Journal of Neurotrauma

Sleep disturbances are commonly reported in children with persistent post-concussion symptoms (PPCS). Melatonin treatment is often recommended, yet supporting evidence is scarce. We aimed to evaluate the efficacy of treatment with melatonin for sleep disturbance in youth with PPCS following mild traumatic brain injury (mTBI). This article is a secondary analysis of a clinical trial of melatonin compared with placebo to treat PPCS. Youth (8–18 years of age) with PPCS and significant sleep-related problems (SRPs) at 4–6 weeks post-injury were eligible. Exclusion criteria: significant medical/psychiatric history; previous concussion/mTBI within 3 months. Treatment groups were: placebo, melatonin 3 mg, or melatonin 10 mg. Primary outcome was change in SRPs measured using the Post-Concussion Symptom Inventory (PCSI) after 2 weeks of treatment. Secondary outcomes included change in actigraphy sleep efficiency, duration, onset latency, and wake-after-sleep-onset. Behavior was measured using Behaviour Assessment for Children (2nd edition). Seventy-two participants (mean age 14.0, standard deviation [SD] = 2.6) years; 60% female) with PPCS and significant sleep disturbance were included in the secondary analysis: placebo (n = 22); melatonin 3 mg (n = 25); melatonin 10 mg (n = 25). Sixty-four participants had actigraphy data. SRPs decreased across all groups over time with a significant effect of melatonin 3 mg (3.7; 95% confidence interval [CI]: 2.1, 5.4) compared with placebo (7.4; 95% CI: 4.2, 10.6) and melatonin 10 mg (6.4; 95% CI: 3.6, 9.2). Sleep duration increased in the melatonin 3 mg (43 min; 95% CI: 6, 93) and melatonin 10 mg groups (55 min; 95% CI: 5, 104) compared with placebo. A per protocol analysis demonstrated improved sleep efficiency in the melatonin 10 mg group (p = 0.029). No serious adverse events were reported. Depressive symptoms significantly decreased with melatonin 3 mg (-4.7; 95% CI: −9.2, −.2) but not with melatonin 10 mg (−1.4, 95% CI: −5.9, 3.2) treatment compared with placebo. Changes in cognition or behavior were otherwise not significantly different between treatment groups. Short-term melatonin is a well-tolerated treatment for sleep disturbance in youth with PPCS following mTBI. In this context, it may also be associated with a reduction in depressive symptoms.

Progression of intracranial hemorrhage (PICH) is a significant cause of secondary brain injury in patients with traumatic brain injury (TBI). Previous studies have implicated a variety of mediators that contribute to PICH. We hypothesized that patients with PICH would display either a hypocoagulable state, hyperfibrinolysis, or both. We conducted a prospective study of adult trauma patients with isolated TBI. Blood was obtained for routine coagulation assays, platelet count, fibrinogen, thrombelastography, markers of thrombin generation, and markers of fibrinolysis at admission and 6, 12, 24, and 48 h. Univariate analyses were performed to compare baseline characteristics between groups. Linear regression models were created, adjusting for baseline differences, to determine the relationship between individual assays and PICH. One hundred forty-one patients met entry criteria, of whom 71 had hemorrhage progression. Patients with PICH had a higher Injury Severity Score and Abbreviated Injury Scale score (head), a lower Glasgow Coma Scale score, and lower plasma sodium on admission. Patients with PICH had higher D-dimers on admission. After adjusting for baseline differences, elevated D-dimers remained significantly associated with PICH compared to patients without PICH at admission. Hypocoagulation was not significantly associated with PICH in these patients. The association between PICH and elevated D-dimers early after injury suggests that fibrinolytic activation may contribute to PICH in patients with TBI.

