NIHSS neither was there any association noted between their presence and in-hospital mortality [Table 2].
Figure 2: A 58-year-old male presented with right-sided weakness. (a) NCCT brain at onset showed left capsuloganglionic bleed measuring 71 mL demonstrating a linear hypodensity within the hematoma. (b) Follow-up NCCT after 24 h showed an increase in the hematoma volume to 149 mL, suggesting significant hematoma expansion

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Table 2: Comparison of clinical, imaging parameters as well as functional parameters in those with and without hypodensity within hematoma (Univariate analysis)

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On multivariate logistic regression analysis, the presence of IHH on NCCT and performance of neurosurgical procedures were independent predictors of poor functional outcome at 90 days post-stroke (mRS of 3 or more), whereas baseline hematoma volume was an independent predictor of hematoma expansion [Table 3].
Table 3: Multivariate logistic regression analysis of variables associated with poor functional outcome at three months (mRS of 3 or more) and hematoma expansion (>6 ml) respectively

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Interobserver agreement between the two observers who evaluated NCCT for the presence of IHH was substantial (K = 0.900, with P < 0.001).

 » Discussion Top

Our study provides evidence regarding the association of IHH on baseline NCCT with larger baseline hematoma volume, hematoma expansion over the next 24 h as well poor 90 days functional outcome in primary ICH, with the strongest correlation observed with the prediction of poor functional outcome. We also identified an increased prevalence of hypodensity within the hematoma in NCCT done within 3 h of symptom onset, even though the presence of IHH was itself associated with significant hematoma expansion, irrespective of their presentation within or beyond 3 h from symptom onset. This would suggest that while the prevalence of IHH is time-dependent, its presence alone would reliably predict hematoma expansion and poor short-term functional outcomes in primary ICH. The differential effects of the number and pattern of IHH on the primary as well as the secondary outcomes could not be assessed on account of the small sample size.

The lack of definitive treatment options for primary ICH even at present has led to many studies over the past two decades[2],[3],[4],[5],[11],[12] to identify clinical as well as imaging parameters potentially predicting functional outcomes and mortality, which could, in turn, be utilized to effectively triage at baseline assessment itself, thereby improving the overall outcomes. As the NCCT brain is the primary investigation utilized for evaluation of suspected ICH, the current impetus is on the identification of potential non-contrast imaging biomarkers, which could stratify those at risk for hematoma expansion and, in turn, poor functional outcomes. Those with larger baseline hematoma volume[3],[9] and irregular margins[2],[3],[9] have been traditionally associated with higher chances of hematoma expansion. Subsequently, the focus has been on the delineation of hematoma heterogeneity which led to the identification of several named signs such as SS,[4],[5],[6] BS,[7] BHS,[8] variably associated with hematoma expansion and functional outcomes in ICH. SS was observed in 30–46% of the study population in previous studies[4],[6] whereas the prevalence of BS and BHS was 16.9%[7] and 14.6%[8] of the study population, respectively. All three signs were predictive of hematoma expansion in spontaneous ICH (P < 0.05),[6],[7],[8] with the presence of SS being associated with higher mortality at 1 month (P = 0.03) and poor functional outcomes at three months (P = 0.045).[4] The specificity of BS and BHS in predicting hematoma expansion in ICH was 95.5%[7] and 94.1%,[8] respectively, despite having low sensitivities (<40%). Despite having a higher sensitivity (46.5%), SS had poorer specificity (71.3%) in predicting early hematoma growth.[10] On account of the lack of standardized definitions, variable sensitivity, and specificity of these above mentioned named NCCT biomarkers, the need of the hour is to develop a widely acceptable, reliable and easily reproducible hematoma heterogeneity imaging biomarker, which could aid in prognostication of ICH subjects.[9] This notion was highlighted by Boulouis et al.[12] in that, presence rather than the pattern of an encapsulated hypodensity within the hematoma was the single most important predictor of hematoma expansion (P < 0.001).

Hematoma expansion in spontaneous ICH, is a time-bound phenomenon, with the majority occurring within the first 6 h, even though it can extend up to 24 h post symptom onset.[3],[5] As ICH is a dynamic illness, the earlier a patient is scanned initially, the greater is the possibility of later demonstrating ICH growth, as roughly one-third of those exhibiting hematoma expansion does so within the first three hours of ICH onset.[16] However, whether the same phenomenon holds good for the prevalence of IHH on baseline NCCT brain is a hitherto unknown domain. Those subjected to earlier baseline NCCT brain have a higher chance of developing hematoma expansion on follow-up imaging, as is being substantiated by incorporation of time from symptom onset to baseline scan as one of the variables in hematoma expansion risk prediction scores such as BAT score[13] and BRAIN score.[14] In the BAT score, one point is given to the presence of BS, two points for any IHH, with two points being allotted to time from symptom onset to NCCT less than 2.5 h. A BAT score of 3 or more predicted hematoma expansion with a sensitivity of 50% and specificity of 89%.[13] BRAIN score, on the other hand, is more extensive, incorporating baseline hematoma volume, recurrent ICH, anticoagulation with warfarin at symptom onset, intraventricular extension, and several hours from symptom onset to baseline NCCT.[14] Out of the total score of 24, the strongest predictors for hematoma expansion were a large baseline hematoma volume of more than 20 mL (7 points), those on warfarin anticoagulation at symptom onset (6 points) and a shorter time from index event to baseline NCCT of less than 3 h (4 points).[14]

