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PubMed2003

Axonal recovery after severe traumatic brain injury demonstrated in vivo by 1H MR spectroscopy.

Proton magnetic resonance spectroscopy (MRS) suggested almost complete axonal recovery 21 months after trauma in a patient with severe diffuse axonal injury. MRS while the patient was comatose showed evidence of severe diffuse axonal injury in occipitoparietal white matter, but occipital grey matter was relatively spared. At 21 months N-acetylaspartate was normal. At 33 months examination showed a Functional Independence Measure of 83 and a Rancho Los Amigos Scale of Cognitive Function of 7-8, a remarkable improvement considering all the initial findings, except those of MRS.

Adult↗
PubMed2004

Effects of pituitary adenylate cyclase activating polypeptide in a rat model of traumatic brain injury.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely distributed neuropeptide that has numerous different actions. Recent studies have shown that PACAP exerts neuroprotective effects not only in vitro but also in vivo, in animal models of global and focal cerebral ischemia, Parkinson's disease and axonal injuries. Traumatic brain injury has an increasing mortality and morbidity and it evokes diffuse axonal injury which further contributes to its damaging effects. The aim of the present study was to examine the possible neuroprotective effect of PACAP in a rat model of diffuse axonal injury induced by impact acceleration. Axonal damage was assessed by immunohistochemistry using an antiserum against beta-amyloid precursor protein, a marker of altered axoplasmic transport considered as key feature in axonal injury. In these experiments, we have established the dose response curves for PACAP administration in traumatic axonal injury, demonstrating that a single post-injury intracerebroventricular injection of 100 microg PACAP significantly reduced the density of damaged, beta-amyloid precursor protein-immunoreactive axons in the corticospinal tract.

Amyloid beta-Protein Precursor↗
PubMed1994

Traumatic brain injury. Predicting course of recovery and outcome for patients admitted to rehabilitation.

OBJECTIVE: To demonstrate that the prognosis for patients with traumatic brain injury (TBI) admitted to rehabilitation can be established with use of principled neurologic diagnosis and predictor variables of established value in neurosurgical populations. DESIGN: A cohort of patients with TBI accumulated at rehabilitation admission were followed up for 1 year. Severity measures (Glasgow Coma Scale score, length of coma, and duration of posttraumatic amnesia) and information to generate neuropathologic profiles were gathered retrospectively and prospectively; outcome measures were obtained prospectively. SETTING: The TBI rehabilitation unit in a freestanding rehabilitation hospital. PATIENTS: A consecutive sample of 243 patients with TBI admitted to a rehabilitation unit (age range, 8 through 89 years). MAIN OUTCOME MEASURES: Functional outcome measured by the Glasgow Outcome Scale at 6 and 12 months after injury. RESULTS: Posttraumatic amnesia had a clear, predictable relationship to length of coma in patients with diffuse axonal injury (R2 = .58, P < .0001). Severity measures, particularly duration of posttraumatic amnesia, correlated with the Glasgow Outcome Scale score at 6 and 12 months after injury (R2 = .45, P < .0001, R2 = .48, P < .0001), strongly in patients with diffuse axonal injury but poorly in patients with primarily focal brain injury. Age was an important factor in recovery, beginning at age 40 years; older patients had significantly longer posttraumatic amnesia and worse functional outcome at any severity. CONCLUSIONS: The early course of recovery and functional outcome in TBI can be characterized in neurorehabilitation populations and is highly dependent on specific neuropathologic diagnosis, severity, and age. Predictions that employ traditional measures of severity are most relevant in patients with diffuse axonal injury. Age has a potent, complex effect on recovery, particularly beyond age 40 years.

Adolescent↗
PubMed2001

Early recovery after closed traumatic head injury: somatosensory evoked potentials and clinical findings.

OBJECTIVE: To determine the ability of somatosensory evoked potentials (SEP) compared with clinical findings to monitor and predict recovery in patients suffering from closed head injury with predominantly diffuse axonal injury (DAI). DESIGN: Prospective cohort study. SETTING: Neurologic intensive care unit (ICU) of a university hospital. PATIENTS: Serial SEP recordings were obtained from 31 consecutive patients with closed head injury. The first SEP was recorded within 48 hrs after trauma, followed by recordings after another 2 days, after which the time interval for each consecutive recording was doubled. Clinical examinations were performed every 6 hrs during the ICU stay and daily after transfer to a general neurologic ward. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-three of 31 patients demonstrated pathologic SEP findings at initial examination. Of these patients, 11 recovered clinically, two remained vegetative, and ten died. In all 11 patients with clinical recovery, SEP also recovered. In 8 of 31 patients, initial SEPs were normal and remained normal until discharge, all eight had a good outcome. Initial SEP findings were related with outcome at 6 months (p = .02), and follow-up studies increased the predictive value of SEP studies (p = .009). Other factors related to outcome included age, severity of DAI, and length of ICU/hospital stay. In the 11 patients with SEP and clinical recovery, early (day 2) and late (>or=2 months) recovery was documented. Early and reliable SEP indicators of improvement included N20-P25-Amplitudes (mean recovery, 8.5 days) and central conduction time (9.6 days). Pupillary light reaction (6.4 days), Babinski reflex (12.4 days), and Glasgow Coma Score (9.6 days) were the most valuable clinical findings. Recovery of the Glasgow Coma Score frequently coincided with reduction of sedatives. In most patients, recovery was detected with SEP before clinical recovery (7/11 patients, time difference 1 wk). CONCLUSIONS: Initial SEP findings correlate with long-term outcome in patients with closed head injury with DAI. Initial bilaterally absent cortical responses in the SEP reliably predicted death, whereas completely normal SEP findings predicted good long-term outcome. Early recovery after DAI can be detected with serial SEP recordings despite sedative medications. Electrophysiologic recovery frequently precedes clinical recovery.

Adult↗
PubMed2002

Cerebral endothelial injury in severe head injury: the significance of measurements of serum thrombomodulin and the von Willebrand factor.

Thrombomodulin (TM), which is located in the surface of the endothelium in the arteries, veins, and capillaries of major organs such as the brain, lungs, liver, kidneys, skeletal muscles, and gastrointestinal tract, is one of several indicators of endothelial injury. Von Willebrand factor (vWf), which is synthesized by endothelial cells, is also an endothelial specific glycoprotein. The serum level of vWf increases in response to various stimuli without endothelial injury. An elevated serum level of vWf may suggest endothelial activation in severe head injury. We hypothesize that the degree of cerebral endothelial activation or injury depends on the type of head injury and that measuring the TM and vWf is useful for predicting delayed traumatic intracerebral hematoma (DTICH), produced by weakness of the vessel wall, occuring either as a direct or indirect effect of head injury. The values of vWf in focal brain injury (ranging from 332.5 +/- 52.8% to 361.7 +/- 86.2%) were significantly higher than those in diffuse axonal injury from 2 h to 7 days after the injury occurred (ranging from 201.6 +/- 59.5% to 242.5 +/- 51.7%). The serum level of TM in focal brain injury (ranging from 3.84 +/- 1.54 to 4.12 +/- 1.46 U/mL) was higher than that in diffuse axonal injury (ranging from 2.96 +/- 0.63 to 3.67 +/- 1.70 U/mL), but these differences were not statistically significant. In patients with DTICH, TM was significantly higher than in patients without DTICH (p < 0.01). The results of our study demonstrate that the degree of endothelial activation in focal brain injury was significantly higher than in diffuse brain injury. In addition, the serum level of TM in patients with DTICH was significantly higher than in patients without DTICH. These findings suggest that cerebral tissue injury is often accompanied by cerebral endothelial activation, and that these two phenomena should be distinguished from each other. The levels of serum TM and vWf appear to be good indicators of the cerebral endothelial injury and of endothelial activation in severe head injury.

Adolescent↗
PubMed1992

[MRI findings of closed head injury in children; with special reference to the effect of central shearing force].

It is considered that shearing effect as introduced by Holbourn may produce central concussion, diffuse brain swelling and diffuse axonal injury according to its grade of force. MRI was performed in 38 children who had been admitted to our hospital during the previous 1 year for the treatment of closed head injury of varying severity. In 8 out of 38 cases, abnormal high signal intensity was observed in the medial and para-medial brain parenchyma on MRI. All of these 8 cases suffered from head trauma caused by motor vehicle accidents. They included 2 cases of cerebral concussion, 1 of diffuse brain swelling, and 5 cases of diffuse axonal injury. In 2 cases of cerebral concussion, MRI (T2 weighted) revealed only localized high intensity in the corpus callosum, while CT showed normal and subarachnoid hemorrhage only at the interposium. These two children had been unconscious for periods of 20 to 30 minutes. In one case of diffuse brain swelling, MRI (T2W) showed a slightly obscure border between gray and white matter due to generally increased intensity. In 5 cases of diffuse axonal injury, most of these cases manifested lesions at the corpus callosum, deep white matter, periventricular gray matter, pons, midbrain and the cerebellum as demonstrated by high signal intensity on MRI (T2W) while CT in the acute stage showed small hemorrhage at the corpus callosum, corticomedullary junction and mid-brain and in the ventricles. Among these, two cases also demonstrated subdural hematoma and cortical contusional hemorrhage. At 3-4 weeks after injury, the area of high intensity previously demonstrated in the deep white matter and the corpus callosum on MRI (T2W) was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Axons↗
PubMed1990

Physical model simulations of brain injury in the primate.

