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Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.

OBJECTIVE The development of persistent hydrocephalus in patients after spontaneous intracerebral hemorrhage (ICH) is still poorly understood and many variables predicting the need for a cerebrospinal fluid (CSF)-shunt have been described in the literature with varying results. The aim of this study is to find predictive factors for shunt dependency. METHODS We performed a retrospective, single-center study of 99 neurosurgically treated patients with spontaneous ICH. Variables, including age, Glasgow Coma Scale (GCS), intraventricular hemorrhage (IVH), location of hemorrhage, acute hydrocephalus and volumetric analysis of IVH, ICH and intraventricular CSF were compared between patients with and without CSF-shunt implantation. Furthermore, receiver operating characteristics (ROC) for ICH, IVH and intraventricular CSF volume parameters were calculated. RESULTS CSF-shunt implantation was performed significantly more often in patients after thalamic (p=0.03) and cerebellar ICH (p=0.04). Moreover, a lower ratio between the total hemorrhage volume and intraventricular CSF volume (p=0.007), a higher IVH distribution in the third ventricle and an acute hydrocephalus (p

ZusammenfassungFür die Implantation von Elektroden bei Verdacht auf insuläre Epilepsie stehen verschiedene Zugänge zur Verfügung: 1) offen über eine Kraniotomie, 2) stereotaktisch, wobei die Elektroden orthogonal oder schräg über den Frontallappen und Parietallappen implantiert werden. Die stereotaktische Implantation wird rahmenbasiert, navigationsbasiert oder roboterunterstützt durchgeführt. Die unterschiedlichen Zugänge haben jeweils Vor- und Nachteile in Bezug auf die Anatomie, Funktion und Abdeckung des Inselkortex. Diese Aspekte werden in dieser Übersichtsarbeit ausgeführt.

Despite the widespread use of intraoperative electrocorticography (iECoG) during resective epilepsy surgery, there is conflicting data on its overall efficacy and inability to predict benefit per pathology. Given the heterogeneity of iECoG use in resective epilepsy surgery, it is important to assess the utility of interictal-based iECoG. This individual patient data (IPD) meta-analysis seeks to identify the benefit of iECoG during resective epilepsy surgery in achieving seizure freedom for various pathologies. Embase, Scopus and PubMed were searched from inception to January 31st, 2021 using the following topics: ‘ecog’, ‘electrocorticography’, ‘epilepsy’. Articles were included if they reported seizure freedom ≥ 12-month follow-up in cohorts with and without iECoG for epilepsy surgery. Non-English, non-comparative iECoG cohorts or less than 10% iECoG use were excluded. This meta-analysis followed the PRISMA 2020 guidelines. The primary outcome was seizure freedom at last follow-up and time to seizure recurrence, if applicable. Forest plots with random effects modeling assessed the relationship between iECoG use and seizure freedom. Cox regression of IPD was performed to identify predictors of longer duration of seizure freedom. Kaplan-Meier curves with log-rank test were created to visualize differences in time to seizure recurrence. Of 7,504 articles identified, 18 were included for study-level analysis. IECoG was not associated with higher seizure freedom at the study level (RR=1.09 95% CI: 0.96-1.23, p=0.19, I2=64%), but on IPD (n= 7 studies, 231 patients) iECoG use was independently associated with more favorable seizure outcomes (HR=0.47, 95% CI: 0.23-0.95, p=0.037). In Kaplan-Meier analysis of specific pathologies, iECoG use was significantly associated with longer seizure freedom only for FCD (p

Objective: The aim of this retrospective cohort study was to assess seizure and memory outcomes following temporal lobe surgery in patients suffering from medically refractory temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS).Methods: A retrospective monocentric data analysis was performed in consecutive patients who were operated on during 2002-2018. In the first decennium, standard temporal lobe resections (TLR) were predominately performed, and later, antero-temporal lobe resections (ATLR) were mainly performed. Seizure and memory outcomes over time were assessed according to ILAE/Engel classification and the Berlin Amnesia Test (BTA), respectively.Results: Altogether, 231 surgeries were performed on 226 patients (mean age, 40 years [range, 10-68 years]; male: female, 1:1.4; mean seizure duration, 25 years; and mean follow-up duration, 4.75 years [range, 1-16]). Recently, outcomes of 78.3% of the patients in the total cohort were classified as Engel class I, with 54.9% of patients being completely seizure free. The recent cohort of ATLR since 2012 showed significant more completely seizure-free patients than before 2012 (Engel IA 46.6% versus 67.7%, p < 0.0025, χ2), although the Kaplan Meier analysis of all patients favors TLR for better seizure outcome (61% ATLR vs 73% TLR seizure free after 5 yrs, log rank p < 0.001). Verbal memory improved significantly in non-dominant patients. Minor neurological complications were noted (permanent severe complications, 0.4%; temporary severe complications, 4.8%).Conclusion: Significant improvements in seizure and memory outcomes were observed over time, with surgical technique and seizure duration as important prognostic factors. Early admittance for surgery may favor an excellent seizure outcome in patients undergoing temporal lobe resection for HS.

Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the system’s molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.

OBJECTIVE Intraoperative neuropathological assessment with conventional frozen sections supports the neurosurgeon in optimizing the surgical strategy. However, preparation and review of frozen sections can take as long as 45 minutes. Stimulated Raman histology (SRH) was introduced as a novel technique to provide rapid high-resolution digital images of unprocessed tissue samples directly in the operating room that are comparable to conventional histopathological images. Additionally, SRH images are simultaneously and easily accessible for neuropathological judgment. Recently, the first study showed promising results regarding the accuracy and feasibility of SRH compared with conventional histopathology. Thus, the aim of this study was to compare SRH with conventional H&E images and frozen sections in a large cohort of patients with different suspected central nervous system (CNS) tumors. METHODS The authors included patients who underwent resection or stereotactic biopsy of suspected CNS neoplasm, including brain and spinal tumors. Intraoperatively, tissue samples were safely collected and SRH analysis was performed directly in the operating room. To enable optimal comparison of SRH with H&E images and frozen sections, the authors created a digital databank that included images obtained with all 3 imaging modalities. Subsequently, 2 neuropathologists investigated the diagnostic accuracy, tumor cellularity, and presence of diagnostic histopathological characteristics (score 0 [not present] through 3 [excellent]) determined with SRH images and compared these data to those of H&E images and frozen sections, if available. RESULTS In total, 94 patients with various suspected CNS tumors were included, and the application of SRH directly in the operating room was feasible in all cases. The diagnostic accuracy based on SRH images was 99% when compared with the final histopathological diagnosis based on H&E images. Additionally, the same histopathological diagnosis was established in all SRH images (100%) when compared with that of the corresponding frozen sections. Moreover, the authors found a statistically significant correlation in tumor cellularity between SRH images and corresponding H&E images (p < 0.0005 and R = 0.867, Pearson correlation coefficient). Finally, excellent (score 3) or good (2) accordance between diagnostic histopathological characteristics and H&E images was present in 95% of cases. CONCLUSIONS The results of this retrospective analysis demonstrate the near-perfect diagnostic accuracy and capability of visualizing relevant histopathological characteristics with SRH compared with conventional H&E staining and frozen sections. Therefore, digital SRH histopathology seems especially useful for rapid intraoperative investigation to confirm the presence of diagnostic tumor tissue and the precise tumor entity, as well as to rapidly analyze multiple tissue biopsies from the suspected tumor margin. A real-time analysis comparing SRH images and conventional histological images at the time of surgery should be performed as the next step in future studies.

Vestibular schwannoma (VS) surgery is feasible for various tumor sizes that are inappropriate for wait and scan or radiosurgery. The predictive value of 2 grading systems was investigated for postoperative hearing preservation (HP) in a large series.Retrospective analysis.Neurosurgical patient database of the University of Erlangen was queried between 2014 and 2017.Retrospective single-center analysis on 138 VSs operated on via a retrosigmoidal approach. The mean tumor size was 20.4 mm (SD, 7.6 mm) with fundal infiltration in 67.4%. The overall resection rate was 93.5%. Tumors were classified preoperatively by the 3-tier Erlangen grading system depending on size or the anatomically based 4-tier Koos grading system.Preoperative hearing preservation was found in 70.3% of patients and was significantly correlated to tumor size (Surgery on small VSs can achieve excellent hearing preservation. Different grading has a significant influence on and correlates with postoperative hearing preservation. Tumor size seems more important than anatomic relationship.

BACKGROUND Medical-imaging-based three-dimensional (3D) printed models enable improvement in skills training, surgical planning, and decision-making. This pilot study aimed to use multimodality imaging and to add and compare 3D ultrasound as a future standard to develop realistic neonatal brain models including the ventricular system. METHODS Retrospective computed tomography (CT), magnetic resonance imaging (MRI), and 3D ultrasound-based brain imaging protocols of five neonatal patients were analyzed and subsequently segmented with the aim of developing a multimodality imaging-based 3D printed model. The ventricular anatomy was analyzed to compare the MRI and 3D ultrasound modalities. RESULTS A realistic anatomical model of the neonatal brain, including the ventricular system, was created using MRI and 3D ultrasound data from one patient. T2-weighted isovoxel 3D MRI sequences were found to have better resolution and accuracy than 2D sequences. The surface area, anatomy, and volume of the lateral ventricles derived from both MRI and 3D ultrasound were comparable. CONCLUSIONS We created an ultrasound- and MRI-based 3D printed patient-specific neonatal brain simulation model that can be used for perioperative management. To introduce 3D ultrasound as a standard for 3D models, additional dimensional correlations between MRI and ultrasound need to be examined. IMPACT We studied the feasibility of implementing 3D ultrasound as a standard for 3D printed models of the neonatal brain. Different imaging modalities were compared and both 3D isotropic MRI and 3D ultrasound imaging are feasible for printing neonatal brain models with good dimensional accuracy and anatomical replication. Further dimensional correlations need to be defined to implement it as a standard to produce 3D printed models.

Background New-onset seizures after cranioplasty (NOSAC) are reported to be a frequent complication of cranioplasty (CP) after decompressive hemicraniectomy (DHC). There are considerable differences in the incidence of NOSAC and contradictory data about presumed risk factors in the literature. We suggest NOSAC to be a consequence of patients’ initial condition which led to DHC, rather than a complication of subsequent CP. We conducted a retrospective analysis to verify our hypothesis. Methods The medical records of all patients ≥ 18 years who underwent CP between 2002 and 2017 at our institution were evaluated including incidence of seizures, time of seizure onset, and presumed risk factors. Indication for DHC, type of implant used, timing of CP, patient age, presence of a ventriculoperitoneal shunt (VP shunt), and postoperative complications were compared between patients with and without NOSAC. Results A total of 302 patients underwent CP between 2002 and 2017, 276 of whom were included in the outcome analysis and the incidence of NOSAC was 23.2%. Although time between DHC and CP differed significantly between DHC indication groups, time between DHC and seizure onset did not differ, suggesting the occurrence of seizures to be independent of the procedure of CP. Time of follow-up was the only factor associated with the occurrence of NOSAC. Conclusion New-onset seizures may be a consequence of the initial condition leading to DHC rather than of CP itself. Time of follow-up seems to play a major role in detection of new-onset seizures.

Objective: Management of patients after failed epilepsy surgery is still challenging. Advanced diagnostic and intraoperative tools including magneto-encephalography (MEG) as well as neuronavigation and intraoperative magnetic resonance imaging (iopMRI) may contribute to a better postoperative seizure outcome in this patient group. Methods: We retrospectively analyzed consecutive patients after reoperation of failed epilepsy surgery for medically refractory epilepsy at the University of Erlangen between 1988 and 2017. Inclusion criteria for patients were available MEG, neuronavigation and iopMRI data. The Engel scale was used to categorize seizure outcome. Results: We report on 27 consecutive patients (13 female/14 male mean age at first surgery 29.4 years) who had operative revision of the first resection after failed epilepsy surgery. An improved seizure outcome postoperatively was observed in 78% of patients (p < 0.001) with 55% seizure free (Engel I) patients after a mean follow-up time of 4.9 years. In detail, 80% of lesional cases were seizure free compared to 59% of MRI negative patients. Localizing MEG spike activity in the vicinity of the first resection cavity was present in 12 of 27 patients (44%) corresponding to 83% (10/12) of MEG localizing spike patients having advanced seizure outcome after operative revision. Conclusion: Re-operation after failed surgery in refractory epilepsy may lead to a better seizure outcome in the majority of patients. Preoperative MEG may support the decision for surgery and may facilitate targeting epileptogenic tissue for re-resection by employing navigation and iopMR imaging.

Objective Depth electrode implantation for invasive monitoring in epilepsy surgery has become a standard procedure. We describe a new frameless stereotactic intervention using robot-guided laser beam for making precise bone channels for depth electrode placement. Methods A laboratory investigation on a head cadaver specimen was performed using a CT scan planning of depth electrodes in various positions. Precise bone channels were made by a navigated robot-driven laser beam (erbium:yttrium aluminum garnet [Er:YAG], 2.94-μm wavelength,) instead of twist drill holes. Entry point and target point precision was calculated using postimplantation CT scans and comparison to the preoperative trajectory plan. Results Frontal, parietal, and occipital bone channels for bolt implantation were made. The occipital bone channel had an angulation of more than 60 degrees to the surface. Bolts and depth electrodes were implanted solely guided by the trajectory given by the precise bone channels. The mean depth electrode length was 45.5 mm. Entry point deviation was 0.73 mm (±0.66 mm SD) and target point deviation was 2.0 mm (±0.64 mm SD). Bone channel laser time was ∼30 seconds per channel. Altogether, the implantation time was ∼10 to 15 minutes per electrode. Conclusion Navigated robot-assisted laser for making precise bone channels for depth electrode implantation in epilepsy surgery is a promising new, exact and straightforward implantation technique and may have many advantages over twist drill hole implantation.

Background Childhood cerebellar pilocytic astrocytomas harbor excellent overall survival rates after surgical resection, but the patients may exhibit specific cognitive and behavioral problems. Functional MRI has catalyzed insights into brain functional systems and has already been linked with the neuropsychological performance. We aimed to exploit the question of whether resting-state functional MRI can be used as a biomarker for the cognitive outcome assessment of these patients. Methods We investigated 13 patients (median age 22.0 years; range 14.9-31.3) after a median interval between surgery and examination of 15.0 years (range 4.2-20.5) and 16 matched controls. All subjects underwent functional 3-Tesla MRI scans in a resting-state condition and battery neuropsychological tests. Results Patients showed a significantly increased functional connectivity in the precuneus compared with controls (P < .05) and at the same time impairments in various domains of neuropsychological functioning such as a lower mean Wechsler Intelligenztest für Erwachsene (WIE) IQ percentile (mean [M] = 48.62, SD = 29.14), lower scores in the Trail Making Test (TMT) letter sequencing (M = 49.54, SD = 30.66), worse performance on the WIE subtest Digit Symbol Coding (M = 38.92, SD = 35.29), subtest Symbol Search (M = 40.75, SD = 35.28), and test battery for attentional performance (TAP) divided attention task (M = 783.92, SD = 73.20). Conclusion Childhood cerebellar tumor treated by resection only strongly impacts the development of precuneus/posterior cingulate cortex functional connectivity. Functional MRI has the potential to help deciphering the pathophysiology of cerebellar-related cognitive impairments in these patients and could be an additional tool in their individual assessment and follow-up.