In our study, we analyzed through the implementation of a uniform study definition, the time-dependent nature of IHH on baseline NCCT brain in spontaneous ICH as well as an assessment of their role in predicting hematoma expansion and short term functional outcomes. IHH was more prevalent in the cohort of spontaneous ICH subjects, whose baseline neuroimaging was done within 3 h of symptom onset, thereby reinstating the time-bound nature of this noninvasive neuroimaging marker of hematoma expansion. However, those with IHH on baseline NCCT had significant hematoma expansion on a 24-hours follow-up scan irrespective of whether the subjects presented within or beyond 3 h from symptom onset. This, in turn, reinstates the importance of performing NCCT within 3 h of symptom onset to identify those with a well-defined hypodensity within the hematoma, in turn effectively triaging the subgroup of spontaneous ICH patients who are likelier to develop hematoma expansion and poor functional outcomes, which could potentially be modified by instituting more aggressive therapeutic and monitoring strategies in the above-said cohort of subjects. Those with IHH, irrespective of the number, pattern or time from symptom onset, had larger baseline hematoma volumes (30 mL or more) [P < 0.001], higher chances for hematoma expansion at 24 h (P = 0.02) and poorer 90 days functional outcomes (mRS of 3 or more) [P = 0.03]. Out of these, the strongest correlation was noted between the presence of IHH and poor functional outcomes at three months, which retained statistical significance even on multivariate logistic regression analyses (P = 0.033). Similar to the findings from the study by Boulouis et al.,[12] our study also understated the fact that it is the presence rather than the pattern of the hematoma hypodensity that predicted poor functional outcomes.

The lack of complexity of this neuroimaging marker coupled with the lack of requirement for contrast study and its easy reproducibility (as reflected by high inter-observer reliability scores) are the major strengths of our study. Besides, the scans were read by neuroradiologists who were blinded to the clinical data. However being a single-centered study with stringent inclusion and exclusion criteria limited the number of study subjects, thereby constituting a major limitation for our study.

In conclusion, well-defined encapsulated IHH is an easily detectable, reliably reproducible noninvasive neuroimaging parameter in primary ICH, which even though being more prevalent in earlier scans performed within 3 h from symptom onset, nevertheless faithfully predicts hematoma expansion irrespective of the time from symptom onset, with the greatest reliability on predicting poorer short-term (3 months) post-stroke functional outcomes. The potential role of this non-contrast neuroimaging marker in triaging those with ICH at risk of poor functional outcomes has to be validated in a larger population across multiple study cohorts.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

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Barras CD, Tress BM, Christensen S, MacGregor L, Collins M, Desmond PM, et al. Density and shape as CT predictors of intracerebral hemorrhage growth. Stroke 2009;40:1325-31.  Back to cited text no. 2
Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke 1998;29:1160-6.  Back to cited text no. 3
Selariu E, Zia E, Brizzi M, Abul-Kasim K. Swirl sign in intracerebral hemorrhage: Definition, prevalence, reliability and prognostic value. BMC Neurology 2012;12:109-14.  Back to cited text no. 4
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Li Q, Zhang G, Huang YJ, Dong MX, Lv FJ, Wei X, et al. Blend sign on computed tomography: Novel and reliable predictor for early hematoma growth in patients with intracerebral hemorrhage. Stroke 2015;46:2119-23.  Back to cited text no. 7
Li Q, Zhang G, Xiong X, Wang XC, Yang WS, Li KW, et al. Black hole sign: Novel imaging marker that predicts hematoma growth in patients with intracerebral hemorrhage. Stroke 2016;47:1777-81.  Back to cited text no. 8
Boulouis G, Morotti A, Charidimou A, Dowlatshahi D, Goldstein JN. Noncontrast computed tomography markers of intracerebral hemorrhage expansion. Stroke 2017;48:1120-5.  Back to cited text no. 9
Xiong X, Li Q, Yang WS, Wei X, Hu X, Wang XC, et al. Comparison of swirl sign and black hole sign in predicting early hematoma growth in patients with spontaneous intracerebral hemorrhage. Med Sci Monit 2018;24:567-73.  Back to cited text no. 10
Connor D, Huynh TJ, Demchuk AM, Dowlatshahi D, Gladstone DJ, Subramaniapillai S, et al. Swirls and spots: Relationship between quantitative and qualitative hematoma heterogeneity, hematoma expansion and the spot sign. Neurovasc Imaging 2015;1:8-15.  Back to cited text no. 11
Boulouis G, Morotti A, Brouwers B, Charidimou A, Jessel MJ, Auriel E, et al. Association between hypodensities detected by computed tomography and hematoma expansion in patients with intracerebral hemorrhage. JAMA Neurol 2016;73:961-8.  Back to cited text no. 12
Morotti A, Dowlatshahi D, Boulouis G, Al-Ajlan F, Demchuk AM, Aviv RI, et al. Predicting intracerebral hemorrhage expansion with non contrast computed tomography: The BAT score. Stroke 2018;49:1163-9.  Back to cited text no. 13
Wang X, Arima H, Al-Shahi Salman R, Woodward M, Heeley E, Stapf C, et al. Clinical prediction algorithm (BRAIN) to determine risk of hematoma growth in acute intracerebral hemorrhage. Stroke 2015;46:376-81.  Back to cited text no. 14
Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304-5.  Back to cited text no. 15
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  [Table 1], [Table 2], [Table 3]


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