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Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Progression of intracranial hemorrhage is a common, potentially devastating complication after moderate/severe traumatic brain injury (TBI). Clinicians have few tools to predict which patients with traumatic intracranial hemorrhage on their initial head computed tomography (hCT) scan will progress. The objective of this investigation was to identify clinical, imaging, and/or protein biomarkers associated with progression of intracranial hemorrhage (PICH) after moderate/severe TBI and to create an accurate predictive model of PICH based on clinical features available at presentation. We analyzed a subset of subjects from the phase II double-blind, multi-center, randomized "Prehospital Tranexamic Acid Use for TBI" trial. This subset was limited to the placebo arm of the parent trial with evidence of hemorrhage on the initial hCT and a follow-up hCT 6 h after. PICH was defined as an increase in hemorrhage size by 30% or more, or the development of new hemorrhage in the intra- and extra-axial intracranial vault between the initial and the follow-up hCT. Two independent radiologists evaluated each hCT, and conflicts were adjudicated by a third. Clinical and radiographic characteristics were collected, along with plasma protein biomarkers at admission. Principal component analysis (PCA) was performed, and each principal component (PC) was interrogated for its association with PICH. Finally, expert opinion and recursive feature extraction (RFE) were used to select input features for the construction of several supervised classification models. Their ability to predict PICH was quantified and compared. In this subset of subjects ( n = 104), 46% ( n = 48) demonstrated PICH. Univariate analyses showed no association between PICH and age, sex, admission Glasgow Coma Scale (GCS), GCS motor subscore, presence of midline shift, admission platelet count or admission INR. Radiographic severity scores (Marshall score [ p = 0.007], Rotterdam score [ p = 0.004]), and initial hematoma volume [ p = 0.005] were associated with PICH. Higher levels of admission glial fibrillary acidic protein ( p < 0.001) and MAP ( p = 0.011) were also associated with PICH. Of the PCs, PC1 was significantly associated with PICH ( p = 0.0125). Using multimodal data input, machine learning classifiers successfully discriminated patients with or without PICH. Models composed of machine-selected features performed better than models composed of expert-selected variables (reaching an average of 77% accuracy, AUC = 0.78 versus AUC = 0.68 for the expert-selected variables). Predictive models utilizing variables measured at admission can accurately predict PICH, confirmed by the 6-hour follow-up hCT. Our best-performing models must now be externally validated in a separate cohort of TBI patients with low GCS and initial hCT positive for hemorrhage.

Importance: Data on the performance of traumatic brain injury (TBI) biomarkers within minutes of injury are lacking., Objectives: To examine the performance of glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein 2 (MAP-2) within 30 and 60 minutes of TBI in identifying intracranial lesions on computed tomography (CT) scan, need for neurosurgical intervention (NSI), and clinically important early outcomes (CIEO)., Design, Setting, and Participants: This cohort study is a biomarker analysis of a multicenter prehospital TBI cohort from the Prehospital Tranexamic Acid Use for TBI clinical trial conducted across 20 centers and 39 emergency medical systems in North America from May 2015 to March 2017. Prehospital hemodynamically stable adult patients with traumatic injury and suspected moderate to severe TBI were included. Blood samples were measured for GFAP, UCH-L1, and MAP-2. Data were analyzed from December 1, 2023, to March 15, 2024., Main Outcomes and Measures: The presence of CT lesions, diffuse injury severity on CT, NSI within 24 hours of injury, and CIEO (composite outcome including early death, neurosurgery, or prolonged mechanical ventilation ≥7 days) within 7 days of injury., Results: Of 966 patients enrolled, 804 patients (mean [SD] age, 41 [19] years; 418 [74.2%] male) had blood samples, including 563 within 60 minutes and 375 within 30 minutes of injury. Among patients with blood drawn within 30 minutes of injury, 212 patients (56.5%) had CT lesions, 61 patients (16.3%) had NSI, and 112 patients (30.0%) had CIEO. Among those with blood drawn within 60 minutes, 316 patients (56.1%) had CT lesions, 95 patients (16.9%) had NSI, and 172 patients (30.6%) had CIEO. All biomarkers showed significant elevations with worsening diffuse injury on CT within 30 and 60 minutes of injury. Among blood samples taken within 30 minutes, GFAP had the highest area under the receiver operating characteristic curve (AUC) to detect CT lesions, at 0.88 (95% CI, 0.85-0.92), followed by MAP-2 (AUC, 0.78; 95% CI, 0.73-0.83) and UCH-L1 (AUC, 0.75; 95% CI, 0.70-0.80). Among blood samples taken within 60 minutes, AUCs for CT lesions were 0.89 (95% CI, 0.86-0.92) for GFAP, 0.76 (95% CI, 0.72-0.80) for MAP-2, and 0.73 (95% CI, 0.69-0.77) for UCH-L1. Among blood samples taken within 30 minutes, AUCs for NSI were 0.78 (95% CI, 0.72-0.84) for GFAP, 0.75 (95% CI, 0.68-0.81) for MAP-2, and 0.69 (95% CI, 0.63-0.75) for UCH-L1; and for CIEO, AUCs were 0.89 (95% CI, 0.85-0.93) for GFAP, 0.83 (95% CI, 0.78-0.87) for MAP-2, and 0.77 (95% CI, 0.72-0.82) for UCH-L1. Combining the biomarkers was no better than GFAP alone for all outcomes. At GFAP of 30 pg/mL within 30 minutes, sensitivity for CT lesions was 98.1% (95% CI, 94.9%-99.4%) and specificity was 34.4% (95% CI, 27.2%-42.2%). GFAP levels greater than 6200 pg/mL were associated with high risk of NSI and CIEO., Conclusions and Relevance: In this cohort study of prehospital patients with TBI, GFAP, UCH-L1, and MAP-2 measured within 30 and 60 minutes of injury were significantly associated with traumatic intracranial lesions and diffuse injury severity on CT scan, 24-hour NSI, and 7-day CIEO. GFAP was the strongest independent marker associated with all outcomes. This study sets a precedent for the early utility of GFAP in the first 30 minutes from injury in future clinical and research endeavors.

