Search

There is a correlation between poor neuropsychological outcome and focal regions of atrophy in patients with subarachnoid hemorrhage (SAH). No study has investigated the impact of global brain atrophy on outcome after SAH. In other neurological disorders, such as multiple sclerosis, a correlation has been found between global atrophy and outcome. This analysis of patients entered into a randomized clinical trial of clazosentan in patients with SAH (CONSCIOUS-1) investigated the relationship between global cerebral atrophy, clinical factors, and outcome.The 413 patients in the CONSCIOUS-1 study underwent cranial computed tomography (CT) on admission and 6 weeks after SAH. After patients with large clip/coil artefacts and those with infarctions on CT were excluded, 97 patients remained and had voxel-based volumetric measurements of the baseline and 6-week CT scans. The percentage difference in volume between times was taken and analysed against clinical variables. Relationships were modeled using univariate and multivariate analysis.Age, female gender, and higher body temperature during the patient's stay in the intensive care unit were significantly correlated with brain atrophy. Greater brain atrophy significantly correlated with poor outcome (modified Rankin scale), more severe neurological deficits on the National Institute of Health Stroke Scale (NIHSS), and poorer health status (EQ-5D).

Magnetic resonance imaging (MRI) has been widely used in intracerebral hemorrhage (ICH) animal models and patients. In the current study, we examined whether MRI can predict at-risk brain tissue during the acute phase and long-term brain tissue loss after ICH. Male Sprague-Dawley rats had an intracaudate injection of autologous whole blood (10, 50 or 100 μL). MRI (T2 and T2*) sequences were performed at days 1, 3, 7, 14, and 28. The volume of brain tissue at risk was calculated as the difference between T2 and T2* lesion volumes. Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) was used as a neuronal marker in the basal ganglia. Brain swelling at day 3 and brain tissue loss at day 28 after ICH were also measured. We found that the difference in lesion volumes between T2 and T2* measured by MRI coincided well with the difference between the volume of the DARPP-32-negative area and that of the hematoma measured in brain sections. Volumes of brain tissue at risk at day 3 correlated with the brain swelling at day 3 (p < 0.01) as well as the final brain tissue loss at day 28 (n = 9, p < 0.05). The results suggest that the difference between T2 lesions and T2* lesions could be an indicator of at-risk brain tissue and it could be used as a predictor of neuronal loss in ICH patients.

Introduction: Traumatic brain injury (TBI) is widely known to cause dynamic changes in cerebral blood flow (CBF). In particular, secondary brain insults have been reported to decrease CBF. The purpose of this study was to clarify the cerebral circulation in different types of TBI., Methods: Sixty-nine patients with TBI were divided into four groups, the subdural hematoma group, the contusion/intracerebral hematoma group, the diffuse axonal injury group, and the diffuse brain swelling group. In these patients, we simultaneously performed Xe-CT and perfusion CT to evaluate the cerebral circulation on post-injury days 1-3. We measured CBF using Xe-CT and mean transit time using perfusion CT and calculated the cerebral blood volume using the AZ-7000 W98 computer system., Results: There were no significant differences in the Glasgow Coma Scale score on arrival or the Glasgow Outcome Scale score between the groups. The patients who had suffered focal TBI displayed more significant cerebral circulation disturbances than those that had suffered diffuse TBI. We were able to evaluate the cerebral circulation of TBI patients using these parameters., Conclusion: Moderate hypothermia therapy, which decreases CBF, the cerebral metabolic rate oxygen consumption (CMRO2), and intracranial pressure might be effective against the types of TBI accompanied by cerebral circulation disturbance. We have to use all possible measures including hypothermia therapy to treat severe TBI patients according to the type of TBI that they have suffered.

Traumatic brain injuries demonstrate various symptoms, including the disturbance of higher brain function, which is not visualized as a morphological lesion on magnetic resonance (MR) imaging. We examined the use of iomazenil single photon emission computed tomography (SPECT) for patients with traumatic brain injury and evaluated its diagnostic value. The study population included patients who were admitted to our hospital for traumatic brain injuries. All patients survived and were discharged from our hospital. MR imaging and iomazenil SPECT were examined during the acute and/or chronic phases. MR images were acquired using a 1.5-T clinical instrument. The T1- and T2-weighted and fluid-attenuated inversion recovery (FLAIR) axial images were evaluated. SPECT images were acquired using a multi-detector SPECT machine 3 h after the intravenous injection of 740 MBq of iomazenil. Axial, statistically analyzed images and stereotactic extraction estimation images were reconstructed and evaluated statistically based on the Z-score for each cerebral cortex. Iomazenil SPECT showed various lesions that were not demonstrated by MR imaging. Some clinical symptoms correlated with the iomazenil SPECT findings. Iomazenil SPECT is thus considered to be valuable for evaluating both brain lesions and the brain function after traumatic brain injury.

Cerebral pressure autoregulation (AR) is a process by which blood flow is kept constant over a specific cerebral perfusion pressure (CPP) range. There have been a number of advances in recent years in the monitoring and modelling of this physiological variable; however, there has been very little work done on the comparison or optimisation of some of the existing models in clinical use today: pressure reactivity index, highest modal frequency techniques and compartmental modelling. Presented here is a methodology for the comparison and optimisation results for these main AR models. By simple mathematical manipulation of the original modelling end points each model can be converted into a form that is directly comparable to the others. Using a standardised data set with known gold standard AR status indications, the models can then be readily assessed. As a consequence each of the models can then be optimised to maximise specificity and sensitivity.

Atrial natriuretic peptide (ANP) plays an important role in body fluid homeostasis. ANP has been established as a marker of cardiac dysfunction and may play a role in brain edema development after traumatic brain injury (TBI). In order to identify its specific assignment following TBI, we related clinical data and treatment variables in 63 patients to longitudinal midregional (MR) proatrail natriuretic peptide (ANP) measurements. ANP correlated significantly to age (p < 0.0001) and vasopressin release (p < 0.001). Following TBI, ANP was increased initially and on day 3 (cut-off 100 pg/L) in 22% of the patients, in 31% on day 7, and was normalized at follow-up examination. The group comparison revealed that ANP levels did not significantly differ with regard to injury severity, but that high ANP levels predicted a worse Glasgow Outcome Score at 6 months (p < 0.05). While the initially intact osmoregulation - a correlation of urine volume and high serum sodium (r = 0.536, p = 0.003) or low urine osmolality (r = -0.556, p = 0.009) - got lost post-injury, the ANP release was triggered by volume load (p < 0.005). High ANP levels correlated with the neuroendocrine stress response, i.e., high cortisol (p = 0.05) and prolactin (p < 0.001) levels. We conclude that MR-proANP measurements reveal a significant predictive function for the prognosis of TBI.

Introduction: An existing monitoring database of brain signal recordings in patients with head injury has been re-evaluated with regard to the accuracy of estimation of non-invasive ICP (nICP) and its components, with a particular interest in the implications for outcome after head injury., Methods: Middle cerebral artery blood flow velocity (FV), ICP and arterial blood pressure (ABP) were recorded. Non-invasive ICP (nICP) was calculated using a mathematical model. Other signals analysed included components of ICP (n" indicates non-invasive): ICP pulse amplitude (Amp, nAmp), amplitude of the respiratory component (Resp, nResp), amplitude of slow vasogenic waves of ICP (Slow, nSlow) and index of compensatory reserve (RAP, nRAP). Mean values of analysed signals were compared against each other and between patients who died and survived., Results: The correlation between ICP and nICP was moderately strong, R = 0.51 (95% prediction interval [PI] 17 mm Hg). The components of nICP and ICP were also moderately correlated with each other: the strongest correlation was observed for Resp vs. nResp (r = 0.66), while weaker for Amp vs. nAmp (r = 0.41). Non-invasive pulse amplitude of ICP showed the strongest association with outcome, with the -difference between those who survived and those who died reaching a significance level of p < 0.000001., Discussion: When compared between patients who died and who survived mean nAmp showed the greatest difference, suggesting its potential to predict mortality after TBI.

Purpose: The aim of the study was to evaluate the late changes seen in Magnetic Resonance Spectroscopy (MRS) of the brain in Acute Lymphoblastic Leukemia (ALL) survivors to assess neurotoxicity following prophylactic treatment with cranial irradiation (CRT) and/or intrathecal (ITMTX) and systemic MTX., Materials and Methods: The study was performed on two groups of patients. The first group consisted of 30 children who received CRT and ITMTX, and the second group was comprised of 15 children treated only with ITMTX. All patients were ALL survivors treated between 1994 and 2002. Radiotherapy was performed using two opposite fields for a total dose of 18 Gy. The children were examined from 6 to 12 years after treatment. All children underwent a physical and neurological examination and MRI/MRS studies. (1)H-MR spectra were acquired from frontal and occipital regions of the brain. Mean values and standard deviations were calculated for following metabolite ratios: NAA/Cr, Cho/Cr, Cho/NAA, and mI/Cr., Results: Three of the 45 children (11%) presented with white matter changes upon MRI examination. All children with MRI abnormalities received CRT. In 13 (31%) children, changes in (1)H-MRS metabolite ratios were seen. We observed decreased NAA/Cr and Cho/Cr ratios. MR spectroscopy showed a significant reduction (P < .05) of the mean NAA/Cr ratio in children given CRT., Conclusion: MRS is a sensitive detector of late metabolic changes after prophylactic treatment for ALL in childhood. It is able to detect metabolic effects of treatment in patients even when no morphologic changes are visible upon MRI.

Purpose: Decompressive craniectomy for traumatic brain injury patients has been shown to reduce intracranial hypertension, while it often results in increased brain edema and/or contralateral space-occupied hematoma. The purpose of this study was to determine the prognosis of bilateral decompressive craniectomy in severe head injury patients with the development of either bilateral or contralateral lesions after ipsilateral decompressive craniectomy., Methods: Twelve patients underwent bilateral decompressive craniectomy among 217 individuals who had been treated with decompressive craniectomy with dural expansion from September 1995 to August 2006. The following patient data were retrospectively collected: age, neurological status at admission, time between injury and surgical decompression, time between first and second decompression, laboratory and physiological data collected in the intensive care unit, and outcome according to the Glasgow Outcome Scale., Results: Patient outcomes fell into the following categories: good recovery (three patients); mild disability (one patient); severe disability (two patients); persistent vegetative state (one patient); and death (five patients). Patients with good outcomes were younger and had better pupil reactions and neurological statuses on admission. Other factors existing prior to the operation did not directly correlate with outcome. At 24 h post-surgery, the average intercranial pressure (ICP), cerebral perfusion pressure (CPP), glucose level, and lactate level in patients with poor outcomes differed significantly from those of patients with a good prognosis., Conclusion: Head injury patients with either bilateral or contralateral lesions have poor prognosis. However, bilateral decompressive craniectomy may be a favorable treatment in certain younger patients with reactive pupils, whose ICP and CPP values are stabilized 24 h post-surgery.

Objective: To investigate the relationships between long-term computer-assisted monitoring of intracranial pressure (ICP) and indices derived from its waveform versus outcome, age, and sex., Materials and Methods: From 1992 to 2002, 429 sedated and ventilated head-injured patients were continuously monitored. ICP and arterial blood pressure (ABP) were recorded directly and stored in bedside computers. Additional calculated variables included: 1) Cerebral perfusion pressure (CPP) = ABP - ICP; 2) a PRx calculated as a moving correlation coefficient between slow waves (of periods from 20 seconds to 3 minutes) of ICP and ABP., Results: Fatal outcome was associated with higher ICP (p < 0.000002), worse PRx (p < 0.0006), and lower CPP (p < 0.001). None of these parameters differentiated severely disabled patients from patients with a favorable outcome. Higher average ICP, lower CPP, worse outcome, and worse pressure reactivity were observed in females than in males (age-matched). Worse outcome, lower mean ICP, worse PRx, and higher CPP were significantly associated with the older age of patients., Conclusion: High ICP and low PRx are strongly associated with fatal outcome. There is a considerable heterogeneity amongst patients; optimization of care depends upon observing the time-trends for the individual patient.

Introduction: Previous studies have shown that edema formation after diffuse traumatic brain injury (TBI) with secondary insult is cytotoxic and not vasogenic. This assumption is based on observations of reduced apparent diffusion coefficient (ADC) and lack of significant accumulation of intravascular tracer in brain tissue. However, ADC reduction does not exclude vasogenic edema, and intravascular tracer can only accumulate when it reaches the tissue and is not perfusion limited. This study aims to confirm tissue delivery of intravascular tracer and lack of BBB opening during a phase of rapid brain swelling after diffuse TBI., Methods: Rats were exposed to either TBI using the impact acceleration model combined with 30 minutes of hypoxia and hypotension, or sham injury. At 2 or 4 hours after injury, ADC and tissue water content were assessed using MRI. Gd-DTPA was given followed by a combination of rapid T2 imaging (60 seconds) and T1 imaging (30 minutes). Signal intensity changes were analyzed to determine a bolus effect (dynamic susceptibility contrast) and longer-term tissue accumulation of Gd-DTPA., Results: Mean increase in cortical water content on the left was 0.8% at 2 hours, 2.1% at 4 hours; on the right it was 0.5% at 2 hours and 1.7% at 4 hours (p < 0.05). Mean ADC reduction over 4 hours was 0.04 x 10(-3) mm2/s on the left and 0.06 x 10(-3) mm2/s on the right. Kinetic analysis of signal intensity changes after Gd-DTPA showed no significant difference in inward transfer coefficient (BBB permeability) between sham injury and 2 or 4 hours post-injury. T2 imaging showed consistent tissue delivery of a bolus of Gd-DTPA to the tissue at 2 and 4 hours post-injury, comparable to sham animals., Conclusions: Progressive cerebral edema formation after diffuse TBI occurred during ADC reduction and without continued BBB permeability. Tissue delivery of Gd-DTPA was confirmed, verifying that lack of tracer accumulation is due to an intact BBB and not to limited perfusion.

Objective: To evaluate hemodynamics in patients with severe traumatic brain injury (TBI) after cerebral perfusion pressure (CPP) management using cerebrospinal fluid (CSF) drainage., Methods: Twenty-six patients with TBI (Glasgow Coma Score = 8 or less) were investigated. Mean arterial blood pressure, CPP, cardiac index (CI), systemic vascular resistance index (SVRI), and central venous pressure were measured. The patients were divided into 2 groups after craniotomy: the intraparenchymal ICP (IP-ICP) monitoring group (n = 14) and ventricular ICP (V-ICP) monitoring group (n = 12). Patient hemodynamics were investigated on the second hospital day to identify differences. Measurements indicated a target CPP above 70 mmHg and a central venous pressure of 8 10 mmHg in both groups. Mannitol administration (IP-ICP group) or CSF drainage (V-ICP group) was performed whenever the CPP remained below 70 mmHg., Results: High SVRI and low CI (p < 0.05) were observed in the IP-ICP group. The V-ICP group exhibited a reduction in the total fluid infusion volume of crystalloid (p < 0.01) and a reduction in the frequency of hypotensive episodes after the mannitol infusion., Conclusions: CPP management using CSF drainage decreases the total infusion volume of crystalloid and may reduce the risk of aggravated brain edema after excess fluid resuscitation.