The objective is to provide a treatment algorithm for pediatric patients with intracranial cavernous malformations (CMs) based on our experience. Patients p p = 0.003) in the surgery group than in conservatively managed patients. In deep CMs, modified Rankin scale (mRS) was higher (4 vs 1, p = 0.003) in the surgery group than in conservatively treated patients. At the time of last follow-up, no differences in Wieser outcome class I were seen (86% vs 67%) in lobar CMs, and mRS scores had aligned between the treatment groups in deep CMs (1 vs 0). We encountered no new permanent neurological deficit at time of last follow-up. We propose a treatment algorithm according to lesion location and size, burden of symptoms, epilepsy workup, and further clinical course during observation. A conservative management is safe in pediatric patients with asymptomatic CMs. Gross total resection should be the aim in patients with symptomatic lobar CMs. A less aggressive approach with subtotal resection, when required to prevent neurological compromise, sustainably improves neurological outcome in patients with deep CMs.

Patient positioning is an integral part of surgical planning, and numerous variations have been suggested to optimize the prone position. So far, however, little attention has been given to address the restrictions and special needs in an intraoperative MRI suite.To share our experience of transforming the modified prone position from the conventional operating room to the intraoperative MRI suite.Two-room 3T intraoperative MRI suite. Detailed description of the technical pearls is provided.Ten procedures in 9 consecutive patients (2 female and 7 male) were performed. The median age was 8 years ranging from 4 to 71 years. We experienced no complication from patient positioning. Neither size (range 104-182 cm) nor weight (range 18-98 kg) of the patients was a limiting factor. In none of them, the surgeon experienced an adverse event from inadequate patient positioning and the surgical goals could be achieved without restrictions. An intraoperative MRI could be acquired in all of them with the same image quality as observed for standard positions.A transition of the modified prone position from the conventional operating room to the intraoperative MRI suite is feasible, if some crucial steps are considered. We provide a detailed technical description that could be used as a guide by others.

Background The role of surgery in the management of pediatric non-pilocytic infiltrative thalamic gliomas needs to be revisited specifically with regard to molecularly defined subtypes. Methods A retrospective review of a consecutive series of children operated on a thalamic tumor between 1992 and May 2018 was performed. Neuroimaging data were reviewed for localization and extent of resection; pathology was re-reviewed according to the current WHO classification, including assessment of histone H3 K27 mutational status. Results Forty-nine patients with a thalamic tumor aged < 18 years at diagnosis were identified. Twenty-five patients (51%) had a non-pilocytic infiltrative glioma, of which the H3 K27M status was available in 22. Fourteen patients were diagnosed as diffuse midline glioma (DMG) H3 K27M mutant. There was no statistically significant difference in survival between patients harboring the H3 K27M mutation and wildtype. Resection (“any resection > 50%” vs “biopsy”) and histological tumor grade (“°II” vs “°III+°IV”) were statistically significant predictors of survival (univariate: p = 0.044 and p = 0.013, respectively). These results remained significant on multivariate analysis (HR 0.371/p = 0.048, HR 9.433/p = 0.035). Conclusion We advocate to still consider an attempt at maximal safe resection in the multidisciplinary treatment of unilateral thalamic non-pilocytic gliomas irrespective of their H3 K27-mutational status.

Objective Cranioplasty (CP) is considered as a straightforward and technically unchallenging operation; however, complication rates are high reaching up to 56%. Presence of a ventriculoperitoneal shunt (VPS) and timing of CP are reported risk factors for complications. Pressure gradients and scarring at the site of the cranial defect seem to be critical in this context. The authors present their experiences and lessons learned. Methods A consecutive series of all patients who underwent CP at the authors’ institution between 2002 and 2017 were included in this retrospective analysis. Complications were defined as all events that required reoperation. Logistic regression analysis and chi-squared test were conducted to evaluate the complication rates according to suspected risk factors. Results A total of 302 patients underwent cranioplasty between 2002 and 2017. The overall complication rate was 17.5%. Complications included epi-/subdural fluid collection (7.3%) including hemorrhage (4.6%) and hygroma (2.6%), bone graft resorption (5.3%), bone graft infection (2.0%), and hydrocephalus (5.7%). Overall, 57 patients (18.9%) had undergone shunt implantation prior to CP. The incidence of epi-/subdural fluid collection was 19.3% in patients with VPS and 4.5% in patients without VPS, OR 5.1 (95% CI 2.1–12.4). Incidence of hygroma was higher in patients who underwent early CP. Patients with temporary shunt ligation for CP did not suffer from complications. Conclusion CP in patients with a VPS remains a high-risk procedure. Any effort to understand the pressure dynamics and to reduce factors that may trigger the formation of a large epidural space must be undertaken.

