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.

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.

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.

External validation of the diagnostic value of perihematomal edema characteristics in neoplastic and non-neoplastic intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Neoplastic intracerebral hemorrhage (ICH) may be incorrectly identified as non-neoplastic ICH on imaging. Relative perihematomal edema (relPHE) on computed tomography (CT) has been proposed as a marker to discriminate neoplastic from non-neoplastic ICH but has not been externally validated. The purpose of this study was to evaluate the discriminatory power of relPHE in an independent cohort. METHODS: A total of 291 patients with acute ICH on CT and follow-up magnetic resonance imaging (MRI) were included in this single-center retrospective study. ICH subjects were dichotomized into non-neoplastic or neoplastic ICH based on the diagnosis on the follow-up MRI. ICH and PHE volumes and density values were derived from semi-manually segmented CT scans. Calculated PHE characteristics for discriminating neoplastic ICH were evaluated using receiver-operating characteristic (ROC) curves. ROC curve-associated cut-offs were calculated and compared between the initial and the validation cohort. RESULTS: A total of 116 patients (39.86%) with neoplastic ICH and 175 (60.14%) with non-neoplastic ICH were included. Median PHE volumes, relPHE, and relPHE adjusted for hematoma density were significantly higher in subjects with neoplastic ICH (all p values <0.001). ROC curves for relPHE had an area under the curve (AUC) of 0.72 (95% confidence interval [CI] 0.66-0.78) and an AUC of 0.81 (95% CI 0.76-0.87) for adjusted relPHE. The cut-offs were identical in the two cohorts, with >0.70 for relPHE and >0.01 for adjusted relPHE. CONCLUSIONS: Relative perihematomal edema and adjusted relPHE accurately discriminated neoplastic from non-neoplastic ICH on CT imaging in an external patient cohort. These results confirmed the findings of the initial study and may improve clinical decision making.

Commercial volumetric MRI reporting tools in multiple sclerosis: a systematic review of the evidence.

PURPOSE: MRI is integral to the diagnosis of multiple sclerosis (MS) and is important for clinical prognostication. Quantitative volumetric reporting tools (QReports) can improve the accuracy and objectivity of MRI-based assessments. Several QReports are commercially available; however, validation can be difficult to establish and does not currently follow a common pathway. To aid evidence-based clinical decision-making, we performed a systematic review of commercial QReports for use in MS including technical details and published reports of validation and in-use evaluation. METHODS: We categorized studies into three types of testing: technical validation, for example, comparison to manual segmentation, clinical validation by clinicians or interpretation of results alongside clinician-rated variables, and in-use evaluation, such as health economic assessment. RESULTS: We identified 10 companies, which provide MS lesion and brain segmentation and volume quantification, and 38 relevant publications. Tools received regulatory approval between 2006 and 2020, contextualize results to normative reference populations, ranging from 620 to 8000 subjects, and require T1- and T2-FLAIR-weighted input sequences for longitudinal assessment of whole-brain volume and lesions. In MS, six QReports provided evidence of technical validation, four companies have conducted clinical validation by correlating results with clinical variables, only one has tested their QReport by clinician end-users, and one has performed a simulated in-use socioeconomic evaluation. CONCLUSION: We conclude that there is limited evidence in the literature regarding clinical validation and in-use evaluation of commercial MS QReports with a particular lack of clinician end-user testing. Our systematic review provides clinicians and institutions with the available evidence when considering adopting a quantitative reporting tool for MS.

Intravenous tPA (Tissue-Type Plasminogen Activator) Correlates With Favorable Venous Outflow Profiles in Acute Ischemic Stroke.

BACKGROUND: Intravenous tPA (tissue-type plasminogen activator) is often administered before endovascular thrombectomy (EVT). Recent studies have questioned whether tPA is necessary given the high rates of arterial recanalization achieved by EVT, but whether tPA impacts venous outflow (VO) is unknown. We investigated whether tPA improves VO profiles on baseline computed tomography (CT) angiography (CTA) images before EVT. METHODS: Retrospective multicenter cohort study of patients with acute ischemic stroke due to large vessel occlusion undergoing EVT triage. Included patients underwent CT, CTA, and CT perfusion before EVT. VO profiles were determined by opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein on CTA as 0, not visible; 1, moderate opacification; and 2, full. Pial arterial collaterals were graded on CTA, and tissue-level collaterals were assessed on CT perfusion using the hypoperfusion intensity ratio. Clinical and demographic data were determined from the electronic medical record. Using multivariable regression analysis, we determined the correlation between tPA administration and favorable VO profiles. RESULTS: Seven hundred seventeen patients met inclusion criteria. Three hundred sixty-five patients received tPA (tPA+), while 352 patients were not treated with tPA (tPA-). Fewer tPA+ patients had atrial fibrillation (n=128 [35%] versus n=156 [44%]; P=0.012) and anticoagulants/antiplatelet treatment before acute ischemic stroke due to large vessel occlusion onset (n=130 [36%] versus n=178 [52%]; P<0.001) compared with tPA- patients. One hundred eighty-five patients (51%) in the tPA+ and 100 patients (28%) in the tPA- group exhibited favorable VO (P<0.001). Multivariable regression analysis showed that tPA administration was a strong independent predictor of favorable VO profiles (OR, 2.6 [95% CI, 1.7-4.0]; P<0.001) after control for favorable pial arterial CTA collaterals, favorable tissue-level collaterals on CT perfusion, age, presentation National Institutes of Health Stroke Scale, antiplatelet/anticoagulant treatment, history of atrial fibrillation and time from symptom onset to imaging. CONCLUSIONS: In patients with acute ischemic stroke due to large vessel occlusion undergoing thrombectomy triage, tPA administration was strongly associated with the presence of favorable VO profiles.

New imaging score for outcome prediction in basilar artery occlusion stroke.

OBJECTIVE: In ischemic posterior circulation stroke, the utilization of standardized image scores is not established in daily clinical practice. We aimed to test a novel imaging score that combines the collateral status with the rating of the posterior circulation Acute Stroke Prognosis Early CT score (pcASPECTS). We hypothesized that this score (pcASCO) predicts functional outcome and malignant cerebellar edema (MCE). METHODS: Ischemic stroke patients with acute BAO who received multimodal-CT and underwent thrombectomy on admission at two comprehensive stroke centers were analyzed. The posterior circulation collateral score by van der Hoeven et al was added to the pcASPECTS to define pcASCO as a 20-point score. Multivariable logistic regression analyses were performed to predict functional independence at day 90, assessed using modified Rankin Scale scores, and occurrence of MCE in follow-up CT using the established Jauss scale score as endpoints. RESULTS: A total of 118 patients were included, of which 84 (71%) underwent successful thrombectomy. Based on receiver operating characteristic curve analysis, pcASCO ≥ 14 classified functional independence with higher discriminative power (AUC: 0.83, 95%CI: 0.71-0.91) than pcASPECTS (AUC: 0.74). In multivariable logistic regression analysis, pcASCO was significantly and independently associated with functional independence (aOR: 1.91, 95%CI: 1.25-2.92, p = 0.003), and MCE (aOR: 0.71, 95%CI: 0.53-0.95, p = 0.02). CONCLUSION: The pcASCO could serve as a simple and feasible imaging tool to assess BAO stroke patients on admission and might be tested as a complementary tool to select patients for thrombectomy in uncertain situations, or to predict clinical outcome. KEY POINTS: • The neurological assessment of basilar artery occlusion stroke patients can be challenging and there are yet no validated imaging scores established in daily clinical practice. • The pcASCO combines the rating of early ischemic changes with the status of the intracranial posterior circulation collaterals. • The pcASCO showed high diagnostic accuracy to predict functional outcome and malignant cerebellar edema and could serve as a simple and feasible imaging tool to support treatment selection in uncertain situations, or to predict clinical outcome.

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.

Computed Tomography Angiography Collateral Profile Is Directly Linked to Early Edema Progression Rate in Acute Ischemic Stroke.

