Phase II Clinical Trial of Atorvastatin in Mild Traumatic Brain Injury.

Statins constitute a class of medications commonly used in the treatment of elevated cholesterol. However, in experimental studies, statins also have other non-cholesterol-mediated mechanisms of action, which may have neuroprotective effects. The aim of this study was to determine whether administration of atorvastatin for 7 days post-injury would improve neurological recovery in patients with mild traumatic brain injury (mTBI). The hypothesis was that atorvastatin administration would reduce post-concussion symptoms and also that atorvastatin administration for 1 week post-injury would be safe. One hundred forty patients with mTBI were planned to be enrolled and randomly assigned to receive atorvastatin 1 mg/kg (up to 80 mg/kg) per day or placebo for 7 days starting within 24 h of injury. Assessments of post-concussion syndrome, post-traumatic stress and depressive symptoms, cognition, memory, verbal fluency, functional, and work status were performed at baseline, 1 week, and 1 and 3 months. The result on the Rivermead Post-Concussion Symptoms Questionnaire at 3 months was the primary outcome. Enrollment in the trial was stopped early because of difficulty in recruiting sufficient numbers of subjects. Fifty-two patients with mTBI were enrolled; 28 patients received atorvastatin and 24 received placebo. The median Rivermead score was 2 for the atorvastatin group, compared to 3.5 for the placebo group, at 3 months post-injury (χ2(1) = 0.0976; p = 0.7547). The change in the Rivermead score between baseline and 3 months was also analyzed. The median decrease in score was 4 for the atorvastatin group and 10.5 for the placebo group (χ2(1) = 0.8750; p = 0.3496). No serious adverse events occurred, and there was no significant difference in the incidence of adverse events in the two treatment groups. Atorvastatin administration for 7 days post-injury was safe, but there were no significant differences in neurological recovery post-mTBI with atorvastatin.

Cortical Thickness in Mild Traumatic Brain Injury.

Magnetic resonance imaging data were acquired at ∼24 h and ∼3 months post-injury on mild traumatic brain injury (mTBI; n = 75) and orthopedic injury (n = 60) cohorts. The mTBI subjects were randomly assigned to a treatment group with atorvastatin or a non-treatment mTBI group. The treatment group was further divided into drug and placebo subgroups. FreeSurfer software package was used to compute cortical thickness based on the three dimensional T1-weighted images at both time-points. Cross-sectional analysis was carried out to compare cortical thickness between the mTBI and control groups. Longitudinal unbiased templates were generated for all subjects and cortical thickness measurements were compared between baseline and follow-up scans in the mTBI group. At baseline, significant reduction in cortical thickness was observed in the left middle temporal and the right superior parietal regions in the mTBI group, relative to the control group (p = 0.01). At follow-up, significant cortical thinning was again observed in the left middle temporal cortex in the mTBI group. Further analysis revealed significant cortical thinning only in the non-treatment group relative to the control group. In the follow-up, small regions with significant but subtle cortical thinning and thickening were seen in the frontal, temporal, and parietal lobes in the left hemisphere in the non-treatment group only. Our results indicate that cortical thickness could serve as a useful measure in identifying subtle changes in mTBI patients.

Loss of Consciousness Is Related to White Matter Injury in Mild Traumatic Brain Injury.

To study the relation of loss of consciousness (LOC) to white matter integrity after mild traumatic brain injury (mTBI), we acquired diffusion tensor imaging (DTI) at 3 Tesla in 79 participants with mTBI and normal computed tomography (age 18 to 50 years) whom we imaged after a mean post-injury interval of 25.9 h (standard deviation = 12.3) and at 3 months. For comparison, 64 participants with orthopedic injury (OI) underwent DTI at similar intervals. Quantitative tractography was used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the left and right uncinate fasciculus (UF), left and right inferior frontal occipital fasciculus (IFOF), and the genu of the corpus callosum. Generalized estimating equation models assessed the association between LOC and both MD and FA across time after mTBI and compared their DTI metrics with the OI group. LOC was significantly related to MD in UF and IFOF (p values ranged from p < 0.0001 to 0.0270) and to FA in left UF (p = 0.0104) and right UF (p = 0.0404). Between-group differences in MD were significant for left UF, left and right IFOF, and the genu of the corpus callosum on initial DTI, but not at 3 months post-injury, and these differences were specific to the mTBI subgroup with LOC. Groups did not differ in FA at either occasion. Early DTI may provide a biomarker for mTBI with LOC, even in patients whose consciousness recovers by arrival in the emergency department. MD better differentiates mTBI from OI than FA on early DTI, but this is specific to mTBI with LOC. DTI findings support a continuum of white matter injury in early mTBI.