This article emphasizes the role of the technological progress in changing the landscape of epilepsy surgery and provides a critical appraisal of robotic applications, laser interstitial thermal therapy, intraoperative imaging, wireless recording, new neuromodulation techniques, and high‐intensity focused ultrasound. Specifically, (a) it relativizes the current hype in using robots for stereo‐electroencephalography (SEEG) to increase the accuracy of depth electrode placement and save operating time; (b) discusses the drawback of laser interstitial thermal therapy (LITT) when it comes to the need for adequate histopathologic specimen and the fact that the concept of stereotactic disconnection is not new; (c) addresses the ratio between the benefits and expenditure of using intraoperative magnetic resonance imaging (MRI), that is, the high technical and personnel expertise needed that might restrict its use to centers with a high case load, including those unrelated to epilepsy; (d) soberly reviews the advantages, disadvantages, and future potentials of neuromodulation techniques with special emphasis on the differences between closed and open‐loop systems; and (e) provides a critical outlook on the clinical implications of focused ultrasound, wireless recording, and multipurpose electrodes that are already on the horizon. This outlook shows that although current ultrasonic systems do have some limitations in delivering the acoustic energy, further advance of this technique may lead to novel treatment paradigms. Furthermore, it highlights that new data streams from multipurpose electrodes and wireless transmission of intracranial recordings will become available soon once some critical developments will be achieved such as electrode fidelity, data processing and storage, heat conduction as well as rechargeable technology. A better understanding of modern epilepsy surgery will help to demystify epilepsy surgery for the patients and the treating physicians and thereby reduce the surgical treatment gap.

BACKGROUND AND OBJECTIVES Fluorescence-guided resection of glioblastomas (GBM) using 5-aminolevulinic acid (5-ALA) improves intraoperative tumor visualization and is thus widely used nowadays. During resection, different fluorescence levels can usually be distinguished within the same tumor. Recently, we demonstrated that strong, vague, and no fluorescence correspond to distinct histopathological characteristics in newly diagnosed GBM. However, the qualitative fluorescence classification by the neurosurgeon is subjective and currently no comprehensive data on interobserver variability is available. The aim of this study was thus to investigate the interobserver variability in the classification of 5-ALA fluorescence levels in newly diagnosed GBM. STUDY DESIGN/MATERIALS AND METHODS A questionnaire investigating the interobserver variability in 5-ALA fluorescence quantification was performed at a nation-wide neurosurgical oncology meeting. The participants involved in the neurosurgical/neurooncological field were asked to categorize 30 cases of 5-ALA fluorescence images derived from GBM resection on a lecture hall screen according to the widely used three-tier fluorescence classification scheme (negative, vague, or strong fluorescence). Additionally, participants were asked for information on their medical background such as specialty, level of training, and experience with 5-ALA fluorescence-guided procedures. Interobserver agreement was defined as the calculated mean κ values for each observer. RESULTS A total of 36 questionnaires were included in the final analysis. The mean average κ value in fluorescence classification within the entire cohort was 0.71 ± 0.12 and 29 (81%) participants had a substantial or almost perfect interobserver agreement (κ values 0.6-1.0). Interobserver agreement was significantly higher in neurosurgeons (mean κ: 0.83) as compared with non-neurosurgeons involved in the neurooncological field (mean κ: 0.52; P

Activating point mutations within the TERT promoter (C228T or C250T) account for the most frequent alteration in aggressive brain tumors. Presence of these alterations results in the generation of binding sites for E-twenty-six (ETS) transcription factors accompanied by enhanced TERT expression. Accordingly, TERT promoter mutations foster cellular immortalization and subsequently tumor aggressiveness. Due to the limitation of treatment options in aggressive brain tumors, including glioblastoma and medulloblastoma, new therapeutic targets need to be discovered. As we previously described a strong interaction of oncogenic MEK/ETS signaling and TERT promoter mutations, we hypothesize that inhibition of these factors halters cell immortalization in TERT-driven brain tumors. Our study included three TERT promoter wild-type (TERTwt), six mutated (TERTmut) glioblastoma and three TERTmut medulloblastoma cell models and tested the effect of MEK inhibitors (U0126 and trametinib) and the ETS inhibitor YK-4-279 on cell viability and clone formation. Cellular senescence upon treatment was evaluated by beta-galactosidase assays. Impact on TERT mRNA expression and TERT promoter activity were analyzed by quantitative real-time PCR and luciferase reporter assays, respectively. Furthermore, the effects on MAPK- and PI3K pathway activation were evaluated by Western blot. Amongst the investigated inhibitors, tumor cells harboring C228T mutation were distinctly more sensitive against trametinib as compared to TERTwt and C250T TERTmut cells. Similar effects were observed on clonogenicity upon long-term exposure to this inhibitor. Regarding MAPK signaling activation, trametinib treatment completely blocked ERK phosphorylation in every cell model, while activation of ETS1 was more effectively reduced in C228T TERTmutcells. Accordingly, exposure to trametinib reduced TERT expression and promoter activity accompanied by induction of cellular senescence in cells with C228T mutation. Impact of trametinib is currently investigated in preclinical experiments using TERTmut brain tumor models. Summarizing, MEK inhibition represents a novel strategy to overcome cell immortalization especially in C228T TERTmut brain tumors.

