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Background Hemorrhage rates of conservatively managed brainstem cavernous malformations (BSCMs) vary widely in the literature. We aimed to elucidate the reason for the variation and to add the results of our experience of BSCMs management over the past decade. Methods We performed a review of consecutive patients with BSCMs referred to our department in the period 2006–2018. A hemorrhagic event was defined as a radiographically verified intralesional and extralesional hemorrhage. Both retrospective and prospective hemorrhage rates were calculated based on the patient age in years, counted either from birth or from the time of initial presentation until the last contact (or until surgical resection). In addition, we retrieved and reviewed publications with a clear definition of hemorrhagic event and a detailed description of BSCM hemorrhage rate. Results In total, 118 patients with BSCMs were reviewed, and 78 patients (mean age on admission 45.9 years) were included in the final analysis. The retrospective and prospective hemorrhage rates were 1.9% (95% confidence interval 1.6%–2.3%) per year and 11.9% (95% confidence interval 7.5%–17.8%), respectively. The retrospective hemorrhage rate in the literature review ranged from 1.9% to 6.8% per year with a median value of 3.8%, whereas the prospective hemorrhage rate ranged between 4.1% and 21.5%, with a median value of 10.2%. Conclusions The reported hemorrhage rates are calculated in 2 different ways. In our patient cohort, both the retrospective and prospective hemorrhage rates were in accordance with those in the literature. The long-term hemorrhage rate lies between the prospective and retrospective rate.

Background Neurosurgical resection is the mainstay of meningioma treatment. Adverse event (AE) rates of meningioma resections are significant, but preoperative risk factors for major AEs in patients undergoing first-time meningioma surgery are largely unknown. The aim of this study was to explore major AEs and identify preoperative risk factors in patients undergoing first-time meningioma surgery. Methods Data on all meningioma resections performed at the University Hospital Zurich from 1 January 2013 to 31 December 2018 were collected in a prospective registry. All AEs that occurred within 3 months of surgery were documented in detail and classified as “minor” or “major.” Statistical analysis included initial individual bivariate analyses of all preoperative factors and the occurrence of major AEs. Statistically significant variables were then included in a logistic regression model to identify predictors. Results Three hundred forty-five patients were included in the study. Mean age was 58.1 years, and 77.1% of patients were female. The overall major AE rate was 20.6%; the most common of which was a new focal neurological deficit (12.8% of patients). Six preoperative factors showed a significant association with the occurrence of major AEs in bivariate analysis. All variables included in the logistic regression model showed increased odds of occurrence of major AE, but only tumor complexity as measured by the Milan Complexity Scale was a statistically significant predictor, with a score of 4 or more having twice the odds of major AEs (OR: 2.00, 95% CI: 1.15–3.48). Conclusion High tumor complexity is an independent predictor of the occurrence of major AEs following meningioma resection. Preoperative assessment of tumor complexity using the Milan Complexity Scale is warranted and can aid communication with patients about AE rates and surgical decision-making.

OBJECTIVE Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized numbers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient’s risk of experiencing any functional impairment. METHODS The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of ≥ 10 points. Two prospective registries in Switzerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS In the development (2437 patients, 48.2% male; mean age ± SD: 55 ± 15 years) and external validation (2427 patients, 42.4% male; mean age ± SD: 58 ± 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69–0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69–0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, although machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case-by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.

BackgroundMaximum safe resection followed by chemoradiotherapy as current standard of care for WHO grade III and IV gliomas can be influenced by the occurrence of perioperative adverse events (AE). The aim of this study was to determine the association of AE with the timing and choice of subsequent treatments as well as with overall survival (OS).MethodsProspectively collected data of 283 adult patients undergoing surgery for WHO grade III and IV gliomas at the University Hospital Zurich between January 2013 and June 2017 were analyzed. We assessed basic patient characteristics, KPS, extent of resection, and WHO grade, and we classified AE as well as modality, timing of subsequent treatment (delay, interruption, or non-initiation), and OS.ResultsIn 117 patients (41%), an AE was documented between surgery and the 3-month follow-up. There was a significant association of AE with an increased time to initiation of subsequent therapy (p = 0.005) and a higher rate of interruption (p < 0.001) or non-initiation (p < 0.001). AE grades correlated with time to initiation of subsequent therapy (p = 0.038). AEs were associated with shorter OS in univariate analysis (p < 0.001).ConclusionAEs are associated with delayed and/or altered subsequent therapy and can therefore limit OS. These data emphasize the importance of safety within the maximum-safe-resection concept.