The role of nitric oxide (NO) in traumatic brain injury (TBI)-induced sensory motor function and brain pathology was examined using intracerebral administration of neuronal nitric oxide synthase (nNOS) antiserum in a rat model. TBI was produced by a making a longitudinal incision into the right parietal cerebral cortex limited to the dorsal surface of the hippocampus. Focal TBI induces profound edematous swelling, extravasation of Evans blue dye, and up-regulation of nNOS in the injured cerebral cortex and the underlying subcortical areas at 5 hours. The traumatized animals exhibited pronounced sensory motor deficit, as seen using Rota-Rod and grid-walking tests. Intracerebral administration of nNOS antiserum (1 : 20) 5 minutes and 1 hour after TBI significantly attenuated brain edema formation, Evans blue leakage, and nNOS expression in the injured cortex and the underlying subcortical regions. The nNOS antiserum-treated rats showed improved sensory motor functions. However, administration of nNOS antiserum 2 hours after TBI did not influence these parameters significantly. These novel observations suggest that NO participates in blood-brain barrier disruption, edema formation, and sensory motor disturbances in the early phase of TBI, and that nNOS antiserum has some potential therapeutic value requiring additional investigation.

The present study examined differences in intracerebral hemorrhage (ICH)-induced brain injury in male and female rats, whether delayed administration of 17beta-estradiol can reduce ICH-induced brain damage, and whether these effects are estrogen receptor (ER)-dependent. Male and female Sprague-Dawley rats received an infusion of 100-microL autologous whole blood into the right basal ganglia. The effects of 1beta-estradiol (5 mg/kg, i.p.) on ICH-induced brain injury were examined by measuring brain edema and neurological deficits 24 hours later. Heme oxygenase-1 (HO-1) was investigated by immuno-analysis. Brain edema was significantly less in female compared to male rats. The ER antagonist ICI182,780 exacerbated ICH-induced brain edema in female but not in male rats, suggesting that ER activation during ICH is protective in female rats. Administration of 17beta-estradiol to male (but not female) rats significantly reduced brain edema, neurological deficits, and ICH-induced increases in brain HO-1 levels when given 2 hours after ICH. This study showed that female rats have less ICH-induced injury than male rats. ER is involved in limiting ICH-induced injury in female rats. ICH-injury in male rats can be reduced by 17beta-estradiol. Since 17beta-estradiol treatment was effective in male rats, it could be a potential therapeutic agent for ICH.

The RESCUEicp (Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of intracranial pressure) study has been established to determine whether decompressive craniectomy has a role in the management of patients with traumatic brain injury and raised intracranial pressure that does not respond to initial treatment measures. We describe the concept of decompressive craniectomy in traumatic brain injury and the rationale and protocol of the RESCUEicp study.

Objectives: To examine changes in cerebrovascular pressure transmission derived from arterial blood pressure (ABP) and intracranial pressure (ICP) recordings by autoregressive moving average modeling technique., Methods: Digitized ICP and ABP recordings were obtained from patients with brain injury. Two groups were defined: Group A with 4 patients who demonstrated plateau waves, and Group B with 4 intracranial hypertensive, hypoperfused patients. For each 16.5 s interval, mean values of ICP, ABP, cerebral perfusion pressure (CPP), and corresponding highest modal frequency (HMF) of cerebrovascular pressure transmission were computed., Results: Mean values of CPP and HMF of 56.2 mmHg and 2.0 Hz for Group A were significantly higher (p < 0.005) than corresponding mean values of 31.9 mmHg and 0.744 Hz for Group B. The mean value of the slope of the regression line between HMF and CPP for group A of -0.034 Hz/mmHg was significantly different (p < 0.025) than the mean value of 0.0077 Hz/mmHg for Group B. Computations of HMF, pressure reactivity, and correlation pressure reactivity index on continuous pressure recordings are illustrated., Conclusions: Values of HMF of cerebrovascular pressure transmission are inversely related to CPP when pressure regulation is thought to be intact, and directly related when regulation is likely lost.

Although decompressive craniectomy following traumatic brain injury is an option in patients with raised intracranial pressure (ICP) refractory to medical measures, its effect on clinical outcome remains unclear. The aim of this study was to evaluate the outcome of patients undergoing this procedure as part of protocol-driven therapy between 2000-2003. This was an observational study combining case note analysis and follow-up. Outcome was assessed at an interval of at least 6 months following injury using the Glasgow Outcome Scale (GOS) score and the SF-36 quality of life questionnaire. Forty-nine patients underwent decompressive craniectomy for raised and refractory ICP (41 [83.7%] bilateral craniectomy and 8 [16.3%] unilateral). Using the Glasgow Coma Scale (GCS), the presenting head injury grade was severe (GCS 3-8) in 40 (81.6%) patients, moderate (GCS 9-12) in 8 (16.3%) patients, and initially mild (GCS 13-15) in 1 (2.0%) patient. At follow-up, 30 (61.2%) patients had a favorable outcome (good recovery or moderate disability), 10 (20.48) remained severely disabled, and 9 (18.4%) died. No patients were left in a vegetative state. Overall the results demonstrated that decompressive craniectomy, when applied as part of protocol-driven therapy, yields a satisfactory rate of favorable outcome. Formal prospective randomized studies of decompressive craniectomy are now indicated.

Hemoglobin degradation products result in brain injury after intracerebral hemorrhage (ICH). Recent studies found that intracerebral infusion of heme oxygenase inhibitors reduces hemoglobin- and ICH-induced brain edema in rats and pigs. The present study examined whether systemic use of zinc protoporphyrin (ZnPP), a heme oxygenase inhibitor, can attenuate brain edema, behavioral deficits, and brain atrophy following ICH. All rats had intracerebral infusion of 100-microL autologous blood. ZnPP (1 nmol/hour/rat) or vehicle was given immediately or 6 hours following ICH. ZnPP was delivered intraperitoneally up to 14 days through an osmotic mini-pump. Rats were killed at day 3 and day 28 after ICH for brain edema and brain atrophy measurements, respectively. Behavioral tests were performed. We found that ZnPP attenuated brain edema in animals sacrificed 3 days after ICH (p < 0.05). ZnPP also reduced ICH-induced caudate atrophy (p < 0.05) and ventricular enlargement (p < 0.05). In addition, ZnPP given immediately or 6 hours after ICH improved neurological deficits (p < 0.05). In conclusion, systemic zinc protoporphyrin treatment started at 0 or 6 hours after ICH reduced brain edema, neurological deficits, and brain atrophy after ICH. These results indicate that heme oxygenase may be a new target for ICH therapeutics.

Neuronal and glial cell death caused by axonal injury sometimes contributes to whole brain pathology after traumatic brain injury (TBI). We show that neuroprotection by 2 types of immunosuppressants, cyclosporin A (CsA) and tacrolimus (FK506), in a cryogenic brain injury model results from inhibition of calcineurin and protection from mitochondrial damage caused by formation of a mitochondrial permeability transition pore induced by cyclophilin D (CyPD), one of the prolyl cis/trans isomerase family members. We evaluated why CsA is neuroprotective by microarray analysis of gene expression in the cryogenic brain injury rat model. Analyses of expression patterns demonstrated that expression of over 14,000 genes changed between the groups with and without CsA treatment, and about 350 genes among them were extracted showing a significant difference. We learned that the differential expression of several gene targets showed specific patterns in a time-dependent manner. These results may help elucidate the mechanisms of neuronal cell death after TBI and the neuroprotective effects of CsA after TBI.

