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Abstract Background Starting the first job as a young physician is a demanding challenge. Certain skills are important to master this transformation that go beyond the theoretical knowledge and practical skills taught in medical school. Competencies such as communication, leadership and career management skills are important to develop as a young physician but are usually not sufficiently taught in medical school in a structured and comprehensive way. Methods We performed an online survey among final year medical students regarding how they perceive their current competency level in communication, leadership and career management skills. We also assessed how they rate the importance to acquire these competencies and the current emphasis during their medical school education regarding these topics. Results Of 450 final year medical students 80 took part in the voluntary survey and 75 complete datasets were returned (16.7%). The majority of respondents rated different communication skills, leadership skills and career management skills as important or very important for their later clinical work. However, most students felt to be poorly or very poorly prepared by the current medical school curriculum, especially for certain leadership and career management skills. Overall, 90.7% of participants expressed interest in an additional educational course that covers subjects of communication, leadership and career management skills during the later stage of medical school, preferably as a hybrid in-person session that also offers synchronous online participation. Conclusions The results of the survey express the need to address communication, leadership and career management skills in the medical curriculum to be better prepare students for the demands of residency and their further course as physicians. An educational format during the final year of medical school may be suitable to address mentioned topics in the framework of clinical practical exposure.

Background: The cranial nerve (CN) V and adjacent neurovascular structures are crucial landmarks in microvascular decompression (MVD). MVD of CN V is the most effective treatment for patients with drug-resistant trigeminal neuralgia (TN) diagnosis. The endoscope-assisted retrosigmoid approach (RSA) provides better exposure and less cerebellar retraction in the corridor towards the cerebellopontine angle (CPA). Methods: Five adult cadaver heads (10 sides) underwent dissection of the MVD in park bench position. MVD was simulated using microsurgical RSA, and the anatomical landmarks were defined. Microsurgical dissections were additionally performed along the endoscopic surgical path. Additionally, we present an illustrative case with TN caused by anterior inferior cerebellar artery (AICA) compression. The CN V and its close relationships were demonstrated. Endoscopic and microscopic three-dimensional pictures were obtained. Results: This study increases the anatomical and surgical orientation for CN V and surrounding structures. The CN V arises from the lateral part of the pons and runs obliquely upward toward the petrous apex. It has motor roots that leave from pons antero-supero-medial direction to the sensory root. The endoscopic instruments provide perfect visualization with minimal cerebellar retraction during MVD. Conclusion: MVD surgically targets the offending vessel(s) leading to TN and aims to create a disconnected area. The combination of preoperative radiographic assessment with and anatomical correlation provides safe and effective application while facilitating selection of the most appropriate approach. The RSA allows satisfactory visualization for CN V. Endoscope-assisted microsurgery through the CPA is a challenge, it should be performed with advanced anatomical knowledge.

BackgroundFacial palsy after vestibular schwannoma surgery is temporary in many cases but can significantly affect patients’ quality of life. Physical training—initially guided and subsequently performed by the patient—is of paramount importance for recovery of facial nerve function. The introduction of medical application software (apps) might improve therapy by maintaining motivation for daily home-based training and surveilling patients’ rehabilitation progress.MethodsWe developed a mobile app, “FACEsemper”, for home-based facial nerve rehabilitation. This app guides patients through a daily training program comprising six variable exercises, each performed in three repetitions. The app allows the user to customize the exercise intensity for different facial areas and includes a reminder function for daily training. Additional features include photo documentation, a calendar function, training report generation, and the possibility of direct communication with the attending physician. The app's usability was prospectively investigated with 27 subjects, including 8 physicians, 9 patients with facial palsy and 10 healthy subjects, over a two-week period. Usability was assessed using various self-rating questionnaires (i.e., mHealth App Usability Questionnaire, MAUQ; System Usability Scale, SUS; Visual Aesthetics of Apps Inventory, VisAAI) and scores were compared across the groups.ResultsThe participants reported an average smartphone use of 12.19 years and completed a mean number of 290 ± 163 facial exercises during the study period. Patients used the app significantly more frequently than the other two groups (p = 0.017). The average total scores of the questionnaires were: MAUQ 5.67/7, SUS 89.6/100, VisAAI 5.88/7 and specific rating 6.13/7. In particular, the simplicity of use and craftsmanship of the app were rated very highly. Usability scores did not significantly differ between groups. A primary limitation identified was malfunction of the daily reminder feature in some Android versions.ConclusionThis usability study demonstrated a positive user experience and excellent usability of the FACEsemper app. However, some limitations and areas for improvement were identified. As a next step, the app should be evaluated in a large patient cohort with facial palsy to determine its potential medical benefits for facial rehabilitation compared to traditional training methods.

Abstract Moyamoya disease (MMD) is a rare stenoocclusive cerebral vasculopathy often treated by neurosurgical revascularization using extracranial-intracranial bypasses to prevent ischemic or hemorrhagic events. Little is known about the vascular risk profile of adult MMD patients compared to the general population. We therefore analyzed 133 adult MMD patients and compared them with data from more than 22,000 patients from the German Health Update database. Patients with MMD showed an age- and sex-adjusted increased prevalence of arterial hypertension, especially in women between 30 and 44 years and in patients of both sexes between 45 and 64 years. Diabetes mellitus was diagnosed significantly more frequently in MMD patients with increasing age, whereas the vascular risk profile in terms of obesity, nicotine and alcohol consumption was similar to that of the general population. Antihypertensive medication was changed one year after surgical revascularization in 67.5% of patients with a tendency towards dose reduction in 43.2% of all patients. After revascularization, physicians need to be aware of a high likelihood of changes in arterial hypertension and should adjust all other modifiable systemic vascular risk factors to achieve the best treatment possible.

