Linezolid brain penetration in neurointensive care patients.

BACKGROUND: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. OBJECTIVES: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients. PATIENTS AND METHODS: Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe. RESULTS: The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L. CONCLUSIONS: Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.

An evaluation of physical and augmented patient-specific intracranial aneurysm simulators on microsurgical clipping performance and skills: a randomized controlled study.

OBJECTIVE: In the era of flow diversion, there is an increasing demand to train neurosurgeons outside the operating room in safely performing clipping of unruptured intracranial aneurysms. This study introduces a clip training simulation platform for residents and aspiring cerebrovascular neurosurgeons, with the aim to visualize peri-aneurysm anatomy and train virtual clipping applications on the matching physical aneurysm cases. METHODS: Novel, cost-efficient techniques allow the fabrication of realistic aneurysm phantom models and the additional integration of holographic augmented reality (AR) simulations. Specialists preselected suitable and unsuitable clips for each of the 5 patient-specific models, which were then used in a standardized protocol involving 9 resident participants. Participants underwent four sessions of clip applications on the models, receiving no interim training (control), a video review session (video), or a video review session and holographic clip simulation training (video + AR) between sessions 2 and 3. The study evaluated objective microsurgical skills, which included clip selection, number of clip applications, active simulation time, wrist tremor analysis during simulations, and occlusion efficacy. Aneurysm occlusions of the reference sessions were assessed by indocyanine green videoangiography, as well as conventional and photon-counting CT scans. RESULTS: A total of 180 clipping procedures were performed without technical complications. The measurements of the active simulation times showed a 39% improvement for all participants. A median of 2 clip application attempts per case was required during the final session, with significant improvement observed in experienced residents (postgraduate year 5 or 6). Wrist tremor improved by 29% overall. The objectively assessed aneurysm occlusion rate (Raymond-Roy class 1) improved from 76% to 80% overall, even reaching 93% in the extensively trained cohort (video + AR) (p = 0.046). CONCLUSIONS: The authors introduce a newly developed simulator training platform combining physical and holographic aneurysm clipping simulators. The development of exchangeable, aneurysm-comprising housings allows objective radio-anatomical evaluation through conventional and photon-counting CT scans. Measurable performance metrics serve to objectively document improvements in microsurgical skills and surgical confidence. Moreover, the different training levels enable a training program tailored to the cerebrovascular trainees' levels of experience and needs.

Malignant transformation of vestibular schwannoma following radiosurgery-a case report and review of the literature.

Malignant transformation of vestibular schwannoma (VS) post-radiosurgery is an extremely rare but life-threatening complication. We present a patient who underwent two surgeries for a benign VS and received Gamma Knife radiosurgery for residual tumour. Five and a half years post-radiosurgery, the patient was reoperated for symptomatic recurrence of the tumour. Histopathology confirmed the diagnosis of a high-grade spindle cell sarcoma. Although near-total resection was uneventful, the patient deteriorated rapidly, and comfort care was chosen. This report is the 13th documented case of histopathologically confirmed malignant transformation of a benign VS that strictly meets the modified Cahan's criteria, suggesting the direct link to radiosurgery-induced malignancy.

Cystic recurrence of vestibular schwannoma post-radiosurgery: an institutional experience.

BACKGROUND: Stereotactic radiosurgery effectively controls vestibular schwannoma (VS). However, in certain cases, microsurgical resection may be necessary for post-radiosurgery tumour progression. The characteristics and microsurgical challenges of uncommon cystic recurrences post-radiosurgery are rarely addressed. METHOD: We retrospectively analysed 24 consecutive patients who underwent microsurgical intervention for recurrent VS post-radiosurgery by the senior author. RESULTS: Tumour recurrence post-radiosurgery occurred as solid growth in 19 patients (79%), while 5 patients (21%) developed large brainstem-compressing cysts. The median time interval for tumour recurrence post-radiosurgery was similar between cystic and non-cystic recurrent VS (30 vs. 25 months; p=0.08). Cystic recurrences occurred in primarily cystic VS in 3 patients, and new cysts developed in 2 patients with primarily solid VS. Intra-operatively, tumours were firm in 18 cases (75%) and strongly adhered to surrounding structures in 14 cases (58%). All cystic cases underwent cyst decompression, while complete resection of solid tumour components was avoided due to neurovascular adherence. At a mean follow-up of 42±39 months, 12 patients (50%) showed contrast-enhancing tumour residuals in follow-up imaging, including all cystic recurrent cases. Tumour residuals remained stable without requiring further intervention, except for one patient revealing malignant tumour transformation. House-Brackmann grade I/II was preserved in 15 patients (62%). Three patients (13%) developed new facial palsy, and two patients (8%) improved to House-Brackmann grade II. Cystic recurrences had a significantly higher frequency of tumour residuals compared to solid recurrences (100% vs. 37%; p=0.01) but similar rates of facial palsy (60% vs. 32%; p=0.24) CONCLUSIONS: Cyst development in VS post-radiosurgery is more common in primary cystic lesions but can also occur in rare cases of primary solid VS. Symptomatic cysts require microsurgical decompression. However, complete resection of the solid tumour component is not crucial for long-term tumour control and should be avoided if it risks neurological function in this delicate area.

The Effect of Oral Nimodipine on Cerebral Metabolism and Hemodynamic Parameters in Patients Suffering Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: Nimodipine is routinely administered to aneurysmal subarachnoid hemorrhage patients to improve functional outcomes. Nimodipine can induce marked systemic hypotension, which might impair cerebral perfusion and brain metabolism. METHODS: Twenty-seven aneurysmal subarachnoid hemorrhage patients having multimodality neuromonitoring and oral nimodipine treatment as standard of care were included in this retrospective study. Alterations in mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), brain tissue oxygen tension (pbtO2), and brain metabolism (cerebral microdialysis), were investigated up to 120 minutes after oral administration of nimodipine (60 mg or 30 mg), using mixed linear models. RESULTS: Three thousand four hundred twenty-five oral nimodipine administrations were investigated (126±59 administrations/patient). After 60 mg of oral nimodipine, there was an immediate statistically significant (but clinically irrelevant) drop in MAP (relative change, 0.97; P<0.001) and CPP (relative change: 0.97; P<0.001) compared with baseline, which lasted for the whole 120 minutes observation period (P<0.001). Subsequently, pbtO2 significantly decreased 50 minutes after administration (P=0.04) for the rest of the observation period; the maximum decrease was -0.6 mmHg after 100 minutes (P<0.001). None of the investigated cerebral metabolites (glucose, lactate, pyruvate, lactate/pyruvate ratio, glutamate, glycerol) changed after 60 mg nimodipine. Compared with 60 mg nimodipine, 30 mg induced a lower reduction in MAP (relative change, 1.01; P=0.02) and CPP (relative change, 1.01; P=0.03) but had similar effects on pbtO2 and cerebral metabolism (P>0.05). CONCLUSIONS: Oral nimodipine reduced MAP, which translated into a reduction in cerebral perfusion and oxygenation. However, these changes are unlikely to be clinically relevant, as the absolute changes were minimal and did not impact cerebral metabolism.

Endovascular thrombectomy with or without intravenous thrombolysis in large-vessel ischemic stroke: A non-inferiority meta-analysis of 6 randomised controlled trials.

