Surgical Management for Primary Intracerebral Hemorrhage.

The incidence of primary intracerebral hemorrhage (ICH) is increasing, particularly in younger patients, in part, because of increased prescription of anticoagulants. The ICH incidence rate from 2016 to 2018 in the United States was nearly 79 per 100,000 person-years and as high as 367 per 100,000 person-years among those 75 years or older. Worldwide, ICH comprises 28% of all new strokes, but a higher disease burden than ischemic stroke because of its higher morbidity and mortality. While mortality seems to be decreasing, functional outcomes are not improving. After negative trials of open surgical evacuation, recent trials of medical management strategies including intensive blood pressure control and prothrombotic agents intended to reduce hematoma expansion failed to demonstrate efficacy. Concomitantly, continued interest in minimally invasive surgical approaches arose from appreciation of secondary iatrogenic injury incurred to subcortical white matter tracts from open surgical techniques. A positive trial of minimally invasive surgery for lobar hemorrhage has recently been reported, bringing new optimism and demanding a reconsideration of surgical management of ICH. In this narrative review, we summarize the landmark studies, review recent literature, and consider the outstanding questions surrounding surgical management of ICH.

Acute Development of Traumatic Intracranial Aneurysms After Civilian Gunshot Wounds to the Head.

In previous studies, the incidence of traumatic intracranial aneurysms (TICAs) after civilian gunshot wound to the head (cGSWH) was ∼3%. Given the use of delayed vessel imaging, we hypothesize that a significant fraction of TICAs is missed on initial non-contrasted scans. This study was designed to characterize acute TICAs using admission computed tomographic angiography (aCTA) in cGSWH. Over the period from 2017 to 2022, 341 patients were admitted to R. Adams Cowley Shock Trauma Center with cGSWH; 136 subjects had aCTA ∼3 (standard deviation [SD] 3.5) h post-injury. Demographics, clinical findings, imaging techniques, endovascular/surgical interventions, and outcomes were analyzed. Mean age was 34.7 (SD 13.1), male:female ratio was 120:16. Average admission Glasgow Coma Scale (GCS) score was 6 (SD 3.9). Entry site was frontal in 41, temporal in 55, parietal in 18, occipital in 6, suboccipital in 9, temporo-parietal in 1, and frontobasal-temporal in 6. Projectiles crossed multiple dural compartments in 76 (55%) patients. 35 TICAs were diagnosed in 28 subject: 24 were located along the middle cerebral artery (MCA), 6 in the anterior cerebral artery (ACA), 3 in the internal carotid artery (ICA), 1 in the posterior cerebral artery (PCA), and 1 in the middle meningeal artery (MMA). Eleven TICAs resolved spontaneously in nine patients. Eight aneurysms were treated by endovascular means, two via combined endovascular/open approaches. Forty-nine patients died, 10 of whom had 15 TICAs. Eighty patients developed intracerebral hematoma s (ICHs). Regression models showed that the presence of an ICH was the main predictor of TICA in cGSWH. Larger ICHs (average 22.3 cc vs. 9.4 cc in patients with and without aneurysms, respectively) in patients with cGSWH suggest hidden TICAs. Nearly 30% of patients had spontaneous resolution within 1 week. When CTA was performed acutely, TICAs were 10 times more frequent in cGSWH than in previous literature, and those patients were more likely to proceed to surgery. Almost one third of patients in this series died from the devastating effects of cGSWH.

Iodine-based dual-energy CT predicts early neurological decline from cerebral edema after large hemispheric infarction.

Background & Purpose: Ischemia affecting two thirds of the MCA territory predicts development of malignant cerebral edema. However, early infarcts are hard to diagnose on conventional head CT. We hypothesize that high-energy (190keV) virtual monochromatic images (VMI) from dual-energy CT (DECT) imaging enables earlier detection of secondary injury from malignant cerebral edema (MCE). Methods: Consecutive LHI patients with NIHSS ≥ 15 and DECT within 10 hours of reperfusion from May 2020 to March 2022 were included. We excluded patients with parenchymal hematoma-type 2 transformation. Retrospective analysis of clinical and novel variables included VMI Alberta Stroke Program Early CT Score (ASPECTS), total iodine content, and VMI infarct volume. Primary outcome was early neurological decline (END). Secondary outcomes included hemorrhagic transformation, decompressive craniectomy (DC), and medical treatment of MCE. Fisher's exact test and Wilcoxon test were used for univariate analysis. Logistic regression was used to develop prediction models for categorical outcomes. Results: Eighty-four LHI patients with a median age of 67.5 [IQR 57,78] years and NIHSS 22 [IQR 18,25] were included. Twenty-nine patients had END. VMI ASPECTS, total iodine content, and VMI infarct volume were associated with END. VMI ASPECTS, VMI infarct volume, and total iodine content were predictors of END after adjusting for age, sex, initial NIHSS, and tPA administration, with a AUROC of 0.691 [0.572,0.810], 0.877 [0.800, 0.954], and 0.845 [0.750, 0.940]. By including all three predictors, the model achieved AUROC of 0.903 [0.84,0.97] and was cross validated by leave one out method with AUROC of 0.827. Conclusion: DECT with high-energy VMI and iodine quantification is superior to conventional CT ASPECTS and is a novel predictor for early neurological decline due to malignant cerebral edema after large hemispheric infarction.

Interleukin-6 in Traumatic Brain Injury: A Janus-Faced Player in Damage and Repair.

Traumatic brain injury (TBI) is a common and often devastating illness, with wide-ranging public health implications. In addition to the primary injury, victims of TBI are at risk for secondary neurological injury by numerous mechanisms. Current treatments are limited and do not target the profound immune response associated with injury. This immune response reflects a convergence of peripheral and central nervous system-resident immune cells whose interaction is mediated in part by a disruption in the blood-brain barrier (BBB). The diverse family of cytokines helps to govern this communication and among these, Interleukin (IL)-6 is a notable player in the immune response to acute neurological injury. It is also a well-established pharmacological target in a variety of other disease contexts. In TBI, elevated IL-6 levels are associated with worse outcomes, but the role of IL-6 in response to injury is double-edged. IL-6 promotes neurogenesis and wound healing in animal models of TBI, but it may also contribute to disruptions in the BBB and the progression of cerebral edema. Here, we review IL-6 biology in the context of TBI, with an eye to clarifying its controversial role and understanding its potential as a target for modulating the immune response in this disease.

Immunomodulatory therapy with glatiramer acetate reduces endoplasmic reticulum stress and mitochondrial dysfunction in experimental autoimmune encephalomyelitis.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and may contribute to the neuronal loss that underlies permanent impairment. We investigated whether glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased inflammation, demyelination, mitochondrial dysfunction, ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can indirectly induce neuroprotective effects in the CNS by mediating ER stress.

Abcc8 (sulfonylurea receptor-1) knockout mice exhibit reduced axonal injury, cytotoxic edema and cognitive dysfunction vs. wild-type in a cecal ligation and puncture model of sepsis.

Sepsis-associated brain injury (SABI) is characterized by an acute deterioration of mental status resulting in cognitive impairment and acquisition of new and persistent functional limitations in sepsis survivors. Previously, we reported that septic mice had evidence of axonal injury, robust microglial activation, and cytotoxic edema in the cerebral cortex, thalamus, and hippocampus in the absence of blood-brain barrier disruption. A key conceptual advance in the field was identification of sulfonylurea receptor 1 (SUR1), a member of the adenosine triphosphate (ATP)-binding cassette protein superfamily, that associates with the transient receptor potential melastatin 4 (TRPM4) cation channel to play a crucial role in cerebral edema development. Therefore, we hypothesized that knockout (KO) of Abcc8 (Sur1 gene) is associated with a decrease in microglial activation, cerebral edema, and improved neurobehavioral outcomes in a murine cecal ligation and puncture (CLP) model of sepsis. Sepsis was induced in 4-6-week-old Abcc8 KO and wild-type (WT) littermate control male mice by CLP. We used immunohistochemistry to define neuropathology and microglial activation along with parallel studies using magnetic resonance imaging, focusing on cerebral edema on days 1 and 4 after CLP. Abcc8 KO mice exhibited a decrease in axonal injury and cytotoxic edema vs. WT on day 1. Abcc8 KO mice also had decreased microglial activation in the cerebral cortex vs. WT. These findings were associated with improved spatial memory on days 7-8 after CLP. Our study challenges a key concept in sepsis and suggests that brain injury may not occur merely as an extension of systemic inflammation. We advance the field further and demonstrate that deletion of the SUR1 gene ameliorates CNS pathobiology in sepsis including edema, axonal injury, neuroinflammation, and behavioral deficits. Benefits conferred by Abcc8 KO in the murine CLP model warrant studies of pharmacological Abcc8 inhibition as a new potential therapeutic strategy for SABI.

Excessive platelet inhibition following Pipeline embolization of intracranial aneurysms.

BACKGROUND: High levels of platelet inhibition have been associated with hemorrhagic complications following Pipeline embolization of intracranial aneurysms. We therefore titrate clopidogrel dosing to maintain a moderate level of platelet inhibition using the VerifyNow P2Y12 assay. However, many patients demonstrate dramatic increases in platelet inhibition following treatment despite being on a consistent antiplatelet regimen. We therefore elected to explore the incidence of this phenomenon and possible predisposing factors. METHODS: All successful Pipeline aneurysm treatments performed at our institution from 2011 to 2019 with moderate procedure-day platelet inhibition levels as indicated by a VerifyNow PRU of 60-235 were included. Patients who received glycoprotein IIb/IIIa inhibitors and those treated for ruptured/symptomatic lesions were excluded. The incidence of excessive platelet inhibition defined by a PRU<60 within 8 weeks of treatment was noted. Multivariable logistic regression was performed to determined independent predictors of the phenomenon. RESULTS: Some 190 treatments were performed in 178 qualifying patients. A post-procedure PRU <60 occurred following 79% of treatments, documented on average after 8.5 (range 1-47) days. A higher procedure day hematocrit level (P=0.003, OR 1.09, 95% CI 1.029 to 1.152) was an independent predictor of reaching a PRU <60, while intra-procedural midazolam exposure (P=0.044, OR 0.44, 95% CI 0.201 to 0.980) and a higher procedure-day PRU (P=0.047, OR 0.99, 95% CI 0.982 to 1.000) were associated with a reduced odds. Time-since-procedure and hematocrit levels were associated with excessive platelet inhibition when excluding patients who initially demonstrated hyperresponse. CONCLUSION: Elevations in platelet inhibition were frequently observed following flow diversion with Pipeline.

Traumatic brain injury alters dendritic cell differentiation and distribution in lymphoid and non-lymphoid organs.

BACKGROUND: Pathophysiological consequences of traumatic brain injury (TBI) mediated secondary injury remain incompletely understood. In particular, the impact of TBI on the differentiation and maintenance of dendritic cells (DCs), which are regarded as the most professional antigen presenting cells of the immune system, remains completely unknown. Here, we report that DC-differentiation, maintenance and functions are altered on day 3 and day 7 after TBI. METHODS: Long bones, spleen, peripheral lymph nodes (pLNs), mesenteric lymph nodes (mLNs), liver, lungs, skin and blood were collected from mice with either moderate-level cortical impact (CCI) or sham on day 1, day 3 or day 7 after TBI. Bone marrow cells were isolated from the tibias and femurs of hind limb through flushing. Tissues were digested with Collagenase-D and DNase I. Skin biopsies were digested in the presence of liberase + DNase I. Single cell suspensions were made, red blood cells were lysed with Ammonium chloride (Stem Cell Technology) and subsequently filtered using a 70 µM nylon mesh. DC subsets of the tissues and DC progenitors of the BM were identified through 10-color flow cytometry-based immunophenotyping studies. Intracellular reactive oxygen species (ROS) were identified through H2DCFDA staining. RESULTS: Our studies identify that; (1) frequencies and absolute numbers of DCs in the spleen and BM are altered on day 3 and day 7 after TBI; (2) surface expression of key molecules involved in antigen presentation of DCs were affected on day 3 and day 7 after TBI; (3) distribution and functions of tissue-specific DC subsets of both circulatory and lymphatic systems were imbalanced following TBI; (4) early differentiation program of DCs, especially the commitment of hematopoietic stem cells to common DC progenitors (CDPs), were deregulated after TBI; and (5) intracellular ROS levels were reduced in DC progenitors and differentiated DCs on day 3 and day 7 after TBI. CONCLUSIONS: Our data demonstrate, for the first time, that TBI affects the distribution pattern of DCs and induces an imbalance among DC subsets in both lymphoid and non-lymphoid organs. In addition, the current study demonstrates that TBI results in reduced levels of ROS in DCs on day 3 and day 7 after TBI, which may explain altered DC differentiation paradigm following TBI. A deeper understanding on the molecular mechanisms that contribute to DC defects following TBI would be essential and beneficial in treating infections in patients with acute central nervous system (CNS) injuries, such as TBI, stroke and spinal cord injury.

Proposal of a Management Algorithm to Predict the Need for Expansion Duraplasty in American Spinal Injury Association Impairment Scale Grades A-C Traumatic Cervical Spinal Cord Injury Patients.

Expansion duraplasty to reopen effaced subarachnoid space and improve spinal cord perfusion, autoregulation, and spinal pressure reactivity index (sPRX) has been advocated in patients with traumatic cervical spinal cord injury (tCSCI). We designed this study to identify candidates for expansion duraplasty, based on the absence of cerebrospinal fluid (CSF) interface around the spinal cord on magnetic resonance imaging (MRI), in the setting of otherwise adequate bony decompression. Over a 61-month period, 104 consecutive American Spinal Injury Association Impairment Scale (AIS) grades A-C patients with tCSCI had post-operative MRI to assess the adequacy of surgical decompression. Their mean age was 53.4 years, and 89% were male. Sixty-one patients had falls, 31 motor vehicle collisions, 11 sport injuries, and one an assault. The AIS grade was A in 56, B in 18, and C in 30 patients. Fifty-four patients had fracture dislocations; there was no evidence of skeletal injury in 50 patients. Mean intramedullary lesion length (IMLL) was 46.9 (standard deviation = 19.4) mm. Median time from injury to decompression was 17 h (interquartile range 15.2 h). After surgery, 94 patients had adequate decompression as judged by the presence of CSF anterior and posterior to the spinal cord, whereas 10 patients had effacement of the subarachnoid space at the injury epicenter. In two patients whose decompression was not definitive and post-operative MRI indicated inadequate decompression, expansion duraplasty was performed. Candidates for expansion duraplasty (i.e., those with inadequate decompression) were significantly younger (p < 0.0001), were AIS grade A (p < 0.0016), had either sport injuries (six patients) or motor vehicle collisions (three patients) (p < 0.0001), had fracture dislocation (p = 0.00016), and had longer IMLL (p = 0.0097). In regression models, patients with sport injuries and inadequate decompression were suitable candidates for expansion duraplasty (p = 0.03). Further, 9.6% of patients failed bony decompression alone and either did (2) or would have (8) benefited from expansion duraplasty.

Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide.

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment.

Decompressive Craniectomy for Stroke: Who, When, and How.

Malignant cerebral edema after large hemispheric infarct is a highly morbid condition, and major, randomized trials over the last 2 decades have affirmed the beneficial effect of surgical intervention in the form of decompressive craniectomy. Early (<48 hours) decompressive craniectomy increases good functional outcomes (mRS 0-3) and reduces mortality. Additionally, trials have found the benefit of surgery to persist in those patients more than 60 years, though the apparent benefit is of lesser magnitude. A summary table of the major randomized trials of decompressive craniectomy is included. A detailed description and figures of the decompressive craniectomy procedure is included. The complications of decompressive craniectomy are also discussed, and recent literature on promising alternatives, both surgical and medical, is reviewed.

Initial Stress Hyperglycemia Is Associated With Malignant Cerebral Edema, Hemorrhage, and Poor Functional Outcome After Mechanical Thrombectomy.

BACKGROUND: Malignant cerebral edema (MCE) and intracranial hemorrhage (ICH) are associated with poor neurological outcomes despite revascularization after mechanical thrombectomy (MT). The factors associated with the development of MCE and ICH after MT are not well understood. OBJECTIVE: To determine periprocedural factors associated with MCE, ICH, and poor functional outcome. METHODS: We retrospectively analyzed anterior cerebral circulation large vessel occlusion cases that underwent MT from 2012 to 2019 at a single Comprehensive Stroke Center. Multivariate logistic regression analyses were performed to determine significant predictors of MCE, ICH, and poor functional outcome (modified Rankin Scale, 3-6) at 90 d. RESULTS: Four hundred patients were included. Significant independent predictors of MCE after MT included initial stress glucose ratio (iSGR) (odds ratio [OR], 14.26; 95% CI, 3.82-53.26; P < .001), National Institutes of Health Stroke Scale (NIHSS) (OR, 1.10; 95% CI, 1.03-1.18; P = .008), internal carotid artery compared with M1 or M2 occlusion, and absence of successful revascularization (OR, 0.16; 95% CI, 0.06-0.44; P < .001). Significant independent predictors of poor functional outcome included MCE (OR, 7.47; 95% CI, 2.20-25.37; P = .001), iSGR (OR, 5.15; 95% CI, 1.82-14.53; P = .002), ICH (OR, 4.77; 95% CI, 1.20-18.69; P = .024), NIHSS (OR, 1.10; 95% CI, 1.05-1.16; P < .001), age (OR, 1.04; 95% CI, 1.03-1.07; P < .001), and thrombolysis in cerebral infarction 2C/3 recanalization (OR, 0.12; 95% CI, 0.05-0.29; P < .001). CONCLUSION: Elevated iSGR significantly increases the risk of MCE and ICH and is an independent predictor of poor functional outcome. Thrombolysis in cerebral infarction 2C/3 revascularization is associated with reduced risk of MCE, ICH, and poor functional outcome. Whether stress hyperglycemia represents a modifiable risk factor is uncertain, and further investigation is warranted.

The utility of platelet inhibition testing in patients undergoing Pipeline embolization of intracranial aneurysms.

BACKGROUND: The utility of using the VerifyNow P2Y12 platelet inhibition assay in patients undergoing Pipeline embolization of intracranial aneurysms remains controversial. As we have routinely employed the assay for patients undergoing flow diversion, we elected to explore the relationship between P2Y12 hyporesponse as indicated by a P2Y12 Reaction Units (PRU) value >200 and treatment outcomes, including intraprocedural platelet aggregation and ischemic complications. METHODS: All successful intracranial aneurysm Pipeline treatments performed at our institution from November 2011 to May 2019 were included. The rate of P2Y12 hyporesponse and treatment outcomes were evaluated. Multivariable logistic regression was utilized to determine independent predictors of treatment outcomes. RESULTS: 333 qualifying treatments were performed in 297 patients. Clopidogrel hyporesponse was initially noted in 24%, falling to 17% by day-of-procedure by dose titration. A glycoprotein (GP) IIb/IIIa inhibitor was administered prophylactically in 3% of cases for persistent, profound hyporesponse. 27 (8.1%) patients developed acute platelet aggregation; only 6 demonstrated day-of-procedure P2Y12 hyporesponse. Day-of-procedure hyporesponse was not associated with intraprocedural platelet aggregation or ischemic complications. Greater Pipeline embolization device (PED) diameter was associated with a reduced odds of platelet aggregation (OR 0.38, 95% CI 0.17 to 0.85; p=0.019). Antiplatelet non-compliance (OR 25.20, 95% CI 3.86 to 164.61; p=0.001) and treatment of posterior circulation aneurysms (OR 5.23, 95% CI 1.22 to 22.33; p=0.026) were the only independent predictors of ischemic complications. CONCLUSIONS: P2Y12 hyporesponse was not associated with acute platelet aggregation or ischemic complications in our patients undergoing Pipeline embolization of intracranial aneurysms, possibly due to aggressive management of the hyporesponse using clopidogrel dose titration and/or GP IIb/IIIa inhibitor administration.

Emerging therapeutic targets for cerebral edema.

INTRODUCTION: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema. AREAS COVERED: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered. EXPERT OPINION: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review.

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials.

Unruptured cerebral aneurysms in elderly patients: key challenges and management.

Unruptured cerebral aneurysms are increasingly identified in elderly patients as the global life expectancy continues to rise and non-invasive vascular imaging becomes more prevalent. The optimal management of unruptured aneurysms in elderly patients remains controversial. Variability in life expectancy, comorbidities and rupture risk coupled with heterogenous endovascular and surgical treatments contribute to a paucity of clear guidelines, and current management is highly individualized. Elderly patients present unique considerations including frailty, cognitive dysfunction, vasculopathy, reduced life expectancy and overall worse prognosis in case of rupture which shape the risks and likelihood of success of endovascular and microsurgical treatment. In this review, we provide a comprehensive overview of unruptured cerebral aneurysms in the elderly, with a particular focus on the natural history, key challenges associated with advanced age, management and future innovations to further refine treatment.Key MessagesThe management of unruptured cerebral aneurysms in elderly patients remains controversial.Key challenges including frailty, cognitive dysfunction, reduced life expectancy, vasculopathy and poor prognosis with aneurysm rupture add complexity to endovascular and surgical decision making not encountered with younger demographics.A thorough understanding of available treatment options, likelihood of treatment success and associated risks weighed against the risk of aneurysm rupture informs patient discussion and management.

Efficacy of Early (≤ 24 Hours), Late (25-72 Hours), and Delayed (>72 Hours) Surgery with Magnetic Resonance Imaging-Confirmed Decompression in American Spinal Injury Association Impairment Scale Grades C and D Acute Traumatic Central Cord Syndrome Caused by Spinal Stenosis.

The therapeutic significance of timing of decompression in acute traumatic central cord syndrome (ATCCS) caused by spinal stenosis remains unsettled. We retrospectively examined a homogenous cohort of patients with ATCCS and magnetic resonance imaging (MRI) evidence of post-treatment spinal cord decompression to determine whether timing of decompression played a significant role in American Spinal Injury Association (ASIA) motor score (AMS) 6 months following trauma. We used the t test, analysis of variance, Pearson correlation coefficient, and multiple regression for statistical analysis. During a 19-year period, 101 patients with ATCCS, admission ASIA Impairment Scale (AIS) grades C and D, and an admission AMS of ≤95 were surgically decompressed. Twenty-four of 101 patients had an AIS grade C injury. Eighty-two patients were males, the mean age of patients was 57.9 years, and 69 patients had had a fall. AMS at admission was 68.3 (standard deviation [SD] 23.4); upper extremities (UE) 28.6 (SD 14.7), and lower extremities (LE) 41.0 (SD 12.7). AMS at the latest follow-up was 93.1 (SD 12.8), UE 45.4 (SD 7.6), and LE 47.9 (SD 6.6). Mean number of stenotic segments was 2.8, mean canal compromise was 38.6% (SD 8.7%), and mean intramedullary lesion length (IMLL) was 23 mm (SD 11). Thirty-six of 101 patients had decompression within 24 h, 38 patients had decompression between 25 and 72 h, and 27 patients had decompression >72 h after injury. Demographics, etiology, AMS, AIS grade, morphometry, lesion length, surgical technique, steroid protocol, and follow-up AMS were not statistically different between groups treated at different times. We analyzed the effect size of timing of decompression categorically and in a continuous fashion. There was no significant effect of the timing of decompression on follow-up AMS. Only AMS at admission determined AMS at follow-up (coefficient = 0.31; 95% confidence interval [CI]:0.21; p = 0.001). We conclude that timing of decompression in ATCCS caused by spinal stenosis has little bearing on ultimate AMS at follow-up.

Genome-Wide Characterization of SARS-CoV-2 Cytopathogenic Proteins in the Search of Antiviral Targets.

Therapeutic inhibition of critical viral functions is important for curtailing coronavirus disease 2019 (COVID-19). We sought to identify antiviral targets through the genome-wide characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins that are crucial for viral pathogenesis and that cause harmful cytopathogenic effects. All 29 viral proteins were tested in a fission yeast cell-based system using inducible gene expression. Twelve proteins, including eight nonstructural proteins (NSP1, NSP3, NSP4, NSP5, NSP6, NSP13, NSP14, and NSP15) and four accessory proteins (ORF3a, ORF6, ORF7a, and ORF7b), were identified that altered cellular proliferation and integrity and induced cell death. Cell death correlated with the activation of cellular oxidative stress. Of the 12 proteins, ORF3a was chosen for further study in mammalian cells because it plays an important role in viral pathogenesis and its activities are linked to lung tissue damage and a cytokine storm. In human pulmonary and kidney epithelial cells, ORF3a induced cellular oxidative stress associated with apoptosis and necrosis and caused activation of proinflammatory response with production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IFN-ß1, possibly through the activation of nuclear factor kappa B (NF-κB). To further characterize the mechanism, we tested a natural ORF3a Beta variant, Q57H, and a mutant with deletion of the highly conserved residue, ΔG188. Compared with wild-type ORF3a, the ΔG188 variant yielded more robust activation of cellular oxidative stress, cell death, and innate immune response. Since cellular oxidative stress and inflammation contribute to cell death and tissue damage linked to the severity of COVID-19, our findings suggest that ORF3a is a promising, novel therapeutic target against COVID-19. IMPORTANCE The ongoing COVID-19 pandemic caused by SARS-CoV-2 has claimed over 5.5 million lives with more than 300 million people infected worldwide. While vaccines are effective, the emergence of new viral variants could jeopardize vaccine protection. Treatment of COVID-19 by antiviral drugs provides an alternative to battle against the disease. The goal of this study was to identify viral therapeutic targets that can be used in antiviral drug discovery. Utilizing a genome-wide functional analysis in a fission yeast cell-based system, we identified 12 viral candidates, including ORF3a, which cause cellular oxidative stress, inflammation, apoptosis, and necrosis that contribute to cytopathogenicity and COVID-19. Our findings indicate that antiviral agents targeting ORF3a could have a great impact on COVID-19.

HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes.

Successful treatment of HIV-infected patients with combinational antiretroviral therapies (cART) can now prolong patients' lives to nearly normal life spans. However, the new challenge faced by many of those HIV-infected patients is chronic neuroinflammation and neurotoxicity that often leads to HIV-associated neurocognitive disorders (HAND). However, the mechanism of neuropathogenesis underlying HAND, especially in those who are under cART, is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. However, the severity of HAND does not always correlate with HIV-1 viral load but, rather, with the extent of glial activation, suggesting that other HIV-associated factors might contribute to HAND. HIV-1 viral protein R (Vpr) could be one of those viral factors because of its association with neuroinflammation and neurotoxicity. The objective of this study was to delineate the specific roles of HIV-1 infection and Vpr in the activation of neuroinflammation and neurotoxicity, and the possible relationships with the Sur1-Trpm4 channel that contributes to neuroinflammation and neuronal death. Here, we show that HIV-1 expression correlates with activation of proinflammatory markers (TLR4, TNF-α, and NF-κB) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic Tg26 mouse brain tissues. We further show that Vpr alone activates the same set of proinflammatory markers and Sur1 in a glioblastoma SNB19 cell line that is accompanied by apoptosis. The Sur1 inhibitor glibenclamide significantly reduced Vpr-induced apoptosis. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptosis are mediated at least in part through the Sur1-Trpm4 channel in astrocytes.IMPORTANCE Effective antiretroviral therapies can now prolong patients' lives to nearly normal life span. The current challenge faced by many HIV-infected patients is chronic neuroinflammation and neurotoxicity that contributes to HIV-associated neurocognitive disorders (HAND). We show here that the expression of HIV-1 infection and Vpr correlates with the activation of proinflammatory markers (Toll-like receptor 4 [TLR4], tumor necrosis factor alpha [TNF-α], and NF-κB) and the sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel in astrocytes of brain tissues. We further show that an FDA-approved Sur1 inhibitory drug called glibenclamide significantly ameliorates apoptotic astrocytic cell death caused by HIV-1 Vpr, which could potentially open the possibility of repurposing glibenclamide for treating HAND.