Search

OBJECTIVES: : To characterize associations between antiepileptic drugs with sedating or anesthetic effects (third-line antiepileptic drugs) vs. other antiepileptic agents, and short-term outcomes, in status epilepticus. Furthermore, to evaluate the role of adverse hemodynamic and respiratory effects of these agents in status epilepticus treatment. DESIGN: : Retrospective comparative analysis. SETTING: : Tertiary academic medical center with two emergency departments and two neurologic intensive care units. PATIENTS: : Adults admitted with a diagnosis of status epilepticus defined as seizures lasting continuously >5 mins, or for discrete periods in succession. INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: : Of 126 patients with 144 separate status epilepticus admissions, 57 were female (45%) with mean age 54.7 ± 15.7 yrs. Status epilepticus was convulsive in 132 cases (92%). Status epilepticus etiologies included subtherapeutic antiepileptic drugs (43%), alcohol or other nonantiepileptic drug (13%), and acute central nervous system disease (12%). Third-line antiepileptic drugs were administered in 47 cases (33%). Seventy-eight status epilepticus episodes (54%) had good outcomes (Glasgow Outcome Score = 1, 2) at the time of hospital discharge. On univariate analysis, poor outcome (Glasgow Outcome Score > 2) was associated with older age (mean 59.8 ± 15.5 vs. 50.5 ± 13.8 yrs, p < .001), acute central nervous system disease (21% vs. 4%, p = .001), mechanical ventilation (76% vs. 53%, p = .004), longer duration of ventilation (median 10 days [range 1-56] vs. 2 days [range 1-10], p < .001), treatment with vasopressors (35% vs. 5%, p < .001), and treatment with third-line antiepileptic drugs (51% vs. 17%, p < .001). Death was associated with acute central nervous system disease, prolonged ventilation, treatment with vasopressors, and treatment with third-line antiepileptic drugs. Predictors of poor outcome among all status epilepticus episodes were older age (odds ratio 1.06; 95% confidence interval 1.03-1.09; p < .001), treatment with third-line antiepileptic therapy (odds ratio 5.64; 95% confidence interval 2.31-13.75; p < .001), and first episode of status epilepticus (odds ratio 3.73; 95% confidence interval 1.38-10.10; p = .010). Among status epilepticus episodes treated by third-line antiepileptic drugs, predictors of poor outcome were older age (odds ratio, 1.09; 95% confidence interval 1.01-1.18; p = .038) and longer ventilation (odds ratio, 1.47; 95% confidence interval 1.08-2.00; p = .015). Predictors of mortality among all status epilepticus episodes were treatment with third-line antiepileptic drugs (odds ratio, 12.08; 95% confidence interval 2.30-63.39; p = .003) and older age (odds ratio, 1.06; 95% confidence interval 1.00-1.12; p = .045). CONCLUSIONS: : Third-line antiepileptic drug therapies with sedating or anesthetic effects predicted poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and duration of mechanical ventilation induced by these agents may be contributing factors, especially when pentobarbital is used. These findings may inform decision making on drug therapy in status epilepticus and help develop safer and more effective treatment strategies to improve outcome. [ABSTRACT FROM AUTHOR]

Background: Post-opioid toxic encephalopathy is described associated with the synthetic opioid, methadone, and after heroin intoxication, (inhaled, injected or ingested).Methods: We describe the clinical and radiologic findings of a 46-year-old man with oxycodone and oxycontin overdose who developed multifocal encephalopathy and severe cerebellitis causing acute obstructive hydrocephalus, and discuss the possible mechanisms involved.Results: Brain MRI showed a non-vascular distribution of diffusion positive lesions in both cerebellar hemispheres and globi pallidi with preserved cerebral perfusion, suggesting an inflammatory process. Management required ventilatory support and intraventricular catheter placement.Conclusions: To our knowledge, this is the first report of this condition associated with oxycodone and oxycontin ingestion. The occurrence of this rare toxic encephalopathy may be related to distribution patterns of opioid receptor subtypes, genetic susceptibility, sensitization, and other specific comorbidities. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Greater demand and limited resources for intensive care monitoring for patients with neurologic disease may change patterns of intensive care unit utilization. The necessity and duration of intensive care unit management for all neurosurgical patients after brain tumor resection are not clear. This study evaluates a) the preoperative and perioperative variables predictive of extended need for intensive care unit monitoring (>1 day); and b) the type and timing of intensive care unit resources in patients for whom less intensive postoperative monitoring may be feasible. DESIGN: Retrospective chart review. SETTING: A neurocritical care unit of a university teaching hospital. PATIENTS: Patients were 158 consecutive postoperative brain tumor resection patients admitted to a neurocritical care unit within a 1-yr period (1998-1999). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients (15%) admitted to the neurocritical care unit for >24 hrs were compared with 135 (85%) patients admitted for <24 hrs. Predictors of >1-day stay in the neurocritical care unit in a logistic regression model were a tumor severity index comprising radiologic characteristics of tumor location, mass effect, and midline shift on the preoperative magnetic resonance imaging scan (odds ratio, 12.5; 95% confidence interval, 3.1-50.5); an intraoperative fluid score comprising estimated blood loss, total volume of crystalloid, and other colloid/hypertonic solutions administered (odds ratio, 1.8; 95% confidence interval, 1.2-2.6); and postoperative intubation (odds ratio, 67.5; 95% confidence interval, 6.5-702.0). Area under the receiver operating characteristic curve for the model of independent predictors for staying >1 day in the neurocritical care unit was 0.91. Neurocritical care unit resource use was reviewed in detail for 134 of 135 patients who stayed in the neurocritical care unit for <1 day. Sixty-five (49%) patients required no interventions beyond postanesthetic care and frequent neurologic exams. A total of 226 intensive care unit interventions were performed (mean +/- sd, 1.7 +/- 2.6) in 69 (51%) patients. Ninety (67%) patients had no further interventions after the first 4 hrs. Neurocritical care unit resource use beyond 4 hrs, largely consisting of intravenous analgesic use (72% of orders), was significantly associated with female gender, benign tumor on frozen section biopsy, and postoperative intubation (chi-square, p <.05). CONCLUSIONS: A small fraction of patients require prolonged intensive care unit stay after craniotomy for tumor resection. A patient's risk of prolonged stay can be well predicted by certain radiologic findings, large intraoperative blood loss, fluid requirements, and the decision to keep the patient intubated at the end of surgery. Of those patients requiring intensive care unit resources beyond the first 4 hrs, the interventions may not be critical in nature. A prospective outcome study is required to determine feasibility, cost, and outcome of patients cared for in extended recovery and then transferred to a skilled nursing ward. [ABSTRACT FROM AUTHOR]

Objective: The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome., Methods: Inclusion criteria in our study were a neuroimaging-confirmed ICH. We evaluated whether sex was associated with ICH severity (hematoma volume and expansion) and poor functional outcomes (modified Rankin Scale >3) 3 or 6 months after the ICH., Results: A total of 4,812 ICH patients were evaluated (mean age 62, 40% female). Males with ICH were younger, more likely to be smokers and have diabetes, and less likely to be on anticoagulants (all p < 0.05). In multivariable analyses, male sex was associated with non-lobar location (odds ratio [OR]: 1.63; 95% confidence interval [CI]: [1.39-1.92]; p < 0.001), larger hemorrhages (beta: 0.16 [0.08-0.23]; p < 0.001) and a higher risk of hematoma expansion (OR: 1.43 [1.20-1.71]; p < 0.001). Despite the larger hemorrhage volume and higher risk of expansion, male sex was associated with a 24% lower risk of poor outcomes (OR: 0.76 [0.64-0.90]; p = 0.002)., Interpretation: Compared to females, males with ICH have larger bleeds and higher risk of hematoma expansion. Despite the larger bleeds and higher risk of hematoma expansion, males with ICH have lower risk of poor outcomes. Our results suggest that the biology and clinical trajectory are different in females and males with ICH, supporting sex-specific research in this condition. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Objectives: Spontaneous intracerebral hemorrhage (ICH) poses high mortality and morbidity rates with limited evidence-based therapeutic approaches. We aimed to evaluate the current evidence for the role of minimally invasive surgery (MIS) in the management of ICH., Methods: This systematic review and meta-analysis followed recommended guidelines and protocols. Medline, Embase, Scopus, and the Cochrane Library were searched from inception up to April 12, 2024. The inclusion was restricted to randomized clinical trials (RCTs) of high quality, ensuring they were not deemed to have a high risk of bias in any of the Cochrane risk of bias tool (RoB2) domains. Primary outcomes were good functional outcome (modified Rankin scale, 0-3) and mortality beyond 90 days. Secondary outcomes were early mortality within 30 days and rebleeding rates. We pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using random-effects models., Results: Fourteen high-quality RCTs were included. There were 3,027 patients with ICH (1,475 randomized to MIS, and 1,452 randomized to medical management or craniotomy). Of included patients, 1,899 (62.7%) were males. MIS resulted in higher odds of achieving long-term good functional outcome (OR, 1.51 [95% CI, 1.25-1.82]), lower odds of long-term mortality (OR, 0.72 [95% CI, 0.57-0.90]) and lower odds of early mortality (OR, 0.73 [95% CI, 0.56-0.95]). Rebleeding rates were similar (OR, 1.10 [95% CI, 0.55-2.19]). The treatment effect of MIS was consistent across multiple sensitivity and subgroup analyses, including individuals with deep ICH., Interpretation: This meta-analysis provides high-quality clinical trial evidence supporting the use of MIS as a primary treatment strategy in the management of ICH. ANN NEUROL 2024., (© 2024 American Neurological Association.)

The quotation, attributed to Confucius many centuries ago, in our opinion, applies to the evolving story of defining a primary surgical treatment for spontaneous intracerebral hemorrhage. The precise quote is: "Keep it simple and focus on what matters. Don't let yourself be overwhelmed." 1 The evidence from multiple trials on intracerebral hemorrhage regarding mortality benefit and potential functional benefit directs us toward the simple task of evacuating the clot, similar to our prime focus on opening the artery in ischemic stroke. We need not be overwhelmed by questions about adjustments to patient selection, comparative techniques, and precision timing, for which we do not have conclusive data. We review the consensus results from the recent MISTIE trial (Minimally Invasive Surgery Plus Alteplase in ICH Evacuation) and ENRICH trial (Early Minimally Invasive Removal of Intracerebral Hemorrhage) and articulate remaining questions where further evidence is needed to challenge equipoise and define future practice.