Biomarkers for acute diagnosis and management of stroke in neurointensive care units.

The effectiveness of current management of critically ill stroke patients depends on rapid assessment of the type of stroke, ischemic or hemorrhagic, and on a patient's general clinical status. Thrombolytic therapy with recombinant tissue plasminogen activator (r-tPA) is the only effective treatment for ischemic stroke approved by the Food and Drug Administration (FDA), whereas no treatment has been shown to be effective for hemorrhagic stroke. Furthermore, a narrow therapeutic window and fear of precipitating intracranial hemorrhage by administering r-tPA cause many clinicians to avoid using this treatment. Thus, rapid and objective assessments of stroke type at admission would increase the number of patients with ischemic stroke receiving r-tPA treatment and thereby, improve outcome for many additional stroke patients. Considerable literature suggests that brain-specific protein biomarkers of glial [i.e. S100 calcium-binding protein B (S100B), glial fibrillary acidic protein (GFAP)] and neuronal cells [e.g., ubiquitin C-terminal hydrolase-L1 (UCH-L1), neuron-specific enolase (NSE), αII-spectrin breakdown products SBDP120, SBDP145, and SBDP150, myelin basic protein (MBP), neurofilament light chain (NF-L), tau protein, visinin-like protein-1 (VLP 1), NR2 peptide] injury that could be detected in the cerebrospinal fluid (CSF) and peripheral blood might provide valuable and timely diagnostic information for stroke necessary to make prompt management and decisions, especially when the time of stroke onset cannot be determined. This information could include injury severity, prognosis of short-term and long-term outcomes, and discrimination of ischemic or hemorrhagic stroke. This chapter reviews the current status of the development of biomarker-based diagnosis of stroke and its potential application to improve stroke care.

Multi-modal MRI of mild traumatic brain injury.

Multi-modal magnetic resonance imaging (MRI) that included high resolution structural imaging, diffusion tensor imaging (DTI), magnetization transfer ratio (MTR) imaging, and magnetic resonance spectroscopic imaging (MRSI) were performed in mild traumatic brain injury (mTBI) patients with negative computed tomographic scans and in an orthopedic-injured (OI) group without concomitant injury to the brain. The OI group served as a comparison group for mTBI. MRI scans were performed both in the acute phase of injury (~24 h) and at follow-up (~90 days). DTI data was analyzed using tract based spatial statistics (TBSS). Global and regional atrophies were calculated using tensor-based morphometry (TBM). MTR values were calculated using the standard method. MRSI was analyzed using LC Model. At the initial scan, the mean diffusivity (MD) was significantly higher in the mTBI cohort relative to the comparison group in several white matter (WM) regions that included internal capsule, external capsule, superior corona radiata, anterior corona radiata, posterior corona radiata, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major and forceps minor of the corpus callosum, superior longitudinal fasciculus, and corticospinal tract in the right hemisphere. TBSS analysis failed to detect significant differences in any DTI measures between the initial and follow-up scans either in the mTBI or OI group. No significant differences were found in MRSI, MTR or morphometry between the mTBI and OI cohorts either at the initial or follow-up scans with or without family wise error (FWE) correction. Our study suggests that a number of WM tracts are affected in mTBI in the acute phase of injury and that these changes disappear by 90 days. This study also suggests that none of the MRI-modalities used in this study, with the exception of DTI, is sensitive in detecting changes in the acute phase of mTBI.

Serial atlas-based diffusion tensor imaging study of uncomplicated mild traumatic brain injury in adults.