Although concussions can result in persistent neurological post-concussion symptoms, they are typically invisible on routine magnetic resonance imaging (MRI) scans. Our study aimed to investigate the use of ultra-high-field diffusion tensor imaging (UHF-DTI) in discerning severity-dependent microstructural changes in the mouse brain following a concussion. Twenty-three C57BL/6 mice were randomly allocated into three groups: the low concussive (LC, n = 9) injury group, the high concussive (HC, n = 6) injury group, and the sham control (SC, n = 7) group. Mice were perfused on day 2 post-injury, and the brains were scanned on a 16.4T MRI scanner with UHF-DTI and neurite orientation dispersion imaging (NODDI). Finite element analysis (FEA) was performed to determine the pattern and extent of the physical impact on the brain tissue. MRI findings were correlated with histopathological analysis in a subset of mice. In the LC group, increased fractional anisotropy (FA) and decreased orientation dispersion index (ODI) but limited neurite density index (NDI) changes were found in the gray matter, and minimal changes to white matter (WM) were observed. The HC group presented increased mean diffusivity (MD), decreased NDI, and decreased ODI in the WM and gray matter (GM); decreased FA was also found in a small area of the WM. WM changes were associated with WM degeneration and neuroinflammation. FEA showed varying region-dependent degrees of stress, in line with the different imaging findings. This study provides evidence that UHF-DTI combined with NODDI can detect concussions of variable intensities. This has significant implications for the diagnosis of concussion in humans.

The topic of potential long-term neurological consequences from having multiple concussions during a career in collision sports is controversial. We sought to investigate white matter microstructure using diffusion tensor imaging (DTI) in retired professional Australian National Rugby League (NRL) players (n = 11) with a history of multiple self-reported concussions compared with age- and education-matched controls (n = 13) who have had no history of brain trauma. Diffusion-weighted images were acquired with a Siemens 3T scanner. All participants completed a clinical interview. There were no significant differences between groups on measures of depression, anxiety, stress, or post-concussion symptoms; however, NRL players scored significantly higher on the alcohol use disorder identification test (AUDIT). Voxelwise analyses of DTI measures were performed using tract-based spatial statistics (TBSS) with age and AUDIT scores included as covariates. TBSS revealed significantly reduced fractional anisotropy (FA), and increased radial diffusivity (RD), axial diffusivity (AD), and trace (TR) in white matter regions of recently retired NRL players compared with controls. FA was significantly reduced in the right superior longitudinal fasciculus and right corticospinal tract while TR, RD, and AD were increased in these regions, as well as the corpus callosum, forceps major, right uncinate fasciculus, and left corticospinal tract. In summary, DTI in a small cohort of recently retired professional NRL players with a history of multiple concussions showed differences in white matter microstructure compared with age- and education-matched controls with no history of brain trauma.

Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in patients under the age of 46 years. Survivors of the initial injury often endure systemic complications such as pulmonary infection, and Pseudomonas aeruginosa is one of the most common causes of nosocomial pneumonia in intensive care units. Female patients are less likely to develop secondary pneumonia after TBI, and pre-clinical studies have revealed a salutary role for estrogen after trauma. Therefore, we hypothesized that female mice would experience less mortality after post-TBI pneumonia with P. aeruginosa. We employed a mouse model of TBI followed by P. aeruginosa pneumonia. Male mice had greater mortality and impaired lung bacterial clearance after post-TBI pneumonia compared with female mice. This was confirmed as a difference in sex hormones, as oophorectomized wild-type mice had mortality and lung bacterial clearance similar to male mice. There were differences in tumor necrosis factor-α secretion in male and female alveolar macrophages after P. aeruginosa infection. Finally, injection of male or oophorectomized wild-type female mice with estrogen restored lung bacterial clearance and prevented mortality. Our model of TBI followed by P. aeruginosa pneumonia is among the first to reveal sex dimorphism in secondary, long-term TBI complications.

A diagnosis of traumatic brain injury (TBI) is typically based on patient medical history, a clinical examination, and imaging tests. Elevated plasma levels of glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NFL) have been observed in numerous studies of TBI patients. It is reasonable to view traumatic optic neuropathy (TON) as a focal form of TBI. The purpose of this study was to assess if circulating GFAP, UCH-L1, and NFL are also elevated in a porcine model of TON. Serum levels of GFAP, UCH-L1, and NFL were measured immediately before optic nerve crush and 1 h post-injury in 10 Yucatan minipigs. Severity of optic nerve crush was confirmed by visual inspection of the optic nerve at time of injury, loss of visual function as measured by flash visual evoked potential (fVEP) at 7 and 14 days, and histological analysis of axonal transport of cholera toxin-β (CT-β) within the optic nerve. Post-crush concentrations of GFAP, UCH-L1, and NFL were all significantly elevated compared with pre-crush concentrations (p < 0.01, p = 0.01, and p < 0.01, respectively). The largest increase was observed for GFAP with the post-injury median concentration increasing nearly sevenfold. The use of these TBI biomarkers for diagnosing and managing TON may be helpful for non-ophthalmologists in particular in diagnosing this condition. In addition, the potential utility of these biomarkers for diagnosing other optic nerve and/or retinal pathologies should be evaluated.