Background The purpose of this study was to identify independent risk factors for incidental durotomy (ID) during decompressive lumbar spine surgery and describe its treatment. Methods This retrospective review includes 650 patients who underwent lumbar decompression at a tertiary institution between January 2015 and October 2019. Data collection was obtained through one independent researcher. The incidence rate and treatment of ID was evaluated by a chart review of operative notes, patient charts, physiotherapy reports, and nursing reports. Results The incidence rate of ID was 12.6%. The most common reason for admission was disc herniation (63.2%), followed by vertebral stenosis (22.1%). ID resulted in significantly longer operation time (p=0.0001) and length of hospitalization (p=0.0001). A correlation between ID and patient's diagnosis (p=0.0078) as well as the chosen type of surgery (p=0.0404) with an odds ratio to cause ID of 1.9 for laminectomy and 1.6 for undercutting compared to microdiscectomy were found. However, age, sex, surgeon experience, lumbar level, revision surgery, as well as multilevel surgery were not significantly correlated with the incidence of ID. Dural tears were closed with dural sealant (47.2%), polyester 4-0 sutures (11.1%) or a combination of both (37.5%) and the majority of patients had bed rest of at least two days. By usage of these treatment methods no patient needed reoperation. Conclusions Diagnosis of vertebrostenosis as well as laminectomy were significantly correlated with the incidence of ID. Treatment with intraoperative closure and postoperative bed rest even though not standardized led to complication free outcomes.

Objectives: Multiple risk factors have been described to be related to external ventricular drain (EVD) associated infections, with results varying between studies. Former studies were limited by a non-uniform definition of EVD associated infection, thus complicating a comparison between studies. In this regard, we assessed risk factors promoting EVD associated infections and propose a modified practice-oriented definition of EVD associated infections.Methods: We performed a retrospective, single-center study on patients who were treated with an EVD, at the neurosurgical intensive care unit (ICU) at a tertiary center between 2008 and 2019. Based on microbiological findings and laboratory results, patients were assigned into an infection and a non-infection group. Patient characteristics and potential risk factors were compared between the two groups (p < 0.05). Receiver operating characteristics (ROC) for significant clinical, serum laboratory and cerebrospinal fluid (CSF) parameters were calculated.Results: In total, 396 patients treated with an EVD were included into the study with a mean age of 54.3 (range: 18–89) years. EVD associated infections were observed in 32 (8.1%) patients. EVD insertion at another hospital (OR 3.86), and an increased CSF sampling frequency of more than every third day (OR 12.91) were detected as major risk factors for an EVD associated infection. The indication for EVD insertion, surgeon's experience, the setting of EVD insertion (ICU vs. operating room) and the operating time did not show any significant differences between the two groups. Furthermore, ROC analysis showed that clinical, serum laboratory and CSF parameters did not provide specific prediction of EVD associated infections (specificity 44.4%). This explains the high overtreatment rate in our cohort with the majority of our patients who received intrathecal vancomycin (63.3%), having either negative microbiological results (n = 12) or were defined as contaminations (n = 7).Conclusions: Since clinical parameters and blood analyzes are not very predictive to detect EVD associated infections in neurosurgical patients, sequential but not too frequent microbiological and laboratory analysis of CSF are still necessary. Furthermore, we propose a uniform classification for EVD associated infections to allow comparability between studies and to sensitize the treating physician in determining the right treatment.

Objectives: We recently introduced a navigated, robot-driven laser beam craniotomy for use with stereoelectroencephalography (SEEG) applications. This method was intended to substitute the hand-held electric power drill in an ex vivo study. The purpose of this in vivo non-recovery pilot study was to acquire data for the depth control unit of this laser device, to test the feasibility of cutting bone channels, and to assess dura perforation and possible cortex damage related to cold ablation.Methods: Multiple holes suitable for SEEG bone channels were planned for the superior portion of two pig craniums using surgical planning software and a frameless, navigated technique. The trajectories were planned to avoid cortical blood vessels using magnetic resonance angiography. Each trajectory was converted into a series of circular paths to cut bone channels. The cutting strategy for each hole involved two modes: a remaining bone thickness mode and a cut through mode (CTR). The remaining bone thickness mode is an automatic coarse approach where the cutting depth is measured in real time using optical coherence tomography (OCT). In this mode, a pre-set measurement, in mm, of the remaining bone is left over by automatically comparing the bone thickness from computed tomography with the OCT depth. In the CTR mode, the cut through at lower cutting energies is managed by observing the cutting site with real-time video.Results: Both anesthesia protocols did not show any irregularities. In total, 19 bone channels were cut in both specimens. All channels were executed according to the planned cutting strategy using the frameless navigation of the robot-driven laser device. The dura showed minor damage after one laser beam and severe damage after two and three laser beams. The cortex was not damaged. As soon as the cut through was obtained, we observed that moderate cerebrospinal fluid leakage impeded the cutting efficiency and interfered with the visualization for depth control. The coaxial camera showed a live video feed in which cut through of the bone could be identified in 84%.Conclusion: Inflowing cerebrospinal fluid disturbed OCT signals, and, therefore, the current CTR method could not be reliably applied. Video imaging is a candidate for observing a successful cut through. OCT and video imaging may be used for depth control to implement an updated SEEG bone channel cutting strategy in the future.

Background Nontectal plate exophytic brainstem gliomas with pilocytic histology are rare and occur mainly in children. Because of their eloquent location, therapy usually consists of bioptic histologic verification and radiotherapy in case of progression. Case Description We report on a 43-year-old patient who presented with intermittent tinnitus and reduced hearing in his left ear, as well as a slight left-sided ataxia. Magnetic resonance imaging revealed a left-sided solid cystic cerebellar-pontine angle (CPA) tumor completely obliterating the CPA. Radiologically, a solid cystic vestibular schwannoma was diagnosed. Intraoperatively, a glossy-grayish, intensively bleeding tumor without any capsule or delineation to the brainstem or cranial nerves was resected using electrophysiologic monitoring. Postoperative histology revealed a pilocytic astrocytoma. Three months postoperatively, hearing was preserved (pure tone average—35 dB) and ataxia was equal to what it was preoperatively, gradually becoming better. Postoperative magnetic resonance scans demonstrated a complete resection of the tumor with completely restored brainstem contours. Conclusions Exophytic brainstem gliomas may occur in the CPA and mimic vestibular schwannoma. Complete resection even with preserved hearing without neurologic deterioration may be feasible.

Objective Intraoperative electrocorticography (iopECoG) can contribute to delineate the resection borders of the anticipated epileptogenic zone in epilepsy surgery. However, it has several caveats that should be considered to avoid incorrect interpretation during intraoperative monitoring. Methods The literature on iopECoG application was reviewed, and pros and cons as well as obstacles to this technique were analyzed. Results The literature of the first half of the nineties was very enthusiastic in using iopECoG for tailoring the resection in temporal as well as extratemporal epilepsy surgery. Mostly, this resulted in a good correlation of postresection ECoG and excellent seizure outcome. In the second half of the nineties, many authors demonstrated lack of correlation between iopECoG and postoperative seizure outcome, especially in surgery for temporal lobe epilepsy with hippocampal sclerosis. In the noughties, investigators found that ECoG was significantly useful in neocortical lesional temporal lobe epilepsy as well as in extratemporal lesional epilepsies. Extratemporal epilepsy without lesions proved to be more a domain of chronic extraoperative ECoG, especially using depth electrode recordings. In recent years, iopECoG detecting high-frequency oscillations (ripples, 80–250 Hz, fast ripples, 250–500 Hz) for tailored resection was found to allow intraoperative prediction of postoperative seizure outcome. Conclusion After a period of scepticism, iopECoG seems back in the focus of interest for intraoperative guidance of resecting epileptogenic tissue to raise postoperative favorable seizure outcome. In temporal and extratemporal lesional epilepsies, especially in cases of focal cortical dysplasia, tuberous sclerosis, or cavernous malformations, an excellent correlation between iopECoG-guided resection and postoperative seizure relief was found.

Medulloblastoma (MB) is the most common embryonal brain tumor in children, characterized by a high level of heterogeneity within this entity. Four major molecular groups have been defined - WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) - differing widely in genetic alterations and patient outcomes. Targeted treatment approaches are limited for high-risk MB including MYC-amplified G3, G4, or MYCN/GLI2-amplified SHH. Based on earlier studies describing the inhibition of cell cycle regulation as a therapeutic vulnerability in high-risk MB, we aimed to explore the efficacy and mode of action of approved CDK4/6 inhibitors in aggressive MB. First the in vitro sensitivity of pediatric G3 (n=5) MB cell models against palbociclib, ribociclib and abemaciclib was evaluated and compared to adult SHH (n=2) cells serving as MYC-negative controls. Abemaciclib most effectively reduced cell viability, exhibiting a mean IC50 value of 0.9 M in G3 compared to 2.1 M in SHH cells (p=0.007). Upon long-term exposure (7-10 days), again abemaciclib most potently decreased clonogenic survival already at 250nM in G3 MB cells. We observed a G1/S phase cell cycle arrest upon abemaciclib treatment and confirmed this by Western blot analyses, showing decreased Rb phosphorylation accompanied by reduced MAPK signaling. Interestingly, abemaciclib treatment distinctly reduced MYC protein and gene expression levels in MYC-amplified G3 cell models. In addition, exposure to abemaciclib decreased GLI2 and TERT mRNA levels, which was accompanied by induction of cellular senescence. Within the ITCC-P4 project, single mouse trials are currently being performed including abemaciclib treatment in orthotopic MB models. The detailed investigation of the precise mode of action in vitro and in vivo is ongoing. Summarizing, the CDK4/6 clinically approved inhibitor abemaciclib shows promising efficacy against high-risk MB in vitro.