Abstract In this report, we applied diffusion tensor imaging (DTI) methods in 36 patients with uncomplicated mild traumatic brain injury (mTBI) and a comparison group of 37 participants with orthopedic injury. Our aim was to characterize regional and global macro- and microstructural attributes of white matter (WM), gray matter (GM), in addition to volume and diffusivity of cerebrospinal fluid (CSF) to identify and differentiate patterns of acute and short-term recovery. Given that previous DTI reports on mTBI in adults using a region-of-interest approach implicated the corona radiata (CR), corpus callosum, and hippocampus, we analyzed and quantified DTI metrics of these regions using atlas-based methods. The normalized volume percentages of global CSF, GM, and WM were not different between the mTBI and orthopedic comparison (OC) groups at either the baseline or follow-up time points or between the baseline and follow-up time points within the OC group (p>0.17; uncorrected for multiple comparisons). The DTI metrics did not differ between groups at either occasion. However, an increase was noted on follow-up in the OC group in the global mean diffusivity of GM (uncorrected p=0.003) and WM (uncorrected p=0.02), indicating a decrease in diffusivity at the 3-month postinjury, as compared to the baseline scan. An analysis of the DTI data collected longitudinally in the CR show insignificant changes in the OC group (p>0.08; N=37). CR radial diffusivity was found to be elevated in the between-group comparison at baseline (mTBI1 vs. OC1), but did not differ in the within-group comparison (mTBI1 vs. mTBI2; N=19), suggesting the possible resolution of edema. Our analysis of the cross-sectional and follow-up data, which is uncorrected for multiple comparisons, demonstrates dissociation between volumetric (macrostructural) and tissue integrity (microstructural) attributes and shows the potential utility of DTI to capture transient edema in the CR.

Preinjury resilience and mood as predictors of early outcome following mild traumatic brain injury.

There is significant heterogeneity in outcomes following mild traumatic brain injury (mTBI). While several host factors (age, gender, and preinjury psychiatric history) have been investigated, the influence of preinjury psychological resilience and mood status in conjunction with mild TBI remains relatively unexplored. Euthymic mood and high resilience are potentially protective against anxiety and postconcussion symptoms, but their relative contributions are currently unknown. This prospective study obtained preinjury estimates of resilience and mood measures in addition to measures of anxiety (Acute Stress Disorder Scale and PTSD-Checklist-Civilian form) and postconcussion symptom severity (Rivermead Post Concussion Symptoms Questionnaire) <24 hours (Baseline), 1 week, and 1 month postinjury in patients with either mTBI (n=46) or a comparison group with orthopedic injuries not involving the head (OI, n=29). The groups did not differ on preinjury resilience or mood status at baseline, but differed significantly on measures of anxiety and postconcussion symptom severity at each subsequent study occasion. Multivariate linear regression analyses were conducted to determine if preinjury resilience and mood were significant contributors to anxiety and postconcussion symptoms during the first month postinjury after accounting for other known host factors (e.g., age at injury, gender, and education). Injury group and preinjury mood status were significant predictors for all three dependent variables at each study occasion (all p<0.007). Preinjury resilience showed a positive trend only for acute stress severity at baseline, but demonstrated significant prediction of all three dependent measures at one week and one month postinjury. These results suggest that preinjury depressed mood and resilience are significant contributors to the severity of postinjury anxiety and postconcussion symptoms, even after accounting for effects of other specific host factors.

CVP and PAoP measurements are discordant during fluid therapy after traumatic brain injury.

The objective of the study was to compare measurements of central venous pressure (CVP) and pulmonary artery occlusion pressures (PAoP) as estimates of intravascular volume during the first 96 hours of fluid therapy after traumatic brain injury (TBI). One thousand five hundred ten simultaneous CVP and PAoP measurements from 31 patients entered into the National Acute Brain Injury Study: Hypothermia (NABISH:H) protocol were retrospectively compared. The effect of fluid administration and body temperature upon the paired measurements was statistically assessed. Agreement between CVP and PAoP values was poor. The CVP and PAoP were equal in only 11% of paired values. The CVP was always higher than PAoP in 1 patient, whereas PAoP always exceeded the CVP in 5 others. In 74% of the pairs, the PAoP was higher than the CVP, whereas in 15%, CVP was greater than PAoP. For any CVP measurement, the PAoP was either 3 mm Hg above or below the CVP in 67% of the pairs and at least 5 mm Hg above or below the CVP in 21% of the pairs. In 21 (68%) patients, PAoP was > or = 5 mm Hg above CVP in more than 4 readings, a clinically important difference. Discordance was not attributed to the fluid administered or to the temperature protocol. Neurological outcome appears affected by the volume of fluid administration. However, during initial therapy, estimates of intravascular volume provided by the CVP and PAoP are discordant. Although documented in other clinical conditions, the disparity noted here after TBI has not been previously reported. Assessment of intravascular volume to avoid hypovolemia should utilize other measurement techniques.

Clinical trials in head injury.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Fluid thresholds and outcome from severe brain injury.

