Background:Intraventricular hemorrhage (IVH) is a common and severe complication of hemorrhagic brain injury. Current treatments offer limited improvement in long-term neurological outcomes. Inflammatory responses in the cerebrospinal fluid (CSF) after IVH are thought to drive secondary injury, but the cellular mechanisms underlying this inflammation remain poorly defined. Methods:We performed single-nucleus RNA sequencing of leukocytes isolated from CSF collected through external ventricular drains in subjects with intracerebral ( n = 6) or subarachnoid ( n = 1) hemorrhage. We characterized transcriptionally distinct subpopulations of neutrophils, monocytes, and lymphocytes by comparison to reference datasets. Cell-cell signaling networks were analyzed to infer cytokine-mediated communication, and a flow cytometry panel was developed to validate transcriptomic findings in independent CSF samples. Results:We obtained 11,191 high-quality nuclei comprising neutrophils (53.8%), monocytes (26.1%), lymphocytes (17.8%), and non-immune cells (2.4%). Neutrophils segregated into Nascent, Quiescent, and Interferon-Activated states. Monocytes exhibited classical phenotypes that include interferon-activated states (characterized by expression of VCAN or PROK2 ) and CXC-chemokine expressing states (characterized by expression of CXCL5 or CXCL8 ). Lymphocytes were mainly naïve and central memory CD4⁺ T cells. Cell-cell signaling analysis predicted strong CXC chemokine signaling from monocytes to neutrophil subsets and IL-1 family-driven inflammatory responses across multiple populations. Type I and III interferon signaling defined a neutrophil population not previously described in the central nervous system. Conclusion:This study delineates the diverse cellular immune landscape of CSF after IVH. Transcriptomic profiles reveal interferon, IL-1, and CXC chemokine signaling networks as potential therapeutic targets to mitigate secondary injury.

Background: Traumatic intracranial aneurysms (TICAs) secondary to penetrating traumatic brain injuries (PTBIs) including gunshot wounds and shell fragments carry a significant risk of rupture, intracerebral hematoma, neurological injury, and death. Although these lesions were previously thought to arise in a delayed fashion, TICAs have been increasingly reported immediately after PTBI. Early detection and endovascular therapies have contributed to a significant evolution in their management. Here, we review and present reported TICAs in the literature spanning both civilian and military contexts. Lesions are analyzed by morphology, location, management strategies, and outcomes. Methods: Case series/reports published between 1940 and 2025 were considered. Injury mechanism, arterial location, diagnostic imaging modality, time to diagnosis, treatment, and outcome data were collected. Only full texts were considered in the final analysis. Results: A total of 250 traumatic intracranial pseudoaneurysms in 227 patients met inclusion criteria for this study. The most common vessel distribution was the middle cerebral artery (MCA, n = 98), followed by the anterior cerebral artery ( n = 68) and internal carotid artery (ICA n = 48, of which 13 were in the cavernous ICA). Historically, TICAs were detected in a delayed fashion using conventional angiography (104 patients, 113 TICAs). In recent years, early detection of TICAs has been facilitated by CT angiography (CTA; 52 patients and 64 TICAs) and digital subtraction angiography (DSA; 52 patients and 53 TICAs). Endovascular surgery and open approaches complement each other in the obliteration of TICAs, with a significant increase in the use of the former during the last three decades. Conclusion: TICAs are complex lesions secondary to PTBIs. Detection, management strategies, and outcomes have evolved over the last several decades. Early detection using CTA and DSA has significantly increased the incidence of these lesions in the acute phase. Vigilant monitoring and delayed follow-up imaging remain essential components of modern management given the risk of delayed aneurysm formation, growth, and recanalization.

One third of epilepsy patients do not achieve sufficient seizure freedom with current standard anti-seizure medications. Better understanding of the pathological mechanisms contributing to epileptogenesis is thus necessary to improve current therapies. SUR1-TRPM4 is a depolarizing ion channel minimally expressed in healthy brain that is upregulated de novo in neurons and glia after epileptogenic CNS injuries such as traumatic brain injury and stroke. However, its role in epilepsy is not well understood. Here, we demonstrate using immunofluorescent microscopy that SUR1-TRPM4 expression is elevated in neurons within electrographically sorted human epileptic brain compared to non-epileptic brain obtained after resection from six drug-resistant temporal lobe epilepsy patients. Additionally, we utilized immunofluorescence and co-immunoprecipitation to observe that SUR1-TRPM4 is upregulated within the hippocampus and temporal cortex in mice after PTZ kindling, a chronic model of rodent epilepsy. Pharmacologic inhibition of SUR1-TRPM4 using either the FDA-approved drug glyburide or 9-phenanthrol, as well as either constitutive or neuron-specific knock-out of this channel, attenuated chronic seizure development in this model. Exogenous overexpression of SUR1-TRPM4 by plasmid transfection in neurons in vitro increased neuronal hyperexcitability in response to low Mg2+ stimulation, while pharmacologic inhibition of endogenous TRPM4 attenuated neuronal population hyperexcitation. Collectively, our results reveal that elevated SUR1-TRPM4 expression found in human and rodent epileptic neurons promotes chronic seizures by increasing neuronal excitation. These findings directly support clinical investigation of SUR1-TRPM4 inhibitors as potential anti-seizure therapies in epilepsy patients and suggest further investigations into the contribution of SUR1-TRPM4 to seizures induced by specific epileptogenic insults, such as TBI, are warranted.

Perihematomal (PH) edema (PHE) is an unvarying sequel of intracerebral hemorrhage (ICH). In contrast to cerebral ischemia, wherein the consequences of edema are incontrovertible, the effects of PHE on clinical outcome after ICH are uncertain. We performed a critical review of publications on the natural history of PHE. We review mechanisms of formation, including clot contraction during the hyperacute phase, and the prognostic utility of PHE. Although data support the hypothesis that PHE adversely affects clinical outcome, data interpretation is hampered by key factors: (1) Since PHE is formed by clot contraction that releases serum (interstitial edema), and blood-brain barrier dysfunction that releases plasma (vasogenic edema), PHE quantification is complex. (2) Although the apparent diffusion coefficient (ADC) is touted as distinguishing vasogenic from cytotoxic (cellular) edema, cellular changes that decrease ADC can be masked by increases in extracellular fluid. (3) Decreased ADC occurs with cytotoxic edema as well as other conditions with increase cellular water, including glial activation, inflammatory cell infiltration and heme degradation products. (4) Decreased ADC often is attributed to tissue ischemia, but assessments have largely failed to demonstrate severe ischemia of PH tissues. PHE is an acceptable predictor of outcome in ICH.

Chronic subdural hematoma (cSDH) is predicted to become the most common neurosurgical pathology by 2030. Surgical evacuation is a critical component of cSDH management, and postoperative monitoring is important given high recurrence rates and concerns related to restarting anticoagulation. Given issues related to cost, radiation exposure, and time for computerized tomography (CT) and magnetic resonance imaging examinations, we developed a novel technique to detect, assess, and quantify residual and/or recurrent subdural hematoma with point-of-care, hand-held ultrasound and sonolucent burr-hole covers placed during the initial surgery. We prospectively collected and retrospectively analyzed clinical and radiographical data for cSDH patients treated with burr-hole evacuation and implanted sonolucent burr-hole covers. Postoperative outpatient follow-up included direct comparison of point-of-care ultrasound (US) and head CT as the gold standard. Implant-to-cortical distance and absolute hematoma thickness were measured using ImageJ and Unity PACS on follow-up scans. Nine patients underwent burr-hole evacuation of cSDH with placement of a sonolucent cover. Hematoma thickness and cover-to-septum pellucidum distance did not differ between the two techniques. Both US and CT detected recurrent subdural hematoma in one of the nine patients. US and CT showed resolution of cSDH for the remaining seven subjects at follow-up, demonstrating 100% concordance between the US and CT methods. No immediate or short-term complications and infections related to the use of the sonolucent cover were noted in this cohort. Ultrasound-based assessment using a sonolucent burr-hole cover showed good concordance with CT for detecting and ruling out recurrent cSDH in a small cohort of patients. Point-of-care US could become a supplemental imaging modality for postoperative evaluation of cSDH.

Pentylenetetrazol (PTZ) kindling is a widely used model for inducing epileptogenesis and evaluating long-term seizure susceptibility differences among animals. This model is typically performed by chronic, repetitive exposures to a constant subconvulsive PTZ dose. However, the effectiveness of the commonly used dose (35 mg/kg) varies among different animal groups due to factors such as species, age, sex, and genetic background. This study characterizes a novel kindling approach, the PTZ Dose Escalation (PTZ-DE) model, which assesses chronic seizure threshold with enhanced sensitivity by empirically determining the minimally effective dose to induce PTZ kindling for specific experimental conditions. The efficacy and validity of the PTZ-DE model were compared to the standard PTZ kindling approach. First, the characteristic increase in chronic seizure response was compared between PTZ-DE and the standard model across animal characteristics (strain, sex). Next, the PTZ-DE model’s validity was assessed by determining whether PTZ-DE could replicate the increased chronic seizure susceptibility previously reported using the standard approach after traumatic brain injury (TBI). Lastly, the PTZ-DE model’s effectiveness in detecting seizure differences was measured in a condition (glyburide treatment) where alterations to chronic seizure susceptibility were not detected with standard kindling. This study observed that, compared to the standard model, the PTZ-DE model corrects for background differences in PTZ susceptibility, replicates known alterations in chronic seizure thresholds, and uncovers changes in seizure threshold previously unidentified by the standard approach. The PTZ-DE model may be a superior approach for discovering new pathological mechanisms of epileptogenesis and for developing targeted therapies for seizure management.

Brain ischemia causes disruption in cerebral blood flow and blood–brain barrier integrity, which are normally maintained by astrocyte endfeet. Emerging evidence points to dysregulation of the astrocyte translatome during ischemia, but its effects on the endfoot translatome are unknown. In this study, we aimed to investigate the early effects of ischemia on the astrocyte endfoot translatome in a rodent cerebral ischemia and reperfusion model of stroke. To do so, we immunoprecipitated astrocyte-specific tagged ribosomes (RiboTag IP) from mechanically isolated brain microvessels. In mice subjected to middle cerebral artery occlusion and reperfusion and contralateral controls, we sequenced ribosome-bound RNAs from perivascular astrocyte endfeet and identified 205 genes that were differentially expressed in the endfoot translatome after ischemia. The main biological processes associated with these differentially expressed genes included proteostasis, inflammation, cell cycle/death, and metabolism. Transcription factors whose targets were enriched amongst upregulated translating genes included HSF1, the master regulator of the heat shock response. The most highly upregulated genes in the translatome were HSF1-dependent Hspa1a and Hspa1b, which encode the inducible HSP70. Using qPCR, Western blot, and immunohistochemistry, we confirmed that HSP70 is upregulated in astrocyte endfeet after ischemia. This coincided with an increase in ubiquitination across the proteome that suggests that ischemia induces a disruption in proteostasis in astrocyte endfeet. These findings suggest a robust proteostasis response to proteotoxic stress in the endfoot translatome after ischemia. Modulating proteostasis in endfeet may be a strategy to preserve endfoot function and BBB integrity after ischemic stroke.

Spinal cord injury (SCI) remains a major unsolved problem that permanently impairs the lives of innumerable individuals worldwide. Although advances in the basic, pre-clinical and clinical sciences of SCI hold promise for patients, clinicians may lack a full insight into the relevant cellular and molecular events, and laboratory researchers may underappreciate how cellular and molecular phenomena translate into meaningful functional outcomes. To help bridge these perspectives, we first review the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, which is the principal instrument used to gauge clinical outcomes in SCI, and the clinically important concept of AIS grade “conversion” (improvement), which occurs in some but not all patients. We then review underlying mechanisms that contribute to the AIS grade and its conversion, including mechanisms of transient neurological dysfunction (neuronal and axonal “stunning”), mechanisms of secondary cell loss (apoptosis, pyroptosis, and necroptosis), and mechanisms of axonal loss (primary axotomy and secondary axonal degeneration). Finally, we briefly review approaches to clinical management that may ameliorate identified mechanisms of secondary tissue loss and neurological dysfunction following SCI.

Diaschisis is a phenomenon in which damage to one brain region leads to dysfunction in remote, yet functionally connected, areas. Although it has been well characterized in stroke, the complex, multifocal nature of traumatic brain injury (TBI) suggests that similar network-level disruptions could occur, yet the presence and impact of diaschisis in TBI remain underexplored. This gap may stem from a historical focus on cerebrovascular events, underrecognition of diaschisis in TBI, and methodological challenges related to TBI’s heterogeneous nature. This review maps diaschisis in TBI by examining models, mechanisms, neuroimaging, clinical features, and therapeutic interventions. A PRISMA-ScR guided search of PubMed, Embase, and Cochrane included studies explicitly addressing diaschisis in TBI from inception up to January 2025. Two independent reviewers screened titles, abstracts, and full texts, with discrepancies resolved by consensus. Twenty-three studies were included, encompassing 110 human participants, 497 animals, and one in vitro model. Among these, 57% used neuroimaging, 39% assessed functional outcomes, and 22% examined potential interventions. The predominant experimental model was rodent-controlled cortical impact, typically simulating moderate TBI. Contrarily, human studies were fewer and focused on severe TBI cases. Crossed cerebellar diaschisis was the most common neuroimaging finding (36%), with MRI used most frequently, followed by PET and SPECT. Across both clinical studies and preclinical models, key mechanisms of diaschisis included deafferentation, reduced metabolism, altered glutamate signaling, hypoperfusion, and distant apoptotic cell death. Motor deficits were more common with better recovery than cognitive impairments. Interventions such as MK-801 and Ifenprodil showed potential to reverse diaschisis, but others had limited effects. This review underscores the limited but growing understanding of diaschisis in TBI. Targeted research on mild-to-moderate TBI, interventions, and imaging-validation trials is needed to improve diagnosis and treatment.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected individuals with pre-existing medical conditions, such as neurocognitive disorders. Premorbid neurocognitive conditions compounded by COVID-19 can escalate into COVID-associated neurological complications, leading to severe illness or even death. As COVID-19 continues to persist and vaccines lose efficacy against emerging variants, individuals with neurocognitive disorders often experience prolonged symptoms that are further exacerbated by repeated breakthrough infections of highly diversified viral variants due to emergence of new viral mutations. Despite the significance of neurocognitive disorders as risk factors for COVID-19-related mortality and long COVID, the underlying causes remain largely unknown. In this study, we report a link between ORF3a expression and COVID-associated neuroinflammation and neurocytotoxicity in postmortem brain tissues from COVID-19 patients. These findings were further verified through neural cell-based in vitro and in vivo animal studies introducing ORF3a either alone or in the context of viral infection. As a membrane-associated protein, ORF3a induces upregulation of Sur1-regulated ion channels, resulting in intracellular Ca2+ influx, apoptosis, and necrosis through both NF-kB-dependent and independent proinflammatory responses in astrocytes. These findings reveal a novel clinical and mechanistic link between ORF3a and Sur1-regulated ion channels, which are highly responsive to neuroinflammatory conditions causing neurodegeneration. Additionally, we have identified a Food and Drug Administration-approved drug, glibenclamide, and a natural antiviral compound glycyrrhizin that effectively mitigates the neuropathological effects of ORF3a, underscoring the therapeutic potential and clinical significance of these findings.IMPORTANCECoronavirus disease 2019 (COVID-19) disproportionately affects individuals with pre-existing neurocognitive conditions primarily due to COVID-19-associated neuroinflammation and neurotoxicity (CNN), which can progress to COVID-associated neurological disorders (CANDs), leading to severe illness and mortality. Despite CNN’s significant contribution to CANDs and related morbidity and mortality, its underlying causes remain poorly understood. Our study identifies ORF3a as a key driver of CNN, establishing a direct clinical and functional link between ORF3a and CNN linking to CANDs. Mechanistically, ORF3a disrupts ion homeostasis in astrocytes by promoting Ca²+ influx through Sur1-regulated ion channels, contributing to CNN. Notably, the Food and Drug Administration-approved drug glibenclamide, a Sur1-specific inhibitor, and the natural compound glycyrrhizin effectively mitigate ORF3a-induced neuropathology, highlighting ORF3a as a promising therapeutic target. These findings present a potential strategy to eliminate CNN and prevent CANDs.

Introduction: Recent large core stroke trials show a benefit for endovascular treatment (EVT) of acute ischemic stroke up to approximately 125 mL. Consequently, clinical trials evaluating neuroprotection in EVT populations may best test proof of concept under this volume threshold. The CHARM trial evaluated the safety and efficacy of intravenous glyburide as a treatment for large hemispheric infarction (LHI) patients at high risk for cerebral edema. Hypothesis: The objective of this analysis was to examine the treatment effect of IV glyburide in EVT patients with baseline infarcts up to 125 mL. Methods: CHARM subjects who were enrolled with CTP or DWI volume 80-125 mL and underwent EVT were included in this analysis. The primary endpoint was a shift analysis on the 90-day modified Rankin Scale (mRS) and included participants aged ≤70 years who received any study drug. Independent variables included age, sex, baseline NIHSS, world region, and tPA. We also examined the frequency of decompressive craniectomy and the amount of midline shift (mm) by treatment group. Results: For a total of 34 subjects (mean age 56 years, 32% female, baseline NIHSS 20, 41% received thrombolysis), the time to thrombectomy was 4.5±2.0 hours and time to study drug was 9.6±1.4 hours. glyburide-treated patients received study drug later than placebo by an average of 1 hour ( P =0.036). The baseline infarct volume was 94±20 mL, which did not differ by treatment arm. glyburide-treated subjects had a favorable outcome (n=18, cOR 7.13, 95%CI 1.51-33.7, P =0.013) relative to placebo (see figure). 90-day mortality occurred less frequently in glyburide treated subjects compared to placebo (5.6% vs 31%, P =0.05). There were no decompressive craniectomies in glyburide treated patients, whereas there were 4 decompressions among the placebo-treated subjects ( P =0.021). The mean midline shift was 4.2 ± 2.5 mm in IV glyburide-treated subjects and 7.6 ± 5.5 mm among placebo-treated subjects ( P =0.024). Conclusions: There is evidence of benefit for IV glyburide in large core EVT treated subjects with a baseline stroke volume ≤125 mL. Although IV glyburide may also have benefit among non-EVT treated subjects, the evolving standard of care of EVT for large core stroke indicates that an efficient, feasible trial design should focus on EVT patients.

Intraventricular hemorrhage (IVH) is a frequent and severe complication of hemorrhagic brain diseases. Treatment options for IVH are limited in their ability to improve long-term functional status. One promising target for treatment is the profound cellular inflammatory response that occurs after injury, but advances have been limited by our incomplete understanding of this phenomenon. We leveraged Recovery After Cerebral Hemorrhage, a prospective, observational study at the University of Maryland, to address this question. We sought to characterize the immune cell populations in the intraventricular cerebrospinal fluid (CSF) of human subjects after IVH. To do so, we generated a single-nucleus RNA sequencing (snRNA-seq) atlas of leukocytes in the CSF after acute brain injury. We performed 10x Genomics snRNA-seq of nuclei isolated from the CSF of 7 patients (ICH=6, SAH=1), yielding 11,191 high-quality transcriptomes. We identified four major cell populations, which we annotated as neutrophils (53.8%), monocytes (26.1%), lymphocytes (17.8%), and other cells (2.4%) based on the expression of canonical gene markers. Sub-clustering revealed distinct subtypes of neutrophils, monocytes, and lymphocytes that shared features with populations previously described in the systemic circulation. Neutrophils were categorized into nascent, quiescent, and interferon-activated states. The interferon-activated state has not been observed in the central nervous system previously. Monocytes were predominantly of a classical phenotype. Lymphocytes were predominantly T-cells, with the largest populations being naïve and central memory CD4+ T-cells. This snRNA-seq data informed the design of a flow cytometry panel that we used to validate the presence of cell subtypes identified by transcriptomics. This analysis demonstrates the feasibility of snRNA-seq approaches to identify previously unexplored pathways and immune cell types that may be relevant to disease. We anticipate that these tools will enable the discovery of new targets to mitigate inflammation-related secondary damage after IVH. ### Competing Interest Statement The authors have declared no competing interest.

Thirty percent of epilepsy patients have seizures despite best medical therapy. While epilepsy surgery has emerged as a promising treatment option for these patients, surgical outcomes vary considerably between patients and have not significantly improved over the years. These stagnant outcomes can be attributed to poor seizure onset zone and epileptic network localization with currently available tools. Lactate production is a well-known consequence of metabolic reprogramming and biomarker in epilepsy. Detection of lactate elevations using conventional magnetic resonance spectroscopy has been extensively studied as an effective tool to non-invasively detect epileptic brain tissue. However, this method suffers from poor spatial resolution, which limits its clinical utility in presurgical resection mapping. In this study, we explore the utility of a recently developed approach, magnetic resonance spectroscopy and spectroscopic imaging of hyperpolarized [1-13C]pyruvate, to identify epileptic tissues via detection of increased lactate production. We found that this approach accurately identifies elevated lactate production in an in vitro model of chronic hyperactivity and in the gold standard mouse epilepsy model, pentylenetetrazol kindling. These data suggest that magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate has the potential to effectively and non-invasively map epileptic foci and should be further explored as a clinical tool to guide epilepsy resection surgery by identifying epileptic tissue in patients.

OBJECTIVE:The Glibenclamide for Large Hemispheric Infarction Analyzing mRS and Mortality (CHARM) trial enrolled participants with large hemispheric infarction, randomized to a placebo or intravenous glyburide. Our objective in this post-hoc study was to evaluate the relationship between baseline stroke volume and the potential efficacy of i.v. glyburide. METHODS:Participants enrolled in CHARM and aged ≤70 years were included if a <125 ml ischemic core lesion volume was measured by computed tomography perfusion or diffusion magnetic resonance imaging. The primary endpoint was a shift analysis on the 90-day modified Rankin Scale. Independent variables included age, sex, baseline National Institutes of Health Stroke Scale, world region, tissue plasminogen activator, and endovascular thrombectomy. RESULTS:A total of 147 participants with a baseline large-core stroke volume <125 ml were available for this analysis (mean age 58 years, 37% women, baseline National Institutes of Health Stroke Scale 18, and the time to study drug was 9.1 ± 2.1 h). The median baseline core volume of 92 mL (IQR 81-107 ml) did not differ by treatment arm. The i.v. glyburide-treated participants had a favorable shift in outcome relative to the placebo (adjusted common odds ratio 2.11, 95% CI 1.10-4.01, p = 0.02). In patients who underwent endovascular thrombectomy, i.v. glyburide-treated subjects had a favorable outcome (adjusted common odds ratio 8.19, 95% CI 1.60-42.0, p = 0.01), fewer decompressive craniectomies (0% vs 25%, P = 0.02), less midline shift (4.2 ± 2.5 mm vs 7.6 ± 5.5 mm, p = 0.02), and lower 90-day mortality (5.6% vs 31%, p = 0.05) compared with the placebo, respectively. INTERPRETATION:This post-hoc analysis of the CHARM trial provides hypothesis-generating evidence that i.v. glyburide may improve outcome in large-core stroke <125 ml, especially among endovascular thrombectomy-treated patients. These results require confirmation in a prospective randomized clinical trial. ANN NEUROL 2025;98:616-624.

Introduction: Two randomized trials have evaluated intravenous (IV) Glyburide for the treatment of large hemispheric infarction (LHI) patients at high risk for cerebral edema. Hypothesis: In this meta-analysis of two randomized trials, we aimed to determine whether subjects with a baseline stroke volume ≤125 mL who were treated with IV Glyburide would have better outcomes than those who received placebo. Methods: The source population included all GAMES-RP and CHARM subjects who were enrolled and treated with IV Glyburide or placebo, were ≤70 years of age, and had a baseline stroke volume ≤125 mL (n=138). The outcome of interest was the modified Rankin Scale (mRS) score at 90 days using 5 categories, where 0-1 and 5-6 were each collapsed into a single category. We used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in the subgroup with a baseline stroke volume ≤125 mL after adjustment for age, sex, baseline NIHSS, region of world, image modality, thrombolysis and thrombectomy (yes versus no). Results: The cohort included a total of 138 subjects with a mean age 58±10 years, 34% female, baseline NIHSS 18 (15-21), 46% received thrombolysis, baseline stroke volume 97 ml (84-108). The median 90-day mRS was 3 (2-4). Among these patients at 90 days, IV Glyburide was associated with better functional outcome (cOR 2.56, 95% CI 1.28-5.11, p=0.008). Conclusions: Individual patient data meta-analysis of 138 subjects enrolled in the GAMES-RP and CHARM trials show that IV Glyburide was associated with an improvement in functional outcome compared to placebo when the baseline stroke volume was ≤125 mL. This finding requires confirmation in a future clinical trial.

Secondary loss of initially spared white and grey matter is a major driver of morbidity after spinal cord injury (SCI). Current treatments have not substantially changed in decades and are limited to surgical decompression and blood pressure management. White matter atrophy after SCI is primarily caused by secondary axonal degeneration (SAD), which is triggered by maladaptive axonal uptake of sodium and calcium through a multitude of ion channels and transporters. While specific inhibitors have been studied, none have been translated into clinical use, in part due to the diverse array of involved channels. Here, we studied whether amiodarone, an FDA-approved antiarrhythmic drug that exerts pleotropic inhibition of multiple sodium and calcium channels, might be neuro- and axonoprotective after SCI precisely because of its broad inhibitory profile. Mice were submitted to off-midline thoracic SCI versus sham surgery and treated with amiodarone versus vehicle control within 15 min and after 4 h of injury. We found that amiodarone treatment after SCI improved locomotor function, which was longitudinally measured over 28 days with the Basso mouse scale, accelerating rotarod, and inclined plane tests. Amiodarone treatment reduced spinal cord atrophy and white matter loss at 28 days after injury, assessed by spinal cord wet weights and by volumetric measurements of grey and white matter in serial coronal sections of spinal cords stained with luxol fast blue and cresyl violet. Amiodarone was directly axonoprotective after SCI, with reduced losses of neurofilament heavy positive axons at 28 days. Interestingly, long-term amiodarone-mediated axonoprotection was accompanied by a reduction of SAD at early time points, measured by counting axonal spheroids 24 h after SCI in fluorescently labeled corticospinal tract axons imaged with light sheet imaging. Overall, these data identify amiodarone as a potentially axonoprotective agent that could be repurposed to treat secondary injury after SCI.

Introduction: The phase III CHARM trial evaluated the safety and efficacy of intravenous glyburide as a treatment for large hemispheric infarction (LHI) patients at high risk for cerebral edema. Hypothesis: We aimed to determine whether subjects who were treated with IV glyburide would have better 12-month outcomes than those who received placebo in the CHARM trial. Methods: The source population included all CHARM subjects who were enrolled and treated with IV glyburide or placebo and had a recorded 12-month outcome. For those subjects missing a 12-month outcome, multiple imputation including baseline covariates and the 90-day modified Rankin Scale (mRS) was used. Shift analysis was performed on the 12-month mRS using 5 categories, where 0-1 and 5-6 were each collapsed into a single category. Independent variables included age, sex, baseline NIHSS, world region, tPA, and thrombectomy. Based on prior analysis, we also examined subjects with a baseline stroke volume ≤125 mL. Results: The cohort included a total of 431 subjects (mean age 58±9 years, 33% female, baseline NIHSS 19 (16-22), 40% received thrombolysis), the median 90-day mRS was 5 (4-6) and the median 12-month mRS was 5 (3-6). A total of 90 subjects (21%) had missing 12-month outcomes (n=38 in glyburide and n=52 in placebo). The correlation between 90d and 12mo mRS was r=0.93, p<0.0001. At 12 months, IV glyburide was not associated with better functional outcome (cOR 1.09, 95% CI 0.73-1.62, p=0.68) in the primary analytic population. However, among the subgroup of subjects with a baseline stroke volume ≤125 mL (n=118), the IV glyburide treatment arm had a favorable effect, cOR 2.26, 95% CI 1.06-4.78, p=0.034 (see figure). This effect was also present among those treated with endovascular thrombectomy at baseline (n=34, cOR 5.52, 95% CI 1.05-28.9, p=0.043). Conclusions: Long term outcomes in the CHARM trial suggests a potential for durable improvement in functional outcome in patients treated with IV glyburide among those with a baseline stroke volume ≤125 mL. Demonstration of clinical efficacy requires a dedicated trial focusing on this patient population.