BACKGROUND: Childhood cerebellar pilocytic astrocytomas harbour excellent overall survival rates after surgical resection, but the patients may exhibit specific cognitive and behavioural problems emphasising our current understanding of the cerebellar role in cognition. Functional MRI has catalysed the mechanistic insights into brain functional systems and has already been linked with the neuropsychological performance. We aimed to exploit the question whether functional MRI can be used as a surrogate measure for the cognitive outcome assessment of these patients. METHODS: We investigated 13 patients (median age 22.0 years, range 15.2 – 31.7) after a median interval between surgery and examination of 15.0 years (range 4.2 – 20.8) and 16 matched controls. All subjects underwent a functional 3T MRI scans in a resting state condition and a battery neuropsychological tests. RESULTS: Patients showed a significantly increased functional connectivity in the precuneus compared to controls (p

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.

Background Drugs that inhibit blood clot formation are a risk factor for the development and recurrence of chronic subdural hematoma (cSDH). The use of non-steroidal antiinflammatory drug (NSAID) was associated with higher bleeding rates in non-neurosurgical patients, but their influence on cranial hematomas is unclear. We sought to better describe the hazard associated with their use in cSDH patients and find additional risk factors. Methods We performed a retrospective analysis of patients undergoing burr hole drainage for cSDH over a time period of 15 years. Demographic and surgical details were extracted from individual patient records. Patients were followed for up to 90 days with SDH recurrence requiring repeat surgery as the primary endpoint. Univariate and multivariate Cox regression models were performed to identify risk factors and their effect size. Results We included 361 patients, who underwent burr hole drainage for cSDH. Recurrences occurred in 73 patients (20.2%) after a median time period of 18 days. Sixty-six patients in our cohort were taking NSAIDs perioperatively. The recurrence rate was not higher in NSAID users compared to other patients with 18.2% and 20.7%, respectively. 23.5% of men, yet only 12.7% of women had recurrences revealing male sex as a risk factor in a uni- and multivariate regression. Not placing a drain was a risk factor for early recurrences, which resulted in a prolonged hospital stay. Conclusions We identified male sex as a risk factor for cSDH recurrence after burr hole drainage, while perioperative NSAID use did not increase recurrence rates.

BACKGROUND High-grade gliomas are among the most aggressive brain tumors across all age groups. BRAF is within the most frequently altered genes in pediatric glioma, sometimes connected with telomerase reverse transcriptase (TERT) promoter mutations, predicting a particularly aggressive course of disease. Precision medicine approaches targeting the MAPK pathway have shown promising results in patients with BRAF-mutated glioma. Although acquired insensitivity to BRAF inhibitors appears as major issue for therapy failure, underlying molecular mechanisms are still poorly understood. METHODS Cell models from an anaplastic pleomorphic xanthoastrocytoma with BRAF V600E and TERT promoter mutations and the recurrent tumor, operated following MAPK pathway-targeting therapy, were established. Furthermore, a dabrafenib-resistant subline of the recurrent tumor was generated. The patient-derived cell models were genetically characterized using array-based genomic hybridization (aCGH). Sensitivity of the cells towards different MAPK pathway inhibitors was tested. Basal expression and activation of MAPK pathway and downstream signals were analyzed by qRT-PCR and Western blots. RESULTS Screening a panel of both primary and immortalized glioma cell models with different BRAF and TERT promoter status revealed significantly induced MAPK pathway activation and enhanced TERT levels in BRAF V600E and TERT promoter double-mutant gliomas. Furthermore, cells with both mutations were hyper-sensitive towards BRAF-targeting agents and BRAF inhibition resulted in reduced TERT levels. ETS1 expression was strongly increased in the recurrent tumor and identified as important player in telomerase re-activation. aCGH revealed gains of chromosomal regions encoding for different ETS-factors in the dabrafenib-resistant subline. Western blot analyses suggested a BRAF/ERK-independent survival mechanism in the dabrafenib-resistant subline. Accordingly, dabrafenib insensitivity triggered cross-resistance towards the MEK inhibitor trametinib. Uncoupled from the MAPK pathway, ETS1 expression was further upregulated in the dabrafenib-resistant subline. CONSLUSION: Taken together, our data demonstrate that MAPK-independent ETS transcription factor upregulation is a central mechanism of BRAF inhibitor therapy failure in BRAF-mutated pediatric glioma patients.