BACKGROUND: It is unclear whether thrombectomy alone is non-inferior to thrombectomy with intravenous thrombolysis in patients with acute ischemic stroke due to large-vessel occlusion. PURPOSE: To perform a comprehensive, trial-level data, non-inferiority meta-analysis of randomised controlled trials comparing endovascular thrombectomy with and without intravenous thrombolysis in patients with ischemic stroke due to large-vessel occlusion of anterior circulation. METHODS: The prespecified primary efficacy outcome was functional independence, defined as a modified Rankin scale (mRS)score of 0 to 2 at 90 days. The two prespecified non-inferiority margins were risk differences of -10% and - 5%. The study was registered in PROSPERO (CRD42022361110) and conducted according to PRISMA guidelines. RESULTS: Six trials were included in this analysis (DIRECT-MT, DEVT, SKIP, MR CLEAN-NO IV, DIRECT-SAFE and SWIFT DIRECT) comprising a total of 2334 patients. Functional independence at 90 days was achieved by 570 (49·0%) of 1164 patients in the thrombectomy alone group and 595 (50·9%) of 1170 patients in the thrombectomy with thrombolysis group (pooled risk difference - 0·02, [95% CI -0·06-0·02]). Combined thrombectomy and thrombolysis were associated with significantly higher rates of successful reperfusion (pooled risk ratio 0·96 [95% CI, 0·93-0·99], p = 0·006) but at the expense of a significantly increased risk of overall - but not symptomatic - intracranial haemorrhage (pooled risk ratio 0·87 [95% CI, 0·77-0·98], p = 0·02). CONCLUSIONS: Compared with a combined treatment approach, thrombectomy alone was non-inferior at -10% non-inferiority margin, but not at a - 5% inferiority margin for functional independence. Current evidence cannot exclude clinically important differences between the two treatment approaches.

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death.

Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death. Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry. We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines. Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.

CD34 microvascularity in low-grade glioma: correlation with 5-aminolevulinic acid fluorescence and patient prognosis in a multicenter study at three specialized centers.

OBJECTIVE: Early markers are urgently needed in low-grade glioma (LGG) evaluation to rapidly estimate the individual patient's prognosis and to determine the optimal postoperative management. Generally, visible 5-aminolevulinic acid (5-ALA) fluorescence is present in only a few LGGs. Recently, the authors identified visible 5-ALA fluorescence as a powerful intraoperative marker for unfavorable outcome in LGG treatment. However, its precise histopathological correlate is unclear. Neoangiogenesis represents a crucial event in tumor evolution, and CD34 is an established marker for vascular endothelial progenitors potentially indicating tumor progression. The aim of this study was thus to correlate 5-ALA fluorescence and CD34 microvascularity as well as to investigate the prognostic value of CD34 in a large series of LGGs. METHODS: In this retrospective study including 3 specialized centers, patients with histopathologically confirmed isocitrate dehydrogenase-mutated LGGs (WHO grade II) receiving 5-ALA prior to resection were included. During surgery, the presence of visible fluorescence was analyzed and one representative tumor sample from the area with the maximum fluorescence effect (tumor with focal fluorescence or nonfluorescing tumor) was selected for each LGG. All fluorescing or nonfluorescing tumor samples were stained for CD34 and semiquantitatively analyzed for microvascular proliferation patterns (physiological vessels, branching capillaries, or microvessel clusters) as well as automatically quantified for CD34 microvessel density (MVD) by standardized histomorphometry software. These semiquantitative/quantitative CD34 data were correlated to the fluorescence status and patient outcome including progression-free survival (PFS), malignant transformation-free survival (MTFS), and overall survival (OS). RESULTS: In a total of 86 LGGs, visible fluorescence was found during surgery in 13 (15%) cases. First, the semiquantitative CD34 score significantly correlated with intraoperative fluorescence (p = 0.049). Accordingly, the quantitative CD34 MVD was significantly higher in tumors showing fluorescence (p = 0.03). Altogether, the semiquantitative CD34 score showed a strong correlation with quantitative CD34 MVD (p < 0.001). At a mean follow-up of 5.4 ± 2.6 years, microvessel clusters in semiquantitative analysis were a prognostic marker for poor PFS (p = 0.01) and MTFS (p = 0.006), but not OS (p = 0.28). Finally, quantitative CD34 MVD > 10 vessels/mm2 was a prognostic marker for poor PFS (p = 0.01), MTFS (p = 0.008), and OS (p = 0.049). CONCLUSIONS: The data indicate that CD34 microvascularity is associated with intraoperative 5-ALA fluorescence and outcomes in patients with LGG. Thus, visible fluorescence in LGGs might indicate increased CD34 microvascularity, serving as an early prognostic marker for unfavorable patient outcome that is already available during surgery.