Cranial dural arteriovenous fistula (cDAVF) may rarely lead to parkinsonism and rapid cognitive decline. Dysfunction of the extrapyramidal system and the thalamus, due to venous congestion of the Galenic system with subsequent parenchymal edema, is likely to represent an important pathophysiological mechanism. Here, we report a case of a 57-year-old man with a cDAVF of the straight sinus (Borden type III; DES-Zurich bridging vein shunt [BVS] type with direct, exclusive, and strained leptomeningeal venous drainage [LVD]) and subsequent edema of both thalami, the internal capsule, the hippocampi, the pallidum, and the mesencephalon. Several attempts at venous embolization were unsuccessful, and the neurological condition of the patient further deteriorated with progressive parkinsonism and intermittent episodes of loss of consciousness (KPS 30). A suboccipital mini-craniotomy was performed and the culminal vein was disconnected from the medial tentorial sinus, achieving an immediate fistula occlusion. Three-month follow-up MRI revealed complete regression of the edema. Clinically, parkinsonism remitted completely, allowing for tapering of dopaminergic medication. His cognition markedly improved in further course. The purpose of this report is to highlight the importance of rapid and complete cDAVF occlusion to reverse venous hypertension and prevent progressive clinical impairment. The review of the literature underlines the high morbidity and mortality of these patients. Microsurgical disconnection of the fistula plays an important role in the management of these patients and, surprisingly, has not been reported so far.

Zusammenfassung. Ein Viertel aller ischämischen Schlaganfälle wird durch atherosklerotisch bedingte Veränderungen der extra- oder intrakraniellen hirnversorgenden Gefässe verursacht. Die Prävalenz atherosklerotisch bedingter, extrakranieller Karotisstenosen steigt mit dem 65. Lebensjahr auf 6–15 % an. Das Risiko eines Schlaganfalls bei einer symptomatischen Karotisstenose, d.h. nach Stroke oder Transienter Ischämischer Attacke (TIA), ist mit 25 % innerhalb von 14 Tagen sehr hoch. Die konservative Therapie mit Reduktion der Risikofaktoren, Thrombozytenaggregationshemmern (TAH), antihypertensiver und lipidsenkender Therapie bildet den Grundpfeiler der Therapie bei Patienten mit asymptomatischer und symptomatischer Karotisstenose. Die Karotis-Endarterektomie (CEA) ist die Behandlungsmethode der 1. Wahl bei symptomatischen Patienten mit einer >50 %igen und bei asymptomatischen Patienten mit einer >60 %igen Stenose. Um eine bestmögliche Behandlung von Patienten mit asymptomatischer und symptomatischer Karotisstenose zu gewährleisten, ist die interdisziplinäre Zusammenarbeit in Diagnostik, Therapie und Nachsorge in einem neuromedizinischen Zentrum der Maximalversorgung erforderlich.

Microsurgical resection of brainstem cavernous malformations (BSCMs) can be performed today with acceptable morbidity and mortality. However, in this highly eloquent location, the indication for surgery remains challenging. We aimed to elaborate a score system that may help clinicians with their choice of treatment in patients with BSCMs in this study. A single-center series of 88 consecutive BSCMs patients with 272 follow-up visits were included in this study. Univariable and multivariable generalized estimating equations (GEE) were constructed to identify the association of variables with treatment decisions. A score scale assigned points for variables that significantly contributed to surgical decision-making. Surgical treatment was recommended in 37 instances, while conservative treatment was proposed in 235 instances. The mean follow-up duration was 50.4 months, and the mean age at decision-making was 45.9 years. The mean BSCMs size was 14.3 ml. In the multivariable GEE model, patient age, lesion size, hemorrhagic event(s), mRS, and axial location were identified as significant factors for determining treatment options. With this proposed score scale (grades 0–XII), non-surgery was the first option at grades 0–III. The crossover point between surgery and non-surgery recommendations lay between grades V and VI while surgical treatment was found in favor at grades VII–X. In conclusion, the proposed BSCM operating score is a clinician-friendly tool, which may help neurosurgeons decide on the treatment for patients with BSCMs.

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.

Objective: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. Methods: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. Results: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6–3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9–1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. Conclusion: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

Introduction The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. Research question This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. Material and methods A multicenter database was retrospectively reviewed. Functional status was assessed before and 3–6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. Results The total sample of 4864 patients had a mean age of 56.4 ​± ​14.4 years. The mean change in pre-to postoperative KPS was −1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was −0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21–1.88) and an odds ratio of 2.04 to die (95%CI 1.33–3.13), compared to younger patients. Discussion Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. Conclusion Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients.

BACKGROUND The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits. OBJECTIVE To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability. METHODS The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries. RESULTS Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced. CONCLUSION Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery.

Background: Clinical management of patients with brainstem cavernous malformations (BSCM) is often challenging due to the unpredictable clinical course and lack of high-quality evidence. Nevertheless, radiologic follow-up is often performed routinely. The objective of this work was to investigate whether active follow-up by serial imaging is justified and how planned imaging will impact clinical decision making in absence of clinical progression. Methods: We included all consecutive patients with BSCM treated and followed at our Department between 2006 and 2018. Results: Of 429 patients with CCM, 118 were diagnosed with BSCM (27.5%). Patients were followed for a mean of 8.1 (± 7.4 SD) years. Conservative treatment was recommended in 54 patients over the complete follow-up period, whereas 64 patients underwent surgical extirpation of BSCM. In total, 75 surgical procedures were performed. Over a period of 961 follow-up years in total, routinely performed follow-up MRI in clinically stable patients did not lead to a single indication for surgery. Conclusion: Due to the difficult-to-predict clinical course of patients with BSCM and the relatively high risk associated with surgery, routine imaging is unlikely to have any influence on surgical decision making in clinically stable patients with BSCM.

BackgroundThe most widely used classifications of adverse events (AE) in surgical neurology assign a grade to AE that depends on the therapy used to treat them or on new neurologic deficits. Both concepts have substantial shortcomings in grading AE severity. We present a novel multidimensional approach to this challenge and aim at validating the new grading system.MethodsThe new Therapy-Disability-Neurology (TDN) grading system classifies AE into five grades, depending on the associated therapy, disability, and neurologic deficits. We conducted a two-center study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between January 2013 and September 2019 at the University Hospital Zurich (USZ) and at the Fondazione IRCCS Istituto Neurologico Carlo Besta (FINCB).FindingsUsing data from USZ, a positive correlation was found between the severity of AE and the length of hospital stay (LOS) as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. Additionally, there was a correlation between the severity of AE and absolute KPS values. When using the same methods on an external validation cohort from FINCB, correlations between the grade of AE, LOS, and KPS at discharge were even more pronounced.InterpretationOur results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is objective, practical, easily interpreted, and enables comparison between different medical centers. The TDN grade will constitute an important step forward towards a more precise and standardized documentation of AE and ultimately lead to a more critical and patient-centered appraisal of process and outcome measures in surgical neurology.FundingNone.

The aim of the present study was to assess the safety of microsurgical resection of intracranial tumors performed by supervised neurosurgical residents. We analyzed prospectively collected data from our institutional patient registry and dichotomized between procedures performed by supervised neurosurgery residents (defined as teaching procedures) or board-certified faculty neurosurgeons (defined as non-teaching procedures). The primary endpoint was morbidity at discharge, defined as a postoperative decrease of ≥10 points on the Karnofsky Performance Scale (KPS). Secondary endpoints included 3-month (M3) morbidity, mortality, the in-hospital complication rate, and complication type and severity. Of 1,446 consecutive procedures, 221 (15.3%) were teaching procedures. Patients in the teaching group were as likely as patients in the non-teaching group to experience discharge morbidity in both uni- (OR 0.85, 95%CI 0.60–1.22, p = 0.391) and multivariate analysis (adjusted OR 1.08, 95%CI 0.74–1.58, p = 0.680). The results were consistent at time of the M3 follow-up and in subgroup analyses. In-hospital mortality was equally low (0.24 vs. 0%, p = 0.461) and the likelihood (p = 0.499), type (p = 0.581) and severity of complications (p = 0.373) were similar. These results suggest that microsurgical resection of carefully selected intracranial tumors can be performed safely by supervised neurosurgical residents without increasing the risk of morbidity, mortality or perioperative complications. Appropriate allocation of operations according to case complexity and the resident’s experience level, however, appears essential.

Purpose Deciding whether to re-operate patients with intracranial tumor recurrence or remnant is challenging, as the data on safety of repeated procedures is limited. This study set out to evaluate the risks for morbidity, mortality, and complications after repeated operations, and to compare those to primary operations. Methods Retrospective observational two-center study on consecutive patients undergoing microsurgical tumor resection. The data derived from independent, prospective institutional registries. The primary endpoint was morbidity at 3 months (M3), defined as significant decrease on the Karnofsky Performance Scale (KPS). Secondary endpoints were mortality, rate and severity of complications according to the Clavien–Dindo Grade (CDG). Results 463/2403 (19.3%) were repeated procedures. Morbidity at M3 occurred in n = 290 patients (12.1%). In univariable analysis, patients undergoing repeated surgery were 98% as likely as patients undergoing primary surgery to experience morbidity (OR 0.98, 95% CI 0.72–1.34, p = 0.889). In multivariable analysis adjusted for age, sex, tumor size, histology and posterior fossa location, the relationship remained stable (aOR 1.25, 95% CI 0.90–1.73, p = 0.186). Mortality was n = 10 (0.4%) at discharge and n = 95 (4.0%) at M3, without group differences. At least one complication occurred in n = 855, and the rate (35.5% vs. 35.9%, p = 0.892) and severity (CDG; p = 0.520) was similar after primary and repeated procedures. Results were reproduced in subgroup analyses for meningiomas, gliomas and cerebral metastases. Conclusions Repeated surgery for intracranial tumors does not increase the risk of morbidity. Mortality, and both the rate and severity of complications are comparable to primary operations. This information is of value for patient counseling and the informed consent process. Electronic supplementary material The online version of this article (10.1007/s11060-018-03058-y) contains supplementary material, which is available to authorized users.

Aberrant receptor kinase signalling and tumour neovascularization are hallmarks of medulloblastoma development and are both considered valuable therapeutic targets. In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis. Therefore, we have been suggested that the clinically approved multi-kinase angiogenesis inhibitor Axitinib, which specifically targets these kinases, might constitute a promising option for medulloblastoma treatment. Indeed, our results delineate anti-neoplastic activity of Axitinib in medulloblastoma cell lines modelling the most aggressive c-myc-amplified Non-WNT/Non-SHH and SHH-TP53-mutated tumours. Exposure of medulloblastoma cell lines to Axitinib results in marked inhibition of proliferation and profound induction of cell death. The differential efficacy of Axitinib is in line with target expression of medulloblastoma cells identifying VEGFR 1/2, PDGFR α/β and c-kit as potential markers for drug application. The high specificity of Axitinib and the consequential low impact on the haematopoietic and immune system render this drug ideal multi-modal treatment approaches. In this context, we demonstrate that the clinically available PI3K inhibitor GDC-0941 enhances the anti-neoplastic efficacy of Axitinib against c-myc-amplified medulloblastoma. Our findings provide a rational to further evaluate Axitinib alone and in combination with other therapeutic agents for the treatment of most aggressive medulloblastoma subtypes.

OBJECTIVESkin depressions may appear as undesired effects after burr-hole trepanation for the evacuation of chronic subdural hematomas (cSDH). Placement of burr-hole covers to reconstruct skull defects can prevent skin depressions, with the potential to improve the aesthetic result and patient satisfaction. The perception of the relevance of this practice, however, appears to vary substantially among neurosurgeons. The authors aimed to identify current practice variations with regard to the application of burr-hole covers after trepanation for cSDH.METHODSAn electronic survey containing 12 questions was sent to resident and faculty neurosurgeons practicing in different parts of the world, as identified by an Internet search. All responses completed between September 2018 and December 2018 were considered. Descriptive statistics and logistic regression were used to analyze the data.RESULTSA total of 604 responses were obtained, of which 576 (95.4%) provided complete data. The respondents’ mean age was 42.4 years (SD 10.5), and 86.5% were male. The sample consisted of residents, fellows, junior/senior consultants, and department chairs from 79 countries (77.4% Europe, 11.8% Asia, 5.4% America, 3.5% Africa, and 1.9% Australasia). Skin depressions were considered a relevant issue by 31.6%, and 76.0% indicated that patients complain about skin depressions more or less frequently. Burr-hole covers are placed by 28.1% in the context of cSDH evacuation more or less frequently. The most frequent reasons for not placing a burr-hole cover were the lack of proven benefit (34.8%), followed by additional costs (21.9%), technical difficulty (19.9%), and fear of increased complications (4.9%). Most respondents (77.5%) stated that they would consider placing burr-hole covers in the future if there was evidence for superiority of the practice. The use of burr-hole covers varied substantially across countries, but a country’s gross domestic product per capita was not associated with their placement.CONCLUSIONSOnly a minority of neurosurgeons place burr-hole covers after trepanation for cSDH on a regular basis, even though the majority of participants reported complaints from patients regarding postoperative skin depressions. There are significant differences in the patterns of care among countries. Class I evidence with regard to patient satisfaction and safety of burr-hole cover placement is likely to have an impact on future cSDH management.

Intra-axial brainstem surgeries are challenging. Many experience-based "safe entry zones (SEZs)" into brainstem lesions have been proposed in the existing literature. The evidence for each one seems limited. English-language publications were retrieved using PubMed/MEDLINE. Studies that focused only on cadaveric anatomy were also included, but the clinical case number was treated as zero. The clinical evidence level was defined as "case report" when the surgical case number was ≤ 5, "limited evidence" when there were more than 5 but less than 25 cases, and "credible evidence" when a publication presented more than 25 cases. Twenty-five out of 32 publications were included, and 21 different SEZs were found for the brainstem: six SEZs were located in the midbrain, 9 SEZs in the pons, and 6 SEZs in the medulla. Case report evidence was found for 10 SEZs, and limited evidence for 7 SEZs. Four SEZs were determined to be backed by credible evidence. The proposed SEZs came from initial cadaveric anatomy studies, followed by some published clinical experience. Only a few SEZs have elevated clinical evidence. The choice of the right approach into the brainstem remains a challenge in each case.

Background: Neuropsychological screening becomes increasingly important for the evaluation of subarachnoid hemorrhage (SAH) and stroke patients. It is often performed during the surveillance period on the intensive (ICU), while it remains unknown, whether the distraction in this environment influences the results. We aimed to study the reliability of the Montreal Cognitive Assessment (MoCA) in the ICU environment. Methods: Consecutive stable patients with recent brain injury (tumor, trauma, stroke, etc.) were evaluated twice within 36 h using official parallel versions of the MoCA (ΔMoCA). The sequence of assessment was randomized into (a) busy ICU first or (b) quiet office first with subsequent crossover. For repeated MoCA, we determined sequence, period, location effects, and the intraclass correlation coefficient (ICC). Results: N = 50 patients were studied [n = 30 (60%) male], with a mean age of 57 years. The assessment's sequence ["ICU first" mean ΔMoCA -1.14 (SD 2.34) vs. "Office first" -0.73 (SD 1.52)] did not influence the MoCA (p = 0.47). On the 2nd period, participants scored 0.96 points worse (SD 2.01; p = 0.001), indicating no MoCA learning effect but a possible difference in parallel versions. There was no location effect (p = 0.31) with ΔMoCA between locations (Office minus ICU) of -0.32 (SD 2.21). The ICC for repeated MoCA was 0.87 (95% CI 0.79-0.92). Conclusions: The reliability of the MoCA was excellent, independent from the testing environment being ICU or office. This finding is helpful for patient care and studies investigating the effect of a therapeutic intervention on the neuropsychological outcome after SAH, stroke or traumatic brain injury.

Among spontaneous intracranial haemorrhages, primary non-traumatic brainstem haemorrhages are associated with the highest mortality rate. Patients classically present with rapid neurological deterioration. Previous studies have found that the severity of initial neurological symptoms and hydrocephalus are predictors of poor outcomes. In addition, radiological parameters aim to classify brainstem haematomas according to volume, extension and impact on prognosis. However, previous studies have failed to agree on a differentiated radiological classification for outcome and functional recovery. Electrophysiology, including motor, auditory and somatosensory evoked potentials, is used to estimate the extent of the initial injury and predict functional recovery. The current management of brainstem haematomas remains conservative, focusing on initial close neurocritical care monitoring. Surgical treatment concepts exist, but similarly to general intracranial haemorrhage management, they continue to be controversial and have not been sufficiently investigated. This is especially the case for haematomas in the posterior fossa, as these are excluded from most current clinical trials. Existing studies were mostly carried out before the present millennium began, and limitations are evident in the adaptation of those results and recommendations to current management, with todayrsquo;s technological and diagnostic possibilities. We therefore recommend the re-evaluation of brainstem haemorrhages in the modern neurosurgical and intensive care environment.

Traumatic intracranial aneurysms (TICA) of the distal anterior cerebral artery (dACA) are exceptionally rare and display therapeutic challenges due to their angioanatomical characteristics. The objective of this work was to discuss the mechanisms of TICA formation of the dACA and to elucidate the best treatment and revascularization strategies in these patients based on two illustrative cases. Case 1: 20-year-old patient with a traumatic, partially thrombosed 14 × 10 mm aneurysm of the right pericallosal artery (rPericA), distal to the origin of the right callosomarginal artery (rCMA). Complete trapping of the right dissection A3 aneurysm and flow replacement extra-to-intracranial (EC-IC) bypass (STA - radial artery - A4) was performed. Case 2: 16-year-old patient with a traumatic polylobulated, partially thrombosed 16 × 10 mm aneurysm of the rPericA. Microsurgical excision of the A3- segment harboring the aneurysm and flow replacement intra-to-intracranial (IC-IC) bypass via reimplantation of the right remaining PericA on the contralateral PericA (end-to-side anastomosis) was performed (in situ bypass). TICA of the dACA are exceptionally rare. Mechanical vessel wall injury and aneurysm formation of the dACA in blunt head trauma is very likely due to the proximity of the dACA with the rigid free edge of the falx. Given their nature as dissecting (complex) aneurysm, trapping and revascularization is a very important strategy. The interhemispheric cistern offers multiple revascularization options with its numerous donor vessels. The IC-IC bypass is often the simplest revascularization construct.

// Rogerio B. Craveiro 1, * , Michael Ehrhardt 1, * , Julia Velz 1 , Martin Olschewski 1 , Barbara Goetz 1 , Torsten Pietsch 2 and Dagmar Dilloo 1 1 Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, D-53113 Bonn, Germany 2 Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany * These authors have contributed equally to this work Correspondence to: Rogerio B. Craveiro, email: Rogerio.craveiro@ukb.uni-bonn.de Keywords: medulloblastoma, Vandetanib, GDC-0941, targeted therapy, multi-kinase inhibitor (MKI) Received: July 27, 2016 Accepted: December 26, 2016 Published: January 31, 2017 ABSTRACT Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis. Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants.

3128 Background: The human leukocyte antigen (HLA) complex regulates the adaptive immune response by showcasing the intracellular and extracellular protein content to the immune system, which is the basis for T cell-dependent tumor rejection. Therefore, a comprehensive map of the entirety of both HLA class I- and class II-presented peptides from various benign tissues is a highly sought after resource, as it enables the definition of tumor-association on the immunologically pivotal level of the HLA ligandome. Methods: Human tissue samples were snap frozen post mortem during autopsy. The study was approved by the local IRB. HLA ligands were immunopurified and characterized using an Orbitrap Fusion Lumos mass spectrometer coupled to an Ultimate 3000 RSLC Nano UHPLC System. Data acquisition was performed as technical triplicates in data-dependent mode, and data were analyzed using the containerized, computational pipeline MHCquant. Results: In this work, we describe the HLA Ligand Atlas, a comprehensive collection of matched HLA class I and class II ligandomes from 29 non-malignant tissues and 13 human subjects (208 samples in total), covering 38 HLA class I, and 17 HLA*DRB alleles and comprising 48,381 HLA class I and 16,146 HLA class II peptides. Nearly 50% of HLA ligands have not been previously described. The HLA Ligand Atlas is publicly available as a raw data resource, but also in the form of a user-friendly web interface that allows users to quickly formulate complex queries against the data set. Both downloadable data and the query interface are available at www.hla-ligand-atlas.org. Conclusions: This data set provides a valuable tool for research in diverse fields such as systems biology, general immunology, autoimmune disease and organ transplantation. Most importantly, the HLA Ligand Atlas provides essential information for translational applications in immuno-oncology. The knowledge of HLA ligands from benign tissues strongly supports the informed design of proteogenomic HLA-dependent target discovery approaches.

Background: The best strategy to perform follow-up of patients with multiple cerebral cavernous malformations (mCCM) is unclear due to the unpredictable clinical course. Still, serial radiological follow-up is often performed. The objective of this work was to critically question whether active follow-up by serial imaging is justified and has an impact on clinical decision making. Methods: We included all consecutive patients with mCCM treated and followed at our Department between 2006 and 2016. Patient data were collected and analyzed retrospectively. Results: From a total number of 406 patients with CCM, n = 73 [18.0%; mean age at first diagnosis 45.2 years (±2.4 SE); n = 42 male (57.5 %)] were found to harbor multiple lesions (≤5 CCM in 58.9%; 6–25 in 21.9%; ≥ 25 in 19.2%). All of them were followed for a mean of 6.8 years (±0.85 SE). Conservative treatment was suggested in 43 patients over the complete follow-up period. Thirty patients underwent surgical extirpation of at least one CCM lesion. Forty-three surgical procedures were performed in total. During 500.5 follow-up years in total, routinely performed follow-up MRI in asymptomatic patients lead to an indication for surgery in only two occasions and even those two were questionable surgical indications. Conclusion: Routinely performed follow-up MRI in asymptomatic patients with mCCM is highly questionable as there is no evidence for therapeutic relevance.

Objective: The best strategy to perform follow-up of patients with multiple cerebral cavernous malformations (mCCM) is unclear due to the mainly unknown and unpredictable clinical course. Still, serial radiological follow-up is often performed. The objective of this work was to critically question whether[for full text, please go to the a.m. URL], 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Spontaneous spinal subarachnoid hemorrhage (SAH) is extremely rare and occurs in1% of all cases of SAH. To the best of our knowledge, only 1 case of spontaneous spinal SAH with later development of a symptomatic spinal arachnoid cyst (SAC) has been described in the literature to date. The objective of the present study was to report the challenging clinical management of SAC based on a literature review.We report the case of a 51-year-old woman with acute onset of back pain, neck pain, and headaches with an angiogram-negative supratentorial SAH. Further magnetic resonance imaging screening of the spine revealed additional subarachnoid blood at the level of the thoracic spine, without evidence of vascular malformations. Several weeks after the hemorrhage, the patient developed progressive numbness in her trunk and lower extremities and weakness in her lower extremities. A follow-up magnetic resonance imaging study revealed a large arachnoid cyst at level T4-T7 with spinal cord compression. The patient underwent left hemilaminectomy at T4-T6 and fenestration of the SAC. In a second surgery, right-sided hemilaminectomy at T7 was performed with complete marsupialization of the larger cyst and placement of an intradural shunt. At the 6-month clinical follow-up examination, she showed improvement of her clinical symptoms.Treatment of secondary SAC is challenging, and surgery of the SAC with or without placement of a shunt is a possible treatment option.

Objective: Spinal cavernous malformations (SCM) were once thought to be rare lesions of the spinal cord. However, with the broad use of modern imaging techniques the incidence of SCM has significantly increased over the last decades. Management of both symptomatic and especially asymptomatic SCM [for full text, please go to the a.m. URL], 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Highlights • Phylogenetic topographic anatomical patterns drive seizure risk in brain tumors. • Seizure risk in brain tumors may be predicted using a generalized additive model. • This may allow to better tailor antiepileptic therapy in brain tumor patients., Objective The aim of this study was to identify relevant risk factors for epileptic seizures upon initial diagnosis of a brain tumor and to develop and validate a machine learning based prediction to allow for a tailored risk-based antiepileptic therapy. Methods Clinical, electrophysiological and high-resolution imaging data was obtained from a consecutive cohort of 1051 patients with newly diagnosed brain tumors. Factor-associated seizure risk difference allowed to determine the relevance of specific topographic, demographic and histopathologic variables available at the time of diagnosis for seizure risk. The data was divided in a 70/30 ratio into a training and test set. Different machine learning based predictive models were evaluated before a generalized additive model (GAM) was selected considering its traceability while maintaining high performance. Based on a clinical stratification of the risk factors, three different GAM were trained and internally validated. Results A total of 923 patients had full data and were included. Specific topographic anatomical patterns that drive seizure risk could be identified. The involvement of allopallial, mesopallial or primary motor/somatosensory neopallial structures by brain tumors results in a significant and clinically relevant increase in seizure risk. While topographic input was most relevant for the GAM, the best prediction was achieved by a combination of topographic, demographic and histopathologic information (Validation: AUC: 0.79, Accuracy: 0.72, Sensitivity: 0.81, Specificity: 0.66). Conclusions This study identifies specific phylogenetic anatomical patterns as epileptic drivers. A GAM allowed the prediction of seizure risk using topographic, demographic and histopathologic data achieving fair performance while maintaining transparency.

IntroductionOutcomes rated on impairment scales are satisfactory after burr hole trepanation for chronic subdural haematoma (cSDH). However, the surgery leads to bony defects in the skull with skin depressions above that are frequently considered aesthetically unsatisfactory by the patients. Those defects could be covered by the approved medical devices (burr hole covers), but this is rarely done today. We wish to assess, whether the application of burr hole covers after trepanation for the evacuation of cSDH leads to higher patient satisfaction with the aesthetical result at 90 days postoperative, without worsening disability outcomes or increasing the complication rate.Methods and analysisThis is a prospective, single-blinded, randomised, controlled, investigator-initiated clinical trial enrolling 80 adult patients with first-time unilateral or bilateral cSDH in Switzerland. The primary outcome is the difference in satisfaction with the aesthetic result of the scar, comparing patients allocated to the intervention (burr hole cover) and control (no burr hole cover) group, measured on the Aesthetic Numeric Analogue scale at 90 days postoperative. Secondary outcomes include differences in the rates of skin depression, complications, as well as neurological, disability and health-related quality of life outcomes until 12 months postoperative.Ethics and disseminationThe institutional review board (Kantonale Ethikkommission Zürich) approved this study on 29 January 2019 under case number BASEC 2018–01180. This study determines, whether a relatively minor modification of a standard surgical procedure can improve patient satisfaction, without worsening functional outcomes or increasing the complication rate. The outcome corresponds to the value-based medicine approach of modern patient-centred medicine. Results will be published in peer-reviewed journals and electronic patient data will be safely stored for 15 years.Trial registration numberNCT03755349.