Predicting Clinical Outcomes 7-10 Years after Severe Traumatic Brain Injury: Exploring the Prognostic Utility of the IMPACT Lab Model and Cerebrospinal Fluid UCH-L1 and MAP-2.

BACKGROUND: Severe traumatic brain injury (TBI) is a major contributor to disability and mortality in the industrialized world. Outcomes of severe TBI are profoundly heterogeneous, complicating outcome prognostication. Several prognostic models have been validated for acute prediction of 6-month global outcomes following TBI (e.g., morbidity/mortality). In this preliminary observational prognostic study, we assess the utility of the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) Lab model in predicting longer term global and cognitive outcomes (7-10 years post injury) and the extent to which cerebrospinal fluid (CSF) biomarkers enhance outcome prediction. METHODS: Very long-term global outcome was assessed in a total of 59 participants (41 of whom did not survive their injuries) using the Glasgow Outcome Scale-Extended and Disability Rating Scale. More detailed outcome information regarding cognitive functioning in daily life was collected from 18 participants surviving to 7-10 years post injury using the Cognitive Subscale of the Functional Independence Measure. A subset (n = 10) of these participants also completed performance-based cognitive testing (Digit Span Test) by telephone. The IMPACT lab model was applied to determine its prognostic value in relation to very long-term outcomes as well as the additive effects of acute CSF ubiquitin C-terminal hydrolase-L1 (UCH-L1) and microtubule associated protein 2 (MAP-2) concentrations. RESULTS: The IMPACT lab model discriminated favorable versus unfavorable 7- to 10-year outcome with an area under the receiver operating characteristic curve of 0.80. Higher IMPACT lab model risk scores predicted greater extent of very long-term morbidity (ß = 0.488 p = 0.000) as well as reduced cognitive independence (ß = - 0.515, p = 0.034). Acute elevations in UCH-L1 levels were also predictive of lesser independence in cognitive activities in daily life at very long-term follow-up (ß = 0.286, p = 0.048). Addition of two CSF biomarkers significantly improved prediction of very long-term neuropsychological performance among survivors, with the overall model (including IMPACT lab score, UCH-L1, and MAP-2) explaining 89.6% of variance in cognitive performance 7-10 years post injury (p = 0.008). Higher acute UCH-L1 concentrations were predictive of poorer cognitive performance (ß = - 0.496, p = 0.029), whereas higher acute MAP-2 concentrations demonstrated a strong cognitive protective effect (ß = 0.679, p = 0.010). CONCLUSIONS: Although preliminary, results suggest that existing prognostic models, including models with incorporation of CSF markers, may be applied to predict outcome of severe TBI years after injury. Continued research is needed examining early predictors of longer-term outcomes following TBI to identify potential targets for clinical trials that could impact long-ranging functional and cognitive outcomes.

Longitudinal Changes in Disability Rating Scale Scores: A Secondary Analysis Among Patients With Severe TBI Enrolled in the Epo Clinical Trial.

OBJECTIVES: Long-term neurological response to treatment after a severe traumatic brain injury (sTBI) is a dynamic process. Failure to capture individual heterogeneity in recovery may impact findings from single endpoint sTBI randomized controlled trials (RCT). The present study re-examined the efficacy of erythropoietin (Epo) and transfusion thresholds through longitudinal modeling of sTBI recovery as measured by the Disability Rating Scale (DRS). This study complements the report of primary outcomes in the Epo sTBI RCT, which failed to detect significant effects of acute treatment at 6 months post-injury. METHODS: We implemented mixed effects models to characterize the recovery time-course and to examine treatment efficacy as a function of time post-injury and injury severity. RESULTS: The inter-quartile range (25th-75th percentile) of DRS scores was 20-28 at week1; 8-24 at week 4; and 3-17 at 6 months. TBI severity group was found to significantly interact with Epo randomization group on mean DRS recovery curves. No significant differences in DRS recovery were found in transfusion threshold groups. CONCLUSIONS: This study demonstrated the value of taking a comprehensive view of recovery from sTBI in the Epo RCT as a temporally dynamic process that is shaped by both treatment and injury severity, and highlights the importance of the timing of primary outcome measurement. Effects of Epo treatment varied as a function of injury severity and time. Future studies are warranted to understand the possible moderating influence of injury severity on treatment effects pertaining to sTBI recovery. (JINS, 2019, 25, 293-301).

