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Traumatic brain injury accounts for up to half of trauma related fatalities. This review describes current management practices including pre-hospital care, surgical interventions and various treatment modalities for intracranial hypertension. The lack of class I evidence for the majority of interventions is highlighted.
Traumatic brain injury (TBI) frequently results in memory problems, and the degree of memory impairment is related to injury severity and is commonly associated with lesions in frontal and temporal brain areas. This study examined the relationship among injury severity, brain lesions, and memory in children with moderate to severe TBI using Donders' (1999) 5-factor model of performance on the California Verbal Learning Test-Children's Version (CVLT-C). Seventy-six children underwent magnetic resonance imaging (MRI) scans 3 months post-TBI and testing 1 year post-TBI. Results showed injury severity (Glasgow Coma Scale) was not predictive of performance on 4 of the 5 factors. Volume of frontal and/or temporal brain lesions was significantly predictive of performance on 3 of the 5 factors. Unexpectedly, lesion volume outside these areas (extra-frontotemporal) was predictive of performance on all 5 factors. In contrast, Verbal IQ at 1 year was most strongly associated with preinjury factors (socioeconomic status and special education involvement), although extra-frontotemporal lesions also contributed to the variability in this measure. Results suggest that in children with moderate to severe TBI, extra-frontal/temporal lesions are predictive of memory outcome 1 year postinjury above and beyond initial severity or frontal/temporal contusions. This finding may relate to widespread diffuse axonal injury, which potentially disconnects brain circuits mediating memory following moderate to severe TBI.
Traumatic brain injury (TBI) produces a tissue-specific decrease in protein levels of microtubule-associated protein 2 (MAP2), an important cross-linking component of the neuronal cytoskeleton. Because moderate brain hypothermia (30 degrees C) reduces certain neurobehavioral deficits produced by TBI, we examined the efficacy of moderate hypothermia (30 degrees C) in reversing the TBI-induced loss of MAP2 protein. Naive, sham-injured, and moderate (2.1 atm) fluid percussion-injured rats were assessed for MAP2 protein content 3 h post injury using quantitative immunoreactivity measurements. Parallel groups of sham-injured and fluid percussion-injured animals were maintained in moderate hypothermia (30 degrees C), as measured by temporalis muscle temperature, for MAP2 quantitation 3 h post injury. No difference in MAP2 levels was observed between naive and sham-injured normothermic animals. Hypothermia alone had no effect on soluble MAP2 levels in sham-injured animals compared with normothermic sham-injured controls (88.0 +/- 7.3%; p > 0.10). Fluid percussion injury dramatically reduced MAP2 levels in the normothermic group (44.3 +/- 5.9%; p < 0.0005) compared with normothermic sham-injured controls. No significant reduction of MAP2 was seen in the hypothermic injured group (95.2 +/- 4.6%; compared with hypothermic sham-injured controls, p > 0.20). Although it is premature to infer any causal link, the data suggest that the attenuation of injury-induced MAP2 loss by hypothermia may contribute to its overall neuroprotective action.
Traumatic brain injury is a common event associated with neurological dysfunction. Oxidative damage, may contribute to some of these pathologic changes. We used a specific and sensitive marker of lipid peroxidation, the isoprostane 8,12-iso-iPF(2alpha) -VI, to investigate whether local and also systemic lipid peroxidation were induced following lateral fluid percussion (FP) brain injury in the rat. Animals were anesthetized and subjected to lateral FP brain injury of moderate severity, or to sham injury as controls. Urine was collected before anesthesia (baseline), 6 and 24 h after injury. Blood was collected at baseline, 1, 6 and 24 h after injury. Animals were killed 24 h after surgery and their brains removed for biochemical analysis. No significant difference was observed at baseline (preinjury) for urine and plasma 8,12-iso-iPF(2alpha) -VI levels between injured and sham-operated animals. By contrast, plasma and urinary levels increased significantly already at 1 and further increased 24 h following brain injury, when compared to sham-operated animals. Finally, compared with sham, injured animals had a significant increase in brain 8,12-iso-iPF(2alpha) -VI levels. These results demonstrate that moderate brain injury induces widespread brain lipid peroxidation, which is accompanied by a similar increase in urine and plasma. Peripheral measurement of 8,12-iso-iPF(2alpha) -VI levels after brain injury may be a reliable marker of brain oxidative damage.
Traumatic brain injury (TBI) is a serious health issue in the United States, killing 100,000 people a year and serving as a source of long-term disability for many more. It is the leading cause of death in patients under the age of 45 years. Successful management of TBI requires first an appreciation that a significant part of the neuronal injury incurred following trauma is secondary and is a result of disordered homeostatic mechanisms rather than the mechanical energy of the initial insult. Key skills in the care of brain-injured patients include adequately gauging the severity of injury, recognizing the primacy of sufficient blood flow and oxygen delivery to the injured brain, and being able to detect and correct when possible local and global physiological abnormalities that frequently put the injured brain at ongoing risk within the intensive care unit. This article discusses these issues, including invasive hemodynamic and intracranial monitoring, useful methods for reducing intracranial pressure, and management of complications arising from acute head injury.
Traumatic brain injury (TBI) causes neuronal apoptosis, inflammation, and reactive astrogliosis, which contribute to secondary tissue loss, impaired regeneration, and associated functional disabilities. Here, we show that up-regulation of cell cycle components is associated with caspase-mediated neuronal apoptosis and glial proliferation after TBI in rats. In primary neuronal and astrocyte cultures, cell cycle inhibition (including the cyclin-dependent kinase inhibitors flavopiridol, roscovitine, and olomoucine) reduced up-regulation of cell cycle proteins, limited neuronal cell death after etoposide-induced DNA damage, and attenuated astrocyte proliferation. After TBI in rats, flavopiridol reduced cyclin D1 expression in neurons and glia in ipsilateral cortex and hippocampus. Treatment also decreased neuronal cell death and lesion volume, reduced astroglial scar formation and microglial activation, and improved motor and cognitive recovery. The ability of cell cycle inhibition to decrease both neuronal cell death and reactive gliosis after experimental TBI suggests that this treatment approach may be useful clinically.
Traumatic brain injury ( TBI) neuropsychiatric sequelae are a significant cause of morbidity in TBI victims. Among the recognized sequelae are anxiety, obsessions, compulsions and obsessive-compulsive disorder (OCD). This review addresses the emergence of OCD and OCD symptoms after TBI with an emphasis on neural circuits that underlie OCD symptom expression that may be affected by the injury. Current studies suggest that post-TBI emergent psychopathology, including OCD, is influenced by underlying sub-clinical diathesis, brain injury lesions sites, environmental stressors and the rehabilitation process. Pre-morbid status can be obtained by structured psychiatric interviews, and TBI brain lesions can be defined with advanced neuroimaging techniques. This information along with the management of family and environmental stressors and the enhanced clinical identification of symptoms of anxiety and OCD can be used in the rehabilitation process to improve prognosis after TBI.
Traumatic brain injury (TBI) is a significant public health problem that affects millions of people annually in the USA. Neuropsychiatric symptoms such as cognitive deficits, depression, mania, anxiety, psychosis, apathy, and sleep disturbance are common after TBI. An extensive array of pharmacological options are available to treat a wide range of neuropsychiatric sequelae of TBI, yet there have been few controlled clinical trials to assess the effects of pharmacotherapy in TBI patients. Treatment of the neuropsychiatric disturbances associated with TBI should result in decreased handicap, improved quality of life, and decreased societal impact. There is a dire need for large, randomized, double blind, placebo-controlled trials that include a broad range of cognitive and behavioral outcome measures.
Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.
Traumatic brain injury (TBI) is associated with primary and secondary injury. A thorough understanding of secondary injury will help to develop effective treatments and improve patient outcome. In this study, the GM model of controlled cortical impact injury (CCII) of Lighthall (1988) was used with modification to induce lateral TBI in rats. Forebrain mitochondria isolated from ipsilateral (IH) and contralateral (CH) hemispheres to impact showed a distinct difference. With glutamate + malate as substrates, mitochondria from the IH showed a significant decrease in State 3 respiratory rates, respiratory control indices (RCI), and P/O ratios. This decrease occurred as early as 1 h and persisted for at least 14 days following TBI. The State 3 respiratory rates, RCI, and P/O ratios could be restored to sham values by the addition of EGTA to the assay mixture. A significant amount of Ca2+ was found to be adsorbed to the mitochondria of both the IH and the CH with higher values seen in the IH. The rate of energy-linked Ca2+ transport in the IH was significantly decreased at 6 and 12 h. These data indicate that CCII-induced TBI perturbs cellular Ca2+ homeostasis and results in excessive Ca2+ adsorption to the mitochondrial membrane, which subsequently inhibits the respiratory chain-linked electron transfer and energy transduction.
Traumatic brain injury (TBI) remains a major public health problem, and there is a great medical need for a pharmacological treatment that could improve long-term outcome. The excitatory neurotransmitter, glutamate, has been implicated in processes leading to neurodegeneration. Traxoprodil (CP-101,606) is a novel and potent glutamate receptor antagonist that is highly selective for the NR2B subunit of the NMDA receptor; it has been shown to be neuroprotective in animal models of brain injury and ischemia. A randomized, double-blind, placebo-controlled study was therefore conducted to assess the efficacy and safety of a 72-h infusion of traxoprodil compared to placebo in subjects with computed tomography scan evidence of severe TBI (GCS 4-8). A total of 404 males and non-pregnant females, aged 16-70, were treated within 8 h of injury. At baseline, subjects were stratified by motor score severity. The results showed that a greater proportion of the traxoprodil-treated subjects had a favorable outcome on the dichotomized Glasgow Outcome Scale (dGOS) at 6 months (delta 5.5%, OR 1.3, p = 0.21, 95% CI:[0.85, 2.06]) and at last visit (delta 7.5%, OR 1.47, p = 0.07, 95% CI:[0.97, 2.25]). The mortality rate with traxoprodil treatment was 7% less than with placebo treatment (OR 1.45, p = 0.08, 95% CI:[0.96, 2.18]). Differences between treatment groups were more pronounced in the severest subset (delta 11.8% for the dGOS at last visit and delta 16.6% for mortality). Traxoprodil was well tolerated. Although these results are intriguing, no definitive claim of efficacy can be made for traxoprodil for the treatment of severe TBI.
Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). The primary objective was to investigate the pharmacokinetics of Anatibant; general safety, local tolerability, levels of the bradykinin metabolite BK1-5 in plasma and cerebrospinal fluid (CSF), intracranial pressure (ICP), and cerebral perfusion pressure were also assessed. We observed a dose-proportionality of the pharmacokinetics, Cmax, and AUC of Anatibant. V(d)/F, Cl/F, and t(1/2) were independent on the dose and protein binding was >97.7%. Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed.
Traumatic brain injury (TBI) is a leading cause of death and functional disability in western countries, affecting mostly young patients. Despite intense and sustained efforts deployed for the development of new therapeutic strategies, no clinical benefit has been shown by any of the investigated compounds. Increasing attention has been drawn during the past two decades to the neuroprotective effects of estrogens, although most of the available data relate to ischemic brain injury. The purpose of the present study was to investigate the potential neuroprotective value of estrogens in TBI as a therapeutic modality. For this purpose, a contusion was created in the parietal cortex by dynamic cortical deformation in two groups of 10 Sprague-Dawley male rats. Following the injury, treated animals received conjugated estrogens for 3 days, using a subcutaneously implanted osmotic pump. Animals were then sacrificed, and TUNEL, anti-active Caspase 3, bcl-2, and bax labeling were performed in paraffin-embedded brain sections, allowing for comparative and quantitative analysis. In estrogen-treated animals, there was a marked and significant reduction of apoptosis in comparison with non-treated animals. The reduction in TUNEL and active Caspase 3 staining was similar and close to 50%. Optical analysis of histological slides prepared by bcl-2 labeling showed a significant increase in bcl-2 expression in estrogen-treated animals compared to non-treated animals. On the contrary, bax expression was not influenced by hormonal treatment, and no difference could be noticed between the two groups. These results support the potential therapeutic value of estrogens in TBI and further clarify their mode of action.
Traumatic brain injury (TBI) results in both acute and chronic disruption of cognitive ability that may be mediated through a disruption of hippocampal circuitry. Experimental models of TBI have demonstrated that cortical contusion injuries can result in the loss of specific neurons in the CA3 subfield of the ipsilateral hippocampus, resulting in partial loss of afferents to the CA1 subfield. Numerous studies have documented the ability of the central nervous system to compensate for deafferentation by initiating a plasticity response capable of restoring lost synaptic contacts. The present study was designed to examine the time course of loss and replacement of synaptic contacts in stratum radiatum dendritic field of CA1. Young adult rats were subjected to a lateral cortical contusion injury and assayed for total synaptic numbers using unbiased stereology coupled with transmission electron microscopy. Injured animals demonstrated a 60% loss of synapses in CA1 at 2 days post-injury, followed by a reinnervation process that was apparent as early as 10 days post-injury. By 60 days post-injury, total synaptic numbers had approached pre-injury levels but were still significantly lower. Some animals were behaviorally tested for spatial memory in a Morris Water Maze at 15 and 30 days post-injury. While there was some improvement in spatial memory, injured animals continued to demonstrate a significant deficit in acquisition. These results show that the hippocampus ipsilateral to the cortical contusion is capable of a significant plasticity response but that synapse replacement in this area does not necessarily result in significant improvement in spatial learning.
