Traumatic brain injury (TBI) is defined as a result of a bump, blow or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. This trauma can lead to temporary or permanent impairments of cognitive, physical and psychosocial functions, and an associated diminished or altered state of consciousness 1).
Current classification of Traumatic Brain Injury (TBI) is suboptimal:
However, TBI patients are often influenced by ethanol, which in itself can attenuate the level of consciousness.
Although GCS is of great descriptive value and is one of the strongest predictors of outcome in TBI, early structural pathological abnormalities detected by computerized tomography (CT) may be of similar predictive value.
Thus, CT imaging could offer a more objective mand reliable approach to stratify patients with TBI.
Mild traumatic brain injury (mTBI)
Adult traumatic brain injury
Acute traumatic brain injury
Chronic traumatic brain injury
CENTER-TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research.
Comparative Effectiveness Research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care and outcome to support optimal personalized patient management 3)
Head impact direction has been identified as an influential risk factor in the risk of traumatic brain injury (TBI) from animal and anatomic research.
Increased risk of incurring a subdural hematoma exists from impacts to the frontal or occipital regions, and parenchymal contusions from impacts to the side of the head. There was no definitive link between impact direction and subarachnoid hemorrhage. In addition, the results indicate that there is a continuum of stresses and strain magnitudes between lesion types when impact location is isolated, with subdural hematoma occurring at lower magnitudes for frontal and occipital region impacts, and contusions lower for impacts to the side.
This hospital data set suggests that there is an effect that impact direction has on TBI depending on the anatomy involved for each particular lesion 4).
After TBI, cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation.
Following TBI, various mediators are released which enhance vasogenic and/or cytotoxic brain edema. These include glutamate, lactate, H(+), K(+), Ca(2+), nitric oxide, arachidonic acid and its metabolites, free oxygen radicals, histamine, and kinins. Thus, avoiding cerebral anaerobic metabolism and acidosis is beneficial to control lactate and H(+), but no compound inhibiting mediators/mediator channels showed beneficial results in conducted clinical trials, despite successful experimental studies.
White matter injury is an important contributor to long term motor and cognitive dysfunction after traumatic brain injury. During brain trauma, acceleration, deceleration, torsion, and compression forces often cause direct damage to the axon tracts, and pathways that are triggered by the initial injury can trigger molecular events that result in secondary axon degeneration. White matter injury is often associated with altered mental status, memory deficits, motor or autonomic dysfunction, and contribute to the development of chronic neurodegenerative diseases. The presence and proper functioning of oligodendrocyte precursor cells offer the potential for repair and recovery of injured white matter. The process of the proliferation, maturation of oligodendrocyte precursor cells and their migration to the site of injury to replace injured or lost oligodendrocytes is known as oligodendrogenesis 5).
The neuropathology of traumatic brain injury (TBI) from various causes in humans is not as yet fully understood.
Penetrating head injury and closed head injury (CHI) that are moderate to severe are more likely than mild TBI (mTBI) to cause gross disruption of the cerebral vasculature. Axonal injury is classically exhibited as diffuse axonal injury (DAI) in severe to moderate CHI. Diffuse axonal injury is also prevalent in penetrating head injury (PHI). It is less so in mTBI. There may be a unique pattern of periventricular axonal injury in explosive blast mTBI. Neuronal injury is more prevalent in PHI and moderate to severe CHI than mTBI. Astrocyte and microglial activation and proliferation are found in all forms of animal TBI models and in severe to moderate TBI in humans. Their activation in mTBI in the human brain has not yet been studied 6).
Computerized tomography (CT) scanning provides an objective assessment of the structural damage to the brain following traumatic brain injury (TBI).
The goals of imaging include:
(1) detecting injuries that may require immediate surgical or procedural intervention
(2) detecting injuries that may benefit from early medical therapy or vigilant neurologic supervision
(3) determining the prognosis of patients to tailor rehabilitative therapy or help with family counseling and discharge planning 7).
Missed or delayed detection of progressive neuronal damage and secondary brain damage after intracranial injuries may have a negative impact on the outcome of patients with traumatic brain injury (TBI) 8).
Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities demonstrated the potential to emerge as part of future clinical care 9).
Despite the obvious advantages of MRI in terms of delineating the extent and severity of brain injury, the MRI suite is not immediately accessible, and CT remains the modality of choice in the acute phase.
The gold standard for diagnosis of TBI is the CT scan; a delay of diagnostics or medical care is the strongest independent predictor of mortality of TBI patients-particularly in the case of a surgically treatable intracranial hematoma 10) 11).
Retrospective data show that routine CT scanning (in the absence of any clinical deterioration) after mild traumatic brain injury or moderate TBI had no therapeutic (interventional) consequences 16) 17).
On the other hand there is a trend towards routine use for patients with severe TBI but the evidence to support this concept is low. Some authors recommend a cCT scan if clinical signs of neurological deterioration occur 18) , other findings suggest that routine cCT might be beneficial in some subgroups of patients 19) 20). In particular patients with multiple trauma and severe TBI and patients who are endotracheally intubated, mechanically ventilated, and sedated might benefit from routine repeated cCT 21). There is only a single study which investigated the role of a follow-up cCT scan exclusively in unconscious, sedated, and mechanically ventilated patients with severe TBI 22). In those patients early clinical signs of neurologic deterioration are potentially difficult to detect. A change in pupils' status, signs of brain herniation, and seizures are commonly clinical signs of severe brain damage and therapeutic intervention might be too late 23).
Discharge after a repeat head CT and brief period of observation in the Emergency Department allowed early discharge of a cohort of mild TBI patients with traumatic ICH without delayed adverse outcomes. Whether this justifies the cost and radiation exposure involved with this pattern of practice requires further study 24).
The proper classification of these patients is of major importance in situations where a CT is not accessible.
A portable screening device that uses near-infrared spectroscopy (NIRS) technology allows a preliminary estimate of an intracranial hematoma.
The use of the device in a military medical rescue center (Kunduz, Afghanistan) is easy to learn and can be repeatedly used even under emergency room conditions. The technique can be applied in penetrating and blunt TBIs in the absence of an immediately available CT scan in rural areas, preclinically, under mass casualty conditions (e.g., in disaster situations) as well as in humanitarian crises or war zones. Nevertheless, further studies to assess the validity of this device are necessary 25).
CT imaging is limited by beam hardening effects, which can partially obscure the posterior fossa, temporal and frontal regions, and partial volume errors. The latter occur when a region of injured tissue has one or more dimensions that are smaller than the resolution of the acquired data 26). This can mean that haemorrhage or other evidence of intracranial pathology may remain undetected. Such issues are of particular concern within the brain stem and spinal cord, where a small area of pathology can result in devastating injury, and in many patients who exhibit evidence of diffuse axonal injury (DAI) after trauma. DAI is a frequent finding after TBI, accounting for up to 50% of trauma patients 27). The regions of the brain that are commonly injured include the grey–white matter interface, corpus callosum and deep white matter, periventricular and hippocampal areas, and brainstem 28). Such regions are best visualized using MRI 29).
Gradient echo MRI is sensitive to changes in magnetic susceptibility which results in lesions of low intensity after haemorrhage within the brain due to local magnetic field inhomogeneities caused by the paramagnetic properties of haemosiderin. By employing a variety of different MR sequences, the extent of brain injury can be demonstrated with high resolution across the brain.
Unlike other organ-based diseases where rapid diagnosis employing biomarkers from blood tests are clinically essential to guide diagnosis and treatment, there are no rapid, definitive diagnostic blood tests for TBI. Over the last decade there has been a myriad of studies exploring many promising biomarkers. Despite the large number of published studies there is still a lack of any FDA-approved biomarkers for clinical use in adults and children. There is now an important need to validate and introduce them into the clinical setting 30).
Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl groups, indicating that markers of oxidative stress could be of predictive value for the selection of therapeutic strategies 31).
Traumatic brain injury is a significant cause of morbidity and mortality in children.
The use of prognostic models is becoming increasingly important in traumatic brain injury (TBI) research for baseline risk stratification in clinical trials and standardization of case-mix in comparative effectiveness research 32)
The traumatic brain injury (TBI) category accounted for the highest annual mean years of potential life lost (YPLL) at 361,748 (33.9% of total neurologic YPLL). Intracerebral hemorrhage, cerebral ischemia, subarachnoid hemorrhage, and anoxic brain damage completed the group of five diagnoses with the highest YPLL. TBI accounted for 12.1% of all inflation adjusted neurologic hospital charges and 22.4% of inflation adjusted charges among neurologic deaths. The in-hospital mortality rate has been stable or decreasing for all of these diagnoses except TBI, which rose from 5.1% in 1988 to 7.8% in 2011.
Missed or delayed detection of progressive neuronal damage after traumatic brain injury (TBI) may have negative impact on the outcome.
Wurmb et al, investigated whether routine follow-up CT is beneficial in sedated and mechanically ventilated trauma patients in a retrospective chart review. A routine follow-up cCT was performed 6 hours after the admission scan in 2 groups of patients, group I: patients with equal or recurrent pathologies and group II: patients with new findings or progression of known pathologies.
A progression of intracranial injury was found in 63 patients (42%) and 18 patients (12%) had new findings in cCT 2 (group II). In group II a change in therapy was found in 44 out of 81 patients (54%). 55 patients with progression or new findings on the second cCT had no clinical signs of neurological deterioration. Of those 24 patients (44%) had therapeutic consequences due to the results of the follow-up cCT.
They found new diagnosis or progression of intracranial pathology in 54% of the patients. In 54% of patients with new findings and progression of pathology, therapy was changed due to the results of follow-up cCT, concluding that in trauma patients who are sedated and ventilated for different reasons a routine follow-up CT is beneficial 33).
Insurance and racial disparities continue to exist for TBI patients. Insurance status appears to have an impact on short- and long-term outcomes to a greater degree than patient race 38).
