Stephen R. McCauley

Lack of effect of induction of hypothermia after acute brain injury

BACKGROUND Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury. METHODS The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury. RESULTS The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group. CONCLUSIONS Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury.

Diffusion tensor imaging of acute mild traumatic brain injury in adolescents

Background: Despite normal CT imaging and neurologic functioning, many individuals report postconcussion symptoms following mild traumatic brain injury (MTBI). This dissociation has been enigmatic for clinicians and investigators. Methods: Diffusion tensor imaging tractography of the corpus callosum was performed in 10 adolescents (14 to 19 years of age) with MTBI 1 to 6 days postinjury with Glasgow Coma Scale score of 15 and negative CT, and 10 age- and gender-equivalent uninjured controls. Subjects were administered the Rivermead Post Concussion Symptoms Questionnaire and the Brief Symptom Inventory to assess self-reported cognitive, affective, and somatic symptoms. Results: The MTBI group demonstrated increased fractional anisotropy and decreased apparent diffusion coefficient and radial diffusivity, and more intense postconcussion symptoms and emotional distress compared to the control group. Increased fractional anisotropy and decreased radial diffusivity were correlated with severity of postconcussion symptoms in the MTBI group, but not in the control group. Conclusions: In adolescents with mild traumatic brain injury (MTBI) with Glasgow Coma Scale score of 15 and negative CT, diffusion tensor imaging (DTI) performed within 6 days postinjury showed increased fractional anisotropy and decreased diffusivity suggestive of cytotoxic edema. Advanced MRI-based DTI methods may enhance our understanding of the neuropathology of TBI, including MTBI. Additionally, DTI may prove more sensitive than conventional imaging methods in detecting subtle, but clinically meaningful, changes following MTBI and may be critical in refining MTBI diagnosis, prognosis, and management.

Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial

BACKGROUND The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. METHODS The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. FINDINGS Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). INTERPRETATION This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.

Postconcussional Disorder Following Mild to Moderate Traumatic Brain Injury: Anxiety, Depression, and Social Support as Risk Factors and Comorbidities

Previous studies of postconcussional disorder (PCD) have utilized a dimensional approach (i.e., number and/or severity ratings of symptoms) to study postconcussional symptoms. This study used a syndromal approach (modified form of the DSM-IV criteria) for investigating risk factors for developing PCD, 3-months postinjury. The head trauma requirement was waived in order to determine specificity of symptoms to traumatic brain injury. Preliminary results from this ongoing study indicated significant risk factors including female gender, poor social support, and elevated self-reported depressive symptoms at 1-month postinjury. Comorbidities included concurrent diagnosis of major depressive disorder and/or posttraumatic stress disorder. Hispanics were significantly less likely to develop PCD than other racial/ethnic groups. PCD resulted more frequently from motor vehicle accidents and assaults. Screening tests for PCD risk factors/comorbidities performed shortly after injury (i.e., during routine follow-up clinic appointments) coupled with appropriate referrals for psychoeducational interventions and support groups may avoid prolonged loss of productivity and poor perceived quality of life in these patients.

Depression and posttraumatic stress disorder at three months after mild to moderate traumatic brain injury

To investigate the frequency and risk factors of major depressive disorder (MDD) after mild to moderate traumatic brain injury (TBI), 69 TBI and 52 general trauma (GT) patients were prospectively recruited and studied at 3-months postinjury. There was a nonsignificant difference in the proportion of MDD patients in the TBI and GT groups. Therefore, a composite MDD group (TBI and GT patients) was compared to patients who were nondepressed. Female gender was related to MDD, but no other risk factors were identified. MDD was associated with disability (Glasgow Outcome Scale, Community Integration Questionnaire) and cognitive impairment. MDD was comorbid with posttraumatic stress disorder. Implications for postacute management of mild to moderate TBI are discussed.

