Defining an Approach to Monitoring Brain Health in Individuals Exposed to Repetitive Head Impacts: Lessons Learned from Radiation Safety.

Recently, there has been increased concern over the effect of repetitive head impacts (RHIs, both concussive and subconcussive impacts) on long-term brain health. This concern has led researchers and policy makers to consider establishing RHI thresholds in order to mitigate the potential long-term effects of RHI exposure. However, the concept of thresholding relies on twin streams of information: 1) biomedical research relevant to the short and long-term risks of exposure to RHIs, and 2) societal standards for "acceptable risk." In the case of RHI, these streams of information have not been cogently combined to inform sensible policy making. In the current editorial, we discuss how the history of radiation safety provides an instructive example of an approach to ford these two streams to derive actionable clinically relevant policies surrounding RHI exposures.

Progesterone Treatment Does Not Decrease Serum Levels of Biomarkers of Glial and Neuronal Cell Injury in Moderate and Severe Traumatic Brain Injury Subjects: A Secondary Analysis of the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) III Trial.

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo (p > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups (p > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome (p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury.

Identification of a neurologic scale that optimizes EMS detection of older adult traumatic brain injury patients who require transport to a trauma center.

OBJECTIVE: We sought to identify a scale or components of a scale that optimize detection of older adult traumatic brain injury (TBI) patients who require transport to a trauma center, regardless of mechanism. METHODS: We assembled a consensus panel consisting of nine experts in geriatric emergency medicine, prehospital medicine, trauma surgery, geriatric medicine, and TBI, as well as prehospital providers, to evaluate the existing scales used to identify TBI. We reviewed the relevant literature and solicited group feedback to create a list of candidate scales and criteria for evaluation. Using the nominal group technique, scales were evaluated by the expert panel through an iterative process until consensus was achieved. RESULTS: We identified 15 scales for evaluation. The panel's criteria for rating the scales included ease of administration, prehospital familiarity with scale components, feasibility of use with older adults, time to administer, and strength of evidence for their performance in the prehospital setting. After review and discussion of aggregated ratings, the panel identified the Simplified Motor Scale, GCS-Motor Component, and AVPU (alert, voice, pain, unresponsive) as the strongest scales, but determined that none meet all EMS provider and patient needs due to poor usability and lack of supportive evidence. The panel proposed that a dichotomized decision scheme that includes domains of the top-rated scales -level of alertness (alert vs. not alert) and motor function (obeys commands vs. does not obey) -may be more effective in identifying older adult TBI patients who require transport to a trauma center in the prehospital setting. CONCLUSIONS: Existing scales to identify TBI are inadequate to detect older adult TBI patients who require transport to a trauma center. A new algorithm, derived from elements of previously established scales, has the potential to guide prehospital providers in improving the triage of older adult TBI patients, but needs further evaluation prior to use.

Menstrual phase as predictor of outcome after mild traumatic brain injury in women.

OBJECTIVE: To determine whether menstrual cycle phase in women at the time of mild traumatic brain injury (mTBI) predicts 1-month outcomes. SETTING: Six emergency departments; 5 in Upstate New York, and 1 in Pennsylvania. PARTICIPANTS: One hundred forty-four female participants (age, 16-60) who presented to participating emergency departments within 4 hours of mTBI. DESIGN: Nested cohort study with neurologic and quality-of-life outcome assessment, 1 month after enrollment. Female subjects aged 16 to 60 enrolled in the parent cohort study, with 1-month neurological determination data available, were classified into menstrual cycle groups by serum progesterone concentration and self-reported contraceptive use. MAIN MEASURES: Rivermead Post Concussion Questionnaire and EuroQoL/EQ5D. RESULTS: Women injured during the luteal phase of their menstrual cycle, when progesterone concentration is high, had significantly lower EuroQoL General Health Ratings and Index Scores than women injured during the follicular phase of their cycle or women taking oral contraceptives. Multivariate analysis confirmed a significant independent effect of menstrual cycle phase on EuroQoL Index Score and the Rivermead Post Concussion Questionnaire Somatic Subscore. CONCLUSION: Menstrual cycle phase and progesterone concentration at the time of mTBI affect 1-month quality-of-life and neurologic outcomes. This association has important implications for treatment and prognosis after mTBI.

Classification accuracy of serum Apo A-I and S100B for the diagnosis of mild traumatic brain injury and prediction of abnormal initial head computed tomography scan.

The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78-0.92]) was similar to that using apoA-I (0.902 [0.87-0.93]), and the sensitivity using S100B (0.252 [0.22-0.28]) was similar to that using apoA-I (0.249 [0.22-0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p=0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p<0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of <0.060 µg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI.

Extracranial sources of S100B do not affect serum levels.

S100B, established as prevalent protein of the central nervous system, is a peripheral biomarker for blood-brain barrier disruption and often also a marker of brain injury. However, reports of extracranial sources of S100B, especially from adipose tissue, may confound its interpretation in the clinical setting. The objective of this study was to characterize the tissue specificity of S100B and assess how extracranial sources of S100B affect serum levels. The extracranial sources of S100B were determined by analyzing nine different types of human tissues by ELISA and Western blot. In addition, brain and adipose tissue were further analyzed by mass spectrometry. A study of 200 subjects was undertaken to determine the relationship between body mass index (BMI) and S100B serum levels. We also measured the levels of S100B homo- and heterodimers in serum quantitatively after blood-brain barrier disruption. Analysis of human tissues by ELISA and Western blot revealed variable levels of S100B expression. By ELISA, brain tissue expressed the highest S100B levels. Similarly, Western blot measurements revealed that brain tissue expressed high levels of S100B but comparable levels were found in skeletal muscle. Mass spectrometry of brain and adipose tissue confirmed the presence of S100B but also revealed the presence of S100A1. The analysis of 200 subjects revealed no statistically significant relationship between BMI and S100B levels. The main species of S100B released from the brain was the B-B homodimer. Our results show that extracranial sources of S100B do not affect serum levels. Thus, the diagnostic value of S100B and its negative predictive value in neurological diseases in intact subjects (without traumatic brain or bodily injury from accident or surgery) are not compromised in the clinical setting.

The economic impact of S-100B as a pre-head CT screening test on emergency department management of adult patients with mild traumatic brain injury.

Recent research suggests that serum S-100B may serve as a good pre-head computed tomography (CT) screening test because of its high sensitivity for abnormal head CT scans. The potential economic impact of using S-100B in the emergency department setting for management of adult patients with isolated mild traumatic brain injury (mTBI) has not been evaluated despite its clinical implementation in Europe. Using evidence from the literature, we constructed a decision tree to compare the average cost per patient of using S-100B as a pre-head CT screening test to the current practice of ordering CT scans based on patients' presenting symptoms without the aid of S-100B. When compared to scanning 45-77% of isolated mTBI patients based upon their presenting symptoms, using S-100B as a pre-head CT screen does not lower hospital costs ($281 versus $160), primarily due to its low specificity for abnormal head CT scans. Sensitivity analyses showed, however, that S-100B becomes cost-lowering when the proportion of mTBI patients being scanned exceeds 78%, or when final CT scan results require 96 min or more than the wait for blood test results. Generally speaking, if blood test results require less time than imaging, and if head CT scan rates for patients with isolated mTBI are relatively high, using S-100B will lower costs. Recommendations for using S-100B as a screening tool should account for setting-specific characteristics and their consequent economic impacts. Despite its high sensitivity and excellent negative predictive value, serum S-100B has low specificity and low positive predictive value, limiting its ability to reduce numbers of CT scans and hospital costs.