Preliminary results on epidemiology, acute hospital care, and neurorehabilitation of TBI are presented of the first ever prospective controlled German study to analyse the use of regional structures and quality management as provided by the German social healthcare system. The sum of inhabitants in Hannover and Münster area was 2,114 million. Within an area of 100 kilometres diameter each. 6.783 acute TBI (58% male) were admitted for acute treatment from March 2000 to 2001. Definition of acute TBI was according to the ICD 10 S-02, S-04, S-06, S-07, S-09 in combination with dizziness or vomiting; retrograde or anterograde amnesia, impaired consciousness, skull fracture, and/or focal neurological impairment. The incidence was 321/100.000 population. Cause of TBI was traffic accident in 26%, during leisure time 35%, at home 30% and at work 15%. Initial GCS (emergency room) was only assessed in 3.731 TBI (=55%). Out of those 3.395 = 90,9% were mild, 145 = 3,9% were moderate, and 191 = 5,2% severe TBI. 28% of 6.783 patients were <1 to 15 years, 18% > 65 years of age. The number admitted to hospital treatment is 5.221 = 77%, of whom 72 patients (=1,4%) died caused by TBI. One year follow-up in 4.307 TBI patients (=63.5%) revealed that only 258 patients (=3,8%) received neurorehabilitation (73% male), but 68% within one month of injury. Five percent of these patients were <16 years of age, 25% > 65 years. Early rehabilitation "B" was performed in 100 patients (=39%), 19% within one week following TBI. The management of frequent complications in 148 patients (=57%) and the high number of one or more different consultations (n = 196) confirmed the author's concept for early neurosurgical rehabilitation in TBI when rehabilitation centres were compared regarding GCS and GOS: Early GOS 1 = 4%; GOS 2 = 2,7%, GOS 3 = 37,3%, GOS 4 = 26,7%, GOS 5 = 29,3%, final GOS scores were 1 = 1,2%, 2 = 1,7%, 3 = 21,8%, 4 = 36,2%, and 5 = 39,1% of all patients at the end of rehabilitation. Mean duration for both "B" and "C" was 41 days compared to 80 days for "D" and "E". An assessment of both GCS and GOS was insufficient.

This study examined the relationship of cumulative percent time that cerebral perfusion pressure (CPP) fell below set thresholds to outcome in individuals with traumatic brain injury (TBI). The sample included 157 patients (16 to 89 years of age, 79%, male) admitted to an intensive care unit at an academic medical center who underwent invasive arterial blood pressure and intracranial pressure monitoring. CPP levels were recorded continuously during the first 96 hours of monitoring. Initial neurologic status was assessed using the post-resuscitation Glasgow Coma Scale. Outcome was evaluated at hospital discharge and at six months post-injury using the Extended Glasgow Outcome Scale (GOSE). The relationship of cumulative periods of low CPP to outcome was evaluated using hierarchical and binary logistic regression analysis, controlling for age, gender, and injury severity. Patients experiencing less cumulative percent time below specific CPP thresholds were more likely to have better outcome at discharge (55 mm Hg, p = .004; 60 mm Hg, p = .008; 65 mm Hg, p = .024; 70 mm Hg, p = .016). Although differences in GOSE scores at six months were not significant, those with less time below CPP thresholds were more likely to survive. Accumulated episodes of low CPP had a stronger negative relationship with outcome in patients with more severe primary brain injury.

The technique of near infrared spectroscopy (NIRS) is based on the principle of light attenuation by the chromophores oxyhaemoglobin (HbO2), deoxyhaemoglobin (Hb) and cytochrome oxidase. Changes in the detected light levels can therefore represent changes in concentrations of these chromophores. Clinical use of NIRS in the brain has been well established in neonates where transillumination is possible. While it has become a useful research tool for monitoring the adult brain, clinical application has been hampered by the fact that it must be applied in reflectance mode. This has resulted in a number of concerns, most significantly the issue of signal contamination by the extracranial tissue layers. Algorithms have been applied to try to overcome this problem, and techniques such as time resolved, phase resolved and spatially resolved spectroscopy have been developed. There has been renewed interest in NIRS as an easy to use, non-invasive technique for measuring tissue oxygenation in the adult brain. Recent technical advances have led to the development of compact, portable instruments that detect changes in optical attenuation of several wavelengths of light. Near infrared spectroscopy is an evolving technology that holds significant potential for technical advancement. In particular, NIRS shows future promise as a clinical tool for bedside cerebral blood flow measurements and as a cerebral imaging modality for mapping structure and function.

Objective: The authors previously introduced a method in which intracranial pressure (ICP) was estimated using parameters (TCD characteristics) derived from cerebral blood flow velocity (FV) and arterial blood pressure (ABP). Some results suggested that this model might be influenced by the patient's state of cerebral autoregulation and other clinical parameters. Hence, it was the aim of the present study to improve the method by modifying the previously used global procedure in certain subgroups of patients., Methods: In 103 traumatic brain injured patients (3-76 years, mean: 31 +/- 16 years) signal data of FV, ABP and ICP were used to generate samples of TCD characteristics together with time corresponding ICP. Fuzzy Pattern Classification was used to identify cluster subsets (classes) of the sample space. On each class a local estimator of ICP was defined. This approach provides a non-invasive assessment of ICP (nICP) as follows: Using FV and ABP the TCD characteristics were computed and related to the matching classes. nICP was calculated as a weighted sum of local ICP estimations., Results: ICP A and B waves and long-term trends could be visibly assessed. The median absolute difference between ICP and nICP was 5.7 mmHg., Conclusions: The class structure of the model facilitates nICP assessment in heterogeneous patient groups and supports a stepwise extension of the target patient group without affecting the former validity.

Authors present a seven years retrospective study on 85 cases of severe brain injuries (SBI) in children (GCS /= 20 mmHg, the Diffuse Axonal Injury (DAI) on MRI and the GCS on admission are factors of prognosis in SBI in children. The politrauma context is an aggravating factor for SBI in this age group. Other factors which influence GCS on admission may have prognostic importance i.e.: prehospital care, transport time and adequate transport conditions.

Introduction: An open collaborative international network has been established which aims to improve inter-centre standards for collection of high-resolution, neurointensive care data on patients with traumatic brain injury. The group is also working towards the creation of an open access, detailed and validated database that will be useful for hypothesis generation. In Part A, we describe the underlying concept of the group and it's aims and in Part B we describe the current status of the groups development., Methods: Four group meetings funded by the EEC have enabled definition of a "Core Dataset" to be collected from all centres regardless of specific project aim. A form based feasibility study was conducted and a prospective data collection exercise of core data using PC and hand held computer based methods is in progress., Findings: A core-dataset was defined and can be downloaded from the BrainIT web-site (go to "Core dataset" link at: www.brainit.org). A form based feasibility study was conducted showing the overall feasibility for collection of the core data elements was high. Software tools for collection of the core dataset have been developed. Currently, 130 patient's data from 16 European centres have been recruited to the joint database as part of an EEC funded proof of concept study., Interpretation: The BrainIT network provides a more standardised and higher resolution data collection mechanism for research groups, organisations and the device industry to conduct multicentre trials of new health care technology in patients with traumatic brain injury.

The application of clinical microdialysis to monitor changes in cerebral extracellular chemistry is now well established in several neurosurgical units worldwide. In neuro-intensive care the technique has been predominantly applied to patients with traumatic brain injury and subarachnoid haemorrhage. There is no doubt that microdialysis has increased and continues to increase our understanding of the pathophysiology of these conditions. Current studies are addressing the potential role of microdialysis as a clinical monitoring technique assisting in the management of patients on an intention to treat basis. This involves establishing the relationship between microdialysis and outcome, and the effect of therapeutic manoeuvres on the chemistry. This manuscript describes the place of microdialysis in traumatic brain injury in terms of the fundamental principles, methodology, pathophysiology and clinical application.

My work in Neurotraumatology was initiated in 1961, when I as a neuropsychologist got a position in a neurosurgical University department. The tasks were to evaluate the mental state of patients, give advices to family members regarding the mental and social prognosis of the patients and to support nurses in the initial care of the patients. Initially the methods that were made use of were tests developed by the German neurologist Kurt Goldstein and traditional psychometric tests, but it was not until the theories of A. R. Luria and his investigation method were applied that a true position as a member of the treatment team was secured. Reading Luria's book "Higher Cortical Functions in Man" made me aware of his theories. The skill to perform the investigation was acquired during visits to Luria's laboratory at the Bourdenko Neurosurgical Institute in Moscow in the nineteen-seventies. Text and material to "Luria's Neuropsychological Investigation" was published in 1974. The early work was further stimulated by the development in the neurosciences regarding brain plasticity and brain repair and experiences from visits to rehabilitation centres in the US, Yehuda Ben-Yishay's center at New York Medical School, George Prigatano's centre at the time in Oklahoma, and Lance Trexler's center at Community Hospital, Indianapolis led in 1985 to the establishment of the first post acute rehabilitation center in Europe: the Center for Rehabilitation of Brain Injury (CRBI) at the University of Copenhagen, DK. The main program was a holistic day program, six hours a day for four months in accordance with the university semesters, and an eigth months follow-up. Groups of 15 persons started together, collaborating in smaller groups. The present director of the CRBI is neuropsychologist Frank Humle. A thorough follow-up of the patients' state and improvement through the course of treatment towards social integration, including getting back to work was performed, and studies have indicated that successful integration of the traumatized patient is possible, provided that an early intensive care is succeeded by a comprehensive, individualized post-acute rehabilitation program, of which follow-up is a part, all within the frame of multidisciplinary collaboration.

Recently, we showed the feasibility of ventilating neurosurgical patients with acute intracranial pathology and concomitant acute respiratory distress syndrome (ARDS) according the so-called Open Lung approach. This technique consists of low tidal volume, elevated positive expiratory pressure (PEEP) level and initial recruitment maneuvers to open up collapsed alveoli. In this report, we focus on our experience to guide recruitment with brain tissue oxygenation (pbrO2) probes. We studied recruitment maneuvers in thirteen patients with ARDS and acute brain injury such as subarachnoid hemorrhage and traumatic brain injury. A pbrO2 probe was implanted in brain tissue at risk for hypoxia. Recruitment maneuvers were performed at an inspired oxygen frcation (FiO2) of 1.0 and a PEEP level of 30 40 cmH2O for 40 seconds. The mean FiO2 necessary for normoxemia could be decreased from 0.85 +/- 0.17 before recruitment to 0.55 +/- 0.12 after 24 hours, while mean PbrO2 (24.6 mmHg before recruitment) did not change. At a mean of 17 minutes after the first recruitment maneuver, PbrO2 showed peak a value of 35.6 +/- 16.6 mmHg, reflecting improvement in arterial oxygenation at an FiO2 of 1.0. Brain tissue oxygenation monitoring provides a useful adjunct to estimate the effects of recruitment maneuvers and ventilator settings in neurosurgical patients with acute lung injury.

Severe head injury in childhood continues to be associated with considerable mortality and morbidity. Early surgical decompression may be beneficial and the objective of this study was to examine the relationship between age-related thresholds of mean intracranial pressure (ICP) and cerebral perfusion pressure (CPP) over the first 6 hours and age outcome in paediatric head injury patients. A total of 209 head injured children admitted to five UK hospitals were studied. Patients aged 2 to 16 years were included if they had a minimum of six hours of invasive pressure monitoring. Mean values of ICP and CPP over this period were calculated and compared to those with independent (good recovery and moderate disability) and poor outcome (severe disability, and death) for different age groups. There were 148 children with independent outcome (92 good recovery, 56 moderately disabled), and 61 with poor outcome (30 severely disabled, 31 deaths). There was a significant difference between those with independent compared to poor outcome in relation to ICP (p < 0.001) and CPP (p < 0.001). Patients were divided into three groups according to age. The sensitivity of ICP and CPP in predicting outcome was similar for all groups but the specificity differed between groups. At a CPP of 50 mmHg the specificity varied between the age groups (2 to 6 years: 0.47, 7 to 10 years: 0.28 and 11 to 16 years: 0.10) and similarly for an ICP of 25 mmHg (2 to 6 years: 0.53, 7 to 10 years: 0.44 and 11 to 16 years: 0.38). Younger children may be able to tolerate lower perfusion pressures and still have an independent outcome. Our threshold values for young children are likely to be important in the identification of patients who might benefit from new treatments such as surgical decompression.

Following traumatic brain injury, as a consequence of ionic disturbances and neurochemical cascades, glucose metabolism is affected. [18F]-2-Fluoro-2-deoxy-D-glucose (FDG) Positron Emission Tomography (FDG-PET) provides a measure of global and regional cerebral metabolic rate of glucose (rCMRglc), but only during the time of the scan. Microdialysis monitors energy metabolites over extended time periods, but only in a small focal volume of the brain. Our objective in this study is to assess the association of parameters derived from these techniques when applied to patients with traumatic brain injury. Eleven sedated, ventilated patients receiving intracranial pressure monitoring and managed using Addenbrooke's Neurosciences Critical Care Unit protocols were monitored. Dialysate values for glucose, lactate, pyruvate, and glutamate, and the lactate to glucose (L/G), lactate to pyruvate (L/P) and pyruvate to glucose (P/G) ratios were determined and correlated with rCMRglc. FDG-PET scans were performed within 24 hours (five patients), or between 1 and 4 days (two patients) or after 4 days (six patients). Two patients were rescanned 4 and 7 days after their initial scan. A 20 mm region of interest (ROI) was defined on co-registered CT scan on two contiguous slices around the microdialysis catheter. Mean (+/-sd) for rCMRglc was 19.1 +/- 5.5 micromol/100 g/min, and the corresponding microdialysis values were: glucose 1.4 +/- 1.4 mmol/ L; lactate 5.3 +/- 3.6 mmol/L; pyruvate 164.1 +/- 142.3 micromol/L; glutamate 15.0 +/- 14.7 micromol/L; L/G 11.0 +/- 16.0; L/P 27.3 +/- 7.9 and P/G 381 +/- 660. There were significant relations between rCMRglc and dialysate lactate (r = 0.58, P = 0.04); pyruvate (r = 0.57, P = 0.04), L/G (r = 0.55, P = 0.05), and the P/G (r = 0.56, P = 0.05) but not between rCMRglc and dialysate glucose, L/P or glutamate in this data set. The results suggest that increases in glucose utilization as assessed by FDG-PET in these patients albeit in mainly healthy tissue are associated with increases in dialysate lactate, pyruvate, L/G and the P/G ratio perhaps indicating a general rise in metabolism rather than a shift towards non-oxidative metabolism. Further observations are required with regions of interest (microdialysis catheters positioned) adjacent to mass lesions notably contusions.

The aim of this open, descriptive and prospective study was to determine if the new monitoring parameter "continuous intracranial compliance (cICC)" decreases with age in patients with traumatic brain injury (TBI). 30 patients with severe and moderate TBI (Glasgow Coma Scale score < or = 10) contributing to a European multicenter study, organized by the Brain-IT group, underwent computerized monitoring of blood pressure, intracranial pressure (ICP), cerebral perfusion pressure and cICC. Regression analyses of individual median ICP and median cICC versus patients' age revealed no significant dependency. Median cICC declined significantly with increasing ICP (when median ICP = 10, 20 and 30 mmHg, cICC = 0.64, 0.56 and 0.42 ml/mmHg respectively, p < 0.05). These three ICP groups were then subdivided according to age (0-20, 21-40, 41-60 and 61-80 years). Median cICC declined with age in both high ICP groups (median ICP = 20,30 mmHg). Percentage cICC values below a set pathological threshold of lower than 0.05 ml/mmHg across the four age groups were 28% (0-20 yrs), 59% (21-40 yrs), 60% (41-60 yrs) and 70% (61-80 yrs) respectively. The observed phenomenon of decreased intracranial volume challenge compensation with advancing age may contribute to the well-known fact of a worse outcome in elderly patients after TBI.

Objective: We investigated the relationship between the intracranial pulse pressure (ICPpp) and the mean intracranial pressure (ICP(M)) in pediatric patients with traumatic brain injury (TBI)., Methods: We screened ICP records of 42 patients admitted to the Pediatric Intensive Care Unit at Doernbecher Children's Hospital (OHSU) for segments in which the ICPM varied at least 5 mmHg. We found 54 ICP segments in 9 pediatric TBI patients (ages 0.2-17.8 years, mean = 9.9). ICP was continuously monitored (fs = 125 Hz). We used an automatic algorithm to detect ICP beat components. We then calculated the ICPpp and ICPM for each beat and created density plots of ICPpp vs. ICPM., Results: The coefficient of linear correlation was r > 0.70 in 43/54 segments (p < 0.01). We found that an underlying linear relationship exits between ICPpp and ICPM in most 1-hour records of pediatric patients with TBI. This finding is consistent with the data in adult studies, suggesting that children with TBI demonstrate similar changes in brain compliance. However, density plots revealed that there are also nonlinear ICPpp-ICPM patterns present that are not captured by linear metrics., Conclusion: Although there is an underlying linear relationship between ICPpp and ICPM, nonlinear patterns are also present. Further research is required to determine if specific nonlinear ICPpp-ICPM patterns correlate with clinically significant information.

A new absolute ICP (aICP) measurement method was designed which does not need calibration. In this study we compared a new method with invasive aICP method in ICU on the patients with closed severe traumatic brain injury. A new method is based on two-depth TCD technique for aICP and external absolute pressure aPe comparison using the eye artery (EA) as natural "balance". The intracranial segment of EA is compressed by aICP and the extracranial segment is compressed by aPe applied to the tissues surrounding the eye. The blood flow parameters in both EA segments are approximately the same when aPe = aICP. Two-depth TCD device is used as an indicator of balance aPe = aICP when the pulsatility index of blood flow velocity waveform in intracranial and extracranial segments are the same. Fifty seven simultaneous invasive and non-invasive aICP measurements were performed in aICP range from 3.0 to 37.0 mmHg. Bland Altman plot of the differences between simultaneous invasive and non-invasive aICP measurements shows the negligible mean difference (mean = 0.94 mmHg) with a standard deviation of 6.18 mmHg. This validation study shows that it is possible to measure aICP non-invasively without calibration of the system with 95% confidence interval of 12 mmHg.

Cerebral ischemia is one of the most important causes of secondary insults following acute brain injury. While intracranial pressure monitoring in the intensive care unit constitutes the cornerstone of neurocritical care monitoring, it does not reflect the state of oxygenation of the injured brain. The holy grail of neuromonitoring is a modality that would reflect accurately real time the status of oxygenation in the tissue of interest, is robust, artefact free and that which provides information that can be used for therapeutic interventions and to improve outcome. Such a device could conceivably be used to augment the sensitivity of current multi-modality monitoring systems in the neurocritical management of brain injured patients. This article examines the availability of data in the literature to support clinical use of local tissue oxygen probes in intensive care.

Background: BrainIT is a multi centre, European project, to collect high quality continuous data from severely head injured patients using a previously defined [6] core data set. This includes minute-by-minute physiological data and simultaneous treatment and management information. It is crucial that the data is correctly collected and validated., Methods: Minute-by-minute physiological monitoring data is collected from the bedside monitors. Demographic and clinical information, intensive care management and secondary insult management data, are collected using a handheld computer. Data is transferred from the handheld device to a local computer where it is reviewed and anonymised before being sent electronically, with the physiological data, to the central database in Glasgow. Automated computer tools highlight missing or ambiguous data. A request is then sent to the contributing centre where the data is amended and returned to Glasgow. Of the required data elements 20% are randomly selected for validation against original documentation along with the actual number of specific episodic events during a known period. This will determine accuracy and the percentage of missing data for each record., Conclusion: Advances in patient care require an improved evidence base. For accurate, consistent and repeatable data collection, robust mechanisms are required which should enhance the reliability of clinical trials, assessment of management protocols and equipment evaluations.

The heterogeneity of the initial insult and subsequent pathophysiology has made both the study of human head injury and design of randomised controlled trials exceptionally difficult. The combination of multimodality bedside monitoring and functional brain imaging positron emission tomography (PET) and magnetic resonance (MR), incorporated within a Neurosciences Critical Care Unit, provides the resource required to study critically ill patients after brain injury from initial ictus through recovery from coma and rehabilitation to final outcome. Methods to define cerebral ischemia in the context of altered cerebral oxidative metabolism have been developed, traditional therapies for intracranial hypertension re-evaluated and bedside monitors cross-validated. New modelling and analytical approaches have been developed.

Proteomics and peptidomics are different and supplemental to genomics, since in contrast to the basically constant genome - the proteome and peptidome are dynamic, constantly changing, and complex networks. Proteomics is traditionally linked to 2D-gel electrophoresis techniques. Concerning peptidomics, three different approaches are currently available, all using mass spectrometry as a key element. The use of proteomics or peptidomics in traumatic brain injury (TBI) research is demanding. From the technical point of view there are high-level requirements concerning the preanalytical phase, specific machinery, sophisticated software and skilled manpower/intellectual input. There are currently no bedside techniques and most methods are suitable for experimental TBI research in specialized laboratories. In screening experiments of CSF following controlled cortical impact in rats we identified several peptides, which, although previously known, were so far not reported in the TBI context or in CSF. Peptidomics and proteomics, as highly complex screening technologies, thus seem to carry a large potential to lead TBI science. Newly "discovered" peptide targets have to be validated with different methodology to establish a real diagnostic or therapeutic value.

Background: The aim of this study was to obtain basic knowledge about the current local conditions and neurointensive care of traumatic brain injury (TBI) in the new multi-centre collaborative BrainIT group., Materials and Methods: The survey comprised a background part on local policies (Part A), and a case study section (Part B). The information was gathered by questionnaire followed by telephone interviews. Twenty-three BrainIT centres participated in the survey and answers from two respondents were available from 18 of the sites., Results: The average proportion of agreement between duplicate respondents was 0.778 (range 0.415-1.00). All BrainIT centres monitored ICP. The treatment protocols seem to have a pattern concerning escalation of treatment of intracranial hypertension: 1/ evacuation of mass lesions and head elevation; 2/ increased sedation and mannitol; 3/ hyperventilation; 4/ ventricular drainage; 5/ craniectomy and barbituates., Conclusions: There seemed to be an agreement on neurointensive care policies within the BrainIT group. The suggested order of treatment was generally in accordance with published guidelines although the suggested order and combinations of different treatments varied. Variation of treatment within the range of prescribed standards provides optimal conditions for an interesting future analysis of treatment and monitoring data in reality using the BrainIT database.

Background: We investigated the difference between two commercially available sensors for continuous monitoring of brain tissue oxygen (PtiO2). One is a single parameter probe for PtiO2 monitoring (Licox), the other is a multiparamter sensor (Neurotrend) further including measurement of brain temperature, pH, and partial pressure of tissue carbon dioxide., Methods: In seven patients after subarachnoid hemorrhage or traumatic brain injury continuous monitoring of PtiO2 was performed simultaneously using Licox and Neurotrend., Findings: Mean PtiO2 was generally lower when assessed by the Neurotrend, as compared with the Licox (Licox 27.7 mmHg vs. Neurotrend 20.9 mmHg; P = 0.028). The amplitude of PtiO2 elevations during ventilation with 100% oxygen was higher with the Licox, but this did not reach statistical significance (Licox 55.2 mmHg vs. Neurotrend 50.2 mmHg, P = 0.082). Regarding clinical stability of the sensors, only one Neurotrend sensor provided valid function over the desired monitoring period. Five Neurotrend sensors dislocated or broke and one sensor did not show any function after insertion. No malfunction occurred with the Licox sensors., Conclusions: Our results suggest that PtiO2 might be lower when assessed by the Neurotrend sensor. The clinical stability of the Neurotrend sensor was of concern and allowed monitoring in one of seven patients over the desired monitoring period of several days only.

Progress in the understanding of the pathophysiologic process and management of brain injury provides a unique challenge to the young investigator. Currently, there are teams both in the laboratory and clinical settings which may or may not interact as a result of the depth and breadth of the problems before them. For example, laboratory teams may be focused on cellular or molecular mechanisms of injury while the clinical investigator is attempting to deal with refractory ICP and it's treatment. It is clear that many aspects of biological research must indeed be approached using molecular techniques of neuroscience and much has been learned. However, the translational aspect of this effort may be elusive as it is unclear at present how these molecular techniques translate into the intensive care unit and the patient. For many, the research paths taken in the laboratory and ICU will always remain independent. For those who desire a more direct pathway to treatment, the "bench to bedside" approach is one which is more likely to yield results. Several examples will be given to strengthen the notion that we must not abandon the translational aspect of research but to embrace the process if we are to further improve outcome from brain injury.

Background: Health-related quality of life (HRQOL) associated or not with the measurement of neuropsychological functioning is a relatively new outcome variable in the field of traumatic brain injury (TBI). In both cases, accuracy and precision are increased in outcome estimation. Validation of generic, cross-culturally (cc) administered HRQOL measures in persons after TBI is not yet well established. Disease-specific HRQOL instruments do not exist in an international context. The objective here is to present the TBI consensus group's (QOLIBRI-Group) approach in cc development of a specific HRQOL measure--the QOLIBRI (Quality of Life after Brain Injury)., Methods: Special issues of TBI-specific instrument creation will be highlighted as well as cc questionnaire construction, development, translation and psychometric testing., Results: The validation process of the preliminary version of the disease-specific QOLIBRI in 15 countries and 13 languages will be described. The QOLIBRI assesses HRQOL within six domains (physical condition, thinking activities, feelings and emotions, functioning in daily life, relationships and social/leisure activities, current situation and future prospects). The QOLIBRI integrates disease-specific issues of TBI patients, i.e. cognition, existential aspects (as the sense of self) etc., which are missing in generic tools., Conclusion: In TBI patients, generic and disease-specific aspects of HRQOL need to be assessed with measures of adequate psychometric quality, applicable across different populations and cultural conditions. The QOLIBRI is a promising instrument for sensitive patient-centered specific outcome evaluation after TBI.

Following traumatic brain injury uncoupling of metabolism from perfusion, reflected by an increase in cellular activity in face of reduced perfusion contributes to secondary tissue damage. Standard autoradiographic techniques employed to study metabolism and perfusion are limited by the inability to perform longitudinal investigations. Therefore, the aims of this study were to investigate if metabolic uncoupling can be studied by applying noninvasive and non-radioactive methods. For this, quantitative EEG analysis and laser Doppler flowmetry were employed to determine changes in EEG activity as a global measure of neuronal activity and pericontusional cortical perfusion during the early phase following controlled cortical impact injury (CCII). In eight rats changes in neuronal activity and pericontusional cortical perfusion were determined before, at 4 and 24 hours after CCII. Neuronal activity was significantly increased by 40% at 4 hours after CCII followed by a significant decrease by 60% at 24 hours compared to pre-trauma levels. Pericontusional cortical perfusion was significantly reduced by 45% and 18% at 4 and 24 hours after CCII. respectively. Non-radioactive methods like quantitative EEG analysis and laser Doppler flowmetry can be used to reveal underlying uncoupling of EEG activity from cortical perfusion which is mostly sustained in the early phase following CCII.

Over the past decade many neuroprotective agents have been developed with the hope of being able to improve outcome in patients with traumatic brain injury. Unfortunately, none of the phase III trials performed have convincingly demonstrated efficacy in the overall population. A common misconception is that consequently these agents are ineffective. Such has not been proven and some trials show evidence of efficacy in subgroups of the population studied. The negative results, as reported in the overall population, may in part be caused by specific aspects of the TBI population, as well as by aspects of clinical trial design and analysis. Clinical trials in TBI pose several complicated design issues. Methodological challenges relate particularly to heterogeneity of the population and to outcome assessment. Heterogeneity pertains both to the range of pathologies included in TBI, and to prognostic factors, each causing specific problems. Mechanistic and/or prognostic targeting, as well as possibilities for covariate adjustment, are suggested as possible solutions to deal with the problems of heterogeneity. The aim in most trials was to demonstrate a 10% absolute improvement in favorable outcome in patients with head injury. This may be considered overoptimistic and unrealistic in relation to the heterogeneous patient population. Specific problems are further incurred by the use of the dichotomized Glasgow Outcome Scale as primary outcome measure. Optimal statistical power may expected to be present when the point of dichotomization results in a 50:50 distribution of outcome categories. It is proposed to differentiate the point of dichotomization according to prognostic risk profile, in order to maintain statistical power. Solutions described may be expected to enhance chances of demonstrating benefit of potentially effective neuroprotective agents in future studies. The complexity of problems occurring in clinical trial design and analysis in TBI is such that a strong and sustained multidisciplinary input and effort is required from all experts involved in the field of neurotrauma.

Objectives: Today, increasingly more patients with severe brain and spinal cord lesions mainly secondary to accidents, violence, stroke, and tumours survive their injuries, in many cases, however, suffering from severe functional impairments of functioning as described by the WHO-ICF criteria. New developments of functional neurorehabilitation in neurosurgery could significantly improve the patients' quality of life (QoL) in terms of brain and body functioning and certain health-related components of well-being (such as social activities and leisure)., Methods: Functional rehabilitation is an original task of neurosurgery from the very outset. Advances in biotechnology regarding both basic research and clinical application have opened up a new and very promising field to restore or compensate impaired or definitively lost organic functions in addition to the conservative rehabilitation methods., Results: Along with the scientific progress in biotechnology and functional MRI and PET, neurosurgeons have become increasingly interested and actively involved in rehabilitation science and neurosurgical re-engineering of the damaged brain and spinal cord. Some of them have developed new specially designed institutions for early (acute) and subacute neurorehabilitation. Attached to the acute services, neurosurgeons thus become responsible for neurorehabilitation and at the same time for the management of all kinds of complications, which significantly improves the early and late functional outcome. At the same time microelectronics, biotechnology, and genetic engineering are being introduced into the field of neurosurgical rehabilitation in a step-by-step manner., Discussion: Progress in the fields of microelectronics, computer technology, and genetic engineering along with rehabilitation science is opening up a new field of unknown chances to partially restore lost body functions and to help improve the quality of life of disabled patients in the sense of ICF. Functional neurosurgery plays a major role in neurosurgical rehabilitation. e.g. functional electrostimulation, brain-stem implants, pain and epilepsy control, restoration of locomotion and grasp faculties, and the use of potent substances such as botulinum toxin (Btx). This demands the capacity of time work and the realization of the necessity to draw up a detailed plan for the restoration of impaired functions prior to enacting a neurosurgical intervention in the sense of a complex neurorehabilitation, and consequently to assume the responsibility for the patient's outcome. From the beginning of neurological surgery, the preservation and restoration of impaired brain and spinal-cord functions as an original task for neurosurgeons demand their involvement with issues of functional neurorehabilitation including neurosurgical re-engineering of the damaged brain and spinal cord. In this connection the close and trusting cooperation with the clinical neuropsychologist from the very outset is an indispensible factor.

Objective: Our previous studies have reported that heterogeneous mechanisms exist in early edema formation in cerebral contusion, and cytotoxic edema plays an important role within 48 hours post-trauma. It is remains unclear, when edema begins to develop following injury. In order to determine the time course of edema development, diffusion imaging and ADC (apparent diffusion co-efficient) mapping was performed in 10 patients within 24 hours post-trauma with cerebral contusion., Methods: Diffusion imaging and ADC mapping were performed employing 1.0 T echo planar MRI. ADC values were indicated as a ration relative to the values of intact brain areas., Results: Within 3 hours post-trauma, diffusion MRI showed no remarkable changes, and the ADC values were within normal limit (ADC ratio (=contused/normal brain) = 1.00 +/- 0.21, (mean +/- SD)). At 6 hours post-trauma, diffusion images demonstrated a low intensity core in the contusion proper and a high intensity rim in the peripheral area of contusion. The ADC value increased in the contusion proper (ADC ratio = 1.26 +/- 0.13) and decreased in the peripheral area (ADC ratio = 0.58 +/- 0.19)., Conclusions: These findings indicated that early cellular swelling in the peripheral area of contusion begins within 6 hours following injury. This delayed occurrence of contusion-induced cellular swelling suggests that the CBF does not decrease to ischemic level immediately following injury.

Object: Understanding the cause of post-traumatic intracranial hypertension requires information about the pathophysiology of edema formation. Secondary insults are known to exacerbate edema formation following experimental contusion, however the influence of these insults on blood brain barrier (BBB) integrity is not known. This study non-invasively assesses the influence of hypoxia and hypotension on BBB permeability following experimental cortical contusion., Methods: Sprague-Dawley rats (350-380 g) were divided into three groups. Group A: (n = 3) Sham, Group B (n = 8) focal injury (controlled cortical impact 6.0 m/sec, 3 mm depth), Group C (n = 8), focal injury with secondary insult. Cortical BBB integrity was assessed four hours post-trauma using an i.v. bolus of 0.2 mmol/kg Gd-DTPA with serial T1 MR images, over 30 minutes. Absolute tissue concentrations of Gd were measured empirically using known references. The time course of accumulation was analyzed with respect to BBB permeability., Results: BBB permeability was greatest in the site of contusion, and Gd accumulation was greatly enhanced by secondary insult (p < 0.01). Regions of lowest ADC and maximal swelling correlated with regions of maximal BBB permeability (p < 0.05)., Conclusions: Secondary insults enhance BBB dysfunction in contusion. Positive relationships between low ADC, tissue swelling and BBB dysfunction suggest synergy between underlying cytotoxic swelling and BBB permeability in contusion. These data also suggest that restoration of BBB integrity after injury may be an energy dependent process. These findings have important implications for the pathophysiology of ICP elevations following cerebral contusion.

The time-course of brain contusion/oedema development as visualised by high-resolution MRI was compared to brain water content following experimental brain contusion. 36 Sprague-Dawley rats underwent Controlled Cortical Impact Injury (CCII), 24 served as controls. In 16 animals serial T2 weighted MRI investigations at 1 h, 4 h, 24 h and 7 d after CCII were performed, in 44 rats hemispheric brain water content was determined at the same time points by wet dry weight method. MRI lesion volume (mm3) and brain water content of injured hemisphere (%) showed for absolute and relative values a strictly parallel course. Significant posttraumatic increases had a maximum at 24 hours. Values on day 7 were below those of 1st h in both methods. The simple non-invasive MRI method quantifies contusion and surrounding penumbra according to elevated tissue water signal. The invasive wet dry weight method quantifies changes of hemispheric brain water content that are likely to take place in contusion core and surrounding penumbra. Therefore, from a theoretical aspect both methods seem comparable. Following experimental brain contusion, the simple MRI method might be an equally sufficient way to describe post-traumatic or post-therapeutic changes of lesion size and brain oedema.

Neurochemical damage following brain injury can be assessed non-invasively by measurement of N-Acetyl-Aspartate (NAA) using Proton Magnetic Resonance Spectroscopy (1HMRS). This report documents results of applying Chemical Shift Imaging (CSI) postprocessing for measuring NAA in traumatically injured brain. Following stabilization, severely head-injured patients (GCS 8 or less) were transported to the MRI suite. Semi-quantitative measurement of NAA, creatine (Cr/PCr) and choline (Cho) were obtained from single voxels (8 cm3) and CSI for acquisition of smaller voxels (2 cm3) throughout areas of the brain. Studies were completed with no complication. In focal injury, SVS positioned at the site of lesion demonstrated reduced NAA, compared to contralateral hemisphere. In diffuse injury, CSI demonstrated uniform reduction of NAA throughout the brain. NAA/Cho showed normal levels within 24 hours of injury averaging 2.4 and decreased over the next 10 days reaching a plateau of 0.75. At 30 days, NAA showed no recovery in poor outcome patients. In patients with good outcome, NAA initially low recovered near baseline levels. CSI provides a comprehensive neurochemical assessment of neuronal damage. NAA decreases and remains low in patients with poor outcome. NAA recovers in patients with favorable outcome, suggesting marginal metabolic impairment and possible re-synthesis of the NAA pool.

Little is known about the incidence of secondary insults, particularly cerebral perfusion pressure insults, in children. The objectives of this study were to assess the duration of CPP insults at three different thresholds in children and to relate CPP insults to outcome. Eighteen children (age < 16, median & mean 8 years) admitted to the Neurointensive Care Unit who had ICP, MAP and CPP continuously monitored were studied. Using the Edinburgh secondary insult analysis program, data was scanned for CPP insults at three different thresholds: CPP < 70 mmHg, < 60 mmHg and < 50 mmHg. Outcome was assessed using the Glasgow Outcome Scale. Thirty percent of the time CPP was between 60 and 70 mmHg, 21% of the time CPP was between 50 and 60 mmHg and 8% of the time the CPP was less than 50 mmHg. Compared with adults, there was more than twice the incidence of CPP insults in all threshold groups. BP remained relatively stable above 70 mmHg across all three CPP threshold groups. However, ICP increased slightly on average from about 13-->17 mmHg when CPP decreased from the < 70 to < 60 mmHg group (p < 0.001). There was a marked increase in ICP to greater than 30 mmHg on average in the CPP < 50 mmHg group (p < 0.001). CPP insults less than 70, 60 and 50 mmHg do occur commonly in children, a larger dataset and possibly longer term follow up measures will be needed to identify potentially treatable physiological factors most effecting the outcome of children.