Reducing acetylated tau is neuroprotective in brain injury.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Establishing a Regional Trauma Preventable/Potentially Preventable Death Rate.

OBJECTIVE: To establish a trauma preventable/potentially preventable death rate (PPPDR) within a heavily populated county in Texas. SUMMARY: The National Academies of Sciences estimated the trauma preventable death rate in the United States to be 20%, issued a call for zero preventable deaths, while acknowledging that an accurate preventable death rate was lacking. In this absence, effective strategies to improve quality of care across trauma systems will remain difficult. METHODS: A retrospective review of death-related records that occurred during 2014 in Harris County, TX, a diverse population of 4.4 million. Patient demographics, mechanism of injury, cause, timing, and location of deaths were assessed. Deaths were categorized using uniform criteria and recorded as preventable, potentially preventable or nonpreventable. RESULTS: Of 1848 deaths, 85% had an autopsy and 99.7% were assigned a level of preventability, resulting in a trauma PPPDR of 36.2%. Sex, age, and race/ethnicity varied across preventability categories (P < 0.01). Of 847 prehospital deaths, 758 (89.5%) were nonpreventable. Among 89 prehospital preventable/potentially preventable (P/PP) deaths, hemorrhage accounted for 55.1%. Of the 657 initial acute care setting deaths, 292 (44.4%) were P/PP; of these, hemorrhage, sepsis, and traumatic brain injury accounted for 73.3%. Of 339 deaths occurring after initial hospitalization, 287 (84.7%) were P/PP, of these 117 resulted from sepsis and 31 from pulmonary thromboembolism, accounted for 51.6%. CONCLUSIONS: The trauma PPPDR was almost double that estimated by the National Academies of Sciences. Data regarding P/PP deaths offers opportunity to target research, prevention, intervention, and treatment corresponding to all phases of the trauma system.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

Outcomes and prognostic factors of pediatric patients with a Glasgow Coma Score of 3 after blunt head trauma.

PURPOSE: This study aims to assess outcomes of pediatric patients with blunt traumatic brain injury (TBI) with a presenting Glasgow Coma Score (GCS) of 3. METHODS: After local institutional review board approval, we identified patients ages 0 to15 years with blunt TBI and a reported GCS of 3 between 2007 and 2017 from a pediatric level 1 trauma center prospective registry. Exclusion criteria were cardiac death on arrival and penetrating injury. We recorded clinical variables from patients with a non-pharmacologic GCS of 3 and pupillary exam documented by a neurosurgical attending or resident. The original Glasgow Outcome Scale (GOS) was used to compare with other studies. Importance of variables to survival was calculated. RESULTS: A total of 88 patients (mean age 6.9 years) were included with a mortality rate of 68%. Twelve percent had a poor long-term outcome (GOS 2 or 3) while 20% had a good long-term outcome (GOS 4 or 5). Median follow-up was 1.8 years. Initial group comparison revealed patients in group 1 (survivors) had less hypotension on arrival (14% SBP < 90 mmHg vs. 66%, p < 0.0001), higher temperatures on arrival (36.3 °C vs 34.9 °C, p = 0.0002), lower ISS (29.7 vs 39.5, p = 0.003), less serious injury to other major organs (34% vs 61%, p = 0.02), more epidural hematomas (24% vs 7%, p = 0.04), and less evidence of brain ischemia on CT (7% vs 39%, p = 0.002) or brainstem infarct, hemorrhage, or herniation (0% vs 27%, p = 0.002). Differences between the 2 groups in age, sex, race, MOI, AIS score, presence of midline shift > 5 mm, or time from injury to hospital arrival or time to surgery were not statistically significant. Classification tree analysis showed that the most important variable for survival was pupillary exam; mortality was 92% in presence of bilateral, fixed dilated pupils. The relative importance of initial temperature, MOI, and hypotension to survivability was 0.79, 0.75, and 0.47, respectively. CONCLUSION: Twenty percent of our pediatric non-pharmacologic GCS 3 cohort had a good functional outcome. Lack of bilaterally fixed and dilated pupils was the most important factor for survival. Temperature, MOI, and hypotension also correlated with survival. The data support selective aggressive management for these patients.

Inflammation in delayed ischemia and functional outcomes after subarachnoid hemorrhage.

BACKGROUND: Inflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions. METHODS: Serum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods (< 24 h, 24-48 h, 3-5 days, and 6-8 days after SAH) and concentration levels of 41 cytokines were measured by multiplex immunoassay. Logistic regression analysis was used to identify cytokines associated with DCI and poor functional outcomes. Correlation networks were constructed to identify cytokine clusters. RESULTS: Of the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes. CONCLUSIONS: Serum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

Golf cart associated traumatic brain injury.

Object: Although contact sport-related head injuries are frequently reported, golf cart accidents may have significant consequences including severe traumatic brain injury (TBI) or head injury. As no standardized regulations exist, this mechanism may be underreported. Methods: A retrospective review of TBI or cranial trauma after a golf cart accident at a level I trauma center over 5 years were performed. Data regarding age, sex, race, initial Glasgow Coma Scale score, alcohol status, type and location of the injury, and outcomes were analyzed and reported in terms of Modified Rankin Scale (MRS). Results: A total of 23 patients with TBI or cranial trauma following golf cart accident were identified. The mean age was 36 years old with the most common injury being skull fracture followed by acute subdural hematoma. Most patients had good outcomes, MRS 0-3, at discharge, but like most forms of TBI, surgical interventions, intracranial pressure monitoring, post-traumatic seizures, hydrocephalus, and death did occur. Conclusions: Head injuries sustained by golf cart accidents are not insignificant and may be underreported. More awareness of these injuries and safety guidelines are needed.

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Adults with severe traumatic brain injury (Glasgow Coma Scale 5-8) and without signs of irreversible brain injury were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6, 9, 12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest-related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included magnetic resonance imaging-based measurements of supratentorial and corpus callosal volumes as well as diffusion tensor imaging-based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months postinjury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pretreatment, posttreatment, and at 1 and 6 month follow-up. There were no serious adverse events. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were downregulated. Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by central nervous system structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are downregulated after cell infusion. Stem Cells 2016 Video Highlight: https://youtu.be/UiCCPIe-IaQ Stem Cells 2017;35:1065-1079.

Coagulopathy as a predictor of mortality after penetrating traumatic brain injury.

STUDY HYPOTHESIS: Traumatic brain injury (TBI) is a leading cause of mortality with penetrating TBI (p-TBI) patients having worse outcomes. These patients are more likely to be coagulopathic than blunt TBI (b-TBI) patients, thus we hypothesize that coagulopathy would be an early predictor of mortality. METHODS: We identified highest-level trauma activation patients who underwent an admission head CT and had ICU admission orders from August 2009-May 2013, excluding those with polytrauma and anticoagulant use. Rapid thrombelastography (rTEG) was obtained after emergency department (ED) arrival and coagulopathy was defined as follows: ACT≥128s, KT≥2.5s, angle≤56°, MA≤55mm, LY-30≥3.0% or platelet count≤150,000/µL. Regression modeling was used to assess the association of coagulopathy on mortality. RESULTS: 1086 patients with head CT scans performed and ICU admission orders were reviewed. After exclusion criteria were met, 347 patients with isolated TBI were analyzed-99 (29%) with p-TBI and 248 (71%) with b-TBI. Patients with p-TBI had a higher mortality (41% vs. 10%, p<0.0001) and a greater incidence of coagulopathy (64% vs. 51%, p<0.003). After dichotomizing p-TBI patients by mortality, patients who died were younger and were more coagulopathic. When adjusting for factors available on ED arrival, coagulopathy was found to be an early predictor of mortality (OR 3.99, 95% CI 1.37, 11.72, p-value=0.012). CONCLUSIONS: This study demonstrates that p-TBI patients with significant coagulopathy have a poor prognosis. Coagulopathy, in conjunction with other factors, can be used to earlier identify p-TBI patients with worse outcomes and represents a possible area for intervention.

Surgical Management of Acute Subdural Hematoma: A Meta-Analysis.