Background: No treatment is available to prevent brain oedema, which can occur after a large hemispheric infarction. Glibenclamide has previously been shown to improve functional outcome and reduce neurological or oedema-related death in patients younger than 70 years who were at risk of brain oedema after an acute ischaemic stroke. We aimed to assess whether intravenous glibenclamide could improve functional outcome at 90 days in patients with large hemispheric infarction., Methods: CHARM was a phase 3, double-blind, placebo-controlled, randomised trial conducted across 143 acute stroke centres in 21 countries. We included patients aged 18-85 years with a large stroke, defined either by an Alberta Stroke Program Early CT Score (ASPECTS) of 1-5 or by an ischaemic core lesion volume of 80-300 mL on CT perfusion or MRI diffusion-weighted imaging. Patients were randomly assigned in a 1:1 ratio to either intravenous glibenclamide (8·6 mg over 72 h) or placebo. The study drug was started within 10 h of stroke onset. The primary efficacy outcome was the shift in the distribution of scores on the modified Rankin Scale at day 90, as a measure of functional outcome. The primary efficacy outcome was analysed in a modified intention-to-treat population, which included all randomly assigned patients aged 18-70 years. The safety population comprised all randomly assigned patients who received a dose. This trial is registered with ClinicalTrials.gov (NCT02864953). The trial was stopped early by the sponsor for strategic and operational reasons (slow enrolment because of COVID-19), before any unblinding or knowledge of the trial results., Findings: Between Aug 29, 2018, and May 23, 2023, 535 patients were enrolled and randomly assigned, of whom 518 received a dose (safety population) and 431 were aged 18-70 years and comprised the modified intention-to-treat population (217 were assigned glibenclamide and 214 placebo). The mean age of patients was 58·7 (SD 9·0) years in the placebo group and 58·0 (9·5) years in the glibenclamide group; the median US National Institutes of Health Stroke Scale (NIHSS) score was 19 (IQR 16-23) in the placebo group and 19 (IQR 16-22) in the glibenclamide group; and the mean time from stroke onset to study drug start was 8·9 h (SD 2·1) in the placebo group and 9·2 h (2·1) in the glibenclamide group. Intravenous glibenclamide was not associated with a favourable shift in the modified Rankin scale at 90 days (common odds ratio [OR] 1·17 [95% CI 0·80-1·71], p=0·42). 90-day mortality was 29% (61 of 214) in the placebo group and 32% (70 of 217) in the glibenclamide group (hazard ratio 1·20 [0·85-1·70]; p=0·30). Serious adverse events in the prespecified safety population were consistent with the known safety profile of glibenclamide and included hypoglycaemia in 15 (6%) of 259 patients in the glibenclamide group and in four (2%) of 259 patients in the placebo group, leading to dose interruption or reduction in seven (3%) patients in the glibenclamide group and in one (<1%) in the placebo group., Interpretation: Intravenous glibenclamide did not improve functional outcome in patients aged 18-70 years after large hemispheric infarction, although the trial was underpowered to make definitive conclusions because it was stopped early. Future prospective evaluation could be warranted to identify a possible benefit of intravenous glibenclamide in specific subgroups., Funding: Biogen., Competing Interests: Declaration of interests KNS has received research support from Biogen administered as a grant to Yale University; other research support from the US National Institutes of Health (NIH), American Heart Association, and Hyperfine, received consulting fees from CSL Behring, Rhaeos, Cerevasc, Astrocyte, Bexorg, and Brain Q; owns equity in Alva Health as a co-founder; and has served on data safety and monitoring board for Zoll, Sense, and Phillips. GWA has received consulting fees from Biogen related to the conduct of the CHARM trial; consulting fees from Genentech and RapidAI; and has equity in RapidAI. JLS has received consulting fees for advising on rigorous and safe clinical trial design and conduct from Biogen, Medtronic, Phenox, and Rapid Medical. BJM has received research support from Biogen administered as a grant to their previous institution (University of Pittsburgh Medical Center); has received grant funding from the NIH; and has equity interest in Celdara Medical. HEH has received consulting fees from Biogen related to the conduct of the CHARM trial; consulting fees from RapidAI; and grant funding from the NIH. CC has received research funding from Biogen related to the conduct of the CHARM trial in France; grant funding from French Ministry of Health and Agence Nationale de la Recherche; and consulting fees from Bayer. KT has received lecture fees from Daiichi-Sankyo, Otsuka, Janssen, Bayer, and Bristol Myers Squibb. RL is an employee of Biogen. MWa, RL, JC, NL, and KD are employees and stockholders of Biogen. RGN reports consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Philips, Hybernia, Hyperfine, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, and Synchron; and stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, CrestecBio, Euphrates Vascular, Vesalio, Viz-AI, RapidPulse, and Perfuze. RGN is one of the Principal Investigators of the “Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW)” trial; is the Principal Investigator of the “Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe (DUSK)” trial; and is an investor in Viz-AI, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, Tulavi Therapeutics, Vastrax, Piraeus Medical, Brain4Care, Quantanosis AI, and Viseon. JMS has received grant funding from the NIH and US Department of Veterans Affairs; consulting fees from Biogen; and owns stocks or options from Remedy Pharmaceuticals, Martin Pharmaceuticals, and Woolsey Pharmaceuticals. WTK has received research funding from Biogen related to the conduct of the CHARM trial; grant funding from the NIH, the American Heart Association, and the Alzheimer's Association; research funding from NControl Therapeutics; research funding from Hyperfine; consulting fees from Biogen, Acasti Pharma, and Astrocyte Pharmaceuticals; and owns stocks or options from Woolsey Pharmaceuticals and Acasti Pharma. BC and MWi declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Cerebral edema is a common, potentially life-threatening complication in critically ill patients with acute brain injury. However, uncertainty remains regarding best monitoring and treatment strategies, which may result in wide practice variations., Methods: A 20-question digital survey on monitoring and management practices was disseminated between July 2022 and May 2023 to clinicians who manage cerebral edema. The survey was promoted through email, social media, medical conferences, and the Neurocritical Care Society Web site. We used the χ 2 test, Fisher's exact test, analysis of variance, and logistic regression to report factors associated with practice variation, diagnostic monitoring methods, and therapeutic triggers based on practitioner and institutional characteristics., Results: Of 321 participants from 160 institutions in 30 countries, 65% were from university-affiliated centers, 74% were attending physicians, 38% were woman, 38% had neurology training, and 55% were US-based. Eighty-four percent observed practice variations at their institutions, with "provider preference" being cited most (87%). Factors linked to variation included gender, experience, university affiliation, and practicing outside the United States. University affiliates tended to use more tests (median 3.87 vs. 3.43, p = 0.01) to monitor cerebral edema. Regarding management practices, 20% of respondents' preferred timing for decompressive hemicraniectomy was after 48 h, and 37% stated that radiographic findings only would be sufficient to trigger surgery. Fifty percent of respondents reported initiating osmotic therapy based on radiographic indications or prophylactically. There were no significant associations between management strategies and respondent or center characteristics. Twenty-seven percent of respondents indicated that they acquired neuroimaging at intervals of 24 h or less. Within this group, attending physicians were more likely to follow this practice (65.5% vs. 34.5%, p = 0.04)., Conclusions: Cerebral edema monitoring and management strategies vary. Features associated with practice variations include both practitioner and institutional characteristics. We provide a foundation for understanding practice patterns that is crucial for informing educational initiatives, standardizing guidelines, and conducting future trials., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) model is a widely recognized prognostic model applied after traumatic brain injury (TBI). However, it was developed with patient cohorts that may not reflect modern practice patterns in North America. We analyzed data from two sources: the placebo arm of the phase II double-blinded, multicenter, randomized controlled trial Prehospital Tranexamic Acid for TBI (TXA) cohort and an observational cohort with similar inclusion/exclusion criteria (Predictors of Low-risk Phenotypes after Traumatic Brain Injury Incorporating Proteomic Biomarker Signatures [PROTIPS] cohort). All three versions of the IMPACT model-core, extended, and laboratory-were evaluated for 6-month mortality (Glasgow Outcome Scale Extended [GOSE] = 1) and unfavorable outcomes (GOSE = 1-4). Calibration (intercept and slope) and discrimination (area under the receiver operating characteristic curve [ROC-AUC]) were used to assess model performance. We then compared three model updating methods-recalibration in the large, logistic recalibration, and coefficient update-with the best update method determined by likelihood ratio tests. In our calibration analysis, recalibration improved both intercepts and slopes, indicating more accurate predicted probabilities when recalibration was done. Discriminative performance of the IMPACT models, measured by AUC, showed mortality prediction ROCs between 0.61 and 0.82 for the TXA cohort, with the coefficient updated Lab model achieving the highest at 0.84. Unfavorable outcomes had lower AUCs, ranging from 0.60 to 0.79. Similarly, in the PROTIPS cohort, AUCs for mortality ranged from 0.75 to 0.82, with the coefficient updated Lab model also showing superior performance (AUC 0.84). Unfavorable outcomes in this cohort presented AUCs from 0.67 to 0.73, consistently lower than mortality predictions. The closed testing procedure using likelihood ratio tests consistently identified the coefficient update model as superior, outperforming the original and recalibrated models across all cohorts. In our comprehensive evaluation of the IMPACT model, the coefficient updated models were the best performing across all cohorts through a structured closed testing procedure. Thus, standardization of model updating procedures is needed to reproducibly determine the best performing versions of IMPACT that reflect the specific characteristics of a dataset.

Despite representing a significant proportion of the U.S. population, there is a paucity of population-based research on the health status and health needs of sexual and gender minority (SGM) individuals in neurology. Compared with heterosexual peers, some SGM populations have a higher burden of chronic health conditions. In parallel, SGM individuals are more likely to experience stigma and discrimination producing psychological distress, which may contribute to and be compounded by reduced health care access and utilization. In this narrative review, we summarize the existing literature on common neurological health conditions such as stroke, headache, epilepsy, movement disorders, and traumatic brain injury through the lens of intersection of SGM identity. Special focus is attuned to social determinants of health and gender-affirming hormonal therapy. Given the limitations in the available literature, there is an urgent unmet need for datasets that include sexual orientation and gender identity information, as well as funding for research that will characterize the prevalence of neurological conditions, unique risk factors, and health outcomes in SGM populations. In the health care community, providers should address deficiencies in their professional training and integrate inclusive language into their clinical skillset to build trust with SGM patients. There is an opportunity in neurology to proactively engage SGM communities, collaborate to remove barriers to care, promote resilience, and develop targeted interventions to ensure high-quality, culturally competent care for SGM populations to improve neurological health for all., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: In patients with disorders of consciousness (DoC), laboratory and molecular biomarkers may help define endotypes, identify therapeutic targets, prognosticate outcomes, and guide patient selection in clinical trials. We performed a systematic review to identify common data elements (CDEs) and key design elements (KDEs) for future coma and DoC research., Methods: The Curing Coma Campaign Biospecimens and Biomarkers work group, composed of seven invited members, reviewed existing biomarker and biospecimens CDEs and conducted a systematic literature review for laboratory and molecular biomarkers using predetermined search words and standardized methodology. Identified CDEs and KDEs were adjudicated into core, basic, supplemental, or experimental CDEs per National Institutes of Health classification based on level of evidence, reproducibility, and generalizability across different diseases through a consensus process., Results: Among existing National Institutes of Health CDEs, those developed for ischemic stroke, traumatic brain injury, and subarachnoid hemorrhage were most relevant to DoC and included. KDEs were common to all disease states and included biospecimen collection time points, baseline indicator, biological source, anatomical location of collection, collection method, and processing and storage methodology. Additionally, two disease core, nine basic, 24 supplemental, and 59 exploratory biomarker CDEs were identified. Results were summarized and generated into a Laboratory Data and Biospecimens Case Report Form (CRF) and underwent public review. A final CRF version 1.0 is reported here., Conclusions: Exponential growth in biomarkers development has generated a growing number of potential experimental biomarkers associated with DoC, but few meet the quality, reproducibility, and generalizability criteria to be classified as core and basic biomarker and biospecimen CDEs. Identification and adaptation of KDEs, however, contribute to standardizing methodology to promote harmonization of future biomarker and biospecimens studies in DoC. Development of this CRF serves as a basic building block for future DoC studies., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Acute brain injury causes loss of functionality in patients that often is devastating. Predicting the degree of functional loss and overall prognosis requires a multifaceted approach to help patients, and more so their families, make important decisions regarding plans and goals of care. A variety of blood-based markers have been studied as one aspect of this determination. In this review, we discuss CNS-derived and systemic markers that have been studied for neuroprognostication purposes. We discuss the foundation of each protein, the conditions in which it has been studied, and how the literature has used these markers for interpretation. We also discuss challenges to using each marker in each section as well., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Systematic use of neurosurgical training simulators across institutions is significantly hindered by logistical and financial constraints., Objective: To evaluate feasibility of large-scale implementation of an intraoperative catastrophe simulation, we introduced a highly portable and low-cost immersive neurosurgical simulator into a nationwide curriculum for neurosurgery residents, during years 2016 to 2019., Methods: The simulator was deployed at 9 Society of Neurological Surgeons junior resident courses and a Congress of Neurological Surgeons education course for a cohort of 526 residents. Heart rate was tracked to monitor physiological responses to simulated stress. Experiential survey data were collected to evaluate simulator fidelity and resident attitudes toward simulation., Results: Residents rated the simulator positively with a statistically significant increase in satisfaction over time accompanying refinements in the simulator model and clinical scenario. The simulated complications induced stress-related tachycardia in most participants (n = 249); however, a cohort of participants was identified that experienced significant bradycardia (n = 24) in response to simulated stress., Conclusion: Incorporation of immersive neurosurgical simulation into the US national curriculum is logistically feasible and cost-effective for neurosurgical learners. Participant surveys and physiological data suggest that the simulation model recreates the situational physiological stress experienced during practice in the live clinical environment. Simulation may provide an opportunity to identify trainees with maladaptive responses to operative stress who could benefit from additional simulated exposure to mitigate stress impacts on performance., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Moderate/severe traumatic brain injury (TBI) causes injury patterns with heterogeneous pathology producing varying outcomes for recovery. Extracellular vesicles (EVs) are particles containing a myriad of molecules involved in cell signaling. EVs may hold promise as biomarkers in TBI because of their encapsulation, including improved stability/decreased degradation. A subset of subjects with and without TBI from a prospective, observational trial of critically ill trauma patients were analyzed. Total EV levels of glial (glial fibrillary acidic protein; GFAP) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], neurofilament light chain [NfL], and total-tau) proteins were measured using single-molecule array technology. Protein levels were winsorized to address outliers and log transformed for analysis. Patients with multiple injuries ( n  = 41) and isolated body injury ( n  = 73) were of similar age and sex. Patients with multiple injuries were, as expected, more severely injured with higher Injury Severity Scores (29 [26-41] vs. 21 [14-26], p  < 0.001) and lower Glasgow Coma Scale scores (12 [4-13] vs. 13 [13-13], p  < 0.001). Total body EVs of GFAP, UCH-L1, and NfL were higher in those with multiple injuries (1768 [932-4780] vs. 239 [63-589], p  < 0.001; 75.4 [47.8-158.3] vs. 41.5 [21.5-67.1], p  = 0.03; 7.5 [3.3-12.3] vs. 2.9 [2.1-4.8], p  < 0.001, respectively). There was a moderate correlation between the Head Abbreviated Injury Score and GFAP (free circulating rho = 0.62, EV rho = 0.64; both p  < 0.001). Brain-derived proteins contained in EV holds promise as an informative approach to biomarker measurement after TBI in hospitalized patients. Future evaluation and longitudinal studies are necessary to draw conclusions regarding the clinical utility of these biomarkers., Competing Interests: No competing financial interests exist., (© Vivian A. Guedes et al., 2022; Published by Mary Ann Liebert, Inc.)

