Non-contrast computed tomography features predict intraventricular hemorrhage growth

Objectives Non-contrast computed tomography (NCCT) markers are robust predictors of parenchymal hematoma expansion in intracerebral hemorrhage (ICH). We investigated whether NCCT features can also identify ICH patients at risk of intraventricular hemorrhage (IVH) growth. Methods Patients with acute spontaneous ICH admitted at four tertiary centers in Germany and Italy were retrospectively included from January 2017 to June 2020. NCCT markers were rated by two investigators for heterogeneous density, hypodensity, black hole sign, swirl sign, blend sign, fluid level, island sign, satellite sign, and irregular shape. ICH and IVH volumes were semi-manually segmented. IVH growth was defined as IVH expansion > 1 mL (eIVH) or any delayed IVH (dIVH) on follow-up imaging. Predictors of eIVH and dIVH were explored with multivariable logistic regression. Hypothesized moderators and mediators were independently assessed in PROCESS macro models. Results A total of 731 patients were included, of whom 185 (25.31%) suffered from IVH growth, 130 (17.78%) had eIVH, and 55 (7.52%) had dIVH. Irregular shape was significantly associated with IVH growth (OR 1.68; 95%CI [1.16–2.44]; p = 0.006). In the subgroup analysis stratified by the IVH growth type, hypodensities were significantly associated with eIVH (OR 2.06; 95%CI [1.48–2.64]; p = 0.015), whereas irregular shape (OR 2.72; 95%CI [1.91–3.53]; p = 0.016) in dIVH. The association between NCCT markers and IVH growth was not mediated by parenchymal hematoma expansion. Conclusions NCCT features identified ICH patients at a high risk of IVH growth. Our findings suggest the possibility to stratify the risk of IVH growth with baseline NCCT and might inform ongoing and future studies. Clinical relevance statement Non-contrast CT features identified ICH patients at a high risk of intraventricular hemorrhage growth with subtype-specific differences. Our findings may assist in the risk stratification of intraventricular hemorrhage growth with baseline CT and might inform ongoing and future clinical studies. Key Points • NCCT features identified ICH patients at a high risk of IVH growth with subtype-specific differences. • The effect of NCCT features was not moderated by time and location or indirectly mediated by hematoma expansion. • Our findings may assist in the risk stratification of IVH growth with baseline NCCT and might inform ongoing and future studies. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-023-09707-9.


Introduction
More than 5.5 million patients suffer from intracerebral hemorrhage (ICH) annually [1] and ICH represents the most severe form of stroke, with mortality and severe disability rates approaching 50% at 1 month and exceeding 75% at 1 year, respectively [2,3].Therapeutic strategies have failed to show overall beneficial treatment effects in previous ICH trials over the past years.Therefore, new candidates for potential treatment strategies are holding vast research attention.Intraventricular extension of intracerebral hemorrhage (IVH) occurs in 40% of ICH patients and is a wellestablished predictor of poor functional outcome [4].IVH is a dynamic and potentially modifiable process (IVH growth) [5,6] which can present either as interval increases in IVH volume (expansion IVH, eIVH) or as a delayed development of IVH (dIVH) on subsequent neuroimaging [7,8].Furthermore, both have shown a strong relationship with a poor functional outcome [5,6] and hold potential to improve outcome prediction models for clinical ICH management [9].Recent evidence suggested that non-contrast computed tomography (NCCT) features might help identify patients at risk of IVH growth; however, the exact relationship with eIVH and dIVH remains unclear [10].Therefore, we hypothesized that both subgroups are independently predicted by distinct NCCT features.Recognizing that eIVH and dIVH vary in terms of chronological order and ICH location on the one hand, and on the other hand are common phenomena in patients with acute HE, we additionally hypothesized a potential link with the effects exerted by the NCCT features [8].To test and evaluate our hypotheses, we performed a three-fold approach: Firstly, we tested and validated the association of NCCT features and IVH growth in an independent multicenter cohort.Secondly, we conducted two subgroup analyses to identify differences in NCCT markers independently associated with eIVH and dIVH.Thirdly, we evaluated if the effects were mediated by acute HE and moderated by ICH location and time.

Clinical variables
Clinical data obtained from medical records included age, sex, history of hypertension and diabetes mellitus, systolic blood pressure, anticoagulation and antiplatelet treatment, Glasgow Coma Scale (GCS) at admission, time from   [13,14].All NCCT markers were rated on axial NCCT images by two raters (J.N. with 6 years of experience in ICH imaging research and L.V. with 3 years of experience in ICH research) to determine the following nine markers as previously reported [15]: (1) irregular shape, (2) satellite sign, (3) island sign which were characterized as markers of shape [16].Markers of density consisted of (1) heterogeneous density, (2) swirl sign, (3) black hole sign, (4) blend sign, (5) fluid sign, and (6) hypodensities [16].All markers were rated inconsideration of the consensus definitions proposed by the International NCCT ICH Study Group [16]: In brief, irregular shape was defined as foci of hematoma margin irregularities in the largest hematoma region according to the Barras shape scales I-V [16,17].The presence of irregular shape was defined after dichotomization with a Barras scale of ≥ III [16].Satellite sign was defined as a hematoma separate from the main hematoma (1-20 mm distance) with a maximum diameter of 10 mm [16,18].The island sign consisted of at least three scattered small hematomas all separate from the main hematoma or at least four small hematomas, some or all of which may connect with the main hematoma [16,19].Heterogeneous density was evaluated as foci of hypoattenuation in within the largest hematoma compared to the brain parenchyma according to the Barras density scales I-V [16,17].The presence of heterogeneous density was defined after dichotomization with a Barras scale of ≥ III [16].The swirl sign was defined as a region of hypo-or isoattenuation compared with the brain parenchyma.The region may be rounded, streaklike, or irregular and does not require a strict encapsulation within the hematoma [20,21].The black hole sign consisted of a relatively hypodense area which is encapsulated within a hyperdense area and which is not connected with the adjacent brain tissue [21,22].The relatively hypodense area has an identifiable border and a difference of at least 28 HU between the two density regions [22,23].Blend sign was defined as a hypoattenuating area adjacent to a hyperattenuating area of the hematoma, with a clear separation between them at a density difference of at least 18 Hounsfield Units (HU) [23,24].Fluid sign referred similarly to the presence of one distinct hypoattenuating area above and one hyperattenuating area below a discrete straight line of separation, yet irrespective of its density measurements [16,25].The imaging sign hypodensities were defined as any hypodense region strictly encapsulated within the hemorrhage with any shape, size, and density which does not require a density measurement [16,26].Illustrative examples on NCCT marker ratings are provided in Supplementary Figure 1.A subset of patients (n = 100) was randomly selected and presented again for a second reading to one rater (J.N. with 6 years of experience in ICH imaging research).Images for the second reading were presented in a random order 3 months later to minimize the recall of the images.

Outcomes
The main outcome of the analysis was the occurrence of any IVH growth.In secondary analysis, the same regression models were repeatedly stratified by the IVH growth type, distinguishing eIVH from dIVH.

Statistical analysis
Data were tested for normality and homogeneity of variance using histogram plots and the Shapiro-Wilk test.
Descriptive statistics are presented as counts (percentages [%]) for categorical variables and compared with the χ 2 test, mean (standard deviation [SD]) for continuous normally distributed variables, and medians (interquartile range [IQR]) for non-normal continuous variables and compared with the Mann-Whitney test, respectively.Interrater agreement for ICH and IVH volume quantifications was calculated and expressed as intraclass correlation coefficient (ICC) with 95% upper and lower confidence intervals (CI) from pairs of two readers (E.V. and L.V.) [27,28].Interrater and intrarater agreements for the readings of NCCT markers were calculated and expressed as Cohen's κ statistic with 95% upper and lower CI [29].

Logistic regression analysis
Multivariate regression analysis was performed to identify independent variables associated with eIVH and dIVH in patients with IVH growth.Candidate variables were selected based on prior knowledge of clinical significance and sample size for the following: age, sex, hypertension, admission GCS, use of oral anticoagulation, and supratentorial ICH location [30].Collinear covariates, as expressed by a variance inflation factor (VIF) of greater than 3, were identified and removed from the model if necessary [31].Variables were fitted together using backward elimination with a p value criterion of less than 0.05 [32].Given for selected variables are odds ratios (OR) with 95%CI and corresponding beta coefficients.For visual display, adjusted beta coefficients of significant independent variables were plotted.A statistically significant difference was set at a p value of less than 0.05.

Moderation and mediation analysis
Time [8,33] and location [34] were hypothesized to moderate the effect of the NCCT markers on IVH growth and subgroups (eIVH and dIVH).The PROCESS SPSS macro version 2.13 model 2 for moderation analysis was used to calculate the regression coefficients for the respective NCCT marker in each group (IVH growth, eIVH, dIVH) independently (Supplementary Material) [35].Hematoma expansion (defined as continuous growth > 6 mL or relative growth > 33%) hypothesized to mediate the effect of NCCT markers on IVH growth and subgroups was assessed in a mediation model (Supplementary Material).
The PROCESS SPSS macro version 2.13 model 4 for mediation analysis was used to calculate three pathways (Supplementary Material) [36].Pathway a determined the regression coefficients for the effect of the NCCT marker on the mediator, pathway b examined the association between the mediator and IVH growth or subgroups, and pathway c estimated the total and direct effect of the NCCT marker on IVH growth and subgroups, respectively.Pathway ab calculated the indirect intervention effects.To test the significance of the indirect effect, the macro generated bias-corrected bootstrapped 95%CI [36].Significant mediation was determined if the CI around the indirect effect did not include zero [36].Analyses were performed using the statistical software package SPSS version 25® (IBM Corporation, 2019) and R Statistics® Version 3.5.1 (R Core Team.R: A Language and Environment for Statistical Computing.R Foundation for Statistical Computing, 2018).

Supplementary analysis
A second multivariate regression analysis was performed to identify the effect of eIVH and dIVH on the functional outcome (Supplementary Table 4).A receiver operating curve (ROC) analysis was performed to evaluate and compare the discriminatory accuracies of IVH growth, HE, and revised HE in the prediction of functional outcome and mortality (Supplementary Material Table 5).

Results
A total of 731 out of 1399 patients met the inclusion criteria, as shown in Fig. 1, and 185 (25.31%) patients suffered from IVH growth, of whom 130 (17.78%) had an eIVH and 55 (7.52%) a dIVH.Patients with IVH growth had a lower admission GCS, shorter time from symptom onset/LSW to imaging, smaller hematoma volumes on both admission and follow-up imaging, and a higher frequency of hematomas in the basal ganglia.Within the IVH growth subgroups, patients with eIVH also had more deep bleedings, in contrast to dIVH that showed with higher frequencies of lobar hematomas.IVH volumes were higher in patients with eIVH compared to those in patients with dIVH on followup imaging.A detailed summary of the study population's characteristic is provided in Table 1.Interobserver agreement for both ICH and IVH segmentations was excellent, as presented in the supplementary material.Interrater agreements for the NCCT features were substantial to excellent (n = 731; Cohen's κ from 0.74 to 0.95) with good to excellent intrarater agreements (n = 100; Cohen's κ from 0.81 to 0.98), as presented in the supplementary material.The presence of irregular shape was associated with 1.68 higher odds of IVH growth after adjustment for potential confounders in multivariable logistic regression (Table 2).In the subgroup analysis, irregular shape remained independently associated with an almost three times higher risk for dIVH (OR 2.72; 95%CI 1.91-3.33;p value 0.016), as shown in Table 3, Finally, the moderator analysis demonstrated that the two interaction terms (Int.1: NCCT marker × time; Int.2: NCCT marker × location) had no significant effect on the direct association between the respective NCCT marker and IVH growth.The effect of the respective NCCT marker on IVH growth and its subtypes was not indirectly mediated by HE.Detailed results are presented in the supplementary material.

Discussion
In this study, we aimed to validate findings on the association of NCCT features with IVH growth and to determine subgroup-specific association with eIVH and dIVH in patients with acute spontaneous ICH.Our results confirmed that NCCT features were strong predictors of IVH growth [10].In our subgroup analysis, eIVH was significantly associated with hypodensities whereas dIVH was significantly associated with irregular shape.Illustrative examples are given in Figures 2 and 3. Further, two important previous findings on the relationship of IVH growth and functional outcome were confirmed: Both eIVH and dIVH had a negative effect on the functional outcome as seen in our multivariate regression analysis (Supplementary Material Table 4) [7,8].Secondly, the revised HE definition had a significantly higher diagnostic accuracy in the prediction of poor functional outcome compared to the conventional definition of HE (Supplementary Table 5) [9,10].The pathophysiological mechanisms underlying these associations still remain unclear.Therefore, we hypothesized a mediation effect of parenchymal hematoma expansion, but our findings did not confirm this hypothesis, suggesting that the link between  NCCT features and IVH growth is not a simple epiphenomenon of parenchymal bleeding [37].Consistent with this finding, we also noted that most patients experiencing IVH growth did not have parenchymal hematoma expansion.We also explored a potential interaction with ICH location and time from onset to initial imaging but found no significant effect of these potential confounders on the association between NCCT features and increased risk of IVH growth [8,33,34].From a clinical perspective, NCCT features may help clinicians in the stratification and early identification of patients at a high risk of neurological deterioration because of IVH growth.Recent results from the STOP-AUST trial indicate that the severity of IVH growth may be attenuated by tranexamic acid treatment following ICH [5].Therefore, NCCT features may improve patients' selection in future clinical trials, identifying subjects at a high risk of IVH growth and therefore more likely to benefit from hemostatic treatment.Some limitations of our analysis should be considered.First, our findings were derived from a retrospective analysis and require prospective validation.Second, the imaging protocol was not standardized across participating sites, although there is no evidence that the NCCT acquisition technique influences NCCT markers' detection [16].Third, imaging data were collected at two time points only and we are unable to assess potential dynamics of IVH volumes beyond this time frame.Fourth, NCCT markers were rated by well-experienced ICH researchers and may vary in raters with different levels of experience; however, results agreed well with our previous findings [15].Finally, blood pressure control and coagulopathy reversal might have influenced the risk of IVH growth and were not accounted for.Finally, the described associations between NCCT markers and IVH growth may not necessarily imply causality, and further research is needed to characterize the underlying biological mechanisms.

Conclusions
NCCT features independently predict IVH growth, and this association was independent of imaging time and ICH location and not mediated by parenchymal hematoma growth HE.Our findings suggest the possibility to stratify the risk of IVH growth with baseline NCCT and might inform ongoing and future studies.

Fig. 2
Fig.2An illustrative example of non-contrast computed tomography (NCCT) markers associated with intraventricular hemorrhage expansion in patients with acute intracerebral hemorrhage.An illustrative example of a patient with intraventricular hemorrhage expansion (eIVH) defined as absolute volume increase of intraventricular hemorrhage (IVH) between admission (left side) and follow-up

Table 1
Baseline demographic and clinical characteristics by patients with intraventricular hemorrhage growth (IVH growth) associated with intracerebral hemorrhage and no IVH growth (no IVH growth) whereas hypodensities were associated with increased odds of eIVH (OR 2.06; 95%CI 1.48-2.64;p value 0.0015).