Anxiety outcomes after traumatic brain injury (TBI) are complex, and the underlying neural mechanisms are poorly understood. Here, we developed a multi-dimensional behavioral profiling approach to investigate anxiety-like outcomes in mice that takes into account individual variability. Departing from the tradition of comparing outcomes in TBI versus sham groups, we identified a subgroup within the TBI group that is vulnerable to anxiety dysfunction, and present increased exploration of the anxiogenic zone compared to sham controls or resilient injured animals, by applying dimensionality reduction, clustering, and post hoc validation to behavioral data obtained from multiple assays for anxiety at several post-injury time points. These vulnerable animals expressed distinct molecular profiles in the corticolimbic network, with downregulation in gamma-aminobutyric acid and glutamate and upregulation in neuropeptide Y markers. Indeed, among vulnerable animals, not resilient or sham controls, severity of anxiety-related outcomes correlated strongly with expression of molecular markers. Our results establish a foundational approach, with predictive power, for reliably identifying maladaptive anxiety outcomes after TBI and uncovering neural signatures of vulnerability to anxiety.

Head injury models are notoriously time consuming and resource demanding in simulations, which prevents routine application. Here, we extend a convolutional neural network (CNN) to instantly estimate element-wise distribution of peak maximum principal strain (MPS) of the entire brain (>36 k speedup accomplished on a low-end computing platform). To achieve this, head impact rotational velocity and acceleration temporal profiles are combined into two-dimensional images to serve as CNN input for training and prediction of MPS. Compared with the directly simulated counterparts, the CNN-estimated responses (magnitude and distribution) are sufficiently accurate for 92.1% of the cases via 10-fold cross-validation using impacts drawn from the real world (n = 5661; range of peak rotational velocity in augmented data extended to 2–40 rad/sec). The success rate further improves to 97.1% for “in-range” impacts (n = 4298). When using the same CNN architecture to train (n = 3064) and test on an independent, reconstructed National Football League (NFL) impact dataset (n = 53; 20 concussions and 33 non-injuries), 51 out of 53, or 96.2% of the cases, are sufficiently accurate. The estimated responses also achieve virtually identical concussion prediction performances relative to the directly simulated counterparts, and they often outperform peak MPS of the whole brain (e.g., accuracy of 0.83 vs. 0.77 via leave-one-out cross-validation). These findings support the use of CNN for accurate and efficient estimation of spatially detailed brain strains across the vast majority of head impacts in contact sports. Our technique may hold the potential to transform traumatic brain injury (TBI) research and the design and testing standards of head protective gears by facilitating the transition from acceleration-based approximation to strain-based design and analysis. This would have broad implications in the TBI biomechanics field to accelerate new scientific discoveries. The pre-trained CNN is freely available online at https://github.com/Jilab-biomechanics/CNN-brain-strains.

Concussion imaging research has primarily focused on neuronal disruption with lesser emphasis directed toward vascular dysfunction. However, blood flow metrics may be more sensitive than measures of neuronal integrity. Vascular dysfunction can be assessed by measuring cerebrovascular reactivity (CVR)—the change in cerebral blood flow per unit change in vasodilatory stimulus. CVR metrics, including speed and magnitude of flow responses to a standardized well-controlled vasoactive stimulus, are potentially useful for assessing individual subjects following concussion given that blood flow dysregulation is known to occur with traumatic brain injury. We assessed changes in CVR metrics to a standardized vasodilatory stimulus during the acute phase of concussion. Using a case control design, 20 concussed participants and 20 healthy controls (HCs) underwent CVR assessment measuring blood oxygen–level dependent (BOLD) magnetic resonance imaging using precise changes in end-tidal partial pressure of CO₂ (PETCO₂). Metrics were calculated for the whole brain, gray matter (GM), and white matter (WM) using sex-stratification. A leave-one-out receiver operating characteristic (ROC) analysis classified concussed from HCs based on CVR metrics. CVR magnitude was greater and speed of response faster in concussed participants relative to HCs, with WM showing higher classification accuracy compared with GM. ROC analysis for WM-CVR metrics revealed an area under the curve of 0.94 in males and 0.90 in females for speed and magnitude of response respectively. These greater than normal responses to a vasodilatory stimulus warrant further investigation to compare the predictive ability of CVR metrics against structural injury metrics for diagnosis and prognosis in acute concussion.

Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1422 patients with TBI and 170 orthopedic trauma controls (OTC) from the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6 months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising, brief, phone-based cognitive screening tool for patients with TBI. Although the BTACT's memory items appear to index verbal Episodic Memory, items that purport to assess EFs may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.

Most individuals with traumatic brain injury (TBI) experience a period of confusion after emergence from coma, termed post-traumatic amnesia, post-traumatic confusional state, or delirium. Recent guidelines suggest the importance of assessment and consistent management during this phase, but current practice worldwide remains unknown. This survey aimed to elucidate current international practice in assessment and treatment of patients in the acute stages of recovery after TBI. The web-based survey was distributed to clinicians working with patients with acute TBI. There were 400 participants (68.8% females), from 41 countries, mostly neuropsychologists, rehabilitation physicians, and occupational therapists (OTs), with an average 12.8 years of experience. Of those working with adults (n = 376, 94%), most described this acute period as post-traumatic amnesia and used its duration to indicate injury severity. More than 85% used a tool to assess patients; in order of frequency, the Glasgow Coma Scale (GCS), Westmead PTA Scale (WPTAS), Galveston Orientation and Amnesia Test, Rancho Los Amigos Scale, and O-Log. Meeting criteria on the assessment tool or clinical judgment determined emergence from this phase, indicated by recovery of orientation, day-to-day memories, and ability to follow commands or participate in rehabilitation. Most patients had physiotherapy, OT, speech therapy, and environmental changes, with a third of participants indicating sedating medication was prescribed during this phase. Findings suggest that, consistent with guidelines, PTA is a widely recognized and measured TBI recovery phase, used to determine injury severity and readiness for therapy.

Living systematic reviews (LSRs) are online summaries of health care research that are updated as new research becomes available. This new development in evidence synthesis is being trialled as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) project. We will develop and sustain an international TBI knowledge community that maintains up-to-date, high quality LSRs of the current state of knowledge in the most important questions in TBI. Automatic search updates will be run three-monthly, and newly identified studies incorporated into the review. Review teams will seek to publish journal updates at regular intervals, with abridged updates available more frequently online. Future project stages include the integration of LSR and other study findings into “living” clinical practice guidance. It is hoped these efforts will go some way to bridging current temporal disconnects between evidence, guidelines, and practice in TBI.

Guidelines aim to improve the quality of medical care and reduce treatment variation. The extent to which guidelines are adhered to in the field of traumatic brain injury (TBI) is unknown. The objectives of this systematic review were to (1) quantify adherence to guidelines in adult patients with TBI, (2) examine factors influencing adherence, and (3) study associations of adherence to clinical guidelines and outcome. We searched EMBASE, MEDLINE, Cochrane Central, PubMed, Web of Science, PsycINFO, SCOPUS, CINAHL, and grey literature in October 2014. We included studies of evidence-based (inter)national guidelines that examined the acute treatment of adult patients with TBI. Methodological quality was assessed using the Research Triangle Institute item bank and Quality in Prognostic Studies Risk of Bias Assessment Instrument. Twenty-two retrospective and prospective observational cohort studies, reported in 25 publications, were included, describing adherence to 13 guideline recommendations. Guideline adherence varied considerably between studies (range 18–100%) and was higher in guideline recommendations based on strong evidence compared with those based on lower evidence, and lower in recommendations of relatively more invasive procedures such as craniotomy. A number of patient-related factors, including age, Glasgow Coma Scale, and intracranial pathology, were associated with greater guideline adherence. Guideline adherence to Brain Trauma Foundation guidelines seemed to be associated with lower mortality. Guideline adherence in TBI is suboptimal, and wide variation exists between studies. Guideline adherence may be improved through the development of strong evidence for guidelines. Further research specifying hospital and management characteristics that explain variation in guideline adherence is warranted.

Accurate diagnosis of traumatic brain injury (TBI) is critical to effective management and intervention, but can be challenging in patients with mild TBI. A substantial number of studies have reported the use of circulating biomarkers as signatures for TBI, capable of improving diagnostic accuracy and clinical decision making beyond current practice standards.

We performed a systematic review and meta-analysis to comprehensively and critically evaluate the existing body of evidence for the use of blood protein biomarkers (S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], neuron specific enolase [NSE], ubiquitin C-terminal hydrolase-L1 [UCH-L1]. tau, and neurofilament proteins) for diagnosis of intracranial lesions on CT following mild TBI. Effects of potential confounding factors and differential diagnostic performance of the included markers were explored. Further, appropriateness of study design, analysis, quality, and demonstration of clinical utility were assessed. Studies published up to October 2016 were identified through searches of MEDLINE^®, Embase, EBM Reviews, the Cochrane Library, World Health Organization (WHO), International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov. Following screening of the identified articles, 26 were selected as relevant. We found that measurement of S100B can help informed decision making in the emergency department, possibly reducing resource use; however, there is insufficient evidence that any of the other markers is ready for clinical application. Our work pointed out serious problems in the design, analysis, and reporting of many of the studies, and identified substantial heterogeneity and research gaps. These findings emphasize the importance of methodologically rigorous studies focused on a biomarker's intended use, and defining standardized, validated, and reproducible approaches. The living nature of this systematic review, which will summarize key updated information as it becomes available, can inform and guide future implementation of biomarkers in the clinical arena.

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non–apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood–brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6–12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.

The mortality of traumatic brain injury (TBI) has been largely static despite advances in monitoring and imaging techniques. Substantial variance exists in outcome, not fully accounted for by baseline characteristics or injury severity, and genetic factors likely play a role in this variance. The aims of this systematic review were to examine the evidence for a link between the apolipoprotein E4 (APOE4) polymorphism and TBI outcomes and where possible, to quantify the effect size via meta-analysis. We searched EMBASE, MEDLINE, CINAHL, and gray literature in December 2017. We included studies of APOE genotype in relation to functional adult TBI outcomes. Methodological quality was assessed using the Quality in Prognostic Studies Risk of Bias Assessment Instrument and the prognostic studies adaptation of the Grading of Recommendations Assessment, Development and Evaluation tool. In addition, we contacted investigators and included an additional 160 patients whose data had not been made available for previous analyses, giving a total sample size of 2593 patients. Meta-analysis demonstrated higher odds of a favorable outcome following TBI in those not possessing an ApoE ɛ4 allele compared with ɛ4 carriers and homozygotes (odds ratio 1.39, 95% confidence interval 1.05 to 1.84; p = 0.02). The influence of APOE4 on neuropsychological functioning following TBI remained uncertain, with multiple conflicting studies. We conclude that the ApoE ɛ4 allele confers a small risk of poor outcome following TBI, with analysis by TBI severity not possible based on the currently available published data. Further research into the long-term neuropsychological impact and risk of dementia is warranted.

Cytokine measurement directly from the brain parenchyma by means of microdialysis has documented the activation of certain procedures in vivo, after brain trauma in humans. However, the intercalation of the micro-catheter insertion with the phenomena triggered by the head trauma renders the assessment of the findings problematic. The present study attempts to elucidate the pure effect of minimal trauma, represented by the insertion of the micro-catheter, on the non-traumatized human brain. Microdialysis catheters were implanted in 12 patients with drug-resistant epilepsy, and subjected to invasive electroencephalography with intracranial electrodes. Samples were collected during the first 5 days of monitoring. The dialysate was analyzed using bead flow cytometry, and the concentrations of interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor-α (TNF-α) were measured. The levels of IL-1 and IL-8 were found to be raised until 48 h post-implantation, and thereafter they reached a plateau of presumably baseline values. The temporal profile of the IL-6 variation was different, with the increase being much more prolonged, as its concentration had not returned to baseline levels at the fifth day post-insertion. TNF-α was found to be significantly raised only 2 h after implantation. IL-10 and IL-12 did not have any significant response to micro-trauma. These findings imply that the reaction of the neuro-inflammatory mechanisms of the brain exist even after minimal trauma, and is unexpectedly intense for IL-6. Questions may arise regarding the objectivity of findings attributed by some studies to inflammatory perturbation after head injury.

Despite many children experiencing fatigue after childhood brain injury, little is known about the predictors of this complaint. To date, traditional indices of traumatic brain injury (TBI) severity have not predicted reliably persisting fatigue (up to three years post-injury). This study aimed to establish whether persisting fatigue is predicted by serum biomarker concentrations in child TBI. We examined whether acute serum biomarker expression would improve prediction models of 12-month fatigue based on injury severity. Blood samples were collected from 87 children (1–17 years at injury) sustaining mild to severe TBI (Glasgow Coma Scale [GCS] range 3–15; mean 12.43; classified as mild TBI [n = 50, 57%] vs. moderate/severe TBI [n = 37, 43%]), and presenting to the emergency departments (ED) and pediatric intensive care units (PICU) at one of three tertiary pediatric hospitals (Royal Children's Hospital (RCH); Hospital for Sick Children (HSC), Toronto; St Justine Children's Hospital (SJH), Montreal). Six serum biomarker concentrations were measured within 24 h of injury (interleukin-6, interleukin-8 [IL-8], soluble vascular cell adhesion molecule [SVCAM], S100 calcium binding protein B [S100B], neuron specific enolase [NSE], and soluble neural cell adhesion molecule [sNCAM]). Fatigue at 12 months post-injury was measured using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (parent report), classified as present/absent using previously derived cut-points. At 12 months post-injury, 22% of participants experienced fatigue. A model including IL-8 was the best serum biomarker for estimating the probability of children experiencing fatigue at 12 months post-injury. The IL-8 also significantly improved predictive models of fatigue based on severity.

Gender may be related with the outcome of patients with acute traumatic brain injury (TBI). We explored the effect of gender on the outcome of 7145 patients with acute TBI. There was no statistical difference between male and female sex in the causes of trauma, age, Glasgow Coma Scale score, computed tomgraphy findings, and surgical management. The mortality of 7145 patients with acute TBI in males and females was 7.48% and 7.22%, respectively, with the corresponding unfavorable outcomes of 16.05% and 17.23%, respectively (p > 0.05 in both cases). The mortality of 1626 patients with severe TBI in males and females was 19.68% and 20.72%, respectively, with the corresponding unfavorable outcomes of 46.96% and 48.85%, respectively (p > 0.05 in both cases). Our data suggest that sex does not play a role in the outcome of patients with acute TBI.

Accurate prognostication of outcomes following traumatic brain injury (TBI) affects not only the aggressiveness of intervention and therapeutic decision-making but also clinicians' ability to provide reliable expectations. To investigate the relative ability of clinicians to accurately predict a patient's outcomes, compared with point-of-care prognostic models, we surveyed clinical providers of 86 patients with moderate-severe TBI at admission, Day 3, and Day 7 post-injury for a patient's predicted mortality and functional outcome at 6 months. The predicted mortality and functional outcomes were compared with actual occurrence of 14-day mortality and functional outcomes at six months. A prognostic score was then calculated utilizing the Corticoid Randomization After Significant Head Injury (CRASH) and International Mission on Prognosis and Analysis of Clinical Trials (IMPACT) models and categorized as high, intermediate, and low likelihood of mortality or poor functional outcome, and compared with clinical predictions. Overall, clinicians of varying backgrounds showed an accurate prediction of survival (87.2–97.4%) but struggled in prognosticating poor functional outcomes (24.3–36.6%). These values did not statistically improve over 7 days. Stratified CRASH (87.2%) and IMPACT (84.9%) accuracy rates were statistically better than clinical judgment alone in predicting functional outcomes (p < 0.0001). Prognostic models calculated at admission showed to be potentially useful, in conjunction with clinical judgment, in accurately predicting both survival and 6-month functional outcomes.

We aim to describe the outcomes after chronic subdural hematoma drainage (CSDH) management in a large cohort of patients on antithrombotic drugs, either antiplatelets or anticoagulants, at presentation and to inform clinical decision making on the timing of surgery and recommencement of these drugs. We used data from a previous UK-based multi-center, prospective cohort study. Outcomes included recurrence within 60 days, functional outcome at discharge, and thromboembolic event during hospital stay. We performed Cox regression on recurrence and multiple logistic regression on functional outcome. There were 817 patients included in the analysis, of which 353 (43.2%) were on an antithrombotic drug at presentation. We observed a gradual reduction in risk of recurrence for patients during the 6 weeks post-CSDH surgery. Neither antiplatelet nor anticoagulant drug use influenced risk of CSDH recurrence (hazard ratio, 0.93; 95% confidence interval [CI], 0.58–1.48; p = 0.76) or persistent/worse functional impairment (odds ratio, 1.08; 95% CI, 0.76–1.55; p = 0.66). Delaying surgery after cessation of antiplatelet drug did not affect risk of bleed recurrence. There were 15 in-hospital thromboembolic events recorded. Events were more common in the group pre-treated with antithrombotic drugs (3.3%) compared to the non-antithrombotic group (0.9%). Patients on an antithrombotic drug pre-operatively were at higher risk of thromboembolic events with no excess risk of bleed recurrence or worse functional outcome after CSDH drainage. The data did not support delaying surgery in patients on antithrombotic therapy. In the absence of a randomized controlled trial, early surgery and early antithrombotic recommencement should be considered in those at high risk of thromboembolic events.

