M. Ross Bullock

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.

Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study

BACKGROUND Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50-60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. METHODS We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. FINDINGS Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72-3·37] and 7·58 [2·64-21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. INTERPRETATION Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. FUNDING US Army CDMRP PH/TBI research programme.

Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: A case control study

IntroductionAuthors of several studies have studied biomarkers and computed tomography (CT) findings in the acute phase after severe traumatic brain injury (TBI). However, the correlation between structural damage as assessed by neuroimaging and biomarkers has not been elucidated. The aim of this study was to investigate the relationships among neuronal (Ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels in serum, neuroradiological findings and outcomes after severe TBI.MethodsThe study recruited patients from four neurotrauma centers. Serum samples for UCH-L1 and GFAP were obtained at the time of hospital admission and every 6 hours thereafter. CT scans of the brain were obtained within 24hrs of injury. Outcome was assessed by Glasgow Outcome Scale (GOS) at discharge and at 6 months.Results81 severe TBI patients and 167 controls were enrolled. The mean serum levels of UCH-L1 and GFAP were higher (p < 0.001) in TBI patients compared to controls. UCH-L1 and GFAP serum levels correlated significantly with Glasgow Coma Scale (GCS) and CT findings. GFAP levels were higher in patients with mass lesions than in those with diffuse injury (2.95 ± 0.48 ng/ml versus 0.74 ± 0.11 ng/ml) while UCH-L1 levels were higher in patients with diffuse injury (1.55 ± 0.18 ng/ml versus 1.21 ± 0.15 ng/ml, p = 0.0031 and 0.0103, respectively). A multivariate logistic regression showed that UCH-L1 was the only independent predictor of death at discharge [adjusted odds ratios 2.95; 95% confidence interval, 1.46-5.97], but both UCH-L1 and GFAP levels strongly predicted death 6 months post-injury.ConclusionsRelationships between structural changes detected by neuroimaging and biomarkers indicate each biomarker may reflect a different injury pathway. These results suggest that protein biomarkers could provide better characterization of subjects at risk for specific types of cellular damage than that obtained with neuroimaging alone, as well as provide valuable information about injury severity and outcome after severe TBI.

Low-Dose Recombinant Tissue-Type Plasminogen Activator Enhances Clot Resolution in Brain Hemorrhage: The Intraventricular Hemorrhage Thrombolysis Trial

Background and Purpose— Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis. Methods— Forty-eight patients were enrolled at 14 centers and randomized to treatment with 3 mg recombinant tissue-type plasminogen activator (rtPA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the 2 groups. Results— Severity factors, including admission Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage volume, and blood pressure were evenly distributed, as were adverse events, except for an increased frequency of respiratory system events in the placebo-treated group. Neither intracranial pressure nor cerebral perfusion pressure differed substantially between treatment groups on presentation, with external ventricular device closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the prespecified threshold for mortality (18% rtPA; 23% placebo), ventriculitis (8% rtPA; 9% placebo), symptomatic bleeding (23% rtPA; 5% placebo, which approached statistical significance; P=0.1). The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. There was a significant beneficial effect of rtPA on rate of clot resolution. Conclusions— Low-dose rtPA for the treatment of intracerebral hemorrhage with intraventricular hemorrhage has an acceptable safety profile compared to placebo and historical controls. Data from a well-designed phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment. Clinical Trial Registration— Participant enrollment began before July 1, 2005.

Exosome-mediated inflammasome signaling after central nervous system injury.

