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Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae . Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications. Neutrophils play critical roles in the host response to bacteria, including the production neutrophil extracellular traps (NET). Here the authors show that NET formation in the context of pneumococcal meningitis impairs bacterial clearance and targeting NET formation in this context could be a potential therapeutic option.

Background Despite recent advances in neuroimaging and neurocritical care, severe traumatic brain injury (TBI) is still a major cause of severe disability and mortality, with increasing incidence worldwide. Antisecretory factor (AF), commercially available as Salovum®, has been shown to lower intracranial pressure (ICP) in experimental models of, e.g., TBI and herpes encephalitis. The aim of this study is to assess the effect of antisecretory factors in adult patients with severe TBI on ICP and inflammatory mediators in extracellular fluid and plasma. Methods/design This is a single-center, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement during 5 days to adults with severe TBI (Glasgow Coma Scale (GCS) < 9), admitted to the neurocritical intensive care unit (NICU) at Skane university hospital, Lund, Sweden. All patients with GCS < 9 and clinical indication for insertion of ICP-monitor and microdialysis catheter will be screened for inclusion and assigned to either the treatment group ( n  = 10) or placebo group ( n  = 10). In both groups, the primary outcome will be ICP (mean values and change from baseline during intervention), registered from high-frequency data monitoring for 5 days. Secondary outcomes will be inflammatory mediators in plasma and intracerebral microdialysis perfusate days 1, 3, and 5 during trial treatment. Trial registration ClinicalTrials.gov NCT04117672 . Registered on September 17, 2017. Protocol version 6 from October 24, 2023.

Background Glioblastoma, IDH wildtype is the most common primary malignant brain tumor in adults. Despite best available treatment, prognosis remains poor. Current standard therapy consists of surgical tumor removal followed by radiotherapy and chemotherapy with the alkylating agent temozolomide. Antisecretory factor (AF), an endogenous protein, may potentiate the effect of temozolomide and alleviate cerebral edema. Salovum® is an egg-yolk powder enriched for AF and is classified as a medical food in the European Union. Salovum® has shown preliminary clinical effect on glioblastoma in a recent pilot study. Here, we aim to assess if add-on Salovum® to temozolomide therapy can improve outcomes in patients with newly diagnosed glioblastoma. Methods This is a multi-center, double-blinded, randomized, placebo-controlled phase II-III clinical trial to investigate superiority of Salovum® over placebo as add-on treatment for glioblastoma during concomitant and adjuvant temozolomide therapy. Patients with newly diagnosed glioblastoma that are planned for temozolomide treatment are screened for eligibility and randomized to receive Salovum® ( n  = 150) or placebo ( n  = 150). An interim analysis will be performed after 80 included patients to guide whether to continue or terminate. Primary endpoint is 12-month overall survival. Secondary outcome is 24-month overall survival. Discussion This study will likely produce high-grade evidence to support or reject Salovum® as add-on treatment for glioblastoma. Trial registration ClinicalTrials.gov NCT05669820 . Registered on January 3, 2023.

Medulloblastoma and glioblastoma are the most common malignant primary brain tumors in children and adults, respectively. Tumor-associated macrophages and microglia are key non-cancerous cell types in these tumors. These cells interact with CD24, a so called “don’t eat me signal” expressed on tumor cells, through Siglec-10, a receptor that contributes to immune evasion by promoting an immunosuppressive environment. The CD24/Siglec-10 interaction in context of malignant brain tumors has been scarcely studied.In silico analyses reveal that CD24 gene expression correlates with specific gene signatures associated with prognosis in both medulloblastoma and glioblastoma. In both human- and mouse brain tumors, Siglec-10 + cells co-express the microglia-associated molecule TREM2. Treatment with mitoxantrone as an immunogenic cell-death-inducing cytostatic agent led to a dose-dependent reduction in cell viability and cell surface CD24 levels in both murine and human brain tumor cell cultures. Intratumoral mitoxantrone administration in a murine CD24-high glioma model extended survival, decreased tumor size, reduced Siglec-10 + /TREM2 + cell populations, and increased anti-tumor CD8 + cells. These findings suggest that targeting the CD24/Siglec-10 axis with mitoxantrone may modulate the tumor microenvironment and enhance anti-tumor immunity.  Keywords : CD24, Siglec-10, Mitoxantrone, Malignant brain tumor, Immunotherapy.

Background Traumatic brain injury (TBI) constitutes a global epidemic. Overall outcome is poor, with mortality ranging from 10 to 70% and significant long-term morbidity. Several experimental reports have claimed effect on traumatic edema, but no clinical trials have shown effect on edema or outcome. Antisecretory factor, an endogenous protein, is commercially available as Salovum®, which is classified as a medical food by the European Union and has shown effect in experimental trauma models and feasibility with signs of effect in 2 pilot case series. The aim of this study is to assess the effect of antisecretory factor in adult patients with severe traumatic brain injury as measured by 30-day mortality, treatment intensity level (TIL), and intracranial pressure (ICP). Methods/design This is a single-center, double-blind, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement to adults with severe TBI (GCS < 9), presenting to the trauma unit at Tygerberg University Hospital, Cape Town, South Africa, that are planned for invasive ICP monitoring and neurointensive care, will be screened for eligibility, and assigned to either treatment group ( n  = 50) or placebo group ( n  = 50). In both groups, the primary outcome will be 30-day mortality, recorded via hospital charts, follow-up phone calls, and the population registry. Secondary outcomes will be treatment intensity level (TIL), scored from hospital charts, and ICP registered from hospital data monitoring. Trial registration ClinicalTrials.gov NCT03339505 . Registered on September 17, 2017. Protocol version 3.0 from November 13, 2020

Purpose Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite the best available treatment, prognosis remains poor. Current standard therapy consists of surgical removal of the tumor followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Experimental studies suggest that antisecretory factor (AF), an endogenous protein with proposed antisecretory and anti-inflammatory properties, may potentiate the effect of TMZ and alleviate cerebral edema. Salovum is an egg yolk powder enriched for AF and is classified as a medical food in the European Union. In this pilot study, we evaluate the safety and feasibility of add-on Salovum in GBM patients. Methods Eight patients with newly diagnosed, histologically confirmed GBM were prescribed Salovum during concomitant radiochemotherapy. Safety was determined by the number of treatment-related adverse events. Feasibility was determined by the number of patients who completed the full prescribed Salovum treatment. Results No serious treatment-related adverse events were observed. Out of 8 included patients, 2 did not complete the full treatment. Only one of the dropouts was due to issues directly related to Salovum, which were nausea and loss of appetite. Median survival was 23 months. Conclusions We conclude that Salovum is safe to use as an add-on treatment for GBM. In terms of feasibility, adherence to the treatment regimen requires a determined and independent patient as the large doses prescribed may cause nausea and loss of appetite. Trial registration ClinicalTrials.gov NCT04116138. Registered on 04/10/2019.

Diagnosis of ventriculostomy related infections (VRI) in the neuro-intensive care unit remains challenging and current biomarkers lack adequate precision. The aim of this study was to explore the potential of Heparin-binding protein (HBP) in cerebrospinal fluid (CSF) as a diagnostic biomarker of VRI. All patients treated with an external ventricular drain (EVD) between January 2009 and March 2010 at Skåne university hospital in Lund, Sweden, were consecutively included. CSF samples obtained during routine care were analyzed for HBP. VRI was defined as a positive bacterial microbiology test result on a CSF sample with an erythrocyte-corrected leukocyte count of > 50 × 106/l. HBP levels at VRI diagnosis was compared to peak HBP levels in non-VRI controls. In total, 394 CSF samples from 103 patients were analyzed for HBP. Seven patients (6.8%) fulfilled VRI criteria. Levels of HBP were significantly higher in VRI subjects (31.7 ng/mL [IQR 26.9–40.7 ng/mL]) compared to non-VRI controls (7.7 ng/mL [IQR 4.1–24.5 ng/mL]) (p = 0.024). The AUC of the receiver operating characteristic (ROC) curve was 0.76 (95% confidence interval [CI], 0.62–0.90). Among non-VRI patients, HBP was highest in patients with acute bacterial meningitis. Patients with subarachnoid hemorrhage displayed higher HBP levels than those with traumatic brain injury or shunt dysfunction. HBP levels were higher in VRI subjects and varied between patients and different diagnoses. To validate the clinical usefulness and added value of HBP as a biomarker for VRI, the results need to be confirmed in larger studies with head-to-head comparisons to current biomarkers. •Ventriculostomy related infections (VRIs) are challenging to diagnose.•Heparin-binding protein (HBP) in CSF could be a clinically relevant biomarker.•CSF HBP was higher in subjects with VRI, compared to non-VRI controls.•The sensitivity and specificity of CSF HBP was lower than in a previous study.•Limitations in the gold-standard (bacterial culture) provide challenges.

Background Current guidelines for the treatment of severe TBI recommend maintaining a cerebral perfusion pressure (CPP) at 60–70 mmHg. In our institution, as well as others, an alternative algorithm—originally named the Lund concept—has been used. This treatment algorithm employs metoprolol and clonidine to limit CPP, accepting levels below 60 mmHg, with the aim of reducing cerebral edema. Previous reports on this algorithm have shown promising outcome in severe TBI cohorts when compared with many contemporary practices; however, no population-based studies have been conducted to validate these findings. Research Question: What is the outcome in adult severe TBI using the Lund Concept algorithm in a population-based cohort and how are CPP levels lower than 60 mmHg tolerated? Methods The study included 135 evaluable adult patients out of 171 admitted with severe TBI over a ten-year period in the southern Swedish healthcare region. Baseline data, intracranial pressure (ICP), CPP, treatment duration, surgical interventions, and administered drugs were correlated to the Glasgow Outcome Scale Extended (GOSE). Results The 30-day and 6-month mortality rates were 16% and 20%, respectively. A favorable outcome (GOSE 5–8) was achieved in 48% of patients. Only increasing age was associated with inferior outcomes. Conclusion The use of a management protocol accepting lower CPP levels than those recommended in existing guidelines was generally well tolerated with outcome in line with comparable reports.

Background Delayed cerebral ischemia (DCI), a complication of subarachnoid hemorrhage (SAH), is linked to cerebral vasospasm and associated with poor long-term outcome. We implemented a structured cerebral microdialysis (CMD) based protocol using the lactate/pyruvate ratio (LPR) as an indicator of the cerebral energy metabolic status in the neurocritical care decision making, using an LPR ≥ 30 as a cutoff suggesting an energy metabolic disturbance. We hypothesized that CMD monitoring could contribute to active, protocol-driven therapeutic interventions that may lead to the improved management of patients with SAH. Methods Between 2018 and 2020, 49 invasively monitored patients with SAH, median Glasgow Coma Scale 11 (range 3–15), and World Federation of Neurosurgical Societies scale 4 (range 1–5) on admission receiving CMD were included. We defined a major CMD event as an LPR ≥ 40 for ≥ 2 h and a minor CMD event as an LPR ≥ 30 for ≥ 2 h. Results We analyzed 7,223 CMD samples over a median of 6 days (5–8). Eight patients had no CMD events. In 41 patients, 113 minor events were recorded, and in 23 patients 42 major events were recorded. Our local protocols were adhered to in 40 major (95%) and 98 minor events (87%), with an active intervention in 32 (76%) and 71 (63%), respectively. Normalization of energy metabolic status (defined as four consecutive samples with LPR < 30 for minor and LPR < 40 for major events) was seen after 69% of major and 59% of minor events. The incidence of DCI-related infarcts was 10% (five patients), with only two observed in a CMD-monitored brain region. Conclusions Active interventions were initiated in a majority of LPR events based on CMD monitoring. A low DCI incidence was observed, which may be associated with the active interventions. The potential aid of CMD in the clinical decision-making targeting DCI needs confirmation in additional SAH studies.