The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.

BACKGROUND: Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. METHODS: Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). RESULTS: 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. CONCLUSION: This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness. TRIAL REGISTRATION: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128.

A study of meningiomas in South Africa: investigating a correlation between clinical presentation, histopathology and genetic markers.

OBJECTIVE: To determine whether there are certain genetic markers which correlate with particular clinical characteristics of meningiomas including multiplicity, recurrence and calvarial erosion. METHODS: Thirty-eight South African-born patients with meningiomas were recruited for this study. At surgery, blood and tumour specimens were obtained for histopathological, cytogenetic and molecular analysis. Loss of heterozygosity (LOH) on chromosomes 1p and 22q were investigated and the NF2 gene on 22q12.2 was screened for disease-causing mutations. RESULTS: The commonest tumour locations were convexity (25%) and parasagittal (21%). The histology results showed that 86.8% of the patients had Grade I tumours and the remainder had Grade II tumours. A pathogenic nonsense mutation, R341X in the NF2 gene was found in only one patient. LOH on each of chromosomes 1p and 22q was observed in 44.7% of patients, but in different individuals. Significant associations were found between having specific tumour characteristics and both male gender (p-value = 0.0059) and 22q LOH (p-value = 0.0425). We estimated that having 22q LOH makes an individual approximately four times more likely to develop a tumour that exhibits multiplicity, recurrence or calvarial erosion (OR = 4.8; 95% CI: 1.2-23.4). Adjusting for gender strengthened this effect (OR = 6.1; 95% CI: 1.1-48.7). CONCLUSIONS: Our data indicate that male patients and patients with a meningioma that has 22q LOH are more likely to develop tumours exhibiting multiplicity, recurrence or calvarial erosion. We recommend that this subset of patients should be followed up more closely. Further study is needed to determine the benefit of adjuvant radiation therapy in this scenario.

Penetrating civilian craniocerebral gunshot wounds: a protocol of delayed surgery.

OBJECTIVE: Several factors have led to our unique approach of delayed definitive débridement. We wanted to evaluate the effectiveness of our management and compare it with the existing data in the literature. METHODS: We retrospectively reviewed the records of 194 patients presenting between January 1996 and October 2003 with penetrating craniocerebral gunshot wounds. After exclusion criteria, 125 patients qualified. RESULTS: Of the patients, 88.8% were male. The mean age was 24.9 +/- 10.9 years. In 70.4% of patients, the presenting Glasgow Coma Scale (GCS) score was 3 to 8. Only 38 (30.4%) of the 125 patients survived, with poor outcome in 2 and good outcome in 36. Bilaterally fixed and dilated pupils and bihemispheric tract on computed tomographic scan were significantly related to poor outcome. There were 49 surgical procedures performed on 27 of the patients, with a mortality rate of 7.4%. Of the 38 survivors, 13 underwent no surgery. Average time to surgery was 11.04 days. Total rate of infection was 8%, and it did not influence outcome. No patient presenting with a GCS score of 3 or 4 survived. Seventeen patients attended follow-up, for a total of 3609 days (average, 212 d) and very few late complications. CONCLUSION: Our supportive care of patients is not optimal. We should have saved more of our patients who presented with GCS scores of 14 and 15 who subsequently died. We have been able to report unconventionally late surgical management of two-thirds of survivors, with no surgery in one-third of survivors. Despite a high rate of infectious complications, infection did not lead to death or disability. Our protocol rarely leads to patients surviving in a permanently vegetative state. In the future, we would perform early surgery for patients who present awake and continue our current management for poor-grade patients. In this way, we will improve the number of good outcomes without increasing the population of severely damaged and dependent survivors.

Intractable intracranial tuberculous infection responsive to thalidomide: report of four cases.

Paradoxical enlargement and development of new intracranial tuberculomas and tuberculous brain abscesses on adequate antituberculosis treatment are well recognized and supposedly cytokine mediated. These lesions are often unresponsive to conventional antituberculosis treatment, corticosteroids, and surgery. We therefore assessed the effect of adjunctive thalidomide, a tumor necrosis factor alpha-modulating drug, in intractable intracranial tuberculosis that did not respond to standard medical and surgical therapy. Four consecutive children (three children with bacteriologic proof and one child with clinical evidence of intracranial tuberculosis) were studied. Three patients each had a giant tuberculous abscess, and the fourth had chronic basal arachnoiditis with progressive loss of vision. Three of the four patients had relentless neurologic deterioration, and all showed disease progression on neuroimaging despite full medical and appropriate surgical treatment. Marked clinical and neuroradiologic improvement occurred after thalidomide was added to the antituberculosis treatment regimen of these four patients. Adjunctive thalidomide might have a role in the management of intractable intracranial tuberculosis and needs further investigation in this regard.

Penetrating civilian craniocerebral gunshot wounds: a protocol of delayed surgery.

OBJECTIVE: Several factors have led to our unique approach of delayed definitive débridement. We wanted to evaluate the effectiveness of our management and compare it with the existing data in the literature. METHODS: We retrospectively reviewed the records of 194 patients presenting between January 1996 and October 2003 with penetrating craniocerebral gunshot wounds. After exclusion criteria, 125 patients qualified. RESULTS: Of the patients, 88.8% were male. The mean age was 24.9 +/- 10.9 years. In 70.4% of patients, the presenting Glasgow Coma Scale (GCS) score was 3 to 8. Only 38 (30.4%) of the 125 patients survived, with poor outcome in 2 and good outcome in 36. Bilaterally fixed and dilated pupils and bihemispheric tract on computed tomographic scan were significantly related to poor outcome. There were 49 surgical procedures performed on 27 of the patients, with a mortality rate of 7.4%. Of the 38 survivors, 13 underwent no surgery. Average time to surgery was 11.04 days. Total rate of infection was 8%, and it did not influence outcome. No patient presenting with a GCS score of 3 or 4 survived. Seventeen patients attended follow-up, for a total of 3609 days (average, 212 d) and very few late complications. CONCLUSION: Our supportive care of patients is not optimal. We should have saved more of our patients who presented with GCS scores of 14 and 15 who subsequently died. We have been able to report unconventionally late surgical management of two-thirds of survivors, with no surgery in one-third of survivors. Despite a high rate of infectious complications, infection did not lead to death or disability. Our protocol rarely leads to patients surviving in a permanently vegetative state. In the future, we would perform early surgery for patients who present awake and continue our current management for poor-grade patients. In this way, we will improve the number of good outcomes without increasing the population of severely damaged and dependent survivors.

Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.

MRC CRASH is a randomised controlled trial (ISRCTN74459797) of the effect of corticosteroids on death and disability after head injury. We randomly allocated 10,008 adults with head injury and a Glasgow Coma Scale score of 14 or less, within 8 h of injury, to a 48-h infusion of corticosteroid (methylprednisolone) or placebo. Data at 6 months were obtained for 9673 (96.7%) patients. The risk of death was higher in the corticosteroid group than in the placebo group (1248 [25.7%] vs 1075 [22.3%] deaths; relative risk 1.15, 95% CI 1.07-1.24; p=0.0001), as was the risk of death or severe disability (1828 [38.1%] vs 1728 [36.3%] dead or severely disabled; 1.05, 0.99-1.10; p=0.079). There was no evidence that the effect of corticosteroids differed by injury severity or time since injury. These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury.

Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial.

BACKGROUND: Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial--a multicentre international collaboration--aimed to confirm or refute such an effect by recruiting 20000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment. METHODS: 10008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797. FINDINGS: Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21.1%] vs 893 [17.9%] deaths; relative risk 1.18 [95% CI 1.09-1.27]; p=0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0.22) or time since injury (p=0.05). INTERPRETATION: Our results show there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.