Neuroinflammation is a response against harmful effects of diverse stimuli and participates in the pathogenesis of brain and spinal cord injury (SCI). The innate immune response plays a role in neuroinflammation following CNS injury via activation of multiprotein complexes termed inflammasomes that regulate the activation of caspase 1 and the processing of the pro‐inflammatory cytokines IL‐1β and IL‐18. We report here that the expression of components of the nucleotide‐binding and oligomerization domain (NOD)‐like receptor protein‐1 (NLRP‐1) inflammasome, apoptosis speck‐like protein containing a caspase recruitment domain (ASC), and caspase 1 are significantly elevated in spinal cord motor neurons and cortical neurons after CNS trauma. Moreover, NLRP1 inflammasome proteins are present in exosomes derived from CSF of SCI and traumatic brain‐injured patients following trauma. To investigate whether exosomes could be used to therapeutically block inflammasome activation in the CNS, exosomes were isolated from embryonic cortical neuronal cultures and loaded with short‐interfering RNA (siRNA) against ASC and administered to spinal cord‐injured animals. Neuronal‐derived exosomes crossed the injured blood–spinal cord barrier, and delivered their cargo in vivo, resulting in knockdown of ASC protein levels by approximately 76% when compared to SCI rats treated with scrambled siRNA. Surprisingly, siRNA silencing of ASC also led to a significant decrease in caspase 1 activation and processing of IL‐1β after SCI. These findings indicate that exosome‐mediated siRNA delivery may be a strong candidate to block inflammasome activation following CNS injury.

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Acute Diagnostic Biomarkers for Spinal Cord Injury: Review of the Literature and Preliminary Research Report

OBJECTIVE Many efforts have been made to create new diagnostic technologies for use in the diagnosis of central nervous system injury. However, there is still no consensus for the use of biomarkers in clinical acute spinal cord injury (SCI). The aims of this review are (1) to evaluate the current status of neurochemical biomarkers and (2) to discuss their potential acute diagnostic role in SCI by reviewing the literature. METHODS PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was searched up to 2012 to identify publications concerning diagnostic biomarkers in SCI. To support more knowledge, we also checked secondary references in the primarily retrieved literature. RESULTS Neurofilaments, cleaved-Tau, microtubule-associated protein 2, myelin basic protein, neuron-specific enolase, S100β, and glial fibrillary acidic protein were identified as structural protein biomarkers in SCI by this review process. We could not find reports relating ubiquitin C-terminal hydrolase-L1 and α-II spectrin breakdown products, which are widely researched in other central nervous system injuries. Therefore, we present our preliminary data relating to these two biomarkers. Some of biomarkers showed promising results for SCI diagnosis and outcome prediction; however, there were unresolved issues relating to accuracy and their accessibility. CONCLUSION Currently, there still are not many reports focused on diagnostic biomarkers in SCI. This fact warranted the need for greater efforts to innovate sensitive and reliable biomarkers for SCI.

Outcome and Surgical Management for Geriatric Traumatic Brain Injury: Analysis of 888 Cases Registered in the Japan Neurotrauma Data Bank

OBJECTIVE As the aged population is rapidly growing globally, geriatric traumatic brain injury (TBI) becomes an increasing problem. There are higher mortality and poorer functional outcome in the geriatric TBI population (≥65 years) compared with younger groups despite neurosurgical interventions. Therefore, current treatment priorities and cost-effectiveness should be critically examined. We evaluated the benefit of surgical management in the elderly (≥65 years) after TBI. METHODS A total of 3194 patients with confirmed TBI were enrolled from 1998 to 2011, in the Japan Neurotrauma Data Bank. Retrospective analysis was conducted from the Japan Neurotrauma Data Bank on 888 (28%) patients (≥65 years) who did and did not undergo surgery. In particular, the effect of low Glasgow coma scale (GCS) (3-5) was compared with outcome with and without surgery. RESULTS Of all the patients 65 years of age and over, 478 (54%) were given surgical management (craniectomy, craniotomy, or burr-hole evacuation). This group of patients had significantly more favorable outcome at 6 months (18% vs. 7%) and less mortality (62% vs. 81%). However, within this surgical group, patients with initial GCS scores of 3-5 had significantly more unfavorable outcome (96% vs. 79%) and more mortality (87% vs. 57%) compared with those with GCS scores of 6-15. CONCLUSIONS We confirmed that age is a major determinant of outcome after TBI. In addition, we found that neurosurgical management is associated with the improvement of the prognosis and a decrease in the rate of mortality in geriatric TBI. However, surgical management was not shown to be an effective treatment in elderly patients with GCS scores of 3-5.