Background: Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes., Methods: Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models., Results: Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all P interaction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); P interaction =0.006), absence of lacunes (OR, 0.37 (0.18-0.80); P interaction =0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); P interaction =0.03)., Conclusions: Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30 mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions., Methods: This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7 days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0-3)., Results: Of 499 enrolled patients, 300 had MRI at median 7.5 days (interquartile range 7-8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80 mm Hg in first 24 h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume (p = 0.03), decrease in SBP ≥ 80 mm Hg from admission to day 1 (p = 0.03), and moderate-to-severe white matter disease (p = 0.01). Patients with DWI lesions had higher odds of severe disability at 1 month (p = 0.04), 6 months (p = 0.036), and 12 months (p < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found., Conclusions: In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24 h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury., (© 2023. The Author(s).)

Background: Serum neutrophil-lymphocyte ratio (NLR) is a surrogate marker for the inflammatory response after intracerebral hemorrhage (ICH) and is associated with perihematomal edema and long-term functional outcomes. Whether NLR is associated with short-term ICH complications is poorly understood. We hypothesized that NLR is associated with 30-day infection and thrombotic events after ICH., Methods: We performed a post hoc exploratory analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial. The study exposure was the serum NLR obtained at baseline and on days 3 and 5. The coprimary outcomes, ascertained at 30 days, were any infection and a thrombotic event, defined as composite of cerebral infarction, myocardial infarction, or venous thromboembolism; both infection and thrombotic event were determined through adjudicated adverse event reporting. Binary logistic regression was used to study the relationship between NLR and outcomes, after adjustment for demographics, ICH severity and location, and treatment randomization., Results: Among the 500 patients enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial, we included 303 (60.6%) without missing data on differential white blood cell counts at baseline. There were no differences in demographics, comorbidities, or ICH severity between patients with and without data on NLR. In adjusted logistic regression models, NLR ascertained at baseline (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.01-1.07, p = 0.03) and NLR ascertained at day 3 were associated with infection (OR 1.15; 95% CI 1.05-1.20, p = 0.001) but not with thrombotic events. Conversely, NLR at day 5 was associated with thrombotic events (OR 1.07, 95% CI 1.01-1.13, p = 0.03) but not with infection (OR 1.13; 95% CI 0.76-1.70, p = 0.56). NLR at baseline was not associated with either outcome., Conclusions: Serum NLR ascertained at baseline and on day 3 after randomization was associated with 30-day infection, whereas NLR obtained on day 5 was associated with thrombotic events after ICH, suggesting that NLR could be a potential early biomarker for ICH-related complications., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood., Methods: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics., Results: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL., Conclusions: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke., Competing Interests: Disclosures Dr Harris reports stock holdings in Eli LIlly and stock holdings in GlaxoSmithKline. Dr Iadecola has served on the scientific advisory board for Broadview Ventures. Dr Falcone has received grants from the National Institutes of Health (NIH) and the American Heart Association outside of the submitted work. Dr Sheth reports compensation from Cerevasc for consultant services; service as President for Advanced Innovation in Medicine; a patent pending for Stroke wearables licensed to Alva Health. Dr Goldstein reports compensation from Cayuga for consultant services; compensation from Prothya for consultant services; compensation from AstraZeneca for consultant services; and compensation from Lumosa for consultant services. Dr Qureshi reports compensation from Chiesi Farmaceutici for consultant services and compensation from Chiesi USA, Inc, for consultant services. Dr Awad reports compensation from Medicoegal consulting for expert witness services. Dr Hanley reports grants from US Department of Defense; grants from National Institute of Neurological Disorders and Stroke (NINDS); grants from NINDS to other; grants from NINDS; compensation from Neurelis, Inc, for consultant services; grants from National Center for Advancing Translational Sciences; grants from NINDS; gifts from Jeffrey and Harriet Legum Professorship in Acute Neurological Medicine at Johns Hopkins University. Dr Kamel is a co-principal investigator for the ARCADIA trial ([Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke]; NIH/NINDS U01NS095869), which received in-kind study drug from the Bristol Myers Squibb-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); Deputy Editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; end point adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. Dr Ziai has received grants from the NIH, serves as the Associate Editor of Neurocritical Care. Dr Murthy has received grant support from the NIH. The other authors report no conflicts.

Background and Objectives: Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes., Methods: We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses., Results: Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis., Conclusion: Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background: Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC., Methods: The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC., Results: There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC., Conclusions: Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Survivors of intracerebral hemorrhage (ICH) face an increased risk of ischemic cardiovascular events. Current ICH guidelines do not provide definitive recommendations regarding the use of antithrombotic and statin therapies. We, therefore, sought to study practice patterns and factors associated with the use of such medications after ICH., Methods: This was a cross-sectional study of patients with ICH in the Get With The Guidelines-Stroke registry, between 2011 and 2021. Patients transferred to another hospital, those who died during hospitalization, and those with missing information on discharge medications were excluded. The study exposure was the proportion of patients who were prescribed antithrombotic or statin medications. We first ascertained the proportion of patients prescribed antithrombotic and lipid-lowering medications at discharge overall and across strata defined by pre-ICH use and history of previous ischemic vascular disease or atrial fibrillation. We then studied factors associated with the discharge prescription of these medications after ICH, using multiple logistic regressions., Results: In the final cohort, 50 416 (10.4%) of 486 586 patients with ICH were prescribed antiplatelet medications, 173 322 (35.1%) of 493 491 patients with ICH were prescribed statins, and 27 085 (5.4%) of 486 585 patients with ICH were prescribed anticoagulation therapy at discharge. The proportion of patients with antiplatelet therapy was 16.6% with pre-ICH use and 15.6% in those with previous ischemic vascular disease. Statins were prescribed to 41.1% and 43.7% of patients on previous lipid-lowering therapy and ischemic vascular disease, respectively. Anticoagulation therapy was restarted in 11.1% of patients. In logistic regression analysis, factors associated with higher use of antithrombotic or statin therapies after ICH were younger age, male sex, pre-ICH medication use, previous ischemic vascular disease, atrial fibrillation, lower admission National Institutes of Health Stroke Scale, longer length of stay, and favorable discharge outcome., Conclusions: Few patients with ICH are prescribed antithrombotic or statin therapies at hospital discharge. Given the emerging association between ICH and future major cardiovascular events, trials examining the net benefit of antiplatelet and lipid-lowering therapy after ICH are warranted., Competing Interests: Disclosures Dr Murthy has received grants from the National Institutes of Health (NIH) and reports personal fees for medicolegal consulting in stroke and neurological disorders. W.C. Ziai has received grants from the NIH, serves as the associate editor of Neurocritical Care, and reports personal fees from C.R. Bard DMC outside the submitted work. Dr Schwamm reported receiving personal fees from the Massachusetts Department of Public Health, Genentech, Penumbra, Diffusion Pharma, and Medtronic; grants from Medtronic and the National Institute of Neurological Disorders and Stroke outside the submitted work; and serving as a volunteer chair of the American Heart Association/American Stroke Association Get With The Guidelines-Stroke ClinicalWork Group and as a consultant to Coverdell grant. Dr Fonarow reported receiving personal fees from AstraZeneca, Amgen, Bayer, Eli Lilly, Janssen, Merck, Novartis, and Pfizer outside the submitted work. Dr Smith reported consulting for Eli Lilly outside the submitted work. Dr Bhatt discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; board of director: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS. LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; inaugural chair: American Heart Association Quality Oversight Committee; consultant: Broadview Ventures and Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial (Portico Re-Sheathable Transcatheter Aortic Valve System US IDE Trial), funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial [Higher-Risk Pulmonary Embolism Thrombolysis Study]), Cleveland Clinic (including for the ExCEED trial [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis], funded by Edwards), Contego Medical (chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Versus Vitamin K Antagonist for Atrial Fibrillation After Transcatheter Aortic Valve Replacement], funded by Daiichi Sankyo; for the ABILITY-DM trial [Randomized Comparison of Abluminus + Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients With Diabetes Mellitus], funded by Concept Medical), Novartis, Population Health Research Institute, Rutgers University (for the NIH-funded MINT trial [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial [Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention] steering committee funded by Boehringer Ingelheim; AEGIS-II [Apolipoprotein A-I Event Reducing in Ischemic Syndrome] executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Rivaroxaban With or Without Aspirin in Stable Cardiovascular Disease] operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees), Wiley (steering committee); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither the author nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronirk, Boston Scientific, Cardiovascular Systems Incorporated, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee: American College of Cardiology; and unfunded research: Flow Co, Takeda. Dr Kamel is a co-principal investigator for the ARCADIA trial [Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke]; (NIH/National Institute of Neurological Disorders and Stroke U01NS095869), which received in-kind study drug from the Bristol Myers Squibb-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); deputy editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; end point adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. Dr Sheth reported receiving grants from the NIH, the American Heart Association, Bard, Hyperfine, and Biogen. He received consulting fees from Zoll and Sense for Data Safety Monitoring Board (DSMB) Committees service and consulting fees from Astrocyte, CSL Behring, and Rhaeos. He also holds equity in Alva outside the submitted work. The other authors report no conflicts.

Background and Objectives: Bayesian analysis of randomized controlled trials (RCTs) can extend the value of trial data beyond interpretations based on conventional p value-based binary cutoffs. We conducted an exploratory post hoc Bayesian reanalysis of the minimally invasive surgery with thrombolysis for intracerebral hemorrhage (ICH) evacuation (MISTIE-3) trial and derived probabilities of potential intervention effect on functional and survival outcomes., Methods: MISTIE-3 was a multicenter phase 3 RCT designed to evaluate the efficacy and safety of the MISTIE intervention. Five hundred and six adults (18 years or older) with spontaneous, nontraumatic, supratentorial ICH of ≥30 mL were randomized to receive either the MISTIE intervention (n = 255) or standard medical care (n = 251). We provide Bayesian-derived estimates of the effect of the MISTIE intervention on achieving a good 365-day modified Rankin Scale score (mRS score 0-3) as relative risk (RR) and absolute risk difference (ARD), and the probabilities that these treatment effects are greater than prespecified thresholds. We used 2 sets of prior distributions: (1) reference priors, including minimally informative, enthusiastic, and skeptical priors, and (2) data-derived prior distribution, using a hierarchical random effects model. We additionally evaluated the potential effects of the MISTIE intervention on 180-day and 30-day mRS and 365-, 180-, and 30-day mortality using data-derived priors., Results: The Bayesian-derived probability that MISTIE intervention has any beneficial effect (RR >1) on achieving a good 365-day mRS score was 70% using minimally informative prior, 87% with enthusiastic prior, 68% with skeptical prior, and 73% with data-derived prior. However, these probabilities were ≤55% for RR >1.10 and 0% for RR >1.52 across a range of priors. The probabilities of achieving RR >1 for 180- and 30-day mRS scores are 65% and 80%, respectively. Furthermore, the probabilities of achieving RR <1 for 365-, 180-, and 30-day mortality are 93%, 98%, and 99%, respectively., Discussion: Our exploratory analyses indicate that across a range of priors, the Bayesian-derived probability of MISTIE intervention having any beneficial effect on 365-day mRS for patients with ICH is between 68% and 87%. These analyses do not change the frequentist-based interpretation of the trial. However, unlike the frequentist p values, which indirectly evaluate treatment effects and only provide an arbitrary binary cutoff (such as 0.05), the Bayesian framework directly estimates the probabilities of potential treatment effects., Trial Registration Information: ClinicalTrials.gov/ct2/show/NCT01827046., Classification of Evidence: This study provides Class II evidence that minimally invasive surgery (MIS) + recombinant tissue plasminogen activator (rt-PA) does not significantly improve functional outcome in patients with ICH. However, this study lacks the precision to exclude a potential benefit of MIS + rt-PA., (© 2023 American Academy of Neurology.)

Background: Intracerebral hemorrhage (ICH) is associated with an increased risk of ischemic stroke. Whether there are racial and ethnic disparities in the risk of ischemic stroke after ICH is poorly understood. We therefore aimed to test the hypothesis that non-Hispanic Black and Hispanic ICH patients have a higher risk of ischemic stroke compared with non-Hispanic White ICH patients., Methods: We performed a retrospective cohort study using the Healthcare Cost and Utilization Project (HCUP) on all hospitalizations at all nonfederal hospitals in Florida from 2005 to 2018 and New York from 2006 to 2016. Race and ethnicity were coded as a single variable in HCUP. We included patients with an ICH, and without a prior or concomitant diagnosis of ischemic stroke, ascertained using validated International Classification of Diseases-Clinical Modification-9 and 10 diagnosis codes. Using Cox proportional hazard models, we studied the relationship between race and risk of ischemic stroke starting from the time of discharge from ICH hospitalization, after adjustment of demographics and vascular comorbidities., Results: We included 91 342 patients with ICH-62% non-Hispanic White, 18% non-Hispanic Black, and 12% Hispanic patients. Non-Hispanic Black and Hispanic patients were younger and had a higher prevalence of cardiovascular comorbidities; however, atrial fibrillation was more prevalent among non-Hispanic White patients. During a median follow-up period of 4.4 years (interquartile range, 1.5-8.1), an incident ischemic stroke occurred in 3377 (6%) non-Hispanic White, 1323 (8%) non-Hispanic Black, and 844 (8%) Hispanic patients. In adjusted Cox models, the risk of an ischemic stroke was significantly higher among non-Hispanic Black patients (hazard ratio, 1.6 [95% CI, 1.5-1.8]) and Hispanic patients (hazard ratio, 1.4 [95% CI, 1.3-1.5]), compared with non-Hispanic White patients. Similar results were obtained in sensitivity analyses when using death as a competing risk and after excluding patients with atrial fibrillation and valvular heart disease., Conclusions: In a large heterogeneous cohort of patients with ICH, we found that non-Hispanic Black and Hispanic patients had a significantly higher risk of ischemic stroke compared with non-Hispanic White patients., Competing Interests: Disclosures Dr Sheth is supported by grants from the National Institutes of Health (NIH) and reports grants from Hyperfine, Bard, Biogen, and personal fees from CSL Behring, Zoll, Rhaeos, Astrocyte, and Sense. He holds equity in Alva. Dr Ziai has received grants from the NIH, serves as the Associate Editor of Neurocritical Care and reports personal fees from C. R. Bard DMC, Integra Life Sciences, and Lumosa Therapeutics outside the submitted work. Dr Iadecola has served on the scientific advisory board for Broadview Ventures and reports grants from the NIH outside the submitted work. Dr Murthy has received grants from the NIH and reports personal fees for medicolegal consulting in stroke and neurological disorders.

Competing Interests: WCZ is supported by grants from the National Institutes of Neurological Disorders and Stroke for other trials in intracerebral haemorrhage. DFH is supported by grants from the National Institutes of Neurological Disorders and Stroke for other trials in intracerebral haemorrhage. MB declares no competing interests.

Competing Interests: WCZ is supported by grants from the National Institute of Neurological Disorders and Stroke and National Institute on Aging for trials in intracerebral haemorrhage, and receives consulting fees from C R Bard, both outside of the area of work commented here. VS declares no competing interests.

Importance: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited., Objective: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery., Design, Setting, and Participants: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022., Exposures: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care., Main Outcomes and Measures: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort., Results: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001)., Conclusions and Relevance: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article., (© 2022. The Author(s).)

Background: The objective of this study was to evaluate factors associated with intraventricular hemorrhage (IVH) expansion and its association with long-term outcomes., Methods: We performed a post hoc analysis of the international, multi-center CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) which enrolled IVH patients between September 1, 2009, and January 31, 2015. The exposure was IVH expansion, defined as >1 mL increase in volume between baseline and stability computed tomography scans, before treatment randomization. We assessed factors associated with IVH expansion and secondarily assessed the relationship of IVH expansion with clinical outcomes: composite of death or major disability (modified Rankin Scale score, >3), and mortality alone at 6 months. The relationship of IVH expansion on ventriculoperitoneal shunt placement was additionally explored. Multivariable logistic regression was used for all analyses., Results: Of 500 IVH patients analyzed, the mean age was 59 (±11) years old, 44% were female and 135 (27%) had IVH expansion. In multivariable regression models, factors associated with IVH expansion were baseline parenchymal intracerebral hemorrhage (ICH) volume (adjusted odds ratio [OR], 1.04 per 1 mL increase [95% CI, 1.01-1.08]), presence of parenchymal hematoma expansion: >33% (adjusted OR, 6.63 [95% CI, 3.92-11.24]), time to stability head CT (adjusted OR, 0.71 per 1 hour increase [95% CI, 0.54-0.94]), and thalamic hematoma location (adjusted OR, 1.68 [95% CI, 1.01-2.79]) while additionally adjusting for age, sex, and race. In secondary analyses, IVH expansion was associated with higher odds of poor 6-month outcomes (adjusted OR, 1.84 [95% CI, 1.12-3.02]) but not mortality (OR, 1.40 [95% CI, 0.78-2.50]) after adjusting for baseline ICH volume, thalamic ICH location, age, anticoagulant use, Glasgow Coma Scale score, any withdrawal of care order, and treatment randomization arm. However, there were no relationships of IVH expansion on subsequent ventriculoperitoneal shunt placement (adjusted OR, 1.02 [95% CI, 0.58-1.80]) after adjusting for similar covariates., Conclusions: In a clinical trial cohort of patients with large IVH, acute hematoma characteristics, specifically larger parenchymal volume, hematoma expansion, and thalamic ICH location were associated with IVH expansion. Given that IVH expansion resulted in poor functional outcomes, exploration of treatment approaches to optimize hemostasis and prevent IVH expansion, particularly in patients with thalamic ICH, require further study., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00784134.

Background and Objectives: To study the relationship between the presence of cerebral microbleeds (CMBs) and acute hematoma characteristics among patients with primary intracerebral hemorrhage (ICH)., Methods: We pooled individual patient data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 (MISTIE III) trial. We included individuals with a brain MRI scan. Exposure was the presence of a CMB. The coprimary outcomes were admission ICH volume and hematoma expansion. Mixed-effects linear and logistic regression models were used, with demographics and comorbid conditions considered fixed effects and the study cohort treated as a random effect. Additional analyses assessed the relationship between CMB topography and number and hematoma characteristics., Results: Of the 1,499 patients with ICH enrolled in the parent trials, 466 (31.1%) were included in this analysis, and 231 (49.6%) patients had CMBs. In adjusted models, presence of CMBs was associated with smaller ICH volume (β = -0.26, 95% confidence interval [CI] -0.44 to -0.08) and lower odds of hematoma expansion (odds ratio 0.65, 95% CI 0.40-0.95; p = 0.04). The strength of association between CMBs and hematoma characteristics increased with increasing number of CMBs. The location of the CMBs and the severity of leukoaraiosis did not modify these results., Discussion: In a pooled cohort of patients with ICH, our results are consistent with the hypothesis that more severe underlying small vessel disease, as represented by CMBs, leads to smaller baseline hematoma volumes and reduced hematoma expansion. Underlying cerebral small vessel disease may be of prognostic significance after ICH., Trial Registration Information: ClinicalTrials.gov Identifier: NCT01176565 and NCT01827046., Classification of Evidence: This study provides Class II evidence that the presence of microbleeds on MRI is associated with a smaller ICH volume at presentation and a lower rate of hematoma expansion on follow-up imaging., (© 2021 American Academy of Neurology.)

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 (β, 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 (β, 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.

Objectives: To determine factors associated with post-stroke depression (PSD) and relationship between PSD and functional outcomes in spontaneous intracerebral hemorrhage (ICH) using prospective data from a large clinical trial., Materials and Methods: MISTIE III, a randomized, multicenter, placebo-controlled trial, was conducted to determine if minimally invasive surgery with thrombolysis improves outcome compared to standard medical care. Our primary outcome was post-stroke depression at 180 days. Secondary outcomes were change in blinded assessment of modified Rankin Scale (mRS) from 30 to 180 days, and from 180 to 365 days. Logistic regression models were used to assess the relationship between PSD and outcomes., Results: Among 379 survivors at day 180, 308 completed Center for Epidemiologic Studies Depression Scale, of which 111 (36%) were depressed. In the multivariable analysis, female sex (Adjusted Odds Ratio [AOR], 95% Confidence Interval [CI]: 1.93 [1.07-3.48]), Hispanic ethnicity (3.05 [1.19-7.85]), intraventricular hemorrhage (1.88 [1.02-3.45]), right-sided lesions (3.00 [1.43-6.29]), impaired mini mental state examination at day 30 (2.50 [1.13-5.54]), and not being at home at day 30 (3.17 [1.05-9.57]) were significantly associated with higher odds of PSD. Patients with PSD were significantly more likely to have unchanged or worsening mRS from day 30 to 180 (42.3% vs. 25.9%; p=0.004), but not from day 180 to 365., Conclusions: We report high burden of PSD in patients with large volume ICH. Impaired cognition and not living at home may be more important than physical limitations in predicting PSD. Increased screening of high-risk post-stroke patients for depression, especially females and Hispanics may be warranted., Competing Interests: Declaration of Competing Interest Ms. Avadhani, Dr. Thompson, Ms. Carhuapoma, Dr. Yenokyan, Ms. McBee, Ms. Lane, Ms. Ostapkovich, and Ms. Stadnik report no disclosures. Drs. Awad and Hanley were awarded significant research support for Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE) III by NIH/NINDS grant U01NS080824. Dr. Ziai is supported by grants R01NS102583, U01NS106513 and U01NS080824. Dr. Awad reports grants from NIH outside the submitted work. Dr. Hanley reports grants from NIH and personal fees from BrainScope, Neurotrope, Op2Lysis, and Portola Pharmaceuticals, outside the submitted work. Dr. Ziai is an associate editor for Neurocritical Care and an assistant editor for Stroke and has received consulting fees from Portola and data monitoring committee fees from C.R. Bard, Inc. outside the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Intracerebral hemorrhage (ICH) results in a cascade of inflammatory cell activation with recruitment of peripheral leukocytes to the brain parenchyma and surrounding the hematoma. We hypothesized that in patients with ICH and intraventricular hemorrhage (IVH), a robust cerebrospinal fluid (CSF) inflammatory response occurs with leukocyte subtypes being affected by alteplase treatment and contributing to outcomes., Methods: Serum and CSF cell counts from patients in the phase 3 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial were analyzed. CSF leukocytes were corrected for the presence of red blood cells. Trends in cell counts were plotted chronologically. Associations were evaluated between serum and CSF leukocyte subtypes and adjudicated functional outcome (modified Rankin Scale; mRS) at 30 and 180 days and bacterial infection according to treatment with intraventricular alteplase versus saline., Results: A total of 279 and 292 patients had ≥3 differential cell counts from serum and CSF, respectively. CSF leukocyte subtypes evolved during IVH resolution with a significantly augmented inflammatory response for all subtypes in alteplase- compared to saline-treated patients. CSF leukocyte subtypes were not associated with detrimental effect on functional outcomes in the full cohort, but all were associated with poor 30-day outcome in saline-treated patients with IVH volume ≥20 mL. Higher serum lymphocytes were associated with good functional outcomes (mRS 0-3) in the entire cohort and saline-treated but not alteplase-treated group. Conversely, increased serum neutrophil-to-lymphocyte ratio (NLR) in the entire cohort and saline group was associated with worse functional outcomes. Higher median serum lymphocytes were associated with the absence of infection at 7 days., Conclusions: Aseptic CSF inflammation after IVH involves all leukocyte subtypes. Serum lymphocytes may be associated with better outcomes by mitigating infection. Alteplase augments the inflammatory response without affecting outcomes., (© 2021. The Author(s).)

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8-48.8] and 14.3 [5.3-38] mL respectively. Mean levels of IL-1β, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9-10 ( p < 0.05) and decreased across subsequent time periods. Levels of IL-1β, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3-8 whereas positive correlations with ICH volume occurred earlier at day 1-2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1-2 and with relative PHE at days 7-8 or 9-10 for IL-1β, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction.

Background and Purpose: Stroke may complicate coronavirus disease 2019 (COVID-19) infection based on clinical hypercoagulability. We investigated whether transcranial Doppler ultrasound has utility for identifying microemboli and clinically relevant cerebral blood flow velocities (CBFVs) in COVID-19., Methods: We performed transcranial Doppler for a consecutive series of patients with confirmed or suspected COVID-19 infection admitted to 2 intensive care units at a large academic center including evaluation for microembolic signals. Variables specific to hypercoagulability and blood flow including transthoracic echocardiography were analyzed as a part of routine care., Results: Twenty-six patients were included in this analysis, 16 with confirmed COVID-19 infection. Of those, 2 had acute ischemic stroke secondary to large vessel occlusion. Ten non-COVID stroke patients were included for comparison. Two COVID-negative patients had severe acute respiratory distress syndrome and stroke due to large vessel occlusion. In patients with COVID-19, relatively low CBFVs were observed diffusely at median hospital day 4 (interquartile range, 3-9) despite low hematocrit (29.5% [25.7%-31.6%]); CBFVs in comparable COVID-negative stroke patients were significantly higher compared with COVID-positive stroke patients. Microembolic signals were not detected in any patient. Median left ventricular ejection fraction was 60% (interquartile range, 60%-65%). CBFVs were correlated with arterial oxygen content, and C-reactive protein (Spearman ρ=0.28 [ P =0.04]; 0.58 [ P <0.001], respectively) but not with left ventricular ejection fraction (ρ=-0.18; P =0.42)., Conclusions: In this cohort of critically ill patients with COVID-19 infection, we observed lower than expected CBFVs in setting of low arterial oxygen content and low hematocrit but not associated with suppression of cardiac output.

Background: Liver disease is associated with altered serum osmolality, increased thrombin generation, and systemic inflammation, all of which may contribute to perihematomal edema (PHE) after intracerebral hemorrhage (ICH). We evaluated the association between a validated liver fibrosis index and PHE growth in a cohort of patients with primary ICH., Methods: We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-ICH. We included adult patients with primary ICH presenting within 6 h of symptom onset. The exposure of interest was the Fibrosis-4 (FIB-4) score, a validated liver fibrosis index; this was modeled as a continuous variable. The primary outcome was absolute PHE growth over 96 h. Secondary outcomes were absolute admission and 96-h PHE volumes. We used multiple linear regression models adjusted for established determinants of PHE. In a secondary analysis, the FIB-4 score was modeled as a categorical variable to compare patients with versus without liver fibrosis., Results: Among 354 patients with ICH, 8% had evidence of liver fibrosis based on a validated cutoff. The FIB-4 score was not associated with PHE growth in unadjusted (β, 0.03; 95% CI, - 0.01 to 0.12) or adjusted models (β, 0.04; 95% CI, - 0.03 to 0.13). In a secondary analysis treating FIB-4 as a categorical variable, patients with liver fibrosis did not have greater PHE growth than those without liver fibrosis. FIB-4 score was also not associated with absolute admission or 96-h PHE volumes., Conclusions: In a multicenter cohort of patients with primary intracerebral hemorrhage, a liver fibrosis score was not associated with PHE volume or growth.

