G. M. Teasdale

Focal Cerebral Ischaemia in the Rat: 1. Description of Technique and Early Neuropathological Consequences Following Middle Cerebral Artery Occlusion

A procedure for occluding the stem of the proximal middle cerebral artery of the rat is described. The operation is performed under anaesthesia through a small subtemporal craniectomy. After occlusion, 3 animals were perfused with carbon black and 8 with a FAM fixative (40% formaldehyde, glacial acetic acid, and methanol). The findings were compared with sham-operated animals. Carbon black studies demonstrated an area of impaired perfusion corresponding to the territory of the occluded artery in each animal. Neuropathological studies invariably showed that there was ischaemic brain damage in the cortex and basal ganglia. The frontal cortex was involved in every animal, as was the lateral part of the neostriatum; the sensorimotor and auditory cortex were involved in most animals, whereas the occipital cortex and medial striatum were involved only infrequently. The damage produced by ischaemia could be readily distinguished from the small local lesion seen at the surgical site in sham-operated animals. The ability to produce a consistent focal ischaemic lesion in the rodent brain provides a technical approach that is sufficiently reproducible to enable investigation of the pathophysiology of ischaemia using recently developed autoradiographic and neurochemical methods.

Clinical Trials in Head Injury

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Association of apolipoprotein E polymorphism with outcome after head injury

BACKGROUND Variation in outcome after head injury is not fully explained by known prognostic features. Polymorphism of the apolipoprotein E gene (APOE) influences neuropathological findings in patients who die from head injuries. More people who die from head injuries than non-head-injured controls have deposits of amyloid beta-protein in the cerebral cortex, with amyloid beta-protein deposits present predominantly in patients with the APOE epsilon4 allele. We report a prospective clinical study to test the hypothesis that patients with APOE epsilon4 have a worse clinical outcome 6 months after head injury than those without APOE epsilon4. METHODS We studied a prospectively recruited series of patients admitted after a head injury to a neurosurgical unit (n=93). Assessment of severity of the initial injury was by means of the Glasgow Coma Score (GCS). Outcome 6 months after injury was assessed by means of the Glasgow Outcome Scale. APOE genotypes were determined from blood samples by standard methods. FINDINGS Detailed information on outcome was available for 89 patients. 17 (57%) of 30 patients with APOE epsilon4 had an unfavourable outcome (dead, vegetative state, or severe disability) compared with 16 (27%) of the 59 patients without APOE epsilon4 (p=0.006). The association remained significant when adjustment was made to control for age, GCS, and computed tomography scan findings (p=0.024). INTERPRETATION Our findings show a significant genetic association of APOE polymorphism with outcome after head injury supporting the hypothesis of a genetically determined influence. Patients with APOE epsilon4 are more than twice as likely as those without APOE epsilon4 to have an unfavourable outcome 6 months after head injury. Further studies are under way to confirm and further evaluate this association.

Disability in young people and adults one year after head injury: prospective cohort study

Abstract Objective: To determine the frequency of disability in young people and adults admitted to hospital with a head injury and to estimate the annual incidence in the community. Design: Prospective, hospital based cohort study, with one year follow up of sample stratified by coma score. Setting: Five acute hospitals in Glasgow. Subjects: 2962 patients (aged 14 years or more) with head injury; 549 (71%) of the 769 patients selected for follow up participated. Main outcome measures: Glasgow outcome scale and problem orientated questionnaire. Results: Survival with moderate or severe disability was common after mild head injury (47%, 95% confidence interval 42% to 52%) and similar to that after moderate (45%, 35% to 56%) or severe injury (48%, 36% to 60%). By extrapolation from the population identified (90% of whom had mild injuries), it was estimated that annually in Glasgow (population 909 498) 1400 young people and adults are still disabled one year after head injury. Conclusion: The incidence of disability in young people and adults admitted with a head injury is higher than expected. This reflects the high rate of sequelae previously unrecognised in the large number of patients admitted to hospital with an apparently mild head injury.

Ischaemic brain damage is still common in fatal non-missile head injury.

A detailed neuropathological examination has been undertaken on a consecutive series of head injuries dying in the Institute of Neurological Sciences, Glasgow, between 1968-72 (151 cases) and 1981-82 (112 cases) in order to determine the frequency and distribution of any ischaemic brain damage. Ischaemic damage was found in the brains of 92% of the 1968-72 cases and in 88% of the 1981-82 cases: there was no statistical difference in the amount of moderately severe and severe ischaemic damage in the two groups, 55% and 54% respectively. There was evidence, however, that an increased number of patients with severe ischaemic brain damage was admitted in 1981-82 as a result of a changed admission policy of the Department of Neurosurgery that resulted in an increased detection of intracranial haematomas. It is concluded that ischaemic brain damage is still common after severe head injury, and it seems likely that it remains an important cause of mortality and morbidity.

Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia.

A method for the volumetric assessment of early cerebral infarction, together with its statistical and biological validation, is described. In halothane anaesthetised rats the stem of the right middle cerebral artery was occluded and 3 hours later (with full monitoring of respiratory and cardiovascular status) the animals were killed by perfusion fixation. In normotensive normocapnic animals the volume of infarction was 52 +/- 4 mm3 in the cerebral cortex and 21 +/- 1 mm3 in the corpus striatum. The reproducibility of the volumetric assessment was found to be excellent (coefficient of correlation 0.995 on 18 replicate measurements). The minimum number of stereotactic levels which must be assessed to yield accurate volumetric measurements of infarction is 8. The method is sensitive at detecting alterations in the amount of infarction. For example, it can readily detect the increase in amount of structural damage in cerebral cortex following a transient episode of hypotension. This approach allows an objective assessment of drug therapy and management strategies in the treatment of cerebral infarction.

Focal Cerebral Ischaemia in the Rat: 2. Regional Cerebral Blood Flow Determined by [14C]Iodoantipyrine Autoradiography following Middle Cerebral Artery Occlusion

Local cerebral blood flow has been measured by quantitative autoradiography, employing [14C]iodoantipyrine as tracer, in rats killed half an hour after occlusion of the middle cerebral artery. The results were compared with pattern of local cerebral blood flow (CBF) in sham-operated rats and with neuropathological findings. In every animal there was a profound reduction (to 13% of control levels) in blood flow in the neocortex previously supplied by the occluded artery. The level of blood flow in the areas in which ischaemic brain damage occurred was 0.24 ±0.03 ml g−1 min−1 (mean ± SEM). This level of CBF is considerably greater than that reported following a similar surgical procedure in cats and primates. Moderate reductions in blood flow were also seen outside the territory of the occluded artery and in parts of the opposite hemisphere. Absolute increases in blood flow (hyperaemia) were seen only in the substantia nigra and globus pallidus ipsilateral to the occlusion. It is suggested that this finding and the reductions in blood flow outside the territory of the middle cerebral artery are reflections of alterations in neuronal function and metabolic activity secondary to the ischaemic lesion.

Focal Cerebral Ischaemia in the Cat: Treatment with the Glutamate Antagonist MK-801 After Induction of Ischaemia

The effects of the glutamate N-methyl-D-aspartate receptor antagonist MK-801 in reducing ischaemic brain damage have been examined in anaesthetised cats, with drug treatment being initiated 2 h after the induction of cerebral ischaemia. Focal cerebral ischaemia was produced by permanent occlusion of one middle cerebral artery, and the animals were killed 6 h later. The amount of early irreversible ischaemic damage was assessed at 16 predetermined stereotactic planes. Treatment with MK-801 (5 mg/kg, i.v.) 2 h after middle cerebral artery occlusion reduced significantly the volume of ischaemic damage (from 1,625 ± 384 mm3 of the cerebral hemisphere in vehicle-treated cats to 792 ± 385 mm3 in MK-801-treated cats). The demonstration of reduced ischaemic brain damage with MK-801, when the agent is administered after the induction of ischaemia, extends the therapeutic potential of such agents in the treatment of focal cerebral ischaemia in humans.

Decompressive craniectomy in traumatic brain injury: the randomized multicenter RESCUEicp study (www.RESCUEicp.com)

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.

Disability in young people and adults after head injury: 12–14 year follow-up of a prospective cohort

Background There is a need to establish how long term outcome evolves after head injury (HI) and factors related to this, to inform opportunities for intervention. Objective To determine late outcome in adults 12–14 years after hospital admission for HI and to examine relationships between injury, early and late factors, and disability. Methods A prospective cohort with HI, whose outcome was reported previously at 1 and 5–7 years after injury, were followed up after 12–14 years. Participants were assessed using structured and validated measures of disability (Glasgow Outcome Scale-Extended), psychological well being, alcohol use and health status. Results Of 219 survivors followed-up at 5–7 years, 34 (15.5%) had died by 12–14 years. Disability remained common in survivors at 12–14 years (51%), as found at 1 and 5–7 years (53%). For those disabled at 1 year, outcome was poor, with 80% dead or disabled at 12–14 years. Older age at injury, a premorbid history of brain illness or physical disability and post-injury low self-esteem and stress were associated with disability at 12–14 years. Disability changed between 5–7 and 12–14 years in 55% of survivors, improving in 23%. Late changes in disability between 5–7 and 12–14 years were associated with self-perceptions of locus of control as being ‘powerful others’ at 5–7 years. Conclusions Disability is common 12–14 years after hospital admission with a HI. For some there is a dynamic process of change in disability over time that is associated with self-perceptions of control that could be a target for intervention based research.