Contusion Progression Following Traumatic Brain Injury: A Review of Clinical and Radiological Predictors, and Influence on Outcome

Abstract: Secondary injuries remain an important cause of the morbidity and mortality associated with traumatic brain injury (TBI). Progression of cerebral contusions occurs in up to 75% of patients with TBI, and this contributes to subsequent clinical deterioration and requirement for surgical intervention. Despite this, the role of early clinical and radiological factors in predicting contusion progression remains relatively poorly defined due to studies investigating progression of all types of hemorrhagic injuries as a combined cohort. In this review, we summarize data from recent studies on factors which predict contusion progression, and the effect of contusion progression on clinical outcomes

The neurological sequelae of pandemics and epidemics

Funder: NIHR Cambridge Biomedical Research Centre (GB)Funder: University of CambridgeAbstract: Neurological manifestations in pandemics frequently cause short and long-term consequences which are frequently overlooked. Despite advances in the treatment of infectious diseases, nervous system involvement remains a challenge, with limited treatments often available. The under-recognition of neurological manifestations may lead to an increase in the burden of acute disease as well as secondary complications with long-term consequences. Nervous system infection or dysfunction during pandemics is common and its enduring consequences, especially among vulnerable populations, are frequently forgotten. An improved understanding the possible mechanisms of neurological damage during epidemics, and increased recognition of the possible manifestations is fundamental to bring insights when dealing with future outbreaks. To reverse this gap in knowledge, we reviewed all the pandemics, large and important epidemics of human history in which neurological manifestations are evident, and described the possible physiological processes that leads to the adverse sequelae caused or triggered by those pathogens

Cerebral Perfusion Pressure Targets Individualized to Pressure-Reactivity Index in Moderate to Severe Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) frequently triggers a disruption of cerebral autoregulation. The cerebral perfusion pressure (CPP) at which autoregulation is optimal ("CPPopt") varies between individuals, and can be calculated based on fluctuations between arterial blood pressure and intracranial pressure. This review assesses the effect of individualizing CPP targets to pressure reactivity index (a measure of autoregulation) in patients with TBI. Cochrane Central Register of Controlled Trials, MEDLINE®, Embase, and Cumulative Index of Nursing and Allied Health Literature were searched in March 2015 for studies assessing the effect of targeting CPPopt in TBI. We included all studies that assessed the impact of targeting CPPopt on outcomes including mortality, neurological outcome, and physiological changes. Risk of bias was assessed using the RTI Item Bank and evidence quality was considered using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Eight cohort studies (based on six distinct data sets) assessing the association between CPPopt and mortality, Glasgow Outcome Scale and physiological measures in TBI were included. The quality of evidence was deemed very low based on the GRADE criteria. Although the data suggest an association between variation from CPPopt and poor clinical outcome at 6 months, the quality of evidence prevents firm conclusions, particularly regarding causality, from being drawn. Available data suggest that targeting CPPopt might represent a technique to improve outcomes following TBI, but currently there is insufficient high-quality data to support a recommendation for use in clinical practice. Further prospective, randomized controlled studies should be undertaken to clarify its role in the acute management of TBI.This is the author accepted manuscript. The final version is available from MAry Ann Liebert via http://dx.doi.org/10.1089/neu.2016.445

Systemic, local, and imaging biomarkers of brain injury: more needed, and better use of those already established?

Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge.We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: Keri Linda H. Carpenter – NIHR BRC Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); Ibrahim Jalloh – MRC (Grant no. G1002277 ID 98489) and NIHR BRC Cambridge; Adel Helmy – MRC/Royal College of Surgeons of England Clinical Research Training Fellowship (Grant no. G0802251) and Raymond and Beverly Sackler Fellowship; Virginia F. J. Newcombe–Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship; Richard J. Shannon–NIHR BRC (Neuroscience Theme; Brain Injury and Repair Theme); Angelos G. Kolias–Royal College of Surgeons of England Research Fellowship, NIHR Academic Clinical Fellowship, and a Raymond and Beverly Sackler Studentship; David Krishna Menon–NIHR Senior Investigator Award; Peter J. Hutchinson – NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship.This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fneur.2015.00026/full#h13

Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.</p

INTERLEUKIN 10 AND HEART FATTY-ACID BINDING PROTEIN AS EARLY OUTCOME PREDICTORS IN PATIENTS WITH TRAUMATIC BRAIN INJURY

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected 6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95–100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI

Interleukin 10 and Heart Fatty Acid-Binding Protein as Early Outcome Predictors in Patients With Traumatic Brain Injury

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected &lt;24 h post trauma. The outcome was measured &gt;6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95-100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI.</p

Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury : A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.Peer reviewe

Understanding the relationship between cognitive performance and function in daily life after traumatic brain injury

Objective Cognitive impairment is a key cause of disability after traumatic brain injury (TBI) but relationships with overall functioning in daily life are often modest. The aim is to examine cognition at different levels of function and identify domains associated with disability. Methods 1554 patients with mild-to-severe TBI were assessed at 6 months post injury on the Glasgow Outcome Scale-Extended (GOSE), the Short Form-12v2 and a battery of cognitive tests. Outcomes across GOSE categories were compared using analysis of covariance adjusting for age, sex and education. Results Overall effect sizes were small to medium, and greatest for tests involving processing speed (eta(2)(p) 0.057-0.067) and learning and memory (eta(2)(p) 0.048-0.052). Deficits in cognitive performance were particularly evident in patients who were dependent (GOSE 3 or 4) or who were unable to participate in one or more major life activities (GOSE 5). At higher levels of function (GOSE 6-8), cognitive performance was surprisingly similar across categories. There were decreases in performance even in patients reporting complete recovery without significant symptoms. Medium to large effect sizes were present for summary measures of cognition (eta(2)(p) 0.111), mental health (eta(2)(p) 0.131) and physical health (eta(2)(p) 0.252). Conclusions This large-scale study provides novel insights into cognitive performance at different levels of disability and highlights the importance of processing speed in function in daily life. At upper levels of outcome, any influence of cognition on overall function is markedly attenuated and differences in mental health are salient.Peer reviewe

Relationship Between Measures of Cerebrovascular Reactivity and Intracranial Lesion Progression in Acute TBI Patients: an Exploratory Analysis

Abstract: Background: Failure of cerebral autoregulation and progression of intracranial lesion have both been shown to contribute to poor outcome in patients with acute traumatic brain injury (TBI), but the interplay between the two phenomena has not been investigated. Preliminary evidence leads us to hypothesize that brain tissue adjacent to primary injury foci may be more vulnerable to large fluctuations in blood flow in the absence of intact autoregulatory mechanisms. The goal of this study was therefore to assess the influence of cerebrovascular reactivity measures on radiological lesion expansion in a cohort of patients with acute TBI. Methods: We conducted a retrospective cohort analysis on 50 TBI patients who had undergone high-frequency multimodal intracranial monitoring and for which at least two brain computed tomography (CT) scans had been performed in the acute phase of injury. We first performed univariate analyses on the full cohort to identify non-neurophysiological factors (i.e., initial lesion volume, timing of scan, coagulopathy) associated with traumatic lesion growth in this population. In a subset analysis of 23 patients who had intracranial recording data covering the period between the initial and repeat CT scan, we then correlated changes in serial volumetric lesion measurements with cerebrovascular reactivity metrics derived from the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC (correlation coefficient between the pulse amplitude of intracranial pressure and cerebral perfusion pressure). Using multivariate methods, these results were subsequently adjusted for the non-neurophysiological confounders identified in the univariate analyses. Results: We observed significant positive linear associations between the degree of cerebrovascular reactivity impairment and progression of pericontusional edema. The strongest correlations were observed between edema progression and the following indices of cerebrovascular reactivity between sequential scans: % time PRx > 0.25 (r = 0.69, p = 0.002) and % time PAx > 0.25 (r = 0.64, p = 0.006). These associations remained significant after adjusting for initial lesion volume and mean cerebral perfusion pressure. In contrast, progression of the hemorrhagic core and extra-axial hemorrhage volume did not appear to be strongly influenced by autoregulatory status. Conclusions: Our preliminary findings suggest a possible link between autoregulatory failure and traumatic edema progression, which warrants re-evaluation in larger-scale prospective studies