Consensus statement from the International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury : Consensus statement.

BACKGROUND: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries. RESULTS: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval. CONCLUSIONS: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction.

The Rationale for Radiation Therapy in Alzheimer's Disease.

Alzheimer's Disease (AD) represents a major health problem without effective treatments. As the incidence of the disease will continue to rise, it is imperative to find new treatment options to halt or slow disease progression. In recent years, several groups have begun to study the utility of low total dose radiation therapy (LTDRT) to inhibit some of the pathological features of AD and improve cognition in a variety of animal models. These preclinical studies have led to Phase 1 and 2 trials in different centers around the world. In this review, we present and interpret the pre-clinical evidence report some preliminary clinical data from a Phase 2 trial in early-stage AD patients.

Perceived Utility of Intracranial Pressure Monitoring in Traumatic Brain Injury: A Seattle International Brain Injury Consensus Conference Consensus-Based Analysis and Recommendations.

BACKGROUND: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed. OBJECTIVE: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion. METHODS: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression. RESULTS: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations. CONCLUSION: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions.

Prognostication and Goals of Care Decisions in Severe Traumatic Brain Injury: A Survey of The Seattle International Severe Traumatic Brain Injury Consensus Conference Working Group.

Abstract Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.

Low Dose Brain Irradiation Reduces Amyloid-ß and Tau in 3xTg-AD Mice.

We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-ß (Aß) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aß and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aß plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation may be beneficial in Alzheimer's disease.

A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

BACKGROUND: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. METHODS: Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. RESULTS: We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. CONCLUSIONS: These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference.

A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

BACKGROUND: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based. METHODS: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations. RESULTS: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination. CONCLUSIONS: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.

Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD).

BACKGROUND AND PURPOSE: To investigate if cranial X-irradiation reduces amyloid-ß (Aß) plaques and influences cognitive function in a transgenic mouse model of AD. METHODS AND MATERIALS: B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aß plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT(2) Profiler), radiation-associated cytokines (Milliplex MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1ß, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aß burden to cognitive function using a Morris water-maze task. RESULTS: Single X-ray doses reduced the number (p=0.002) and size (p=0.01) of Aß plaques. Low-dose fractionation produced greater 50.6% (1 Gy × 10), 72% (2 Gy × 5) and 78% (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p=0.004) and proteomic (MIP-2, 8-fold, p=0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p=0.001). The reduction in Aß burden (2 Gy × 5) was associated with cognitive improvement (p=0.012). CONCLUSION: This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-ß plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.

Gene expression following traumatic brain injury in humans: analysis by microarray.

Global changes in gene expression were analyzed in pericontusional tissue taken during surgery from 4 patients with traumatic brain injury (TBI), in cerebral infarction tissue from a patient with vasculitis and in normal brain tissue resected during craniotomy for meningioma. Of approximately 1,200 genes showing some level of expression by cDNA microarray hybridization, 104 ( approximately 8%) showed differential expression in traumatized tissue. Genes controlling transcriptional regulation, intermediary and energy metabolism, signal transduction, and intercellular adhesion and recognition were differentially affected most often. Four genes previously shown to be associated with TBI (c-Fos, Jun B, HSP70, and Zif/268) were all found to be up-regulated in at least one TBI patient. Thus, the robust response to TBI of several immediate early genes is confirmed, and a longer list of candidate genes from other functional categories is suggested for further studies aimed at understanding the molecular and cellular consequences of TBI.

Free fatty acids in cerebrospinal fluids from patients with traumatic brain injury.

Free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) are recognized as markers of brain damage in animal studies. There is, however, relatively little information regarding FFA concentrations in human CSF in normal and pathological conditions. The present study examined FFA concentrations in CSF from 15 patients with traumatic brain injury (TBI) and compared the data with values obtained from 73 contemporary controls. Concentrations of specific FFAs from TBI patients, obtained within 48 h of the insult were significantly greater than those in the control group (arachidonic, docosahexaenoic and myristic, P<0.001; oleic, palmitic, P<0.01; linoleic, P<0.05). Higher concentrations of total polyunsaturated fatty acids (P<0.001) and of arachidonic, myristic and palmitic acids measured individually in CSF (P<0.01) obtained 1 week after the insult were associated with a worse outcome at the time of hospital discharge using the Glasgow Outcome Scale. This preliminary investigation suggests that CSF FFA concentrations may be useful as a predictive marker of outcome following TBI.

Free fatty acids in human cerebrospinal fluid following subarachnoid hemorrhage and their potential role in vasospasm: a preliminary observation.

