Neutrophil extracellular trap biomarkers in aneurysmal subarachnoid hemorrhage: early decline of DNase 1 activity associated with delayed cerebral ischemia.

Introduction: High-mobility group box 1 (HMGB1) protein is a critical mediator of neutrophil extracellular trap (NET) formation (NETosis). Myeloperoxidase (MPO)-DNA complexes, a biomarker of NETs, and HMGB1 have been associated with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Additional mechanistic NET-related biomarkers and their role in the neuroinflammatory cascade surrounding DCI remain to be explored. Methods: A post-hoc analysis of a prospective, blinded, single-center biomarker observational study was performed. De novo measurements of serum citrullinated histone H3-DNA complexes (H3Cit-DNA), peptidylarginine deiminase 4 (PAD4), cell-free DNA (cf-DNA), and DNase 1 activity were conducted on admission (D0) and day 4 (D4). Delayed cerebral infarction (DCI) was defined as new cerebral infarction on CT head not present on the post-treatment scan. Results: H3Cit-DNA, PAD4, cf-DNA, and DNase 1 activity were within quantifiable ranges in all serum samples analyzed at D0 and D4. Admission biomarker levels were not associated with DCI development. From D0 to D4, in both the DCI and the non-DCI groups, H3Cit-DNA levels significantly decreased, cf-DNA levels significantly increased, and PAD4 levels remained stable. In contrast, DNase 1 activity significantly decreased from D0 to D4 in the DCI group (p < 0.001) but not in the non-DCI group. Conclusion: This exploratory analysis demonstrated NET-related biomarkers such as H3Cit-DNA, PAD4, cf-DNA, and DNase 1 activity in all aSAH patients. A decline of systemic DNase 1 activity in the early phase might increase the risk of delayed cerebral ischemia.

Sex Differences in Perihematomal Edema Volume and Outcome After Intracerebral Hemorrhage.

BACKGROUND: Although larger hematoma volume is associated with worse outcome after intracerebral hemorrhage (ICH), the association between perihematomal edema (PHE) volume and outcome remains uncertain, as does the impact of sex on PHE and outcome. Here we aimed to determine whether larger PHE volume is associated with worse outcome and whether PHE volume trajectories differ by sex. METHODS: We conducted a post hoc analysis of the Factor VIIa for Acute Hemorrhagic Stroke Treatment (FAST) trial, which randomized patients with ICH to receive recombinant activated factor VIIa or placebo. Computerized planimetry calculated PHE and ICH volumes on serial computed tomography (CT) scans (at baseline [within 3 h of onset], at 24 h, and at 72 h). Generalized estimating equations examined interactions between sex, CT time points, and FAST treatment arm on PHE and ICH volumes. Mixed and multivariable logistic models examined associations between sex, PHE, and outcomes. RESULTS: A total of 781 patients with supratentorial ICH (mean age 65 years) were included. Compared to women (n = 296), men (n = 485) had similar median ICH (14.9 vs. 13.6 mL, p = 0.053) and PHE volumes (11.1 vs. 10.5 mL, p = 0.56) at baseline but larger ICH and PHE volumes at 24 h (19.0 vs. 14.0 mL, p < 0.001; 22.2 vs. 15.7 mL, p < 0.001) and 72 h (16.0 vs. 11.8 mL, p < 0.001; 28.7 vs. 19.9 mL, p < 0.001). Men had higher absolute early PHE expansion (p < 0.001) and more hematoma expansion (growth ≥ 33% or 6 mL at 24 h, 33% vs. 22%, p < 0.001). An interaction between sex and CT time points on PHE volume (p < 0.001), but not on ICH volume, confirmed a steeper PHE trajectory in men. PHE expansion (per 5 mL, odds radio 1.19, 95% confidence interval 1.10-1.28), but not sex, was associated with poor outcome. CONCLUSIONS: Early PHE expansion and trajectory in men were significantly higher. PHE expansion was associated with poor outcomes independent of sex. Mechanisms leading to sex differences in PHE trajectories merit further investigation.

Imaging Biomarkers and Prevalence of Complex Aortic Plaque in Cryptogenic Stroke: A Systematic Review.

BACKGROUND: Complex aortic plaque (CAP) is a potential embolic source in patients with cryptogenic stroke (CS). We review CAP imaging criteria for transesophageal echocardiogram (TEE), computed tomography angiography (CTA), and magnetic resonance imaging and calculate CAP prevalence in patients with acute CS. METHODS AND RESULTS: PubMed and EMBASE databases were searched up to December 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Two independent reviewers extracted data on study design, imaging techniques, CAP criteria, and prevalence. The Cochrane Collaboration tool and Guideline for Reporting Reliability and Agreement Studies were used to assess risk of bias and reporting completeness, respectively. From 2293 studies, 45 were reviewed for CAP imaging biomarker criteria in patients with acute CS (N=37 TEE; N=9 CTA; N=6 magnetic resonance imaging). Most studies (74%) used ≥4 mm plaque thickness as the imaging criterion for CAP although ≥1 mm (N=1, CTA), ≥5 mm (N=5, TEE), and ≥6 mm (N=2, CTA) were also reported. Additional features included mobility, ulceration, thrombus, protrusions, and assessment of plaque composition. From 23 prospective studies, CAP was detected in 960 of 2778 patients with CS (0.32 [95% CI, 0.24-0.41], I2=94%). By modality, prevalence estimates were 0.29 (95% CI, 0.20-0.40; I2=95%) for TEE; 0.23 (95% CI, 0.15-0.34; I2=87%) for CTA and 0.22 (95% CI, 0.06-0.54; I2=92%) for magnetic resonance imaging. CONCLUSIONS: TEE was commonly used to assess CAP in patients with CS. The most common CAP imaging biomarker was ≥4 mm plaque thickness. CAP was observed in one-third of patients with acute CS. However, high study heterogeneity suggests a need for reproducible imaging methods.

Clinical Grading Scales and Neuroprognostication in Acute Brain Injury.

Prediction of neurological clinical outcome after acute brain injury is critical because it helps guide discussions with patients and families and informs treatment plans and allocation of resources. Numerous clinical grading scales have been published that aim to support prognostication after acute brain injury. However, the development and validation of clinical scales lack a standardized approach. This in turn makes it difficult for clinicians to rely on prognostic grading scales and to integrate them into clinical practice. In this review, we discuss quality measures of score development and validation and summarize available scales to prognosticate outcomes after acute brain injury. These include scales developed for patients with coma, cardiac arrest, ischemic stroke, nontraumatic intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury; for each scale, we discuss available validation studies.

Sex differences in perihematomal edema volume and outcome after intracerebral hemorrhage.

Objective: To determine whether in patients with intracerebral hemorrhage (ICH) perihematomal edema (PHE) volume trajectories differ by sex. Methods: We conducted a post-hoc analysis of the Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment (FAST) trial that randomized patients with ICH to receive recombinant activated Factor VIIa or placebo. Computerized planimetry calculated PHE and ICH volumes on serial CT scans (at baseline [within 3 hours of onset], at 24, and at 72 hours). Generalized estimating equations examined interactions between sex, CT-timepoints, and FAST treatment-arm on PHE and ICH volumes. Mixed and multivariate logistic models examined associations between sex, PHE, and outcomes. Results: 781 with supratentorial ICH (mean age 65 years) were included. Compared to women (n=296), men (n=485) had similar median ICH (14.9 versus 13.6 ml, p=0.053), and PHE volumes (11.1 versus 10.5 ml, p=0.56) at baseline but larger ICH and PHE at 24 hours (19.0 versus 14.0, p<0.001; 22.2 versus 15.7, p<0.001) and 72 hours (16.0 versus 11.8, p<0.001; 28.7 versus 19.9, p<0.001). Men had higher absolute PHE expansion (p<0.001), and more hematoma expansion (growth ≥33% or 6 mL at 24 hours, 33% versus 22%, p<0.001). An interaction between sex and CT-timepoints on PHE (p<0.001) but not on ICH volumes confirmed a steeper PHE trajectory in men. PHE expansion (per 5mL, odds radio, 1.19, 95%-confidence interval 1.10-1.28), but not sex, was associated with poor outcome. Conclusions: PHE expansion and trajectory in men were significantly higher. PHE expansion was associated with poor outcomes independent of sex. Mechanisms leading to sex differences in PHE trajectories merit further investigation. What is already known on this topic: Prior research has reported sex differences in intracerebral hemorrhage (ICH) characteristics and some studies suggest worse outcome after ICH in women. However, we do not have a good understanding whether there are sex differences in perihematomal edema (PHE) volume trajectories, or whether sex, independent of confounders, is associated with poor after ICH. What this study adds: In this post-hoc analysis of 781 patients with supratentorial ICH from the Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment (FAST) trial in which patients underwent brain CT imaging time-locked to symptom onset (within 3 hours of symptom onset, at 24 hours, and at 72 hours), men compared to women had similar ICH and PHE volumes at baseline, but larger ICH expansion and PHE expansion on follow up imaging. The PHE but not the ICH volume trajectory across scans was significantly higher in men than in women. While PHE expansion was associated with poor outcome at 90 days, outcome between the sexes was similar at 90 days, and sex was not associated with outcome. How this study might affect research practice or policy: The finding of heightened early PHE and ICH expansion in men may inform study design, patient recruitment strategies, and pre-specification of subgroup analyses in future interventional trials. The findings of this study also suggest that focusing on sex-specific factors may allow novel mechanistic insight into PHE, a major cause of secondary injury and poor outcome after ICH.