Abstract Background The DNA damage response (DDR) is a physiological network preventing malignant transformation, e.g. by halting cell cycle progression upon DNA damage detection and promoting DNA repair. Glioblastoma are incurable primary tumors of the nervous system and DDR dysregulation contributes to acquired treatment resistance. Therefore, DDR targeting is a promising therapeutic anti-glioma strategy. Here, we investigated Ataxia telangiectasia and Rad3 related (ATR) inhibition (ATRi) and functionally-instructed combination therapies involving ATRi in experimental glioma. Methods We used acute cytotoxicity to identify treatment efficacy as well as RNAseq and DigiWest protein profiling to characterize ATRi-induced modulations within the molecular network in glioma cells. Genome-wide CRISPR/Cas9 functional genomic screens and subsequent validation with functionally-instructed compounds and selected shRNA-based silencing were employed to discover and investigate molecular targets modifying response to ATRi in glioma cell lines in vitro, in primary cultures ex vivo and in zebrafish and murine models in vivo. Results ATRi monotherapy displays anti-glioma efficacy in vitro and ex vivo and modulates the molecular network. We discovered molecular targets by genome-wide CRISPR/Cas9 loss-of-function and activation screens that enhance therapeutic ATRi effects. We validated selected druggable targets by a customized drug library and functional assays in vitro, ex vivo and in vivo. Conclusion In conclusion, our study leads to the identification of novel combination therapies involving ATRi that could inform future preclinical studies and early phase clinical trials.

BackgroundNeoplastic lesions affecting peripheral nerves are rare in the general population and, most often, are benign peripheral nerve sheath tumors. However, a minority of lesions represent high-grade malignancies associated with a poor prognosis, such as malignant peripheral nerve sheath tumors (MPNSTs). Very rarely, these tumors represent peripheral non-nerve sheath tumors (PNNSTs), such as hematological neoplasms that impair nerve function. These can be hard to distinguish from MPNSTs and other lesions arising from the nerve itself. In the present case report, we describe a rare case of direct infiltration of nerves by tumor cells of a hematological neoplasm.MethodsWe report the case of a 90-year-old woman with acute onset of right-sided foot palsy, sensory loss, and pain, caused by an extensive solitary mass of the sciatic nerve in the thigh. We present and discuss the clinical presentation, multimodal diagnostic procedures, and treatment.ResultsMRI of the right thigh and the caudal pelvis revealed a contrast-enhancing lesion infiltrating the sciatic nerve. Additionally performed staging imaging was non-revealing. After multidisciplinary discussion in the neuro-oncology tumor board, a MPNST was suspected and the patient underwent radical tumor resection. However, final histopathology revealed a diffuse large B-cell lymphoma (DLBCL). The patient received adjuvant palliative local radiotherapy which led to acceptable symptom control.ConclusionRare PNNSTs, including extranodal manifestations of DLBCL can have similar clinical and radiological diagnostical features as PNSTs. Comprehensive diagnostic workup of contrast-enhancing lesions affecting peripheral nerves including MRI and metabolic imaging are recommended. Discussion in interdisciplinary tumor boards facilitates finding individual treatment approaches.

Abstract Objective Invasive video‐electroencephalography (iVEEG) is the gold standard for evaluation of refractory temporal lobe epilepsy before second stage resective surgery (SSRS). Traditionally, the presumed seizure onset zone (SOZ) has been covered with subdural electrodes (SDE), a very invasive procedure prone to complications. Temporal stereoelectroencephalography (SEEG) with conventional frame‐based stereotaxy is time‐consuming and impeded by the geometry of the frame. The introduction of robotic assistance promised a simplification of temporal SEEG implantation. However, the efficacy of temporal SEEG in iVEEG remains unclear. The aim of this study was therefore to describe the efficiency and efficacy of SEEG in iVEEG of temporal lobe epilepsy. Methods This retrospective study enrolled 60 consecutive patients with medically intractable epilepsy who underwent iVEEG of a potential temporal SOZ by SDE (n = 40) or SEEG (n = 20). Surgical time efficiency was analyzed by the skin‐to‐skin time (STS) and the total procedure time (TPT) and compared between groups (SDE vs SEEG). Surgical risk was depicted by the 90‐day complication rate. Temporal SOZ were treated by SSRS. Favorable outcome (Engel°1) was assessed after 1 year of follow‐up. Results Robot‐assisted SEEG significantly reduced the duration of surgery (STS and TPT) compared to SDE implantations. There was no significant difference in complication rates. Notably, all surgical revisions in this study were attributed to SDE. Unilateral temporal SOZ was detected in 34/60 cases. Of the 34 patients, 30 underwent second stage SSRS. Both SDE and SEEG had a good predictive value for the outcome of temporal SSRS with no significant group difference. Significance Robot‐assisted SEEG improves the accessibility of the temporal lobe for iVEEG by increasing surgical time efficiency and by simplifying trajectory selection without losing its predictive value for SSRS.

ObjectiveThe various causes of facial palsy, diagnostic methods and treatment approaches frequently involve different medical specialities. Nevertheless, there exist only few specialized consultation and therapy services for patients with facial palsy (FP) in Germany. The aim of the present study was to evaluate factors affecting quality of life (QoL) and treatment satisfaction of patients presenting to an interdisciplinary facial nerve outpatient clinic.MethodsThe study analyzed patients presenting to the interdisciplinary facial palsy outpatient clinic in Tuebingen between February 2019 and December 2022. General satisfaction and QoL was estimated by numerous self-rating questionnaires: ZUF-8, SF-36, FDI, FaCE, PHQ-9. An ANOVA was performed to analyze determinants affecting the ZUF-8. Correlation analyses between cause and regeneration of FP as well as questionnaire scores were performed. Results were compared with a group of patients who were managed in an unidisciplinary setting.ResultsIn total, 66 patients with FP were enrolled. FP patients showed increased levels of depression (PHQ-9: 14.52 ± 3.8) correlating with recovery of the palsy (p = 0.008), FaCE (p

ObjectiveObservation, radiotherapy and surgery are treatment options in vestibular schwannomas (VS). Decision making differs between centers and is usually based on tumor characteristics (e.g., size) and the expected physical health (PH) outcome (i.e., hearing and facial function). However, mental health (MH) is often under-reported. The objective of the present study was to ascertain the impact of VS treatment on PH and MH.MethodsPH and MH were assessed in a prospective cross-sectional study including 226 patients with unilateral sporadic VS before and after surgical removal (SURG). Quality-of-life (QoL) was estimated by self-rating questionnaires: general Short-Form Health Survey (SF-36), Penn Acoustic Neuroma Quality-of-Life Scale (PANQOL), Dizziness Handicap Inventory (DHI), Hearing Handicap Inventory (HHI), Tinnitus Handicap Inventory (THI), and Facial Disability Index (FDI). QoL changes over time as well as predictive factors were accessed by multivariate analyses of covariance (MANCOVA).ResultsIn total, 173 preoperative and 80 postoperative questionnaires were analyzed. There was a significant PH deterioration related to facial function (FDI, PANQOL-face) after surgery. In line with facial rehabilitation, however, FDI improved within the first five years after surgery and did not differ compared to the preoperative patient cohort, eventually. In contrast, MH (i.e., PANQOL-anxiety) and general health (i.e., PANQOL-GH) improved with surgery and correlated with the extent-of-resection.ConclusionPhysical and mental health is significantly influenced by VS surgery. While PH might decrease after surgery, MH potentially increases when patient is cured. Practitioners should take MH into account before advising an incompletely VS treatment (e.g., subtotal resection, observation or radiosurgery).

BackgroundDespite the ongoing debate on the risk–benefit ratio of vestibular schwannoma (VS) treatment options, watchful observation and radiation are usually favored in the elderly (>65 years). If surgery is inevitable, a multimodal approach after deliberate subtotal resection has been described as a valid option. The relationship between the extent of resection (EOR) of surgical and functional outcomes and recurrence-free survival (RFS) remains unclear. This present study aims to evaluate the functional outcome and RFS of the elderly in relation to the EOR.MethodsThis matched cohort study analyzed all consecutive elderly VS patients treated at a tertiary referral center since 2005. A separate cohort (

Background and Objectives: Cavernous malformations (CM) are vascular malformations with low blood flow. The removal of brainstem CMs (BS) is associated with high surgical morbidity, and there is no general consensus on when to treat deep-seated BS CMs. The aim of this study is to compare the surgical outcomes of a series of deep-seated BS CMs with the surgical outcomes of a series of superficially located BS CMs operated on at the Department of Neurosurgery, College of Tuebingen, Germany. Materials and Methods: A retrospective evaluation was performed using patient charts, surgical video recordings, and outpatient examinations. Factors were identified in which surgical intervention was performed in cases of BS CMs. Preoperative radiological examinations included MRI and diffusion tensor imaging (DTI). For deep-seated BS CMs, a voxel-based 3D neuronavigation system and electrophysiological mapping of the brainstem surface were used. Results: A total of 34 consecutive patients with primary superficial (n = 20/58.8%) and deep-seated (n = 14/41.2%) brainstem cavernomas (BS CM) were enrolled in this comparative study. Complete removal was achieved in 31 patients (91.2%). Deep-seated BS CMs: The mean diameter was 14.7 mm (range: 8.3 to 27.7 mm). All but one of these lesions were completely removed. The median follow-up time was 5.8 years. Two patients (5.9%) developed new neurologic deficits after surgery. Superficial BS CMs: The median diameter was 14.9 mm (range: 7.2 to 27.3 mm). All but two of the superficial BS CMs could be completely removed. New permanent neurologic deficits were observed in two patients (5.9%) after surgery. The median follow-up time in this group was 3.6 years. Conclusions: The treatment of BS CMs remains complex. However, the results of this study demonstrate that with less invasive posterior fossa approaches, brainstem mapping, and neuronavigation combined with the use of a blunt “spinal cord” dissection technique, deep-seated BS CMs can be completely removed in selected cases, with good functional outcomes comparable to those of superficial BS CM.

Introduction and research question: The use of an endoscope in skull base surgery provides a panoramic close-up view over the intracranial structures from multiple angles with excellent illumination, thus permitting greater extent of resection of tumors arising at sellar area, mostly represented by PitNet - Pituitary neuroendocrine tumors, with higher likelihood of preserving vital/intact gland tissue. For this refined specialty of neurosurgery, unique skills need to be acquired along a steep learning curve. Material and methods: EANS (European Association of Neurosurgical Societies) skull base section panelists were enrolled and 11 completed the survey: the goal was to provide a consensus statement of the endoscopic endonasal approach for pituitary adenoma surgery. Results: The survey consisted of 44 questions covering demographics data (i.e., academic/non-academic center, case load, years of experience), surgical techniques (i.e., use of neuronavigation, preoperative imaging), and follow-up management. Discussion and conclusions: In this paper we identified a series of tips and tricks at different phases of an endoscopic endonasal pituitary surgery procedure to underline the crucial steps to perform successful surgery and reduce complications: we took in consideration the principles of the surgical technique, the knowledge of the anatomy and its variations, and finally the importance of adjoining specialties experts.

Abstract Background Medical students show varying clinical practical skills when entering their final year clinical clerkship, which is the final period to acquire and improve practical skills prior to their residency. We developed a one-on-one mentoring program to allow individually tailored teaching of clinical practical skills to support final year students with varying skill sets during their neurosurgical clinical clerkship. Methods Each participating student (n = 23) was paired with a mentor. At the beginning students were asked about their expectations, teaching preferences and surgical interest. Regular meetings and evaluations of clinical practical skills were scheduled every 2 weeks together with fixed rotations that could be individually adjusted. The one-on-one meetings and evaluations with the mentor gave each student the chance for individually tailored teaching. After completion of the program each student evaluated their experience. Results The mentoring program was well received by participating students and acquisition or improvement of clinical practical skills was achieved by most students. A varying practical skill level and interest in the field of surgery was seen. Conclusions A neurosurgical one-on-one mentoring program is well received by final year medical students and allows for individually tailored learning of clinical practical skills.

Abstract Tinnitus is attributed to partial sensory deafferentation resulting in a central maladaptive neuroplasticity. Unfortunately, the agent of deafferentation is usually unknown or irreversible. In patients with unilateral vestibular schwannoma (VS), however, the auditory nerve is affected by a benign tumor. Hence, removal of the tumor can cease the tinnitus. In turn, sustaining complaints after surgery indicate cortical neuroplasticity. The present study is a cross sectional study which aims to track cortical structural changes by surface-based morphometry in 46 VS patients with sustained (i.e. centralized) or ceased (i.e. peripheral) tinnitus after surgery. A volumetric analysis of cortical and subcortical gray matter (GM) anatomy was performed on preoperative high-resolution MRI and related to the presence of hearing impairment, pre- and/or postoperative tinnitus. Patients with sustained (i.e. chronic) tinnitus showed an increased GM volume of the bilateral caudate nucleus, the contralateral superior colliculus, the middle frontal and middle temporal gyrus, the fusiform gyrus as well as the ipsilateral pars orbitalis when compared to those patients in whom tinnitus ceased postoperatively. Chronic tinnitus in VS patients is associated with characteristic structural changes in frontal, temporal and subcortical areas. Notably, a significant GM change of the caudate nucleus was detected providing further support for the striatal gaiting model of tinnitus.

Abstract Objective Vestibular schwannomas (VS) are benign slow growing tumors arising from the vestibular nerve. The role of cyclooxygenase 2 (COX2) in tumor development of growth has been addressed in a few studies with contradictory results and suggestions. We recently analyzed the immunohistochemical expression of COX2 in 1044 VS samples and described an association of higher COX2 expression with proliferation but found no influence by regular intake of acetylsalicylic acid. We now collected volumetric radiographic data of the preoperative tumor volume and growth to further test the role of COX2 in VS growth. Methods Preoperative images of 898 primary sporadic vestibular schwannomas were assessed, and sufficient preoperative imaging was used for the volumetric measurement preoperative tumor volume (n = 747) and preoperative relative tumor growth (n = 171). Clinical parameters and results of the immunohistochemical expression of COX2 and MIB1 in resected tumor tissue samples were obtained from our prior study. ANOVA, CART-analysis and multivariate nominal logistic regression were used for statistical analysis. Results Larger preoperative tumor volumes were observed with tumors of younger patients (p = 0.0288) and with higher COX2 expression scores (p

Introduction Meningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two ‘Core Outcome Sets’ (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysis Two systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups.Ethics and dissemination Institutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surveys and consensus meetings. The two systematic literature reviews and two final COS will be published and freely available.Trial registration number COMET study ID 1508

Background‘Crowned dens syndrome' (CDS) is a special form of calcium pyrophosphate dihydrate deposition disease which is characterized radiologically by a halo-like or crown-like distribution in the periodontoid region and clinically by cervical pain. Herein, we will describe our experience of posterolateral epidural supra-C2-root approach (PESCA) for biopsy of retro-odontoid lesions in one surgical session after occipitocervical fixation and decompression in a patient with CDS and massive brainstem compression.Case PresentationA 70-year-old woman presented to our department with a 4-week history of progressive walking impairment, neck pain, neck rigidity, fever, dizziness, slight palsy of the left hand, and multiple fall episodes. Magnetic resonance imaging (MRI) of the craniovertebral junction (CVJ) and cervical spine revealed a lesion of the odontoid process and the retro-odontoid region with mainly solid components, as well as small cystic components, and brainstem compression and displacement. In first step, fusion surgery of the CVJ C0–C4 was performed with occiptocervical decompression. After fusion and decompression the lower lateral part of the C1 arc and the lateral superior part of the left side of the C2 arc were removed. The entry point was located directly above the superior part of the C2 root. A biopsy of the lateral portions of the lesions was obtained by bioptic forceps under microscope guidance. Pathologic examination of the mass revealed deposition of birefringent crystals compatible with calcium pyrophosphate. In addition to the clinical symptoms (especially neck pain), the diagnosis of CDS was made. Non-steroidal inflammatory drugs (NSAIDs) and colchicine (and later magnesium) were started. At follow-up examination 6 months after surgery, an MRI scan of the cervical spine revealed regression of the pannus and the cyst with replacement of the brainstem, clinical improvement of walking, and increased strength of the left hand.ConclusionsThis study demonstrates that PESCA can be used to obtain tissue for pathological analysis in one surgical sitting after fusion and decompression and that fusion, decompression, and PESCA (in the same session) together with subsequent conservative management could be a good alternative for the treatment of CDS.

Majority of lower grade glioma (LGG) are located eloquently rendering surgical resection challenging. Aim of our study was to assess rate of permanent deficits and its predisposing risk factors. We retrieved 83 patients harboring an eloquently located LGGs from the prospective LoG-Glio Database. Patients without surgery or incomplete postoperative data were excluded. Sign rank test, explorative correlations by Spearman ρ and multivariable regression for new postoperative deficits were calculated. Eloquent region involved predominantly motor (45%) and language (40%). At first follow up after 3 months permanent neuro-logical deficits (NDs) were noted in 39%. Mild deficits remained in 29% and severe deficits in 10%. Complete tumor removal (CTR) was successfully in 62% of intended cases. Postoperative and 3-month follow up National Institute of Health Stroke Score (NIHSS) showed significantly lower values than preoperatively (p0 (p=0.021, OR 8.5) were independent predictors for permanent postoperative deficit according to NIHSS at 3-month according to multivariable regression model. Patients harboring eloquently located LGG are highly vulnerable for permanent deficits. Almost one third of patients have a permanent reduction of their functional status based on ECOG. Risk of an extended resection has to be balanced with the respective oncological benefit. Especially, patients with impaired pre-operative status are at risk for new permanent deficits. There is a relevant improvement of neurological symptoms in the first year after surgery, especially for patients with slight aphasia.

BackgroundIn the rehabilitation of postoperative facial palsy, physical therapy is of paramount importance. However, in the early rehabilitation phase, voluntary movements are often limited, and thus, the motivation of patients is impacted. In these situations, biofeedback of facial electromyographic (EMG) signals enables the visual representation of the rehabilitation progress, even without apparent facial movements. In the present study, we designed and evaluated a custom-made EMG biofeedback system enabling cost-effective facial rehabilitation.MethodsThis prospective study describes a custom-made EMG system, consisting of a microcontroller board and muscle sensors, which was used to record the EMG of frontal and zygomatic facial muscles during frowning and smiling. First, the mean EMG amplitudes and movement onset detection rates (ACC) achieved with the custom-made EMG system were compared with a commercial EMG device in 12 healthy subjects. Subsequently, the custom-made device was applied to 12 patients with and without postoperative facial paresis after neurosurgical intervention. Here, the ratio [laterality index (LI)] between the mean EMG amplitude of the healthy and affected side was calculated and related to the facial function as measured by the House and Brackmann scale (H&B) ranging from 1 (normal) to 6 (total paralysis).ResultsIn healthy subjects, a good correlation was measured between the mean EMG amplitudes of the custom-made and commercial EMG device for both frontal (r = 0.84, p = 0.001) and zygomatic muscles (r = 0.8, p = 0.002). In patients, the LI of the frontal and zygomatic muscles correlated significantly with the H&B (r = −0.83, p = 0.001 and r = −0.65, p = 0.023). The ACC of the custom-made EMG system varied between 65 and 79% depending on the recorded muscle and cohort.ConclusionThe present study demonstrates a good application potential of our custom-made EMG biofeedback device to detect facial EMG activity in healthy subjects as well as patients with facial palsies. There is a correlation between the electrophysiological measurements and the clinical outcome. Such a device might enable cost-efficient home-based facial EMG biofeedback. However, movement detection accuracy should be improved in future studies to reach ranges of commercial devices.

The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1–mutated (IDH1-mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq. We discovered comparison-specific metabolites and pathways modulated by IDH1 (IDH1 mutation status cohort) and tumor entity. The Longitudinal investigation cohort provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan-Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces potentially novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies, aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so-far–unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.

ObjectiveHealth-related quality of life (HRQoL) and self-reported outcome measures have a relevant impact on the medical decision-making process. They capture either the current status and allow for multiple prospective evaluations in the course of a treatment or rely on the retrospective comparison of health of patients before and after an intervention to assess its benefit. Importantly, these patient-assessed measures may be influenced by psychological factors. We compared HRQoL and perceived benefit in the course of surgical vestibular schwannoma (VS) treatment, as assessed by the patients from a prospective and retrospective point-of-view, and evaluated the influence of co-morbid depression.MethodsWithin a prospective observational single-center study, forty-three patients with VS were investigated before and after retrosigmoid tumor resection. SF-36, Beck Depression Inventory and patient-assessed clinical symptoms were acquired before surgery and at follow-up. At follow-up, the Glasgow Benefit Inventory (GBI) was acquired as well.ResultsSF-36 scores were significantly lower than the age and sex matched normative data in six and three out of eight categories before and after surgery, respectively. Three categories improved significantly after vs. before surgery; one of them (global health) reached a minimal clinical important difference. In contrast, patients reported predominantly a deterioration, when asked for a retrospective evaluation of the benefit (i.e., GBI). Depression correlated with both SF-36 and GBI, determined dissatisfaction, improved significantly after surgery and was the measure that had the largest impact on HRQoL.ConclusionProspective and retrospective HRQoL measures may lead to different findings and can be confounded by psychological factors.

ObjectiveThe role of resection in progressive glioblastoma (GBM) to prolong survival is still controversial. The aim of this study was to determine 1) the predictors of post-progression survival (PPS) in progressive GBM and 2) which subgroups of patients would benefit from recurrent resection.MethodsWe have conducted a retrospective bicentric cohort study on isocitrate dehydrogenase (IDH) wild-type GBM treated in our hospitals between 2006 and 2015. Kaplan-Maier analyses and univariable and multivariable Cox regressions were performed to identify predictors and their influence on PPS.ResultsOf 589 patients with progressive IDH wild-type GBM, 355 patients were included in analyses. Median PPS of all patients was 9 months (95% CI 8.0-10.0), with complete resection 12 months (95% CI 9.7-14.3, n=81), incomplete resection 11 months (95% CI 8.9-13.1, n=70) and without resection 7 months (95% CI 06-08, n=204). Multivariable Cox regression demonstrated a benefit for PPS with complete (HR 0.67, CI 0.49-0.90) and incomplete resection (HR 0.73, 95% CI 0.51-1.04) and confirmed methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter, lower age at diagnosis, absence of deep brain and multilocular localization, higher Karnofsky Performance Status (KPS) and recurrent therapies to be associated with longer PPS. In contrast, traditional eloquence and duration of progression-free survival had no effect on PPS. Subgroup analyses showed that all subgroups of confirmed predictors benefited from resection, except for patients in poor condition with a KPS

Introduction: The evolution of cavernous sinus meningiomas (CSMs) might be unpredictable and the efficacy of their treatments is challenging due to their indolent evolution, variations and fluctuations of symptoms, heterogeneity of classifications and lack of randomized controlled trials. Here, a dedicated task force provides a consensus statement on the overall management of CSMs. Research question: To determine the best overall management of CSMs, depending on their clinical presentation, size, and evolution as well as patient characteristics. Material and methods: Using the PRISMA 2020 guidelines, we included literature from January 2000 to December 2020. A total of 400 abstracts and 77 titles were kept for full-paper screening. Results: The task force formulated 8 recommendations (Level C evidence). CSMs should be managed by a highly specialized multidisciplinary team. The initial evaluation of patients includes clinical, ophthalmological, endocrinological and radiological assessment. Treatment of CSM should involve experienced skull-base neurosurgeons or neuro-radiosurgeons, radiation oncologists, radiologists, ophthalmologists, and endocrinologists. Discussion and conclusion: Radiosurgery is preferred as first-line treatment in small, enclosed, pauci-symptomatic lesions/in elderly patients, while large CSMs not amenable to resection or WHO grade II-III are candidates for radiotherapy. Microsurgery is an option in aggressive/rapidly progressing lesions in young patients presenting with oculomotor/visual/endocrinological impairment. Whenever surgery is offered, open cranial approaches are the current standard. There is limited experience reported about endoscopic endonasal approach for CSMs and the main indication is decompression of the cavernous sinus to improve symptoms. Whenever surgery is indicated, the current trend is to offer decompression followed by radiosurgery.

Introduction: Cushing's disease is a state of chronic and excessive cortisol levels caused by a pituitary adenoma Research question: CD is a complex entity and often entails difficulties in its diagnosis and management. For that reason, there are still controversial points to that respect. The aim of this consensus paper of the skull base section of the EANS is to review the main aspects of the disease a neurosurgeon has to know and also to offer updated recommendations on the controversial aspects of its management. Material and methods: PUBMED database was used to search the most pertinent articles published on the last 5 years related with the management of CD. A summary of literature evidence was proposed for discussion within the EANS skull base section and other international experts. Results: This article represents the consensual opinion of the task force regarding optimal management and surgical strategy in CD Discussion and conclusion: After discussion in the group several recommendations and suggestions were elaborated. Patients should be treated by an experienced multidisciplinary team. Accurate clinical, biochemical and radiological diagnosis is mandatory. The goal of treatment is the complete adenoma resection to achieve permanent remission. If this is not possible, the treatment aims to achieving eucortisolism. Radiation therapy is recommended to patients with CD when surgical options have been exhausted. All patients in remission should be tested all life-long.

Glioblastomas are incurable primary brain tumors harboring a heterogeneous landscape of genetic and metabolic alterations. Longitudinal imaging by MRI and [18F]FET-PET measurements enable us to visualize the features of evolving tumors in a dynamic manner. Yet, close-meshed longitudinal imaging time points for characterizing temporal and spatial metabolic alterations during tumor evolution in patients is not feasible because patients usually present with already established tumors. The replication-competent avian sarcoma-leukosis virus (RCAS)/tumor virus receptor-A (tva) system is a powerful preclinical glioma model offering a high grade of spatial and temporal control of somatic gene delivery in vivo. Consequently, here, we aimed at using MRI and [18F]FET-PET to identify typical neuroimaging characteristics of the platelet-derived growth factor B (PDGFB)-driven glioma model using the RCAS-tva system. Our study showed that this preclinical glioma model displays MRI and [18F]FET-PET features that highly resemble the corresponding established human disease, emphasizing the high translational relevance of this experimental model. Furthermore, our investigations unravel exponential growth dynamics and a model-specific tumor microenvironment, as assessed by histology and immunochemistry. Taken together, our study provides further insights into this preclinical model and advocates for the imaging-stratified design of preclinical therapeutic interventions.

Abstract Acetylsalicylic acid has been linked to a lower risk for different cancer types, presumably through its inhibitory effect on cyclooxygenase 2. This has also been investigated in vestibular schwannomas with promising results suggesting an antiproliferative effect and recently the intake has been recommended for vestibular schwannomas as a conservative treatment option. We constructed tissue microarrays from paraffin-embedded tissue samples of 1048 vestibular schwannomas and analyzed the expression of cyclooxygenase 2 and the proliferation marker MIB1 (Molecular Immunology Borstel) via immunohistochemistry together with clinical data (age, gender, tumor extension, prior radiotherapy, neurofibromatosis type 2, tumor recurrence, cyclooxygenase 2 responsive medication). Univariate analysis showed that cyclooxygenase 2 expression was increased with age, female gender, prior radiotherapy and larger tumor extension. MIB1 expression was also associated with higher cyclooxygenase 2 expression. Schwannomas of neurofibromatosis type 2 patients had lower cyclooxygenase 2 levels. Use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs, glucocorticoids or other immunosuppressants did not show differences in cyclooxygenase 2 or MIB1 expression. Instead, cyclooxygenase 2 expression increases with tumor extension while MIB1 expression is not associated with tumor size. Overall, cyclooxygenase 2 expression is associated with proliferation but not influenced by regular intake of acetylsalicylic acid or other cyclooxygenase 2-responsive medications. Acetylsalicylic acid intake does not alter cyclooxygenase 2 expression and has no antiproliferative effect in vestibular.

Glioblastoma is an aggressive primary brain tumor with bad prognosis. On the other hand, oncolytic measles virus (MeV) therapy is an experimental glioma treatment strategy with clinical safety and first evidence of anti-tumoral efficacy. Therefore, we investigated the combination of MeV with conventional therapies by cytotoxic survival assays in long-term glioma cell lines LN229, LNZ308, and glioma stem-like GS8 cells, as well as the basal viral infectivity in primary glioblastoma cultures T81/16, T1094/17, and T708/16. We employed Chou-Talalay analysis to identify the synergistic treatment sequence chemotherapy, virotherapy, and finally radiotherapy (CT-VT-RT). RNA sequencing and immunopeptidome analyses were used to delineate treatment-induced molecular and immunological profiles. CT-VT-RT displayed synergistic anti-glioma activity and initiated a type 1 interferon response, along with canonical Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling, and downstream interferon-stimulated genes were induced, resulting in apoptotic cascades. Furthermore, antigen presentation along with immunostimulatory chemokines was increased in CT-VT-RT-treated glioma cells, indicating a treatment-induced pro-inflammatory phenotype. We identified novel treatment-induced viral and tumor-associated peptides through HLA ligandome analysis. Our data delineate an actionable treatment-induced molecular and immunological signature of CT-VT-RT, and they could be exploited for the design of novel tailored treatment strategies involving virotherapy and immunotherapy. Keywords: glioblastoma, immunopeptidome, oncolytic measles virus, personalized medicine, BATF2, SAMD9

Background: Vestibular schwannomas (VS) are brain tumors affecting the vestibulocochlear nerve. Thus, VS patients suffer from tinnitus (TN). While the pathophysiology is mainly unclear, there is an increasing interest in repetitive transcranial magnetic stimulation (rTMS) for TN treatment. However, the results have been divergent. In addition to the methodological aspects, the heterogeneity of the patients might affect the outcome. Yet, there is no study evaluating rTMS exclusively in VS-associated tinnitus. Thus, the present pilot study evaluates low-frequency rTMS to the right dorsolateral pre-frontal cortex (DLPFC) in a VS-associated tinnitus.Methods: This prospective pilot study enrolled nine patients with a monoaural VS-associated tinnitus ipsilateral to the tumor. Patients were treated with a 10-day rTMS regime (1 Hz, 100% RMT, 1,200 pulses, right DLPFC). The primary endpoint of the study was the reduction of TN distress (according to the Tinnitus Handicap Inventory, THI). The secondary endpoint was a reduction of TN intensity (according to the Tinnitus Matching Test, TMT) and the evaluation of factors predicting tinnitus outcome (i.e., hearing impairment, TN duration, type of tinnitus).Results: No complications or side effects occurred. There was one drop-out due to a non-responsiveness of the complaint. There was a significant acute effect of rTMS on the THI and TMT. However, there was no significant long-term effect after 4 weeks. While the THI failed to detect any clinically relevant acute effect of rTMS in 56% of the patients, TMT revealed a reduction of TN intensity for more than 20 in 89% and for more than 50 in 56% of the patients. Notably, the acute effect of rTMS was influenced by the TN type and duration. In general, patients with a tonal TN and shorter TN duration showed a better response to the rTMS therapy.Conclusion: The present pilot study is the first one to exclusively evaluate the effect of low-frequency rTMS to the right DLPFC in a VS-associated tinnitus. Our results prove the feasibility and the efficacy of rTMS in this patient cohort. There is a significant acute but a limited long-term effect. In addition, there is evidence that patients with a tonal tinnitus and shorter tinnitus duration might have the strongest benefit. A larger, randomized controlled study is necessary to prove these initial findings.

Objective: To evaluate the clinical value of early post-operative computed tomographic angiography (CTA) after direct extracranial-intracranial (EC-IC) bypass surgery in moyamoya patients.Methods: A retrospective analysis of all adult moyamoya patients treated at our center from 2013 to 2019 with a direct EC-IC bypass was performed. Early post-operative CTA (within 24 h after surgery) was compared with conventional digital subtraction angiography (DSA) 6–12 months after surgery. If available, magnetic resonance time-of-flight angiography (MR-TOF) was evaluated 3 months and 6–12 months post-operatively as well. Imaging results were analyzed and compared with CTA, MR-TOF and DSA, whereat DSA was used as the final and definite modality to decide on bypass patency.Results: A total of 103 direct EC-IC bypasses in 63 moyamoya patients were analyzed. All inclusion criteria were met in 32 patients (53 direct bypasses). In 84.9% the bypass appeared definitively, in 5.7% uncertainly and in 9.4% not patent according to early post-operative CTA. MR-TOF suggested definitive bypass patency in 86.8% 3 months after surgery and in 93.5% 6–12 months after surgery. DSA 6–12 months post-operatively showed a patency in 98.1% of all bypasses. The positive predictive value (to correctly detect an occluded bypass) on post-operative CTA was 12.5%, the negative predictive value (to correctly detect a patent bypass) was 100% with a sensitivity of 100% and a specificity of 86.5%.Conclusion: Early post-operative CTA has a high predictive value to confirm the patency of a bypass. On the other hand, a high false positive rate of (according to CTA) occluded bypasses after direct EC-IC bypass surgery can be seen. This must be considered critically when initiating possible therapeutic measures.

Background: The integrity of the motor system can be examined by applying navigated transcranial magnetic stimulation (nTMS) to the cortex. The corresponding motor-evoked potentials (MEPs) in the target muscles are mirroring the status of the human motor system, far beyond corticospinal integrity. Commonly used time domain features of MEPs (e.g., peak-to-peak amplitudes and onset latencies) exert a high inter-subject and intra-subject variability. Frequency domain analysis might help to resolve or quantify disease-related MEP changes, e.g., in brain tumor patients. The aim of the present study was to describe the time-frequency representation of MEPs in brain tumor patients, its relation to clinical and imaging findings, and the differences to healthy subject.Methods: This prospective study compared 12 healthy subjects with 12 consecutive brain tumor patients (with and without a paresis) applying nTMS mapping. Resulting MEPs were evaluated in the time series domain (i.e., amplitudes and latencies). After transformation into the frequency domain using a Morlet wavelet approach, event-related spectral perturbation (ERSP), and inter-trial coherence (ITC) were calculated and compared to diffusion tensor imaging (DTI) results.Results: There were no significant differences in the time series characteristics between groups. MEPs were projecting to a frequency band between 30 and 300 Hz with a local maximum around 100 Hz for both healthy subjects and patients. However, there was ERSP reduction for higher frequencies (>100 Hz) in patients in contrast to healthy subjects. This deceleration was mirrored in an increase of the inter-peak MEP latencies. Patients with a paresis showed an additional disturbance in ITC in these frequencies. There was no correlation between the CST integrity (as measured by DTI) and the MEP parameters.Conclusion: Time-frequency analysis may provide additional information above and beyond classical MEP time domain features and the status of the corticospinal system in brain tumor patients. This first evaluation indicates that brain tumors might affect cortical physiology and the responsiveness of the cortex to TMS resulting in a temporal dispersion of the corticospinal transmission.

Characterization of brain tumours requires neuropathological expertise and is generally performed by histological evaluation and molecular analysis. One emerging technique to assist pathologists in future tumour diagnostics is multimodal optical spectroscopy. In the current clinical routine, tissue preprocessing with formalin is widely established and suitable for spectroscopic investigations since degradation processes impede the measurement of native tissue. However, formalin fixation results in alterations of the tissue chemistry and morphology for example by protein cross-linking. As optical spectroscopy is sensitive to these variations, we evaluate the effects of formalin fixation on multimodal brain tumour data in this proof-of-concept study. Nonfixed and formalin-fixed cross sections of different common human brain tumours were subjected to analysis of chemical variations using ultraviolet and Fourier-transform infrared microspectroscopy. Morphological changes were assessed by elastic light scattering microspectroscopy in the visible wavelength range. Data were analysed with multivariate data analysis and compared with histopathology. Tissue type classifications deduced by optical spectroscopy are highly comparable and independent from the preparation and the fixation protocol. However, formalin fixation leads to slightly better classification models due to improved stability of the tissue. As a consequence, spectroscopic methods represent an appropriate additional contrast for chemical and morphological information in neuropathological diagnosis and should be investigated to a greater extent. Furthermore, they can be included in the clinical workflow even after formalin fixation.

Vestibular schwannomas (VS) usually manifest between the 5th and 8th decade of life. Most pediatric cases are associated with Neurofibromatosis type 2 and sporadic VS are rare in this age group. Few case series have been published. We report on our institutional series of sporadic VS in children. We included all cases between 2003 and 2021; 28 of 1635 patients harbored a sporadic VS and were younger than 21 years old. A retrospective review of clinical parameters and surgical data as well as outcomes was performed. All procedures were performed via a retrosigmoid approach. Preoperative imaging was assessed, and tumor volumetry was performed. Mean follow-up was 28 months, symptomatology was diverse. Most children and adolescents presented with hearing loss and tinnitus. All cases with multiple preoperative magnetic resonance imaging scans showed volumetric tumor growth between 1 and 18%/month (mean 8.9 ± 5.6%). Cystic tumor morphology and bone erosion was seen in larger tumors. Gross total resection was possible in 78% of patients and no recurrence was observed. All patients with subtotal resection showed tumor regrowth. Sporadic VS in children are rare and present with a high clinical variability. Surgical resection is the primary therapy and is feasible with favorable results comparable to the adult age group.

Object: There is an increasing interest in preoperative diffusion tensor imaging-based fiber tracking (DTI-FT) to preserve function during surgeries in motor eloquent brain regions. However, DTI tractography is challenged by inherent presumptions during particular tracking steps [e.g., deterministic vs. probabilistic DTI, fractional anisotropy (FA) and fiber length (FL) thresholding] and the missing “ground truth” information. In the present study, we intended to establish an objective, neurophysiology-driven approach for parameter selection during DTI-FT of the corticospinal tract integrating both imaging and neurophysiological information.Methods: In ten patients with lesions in eloquent motor areas, preoperative navigated transcranial magnetic stimulation (nTMS) was performed, followed by individual deterministic DTI-FT from a grid of cortical seed points. We investigated over 300 combinations of FA and FL thresholds and applied subsequently a multidimensional mathematical modeling of this empirical data. Optimal DTI parameters were determined by the relationship between DTI-FT (i.e., number of fibers, NoF) and nTMS (i.e., amplitudes of motor-evoked potentials) results. Finally, neurophysiological DTI parameters and the resulting tractography were compared to the current standard approaches of deterministic DTI fiber tracking with a 75% and 50% FA and a FL threshold of 110 mm as well as with intraoperative direct cortical and subcortical stimulation.Results: There was a good goodness-of-fit for the mathematical model (r2 = 0.68 ± 0 13; range: 0.59–0.97; n = 8) except of two cases. Neurophysiology-driven parameter selection showed a high correlation between DTI-FT and nTMS results (r = 0.73 ± 0.16; range: 0.38–0.93). In comparison to the standard approach, the mathematically calculated thresholds resulted in a higher NoF in 75% of patients. In 50% of patients this approach helped to clarify the exact tract location or to detect additional functional tracts, which were not identified by the standard approach. This was confirmed by direct cortical or subcortical stimulation.Conclusion: The present study evaluates a novel user-independent method to extract objective DTI-FT parameters that were completely based on neurophysiological data. The findings suggest that this method may improve the specificity and sensitivity of DTI-FT and thereby overcome the disadvantages of current approaches.