Objectives: Intracranial pressure (ICP) monitors have been used in some patients with spontaneous intracranial hemorrhage (ICH) to provide information to guide treatment without clear evidence for its use in this population. We assessed the impact of ICP monitor placement, including external ventricular drains and intraparenchymal monitors, on neurologic outcome in this population., Materials and Methods: In this secondary analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III trial, the primary outcome was poor outcome (modified Rankin Scale score 4-6) and the secondary outcome was death, at 1 year from onset. We compared outcomes in patients with or without an ICP monitor using unadjusted and adjusted logistic regression models. The analyses were repeated in a balanced cohort created with propensity score matching., Results: Seventy patients underwent ICP monitor placement and 424 did not. Poor outcome was seen in 77.1% of patients in the ICP-monitor subgroup compared with 53.8% in the no-monitor subgroup (p<0.001). Of patients in the ICP-monitor subgroup, 31.4% died, compared with 21.0% in the no-monitor subgroup (p=0.053). In multivariate models, ICP monitor placement was associated with a >2-fold greater risk of poor outcome (odds ratio 2.76, 95% CI 1.30-5.85, p=0.008), but not with death (p=0.652). Our findings remained consistent in the propensity score-matched cohort., Conclusion: These results question whether ICP monitor-guided therapy in patients with spontaneous nontraumatic ICH improves outcome. Further work is required to define the causal pathway and improve identification of patients that might benefit from invasive ICP monitoring., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14 + monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E 2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE 2 , which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Purpose: Punctate ischemic lesions noted on diffusion-weighted imaging (DWI) are associated with poor functional outcomes after intracerebral hemorrhage (ICH). Whether these lesions increase long-term risk of stroke is poorly understood., Methods: We pooled individual patient data from the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage) and the MISTIE III trial (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3). We included subjects with a magnetic resonance imaging scan. The exposure was a DWI lesion. The primary outcome was any stroke, defined as a composite of ischemic stroke or recurrent ICH, whereas secondary outcomes were incident ischemic stroke and recurrent ICH. Using multivariate Cox regression analysis, we evaluated the risk of stroke., Results: Of 505 patients with ICH with magnetic resonance imaging, 466 were included. DWI lesions were noted in 214 (45.9%) subjects, and 34 incident strokes (20 ischemic stroke and 14 recurrent ICH) were observed during a median follow-up of 324 days (interquartile range, 91-374). Presence of a DWI lesion was associated with a 6.9% (95% CI, 2.2-11.6) absolute increase in risk of all stroke (hazard ratio, 2.6 [95% CI, 1.2-5.7]). Covariate adjustment with Cox regression models also demonstrated this increased risk. In the secondary analyses, there was an increased risk of ischemic stroke (hazard ratio, 3.5 [95% CI, 1.1-11.0]) but not recurrent ICH (hazard ratio, 1.7 [95% CI, 0.6-5.1])., Conclusions: In a heterogeneous cohort of patients with ICH, presence of a DWI lesion was associated with a 2.5-fold heightened risk of stroke among ICH survivors. This elevated risk persisted for ischemic stroke but not for recurrent ICH.

Intracerebral haemorrhage (ICH) accounts for half of the disability-adjusted life years lost due to stroke worldwide. Care pathways for acute stroke result in the rapid identification of ICH, but its acute management can prove challenging because no individual treatment has been shown definitively to improve its outcome. Nonetheless, acute stroke unit care improves outcome after ICH, patients benefit from interventions to prevent complications, acute blood pressure lowering appears safe and might have a modest benefit, and implementing a bundle of high-quality acute care is associated with a greater chance of survival. In this article, we address the important questions that neurologists face in the diagnosis and acute management of ICH, and focus on the supporting evidence and practical delivery for the main acute interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Intracerebral hemorrhage (ICH) represents a major, global, unmet health need with few treatments. A significant minority of ICH patients present taking an anticoagulant; both vitamin-K antagonists and increasingly direct oral anticoagulants. Anticoagulants are associated with an increased risk of hematoma expansion, and rapid reversal reduces this risk and may improve outcome. Vitamin-K antagonists are reversed with prothrombin complex concentrate, dabigatran with idarucizumab, and anti-Xa agents with PCC or andexanet alfa, where available. Blood pressure lowering may reduce hematoma growth and improve clinical outcomes and careful (avoiding reductions ≥60 mm Hg within 1 h), targeted (as low as 120-130 mm Hg), and sustained (minimizing variability) treatment during the first 24 h may be optimal for achieving better functional outcomes in mild-to-moderate severity acute ICH. Surgery for ICH may include hematoma evacuation and external ventricular drainage to treat hydrocephalus. No large, well-conducted phase III trial of surgery in ICH has so far shown overall benefit, but meta-analyses report an increased likelihood of good functional outcome and lower risk of death with surgery, compared to medical treatment only. Expert supportive care on a stroke unit or critical care unit improves outcomes. Early prognostication is difficult, and early do-not-resuscitate orders or withdrawal of active care should be used judiciously in the first 24-48 h of care. Implementation of acute ICH care can be challenging, and using a care bundle approach, with regular monitoring of data and improvement of care processes can ensure consistent and optimal care for all patients.