Purpose of Review: Precision treatments to address the multifaceted pathophysiology of traumatic brain injury (TBI) are desperately needed, which has led to the intense study of fluid-based protein biomarkers in TBI. Mass Spectrometry (MS) is increasingly being applied to biomarker discovery and quantification in neurological disease to explore the proteome, allowing for more flexibility in biomarker discovery than commonly encountered antibody-based assays. In this narrative review, we will provide specific examples of how MS technology has advanced translational research in traumatic brain injury (TBI) focusing on clinical studies, and looking ahead to promising emerging applications of MS to the field of Neurocritical Care., Recent Findings: Proteomic biomarker discovery using MS technology in human subjects has included the full range of injury severity in TBI, though critically ill patients can offer more options to biofluids given the need for invasive monitoring. Blood, urine, cerebrospinal fluid, brain specimens, and cerebral extracellular fluid have all been sources for analysis. Emerging evidence suggests there are distinct proteomic profiles in radiographic TBI subtypes, and that biomarkers may be used to distinguish patients sustaining TBI from healthy controls. Metabolomics may offer a window into the perturbations of ongoing cerebral insults in critically ill patients after severe TBI., Summary: Emerging MS technologies may offer biomarker discovery and validation opportunities not afforded by conventional means due to its ability to handle the complexities associated with the proteome. While MS techniques are relatively early in development in the neurosciences space, the potential applications to TBI and neurocritical care are likely to accelerate in the coming decade., Competing Interests: Funding and/or Conflicts of interests/Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. Research reported in this publication was supported by the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health under Award Number K23NS110828. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Portions of this research were also supported by NIH NIGMS GM103493. Work was performed in the Environmental Molecular Sciences Laboratory, a U. S. Department of Energy Office of Biological and Environmental Research national scientific user facility located at Pacific Northwest National Laboratory in Richland, Washington. Pacific Northwest National Laboratory is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05–76RLO 1830.

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment., Competing Interests: Declaration of interests J.M.S. has a patent related to the study and serves on the Board of Directors for Remedy Pharmaceuticals. H.E.H., B.J.M., W.T.K., and K.N.S. received grants from Remedy Pharmaceuticals outside the submitted work. H.E.H., K.N.S., and W.T.K. received research grants from Biogen and the American Heart Association. W.T.K. received grants and personal fees from NControl Therapeutics outside the submitted work. K.N.S. received grants from Bard, Hyperfine, and Astrocyte outside the submitted work. H.E.H., B.J.M., J.M.S., and W.T.K. received personal fees from Biogen outside the submitted work. During the peer review process, Biogen had the opportunity to review the manuscript. The authors retained full editorial control of the manuscript and provided their final approval of all content., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To define clinical, radiographic, and blood-based biomarker features to be incorporated into a classification model of progression of intracranial hemorrhage (PICH), and to provide a pilot assessment of those models., Methods: Patients with hemorrhage on admission head computed tomography were identified from a prospectively enrolled cohort of subjects with traumatic brain injury. Initial and follow-up images were interpreted both by 2 independent readers, and disagreements adjudicated. Admission plasma samples were analyzed and principal components (PCs) composed of the immune proteins (IPs) significantly associated with the outcome of interest were selected for further evaluation. A series of logistic regression models were constructed based on (1) clinical variables (CV) and (2) clinical variables + immune proteins (CV+IP). Error rates of these models for correct classification of PICH were estimated; significance was set at P < .05., Results: We identified 106 patients, 36% had PICH. Dichotomized admission Glasgow Coma Scale (P = .004), Marshall score (P = .004), and 3 PCs were significantly associated with PICH. For the CV only model, sensitivity was 1.0 and specificity was 0.29 (95% CI, 0.07-0.67). The CV+IP model performed significantly better, with a sensitivity of 0.93 (95% CI, 0.64-0.99) and a specificity of 1.0 (P = .008). Adjustments to refine the definition of PICH and better define radiographic predictors of PICH did not significantly improve the models' performance., Conclusions: In this pilot investigation, we observed that composites of IPs may improve PICH classification models when combined with CVs. However, overall model performance must be further optimized; results will inform feature inclusion included in follow-up models., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Antibody mediated strategies for protein biomarker detection are common, but may limit discovery. We hypothesized that the use of antibody-free proteomics is feasible for detecting protein biomarkers in plasma of patients sustaining major trauma. A subset of subjects with major trauma from a prospective observational trial were analyzed. Patients were assigned to one of four groups based on their presenting Abbreviated Injury Severity Score (AIS). Sensitive, antibody-free selective reaction monitoring (SRM) mass spectrometry (MS), with spiked-in isotopically labeled synthetic peptides, was used for targeted protein quantification of a panel of 10 prospective targets. An overall tiered sensitivity analytical approach was used for peptide detection and quantification based upon plasma immunoaffinity depletion and PRISM fractionation. Forty-four patients were included in the analysis, of which 82% were men with a mean age of 50 (±19) years. Half had isolated head injury ( n  = 22), with the remaining patients experiencing multiple injuries or polytrauma ( n  = 14), isolated body injury ( n  = 2), or minor injury ( n  = 6). Peptides from 3 proteins (vascular adhesion molecule 1 [VCAM1], intercellular adhesion molecule 1 [ICAM1], and matrix metalloproteinase 9 [MMP9]) were detected and quantified in non-depleted processed plasma. Peptides from 2 proteins (angiopoietin 2 [Ang2] and plasminogen activator inhibitor-1 [PAI1]) were detected and quantification in depleted plasma, whereas the remaining 5 of the 10 prospective targets were undetected. VCAM1 ( p  = 0.02) and MMP9 ( p  = 0.03) were significantly upregulated in in the major trauma groups (1-3) versus mild injury group (4), whereas the others were not. There were no differences in protein expression between patients with traumatic brain injury (TBI; groups 1 and 2) versus those without TBI (groups 3 and 4). We detected non-specific upregulation of proteins reflecting blood-brain barrier breakdown in severely injured patients, indicating label-free MS techniques are feasible and may be informative., Competing Interests: No competing financial interests exist., (© H.E. Hinson et al., 2021; Published by Mary Ann Liebert, Inc.)