Background and Purpose- Poor collateral flow is associated with poor clinical outcome in acute ischemic stroke and may indicate futile recanalization after successful thrombectomy. Pronounced early formation of cerebral ischemic edema may be the link between poor collateral status and declined functional outcome, but this relationship has not been investigated yet. We hypothesized that collateral status is associated with early lesion water uptake as quantitative marker for edema progression. Methods- One hundred seventy-six patients with middle cerebral artery stroke who underwent mechanical thrombectomy were analyzed. Status of cerebral collateral circulation (collaterals status [CS]) was derived using an established 5-point scoring system in admission computed tomography angiography, and good collaterals were defined as CS 3 to 4. Ischemic brain edema dynamics were quantified using early edema progression rate (EPR). EPR was derived from quantitative lesion water uptake in admission computed tomography divided by time from symptom onset to imaging. Good clinical outcome was defined as modified Rankin Scale score 0 to 2 after 90 days. Results- The median EPR was 1.4% per hour (interquartile range, 0.5-3.5%) in patients with good collaterals, which was lower than the median EPR in patients with poor collaterals of 5.8% per hour (interquartile range, 2.1-5.9%; P<0.0001). In multivariable regression analysis, lower CS was significantly and independently associated with higher EPR (1.6% EPR per 1-point CS; P=0.002). A higher EPR was associated with reduced likelihood of good clinical outcome: odds ratio 0.87; (95% CI, 0.76-0.99; P=0.03). Conclusions- Patients with poor CS had significantly higher EPR, which was associated with worse clinical outcome. These patients might benefit from adjuvant antiedematous treatment.

Histological Clot Composition Is Associated With Preinterventional Clot Migration in Acute Stroke Patients.

Background and Purpose- The introduction of stent retrievers allows for a complete extraction and histological analysis of human clots. Initial studies describe an impact of preinterventional clot migration on technical and clinical success of thrombectomy and an association with worse clinical outcome. We, therefore, performed a large study of consecutive patients whose clots have been histologically analyzed and tried to determine whether clot composition influences the rates of clot migration and thereby interventional and clinical outcome. Methods- We retrospectively evaluated data of a prospectively collected cohort of 198 consecutive patients with occlusion of the middle cerebral artery. We investigated the relationship between clot histology expressed as percentage of the main components (fibrin, erythrocytes [red blood cell], and white blood cells), the preinterventional computed tomography attenuation of the emboli, embolus length, and clot migration. We defined a binary outcome (clot migration versus no clot migration). The impact of embolus composition and computed tomography features was assessed in univariable and multivariable logistic regression models. Results- One hundred sixty-three patients fulfilled the inclusion criteria, of which 36 (22.1%) showed a clot migration. Patients with proven clot migration had significantly higher levels of red blood cells than patients without clot migration (median 50% versus 26%, P<0.001). Lower amounts of fibrin were significantly more often observed in patients in the clot migration group as compared to the no clot migration group (43.5% versus 62.0%, P<0.001). Stroke cause did not differ between migrated and stable emboli. Multivariable analysis identified a higher amount of erythrocytes (adjusted odds ratio, 1.03 per median percentage, P<0.001) and a shorter embolus length (adjusted odds ratio, 0.90 per mm, P<0.008) as independent predictors of clot migration. Conclusions- Erythrocyte-rich clots and a shorter embolus length are independent reliable predictors for clot migration. This finding is clinically important as clot migration might have a negative impact on technical and clinical outcomes of patients suffering from emergent vessel occlusions of the middle cerebral artery undergoing endovascular therapy.

Spectrally fat-suppressed coronal 2D TSE sequences may be more sensitive than 2D STIR for the detection of hyperintense optic nerve lesions.

OBJECTIVES: The aim of the study is to compare coronal spectrally fat-suppressed 2D turbo spin-echo (TSE) with 2D short-tau inversion-recovery (STIR) sequences for the detection of optic nerve hyperintensities in patients with acute optic nerve neuritis (ON). METHODS: A retrospective review of patients with suspected unilateral ON and pathological visual evoked potentials, who received coronal TSE and STIR sequences with similar fast and clinically feasible acquisition times in addition to our standard imaging protocol. All images were evaluated and compared concerning the presence of optic nerve lesions, lesion lengths, and signal intensities in different anatomical parts of the optic nerves and CNR measures. A summary confidence score (CS) was calculated based on each reader's subjective confidence regarding the scoring items. RESULTS: Interobserver agreements regarding the detection of optic nerve lesions were excellent for both sequences (TSE, κ = 0.89 and STIR, κ = 0.80). Greater extensions (17.4 ± 6.3 mm vs. 14.1 ± 5.8 mm), as well as higher numbers of optic nerve lesions in symptomatic nerves, were detected on TSE (49/52) compared with STIR (45/52) sequences (both p < 0.001). Overall CS were significantly (p < 0.001) higher for TSE (2.8) compared with STIR (2.1) sequences regarding the presence or absence of optic nerve lesions. CNR ratios of lesions' mean signal intensities vs. ipsilateral surrounding orbital fat and vs. signal intensity measurements from contralateral optic nerves were significantly higher on TSE compared with STIR (p < 0.001 for both comparisons). CONCLUSION: Spectrally fat-suppressed coronal 2D TSE sequences appear to be more sensitive for the detection of hyperintense optic lesions compared with 2D STIR sequences. KEY POINTS: • Spectrally fat-suppressed TSE sequences showed higher detection rates of hyperintense optic nerve lesions, as well as a higher reader confidence scores compared with STIR. • Optic nerve signal abnormalities on TSE sequences were brighter and showed a greater expansion along the optic nerve course. • CNR measures were significantly higher on TSE compared with STIR, when comparing the ratios of mean signal intensities of optic nerve lesions to ipsilateral orbital fat and to contralateral healthy optic nerves of both sequences.

Recanalization Rate per Retrieval Attempt in Mechanical Thrombectomy for Acute Ischemic Stroke.

Background and Purpose- In acute ischemic stroke, mechanical thrombectomy allows flow restoration in the majority of cases. In case of an unsuccessful retrieval, little is known about how many retrieval attempts should be performed before stopping the procedure. This study assessed the recanalization rate and clinical outcome per retrieval maneuver. Methods- In this analysis, 330 patients with acute large vessel occlusion treated exclusively with stentrieval devices were included. Successful recanalization was defined as Thrombolysis in Cerebral Infarction 2b-3, a good clinical outcome was defined as modified Rankin Scale at 90 days of ≤2. Results- The median number of retrieval attempts was 1 (interquartile range, 1-2, maximum 8). Recanalization rates per retrieval attempt were highest for the first retrieval (46.8%) and lowest for the fifth retrieval (22.7%). After 3 retrieval attempts, 67.9% of patients were successfully recanalized. Patients with 1 to 3 retrieval attempts had higher rates of good clinical outcome (28.9% versus 7.4%; P=0.018). The number of passes was an independent negative predictor of good clinical outcome (adjusted odds ratio, 0.65; 95% CI, 0.435-0.970; P=0.035). Conclusions- Two-thirds of occlusions were successfully recanalized with up to 3 retrieval attempts. Further attempts had good recanalization rates, but the rate of favorable clinical outcome did not improve.

Triage of 5 Noncontrast Computed Tomography Markers and Spot Sign for Outcome Prediction After Intracerebral Hemorrhage.

Background and Purpose- Besides the established spot sign (SS) in computed tomography angiography (CTA), there is growing evidence that different imaging markers in noncontrast CT offer great value for outcome prediction in patients with intracerebral hemorrhage (ICH). However, it is unclear how the concurrent presence of each sign independently contributes to the predictive power of poor outcome. We, therefore, aimed to clarify the predictive value of 5 recently published noncontrast CT parameters (blend sign, black hole sign, island sign, hematoma heterogeneity, and hypodensities) and the established SS in 1 consecutive series of patients with ICH. Methods- Retrospective study of patients with ICH at 2 German tertiary stroke centers; inclusion criteria were (1) spontaneous ICH and (2) noncontrast CT and CTA performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (good outcome [modified Rankin Scale score of ≤3] versus poor outcome [modified Rankin Scale score of >3]) at discharge. The predictive value of each sign was assessed in univariate and multivariable logistic regression models. Results- Of 201 patients with spontaneous ICH, 28 (13.9%) presented with black hole sign, 38 (18.9%) with blend sign, 120 (59.7%) with hypodensities, 97 (48.3%) with heterogeneous densities, 53 with island sign (26.4%), and 45 (22.4%) with SS. In univariable logistic regression, higher hematoma volume ( P<0.001), intraventricular hemorrhage ( P=0.002), and the presence of black hole sign/blend sign/hypodensities/island sign/SS/heterogeneous density (all P<0.001) on admission CT were associated with poor outcome. Multivariable analysis confirmed intraventricular hemorrhage (odds ratio, 2.20; P=0.025), higher hematoma volume (odds ratio, 1.02 per mL; P<0.019), the presence of hypodensities (odds ratio, 2.47; P=0.018), and SS (odds ratio, 12.22; P<0.001) as independent predictors of poor outcome. Conclusions- This study demonstrates the degree of interaction between 5 recent noncontrast CT imaging markers and SS and their individual contribution for outcome prediction in patients with ICH. Of the CT variables indicating poor outcome SS on CTA and hypodensities were the most reliable outcome predictors.

Novel functional role of GH/IGF-I in neonatal lung myofibroblasts and in rat lung growth after intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is a risk factor for neonatal chronic lung disease (CLD) characterized by reduced alveoli and perturbed matrix remodeling. Previously, our group showed an activation of myofibroblasts and matrix remodeling in rat lungs after IUGR. Because growth hormone (GH) and insulin-like growth factor I (IGF-I) regulate development and growth, we queried 1) whether GH/IGF-I signaling is dysregulated in lungs after IUGR and 2) whether GH/IGF-I signaling is linked to neonatal lung myofibroblast function. IUGR was induced in Wistar rats by isocaloric low-protein diet during gestation. Lungs were obtained at embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Murine embryonic fibroblasts (MEF) or primary neonatal myofibroblasts from rat lungs of control (pnFCo) and IUGR (pnFIUGR) were used for cell culture studies. In the intrauterine phase (E21), we found a reduction in GH receptor (GH-R), Stat5 signaling and IGF-I expression in lungs after IUGR. In the postnatal phase (P3-P23), catchup growth after IUGR was linked to increased GH mRNA, GH-R protein, activation of proliferative Stat5/Akt signaling, cyclin D1 and PCNA in rat lungs. On P23, a thickening of the alveolar septae was related to increased vimentin and matrix deposition, indicating fibrosis. In cell culture studies, nutrient deprivation blocked GH-R/IGF-IR signaling and proliferation in MEFs; this was reversed by IGF-I. Proliferation and Stat5 activation were increased in pnFIUGR. IGF-I and GH induced proliferation and migration of pnFCo; only IGF-I had these effects on pnFIUGR. Thus, we show a novel mechanism by which the GH/IGF-I axis in lung myofibroblasts could account for structural lung changes after IUGR.

Novel role of NPY in neuroimmune interaction and lung growth after intrauterine growth restriction.

Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous system, regulates proliferation and immune response, we hypothesized that dysregulated NPY after IUGR is linked to IL-6, impaired myofibroblast function, and alveolar growth. IUGR was induced in rats by isocaloric low-protein diet; lungs were analyzed on embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Finally, primary neonatal lung myofibroblasts (pnF) and murine embryonic fibroblasts (MEF) were used to assess proliferation, apoptosis, migration, and IL-6 expression. At E21, NPY and IL-6 expression was decreased, and AKT/PKC and STAT3/AMPKα signaling was reduced. Early reduction of NPY/IL-6 was associated with increased chord length in lungs after IUGR at P3, indicating reduced alveolar formation. At P23, however, IUGR rats exhibited a catch-up of body weight and alveolar growth coupled with more proliferating myofibroblasts. These structural findings after IUGR were linked to activated NPY/PKC, IL-6/AMPKα signaling. Complementary, IUGR-pnF showed increased survival, impaired migration, and reduced IL-6 compared with control-pnF (Co-pnF). In contrast, NPY induced proliferation, migration, and increased IL-6 synthesis in fibroblasts. Additionally, NPY-/- mice showed reduced IL-6 signaling and less proliferation of lung fibroblasts. Our study presents a novel role of NPY during alveolarization: NPY regulates 1) IL-6 and lung STAT3/AMPKα signaling, and 2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth.

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.

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.

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.

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.