Voxel-Based Analysis of Diffusion Tensor Imaging in Mild Traumatic Brain Injury in Adolescents

BACKGROUND AND PURPOSE: DTI of normal-appearing WM as evaluated by conventional MR imaging in mTBI has the potential to identify important regional abnormalities that relate to PCS. VBA was used to examine WM changes in acute mTBI. MATERIALS AND METHODS: WM was assessed between 1 and 6 days postinjury with voxel-based DTI analyses in 10 adolescent patients with mTBI and 10 age-matched control participants. In addition to the voxel-based group, analysis used to identify brain pathology across all patients with mTBI, 2 voxel-based linear regressions were performed. These analyses investigated the relation between 1) the ADC and PCS severity scores, and 2) ADC and scores on the BSI of emotional symptoms associated with mTBI. We hypothesized that frontotemporal WM changes would relate to symptoms associated with PCS and endorsed on the BSI. RESULTS: Patients with mTBI demonstrated significant reductions in ADC in several WM regions and in the left thalamus. As expected, no increases in ADC were found in any region of interest. All injury-affected regions showed decreased radial diffusivity, unchanged AD, and increased FA, which is consistent with axonal cytotoxic edema, reflective of acute injury. CONCLUSIONS: Whole-brain WM DTI measures can detect abnormalities in acute mTBI associated with PCS symptoms in adolescents.

Recommendations for the Use of Common Outcome Measures in Pediatric Traumatic Brain Injury Research

This article addresses the need for age-relevant outcome measures for traumatic brain injury (TBI) research and summarizes the recommendations by the inter-agency Pediatric TBI Outcomes Workgroup. The Pediatric Workgroups recommendations address primary clinical research objectives including characterizing course of recovery from TBI, prediction of later outcome, measurement of treatment effects, and comparison of outcomes across studies. Consistent with other Common Data Elements (CDE) Workgroups, the Pediatric TBI Outcomes Workgroup adopted the standard three-tier system in its selection of measures. In the first tier, core measures included valid, robust, and widely applicable outcome measures with proven utility in pediatric TBI from each identified domain including academics, adaptive and daily living skills, family and environment, global outcome, health-related quality of life, infant and toddler measures, language and communication, neuropsychological impairment, physical functioning, psychiatric and psychological functioning, recovery of consciousness, social role participation and social competence, social cognition, and TBI-related symptoms. In the second tier, supplemental measures were recommended for consideration in TBI research focusing on specific topics or populations. In the third tier, emerging measures included important instruments currently under development, in the process of validation, or nearing the point of published findings that have significant potential to be superior to measures in the core and supplemental lists and may eventually replace them as evidence for their utility emerges.

Longitudinal Changes in the Corpus Callosum following Pediatric Traumatic Brain Injury

Background: Atrophy of the corpus callosum (CC) is a documented consequence of moderate-to-severe traumatic brain injury (TBI), which has been expressed as volume loss using quantitative magnetic resonance imaging (MRI). Other advanced imaging modalities such as diffusion tensor imaging (DTI) have also detected white matter microstructural alteration following TBI in the CC. The manner and degree to which macrostructural changes such as volume and microstructural changes develop over time following pediatric TBI, and their relation to a measure of processing speed is the focus of this longitudinal investigation. As such, DTI and volumetric changes in the CC in participants with TBI and a comparison group at approximately 3 and 18 months after injury as well as their relation to processing speed were determined. Methods: Forty-eight children and adolescents aged 7–17 years who sustained either complicated mild or moderate-to-severe TBI (n = 23) or orthopedic injury (OI; n = 25) were studied. The participants underwent brain MRI and were administered the Eriksen flanker task at both time points. Results: At 3 months after injury, there were significant group differences in DTI metrics in the total CC and its subregions (genu/anterior, body/central and splenium/posterior), with the TBI group demonstrating significantly lower fractional anisotropy (FA) and a higher apparent diffusion coefficient (ADC) in comparison to the OI group. These group differences were also present at 18 months after injury in all CC subregions, with lower FA and a higher ADC in the TBI group. In terms of longitudinal changes in DTI, despite the group difference in mean FA, both groups generally demonstrated a modest increase in FA over time though this increase was only significant in the splenium/posterior subregion. Interestingly, the TBI group also generally demonstrated ADC increases from 3 to 18 months though the OI group demonstrated ADC decreases over time. Volumetrically, the group differences at 3 months were marginal for the midanterior and body/central subregions and total CC. However, by 18 months, the TBI group demonstrated a significantly decreased volume in all subregions except the splenium/posterior area relative to the OI group. Unlike the OI group, which showed a significant volume increase in subregions of the CC over time, the TBI group demonstrated a significant and consistent volume decrease. Performance on a measure of processing speed did not differentiate the groups at either visit, and only the OI group showed significantly improved performance over time. Processing speed was related to FA in the splenium/posterior and total CC only in the TBI group on both occasions, with a stronger relation at 18 months. Conclusion: In response to TBI, macrostructural volume loss in the CC occurred over time; yet, at the microstructural level, DTI demonstrated both indicators of continued maturation and development even in the damaged CC, as well as evidence of potential degenerative change. Unlike volumetrics, which likely reflects the degree of overall neuronal loss and axonal damage, DTI may reflect some aspects of postinjury maturation and adaptation in white matter following TBI. Multimodality imaging studies may be important to further understand the long-term consequences of pediatric TBI.

Validity and Sensitivity to Change of the Extended Glasgow Outcome Scale in Mild to Moderate Traumatic Brain Injury

Using a structured outcome interview, this study addressed the validity and sensitivity to change of the Glasgow Outcome Scale (GOS) and the Extended GOS (GOSE) in a prospective study of patients who sustained mild (n = 30) to moderate (n = 13) traumatic brain injury (TBI) or general trauma (n = 44). The patients were recruited from the emergency center or inpatient units of Ben Taub General Hospital and invited to participate in follow-up examinations at 3 and 6 months. Using a series of functional outcome measures, assessment of affective status, and neuropsychological tests as criteria, the validity of the GOSE generally exceeded the GOS. Analysis of the outcome data for the patients who completed both the 3-month and 6-month assessments disclosed that the GOSE was more sensitive to change than the GOS. Comparison of the 3-month outcome data disclosed that the GOSE and GOS scores did not differ for the TBI and general trauma groups. These findings lend further support for utilization of the GOSE in clinical trials when it is based on a structured interview.

Evaluating the Relationship between Memory Functioning and Cingulum Bundles in Acute Mild Traumatic Brain Injury Using Diffusion Tensor Imaging

Compromised memory functioning is one of the commonly reported cognitive sequelae seen following mild traumatic brain injury (mTBI). Diffusion tensor imaging (DTI) has been shown to be sufficiently sensitive at detecting early microstructural pathological alterations after mTBI. Given its location and shape, the cingulate, which is comprised of the cingulate gyrus (gray matter) and cingulum bundles (white matter), is selectively vulnerable to mTBI. In this study we examined the integrity of cingulum bundles using DTI, and the relationship between cingulum bundles and memory functioning. Twelve adolescents with mTBI and 11 demographically-matched healthy controls were studied. All participants with mTBI had a Glasgow Coma Scale score of 15, and were without intracranial findings on CT scan. Brain scans were performed on average 2.92 days post-injury, and all participants were administered the Verbal Selective Reminding Test (VSRT), an episodic verbal learning and memory task. Participants with mTBI had a significantly lower apparent diffusion coefficient (ADC) bilaterally than controls (p < 0.001). Despite the marginal significance of the group difference in fractional anisotropy (FA), the effect size between groups was moderate (d = 0.66). Cognitively, healthy controls performed better than the TBI group on immediate and delayed recall; however, the difference did not reach statistical significance. In the mTBI group, FA of the left cingulum bundle was significantly correlated with 30-min delayed recall (r = -0.56, p = 0.05). A marginally significant correlation was found between ADC of the left cingulum bundle and the total words of immediate recall (r = 0.59, p = 0.07). No significant correlation was found between DTI metrics and memory functioning for the control group. These preliminary findings indicate that cingulate injury likely contributes to the cognitive sequelae seen during the early phase post-mTBI.