Treatments and rehabilitation in the acute and chronic state of traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of acquired disability globally, and effective treatment methods are scarce. Lately, there has been increasing recognition of the devastating impact of TBI resulting from sports and other recreational activities, ranging from primarily sport-related concussions (SRC) but also more severe brain injuries requiring hospitalization. There are currently no established treatments for the underlying pathophysiology in TBI and while neuro-rehabilitation efforts are promising, there are currently is a lack of consensus regarding rehabilitation following TBI of any severity. In this narrative review, we highlight short- and long-term consequences of SRCs, and how the sideline management of these patients should be performed. We also cover the basic concepts of neuro-critical care management for more severely brain-injured patients with a focus on brain oedema and the necessity of improving intracranial conditions in terms of substrate delivery in order to facilitate recovery and improve outcome. Further, following the acute phase, promising new approaches to rehabilitation are covered for both patients with severe TBI and athletes suffering from SRC. These highlight the need for co-ordinated interdisciplinary rehabilitation, with a special focus on cognition, in order to promote recovery after TBI.

Pituitary function within the first year after traumatic brain injury or subarachnoid haemorrhage.

PURPOSE: Reports on long-term variations in pituitary function after traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) diverge. The aim of the current study was to evaluate the prevalence and changes in pituitary function during the first year after moderate and severe TBI and SAH and to explore the relation between pituitary function and injury variables. METHODS: Adults with moderate and severe TBI or SAH were evaluated at 10 days, 3, 6 and 12 months post-injury/illness. Demographic, clinical, radiological, laboratory, including hormonal data were collected. RESULTS: A total of 91 adults, 56 (15 women/41 men) with TBI and 35 (27 women/8 men) with SAH were included. Perturbations in pituitary function were frequent early after the event but declined during the first year of follow-up. The most frequent deficiency was hypogonadotrope hypogonadism which was seen in approximately 25 % of the patients. Most of the variations were transient and without clinical significance. At 12 months, two patients were on replacement with hydrocortisone, four men on testosterone and one man on replacement with growth hormone. No relations were seen between hormonal levels and injury variables. CONCLUSIONS: Perturbations in pituitary function continue to occur during the first year after TBI and SAH, but only a few patients need replacement therapy. Our study could not identify a marker of increased risk of pituitary dysfunction that could guide routine screening. However, data demonstrate the need for systematic follow-up of pituitary function after moderate or severe TBI or SAH.

Brain-Derived Microparticles in Patients with Severe Isolated TBI.

PRIMARY OBJECTIVE: to investigate the presence of circulating microparticles (MPs) of brain tissue origin in the systemic and cerebrovenous blood of patients with severe traumatic brain injury (TBI). RESEARCH DESIGN: Prospective observational study in 15 consecutive patients with severe isolated TBI. METHODS AND PROCEDURES: We repeatedly measured concentrations of MPs expressing glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and aquaporin-4 (AQP4), in arterial and cerebrovenous blood at admittance to hospital and up to 72 hours after the injury. MAIN OUTCOMES AND RESULTS: Concentrations of MPs expressing GFAP and AQP4 were significantly higher in the TBI group compared with healthy controls: GFAP 2.0 [1.1-7.9] vs. 1.3 [1-2.1] × 106/mL, p < 0.001; AQP4 0.1 [0.07-0.22] vs. 0.08 [0.06-0.11] × 106/mL, p < 0.001 (median, range). No transcranial gradients were found. Levels of NSE-expressing MPs were also higher in the TBI group compared with healthy controls: 0.4 [0.25-2.1] vs. 0.26 [0.13-0.98] × 106/mL, p < 0.05; however, regarding NSE-positive non-platelet MPs, there were no differences between patients and controls. CONCLUSIONS: Patients with TBI have higher numbers of brain-derived MPs. Further studies are needed, however, to identify specific and sensitive MP markers of brain injury.

Kinetic modelling of serum S100b after traumatic brain injury.

