Mette Katrine Schulz

Use of intracranial pressure monitoring in bacterial meningitis: a 10-year follow up on outcome and intracranial pressure versus head CT scans

Abstract Background: The aim of this study was to evaluate the clinical outcome of patients with severe bacterial meningitis where intracranial pressure (ICP) monitoring has been performed. Methods: A retrospective observational study including patients admitted 1st. January 2005 to 31st. December 2014. Thirty nine patients age 18–89 years were included. All the patients received intensive care with mechanical ventilation, ICP monitoring, sedation, antibiotics and corticosteroids according to current guidelines. Clinical outcome was defined as death during hospitalization or survival at hospital discharge. Results: The most common pathogen was Streptococcus pneumoniae (26; 67%). Thirteen patients died (33%) and neurologic impairment was noted in twenty two (84.6%) surviving patients. In S. pneumoniae cases patients with adverse outcome were significantly older (p = 0.0024) and immunosuppressed (p = 0.034). Lower mean-cerebral perfusion pressure (CPP) was found to correlate with adverse outcome (p = 0.005). Cerebrospinal fluid (CSF) was drained in fourteen patients. Increased ICP (>20 mmHg) was observed in twenty four patients. No significant correlation was found between measured ICP and head CT scans with signs of elevated ICP. Conclusions: Patients with severe meningitis should be admitted to intensive care units and evaluated for ICP monitoring regardless of head CT findings.

Estimation of Tumor Volumes by 11C-MeAIB and 18F-FDG PET in an Orthotopic Glioblastoma Rat Model

Brain tumor volume assessment is a major challenge. Molecular imaging using PET may be a promising option because it reflects the biologically active cells. We compared the agreement between PET- and histology-derived tumor volumes in an orthotopic glioblastoma rat model with a noninfiltrating (U87MG) and an infiltrating (T87) tumor phenotype using 2 different radiotracers, 2 different image reconstruction algorithms, parametric imaging, and 2 different image segmentation techniques. Methods: Rats with U87MG- and T87-derived glioblastomas were continuously scanned with PET for 1 h starting immediately after the injection of 11C-methylaminoisobutyric acid (11C-MeAIB). One hour later, 18F-FDG was injected, followed by a 3-h dynamic PET scan. Images were reconstructed using 2-dimensional ordered-subsets expectation maximization and 3-dimensional maximum a posteriori probability (MAP3D) algorithms. In addition, a parametric image, encompassing the entire tumor kinetics in a single image, was calculated on the basis of the 11C-MeAIB images. All reconstructed images were segmented by fixed thresholding of maximum voxel intensity (VImax) and mean background intensity. The agreement between PET- and histology-derived tumor volumes and intra- and interobserver agreement of the PET-derived volumes were evaluated using Bland–Altman plots. Results: By PET, the mean U87MG tumor volume was 35.0 mm3 using 18F-FDG and 34.1 mm3 with 11C-MeAIB, compared with 33.7 mm3 by histology. Corresponding T87 tumor volumes were 122.1 mm3 using 18F-FDG, 118.3 mm3 with 11C-MeAIB, and 125.4 mm3 by histology. None of these volumes were significantly different. The best agreement between PET- and histology-derived U87MG tumor volumes was achieved with 11C-MeAIB, MAP3D reconstruction, and fixed thresholding of VImax. The intra- and interobserver agreement was high using this method. For T87 tumors, the best agreement between PET- and histology-derived volumes was obtained using 18F-FDG, MAP3D reconstruction, and fixed thresholding of mean background intensity. The agreement using 11C-MeAIB, parametric imaging, and fixed thresholding of VImax was slightly inferior, but the intra- and interobserver agreement was clearly superior. Conclusion: Estimation of tumor volume by PET of noninfiltrating brain tumors was accurate and reproducible. In contrast, tumor volume estimation by PET of infiltrating brain tumors was difficult and hard to reproduce. On the basis of our results, PET evaluation of highly infiltrating brain tumors should be further developed.

Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures

Glioblastomas always recur despite surgery, radiotherapy and chemotherapy. A key player in the therapeutic resistance may be immature tumor cells with stem-like properties (TSCs) escaping conventional treatment. A group of promising molecular targets are microRNAs (miRs). miRs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. In this study we aimed to identify over-expressed TSC-related miRs potentially amenable for therapeutic targeting. We used non-differentiated glioblastoma spheroid cultures (GSCs) containing TSCs and compared these to xenografts using a NanoString nCounter platform. This revealed 19 over-expressed miRs in the non-differentiated GSCs. Additionally, non-differentiated GSCs were compared to neural stem cells (NSCs) using a microarray platform. This revealed four significantly over-expressed miRs in the non-differentiated GSCs in comparison to the NSCs. The three most over-expressed miRs in the non-differentiated GSCs compared to xenografts were miR-126, -137 and -128. KEGG pathway analysis suggested the main biological function of these over-expressed miRs to be cell-cycle arrest and diminished proliferation. To functionally validate the profiling results suggesting association of these miRs with stem-like properties, experimental over-expression of miR-128 was performed. A consecutive limiting dilution assay confirmed a significantly elevated spheroid formation in the miR-128 over-expressing cells. This may provide potential therapeutic targets for anti-miRs to identify novel treatment options for GBM patients.

The risk of developing seizures before and after primary brain surgery of low- and high-grade gliomas

OBJECTIVE To identify risk factors for developing seizures pre- and postoperatively in low- and high-grade gliomas. PATIENTS AND METHODS 282 patients undergoing neurosurgical tumor resection between 2013-2015 were included in the present single-center retrospective cohort study. Seizure incidences according to various variables were described. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors for both pre- and postoperative seizures. RESULTS 37.6% of patients presented with seizures before surgery, 18.4% developed seizures in the postoperative course, and 55.0% had no record of seizures pre- or postoperatively. Focal, cognitive, and other symptoms, tumors located in a non-eloquent area, and tumors ≥ 40 mm in diameter were found to be associated with a reduced risk of preoperative seizures, whereas hypertension or no comorbidity posed an increased risk. The presence of seizures pre- or perioperatively (≤ 24 h before and after surgery), and tumors located in the thalamus were associated with an increased risk of seizures in the postoperative course. CONCLUSION Predictors for pre- and postoperative seizures identified in this study should be taken into account and integrated into the present knowledge, when determining patients at increased risk of developing seizures. Future prospective studies investigating the efficacy of prophylactic antiepileptic therapy in subgroups of glioma patients are needed before applied into clinical practice.

Patterns of cerebral tissue oxygen tension and cytoplasmic redox state in bacterial meningitis

Compromised cerebral energy metabolism is common in patients with bacterial meningitis. In this study, simultaneous measurements of cerebral oxygen tension and lactate/pyruvate ratio were compared to explore whether disturbed energy metabolism was usually caused by insufficient tissue oxygenation or compromised oxidative metabolism of pyruvate indicating mitochondrial dysfunction.