BACKGROUND AND OBJECTIVE: Traumatic acute subdural hematoma (ASDH) is a medical emergency that requires prompt neurosurgical intervention. Urgent surgical evacuation may be performed with craniotomy (CO) and decompressive craniectomy (DC). However, a meta-analysis evaluating confounders, pooled functional outcomes, and mortality analyses at different time points has not been performed. METHODS: A systematic search was conducted until August 28, 2023. We identified studies performing ASDH evacuation with CO or DC. Outcomes included Glasgow Coma Scale (GCS), Glasgow Outcome Scale (GOS), GOS-Extended, mortality, procedure-related complications, and reoperation. Variables were assessed using risk ratio (RR) and mean difference. RESULTS: Among 684 published articles, we included the Randomized Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation of ASDH (RESCUE-ASDH) trial, 4 propensity score-matched (PSM) cohorts, and 13 observational cohort studies. A total of 8886 patients underwent CO or DC. GCS at admission in unmatched cohorts was significantly worse in the DC group (mean difference = 2.20 [95% CI = 1.86-2.55], P < .00001). GOS-Extended scores were similar among CO and DC (RR = 1.10 [95% CI = 0.85-1.42], P = .49), including the RESCUE-ASDH trial. GOS at the last follow-up in unmatched cohorts significantly favored CO (RR = 1.66 [95% CI = 1.02-2.70], P = .04). Similarly, while short-term mortality favored CO over DC (RR = 0.69 [95% CI = 0.51-0.93], P = .02), both the RESCUE-ASDH trial and the PSM-cohorts yielded similar mortality rates among groups (P > .05). Mortality at the last follow-up in unmatched patients favored CO (RR = 0.60 [95% CI = 0.47-0.77], P < .0001). Procedure-related complications (RR = 0.74 [0.50-1.09], P = .12) and reoperation rates (RR = 0.74 [0.50-1.09], P = .12) were similar. CONCLUSION: Patients with ASDH undergoing DC across unmatched cohorts had a worse GCS at admission. Although ASDH mortality was lower in the CO group, these findings are derived from unmatched cohorts, potentially confounding previous analyses. Notably, population-matched studies, such as the RESCUE-ASDH trial and PSM cohorts, showed similar effectiveness in mortality and functional outcomes between CO and DC. Reoperation and complication rates were comparable among surgical approaches. Considering the prevalence of unmatched cohorts, our findings highlight the need of future clinical trials to validate the findings of the RESCUE-ASDH trial.

Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury.

BACKGROUND: Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. METHODS: We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. RESULTS: Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. CONCLUSIONS: The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

Middle meningeal artery embolization reduces recurrence following surgery for septated chronic subdural hematomas.

BACKGROUND: Septated chronic subdural hematomas (cSDH) have high rates of recurrence despite surgical evacuation. Middle meningeal artery embolization (MMAE) has emerged as a promising adjuvant for secondary prevention, yet its efficacy remains ill-defined. METHODS: This is a retrospective review of septated cSDH cases treated at our institution. The surgery-only group was derived from cases performed before 2018, and the surgery+MMAE group was derived from cases performed 2018 or later. The primary outcome was reoperation rate. Secondary outcomes were recurrence, change in hematoma thickness, and midline shift. RESULTS: A total of 34 cSDHs in 28 patients (surgery+MMAE) and 95 cSDHs in 83 patients (surgery-only) met the inclusion criteria. No significant difference in baseline characteristics between groups was identified. The reoperation rate was significantly higher in the surgery-only group (n = 16, 16.8%) compared with the surgery+MMAE cohort (n = 0, 0.0%) (p=0.006). A reduced incidence of recurrence (p=0.011) was also seen in the surgery+MMAE group. CONCLUSIONS: MMAE for septated cSDH was found to be highly effective in preventing recurrence and reoperation. MMAE is an adjunct to surgical evacuation may be of particular benefit in this patient cohort.

Middle Meningeal Artery Embolization for Chronic Subdural Hematomas With Concurrent Antithrombotics.