Past, Present, and Future of Traumatic Brain Injury Research

Traumatic brain injury (TBI) is the greatest cause of death and severe disability in young adults; its incidence is increasing in the elderly and in the developing world. Outcome from severe TBI has improved dramatically as a result of advancements in trauma systems and supportive critical care, however we remain without a therapeutic which acts directly to attenuate brain injury. Recognition of secondary injury and its molecular mediators has raised hopes for such targeted treatments. Unfortunately, over 30 late-phase clinical trials investigating promising agents have failed to translate a therapeutic for clinical use. Numerous explanations for this failure have been postulated and are reviewed here. With this historical context we review ongoing research and anticipated future trends which are armed with lessons from past trials, new scientific advances, as well as improved research infrastructure and funding. There is great hope that these new efforts will finally lead to an effective therapeutic for TBI as well as better clinical management strategies.

Traumatic brain injury: therapeutic challenges and new directions.

The realization of a successful pharmacological treatment for use in severe clinical traumatic brain injury (TBI) has eluded researchers for at least 3 decades in spite of the fact that several excellent candidate compounds have been identified in preclinical studies. As with developing therapies for stroke, in which more than 140 trials have been negative, there is a perception in the pharmaceutical industry, as well as in the biotechnology investment sector, that TBI represents an indication that is unattractive for further investment and development. Some have coined the term “valley of death” to describe the dichotomy that separates robustly successful, preclinical TBI science from the failures of clinical trials. Yet, now more than ever, substantial changes in the field have made successful translation of pharmacological neuroprotection in traumatic brain injury a strong, tangible reality for the next few years. The need to develop new therapies in TBI has never been stronger, even though its incidence has fallen in Europe, Japan, Australia, and North America. TBI remains the most significant cause of mortality and morbidity in persons less than 45 years of age throughout the world, and there has been a massive increase in its incidence in the “powerhouse developing nations” of Brazil, China, and India, especially, where increasing motorization has led to an epidemic increase in TBI. The future socioeconomic impact of head injury survivors in these countries may be even more profound than in the United States and Europe, where 1 in 200 families supports a TBI survivor. How can such therapies be implemented? All who are involved in the bench-to-bedside translation of TBI therapies need to learn lessons from the failures of the past; in 2009, many factors are interacting to make the likelihood of successful translation increasingly probable. For example, translation of therapies from theoretical concepts to a “clinic-ready” drug is now much more rapid than ever previously, thanks to such novel pharmacological techniques as structure-affinity relationship analysis, high throughput screening, more rapid information sharing, and far more efficient safety testing. New mechanisms, such as apoptotic cell death and the importance of neurotrophins in sustaining neuronal preservation in the face of injury, have now been shown to be robust in TBI, both in animal models and in humans, and moreover, new drugs aimed at both these mechanisms have already entered clinical phase IIA trials as rapidly as within 5 years of discovery of the mechanism. In recent years there has been growing concern among preclinical scientists who evaluated therapies in rodent models of TBI, as well as among funding agencies, that these models may be fundamentally incapable of effectively reproducing the complexity of severe human TBI, which is characterized by multiple interacting pathomechanisms within the same patient at the same or different times. For example, diffuse axonal injury, ischemic/hypoxic neuronal damage, increased intracranial pressure, and contusions are present in the majority of severe TBI patients, yet have not been combined in any single, small animal model. This has led to the important insight that multiple concurrent or sequential therapies are likely to be needed to influence these processes, and the National Institutes of Health National Institute of Neurological Disorders and Stroke have taken steps to pursue that aim. Nevertheless, despite this limitation, rodent models have produced a wealth of new molecular and biochemical results that have demonstrated homology in human TBI. For example, the realization of the importance of specific mitochondrial damage and the increasing importance of neurogenic inflammation have led to human phase III trials (cyclosporin A) without the intermediate step of using large animal gyrencephalic models. Thus, the concept of the “magic silver bullet,” which dominated thinking 2 decades ago, has been replaced with the view that the most likely successful interventions in TBI will be simultaneous multiple treatments, so-called “multipotential therapies” or alternatively, multifunctional drugs that target different harmful pathomechanisms. In this issue, several of these multipotential therapies are reviewed—hypothermia, statins, magnesium, progesterone, and others. As with preclinical drug development, clinical trial design has recently been critically examined, and the landmark studies of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) group have led to critical reanalysis of previous trials with formulation of new recommendations which offer the tangible prospect of improving clinical phase III and phase II trial design, not only in terms of number of Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics