Neurological Death Research Articles

Postoperative disability and one-year outcomes for patients suffering a stroke after carotid endarterectomy

ObjectiveAlthough post-carotid endarterectomy (CEA) strokes are rare, they can be devastating. The degree of disability that patients develop after such events and its effects on long-term outcomes are unclear. Our goal was to assess the extent of postoperative disability in patients suffering strokes after CEA and evaluate its association with long-term outcomes. MethodsThe Vascular Quality Initiative CEA registry (2016-2020) was queried for CEAs performed for asymptomatic or symptomatic indications in patients with preoperative modified Rankin Scale (mRS) scores of 0 to 1. The mRS grades stroke-related disability as 0 (none), 1 (not significant), 2 to 3 (moderate), 4 to 5 (severe), and 6 (dead). Patients suffering postoperative strokes with recorded mRS scores were included. Postoperative stroke-related disability based on mRS and its association with long-term outcomes were analyzed. ResultsAmong 149,285 patients undergoing CEA, there were 1178 patients without preoperative disability who had postoperative strokes and reported mRS scores. Mean age was 71 ± 9.2 years, and 59.6% of patients were male. Regarding ipsilateral cortical symptoms within 6 months preoperatively, 83.5% of patients were asymptomatic, 7.3% had transient ischemic attacks, and 9.2% had strokes. Postoperative stroke-related disability was classified as mRS 0 (11.6%), 1 (19.5%), 2 to 3 (29.4%), 4 to 5 (31.5%), and 6 (8%). One-year survival stratified by postoperative stroke-related disability was 91.4% for mRS 0, 95.6% for mRS 1, 92.1% for mRS 2 to 3, and 81.5% for mRS 4 to 5 (P < .001). Multivariable analysis demonstrated that while severe postoperative disability was associated with increased death at 1 year (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.5-5.89; P = .002), moderate postoperative disability had no such association (HR, 0.95; 95% CI, 0.45-2; P = .88). One-year freedom from subsequent ipsilateral neurological events or death stratified by postoperative stroke-related disability was 87.8% for mRS 0, 93.3% for mRS 1, 88.5% for mRS 2 to 3, and 77.9% for mRS 4 to 5 (P < .001). Severe postoperative disability was independently associated with increased ipsilateral neurological events or death at 1 year (HR, 2.34; 95% CI, 1.25-4.38; P = .01). However, moderate postoperative disability exhibited no such association (HR, 0.92; 95% CI, 0.46-1.82; P = .8). ConclusionsThe majority of patients without preoperative disability who suffered strokes after CEA developed significant disability. Severe stroke-related disability was associated with higher 1-year mortality and subsequent neurological events. These data can improve informed consent for CEA and guide prognostication after postoperative strokes.

Minimizing Intracranial Disease Before Stereotactic Radiation in Single or Solitary Brain Metastases.

Stereotactic radiotherapy (SRT) in multiple fractions (typically ≤5) can effectively treat a wide range of brain metastases, including those less suitable for single-fraction stereotactic radiosurgery (SRS). Prior prospective studies on surgical resection with stereotactic radiation have focused exclusively on SRS, and retrospective studies have shown equivocal results regarding whether surgery is associated with improved outcomes compared with SRT alone. We compared resection with postoperative cavity SRT or SRS to SRT alone in patients with 1 brain metastasis, while including patients receiving SRS alone as an additional reference group. We studied 716 patients in a retrospective, single-institution cohort diagnosed with single or solitary brain metastases from 2007 to 2020. Patients receiving whole-brain radiotherapy were excluded. Cox proportional hazards models were constructed for overall survival and additional intracranial outcomes. After adjustment for potential confounders, surgery with cavity SRT/SRS was associated with decreased all-cause mortality (hazard ratio [HR]: 0.39, 95% CI [0.27-0.57], P = 1.52 × 10 -6 ) compared with SRT alone, along with lower risk of neurological death attributable to intracranial tumor progression (HR: 0.46, 95% CI [0.22-0.94], P = 3.32 × 10 -2 ) and radiation necrosis (HR: 0.15, 95% CI [0.06-0.36], P = 3.28 × 10 -5 ). Surgery with cavity SRS was also associated with decreased all-cause mortality (HR: 0.52, 95% CI [0.35-0.78], P = 1.46 × 10 -3 ), neurological death (HR: 0.30, 95% CI [0.10-0.88], P = 2.88 × 10 -2 ), and radiation necrosis (HR: 0.14, 95% CI [0.03-0.74], P = 2.07 × 10 -2 ) compared with SRS alone. Surgery was associated with lower risk of all-cause mortality and neurological death in cardinality-matched subsets of the cohort. Among surgical patients, gross total resection was associated with extended overall survival (HR: 0.62, 95% CI [0.40-0.98], P = 4.02 × 10 -2 ) along with lower risk of neurological death (HR: 0.31, 95% CI [0.17-0.57], P = 1.84 × 10 -4 ) and local failure (HR: 0.34, 95% CI [0.16-0.75], P = 7.08 × 10 -3 ). In patients with 1 brain metastasis, minimizing intracranial disease specifically before stereotactic radiation is associated with improved oncologic outcomes.

Abstract 1190: Mimicking CAFs, pial cells support leptomeningeal metastasis

Abstract Leptomeningeal metastasis (LM), the spread of cancer into cerebrospinal fluid (CSF)-filled coverings of the brain and spinal cord, is a dismal complication of cancer leading to rapid neurologic disability and death. While a diverse array of primary tumors may result in LM, recent work from our laboratory (Chi Y et al 2020 Science) demonstrates a conserved transcriptional signature, independent of primary tumor, suggesting that tumor-microenvironmental interactions play a dominant role in this pathology. We have proteomically interrogated CSF collected from breast (n = 45), lung (n = 30), and melanoma (n = 27) patients with and without LM. We detect robust expression of inflammatory cytokines in all LM+ samples, 15 of these cytokines including IL8, IL6, and CXCL1 are conserved across tumor types in the presence of LM. Because cancer cells in the CSF do not express mRNA associated with these cytokines, we hypothesized that these inflammatory cytokines may originate from the microenvironment. Within the leptomeninges, LM cells adhere to and interact with the innermost layer of the meninges, the pia mater, which contains fibroblast-like cells. Co-culture of cancer cells with pial cells induced changes in the pial cell transcriptome and secretome, leading to increased IL8, IL6, and CXCL1 production. This communication between cancer cells and pial cells is preserved in the absence of direct cell-cell contact. To identify cancer cell signal(s) responsible for these pial cell changes, we subjected cancer cell conditioned media to gel filtration, and uncovered TGFBI as a key secreted factor inducing pial cell transcriptional changes. These pial cells support cancer cell growth in vivo, as measured by co-implantation experiments. In autopsy samples, we detect IL8, IL6, and CXCL1 expression in the pia of patients harboring LM. Taken together, these observations support a cancer-associated-fibroblast like role for pial cells in the setting of LM. We are currently carrying out single cell RNA sequencing of both human and mouse LM samples to capture heterogeneity in both cancer and pial cell responses, and to place these cells in the larger context of the CAF knowledgebase. Our work extends the CAF phenotype beyond classical fibroblasts to include pial cells, suggesting novel therapeutic opportunities within CNS malignancies. Citation Format: Jenna Snyder, Jan Remsik, Nicholas Prescott, Adrienne Boire. Mimicking CAFs, pial cells support leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1190.

563 Post-Approval Three Year Outcomes Study of the Neuroform Atlas Stent for Treatment of Wide-Neck Intracranial Aneurysms

INTRODUCTION: Favorable safety and effectiveness outcomes were presented previously for the Neuroform Atlas Stent following the completion of its pre-market study (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular, Intracranial Aneurysms with the Neuroform Atlas Stent System]) in anterior and posterior cohorts. METHODS: The ATLAS post-approval study was a multicenter, prospective, single-arm, open-label study of wide neck (neck ≥ 4mm or dome-to-neck ratio &lt;2) intracranial aneurysms in the anterior and posterior circulations treated with the Neuroform Atlas Stent and approved coils. The primary effectiveness endpoint was complete occlusion (Raymond-Roy class 1) on angiography in the absence of retreatment or significant parent artery stenosis (&gt;50%) through 3 years post-procedure. The primary safety endpoint was occurrence of major stroke, ipsilateral stroke, or neurological death through 3 years post-procedure. Independent adjudication of primary endpoint outcomes was completed by an Imaging Core Laboratory and Clinical Events Committee. RESULTS: A total of 146 anterior and 101 posterior cohort subjects from the pre-market study population were enrolled for continued follow-up. Subject demographics and aneurysm anatomy were representative of pivotal trial findings. For anterior subjects, the mean aneurysm size was 6.1±2.4 mm and the mean dome-to-neck ratio was 1.2±0.3 mm. In posterior subjects, the mean aneurysm size was 7±2.7 mm and the mean dome-to-neck ratio was 1.2±0.4 mm. At 3-year follow-up, the percent of target aneurysm progressive occlusion rated the same or better was 84.4% (95% CI, 67.2% - 94.7%) of anterior subjects and 90.0% (95% CI, 73.5% - 97.9%) of posterior subjects. A primary safety event was reported in 0.7% (1/146) of anterior and 1.0% (1/101) of posterior subjects, respectively, with no neurological deaths. CONCLUSIONS: The results of the ATLAS post-approval study demonstrate durable treatment effectiveness and favorable safety outcomes.

When is a person dead? The Canadian public’s understanding of death and death determination: a nationwide survey

PurposeWe aimed to describe the Canadian public’s understanding and perception of how death is determined in Canada, their level of interest in learning about death and death determination, and their preferred strategies for informing the public.MethodsWe conducted a nationwide cross-sectional survey of a representative sample of the Canadian public. The survey presented two scenarios of a man who met current criteria for neurologic death determination (scenario 1) and a man who met current criteria for circulatory death determination (scenario 2). Survey questions evaluated understanding of how death is determined, acceptance of death determination by neurologic and circulatory criteria, and interest and preferred strategies in learning more about the topic.ResultsAmong 2,000 respondents (50.8% women; n = 1,015), nearly 67.2% believed that the man in scenario 1 was dead (n = 1,344) and 81.2% (n = 1,623) believed that the man in scenario 2 was dead. Respondents who believed that the man was not dead or were unsure endorsed several factors that may increase their agreement with the determination of death, including requiring more information about how death was determined, seeing the results of brain imaging/tests, and a third doctor’s opinion. Predictors of disbelief that the man in scenario 1 is dead were younger age, being uncomfortable with the topic of death, and subscribing to a religion. Predictors of disbelief that the man in scenario 2 is dead were younger age, residing in Quebec (compared with Ontario), having a high school education, and subscribing to a religion. Most respondents (63.3%) indicated interest in learning more about death and death determination. Most respondents preferred to receive information about death and death determination from their health care professional (50.9%) and written information provided by their health care professional (42.7%).ConclusionAmong the Canadian public, the understanding of neurologic and circulatory death determination is variable. More uncertainty exists with death determination by neurologic criteria than with circulatory criteria. Nevertheless, there is a high level of general interest in learning more about how death is determined in Canada. These findings provide important opportunities for further public engagement.

391 Stereotactic Radiosurgery for Intermediate and High-Grade Arteriovenous Malformations: Outcomes Stratified by the Supplemented Spetzler-Martin Grading System

INTRODUCTION: The Supplemented Spetzler-Martin (Supp-SM) grading system is predictive of surgical risk for patients with brain arteriovenous malformations (AVM). METHODS: 219 patients had SRS from 1990 to 2016 for SM III (n = 154) or SM IV-V (n = 65) AVM. The Supp-SM grades were 4 (n = 14, 6%), 5 (n = 36, 16%), 6 (n = 67, 31%), 7 (n = 76, 35%), and 8-9 (n = 26, 12%). 60 patients (27%) had deep AVM (basal ganglia, thalamus, or brainstem). 39 patients (18%) had volume-staged SRS; 41 (19%) underwent repeat SRS. The median follow-up was 69 months for grade III AVM and 113 months for grade IV-V AVM. RESULTS: 163 patients (74%) had obliteration at a median of 38 months after initial SRS. The obliteration rates at 4 and 8 years were 59% and 76%, respectively. 31 patients (14%) had post-SRS deficits from hemorrhage (n = 7, 3%) or radiation injury (n = 24, 11%). 6 patients (3%) died after SRS (hemorrhage, n = 5; radiation injury, n = 1). The rates of neurologic decline or death at 4 and 8 years were 11% and 18%, respectively. Factors predictive of non-obliteration were deep location (HR 0.57, 95% CI 0.39-0.82, p = 0.003) and increasing AVM volume (HR 0.96, 95% CI 0.93-0.99, p = 0.002). Increasing AVM volume was the only factor associated with neurologic decline (HR 1.05, 95% CI 1.02-1.08, p = 0.002). The Supp-SM grading system did not correlate with obliteration (HR 0.94, 95% CI 0.82-1.09, p = 0.43) or neurologic decline (HR 1.15, 95% CI 0.84-1.56, p = 0.38). CONCLUSIONS: The Supp-SM grading system was not predictive of outcomes after SRS of intermediate or high-grade AVM. In a cohort which included a high percentage (47%) of “inoperable” AVM (Supp-SM ≥7), most patients had obliteration after SRS, although the chance of neurologic decline was significant.

Variant enterovirus A71 found in immune-suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease outbreaks with neurological complications and deaths. We previously isolated an EV-A71 variant in the stool, cerebrospinal fluid, and blood of an immunocompromised patient who had a leucine-to-arginine substitution on the VP1 capsid protein, resulting in increased heparin sulfate binding. We show here that this mutation increases the virus's pathogenicity in orally infected mice with depleted B cells, which mimics the patient's immune status, and increases susceptibility to neutralizing antibodies. However, a double mutant with even greater heparin sulfate affinity is not pathogenic, suggesting that increased heparin sulfate affinity may trap virions in peripheral tissues and reduce neurovirulence. This research sheds light on the increased pathogenicity of variant with heparin sulfate (HS)-binding ability in individuals with decreased B cell immunity.

Myeloid-associated differentiation marker is an essential host factor for human parechovirus PeV-A3 entry

Human parechovirus (PeV-A) is an RNA virus that belongs to the family Picornaviridae and it is currently classified into 19 genotypes. PeV-As usually cause mild illness in children and adults. Among the genotypes, PeV-A3 can cause severe diseases in neonates and young infants, resulting in neurological sequelae and death. In this study, we identify the human myeloid-associated differentiation marker (MYADM) as an essential host factor for the entry of six PeV-As (PeV-A1 to PeV-A6), including PeV-A3. The infection of six PeV-As (PeV-A1 to PeV-A6) to human cells is abolished by knocking out the expression of MYADM. Hamster BHK-21 cells are resistant to PeV-A infection, but the expression of human MYADM in BHK-21 confers PeV-A infection and viral production. Furthermore, VP0 capsid protein of PeV-A3 interacts with one extracellular domain of human MYADM on the cell membrane of BHK-21. The identification of MYADM as an essential entry factor for PeV-As infection is expected to advance our understanding of the pathogenesis of PeV-As.

Assessment of the therapeutic potential of probiotics against carbon quantum dots-induced neurotoxicity in common carp (Cyprinus carpio)

Carbon quantum dots (CQDs) have received increasing attention in recent years for their potential toxicity. However, little is known about their neurobehavioral toxicity. This study aimed to investigate the potential mechanisms by which probiotics reduce CQDs neurotoxicity from a brain-gut axis perspective by exposing carp to CQDs and/or probiotics for five weeks. The results showed that CQDs accumulation in the brain reduces the expression of blood-brain-barrier (BBB) related genes in carp, leading to brain damage. In addition, CQDs impaired motor behavior and inhibited acetylcholinesterase activity. These abnormalities were alleviated by probiotic supplementation. Microbiomic analysis showed that probiotics improved the imbalance of intestinal flora caused by CQDs and increased the abundance of Firmicutes. Serum metabolomic analysis showed that probiotic supplementation restored the abnormal metabolic levels associated with neurological, inflammatory, and apoptotic cell death caused by CQDs. Overall, probiotic supplementation improved the CQDs-induced changes in brain damage, gut microbiology, and systemic metabolism. These results suggests that CQDs may cause neurotoxicity via the brain-gut microbial axis.

Baseline brain imaging signs in patients with ischaemic stroke by the presence of atrial fibrillation: the ENCHANTED trial

BackgroundWe aimed to assess the association of atrial fibrillation (AF) on outcomes in a post hoc analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) and how this association is modified by baseline imaging features.MethodsInverse probability of treatment weight was used to remove baseline imbalances between those with and without AF. The primary outcome was the modified Rankin Scale (mRS) scores at 90 days. Secondary outcomes were symptomatic intracerebral haemorrhage (sICH), early neurological deterioration or death within 24 h, and death at 90 days. The logistic regression model was used to determine the associations.ResultsOf the 3285 patients included in this analysis, 636 (19%) had AF at baseline. Compared with non-AF, AF was not significantly associated with an unfavourable shift of mRS (odds ratio 1.09; 95% confidence interval, 0.96–1.24), but with sICH (2.82; 1.78-4.48; IST-3 criteria), early neurological deterioration or death within 24 h (1.31; 1.01-1.70), and death (1.42; 1.12-1.79). Among patients with acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions), AF was associated with the increased risk of all the poor outcomes (all P < 0.04 for interaction).ConclusionsWe found AF increased risk of sICH, early neurological deterioration or death and death, but not unfavourable functional recovery at day 90 after thrombolysis in patients with AIS. The presence of acute ischaemic brain imaging signs at stroke presentation could be used to improve risk stratification in the presence of AF.Trial registrationThe trial is registered at ClinicalTrials.gov (NCT01422616).

Regression analysis of bleeding factors and the correlation between FPE and NLR after mechanical thrombectomy for acute anterior circulation large vessel occlusion

ABSTRACT Acute anterior circulation large vessel occlusion refers to a blockage in the blood flow of one of the major blood vessels in the anterior (front) part of the brain. Acute anterior circulation large vessel occlusion can lead to a range of symptoms, including sudden headache, difficulty speaking or understanding speech, weakness or numbness on one side of the body and loss of vision in one eye. According to relevant data, mechanical thrombectomy in the treatment of the large vessel recanalization rate can reach 70%. However, hemorrhage is one of the serious complications after mechanical thrombectomy, and it is the main factor leading to the deterioration of neurological function and death of patients after large blood vessels. Therefore, the risk factors of bleeding in patients were analyzed before surgery, and effective prevention during and after surgery had positive significance for patients undergoing mechanical thrombectomy. This study uses regression analysis to analyze the correlation between bleeding factors and FPE and NLR after mechanical thrombectomy for acute anterior circulation large vessel occlusion. We retrospectively analyzed 81 patients with acute anterior circulation large vessel occlusion who underwent mechanical embolization in our hospital from September 2019 to January 2022 and separated them into a bleeding group (46 patients) and a non-bleeding group (35 patients) based on the presence or absence of bleeding after surgery.

Clinical characteristics of meconium aspiration syndrome in neonates with different gestational ages and the risk factors for neurological injury and death: A 9-year cohort study.

The presence of meconium is associated with gestational age, and the incidence of meconium aspiration syndrome (MAS) increases with gestational age. Our study compared the differences in the clinical characteristics of patients with MAS at different gestational ages and discussed the risk factors for neurological injury and death from MAS. A total of 294 neonates diagnosed with MAS between 2013 and 2021 were included. Patients were divided into preterm, early-term, full-term, and late-term groups according to gestational age. We compared the patients' basic demographic, treatment, complications, and clinical outcomes in the different groups. We also analyzed the risk factors of neurological injury and death in patients with MAS. The mean age at admission (0.55 ± 0.9 h) was lower and the proportion of cesarean deliveries (90.00%, 27/30) was higher in the preterm group than in the other three groups. There was no statistically significant difference among the four groups regarding 1- and 5-min Apgar scores and the need for delivery room resuscitation. In terms of complications, early-term infants had the highest incidence of neurological injury (52.9%, 27/51), and late-term infants had the highest incidence of pneumothorax (37.8%, 17/45). The overall mortality rate of children with MAS was 7.80% (23/294), and the difference in mortality rates among the four groups was not significant. Low 1-min Apgar score and gestational age, metabolic acidosis, and respiratory failure were independent risk factors for neurological injury; metabolic acidosis, respiratory failure, and sepsis were independent risk factors for death in neonates with MAS. The clinical characteristics of MAS neonates of different gestational age are different mainly in complications. Early-term infants are more likely to complicate with neurological injury, and late-term infants are more likely to complicate with pneumothorax. Low 1-min Apgar score and gestational age, metabolic acidosis, and respiratory failure were established as risk factors for neurological injury; metabolic acidosis, respiratory failure, and sepsis were independent risk factors for death in neonates with MAS.

Managing severe hypertension in children.

Severe childhood hypertension is uncommon and frequently not recognised and is best defined as a systolic blood pressure (SBP) above the stage 2 threshold of the 95th centile + 12mmHg. If no signs of end-organ damage are present, this is urgent hypertension which can be managed by the slow introduction of oral or sublingual medication, but if signs are present, the child has emergency hypertension (or hypertensive encephalopathy if they include irritability, visual impairment, fits, coma, or facial palsy), and treatment must be started promptly to prevent progression to permanent neurological damage or death. However, detailed evidence from case series shows that the SBP must be lowered in a controlled manner over about 2days by infusing short-acting intravenous hypotensive agents, with saline boluses ready in case of overshoot, unless the child had documented normotension within the last day. This is because sustained hypertension may increase pressure thresholds of cerebrovascular autoregulation which take time to reverse. A recent PICU study that suggested otherwise was significantly flawed. The target is to reduce the admission SBP by its excess, to just above the 95th centile, in three equal steps lasting about ≥ 6h, 12h, and finally ≥ 24h, before introducing oral therapy. Few of the current clinical guidelines are comprehensive, and some advise reducing the SBP by a fixed percentage, which may be dangerous and has no evidence base. This review suggests criteria for future guidelines and argues that these should be evaluated by establishing prospective national or international databases.

Abstract P1-10-10: Radiation Treatment Patterns for Elderly Women with Breast Cancer Brain Metastases

Abstract Background Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in elderly patients, there is limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of elderly breast cancer patients with BM (≥ 65 yo) treated at our institution and compared them to younger patients. Methods An IRB-approved single-institutional review of biopsy-proven breast cancer patients with BM treated with 1 to 5-fraction stereotactic radiation therapy (SRT) from 2015 to 2020 was performed. Primary endpoint was intracranial progression free survival (PFS) defined as time interval between end of SRT to date of first CNS progression. Secondary endpoints were overall survival (OS) from end of SRT, and radiation treatment patterns. Kaplan-Meier estimates, and Cox proportional hazard regression method were used for survival analyses. SPSS v26.0 was used for statistical analysis and p-value &amp;lt; 0.05 was considered significant. Results A total of 115 metastatic breast cancer patients with BMs were included of which N=29 were ≥65 yo and N=86 were &amp;lt; 65 yo. They received a total of 43 and 143 courses of stereotactic linac-based radiation therapy (RT) respectively to a mean number of 4.3 BM lesions (range 1-22). Median age at RT was 70 years (range 65-84) compared to 50.5 years (31-64) in younger patients. About 55.2% of elderly patients were ER/PR positive/Her2 negative (vs 24.4% in younger cohort), 31% were Her2 positive (vs 41.9%) and 13.8% were triple negative (vs 33.7%). Among patient characteristics, there was significant difference among elderly and young patients in hormone receptor status (p = 0.016); CNS only oligometastatic disease (0% vs 11.2%, p = 0.005); and the presence of extracranial disease at SRS (97.7% vs 79.7%, p &amp;lt; 0.001). There was no significant difference between the two age groups in Karnofsky performance score (KPS) (62.7% vs 45.5% with KPS ≤ 80, p = 0.131), number of brain lesions treated (23.2% vs 30.1% with ≥ 5 BMs, p = 0.445), number of patients receiving prior whole brain radiotherapy (WBRT) (10.3% vs 19.8%, p = 0.062), surgery (23.2% vs 30.1%, p = 0.592), systemic therapy (including chemotherapy, targeted therapy and endocrine therapy) after SRT (86% vs 86.7%, p = 0.543), and salvage WBRT (10.3% vs 19.8%, p = 0.134). Median OS after RT was poorer in patients ≥ 65 yo compared to younger patients (7.9 months vs 14.4 months, p = 0.020), while intracranial PFS from RT was similar (8.5m vs 6.5m, p =0.345). The rates of freedom from neurological death and leptomeningeal disease (LMD) at 1 year were similar between the two groups (83.3% vs 87%, p = 0.780 and 87.6% vs 73.3%, p = 0.627, respectively). On univariate analysis, significant predictors of survival were age ≥65 yo (hazard risk, HR = 1.56), KPS &amp;lt; 80 (HR = 1.69), extracranial progression at RT (HR = 2.44), systemic therapy after RT (HR = 0.28) and LMD (HR = 1.57). On multivariate analysis, age was not a significant factor for survival after adjusting for KPS, extracranial progression and systemic therapy. Conclusions Although elderly women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and outcomes for breast cancer patients with BMs and personalized decision making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in elderly patients. Citation Format: Rituraj Upadhyay, Haley K. Perlow, Nicole Williams, Brett Klamer, Julia White, Jose G. Bazan, Sachin R. Jhawar, Dukagjin M. Blakaj, John Grecula, Andrea Arnett, Evan Thomas, Arnab Chakravarti, Raju R. Raval, Maryam Lustberg, Joshua Palmer, Sasha Beyer. Radiation Treatment Patterns for Elderly Women with Breast Cancer Brain Metastases [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-10.

Abstract Number ‐ 33: Patients Treated with The Pipeline Shield Flow Diverter Enrolled Within the INSPIRE Study: Primary analysis

Introduction The INSPIRE study collects post‐market data on multiple devices from more than 40 centers world‐wide. One of these devices is the PipelineTM Flex flow diverter with Shield TechnologyTM (Pipeline Shield) for the treatment of intracranial aneurysms. The Shield surface modification is designed to enhance endothelization of the device with low thromboembolic risks. We analyze the efficacy and safety outcomes after Pipeline Shield therapy at the 1‐year follow‐up in a large prospective study. Methods INSPIRE is a prospective, multicenter, single arm study. Patients are followed for 1‐year post‐procedure and results are adjudicated by an independent Clinical Events Committee and Imaging Core Laboratory. All patients were treated per their hospital’s standard of care. The primary safety endpoint was neurological death or major stroke in the treated vascular area. The primary efficacy endpoint was complete aneurysm occlusion without significant parent artery stenosis (&gt;50%) or retreatment. For this analysis, the last‐available observation was carried forward to overcome differences between centers’ imaging schedules. Results A total of 537 patients were enrolled, with 504 patients with 488 aneurysms included in the analysis (mean age 53.8±12.2, 77.0% [388/504] female). The majority of aneurysms were located in the ICA (74.2%, 362/488). Of the remaining aneurysms, 16.0% (78/488) were in the anterior circulation and 9.8% (48/488) were in the posterior circulation. The majority of aneurysms were saccular (89.3% [436/488]). A total of 47.1% of aneurysms were small (&lt; 7mm, 230/488), 30.9% were medium (7‐&lt; 13 mm, 151/488), 16.8% were large (13‐&lt; 25 mm, 82/488), and 5.1% were giant (&gt; = 25 mm, 25/488). Adjunctive devices were used in 20.9% (102/488) of cases, including balloon (42.2% [19/43]), coil (63.7%, [65/102]), stent (5.9% [6/102]), or flow diverter (9.8% [10/102]). At 1‐year post‐procedure, complete occlusion (Raymond Roy Class I) was achieved in 74.9% (326/435) aneurysms. The primary safety endpoint occurred in 2.2% (11/504) patients. The primary endpoint was achieved in 73.2% (290/396) cases; reasons for primary endpoint failure included residual neck (5.8% [23/396]), residual aneurysm (19.4% [77/396]), stenosis &gt;50% (1.0% [4/396]), and re‐treatment (1.5% [6/396]). Among ICA aneurysms, complete occlusion was achieved in 78.1% (249/319). The primary safety endpoint occurred in 2.0% (7/356) patients. The primary endpoint was achieved in 77.1% (225/292) cases; reasons for primary endpoint failure among ICA aneurysms included residual neck (5.5% [16/292]), residual aneurysm (16.4% [48/292]), stenosis &gt;50% (0.7% [2/292]), and re‐treatment (1.4% [67/292]). Conclusions INSPIRE data suggests good rates of complete occlusion, efficacy, and safety among a large cohort of patients with aneurysms in a variety of challenging locations and sizes treated with the Pipeline Shield device, with adjudication by CEC and Imaging Core Lab ensuring high quality of these data.

Stereotactic radiosurgery for intermediate- and high-grade arteriovenous malformations: outcomes stratified by the supplemented Spetzler-Martin grading system.

The supplemented Spetzler-Martin (Supp-SM) grading system was developed to improve the predictive accuracy of surgical risk for patients with brain arteriovenous malformations (AVMs). The aim of this study was to apply the Supp-SM grading system to patients having stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) intermediate- (grade III) or high-grade (grade IV-V) AVMs to enable comparison with published microsurgical series. In 219 patients who underwent SRS during the period from 1990 to 2016, the Supp-SM grade was calculated for SM grade III (n = 154) or SM grade IV-V (n = 65) AVMs. The Supp-SM grades in these patients were 4 (n = 14, 6%), 5 (n = 36, 16%), 6 (n = 67, 31%), 7 (n = 76, 35%), and 8-9 (n = 26, 12%). Sixty patients (27%) had deep AVMs (basal ganglia, thalamus, or brainstem). Thirty-nine patients (18%) had volume-staged SRS; 41 patients (19%) underwent repeat SRS. The median follow-up period was 69 months for SM grade III AVMs and 113 months for SM grade IV-V AVMs. AVM obliteration was confirmed in 163 patients (74%) at a median of 38 months after initial SRS. The obliteration rates at 4 and 8 years were 59% and 76%, respectively. Thirty-one patients (14%) had post-SRS deficits from hemorrhage (n = 7, 3%) or radiation injury (n = 24, 11%). Six patients (3%) died after SRS (hemorrhage, n = 5; radiation injury, n = 1). The rates of neurological decline or death at 4 and 8 years were 11% and 18%, respectively. Factors predictive of nonobliteration were deep location (HR 0.57, 95% CI 0.39-0.82, p = 0.003) and increasing AVM volume (HR 0.96, 95% CI 0.93-0.99, p = 0.002). Increasing AVM volume was the only factor associated with neurological decline (HR 1.05, 95% CI 1.02-1.08, p = 0.002). The Supp-SM grading score did not correlate with either obliteration (HR 0.94, 95% CI 0.82-1.09, p = 0.43) or neurological decline (HR 1.15, 95% CI 0.84-1.56, p = 0.38). The Supp-SM grading system was not predictive of outcomes after SRS of intermediate- or high-grade AVM. In a cohort that included a high percentage (47%) of "inoperable" AVMs according to Supp-SM grade (≥ 7), most patients had obliteration after SRS, although there was a high risk of neurological decline.

The burden of unhelmeted motorcycle injury: A nationwide scoring-based analysis of helmet safety legislation.

Motorcycle collisions comprise a large portion of motor vehicle injuries and fatalities with over 80,000 injuries and 5,500 fatalities per year in the United States. Unhelmeted riders have poor medical outcomes and generate billions in costs. Despite helmet use having been shown to lower the risk of neurological injury and death, helmet compliance is not universal, and legislation concerning helmet use also varies widely across the United States. In this study, we systematically reviewed helmet-related statutes from all US jurisdictions. We evaluated the stringency of these statutes using a legislative scoring system termed the Helmet Safety Score (HSS) ranging from 0-7 points, with higher scores denoting more stringent statutes. Regression modeling was used to predict unhelmeted mortality using our safety scores. The mean score across all jurisdictions was 4.73. We found jurisdictions with higher HSS's generally had lower percentages of unhelmeted fatalities in terms of total fatalities as well as per 100,000 people and 100,000 registered motorcycles. In contrast, some lower-scoring jurisdictions had over 100 times more unhelmeted fatalities than higher-scoring jurisdictions. Our HSS significantly predicted unhelmeted motorcycle fatalities per 100,000 people (β=-0.228 per 1-point increase, 95% CI: -0.288 to -0.169, p < .0001) and per 100,000 registered motorcycles (β=-6.17 per 1-point increase, 95% CI: -8.37 to -3.98, p < .0001) in each state. Aspects of our score concerning helmet exemptions for riders and motorcycle-type vehicles independently predicted higher fatalities (p < .0001). Higher safety scores predicted lower unhelmeted fatalities. Stringent helmet laws may be an effective mechanism for decreasing unhelmeted mortality. Therefore, universal helmet laws may be one such mechanism to decrease motorcycle-related neurological injury and fatality burden. In states with existing helmet laws, elimination of exemptions for certain riders and motorcycle-type vehicles may also decrease fatalities.

Encephalitis matters

Mental-health issues are the focus of this year's World Encephalitis Day, on Feb 22. On this date, in line with their Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders, WHO will release a meeting report on Why Encephalitis Matters.1WHO. Why encephalitis matters: meeting report (in press).Google Scholar Suicide is one of the top three causes of death in children and young adults.2WHOSuicide.https://www.who.int/news-room/fact-sheets/detail/suicideDate: June 17, 2021Date accessed: January 25, 2023Google Scholar In people with a neurological disorder, suicide rates might double those of people without a neurological disorder.3Erlangsen A Stenager E Conwell Y et al.Association Between Neurological Disorders and Death by Suicide in Denmark.JAMA. 2020; 323: 444-454Crossref PubMed Scopus (46) Google Scholar In fact, more than 37% of survivors of encephalitis report that they had thought about or attempted suicide4Abdat Y Butler M Zandi M et al.Mental health outcomes of encephalitis, an international web-based study.medRxi. 2023; (published online Feb 7.) (preprint).https://doi.org/10.1101/2023.02.03.23285344Google Scholar and about 12% of patients affected by autoimmune encephalitis had suicidal behaviours during the early stages of their illness, and nearly half of them carried out a suicide attempt.5Tellez-Martinez A Restrepo-Martinez M Espinola-Nadurille M et al.Suicidal thoughts and behaviors in anti-NMDAR encephalitis: psychopathological features and clinical outcomes.J Neuropsychiatry Clin Neurosci. 2023; (in press).Google Scholar The mental health issues associated with neurological diseases are usually treatable,6Gold SM Köhler-Forsberg O Moss-Morris R et al.Comorbid depression in medical diseases.Nat Rev Dis Primers. 2020; 6: 69Crossref PubMed Scopus (116) Google Scholar but the psychiatric sequelae of encephalitis have been far less investigated than neurological outcomes; hence, the need for more research addressing their nature, causes, and effects.7Hansen N Timäus C Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge.J Neural Transm. 2021; 128: 1-14Crossref PubMed Scopus (7) Google Scholar Mental health issues following encephalitis might be caused by the biological effects of inflammation on the brain during the acute stages of the disease, by psychological responses to traumatic ill-health, or by adverse effects of treatments. Stigma about mental health can be a barrier for patients and families to speaking up, and we hope that, on this World Encephalitis Day, we get closer to addressing it. Famous landmarks and buildings around the world have agreed to light up in red on Feb 22, from Niagara Falls in Canada to the Dancing House in Prague, Czech Republic. Careful risk assessment can help reduce the impact of suicidal thoughts and behaviours; anyone affected by encephalitis and mental health concerns should know that these conditions are often treatable.

Cannabidiol's neuroprotective properties and potential treatment of traumatic brain injuries.

Cannabidiol (CBD) has numerous pharmacological targets that initiate anti-inflammatory, antioxidative, and antiepileptic properties. These neuroprotective benefits have generated interest in CBD's therapeutic potential against the secondary injury cascade from traumatic brain injury (TBI). There are currently no effective broad treatment strategies for combating the damaging mechanisms that follow the primary injury and lead to lasting neurological consequences or death. However, CBD's effects on different neurotransmitter systems, the blood brain barrier, oxidative stress mechanisms, and the inflammatory response provides mechanistic support for CBD's clinical utility in TBI. This review describes the cascades of damage caused by TBI and CBD's neuroprotective mechanisms to counter them. We also present challenges in the clinical treatment of TBI and discuss important future clinical research directions for integrating CBD in treatment protocols. The mechanistic evidence provided by pre-clinical research shows great potential for CBD as a much-needed improvement in the clinical treatment of TBI. Upcoming clinical trials sponsored by major professional sport leagues are the first attempts to test the efficacy of CBD in head injury treatment protocols and highlight the need for further clinical research.

Neuroinflammation of traumatic brain injury: Roles of extracellular vesicles.

Traumatic brain injury (TBI) is a major cause of neurological disorder or death, with a heavy burden on individuals and families. While sustained primary insult leads to damage, subsequent secondary events are considered key pathophysiological characteristics post-TBI, and the inflammatory response is a prominent contributor to the secondary cascade. Neuroinflammation is a multifaceted physiological response and exerts both positive and negative effects on TBI. Extracellular vesicles (EVs), as messengers for intercellular communication, are involved in biological and pathological processes in central nervous system (CNS) diseases and injuries. The number and characteristics of EVs and their cargo in the CNS and peripheral circulation undergo tremendous changes in response to TBI, and these EVs regulate neuroinflammatory reactions by activating prominent receptors on receptor cells or delivering pro- or anti-inflammatory cargo to receptor cells. The purpose of this review is to discuss the possible neuroinflammatory mechanisms of EVs and loading in the context of TBI. Furthermore, we summarize the potential role of diverse types of cell-derived EVs in inflammation following TBI.