BACKGROUND: An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury. METHODS: Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling. RESULTS: We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 µg/L (95 % credible interval [0.10, 0.12]). CONCLUSIONS: Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.

Mechanisms of blast induced brain injuries, experimental studies in rats.

Traumatic brain injuries (TBI) potentially induced by blast waves from detonations result in significant diagnostic problems. It may be assumed that several mechanisms contribute to the injury. This study is an attempt to characterize the presumed components of the blast induced TBI. Our experimental models include a blast tube in which an anesthetized rat can be exposed to controlled detonations of explosives that result in a pressure wave with a magnitude between 130 and 260 kPa. In this model, the animal is fixed with a metal net to avoid head acceleration forces. The second model is a controlled penetration of a 2mm thick needle. In the third model the animal is subjected to a high-speed sagittal rotation angular acceleration. Immunohistochemical labeling for amyloid precursor protein revealed signs of diffuse axonal injury (DAI) in the penetration and rotation models. Signs of punctuate inflammation were observed after focal and rotation injury. Exposure in the blast tube did not induce DAI or detectable cell death, but functional changes. Affymetrix Gene arrays showed changes in the expression in a large number of gene families including cell death, inflammation and neurotransmitters in the hippocampus after both acceleration and penetration injuries. Exposure to the primary blast wave induced limited shifts in gene expression in the hippocampus. The most interesting findings were a downregulation of genes involved in neurogenesis and synaptic transmission. These experiments indicate that rotational acceleration may be a critical factor for DAI and other acute changes after blast TBI. The further exploration of the mechanisms of blast TBI will have to include a search for long-term effects.

ß-Blocker after severe traumatic brain injury is associated with better long-term functional outcome: a matched case control study.

PURPOSE: Severe traumatic brain injury (TBI) is the predominant cause of death and disability following trauma. Several studies have observed improved survival in TBI patients exposed to ß-blockers, however, the effect on functional outcome is poorly documented. METHODS: Adult patients with severe TBI (head AIS ≥ 3) were identified from a prospectively collected TBI database over a 5-year period. Patients with neurosurgical ICU length of stay <48 h and those dying within 48 h of admission were excluded. Patients exposed to ß-blockers ≤ 48 h after admission and who continued with treatment until discharge constituted ß-blocked cases and were matched to non ß-blocked controls using propensity score matching. The outcome of interest was Glasgow Outcome Scores (GOS), as a measure of functional outcome up to 12 months after injury. GOS ≤ 3 was considered a poor outcome. Bivariate analysis was deployed to determine differences between groups. Odds ratio and 95% CI were used to assess the effect of ß-blockers on GOS. RESULTS: 362 patients met the inclusion criteria with 21% receiving ß-blockers during admission. After propensity matching, 76 matched pairs were available for analysis. There were no statistical differences in any variables included in the analysis. Mean hospital length of stay was shorter in the ß-blocked cases (18.0 vs. 26.8 days, p < 0.01). The risk of poor long-term functional outcome was more than doubled in non-ß-blocked controls (OR 2.44, 95% CI 1.01-6.03, p = 0.03). CONCLUSION: Exposure to ß-blockers in patients with severe TBI appears to improve functional outcome. Further prospective randomized trials are warranted.

Intravenous glutamine supplementation to head trauma patients leaves cerebral glutamate concentration unaffected.

