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Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.

ZusammenfassungDurch die Einführung moderner Techniken für die neurochirurgische Intervention bei nichtläsionellen (NL) MRT-negativen medikamentös therapierefraktären Epilepsien (temporal, aber v. a. auch extratemporal) zeigte sich im letzten Jahrzehnt sowohl bei Kindern und Adoleszenten als auch bei Erwachsenen eine deutliche Zunahme diese Eingriffe um etwa 10–15 % [1]. Für die prächirurgische Evaluation von NL-Epilepsien ist das invasive Monitoring zur Diagnostik einer fokalen Epilepsie bzw. zur Definition der potenziellen epileptogenen Zone für eine mögliche Resektion oder Ablation – insbesondere extratemporal – wünschenswert. Die Technik der invasiven Abklärung von NL-Epilepsien hat im letzten Jahrzehnt eine grundsätzliche Strategieänderung erfahren, weg von über eine Kraniotomie eingebrachten subduralen Elektroden, hin zum weniger invasiven Stereo-EEG (sEEG) mit Tiefenelektroden. Das minimal-invasive und weniger komplikationsbehaftete sEEG kann auch tief gelegene Anfallsgeneratoren und unter Einbeziehung von künstlicher Intelligenz (AI) auch sterische Ausdehnung der potenziellen epileptogenen Zone darstellen, was für eine mögliche Resektion bei nichtläsionellen Epilepsien Voraussetzung ist. In sprachrelevanten Kortexarealen bleiben allerdings das Monitoring und Mapping mit Subduralelektroden alternativlos. Gleichzeitig ermöglichen neue Techniken in der Neurochirurgie wie Neuronavigation, Neuromonitoring (IONM) und intraoperative MR-Bildgebung, Robotik und Laserablation (LITT) die Schonung von eloquenten Hirnarealen in der Nachbarschaft der epileptogenen Zone. Zusätzlich können neuerdings traditionelle Techniken (Elektrokortikographie (ECoG) und Neuromonitoring (IONM)) mit der Bildgebung direkt durch Dateneinspiegelung ins Operationsmikroskop in den operativen Situs zur Resektion miteinbezogen werden. Diese Entwicklungen haben dazu geführt, dass für immer mehr NL-fokale Epilepsien die Resektion möglich ist und dass sich das postoperative Epilepsie-Outcome von NL-Epilepsien deutlich verbessert hat.

OBJECTIVE Since the publication of A Randomized Trial of Unruptured Brain AVMs (ARUBA), the management of unruptured brain arteriovenous malformations (bAVMs) has been controversially discussed. Long-term follow-up data on the exclusively conservative management of unruptured bAVMs are scarce. The authors evaluated the long-term outcomes of patients with unruptured untreated bAVMs in a real-life cohort. METHODS A retrospective observational cohort of 107 patients (of 897 bAVM patients referred to the authors’ institution) with a diagnosis of unruptured and conservatively managed bAVMs is presented. AVMs of all Spetzler-Martin grades were observed. The mean follow-up period was 84 months. In 44% of patients, a follow-up period of 5 years or longer was observed. A national death register comparison completed the outcome analysis. RESULTS The median age at diagnosis, sex distribution, neurological presentation, and modified Rankin Scale score were comparable to the patients in the medical management arm of the ARUBA study. Patients were mainly young, predominantly male, and in good clinical condition. Similar to the ARUBA cohort, 77% of this study’s cohort presented in an excellent clinical status at the time of last follow-up. However, 17% of patients had at least one hemorrhage, resulting in an overall annual hemorrhage risk of 2.7% in the observation period. Moreover, the cumulative 1-, 5-, and 10-year overall hemorrhage rates were 3.0%, 11.3%, and 15.3%, respectively. Consequently, the long-term follow-up AVM-related mortality rate amounted to 8%. The estimated median overall survival after AVM diagnosis was 19.3 years (95% CI 14.0–24.6 years). A multivariate Cox regression model revealed temporal and deep-seated localization as an independent risk factor for AVM hemorrhage, while the presence of seizures reached borderline significance as a risk factor. CONCLUSIONS The authors’ results represent the long-term course of unruptured untreated bAVMs. Their data support the conclusion that even in the post-ARUBA era, tailored active treatment options may be offered to patients with unruptured bAVMs. For patient counseling, individual risk factors should be weighed against the center’s treatment-specific risks.

Anterior temporal lobectomy (ATL) and transsylvian selective amygdalohippocampectomy (tsSAHE) are effective treatment strategies for intractable temporal lobe epilepsy but may cause visual field deficits (VFDs) by damaging the optic radiation (OpR). Due to the OpR's considerable variability and because it is indistinguishable from surrounding tissue without further technical guidance, it is highly vulnerable to iatrogenic injury. This imaging study uses a multimodal approach to assess visual outcomes after epilepsy surgery.We studied 62 patients who underwent ATL (n=32) or tsSAHE (n=30). Analysis of visual outcomes was conducted in four steps, including the assessment of (1) perimetry outcomes (VFD incidences/extents, n=44/40), (2) volumetric OpR-tractography-damages (n=55), and the (3) relation of volumetric OpR-tractography-damages and perimetry outcomes (n=35). Furthermore, (4) Fixel-Based-Analysis was performed to assess micro- and macrostructural changes within the OpR following surgery (n=36).Altogether, 56% of all patients had postoperative VFDs (78.9% after ATL, 36.36% after tsSAHE, p=0.011). VFDs and OpR-tractography-damages tended to be more severe within the ATL group (ATL vs. tsSAHE, integrity contralateral upper quadrant: 65% vs. 97%, p=0.002; OpR-tractography-damage: 69.2mmIn the context of controversial visual outcomes following epilepsy surgery, this study provides clinical as well as neuroimaging evidence for a higher risk and greater severity of postoperative VFDs after ATL compared to tsSAHE. Volumetric OpR-tractography-damage is a feasible parameter to reliably predict this morbidity in both treatment groups and may ultimately support personalized planning of surgical candidates. Advanced diffusion-analysis tools such as FBA offer a structural explanation of surgically induced visual pathway damage, allowing to non-invasively quantify and visualize micro- and macrostructural tract affection.

OBJECTIVE The objective of this study was to assess and compare the potential of 5-aminolevulinic acid (5-ALA) and Raman spectroscopy (RS) in detecting tumor-infiltrated brain in patients with glioblastoma (GBM). METHODS Between July 2020 and October 2021, the authors conducted a prospective clinical trial with 15 patients who underwent neurosurgical treatment of newly diagnosed and histologically verified GBM. A solid contrast-enhancing tumor core and peritumoral tissue were investigated intraoperatively for cancer cells by using 5-ALA and RS to achieve pathology-tailored maximum resection. In each case, a minimum of 10 biopsies were sampled from navigation-guided areas. Two neuropathologists examined the biopsies for the presence of neoplastic cells. The detection performance of 5-ALA and RS alone and in combination was assessed. Pre- and postoperative MRI, Karnofsky Performance Status (KPS), and National Institutes of Health Stroke Scale (NIHSS) scores were compared, and median progression-free survival (PFS) was evaluated. RESULTS A total of 185 biopsy samples were harvested from the contrast-enhancing tumor core (n = 19) and peritumoral tissue (n = 166). In the tumor core, 5-ALA and RS each showed a sensitivity of 100%. In the peritumoral tissue, 5-ALA was less sensitive than RS in detecting cancer (46% vs 69%) but showed higher specificity (81% vs 57%). When the two methods were combined, the accuracy of tumor detection was increased by about 10%. Pathology-tailored resection led to a 52% increase in resection volume comparing the volume of preoperative contrast enhancement with the postoperative resection cavity on MRI (p = 0.0123). Eloquent brain involvement prevented gross-total resection in 4 patients. Four weeks after surgery, mean KPS (p = 0.7637) and NIHSS scores (p = 0.3146) were not significantly different from preoperative values. Of the 13 patients who had received postoperative chemoradiotherapy, 4 did not show any progression after a median follow-up of 14 months. The remaining 9 patients had a median PFS of 8 months. CONCLUSIONS According to the study data, RS is capable of detecting tumor-infiltrated brain with higher sensitivity but lower specificity than the current standard of 5-ALA. With further technological and workflow advancements, RS in combination with protoporphyrin IX fluorescence may contribute to pathology-tailored glioma resection in the future.

OBJECTIVE The purpose of this study was to assess the impact of temporal muscle thickness (TMT), a surrogate marker for sarcopenia, in radiosurgically treated patients with brain metastases (BMs) from non–small cell lung cancer (NSCLC). METHODS For 566 patients with BMs from NSCLC in the period between June 2012 and December 2019, TMT values were retrospectively measured on the planning brain magnetic resonance imaging (MRI) studies that had been obtained before their first Gamma Knife radiosurgery treatment (GKRS1). Predefined sex-specific TMT cutoff values were used to stratify the study cohort into patients at risk for sarcopenia and patients with normal muscle status. Cox regression models adjusted for other prognostic parameters were used to evaluate sarcopenia as an independent prognostic factor. RESULTS In sarcopenia patients with a TMT below the sex-specific cutoff values, the risk of death was significantly increased (HR 1.908, 95% CI 1.550–2.349, p < 0.001). In addition, sarcopenia was revealed as an independent prognostic factor even after adjusting for age groups, sex, number of BMs, presence of extracranial metastases, NSCLC subtypes, Karnofsky Performance Status groups, recursive partitioning analysis classes, and concomitant immunotherapy or targeted therapy (HR 1.680, 95% CI 1.347–2.095, p < 0.001). However, patients at risk for sarcopenia showed no significant differences in the estimated mean time until local BM progression after GKRS1, compared to patients with normal muscle status (p = 0.639). CONCLUSIONS TMT obtained from planning MRI studies is an independent prognostic marker in radiosurgically treated patients with BMs from NSCLC and may aid patient stratification in future clinical trials.

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico-pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular-genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro-clinical-imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico-pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and "no definite FCD on histopathology" as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi-layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

OBJECTIVE The goal of this study was to evaluate the feasibility, benefit, and safety of awake brain surgery (ABS) and intraoperative language mapping in children and adolescents with structural epilepsies. Whereas ABS is an established method to monitor language function in adults intraoperatively, reports of ABS in children are scarce. METHODS A retrospective chart review of pediatric patients ≤ 18 years of age who underwent ABS and cortical language mapping for supratentorial tumors and nontumoral epileptogenic lesions between 2008 and 2019 was conducted. The authors evaluated the global intellectual and specific language performance by using detailed neuropsychological testing, the patient’s intraoperative compliance, results of intraoperative language mapping assisted by electrocorticography (ECoG), and postsurgical language development and seizure outcomes. Descriptive statistics were used for this study, with a statistical significance of p < 0.05. RESULTS Eleven children (7 boys) with a median age of 13 years (range 10–18 years) underwent ABS for a lesion in close vicinity to cortical language areas as defined by structural and functional MRI (left hemisphere in 9 children, right hemisphere in 2). Patients were neurologically intact but experiencing seizures; these were refractory to therapy in 9 patients. Compliance during the awake phase was high in 10 patients and low in 1 patient. Cortical mapping identified eloquent language areas in 6/10 (60%) patients and was concordant in 3/8 (37.5%), discordant in 3/8 (37.5%), and unclear in 2/8 (25%) patients compared to preoperative functional MRI. Stimulation-induced seizures occurred in 2 patients and could be interrupted easily. ECoG revealed that afterdischarge potentials (ADP) were involved in 5/9 (56%) patients with speech disturbances during stimulation. None of these patients harbored postoperative language dysfunction. Gross-total resection was achieved in 10/11 (91%) patients, and all were seizure free after a median follow-up of 4.3 years. Neuropsychological testing using the Wechsler Intelligence Scale for Children and the verbal learning and memory test showed an overall nonsignificant trend toward an immediate postoperative deterioration followed by an improvement to above preoperative levels after 1 year. CONCLUSIONS ABS is a valuable technique in selected pediatric patients with lesions in language areas. An interdisciplinary approach, careful patient selection, extensive preoperative training of patients, and interpretation of intraoperative ADP are pivotal to a successful surgery.

Purpose Developmental gene expression data from medulloblastoma (MB) supported by retrospective MR imaging studies suggest that WNT-MB originate from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH-activated MB arise from cerebellar precursor matrix regions. This study aims to analyze detailed intraoperative data with regard to the site of origin (STO) and compare these findings with the hypothesized regions of origin associated with the molecular group. Methods A review of the institutional database identified 58 pediatric patients who were operated on a MB at our department between 1996 and 2020 and had a detailed operative report, surgical video as well as clinical and genetic classification data available for analysis. The STO was assessed based on intraoperative findings of an expert neurosurgeon blinded to the molecular group information. Results Using the intraoperatively defined STO, “correct” prediction of molecular groups was feasible in 20% of WNT-MB, 60% of SHH-MB and 71% of non-WNT/non-SHH activated MB. The positive predictive values of the neurosurgical inspection to detect the molecular group were 0.21 (95% CI 0.08–0.48) for WNT-MB, 0.86 (95% CI 0.49–0.97) for SHH-MB and 0.73 (95% CI 0.57–0.85) for non-WNT/non-SHH activated MB. Conclusions The present study demonstrated a limited predictive value of the intraoperatively observed STO for the prediction of the molecular group of MB. Thus, our findings challenge the current concept of the molecular group-specific origins based on developmental gene expression data and neuroradiological STO definitions.

SummaryBackgroundThe global launch of ChatGPT on November 30, 2022 has sparked widespread public interest in large language models (LLMs), and interest in the medical community is growing. Indeed, recent preprints on medRxiv have examined ChatGPT and GPT-3 in the context of standardized exams, such as the United States Medical Licensing Examination. These studies demonstrate modest performance relative to national averages. In this work, we enhance OpenAI’s GPT-3 model through zero-shot learning, anticipating that it outperforms experienced neurosurgeons in written question-answer tasks for common clinical and surgical questions on vestibular schwannoma. We aimed to address LLM accountability by including in-text citations and references to the responses provided by GPT-3.MethodsThe analysis involved (i) creating a dataset through web scraping, (ii) developing a chat-based platform called neuroGPT-X, (iii) enlisting expert neurosurgeons across international centers to create and answer questions and evaluate responses, and (iv) analyzing the evaluation results on the management of vestibular schwannoma. The survey had a blinded and unblinded phase. In the blinded phase, a neurosurgeon with 30+ years of experience curated 15 questions regarding common clinical and surgical contexts of vestibular schwannoma. Then, four neurosurgeons, ChatGPT (January 30, 2023 model, akanaiveGPT), and a context-enriched GPT model independently provided their responses. Three experienced neurosurgeons blindly evaluated the responses for accuracy, coherence, relevance, thoroughness, speed, and overall rating. Then, all seven neurosurgeons were unblinded to all responses and provided their thoughts on the potential of expert LLMs in the clinical setting.FindingsBoth the naive and content-enriched GPT models provided faster responses to the standardized question set (p0.999) or performance across the aforementioned domains (p>0.999). Of interest, all expert surgeons expressed concerns about the reliability of GPT in accurately addressing the nuances and controversies surrounding the management of vestibular schwannoma. Further, we developed neuroGPT-X, a chat-based platform designed to provide point-of-care clinical support and mitigate limitations of human memory. neuroGPT-X incorporates features such as in-text citations and references to enable accurate, relevant, and reliable information in real-time.InterpretationA context-enriched GPT model provided non-inferior responses compared to experienced neurosurgeons in generating written responses to a complex neurosurgical problem for which evidence-based consensus for management is lacking. We show that context enrichment of LLMs is well-suited to transform clinical practice by providing subspecialty-level answers to clinical questions in an accountable manner.Research in ContextEvidence before this studyWe searched PubMed for “(vestibular schwannoma OR acoustic schwannoma) AND (GPT-3 OR Generative Pretrained Transformer OR large language model)” with no filters and identified no relevant articles. We then searched PubMed using the string “(subspecialty OR neurosurgery OR physician) AND (GPT-3 OR Generative Pretrained Transformer OR large language model) AND (fine-tuning OR context enrichment)” with no filters and identified three studies. One study noted that domain-specific knowledge enhanced pre-trained language models.Added value of this studyTo our knowledge, this is the first study to show the non-inferiority of a context-enriched LLM in a question-answer task on common clinical and surgical questions compared to experienced neurosurgeons worldwide, determined by their neurosurgical colleagues. Furthermore, we developed the first online platform incorporating an LLM, chat memory, in-text citations, and references regarding comprehensive vestibular schwannoma management. To assess the model’s performance, a neurosurgeon with 30+ years of experience managing patients with vestibular schwannoma curated 15 questions to the model, ChatGPT, and four international expert neurosurgeons. A separate, blinded group of three expert neurosurgeons assessed these answers for accuracy, coherence, relevance, thoroughness, speed, and overall rating. This study demonstrated the capability of context-enriched LLMs as point-of-care informational aids. Importantly, all expert surgeons raised questions regarding the nuances and role of human experience and intuition that GPT may not capture in generating opinions or recommendations.Implications of all the available evidenceThe present study, with its subspecialist-level performance and interpretable results, suggests that context-enriched LLMs show promise as a point-of-care medical resource. Evaluations from experienced neurosurgeons showed that a context-enriched GPT model was rated similarly to neurosurgeon responses across evaluation domains in this study. This work serves as a springboard for expanding this tool into more medical specialties, incorporating evidence-based clinical information, and developing expert-level dialogue surrounding LLMs in healthcare.

Fluorescence guidance is widely utilized to improve the precision of cancer surgery. 5-aminolevulinic acid, the most widely used fluorophore in glioma surgery, is thought to cause selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumor cells. 5-aminolevulinic acid is highly specific for densely tumor-infiltrated tissue but less effective for visualizing the tumor periphery. To improve clinical detection of PpIX, we developed a microscope to perform paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF) and validated it in 175 fresh tumor specimens from 75 high-grade glioma patients across three institutions. Here, we demonstrate that intracellular PpIX accumulation occurs most prominently in histiocytic, rather than neoplastic, appearing cells. Spatially resolved metabolomics, transcriptomics and RNA sequencing revealed that PPIX is most avidly concentrated in tumor associated macrophages. There was no correlation between the degree of tissue cellularity and PpIX concentration across all imaged specimens (R=-0.21). Our findings encourage reconsideration of the existing theory of 5-ALA-induced glioma cell fluorescence and demonstrate how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of human gliomas.

Objective To analyze characteristics associated with long-term pain relief after microvascular decompression (MVD) for trigeminal neuralgia (TGN). Description of associated morbidity and complication avoidance. Methods One hundred sixty-five patients with TGN underwent 171 MVD surgeries at the authors’ institution. Patient characteristics and magnetic resonance imaging (MRI) datasets were obtained through the hospital’s archiving system. Patients provided information about pre- and post-operative pain characteristics and neurologic outcome. Favorable outcome was defined as a Barrow Neurological Institute (BNI) pain intensity score of I to III with post-operative improvement of I grade. Results Type of TGN pain with purely paroxysmal pain (p = 0.0202*) and TGN classification with classical TGN (p = 0.0372*) were the only significant predictors for long-term pain relief. Immediate pain relief occurred in 90.6% of patients with a recurrence rate of 39.4% after 3.5 ± 4.6 years. MRI reporting of a neurovascular conflict had a low negative predictive value of 39.6%. Mortality was 0% with major complications observed in 8.2% of patients. Older age was associated with lower complication rates (p = 0.0009***). Re-MVD surgeries showed improved long-term pain relief in four out of five cases. Conclusions MVD is a safe and effective procedure even in the elderly. It has the unique potential to cure TGN if performed on a regular basis, and if key surgical steps are respected. Early MVD should be offered in case of medical treatment failure and paroxysmal pain symptoms. The presence of a neurovascular conflict on MRI is not mandatory. In case of recurrence, re-MVD is a good treatment option that should be discussed with patients. Highlights • Long-term analysis of pain relief after MVD. • Positive predictors for outcome: classical TGN and purely paroxysmal pain. • Presence of neurovascular conflict in MRI is not mandatory for MVD surgery. • Analysis of complications and surgical nuances for avoidance. • MVD is a safe procedure also in the elderly.

ThePTPN11gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations ofPTPN11and otherRAS-/MAP-Kinase signaling pathwaygenescause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of thePTPN11gene compared to GG with other common MAP-Kinase signaling pathway alterations. Seventy-two GG were submitted to whole exome sequencing and genotyping and 86 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. Clinical data were retrieved from hospital files including postsurgical disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG withPTPN11alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains inFGFR4, RHEB, NF1, KRASas well asBRAFV600Ealterations. Histopathology revealed an atypical and complex glio-neuronal phenotype with subpial tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG andPTPN11alterations were free of disabling-seizures two years after surgery (38% Engel I). This was remarkably different from our series of GG withBRAFV600Emutations (85% Engel I). Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized byPTPN11and other Noonan syndrome-related alterations of theRAS-/MAP-Kinase signaling pathway. These findings need prospective validation in clinical practice as they argue for an adapted WHO grading system in developmental, glio-neuronal tumors associated with early-onset focal epilepsy. These findings also open avenues for targeted medical treatment.

We report the case of a 22-year-old woman presenting with an acute onset of dizziness, gait dysbalance and blurred vision. Magnetic resonance imaging included 3 Tesla and 7 Tesla imaging and revealed a T2-hyperintense, T1-hypointense, non-contrast-enhancing lesion strictly confined to the white matter affecting the right optic radiation. An extensive ophthalmologic examination yielded mild quadrantanopia but no signs of optic neuropathy. The lesion was biopsied. The neuropathological evaluation revealed a demyelinating lesion with marked tissue vacuolization and granular myelin disintegration accompanied by mild T cell infiltration and a notable absence of myelin uptake by macrophages. Oligodendrocytes were strikingly enlarged, displaying oncocytic characteristics and showed cytoplasmic accumulation of mitochondria, which had mildly abnormal morphology on electron microscopy. The diagnosis of multiple sclerosis was excluded. Harding's disease, a variant of Leber's hereditary optic neuropathy, was then suspected. However, neither PCR for relevant mutations nor whole exome sequencing yielded known pathogenetic mutations in the patient's genome. We present a pattern of demyelinating tissue injury of unknown etiology with an oncocytic change of oligodendrocytes and a lack of adequate phagocytic response by macrophages, which to the best of our knowledge, has not been described before.

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 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.

To investigate predictive value of preradiosurgery leukocyte-based prognostic ratios in a selected cohort of non-small cell lung cancer (NSCLC) patients with radiosurgery-treated brain metastases (BM) and concomitant immunotherapy (IT) or targeted therapy (TT).We performed a retrospective analysis of 166 patients with NSCLC BM treated with Gamma Knife radiosurgery. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio were assessed within 14 days before radiosurgery.In radiosurgically treated patients with NSCLC BM with concomitant IT or TT, estimated median survival after first Gamma Knife radiosurgery treatment was significantly longer in patients with NLR cutoff value5 (P = 0.038). Consequently, the Cox regression model for NLR cutoff value groups revealed a significant hazard ratio of 1.519 (95% confidence interval 1.020-2.265, P = 0.040). In addition, each increase in NLR of 1 equaled an increase of 5.4% in risk of death (hazard ratio 1.054, 95% confidence interval 1.024-1.085, P0.001). After adjusting for sex, age, Karnofsky performance scale, and presence of extracranial metastases, NLR remained a significant and independent predictor for survival (hazard ratio 1.047, 95% confidence interval 1.017-1.078, P = 0.002). In contrast, platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio did not exhibit the same predictive value among patients with radiosurgery-treated BM with concomitant IT or TT.In patients with NSCLC BM treated with radiosurgery with concomitant IT or TT, preradiosurgery NLR represents a simple prognostic predictor for survival and is superior to other leukocyte-based ratios. NLR may be relevant for clinical decision making, therapeutic evaluation, patient counseling, and appropriate stratification of future clinical trials among patients with radiosurgery-treated BM.

Purpose To investigate the clinical value of the inflammation based prognostic scores for patients with radiosurgically treated brain metastases (BM) originating from non-pulmonary primary tumor (PT). Methods A retrospective analysis of 340 BM patients of different PT origin (melanoma, breast, gastrointestinal, or genitourinary cancer) was performed. Pre-radiosurgical laboratory prognostic scores, such as the Neutrophil-to-Lymphocyte Ratio (NLR), the Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), and the modified Glasgow Prognostic Score (mGPS), were investigated within 14 days before the first Gamma Knife radiosurgical treatment (GKRS1). Results In our study cohort, the estimated survival was significantly longer in patients with NLR 4 (p = 0.001) and in patients with a mGPS score of 0 (p Conclusions Summarizing previously published and present data, pre-radiosurgical mGPS and NLR groups seem to be the most effective and simple independent prognostic factors to predict clinical outcome in radiosurgically treated BM patients.

OBJECTIVES To assesses the postoperative outcome and the applicability of current Chiari 1 malformation (CM1) scores in a tailored surgical treatment approach in patients with CM1. METHODS This retrospective single center study analyzed 81 surgically treated patients between 2000 and 2020. Based on our institutional policy, four types of approaches were performed in that period based on a case by case decision: 1) Foramen magnum decompression (FMD) with dura splitting (FMDds), 2) FMD with duraplasty (FMDdp), 3) FMD with duraplasty and tonsillar manipulation (FMDao) and 4) tonsillar resection/reduction (TR). Patient characteristics, the Chicago Chiari Outcome Scale (CCOS), Chiari Severity Index (CSI), and the fourth ventricular roof angle (FVRA) were compared among the four groups to establish a treatment algorithm. RESULTS FMDds, FMDdp, FMDao and TR was performed in 11 (14%), 24 (30%), 21 (26%) and 25 (31%) patients, respectively. After a mean follow-up time of 6.6 years, 8/11 (73%), 19/24 (79%), 19/21 (90%) and 24/24 (100%) patients had a CCOS of 13–16 points after FMDds, FMDdp, FMDao and TR, respectively. Overall, 6/11 (55%), 4/17 (24%), 3/18 (17%) and 7/24 (29%) patients had a CSI grade 1 before FMDds, FMDdp, FMDao and TR. A weak negative and statistically not significant correlation between CCOS and CSI was observed (p = 0.07, n = 69). The preoperative FVRA was

Zusammenfassung Hintergrund Die chirurgische Therapie der posterioren Epilepsie stellt innerhalb der epilepsiechirurgischen Eingriffe eine besondere Herausforderung dar. Fragestellung Die Arten der Eingriffe zur chirurgischen Therapie der posterioren Epilepsie Material und Methode Darstellung der verschiedenen Eingriffsarten auf Basis der historischen und rezenten technischen Entwicklungen. Ergebnisse Elektrodenimplantation, resektive und diskonnektive Verfahren sowie neue Methoden tragen dazu bei, das Anfallsoutcome der posterioren Epilepsie zu verbessern.

Zusammenfassung Hintergrund Posteriore Epilepsien (PE), also fokale Epilepsien mit Ursprungszonen in den hinteren Anteilen des Neokortex (Parietallappen, Okzipitallappen, dorsaler Temporallappen), sind eine diagnostische und therapeutische Herausforderung mit einem großen Spektrum an möglichen Ätiologien. Fragestellung Das ätiologische Spektrum der PE wird dargestellt. Material und Methode Illustration auf der Basis langjähriger eigener Erfahrung und mit Befundbeispielen eigener Fälle. Ergebnisse Die PE ist vielgestaltig. Die Kenntnis des breiten Spektrums der möglichen Ätiologien ist wichtig, um eine PE mit ihrer Ätiologie verlässlich zu erkennen und ausgewählten Patienten eine gezielte Behandlung anbieten zu können. Erfolgreiche Epilepsiechirurgie ist nicht selten möglich. Background Posterior epilepsies (PE), i.e. focal epilepsies with epileptogenic zones within the posterior parts of the neocortical mantle (parietal, occipital and dorsal temporal lobes), represent a diagnostic and therapeutic challenge encompassing a wide spectrum of possible etiologies. Objective The etiological spectrum of PE is presented. Material and methods Illustration based on the longstanding personal expertise of the authors with examples of findings in personal cases. Results The PE is complex. Knowledge of the broad spectrum of possible etiologies is important in order to be able to reliably identify a PE including its etiology and to offer targeted treatment to selected patients. Successful epilepsy surgery is often possible.

(1) Background: Recent developments in 7T magnetic resonance spectroscopic imaging (MRSI) made the acquisition of high-resolution metabolic images in clinically feasible measurement times possible. The amino acids glutamine (Gln) and glycine (Gly) were identified as potential neuro-oncological markers of importance. For the first time, we compared 7T MRSI to amino acid PET in a cohort of glioma patients. (2) Methods: In 24 patients, we co-registered 7T MRSI and routine PET and compared hotspot volumes of interest (VOI). We evaluated dice similarity coefficients (DSC), volume, center of intensity distance (CoI), median and threshold values for VOIs of PET and ratios of total choline (tCho), Gln, Gly, myo-inositol (Ins) to total N-acetylaspartate (tNAA) or total creatine (tCr). (3) Results: We found that Gln and Gly ratios generally resulted in a higher correspondence to PET than tCho. Using cutoffs of 1.6-times median values of a control region, DSCs to PET were 0.53 ± 0.36 for tCho/tNAA, 0.66 ± 0.40 for Gln/tNAA, 0.57 ± 0.36 for Gly/tNAA, and 0.38 ± 0.31 for Ins/tNAA. (4) Conclusions: Our 7T MRSI data corresponded better to PET than previous studies at lower fields. Our results for Gln and Gly highlight the importance of future research (e.g., using Gln PET tracers) into the role of both amino acids.

Introduction Pilocytic astrocytoma (PA) is the most common primary brain neoplasm in children and treated in curative intent with gross total resection (GTR). However, PA is rare in adults, resulting in limited knowledge on the natural clinical course. This study aimed to describe the clinical course and identify prognostic factors of adult patients with PA. Methods 46 patients ≥ 18 years at diagnosis of PA and neurosurgical resection or biopsy between 2000 and 2018 were identified from the Neuro-Biobank of the Medical University of Vienna. In two cases with differing histopathological diagnosis at recurrence, DNA methylation analysis was performed using Illumina Infinium HumanMethylation850 BeadChip (850 k) arrays and the Molecular Neuropathology classifier. Clinico-pathological features were correlated with patient outcomes. Results Median age at diagnosis was 32.5 years (range: 19–75) and median Ki67 proliferation index was 2.8% (0.5–13.4%). Tumor location significantly correlated with resectability (p 40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p Conclusions Tumor recurrence or progression in adult PA patients was higher than the one reported in pediatric patients. Higher age and BMI were associated with impaired prognosis.

Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.

Detailed anatomic visualization of the root entry zone of the trigeminal nerve is crucial to successfully perform microvascular decompression surgery (MVD) in patients with trigeminal neuralgia.To determine advantages and disadvantages using a 3-dimensional (3D) exoscope for MVD surgery.A 4K 3D exoscope (ORBEYE) was used by a single surgical team for MVD in a retrospective case series of 8 patients with trigeminal neuralgia in a tertiary center. Clinical and surgical data were collected, and advantages/disadvantages of using the exoscope for MVD were recorded after each surgery. Descriptive statistics were used to summarize the data.Adequate MVD of the trigeminal nerve root was possible in all patients by exclusively using the exoscope. It offered bright visualization of the cerebellopontine angle and the root entry zone of the trigeminal nerve that was comparable with a binocular operating microscope. The greatest advantages of the exoscope included good optical quality, the pronounced depth of field of the image for all observers, and its superior surgeon ergonomics. Disadvantages were revealed with overexposure at deep surgical sites and the lack of endoscope integration. In 6 patients, facial pain improved significantly after surgery (Barrow Neurological Institute pain intensity score I in 5 and III in 1 patient), whereas it did not in 2 patients (Barrow Neurological Institute score IV and V). No complications occurred.Utilization of a 3D exoscope for MVD is a safe and feasible procedure. Surgeons benefit from better ergonomics, excellent image quality, and an improved experience for observers.

Brain organoids differentiated from human induced pluripotent stem cells provide a unique opportunity to investigate the development, organization and connectivity of neurons in a complex cellular environment. However, organoids usually lack microglia, brain-resident immune cells which are both present in the early human embryonic brain and participate in neuronal circuit development.Here, we find that microglia innately develop in unguided retinal organoid differentiation between week 3 and 4 in 2.5D culture and appear later in floating, non-pigmented, 3D-cystic compartments. We enriched for cystic structures using a low-dosed BMP4 application and performed mass spectrometry, thus defining the protein composition of microglia-containing compartments. We found that cystic compartments expressed both mesenchymal and epithelial markers with microglia enriched in the mesenchymal region. Interestingly, microglia-like cells started to express the border-associated macrophage marker CD163. The preferential localization of human microglia to a mesenchymal compartment provides insight into the behavior and migration of microglia. The model will ultimately allow detailed study of these enigmatic cells and how they enter and distribute within the human brain.

ZusammenfassungDie chirurgische Therapie der therapierefraktären Temporallappenepilepsie ist der medikamentösen weitaus überlegen, und es kann bei 60–80% der Patienten eine Anfallsfreiheit erreicht werden. Aufgrund der Fortschritte in den diagnostischen Verfahren, insbesondere der MR-Bildgebung, haben sich verschiedene chirurgische Techniken entwickelt. Allen gemeinsam ist der Einschluss der medialen temporalen Strukturen (Amygdala, Hippocampus, Parahippocampus) in die Resektion. Unterschiede zwischen der vorderen Temporallappenresektion und der anteromedialen Temporallappenresektion bestehen im Ausmaß der lateralen temporalen Resektion. Im Falle einer selektiven Resektion des medialen Temporallappens werden unterschiedliche Zugangswege vorgeschlagen. Im Hinblick auf Anfallsfreiheit und Minimierung der neuropsychologischen Morbidität ist die Wahl des jeweiligen resektiven Verfahrens sowohl zentrums- als auch chirurgenabhängig. Gleichzeitig zielen sie darauf ab, die Morbidität v. a. im Hinblick auf das neuropsychologische Outcome zu reduzieren. Diesen Gedanken führen minimal-invasive Methoden wie die Laserablation (LITT) fort. Durch diese erhofft man sich, das gute Anfallsoutcome der offenen Resektionen beibehalten zu können und gleichzeitig die mit einer Resektion verbundenen Kollateralschäden zu minimieren. Des Weiteren soll die minimal-invasive Natur dieser Methoden die Hemmschwelle der Patienten für einen Eingriff senken und so die Anzahl der epilepsiechirurgischen Kandidaten, die sich nicht einem offen chirurgischen Eingriff unterziehen wollen, reduzieren. Die Erfahrungen mit diesen Methoden sind noch vergleichsweise gering, und es bleibt abzuwarten, ob sie ein ebenso gutes Anfallsoutcome im Langzeitverlauf bei so geringer Komplikationsrate, wie es die resektive chirurgische Therapie der Temporallappenepilepsie hat, erreichen kann.

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 IIIII. 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.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".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.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.

Subependymal giant cell astrocytomas (SEGAs) are circumscribed gliomas strongly associated with tuberous sclerosis (TS). TS, a rare genetic disorder caused by inactivating mutations in either of the TSC genes (TSC1/2), leads to upregulation of the mTOR pathway and consecutive cell growth. CNS manifestations other than SEGAs include cortical tubers, white matter glioneuronal hamartomas and subependymal nodules (SENs), which, although regarded as distinct morphological phenotypes, share certain histological characteristics including ballooned astrocytes and giant ganglion-like cells. SEGAs, thought to develop from the median ganglionic eminence (MGE), are most commonly located periventricularly. However, rare cases of extraventricular SEGAs have been reported. We report a case of a cortico-subcortically located SEGA in a TS patient. A two-month-old female TS patient with multiple cortical tubers presented with treatment-resistant epilepsy. A 4cm sized tuber located in the right temporal lobe, showing a transmantle sign on MRI but no typical imaging appearance of SEGA, was surgically resected. Histological evaluation revealed typical morphological characteristics of a tuber with dysmorphic neurons, balloon cells and calcifications in the cortex and adjacent white matter. Focally, a cortico-subcortically located, well delineated area with increased cellularity and morphological features of a SEGA was found. Single mitotic figures were detectable. Immunhistochemically, these cells were strongly positive for GFAP, vimentin, and nestin. Scattered S100-, NeuN-, MAP2- and SMI32-positive cells were present. No expression of class-III-b-tubulin and TTF1a was found. pS6 was expressed in a small fraction of cells. CD34 showed a dense capillary network within the lesion. This case is consistent with prior case reports of SEGA-tissue in tubers of TS patients. However, the SEGA tissue of this case did not display TTF1a-expression, characteristic for SEGAs and considered as a marker for cells originating from the MGE, thus implying a different cellular lineage.

Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th–April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017–2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017–2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.

Objective: Increasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well-characterized patients with TSC and FCD2B. Methods: We applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed. Results: Protein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns. Significance: Our results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.

OBJECTIVE The authors sought to evaluate clinical outcome in patients with large, high-risk brain metastases (BMs) treated with different dose strategies by use of two-fraction dose-staged Gamma Knife radiosurgery (GKRS). METHODS A retrospective analysis was performed with data from 142 patients from two centers who had been treated with two-fraction dose-staged GKRS between June 2015 and January 2020. Depending on the changes in marginal dose between the first (GKRS1) and second (GKRS2) GKRS treatments, the study population was divided into three treatment groups: dose escalation, dose maintenance, and dose de-escalation. RESULTS The 142 study patients underwent two-fraction dose-staged GKRS treatments for 166 large, high-risk BMs. The median tumor volume of 7.4 cm3 decreased significantly from GKRS1 to GKRS2 (4.4 cm3; p < 0.001), and to the last follow-up (1.8 cm3; p < 0.001). These significant differences in BM volume reduction were achieved in all three treatment groups. However, differences according to the primary tumor histology were apparent: while dose maintenance seemed to be the most effective treatment strategy for BMs from lung cancer or melanoma, dose escalation was the most beneficial treatment option for BMs from breast, gastrointestinal, or genitourinary cancer. Of note, the vast majority of patients who underwent dose-staged BM treatment did not show any significant postradiosurgical complications. CONCLUSIONS In patients with large, high-risk BMs, dose-staged GKRS treatment represents an effective local treatment method with acceptable complication risks. Different dose-strategy options are available that may be chosen according to the primary tumor histology and treatment volume but may also be tailored to the findings at GKRS2.

Introduction Intraoperative magnetic resonance imaging (iopMRI) is increasingly incorporated into neurosurgery to improve outcomes. However, its usefulness in epilepsy surgery remains debated. To elucidate its current role we conducted a systematic review of the data published to date. Evidence acquisition We performed a systematic review of the available literature using the PubMed, Scopus, and Embase database. Only articles detailing the usefulness of iopMRI in quantifiable measures were included. Different aspects of iopMRI in epilepsy surgery were analysed and two meta-analyses summarizing its impact on extent of resection and seizure outcomes performed. Evidence synthesis A total of 33 articles met the inclusion criteria, comprising a total of 1313 patients, both children and adults operated under iopMRI guidance. The mean rate of return to surgery was 29.2% in 30 articles reporting this number. Eleven publications were eligible for meta-analysis of seizure outcome in patients with refractory epilepsy, who had undergone surgery with iopMRI (n= 294) compared to controls (n=298). Eight articles described the impact of iopMRI on the radiological extent of resection. In both regards, usage of iopMRI improved outcomes in our meta-analysis with an OR of 3.8 and 4.75, respectively. Conclusions This work presents the first meta-analysis of the value of iopMRI in epilepsy surgery. Its use resulted in an improvement of the desired extent of resection and led to a better seizure outcome compared to conventional surgery. Understanding its benefits might help improve surgical strategies in traditional, open epilepsy surgery.

BACKGROUND In precision oncology ex vivo drug screening systems have the potential to improve clinical outcomes. Traditionally, cancer drugs are tested on cancer cell line models, but these cannot represent an individual patient and are biologically too distinct. Drug screening systems usually rely on viability assays and correlations to genomic alterations. Beside genomic alterations, the cellular metabolism is significantly altered which may lead to drug resistance. Here we aim to establish a drug screening platform using tumor cells derived directly from the individual patient glial tumor tissue, create patient derived tumor cells (PDCs) and combine the outcomes from standardized viability- and genetic-assays with a new developed metabolomics platform. Materials and METHODS Fresh native tissue from patients harbouring low- and high-grade glioma are collected (n=46). Tumor tissue used for NMR-based metabolomic analyses and targeted sequencing analyses as well as PDC isolation. To preserve the original tumor similarity, tissue is short term cultured for two weeks, and PDCs are seeded and treated with a panel of clinical- and preclinical drugs followed by viability assessment, sequencing and metabolomic profiling. RESULTS Culturing of PDCs is successful in ≥ 85% of patient cases, provided that at least 2 g of tumor tissue is available. The automatized high throughput ex vivo drug response identifies drug candidates, which might become relevant for therapeutic approaches in future. It is possible to distinguish between IDH1-wild-type and IDH1-mutant tumors based on the metabolomic profile, which is confirmed by immunohistochemical staining and molecular analysis of IDH1 R132H-mutation. Strong metabolomic variations have been identified, including GABA, lactate, and myo-inositol levels between tumor and healthy tissue. CONCLUSION Entangling drug screening and genetic assays with metabolomic profiling of glial tumors enriches the information about cellular drug response and paves the way for future clinical studies and better understanding of underlying drug resistance mechanisms in gliomas.

Fluorescence guidance is widely utilized to improve the precision of cancer surgery. 5-aminolevulinic acid, the most widely used fluorophore in glioma surgery, is thought to cause selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumor cells by exploiting pathologic alterations in heme biosynthetic pathways. PpIX-induced fluorescence is highly specific for densely tumor-infiltrated tissue but less effective for visualizing the tumor periphery. To improve clinical detection of PpIX, we developed a microscope to perform paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF) and validated it in 175 fresh, unprocessed core tumor specimens from 75 high-grade glioma patients and three central nervous system lymphoma patients across three institutions. Surprisingly, intracellular PpIX accumulation was observed primarily in cells with histiocytic, rather than neoplastic morphology, and the number of cells concentrating PpIX within the cytoplasm was associated with the abundance of CD163 positive cells (p< 0.02). There was no correlation between the degree of tumor cellularity and the concentration of PpIX across all imaged specimens (R=-0.21). Our findings encourage reconsideration of the existing theory of 5-ALA-induced tumor cell fluorescence in gliomas and demonstrate how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of human gliomas.

PURPOSE Recently, a 3D-concentric ring trajectory (CRT)-based free induction decay (FID)-MRSI sequence was introduced for fast high-resolution metabolic imaging at 7 T. This technique provides metabolic ratio maps of almost the entire brain within clinically feasible scan times, but its robustness has not yet been thoroughly investigated. Therefore, we have assessed quantitative concentration estimates and their variability in healthy volunteers using this approach. METHODS We acquired whole-brain 3D-CRT-FID-MRSI at 7 T in 15 min with 3.4 mm nominal isometric resolution in 24 volunteers (12 male, 12 female, mean age 27 ± 6 years). Concentration estimate maps were calculated for 15 metabolites using internal water referencing and evaluated in 55 different regions of interest (ROIs) in the brain. Data quality, mean metabolite concentrations, and their inter-subject coefficients of variation (CVs) were compared for all ROIs. RESULTS Of 24 datasets, one was excluded due to motion artifacts. The concentrations of total choline, total creatine, glutamate, myo-inositol, and N-acetylaspartate in 44 regions were estimated within quality thresholds. Inter-subject CVs (mean over 44 ROIs/minimum/maximum) were 9%/5%/19% for total choline, 10%/6%/20% for total creatine, 11%/7%/24% for glutamate, 10%/6%/19% for myo-inositol, and 9%/6%/19% for N-acetylaspartate. DISCUSSION We defined the performance of 3D-CRT-based FID-MRSI for metabolite concentration estimate mapping, showing which metabolites could be robustly quantified in which ROIs with which inter-subject CVs expected. However, the basal brain regions and lesser-signal metabolites in particular remain as a challenge due susceptibility effects from the proximity to nasal and auditory cavities. Further improvement in quantification and the mitigation of B0 /B1 -field inhomogeneities will be necessary to achieve reliable whole-brain coverage.

Cerebral organoids differentiated from human-induced pluripotent stem cells (hiPSC) provide a unique opportunity to investigate brain development. However, organoids usually lack microglia, brain-resident immune cells, which are present in the early embryonic brain and participate in neuronal circuit development. Here, we find IBA1

BACKGROUND: Medulloblastoma (MB) are the most common malignant brain tumor in childhood. Developmental gene expression data supported by neuroradiological studies suggest that Wingless (WNT)-MB originate from the lower rhombic lip (LRL), Sonic-Hedgehog (SHH)-MB from the cerebellar hemispheres, and Group 3 and Group 4 MB from the cerebellar vermis. However, there is still insufficient evidence from a neurosurgical perspective supporting this proposed concept. METHODS: Clinical and molecular data from patients aged under 18 years at time of diagnosis who were operated on a histologically confirmed MB at the Department of Neurosurgery of the Medical University of Vienna between 1990 and 2020 were retrospectively analyzed. The location of the tumor origin was defined based on operative reports, surgical videos and preoperative imaging data by an experienced neurosurgeon blinded to the subgroup information. RESULTS: Sufficient data were available in 53 patients. In 28.6% (2 / 7) WNT-MB, 66.7% (6 / 9) SHH-MB and 70.3% (26 / 37) Group 3 and Group 4 MB, the intraoperatively defined site of origin corresponded well with the cellular origin suspected from the molecular subgroup. Within the WNT-subgroup, 57.1% (4 / 7) originated from the vermis, 28.6% (2 / 7) from the LRL and 14.3% (1 / 7) from the cerebellar hemisphere. The origin of SHH-MB was predominantly located in cerebellar hemispheres (66.7% (6 / 9)), while 33.3% (3 / 9) originated from the vermis. Of Group 3 and Group 4 MB, 70.3% (26 / 37) had their origin in the vermis and 29.7% (11 / 37) in the LRL.CONCLUSION: Our results indicate that there is a considerable level of inconsistency between the intraoperatively observed site of origin and the expected cellular origin based on the molecular subgroup, especially in WNT-MB. This discrepancy needs to be discussed when it comes to surgical decision-making accounting for risk stratification.

The world currently faces the novel severe acute respiratory syndrome coronavirus 2 pandemic. Little is known about the effects of a pandemic on non-elective neurosurgical practices, which have continued under modified conditions to reduce the spread of COVID-19. This knowledge might be critical for the ongoing second coronavirus wave and potential restrictions on health care. We aimed to determine the incidence and 30-day mortality rate of various non-elective neurosurgical procedures during the COVID-19 pandemic. A retrospective, multi-centre observational cohort study among neurosurgical centres within Austria, the Czech Republic, and Switzerland was performed. Incidence of neurosurgical emergencies and related 30-day mortality rates were determined for a period reflecting the peak pandemic of the first wave in all participating countries (i.e. March 16th–April 15th, 2020), and compared to the same period in prior years (2017, 2018, and 2019). A total of 4,752 emergency neurosurgical cases were reviewed over a 4-year period. In 2020, during the COVID-19 pandemic, there was a general decline in the incidence of non-elective neurosurgical cases, which was driven by a reduced number of traumatic brain injuries, spine conditions, and chronic subdural hematomas. Thirty-day mortality did not significantly increase overall or for any of the conditions examined during the peak of the pandemic. The neurosurgical community in these three European countries observed a decrease in the incidence of some neurosurgical emergencies with 30-day mortality rates comparable to previous years (2017–2019). Lower incidence of neurosurgical cases is likely related to restrictions placed on mobility within countries, but may also involve delayed patient presentation.

Objective Reliable localization of the epileptogenic zone is necessary for successful epilepsy surgery. Neurophysiological biomarkers include ictal onsets and interictal spikes. Furthermore, the epileptic network shows oscillations with potential localization value and pathomechanistic implications. The cellular origin of such markers in invasive EEG in vivo remains to be clarified. Methods In the presented pilot study, surgical brain samples and invasive EEG recordings of seven patients with surgically treated Focal Cortical Dysplasia (FCD) type II were coregistered using a novel protocol. Dysmorphic neurons and balloon cells were immunohistochemically quantified. Evaluated markers included seizure onset, spikes, and oscillatory activity in delta, theta, gamma and ripple frequency bands, as well as sample entropy and phase-amplitude coupling between delta, theta, alpha and beta phase and gamma amplitude. Results Correlations between histopathology and neurophysiology provided evidence for a contribution of dysmorphic neurons to interictal spikes, fast gamma activity and ripples. Furthermore, seizure onset and phase-amplitude coupling in areas with dysmorphic neurons suggests preserved connectivity is related to seizure initiation. Balloon cells showed no association. Conclusions Phase-amplitude coupling, spikes, fast gamma and ripples are related to the density of dysmorphic neurons and localize the seizure onset zone. Significance The results of our pilot study provide a new powerful tool to address the cellular source of abnormal neurophysiology signals to leverage current and novel biomarkers for the localization of epileptic activity in the human brain.

Normal variants, although not occurring frequently, may appear similar to epileptic activity. Misinterpretation may lead to false diagnoses. In the context of presurgical evaluation, normal variants may lead to mislocalizations with severe impact on the viability and success of surgical therapy. While the different variants are well known in EEG, little has been published in regard to their appearance in magnetoencephalography. Furthermore, there are some magnetoencephalography normal variants that have no counterparts in EEG. This article reviews benign epileptiform variants and provides examples in EEG and magnetoencephalography. In addition, the potential of oscillatory configurations in different frequency bands to appear as epileptic activity is discussed.

BACKGROUND AND OBJECTIVES Complete neurosurgical resection of intracranial meningiomas is essential to avoid residual tumor tissue and thus minimize the risk of tumor recurrence. However, local recurrence of meningiomas is not uncommon mainly due to insufficient intraoperative detection of residual tumor tissue within the tumor bulk or peritumoral tissue such as bone and satellite lesions. Although 5-aminolevulinic acid (5-ALA) induced fluorescence was found to visualize the majority of meningiomas, no comprehensive histopathological assessment of fluorescing samples from the tumor bulk and peritumoral tissue is available. The aim of our study was thus to histopathologically analyze a large series of tissue samples derived from meningioma surgery to assess the positive predictive value (PPV) of visible 5-ALA fluorescence. STUDY DESIGN/MATERIALS AND METHODS In this study, we retrospectively investigated a series of tissue samples with visible 5-ALA fluorescence collected during surgery of intracranial meningiomas from the tumor bulk and peritumoral tissue including the bone flap, dura/dural tail, arachnoidea, adjacent cortex, and satellite lesions. The tumor diagnosis was established according to the World Health Organization (WHO) criteria and all collected fluorescing samples were screened for presence of tumor tissue to calculate the PPV. RESULTS Altogether, 191 tissue samples with visible 5-ALA fluorescence derived during surgery of 85 meningiomas (63 WHO grade I, 17 WHO grade II, and 5 WHO grade III) were included. In detail, 158 samples from the tumor bulk and 33 specimens from the peritumoral tissue were investigated. According to histopathological analysis, the PPV of 5-ALA fluorescence was significantly higher in samples from the tumor bulk (100%) as compared with peritumoral tissue (73%; P

OBJECTIVEGross-total resection (GTR) is the treatment of choice in the majority of patients suffering from spinal ependymal tumors. In such tumors, the extent of resection (EOR) is considered the key factor for tumor recurrence and thus patient prognosis. However, incomplete resection is not uncommon and leads to increased risk of tumor recurrence. One important cause of incomplete resection is insufficient intraoperative visualization of tumor tissue as well as residual tumor tissue. Therefore, the authors investigated the value of 5-aminolevulinic acid (5-ALA)–induced fluorescence in a series of spinal ependymal tumors for improved tumor visualization.METHODSAdult patients who underwent preoperative 5-ALA administration and surgery for a spinal ependymal tumor were included in this study. For each tumor, a conventional white-light microsurgical resection was performed. Additionally, the fluorescence status (strong, vague, or no fluorescence) and fluorescence homogeneity (homogenous or inhomogeneous) of the spinal ependymal tumors were evaluated during surgery using a modified neurosurgical microscope. In intramedullary tumor cases with assumed GTR, the resection cavity was investigated for potential residual fluorescing foci under white-light microscopy. In cases with residual fluorescing foci, these areas were safely resected and the corresponding samples were histopathologically screened for the presence of tumor tissue.RESULTSIn total, 31 spinal ependymal tumors, including 27 intramedullary tumors and 4 intradural extramedullary tumors, were included in this study. Visible fluorescence was observed in the majority of spinal ependymal tumors (n = 25, 81%). Of those, strong fluorescence was noted in 23 of these cases (92%), whereas vague fluorescence was present in 2 cases (8%). In contrast, no fluorescence was observed in the remaining 6 tumors (19%). Most ependymal tumors demonstrated an inhomogeneous fluorescence effect (17 of 25 cases, 68%). After assumed GTR in intramedullary tumors (n = 15), unexpected residual fluorescing foci within the resection cavity could be detected in 5 tumors (33%). These residual fluorescing foci histopathologically corresponded to residual tumor tissue in all cases.CONCLUSIONSThis study indicates that 5-ALA fluorescence makes it possible to visualize the majority of spinal ependymal tumors during surgery. Unexpected residual tumor tissue could be detected with the assistance of 5-ALA fluorescence in approximately one-third of analyzed intramedullary tumors. Thus, 5-ALA fluorescence might be useful to increase the EOR, particularly in intramedullary ependymal tumors, in order to reduce the risk of tumor recurrence.

To determine patients' characteristics and regions in the temporal lobe where resections lead to a decline in picture naming.311 patients with left hemispheric dominance for language were included who underwent epilepsy surgery at the Epilepsy Center of Erlangen and whose picture naming scores (Boston Naming Test, BNT) were available preoperatively and 6-months postoperatively. Surgical lesions were mapped to an averaged template based on preoperative and postoperative MRI using voxel-based lesion-symptom mapping (VBLSM). Postoperative brain shifts were corrected. The relationship between lesioned brain areas and the presence of a postoperative naming decline was examined voxel-wise while controlling for effects of overall lesion size at first in the total cohort and then restricted to temporal lobe resections.In VBLSM in the total sample, a decline in BNT score was significantly related to left temporal surgery. When only considering patients with left temporal lobe resections (n = 121), 40 (33.1%) significantly worsened in BNT postoperatively. VBLSM including all patients with left temporal resections generated no significant results within the temporal lobe. However, naming decline of patients with epilepsy onset after 5 years of age was significantly associated with resections in the left inferior temporal (extent of BNT decline range: 10.8- 14.4%) and fusiform gyrus (decline range: 12.1-18.4%).Resections in the posterior part of the dominant fusiform and inferior temporal gyrus was associated with a risk of deterioration in naming performance at six months after surgery in patients with epilepsy onset after 5 years of age but not with earlier epilepsy onset.

This study aims to investigate the diffusion metrics of left versus right temporal lobe epilepsy in a well-defined subgroup of patients with mesial temporal lobe epilepsy (mTLE) because of unilateral hippocampal sclerosis while taking into account interhemispheric differences. Eighteen patients with TLE [nine left temporal lobe epilepsy (LTLE) and nine right temporal lobe epilepsy (RTLE)] and a norm group of 36 nonepileptic individuals were scanned with a multiband accelerated diffusion tensor imaging protocol at 3T. The scalar diffusion tensor parameters fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) and, after projection on a symmetric skeleton, their hemispheric difference (dFA, dMD, and dRD) were analyzed using tract-based spatial statistics. In the cluster with significantly (P0.008) different dFA, dMD, and dRD between right TLE and left TLE, the hemispheric difference in the mean scalar indices (dmFA, dmMD, and dmRD) was assessed and tested for differences using a one-way analysis of variance and for correlation with patient age, seizure onset, or duration of epilepsy using Pearson's correlation. Patients with LTLE showed lower dFA, higher dMD, and higher dRD (P0.008) compared with patients with RTLE in a cluster including parts of the uncinated and inferior longitudinal fasciculus and the inferior fronto-occipital fasciculus. dmFA, dmMD, and dmRD differed significantly between groups (P10, corrected) and showed no correlation with patient age, seizure onset, or duration of epilepsy. The exclusion of bilateral interindividual variance through the calculation of the hemispheric difference of the diffusion metrics by the symmetric variant of tract-based spatial statistics allows for a sensitive differentiation of LTLE and RTLE with unilateral hippocampal sclerosis.

BackgroundComplex 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.MethodsBetween 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.ResultsAfter 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.ConclusionsThe 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.