Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats

OBJECT: The authors tested the hypothesis that intracranial bone marrow (BM) transplantation after traumatic brain injury (TBI) in rats provides therapeutic benefit. METHODS: Sixty-six adult Wistar rats, weighing 275 to 350 g each, were used for the experiment. Bone marrow prelabeled with bromodeoxyuridine (BrdU) was harvested from tibias and femurs of healthy adult rats. Other animals were subjected to controlled cortical impact, and BM was injected adjacent to the contusion 24 hours after the impact. The animals were killed at 4, 7, 14, or 28 days after transplantation. Motor function was evaluated both before and after the injury by using the rotarod test. After the animals had been killed, brain sections were examined using hemotoxylin and eosin and immunohistochemical staining methods. Histological examination revealed that, after transplantation, BM cells survived, proliferated, and migrated toward the injury site. Some of the BrdU-labeled BM cells were reactive, with astrocytic (glial fibrillary acid protein) and neuronal (NeuN and microtubule-associated protein) markers. Transplanted BM expressed proteins phenotypical of intrinsic brain cells, that is, neurons and astrocytes. A statistically significant improvement in motor function in rats that underwent BM transplantation, compared with control rats, was detected at 14 and 28 days posttransplantation. CONCLUSIONS: On the basis of their findings, the authors assert that BM transplantation improves neurological outcome and that BM cells survive and express nerve cell proteins after TBI.     

Severe brief pressure-controlled hemorrhagic shock after traumatic brain injury exacerbates functional deficits and long-term neuropathological damage in mice

Abstract Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n=10/group): sham, HS, controlled cortical impact (CCI), and CCI+HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP]=25-27?mm Hg for 35?min) and its treatment after mild to moderate CCI including, a 90?min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP >70?mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14-20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n=60) at 24?h, 7 days, or 21 days (n=5/group/time point). HS reduced MAP during the shock phase in the HS and CCI+HS groups (p<0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI+HS group (p<0.05), and were increased in HS versus sham and CCI animals (p<0.05). MWM latency was increased on days 14 and 15 after CCI+HS (p<0.05). Swim speed and visible platform latency were impaired in the CCI+HS group (p<0.05). CCI+HS animals had increased contusion volume versus the CCI group (p<0.05). Hemispheric volume loss was increased 33.3% in the CCI+HS versus CCI group (p<0.05). CA1 cell loss was seen in CCI+HS and CCI animals at 24?h and 7 days (p<0.05). CA3 cell loss was seen after CCI+HS (p<0.05 at 24?h and 7 days). CA1 cell loss at 21 days was seen only in CCI+HS animals (p<0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.     

Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury

Presence of the apolipoprotein E (APOE) 4 allele has been associated with increased incidence and faster progression of neurodegenerative diseases, poorer recovery from neurologic insult, and decreased cognitive function in the well-elderly. The specific association between APOE genotype and recovery from severe traumatic brain injury (TBI) is conflicting with many groups finding the APOE 4 allele to be associated with poorer outcome while others have found no association. The purpose of this study was to investigate the association between APOE 4 allele presence and recovery during the two years after injury from severe TBI in light of other potential covariates, such as age, race, gender, hypotension or hypoxia before hospital admission and severity of injury. APOE genotype was determined for 123 subjects with severe TBI. Glasgow outcome score (GOS) and mortality were collected at 3, 6, 12, and 24 months after injury. Results showed individuals improved over the two year period following injury and those with the 4 allele had a slower recovery rate than those without the APOE 4 allele over the two year period. We did not however find significant differences in GOS at individual time points when controlling for other covariates. Our findings suggest that APOE 4 allele presence influences recovery rate from severe TBI independent of other covariates. The findings of this study are unique in that they address not only the relationship between APOE 4 allele presence and outcome from severe TBI, but also describe differences in trajectory of recovery by APOE 4 allele presence.     

Impact of clinically significant heterotopic ossification on functional outcome after traumatic brain injury.

OBJECTIVE: To assess heterotopic ossification's (HO) impact on functional outcome after TBI. DESIGN: Retrospective with matched control group, single center. SETTING: TBI Model System of Care at the Medical College of Virginia of Virginia Commonwealth University, Richmond, VA. PARTICIPANTS: Twenty-six patients with TBI and triple-phase bone scan confirmed HO were matched with 26 patients without clinical evidence of HO. MAIN OUTCOME MEASURES: Acute and rehabilitation lengths of stay (LOS), Admission and Discharge Functional Independence Measure (FIM) scores, FIM change, FIM efficiency (FIM gains per week), and discharge disposition. RESULTS: The two groups had similar acute care LOS. Patients with HO had significantly longer inpatient rehabilitation LOS and significantly lower FIM mobility and activities of daily living subscale scores on admission and discharge. FIM efficiency was significantly lower for the group with HO. Significantly fewer patients with HO were able to be discharged to home. CONCLUSIONS: HO is associated with a poorer functional outcome; however, it is not clear whether HO causes the decreased function or whether it may serve more generally as an indicator of those patients who will not progress as far or as rapidly during inpatient rehabilitation.     

Timing of surgery after multisystem injury with traumatic brain injury: effect on neuropsychological and functional outcome

OBJECTIVE: The optimal timing for noncranial surgery after multisystem injury is not known. Early surgery may lead to decreased pulmonary complications and length of stay, but also predispose to secondary brain injury if decreased cerebral perfusion occurs intraoperatively. Previous work has not consistently evaluated neuropsychological or functional outcome. We sought to determine whether 6-month neuropsychological and functional outcome was associated with timing of noncranial surgery after traumatic brain injury. MATERIALS: We performed a cohort study to evaluate the effect of timing of non-neurosurgical operative interventions on neuropsychological and functional outcome, morbidity, and mortality. Early surgery was defined as 24 hours after injury but during the same admission. Patients with a nonoperative brain injury and an operative facial or orthopedic fracture were selected from two randomized trials previously performed at our Level I trauma center. Data were abstracted from medical records and outcome had been prospectively gathered as part of the two clinical trials. RESULTS: Patients undergoing early or late surgery had similar demographics, overall injury severity, traumatic brain injury severity, and admission characteristics. The early group had more open orthopedic fractures, but also underwent multiple operations more often than did the late group. At 6 months postinjury, patients in the early group had a better composite neuropsychological score than did those in the late group on unadjusted analysis and after including a propensity score. After adjusting for potential confounders, this difference was significant. No significant differences in return to work or Glasgow Outcome Score were noted. The late group had a higher incidence of pneumonia and a longer hospital stay (p<0.10). CONCLUSIONS: In traumatic brain injury patients with multisystem trauma, early timing of orthopedic and facial fracture fixation under general anesthesia was not associated with worse neuropsychological or functional outcome when compared with the outcomes associated with late surgery. Clinical conclusions may be limited by inherent selection bias and unmeasured confounding. However, these results contribute to equipoise regarding timing of surgery after multiple injuries, and emphasize the need for a randomized trial.     

Depression, cognition, and functional correlates of recovery outcome after traumatic brain injury

The present study investigated the prevalence and magnitude of depressive symptomatology in a sample of patients who had sustained traumatic brain injury (TBI) six months eariler. Depression was examined as a function of recovery outcome status, and its association with neuropsychological functioning, personal competency, and employability was also explored. Subjects were 100 patients who had previously sustained moderate-to-severe TBI who were enrolled as research subjects in the UCLA Brain Injury Reserch Center, and 30 matched control subjects who had sustained traumtic injuries other than to the head six months prior to evaluation. The results showed a significant association between depression and recovery status as measured by the Glasgow Outcome Scale (GOS). A significant majority of depressed subjects were found in the poorer GOS outcome groups (severe and moderate disability), compared to TBI subjects who had good GOS outcomes, and control subjects. This association was also reflected in the magnitude of the mean depression scores on two self report measures of depression. However, no association was found between depression status and performance on the neuropsychological measures. Effects of depression were found only on an examiner-rated Patient Competency scale, and a metacognition measure based on self-report. These results are discussed in terms of brain injury severity, recovery status, and metacognition issues in TBI and other disorders.     

Functional outcome after violence related traumatic brain injury

Violent injuries have become an increasingly prevalent cause of traumatic brain injury TBI . These injuries can be classified as either penetrating or non penetrating in nature. While much of the research on violence has been within a military population, there exists a marked difference between military and civilian injuries. Prior work has reported relatively poor outcomes for those individuals who have suffered penetrating TBIs, but little has been done to assess specific functional outcome parameters in survivors. We examined 25 subjects that had sustained blunt injuries and 25 cases with penetrating injuries as a result of a violent act. Cases were matched by initial Glasgow Coma Scale GCS , age and educational level. Mean GCS for this study sample was 8.8. The following outcome variables were assessed at rehabilitation admission and discharge and at 1 year post injury: Disability Rating Scale DRS , Rancho Los Amigos Scale LCFS , Functional Independence Measure FIM ambulation, expression items , length of stay, and cost of care. Student s t tests were performed to assess for differences between the two groups. No significant differences were noted between the groups for any of the outcome variables. Although penetrating injuries may have a higher initial mortality, those who survive to come to rehabilitation appear to have similar outcomes to those patients with non penetrating violence related injuries.     

Long-term neuropsychological outcome after traumatic brain injury.

OBJECTIVE: To describe neuropsychological outcome 5 years after injury in persons with traumatic brain injury (TBI) who received inpatient medical rehabilitation. To determine the magnitude and pattern neuropsychological recovery from 1 year to 5 years after injury. DESIGN: Longitudinal cohort study with inclusion based on the availability of neuropsychological data at 1 year and 5 years after injury. SETTING: National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems of Care. PARTICIPANTS: One hundred eighty-two persons with complicated mild to severe traumatic brain injury. PRIMARY OUTCOME MEASURES: Digits Forward and Backward, Logical Memory I and II, Token Test, Controlled Oral Word Association Test, Symbol Digit Modalities Test, Trail Making Test, Rey Auditory Verbal Learning Test, Visual Form Discrimination, Block Design, Wisconsin Card Sorting Test, and Grooved Pegboard. RESULTS: Significant variability in outcome was found 5 years after TBI, ranging from no measurable impairment to severe impairment on neuropsychological tests. Improvement from 1 year after injury to 5 years was also variable. Using the Reliable Change Index, 22.2% improved, 15.2% declined, and 62.6% were unchanged on test measures. CONCLUSIONS: Neuropsychological recovery after TBI is not uniform across individuals and neuropsychological domains. For a subset of persons with moderate to severe TBI, neuropsychological recovery may continue several years after injury with substantial recovery. For other persons, measurable impairment remains 5 years after injury. Improvement was most apparent on measures of cognitive speed, visuoconstruction, and verbal memory.     

Contribution of functional ratings to prediction of longterm employment outcome after traumatic brain injury

The present study investigated the contribution of functional ratings to prediction of employment outcome after traumatic brain injury (TBI). Previous studies have suggested that functional ratings obtained at a significant time post-injury can supplement neurologic, pre-injury, neuropsychologic, and other post-injury variables in predicting long-term employment outcome. Functional ratings studied were patients' needs for physical, cognitive, and behavioural supervision. This investigation also addressed the issue of predicting long-term outcome for the select group of TBI patients who receive post-acute brain injury rehabilitation. Subjects were 76 patients with TBI. The mean age (25th, 50th, and 75th percentiles) was 32 (22, 28, 39) years and mean premorbid education level was 13 (12, 12, 14) years. Predictors studied were severity of injury, premorbid education level, pre-injury substance use, and needs for physical, cognitive and behavioural supervision at discharge from post-acute rehabilitation. Supervision needs ratings were obtained an average of 9.6 (4.2, 5.9, 11.2) months post-injury. Productivity status was assessed an average of 22.5 (12.6, 20.7, 30.5) months post-injury and 12.9 (4.9, 12.4, 16.6) months post-discharge from treatment. Spearman correlation coefficients revealed that premorbid educational level, pre-injury substance use, and needs for physical and behavioural supervision were related to long-term functional outcome (p < 0.05). However, multiple logistic regression analysis revealed that only level of pre-injury substance use was predictive of long-term productivity outcome once adjusted for the effects of the other predictors. Patients with no history of pre-injury substance use were more than eight times as likely to be employed at follow-up as those with a history of pre-injury substance abuse (p < 0.01).     

GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome

Research indicates that glial fibrillary acidic protein (GFAP), part of the astroglial skeleton, could be a marker of traumatic brain injury (TBI). S100B, an astroglial protein, is an acknowledged marker of TBI. Our goal was to analyze the relationship of GFAP/S100B to brain damage and outcome, and to compare the accuracy of GFAP/S100B for prediction of mortality after TBI. Our prospective study included 92 patients admitted <12 h after TBI (median injury severity score 25, median Glasgow Coma Scale 6). TBI was verfied by computerized tomography. GFAP/S100B were measured immunoluminometrically at admission and daily in the intensive care unit (average 10 days, range 1-21 days). We compared GFAP/S100B in non-survivors versus survivors, accuracy for mortality prediction according to receiver operated characteristic curve analysis, correlation between GFAP and S100B, relationship of GFAP/S100B to computerized tomography, cerebral perfusion pressure (CPP), mean arterial pressure (MAP) and 3-month Glasgow Outcome Score (GOS). GFAP (p < 0.005) and S100B (p < 0.0005) were higher in non-survivors than survivors. Both GFAP and S100B were accurate for mortality prediction (area under curve 0.84 versus 0.78 at <12 h after TBI). GFAP and S100B release correlated better later than 36 h after TBI (r = 0.75) than earlier (r = 0.58). GFAP was lower in focal lesions of <25 mL than in shifts of >0.5 cm (p < 0.0005) and non-evacuated mass lesions of >25 mL (p < 0.005). S100B was lower in focal lesions of <25 mL than in non-evacuated mass lesions (p < 0.0005) and lower in swelling than in shifts of >0.5 cm (p < 0.005). GFAP and S100B were lower in ICP < 25 than ICP > or = 25 (p < 0.0005), in CPP > or = 60 than CPP < 60 (p < 0.0005), in MAP > 70 than MAP < or = 70 mm Hg, and in GOS 4-5 than GOS 1 (p < 0.0005). Both measurement of GFAP and S100B is a useful non-invasive means of identifying brain damage with some differences based on the pattern of TBI and accompanying multiple trauma and/or shock.     

Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin

OBJECT: This study was designed to investigate the neuroprotective properties of recombinant erythropoietin (EPO) and carbamylated erythropoietin (CEPO) administered following traumatic brain injury (TBI) in rats. METHODS: Sixty adult male Wistar rats were injured with controlled cortical impact, and then EPO, CEPO, or a placebo (phosphate-buffered saline) was injected intraperitoneally. These injections were performed either 6 or 24 hours after TBI. To label newly regenerating cells, bromodeoxyuridine was injected intraperitoneally for 14 days after TBI. Blood samples were obtained on Days 1, 2, 3, 7, 14, and 35 to measure hematocrit. Spatial learning was tested using the Morris water maze. All rats were killed 35 days after TBI. Brain sections were immunostained as well as processed for the enzyme-linked immunosorbent assay to measure brain-derived neurotrophic factor (BDNF). RESULTS: A statistically significant improvement in spatial learning was seen in rats treated with either EPO or CEPO 6 or 24 hours after TBI (p < 0.05); there was no difference in the effects of EPO and CEPO. Also, these drugs were equally effective in increasing the number of newly proliferating cells within the dentate gyrus at both time points. A statistically significant increase in BDNF expression was seen in animals treated with both EPO derivatives at 6 or 24 hours after TBI. Systemic hematocrit was significantly increased at 48 hours and 1 and 2 weeks after treatment with EPO but not with CEPO. CONCLUSIONS: These data demonstrate that at the doses used, EPO and CEPO are equally effective in enhancing spatial learning and promoting neural plasticity after TBI.     

Neuropsychological testing and functional outcome for individuals with traumatic brain injury

The relationship between performance on neuropsychological measures and the vocational and inde pendent living functioning of individuals with traumatic brain injury was examined. The Wechsler Adult Intelligence Scale Revised WAIS R IQ and Stroop Color and Word Test scores differentiated individuals who required no assistance with activities of daily living from those requiring some level of assistance. Only the Stroop Color and Word Test scores differentiated individuals who were com petitively employed or engaged in degree oriented education from those who were unemployed or in sheltered or supported employment. Wechsler Memory Scale Revised WMS-R scores did not differentiate these groups.     

Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome

Caspase-3 is a cysteine protease that is strongly implicated in neuronal apoptosis. Activation of caspase-3 may be induced by at least two major initiator pathways: a caspase-8-mediated pathway activated through cell surface death receptors (extrinsic pathway), and a caspase-9-mediated pathway activated by signals from the mitochondria that lead to formation of an apoptosomal complex (intrinsic pathway). In the present studies, we compare the activation of caspases-3, -8, and -9 after lateral fluid-percussion traumatic brain injury (TBI) in rats. Immunoblot analysis identified cleaved forms of caspases-3 and -9, but not caspase-8, at 1, 12, and 48 h after injury. Immunocytochemistry specific for cleaved caspases-3 and -9 revealed their expression primarily in neurons. These caspases were also frequently localized in TUNEL-positive cells, some of which demonstrated morphological features of apoptosis. However, caspases-3 and -9 were also found in neurons that were not TUNEL-positive, and other TUNEL-positive cells did not show activated caspases. In contrast to caspases-3 or -9, caspase-8 expression was only minimally changed by injury. An increase in expression of this caspase was undetectable by immunoblotting methods, and appeared as positive immunostaining restricted to a few cells within the injured cortex. Treatment with the pan-caspase inhibitor z-VAD-fmk at 15 min after TBI improved performance on motor and spatial learning tests. These data suggest that several caspases may be involved in the pathophysiology of TBI and that pan-caspase inhibition strategies may improve neurological outcomes.     

Serum biomarker concentrations and outcome after pediatric traumatic brain injury

Predicting outcome after pediatric traumatic brain injury (TBI) is important for providing information to families and prescribing rehabilitation services. The study objective was to assess whether biomarkers concentrations obtained at the time of injury are associated with outcome. Serial serum concentrations of neuron-specific enolase (NSE), S100B and myelin basic protein (MBP) were measured in 152 children with acute TBI. Outcome was assessed with the Glasgow Outcome Scale (GOS) score and/or GOS-Extended Pediatric (GOS-E Peds). Spearman's rank correlation and binary logistic regression assessed the relationship between biomarker concentrations and outcome. For all biomarkers and time points, higher biomarker concentrations were associated with worse outcome. Initial and peak NSE concentrations and initial MBP concentrations were more strongly correlated with outcome in children < or =4 years compared with those >4 years of age. Using binary logistic regression to evaluate the simultaneous affect of all biomarkers on outcome, there was significant overall model fit predicting a dichotomous GOS from biomarker concentrations with a 77% correct classification rate and a negative and positive predictive value of 97% and 75%, respectively. We conclude that NSE, S100B, and MBP concentrations obtained at the time of TBI may be useful in predicting outcome. Future studies should focus on assessing the differential benefit of biomarkers compared with clinical variables and in assessing a continuous rather than categorical outcome variable.     

Blood pressure and outcome after severe pediatric traumatic brain injury

BACKGROUND: The relationship between systolic blood pressure and outcome in children after severe traumatic brain injury (TBI) is unclear. We examined the relationship between age-appropriate systolic blood pressure (AASBP) percentile and outcome after severe pediatric TBI. METHODS: We examined the association between AASBP percentiles and outcome in 172 children younger than 14 years of age with a Glasgow Coma Scale score < 9. Outcome was evaluated using discharge Glasgow Outcome Scale score. Poor outcome was defined as a Glasgow Outcome Scale score < 4. RESULTS: Poor outcome was associated with AASBP < 75th percentile (odds ratio, 4.2; 95% confidence interval, 2.1-8.3). Patients with systolic blood pressure (SBP) > or = 90 mm Hg and AASBP < 75th percentile had a higher odds for poor outcome compared with patients with SBP > or = 90 mm Hg and AASBP > or = 75th percentile (odds ratio, 3.5; 95% confidence interval, 1.7-7.3). CONCLUSION AASBP < 75th percentile was associated with poor outcome after severe pediatric TBI, even when SBP was > or = 90 mm Hg.     

Cognitive orientation in rehabilitation and neuropsychological outcome after traumatic brain injury

This study evaluated the ability of the Orientation Log (O-Log) to predict cognitive outcome at rehabilitation discharge, as well as future neuropsychological outcome. The hypothesis was that patients who demonstrated better orientation upon admission would achieve superior functional cognitive outcome at discharge and on subsequent neuropsychological assessment. Sixty individuals receiving inpatient rehabilitation following a new-onset TBI participated. Orientation data was collected using the O-Log during morning bedside rounds. Outcome data was collected at 6 and 12 months post-injury. Significant correlations were found between the O-log and measures of memory, executive functioning, basic verbal skills, and estimated intellectual ability. When compared to the other predictor variables, step-wise multiple regression analyses revealed that the minimum O-Log score was the primary significant predictor of performance on six neuropsychological and functional outcome measures. Results of this study suggest that evaluating orientation with the O-Log during acute rehabilitation may reflect level of injury severity and aid in predicting cognitive outcome.