Caryn R. Harper

Physiologic and functional outcome correlates of brain tissue hypoxia in traumatic brain injury

Objective:Assess the prevalence of brain tissue hypoxia in patients with severe traumatic brain injuries (TBI), and to characterize the relationship between brain tissue hypoxia and functional outcome. Design:Retrospective review of severe TBI patients. Setting:Intensive care unit of a level I trauma center. Patients:Twenty-seven patients with severe TBI requiring intracranial pressure (ICP) monitoring. Median age was 22 yrs, and a majority (63%) had traumatic subarachnoid hemorrhage. Interventions:Hourly assessments of ICP, brain tissue oxygen, mean arterial pressure, fraction of inspired oxygen (Fio2), partial pressure of arterial carbon dioxide (Paco2), and hemoglobin concentration (hemoglobin) were recorded. Outcome was assessed 6–9 months postinjury. Measurements and Main Results:Mean (sd) ICP and BTpo2 were 13.7 (6.6) cm H2O and 30.8 (13.6) mm Hg. A total of 13.5% (379) of the BTpo2 values recorded were <20 mm Hg, only 86 of which were associated with ICP ≥20 cm H2O. This prevalence was comparable with episodes of ICP elevations above 20 cm H2O (14.1%, 397). Hypoxic episodes were more common when cerebral perfusion pressure was below 60 mm Hg (relative risk = 3.0, p < 0.0001). We did not find an association in hypoxic risk and hemoglobin in the range of 7–12 g/dL or Paco2 in the range of 25–40 mm Hg. Subjects with hourly episodes (epochs) of hypoxia >20% of the time had poorer scores on outcome measures compared with those with fewer hypoxic epochs. Conclusions:Hypoxic episodes are common after severe TBI, and most are independent of ICP elevations. Most episodes of hypoxia occur while cerebral perfusion pressure and mean arterial pressure are within the accepted target range. There is no clear association between Paco2 and hemoglobin with BTpo2. The young age and high prevalence of traumatic subarachnoid hemorrhage in this cohort may limit its generalizability. Increased frequency of hypoxic episodes is associated with poor functional outcome.

Impact of Age on Long-Term Recovery From Traumatic Brain Injury

OBJECTIVE To determine whether older persons are at increased risk for progressive functional decline after traumatic brain injury (TBI). DESIGN Longitudinal cohort study. SETTING Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers. PARTICIPANTS Subjects enrolled in the TBIMS national dataset. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Disability Rating Scale (DRS), FIM instrument cognitive items, and the Glasgow Outcome Scale-Extended. RESULTS Participants were separated into 3 age tertiles: youngest (16-26y), intermediate (27-39y), and oldest (> or =40y). DRS scores were comparable across age groups at admission to a rehabilitation center. The oldest group was slightly more disabled at discharge from rehabilitation despite having less severe acute injury severity than the younger groups. Although DRS scores for the 2 younger groups improved significantly from year 1 to year 5, the greatest magnitude of improvement in disability was seen among the youngest group. In addition, after dividing patients into groups according to whether their DRS scores improved (13%), declined (10%), or remained stable (77%) over time, the likelihood of decline was found to be greater for the 2 older groups than for the youngest group. A multiple regression model showed that age has a significant negative influence on DRS score 5 years post-TBI after accounting for the effects of covariates. CONCLUSIONS This study supported our primary hypothesis that older patients show greater decline over the first 5 years after TBI than younger patients. In addition, the greatest amount of improvement in disability was observed among the youngest group of survivors. These results suggest that TBI survivors, especially older patients, may be candidates for neuroprotective therapies after TBI.

Cerebral Atrophy after Traumatic White Matter Injury: Correlation with Acute Neuroimaging and Outcome

Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = -0.69, -0.59, -0.58, respectively; p <0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = -0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = -0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.

Regionally Selective Atrophy after Traumatic Axonal Injury

OBJECTIVES To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome. DESIGN Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging-based morphometric analysis. SETTING Inpatient traumatic brain injury unit. PATIENTS OR OTHER PARTICIPANTS Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls. MAIN OUTCOME MEASURE Changes in global and regional brain volumes between initial and follow-up magnetic resonance imaging were used to assess the spatial distribution of posttraumatic volume loss. The Glasgow Outcome Scale-Extended score was the primary measure of functional outcome. RESULTS Patients underwent substantial global atrophy with mean whole-brain parenchymal volume loss of 4.5% (95% confidence interval, 2.7%-6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole-brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus. CONCLUSION Traumatic axonal injury leads to substantial posttraumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.

Assessing Spatial Relationships between Axonal Integrity, Regional Brain Volumes, and Neuropsychological Outcomes after Traumatic Axonal Injury

Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearsons correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.

Evaluation of seizure-like episodes in survivors of moderate and severe traumatic brain injury.

Background:Transient paroxysmal alterations of consciousness or behavior are common sequelae of moderate and severe traumatic brain injury (TBI). Clinicians caring for patients with such episodes often diagnose them as epileptic seizures, a frequent and well-studied complication of TBI. As it is difficult to confirm this diagnosis, antiepileptic drugs are often used empirically. However, as such therapy is frequently ineffective, we studied the usefulness of prolonged video electroencephalogram (VEEG) monitoring in the clinical management of paroxysmal behaviors in TBI survivors. Methods:Records of patients referred evaluation in an epilepsy monitoring unit for management of medically intractable epilepsy were retrospectively reviewed. Patients with a documented history of moderate-to-severe brain injury preceding the onset of epilepsy were identified. These patients were studied by simultaneous videotape and scalp electroencephalographic recordings, and the majority also underwent magnetic resonance imaging and neuropsychologic studies. Results:Of the 1858 consecutive admissions over a 66-month period, 127 (7%) fulfilled enrollment criteria. VEEG monitoring was conducted for an average of 4.6 days. Monitoring was successful in establishing a diagnosis in 82% of the cases referred: 62% had focal seizures, 6% had generalized seizures, and 33% had psychogenic nonepileptic seizures. Of those with temporal lobe epilepsy, 53% had mesial temporal sclerosis, as shown by magnetic resonance imaging. Conclusions:VEEG is a useful procedure in the evaluation of TBI survivors with spells. The yield of diagnoses that may alter treatment is substantial. Additionally, mesial temporal sclerosis is associated with TBI. Given the variety of seizure types found in survivors of moderate-to-severe TBI, obtaining specific diagnosis of seizure type by VEEG monitoring impacts treatment options.

Ethnic differences in rehabilitation placement and outcome after TBI.

ObjectiveTo determine whether race/ethnicity and proficiency with the English language influence access to rehabilitation services, and ultimately outcome after traumatic brain injury (TBI). DesignA retrospective correlational investigation. Setting and ParticipantsPostrehabilitation outpatients with blunt TBI. A total of 476 patients were examined 6 months postinjury, of which 109 (23%) were Hispanics, and of those 42 were predominantly Spanish speaking. Main Outcome MeasuresAccess to rehabilitation services, Glasgow Outcome Scale-Extended. ResultsInsurance, age, and injury severity had the greatest influence on receipt of rehabilitation services; however, higher rates of severe disability were found among Hispanics and Spanish speakers than non-Hispanic whites and non-Hispanic English speakers, respectively. ConclusionsInsurance status has a larger influence on receipt of rehabilitation services than ethnicity or proficiency with the English language, but language proficiency is a significant predictor of severe disability.

Brain morphometry changes and depressive symptoms after traumatic brain injury

Traumatic brain injury (TBI) is associated with an increased risk of depressive symptoms. Recent imaging studies on spontaneous depression have implicated several brain structures; however, few studies have done the same for post-TBI depression. We report on a pilot observational study correlating atrophy of brain regions of interest in subjects after TBI with depressive symptoms measured by the Beck Depression Inventory-II. Regional brain volumes were calculated on both acute and 6-month MRI using an automated segmentation algorithm (FreeSurfer). Percent volume changes in brain regions were correlated with BDI-II scores using Spearmans rank order correlation coefficient. Correction for multiple comparisons was performed using the false discovery rate (FDR). Three regions of interest (left rostral anterior cingulate and bilateral orbitofrontal cortex) were found to be significantly correlated with depressive symptoms (FDR 0.05). With FDR 0.1, six regions were significantly correlated. The use of volumetric analysis of brain regions of interest to study post-TBI depression is worthy of further study. Regions associated with depressive symptoms in this pilot study were similar to those implicated in study of spontaneous depression.

Diffusion Tensor Imaging Biomarkers for Traumatic Axonal Injury: Analysis of Three Analytic Methods

Traumatic axonal injury (TAI) is a common mechanism of traumatic brain injury not readily identified using conventional neuroimaging modalities. Novel imaging modalities such as diffusion tensor imaging (DTI) can detect microstructural compromise in white matter (WM) in various clinical populations including TAI. DTI-derived data can be analyzed using global methods (i.e., WM histogram or voxel-based approaches) or a regional approach (i.e., tractography). While each of these methods produce qualitatively comparable results, it is not clear which is most useful in clinical research and ultimately in clinical practice. This study compared three methods of analyzing DTI-derived data with regard to detection of WM injury and their association with clinical outcomes. Thirty patients with TAI and 19 demographically similar normal controls were scanned using a 3 Tesla magnet. Patients were scanned approximately eight months postinjury, and underwent an outcomes assessment at that time. Histogram analysis of fractional anisotropy (FA) and mean diffusivity showed global WM integrity differences between patients and controls. Voxel-based and tractography analyses showed significant decreases in FA within centroaxial structures involved in TAI. All three techniques were associated with functional and cognitive outcomes. DTI measures of microstructural integrity appear robust, as the three analysis techniques studied showed adequate utility for detecting WM injury.

Nonverbal Learning Disabilities, Asperger's Syndrome, Pervasive Developmental Disorder — Should We Care?

From the Departments of Pathology, Neurology, Pediatrics, Psychiatry & Behavioral Sciences, and Orthopaedic Surgery (Dr Brumback), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, OK; the Department of Neurology (Ms Harper), University of Texas Southwestern Medical Center-Dallas; and the Departments of Neurology and Pediatrics (Dr Weinberg), University of Texas Southwestern Medical Center-Dallas, and Division of Pediatric Neurology, Children’s Medical Center of Dallas, TX. Address corresondence to Dr Roger A. Brumback, OUHSC-BMSB 451, 940 Stanton L. Young Boulevard, Oklahoma City, OK 73104-5042. Words are often considered the feature that differentiates