Biomarkers improve clinical outcome predictors of mortality following non-penetrating severe traumatic brain injury.

OBJECTIVE: This study assessed whether early levels of biomarkers measured in CSF within 24-h of severe TBI would improve the clinical prediction of 6-months mortality. METHODS: This prospective study conducted at two Level 1 Trauma Centers enrolled adults with severe TBI (GCS ≤8) requiring a ventriculostomy as well as control subjects. Ventricular CSF was sampled within 24-h of injury and analyzed for seven candidate biomarkers (UCH-L1, MAP-2, SBDP150, SBDP145, SBDP120, MBP, and S100B). The International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) scores (Core, Extended, and Lab) were calculated for each patient to determine risk of 6-months mortality. The IMPACT models and biomarkers were assessed alone and in combination. RESULTS: There were 152 patients enrolled, 131 TBI patients and 21 control patients. Thirty six (27 %) patients did not survive to 6 months. Biomarkers were all significantly elevated in TBI versus controls (p < 0.001). Peak levels of UCH-L1, SBDP145, MAP-2, and MBP were significantly higher in non-survivors (p < 0.05). Of the seven biomarkers measured at 12-h post-injury MAP-2 (p = 0.004), UCH-L1 (p = 0.024), and MBP (p = 0.037) had significant unadjusted hazard ratios. Of the seven biomarkers measured at the earliest time within 24-h, MAP-2 (p = 0.002), UCH-L1 (p = 0.016), MBP (p = 0.021), and SBDP145 (0.029) had the most significant elevations. When the IMPACT Extended Model was combined with the biomarkers, MAP-2 contributed most significantly to the survival models with sensitivities of 97-100 %. CONCLUSIONS: These data suggest that early levels of MAP-2 in combination with clinical data provide enhanced prognostic capabilities for mortality at 6 months.

Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: effect of availability of exception from informed consent.

BACKGROUND: The Final Rule regulations were developed to allow exception from informed consent (EFIC) to enable clinical trial research in emergency settings where major barriers exist for informed consent. There is little known evidence of the effect of the Final Rule in minority enrollment in clinical trials, particularly in traumatic brain injury (TBI) trials. A clinical trial funded by the National Institute of Neurological Disorders and Stroke was conducted to study the effects of erythropoietin on cerebral vascular dysfunction and anemia in subjects with TBI. There were periods of time when EFIC was and was not available for enrollment into the study. PURPOSE: To explore the effect of EFIC availability on TBI trial enrollment of minority versus non-minority subjects. METHODS: Minority status of screened (n = 289) and enrolled (n = 191) TBI subjects was determined for this study. We tested for the presence of a minority and EFIC availability interaction in a multiple logistic regression model after controlling for EFIC and minority group main effects and other covariates. RESULTS: An interaction between the availability of EFIC minority and non-minority enrollment was not detected (odds ratio = 1.22; 95% confidence interval (CI) = 0.29-5.16). LIMITATIONS: Our study was conducted at a single site, and the CI for the EFIC and minority interaction term was wide. Therefore, a small interaction effect cannot be ruled out. CONCLUSION: EFIC increased the odds of being enrolled regardless of minority status.

Preinjury coping, emotional functioning, and quality of life following uncomplicated and complicated mild traumatic brain injury.

OBJECTIVE: To identify preinjury coping profiles among adults with uncomplicated mild traumatic brain injury (mTBI) and complicated mTBI and to determine whether preinjury coping profiles contribute to the prediction of emotional functioning and quality of life (QOL) 3 months post-mTBI. PARTICIPANTS: One hundred eighty-seven persons with medically documented mTBI (uncomplicated mTBI, n = 89; complicated mTBI, n = 98) were recruited from the emergency center of a level I trauma center and followed in community 3 months post-mTBI. MEASURES: The Ways of Coping Questionnaire was administered within 2 weeks of injury. Cluster analysis was used to group participants on basis of their preinjury use of problem-focused and avoidant coping strategies. The Brief Symptom Inventory and the 36-item Short-Form Health Survey were administered 3 months postinjury. RESULTS: Cluster analysis distinguished 3 distinct preinjury coping profiles that were differentially associated with outcomes. Participants who used avoidant coping showed the worse emotional functioning and QOL outcomes, although this cluster also reported high usage of problem-focused strategies. Preinjury coping profiles explained a significant proportion of the variance in depression, anxiety, and mental health QOL at 3 months postinjury beyond that accounted for by demographic characteristics and mTBI severity. CONCLUSIONS: Cluster analysis holds practical value in illustrating the pattern of coping strategies used by person with uncomplicated and complicated mTBI. It appears worthwhile to address coping in future trials of interventions that are aimed at improving emotional functioning after mTBI.

Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial.

IMPORTANCE: There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury. OBJECTIVE: To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL. INTERVENTIONS: Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells. MAIN OUTCOMES AND MEASURES: Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury. RESULTS: There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, -0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009). CONCLUSIONS AND RELEVANCE: In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313716.

The effect of blood alcohol level and preinjury chronic alcohol use on outcome from severe traumatic brain injury in Hispanics, anglo-Caucasians, and African-americans.

OBJECTIVE: To examine (a) ethnic differences in blood alcohol level (BAL) and preinjury chronic alcohol use (PI-ETOH) within a severe closed head injury (CHI) sample and (b) the main and interaction effects of BAL, PI-ETOH, and ethnicity on functional outcome following severe CHI. PARTICIPANTS: A total of 434 Hispanic, Anglo-Caucasian, and African-American individuals with severe CHI. DESIGN: Retrospective cohort study. SETTING: Consecutive admissions to a level 1 trauma center. MAIN MEASURES: After admission to the trauma center, BAL was collected for each patient. Additional information regarding PI-ETOH was collected in a subset of patients (N = 116). Functional outcome was measured using the Disability Rating Scale (DRS) at 6 months after injury. RESULTS: A one-way analysis of variance revealed ethnic differences in mean BAL. Hierarchical multiple regression indicated that BAL did not predict DRS outcomes after controlling for pertinent covariates. An interaction effect between PI-ETOH and ethnicity was observed, such that presence of chronic alcohol use predicted worse functional outcome for Anglo-Caucasians and African-Americans, but more favorable outcome for Hispanics. CONCLUSIONS: Ethnic differences in BALs within our severe traumatic brain injury sample mirrored ethnic drinking patterns observed in the general population, with Hispanics having the highest BALs. A paradoxical relationship between PI-ETOH and functional outcome was observed for Hispanics.

Disability Rating Scale in the First Few Weeks After a Severe Traumatic Brain Injury as a Predictor of 6-Month Functional Outcome.

BACKGROUND: An early acute marker of long-term neurological outcome would be useful to help guide clinical decision making and therapeutic effectiveness after severe traumatic brain injury (TBI). We investigated the utility of the Disability Rating Scale (DRS) as early as 1 wk after TBI as a predictor of favorable 6-mo Glasgow Outcome Scale extended (GOS-E). OBJECTIVE: To determine the predictability of a favorable 6-mo GOS-E using the DRS measured during weeks 1 to 4 of injury. METHODS: The study is a sub analysis of patients enrolled in the Epo Severe TBI Trial (n = 200) to train and validate L1-regularized logistic regression models. DRS was collected at weeks 1 to 4 and GOS-E at 6 mo. RESULTS: The average area under the receiver operating characteristic curve was 0.82 for the model with baseline demographic and injury severity variables and week 1 DRS and increased to 0.88 when including weekly DRS until week 4. CONCLUSION: This study suggests that week 1 to 4 DRS may be predictors of favorable 6-mo outcome in severe TBI patients and thus useful both for clinical prognostication as well as surrogate endpoints for adaptive clinical trials.

Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury.

OBJECTIVE: Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome. DESIGN: This study was designed as prospective case control study. PATIENTS: This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons. SETTING: : Two hospital system level I trauma centers. MEASUREMENTS AND MAIN RESULTS: Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (+/-7.9) compared with 2.7 ng/mL (+/-0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score. CONCLUSIONS: These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

Bilingualism and attention: a study of balanced and unbalanced bilingual deaf users of American Sign Language and English.

Early deafness is thought to affect low-level sensorimotor processing such as selective attention, whereas bilingualism is thought to be strongly associated with higher order cognitive processing such as attention switching under cognitive load. This study explores the effects of bimodal-bilingualism (in American Sign Language and written English) on attention switching, in order to contrast the roles of bilingual proficiency and age of acquisition in relation to cognitive flexibility among deaf adults. Results indicated a strong high-proficiency bilingual advantage in the higher order attention task. The level of proficiency in 2 languages appears to be the driving force for cognitive flexibility. However, additional data are needed to reach conclusive interpretation for the influence of age of second language acquisition on higher order attention-switching ability and associated cognitive flexibility.

Glasgow Outcome Scale Measures and Impact on Analysis and Results of a Randomized Clinical Trial of Severe Traumatic Brain Injury.

The original unstructured Glasgow Outcome Scale (uGOS) and the newer structured interviews GOS and the Extended GOS (GOS-E) have been used widely as outcomes in severe traumatic brain injury (TBI) trials. We compared outcome categories (ranging from dead [D] to good recovery [GR]) for each measure in a randomized trial of transfusion threshold and the implications of measure choice and analysis methods for the results of the trial. We planned to explore patient symptomology possibly driving any discrepancies between the patient's uGOS and GOS scores. Category correspondence between uGOS and GOS scores occurred in 160 (88.4%) of the 181 analyzed cases. The GOS-E and GOS instruments incorporated more behavioral/cognitive/social and other components, leading to a worse outcome in some cases than for the uGOS. Choice of outcome measure and analysis led to incongruous conclusions. Dichotomizing uGOS into favorable outcome (GR and moderate disability [MD] categories) versus unfavorable (severe disability [SD], vegetative state [VS], and D categories), we observed a significant effect of transfusion threshold (odds ratio [OR] = 0.51, p = 0.03; adjusted OR = 0.40, p = 0.02). For the same dichotomization of GOS and GOS-E, the effect was not statistically significant but the ORs were similar (ORs between 0.57 and 0.68, p > 0.15 for all). An effect was not detected using ordinal logistic regression or sliding dichotomy method for all three measures. Differences in categorizations of subjects between moderate and severe disability among the scales impacted conclusions of the trial. In future studies, particular attention should be given to implementing GOS measures and describing the methodology for how outcomes were ascertained.

Auditory interhemispheric transfer in relation to patterns of partial agenesis and hypoplasia of the corpus callosum in spina bifida meningomyelocele.

Spina bifida meningomyelocele with hydrocephalus (SBM) is commonly associated with anomalies of the corpus callosum (CC). We describe MRI patterns of regional CC agenesis and relate CC anomalies to functional laterality based on a dichotic listening test in 90 children with SBM and 27 typically developing controls. Many children with SBM (n = 40) showed regional CC anomalies in the form of agenesis of the rostrum and/or splenium, and a smaller number (n = 20) showed hypoplasia (thinning) of all CC regions (rostrum, genu, body, and splenium). The expected right ear advantage (REA) was exhibited by normal controls and children with SBM having a normal or hypoplastic splenium. It was not shown by children with SBM who were left handed, missing a splenium, or had a higher level spinal cord lesion. Perhaps the right hemisphere of these children is more involved in processing some aspects of linguistic stimuli.

Sleep disturbances and internalizing behavior problems following pediatric traumatic injury.

OBJECTIVE: This prospective longitudinal study investigated sleep disturbance (SD) and internalizing problems after traumatic injury, including traumatic brain injury (TBI) or extracranial/bodily injury (EI) in children and adolescents, relative to typically developing (TD) children. We also examined longitudinal relations between SD and internalizing problems postinjury. METHOD: Participants (N = 87) ages 8-15 included youth with TBI, EI, and TD children. Injury groups were recruited from a Level 1 trauma center after sustaining vehicle-related injuries. Parent-reported SD and internalizing problems were assessed at preinjury/baseline, and 6 and 12 months postinjury. Linear mixed models evaluated the relation of group and time of assessment on outcomes. RESULTS: Controlling for age, the combined traumatic injury group experienced significantly higher postinjury levels of SD (p = .042) and internalizing problems (p = .024) than TD children; however, TBI and EI injury groups did not differ from each other. Injury severity was positively associated with SD in the EI group only, but in both groups SD was associated with additional postinjury sequelae, including fatigue and externalizing behavior problems. Internalizing problems predicted subsequent development of SD but not vice versa. The relation between injury and SD 1 year later was consistent with mediation by internalizing problems at 6 months postinjury. CONCLUSIONS: Children with both types of traumatic injury demonstrated higher SD and internalizing problems than healthy children. Internalizing problems occurring either prior to or following pediatric injury may be a risk factor for posttraumatic SD. Consequently, internalizing problems may be a promising target of intervention to improve both SD and related adjustment concerns. (PsycINFO Database Record

Temporal Profile of Microtubule-Associated Protein 2: A Novel Indicator of Diffuse Brain Injury Severity and Early Mortality after Brain Trauma.

This study compared cerebrospinal fluid (CSF) levels of microtubule-associated protein 2 (MAP-2) from adult patients with severe traumatic brain injury (TBI) with uninjured controls over 10 days, and examined the relationship between MAP-2 concentrations and acute clinical and radiologic measures of injury severity along with mortality at 2 weeks and over 6 months. This prospective study, conducted at two Level 1 trauma centers, enrolled adults with severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring a ventriculostomy, as well as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 h following TBI and analyzed via enzyme-linked immunosorbent assay for MAP-2 (ng/mL). Injury severity was assessed by the GCS score, Marshall Classification on computed tomography (CT), Rotterdam CT score, and mortality. There were 151 patients enrolled-130 TBI and 21 control patients. MAP-2 was detectable within 6 h of injury and was significantly elevated compared with controls (p < 0.001) at each time-point. MAP-2 was highest within 72 h of injury and decreased gradually over 10 days. The area under the receiver operating characteristic curve for deciphering TBI versus controls at the earliest time-point CSF was obtained was 0.96 (95% CI 0.93-0.99) and for the maximal 24-h level was 0.98 (95% CI 0.97-1.00). The area under the curve for initial MAP-2 levels predicting 2-week mortality was 0.80 at 6 h, 0.81 at 12 h, 0.75 at 18 h, 0.75 at 24 h, and 0.80 at 48 h. Those with Diffuse Injury III-IV had much higher initial (p = 0.033) and maximal (p = 0.003) MAP-2 levels than those with Diffuse Injury I-II. There was a graded increase in the overall levels and peaks of MAP-2 as the degree of diffuse injury increased within the first 120 h post-injury. These data suggest that early levels of MAP-2 reflect severity of diffuse brain injury and predict 2-week mortality in TBI patients. These findings have implications for counseling families and improving clinical decision making early after injury and guiding multidisciplinary care. Further studies are needed to validate these findings in a larger sample.

Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury.

Following traumatic brain injury (TBI), the cytoskeletal protein alpha-II-spectrin is proteolyzed by calpain and caspase-3 to signature breakdown products. To determine whether alpha -II-spectrin proteolysis is a potentially reliable biomarker for TBI in humans, the present study (1) examined levels of spectrin breakdown products (SBDPs) in cerebrospinal fluid (CSF) from adults with severe TBI and (2) examined the relationship between these levels, severity of injury, and clinical outcome. This prospective case control study enrolled 41 patients with severe TBI, defined by a Glasgow Coma Scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring. Patients without TBI requiring CSF drainage for other medical reasons served as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, and 120 h following TBI and analyzed for SBDPs. Outcome was assessed using the Glasgow Outcome Score (GOS) 6 months after injury. Calpain and caspase-3 mediated SBDP levels in CSF were significantly increased in TBI patients at several time points after injury, compared to control subjects. The time course of calpain mediated SBDP150 and SBDP145 differed from that of caspase-3 mediated SBDP120 during the post-injury period examined. Mean SBDP densitometry values measured early after injury correlated with severity of injury, computed tomography (CT) scan findings, and outcome at 6 months post-injury. Taken together, these results support that alpha -II-spectrin breakdown products are potentially useful biomarker of severe TBI in humans. Our data further suggests that both necrotic/oncotic and apoptotic cell death mechanisms are activated in humans following severe TBI, but with a different time course after injury.

Plasticity of Interhemispheric Temporal Lobe White Matter Pathways Due to Early Disruption of Corpus Callosum Development in Spina Bifida.

Spina bifida myelomeningocele (SBM) is commonly associated with anomalous development of the corpus callosum (CC) because of congenital partial hypogenesis and hydrocephalus-related hypoplasia. It represents a model disorder to examine the effects of early disruption of CC neurodevelopment and the plasticity of interhemispheric white matter connections. Diffusion tensor imaging was acquired on 76 individuals with SBM and 27 typically developing individuals, aged 8-36 years. Probabilistic tractography was used to isolate the interhemispheric connections between the posterior superior temporal lobes, which typically traverse the posterior third of the CC. Early disruption of CC development resulted in restructuring of interhemispheric connections through alternate commissures, particularly the anterior commissure (AC). These rerouted fibers were present in people with SBM and both CC hypoplasia and hypogenesis. In addition, microstructural integrity was reduced in the interhemispheric temporal tract in people with SBM, indexed by lower fractional anisotropy, axial diffusivity, and higher radial diffusivity. Interhemispheric temporal tract volume was positively correlated with total volume of the CC, such that more severe underdevelopment of the CC was associated with fewer connections between the posterior temporal lobes. Therefore, both the macrostructure and microstructure of this interhemispheric tract were reduced, presumably as a result of more extensive CC malformation. The current findings suggest that early disruption in CC development reroutes interhemispheric temporal fibers through both the AC and more anterior sections of the CC in support of persistent hypotheses that the AC may serve a compensatory function in atypical CC development.

Spinal lesion level in spina bifida: a source of neural and cognitive heterogeneity.

OBJECT: The aim of this study was to evaluate whether the level of a spinal lesion is associated with variations in anomalous brain development and neurobehavioral outcomes in children suffering from the meningomyelocele form of spina bifida and hydrocephalus (SBM-H). METHODS: Two hundred sixty-eight children with SBM-H were divided into upper (T-12 and above; 82 patients) and lower (L-1 and below; 186 patients) lesion-level groups. Magnetic resonance images were qualitatively coded by radiologists and quantitatively segmented for cerebrum and cerebellum volumes. Psychometric assessments of handedness, intelligence, academic skills, and adaptive behavior were compared between lesion-level groups and also used to determine the number of children who met research-based criteria for mental retardation, attention deficit hyperactivity disorder, and learning disabilities. The magnetic resonance images obtained in children with upper-level spinal lesions demonstrated more qualitative abnormalities in the midbrain and tectum, pons, and splenium, although not in the cerebellum, compared with images obtained in children with lower-level spinal lesions. Upper-level lesions were also associated with reductions in cerebrum and cerebellum volumes, lower scores on measures of intelligence, academic skills, and adaptive behavior, and with a higher frequency of individuals meeting the criteria for mental retardation. Hispanic children (who were also more economically disadvantaged) were more likely to have upper-level lesions and poorer neurobehavioral outcomes, but lesion-level effects were generally independent of ethnicity. CONCLUSIONS: A higher level of spinal lesion in SBM-H is a marker for more severe anomalous brain development, which is in turn associated with poorer neurobehavioral outcomes in a wide variety of domains that determine levels of independent functioning for these children at home and school.

Attention problems and executive functions in children with spina bifida and hydrocephalus.

This study addressed the incidence of Attention-Deficit/Hyperactivity Disorder (ADHD) subtypes in children with spina bifida meningomyelocele and shunted hydrocephalus (SBH) as well as differences in executive functions among these subtypes. Parent rating scales revealed that 31% of the group with SBH could be identified with AD/HD, mostly the Inattentive type (23%). The group with SBH differed from normal controls on cognitive measures of executive functions, but subtype differences were not significant. Multivariate tests showed that children with SBH were rated with greater difficulties on the Behavior Rating Inventory of Executive Function (BRIEF) compared to controls; those with SBH and any subtype of ADHD differed from those with SBH and no ADHD; and those with ADHD (Combined Type) differed significantly from those with ADHD (Predominantly Inattentive Type). Subtype differences on univariate tests in the latter comparison were significant on the BRIEF Inhibit scale, showing more disinhibition in those with SBH and ADHD (Combined Type), but no significant differences were apparent on the BRIEF Sustain, Shift, and Initiate scales. The results show that the incidence of ADHD in children with SBH exceeds the population rate, is represented by problems with inattention rather than with impulsivity and hyperactivity; and that as with non-brain injured individuals, subtype differences in cognitive function remain to more clearly delineated.

Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury.

BACKGROUND: The effect of red blood cell (RBC) storage on oxygenation in critically ill patients is still unknown. The objective of this study was to determine the association of RBC storage with oxygenation, long-term neurologic recovery, and death after traumatic brain injury. METHODS: We used data from a 2 × 2 factorial randomized controlled trial of administration of erythropoietin or placebo and of assignment to transfusion threshold of less than 7g/dL or less than 10 g/dL in neurosurgical intensive care units in two US Level 1 trauma centers. Patients had severe traumatic brain injury with closed head injury, were unable to follow commands, and were enrolled within 6 hours of injury. Blood oxygenation 1 hour after the transfusion as measured by jugular venous oxygen saturation (n = 59) was the primary outcome. Secondary outcomes were brain tissue oxygenation (n = 77), 6-month Glasgow Outcome Scale (GOS) score (n = 122) collected using a structured interview and dichotomized into favorable (good recovery or moderate disability) or unfavorable outcome (severe disability, vegetative state, or dead), and mortality (n = 125). RBC age was defined as the maximum age of RBCs over all units in one transfusion per patient. For long-term outcomes, RBC age was defined as the mean age over all units given. RESULTS: We failed to detect an association of RBC age with jugular venous oxygen saturation (linear regression ß = 1.59; 95% confidence interval [CI], -2.99 to 6.18; p = 0.49), brain tissue oxygenation (linear regression ß = 0.20; 95% CI, -0.23 to 0.63; p = 0.36), GOS score (odds ratio, 1.37; 95% CI, 0.53-3.57; p = 0.52), and mortality (hazard ratio, 1.35; 95% CI, 0.61-2.98; p = 0.46). CONCLUSION: Limitations of this study include the fact that the RBC ages were not randomized, although this was a prospective study. We conclude that older blood does not seem to have adverse effects in severe traumatic brain injury. LEVEL OF EVIDENCE: Prognostic study, level III.

Effect of Hemoglobin Transfusion Threshold on Cerebral Hemodynamics and Oxygenation.

Cerebral dysfunction caused by traumatic brain injury may adversely affect cerebral hemodynamics and oxygenation leading to worse outcomes if oxygen capacity is decreased due to anemia. In a randomized clinical trial of 200 patients comparing transfusion thresholds <7 g/dl versus 10 g/dl, where transfusion of leukoreduced packed red blood cells was used to maintain the assigned hemoglobin threshold, no long-term neurological difference was detected. The current study examines secondary outcome measures of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain tissue oxygenation (PbtO2) in patients enrolled in this randomized clinical trial. We observed a lower hazard for death (hazard ratio [HR]=0.12, 95% confidence interval [CI]=0.02-0.99) during the first 3 days post-injury, and a higher hazard for death after three days (HR=2.55, 95% CI=1.00-6.53) in the 10 g/dl threshold group as compared to the 7 g/dL threshold group. No significant differences were observed for ICP and CPP but MAP was slightly lower in the 7 g/dL group, although the decreased MAP did not result in increased hypotension. Overall brain tissue hypoxia events were not significantly different in the two transfusion threshold groups. When the PbtO2 catheter was placed in normal brain, however, tissue hypoxia occurred in 25% of patients in the 7 g/dL threshold group, compared to 10.2% of patients in the 10 g/dL threshold group (p=0.04). Although we observed a few differences in hemodynamic outcomes between the transfusion threshold groups, none were of major clinical significance and did not affect long-term neurological outcome and mortality.