OBJECTIVE: To determine, by retrospective analysis, critical thresholds for intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and fluid balance associated with poor outcome in patients with severe brain injury. DESIGN: Retrospective review of patient data from the prospective, randomized, multicenter National Acute Brain Injury Study: Hypothermia, comparing outcome results at 6 months after injury with intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and fluid balance measurements recorded during the 96-hr period after randomization. SETTING: Emergency departments and intensive care units in 11 metropolitan tertiary care university hospitals. PATIENTS: A total of 392 patients, aged 16-65 yrs, with severe, nonpenetrating brain injuries and a Glasgow Coma Scale score of 3-8 after resuscitation, who were enrolled in a study designed to determine the treatment effect of moderate hypothermia in patients with severe brain injury. INTERVENTION: Standard brain injury treatment for 193 randomly assigned patients and standard treatment plus hypothermia for 48 hrs for 199 patients. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure levels of 20, 25, and 30 mm Hg, mean arterial pressure levels of 70 and 80 mm Hg, cerebral perfusion pressure levels of 50, 60, and 70 mm Hg, and fluid balance levels in quartiles were examined for their effect on outcome as measured by the Glasgow Outcome Scale at 6 months after injury. When considered separately, any of the following-intracranial pressure >25 mm Hg, mean arterial pressure <70 mm Hg, or cerebral perfusion pressure <60 mm Hg and fluid balance lower than -594 mL-was associated with an increased percentage of patients with poor outcome. When the variables were combined into a stepwise logistic regression model, Glasgow Coma Scale score at admission, age, mean arterial pressure <70 mm Hg, fluid balance lower than -594 mL, and intracranial pressure > 25 mm Hg, in that order, were the most powerful variables in determining outcome. CONCLUSIONS: Exceeding thresholds of intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and fluid volume may be detrimental to severe brain injury outcome. Fluid balance lower than -594 mL was associated with an adverse effect on outcome, independent of its relationship to intracranial pressure, mean arterial pressure, or cerebral perfusion pressure.

Hypothermia on admission in patients with severe brain injury.

Data from the "National Acute Brain Injury Study: Hypothermia" were examined to identify the impact of hypothermia on admission. In all patients, temperature was measured at randomization using bladder catheters with thermistors. Patients assigned to hypothermia were cooled using fluid-circulating pads. Outcome was assessed at 6 months using the dichotomized Glasgow Outcome Scale (good outcome = good recovery/moderate disability; poor outcome = severe disability/vegetative/dead). One-hundred and two patients (hypothermia, 62; normothermia, 40) were hypothermic on admission (< or =35.0 degrees C). Hypothermia-on-admission patients assigned to normothermia (n = 40) had a 78% poor outcome, and normothermia-on-admission patients assigned to normothermia had a 52% poor outcome (p < 0.004). Hypothermia-on-admission patients assigned to hypothermia had a lower percentage of poor outcomes than those assigned to normothermia (hypothermia, 61%; normothermia, 78%; p = 0.09). Patients over 45 years of age had an adverse effect of hypothermia regardless of admission temperature due to medical complications. Patients who were hypothermic on admission, age < or = 45 years (n = 81), and assigned to hypothermia had a significantly lower percentage of poor outcomes than those assigned to normothermia (hypothermia, 52%; normothermia, 76%; p = 0.02). Factors associated with hypothermia on admission were increased age, prehospital hypotension, smaller size, positive blood alcohol, larger volume of pre-hospital fluids, slightly higher injury severity, and winter enrollment The treatment effect was found in all of the four centers, which randomized the majority (80%) of the patients. It is unclear whether the improved outcome when hypothermia is maintained is a beneficial effect of very early hypothermia induction or an adverse effect of permitting the patients to rewarm passively.

Misclassification and treatment effect on primary outcome measures in clinical trials of severe neurotrauma.

The power of clinical trials depends mainly on the choice of the primary outcome measure, the statistical test, and the sample size. The most widely used outcome measure has been the five-category Glasgow Outcome Scale (GOS). Contrary to intuition, we show that more categories do not necessarily increase the power of a trial and actually can decrease power. This is so for two reasons. The more categories of outcome measure used, the more the likelihood for misclassifications. The effect of 0%, 10%, and 20% misclassification rate upon power is illustrated. Misclassification rates in two completed trials are examined based on comparative overlap in GOS and Disability Rating Scale (DRS) categories. The outcome results of the "National Acute Brain Injury Study: Hypothermia" indicate that the ideal number of categories also depends upon the effect of study treatment. In the recently completed hypothermia trial, the use of a dichotomized GOS (good recovery/moderate disability versus severe disability/vegetative/dead) is shown to be more sensitive than use of three or more categories of the GOS. The results point to the importance of training study investigators who will collect the outcome data. The results also indicate that the number of categories should be carefully determined using the pilot data or the data from phase II trials.