Purpose: To compare physicians' ability to read Alberta Stroke Program Early CT Score (ASPECTS) in patients with a large vessel occlusion within 6 hours of symptom onset when assisted by a machine learning-based automatic software tool, compared with their unassisted score., Materials and Methods: 50 baseline CT scans selected from two prior studies (CRISP and GAMES-RP) were read by 3 experienced neuroradiologists who were provided access to a follow-up MRI. The average ASPECT score of these reads was used as the reference standard. Two additional neuroradiologists and 6 non-neuroradiologist readers then read the scans both with and without assistance from the software reader-augmentation program and reader improvement was determined. The primary hypothesis was that the agreement between typical readers and the consensus of 3 expert neuroradiologists would be improved with software augmented vs. unassisted reads. Agreement was based on the percentage of the individual ASPECT regions (50 cases, 10 regions each; N=500) where agreement was achieved., Results: Typical non-neuroradiologist readers agreed with the expert consensus read in 72% of the 500 ASPECTS regions, evaluated without software assistance. The automated software alone agreed in 77%. When the typical readers read the scan in conjunction with the software, agreement improved to 78% (P<0.0001, test of proportions). The software program alone achieved correlations for total ASPECT scores that were similar to the expert readers who had access to the follow-up MRI scan to help enhance the quality of their reads., Conclusion: Typical readers had statistically significant improvement in their scoring of scans when the scan was read in conjunction with the automated software, achieving agreement rates that were comparable to neuroradiologists., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of early tranexamic acid (TXA) administration on circulating markers of endotheliopathy., Setting: Twenty trauma centers in the United States and Canada., Participants: Patients with moderate-to-severe traumatic brain injury (TBI) (MS-TBI) and intracranial hemorrhage who were not in shock (systolic blood pressure ≥90 mm Hg)., Design: TXA (2 g) or placebo administered prior to hospital arrival, less than 2 hours postinjury. Blood samples and head computed tomographic scan collected upon arrival. Plasma markers measured using Luminex analyte platform. Differences in median marker levels evaluated using t tests performed on log-transformed variables. Comparison groups were TXA versus placebo and less than 45 minutes versus 45 minutes or more from time of injury to treatment administration., Main Measures: Plasma levels of angiopoietin-1, angiopoietin-2, syndecan-1, thrombomodulin, thrombospondin-2, intercellular adhesion molecule 1, vascular adhesion molecule 1., Results: Demographics and Injury Severity Score were similar between the placebo (n = 129) and TXA (n = 158) groups. Levels of syndecan-1 were lower in the TXA group (median [interquartile range or IQR] = 254.6 pg/mL [200.7-322.0] vs 272.4 pg/mL [219.7-373.1], P = .05. Patients who received TXA less than 45 minutes postinjury had significantly lower levels of angiopoietin-2 (median [IQR] = 144.3 pg/mL [94.0-174.3] vs 154.6 pg/mL [110.4-209.8], P = .05). No differences were observed in remaining markers., Conclusions: TXA may inhibit early upregulation of syndecan-1 and angiopoietin-2 in patients with MS-TBI, suggesting attenuation of protease-mediated vascular glycocalyx breakdown. The findings of this exploratory analysis should be considered preliminary and require confirmation in future studies.

Background: Early identification of traumatic intracranial hemorrhage (ICH) has implications for triage and intervention. Blood-based biomarkers were recently approved by the Food and Drug Administration (FDA) for prediction of ICH in patients with mild traumatic brain injury (TBI). We sought to determine if biomarkers measured early after injury improve prediction of mortality and clinical/radiologic outcomes compared with Glasgow Coma Scale (GCS) alone in patients with moderate or severe TBI (MS-TBI)., Methods: We measured glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) on arrival to the emergency department (ED) in patients with blunt TBI enrolled in the placebo arm of the Prehospital TXA for TBI Trial (prehospital GCS score, 3-12; SPB, > 90). Biomarkers were modeled individually and together with prehospital predictor variables [PH] (GCS score, age, sex). Data were divided into a training data set and test data set for model derivation and evaluation. Models were evaluated for prediction of ICH, mass lesion, 48-hour and 28-day mortality, and 6-month Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). Area under the curve (AUC) was evaluated in test data for PH alone, PH + individual biomarkers, and PH + three biomarkers., Results: Of 243 patients with baseline samples (obtained a median of 84 minutes after injury), prehospital GCS score was 8 (interquartile range, 5-10), 55% had ICH, and 48-hour and 28-day mortality were 7% and 13%, respectively. Poor neurologic outcome at 6 months was observed in 34% based on GOS-E of 4 or less, and 24% based on DRS greater than or equal to7. Addition of each biomarker to PH improved AUC in the majority of predictive models. GFAP+PH compared with PH alone significantly improved AUC in all models (ICH, 0.82 vs. 0.64; 48-hour mortality, 0.84 vs. 0.71; 28-day mortality, 0.84 vs. 0.66; GOS-E, 0.78 vs. 0.69; DRS, 0.84 vs. 0.81, all p < 0.001)., Conclusion: Circulating blood-based biomarkers may improve prediction of neurological outcomes and mortality in patients with MS-TBI over prehospital characteristics alone. Glial fibrillary acidic protein appears to be the most promising. Future evaluation in the prehospital setting is warranted., Level of Evidence: Prospective, Prognostic and Epidemiological, level II.

Background/objective: Malignant edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo., Methods: GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by "osmolar load". Radiographic edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a., Results: Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27-55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146-211] mL v. 139 [112-170] mL; P=0.046). Adjudicated malignant edema (75% v. 16%; P<0.001) was more common in the osmotherapy treated group. There were no differences in the proportion of patients receiving osmotherapy or the median total osmolar load between treatment arms. Most patients (76%) had a decrease in consciousness (NIHSS item 1A ≥1) on the day they began receiving osmotherapy., Conclusions: In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined., Competing Interests: Declaration of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background and Purpose- We compared the Alberta Stroke Program Early CT Score (ASPECTS), calculated using a machine learning-based automatic software tool, RAPID ASPECTS, as well as the median score from 4 experienced readers, with the diffusion-weighted imaging (DWI) ASPECTS obtained following the baseline computed tomography (CT) in patients with large hemispheric infarcts. Methods- CT and magnetic resonance imaging scans from the GAMES-RP study, which enrolled patients with large hemispheric infarctions (82-300 mL) documented on DWI-magnetic resonance imaging, were evaluated by blinded experienced readers to determine both CT and DWI ASPECTS. The CT scans were also evaluated by an automated software program (RAPID ASPECTS). Using the DWI ASPECTS as a reference standard, the median CT ASPECTS of the clinicians and the automated score were compared using the interclass correlation coefficient. Results- The median CT ASPECTS for the clinicians was 5 (interquartile range, 4-7), for RAPID ASPECTS 3 (interquartile range, 1-6), and for DWI ASPECTS 3 (2-4). Median error for RAPID ASPECTS was 1 (interquartile range, -1 to 3) versus 3 (interquartile range, 1-4) for clinicians ( P <0.001). The automated score had a higher level of agreement with the median of the DWI ASPECTS, both for the full scale and when dichotomized at <6 versus 6 or more (difference in intraclass correlation coefficient, P =0.001). Conclusions- RAPID ASPECTS was more accurate than experienced clinicians in identifying early evidence of brain ischemia as documented by DWI.

Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20-0.26; P <0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (β=-2.80; 95% CI, -5.07 to -0.53; P =0.016) and reduced MLS (β=-1.50; 95% CI, -2.71 to -0.28; P =0.016). Treatment with intravenous glibenclamide reduced both gray and white matter water uptake. In mediation analysis, gray matter NWU (β=0.15; 95% CI, 0.11-0.20; P <0.001) contributed to a greater proportion of MLS mass effect, as compared with white matter NWU (β=0.08; 95% CI, 0.03-0.13; P =0.001). Conclusions- In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

Objective: To measure the attitudes and knowledge of American Academy of Neurology (AAN) member neurologists in caring for sexual and gender minority (SGM) patients (e.g., those who identify in the lesbian, gay, bisexual, transgender, queer, or questioning [LGBTQ+] spectrum) to inform future educational offerings., Methods: A questionnaire was created in an iterative process by the LGBTQ+ Survey Task Force, consisting of 21 questions examining self-reported knowledge, attitudes, and clinical preparedness in caring for SGM patients. Participants responded to each statement with a 5-point Likert scale ("strongly disagree" to "strongly agree"). The survey was distributed via electronic and conventional mail to a random, representative sample of 1,000 AAN members., Results: The response rate was 13.5% (n = 135). Most respondents (60%-66%) were aware of local and national barriers that inhibit SGM individuals from using health care services; the majority (73%-91%) felt comfortable assessing SGM patients. Over half believed sexual orientation (SO) and gender identity (GI) to be social determinants of health (61% and 57%, respectively). Yet a third would not tailor neurologic care based on a patient's SGM identity, and 43% believed that SO/GI has no bearing on the management of neurologic illness., Conclusions: Most neurologists surveyed were aware of overarching barriers to care experienced by SGM individuals; however, a minority of respondents recognized the intersection of SGM identity with neurologic health. Our results highlight awareness gaps that could be addressed via targeted educational opportunities, ensuring that neurologists provide high-quality neurologic care to patients of all sexual orientations and gender identities., (© 2019 American Academy of Neurology.)

Purpose of Review: Chimeric antigen receptor T cell (CAR-T) adoptive cell therapy is an effective treatment for patients with refractory B cell malignancies. As its use has grown, there has been an increase in the incidence of a serious, potentially fatal neurotoxicity known as immune effector cell-associated neurotoxicity syndrome (ICANS). This review discusses the clinical manifestations of this neurotoxicity syndrome, current grading systems, management strategies, and proposed biologic mechanisms leading to neurotoxicity., Recent Findings: Current research suggests that patients with a higher disease burden and higher CAR-T cell doses are positively associated with the development of ICANS, as are elevated serum levels of proinflammatory cytokines and the presence of cytokine release syndrome (CRS). While patterns observed on neuroimaging and electroencephalogram (EEG) are non-specific for the diagnosis of ICANS, each modality may provide helpful clinical information such as the detection of cerebral edema, the most serious of associated symptoms. Anti-epileptic medications and corticosteroids may ameliorate the symptoms of ICANS. The mechanism for ICANS is currently unknown; however, systemic inflammation and cytokine production triggering a cascade of endothelial activation and BBB disruption likely contribute. With limited treatment options available, further clinical research into the precise mechanism and treatment is urgently needed as the use of CAR-T and other adoptive cell therapies continues to grow.

Objective: In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints., Methods: Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined., Results: In the per-protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift ( p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels ( p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of ≥4 during the infusion period (n = 7 [37%] in IV glyburide vs n = 12 [71%] in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016)., Conclusion: IV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings., Clinicaltrialsgov Identifier: NCT01794182., Level of Evidence: This study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints., (© 2018 American Academy of Neurology.)

