Impact of ABCC8 and TRPM4 genetic variation in central nervous system dysfunction associated with pediatric sepsis.

BACKGROUND: Sepsis-associated brain injury is associated with deterioration of mental status, persistent cognitive impairment, and morbidity. The SUR1/TRPM4 channel is a non-selective cation channel that is transcriptionally upregulated in the central nervous system with injury, allowing sodium influx, depolarization, cellular swelling, and secondary injury. We hypothesized that genetic variation in ABCC8 (SUR1 gene) and TRPM4 would associate with central nervous system dysfunction in severe pediatric sepsis. METHODS: 326 children with severe sepsis underwent whole exome sequencing in an observational cohort. We compared children with and without central nervous system dysfunction (Glasgow Coma Scale <12) to assess for associations with clinical characteristics and pooled rare variants in ABCC8 and TRPM4. Sites of variation were mapped onto protein structure and assessed for phenotypic impact. RESULTS: Pooled rare variants in either ABCC8 or TRPM4 associated with decreased odds of central nervous system dysfunction in severe pediatric sepsis (OR 0.14, 95% CI 0.003-0.87), p-value = 0.025). This association persisted following adjustment for race, organ failure, viral infection, and continuous renal replacement therapy (aOR 0.11, 95% CI 0.01-0.59, p-value = 0.038). Structural mapping showed that rare variants concentrated in the nucleotide-binding domains of ABCC8 and N-terminal melastatin homology region of TRPM4. CONCLUSION: This study suggests a role for the ABCC8/TRPM4 channel in central nervous system dysfunction in severe pediatric sepsis. While exploratory, the lack of therapies to prevent or mitigate central nervous system dysfunction in pediatric sepsis warrants further studies to clarify the mechanism and confirm the potential protective effect of these rare ABCC8/TRPM4 variants.

A Mouse Model of Temporal Lobe Contusion.

Trauma to the brain can induce a contusion characterized by a discrete intracerebral or diffuse interstitial hemorrhage. In humans, "computed tomography-positive," that is, hemorrhagic, temporal lobe contusions (tlCont) have unique sequelae. TlCont confers significantly increased odds for moderate or worse disability and the inability to return to baseline work capacity compared to intra-axial injuries in other locations. Patients with tlCont are at elevated risks of memory dysfunction, anxiety, and post-traumatic epilepsy due to involvement of neuroanatomical structures unique to the temporal lobe including the amygdala, hippocampus, and ento-/perirhinal cortex. Because of the relative inaccessibility of the temporal lobe in rodents, no preclinical model of tlCont has been described, impeding progress in elucidating the specific pathophysiology unique to tlCont. Here, we present a minimally invasive mouse model of tlCont with the contusion characterized by a traumatic interstitial hemorrhage. Mortality was low and sensorimotor deficits (beam walk, accelerating rotarod) resolved completely within 3-5 days. However, significant deficits in memory (novel object recognition, Morris water maze) and anxiety (elevated plus maze) persisted at 14-35 days and nonconvulsive electroencephalographic seizures and spiking were significantly increased in the hippocampus at 7-21 days. Immunohistochemistry showed widespread astrogliosis and microgliosis, bilateral hippocampal sclerosis, bilateral loss of hippocampal and cortical inhibitory parvalbumin neurons, and evidence of interhemispheric connectional diaschisis involving the fiber bundle in the ventral corpus callosum that connects temporal lobe structures. This model may be useful to advance our understanding of the unique features of tlCont in humans.

Predictors of Neurological Outcomes in Patients with Poor Glasgow Coma Scale Scores 1 Week After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: This study assessed neurological outcomes and variables associated with favorable outcomes in aneurysmal subarachnoid hemorrhage patients with low functional status (Glasgow Coma Scale [GCS] score ≤8) on postbleed day 7 (PBD7). METHODS: A retrospective analysis was conducted of all patients in the Barrow Ruptured Aneurysm Trial (January 1, 2014-July 31, 2019) treated for a ruptured aneurysm and who had a GCS score ≤8 on PBD7. The primary outcome was a favorable neurological outcome (modified Rankin Scale score ≤2) at last follow-up. RESULTS: Of 312 patients, 63 had low GCS scores at PBD7. These patients had a significantly greater proportion of poor Hunt and Hess scale grades (≥4) (44/63 [70%] vs. 49/249 [19.7%], P < 0.001) and poor Fisher grades (grade = 4) (58/63 [92%] vs. 174/249 [69.9%], P < 0.001) compared to patients who did not have low GCS scores on PBD7, but no differences were found in age, sex, anterior location, aneurysm size, or type of treatment. Of the 63 patients, 7 (11%) experienced a favorable neurological outcome. On univariate analysis, none of the physical examination reflexes predicted a favorable neurological outcome. The middle cerebral artery aneurysm territory was the only significant predictor of a favorable neurological outcome by multivariate analysis (odds ratio, 10.8; 95% confidence interval, 1.16-100], P = 0.04). CONCLUSIONS: This study yielded no significant physical examination findings that predict a favorable outcome in patients with a GCS score ≤8 on PBD7. This finding may inform the decision of whether to prolong hospital management or arrange for end-of-life care.

A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets.

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.

The Influence of CYP2B6 Variants and Administration of Propofol on Patient Outcomes after Traumatic Brain Injury.

Management of severe traumatic brain injury (sTBI) typically involves the use of sedation, which inherently results in benefits and risks. The cytochrome P450 enzyme CYP2B6 is involved in the biotransformation of particular drug classes, including many intravenous sedatives. Variants of the CYP2B6 gene can lead to decreased systemic clearance of some sedatives, including propofol. This study aimed to investigate the relationship of CYP2B6 gene variation and patient outcomes after TBI while also considering propofol administration. Patients who sustained a non-penetrating sTBI and admitted to a single-center Level 1 trauma hospital were included in this study (n = 440). The *6 functional allele of CYP2B6 that leads to reduced enzyme expression and activity required genotyping two single nucleotide polymorphisms, rs3745274 and rs2279343. Patient outcomes were evaluated using the Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) at 3 and 6 months post-injury. Data on sedative administration were abstracted from medical records. Individuals homozygous for the alleles coding for the reduced enzyme expression and activity were more likely to have worse outcomes. A relationship between propofol administration and 3-month GOS and 6-month DRS was noted when controlling for CYP2B6 genotype. These findings suggest that genetic variation in CYP2B6 may influence the impact of intravenous sedation on patient outcomes after TBI and warrants further investigation.

Cerebral Edema Monitoring and Management Strategies: Results from an International Practice Survey.

BACKGROUND: Cerebral edema is a common, potentially life-threatening complication in critically ill patients with acute brain injury. However, uncertainty remains regarding best monitoring and treatment strategies, which may result in wide practice variations. METHODS: A 20-question digital survey on monitoring and management practices was disseminated between July 2022 and May 2023 to clinicians who manage cerebral edema. The survey was promoted through email, social media, medical conferences, and the Neurocritical Care Society Web site. We used the χ2 test, Fisher's exact test, analysis of variance, and logistic regression to report factors associated with practice variation, diagnostic monitoring methods, and therapeutic triggers based on practitioner and institutional characteristics. RESULTS: Of 321 participants from 160 institutions in 30 countries, 65% were from university-affiliated centers, 74% were attending physicians, 38% were woman, 38% had neurology training, and 55% were US-based. Eighty-four percent observed practice variations at their institutions, with "provider preference" being cited most (87%). Factors linked to variation included gender, experience, university affiliation, and practicing outside the United States. University affiliates tended to use more tests (median 3.87 vs. 3.43, p = 0.01) to monitor cerebral edema. Regarding management practices, 20% of respondents' preferred timing for decompressive hemicraniectomy was after 48 h, and 37% stated that radiographic findings only would be sufficient to trigger surgery. Fifty percent of respondents reported initiating osmotic therapy based on radiographic indications or prophylactically. There were no significant associations between management strategies and respondent or center characteristics. Twenty-seven percent of respondents indicated that they acquired neuroimaging at intervals of 24 h or less. Within this group, attending physicians were more likely to follow this practice (65.5% vs. 34.5%, p = 0.04). CONCLUSIONS: Cerebral edema monitoring and management strategies vary. Features associated with practice variations include both practitioner and institutional characteristics. We provide a foundation for understanding practice patterns that is crucial for informing educational initiatives, standardizing guidelines, and conducting future trials.

Exosomes in Vascular/Neurological Disorders and the Road Ahead.

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.

Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Controversy remains regarding the appropriate screening for intracranial aneurysms or for the treatment of aneurysmal subarachnoid hemorrhage (aSAH) for patients without known high-risk factors for rupture. This study aimed to assess how sex affects both aSAH presentation and outcomes for aSAH treatment. METHOD: A retrospective cohort study was conducted of all patients treated at a single institution for an aSAH during a 12-year period (August 1, 2007-July 31, 2019). An analysis of women with and without high-risk factors was performed, including a propensity adjustment for a poor neurologic outcome (modified Rankin Scale [mRS] score > 2) at follow-up. RESULTS: Data from 1014 patients were analyzed (69% [n = 703] women). Women were significantly older than men (mean ± SD, 56.6 ± 14.1 years vs 53.4 ± 14.2 years, p < 0.001). A significantly lower percentage of women than men had a history of tobacco use (36.6% [n = 257] vs 46% [n = 143], p = 0.005). A significantly higher percentage of women than men had no high-risk factors for aSAH (10% [n = 70] vs 5% [n = 16], p = 0.01). The percentage of women with an mRS score > 2 at the last follow-up was significantly lower among those without high-risk factors (34%, 24/70) versus those with high-risk factors (53%, 334/633) (p = 0.004). Subsequent propensity-adjusted analysis (adjusted for age, Hunt and Hess grade, and Fisher grade) found no statistically significant difference in the odds of a poor outcome for women with or without high-risk factors for aSAH (OR = 0.7, 95% CI = 0.4-1.2, p = 0.18). CONCLUSIONS: A higher percentage of women versus men with aSAH had no known high-risk factors for rupture, supporting more aggressive screening and management of women with unruptured aneurysms.

Modafinil Therapy and Mental Status Following Aneurysmal Subarachnoid Hemorrhage: Comprehensive Stroke Center Analysis.

BACKGROUND: Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating fatigue in stroke survivors, but data pertaining to its use in the acute setting are scarce. This study sought to assess the effects of modafinil use on mental status after aSAH. METHODS: Modafinil timing and dosage, neurological examination, intubation status, and physical and occupational therapy participation were documented. Repeated-measures paired tests were used for a before-after analysis of modafinil recipients. Propensity score matching (1:1 nearest neighbor) for modafinil and no-modafinil cohorts was used to compare outcomes. RESULTS: Modafinil (100-200 mg/day) was administered to 21% (88/422) of aSAH patients for a median (IQR) duration of 10.5 (4-16) days and initiated 14 (7-17) days after aSAH. Improvement in mentation (alertness, orientation, or Glasgow Coma Scale score) was documented in 87.5% (77/88) of modafinil recipients within 72 hours and 86.4% (76/88) at discharge. Of 37 intubated patients, 10 (27%) were extubated within 72 hours after modafinil initiation. Physical and occupational therapy teams noted increased alertness or participation in 47 of 56 modafinil patients (83.9%). After propensity score matching for baseline covariates, the modafinil cohort had a greater mean (SD) change in Glasgow Coma Scale score than the no-modafinil cohort at discharge (2.2 [4.0] vs. -0.2 [6.32], P = 0.003). CONCLUSIONS: A temporal relationship with improvement in mental status was noted for most patients administered modafinil after aSAH. These findings, a favorable adverse-effect profile, and implications for goals-of-care decisions favor a low threshold for modafinil initiation in aSAH patients in the acute-care setting.

Clinical Outcomes After Traumatic Brain Injury and Exposure to Extracranial Surgery: A TRACK-TBI Study.

Importance: Traumatic brain injury (TBI) is associated with persistent functional and cognitive deficits, which may be susceptible to secondary insults. The implications of exposure to surgery and anesthesia after TBI warrant investigation, given that surgery has been associated with neurocognitive disorders. Objective: To examine whether exposure to extracranial (EC) surgery and anesthesia is related to worse functional and cognitive outcomes after TBI. Design, Setting, and Participants: This study was a retrospective, secondary analysis of data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, a prospective cohort study that assessed longitudinal outcomes of participants enrolled at 18 level I US trauma centers between February 1, 2014, and August 31, 2018. Participants were 17 years or older, presented within 24 hours of trauma, were admitted to an inpatient unit from the emergency department, had known Glasgow Coma Scale (GCS) and head computed tomography (CT) status, and did not undergo cranial surgery. This analysis was conducted between January 2, 2020, and August 8, 2023. Exposure: Participants who underwent EC surgery during the index admission were compared with participants with no surgery in groups with a peripheral orthopedic injury or a TBI and were classified as having uncomplicated mild TBI (GCS score of 13-15 and negative CT results [CT- mTBI]), complicated mild TBI (GCS score of 13-15 and positive CT results [CT+ mTBI]), or moderate to severe TBI (GCS score of 3-12 [m/sTBI]). Main Outcomes and Measures: The primary outcomes were functional limitations quantified by the Glasgow Outcome Scale-Extended for all injuries (GOSE-ALL) and brain injury (GOSE-TBI) and neurocognitive outcomes at 2 weeks and 6 months after injury. Results: A total of 1835 participants (mean [SD] age, 42.2 [17.8] years; 1279 [70%] male; 299 Black, 1412 White, and 96 other) were analyzed, including 1349 nonsurgical participants and 486 participants undergoing EC surgery. The participants undergoing EC surgery across all TBI severities had significantly worse GOSE-ALL scores at 2 weeks and 6 months compared with their nonsurgical counterparts. At 6 months after injury, m/sTBI and CT+ mTBI participants who underwent EC surgery had significantly worse GOSE-TBI scores (B = -1.11 [95% CI, -1.53 to -0.68] in participants with m/sTBI and -0.39 [95% CI, -0.77 to -0.01] in participants with CT+ mTBI) and performed worse on the Trail Making Test Part B (B = 30.1 [95% CI, 11.9-48.2] in participants with m/sTBI and 26.3 [95% CI, 11.3-41.2] in participants with CT+ mTBI). Conclusions and Relevance: This study found that exposure to EC surgery and anesthesia was associated with adverse functional outcomes and impaired executive function after TBI. This unfavorable association warrants further investigation of the potential mechanisms and clinical implications that could inform decisions regarding the timing of surgical interventions in patients after TBI.

Cerebrospinal Fluid Biomarkers for Diagnosis and the Prognostication of Acute Ischemic Stroke: A Systematic Review.

Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.

Glibenclamide for Brain Contusions: Contextualizing a Promising Clinical Trial Design that Leverages an Imaging-Based TBI Endotype.

TBI heterogeneity is recognized as a major impediment to successful translation of therapies that could improve morbidity and mortality after injury. This heterogeneity exists on multiple levels including primary injury, secondary injury/host-response, and recovery. One widely accepted type of primary-injury related heterogeneity is pathoanatomic-the intracranial compartment that is predominantly affected, which can include any combination of subdural, subarachnoid, intraparenchymal, diffuse axonal, intraventricular and epidural hemorrhages. Intraparenchymal contusions carry the highest risk for progression. Contusion expansion is one of the most important drivers of death and disability after TBI. Over the past decade, there has been increasing evidence of the role of the sulfonylurea-receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel in secondary injury after TBI, including progression of both cerebral edema and intraparenchymal hemorrhage. Inhibition of SUR1-TRPM4 with glibenclamide has shown promising results in preclinical models of contusional TBI with benefits against cerebral edema, secondary hemorrhage progression of the contusion, and improved functional outcome. Early-stage human research supports the key role of this pathway in contusion expansion and suggests a benefit with glibenclamide inhibition. ASTRAL is an ongoing international multi-center double blind multidose placebo-controlled phase-II clinical trial evaluating the safety and efficacy of an intravenous formulation of glibenclamide (BIIB093). ASTRAL is a unique and innovative study that addresses TBI heterogeneity by limiting enrollment to patients with the TBI pathoanatomic endotype of brain contusion and using contusion-expansion (a mechanistically linked secondary injury) as its primary outcome. Both criteria are consistent with the strong supporting preclinical and molecular data. In this narrative review, we contextualize the development and design of ASTRAL, including the need to address TBI heterogeneity, the scientific rationale underlying the focus on brain contusions and contusion-expansion, and the preclinical and clinical data supporting benefit of SUR1-TRPM4 inhibition in this specific endotype. Within this framework, we summarize the current study design of ASTRAL which is sponsored by Biogen and actively enrolling with a goal of 160 participants.

Association between external ventricular drain removal or replacement and prophylactic anticoagulation in patients with aneurysmal subarachnoid hemorrhage: a propensity-adjusted analysis.

BACKGROUND: Withholding prophylactic anticoagulation from patients with aneurysmal subarachnoid hemorrhage (aSAH) before external ventricular drain (EVD) removal or replacement remains controversial. This study analyzed whether prophylactic anticoagulation was associated with hemorrhagic complications related to EVD removal. METHOD: All aSAH patients treated from January 1, 2014, to July 31, 2019, with an EVD placed were retrospectively analyzed. Patients were compared based on the number of prophylactic anticoagulant doses withheld for EVD removal (> 1 vs. ≤ 1). The primary outcome analyzed was deep venous thrombosis (DVT) or pulmonary embolism (PE) after EVD removal. A propensity-adjusted logistic-regression analysis was performed for confounding variables. RESULTS: A total of 271 patients were analyzed. For EVD removal, > 1 dose was withheld from 116 (42.8%) patients. Six (2.2%) patients had a hemorrhage associated with EVD removal, and 17 (6.3%) patients had a DVT or PE. No significant difference in EVD-related hemorrhage after EVD removal was found between patients with > 1 versus ≤ 1 dose of anticoagulant withheld (4 of 116 [3.5%] vs. 2 of 155 [1.3%]; p = 0.41) or between those with no doses withheld compared to ≥ 1 dose withheld (1 of 100 [1.0%] vs. 5 of 171 [2.9%]; p = 0.32). After adjustment, withholding > 1 dose of anticoagulant versus ≤ 1 dose was associated with the occurrence of DVT or PE (OR 4.8; 95% CI, 1.5-15.7; p = 0.009). CONCLUSIONS: In aSAH patients with EVDs, withholding > 1 dose of prophylactic anticoagulant for EVD removal was associated with an increased risk of DVT or PE and no reduction in catheter removal-associated hemorrhage.

Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.

Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain's capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na+/Ca2+ exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na+ through SUR1-TRPM4 induced Ca2+ transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca2+. This increase in Ca2+ stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients.

Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage Receiving Sulfonylureas: A Propensity-Adjusted Analysis.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with increased blood-brain barrier permeability, disrupted tight junctions, and increased cerebral edema. Sulfonylureas are associated with reduced tight-junction disturbance and edema and improved functional outcome in aSAH animal models, but human data are scant. We analyzed neurological outcomes in aSAH patients prescribed sulfonylureas for diabetes mellitus. METHODS: Patients treated for aSAH at a single institution (August 1, 2007-July 31, 2019) were retrospectively reviewed. Patients with diabetes were grouped by presence or absence of sulfonylurea therapy at hospital admission. The primary outcome was favorable neurologic status at last follow-up (modified Rankin Scale score ≤2). Variables with an unadjusted P-value of <0.20 were included in a propensity-adjusted multivariable logistic regression analysis to identify predictors of favorable outcomes. RESULTS: Of 1013 aSAH patients analyzed, 129 (13%) had diabetes at admission, and 16 of these (12%) were receiving sulfonylureas. Fewer diabetic than nondiabetic patients had favorable outcomes (40% [52/129] vs. 51% [453/884], P = 0.03). Among diabetic patients, sulfonylurea use (OR 3.90, 95% CI 1.05-15.9, P = 0.046), Charlson Comorbidity Index <4 (OR 3.66, 95% CI 1.24-12.1, P = 0.02), and absence of delayed cerebral infarction (OR 4.09, 95% CI 1.20-15.5, P = 0.03) were associated with favorable outcomes in the multivariable analysis. CONCLUSIONS: Diabetes was strongly associated with unfavorable neurologic outcomes. An unfavorable outcome in this cohort was mitigated by sulfonylureas, supporting some preclinical evidence of a possible neuroprotective role for these medications in aSAH. These results warrant further study on dose, timing, and duration of administration in humans.

Socioeconomic Drivers of Outcomes After Aneurysmal Subarachnoid Hemorrhage Treatment at a Large Comprehensive Stroke Center.

BACKGROUND: Sparse data exist on socioeconomic disparities among patients treated for aneurysmal subarachnoid hemorrhage (aSAH). The authors analyzed factors possibly influencing patient outcomes, including having a primary care physician (PCP) at admission, family/caregiver support, a foreign language barrier, primary payer status, and race. METHODS: Socioeconomic data were abstracted for patients treated endovascularly or microsurgically for aSAH at a single center (January 1, 2014-July 31, 2019). Binary logistic regression analyses were used to identify independent predictors of an unfavorable outcome (modified Rankin Scale [mRS] score >2) and for predictive modeling. RESULTS: Among 422 patients, the median (interquartile range) follow-up was 2 (1-23) months. Lack of caregiver support was the only socioeconomic factor associated with an unfavorable outcome at discharge. Independent predictors of mRS score >2 at last follow-up included baseline markers of disease severity (P ≤ 0.03), nonwhite race (OR, 1.69; P = 0.047), lack of caregiver support (OR, 5.55; P = 0.007), and lack of a PCP (OR, 1.96; P = 0.007). Adjusting for follow-up mediated the effects of race and PCP, although caregiver support remained significant and PCP was associated with a lower mortality risk independent of follow-up (OR, 0.51; P = 0.047). Predischarge socioeconomic factors, alongside disease severity, predicted a follow-up mRS score >2 with excellent discrimination (area under the receiver operating curve, 0.81; 95% CI, 0.77-0.86). CONCLUSIONS: At a large, urban, comprehensive stroke center, patients with PCPs, caregiver support, and white race had significantly better long-term outcomes after aSAH. These results reflect disparities in access to healthcare after aSAH for vulnerable populations with extensive lifetime needs.

Precision Medicine in Neurocritical Care for Cerebrovascular Disease Cases.

Scientific advances have informed many aspects of acute stroke care but have also highlighted the complexity and heterogeneity of cerebrovascular diseases. While practice guidelines are essential in supporting the clinical decision-making process, they may not capture the nuances of individual cases. Personalized stroke care in ICU has traditionally relied on integrating clinical examinations, neuroimaging studies, and physiologic monitoring to develop a treatment plan tailored to the individual patient. However, to realize the potential of precision medicine in stroke, we need advances and evidence in several critical areas, including data capture, clinical phenotyping, serum biomarker development, neuromonitoring, and physiology-based treatment targets. Mathematical tools are being developed to analyze the multitude of data and provide clinicians with real-time information and personalized treatment targets for the critical care management of patients with cerebrovascular diseases. This review summarizes research advances in these areas and outlines principles for translating precision medicine into clinical practice.