From Awareness to Prognosis: Ethical Implications of Uncovering Hidden Awareness in Behaviorally Nonresponsive Patients.

Long-term patient outcomes after severe brain injury are highly variable, and reliable prognostic indicators are urgently needed to guide treatment decisions. Functional neuroimaging is a highly sensitive method of uncovering covert cognition and awareness in patients with prolonged disorders of consciousness, and there has been increased interest in using it as a research tool in acutely brain injured patients. When covert awareness is detected in a research context, this may impact surrogate decisionmaking-including decisions about life-sustaining treatment-even though the prognostic value of covert consciousness is currently unknown. This paper provides guidance to clinicians and families in incorporating individual research results of unknown prognostic value into surrogate decisionmaking, focusing on three potential issues: (1) Surrogate decisionmakers may misinterpret results; (2) Results may create false hope about the prospects of recovery; (3) There may be disagreement about the meaningfulness or relevance of results, and appropriateness of continued care.

Concussion and the severity of head impacts in mixed martial arts.

Concern about the consequences of head impacts in US football has motivated researchers to investigate and develop instrumentation to measure the severity of these impacts. However, the severity of head impacts in unhelmeted sports is largely unknown as miniaturised sensor technology has only recently made it possible to measure these impacts in vivo. The objective of this study was to measure the linear and angular head accelerations in impacts in mixed martial arts, and correlate these with concussive injuries. Thirteen mixed martial arts fighters were fitted with the Stanford instrumented mouthguard (MiG2.0) participated in this study. The mouthguard recorded linear acceleration and angular velocity in 6 degrees of freedom. Angular acceleration was calculated by differentiation. All events were video recorded, time stamped and reported impacts confirmed. A total of 451 verified head impacts above 10g were recorded during 19 sparring events (n = 298) and 11 competitive events (n = 153). The average resultant linear acceleration was 38.0624.3g while the average resultant angular acceleration was 256761739 rad/s2. The competitive bouts resulted in five concussions being diagnosed by a medical doctor. The average resultant acceleration (of the impact with the highest angular acceleration) in these bouts was 86.7618.7g and 756163438 rad/s2. The average maximum Head Impact Power was 20.6kW in the case of concussion and 7.15kW for the uninjured athletes. In conclusion, the study recorded novel data for sub-concussive and concussive impacts. Events that resulted in a concussion had an average maximum angular acceleration that was 24.7% higher and an average maximum Head Impact Power that was 189% higher than events where there was no injury. The findings are significant in understanding the human tolerance to short-duration, high linear and angular accelerations.

A Surviving Case of Acanthamoeba Granulomatous Amebic Encephalitis in a Hematopoietic Stem Cell Transplant Recipient.

BACKGROUND Acanthamoeba are free-living amoebae with potential to infect immunocompromised hosts. The mortality rate of granulomatous amebic encephalitis (GAE) due to Acanthamoeba exceeds 90% and there are currently no reports of survival of this infection in recipients of hematopoietic stem cell transplant. CASE REPORT We report herein the case of a 32-year-old man presenting to our service with abrupt neurological deterioration and seizures 5 months after allogeneic stem cell transplantation for Hodgkin lymphoma. Clinical and imaging findings were non-specific at presentation. Multiple circumscribed, heterogenous, mass-like lesions were identified on MRI. Brain biopsy was performed and revealed multiple cysts and trophozoites suggesting a diagnosis of granulomatous amebic encephalitis. PCR testing confirmed Acanthamoeba. Treatment with miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole was instituted and the patient survived and shows continued improvement with intensive rehabilitation. CONCLUSIONS We report the first successful outcome in this setting. The diagnosis would have been missed on cerebrospinal fluid analysis alone, but was rapidly made by histological analysis of brain biopsy. This diagnostically challenging infection is likely under-recognized. Early brain biopsy and commencement of a prolonged miltefosine-containing anti-ameba regimen can be curative.

Multi-Directional Dynamic Model for Traumatic Brain Injury Detection.

Given the worldwide adverse impact of traumatic brain injury (TBI) on the human population, its diagnosis and prediction are of utmost importance. Historically, many studies have focused on associating head kinematics to brain injury risk. Recently, there has been a push toward using computationally expensive finite element (FE) models of the brain to create tissue deformation metrics of brain injury. Here, we develop a new brain injury metric, the brain angle metric (BAM), based on the dynamics of a 3 degree-of-freedom lumped parameter brain model. The brain model is built based on the measured natural frequencies of an FE brain model simulated with live human impact data. We show that it can be used to rapidly estimate peak brain strains experienced during head rotational accelerations that cause mild TBI. In our data set, the simplified model correlates with peak principal FE strain (R2 = 0.82). Further, coronal and axial brain model displacement correlated with fiber-oriented peak strain in the corpus callosum (R2 = 0.77). Our proposed injury metric BAM uses the maximum angle predicted by our brain model and is compared against a number of existing rotational and translational kinematic injury metrics on a data set of head kinematics from 27 clinically diagnosed injuries and 887 non-injuries. We found that BAM performed comparably to peak angular acceleration, translational acceleration, and angular velocity in classifying injury and non-injury events. Metrics that separated time traces into their directional components had improved model deviance compare with those that combined components into a single time trace magnitude. Our brain model can be used in future work to rapidly approximate the peak strain resulting from mild to moderate head impacts and to quickly assess brain injury risk.

Dynamic Blood-Brain Barrier Regulation in Mild Traumatic Brain Injury.

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI.

Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE.

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury.

Traumatic brain injury is the leading cause of death in children and young adults globally. Malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RNA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology.