Mild Traumatic Brain Injury (mTBI), or concussion, is a major public health concern. There is controversy in the literature regarding the true incidence of postconcussion syndrome (PCS), with the ...constellation of physical, cognitive, emotional, and sleep symptoms after mTBI. In the current study, we report on the incidence and evolution of PCS symptoms and patient outcomes after mTBI at 3, 6, and 12 months in a large, prospective cohort of mTBI patients. Participants were identified as part of the prospective, multi-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study. The study population was mTBI patients (Glasgow Coma Scale score of 13-15) presenting to the emergency department, including patients with a negative head computed tomography discharged to home without admission to hospital; 375 mTBI subjects were included in the analysis. At both 6 and 12 months after mTBI, 82% (n=250 of 305 and n=163 of 199, respectively) of patients reported at least one PCS symptom. Further, 44.5 and 40.3% of patients had significantly reduced Satisfaction With Life scores at 6 and 12 months, respectively. At 3 months after injury, 33% of the mTBI subjects were functionally impaired (Glasgow Outcome Scale-Extended score ≤6); 22.4% of the mTBI subjects available for follow-up were still below full functional status at 1 year after injury. The term "mild" continues to be a misnomer for this patient population and underscores the critical need for evolving classification strategies for TBI for targeted therapy.
There is a national debate regarding the existence of a relationship between contact sport participation and future risk of neurodegenerative disease. We employed bibliometrics and altmetrics to ...quantify the academic, popular, and social media impact of published scientific articles that report an association between contact sports or military service with chronic traumatic encephalopathy (CTE+), and compare with those scientific articles that report null or no association of contact sports or military service with CTE (CTE-). In this cross-sectional study, we extracted number of citations, total link strength, altmetric score, number of news stories, media outlets, and Twitter interaction from published CTE articles. The top 10 most cited articles were statistically compared on these outcomes using Mann-Whitney U tests. CTE+ publications had an average of 101 citations per article, Altmetric score of 272, 36 news stories in 26 media outlets, and upper-bound of Twitter users of 402,159. CTE- publications had an average of 29 citations per article, Altmetric score of 39, two news stories and media outlets, and upper-bound of Twitter users of 91,070. Top 10 CTE+ publications had, on average, 94% more citations (
< 0.001), 95% higher altmetric scores (
= 0.01), 99% higher number of news stories (
= 0.01), 98% higher number of media outlets (
= 0.01), and reached 95% more Twitter users than top 10 CTE- publications (
= 0.11). The bibliometric analysis indicates a significant inequality in media dissemination and popular consumption of scientific findings that do not support a relationship between contact sports or military service and future neurodegeneration.
A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess ...whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study.
Randomized prospective clinical trial.
Ten ICUs in the United States.
One hundred nineteen severe traumatic brain injury patients.
Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended.
A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy.
Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.
The most extensively validated prognostic models for traumatic brain injury (TBI) are the Corticoid Randomization after Significant Head Injury (CRASH) and International Mission on Prognosis and ...Analysis of Clinical Trials (IMPACT). Model characteristics outside of area under the curve (AUC) are rarely reported.
To report the discriminative validity and overall model performance of the CRASH and IMPACT models for prognosticating death at 14 days (CRASH) and 6 months (IMPACT) and unfavorable outcomes at 6 months after TBI.
This retrospective cohort study included prospectively collected patients with severe TBI treated at a single level I trauma center (n = 467). CRASH and IMPACT percent risk values for the given outcome were computed. Unfavorable outcome was defined as a Glasgow Outcome Scale-Extended score of 1 to 4 at 6 months. Binary logistic regressions and receiver operating characteristic analyses were used to differentiate patients from the CRASH and IMPACT prognostic models.
All models had low R 2 values (0.17-0.23) with AUC values from 0.77 to 0.81 and overall accuracies ranging from 72.4% to 78.3%. Sensitivity (35.3-50.0) and positive predictive values (66.7-69.2) were poor in the CRASH models, while specificity (52.3-53.1) and negative predictive values (58.1-63.6) were poor in IMPACT models. All models had unacceptable false positive rates (20.8%-33.3%).
Our results were consistent with previous literature regarding discriminative validity (AUC = 0.77-0.81). However, accuracy and false positive rates of both the CRASH and IMPACT models were poor.
More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based ...brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI.
This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9–15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT.
Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931–0·995) and an NPV of 0·996 (0·987–0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative.
These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted.
Banyan Biomarkers and US Army Medical Research and Materiel Command.
Objective
To determine the clinical relevance, if any, of traumatic intracranial findings on early head computed tomography (CT) and brain magnetic resonance imaging (MRI) to 3‐month outcome in mild ...traumatic brain injury (MTBI).
Methods
One hundred thirty‐five MTBI patients evaluated for acute head injury in emergency departments of 3 LEVEL I trauma centers were enrolled prospectively. In addition to admission head CT, early brain MRI was performed 12 ± 3.9 days after injury. Univariate and multivariate logistic regression were used to assess for demographic, clinical, socioeconomic, CT, and MRI features that were predictive of Extended Glasgow Outcome Scale (GOS‐E) at 3 months postinjury.
Results
Twenty‐seven percent of MTBI patients with normal admission head CT had abnormal early brain MRI. CT evidence of subarachnoid hemorrhage was associated with a multivariate odds ratio of 3.5 (p = 0.01) for poorer 3‐month outcome, after adjusting for demographic, clinical, and socioeconomic factors. One or more brain contusions on MRI, and ≥4 foci of hemorrhagic axonal injury on MRI, were each independently associated with poorer 3‐month outcome, with multivariate odds ratios of 4.5 (p = 0.01) and 3.2 (p = 0.03), respectively, after adjusting for head CT findings and demographic, clinical, and socioeconomic factors.
Interpretation
In this prospective multicenter observational study, the clinical relevance of abnormal findings on early brain imaging after MTBI is demonstrated. The addition of early CT and MRI markers to a prognostic model based on previously known demographic, clinical, and socioeconomic predictors resulted in a >2‐fold increase in the explained variance in 3‐month GOS‐E. ANN NEUROL 2013;73:224–235
Annually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and ...prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.
To examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.
In the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean SD, 176.4 44.5 days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.
Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.
In the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale GCS score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).
Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.
Summary Background Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50–60% of patients after traumatic brain ...injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. Methods We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. Findings Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 95% CI 0·72–3·37 and 7·58 2·64–21·8, respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. Interpretation Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. Funding US Army CDMRP PH/TBI research programme.
Abstract
BACKGROUND
Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal ...cord injury (SCI).
OBJECTIVE
To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI.
METHODS
Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI.
RESULTS
Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant.
CONCLUSION
A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.
PDF