OBJECTIVE: There is reluctance to use glutamine-containing i.v. nutrition for neurosurgical patients, as this may result in elevated intracerebral glutamate levels, which are thought to be associated with neuronal injury and cell swelling, causing an increase in ICP and an unfavourable outcome. As general ICU patients benefit from i.v. glutamine supplementation in terms of reduced mortality and morbidity, neurosurgical patients might also be candidates for such treatment, if the possible relation between i.v. glutamine supplementation and a possible increase in cerebral glutamate could be sorted out. DESIGN AND SETTING: The study protocol had a crossover design with a 24h treatment period and a 24h placebo period in random order. Treatment was a glutamine containing dipeptide, L-alanyl-L-glutamine 200mg/ml, for 20h; placebo was saline. The rate of infusion was 0.125ml/kg/h, which is equal to 0.34g/kg of glutamine over the 20h period. Microdialysate was collected for analysis in 120min portions. The flow through the microdialysis catheter was 0.3microl/min. SUBJECTS: Patients with severe head trauma (GCS

Increase of insulin-like growth factor (IGF)-1, IGF binding protein-2 and -4 mRNAs following cerebral contusion.

The insulin-like growth factor (IGF) system has a role in repair following hypoxic-ischemic injury in many tissues including the brain. To study the involvement of the IGF system following head trauma, we used a rat contusion model, which produces a focal lesion of the cerebral cortex. Molecules in the IGF system were analyzed using in situ hybridization at different times following impact. We observed a dramatic up-regulation of insulin-like growth factor binding protein-2 (IGFBP-2) mRNA in cortical areas adjacent to the injury 24 h after impact, with a peak 10-fold increase engaging most of the ipsilateral cortex 2 and 3 days post-contusion. Seven days after the contusion, IGFBP-2 expression was only moderately up-regulated and again concentrated around the injury. IGFBP-4 mRNA levels increased 4-fold ipsilateral to the site of injury, with retained pattern of cortical expression. IGFBP-3, IGFBP-5 and IGFBP-6 mRNA all displayed distinct expression patterns in the brain but no significant changes were observed following injury. In contrast, IGF-1 mRNA levels were very low prior to contusion, but increased markedly at the site of injury with a peak at day 3. We were unable to detect any changes in the type 1 IGF-receptor or IGF-2 mRNA following contusion. The neuropeptide cholecystokinin (CCK) mRNA was clearly up-regulated following contusion, with an even distribution over the ipsilateral cortex. The expression pattern of molecules in the IGF system post-contusion differs in part to changes observed following hypoxic-ischemia or ischemia alone, perhaps reflecting different regulatory mechanisms depending on the type of injury.

Complement activation in the human brain after traumatic head injury.

The complement cascade has been suggested to be involved in the development of secondary brain injuries following brain contusions, based on animal experiments. The aim of the present study was to examine the possible involvement of the complement cascade following traumatic head injury in the human brain. Sixteen patients were included in this study, 12-77 years of age, treated at the neurointensive care unit for traumatic brain contusions. All of these patients were operated with frontal or temporal lobe resection due to intractable intracranial hypertension. The resected tissue was analyzed with regard to components related to complement activation. The time interval between accident and operation was 2-82 h. Brain tissue from three patients operated with hippocampectomy due to epilepsy, including temporal lobe resection, were used as controls. We found increased immunoreactivity for complement components C1q, C3b, and C3d and the membrane attack complex (MAC), C5b-9, in the immediate vicinity of neurons in the penumbra area of the contusion. These findings constitute histological evidence for activation of the complement cascade in the penumbra of cortical contusions in the human brain. Using in situ hybridization, we also found C3-mRNA in the penumbra, suggesting a local synthesis of complement. Furthermore, upregulation of the endogenous complement regulator clusterin was found in some neurons in the same area. We suggest that unknown compounds in the debris from injured neurons or myelin breakdown products trigger complement activation, including formation of C5b-9. Activated complement components may stimulate accumulation of inflammatory cells and formation of brain edema, as well as having membrane destructive effects by the end product MAC, thereby being mediators in the development of secondary brain damage.

A one-step immunohistochemical method for detection of blood-brain barrier disturbances for immunoglobulins in lesioned rat brain with special reference to false-positive labelling in immunohistochemistry.