Diffuse brain injuries resulting from non-impact rotational acceleration are investigated with the aid of physical models of the skull-brain structure. These models provide a unique insight into the relationship between the kinematics of head motion and the associated deformation of the surrogate brain material. Human and baboon skulls filled with optically transparent surrogate brain tissue are subjected to lateral rotations like those shown to produce diffuse injury to the deep white matter in the brain of the baboon. High-speed cinematography captures the deformations of the grids embedded within the surrogate brain tissue during the applied load. The overall deformation pattern is compared to the pathological portrait of diffuse brain injury as determined from animal studies and autopsy reports. Shear strain and pathology spatial distributions mirror each other. Load levels and resulting surrogate brain tissue deformations are related from one species to the other. Increased primate brain mass magnified the strain amplified without significantly altering the spatial distribution. An empirically-derived value for a critical shear strain associated with the onset of severe diffuse axonal injury in primates is determined, assuming constitutive similarity between baboon and human brain tissue. The primate skull physical model data and the critical shear strain associated with the threshold for severe diffuse axonal injury were used to scale data obtained from previous studies to man, and thus derive a diffuse axonal injury tolerance for rotational acceleration for humans.

Animals↗
PubMed2000

[Traumatic brain injury in children].

We investigated the prognosis of 42 children with traumatic brain injuries. The main etiology was a traffic accident in 46 cases, especially during walking and bicycling, and child abuse in 7 cases. Eighteen cases of acute subdural hematoma 18 cases distributed at all ages, 9 cases of diffuse axonal injury mainly during school age, 4 cases of chronic subdural hematoma under 2 years. These were all caused by child abuse. Fifteen cases showed a good prognosis with independent activities of daily living (ADL). The main type of injury was diffuse axonal injury in this group. Twelve cases showed a bad prognosis with completely dependent ADL. The bad prognostic factors were chronic subdural hematoma caused by child abuse, consciousness loss with Glasgow Coma Scale less than 8 or lasting more than 2 weeks. After rehabilitation in our hospital, 37 cases returned to school: an ordinary class in 20 cases, a special class in an ordinary school in 5 cases and a special class in 12 cases. About half of the cases returned to an ordinary class, although with problems such as learning difficulty, danger and bullying.

Accidents, Traffic↗
PubMed2001

Current aspects of pathophysiology and cell dysfunction after severe head injury.

Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brains response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. We will focus on several topics that we consider to be the most significant: diffuse axonal injury, ischemia and the cascades it generates, metabolic derangements, excitotoxicity, oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed after closed head injury are not single events but processes set in motion by the mechanical impact. These processes are not finished until an unpredictable time after injury. We will discuss recent evidence showing that in diffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the non-ischemic forms of brain hypoxia. The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.

Axons↗
PubMedDate not supplied

The contusion index: a reappraisal in human and experimental non-missile head injury.

A previously described method of quantifying cerebral contusions in man (the contusion index) caused by non-missile head injury has been modified and applied to a larger series of cases, and used to assess contusions in experimental head injuries. The initial findings in man have been confirmed, viz. that contusions are most severe in the frontal and temporal lobes; that contusions may be entirely absent in a patient dying as a result of a head injury; that there is no correlation between the severity of contusions and the nature of the injury; that the concept of contrecoup must continue to be questioned; that contusions are more severe in patients who have a fracture of the skull in comparison to those who do not; that contusions are more severe in patients who do not experience a lucid interval than in those who do; and that contusions are less severe in patients with diffuse axonal injury than in those who do not have diffuse axonal injury. The distribution of contusions in subhuman primates is similar to that seen in man, and they occur more frequently with short duration than with long duration acceleration.

Adolescent↗
PubMed2005

Evaluation of traumatic brain injured patients in correlation with functional status by localized 1H-MR spectroscopy.

OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (1H-MRS) could be a useful tool for detecting microscopic diffuse axonal injury to evaluate the functional status of patients with traumatic brain injury (TBI). DESIGN: A comparative study. SETTING: An inpatient rehabilitation unit in Korea. SUBJECTS: We examined eight adult patients who had severe TBI approximately five months before. Fourteen normal controls were employed for comparison. MAIN MEASURES: Image-guided localized in vivo 1H-MRS was performed in the parietal white matter and occipital grey matter regions in brain in which no definite abnormalities in MR imaging were found at the time of 1H-MRS examination. We evaluated functional status for all patients with the Functional Independence Measure (FIM) on the same day as the 1H-MRS examination and compared the results. RESULTS: In the parietal white matter, the [N-acetyl aspartate/creatine] ratios were significantly lower, and the [choline/creatine] and [myo-inositol/creatine] ratios were significantly higher than those of normal controls. Significant correlations of the IN-acetyl aspartate/creatine] and [myo-inositol/creatine] ratios in the parietal white matter with FIM scores were observed (p < 0.05). CONCLUSIONS: A spectral feature of the decreased [N-acetyl aspartate/creatine] and increased [choline/creatine] and [myo-inositol/creatine] ratios in parietal white matter may be a marker for diffuse axonal injury in patients with TBI and has a significant correlation with the functional status of the patients. Localized 1H-MRS has the potential to be used for detecting diffuse axonal injury in vivo in TBI patients, which can be used to guide evaluation of the functional status of TBI patients receiving rehabilitation.

Activities of Daily Living↗
PubMed2001

The structural basis of moderate disability after traumatic brain damage.

The objective was to discover the nature of brain damage in survivors of head injury who are left with moderate disability. Macroscopic and microscopic examination was carried out on the brains of 20 persons who had died long after a head injury that had been treated in a neurosurgical unit. All had become independent but had various disabilities (moderate disability on the Glasgow outcome scale) Most deaths had been sudden, which had led to their referral from forensic pathologists. Post-traumatic epilepsy was a feature in 75%. An intracranial haematoma had been evacuated in 75%, and in 11 of the 15 with epilepsy. Diffuse axonal injury was found in six patients, five of the mildest type (grade 1) and one of grade 2. No patient had diffuse thalamic damage but one had a small focal ischaemic lesion in the thalamus. No patient had severe ischaemic brain damage, but three had moderate lesions which were bilateral in only one. No patient had severe cortical contusions. In conclusion, the dominant lesion was focal damage from an evacuated intracranial haematoma. Severe diffuse damage was not found, with diffuse axonal injury only mild and thalamic damage in only one patient.

Adult↗
PubMed1998

Neuroprotective effects of MgSO4 and MgCl2 in closed head injury: a comparative phosphorus NMR study.

Previous studies have shown that free magnesium levels decline after traumatic brain injury and that magnesium salt administration improves posttraumatic outcome. These earlier studies, however, have been limited to models of injury that do not produce a significant degree of diffuse axonal injury and have used either MgSO4 or MgCl2 as the magnesium salt. The present study compares the neuroprotective efficacy of MgSO4 and MgCl2 in a severe model of diffuse axonal injury in rats using phosphorus nuclear magnetic resonance spectroscopy and the rotarod test to monitor effects on metabolism and neurologic outcome, respectively. Both MgSO4 and MgCl2 given as a bolus of 100 micromoles/kg at 30 min after severe, closed head injury significantly improved brain intracellular free magnesium concentration and neurologic outcome. These findings suggest that both salts penetrate the blood-brain barrier after brain trauma, enter injured tissue, and subsequently improve neurologic outcome.

Animals↗
PubMed1999

Optimization of magnesium therapy after severe diffuse axonal brain injury in rats.

A number of studies have demonstrated that magnesium salts given after traumatic brain injury improve subsequent neurologic outcome. However, given that these earlier studies have used a number of different salts, dosages, and routes of administration, follow-up studies of the neuroprotective properties of magnesium are complicated, with comparisons to the earlier literature virtually impossible. The present study has therefore characterized the dose-response characteristics of the most commonly used sulfate and chloride salts of magnesium in a severe model of diffuse traumatic axonal injury in rats. Both magnesium salts improved neurologic outcome in rats when administered as a bolus at 30 min after injury. The i.v. and i.m. optima of each salt was 250 micromol/kg and 750 micromol/kg, respectively. The identical concentrations required for improved neurologic outcome suggest that improvement in outcome was dependent on the magnesium cation and not the associated anion. Subsequent magnetic resonance studies demonstrated that the administered magnesium penetrated the blood-brain barrier after injury and resulted in an increased brain intracellular free magnesium concentration and associated bioenergetic state as reflected in the cytosolic phosphorylation potential. Both of these metabolic parameters positively correlated with resultant neurologic outcome measured daily in the same animals immediately before the magnetic resonance determinations.

Animals↗
PubMed2005

Neuropsychological sequelae of diffuse traumatic brain injury.

PRIMARY OBJECTIVES: Description and analysis of neuropsychological deficits following brain trauma with diffuse lesion probably corresponding to diffuse axonal injury (DAI). RESEARCH DESIGN: A series of 111 patients suffering from traumatic brain injury could be investigated neuropsychologically within the first 4 weeks after injury and re-assessed after 5-8 months. They included 11 subjects with CT-evidence of diffuse axonal injury, but no CT-signs of focal contusions. Eleven patients with focal frontal contusions but no CT signs of DAI were matched to and compared with the DAI subjects. Seventeen TBI patients with normal CT scans served as controls. RESULTS: When assessed within the first 4 weeks after TBI, both DAI and frontal contusion patients exhibited behavioural abnormalities and deficits in Wechsler Similarities. The DAI patients were also impaired in Digit Span backward and Stroop interference. When re-assessed, the DAI patients showed considerable deficits in the California Verbal Learning Test and in the Wisconsin Card Sorting Test. CONCLUSIONS: DAI leads to neuropsychological impairment dominated by executive and memory dysfunction.

Adolescent↗
PubMed2001

Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels.

Diffuse axonal injury (DAI) is one of the most common and important pathologies resulting from the mechanical deformation of the brain during trauma. It has been hypothesized that calcium influx into axons plays a major role in the pathophysiology of DAI. However, there is little direct evidence to support this hypothesis, and mechanisms of potential calcium entry have not been explored. In the present study, we used an in vitro model of axonal stretch injury to evaluate the extent and modulation of calcium entry after trauma. Using a calcium-sensitive dye, we observed a dramatic increase in intra-axonal calcium levels immediately after injury. Axonal injury in a calcium-free extracellular solution resulted in no change in calcium concentration, suggesting an extracellular source for the increased post-traumatic calcium levels. We also found that the post-traumatic change in intra-axonal calcium was completely abolished by the application of the sodium channel blocker tetrodotoxin or by replacement of sodium with N-methyl-d-glucamine. In addition, application of the voltage-gated calcium channel (VGCC) blocker omega-conotoxin MVIIC attenuated the post-traumatic increase in calcium. Furthermore, blockade of the Na(+)-Ca(2+) exchanger with bepridil modestly reduced the calcium influx after injury. In contrast to previously proposed mechanisms of calcium entry after axonal trauma, we found no evidence of calcium entry through mechanically produced pores (mechanoporation). Rather, our results suggest that traumatic deformation of axons induces abnormal sodium influx through mechanically sensitive Na(+) channels, which subsequently triggers an increase in intra-axonal calcium via the opening of VGCCs and reversal of the Na(+)-Ca(2+) exchanger.

Axons↗
PubMed2001

Brain injury: the pathophysiology of the first hours.'Talk and Die revisited'.

In the 25 years since the 'Talk and Die' paper there have been substantial advances in the management of patients with severe closed head injury. This paper discusses developments in understanding of primary and secondary injury. Current management focuses on preventing secondary brain injury. That this has been successful is illustrated by a fall in mortality in recent decades. Evidence based guidelines have set standards of management but they do not take into account variations between individuals, between regions of the brain and variations with time from injury. Various monitoring techniques such as transcranial doppler, jugular venous oxygen saturation and ICP waveform analysis attempt to set individual therapeutic endpoints and to target therapy appropriately. Primary injury is no longer seen as a single irreversible event occurring at the time of impact, but rather as a process initiated by the impact and evolving over subsequent hours and days. Experimental studies have identified agents which reduce the evolution of brain injury and improve outcome. An experimental model of brain injury developed by the Adelaide He ad Injury Group identifies diffuse axonal injury as a target for therapeutic manipulation. Magnesium has been shown in other studies to improve outcome after diffuse brain injury. This has now been linked with upregulation of beta amyloid precursor prote in. Although this and several other experimental therapies have shown great promise, they have not so far produced benefit in large clinical studies. Avoiding secondary insults will remain the goal of management for the foreseeable future. Halting the evolution of the primary injury remains a highly sought after goal. Although elusive so far, it is likely to be the next major advance in clinical care.

Axons↗