BACKGROUND: Chronic subdural hematoma (CSDH) is an increasingly prevalent disease in the aging population. Patients with CSDH frequently suffer from concurrent vascular disease or develop secondary thrombotic complications requiring antithrombotic treatment. OBJECTIVE: To determine the safety and impact of early reinitiation of antithrombotics after middle meningeal artery embolization for chronic subdural hematoma. METHODS: This is a single-institution, retrospective study of patients who underwent middle meningeal artery (MMA) embolizations for CSDH. Patient with or without antithrombotic initiation within 5 days postembolization were compared. Primary outcome was the rate of recurrence within 60 days. Secondary outcomes included rate of reoperation, reduction in CSDH thickness, and midline shift. RESULTS: Fifty-seven patients met inclusion criteria. The median age was 66 years (IQR 58-76) with 21.1% females. Sixty-six embolizations were performed. The median length to follow-up was 20 days (IQR 14-44). Nineteen patients (33.3%) had rapid reinitiation of antithrombotics (5 antiplatelet, 11 anticoagulation, and 3 both). Baseline characteristics between the no antithrombotic (no-AT) and the AT groups were similar. The recurrence rate was higher in the AT group (no-AT vs AT, 9.3 vs 30.4%, P = .03). Mean absolute reduction in CSDH thickness and midline shift was similar between groups. Rate of reoperation did not differ (4.7 vs 8.7%, P = .61). CONCLUSION: Rapid reinitiation of AT after MMA embolization for CSDH leads to higher rates of recurrence with similar rates of reoperation. Care must be taken when initiating antithrombotics after treatment of CSDH with MMA embolization.

Middle meningeal artery embolization of septated chronic subdural hematomas.

INTRODUCTION: Middle meningeal artery embolization (MMAE) has emerged as a promising new treatment for patients with chronic subdural hematomas (cSDH). Its efficacy, however, upon the subtype with a high rate of recurrence-septated cSDH-remains undetermined. METHODS: From our prospective registry of patients with cSDH treated with MMAE, we classified patients based on the presence or absence of septations. The primary outcome was the rate of recurrence of cSDH. Secondary outcomes included a reduction in cSDH thickness, midline shift, and rate of reoperation. RESULTS: Among 80 patients with 99 cSDHs, the median age was 68 years (IQR 59-77) with 20% females. Twenty-eight cSDHs (35%) had septations identified on imaging. Surgical evacuation with burr holes was performed in 45% and craniotomy in 18.8%. Baseline characteristics between no-septations (no-SEP) and septations (SEP) groups were similar except for median age (SEP vs no-SEP, 72.5 vs. 65.5, p = 0.016). The recurrence rate was lower in the SEP group (SEP vs. no-SEP, 3 vs. 16.7%, p = 0.017) with higher odds of response from MMAE for septated lesions even when controlling for evacuation strategy and antithrombotic use (OR = 0.06, CI [0.006-0.536], p = 0.012). MMAE resulted in higher mean absolute thickness reduction (SEP vs. no-SEP, -8.2 vs. -4.8 mm, p = 0.016) with a similar midline shift change. The rate of reoperation did not differ (6.2 vs. 3.1%, p = 0.65). CONCLUSION: MMAE appears to be equal to potentially more effective in preventing the recurrence of cSDH in septated lesions. These findings may aid in patient selection.

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.

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.

Thirty-two nails injected into the head: An operative report and review of the literature.

Background: Self-inflicted nail gun injuries are a rare phenomenon that can result in traumatic damage. The velocity of the nail is generally fast enough to penetrate the skull. However, the extent of damage depends on the exact angle and structures of the brain encountered by the nails. Case Description: A 55-year-old male presented with 32 nails in the head and was found down. Initially, the patient presented with localization but had to be intubated soon after due to declining condition. This report describes the operative technique for safe removal of all nails, separated into six categories based on location and structures of the brain encountered. A review of literature revealed potential complications such as hemorrhage and infections and how to protect against these undesired effects. Conclusion: Self-inflicted nail gun head injuries are an uncommon form of traumatic head injury. Some important tools that helped prevent our patient from developing major complications included stereotactic navigation, antibiotic prophylaxis, and angiography to carefully monitor for vascular injuries.

White matter connectivity for early prediction of Alzheimer's disease.

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) remains challenging. It is speculated that structural atrophy in white matter tracts commences prior to the onset of AD symptoms. OBJECTIVE: We hypothesize that disruptions in white matter tract connectivity precedes the onset of AD symptoms and these disruptions could be leveraged for early prediction of AD. METHODS: Diffusion tensor images (DTI) from 52 subjects with mild cognitive impairment (MCI) were selected. Subjects were dichotomized into two age and gender matched groups; the MCI-AD group (22 subjects who progressed to develop AD) and the MCI-control group (who did not develop AD). DTI images were anatomically parcellated into 90 distinct regions ROIs followed by tractography methods to obtain different biophysical networks. Features extracted from these networks were used to train predictive algorithms with the objective of discriminating the MCI-AD and MCI-control groups. Model performance and best features are reported. RESULTS: Up to 80% prediction accuracy was achieved using a combination of features from the 'right anterior cingulum' and 'right frontal superior medial'. Additionally, local network features were more useful than global in improving the model's performance. CONCLUSION: Connectivity-based characterization of white matter tracts offers potential for early detection of MCI-AD and in the discovery of novel imaging biomarkers.

Blunt Traumatic Vertebral Artery Injuries: Incidence, Therapeutic Management, and Outcomes.

BACKGROUND: Blunt cerebrovascular injury (BCVI) is a term for injuries to the carotid and vertebral arteries (blunt vertebral artery injury [BVAI]) caused by blunt trauma. Computed tomographic angiography is currently the best screening test for BCVI. The subsequent management of any identified vessel injury, however, is not clearly defined. OBJECTIVE: To describe one of the largest cohorts of isolated vertebral artery injuries and report the evolution of treated and untreated lesions and clinical outcomes of treatment regimens used to reduce the risk of injury-related stroke. METHODS: The list included patients who presented to or were transferred to a level 1 trauma center and found to have an isolated BVAI. Patients were included if imaging was performed within 24 hours of presentation. Data collected included location and grade of injury, timing and type of initial therapy, follow-up imaging, evolution of the disease, and associated strokes. RESULTS: A total of 156 patients were included in the analysis. Most patients (135/156) were treated with aspirin alone, 3 with anticoagulation therapy, and 18 did not receive treatment. Three strokes were detected within 24 hours of admission and before treatment initiation. No strokes were detected during the length of the hospitalization for any other patient. CONCLUSION: Our data demonstrate that the risk of stroke after cervical vertebral artery injury is low, and aspirin as a prophylactic is efficacious in grade I and IV injuries. There are limited data regarding grade II and grade III injuries. The benefit of early interval imaging follow-up is unclear and warrants investigation.

Developing a National Trauma Research Action Plan: Results from the Neurotrauma Research Panel Delphi Survey.

BACKGROUND: In 2016, the National Academies of Science, Engineering and Medicine called for the development of a National Trauma Research Action Plan. The Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care. Given the public health burden of injuries to the central nervous system, neurotrauma was one of 11 panels formed to address this recommendation with a gap analysis and generation of high-priority research questions. METHODS: We recruited interdisciplinary experts to identify gaps in the neurotrauma literature, generate research questions, and prioritize those questions using a consensus-driven Delphi survey approach. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the importance of the questions on a 9-point Likert scale. Consensus was defined as 60% or greater of panelists agreeing on the priority category. We then coded research questions using an National Trauma Research Action Plan taxonomy of 118 research concepts, which were consistent across all 11 panels. RESULTS: Twenty-eight neurotrauma experts generated 675 research questions. Of these, 364 (53.9%) reached consensus, and 56 were determined to be high priority (15.4%), 303 were deemed to be medium priority (83.2%), and 5 were low priority (1.4%). The research topics were stratified into three groups-severe traumatic brain injury (TBI), mild TBI (mTBI), and spinal cord injury. The number of high-priority questions for each subtopic was 46 for severe TBI (19.7%), 3 for mTBI (4.3%) and 7 for SCI (11.7%). CONCLUSION: This Delphi gap analysis of neurotrauma research identified 56 high-priority research questions. There are clear areas of focus for severe TBI, mTBI, and spinal cord injury that will help guide investigators in future neurotrauma research. Funding agencies should consider these gaps when they prioritize future research. LEVEL OF EVIDENCE: Diagnostic Test or Criteria, Level IV.