Harris et al, suggest a link between head injury and Parkinson's disease and indicates further scrutiny of workplace incurred head injuries is warranted 41).
Olfactory loss due to head trauma is a frequent finding. It is attributed to the tearing or severing of the olfactory fibers at the cribriform plate. In contrast, posttraumatic gustatory loss is observed and reported rarely and the underlying mechanism is less understood. Rahban et al. present a case of a concomitant post-traumatic anosmia and ageusia. Imaging showed a considerable frontobasal brain damage and it is speculated that the gustatory impairment is due to a central injury of the secondary taste cortex. Based on this observation, Rahban et al.we believe that this clinical presentation might be much more frequent than previously reported 42).
Autonomic impairment after acute traumatic brain injury has been associated independently with both increased morbidity and mortality. Links between autonomic impairment and increased intracranial pressure or impaired cerebral autoregulation have been described as well. However, relationships between autonomic impairment, intracranial pressure, impaired cerebral autoregulation, and outcome remain poorly explored.
Treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood.
Management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies.
Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use.
Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI.
The potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model.
Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI 43).
Research in traumatic brain injury (TBI) is challenging for several reasons; in particular, the heterogeneity between patients regarding causes, pathophysiology, treatment, and outcome. Advances in basic science have failed to translate into successful clinical treatments, and the evidence underpinning guideline recommendations is weak. Because clinical research has been hampered by non-standardised data collection, restricted multidisciplinary collaboration, and the lack of sensitivity of classification and efficacy analyses, multidisciplinary collaborations are now being fostered. Approaches to deal with heterogeneity have been developed by the IMPACT study group. These approaches can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid haemorrhage. Rather than trying to limit heterogeneity, we might also be able to exploit it by analysing differences in treatment and outcome between countries and centres in comparative effectiveness research. This approach has great potential to advance care in patients with TBI 44).
Due to the marked heterogeneity of human traumatic brain injury (TBI), none of the available animal model can reproduce the entire spectrum of TBI, especially mild focal TBI.
A stereotaxic coupled weight drop device was designed. Principle arm of device carries up to 500g weights which their force was conveyed to animal skull through a thin nail like metal tip. To determine the optimal configuration of the device to induce mild TBI, six different trials were designed. The optimal configuration of the instrument was used for evaluation of behavioral, histopathological and molecular changes of mild TBI.
Neurologic and motor coordination deficits observed sharply within 24h post injury period. Histological studies revealed a remarkable increase in the number of dark neurons in trauma site. TBI increased the expression of apoptotic proteins, Bax, BCl2 and cleaved caspase-3 in the hippocampus.
This device is capable to produce variable severity of TBI from mild to severe. The main advantage of the new TBI model is induction of mild local unilateral brain injury instead of traumatization of the whole brain. This model does not require craniotomy for induction of brain injury.
This novel animal TBI model mimics human mild focal brain injury. This model is suitable for evaluation of pathophysiology as well as screening of new therapies for mild TBI 45).
Mechanical TBI models
fluid percussion injury
Brain Injury Association of Tasmania http://www.biat.org.au
Brain Injury Network of South Australia http://www.binsa.org
Brain Injury Association of NSW http://www.biansw.org.au
634 consecutive neurosurgical trauma patients, who presented with mild-to-severe traumatic brain injury (TBI) from January 2013 to April 2014 at a tertiary care center in rural Nepal. All pertinent medical records (including all available imaging studies) were reviewed by the neurosurgical consultant and the radiologist on call. Patients' worst CT image scores and their outcome at 30 days were assessed and recorded. They then assessed their independent performance in predicting the mortality and also tried to seek the individual variables that had significant interplay for determining the same.
Both imaging score Marshall CT classification and Rotterdam CT score can be used to reliably predict mortality in patients with acute TBI with high prognostic accuracy. Other specific CT characteristics that can be used to predict early mortality are traumatic subarachnoid hemorrhage, midline shift, and status of the peri-mesencephalic cisterns.
They demonstrated in this cohort that though the Marshall CT classification has the high predictive power to determine the mortality, better discrimination could be sought through the application of the Rotterdam CT score that encompasses various individual CT parameters. They thereby recommend the use of such comprehensive prognostic model so as to augment the predictive power for properly dichotomizing the prognosis of the patients with TBI. In the future, it will therefore be important to develop prognostic models that are applicable for the majority of patients in the world they live in, and not just a privileged few who can use resources not necessarily representative of their societal environment 47).
Manual of Traumatic Brain Injury: Assessment and Management
Management of Adults With Traumatic Brain Injury
Understanding Traumatic Brain Injury: Current Research and Future Directions
Textbook of Traumatic Brain Injury
Brain Injury Medicine, 2nd Edition: Principles and Practice
TRAUMATIC BRAIN INJURY, AN ISSUE OF NEUROSURGERY CLINICS OF NORTH AMERICA, 1E (THE CLINICS: SURGERY)