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Background: To determine if the density distribution proportion of Hounsfield unit (HUdp) in head computed tomography (HCT) images can be used to quantitatively measure cerebral edema in survivors of out-of-hospital cardiac arrest (OHCA)., Methods: This retrospective observational study included adult comatose OHCA survivors who underwent HCT within 6 h (first) and 72-96 h (second), all performed using the same CT scanner. Semi-automated quantitative analysis was used to identify differences in HUdp at specific HU ranges across the intracranial component based on neurological outcome. Cerebral edema was defined as the increased displacement of the sum of HUdp values (ΔHUdp) at a specific range between two HCT scans. Poor neurological outcome was defined as cerebral performance categories 3-5 at 6 months after OHCA., Results: Twenty-three (42%) out of 55 patients had poor neurological outcome. Significant HUdp differences were observed between good and poor neurological outcomes in the second HCT scan at HU = 1-14, 23-35, and 39-56 (all P < 0.05). Only the ΔHUdp = 23-35 range showed a significant increase and correlation in the poor neurological outcome group (4.90 vs. -0.72, P < 0.001) with the sum of decreases in the other two ranges (r = 0.97, P < 0.001). Multivariate logistic regression analysis demonstrated a significant association between ΔHUdp = 23-35 range and poor neurological outcomes (adjusted OR, 1.12; 95% CI: 1.02-1.24; P = 0.02)., Conclusion: In this cohort study, the increased displacement in ΔHUdp = 23-35 range is independently associated with poor neurological outcome and provides a quantitative assessment of cerebral edema formation in OHCA survivors., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury., (© 2023. The Author(s).)

Poor functional outcome is associated with perihematomal edema (PHE) expansion after intracerebral hemorrhage (ICH). The inflammatory response is crucial for the onset and progression of PHE. This study aimed to determine the connection between admission neutrophil-lymphocyte ratio (NLR) and early PHE development. We retrospectively analyzed patients with ICH admitted to the Chaohu Affiliated Hospital of Anhui Medical University from January 2021 to December 2022. The primary outcome measure was absolute PHE, defined as the volume of the follow-up PHE minus admission PHE. A semiautomated measurement tool (3D Slicer) was used to calculate the volumes of cerebral hematoma and cerebral edema. Spearman's correlation analysis determined the relationship between NLR and absolute PHE. The multiple linear regression model was constructed to analyze the predictive relation of admission NLR on early PHE expansion. A total of 117 patients were included. The median hematoma and PHE volumes on admission were 9.38 mL (interquartile range [IQR], 4.53-19.54) and 3.54 mL (IQR, 1.33-7.1), respectively. The median absolute PHE was 2.26 mL (IQR, 1.25-4.23), and the median NLR was 3.10 (IQR, 2.26-3.86). Spearman's correlation test showed a positive correlation between admission NLR and absolute PHE (r = .548, P < .001). Multiple linear regression analyses suggested that for every 1-unit increase in admission NLR (B = .176, SE = .043, Beta = .275, P < .001), there was a 0.176 mL increase in absolute PHE. Admission neutrophil-to-lymphocyte ratio (NLR) significantly and positively predicted early perihematomal edema (PHE) expansion., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The occurrence of early brain injury (EBI) following subarachnoid hemorrhage (SAH) is crucial in the prognosis of SAH; however, no effective treatment for EBI has been developed. Gut microbiome (GM) composition influences the outcome of various diseases, including ischemic stroke. Here, we evaluated whether prior GM alteration could prevent EBI following SAH. We altered the GM of 7-week-old male rats by administering antibiotic-containing water for 2 weeks and performing fecal microbiome transplantation after antibiotic induction. Composition of the GM was profiled using 16S rRNA. We induced SAH by injecting blood in the subarachnoid space of control rats and rats with altered GM. We evaluated EBI indicators such as neurological score, brain water content, Evans blue extravasation, and neuronal injury. Additionally, we studied inflammatory cells using immunohistochemistry, immunocytochemistry, quantitative PCR, and flow cytometry. EBI was significantly averted by alterations in GM using antibiotics. The altered GM significantly prevented neutrophil infiltration into the brain among inflammatory cells, and this anti-inflammatory effect was observed immediately following SAH onset. The altered GM also prevented neutrophil extracellular trap formation in the brain and blood, indicating the systemic protective effect. The cause of the protective effect was attributed to a significant decrease in aged neutrophils (CXCR4 high CD62L low ) by the altered GM. These protective effects against EBI disappeared when the altered GM was recolonized with normal flora. Our findings demonstrated that EBI following SAH is associated with GM, which regulated neutrophil infiltration., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mucormycosis is a disease caused by fungi of the Mucorales family, widespread in the environment, with pronounced angiotropism and the ability to angioinvasion, leading to thrombosis with surrounding necrosis. The main triggers for the development of mucormycosis are: immunodeficiency states, use of glucocorticosteroid drugs, decompensation of diabetes mellitus, concomitant diseases, age > 65 years. We present a clinical case of rhinocerebral mucormycosis in a 79-year-old patient against the background of uncontrolled type 2 diabetes mellitus with ketoacidosis, a condition after previous glucocorticosteroid therapy for COVID-19 (according to the severity of the disease). After suffering a new coronavirus infection caused by the SARS-CoV-2 virus, she was admitted to the hospital with complaints characteristic of mucormycosis. On the 5 th day of hospital stay, the patient's condition worsened significantly, despite the correction of the therapy, and on the 12 th day the patient died. According to the results of the autopsy, it was established that the rhinocerebral mucormycosis was complicated by thrombosis of the anterior and posterior left cerebral arteries with subsequent infarctions in the frontal lobe and parieto-occipital region of the brain left hemisphere, cerebral edema, which was the immediate cause of death.

Elevated lactate levels are associated with a poor prognosis in patients with sepsis and shock. Intravenous glycerol administration is often used in Japan to treat patients with acute stroke or brain trauma, but such treatment can cause elevated lactate levels. We experienced a case of transient hyperlactatemia induced by intravenous glycerol administration in a patient with brain trauma. A 74-year-old woman underwent decompressive craniotomy because of loss of consciousness and brain edema. Glycerol was administered after the operation for management of the brain edema. Although the patient's hemodynamics remained stable, her lactate level decreased and increased repeatedly. We recognized that the elevation in her lactate level was associated with the administration of intravenous glycerol. This case suggests that intravenous glycerol administration can induce transient hyperlactatemia.

Pediatric patients suffering traumatic brain injuries may require a decompressive craniectomy to accommodate brain swelling by removing a portion of the skull. Once the brain swelling subsides, the preserved calvarial bone flap is ideally replaced as an autograft during a cranioplasty to restore protection of the brain, as it can reintegrate and grow with the patient during immature skeletal development. However, pediatric patients exhibit a high prevalence of calvarial bone flap resorption post-cranioplasty, causing functional and cosmetic morbidity. This review examines possible solutions for mitigating pediatric calvarial bone flap resorption by delineating methods of stimulating mechanosensitive cell populations with mechanical forces. Mechanotransduction plays a critical role in three main cell types involved with calvarial bone repair, including mesenchymal stem cells, osteoblasts, and dural cells, through mechanisms that could be exploited to promote osteogenesis. In particular, physiologically relevant mechanical forces, including substrate deformation, external forces, and ultrasound, can be used as tools to stimulate bone repair in both in vitro and in vivo systems. Ultimately, combating pediatric calvarial flap resorption may require a combinatorial approach using both cell therapy and bioengineering strategies., (© 2023 Wiley Periodicals LLC.)

A 19-year-old woman with known maple syrup urine disease presented to hospital with metabolic crisis in the setting of influenza type A infection and intractable vomiting, rapidly progressing to acute cerebral oedema manifesting as refractory seizures and decreased level of consciousness needing emergency intubation and mechanical ventilation, continuous veno-venous haemodiafiltration and thiopentone coma. A computed tomography scan and magnetic resonance imaging of the brain demonstrated classic signs of cerebral oedema secondary to a metabolic crisis from the metabolic disorder. Her management posed multiple challenges to all teams involved due to lack of familiarity and experience in managing this clinical scenario in the adult intensive care setting., Competing Interests: Declaration of conflicting interestsThe authors declare no conflict of interest with respect to the research, authorship and/or publication.

Objective: This study aimed at studying the challenges and outcomes of live-donor liver transplantation (LDLT) for pediatric acute liver failure (PALF)., Study Design: A total of 315 patients with PALF were treated over a period of 11 years. 42 underwent LT (41 LDLT and one DDLT), constituting 38% (41/110) of all pediatric transplants during this duration. The outcomes of LDLT for PALF were analyzed., Results: All the 41 children who underwent LT met the Kings College criteria (KCC). The etiology was indeterminate in 46.3% (n = 19) children. 75.6% (n = 31) were on mechanical ventilation for grade 3/4 hepatic encephalopathy. There was presence of cerebral edema on a computed tomography scan of the brain in 50% of the children. One-third of our children required hemodynamic support with vasopressors. Systemic inflammatory response syndrome and sepsis were observed in 46.3% and 41.4% of patients, respectively. Post-LDLT 1- and 5-yr patient and graft survival were 75.6% and 70.9%, respectively. The survival in children satisfying KCC but did not undergo LT was 24% (38/161). Vascular and biliary complication rates were 2.4% and 4.8%, respectively. No graft loss occurred because of acute rejection. In multivariate analysis, pre-LT culture positivity and cerebral edema, persistence of brain edema after transplantation, and resultant pulmonary complications were significantly associated with post-LT death. Thirteen (32%) children who underwent plasmapheresis prior to LT had better post-LT neurological recovery, as evidenced by early extubation., Conclusion: LDLT for PALF is lifesaving and provides a unique opportunity to time transplantation. Good long-term survival can be achieved, despite the majority of patients presenting late for transplantation. Early referral and better selection can save more lives through timely transplantation., (© 2023. Asian Pacific Association for the Study of the Liver.)

Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI) 1 . Noradrenaline levels are increased after TBI 2-4 , and the amplitude of the increase in noradrenaline predicts both the extent of injury 5 and the likelihood of mortality 6 . Glymphatic impairment is both a feature of and a contributor to brain injury 7,8 , but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Dialysis is complicated in the setting of acute brain injury (ABI) due to several factors including acute solute shifts, acid base changes, need for anticoagulation, and changes in intracranial pressure. For these reasons, continuous renal replacement therapy (CRRT) is often the chosen modality for renal replacement needs in these patients. Peritoneal dialysis (PD) is less discussed but shares many of the benefits often attributed to CRRT. We describe, from both nephrology and neurosurgical perspectives, a case successfully managed with PD., Case: A 25-year-old male with history of end-stage kidney disease (ESKD) secondary to focal segmental glomerulosclerosis on continuous cycling PD for 5 years presented to the hospital with headache and altered mental status. Initial imaging revealed a large intraventricular hemorrhage extending to the fourth ventricle. He underwent an emergent right depressive hemicraniectomy and clot evacuation. Post-operative imaging revealed worsening cerebral edema, intraventricular hemorrhage, and hydrocephalus. The decision was made to continue PD, noting that it retains many of the benefits of CRRT (which it is in fact, a form of) which he tolerated well until the need for a percutaneous gastrostomy tube arose. He was transiently transitioned to hemodialysis but returned to PD once his gastrostomy healed. He continued PD for 1 year without complication and eventually received a kidney transplant., Discussion: In managing patients with ABI undergoing dialysis, a number of considerations must be undertaken including avoidance of hypotension to maintain cerebral perfusion pressure and minimize ischemia reperfusion injury, avoidance of anticoagulants that can precipitate or worsen bleeding, the potential for cerebral edema due to rapid solute clearance and osmotic dissipation of therapeutic hypernatremia, and the mitigation of intracellular acidosis from bicarbonate delivery. Although underutilized, PD may potentially serve as a viable option for dialysis in the setting of ABI as demonstrated by the case presented.

Aneurysmal subarachnoid hemorrhage is a medical condition that can lead to intracranial hypertension, negatively impacting patients' outcomes. This review article explores the underlying pathophysiology that causes increased intracranial pressure (ICP) during hospitalization. Hydrocephalus, brain swelling, and intracranial hematoma could produce an ICP rise. Although cerebrospinal fluid withdrawal via an external ventricular drain is commonly used, ICP monitoring is not always consistently practiced. Indications for ICP monitoring include neurological deterioration, hydrocephalus, brain swelling, intracranial masses, and the need for cerebrospinal fluid drainage. This review emphasizes the importance of ICP monitoring and presents findings from the Synapse-ICU study, which supports a correlation between ICP monitoring and treatment with better patient outcomes. The review also discusses various therapeutic strategies for managing increased ICP and identifies potential areas for future research., (© 2023. The Author(s).)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cerebral malaria (CM) remains a common cause of death of children in Africa with annual mortality of 400 000. Malarial retinopathy is a unique set of fundus signs which has diagnostic and prognostic value in CM. Assessment of malarial retinopathy is now widely utilised in clinical care, and routinely incorporated into clinical studies to refine entry criteria. As a visible part of the central nervous system, the retina provides insights into the pathophysiology of this infectious small-vessel vasculitis with adherent parasitised red blood cells. Fluorescein angiography and optical coherence tomography (OCT) have shown that patchy capillary non-perfusion is common and causes ischaemic changes in the retina in CM. It is likely this is mirrored in the brain and may cause global neurological impairments evident on developmental follow up. Three types of blood-retina barrier breakdown are evident: large focal, punctate, and vessel leak. Punctate and large focal leak (haemorrhage in formation) are associated with severe brain swelling and fatal outcome. Vessel leak and capillary non-perfusion are associated with moderate brain swelling and neurological sequelae. These findings imply that death and neurological sequelae have separate mechanisms and are not a continuum of severity. Each haemorrhage causes a temporary uncontrolled outflow of fluid into the tissue. The rapid accumulation of haemorrhages, as evidenced by multiple focal leaks, is a proposed mechanism of severe brain swelling, and death. Current studies aim to use optic nerve head OCT to identify patients with severe brain swelling, and macula OCT to identify those at risk of neurological sequelae., (© 2023. The Author(s).)

Background /objective: Acute kidney injury (AKI) is a significant complication in critical care units (CCU). Non-neurological complications such as AKI are an independent predictor of poor clinical outcomes, with an increase in morbidity and mortality, financial costs, and worse functional recovery. This work aims to estimate the incidence of AKI and evaluate the risk factors and complications of AKI in neurocritical patients hospitalized in the CCU., Methods: A retrospective cohort study was conducted. Patients admitted to the neurocritical care unit between 2016 and 2018 with a stay longer than 48 h were retrospectively analyzed in regard to the incidence, risk factors, and outcomes of AKI., Results: The study population comprised 213 neurocritical patients. The incidence of AKI was 23.5%, with 58% KDIGO 1 and 2% requiring renal replacement therapy. AKI was an independent predictor of prolonged use of mechanical ventilation, cerebral edema, and mortality. Cerebral edema [OR 4.40 (95% CI 1.98-9.75) p < 0.001] and a change in chloride levels greater than 4 mmol/L at 48 h (OR 2.44 (95% CI 1.10-5.37) p = 0.027) were risk factors for developing AKI in the first 14 days of hospitalization., Conclusion: There is a high incidence of AKI in neurocritical patients; it is associated with worse clinical outcomes regardless of the CCU admission etiology or AKI severity., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background/objective: Hypertonic sodium chloride (HTS) is used for emergent treatment of acute cerebral edema and other neurologic emergencies. Central access is not commonly available in emergent situations and 3% HTS is utilized peripherally. Many studies have shown the safety of its administration at rates up to 75 mL/h, but there is a lack of data to establish the safety of peripherally administered, rapid bolus dosing in emergent situations. The objective of this study is to describe the safety of rapid, peripherally administered (≥ 250 mL/h) 3% HTS for neurologic emergencies., Methods: This is a retrospective, cohort study including adult patients receiving 3% HTS via a peripheral IV site for elevated intracranial pressure, cerebral edema, or other neurological emergencies at a rate of at least 250 m/h between May 5, 2018 - September 30, 2021. Patients were excluded if they simultaneously received another hypertonic saline fluid. Baseline characteristics collected included HTS dose, rate and site of administration, indication for use and patient demographics. The primary safety outcome was incidence of extravasation and phlebitis within one hour of HTS administration., Results: There were 206 patients receiving 3% HTS who were screened, and 37 patients met inclusion criteria. The most common reason for exclusion was administration at a rate < 250 m/h. The median age was 60 (IQR 45, 72) with 51.4% being male. The most common indications for HTS were traumatic brain injury (45.9%) and intracranial hemorrhage (37.8%). The most common administration location was the emergency department (78.4%). The median IV-gauge (n = 29) was 18 (IQR 18, 20), with the most common placement site being antecubital (48.6%). The median dose of HTS was 250 mL (IQR 250, 350), with a median administration rate of 760 mL/h (IQR 500, 999). There were no episodes of extravasation or phlebitis noted., Conclusions: Rapid, peripheral administration of 3% HTS boluses is a safe alternative for treatment of neurologic emergencies. Administration at rates up to 999 mL/h did not result in extravasation or phlebitis., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest related to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

With advances and developments in hysteroscopy, cystoscopy, transurethral resection of bladder tumor, and arthroscopy, transurethral resection of prostate (TURP) syndrome has been increasingly reported. TURP syndrome is often accompanied by severe hyponatremia, fluid overload, and a plasma hypotonic state, resulting in heart failure and pulmonary and cerebral edema. Conventional treatment methods, such as intravenous infusion of hyperosmotic saline, can rapidly reverse the downward trend of serum sodium levels in efforts to prevent and treat cerebral edema. However, this may not be suitable for patients with cardiac and renal insufficiency and may induce central pontine myelinolysis due to the possibility of worsening volume load and difficulty in controlling the correction rate of serum sodium. The patient described in this report presented with severe hyponatremia (sodium<100 mmol/L) combined with intraoperative pulmonary edema; his cardiac function and oxygenation status deteriorated after an intravenous infusion of 3% hypertonic saline. He underwent continuous renal replacement therapy (CRRT) to prevent the progression of multiple-organ edema and cardiac insufficiency. CRRT has demonstrated efficacy in the treatment of chronic hyponatremia in patients with renal failure, and can slowly and continuously correct water-electrolyte imbalance, acid-base imbalance, and volume overload. TURP syndrome with severe hyponatremia and pulmonary edema was diagnosed; accordingly, the patient was treated with 3% hypertonic saline, furosemide, and CRRT, without the development of overt neurological sequelae., (Copyright © 2022 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Background: Malignant cerebral edema (MCE) is a common and feared complication after endovascular thrombectomy (EVT) in acute ischemic stroke (AIS). This study aimed to establish a nomogram to predict MCE in anterior circulation large vessel occlusion stroke (LVOS) patients receiving EVT in order to guide the postoperative medical care in the acute phase., Methods: In this retrospective cohort study, 381 patients with anterior circulation LVOS receiving EVT were screened from 636 hospitalized patients with LVOS at 2 stroke medical centers. Clinical baseline data and imaging data were collected within 2-5 days of admission to the hospital. The patients were divided into 2 groups based on whether MCE occurred after EVT. Multivariate logistic regression analysis was used to evaluate the independent risk factors for MCE and to establish a nomogram., Results: Sixty-six patients out of 381 (17.32%) developed MCE. The independent risk factors for MCE included admission National Institutes of Health Stroke Scale (NIHSS) ≥16 (odds ratio [OR] 1.851; 95% CI 1.029-3.329; P = 0.038), ASPECT score (OR 0.621; 95% CI 0.519-0.744; P < 0.001), right hemisphere (OR 1.636; 95% CI 0.941-2.843; P = 0.079), collateral circulation (OR 0.155; 95% CI 0.074-0.324; P < 0.001), recanalization (OR 0.223; 95% CI 0.109-0.457; P < 0.001), hematocrit (OR, 0.937; 95% CI: 0.892-0.985; P =0.010), and glucose (OR 1.118; 95% CI 1.023-1.223; P = 0.036), which were adopted as parameters of the nomogram. The receiver operating characteristic curve analysis showed that the area under the curve of the nomogram in predicting MCE was 0.901(95% CI 0.848-0.940; P < 0.001). The Hosmer-Lemeshow test results were not significant (P = 0.685), demonstrating a good calibration of the nomogram., Conclusions: The novel nomogram composed of admission NIHSS, ASPECT scores, right hemisphere, collateral circulation, recanalization, hematocrit, and serum glucose provide a potential predictor for MCE in patients with AIS after EVT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Sepsis-associated encephalopathy (SAE), characterized by cognitive and emotional impairments, is not well investigated in sepsis survivors. Growth arrest-specific gene 6 (Gas6) has been extensively used to treat cerebral diseases. This study aimed to evaluate the neuroprotective effects of Gas6 in post-septic mice and to determine the underlying mechanisms of action., Methods: Mice underwent cecal ligation and puncture (CLP) for sepsis induction. Mice were then immediately injected with 6 µg of Gas6 via the tail vein, and the effect was evaluated after 24 hours. The neurological severity score (NSS) was used to assess neurological deficits in post-septic mice. In addition, brain edema was evaluated by measuring the brain water content and blood-brain barrier (BBB) permeability using Evans blue (EB) dye extravasation. Western blotting and immunofluorescence assays were performed to determine the expression of tight junction (TJ)-associated proteins such as occludin and zonula occludens-1 (ZO-1)., Results: Post-septic mice exhibited increased NSS, brain edema, and BBB permeability. However, acute Gas6 treatment attenuated the severe effects of sepsis on neurologic function in mice. Therefore, Gas6 attenuates brain edema and restores BBB permeability. These findings suggest that Gas6 could alleviate neurological deficits, brain edema, BBB damage, and reverse the decreased expression of occludin and ZO-1 in the brain tissue to protect against SAE., Conclusion: Gas6 protects against SAE by restoring the impaired BBB permeability., (© 2023 by the Association of Clinical Scientists, Inc.)

Nonhepatic hyperammonemia syndrome is a rare cause of neurologic dysfunction and cerebral edema and has most commonly been reported in posttransplant patients. Only recently has opportunistic infection with Ureaplasma species and Mycoplasma hominis been found to be key to the pathogenesis. We describe the cases of 3 immunosuppressed patients who developed hyperammonemia syndrome with new-onset refractory status epilepticus and diffuse cerebral edema. PCR was positive for M hominis in 1 patient and Ureaplasma parvum in the other 2. Despite early diagnostic suspicion and aggressive management with empirical antibiotics, seizure control, hypertonic saline, and ammonia elimination, none of our patients survived this life-threatening infection. Nonhepatic hyperammonemia and new-onset seizures can be presenting features of disseminated Ureaplasma species and M hominis infections in posttransplant patients. Immunosuppression in the absence of organ transplantation is likely sufficient to trigger this entity, as was the case in our third patient. When suspected, empiric combination antibiotics should be used due to high likelihood of resistance. The diagnostic test of choice is PCR. Patients with hyperammonemia syndrome associated with these infections typically have a poor prognosis. Early recognition and aggressive multimodal interventions may be key to ameliorating the high mortality and severe neurologic sequelae from this entity., (© 2022 American Academy of Neurology.)

Changes in serum sodium concentrations are frequently encountered by anesthesiologists, are complex and are often inadequately treated. Feared consequences include neurological complications, such as cerebral hemorrhage, cerebral edema and coma. Dysnatremia is always accompanied disturbances in the water balance. Accordingly, these are routinely classified based on the tonicity; however, in the daily routine and especially in the acute setting, the volume status and extracellular volume are often difficult to assess. Severe symptomatic hyponatremia with impending cerebral edema is treated by administration of hypertonic saline solution. If the rise in serum sodium is too rapid, there is a risk of central pontine myelinolysis. In a second step, the cause of the hyponatremia can be investigated and the appropriate treatment can be initiated. In the case of hypernatremia, the etiology of the disorder must be clarified before treatment. The goal is to compensate for the water deficiency by correcting the cause, specific volume therapy and, if necessary, drug support. A slow and controlled compensation must be closely monitored in order to avoid neurological complications. An algorithm has been developed that provides an overview of the dysnatremias, aids with making the diagnosis and gives recommendations for treatment measures in the clinical routine., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship., Methods: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift., Results: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (β = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results., Interpretation: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804., (© 2022 American Neurological Association.)

Background and Objectives: Perihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from 2 centers, we sought to determine whether sST2 was associated with functional outcome, PHE, and the immune response following IPH., Methods: Patients with deep IPH were enrolled within 36 hours of ictus, and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as a modified Rankin Scale score of 0-3 at 90 days. Linear mixed-effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region., Results: The 55 included patients had a median admission Glasgow Coma Scale score of 14 (interquartile range [IQR] 9-15), an intracerebral hemorrhage (ICH) score of 1 (IQR 1-2), and a hematoma volume of 8.6 mL (IQR 3.4-13.8 mL). Receiver operating curve analysis found the sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632-0.894) and Youden optimum cut point of 61.8 ng/mL ( p < 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted odds ratio 2.53, 95% CI 1.03-6.19, p = 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (β = 1.07, 95% CI 0.51-1.63, p < 0.001). High sST2 was associated with a shift toward an innate peripheral immune response (monocytes and natural killer cells; 68.6% ± 5.1% vs 47.5% ± 4.0%; p = 0.003)., Discussion: Our findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify patients with IPH at highest risk for immune-mediated injury or limit injury through targeted interventions., (© 2022 American Academy of Neurology.)

Introduction: In infants who have suffered head trauma there are two possible explanations for retinal hemorrhage (RH): direct vitreous shaking and occurrence in association with intracranial lesions. Which possibility is more plausible was examined., Material and Methods: This multicenter, retrospective study reviewed the clinical records of children younger than four years with head trauma who had been diagnosed with any findings on head computed tomography (CT) and/or magnetic resonance imaging (MRI). Of 452 cases, 239 underwent an ophthalmological examination and were included in this study. The relationships of RH with intracranial findings and the cause of injury were examined., Result: Odds ratios for RH were significant for subdural hematoma (OR 23.41, p = 0.0004), brain edema (OR 5.46, p = 0.0095), nonaccidental (OR 11.26, p<0.0001), and self-inflicted falls (OR 6.22, p = 0.0041)., Conclusion: Although nonaccidental, brain edema and self-inflicted falls were associated with RH, subdural hematoma was most strongly associated with RH., Competing Interests: Masahiro Nonaka and Young-Soo Park have written statements and appeared in court in child abuse cases both on the request of the prosecutor and the defense. Atsuko Harada has written statements and appeared in court in child abuse cases on the request of the prosecutor. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Kato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain's myeloid cells for the treatment of ICH., (© 2023. The Author(s).)

Introduction: Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature., Methods: A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with "brain tumors", "brain edema" and "animal models"., Results: We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof., Conclusion: No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models., (© 2023. The Author(s).)

Background: Peritumoral brain edema (PTBE) is a common complication related to intracranial meningiomas. In several studies, researchers have investigated the pathogenesis of PTBE, and the factors involved in its development in patients with intracranial meningiomas have been reported. However, very little is known about the clinical effect of PTBE on patients with intracranial meningiomas; therefore, a systematic examination of this matter is necessary., Methods: In this study, we performed a systematic examination of 696 patients with primary intracranial meningiomas to assess the effect of preoperative PTBE on preoperative symptoms, neurological deficits and postoperative complications, and long-term outcomes with a follow-up period of 16.8 years. We performed a univariate analysis and multiple regression for specific outcomes and adjusted for other relevant clinical factors., Results: A total of 627 (90.1%) patients were symptomatic preoperatively. One hundred eighty-eight (90.8%) patients with small to moderate PTBE and 125 (98.4%) patients with severe PTBE presented with symptoms significantly more often than the 314 (86.7%) patients without PTBE (p < 0.001, univariate analysis). Cognitive deficits, palsy and seizure were significantly more present, preoperatively, in patients with PTBE than in patients without PTBE (p < 0.001, univariate analysis). Two hundred fifty-five (36.6%) patients experienced surgical and systemic complications postoperatively. The complication rate was significantly higher in patients with PTBE; 41.5% for patients with small to moderate PTBE and 52.8% for patients with severe PTBE, compared to 28.2% of patients without PTBE (p < 0.001, univariate analysis). Furthermore, pre- and postoperative KPS scores were significantly lower in patients with PTBE (p < 0.001). Patients with PTBE required additional medical support significantly more often (p < 0.001) and had a significantly longer hospital stay (p < 0.001). The mortality rate was higher in patients with PTBE immediately after surgery and in the follow-up period; however, the difference was not significant. The neurological condition of all patients improved in the follow-up and did not show significant differences between patients with and without preoperative PTBE (p = 0.6361). Multiple logistic regression analyses revealed a significant association between PTBE and the presence of preoperative cognitive deficits, the incidences of seizure and postoperative complications, and low pre- and postoperative KPS scores., Conclusions: Preoperative PTBE significantly increased the incidences of specific preoperative symptoms, neurological deficits and postoperative complications in patients with intracranial meningiomas. After surgery, patients with preoperative PTBE required medical support significantly more often than patients without PTBE. However, all patients had favorable outcomes after surgery., (© 2023. The Author(s).)

Aim: To evaluate the association between global cerebral edema (GCE) after subarachnoid hemorrhage (SAH) and its impact on functional outcome evaluated by the modified Rankin scale (mRS)., Material and Methods: This is a prospective cohort study with patients who were admitted to the hospital due to SAH. During the period from January 2018 to November 2019, 107 patients with intracranial aneurysms were enrolled. Using univariate and multivariate analysis, we sought to identify predictors and evaluated the impact of GCE on outcome after 6 months using the mRS., Results: GCE was present in 54 (50.5%) patients, of which 27 (25.2%) were mild, 20 (18.7%) moderate and 7 (6.5%) were severe. Univariate analysis identified high Hunt-Hess and Glasgow coma scale on clinical admission as predictors factors of GCE (p < 0.05), and higher modified Fisher scale as a radiological predictor of Glasgow coma scale (p < 0.05). Thirty-three (30.8%) patients were deceased at 6 months. Death or severe disability were predicted by higher age, poor clinical scale on admission and severe GCE (p < 0.05)., Conclusion: GCE on admission is independently associated with poor clinical outcomes at discharge, and six months after SAH. Given its strong association with poor clinical grade on admission, GCE should be considered a straightforward and radiological important marker of early brain injury, with ominous implications.

After orthotopic lung transplantation, hyperammonemia can be a rare complication secondary to infection by organisms that produce urease or inhibit the urea cycle. This can cause neurotoxicity, cerebral edema, and seizures. Ammonia is unique in that it has a large volume of distribution. However, it is also readily dialyzable given its small molecular weight. As such, removal of ammonia requires renal replacement modalities that can both rapidly remove ammonia from the plasma space and allow for continuous removal to prevent rebound accumulation from intracellular stores. Prevention of iatrogenic osmotic lowering in this setting is required to prevent worsening of cerebral edema. Herein, we describe use of sequential in-line renal replacement therapy using both intermittent hemodialysis and continuous venovenous hemofiltration within an extracorporeal membrane oxygenation circuit in conjunction with higher sodium dialysate and 7.5% hypertonic saline to achieve these treatment goals.

We have previously shown that selective inhibition of histone deacetylase 3 (HDAC3) decreases infarct volume and improves long-term functional outcomes after stroke. In this study, we examined the effects of HDAC3 inhibition on cerebral edema and blood-brain barrier (BBB) leakage and explored its underlying mechanisms. Adult male Wistar rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and randomly treated i.p. with either vehicle or a selective HDAC3 inhibitor (RGFP966) at 2 and 24 h after stroke. Modified neurological severity scores (mNSS) were calculated at 2 h, 1 day, and 3 days. H&E, Evans blue dye (EBD) assay, and fluorescein isothiocyanate (FITC)-dextran were employed to assess cerebral edema and BBB leakage. Western blot for matrix metalloproteinase-9 (MMP9), MMP-9 zymography, and immunostaining for HDAC3, GFAP, Iba-1, albumin, aquaporin-4, claudin-5, ZO-1, and NF-kB were performed. Early RGFP966 administration decreased cerebral edema (p = 0.002) and BBB leakage, as measured by EBD assay, FITC-dextran, and albumin extravasation (p < 0.01). RGFP966 significantly increased tight junction proteins (claudin-5 and ZO-1) in the peri-infarct area. RGFP966 also significantly decreased HDAC3 in GFAP + astrocytes, which correlated with better mNSS (r = 0.67, p = 0.03) and decreased cerebral edema (r = 0.64, p = 0.04). RGFP966 decreased aquaporin-4 in GFAP + astrocytes (p = 0.002), as well as, the inflammatory markers Iba-1, NF-kB, and MMP9 in the ischemic brain (p < 0.05). Early HDAC3 inhibition decreases cerebral edema and BBB leakage. BBB protection by RGFP966 is mediated in part by the upregulation of tight junction proteins, downregulation of aquaporin-4 and HDAC3 in astrocytes, and decreased neuroinflammation., (© 2022. The Author(s).)

Background: Mild hypothermia has been identified to reduce brain injury following intracerebral hemorrhage (ICH) by protecting neuron cells through several pathways. However, the role of hypothermia in brain function following ICH and the related mechanisms have not been well identified. Ubiquitination-mediated inflammation plays important roles in the pathogenesis of immune diseases. The experiment analyzed anti-inflammatory effects of mild hypothermia following ICH., Methods: The model of ICH was induced by injecting autologous blood. Neuregulin receptor degradation protein-1 (Nrdp1) and downstream molecule were analyzed. In addition, brain inflammatory response, brain edema, and neurological functions of ICH mice were also assessed., Results: We found that mild hypothermia attenuated proinflammatory factors production after ICH. Mild hypothermia significantly inhibited BBB injury, water content, and neurological damage following ICH in vivo. Moreover, mild hypothermia also increased Nrdp1/MyD88 levels and thus affect neuronal apoptosis and inflammation., Conclusions: Taken together, these results suggest that mild hypothermia can attenuate the neuroinflammatory response and neuronal apoptosis after ICH through the regulation of the Nrdp1 levels., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Post-resuscitation cerebral ischemia-reperfusion injury (IRI) is a vital contributor to poor neurological prognosis. Exploring novel therapeutics that attenuate cerebral IRI is of great significance. Inflammation plays a role in the development of cerebral IRI after successful cardiopulmonary resuscitation (CPR). Monoacylglycerol lipase (MAGL) is an enzyme that is predominantly responsible for the metabolism of endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) metabolites, which are associated with inflammation. Therefore, we investigated the efficacy of the MAGL inhibitor, JZL184, on cerebral IRI and further compared the effects to therapeutic hypothermia (TH). Thirty-six rats were randomized into three groups: 1) JZL184; 2) Control; 3) TH (N = 12 for each group). Animals underwent 6 min of ventricular fibrillation (VF) followed with 8 min of CPR. After return of spontaneous circulation (ROSC), rats received an intraperitoneal injection of JZL184 (16 mg/kg) or DMSO (20 mg/ml) or body cooling was initiated. Cerebral microcirculation, brain edema, blood brain barrier (BBB) permeability, serum neuron-specific enolase (NSE), S-100β, interleukin-6 (IL-6) and interleukin-10 (IL-10) were quantified at 6 h post ROSC. Compared to control, treatment with JZL184 or TH was associated with significantly ameliorated cerebral microcirculation, mitigated brain edema, attenuated BBB permeability, decreased serum levels of NSE, S-100β and IL-6, and increased serum IL-10 levels (p < 0.05). There was no significant difference in the above measurements between JZL184 and TH. JZL184 has comparable neuroprotective effects to therapeutic hypothermia on global cerebral IRI in a rat model of cardiac arrest (CA)., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

High-altitude cerebral edema (HACE), a potentially lethal disease, is associated with a time-dependent exposure to altitude-related hypobaric hypoxia (HH) and has reportedly been associated with microglia hyperactivation. Catechins are substances with good antioxidant properties, among which (-)-epigallocatechin gallate (EGCG) may play a neuroprotective role through the inhibition of microglia overactivation; however, the function of its analog- (-)-epicatechin gallate (ECG)-requires further elucidation. The aim of the present study was to investigate whether ECG prevented HACE by inhibiting HH-activated microglia. Primary microglia exposed to lipopolysaccharide (LPS)/ATP were co-treated with EGCG, ECG, and (-)-epigallocatechin, and ECG and EGCG exerted significant anti-inflammatory and neuroprotective effects. ECG inhibited the NF-κB pathway to prevent the activation of microglia induced by 1% O 2 . In addition, ECG ameliorated the increase in brain water content and aquaporin 4 expression induced by HH in mice. ECG also reduced the number of Iba1 + microglia in the brain, the release of proinflammatory factors, and the recruitment of microglia to blood vessels in HH-exposed mice. The outcomes of the present study revealed that ECG alleviated hypoxic hyperactivated microglia, reduced the neuroinflammation and blood-brain barrier permeability, and prevented HACE by inhibiting NF-κB signaling., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: High-altitude cerebral edema (HACE) is a serious and potentially fatal brain injury that is caused by acute hypobaric hypoxia (HH) exposure. Vasogenic edema is the main pathological factor of this condition. Hypoxia-induced disruptions of tight junctions in the endothelium trigger blood‒brain barrier (BBB) damage and induce vasogenic edema. Nuclear respiratory factor 1 (NRF1) acts as a major regulator of hypoxia-induced endothelial cell injury, and caveolin-1 (CAV-1) is upregulated as its downstream gene in hypoxic endothelial cells. This study aimed to investigate whether CAV-1 is involved in HACE progression and the underlying mechanism., Methods: C57BL/6 mice were exposed to HH (7600 m above sea level) for 24 h, and BBB injury was assessed by brain water content, Evans blue staining and FITC-dextran leakage. Immunofluorescence, transmission electron microscope, transendothelial electrical resistance (TEER), transcytosis assays, and western blotting were performed to confirm the role and underlying mechanism of CAV-1 in the disruption of tight junctions and BBB permeability. Mice or bEnd.3 cells were pretreated with MβCD, a specific blocker of CAV-1, and the effect of CAV-1 on claudin-5 internalization under hypoxic conditions was detected by immunofluorescence, western blotting, and TEER. The expression of NRF1 was knocked down, and the regulation of CAV-1 by NRF1 under hypoxic conditions was examined by qPCR, western blotting, and immunofluorescence., Results: The BBB was severely damaged and was accompanied by a significant loss of vascular tight junction proteins in HACE mice. CAV-1 was significantly upregulated in endothelial cells, and claudin-5 explicitly colocalized with CAV-1. During the in vitro experiments, hypoxia increased cell permeability, CAV-1 expression, and claudin-5 internalization and downregulated tight junction proteins. Simultaneously, hypoxia induced the upregulation of CAV-1 by activating NRF1. Blocking CAV-1-mediated intracellular transport improved the integrity of TJs in hypoxic endothelial cells and effectively inhibited the increase in BBB permeability and brain water content in HH animals., Conclusions: Hypoxia upregulated CAV-1 transcription via the activation of NRF1 in endothelial cells, thus inducing the internalization and autophagic degradation of claudin-5. These effects lead to the destruction of the BBB and trigger HACE. Therefore, CAV-1 may be a potential therapeutic target for HACE. Video abstract., (© 2022. The Author(s).)

Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, and histological examination were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion. Here, in rat model of cardiac arrest with brain edema combined with neuroinflammation, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Of note, the above effects of GLB could be achieved by knockdown of Trpm4. In vitro under circumstance of eliminating distractions from brain edema, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca 2+ influx, which in turn magnified the K + efflux via the Na + influx-driven opening of K + channels, leading to the NLRP3 inflammasome activation. These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K + efflux and promotes NLRP3 inflammasome activation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Conflicting data exist regarding the association of perihematomal edema (PHE) with outcomes after intracerebral hemorrhage (ICH). We performed a post hoc analysis of the ICH Deferoxamine trial to examine whether an early change in ventricular size (VS), as a composite measure of PHE growth and mass effect, intraventricular hemorrhage, and hydrocephalus, is a more accurate predictor of outcome than PHE measures alone., Methods: Computerized tomography scans were performed at baseline and after 72-96 h. We evaluated measures of PHE and change in VS as predictors of outcome, assessed by a dichotomized modified Rankin Scale score (0-2 versus 3-6), primarily at 90 days and secondarily at 30 days. A multivariable logistic regression model was fitted for each predictor, with adjustment for the same confounders., Results: A total of 248 participants were included after we excluded those requiring external ventricular drains. On univariate analyses, older age, female sex, lower Glasgow Coma Scale score and baseline temperature, greater ICH volume, absolute PHE volume, edema extension distance at presentation, lesser changes in relative PHE volume and edema extension distance, and an increase in VS were associated with poor outcome. In multivariable analyses, only the increase in VS was associated with lower odds of modified Rankin Scale scores 0-2 at 90 days (odds ratio 0.927, 95% confidence interval 0.866-0.970, p = 0.001) and 30 days (odds ratio 0.931, 95% confidence interval 0.888-0.975, p = 0.003)., Conclusions: Within the context of a randomized controlled trial with standardized imaging and functional assessments, we did not find significant associations between measures of PHE and outcome but documented an independent association between early increase in VS and lower odds of good clinical outcome., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

High-altitude cerebral edema (HACE) is a potentially fatal encephalopathy associated with a time-dependent exposure to the hypobaric hypoxia of altitude. The formation of HACE is affected by both vasogenic and cytotoxic edema. The over-activated microglia potentiate the damage of blood-brain barrier (BBB) and exacerbate cytotoxic edema. In light with the activation of microglia in HACE, we aimed to investigate whether the over-activated microglia were the key turning point of acute mountain sickness to HACE. In in vivo experiments, by exposing mice to hypobaric hypoxia (7000 m above sea level) to induce HACE model, we found that microglia were activated and migrated to blood vessels. Microglia depletion by PLX5622 obviously relieved brain edema. In in vitro experiments, we found that hypoxia induced cultured microglial activation, leading to the destruction of endothelial tight junction and astrocyte swelling. Up-regulated nuclear respiratory factor 1 (NRF1) accelerated pro-inflammatory factors through transcriptional regulation on nuclear factor kappa B p65 (NF-κB p65) and mitochondrial transcription factor A (TFAM) in activated microglia under hypoxia. NRF1 also up-regulated phagocytosis by transcriptional regulation on caveolin-1 (CAV-1) and adaptor-related protein complex 2 subunit beta (AP2B1). The present study reveals a new mechanism in HACE: hypoxia over-activates microglia through up-regulation of NRF1, which both induces inflammatory response through transcriptionally activating NF-κB p65 and TFAM, and enhances phagocytic function through up-regulation of CAV-1 and AP2B1; hypoxia-activated microglia destroy the integrity of BBB and release pro-inflammatory factors that eventually induce HACE., (© The Author(s) (2022). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Background: Brain oedema after cardiac arrest is strongly associated with poor neurological outcomes. Excessive sodium supplementation may increase serum osmolarity and facilitate brain oedema development in cardiac arrest survivors. We aimed to investigate the association of serum sodium levels with long-term neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors., Methods: This retrospective observational study used a multicentre prospective cohort registry of OHCA survivors collected between December 2013 and February 2018. We analyzed the association of serum sodium levels at the return of spontaneous circulation (ROSC) (Sodium 0H) and at 24 h after ROSC (Sodium 24H) with 1-year neurological outcomes in OHCA survivors. Patients with 1-year cerebral performance categories (CPC) 1 and 2 were included in the good outcome group while those with CPC 3, 4, and 5 were included in the poor outcome group., Results: Among 277 patients, 84 (30.3%) and 193 (69.7%) were in the good and poor outcome groups, respectively. Compared with the good outcome group, the poor outcome group showed significantly higher Sodium 24H levels (140 mEq/L vs. 137.4 mEq/L, p < 0.001). Increased serum sodium levels per 1 mEq/L increased the risk of poor 1-year CPC by 13% (adjusted odds ratio = 1.13; 95% CI, 1.04⎼1.23; p = 0.004)., Conclusions: Relatively high Sodium 24H levels showed a strong and independent association with poor long-term neurological outcomes in OHCA survivors. These findings may be applied in therapeutic strategies for improving neurological outcomes in OHCA survivors., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Hemorrhagic shock and encephalopathy syndrome (HSES) is a severe subtype of acute encephalopathy with a poor prognosis. The factors associated with acute neurological outcomes in patients with HSES remain unclear. This study aimed to determine the clinical features, laboratory and radiological findings, and treatments that determine the acute outcomes of HSES., Methods: Forty children with HSES registered in a database of Osaka City General Hospital between 1995 and 2020 were included in this observational study. We retrospectively collected data on clinical features, laboratory and radiological items, and treatments. We divided acute neurological outcomes into two groups: the non-death and death groups in 1 week. Correlations were assessed between these items and acute neurological outcomes., Results: Twenty-seven and 13 patients comprised the non-death and death groups, respectively. Univariate logistic regression analysis showed that higher body temperature, presence of hemorrhagic episode, elevated lactate level, high glucose level in the cerebrospinal fluid, and brain edema at initial computed tomography (CT) were correlated with the death group. Regarding treatments, barbiturate therapy, intravenous immunoglobulin, and intravenous methylprednisolone were significantly initiated in the non-death group. The multivariate logistic regression model showed higher body temperature (odds ratio [OR], 4.210 [1.409-12.584]; p = 0.010) and brain edema on initial head CT (OR, 46.917 [3.995-550.976]; p = 0.002) were independent factors., Conclusions: Higher body temperature and brain edema at the onset of HSES were associated with acute outcomes. The results of this study may be useful for treatment planning and acute outcomes in patients with HSES., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sphenoidal meningiomas constitute 18% of intracranial masses, and still present a difficult surgical challenge. PTBE has been associated with several complications and future recurrence. This study aims to evaluate the outcome of the operatively treated sphenoid wing meningiomas in relation to PTBE as a prognostic factor in a series of 65 patients. The clinical materials of 65 patients with SWM treated microsurgically between 2007 and 2020 were analyzed retrospectively. Follow-up ranged from 6 to 156 months (median, 86). Clinical outcomes include postoperative major neurological deficit, quality of life using KPS, recurrence, and mortality rates. The mean age of patients was 53.9 years (range 20-74), males 24.6% and females75.4%. An edema index (EI) of 1 (40%) was considered as absent edema, and EI > 1 (60%) indicated present edema. Total resection (Simpson I-II) was achieved in 64.6% and subtotal (Simpson IV) in 13.8%. Postoperative complications included vision impairment in 3 patients, motor weakness 6, third nerve palsy 6, intraoperative bleeding and edema 5, and MCA infarct 2, recurrence in 17% and 7.7% died. In univariate analysis, we found that the PTBE is one of the serious risk factors in the immediate surgical outcomes and complication, though more data is needed to support this claim, while having a negative effect on postoperative KPS at short-term follow up (χ 2  = 6.44, p = 0.011). PTBE was associated with decline in KPS and quality of life in the early postoperative period (three months) while showing no significant effect at long-term outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI., Methods: We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries., Results: Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10 -8 ). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818., Conclusions: We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Vitamin D (VD) deficiency is associated with neuroinflammation and neurocognitive deficits in patients with traumatic brain injury (TBI). The present study was aimed at investigating the therapeutic effects of VD and the molecular mechanisms after TBI. After the intraperitoneal injection of VD (1  μ g/kg), sensorimotor and cognitive function was assessed via a series of behavioral tests in TBI rats. Traumatic outcomes were investigated by brain edema, blood-brain barrier (BBB) disruption, and morphologic staining. In vitro, cellular viability and cytotoxicity in primary hippocampal neurons were detected via the MTT method and LDH release. Hippocampal oxidative stress-related enzymes and proinflammatory mediators and the serum concentration of VD were analyzed by ELISA. The expression of VDR, TLR4, MyD88, and NF- κ B p65 was measured by Western blot. Furthermore, the levels of M1/M2 microglial markers were quantified using real-time PCR and Western blot. VD treatment significantly increased the serum level of VD and the hippocampal expression of VDR. VD not only effectively alleviated neurocognitive deficits, brain edema, and BBB disruption but also promoted hippocampal neuronal survival in vivo and in vitro. Moreover, VD therapy prevented excessive neuroinflammation and oxidative stress caused by TBI. Mechanically, the hippocampal expression of TLR4, MyD88, and nuclear NF- κ B p65 was elevated in the TBI group but robustly restrained by VD treatment. Taken together, VD provides an important neuroprotection through modulating hippocampal microglial M2 polarization and neuroinflammation via the TLR4/MyD88/NF- κ B pathway., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Hongsheng Jiang et al.)

Spontaneous intracerebral hemorrhage (ICH) is associated with high mortality and disability rates. The microglia-induced inflammatory response is a critical factor determining brain tissue damage after ICH. Raddeanin A (RA) is a natural triterpenoid compound with anti-inflammatory effects, although its effects on ICH and the underlying molecular mechanism have not been elucidated. In this study, we found that RA reduced the volume of cerebral hematoma and cerebral edema, attenuated neuronal apoptosis and improved the behavioral indices in a murine model of acute cerebral hemorrhage. Mechanistically, RA downregulated the TLR4-mediated pro-inflammatory effectors, reduced infiltration of microglia in peri-intracerebral hemorrhage and inhibited apoptosis of neurons co-cultured with activated microglia. In conclusion, RA can alleviate ICH-related tissue damage and promote the recovery of neuronal function by suppressing microglia-induced inflammation and apoptosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Periostin is found associated with trauma severity and mortality following head injury. In this study, the role and mechanism of periostin in the traumatic brain injury were investigated., Methods: Male Sprague-Dawley adult rats underwent sham or TBI modeling. Vehicle or recombinant periostin was administered intracerebroventricularly at 30 minutes post-TBI, and U0126, a specific MEK1/2 inhibitor, was administered intravenously at 30 minutes pre-TBI. Garcia neuroscore, limb function and brain water content assessments, as well as TUNEL and Western blotting assays were performed to evaluate the status of the above rats at 24 hours post-TBI. Finally, the motor test and Morris water maze test were performed to measure the effects of periostin and U0126 in the late phase of TBI., Results: Periostin expression significantly increased 24 hours post-TBI. Treatment with R-periostin aggravated post-TBI neurobehavioral impairment, brain edema, induced apoptosis and raised the quantity of phospho-p38, phospho-JNK, phospho-ERK and MMP-9, and lowered the expression of ZO-1. However, U0126, a kind of inhibitor of MEK, lowered the quantities of phospho-ERK and MMP-9, raised the expression of ZO-1, and suppressed apoptosis. U0126 also ameliorated the neurobehavioral impairments and brain edema induced by R-periostin. Additionally, U0126 didn't inhibit the expression of periostin in the early phase of TBI model. IU0126 was also able to ameliorate the pathological conditions in the late phase of TBI., Discussion: Periostin could aggravate neurobehavioral impairments and brain edema following TBI, and was involved in the early phase of TBI via the MAPK/ERK pathway.

Background and Objectives : The incidence of severe and moderate forms of DKA as the initial presentation of type 1 diabetes mellitus (T1D) is increasing, especially during the COVID-19 pandemic. This poses a higher risk of developing cerebral edema as a complication of diabetic ketoacidosis (DKA), as well as morbidity and mortality rates. The aim of this study was to determine the trend and clinical features of children treated in the last 10 years in the Pediatric Intensive Care Unit (PICU) due to the development of DKA. Materials and Methods : This retrospective study was performed in the PICU, Clinical Hospital Centre Rijeka, in Croatia. All children diagnosed with DKA from 2011-2020 were included in this study. Data were received from hospital medical documentation and patient paper history. The number of new cases and severity of DKA were identified and classified using recent International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines. Results : In this investigation period, 194 children with newly diagnosed T1D were admitted to our hospital: 58 of them were treated in the PICU due to DKA; 48 had newly diagnosed T1D (48/58); and ten previously diagnosed T1D (10/58). DKA as the initial presentation of T1D was diagnosed in 24.7% (48/194). Moderate or severe dehydration was present in 76% of the children at hospital admission. Polyuria, polydipsia, and Kussmaul breathing were the most common signs. Three patients (5.2%) developed cerebral edema, of whom one died. Conclusions : During the investigation period a rising trend in T1D was noted, especially in 2020. About one quarter of children with T1D presented with DKA at initial diagnosis in western Croatia, most of them with a severe form. Good education of the general population, along with the patients and families of children with diabetes, is crucial to prevent the development of DKA and thus reduce severe complications.

Traveling to high altitudes for entertainment or work is sometimes associated with acute high altitude pathologies. In the past, scientific literature from the lowlander point of view was primarily based on mountain climbing. Sea level scientists developed all guidelines, but they need modifications for medical care in high altitude cities. Acute Mountain Sickness, High Altitude Pulmonary Edema, and High Altitude Cerebral Edema are medical conditions that some travelers can face. We present how to diagnose and treat acute high altitude pathologies, based on 51 years of high altitude physiology research and medical practice in hypobaric hypoxic diseases in La Paz, Bolivia (3,600 m; 11,811 ft), at the High Altitude Pulmonary and Pathology Institute (HAPPI - IPPA). These can occasionally present after flights to high altitude cities, both in lowlanders or high-altitude residents during re-entry. Acute high altitude ascent diseases can be adequately diagnosed and treated in high altitude cities following the presented guidelines. Treating these high-altitude illnesses, we had no loss of life. Traveling to a high altitude with sound medical advice should not be feared as it has many benefits. Nowadays, altitude descent and evacuation are not mandatory in populated highland cities, with adequate medical resources., (© 2022 Gustavo R. Zubieta-Calleja and Natalia Zubieta-DeUrioste, published by De Gruyter, Berlin/Boston.)

Background: Factors contributing to cerebral edema in the post-hyperacute period of ischemic stroke (first 24-72 hours) are poorly understood. Blood-brain barrier (BBB) disruption and postischemic hyperperfusion reflect microvascular dysfunction and are associated with hemorrhagic transformation. We investigated the relationships between BBB integrity, cerebral blood flow, and space-occupying cerebral edema in patients who received acute reperfusion therapy., Methods: We performed a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK and EXTEND-IA TNK part 2 trials who had MRI with dynamic susceptibility contrast-enhanced perfusion-weighted imaging 24 hours after treatment. We investigated the associations between BBB disruption and cerebral blood flow within the infarct with cerebral edema assessed using 2 metrics: first midline shift (MLS) trichotomized as an ordinal scale of negligible (<1 mm), mild (≥1 to <5 mm), or severe (≥5 mm), and second relative hemispheric volume (rHV), defined as the ratio of the 3-dimensional volume of the ischemic hemisphere relative to the contralateral hemisphere., Results: Of 238 patients analyzed, 133 (55.9%) had negligible, 93 (39.1%) mild, and 12 (5.0%) severe MLS at 24 hours. The associated median rHV was 1.01 (IQR, 1.00-1.028), 1.03 (IQR, 1.01-1.077), and 1.15 (IQR, 1.08-1.22), respectively. MLS and rHV were associated with poor functional outcome at 90 days ( P<0 .002). Increased BBB permeability was independently associated with more edema after adjusting for age, occlusion location, reperfusion, parenchymal hematoma, and thrombolytic agent used (MLS cOR, 1.12 [95% CI, 1.03-1.20], P =0.005; rHV β, 0.39 [95% CI, 0.24-0.55], P <0.0001), as was reduced cerebral blood flow (MLS cOR, 0.25 [95% CI, 0.10-0.58], P =0.001; rHV β, -2.95 [95% CI, -4.61 to -11.29], P =0.0006). In subgroup analysis of patients with successful reperfusion (extended Treatment in Cerebral Ischemia 2b-3, n=200), reduced cerebral blood flow remained significantly associated with edema (MLS cOR, 0.37 [95% CI, 0.14-0.98], P =0.045; rHV β, -2.59 [95% CI, -4.32 to -0.86], P =0.004)., Conclusions: BBB disruption and persistent hypoperfusion in the infarct after reperfusion treatment is associated with space-occupying cerebral edema. Further studies evaluating microvascular dysfunction during the post-hyperacute period as biomarkers of poststroke edema and potential therapeutic targets are warranted.

We present an unusual case of a woman in her 30s who was admitted for diabetic ketoacidosis (DKA) in the setting of newly diagnosed but late COVID-19 infection with associated Klebsiella pneumoniae infection. Her altered mental status, out of proportion with her metabolic decompensation, revealed a superimposed cerebral venous sinus thrombosis (CVST) with fulminant cerebral oedema and ultimately brain death. This unusual and fulminant case of cerebral oedema in the setting of COVID-19 infection with bacterial infection, DKA and CVST was the perfect storm with multiple interwoven factors. It offered diagnostic and treatment challenges with an unfortunate outcome. This unique case is a reminder that it is important to consider a broad neurological differential in patients with COVID-19 with unexplained neurological manifestations, which may require specific neurointensive care management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)