A reassessment of hemoglobin and hematoma expansion in intracerebral hemorrhage.

BACKGROUND: In patients with spontaneous intracerebral hemorrhage (ICH), prior studies identified an increased risk of hematoma expansion (HE) in those with lower admission hemoglobin (Hgb) levels. We aimed to reproduce these findings in an independent cohort. METHODS: We conducted a cohort study of patients admitted to a Comprehensive Stroke Center for acute ICH within 24 hours of onset. Admission laboratory and CT imaging data on ICH characteristics including HE (defined as >33% or >6 mL), and 3-month outcomes were collected. We compared laboratory data between patients with and without HE and used multivariable logistic regression to determine associations between Hgb, HE, and unfavorable 3-month outcomes (modified Rankin Scale 4-6) while adjusting for confounders including anticoagulant use, and laboratory markers of coagulopathy. RESULTS: Among 345 patients in our cohort (mean [SD] age 72.9 [13.7], 49% male), 71 (21%) had HE. Patients with HE had similar Hgb versus those without HE (mean [SD] 13.1 [1.8] g/dl vs. 13.1 [1.9] g/dl, p=0.92). In fully adjusted multivariable models, Hgb was not associated with HE (OR per 1g/dl 1.01, 95% CI 0.86 -1.17, p = 0.94), however higher admission Hgb levels were associated with lower odds of unfavorable 3-month outcome (OR 0.83 per 1 g/dl Hgb, 95% CI 0.72-0.96, p=0.01). CONCLUSION: We did not confirm a previously reported association between admission Hgb and HE in patients with ICH, although Hgb and HE were both associated with poor outcome. These findings suggest that the association between Hgb and poor outcome is mediated by other factors.

Impact of white matter hyperintensities on subjective cognitive decline phenotype in a diverse cohort of cognitively normal older adults.

OBJECTIVES: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. METHODS/DESIGN: A retrospective, cross-sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none-to-mild (n = 202) and moderate-to-severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p-values adjusted for demographics using multivariable logistic regression. RESULTS: Moderate-to-severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short-term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate-to-severe WMH participants scored lower on the Mini-Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. CONCLUSIONS: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain-specific tests in verbal memory and visual working/associative memory.

Association Between Soluble Intercellular Adhesion Molecule-1 and Intracerebral Hemorrhage Outcomes in the FAST Trial.

BACKGROUND: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. METHODS: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4-6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. RESULTS: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15-2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06-1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11-1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. CONCLUSIONS: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes.

Always Look on the Bright Side: Associations of Optimism With Functional Outcomes After Stroke.

Background Psychological health is as an important contributor to recovery after cardiovascular disease, but the roles of both optimism and depression in stroke recovery are not well characterized. Methods and Results A total of 879 participants in the SRUP (Stroke Recovery in Underserved Populations) 2005 to 2006 Study, aged ≥50 years, with incident stroke admitted to a rehabilitation facility were included. Optimism was assessed by the question: "Are you optimistic about the future?" Depression was defined by Center for Epidemiologic Studies Depression scale score >16. Participants were categorized into 4 groups: optimistic/without depression (n=581), optimistic/with depression (n=197), nonoptimistic/without depression (n=36), and nonoptimistic/with depression (n=65). Functional Independence Measure scores were used to assess stroke outcomes at discharge, 3 months after discharge, and 1 year after discharge with adjusted linear mixed models to estimate score trajectories. Participants were a mean age of 68 years (SD, 13 years), 52% were women, and 74% were White race. The optimistic/without depression group experienced the most recovery of total Functional Independence Measure scores in the first 3 months, 24.0 (95% CI, 22.5-25.4), followed by no change in the following 9 months, -0.3 (95% CI, -2.3 to 1.7), similar to the optimistic/with depression group with rapid recovery in 0 to 3 months, 21.1 (95% CI, 18.6-23.6) followed by minimal change in 3 to 12 months, 0.7 (95% CI, -2.8 to 4.1). The nonoptimistic groups demonstrated slow but continued recovery throughout the 12-month period, with overall change, 25.4 (95% CI, 17.6-33.2) in the nonoptimistic/without depression group and 17.6 (95% CI, 12.0-23.1) in the nonoptimistic/with depression group. There was robust effect modification between optimism and depression (Pinteraction<0.001). Conclusions In this longitudinal cohort, optimism and depression are synergistically associated with functional recovery after stroke. Measuring optimism status may help identify individuals at risk for worse poststroke recovery.

Perspective: COVID-19 and Its Neurologic Sequelae.

COVID-19 led to a catastrophic, international, public health crisis after its first detection in 2019 [1]. Though it is primarily a respiratory virus, it impacts the central and peripheral nervous systems leading to further COVID-19-associated disability [2]. This Perspective reviews our current understanding of the neurological sequelae of COVID-19 and the gaps in our understanding of their treatment and epidemiology.

Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

IMPORTANCE: Myeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps (NETs), have been associated with arterial and venous thrombosis. Their role in aneurysmal subarachnoid hemorrhage (aSAH) is unknown. OBJECTIVES: To assess whether serum MPO-DNA complexes are present in patients with aSAH and whether they are associated with delayed cerebral ischemia (DCI). DESIGN SETTING AND PARTICIPANTS: Post-hoc analysis of a prospective, observational single-center study, with de novo serum biomarker measurements in consecutive patients with aSAH between July 2018 and September 2020, admitted to a tertiary care neuroscience ICU. MAIN OUTCOMES AND MEASURES: We analyzed serum obtained at admission and hospital day 4 for concentrations of MPO-DNA complexes. The primary outcome was DCI, defined as new infarction on brain CT. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial Doppler parameters. We used Wilcoxon signed-rank-test to assess for differences between paired measures. RESULTS: Among 100 patients with spontaneous subarachnoid hemorrhage, mean age 59 years (sd ± 13 yr), 55% women, 78 had confirmed aSAH. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/mL (interquartile range [IQR], 18-43 ng/mL) at admission, and 22 ng/mL (IQR, 11-31 ng/mL) on day 4 (unpaired test; p = 0.015). We found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test; p = 0.036) but not in those without DCI (p = 0.17). There was a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p = 0.006) but not in those without clinical vasospasm (p = 0.47). CONCLUSIONS AND RELEVANCE: This is the first study to detect the NET biomarkers MPO-DNA complexes in peripheral serum of patients with aSAH and to associate them with DCI. A pronounced reduction in MPO-DNA levels might serve as an early marker of DCI. This diagnostic potential of MPO-DNA complexes and their role as potential therapeutic targets in aSAH should be explored further.

