Anat Biegon

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.

Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial.

OBJECTIVE To establish the safety of intravenous dexanabinol in severe head injury. DESIGN Prospective, randomized, double-blind, placebo- (vehicle) controlled, multicenter, escalating dose study of a single administration of drug (48 or 150 mg) or vehicle (1 or 3 mL). SETTING All Israeli neurosurgical intensive care units (a total of six units). PATIENTS Sixty-seven patients, aged 16-65 yrs, Glasgow Coma Scale score of 4-8, injured within 6 hrs of treatment. MEASUREMENTS AND MAIN RESULTS Intracranial pressure, cerebral perfusion pressure, blood pressure, and heart rate were measured continuously in the intensive care unit. Adverse medical events were recorded and clinical outcome was assessed by the Glasgow outcome scale throughout a 6-month follow-up period. A highly significant reduction in the percentage of time with intracranial pressure >25, cerebral perfusion pressure <50, and systolic blood pressure <90 mm Hg was observed in the drug-treated group. The nature and incidence of adverse medical events were similar in the two groups. The percentage of patients achieving good neurologic outcome on the Glasgow outcome scale was 21% and 14% higher in the drug-treated group at 3 and 6 months, respectively. Statistical analysis of these differences by a logistic model using dose, entry Glasgow coma scale score, and computed tomograph as covariates yielded p values for the effect of treatment of .03 and .14 at 3 and 6 months, respectively. CONCLUSIONS Dexanabinol was safe and well tolerated in severe head injury. The treated patients achieved significantly better intracranial pressure/cerebral perfusion pressure control without jeopardizing blood pressure. A trend toward faster and better neurologic outcome was also observed.

Inhibition of NR2B Phosphorylation Restores Alterations in NMDA Receptor Expression and Improves Functional Recovery following Traumatic Brain Injury in Mice

Traumatic brain injury (TBI) triggers a massive glutamate efflux, hyperactivation of N-methyl-D-aspartate receptors (NMDARs) and neuronal cell death. Previously it was demonstrated that, 15 min following experimentally induced closed head injury (CHI), the density of activated NMDARs increases in the hippocampus, and decreases in the cortex at the impact site. Here we show that CHI-induced alterations in activated NMDARs correlate with changes in the expression levels of the major NMDARs subunits. In the hippocampus, the expression of NR1, NR2A, and NR2B subunits as well as the GluR1 subunit of the AMPA receptor (AMPAR) were increased, while in the cortex at the impact site, we found a decrease in the expression of these subunits. We demonstrate that CHI-induced increase in the expression of NMDAR subunits and GluR1 in the hippocampus, but not in the cortex, is associated with an increase in NR2B tyrosine phosphorylation. Furthermore, inhibition of NR2B-phosphorylation by the tyrosine kinase inhibitor PP2 restores the expression of this subunit to its normal levels. Finally, a single injection of PP2, prior to the induction of CHI, resulted in a significant improvement in long-term recovery of motor functions observed in CHI mice. These results provide a new mechanism by which acute trauma contributes to the development of secondary damage and functional deficits in the brain, and suggests a possible role for Src tyrosine kinase inhibitors as preoperative therapy for planned neurosurgical procedures.

Cognitive Deficits Post-Traumatic Brain Injury and Their Association with Injury Severity and Gray Matter Volumes

Traumatic brain injury (TBI) is known to have a substantial though highly variable impact on cognitive abilities. Due to the wide range of cognitive abilities among healthy individuals, an objective assessment of TBI-related cognitive loss requires an accurate measurement of pre-morbid cognitive performance. To address this problem, we recruited 50 adults who sustained a TBI and had performed a cognitive baseline assessment in adolescence as part of the aptitude tests mandated by the Israeli Defense Forces. This group was matched with non-injured controls (n = 35). Pre- and post-injury cognitive assessments consisted of three domains-namely, verbal abstraction, mathematical reasoning, and non-verbal abstract reasoning (from the Wechsler Adult Intelligence Scale-Third Edition). The difference between post- and pre-injury scores was calculated as a measure of domain-specific cognitive decline. Voxel-based regression was used to correlate cognitive decline with modulated gray matter probability maps controlling for age, Glasgow Coma Scale, and total intracranial volume. Using objectively assessed cognitive scores, we found that abstract reasoning declined in both moderate-severe and mild TBI patients, whereas verbal abstraction declined only in the moderate-severe group. Mathematical reasoning was not affected by TBI. In the TBI patients, non-verbal abstract reasoning post-pre-injury change scores were negatively correlated with the volume of the insula. We conclude that access to pre-morbid neuropsychological data may have facilitated the discovery of the effects of mild TBI on abstract reasoning, as well as a significant correlation between TBI-related decline in this cognitive domain and the volume of the bilateral insula, both of which had not been appreciated in the past.