How much of the variance in functional outcome related to intracerebral hemorrhage volume is already apparent in neurological status at admission?

BACKGROUND: Hematoma volume is a major pathophysiological hallmark of acute intracerebral hemorrhage (ICH). We investigated how the variance in functional outcome induced by the ICH volume is explained by neurological deficits at admission using a mediation model. METHODS: Patients with acute ICH treated in three tertiary stroke centers between January 2010 and April 2019 were retrospectively analyzed. Mediation analysis was performed to investigate the effect of ICH volume (0.8 ml (5% quantile) versus 130.6 ml (95% quantile)) on the risk of unfavorable functional outcome at discharge defined as modified Rankin Score (mRS) ≥ 3 with mediation through National Institutes of Health Stroke Scale (NIHSS) at admission. Multivariable regression was conducted to identify factors related to neurological improvement and deterioration. RESULTS: Three hundred thirty-eight patients were analyzed. One hundred twenty-one patients (36%) achieved mRS ≤ 3 at discharge. Mediation analysis showed that NIHSS on admission explained 30% [13%; 58%] of the ICH volume-induced variance in functional outcome at smaller ICH volume levels, and 14% [4%; 46%] at larger ICH volume levels. Higher ICH volume at admission and brainstem or intraventricular location of ICH were associated with neurological deterioration, while younger age, normotension, lower ICH volumes, and lobar location of ICH were predictors for neurological improvement. CONCLUSION: NIHSS at admission reflects 14% of the functional outcome at discharge for larger hematoma volumes and 30% for smaller hematoma volumes. These results underscore the importance of effects not reflected in NIHSS admission for the outcome of ICH patients such as secondary brain injury and early rehabilitation.

Predictors of severe intracerebral hemorrhage expansion.

BACKGROUND: Severe hematoma expansion (sHE) has the strongest impact on intracerebral hemorrhage (ICH) outcome. We investigated the predictors of sHE. METHODS: Retrospective analysis of ICH patients admitted at nine sites in Italy, Germany, China, and Canada. The following imaging features were analyzed: non-contrast CT (NCCT) hypodensities, heterogeneous density, blend sign, irregular shape, and CT angiography (CTA) spot sign. The outcome of interest was sHE, defined as volume increase >66% and/or >12.5 from baseline to follow-up NCCT. Predictors of sHE were explored with logistic regression. RESULTS: A total of 1472 patients were included (median age 73, 56.6% males) of whom 223 (15.2%) had sHE. Age (odds ratio (OR) per year, 95% confidence interval (CI), 1.02 (1.01-1.04)), Anticoagulant treatment (OR 3.00, 95% CI 2.09-4.31), Glasgow Coma Scale (OR 0.93, 95% CI 0.89-0.98), time from onset/last known well to imaging, (OR per h 0.96, 95% CI 0.93-0.99), and baseline ICH volume, (OR per mL 1.02, 95% CI 1.02-1.03) were independently associated with sHE. Ultra-early hematoma growth (baseline volume/baseline imaging time) was also a predictor of sHE (OR per mL/h 1.01, 95% CI 1.00-1.02). All NCCT and CTA imaging markers were also predictors of sHE. Amongst imaging features NCCT hypodensities had the highest sensitivity (0.79) whereas the CTA spot sign had the highest positive predictive value (0.51). CONCLUSIONS: sHE is common in the natural history of ICH and can be predicted with few clinical and imaging variables. These findings might inform clinical practice and future trials targeting active bleeding in ICH.

Functional outcome improvement from 3 to 12 months after intracerebral hemorrhage.

INTRODUCTION: Most intracerebral hemorrhage (ICH) trials assessed outcome at 3 months but the recovery trajectory of ICH survivors may continue up to 1 year after the index event. We aimed to describe the predictors of functional outcome improvement from 3 to 12 months after ICH. MATERIALS AND METHODS: Retrospective analysis of patients admitted to six European Stroke Centers for supratentorial ICH. Functional outcome was measured with the modified Rankin Scale (mRS) at 3 and 12 months. Predictors of functional outcome improvement were explored with binary logistic regression. RESULTS: We included 703 patients, of whom 245 (34.9%) died within 3 months. Among survivors, 131 (28.6%) had an mRS improvement, 78 (17.0%) had a worse mRS and 249 (54.4%) had a stable functional status at 12 months. Older age and the presence of baseline disability (defined as pre-stroke mRS > 1), were associated with lower odds of functional outcome improvement (Odds Ratio (OR) 0.98 per year increase, 95% Confidence Interval (CI) 0.96-1.00, p = 0.017 and OR 0.45, 95% CI 0.25-0.81, p = 0.008 respectively). Conversely, deep ICH location increased the probability of long term mRS improvement (OR 1.67, 95% CI, 1.07-2.61, p = 0.023). Patients with mild-moderate disability at 3 months (mRS 2-3) had the highest odds of improvement at 12 months (OR 8.76, 95% CI 3.68-20.86, p < 0.001). DISCUSSION AND CONCLUSION: Long term recovery is common after ICH and associated with age, baseline functional status, mRS at 3 months and hematoma location. Our findings might inform future trials and improve long-term prognostication in clinical practice.

Predictors and Prognostic Impact of Hematoma Expansion in Infratentorial Cerebral Hemorrhage.

BACKGROUND: Hematoma expansion (HE) is common and predicts poor outcome in patients with supratentorial intracerebral hemorrhage (ICH). We investigated the predictors and prognostic impact of HE in infratentorial ICH. METHODS: We conducted a retrospective analysis of patients with brainstem and cerebellar ICH admitted at seven sites. Noncontrast computed tomography images were analyzed for the presence of hypodensities according to validated criteria, defined as any hypodense region strictly encapsulated within the hemorrhage with any shape, size, and density. Occurrence of HE (defined as > 33% and/or > 6-mL growth) and mortality at 90 days were the outcomes of interest. Their predictors were investigated using logistic regression with backward elimination at p < 0.1. Logistic regression models for HE were adjusted for baseline ICH volume, antiplatelet and anticoagulant treatment, onset to computed tomography time, and presence of hypodensities. The logistic regression model for mortality accounted for the ICH score and HE. RESULTS: A total of 175 patients were included (median age 75 years, 40.0% male), of whom 38 (21.7%) had HE and 43 (24.6%) died within 90 days. Study participants with HE had a higher frequency of hypodensities (44.7 vs. 24.1%, p = 0.013), presentation within 3 h from onset (39.5 vs. 24.8%, p = 0.029), and 90-day mortality (44.7 vs. 19.0%, p = 0.001). Hypodensities remained independently associated with HE after adjustment for confounders (odds ratio 2.44, 95% confidence interval 1.13-5.25, p = 0.023). The association between HE and mortality remained significant in logistic regression (odds ratio 3.68, 95% confidence interval 1.65-8.23, p = 0.001). CONCLUSION: Early presentation and presence of noncontrast computed tomography hypodensities were independent predictors of HE in infratentorial ICH, and the occurrence of HE had an independent prognostic impact in this population.

Effects of Mobile Stroke Unit dispatch on blood pressure management and outcomes in patients with intracerebral haematoma: Results from the Berlin_Prehospital Or Usual Care Delivery in acute Stroke (B_PROUD) controlled intervention study.

INTRODUCTION: In patients with acute intracerebral haemorrhage (ICH) and elevated systolic blood pressure (BP), guidelines suggest that systolic BP reduction to <140 mmHg should be rapidly initiated. Compared with conventional care, Mobile Stroke Units (MSUs) allow for earlier ICH diagnosis through prehospital imaging and earlier BP lowering. PATIENTS AND METHODS: ICH patients were prospectively evaluated as a cohort of the controlled B_PROUD-study in which MSU availability alone determined MSU dispatch in addition to conventional ambulance. We used inverse probability of treatment weighting to adjust for confounding to estimate the effect of additional MSU dispatch in ICH patients. Outcomes of interest were 7-day mortality (primary), systolic BP (sBP) at hospital arrival, dispatch-to-imaging time, largest haematoma volume, anticoagulation reversal, length of in-hospital stay, 3-month functional outcome. RESULTS: Between February 2017 and May 2019, MSUs were dispatched to 95 (mean age: 72 ± 13 years, 45% female) and only conventional ambulances to 78 ICH patients (mean age: 71 ± 12 years, 44% female). After adjusting for confounding, we found shorter dispatch-to-imaging time (mean difference: -17.75 min, 95% CI: -27.16 to -8.21 min) and lower sBP at hospital arrival (mean difference = -16.31 mmHg, 95% CI: -30.64 to -6.19 mmHg) in the MSU group. We found no statistically significant difference for the other outcomes, including 7-day mortality (adjusted odds ratio: 1.43, 95% CI: 0.68 to 3.31) or favourable outcome (adjusted odds ratio = 0.67, 95% CI: 0.27 to 1.67). CONCLUSIONS: Although MSU dispatch led to sBP reduction and lower dispatch-to-imaging time compared to conventional ambulance care, we found no evidence of better outcomes in the MSU dispatch group.

Spreading Depolarizations Suppress Hematoma Growth in Hyperacute Intracerebral Hemorrhage in Mice.

BACKGROUND: Spreading depolarizations (SDs) occur in all types of brain injury and may be associated with detrimental effects in ischemic stroke and subarachnoid hemorrhage. While rapid hematoma growth during intracerebral hemorrhage triggers SDs, their role in intracerebral hemorrhage is unknown. METHODS: We used intrinsic optical signal and laser speckle imaging, combined with electrocorticography, to investigate the effects of SD on hematoma growth during the hyperacute phase (0-4 hours) after intracortical collagenase injection in mice. Hematoma expansion, SDs, and cerebral blood flow were simultaneously monitored under normotensive and hypertensive conditions. RESULTS: Spontaneous SDs erupted from the vicinity of the hematoma during rapid hematoma growth. We found that hematoma growth slowed down by >60% immediately after an SD. This effect was even stronger in hypertensive animals with faster hematoma growth. To establish causation, we exogenously induced SDs (every 30 minutes) at a remote site by topical potassium chloride application and found reduced hematoma growth rate and final hemorrhage volume (18.2±5.8 versus 10.7±4.1 mm3). Analysis of cerebral blood flow using laser speckle flowmetry revealed that suppression of hematoma growth by spontaneous or induced SDs coincided and correlated with the characteristic oligemia in the wake of SD, implicating the vasoconstrictive effect of SD as one potential mechanism of action. CONCLUSIONS: Our findings reveal that SDs limit hematoma growth during the early hours of intracerebral hemorrhage and decrease final hematoma volume.

Association Between Hematoma Expansion Severity and Outcome and Its Interaction With Baseline Intracerebral Hemorrhage Volume.

BACKGROUND AND OBJECTIVES: Hematoma expansion (HE) is a major determinant of neurologic deterioration and poor outcome in intracerebral hemorrhage (ICH) and represents an appealing therapeutic target. We analyzed the prognostic effect of different degrees of HE. METHODS: This was a retrospective analysis of patients with ICH admitted at 8 academic institutions in Italy, Germany, Canada, China, and the United States. All patients underwent baseline and follow-up imaging for HE assessment. Relative HE (rHE) was classified as follows: none (<0%), mild (0%-33%), moderate (33.1%-66%), and severe (>66%). Absolute HE (aHE) was classified as none (<0 mL), mild (0-6.0 mL), moderate (6.1-12.5 mL), and severe (>12.5 mL). Predictors of poor functional outcome (90 days modified Rankin Scale 4-6) were explored with logistic regression. RESULTS: We included 2,163 patients, of whom 1,211 (56.0%) had poor outcome. The occurrence of severe aHE or rHE was more common in patients with unfavorable outcome (13.9% vs 6.5%, p < 0.001 and 18.3% vs 7.2%, p < 0.001 respectively). This association was confirmed in logistic regression (rHE odds ratio [OR] 1.98, 95% CI 1.38-2.82, p < 0.001; aHE OR 1.73, 95% CI 1.23-2.45, p = 0.002) while there was no association between mild or moderate HE and poor outcome. The association between severe HE and poor outcome was significant only in patients with baseline ICH volume below 30 mL. DISCUSSION: The strongest association between HE and outcome was observed in patients with smaller initial volume experiencing severe HE. These findings may inform clinical trial design and guide clinicians in selecting patients for antiexpansion therapies.

