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Timely diagnosis and management of pediatric acute liver failure (PALF) is of paramount importance to improve survival. The Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition invited national and international experts to identify and review important management and research questions. These covered the definition, age appropriate stepwise workup for the etiology, non-invasive diagnosis and management of cerebral edema, prognostic scores, criteria for listing for liver transplantation (LT) and bridging therapies in PALF. Statements and recommendations based on evidences assessed using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were developed, deliberated and critically reappraised by circulation. The final consensus recommendations along with relevant published background information are presented here. We expect that these recommendations would be followed by the pediatric and adult medical fraternity to improve the outcomes of PALF patients., (© 2024. Asian Pacific Association for the Study of the Liver.)

This study aimed to investigate the effects of mild therapeutic hypothermia combined with stereotactic aspiration of spontaneous intracerebral hematoma on neurological function, inflammatory markers, cerebral hematoma, and cerebral edema in patients with severe cerebral hemorrhage. The clinical data of 86 patients with severe cerebral hemorrhage treated at our hospital between March 2020 and January 2022 were retrospectively analyzed. The patients were grouped according to their treatment plans: the control group consisted of 40 patients who underwent stereotactic aspiration of the spontaneous intracerebral hematoma, whereas the study group consisted of 46 patients who received adjuvant mild therapeutic hypothermia in addition to the aforementioned treatment. Clinical efficacy, neurological function (NIHSS score), daily living ability (BI score), cerebral hematoma, cerebral edema, cerebral hemodynamics (PI, RI, Vm, Vd), inflammatory markers (IL-6, IL-8, TNF-α, hs-CRP), oxidative stress indicators (SOD, MDA, 8-iso-PGF2α), serum-related factors (MMP-9, ICAM-1, ET-1, NO), and prognosis were compared between the groups. The total efficacy rate in the study group (95.65%) was significantly higher than that in the control group (77.50%) (P < 0.05). Post-treatment NIHSS scores, intracranial hematoma volume, perihematoma edema volume, cerebral edema volume, RI, serum IL-6, IL-8, TNF-α, hs-CRP, MDA, and 8-iso-PGF2α levels were significantly lower in both groups, with the study group showing even greater reductions. The BI score and PI, Vm, Vd, SOD, and NO levels were significantly higher in the study group (P < 0.05). At the 6-month follow-up, the prognosis of patients in the intervention group was significantly better than that of patients in the control group (P < 0.05). The combination of mild therapeutic hypothermia with stereotactic aspiration of a spontaneous intracerebral hematoma has demonstrated efficacy in the treatment of severe cerebral hemorrhage. This approach effectively reduces cerebral hematoma and edema, improves daily living ability, alleviates neurological deficits, regulates cerebral hemodynamics, suppresses inflammatory responses and oxidative stress, modulates serum-related factor levels, and enhances patient prognosis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Acute liver failure, commonly caused by acetaminophen overdose, is associated with numerous systemic complications including cerebral edema, hypotension, acute kidney injury, and infection. Management is primarily supportive, with an emphasis on excellent neurocritical care. Although some antidotes and targeted treatments exist, the only definitive treatment remains orthotopic liver transplant., (Copyright © 2024 American Academy of Physician Associates.)

The management of acute liver failure (ALF) in modern hepatology intensive care units (ICU) has improved patient outcomes. Critical care management of hepatic encephalopathy, cerebral edema, fluid and electrolytes; prevention of infections and organ support are central to improved outcomes of ALF. In particular, the pathogenesis of encephalopathy is multifactorial, with ammonia, elevated intra-cranial pressure and systemic inflammation playing a central role. Although ALF remains associated with high mortality, the availability of supportive care, including organ failure support such as plasma exchange, timely mechanical ventilation or continuous renal replacement therapy, either conservatively manages patients with ALF or offers bridging therapy until liver transplantation. Thus, appropriate critical care management has improved the likelihood of patient recovery in ALF. ICU care interventions such as monitoring of cerebral edema, fluid status assessment and interventions for sepsis prevention, nutritional support and management of electrolytes can salvage a substantial proportion of patients. In this review, we discuss the key aspects of critical care management of ALF., (© 2024. Indian Society of Gastroenterology.)

Cerebral edema frequently develops in the setting of brain infection and can contribute to elevated intracranial pressure, a medical emergency. How excess fluid is cleared from the brain is not well understood. Previous studies have shown that interstitial fluid is transported out of the brain along perivascular channels that collect into the cerebrospinal fluid (CSF)-filled subarachnoid space. CSF is then removed from the central nervous system through venous and lymphatic routes. The current study tested the hypothesis that increasing lymphatic drainage of CSF would promote clearance of cerebral edema fluid during infection with the neurotropic parasite Toxoplasma gondii. Fluorescent microscopy and magnetic resonance imaging was used to show that C57BL/6 mice develop vasogenic edema 4 to 5 weeks after infection with T. gondii. Tracer experiments were used to evaluate how brain infection affects meningeal lymphatic function, which demonstrated a decreased rate in CSF outflow in T. gondii-infected mice. Next, mice were treated with a vascular endothelial growth factor (VEGF)-C-expressing viral vector, which induced meningeal lymphangiogenesis and improved CSF outflow in chronically infected mice. No difference in cerebral edema was observed between mice that received VEGF-C and those that rececived sham treatment. Therefore, although VEGF-C treatment can improve lymphatic outflow in mice infected with T. gondii, this effect does not lead to increased clearance of edema fluid from the brains of these mice., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Endovascular treatment (EVT) is a therapeutic option for cerebral venous thrombosis (CVT); however, its benefit over conservative medical management has not been proven. Whether the current patient selection practices are appropriate for EVT is unclear., Methods: This was a nationwide study of the 2016-2020 National Inpatient Sample database. Adult CVT patients and EVT treatments were identified. Patient demographics, medical comorbidities, CVT risk factors, and CVT manifestations were identified. Presence of radiographic signs of advanced and severe CVT (venous infarction, cerebral edema, and intracranial hemorrhage) was recorded. Primary and secondary outcomes were good discharge outcomes and in-hospital mortality, respectively., Results: A total of 17,130 CVT patients were identified, and 56.7% had good discharge outcomes, while 4.6% died during hospitalization. 945 (5.5%) received EVT, and EVT patients were more likely to have cerebral infarction (35.4 vs. 21.8%, p &lt; 0.001), edema (35.4 vs. 20.1%, p &lt; 0.001), and hemorrhage (37.6 vs. 19.7%, p &lt; 0.001). After multivariable adjustments, EVT for patients without infarction, edema, or hemorrhage was moderately associated with higher odds of good outcomes (OR 1.86 [95% CI 0.98-3.53], p = 0.059) and resulted in zero deaths. However, with the increasing burden of radiographic signs of advanced CVT measured by the cumulative presence of infarction, edema, and hemorrhage, EVT was associated with decreasing odds of good outcomes and increasing odds of in-hospital mortality compared to medical management (interaction p = 0.046 and 0.029, respectively)., Conclusions: EVT may lead to higher rates of favorable hospitalization outcomes in patients who have not yet developed overt parenchymal manifestations of backpressure changes; presence of infarction, edema, and hemorrhage may diminish the short-term effectiveness of EVT., (© 2023 S. Karger AG, Basel.)

Objective: To explore the high-efficiency and low-risk prevention and treatment strategies for stem cells from human exfoliated deciduous teeth (SHED) for high-altitude cerebral oedema., Methods: A low-pressure and low-oxygen tank mimicking high-altitude conditions was used to establish the high-altitude cerebral oedema animal model. The preventive effects of SHED for cerebral oedema were then evaluated by haematoxylin and eosin (H&E) and histological staining. In vitro, SHED was co-cultured with BV-2 to analyse the effects of SHED by western blot and immunofluorescence staining., Results: SHED can prevent and treat cerebral oedema in a high altitude rat animal model. Mechanistically, SHED treatment can protect brain cells from apoptosis induced by high altitude condition. Moreover, SHED treatment can inhibit M1-type polarisation and promote M2-type polarisation of microglia cells via the suppression of hypoxia inducible factor (HIF)- 1α-mediated extracellular signal-regulated kinase (ERK) signalling activated in high altitude condition., Conclusion: SHED treatment can relieve high-altitude cerebral oedema via inhibiting HIF- 1α-mediated ERK signalling, which indicates that SHED is a promising alternative strategy to prevent and treat high-altitude cerebral oedema.

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Traumatic brain injury (TBI) is an important health and social problem. The mechanism of damage of this entity could be divided into two phases: (1) a primary acute injury because of the traumatic event; and (2) a secondary injury due to the hypotension and hypoxia generated by the previous lesion, which leads to ischemia and necrosis of neural cells. Cerebral edema is one of the most important prognosis markers observed in TBI. In the early stages of TBI, the cerebrospinal fluid compensates the cerebral edema. However, if edema increases, this mechanism fails, increasing intracranial pressure. To avoid this chain effect, several treatments are applied in the clinical practice, including elevation of the head of the bed, maintenance of normothermia, pain and sedation drugs, mechanical ventilation, neuromuscular blockade, controlled hyperventilation, and fluid therapy (FT). The goal of FT is to improve the circulatory system to avoid the lack of oxygen to organs. Therefore, rapid and early infusion of large volumes of crystalloids is performed in clinical practice to restore blood volume and blood pressure. Despite the relevance of FT in the early management of TBI, there are few clinical trials regarding which solution is better to apply. The aim of this study is to provide a narrative review about the role of the different types of FT used in the daily clinical practice on the management of TBI. To achieve this objective, a physiopathological approach to this entity will be also performed, summarizing why the different types of FT are used., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Treating pediatric patients with diabetic ketoacidosis (DKA) during transport can be complex and multifactorial. Cerebral edema is a frequent occurrence in pediatric patients with DKA; however, the signs often occur in a subtle manner. Overzealous correction of their blood glucose may result in cerebral edema as well as a cascade of electrolyte abnormalities. Pediatric patients with diabetes mellitus are prone to developing DKA. Serious complications from DKA in pediatrics often present acutely and rapidly., (Copyright © 2023 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Risk factors and predictors of malignant cerebral edema (MCE) after successful endovascular thrombectomy (EVT) were not fully explored. This study aimed to evaluate the incidence and risk factors of MCE after successful reperfusion., Methods: We retrospectively analyzed consecutive ischemic stroke patients who underwent EVT in our institution from November 2015 to April 2022. Patients who failed to achieve successful reperfusion (modified thrombolysis in cerebral infarction [mTICI]<2b) were excluded. Based on multivariate logistic models, the best-fit monogram was established. The discriminative performance was assessed by the receiver operating characteristics curve (ROC)., Results: A total of 307 patients were included and 48 (15.6%) were diagnosed with MCE after successful reperfusion. Patients with MCE after successful reperfusion had a lower 3-month favorable outcome (15.2% versus 59.6%; p<0.001), a lower 3-month good outcome (17.4% versus 68.4%; p<0.001), and a higher rate of mortality at 3-month (54.3% versus 8.8%; p<0.001) compared with patients without MCE. Predictors of MCE after successful reperfusion included admission glucose level, baseline National Institutes of Health Stroke Scale (NIHSS) score, stroke etiology, occlusion site and puncture-to-reperfusion (PTR) time>120 min. The area under the curve (AUC) of the nomogram was 0.805 (95% CI, 0.756-0.847)., Conclusions: MCE after successful reperfusion is associated with poor outcome and mortality. A nomogram containing admission glucose level, baseline NIHSS score, stroke etiology, occlusion site and PTR time>120 min may predict the risk of MCE after successful reperfusion in patients with acute ischemic stroke and treated successfully with EVT., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Meningiomas is a tumor of the meninges and is among the most common intracranial neoplasms in adults, accounting for over a third of all primary brain tumors in the United States. Meningiomas can be associated with peritumoral brain edema (PTBE) which if not managed appropriately can lead to poor clinical outcomes. In this review, we summarize the relevant pathophysiology, predictors, and principles for treatment of PTBE. The results of various case-reports and case-series have found that meningioma-associated PTBE have patterns in age, tumor size, and hormone receptor positivity. Our study describes how increased age, increased tumor size, tumor location in the middle fossa, and positive expression of hormone receptors, VEGF, and MMP-9 can all be predictors for worse clinical outcomes. We also characterize treatment options for PTBE such as glucocorticoids and VEGF inhibitors along with the ongoing clinical trials attempting to alleviate PTBE in meningioma cases. The trends summarized in this review can be used to better predict the behavior of meningioma-associated PTBE and establish prognosis models to identify at risk patients., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Brain edema is one of the most devastating consequences of ischemic stroke. Malignant cerebral edema is the main reason accounting for the high mortality rate of large hemispheric strokes. Despite decades of tremendous efforts to elucidate mechanisms underlying the formation of ischemic brain edema and search for therapeutic targets, current treatments for ischemic brain edema remain largely symptom-relieving rather than aiming to stop the formation and progression of edema. Recent preclinical research reveals novel cellular mechanisms underlying edema formation after brain ischemia and reperfusion. Advancement in neuroimaging techniques also offers opportunities for early diagnosis and prediction of malignant brain edema in stroke patients to rapidly adopt life-saving surgical interventions. As reperfusion therapies become increasingly used in clinical practice, understanding how therapeutic reperfusion influences the formation of cerebral edema after ischemic stroke is critical for decision-making and post-reperfusion management. In this review, we summarize these research advances in the past decade on the cellular mechanisms, and evaluation, prediction, and intervention of ischemic brain edema in clinical settings, aiming to provide insight into future preclinical and clinical research on the diagnosis and treatment of brain edema after stroke., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain injury remains a major problem in patients suffering cardiac arrest (CA). Disruption of the blood-brain barrier (BBB) is an important factor leading to brain injury. Therapeutic hypothermia is widely accepted to limit neurological impairment. However, the efficacy is incomplete. Hydrogen sulfide (H 2 S), a signaling gas molecule, has protective effects after cerebral ischemia reperfusion injury. This study showed that combination of hypothermia and H 2 S after resuscitation was more beneficial for attenuated BBB disruption and brain edema than that of hypothermia or H 2 S treatment alone. CA was induced by ventricular fibrillation for 4 min. Hypothermia was performed by applying alcohol and ice bags to the body surface under anesthesia. We used sodium hydrosulphide (NaHS) as the H 2 S donor. We found that global brain ischemia induced by CA and cardiopulmonary resuscitation (CPR) resulted in brain edema and BBB disruption; Hypothermia or H 2 S treatment diminished brain edema, decreased the permeability and preserved the structure of BBB during the early period of CA and resuscitation, and more importantly, improved the neurologic function, increased the 7-day survival rate after resuscitation; the combination of hypothermia and H 2 S treatment was more beneficial than that of hypothermia or H 2 S treatment alone. The beneficial effects were associated with the inhibition of matrix metalloproteinase-9 expression, attenuated the degradation of the tight junction protein occludin, and subsequently protected the structure of BBB. These findings suggest that combined use of therapeutic hypothermia and hydrogen sulfide treatment during resuscitation of CA patients could be a potential strategy to improve clinical outcomes and survival rate., (© 2022. The Author(s).)

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.

Background: The pathophysiology of traumatic brain injury (TBI) is caused by the initial physical damage and by the subsequent biochemical damage (secondary brain injury). Oxidative stress is deeply involved in secondary brain injury, so molecular hydrogen therapy may be effective for TBI. Hydrogen gas shows the optimal effect at concentrations of 2% or higher, but can only be used up to 1.3% in the form of a gas cylinder mixed with oxygen gas, which may not be sufficiently effective. The partial pressure of hydrogen increases in proportion to the pressure, so hyperbaric hydrogen therapy (HBH2) is more effective than that at atmospheric pressure., Methods: A total of 120 mice were divided into three groups: TBI + non-treatment group (TBI group; n = 40), TBI + HBH2 group (n = 40), and non-TBI + non-treatment group (sham group; n = 40). The TBI and TBI + HBH2 groups were subjected to moderate cerebral contusion induced by controlled cortical impact. The TBI + HBH2 group received hyperbaric hydrogen therapy at 2 atmospheres for 90 minutes, at 30 minutes after TBI. Brain edema, neuronal cell loss in the injured hippocampus, neurological function, and cognitive function were evaluated., Results: The TBI + HBH2 group showed significantly less cerebral edema (p ≺ 0.05). Residual hippocampal neurons were significantly more numerous in the TBI + HBH2 group on day 28 (p ≺ 0.05). Neurological score and behavioral tests showed that the TBI + HBH2 group had significantly reduced hyperactivity on day 14 (p ≺ 0.01)., Conclusion: Hyperbaric hydrogen therapy may be effective for posttraumatic secondary brain injury., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Intracerebral hemorrhage (ICH) accounts for about 10% of all strokes in the United States of America causing a high degree of disability and mortality. There is initial (primary) brain injury due to the mechanical disruption caused by the hematoma. There is then secondary injury, triggered by the initial injury but also the release of various clot-derived factors (e.g., thrombin and hemoglobin). ICH alters brain fluid homeostasis. Apart from the initial hematoma mass, ICH causes blood-brain barrier disruption and parenchymal cell swelling, which result in brain edema and intracranial hypertension affecting patient prognosis. Reducing brain edema is a critical part of post-ICH care. However, there are limited effective treatment methods for reducing perihematomal cerebral edema and intracranial pressure in ICH. This review discusses the mechanisms underlying perihematomal brain edema formation, the effects of sex and age, as well as how edema is resolved. It examines progress in pharmacotherapy, particularly focusing on drugs which have been or are currently being investigated in clinical trials., Competing Interests: Declaration of Competing Interest Yingfeng Wan, Katherine G Holste, Ya Hua, Richard F. Keep, and Guohua Xi declare no conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

We report a case of a previously healthy early adolescent female who presented with meningococcal meningitis. While in hospital, she had marked neurologic deterioration with clinical herniation from malignant cerebral oedema. She was transferred to a neurocritical care centre where she underwent invasive intracranial pressure (ICP) and brain tissue oxygen (P bt O 2 ) monitoring. Early in her course, she demonstrated a compete absence of autoregulation, with pressure passive cerebral blood flow. As a result, maintaining a mean arterial pressure between 50 mm Hg and 60 mm Hg, which ensured adequate cerebral oxygenation, while avoiding increases in ICP. Although her course was initially complicated by bilateral optic neuropathy, she has subsequently made a full neurologic recovery and is now undertaking postsecondary education. This case highlights that access to specialist neurocritical care, guided by neurophysiologic monitoring of ICP and P bt O 2 , may help improve outcomes, even among those patients with catastrophic cerebral oedema from bacterial meningitis., Competing Interests: Competing interests: MS is supported by the Vancouver Coastal Health Research Institute Clinician Scientist Award, and the Michael Smith Foundation for Health Research Health-Professional Investigator Award. DG is funded by the Michael Smith Foundation for Health Research Health-Professional Investigator Award., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes mellitus, which may lead to significant morbidity and mortality., Objectives: To compare the safety and efficacy of liberalised versus conservative intravenous fluid regimens in the management of DKA in children., Data Source and Study Selection: Databases from inception to January 2022: MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials were included. Only randomised controlled trials (RCTs) that included children aged under 18 years were assessed. Two reviewers performed data assessment and extraction., Data Extraction and Synthesis: Three studies out of 1536 citations were included., Main Outcomes: The time to the recovery from the DKA; the frequency of paeditric intensive care unit (PICU) admissions; development of brain oedema; reduction in Glasgow Coma Scale (GCS); development of acute kidney injury and all-cause mortality., Results: We included three RCTs (n=1457). No evidence of difference was noted in the GCS reduction (risk ratio (RR)=0.77, 95% CI 0.44 to 1.36) or development of brain oedema (RR=0.50, 95% CI 0.15 to 1.68). The time to recovery from DKA was longer in the conservative group (mean difference=1.42, 95% CI 0.28 to 2.56). Time to hospital discharge, adverse or serious adverse events were comparable in the two studied groups., Conclusion: There is no evidence from this meta-analysis that rate of fluid administration has any effect on adverse neurological and other outcomes or length of hospital stay., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Acute liver failure is a rare but important clinical syndrome, with a high mortality rate. Prompt recognition, appropriate management and early referral to a liver transplant centre can lead to good outcomes in these critically unwell patients. This article gives an overview of the key clinical challenges and optimal management of patients with acute liver failure. Acute liver failure is defined and a comprehensive list of aetiologies and suggested investigations is provided. The clinical challenges of sepsis, renal impairment, coagulopathy, hypoglycaemia, haemodynamic instability and cerebral oedema are discussed. Quadruple H therapy, a combination of therapies aimed to reduce cerebral oedema in acute liver failure, is described. A systemic guide to managing patients with acute liver failure is provided, as are indications for referral to a liver transplant centre.

The prognosis of patients with spontaneous intracerebral hemorrhage (sICH) is poor. It is of great significance to improve the neurological function of these patients and make them return to society. However, to date, no treatment has been proved to significantly improve the neurological prognosis of sICH patients. The perihematomal edema (PHE) is a quantifiable marker of secondary brain injury (SBI) after ICH. It is associated with dysfunction of ion channels of vascular endothelial cells, inflammatory response induced-blood brain barrier dysfunction, and iron deposition caused by red blood cell degradation after ICH. Given that the space-occupying effect of PHE, the direct relation with SBI, long growth course and variable growth of PHE among individuals, interrupting the expansion of PHE has become a therapeutic target to improve neurological outcomes in ICH patients. Conducting an integrated and individualized strategy of critical care management and performing the corresponding pre-clinical and translational clinical research targeting the pathophysiological mechanism, nature course, and risk factors of PHE deserves further exploration.

Objectives: This study aimed to identify and evaluate the intracranial transplantation of dental pulp stem cells (DPSCs) as a possible ischemic stroke therapy that mitigates neuronal death/apoptosis., Materials and Methods: DPSCs were isolated from the impacted third molars of healthy volunteers and then intracranially injected at 24 h post-ischemic stroke to Sprague Dawley rats that had been subjected to 2 h of middle cerebral artery occlusion. Neurological functional deficits were assessed using the modified neurological severity score (mNSS), and cerebral edema was quantified using brain water content. Neuronal death/apoptosis was indicated by TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, NeuN immunofluorescence and immunohistochemistry, and Western blot analysis of the protein expression of anti-apoptotic indicator of Bcl-2 and apoptotic indicators of Bax and caspase 3., Results: DPSC transplantation could ameliorate neurological dysfunction and brain edema, reduce infarct volume, decrease the percentage of TUNEL-positive nuclei, increase the number and percentage of NeuN-positive cells in ischemic penumbra, increase the ratio of Bcl-2 and Bax and down-regulate the production of caspase 3 in the cortical infarct zone., Conclusions: DPSC therapy via intracranial injection exerted remarkably neuroprotection mainly by inhibiting neuronal death/apoptosis., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Intracerebral hemorrhage remains the deadliest form of stroke worldwide, inducing neuronal death through a wide variety of pathways. Therapeutic hypothermia is a robust and well-studied neuroprotectant widely used across a variety of specialties., Aims: This review summarizes results from preclinical and clinical studies to highlight the overall effectiveness of therapeutic hypothermia to improve long-term intracerebral hemorrhage outcomes while also elucidating optimal protocol regimens to maximize therapeutic effect., Summary of Review: A systematic review was conducted across three databases to identify trials investigating the use of therapeutic hypothermia to treat intracerebral hemorrhage. A random-effects meta-analysis was conducted on preclinical studies, looking at neurobehavioral outcomes, blood brain barrier breakdown, cerebral edema, hematoma volume, and tissue loss. Several mixed-methods meta-regression models were also performed to adjust for variance and variations in hypothermia induction procedures. Twwenty-one preclinical studies and five human studies were identified. The meta-analysis of preclinical studies demonstrated a significant benefit in behavioral scores (ES = -0.43, p = 0.02), cerebral edema (ES = 1.32, p = 0.0001), and blood brain barrier (ES = 2.73, p ≤ 0.00001). Therapeutic hypothermia was not found to significantly affect hematoma expansion (ES = -0.24, p = 0.12) or tissue loss (ES = 0.06, p = 0.68). Clinical study outcome reporting was heterogeneous; however, there was recurring evidence of therapeutic hypothermia-induced edema reduction., Conclusions: The combined preclinical evidence demonstrates that therapeutic hypothermia reduced multiple cell death mechanisms initiated by intracerebral hemorrhage; yet, there is no definitive evidence in clinical studies. The cooling strategies employed in both preclinical and clinical studies were highly diverse, and focused refinement of cooling protocols should be developed in future preclinical studies. The current data for therapeutic hypothermia in intracerebral hemorrhage remains questionable despite the highly promising indications in preclinical studies. Definitive randomized controlled studies are still required to answer this therapeutic question.

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: Remote ischemic conditioning can promote hematoma resolution, attenuate brain edema, and improve neurological recovery in animal models of intracerebral hemorrhage., Aims: This study aimed to evaluate the safety and preliminary efficacy of remote ischemic conditioning in patients with intracerebral hemorrhage., Methods: In this multicenter, randomized, controlled trial, 40 subjects with supratentorial intracerebral hemorrhage presenting within 24-48 h of onset were randomly assigned to receive medical therapy plus remote ischemic conditioning for consecutive seven days or medical therapy alone. The primary safety outcome was neurological deterioration within seven days of enrollment, and the primary efficacy outcome was the changes of hematoma volume on CT images. Other outcomes included hematoma resolution rate at 7 days ([hematoma volume at 7 days - hematoma volume at baseline]/hematoma volume at baseline), perihematomal edema (PHE), and functional outcome at 90 days., Results: The mean age was 59.3 ± 11.7 years and hematoma volume was 13.9 ± 4.5 mL. No subjects experienced neurological deterioration within seven days of enrollment, and no subject died or experienced remote ischemic conditioning-associated adverse events during the study period. At baseline, the hematoma volumes were 14.19 ± 5.07 mL in the control group and 13.55 ± 3.99 mL in the remote ischemic conditioning group, and they were 8.54 ± 3.99 mL and 6.95 ± 2.71 mL at seven days after enrollment, respectively, which is not a significant difference ( p  > 0.05 each). The hematoma resolution rate in the remote ischemic conditioning group (49.25 ± 9.17%) was significantly higher than in the control group (41.92 ± 9.14%; MD, 7.3%; 95% CI, 1.51-13.16%; p  = 0.015). The absolute PHE volume was 17.27 ± 8.34 mL in the control group and 12.92 ± 7.30 mL in the remote ischemic conditioning group at seven days after enrollment, which is not a significant between-group difference ( p  = 0.087), but the relative PHE in the remote ischemic conditioning group (1.77 ± 0.39) was significantly lower than in the control group (2.02 ± 0.27; MD, 0.25; 95% CI, 0.39-0.47; p  = 0.023). At 90-day follow-up, 13 subjects (65%) in the remote ischemic conditioning group and 12 subjects (60%) in the control group achieved favorable functional outcomes (modified Rankin Scale score ≤ 3), which is not a significant between-group difference ( p  = 0.744)., Conclusions: Repeated daily remote ischemic conditioning for consecutive seven days was safe and well tolerated in patients with intracerebral hemorrhage, and it may be able to improve hematoma resolution rate and reduce relative PHE. However, the effects of remote ischemic conditioning on the absolute hematoma and PHE volume and functional outcomes in this patient population need further investigations. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03930940.

Despite a great amount of effort, there is still a need for reliable treatments of traumatic brain injury (TBI). Recently, stem cell therapy has emerged as a new avenue to address neuronal regeneration after TBI. However, the environment of TBI lesions exerts negative effects on the stem cells efficacy. Therefore, to maximize the beneficial effects of stem cells in the course of TBI, we evaluated the effect of human neural stem/progenitor cells (hNS/PCs) and curcumin-loaded niosome nanoparticles (CM-NPs) on behavioral changes, brain edema, gliosis, and inflammatory responses in a rat model of TBI. After TBI, hNS/PCs were transplanted within the injury site and CM-NPs were orally administered for 10 days. Finally, the effect of combination therapy was compared to several control groups. Our results indicated a significant improvement of general locomotor activity in the hNS/PCs + CM-NPs treatment group compared to the control groups. We also observed a significant improvement in brain edema in the hNS/PCs + CM-NPs treatment group compared to the other groups. Furthermore, a significant decrease in astrogliosis was seen in the combined treatment group. Moreover, TLR4-, NF-κB-, and TNF-α- positive cells were significantly decreased in hNS/PCs + CM-NPs group compared to the control groups. Taken together, this study indicated that combination therapy of stem cells with CM-NPs can be an effective therapy for TBI., (© 2022. The Author(s).)

Background: Traumatic brain edema occurs commonly brain injury, and most manifests as pericontusional edema of brain contusions. On the basis of evidence-based medicine, apart from recommending craniotomy and mannitol, there are few particularly effective measures to prevent and treat traumatic brain edema. It is uncertain whether an early complementary acupuncture treatment would improve long-term outcomes of patients with traumatic brain edema. The aim of this study is to assess the efficacy and the safety of early complementary acupuncture for patients with traumatic brain edema., Methods: This study is an actively accruing, single-center, single-blinded, 2-arm, randomized controlled trial. Patients with traumatic brain injury, a Glasgow Coma Scale score of 6∼12, and brain edema on computed tomography scan will be divided into 2 groups on the basis of stratified block randomization. All patients will receive conventional treatment, and the study group will undergo additional acupuncture therapy (start within 72 hours after the injury) once a day for 28 days. The primary outcome is the dichotomized Glasgow Outcome Score at 6 months and 12 months after injury, and the secondary outcomes are the Glasgow Coma Scale, the volume of traumatic brain edema, the serum levels of C-reactive protein and interleukin-6, and the Modified Barthel Index., Discussion: This study will provide data regarding the efficacy of early complementary acupuncture for traumatic brain edema. If the study yields positive results, its findings may offer insights into a valuable complementary option of acupuncture for traumatic brain edema that could provide pilot evidence for large, randomized, controlled trials.Trial registration: This trial has been published in the Chinese Clinical Trial Register, http://www.chictr.org.cn/edit.aspx?pid=141208&htm=4 (Identifier: ChiCTR2100053794, registered on December 3, 2021)., Competing Interests: All authors have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The case report presents the case of a five-year-old boy who fell off a scooter and sustained a blow to the left temporal region of his head. During a CT examination in the district hospital he suddenly showed a deterioration in the level of consciousness. Subsequent treatment along with transport to a specialized department were aimed at preventing secondary pathological changes and maintaining pressure-volume homeostasis of the brain. High-quality controlled ventilation with effective pharmacotherapy and gentle transport were essential. At the target specialized department, cerebral oedema in the left temporal region and aspiration in the right upper lung lobe were identified. The boy was extubated after 6 hours of controlled ventilation and discharged to an intermediate care bed two days later without any serious consequences. Key words: cerebral oedema, haemodynamic swelling, severe head injury.

Edema coursing the optic apparatus has traditionally been associated with sellar and para-sellar tumors. However, postoperative aneurysmal volume expansion following endovascular treatment has been reported to induce cranial neuropathies, such as vision loss in rare instances. Here, we present a case report of worsening optic tract edema associated with bilateral visual acuity deficit following treatment of a large left paraophthalmic aneurysm with pipeline-assisted coiling. Rapid resolution of visual deficit was observed following administration of corticosteroids. A 42-year-old female with a 6-month history of worsening left eye vision and sentinel headache presented with left visual field cut and decreased left visual acuity. She was found to have a large paraophthalmic aneurysm which was treated with pipeline-assisted coiling. Within one week post-treatment, the patient presented to the emergency department with worsening right visual complaints. On magnetic resonance imaging, T2 hyperintensities coursing the right posterior optic nerve, optic chiasm, and bilateral optic tracts were noted. Angiography demonstrated an expanding neck remnant. The patient was treated with oral corticosteroids and repeat pipeline stenting. At four week follow up, she demonstrated significant improvement of symptoms and reduced T2 hyperintensities. With the advancement in endovascular technique for the treatment of large aneurysms, more patients are electing endovascular treatment over microsurgical clipping. Given the possibility of continued growth following endovascular treatment, patient counseling regarding risks and side effects is paramount., (Copyright © 2021. Published by Elsevier B.V.)

Decompressive craniectomy is an effective strategy to reduce intracranial hypertension after traumatic brain injury (TBI), but it is related to many postoperative complications, such as delayed intracranial hematoma and diffuse brain swelling. Our previous studies have demonstrated that controlled decompression (CDC) surgery attenuates brain injury and reduces the rate of complications after TBI. Here, we investigated the potential molecular mechanisms of CDC in experimental models. The in vitro experiments were performed in a traumatic neuronal injury (TNI) model following compression treatment in primary cultured cortical neurons. We found that compression aggravates TNI-induced neuronal injury, which was significantly attenuated by CDC for 2 h or 3 h. The results of immunocytochemistry showed that CDC reduced neuronal necroptosis and activation of RIP3 induced by TNI and compression, with no effect on RIP1 activity. These protective effects were associated with decreased levels of inflammatory cytokines and preserved intracellular Ca 2+ homeostasis. In addition, the expression of the two-pore domain K + channel TREK-1 and its activity was increased by compression and prolonged by CDC. Treatment with the TREK-1 blockers, spadin or SID1900, could partially prevent the effects of CDC on intracellular Ca 2+ metabolism, necroptosis, and neuronal injury following TNI and compression. Using a traumatic intracranial hypertension model in rats, we found that CDC for 20 min or 30 min was effective in alleviating brain edema and locomotor impairment in vivo. CDC significantly inhibited neuronal necroptosis and neuroinflammation and increased TREK-1 activation, and the CDC-induced protection in vivo was attenuated by spadin and SID1900. In summary, CDC is effective in alleviating compressive neuronal injury both in vitro and in vivo, which is associated with the TREK-1-mediated attenuation of intracellular Ca 2+ overload, neuronal necroptosis, and neuroinflammation., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Tao Chen et al.)

As swelling occurs, CSF is preferentially displaced from the ischemic hemisphere. The ratio of CSF volume in the stroke-affected hemisphere to that in the contralateral hemisphere may quantify the progression of cerebral edema. We automatically segmented CSF from 1,875 routine CTs performed within 96 hours of stroke onset in 924 participants of a stroke cohort study. In 737 subjects with follow-up imaging beyond 24-hours, edema severity was classified as affecting less than one-third of the hemisphere (CED-1), large hemispheric infarction (LHI, over one-third the hemisphere), without midline shift (CED-2) or with midline shift (CED-3). Malignant edema was LHI resulting in deterioration, requiring osmotic therapy, surgery, or resulting in death. Hemispheric CSF ratio was lower on baseline CT in those with LHI (0.91 vs. 0.97, p < 0.0001) and decreased more rapidly in those with LHI who developed midline shift (0.01 per hour for CED-3 vs. 0.004/hour CED-2). The ratio at 24-hours was lower in those with midline shift (0.41, IQR 0.30-0.57 vs. 0.66, 0.56-0.81 for CED-2). A ratio below 0.50 provided 90% sensitivity, 82% specificity for predicting malignant edema among those with LHI (AUC 0.91, 0.85-0.96). This suggests that the hemispheric CSF ratio may provide an accessible early biomarker of edema severity.

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.

Purpose of Review: This article reviews the pathophysiology and management of cerebral edema, brain compression, and elevated intracranial pressure (ICP). It also provides a brief introduction to the concept of the glymphatic system and select cellular contributors to cerebral edema., Recent Findings: Cerebral edema and brain compression should be treated in a tiered approach after the patient demonstrates a symptomatic indication to start treatment. All patients with acute brain injury should be treated with standard measures to optimize intracranial compliance and minimize risk of ICP elevation. When ICP monitors are used, therapies should target maintaining ICP at 22 mm Hg or less. Evidence exists that serial clinical examination and neuroimaging may be a reasonable alternative to ICP monitoring; however, clinical trials in progress may demonstrate advantages to advanced monitoring techniques. Early decompressive craniectomy and hypothermia are not neuroprotective in traumatic brain injury and should be reserved for situations refractory to initial medical interventions. Medical therapies that acutely lower plasma osmolality may lead to neurologic deterioration from osmotic cerebral edema, and patients with acute brain injury and renal or liver failure are at elevated risk., Summary: A tiered approach to the management of cerebral edema and brain compression can reduce secondary brain injury when implemented according to core physiologic principles. However, our knowledge of the pathophysiology of acute brain injury is incomplete, and the conceptual framework underlying decades of clinical management may need to be revised in response to currently evolving discoveries regarding the pathophysiology of acute brain injury., (Copyright © 2021 American Academy of Neurology.)

Objective: Cerebral edema characterized as an abnormal accumulation of interstitial fluid has not been treated effectively. We propose a novel edema treatment approach to drive edematous fluid out of the brain by direct current utilizing brain tissue's electroosmotic property., Methods: A finite element (FE) head model is developed and employed to assess the feasibility of the approach. First, the capacity of the model for electric field prediction is validated against human experiments. Second, two electrode configurations (S and D-montage) are designed to evaluate the distribution of the electric field, electroosmotic flow (EOF), current density, and temperature across the brain under an applied direct current., Results: The S-montage is shown to induce an average EOF velocity of 7e-4 mm/s underneath the anode by a voltage of 15 V, and the D-montage induces a velocity of 9e-4 mm/s by a voltage of 5 V. Meanwhile, the brain temperature in both configurations is below 38 °C, which is within the safety range. Further, the magnitude of EOF is proportional to the electric field, and the EOF direction follows the current flow from anode to cathode. The EOF velocity in the white matter is significantly higher than that in the gray matter under the anode where the fluid is to be drawn out., Conclusion: The proposed electroosmosis based approach allows alleviating brain edema within the critical time window by direct current., Significance: The approach may be further developed as a new treatment solely or as a complement to existing conventional treatments of edema.

Background: Hyperosmotic therapy is a mainstay treatment for cerebral edema. Although often effective, its disadvantages include mainly acting on the normal brain region with limited effectiveness in eliminating excess fluid in the edema region. This study investigates how to configure our previously proposed novel electroosmosis based edema treatment as a complement to hyperosmotic therapy., Methods: Three electrode configurations are designed to drive the excess fluid out of the edema region, including 2-electrode, 3-electrode, and 5-electrode designs. The focality and directionality of the induced electroosmotic flow (EOF) are then investigated using the same patient-specific head model with localized edema., Results: The 5-electrode design shows improved EOF focality with reduced effect on the normal brain region than the other two designs. Importantly, this design also achieves better directionality driving excess edema tissue fluid to a larger region of surrounding normal brain where hyperosmotic therapy functions better. Thus, the 5-electrode design is suggested to treat edema more efficiently via a synergic effect: the excess fluid is first driven out from the edema to surrounding normal brain via EOF, where it can then be treated with hyperosmotic therapy. Meanwhile, the 5-electrode design drives 2.22 mL excess fluid from the edema region in an hour comparable to the other designs, indicating a similar efficiency of EOF., Conclusions: The results show that the promise of our previously proposed novel electroosmosis based edema treatment can be designed to achieve better focality and directionality towards a complement to hyperosmotic therapy., (© 2021. The Author(s).)

Introduction: Moyamoya disease (MMD) and posterior reversible encephalopathy syndrome (PRES) share similar pathophysiological characteristics of endothelial dysfunction and impaired cerebral autoregulation. However, there have never been any published studies to demonstrate the relationship between these 2 rare diseases., Patient Concerns: A 26-year-old Asian man presented with a throbbing headache, blurred vision, and extremely high blood pressure. We initially suspected acute cerebral infarction based on the cerebral computed tomography, underlying MMD, and prior ischemic stroke. However, the neurological symptoms deteriorated progressively., Diagnosis: Cerebral magnetic resonance imaging indicated the presence of vasogenic edema rather than cerebral infarction., Interventions and Outcomes: An appropriate blood pressure management prevents the patient from disastrous outcomes successfully. Cerebral magnetic resonance imaging at 2 months post treatment disclosed the complete resolution of cerebral edema. The patient's recovery from clinical symptoms and the neuroimaging changes supported the PRES diagnosis., Conclusion: This report suggests that patients with MMD may be susceptible to PRES. It highlights the importance of considering PRES as a differential diagnosis while providing care to MMD patients with concurrent acute neurological symptoms and a prompt intervention contributes to a favorable clinical prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/objectives: We postulated that renal replacement therapy (RRT) in ICH patients with advanced chronic kidney disease (CKD) is associated with increased frequency and size of perihematomal edema (PHE) expansion and worse patient outcomes., Methods: The Get With the Guidelines-Stroke Registry was queried for all patients admitted with ICH (N = 1089). Secondary causes, brainstem ICH, and initial HV < 7 cc were excluded. We identified patients with advanced CKD with and without RRT following admission for ICH. ABC/2 formula was used to measure hematoma volume (HV) and PHE. Patient outcomes were 30-day mortality, 90-day modified Rankin Scale score, and discharge disposition. We used propensity scores and optimal matching to adjust for multiple covariates., Results: At 48 h post-ICH, PHE expansion was a significant predictor of poor patient outcomes in our cohort. Patients with CKD who received sustained low-efficacy dialysis (SLED) treatment had larger 48 h PHE growth compared to both untreated CKD group (average treatment effect (ATE), 11.5; 95% CI, 4.9-18.1; p < 0.01) and all untreated patients (ATE, 7.43; 95% CI, 4.7-10.2; p < 0.01). Moreover, patients with RRT had significantly worse functional and mortality outcomes., Conclusions: SLED treatment in ICH patients with CKD was associated with significant increase in rate and frequency of PHE expansion. Absolute increase in PHE during 48-h post-ICH was associated with increased mortality and worse functional outcomes. Further prospective and multicenter evaluation is needed to differentiate the effects of RRT on hematoma dynamics and patient outcomes from those attributed to CKD., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Focal brain edema in unruptured brain arteriovenous malformations (AVMs) is rare and associated with venous outflow abnormalities and aneurysm growth. These patients have an increased rate of progressive neurologic symptoms, as well as a potentially increased risk of hemorrhage. In this study, we aim to assess in further detail the relationship between perifocal edema and enhancement of the vessel wall in symptomatic patients with an unruptured brain AVM., Methods: A single-center retrospective cohort study of all patients presenting with an unruptured AVM at Toronto Western Hospital from 2009 to 2019 was performed. Patients were included for review if they had focal edema surrounding an AVM on magnetic resonance imaging (MRI) and a contrast-enhanced MRI scan. Associated digital subtraction angiography studies were reviewed., Results: A total of 122 patients presented with an unruptured AVM. Twelve symptomatic patients presented with focal edema surrounding the AVM. Six patients had focal edema and contrast-enhanced MRI performed. All 6 demonstrated luminal thrombosis at the level of the brain edema on MRI. Moreover, the vessel wall demonstrated enhancement at the level of the luminal thrombus in all., Conclusions: Vessel wall enhancement, perifocal edema, and luminal thrombosis demonstrated in all patients with unruptured AVM points towards a common mechanism. We suspect an interplay between vascular hypoxia, the innate immune system, and thrombosis formation. Current research in the field of immunothrombosis supports this theory. Unravelling the mechanisms involved is important because it might guide therapy for patients with an unruptured AVM towards noninvasive options., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra., Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function., Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26)., Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Hyperosmolar therapy is a cornerstone for the management of elevated intracranial pressure in patients with devastating neurological injuries. Its discovery and use in various pathologies has become a valuable therapy in modern neurological critical care across the globe. Although hyperosmolar therapy is used routinely, the history of its origin is still elusive to many physicians. Understanding the basis of discovery and use of different hyperosmolar agents lends insight into the complex management of elevated intracranial pressure. There are very few practices in medicine which has stood the test of time. The discovery of hyperosmolar therapy has not only provided us a wealth of data for the management of intracranial hypertension but has also allowed us to develop new treatment strategies by improving our understanding of the molecular mechanisms of cerebral inflammation, blood-brain permeability, and cerebral edema in all modes of neuronal injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cerebral edema following ischemic stroke is predictive of the severity of the eventual stroke related damage, however the effective treatment is limited. The glymphatic system is a recently identified waste clearance pathway in the brain, found in the paravascular space and mainly composed of astrocytes and their aquaporin-4 (AQP4) water channels. In this review, we primarily focus on the role of the glymphatic system in the formation of cerebral edema after ischemic stroke. There is still no definite conclusion whether the influx of cerebrospinal fluid (CSF) in the glymphatic system is increased or not after ischemic stroke. However, the reduced interstitial fluid (ISF) clearance after ischemic stroke is definite. Additionally, AQP4 as the most important part of glymphatic system plays a complex bimodal in cerebral edema after ischemic stroke. Most of the research has found that AQP4 deletion in animals reduces cerebral edema after acute ischemic stroke compared with wild type animal models. The mislocalization of astrocytic AQP4 was also presented after ischemic stroke. As the cerebral edema after ischemic stroke is difficult to treat, we discuss several potential treatment targets related to glymphatic system. More studies are needed to explore the role of glymphatic system in the formation of cerebral edema after ischemic stroke and develop probable treatment strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To investigate whether blood-brain barrier (BBB) served a key role in the edema-relief effect of bloodletting puncture at hand twelve Jing-well points (HTWP) in traumatic brain injury (TBI) and the potential molecular signaling pathways., Methods: Adult male Sprague-Dawley rats were assigned to the sham-operated (sham), TBI, and bloodletting puncture (bloodletting) groups (n=24 per group) using a randomized number table. The TBI model rats were induced by cortical contusion and then bloodletting puncture were performed at HTWP twice a day for 2 days. The neurological function and cerebral edema were evaluated by modified neurological severity score (mNSS), cerebral water content, magnetic resonance imaging and hematoxylin and eosin staining. Cerebral blood flow was measured by laser speckles. The protein levels of aquaporin 4 (AQP4), matrix metalloproteinases 9 (MMP9) and mitogen-activated protein kinase pathway (MAPK) signaling were detected by immunofluorescence staining and Western blot., Results: Compared with TBI group, bloodletting puncture improved neurological function at 24 and 48 h, alleviated cerebral edema at 48 h, and reduced the permeability of BBB induced by TBI (all P<0.05). The AQP4 and MMP9 which would disrupt the integrity of BBB were downregulated by bloodletting puncture (P<0.05 or P<0.01). In addition, the extracellular signal-regulated kinase (ERK) and p38 signaling pathways were inhibited by bloodletting puncture (P<0.05)., Conclusions: Bloodletting puncture at HTWP might play a significant role in protecting BBB through regulating the expressions of MMP9 and AQP4 as well as corresponding regulatory upstream ERK and p38 signaling pathways. Therefore, bloodletting puncture at HTWP may be a promising therapeutic strategy for TBI-induced cerebral edema.

Background: All of the existing medication and surgical therapies currently cannot completely inhibit intracerebral hemorrhage (ICH)-mediated brain damage, resulting in disability in different degrees in the involved patients. Normobaric oxygenation (NBO) was reported attenuating ischemic brain injury. Herein, we aimed to explore the safety and efficacy of NBO on rescuing the damaged brain tissues secondary to acute ICH, especially those in the perihematoma area being threatened by ischemia and hypoxia., Methods: A total of 150 patients confirmed as acute spontaneous ICH by computed tomography (CT) within 6 h after symptoms onset, will enroll in this study after signing the informed consent, and enter into the NBO group or control group randomly according to a random number. In the NBO group, patients will inhale high-flow oxygen (8 L/min, 1 h each time for 6 cycles daily) and intake low-flow oxygen (2 L/min) in intermittent periods by mask for a total of 7 days. While in the control group, patients will breathe in only low-flow oxygen (2 L/min) by mask for 7 consecutive days. Computed tomography and perfusion (CT/CTP) will be used to evaluate cerebral perfusion status and brain edema. CT and CTP maps in the two groups at baseline and day 7 and 14 after NBO or low-flow oxygen control will be compared. The primary endpoint is mRS at both Day14 post-ICH and the end of the 3rd month follow-up. The secondary endpoints include NIHSS and plasma biomarkers at baseline and Day-1, 7, and 14 after treatment, as well as the NIHSS at the end of the 3rd month post-ICH and the incidence of bleeding recurrence and the mortalities within 3 months post-ICH., Discussion: This study will provide preliminary clinical evidence about the safety and efficacy of NBO on correcting acute ICH and explore some mechanisms accordingly, to offer reference for larger clinical trials in the future., Trial Registration: ClinicalTrials.gov NCT04144868 . Retrospectively registered on October 29, 2019.

Neurocysticercosis (NCC) is a disease caused by infection of the central nervous system with the larval stage of the tapeworm Taenia solium. This disease is endemic in many parts of the world, including Africa, Asia, and Latin America, where animal husbandry practices are common such that pigs reared for human consumption ingest feces from humans infected with T. solium . Neurocysticercosis is rarely acquired in economically affluent regions, including North America, Central Europe, Japan, and Australasia, and in countries where pork consumption is discouraged by religious or social practices. In these countries, NCC is usually diagnosed in immigrants or returning travelers who have spent time in endemic regions. Here, we report a case of NCC in a 25-year-old woman presenting with worsening visual symptoms in association with headache, diagnosed previously as a migraine with visual aura. This person had always lived in Australia and had never traveled overseas to a country endemic for T. solium . The unusual features of the clinical presentation and epidemiology are highlighted to raise physicians' awareness that attention needs to be paid to the risk of autochthonous infection occurring in non-endemic countries.