Early Deterioration, Hematoma Expansion, and Outcomes in Deep Versus Lobar Intracerebral Hemorrhage: The FAST Trial.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), it is unclear whether early neurological deterioration, hematoma expansion (HE), and outcome vary by supratentorial ICH location (deep versus lobar). Herein, we assessed these relationships in a clinical trial cohort that underwent brain imaging early after symptom onset. We hypothesized that HE would occur more frequently, and outcome would be worse in patients with deep ICH. METHODS: We performed a post hoc analysis of the FAST (Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment) trial including all patients with supratentorial hemorrhage. Enrolled patients underwent brain imaging within 3 hours of symptom onset and 24 hours after randomization. Multivariable regression was used to test the association between ICH location and 3 outcomes: HE (increase of ≥33% or 6mL), early neurological deterioration (decrease in Glasgow Coma Scale score ≥2 points or increase in National Institutes of Health Stroke Scale ≥4 points within 24 hours of admission), and 90-day outcome (modified Rankin Scale). RESULTS: Of 841 FAST trial patients, we included 728 (mean age 64 years, 38% women) with supratentorial hemorrhages (deep n=623, lobar n=105). HE (44 versus 27%, P=0.001) and early neurological deterioration (31 versus 17%, P=0.001) were more common in lobar hemorrhages. Deep hemorrhages were smaller than lobar hemorrhages at baseline (12 versus 35mL, P<0.001) and 24 hours (14 versus 38mL, P<0.001). Unadjusted 90-day outcome was worse in lobar compared with deep ICH (median modified Rankin Scale score 5 versus 4, P=0.03). However, when adjusting for variables included in the ICH score including ICH volume, deep location was associated with worse and lobar location with better outcome (odds ratio lobar location, 0.58 [95% CI, 0.38-0.89]; P=0.01). CONCLUSIONS: In this secondary analysis of randomized trial patients, lobar ICH location was associated with larger ICH volume, more HE and early neurological deterioration, and worse outcome than deep ICH. After adjustment for prognostic variables, however, deep ICH was associated with worse outcome, likely due to their proximity to eloquent brain structures.

Association Between Intraventricular Alteplase Use and Parenchymal Hematoma Volume in Patients With Spontaneous Intracerebral Hemorrhage and Intraventricular Hemorrhage.

Importance: Intraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists. Objective: To evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes. Design, Setting, and Participants: This cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021. Exposure: Randomization to receive intraventricular alteplase. Main Outcomes and Measures: The primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location. Results: A total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P < .001). In the primary analysis, alteplase use was associated with a change in the parenchymal ICH volume in the unadjusted analysis per 1-mL change (ß, 1.37; 95% CI, 0.92-1.81; P < .001) and in multivariable linear regression analysis that was adjusted for demographic characteristics, stability ICH and IVH volumes, ICH location, and time to first dose of study drug per 1-mL change (ß, 1.20; 95% CI, 0.79-1.62; P < .001). In the secondary analyses, no association was found between change in parenchymal ICH volume and poor outcome (odds ratio [OR], 0.97; 95% CI 0.87-1.10; P = .64) or mortality (OR, 0.97; 95% CI 0.99-1.08; P = .59). Similar results were observed in the subgroup analyses. Conclusions and Relevance: This study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.

Portable, bedside, low-field magnetic resonance imaging for evaluation of intracerebral hemorrhage.

Radiological examination of the brain is a critical determinant of stroke care pathways. Accessible neuroimaging is essential to detect the presence of intracerebral hemorrhage (ICH). Conventional magnetic resonance imaging (MRI) operates at high magnetic field strength (1.5-3 T), which requires an access-controlled environment, rendering MRI often inaccessible. We demonstrate the use of a low-field MRI (0.064 T) for ICH evaluation. Patients were imaged using conventional neuroimaging (non-contrast computerized tomography (CT) or 1.5/3 T MRI) and portable MRI (pMRI) at Yale New Haven Hospital from July 2018 to November 2020. Two board-certified neuroradiologists evaluated a total of 144 pMRI examinations (56 ICH, 48 acute ischemic stroke, 40 healthy controls) and one ICH imaging core lab researcher reviewed the cases of disagreement. Raters correctly detected ICH in 45 of 56 cases (80.4% sensitivity, 95%CI: [0.68-0.90]). Blood-negative cases were correctly identified in 85 of 88 cases (96.6% specificity, 95%CI: [0.90-0.99]). Manually segmented hematoma volumes and ABC/2 estimated volumes on pMRI correlate with conventional imaging volumes (ICC = 0.955, p = 1.69e-30 and ICC = 0.875, p = 1.66e-8, respectively). Hematoma volumes measured on pMRI correlate with NIH stroke scale (NIHSS) and clinical outcome (mRS) at discharge for manual and ABC/2 volumes. Low-field pMRI may be useful in bringing advanced MRI technology to resource-limited settings.

Prognostication after intracerebral hemorrhage: a review.

BACKGROUND: Approximately half of patients with spontaneous intracerebral hemorrhage (ICH) die within 1 year. Prognostication in this context is of great importance, to guide goals of care discussions, clinical decision-making, and risk stratification. However, available prognostic scores are hardly used in clinical practice. The purpose of this review article is to identify existing outcome prediction scores for spontaneous intracerebral hemorrhage (ICH) discuss their shortcomings, and to suggest how to create and validate more useful scores. MAIN TEXT: Through a literature review this article identifies existing ICH outcome prediction models. Using the Essen-ICH-score as an example, we demonstrate a complete score validation including discrimination, calibration and net benefit calculations. Score performance is illustrated in the Erlangen UKER-ICH-cohort (NCT03183167). We identified 19 prediction scores, half of which used mortality as endpoint, the remainder used disability, typically the dichotomized modified Rankin score assessed at variable time points after the index ICH. Complete score validation by our criteria was only available for the max-ICH score. Our validation of the Essen-ICH-score regarding prediction of unfavorable outcome showed good discrimination (area under the curve 0.87), fair calibration (calibration intercept 1.0, slope 0.84), and an overall net benefit of using the score as a decision tool. We discuss methodological pitfalls of prediction scores, e.g. the withdrawal of care (WOC) bias, physiological predictor variables that are often neglected by authors of clinical scores, and incomplete score validation. Future scores need to integrate new predictor variables, patient-reported outcome measures, and reduce the WOC bias. Validation needs to be standardized and thorough. Lastly, we discuss the integration of current ICH scoring systems in clinical practice with the awareness of their shortcomings. CONCLUSION: Presently available prognostic scores for ICH do not fulfill essential quality standards. Novel prognostic scores need to be developed to inform the design of research studies and improve clinical care in patients with ICH.

Intracerebral Hemorrhage with Intraventricular Extension Associated with Loss of Consciousness at Symptom Onset.

BACKGROUND: In patients with spontaneous intracerebral hemorrhage (ICH), pre-hospital markers of disease severity might be useful to potentially triage patients to undergo early interventions. OBJECTIVE: Here, we tested whether loss of consciousness (LOC) at the onset of ICH is associated with intraventricular hemorrhage (IVH) on brain computed tomography (CT). METHODS: Among 3000 ICH cases from ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage study, NS069763), we included patients with complete ICH/IVH volumetric CT measurements and excluded those with seizures at ICH onset. Trained investigators extracted data from medical charts. Mental status at symptom onset (categorized as alert/oriented, alert/confused, drowsy/somnolent, coma/unresponsive/posturing) and 3-month disability (modified Rankin score, mRS) were assessed through standardized interviews of participants or dedicated proxies. We used logistic regression and mediation analysis to assess relationships between LOC, IVH, and unfavorable outcome (mRS 4-6). RESULTS: Two thousand seven hundred and twenty-four patients met inclusion criteria. Median admission Glasgow Coma Score was 15 (interquartile range 11-15). 46% had IVH on admission or follow-up CT. Patients with LOC (mental status: coma/unresponsive, n = 352) compared to those without LOC (all other mental status, n = 2372) were younger (60 vs. 62 years, p = 0.005) and had greater IVH frequency (77 vs. 41%, p < 0.001), greater peak ICH volumes (28 vs. 11 ml, p < 0.001), greater admission systolic blood pressure (200 vs. 184 mmHg, p < 0.001), and greater admission serum glucose (158 vs. 127 mg/dl, p < 0.001). LOC was independently associated with IVH presence (odds ratio, OR, 2.6, CI 1.9-3.5) and with unfavorable outcome (OR 3.05, CI 1.96-4.75). The association between LOC and outcome was significantly mediated by IVH (beta = 0.24, bootstrapped CI 0.17-0.32). CONCLUSION: LOC at ICH onset may be a useful pre-hospital marker to identify patients at risk of having or developing IVH.