The present study was attempted to assess the mechanisms underlying the beneficial effects of hyperbaric oxygen (HBO₂; 100% O₂ at 253 kpa) in treating experimental heatstroke. Anesthetized rats were divided into five major groups: normothermic control (NC) rats treated with normobaric air (NBA; 21% O₂ at 101 kpa; NC + NBA); NC rats treated with HBO₂ (NC + HBO₂); heatstroke (HS) rats treated with NBA (HS + NBA); HS rats treated with hyperbaric air (HBA; 21% at 253 kpa; HS + HBA); and HS rats treated with HBO₂ (HS + HBO₂). HS groups were exposed to heat (43°C) for exactly 68 min and then allowed to recover at 26°C. HBA or HBO₂ was adopted 68 or 78 min after the start of heat exposure. Survival time values for (HS + NBA) rats, (HS + HBA) rats at 68 min, (HS + HBA) rats at 78 min, (HS + HBO₂) rats at 68 min, and (HS + HBO₂) rats at 78 min were found to be 90 ± 3, 133 ± 12, 109 ± 9, 240 ± 18, and 170 ± 15 min, respectively. Resuscitation with HBA or HBO₂ at 68 min was superior to those treated at 78 min in prolonging the survival time values. All (HS + NBA) animals displayed hyperthermia, hypotension, and increased cellular levels of ischemia, oxidative stress and damage markers, pro-inflammatory cytokines, and an indicator of polymorphonuclear cell accumulation in their hypothalamus as compared to those of NCs. Heat-induced hyperthermia was not affected by HBA or HBO₂ treatment. However, heat-induced hypotension and hypothalamic ischemia, oxidative stress, neuronal damage, and inflammation were all significantly reduced by HBA or HBO₂ therapy. Compared to those of HBA therapy, HBO₂ therapy had a significantly higher beneficial effect in treating heatstroke. Our results suggested that HBO₂ improved heatstroke outcomes, in part, by restoring normal hypothalamic function. Delaying the onset of HBO₂ therapy reduced the therapeutic efficiency.

Seizures are important neurological complications after traumatic brain injury (TBI) and are reported for up to 50% of patients with TBI. Despite several studies, no drug strategy has been able to alter the biological events leading to epileptogenesis. The glial water channel, aquaporin-4 (AQP4), was shown to facilitate cytotoxic cell swelling in ischemia and glial scar formation after stab wound injury. In this study, we examined post-traumatic seizure susceptibility of AQP4-deficient mice (AQP4^–/–) after injection of pentylenetetrazole (PTZ) 1 month after controlled cortical impact (CCI) and compared them to wild-type sham injury controls. After PTZ injection, AQP4^–/– mice demonstrated dramatically shortened seizure latency (120 ± 40 vs. 300 ± 70 sec; p < 0.001) and increased seizure severity (grade 7.5 ± 0.4 vs. 5.8 ± 0.4; p < 0.001) compared to their wild-type counterparts. Morphometric analysis demonstrated a significant 2-fold reduction in astrocytosis, with a concomitant increase in microgliosis in injured AQP4-null mice compared to their injured wild-type counterparts (44 ± 2 vs. 24 ± 3 cells per high power field [cells/hpf], respectively; p < 0.0001). Minocycline, an inhibitor of microglia, reversed the post-TBI epilepsy phenotype of AQP4-null mice. After minocycline treatment, AQP4^–/– mice demonstrated similar latency of seizures evoked by PTZ (723 ± 35 vs. 696 ± 38 sec; p > 0.05) and severity of seizures evoked by PTZ (grade 4.0 ± 0.5 vs. 3.81 ± 0.30; p > 0.05) compared to wild-type counterparts. Immunohistochemical analysis demonstrated decreased immunostaining of microglia to levels comparable to wild-type (12 ± 2 vs. 11 ± 4 cells/hpf, respectively; p > 0.05). Taken together, these results suggest a protective role of AQP4 in post-traumatic seizure susceptibility by promoting astrogliosis, formation of a glial scar, and preventing microgliosis.