Background: We sought to determine the outcome of suicidal hanging and the impact of targeted temperature management (TTM) on hanging-induced cardiac arrest (CA) through an Eastern Association for the Surgery of Trauma (EAST) multicenter retrospective study., Methods: We analyzed hanging patient data and TTM variables from January 1992 to December 2015. Cerebral performance category score of 1 or 2 was considered good neurologic outcome, while cerebral performance category score of 3 or 4 was considered poor outcome. Classification and Regression Trees recursive partitioning was used to develop multivariate predictive models for survival and neurologic outcome., Results: A total of 692 hanging patients from 17 centers were analyzed for this study. Their overall survival rate was 77%, and the CA survival rate was 28.6%. The CA patients had significantly higher severity of illness and worse outcome than the non-CA patients. Of the 175 CA patients who survived to hospital admission, 81 patients (46.3%) received post-CA TTM. The unadjusted survival of TTM CA patients (24.7% vs 39.4%, p < 0.05) and good neurologic outcome (19.8% vs 37.2%, p < 0.05) were worse than non-TTM CA patients. However, when subgroup analyses were performed between those with an admission Glasgow Coma Scale score of 3 to 8, the differences between TTM and non-TTM CA survival (23.8% vs 30.0%, p = 0.37) and good neurologic outcome (18.8% vs 28.7%, p = 0.14) were not significant. Targeted temperature management implementation and post-CA management varied between the participating centers. Classification and Regression Trees models identified variables predictive of favorable and poor outcome for hanging and TTM patients with excellent accuracy., Conclusion: Cardiac arrest hanging patients had worse outcome than non-CA patients. Targeted temperature management CA patients had worse unadjusted survival and neurologic outcome than non-TTM patients. These findings may be explained by their higher severity of illness, variable TTM implementation, and differences in post-CA management. Future prospective studies are necessary to ascertain the effect of TTM on hanging outcome and to validate our Classification and Regression Trees models., Level of Evidence: Therapeutic study, level IV; prognostic study, level III.

Background and Purpose: We aimed to determine whether subjects aged ≤70 years who were treated with intravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo., Methods: GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82-300 cm 3 ) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood-brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift)., Results: Participants ≤70 years of age treated with intravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P =0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P =0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index ( P =0.03) and EuroQol group 5-dimension ( P =0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P <0.001) and decreased midline shift (4.7 versus 9 mm; P <0.001) compared with participants who received placebo., Conclusions: In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182., (© 2018 American Heart Association, Inc.)

Background: Fever is strongly associated with poor outcome after traumatic brain injury (TBI). We hypothesized that early fever is a direct result of brain injury and thus would be more common in TBI than in patients without brain injury and associated with inflammation., Methods: We prospectively enrolled patients with major trauma with and without TBI from a busy Level I trauma center intensive care unit (ICU). Patients were assigned to one of four groups based on their presenting Head Abbreviated Injury Severity Scale scores: multiple injuries: head Abbreviated Injury Scale (AIS) score greater than 2, one other region greater than 2; isolated head: head AIS score greater than 2, all other regions less than 3; isolated body: one region greater than 2, excluding head/face; minor injury: no region with AIS greater than 2. Early fever was defined as at least one recorded temperature greater than 38.3°C in the first 48 hours after admission. Outcome measures included neurologic deterioration, length of stay in the ICU, hospital mortality, discharge Glasgow Outcome Scale-Extended, and plasma levels of seven key cytokines at admission and 24 hours (exploratory)., Results: Two hundred sixty-eight patients were enrolled, including subjects with multiple injuries (n = 59), isolated head (n = 97), isolated body (n = 100), and minor trauma (n = 12). The incidence of fever was similar in all groups irrespective of injury (11-24%). In all groups, there was a significant association between the presence of early fever and death in the hospital (6-18% vs. 0-3%), as well as longer median ICU stays (3-7 days vs. 2-3 days). Fever was significantly associated with elevated IL-6 at admission (50.7 pg/dL vs. 16.9 pg/dL, p = 0.0067) and at 24 hours (83.1 pg/dL vs. 17.1 pg/dL, p = 0.0025) in the isolated head injury group., Conclusion: Contrary to our hypothesis, early fever was not more common in patients with brain injury, though fever was associated with longer ICU stays and death in all groups. Additionally, fever was associated with elevated IL-6 levels in isolated head injury., Level of Evidence: Prognostic and Epidemiological study, level III.

Severe traumatic brain injury (sTBI) is a major contributor to long-term disability and a leading cause of death worldwide. Medical management of the sTBI patient, beginning with prehospital triage, is aimed at preventing secondary brain injury. This review discusses prehospital and emergency department management of sTBI, as well as aspects of TBI management in the intensive care unit where advances have been made in the past decade. Areas of emphasis include intracranial pressure management, neuromonitoring, management of paroxysmal sympathetic hyperactivity, neuroprotective strategies, prognostication, and communication with families about goals of care. Where appropriate, differences between the third and fourth editions of the Brain Trauma Foundation guidelines for the management of severe traumatic brain injury are highlighted.

Traumatic brain injury (TBI) is a serious health care problem on both individual and public health levels. As a major cause of death and disability in the United States, it is associated with a significant economic and public health burden. Although the evidence to support the use of induced hypothermia on neurologic outcome after cardiac arrest is well established, its use in treating TBI remains controversial. Hypothermia has the potential to mitigate some of the destructive processes that occur as part of secondary brain injury after TBI. Hypothermia can be helpful in lowering intracranial pressure, for example, but its influence on functional outcome is unclear. There is insufficient evidence to support the broad use of prophylactic hypothermia for neuroprotection after TBI. Investigators are beginning to more carefully select patients for temperature modulating therapies, in a more personalized approach. Examples include targeting immunomodulation and scaling hypothermia to achieve metabolic targets. This review will summarize the clinical evidence for the use of hypothermia to limit secondary brain injury following acute TBI., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: Paroxysmal sympathetic hyperactivity (PSH) is characterized by episodic, hyperadrenergic alterations in vital signs after traumatic brain injury (TBI). We sought to apply an objective scale to the vital sign alterations of PSH in order to determine whether 1 element might be predictive of developing PSH., Setting/participants/design: We conducted an observational study of consecutive TBI patients (Glasgow Coma Scale score ≤12) and monitored the cohort for clinical evidence of PSH. PSH was defined as a paroxysm of 3 or more of the following characteristics: (1) tachycardia, (2) tachypnea, (3) hypertension, (4) fever, (5) dystonia (rigidity or decerebrate posturing), and (6) diaphoresis, with no other obvious causation (ie, alcohol withdrawal, sepsis)., Main Measures: The Modified Clinical Feature Severity Scale (mCFSS) was applied to each participant once daily for the first 5 days of hospitalization., Results: Nineteen (11%) of the 167 patients met criteria for PSH. Patients with PSH had a higher 5-day cumulative mCFSS score than those without PSH (median [interquartile range] = 36 [29-42] vs 29 [22-35], P = .01). Of the 4 components of the mCFSS, elevated temperature appeared to be most predictive of the development of PSH, especially during the first 24 hours (odds ratio = 1.95; 95% confidence interval, 1.12-3.40)., Conclusion: Early fever after TBI may signal impending autonomic dysfunction.

Object: Deep vein thrombosis (DVT) is a common complication of aneurysmal subarachnoid hemorrhage (aSAH). The time period of greatest risk for developing DVT after aSAH is not currently known. aSAH induces a prothrombotic state, which may contribute to DVT formation. Using repeated ultrasound screening, the hypothesis that patients would be at greatest risk for developing DVT in the subacute post-rupture period was tested., Methods: One hundred ninety-eight patients with aSAH admitted to the Oregon Health & Science University Neurosciences Intensive Care Unit between April 2008 and March 2012 were included in a retrospective analysis. Ultrasound screening was performed every 5.2 ± 3.3 days between admission and discharge. The chi-square test was used to compare DVT incidence during different time periods of interest. Patient baseline characteristics as well as stroke severity and hospital complications were evaluated in univariate and multivariate analyses., Results: Forty-two (21%) of 198 patients were diagnosed with DVT, and 3 (2%) of 198 patients were symptomatic. Twenty-nine (69%) of the 42 cases of DVT were first detected between Days 3 and 14, compared with 3 cases (7%) detected between Days 0 and 3 and 10 cases (24%) detected after Day 14 (p < 0.05). The postrupture 5-day window of highest risk for DVT development was between Days 5 and 9 (40%, p < 0.05). In the multivariate analysis, length of hospital stay and use of mechanical prophylaxis alone were significantly associated with DVT formation., Conclusions: DVT formation most commonly occurs in the first 2 weeks following aSAH, with detection in this cohort peaking between Days 5 and 9. Chemoprophylaxis is associated with a significantly lower incidence of DVT.

Moderate and severe traumatic brain injury (TBI) is the leading cause of morbidity and mortality among young individuals in high-income countries. Its pathophysiology is divided into two major phases: the initial neuronal injury (or primary injury) followed by secondary insults (secondary injury). Multimodality monitoring now offers neurointensivists the ability to monitor multiple physiologic parameters that act as surrogates of brain ischemia and hypoxia, the major driving forces behind secondary brain injury. The heterogeneity of the pathophysiology of TBI makes it necessary to take into consideration these interacting physiologic factors when recommending for or against any therapies; it may also account for the failure of all the neuroprotective therapies studied so far. In this review, the authors focus on neuroclinicians and neurointensivists, and discuss the developments in therapeutic strategies aimed at optimizing intracranial pressure and cerebral perfusion pressure, and minimizing cerebral hypoxia. The management of moderate to severe TBI in the intensive care unit is moving away from a pure "threshold-based" treatment approach toward consideration of patient-specific characteristics, including the state of cerebral autoregulation. The authors also include a concise discussion on the management of medical and neurologic complications peculiar to TBI as well as an overview of prognostication., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Despite advances in both prevention and treatment, traumatic brain injury (TBI) remains one of the most burdensome diseases; 2% of the US population currently lives with disabilities resulting from TBI. Recent advances in the understanding of inflammation and its impact on the pathophysiology of trauma have increased the interest in inflammation as a possible mediator in TBI outcome., Objectives: The goal of this systematic review is to address the question: "What is the evidence in humans that inflammation is linked to secondary brain injury?" As the experimental evidence has been well described elsewhere, this review will focus on the clinical evidence for inflammation as a mechanism of secondary brain injury., Data Sources: Medline database (1996-Week 1 June 2014), Pubmed and Google Scholar databases were queried for relevant studies., Study Eligibility Criteria: Studies were eligible if participants were adults and/or children who sustained moderate or severe TBI in the acute phase of injury, published in English. Studies published in the last decade (since 2004) were preferentially included. Trials could be observational or interventional in nature., Appraisal and Synthesis Methods: To address the quality of the studies retrieved, we applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria to assess the limitations of the included studies., Results: Trauma initiates local central nervous system as well as systemic immune activation. Numerous observational studies describe elevation of pro-inflammatory cytokines that are associated with important clinical variables including neurologic outcome and mortality. A small number of clinical trials have included immunomodulating strategies, but no intervention to date has proven effective in improving outcomes after TBI., Limitations: Inclusion of studies not initially retrieved by the search terms may have biased our results. Additionally, some reports may have been inadvertently excluded due to use of non-search term key words. Conclusions and Implications of Key Findings Clinical evidence of inflammation causing secondary brain injury in humans is gaining momentum. While inflammation is certainly present, it is not clear from the literature at what juncture inflammation becomes maladaptive, promoting secondary injury rather than facilitating repairand identifying patients with maladaptive inflammation (neuro-inflammation, systemic, or both) after TBI remains elusive. Direct agonism/antagonism represents an exciting target for future study., Level of Evidence: Systematic review, level III.

Primary Objective: Paroxysmal sympathetic hyperactivity (PSH) is observed in a sub-set of patients with moderate-to-severe traumatic brain injury (TBI). The neuroanatomical basis of PSH is poorly understood. It is hypothesized that PSH is linked to changes in connectivity within the central autonomic network., Research Design: Retrospective analysis in a sub-set of patients from a multi-centre, prospective cohort study Methods and procedures: Adult patients who were <3 weeks after severe TBI were enrolled and screened for PSH using a standard definition. Patients underwent multimodal MRI, which included quantitative diffusion tensor imaging., Main Outcomes and Results: Principal component analysis (PCA) was used to resolve the set of tracts into components. Ability to predict PSH was evaluated via area under the receiver operating characteristic (AUROC) and tree-based classification analyses. Among 102 enrolled patients, 16 met criteria for PSH. The first principle component was significantly associated (p = 0.024, AUROC = 0.867) with PSH status even after controlling for age and admission GCS. In a classification tree analysis, age, GCS and decreased FA in the splenium of the corpus callosum and in the right posterior limb of the internal capsule discriminated PSH vs no PSH with an AUROC of 0.933., Conclusions: Disconnection involving the posterior corpus callosum and of the posterior limb of the internal capsule may play a role in the pathogenesis or expression of PSH.