OBJECT: The mechanisms leading to vasospasm following subarachnoid hemorrhage (SAH) remain unclear. Accumulation in cerebrospinal fluid (CSF) of free fatty acids (FFAs) may play a role in the development of vasospasm; however, in no previous study have concentrations of FFAs in CSF been examined after SAH. METHODS: We collected samples of CSF from 20 patients with SAH (18 cases of aneurysmal SAH and two cases of spontaneous cryptogenic SAH) and used a high-performance liquid chromatography assay to determine the FFA concentrations in these samples. We then compared these findings with FFA concentrations in the CSF of control patients. All FFA concentrations measured 24 hours after SAH were significantly greater than control concentrations (p < 0.01 for palmitic acid and < 0.001 for all other FFAs). All measured FFAs remained elevated for the first 48 hours after SAH (p < 0.05 for linoleic acid, p < 0.01 for palmitic acid, and p < 0.001 for the other FFAs). After 7 days, a second elevation in all FFAs was observed (p < 0.05 for linoleic acid, p < 0.01 for palmitic acid, and p < 0.001 for the other FFAs). Samples of CSF collected within 48 hours after SAH from patients in whom angiography and clinical examination confirmed the development of vasospasm after SAH were found to have significantly higher concentrations of arachidonic, linoleic, and palmitic acids than samples collected from patients in whom vasospasm did not develop (p < 0.05). CONCLUSIONS: Following SAH, all FFAs are initially elevated. A secondary elevation occurs between 8 and 10 days after SAH. This study provides preliminary evidence of FFA elevation following SAH and of a potential role for FFAs in SAH-induced vasospasm. A prospective study is warranted to determine if CSF concentrations of FFAs are predictive of vasospasm.

Neurotrauma: the role of CT angiogram.

Cerebrovascular injuries can occur in blunt or penetrating head and neck trauma. A high index of suspicion based on mechanism of injury and clinical assessment warrants screening for intracranial and extracranial vascular lesions. Conventional angiogram has been and remains the gold standard for diagnosis of these injuries, but computerized tomography angiography offers a fast, noninvasive method of imaging for neurotrauma patients. Advantages and disadvantages of each modality are discussed.

Significance of computed tomography mixed density in traumatic extra-axial hemorrhage.

Computed tomography (CT) mixed density of traumatic extra-axial hemorrhages (TEH) or the 'swirl sign' has been reported to correlate with active bleeding found at craniotomy and poor outcome. This study was done to test the hypothesis that mixed density of TEH detected by third or fourth generation CT correlated with the type of bleeding or clinical outcome. All cases of TEH operated at Detroit Receiving Hospital from 1991-1997 were reviewed for type of bleeding (active vs. not active; arterial vs. venous); Glasgow Coma Scale (severe 1-8, not severe 9-15); and Glasgow Outcome Score (1-3 poor; 4,5 good). CT density (CTD) of 51 cases with specific written documentation of bleeding type were then independently reviewed (SKS and MHR) and classified into TEH with mixed or high density. Data was analyzed using corrected Chi Square analysis, Fischer's Exact Test and Pearson's Correlation (SPSS 6.0). The Pearson Chi Square probability for correlation follows: CTD vs. active bleeding, 0.21; CTD vs. arterial, 0.41; CTD vs. severity, 0.57; and CTD vs. outcome, 0.81. No other statistical analysis identified a significant correlation, thus the null hypothesis could not be rejected. CT mixed density was not found to be correlated by more than chance with bleeding type, injury severity or outcome. Surgeon inaccuracy in documentation of bleeding type and use of later generation CT may account for the discrepancy between this and previous studies. Nevertheless, we conclude clinical exam and other published CT criteria are better indicators of injury severity and outcome.

Chiari I malformation associated with thoracic epidural cord lesion: case report.

Many spinal cord lesions have been described previously, in association with Chiari I lesions. The authors report a unique case of a 29-year-old patient with a Chiari I malformation and an upper thoracic epidural lesion causing headaches, dysphagia and Brown-Sequard syndrome. The patient underwent a suboccipital decompression as well as a thoracic laminectomy and resection of the epidural lesion. Pathologic analysis revealed that the thoracic lesion was fibro-adipose tissue. A review of the literature failed to show any other similar cases. We discuss the possible etiologies of this case.

Concussion 101: the current state of concussion education programs.

Concussion is an important cause of morbidity in young student athletes. The prevention, accurate diagnosis, and prompt management of concussions require that players, parents, coaches, and medical personnel are accurately educated on current concussion data and guidelines. All states have laws that mandate concussion education for high school athletes. There is currently no uniform educational program to disseminate information to student athletes regarding concussions. This article highlights a few nationally recognized educational programs that aim to accurately and effectively inform all members of the athletic, academic, and medical communities about the importance and urgency of concussion.