Traumatic brain injury causes unpredictable errors in the patient's gait by introducing varying mixtures of spasticity, contractures, primitive flexion and extension synergies, and impaired selective control. Surgical release or transfer of the offending muscles can improve the patient's ability to walk if functional errors have been accurately identified. While clinical testing is inadequate, instrumented motion analysis and dynamic electromyography can supply an accurate definition of the abnormalities in muscle action and provide guidelines for distinguishing local from referred motion errors. Examples of the diagnostic differences related to the equinovarus foot and the common types of knee dysfunction are presented.
Traumatic brain injury (TBI) is characterized by a high mortality which is largely determined by the initial cerebral trauma, secondary brain injury or indirectly during a Multiple Organ Dysfunction Syndrome (MODS). Therefore, we analyzed IL-6, IL-8, and IL-10 in cerebrospinal fluid (CSF) and in plasma with respect to blood-brain barrier (BBB) integrity in 29 patients suffering from isolated TBI. IL-6 and IL-8 were significantly increased compared to baseline levels early after trauma in CSF and plasma. In all patients CSF IL-6 and IL-8 were found to be higher than corresponding plasma levels. IL-10 in plasma was significantly increased above control plasma values, however, without a significant difference to the corresponding CSF values. BBB dysfunction was temporary present in 23 patients. Significant correlations between BBB dysfunction and cytokines were not found. Thus, alterations of the BBB seems not to influence the distribution pattern of interleukines in CSF and plasma after trauma.
Traumatic brain injury (TBI) leads to mossy fiber reorganization, which is considered to be a causative factor in the development of temporal lobe epilepsy. However, the underlying mechanism is not fully understood. Emerging evidence suggests that TrkB-ERK1/2-CREB/Elk-1 pathways are highly related to synaptic plasticity. This study used the rat fluid-percussion injury model to investigate activation of TrkB-ERK1/2-CREB/Elk-1 signaling pathways after TBI. Rats were subjected to 2.0-atm parasagittal TBI followed by 30 minutes, 4 hours, 24 hours, and 72 hours of recovery. After TBI, striking activation of TrkB-ERK1/2-CREB/Elk-1 signaling pathways in mossy fiber organization were observed with confocal microscopy and Western blot analysis. ERK1/2 was highly phosphorylated predominantly in hippocampal mossy fibers, whereas TrkB was phosphorylated both in the mossy fibers and the dentate gyrus region at 30 minutes and 4 hours of recovery after TBI. CREB was also activated at 30 minutes, peaked at 24 hours of recovery, and returned to the control level at 72 hours of recovery in dentate gyrus granule cells. Elk-1 phosphorylation was seen in CA3 neurons at 4 hours after TBI. The results suggest that the signaling pathways of TrkB-ERK1/2-CREB/Elk-1 are highly activated in mossy fiber organization, which may contribute to mossy fiber reorganization seen after TBI.
Traumatic brain injury (TBI) is predominantly a clinical problem of young persons, resulting in chronic cognitive and behavioral deficits. Specifically, the physiological response to a diffuse biomechanical injury in a maturing brain can clearly alter normal neuroplasticity. To properly evaluate and investigate developmental TBI requires an understanding of normal principles of cerebral maturation, as well as a consideration of experience-dependent changes. Changes in neuroplasticity may occur through many age-specific processes, and our understanding of these responses at a basic neuroscience level is only beginning. In this article, we will particularly discuss mechanisms of TBI-induced altered developmental plasticity such as altered neurotransmission, distinct molecular responses, cell death, perturbations in neuronal connectivity, experience-dependent 'good plasticity' enhancements and chronic 'bad plasticity' sequelae. From this summary, we can conclude that 'young is not always better' and that the developing brain manifests several crucial vulnerabilities to TBI.