Disturbances of the blood-brain barrier (BBB) following brain lesions lead to extravasation of serum proteins that can be detected by immunohistochemical methods in tissue sections. Here, extravasated immunoglobulins were visualized by a 1-step technique using rabbit anti-rat immunoglobulins conjugated to horseradish peroxidase (HRP). This method is associated with a lower background staining than the conventional 3-step peroxidase-antiperoxidase (PAP) technique using rabbit antibodies against rat whole-serum proteins or immunoglobulins (IgG). Further tests using a direct conjugate of rabbit anti-rat immunoglobulins to fluorescein isothiocyanate (FITC) showed usefulness of the approach for fluorescence microscopy. Additional experiments showed that antibodies directed against mouse immunoglobulins as used for detection of mouse monoclonal antibodies can cross-react with extravasated rat immunoglobulins. Therefore, immunohistochemical studies on lesioned rat brain should routinely include a visualization of areas containing extravasated serum proteins including immunoglobulins.

Immunohistochemical studies with antibodies to neurofilament proteins on axonal damage in experimental focal lesions in rat.

Immunohistochemistry with monoclonal antibodies against neurofilament (NF) proteins of middle and high molecular weight class, NF-M and NF-H, was used to study axonal injury in the borderzone of focal lesions in rats. Focal injury in the cortex was produced by infusion of lactate at acid pH or by stab caused by needle insertion. Infarcts in substantia nigra pars reticulata were evoked by prolonged pilocarpine-induced status epilepticus. Immunohistochemical staining for NFs showed characteristic terminal clubs of axons in the borderzone of lesions. Differences in the labelling pattern occurred with different antibodies which apparently depended on molecular weight class of NFs and phosphorylation state. These immunohistochemical changes of NFs can serve as a marker for axonal damage in various experimental traumatic or ischemic lesions.

Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat.

The aim of the present study was to examine the glial cell response and the possible involvement of the complement cascade following a cerebral cortical contusion. The lesion was produced using a standardized weight-drop technique in adult rats. The blood-brain barrier was damaged, as demonstrated by a decrease of immunoreactivity for a tight junction protein normally expressed by endothelial cells of small vessels in the central nervous system. Increased immunoreactivity for microglial (OX42) and astroglial cells (glial fibrillary acidic protein), as well as macrophages expressing ED1-immunoreactivity (IR) were found in the vicinity of the lesion at all postoperative survival times (2-14 days). In the present study complement factor C3d- and C9-IR was found around the lesion, indicating that activation of the complement cascade had taken place. Furthermore, immunoreactivity for the putative complement inhibitor clusterin (sulfated glycoprotein-2) was found in some of the injured neurons. The contralateral hemisphere showed no evidence of the reaction found in the ipsilateral hemisphere. The balance between complement activation and complement inhibitors may have an impact on the degenerative components in the brain following traumatic injury and in particular on the events leading to nerve cell death.

Intracranial Pressure Monitoring: Invasive versus Non-Invasive Methods-A Review.

Monitoring of intracranial pressure (ICP) has been used for decades in the fields of neurosurgery and neurology. There are multiple techniques: invasive as well as noninvasive. This paper aims to provide an overview of the advantages and disadvantages of the most common and well-known methods as well as assess whether noninvasive techniques (transcranial Doppler, tympanic membrane displacement, optic nerve sheath diameter, CT scan/MRI and fundoscopy) can be used as reliable alternatives to the invasive techniques (ventriculostomy and microtransducers). Ventriculostomy is considered the gold standard in terms of accurate measurement of pressure, although microtransducers generally are just as accurate. Both invasive techniques are associated with a minor risk of complications such as hemorrhage and infection. Furthermore, zero drift is a problem with selected microtransducers. The non-invasive techniques are without the invasive methods' risk of complication, but fail to measure ICP accurately enough to be used as routine alternatives to invasive measurement. We conclude that invasive measurement is currently the only option for accurate measurement of ICP.

Oxygenation and cerebral perfusion pressure improved in the prone position.

BACKGROUND: Treatment of patients in the prone position is a well-established method to improve oxygenation in general intensive care unit (ICU) practice. This method is rarely used in a neurosurgical ICU, considering the risk of intracranial hypertension. The aim of this study was to analyse the effect of prone position on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and systemic oxygenation in patients with reduced intracranial compliance. We hypothesize that the beneficial effects of prone position can outweigh the hazardous effects on the intracranial pressure. METHODS: Eight patients with traumatic brain injury or subarachnoid hemorrhage (SAH) were studied in the supine and prone posture. Hemodynamics, arterial oxygenation, respiratory mechanics, ICP and CPP were continuously measured. RESULTS: A significant improvement in PaO(2) was observed in the prone position, from 12.6 +/- 1.4 kPa to 15.7 +/- 3.2 kPa (P= 0.02). Both intracranial pressure and mean arterial pressure increased in the prone position, from 12 +/- 6 to 15 +/- 4 mmHg (P= 0.03) and from 78 +/- 8 to 88 +/- 8 mmHg (P= 0.005), respectively. Arterial pressure increased to a greater extent than ICP, resulting in improved CPP, from 66 +/- 7 to 73 +/- 8 mmHg (P= 0.03) in the prone position. CONCLUSIONS: The prone position can be used to improve the oxygenation as well as CPP in patients with traumatic brain injury or SAH. However, this method results in raised ICP, and should be used cautiously in patients with reduced intracranial compliance.

Improved trauma care after reorganisation: a retrospective analysis.

OBJECTIVE: To shorten the time to make a diagnosis and to begin definitive treatment of severely injured patients, thereby improving their medical care. DESIGN: Retrospective analysis. SETTING: Teaching hospital, Sweden. SUBJECTS: 61 patients who had sustained high-energy injuries, including head injury which required surgical intervention, and fracture of the femoral shaft before (1987-1988 n = 23) and after (1991-1993 n = 38) the reorganisation. INTERVENTION: Trauma care was reorganised during the year 1989-1990 and the concept of early multidisiplinary treatment with the general surgeon as trauma-leader was adopted. MAIN OUTCOME MEASURES: The time required to make a diagnosis and begin definitive treatment as well as the assessment of medical care taking account of the patient's general condition and other injuries. RESULT: The immediate medical care was classified as delayed or inappropriate in 9 of 23 patients before, and in 2 of 38 patients after, the reorganisation (p = 0.001). The time needed to make a diagnosis was less than 4 hours in all cases. The time needed to start definitive treatment of head injuries was less than four hours in 9 of 12 patients before, and in 18 of 21 patients after the reorganisation. The internal fixation of femoral fractures was started within four hours in 2 of 11 femoral fractures before, compared with 12 of 17, after the reorganisation. CONCLUSION: The time to beginning definitive treatment of severe injuries was shorter after the reorganisation, as a result of early participation of members of the trauma team.

Diffusion-weighted MR and apparent diffusion coefficient in the evaluation of severe brain injury.

PURPOSE: To study apparent diffusion coefficient (ADC) maps in severely brain-injured patients. MATERIAL AND METHODS: Four deeply comatose patients with severe brain injury were investigated with single-shot, diffusion-weighted, spin-echo echoplanar imaging. The tetrahedral diffusion gradient configuration and four iterations of a set of b-values (one time of 0 mm2/s, and four times of 1000 mm2/s) were used to create isotropic ADC maps with high signal-to-noise ratio. ADC values of gray and white matter were compared among patients and 4 reference subjects. RESULTS: One patient was diagnosed as clinically brain dead after the MR examination. The patient's ADC values of gray and white matter were significantly lower than those of 3 other brain-injured patients. In addition the ADC value of white matter was significantly lower than that of gray matter. CONCLUSION: The patient with fatal outcome shortly after MR examination differed significantly from other patients with severe brain injury but non-fatal outcome, with regard to ADC values in gray and white matter. This might indicate a prognostic value of ADC maps in the evaluation of traumatic brain injury.