Meropenem Population Pharmacokinetics and Simulations in Plasma, Cerebrospinal Fluid, and Brain Tissue.

Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis of a previously published prospective study of patients admitted to the neurointesive care unit between 2016 and 2019 who received 2 g of meropenem intravenously every 8 h. Meropenem concentration was determined in blood, cerebrospinal fluid (CSF), and brain microdialysate. Meropenem was described by a six-compartment model: two compartments in the blood, two in the CSF, and two in the brain tissue. Creatinine clearance and brain glucose were included as covariates. The median elimination rate constant was 1.26 h-1, the central plasma volume was 5.38 L, and the transfer rate constants from the blood to the CSF and from the blood to the brain were 0.001 h-1 and 0.02 h-1, respectively. In the first 24 h, meropenem 2 g, administered every 8 h via intermittent and extended infusions achieved good target attainment in the CSF and brain, but continuous infusion (CI) was better at steady-state. Administering a 3 g loading dose (LD) followed by 8 g CI was beneficial for early target attainment. In conclusion, a meropenem PK model was developed using blood, CSF, and brain microdialysate samples. An 8 g CI may be needed for good target attainment in the CSF and brain. Giving a LD prior to the CI improved the probability of early target attainment.

Analysis of corticosteroid and antiepileptic drug treatment effects on heme biosynthesis mRNA expression in lower-grade gliomas: Potential implications for 5-ALA metabolization.

OBJECTIVES: Intraoperative visualization of gliomas with 5-aminolevulinic acid (5-ALA) induced fluorescence constitutes a powerful technique. While visible fluorescence is typically observed in high-grade gliomas, fluorescence is considerably less common in lower-grade gliomas (LGGs) WHO grade II&III. Whereas the exact mechanisms determining fluorescence in LGGs are not fully understood, metabolization of non-fluorescent 5-ALA to fluorescent Protoporphyrin IX by specific heme biosynthesis enzymes/transporters has been identified as relevant mechanism influencing fluorescence behavior. Furthermore, recent in-vitro studies have suggested preoperative treatment with corticosteroids and anti-epileptic drugs (AED) as potential factors influencing 5-ALA induced fluorescence. METHODS: The goal of this study was thus to investigate the effect of preoperative corticosteroid/AED treatment on heme biosynthesis mRNA expression in a clinically relevant patient population. For this purpose, we analyzed the mRNA expression levels of specific heme biosynthesis factors including ALAD, HMBS, UROS, UROD, CPOX, PPOX, FECH, ABCB6, ACG2, SLC15A1 and SLC15A2, ABCB1, ABCB10 in a cohort of LGGs from "The Cancer Genome Atlas". RESULTS: Altogether, 403 patients with available data on preoperative corticosteroid/AED treatment and heme biosynthesis mRNA expression were identified. Regarding corticosteroid treatment, no significant differences in expression of any of the 11 investigated heme biosynthesis factors were found. In contrast, a marginal yet statistically significant increase in SLC15A1 levels and decrease in ABCB6 levels were observed in patients with preoperative AED treatment. CONCLUSION: While no significant differences in heme biosynthesis mRNA expression were observed according to preoperative corticosteroid treatment, changes in SLC15A1 as well as ABCB6 expression were detected in patients treated with AED. However, since these alterations were minor and have opposing effects on 5-ALA metabolization, our findings do not support a distinct effect of AED and corticosteroid treatment on heme biosynthesis regulation in LGGs.

Combined standard bypass and parent artery occlusion for management of giant and complex internal carotid artery aneurysms.

BACKGROUND: Complex aneurysms do not have a standard protocol for treatment. In this study, we investigate the safety and efficacy of microsurgical revascularization combined with parent artery occlusion (PAO) in giant and complex internal carotid artery (ICA) aneurysms. METHODS: Between 1998 and 2017, 41 patients with 47 giant and complex ICA aneurysms were treated by an a priori planned combined treatment strategy. Clinical and radiological outcomes were stratified according to mRS and Raymond classification. Bypass patency was assessed. Median follow-up time was 3.9 years. RESULTS: After successful STA-MCA bypass, staged endovascular (n=37) or surgical (n=1) PAO was executed in 38 patients following a negative balloon occlusion test. Intolerance to PAO led to stent/coil treatments in two patients. Perioperative bypass patency was confirmed in 100% of completed STA-MCA bypass procedures. Long-term overall bypass patency rate was 99%. Raymond 1 occlusion and good outcome were achieved in 95% and 97% (mRS 0-2) of cases, respectively. No procedure-related mortality was encountered. Eighty-four percent of patients with preoperative cranial nerve compression syndromes improved during follow-up. CONCLUSIONS: The combined approach of STA-MCA bypass surgery followed by parent artery occlusion achieves high aneurysm occlusion and low morbidity rates in the management of giant and complex ICA aneurysms. This combined indirect approach represents a viable alternative to flow diversion in patients with cranial nerve compression syndromes or matricidal aneurysms, and may serve as a backup strategy in cases of peri-interventional complications or lack of suitable endovascular access.

Brain Tissue Oxygen Response as Indicator for Cerebral Lactate Levels in Aneurysmal Subarachnoid Hemorrhage Patients.

BACKGROUND: Early detection of cerebral ischemia and metabolic crisis is crucial in critically ill subarachnoid hemorrhage (SAH) patients. Variable increases in brain tissue oxygen tension (PbtO2) are observed when the fraction of inspired oxygen (FiO2) is increased to 1.0. The aim of this prospective study was to evaluate whether a 3-minute hyperoxic challenge can identify patients at risk for cerebral ischemia detected by cerebral microdialysis. METHODS: Twenty consecutive severe SAH patients undergoing continuous cerebral PbtO2 and microdialysis monitoring were included. FiO2 was increased to 1.0 for 3 minutes (the FiO2 challenge) twice a day and PbtO2 responses during the FiO2 challenges were related to cerebral microdialysis-measures, ie, lactate, the lactate-pyruvate ratio, and glycerol. Multivariable linear and logistic regression models were created for each outcome parameter. RESULTS: After predefined exclusions, 274 of 400 FiO2 challenges were included in the analysis. Lower absolute increases in PbtO2 (∆PbtO2) during FiO2 challenges were significantly associated with higher cerebral lactate concentration (P<0.001), and patients were at higher risk for ischemic lactate levels >4 mmol/L (odds ratio 0.947; P=0.04). Median (interquartile range) ∆PbtO2 was 7.1 (4.6 to 12.17) mm Hg when cerebral lactate was >4 mmol/L and 10.2 (15.76 to 14.24) mm Hg at normal lactate values (≤4 mmol/L). Median ∆PbtO2 was significantly lower during hypoxic than during hyperglycolytic lactate elevations (4.6 vs. 10.6 mm Hg, respectively; P<0.001). Lactate-pyruvate ratio and glycerol levels were mainly determined by baseline characteristics. CONCLUSIONS: A 3-minute FiO2 challenge is an easy to perform and feasible bedside diagnostic tool in SAH patients. The absolute increase in PbtO2 during the FiO2 challenge might be a useful surrogate marker to estimate cerebral lactate concentrations and might be used to identify patients at risk for impending ischemia.

Reply to Stummer, W.; Thomas, C. Comment on "Hosmann et al. 5-ALA Fluorescence Is a Powerful Prognostic Marker during Surgery of Low-Grade Gliomas (WHO Grade II)-Experience at Two Specialized Centers. Cancers 2021, 13, 2540".

We greatly appreciate Dr. Stummer's and Dr. Thomas's interest in our study and their important comments [...].

Quantitative analysis of human brain microdialysate for target site pharmacokinetics of major anesthetics ketamine, midazolam and propofol.

Brain microdialysis samples of intensive care patients treated with the essential anesthetics ketamine, midazolam and propofol were investigated. Importantly, despite decades of clinical use, comprehensive human cerebral pharmacokinetic data of these drugs is still missing. To encounter this apparent lack of knowledge, we combined cerebral microdialysis with leading-edge analytical instrumentation to monitor the neurochemistry of living human patients. For the quantitative analysis, high performing analytical approaches were developed that can handle minute sample volumes and possible ultralow target analyte levels. The developed methods provided detection limits below 100 ng L-1 for all target analytes and high precision (below 4% RSD intraday). Methods were linear between LODs and 100 µg L-1 for ketamine, 75 µg L-1 for midazolam and 10 µg L-1 for propofol respectively, with coefficients of determination R2≥ 0.999. Further, being aware of the error-prone and demanding translation of microdialysis levels to interstitial concentrations, in vitro approaches for recovery testing of microdialysis probes as well as internal normalization approaches were conducted. Thus, we herein report the first cerebral pharmacokinetic data of ketamine, midazolam and propofol determined in microdialysis samples of 15 neurointensive care patients. We could prove blood-brain barrier penetration of all of the investigated anesthetics and could correlate applied dosages and actual brain exposition of ketamine. However, we emphasize the need of an expanded prospective study including individual microdialysis recovery testing as well as matched serum and/or cerebrospinal fluid collection for a more comprehensive cerebral pharmacokinetic understanding.

Meropenem concentrations in brain tissue of neurointensive care patients exceed CSF levels.

BACKGROUND: Inadequate antibiotic exposure in cerebral infections might have detrimental effects on clinical outcome. Commonly, antibiotic concentrations within the CSF were used to estimate cerebral target levels. However, the actual pharmacological active unbound drug concentration beyond the blood-brain barrier is unknown. OBJECTIVES: To compare meropenem concentrations in blood, CSF and cerebral microdialysate of neurointensive care patients. PATIENTS AND METHODS: In 12 patients suffering subarachnoid haemorrhage, 2000 mg of meropenem was administered every 8 h due to an extracerebral infection. Meropenem concentrations were determined in blood, CSF and cerebral microdialysate at steady state (n = 11) and following single-dose administration (n = 5). RESULTS: At steady state, the free AUC0-8 was 233.2 ± 42.7 mg·h/L in plasma, 7.8 ± 1.9 mg·h/L in CSF and 26.6 ± 14.0 mg·h/L in brain tissue. The brain tissue penetration ratio (AUCbrain/AUCplasma) was 0.11 ± 0.06, which was more than 3 times higher than in CSF (0.03 ± 0.01), resulting in an AUCCSF/AUCbrain ratio of 0.41 ± 0.16 at steady state. After single-dose administration similar proportions were achieved (AUCbrain/AUCplasma = 0.09 ± 0.08; AUCCSF/AUCplasma = 0.02 ± 0.00). Brain tissue concentrations correlated well with CSF concentrations (R = 0.74, P < 0.001), but only moderately with plasma concentrations (R = 0.51, P < 0.001). Bactericidal thresholds were achieved in both plasma and brain tissue for MIC values ≤16 mg/L. In CSF, bactericidal effects were only reached for MIC values ≤1 mg/L. CONCLUSIONS: Meropenem achieves sufficient bactericidal concentrations for the most common bacterial strains of cerebral infections in both plasma and brain tissue, even in non-inflamed brain tissue. CSF concentrations would highly underestimate the target site activity of meropenem beyond the blood-brain barrier.

The Evoked Potential Score for SSEP and BAEP-A Prognostic Marker for the Long-Term Neurological Outcome in Patients after Poor-Grade Subarachnoid Hemorrhage.

OBJECTIVE: Evoked potentials are widely used in comatose patients to evaluate neurological function; however, prognostic relevance in patients after SAH is barely investigated. Therefore, we aimed to investigate the prognostic value of the proposed Evoked Potential Score (EPS) for somatosensory (SSEP) and brainstem auditory evoked potentials (BAEP) on the neurological outcome in patients after poor-grade SAH. METHODS: We retrospectively analyzed patients after poor grade SAH (Hunt and Hess (HH) grade IV and V) that were admitted to the ICU at the Department of Neurosurgery, MUV, between 2014 and 2017. Measurements of SSEP and BAEP were evaluated separately as well as in a combined model, using the EPS at admission and before ventilator weaning and correlated with the grade of the modified ranking scale at the last available follow up. RESULTS: In total, 48 patients after SAH HH IV/V were included in this study. The EPS for SSEP at admission (p = 0.007) and both the EPS for SSEP (p = <0.0001) and BAEP (p = 0.036) before ventilator weaning were significant prognostic markers for neurological improvement at a mean follow-up period of 14.1 months. In addition, the combined model of the EPS for SSEP/BAEP performed as a prognostic marker for neurological improvement ("at admission" p = 0.007; "before ventilator weaning" p < 0.001). CONCLUSIONS: In the first series to date we found a high prognostic significance for the EPS as a combined model, as well as a separate analysis for SSEP and BAEP in patients after SAH IV and V. In the future, these findings potentially support physicians in ethically challenging decision-making processes and in advice for patients' families under consideration of an individual evaluation of each patient.

5-ALA Fluorescence Is a Powerful Prognostic Marker during Surgery of Low-Grade Gliomas (WHO Grade II)-Experience at Two Specialized Centers.

The prediction of the individual prognosis of low-grade glioma (LGG) patients is limited in routine clinical practice. Nowadays, 5-aminolevulinic acid (5-ALA) fluorescence is primarily applied for improved intraoperative visualization of high-grade gliomas. However, visible fluorescence is also observed in rare cases despite LGG histopathology and might be an indicator for aggressive tumor behavior. The aim of this study was thus to investigate the value of intraoperative 5-ALA fluorescence for prognosis in LGG patients. We performed a retrospective analysis of patients with newly diagnosed histopathologically confirmed LGG and preoperative 5-ALA administration at two independent specialized centers. In this cohort, we correlated the visible intraoperative fluorescence status with progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS). Altogether, visible fluorescence was detected in 7 (12%) of 59 included patients in focal intratumoral areas. At a mean follow-up time of 5.3 ± 2.9 years, patients with fluorescing LGG had significantly shorter PFS (2.3 ± 0.7 vs. 5.0 ± 0.4 years; p = 0.01), MTFS (3.9 ± 0.7 vs. 8.0 ± 0.6 years; p = 0.03), and OS (5.4 ± 1.0 vs. 10.3 ± 0.5 years; p = 0.01) than non-fluorescing tumors. Our data indicate that visible 5-ALA fluorescence during surgery of pure LGG might be an already intraoperatively available marker of unfavorable patient outcome and thus close imaging follow-up might be considered.

How to predict the consistency and vascularity of meningiomas by MRI: an institutional experience.

OBJECTIVE: In surgery for meningiomas tumor location and extension is currently the only MRI characteristic used to predict the feasibility and difficulty of the resection. Key surgical tumor characteristics such as consistency and vascularity remain obscured until the tumor is exposed. We therefore aimed to identify MRI sequences able to predict these crucial meningioma features. METHODS: We retrospectively reviewed our imaging database on cranial meningiomas and correlated MRI T2W, T1W, and FLAIR images with the consistency and vascularity reported by the surgeon in the operative notes. The reported consistency was classified into three grades [°I (soft) to °III (hard)]. Vascularity was grouped into little (°I) versus strong (°II). MRI signal intensity (SI) ratios were calculated with ROIs in the meningioma, the buccinator muscle and the frontal white matter. RESULTS: Of the 172 reviewed patients, 44 met the strict inclusion criteria with respect to the quality of the OR notes. The included meningiomas were located at the convexity (11/44), falcine (3/44), skull base (14/44), and posterior fossa (16/44). Twenty-four meningiomas (54.5%) were classified as consistency grade (°)I, seven (15.9%) °II, and thirteen (29.5%) °III. The grade of vascularization was little in 12 and strong in 14. The higher the ratio on T2W images the softer (p = 0.020) and the more vascularized (p = 0.001) the tumor presented. DISCUSSION: T2W MR images may be helpful to characterize meningiomas with regard to the expected consistency and grade of vascularization.