External Validation and Retraining of DeepBleed: The First Open-Source 3D Deep Learning Network for the Segmentation of Spontaneous Intracerebral and Intraventricular Hemorrhage.

BACKGROUND: The objective of this study was to assess the performance of the first publicly available automated 3D segmentation for spontaneous intracerebral hemorrhage (ICH) based on a 3D neural network before and after retraining. METHODS: We performed an independent validation of this model using a multicenter retrospective cohort. Performance metrics were evaluated using the dice score (DSC), sensitivity, and positive predictive values (PPV). We retrained the original model (OM) and assessed the performance via an external validation design. A multivariate linear regression model was used to identify independent variables associated with the model's performance. Agreements in volumetric measurements and segmentation were evaluated using Pearson's correlation coefficients (r) and intraclass correlation coefficients (ICC), respectively. With 1040 patients, the OM had a median DSC, sensitivity, and PPV of 0.84, 0.79, and 0.93, compared to thoseo f 0.83, 0.80, and 0.91 in the retrained model (RM). However, the median DSC for infratentorial ICH was relatively low and improved significantly after retraining, at p < 0.001. ICH volume and location were significantly associated with the DSC, at p < 0.05. The agreement between volumetric measurements (r > 0.90, p > 0.05) and segmentations (ICC ≥ 0.9, p < 0.001) was excellent. CONCLUSION: The model demonstrated good generalization in an external validation cohort. Location-specific variances improved significantly after retraining. External validation and retraining are important steps to consider before applying deep learning models in new clinical settings.

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.

Using Noncontrast Computed Tomography to Improve Prediction of Intracerebral Hemorrhage Expansion.

BACKGROUND: Noncontrast computed tomography hypodensities are a validated predictor of hematoma expansion (HE) in intracerebral hemorrhage and a possible alternative to the computed tomography angiography (CTA) spot sign but their added value to available prediction models remains unclear. We investigated whether the inclusion of hypodensities improves prediction of HE and compared their added value over the spot sign. METHODS: Retrospective analysis of patients admitted for primary spontaneous intracerebral hemorrhage at the following 8 university hospitals in Boston, US (1994-2015, prospective), Hamilton, Canada (2010-2016, retrospective), Berlin, Germany (2014-2019, retrospective), Chongqing, China (2011-2015, retrospective), Pavia, Italy (2017-2019, prospective), Ferrara, Italy (2010-2019, retrospective), Brescia, Italy (2020-2021, retrospective), and Bologna, Italy (2015-2019, retrospective). Predictors of HE (hematoma growth >6 mL and/or >33% from baseline to follow-up imaging) were explored with logistic regression. We compared the discrimination of a simple prediction model for HE based on 4 predictors (antitplatelet and anticoagulant treatment, baseline intracerebral hemorrhage volume, and onset-to-imaging time) before and after the inclusion of noncontrast computed tomography hypodensities, using receiver operating characteristic curve and De Long test for area under the curve comparison. RESULTS: A total of 2465 subjects were included, of whom 664 (26.9%) had HE and 1085 (44.0%) had hypodensities. Hypodensities were independently associated with HE after adjustment for confounders in logistic regression (odds ratio, 3.11 [95% CI, 2.55-3.80]; P<0.001). The inclusion of noncontrast computed tomography hypodensities improved the discrimination of the 4 predictors model (area under the curve, 0.67 [95% CI, 0.64-0.69] versus 0.71 [95% CI, 0.69-0.74]; P=0.025). In the subgroup of patients with a CTA available (n=895, 36.3%), the added value of hypodensities remained statistically significant (area under the curve, 0.68 [95% CI, 0.64-0.73] versus 0.74 [95% CI, 0.70-0.78]; P=0.041) whereas the addition of the CTA spot sign did not provide significant discrimination improvement (area under the curve, 0.74 [95% CI, 0.70-0.78]). CONCLUSIONS: Noncontrast computed tomography hypodensities provided a significant added value in the prediction of HE and appear a valuable alternative to the CTA spot sign. Our findings might inform future studies and suggest the possibility to stratify the risk of HE with good discrimination without CTA.

Multilesion Segmentations in Patients with Intracerebral Hemorrhage: Reliability of ICH, IVH and PHE Masks.

Background and Purpose: Fully automated methods for segmentation and volume quantification of intraparenchymal hemorrhage (ICH), intraventricular hemorrhage extension (IVH), and perihematomal edema (PHE) are gaining increasing interest. Yet, reliabilities demonstrate considerable variances amongst each other. Our aim was therefore to evaluate both the intra- and interrater reliability of ICH, IVH and PHE on ground-truth segmentation masks. Methods: Patients with primary spontaneous ICH were retrospectively included from a German tertiary stroke center (Charité Berlin; January 2016−June 2020). Baseline and follow-up non-contrast Computed Tomography (NCCT) scans were analyzed for ICH, IVH, and PHE volume quantification by two radiology residents. Raters were blinded to all demographic and outcome data. Inter- and intrarater agreements were determined by calculating the Intraclass Correlation Coefficient (ICC) for a randomly selected set of patients with ICH, IVH, and PHE. Results: 100 out of 670 patients were included in the analysis. Interrater agreements ranged from an ICC of 0.998 for ICH (95% CI [0.993; 0.997]), to an ICC of 0.979 for IVH (95% CI [0.984; 0.993]), and an ICC of 0.886 for PHE (95% CI [0.760; 0.938]), all p-values < 0.001. Intrarater agreements ranged from an ICC of 0.997 for ICH (95% CI [0.996; 0.998]), to an ICC of 0.995 for IVH (95% CI [0.992; 0.996]), and an ICC of 0.980 for PHE (95% CI [0.971; 0.987]), all p-values < 0.001. Conclusion Manual segmentations of ICH, IVH, and PHE demonstrate good-to-excellent inter- and intrarater reliabilities, with the highest agreement for ICH and IVH and lowest for PHE. Therefore, the degree of variances reported in fully automated quantification methods might be related amongst others to variances in ground-truth masks.

Non-contrast CT markers of intracerebral hemorrhage expansion: The influence of onset-to-CT time.

BACKGROUND: Hematoma expansion (HE) is an appealing therapeutic target in intracerebral hemorrhage (ICH) and non-contrast computed tomography (NCCT) features are promising predictors of HE. AIMS: We investigated whether onset-to-CT time influences the diagnostic performance of NCCT markers for HE. METHODS: Retrospective multicentre analysis of patients with primary ICH. The following NCCT markers were analyzed: hypodensities, heterogeneous density, blend sign, and irregular shape. HE was defined as growth ⩾6 mL and/or ⩾33%. We calculated the sensitivity, specificity, positive, and negative predictive values (PPVs and NPVs) of NCCT markers for HE, stratified by onset-to-CT time (<2 h, 2-4 h, 4-6 h, >6 h). RESULTS: We included 1135 patients (median age 69, 53% males), of whom 307 (27%) experienced HE.Overall hypodensities had the highest sensitivity (0.68) and blend sign the highest specificity (0.87) for HE. Hypodensities were more common and had higher sensitivity (0.80) in patients with imaging within 2 h. The same result was observed for heterogeneous density, whereas irregular shape had a similar prevalence across time strata and higher sensitivity (0.79) beyond 6 h from onset. The frequency of blend sign increased with longer onset-to-CT time, whereas its specificity declined after 6 h from onset. CONCLUSION: The diagnostic performance of NCCT markers is influenced by imaging time. Hypodensities identified four out of five patients with HE within 2 h from onset, whereas irregular shape performed better in late presenters. Our findings may improve the use of NCCT markers in future studies and trials targeting HE.

Diagnostic Accuracy and Reliability of Noncontrast Computed Tomography Markers for Acute Hematoma Expansion among Radiologists.

BACKGROUND: Noncontrast Computed Tomography (NCCT) features are promising markers for acute hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH). It remains unclear whether accurate identification of these markers is also reliable in raters with different levels of experience. METHODS: Patients with acute spontaneous ICH admitted at four tertiary centers in Germany and Italy were retrospectively included from January 2017 to June 2020. In total, nine NCCT markers were rated by one radiology resident, one radiology fellow, and one neuroradiology fellow with different levels experience in ICH imaging. Interrater reliabilities of the resident and radiology fellow were evaluated by calculated Cohen's kappa (κ) statistics in reference to the neuroradiology fellow who was referred as the gold standard. Gold-standard ratings were evaluated by calculated interrater κ statistics. Global interrater reliabilities were evaluated by calculated Fleiss kappa statistics across all three readers. A comparison of receiver operating characteristics (ROCs) was used to evaluate differences in the diagnostic accuracy for predicting acute hematoma expansion (HE) among the raters. RESULTS: Substantial-to-almost-perfect interrater concordance was found for the resident with interrater Cohen's kappa from 0.70 (95% CI 0.65-0.81) to 0.96 (95% CI 0.94-0.98). The interrater Cohen's kappa for the radiology fellow was moderate to almost perfect and ranged from 0.58 (95% CI 0.52-0.65) to 94 (95% CI 92-0.97). The intrarater gold-standard Cohen's kappa was almost perfect and ranged from 0.79 (95% CI 0.78-0.90) to 0.98 (95% CI 0.78-0.90). The global interrater Fleiss kappa ranged from 0.62 (95%CI 0.57-0.66) to 0.93 (95%CI 0.89-0.97). The diagnostic accuracy for the prediction of acute hematoma expansion (HE) was different for the island sign and fluid sign, with p-values < 0.05. CONCLUSION: The NCCT markers had a substantial-to-almost-perfect interrater agreement among raters with different levels of experience. Differences in the diagnostic accuracy for the prediction of acute HE were found in two out of nine NCCT markers. The study highlights the promising utility of NCCT markers for acute HE prediction.

Volumetric accuracy of different imaging modalities in acute intracerebral hemorrhage.

BACKGROUND: Follow-up imaging in intracerebral hemorrhage is not standardized and radiologists rely on different imaging modalities to determine hematoma growth. This study assesses the volumetric accuracy of different imaging modalities (MRI, CT angiography, postcontrast CT) to measure hematoma size. METHODS: 28 patients with acute spontaneous intracerebral hemorrhage referred to a tertiary stroke center were retrospectively included between 2018 and 2019. Inclusion criteria were (1) spontaneous intracerebral hemorrhage (supra- or infratentorial), (2) noncontrast CT imaging performed on admission, (3) follow-up imaging (CT angiography, postcontrast CT, MRI), and (4) absence of hematoma expansion confirmed by a third cranial image within 6 days. Two independent raters manually measured hematoma volume by drawing a region of interest on axial slices of admission noncontrast CT scans as well as on follow-up imaging (CT angiography, postcontrast CT, MRI) using a semi-automated segmentation tool (Visage image viewer; version 7.1.10). Results were compared using Bland-Altman plots. RESULTS: Mean admission hematoma volume was 18.79 ± 19.86 cc. All interrater and intrarater intraclass correlation coefficients were excellent (1; IQR 0.98-1.00). In comparison to hematoma volume on admission noncontrast CT volumetric measurements were most accurate in patients who received postcontrast CT (bias of - 2.47%, SD 4.67: n = 10), while CT angiography often underestimated hemorrhage volumes (bias of 31.91%, SD 45.54; n = 20). In MRI sequences intracerebral hemorrhage volumes were overestimated in T2* (bias of - 64.37%, SD 21.65; n = 10). FLAIR (bias of 6.05%, SD 35.45; n = 13) and DWI (bias of-14.6%, SD 31.93; n = 12) over- and underestimated hemorrhagic volumes. CONCLUSIONS: Volumetric measurements were most accurate in postcontrast CT while CT angiography and MRI sequences often substantially over- or underestimated hemorrhage volumes.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage Related to Different Oral Anticoagulants.

BACKGROUND: There is a need to examine the effects of different types of oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) on perihematomal edema (PHE), which is gaining considerable appeal as a biomarker for secondary brain injury and clinical outcome. METHODS: In a large multicenter approach, computed tomography-derived imaging markers for PHE (absolute PHE, relative PHE (rPHE), edema expansion distance (EED)) were calculated for patients with OAC-ICH and NON-OAC-ICH. Exploratory analysis for non-vitamin-K-antagonist OAC (NOAC) and vitamin-K-antagonists (VKA) was performed. The predictive performance of logistic regression models, employing predictors of poor functional outcome (modified Rankin scale 4-6), was explored. RESULTS: Of 811 retrospectively enrolled patients, 212 (26.14%) had an OAC-ICH. Mean rPHE and mean EED were significantly lower in patients with OAC-ICH compared to NON-OAC-ICH, p-value 0.001 and 0.007; whereas, mean absolute PHE did not differ, p-value 0.091. Mean EED was also significantly lower in NOAC compared to NON-OAC-ICH, p-value 0.05. Absolute PHE was an independent predictor of poor clinical outcome in NON-OAC-ICH (OR 1.02; 95%CI 1.002-1.028; p-value 0.027), but not in OAC-ICH (p-value 0.45). CONCLUSION: Quantitative markers of early PHE (rPHE and EED) were lower in patients with OAC-ICH compared to those with NON-OAC-ICH, with significantly lower levels of EED in NOAC compared to NON-OAC-ICH. Increase of early PHE volume did not increase the likelihood of poor outcome in OAC-ICH, but was independently associated with poor outcome in NON-OAC-ICH. The results underline the importance of etiology-specific treatment strategies. Further prospective studies are needed.

Spreading depression as an innate antiseizure mechanism.

Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.

Imaging-Based Outcome Prediction of Acute Intracerebral Hemorrhage.

We hypothesized that imaging-only-based machine learning algorithms can analyze non-enhanced CT scans of patients with acute intracerebral hemorrhage (ICH). This retrospective multicenter cohort study analyzed 520 non-enhanced CT scans and clinical data of patients with acute spontaneous ICH. Clinical outcome at hospital discharge was dichotomized into good outcome and poor outcome using different modified Rankin Scale (mRS) cut-off values. Predictive performance of a random forest machine learning approach based on filter- and texture-derived high-end image features was evaluated for differentiation of functional outcome at mRS 2, 3, and 4. Prediction of survival (mRS ≤ 5) was compared to results of the ICH Score. All models were tuned, validated, and tested in a nested 5-fold cross-validation approach. Receiver-operating-characteristic area under the curve (ROC AUC) of the machine learning classifier using image features only was 0.80 (95% CI [0.77; 0.82]) for predicting mRS ≤ 2, 0.80 (95% CI [0.78; 0.81]) for mRS ≤ 3, and 0.79 (95% CI [0.77; 0.80]) for mRS ≤ 4. Trained on survival prediction (mRS ≤ 5), the classifier reached an AUC of 0.80 (95% CI [0.78; 0.82]) which was equivalent to results of the ICH Score. If combined, the integrated model showed a significantly higher AUC of 0.84 (95% CI [0.83; 0.86], P value <0.05). Accordingly, sensitivities were significantly higher at Youden Index maximum cut-offs (77% vs. 74% sensitivity at 76% specificity, P value <0.05). Machine learning-based evaluation of quantitative high-end image features provided the same discriminatory power in predicting functional outcome as multidimensional clinical scoring systems. The integration of conventional scores and image features had synergistic effects with a statistically significant increase in AUC.