All Three Supersystems-Nervous, Vascular, and Immune-Contribute to the Cortical Infarcts After Subarachnoid Hemorrhage.

The recently published DISCHARGE-1 trial supports the observations of earlier autopsy and neuroimaging studies that almost 70% of all focal brain damage after aneurysmal subarachnoid hemorrhage are anemic infarcts of the cortex, often also affecting the white matter immediately below. The infarcts are not limited by the usual vascular territories. About two-fifths of the ischemic damage occurs within ~ 48 h; the remaining three-fifths are delayed (within ~ 3 weeks). Using neuromonitoring technology in combination with longitudinal neuroimaging, the entire sequence of both early and delayed cortical infarct development after subarachnoid hemorrhage has recently been recorded in patients. Characteristically, cortical infarcts are caused by acute severe vasospastic events, so-called spreading ischemia, triggered by spontaneously occurring spreading depolarization. In locations where a spreading depolarization passes through, cerebral blood flow can drastically drop within a few seconds and remain suppressed for minutes or even hours, often followed by high-amplitude, sustained hyperemia. In spreading depolarization, neurons lead the event, and the other cells of the neurovascular unit (endothelium, vascular smooth muscle, pericytes, astrocytes, microglia, oligodendrocytes) follow. However, dysregulation in cells of all three supersystems-nervous, vascular, and immune-is very likely involved in the dysfunction of the neurovascular unit underlying spreading ischemia. It is assumed that subarachnoid blood, which lies directly on the cortex and enters the parenchyma via glymphatic channels, triggers these dysregulations. This review discusses the neuroglial, neurovascular, and neuroimmunological dysregulations in the context of spreading depolarization and spreading ischemia as critical elements in the pathogenesis of cortical infarcts after subarachnoid hemorrhage.

EpiDiP/NanoDiP: a versatile unsupervised machine learning edge computing platform for epigenomic tumour diagnostics.

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame.

Navigated bedside implantation of external ventricular drains with mobile health guidance: technical note and case series.

PURPOSE: External ventricular drain (EVD) implantation is one of the fundamental procedures of emergency neurosurgery usually performed freehand at bedside or in the operating room using anatomical landmarks. However, this technique is frequently associated with malpositioning leading to complications or dysfunction. Here, we describe a novel navigated bedside EVD insertion technique, which is evaluated in a clinical case series with the aim of safety, accuracy, and efficiency in neurosurgical emergency settings. METHODS: From 2021 to 2022, a mobile health-assisted navigation instrument (Thomale Guide, Christoph Miethke, Potsdam, Germany) was used alongside a battery-powered single-use drill (Phasor Health, Houston, USA) for bedside EVD placement in representative neurosurgical pathologies in emergency situations requiring ventricular cerebrospinal fluid (CSF) relief and intracranial pressure (ICP) monitoring. RESULTS: In all 12 patients (8 female and 4 male), navigated bedside EVDs were placed around the foramen of Monro at the first ventriculostomy attempt. The most frequent indication was aneurysmal subarachnoid hemorrhage. Mean operating time was 25.8 ± 15.0 min. None of the EVDs had to be revised due to malpositioning or dysfunction. Two EVDs were converted into a ventriculoperitoneal shunt. Drainage volume was 41.3 ± 37.1 ml per day in mean. Mean length of stay of an EVD was 6.25 ± 2.8 days. Complications included one postoperative subdural hematoma and cerebrospinal fluid infection, respectively. CONCLUSION: Combining a mobile health-assisted navigation instrument with a battery-powered drill and an appropriate ventricular catheter may enable and enhance safety, accuracy, and efficiency in bedside EVD implantation in various pathologies of emergency neurosurgery without adding relevant efforts.

Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Template-based target point localization for occlusion of the middle meningeal artery during evacuation of space-occupying chronic subdural hematoma.

OBJECTIVE: Endovascular middle meningeal artery (MMA) occlusion may help reduce the risk of recurrence after burr hole evacuation of chronic subdural hematoma (cSDH) but carries an additional periprocedural risk and remains hampered by logistical and financial requirements. In this study, the authors aimed to describe a simple and fast technique for preoperative MMA localization to permit burr hole cSDH evacuation and MMA occlusion through the same burr hole. METHODS: The authors performed a preclinical anatomical and prospective clinical study, followed by a retrospective feasibility analysis. An anatomical cadaver study with 33 adult human skulls (66 hemispheres) was used to localize a suitable frontal target point above the pterion, where the MMA can be accessed via burr hole trephination. Based on anatomical landmark measurements, the authors designed a template for projected localization of this target point onto the skin. Next, the validity of the template was tested using image guidance in 10 consecutive patients undergoing elective pterional craniotomy, and the feasibility of the target point localization for cSDH accessibility was determined based on hematoma localization in 237 patients who were treated for a space-occupying cSDH in the authors' department between 2014 and 2018. RESULTS: In the anatomical study, the mean perpendicular distance from the zygomatic process to the target point in the frontoparietal bone was 4.1 cm (95% CI 4-4.2 cm). The mean length along the upper margin of the zygomatic process from the middle of the external auditory canal to the point of the perpendicular distance was 2.3 cm (95% CI 2.2-2.4 cm). The template designed according to these measurements yielded high agreement between the template-based target point and the proximal MMA groove inside the frontoparietal bone (right 90.9%; left 93.6%). In the clinical validation, we noted a mean distance of 4 mm (95% CI 2.1-5.9 mm) from the template-based target point to the actual MMA localization. The feasibility analysis yielded that 95% of all cSDHs in this cohort would have been accessible by the new frontal burr hole localization. CONCLUSIONS: A template-based target point approach for MMA localization may serve as a simple, fast, reliable, and cost-effective technique for surgical evacuation of space-occupying cSDHs with MMA obliteration through the same burr hole in a single setting.

Human Taenia martis Neurocysticercosis, Switzerland.

Neurocysticercosis is almost exclusively caused by Taenia solium tapeworms. We describe a case of neurocysticercosis in Switzerland caused by infection with Taenia martis, the marten tapeworm, and review all 5 published cases of human infection with the marten tapeworm. In epidemiologically nonplausible cases of neurocysticercosis, zoonotic spillover infections should be suspected.

Opportunities and challenges of supervised machine learning for the classification of motor evoked potentials according to muscles.

BACKGROUND: Even for an experienced neurophysiologist, it is challenging to look at a single graph of an unlabeled motor evoked potential (MEP) and identify the corresponding muscle. We demonstrate that supervised machine learning (ML) can successfully perform this task. METHODS: Intraoperative MEP data from supratentorial surgery on 36 patients was included for the classification task with 4 muscles: Extensor digitorum (EXT), abductor pollicis brevis (APB), tibialis anterior (TA) and abductor hallucis (AH). Three different supervised ML classifiers (random forest (RF), k-nearest neighbors (kNN) and logistic regression (LogReg)) were trained and tested on either raw or compressed data. Patient data was classified considering either all 4 muscles simultaneously, 2 muscles within the same extremity (EXT versus APB), or 2 muscles from different extremities (EXT versus TA). RESULTS: In all cases, RF classifiers performed best and kNN second best. The highest performances were achieved on raw data (4 muscles 83%, EXT versus APB 89%, EXT versus TA 97% accuracy). CONCLUSIONS: Standard ML methods show surprisingly high performance on a classification task with intraoperative MEP signals. This study illustrates the power and challenges of standard ML algorithms when handling intraoperative signals and may lead to intraoperative safety improvements.

Comparison of intraoperative CT- and cone beam CT-based spinal navigation for the treatment of atlantoaxial instability.

BACKGROUND CONTEXT: Due to the complexity of neurovascular structures in the atlantoaxial region, spinal navigation for posterior C1-C2 instrumentation is nowadays a helpful tool to increase accuracy of surgery and safety of patients. Many available intraoperative navigation devices have proven their reliability in this part of the spine. Two main imaging techniques are used: intraoperative CT (iCT) and cone beam computed tomography (CBCT). PURPOSE: Comparison of iCT- and CBCT-based technologies for navigated posterior instrumentation in C1-C2 instability. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: A total of 81 consecutive patients from July 2014 to April 2020. OUTCOME MEASURES: Screw accuracy and operating time. METHODS: Patients with C1-C2 instability received posterior instrumentation using C2 pedicle screws, C1 lateral mass or pedicle screws. All screws were inserted using intraoperative imaging either using iCT or CBCT systems and spinal navigation with autoregistration technology. Following navigated screw insertion, a second intraoperative scan was performed to assess the accuracy of screw placement. Accuracy was defined as the percentage of correctly placed screws or with minor cortical breach (<2 mm) as graded by an independent observer compared to misplaced screws. RESULTS: A total of 81 patients with C1-C2 instability were retrospectively analyzed. Of these, 34 patients were operated with the use of iCT and 47 with CBCT. No significant demographic difference was found between groups. In the iCT group, 97.7% of the C1-C2 screws were correctly inserted; 2.3% showed a minor cortical breach (<2 mm); no misplacement (>2 mm). In the CBCT group, 98.9% of screws were correctly inserted; no minor pedicle breach; 1.1% showed misplacement >2 mm. Accuracy of screw placement demonstrated no significant difference between groups. Both technologies allowed sufficient identification of screw misplacement intraoperatively leading to two screw revisions in the iCT and three in the CBCT group. Median time of surgery was significantly shorter using CBCT technology (166.5 minutes [iCT] vs 122 minutes [CBCT]; p<.01). CONCLUSIONS: Spinal navigation using either iCT- or CBCT-based systems with autoregistration allows safe and reliable screw placement and intraoperative assessment of screw positioning. Using the herein presented procedural protocols, CBCT systems allow shorter operating time.

Resolution of Cerebral Inflammation Following Subarachnoid Hemorrhage.

BACKGROUND: Aneurismal subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that, despite improvement through therapeutic interventions, remains a devastating cerebrovascular disorder that has a high mortality rate and causes long-term disability. Cerebral inflammation after SAH is promoted through microglial accumulation and phagocytosis. Furthermore, proinflammatory cytokine release and neuronal cell death play key roles in the development of brain injury. The termination of these inflammation processes and restoration of tissue homeostasis are of utmost importance regarding the possible chronicity of cerebral inflammation and the improvement of the clinical outcome for affected patients post SAH. Thus, we evaluated the inflammatory resolution phase post SAH and considered indications for potential tertiary brain damage in cases of incomplete resolution. METHODS: Subarachnoid hemorrhage was induced through endovascular filament perforation in mice. Animals were killed 1, 7 and 14 days and 1, 2 and 3 months after SAH. Brain cryosections were immunolabeled for ionized calcium-binding adaptor molecule-1 to detect microglia/macrophages. Neuronal nuclei and terminal deoxyuridine triphosphate-nick end labeling staining was used to visualize secondary cell death of neurons. The gene expression of various proinflammatory mediators in brain samples was analyzed by quantitative polymerase chain reaction. RESULTS: We observed restored tissue homeostasis due to decreased microglial/macrophage accumulation and neuronal cell death 1 month after insult. However, the messenger RNA expression levels of  interleukin 6  and  tumor necrosis factor α were still elevated at 1 and 2 months post SAH, respectively. The gene expression of interleukin 1ß reached its maximum on day 1, whereas at later time points, no significant differences between the groups were detected. CONCLUSIONS: By the herein presented molecular and histological data we provide an important indication for an incomplete resolution of inflammation within the brain parenchyma after SAH. Inflammatory resolution and the return to tissue homeostasis represent an important contribution to the disease's pathology influencing the impact on brain damage and outcome after SAH. Therefore, we consider a novel complementary or even superior therapeutic approach that should be carefully rethought in the management of cerebral inflammation after SAH. An acceleration of the resolution phase at the cellular and molecular levels could be a potential aim in this context.

A minimally invasive tubular retractor-assisted retropleural approach for thoracic disc herniations - case series and technical note.

PURPOSE: Thoracic disc herniations are uncommon and carry a high risk for neurological deterioration. Traditional surgical approaches include thoracotomy, costotransversectomy or posterior approaches with considerable morbidity. In this technical note with case series, we describe a minimally invasive tubular retractor-assisted retropleural approach for simple and less invasive microsurgical exploration of thoracic disc herniations from a lateral angle. METHODS: Surgical technique consisted of partial rib resection and retropleural dissection followed by the placement of a tubular retractor (METRx Tubes, Medtronic) for an anterior-lateral exposure of the disc and neuroforamen. Epidemiological, clinical and surgical patient data were acquired. RESULTS: Between 2017 and 2020, six patients were surgically treated using the minimally invasive tubular retractor-assisted retropleural approach. Microsurgical exposure of the disc and neural structures was achieved from a lateral direction without requiring thoracotomy or lung deflation. Control imaging confirmed resection in all cases without relevant residuum. As postoperative complications, one dural injury and one postoperative pneumothorax occured. No neurologic deterioration or recurrence occurred during a median follow-up of 3 months. CONCLUSION: The described tubular retractor-assisted retropleural exposure serves as a feasible minimally invasive microsurgical approach to the anterior-lateral thoracic spine.

A Case of Fulminant Listeria Rhombencephalitis with Brainstem Abscesses in a 37-Year-Old Immunocompetent Patient: From Vestibular Neuritis to Ondine's Curse.

We present a rare case of Listeria monocytogenes (LM) rhombencephalitis with the formation of multifocal abscesses in a young immunocompetent patient. His initial symptoms of dizziness, headache, and feeling generally unwell were put down to a coincidental coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The unfortunate rapid progression to trigeminal, hypoglossal, vagal, facial, and abducens nuclei palsies, and then an acquired central hypoventilation syndrome, known as Ondine's curse, required a prolonged intensive care unit (ICU) stay, and prolonged mechanical ventilation. As they continued to deteriorate despite targeted antibiotic treatment, surgical drainage of the abscesses was seen as the only meaningful available treatment option left to contain the disease. Postoperatively, the patient's strength rapidly improved as well as the severity of the cranial nerve palsies. After prolonged rehabilitation, at 3 months of follow-up, the patient was weaned off mechanical ventilation, independently mobile, and was left with only minor residual neurologic deficits. This case highlights a number of interesting findings only touched upon in current literature including the route of entry of LM into the central nervous system, the rare entity of acquired central hypoventilation syndrome, and finally the use of surgical intervention in cerebral LM infections.

TLR4-Pathway-Associated Biomarkers in Subarachnoid Hemorrhage (SAH): Potential Targets for Future Anti-Inflammatory Therapies.

Subarachnoid hemorrhage is associated with severe neurological deficits for survivors. Among survivors of the initial bleeding, secondary brain injury leads to additional brain damage. Apart from cerebral vasospasm, secondary brain injury mainly results from cerebral inflammation taking place in the brain parenchyma after bleeding. The brain's innate immune system is activated, which leads to disturbances in brain homeostasis, cleavage of inflammatory cytokines and, subsequently, neuronal cell death. The toll-like receptor (TLR)4 signaling pathway has been found to play an essential role in the pathophysiology of acute brain injuries such as subarachnoid hemorrhage (SAH). TLR4 is expressed on the cell surface of microglia, which are key players in the cellular immune responses of the brain. The participants in the signaling pathway, such as TLR4-pathway-like ligands, the receptor itself, and inflammatory cytokines, can act as biomarkers, serving as clues regarding the inflammatory status after SAH. Moreover, protein complexes such as the NLRP3 inflammasome or receptors such as TREM1 frame the TLR4 pathway and are indicative of inflammation. In this review, we focus on the activity of the TLR4 pathway and its contributors, which can act as biomarkers of neuroinflammation or even offer potential new treatment targets for secondary neuronal cell death after SAH.

Outlines to Initiate Epilepsy Surgery in Low- and Middle-Income Countries.

Surgery is an essential treatment option for patients with drug-resistant epilepsy. While most epilepsy patients worldwide live in low- and middle-income countries (LMIC), most of these countries do not have epilepsy surgery, and those that do have surgical epilepsy services lack capacities. The rapidly growing population in LMIC further widens the gap between the number of patients who can potentially benefit from surgery and those who can actually receive it. This makes the initiation of new surgical epilepsy centers in those countries an urgent issue. Epilepsy surgery is feasible in LMIC, even in resource-poor settings, but lack of local expertise is a major obstacle to the introduction of new surgical services. Importantly, expertise deficits can be compensated by collaborating with a well-established epilepsy center for knowledge transfer, skill building and mentoring. Such projects need to be organized in a multidisciplinary team, should focus on the given circumstances, and should use technologies and personnel that are reasonably available and can function sustainably. Local cultural factors and improvement of patients' quality of life are further spotlights reflected by an increasing number of studies. As a general outline for a new surgical epilepsy program in LMIC, it is recommended to initially focus on patients with mesial temporal lobe epilepsy due to hippocampal sclerosis or other well defined pathologies. These constellations have an excellent surgical outcome in terms of seizure control, can be diagnosed by non-invasive methods, and can be reliably identified even under low-resource conditions. Moreover, surgery can be performed with a highly standardized approach and at reasonable costs, and the vast majority of patients will benefit from surgical intervention. The range of services can then be gradually expanded, depending on growing expertise, local needs, prospects and constraints. Although the introduction of surgical epilepsy services in LMIC can face several challenges, none of them should be a permanent barrier for further establishments.

Minocycline Attenuates Microglia/Macrophage Phagocytic Activity and Inhibits SAH-Induced Neuronal Cell Death and Inflammation.

BACKGROUND: Neuroprotective treatment strategies aiming at interfering with either inflammation or cell death indicate the importance of these mechanisms in the development of brain injury after subarachnoid hemorrhage (SAH). This study was undertaken to evaluate the influence of minocycline on microglia/macrophage cell activity and its neuroprotective and anti-inflammatory impact 14 days after aneurismal SAH in mice. METHODS: Endovascular filament perforation was used to induce SAH in mice. SAH + vehicle-operated mice were used as controls for SAH vehicle-treated mice and SAH + minocycline-treated mice. The drug administration started 4 h after SAH induction and was daily repeated until day 7 post SAH and continued until day 14 every second day. Brain cryosections were immunolabeled for Iba1 to detect microglia/macrophages and NeuN to visualize neurons. Phagocytosis assay was performed to determine the microglia/macrophage activity status. Apoptotic cells were stained using terminal deoxyuridine triphosphate nick end labeling. Real-time quantitative polymerase chain reaction was used to estimate cytokine gene expression. RESULTS: We observed a significantly reduced phagocytic activity of microglia/macrophages accompanied by a lowered spatial interaction with neurons and reduced neuronal apoptosis achieved by minocycline administration after SAH. Moreover, the SAH-induced overexpression of pro-inflammatory cytokines and neuronal cell death was markedly attenuated by the compound. CONCLUSIONS: Minocycline treatment may be implicated as a therapeutic approach with long-term benefits in the management of secondary brain injury after SAH in a clinically relevant time window.

Utilization of Epidural Electrodes as a Diagnostic Tool in Intractable Epilepsy-A Technical Note.

The utilization of epidural electrodes in the preoperative evaluation of intractable epilepsy is a valuable but underrepresented tool. In recent years, we have adapted the use of cylindrical epidural 1-contact electrodes (1-CE) instead of Peg electrodes. 1-CEs are more versatile since their explantation is a possible bedside procedure. Here we report our experience with 1-CEs as well as associated technical nuances. This retrospective analysis included 56 patients with intractable epilepsy who underwent epidural electrode placement for presurgical evaluation at the Department of Neurosurgery at the Charité University Hospital from September 2011 to July 2021. The median age at surgery was 36.3 years (range: 18-87), with 30 (53.6%) female and 26 (46.4%) male patients. Overall, 507 electrodes were implanted: 93 Fo electrodes, 33 depth electrodes, and 381 epidural electrodes, with a mean total surgical time of 100.5 ± 38 min and 11.8 ± 5 min per electrode. There was a total number of 24 complications in 21 patients (8 Fo electrode dislocations, 6 CSF leaks, 6 epidural electrode dislocations or malfunction, 3 wound infections, and 2 hemorrhages); 11 of these required revision surgery. The relative electrode complication rates were 3/222 (1.4%) in Peg electrodes and 3/159 (1.9%) in 1-CE. In summary, epidural recording via 1-CE is technically feasible, harbours an acceptable complication rate, and adequately replaces Peg electrodes.

Clinical implementation of a 3D4K-exoscope (Orbeye) in microneurosurgery.

Exoscopic surgery promises alleviation of physical strain, improved intraoperative visualization and facilitation of the clinical workflow. In this prospective observational study, we investigate the clinical usability of a novel 3D4K-exoscope in routine neurosurgical interventions. Questionnaires on the use of the exoscope were carried out. Exemplary cases were additionally video-documented. All participating neurosurgeons (n = 10) received initial device training. Changing to a conventional microscope was possible at all times. A linear mixed model was used to analyse the impact of time on the switchover rate. For further analysis, we dichotomized the surgeons in a frequent (n = 1) and an infrequent (n = 9) user group. A one-sample Wilcoxon signed rank test was used to evaluate, if the number of surgeries differed between the two groups. Thirty-nine operations were included. No intraoperative complications occurred. In 69.2% of the procedures, the surgeon switched to the conventional microscope. While during the first half of the study the conversion rate was 90%, it decreased to 52.6% in the second half (p = 0.003). The number of interventions between the frequent and the infrequent user group differed significantly (p = 0.007). Main reasons for switching to ocular-based surgery were impaired hand-eye coordination and poor depth perception. The exoscope investigated in this study can be easily integrated in established neurosurgical workflows. Surgical ergonomics improved compared to standard microsurgical setups. Excellent image quality and precise control of the camera added to overall user satisfaction. For experienced surgeons, the incentive to switch from ocular-based to exoscopic surgery greatly varies.

Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia.

Despite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells. Interferon (IFN)-γ, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3ßS9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in IFN-γ treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705 . Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.

Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry.

Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298).

RNase A Inhibits Formation of Neutrophil Extracellular Traps in Subarachnoid Hemorrhage.

Background: Subarachnoid hemorrhage (SAH) caused by rupture of an intracranial aneurysm, is a life-threatening emergency that is associated with substantial morbidity and mortality. Emerging evidence suggests involvement of the innate immune response in secondary brain injury, and a potential role of neutrophil extracellular traps (NETs) for SAH-associated neuroinflammation. In this study, we investigated the spatiotemporal patterns of NETs in SAH and the potential role of the RNase A (the bovine equivalent to human RNase 1) application on NET burden. Methods: A total number of n=81 male C57Bl/6 mice were operated utilizing a filament perforation model to induce SAH, and Sham operation was performed for the corresponding control groups. To confirm the bleeding and exclude stroke and intracerebral hemorrhage, the animals received MRI after 24h. Mice were treated with intravenous injection of RNase A (42µg/kg body weight) or saline solution for the control groups, respectively. Quadruple-immunofluorescence (IF) staining for cell nuclei (DAPI), F-actin (phalloidin), citrullinated H3, and neurons (NeuN) was analyzed by confocal imaging and used to quantify NET abundance in the subarachnoid space (SAS) and brain parenchyma. To quantify NETs in human SAH patients, cerebrospinal spinal fluid (CSF) and blood samples from day 1, 2, 7, and 14 after bleeding onset were analyzed for double-stranded DNA (dsDNA) via Sytox Green. Results: Neutrophil extracellular traps are released upon subarachnoid hemorrhage in the SAS on the ipsilateral bleeding site 24h after ictus. Over time, NETs showed progressive increase in the parenchyma on both ipsi- and contralateral site, peaking on day 14 in periventricular localization. In CSF and blood samples of patients with aneurysmal SAH, NETs also increased gradually over time with a peak on day 7. RNase application significantly reduced NET accumulation in basal, cortical, and periventricular areas. Conclusion: Neutrophil extracellular trap formation following SAH originates in the ipsilateral SAS of the bleeding site and spreads gradually over time to basal, cortical, and periventricular areas in the parenchyma within 14days. Intravenous RNase application abrogates NET burden significantly in the brain parenchyma, underpinning a potential role in modulation of the innate immune activation after SAH.

Surgical revision after Vagus Nerve Stimulation. A case series.

With increasing use of vagus nerve stimulation (VNS) as an adjunct treatment for drug-resistant epilepsy, revision surgery of VNS grows in importance. Indications for revision surgery are diverse and extend of surgery varies. We report a retrospective review on indications and complications of VNS revision surgery at our center. Of 90 VNS procedures 54.4% were revision surgeries. Among those the vast majority was due to depletion of the battery. The entire system was explanted in 15 patients, due to no beneficial effect detected (n = 4), due to irritating side effects (n = 4), and so further diagnostics could cbe carried out (n = 7). Interestingly in three of the patients who underwent further diagnostics, resective epilepsy surgery was performed. Surgical complications occurred in 8.2%. In our experience, revision surgery of VNS was a frequent and safe procedure. There is a need to carefully reviewthe initial indication for VNS implantation prior to revision surgery.