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BackgroundSeveral prognostic models for outcomes after chronic subdural hematoma (CSDH) treatment have been published in recent years. However, these models are not sufficiently validated for use in daily clinical practice. We aimed to assess the performance of existing prediction models for outcomes in patients diagnosed with CSDH.MethodsWe systematically searched relevant literature databases up to February 2021 to identify prognostic models for outcome prediction in patients diagnosed with CSDH. For the external validation of prognostic models, we used a retrospective database, containing data of 2384 patients from three Dutch regions. Prognostic models were included if they predicted either mortality, hematoma recurrence, functional outcome, or quality of life. Models were excluded when predictors were absent in our database or available for ResultsWe identified 1680 original publications of which 1656 were excluded based on title or abstract, mostly because they did not concern CSDH or did not define a prognostic model. Out of 18 identified models, three could be externally validated in our retrospective database: a model for 30-day mortality in 1656 patients, a model for 2 months, and another for 3-month hematoma recurrence both in 1733 patients. The models overestimated the proportion of patients with these outcomes by 11% (15% predicted vs. 4% observed), 1% (10% vs. 9%), and 2% (11% vs. 9%), respectively. Their discriminative ability was poor to modest (C of 0.70 [0.63–0.77]; 0.46 [0.35–0.56]; 0.59 [0.51–0.66], respectively).ConclusionsNone of the examined models showed good predictive performance for outcomes after CSDH treatment in our dataset. This study confirms the difficulty in predicting outcomes after CSDH and emphasizes the heterogeneity of CSDH patients. The importance of developing high-quality models by using unified predictors and relevant outcome measures and appropriate modeling strategies is warranted.

Delirium is a frequent occurring complication in surgical patients. Nevertheless, a scientific work-up of the clinical relevance of delirium after intracranial surgery is lacking. We conducted a systematic review (CRD42020166656) to evaluate the current diagnostic work-up, incidence, risk factors and health outcomes of delirium in this population. Five databases (Embase, Medline, Web of Science, PsycINFO, Cochrane Central) were searched from inception through March 31st, 2021. Twenty-four studies (5589 patients) were included for qualitative analysis and twenty-one studies for quantitative analysis (5083 patients). Validated delirium screening tools were used in 70% of the studies, consisting of the Confusion Assessment Method (intensive care unit) (45%), Delirium Observation Screening Scale (5%), Intensive Care Delirium Screening Checklist (10%), Neelon and Champagne Confusion Scale (5%) and Nursing Delirium Screening Scale (5%). Incidence of post-operative delirium after intracranial surgery was 19%, ranging from 12 to 26% caused by variation in clinical features and delirium assessment methods. Meta-regression for age and gender did not show a correlation with delirium. We present an overview of risk factors and health outcomes associated with the onset of delirium. Our review highlights the need of future research on delirium in neurosurgery, which should focus on optimizing diagnosis and assessing prognostic significance and management.

BACKGROUND Although prognosis is poor in high-grade glioma (HGG) patients, some become a long-term survivor (LTS). Health-related quality of life (HRQOL) and cognition are seen as indicators for quality of survival in HGG but data in LTS and their caregivers are scarce. We aim to investigate cognition and HRQOL in LTS with evaluation by their proxies. MATERIAL AND METHODS We included LTS with initial HGG-diagnosis between 1999–2014. Cognition was assessed with: Boston Naming Test, shortened Token Test, verbal (Category and Letter) Fluency, Diagnostic Instrument of Mild Aphasia, Hopkins Verbal Learning Test and Trail Making Test (A, B, B/A) and HRQOL with: EORTC Quality of Life Questionnaire (C30) and Brain Cancer Module (BN20). 15 Proxies evaluated patients’ HRQOL with: C30, BN20 and they filled in a burden scale: Caregiver Strain Index (CSI). RESULTS 21 patients with grade III or IV glioma and 7 years (range 5–20 years) median survival after diagnosis participated. Compared to normative data patients deviated significantly on HVLT (direct recall, delayed recall, recognition true positives), TMT (A, B and B/A), BNT and CF (p12 years survival compared to patients with CONCLUSION Most LTS suffer from cognitive impairments. Despite worse prognosis and cognitive impairments, at group level patients report relatively intact QoL, which is supported by their proxies. However, at the individual level severity of impairments is variable and high caregiver strain is reported in one-third of the proxies. Objective cognitive functioning was only modestly associated with subjective experience in patients. A patient-tailored approach is recommended to investigate individual impairments and needs for rehabilitation and support for patients and also for their carers.

BACKGROUND Onco-neurosurgical practice still relies heavily on pre-operatively acquired images to guide intra-operative decision-making for safe tumor removal, a practice with inherent pitfalls such as registration inaccuracy due to brain shift, and lack of real-time (functional) feedback. Exploiting the opportunity for real-time imaging of the exposed brain can improve intra-operative decision-making, neurosurgical safety and patient outcomes. Previously, we described functional Ultrasound (fUS) as a high-resolution, depth-resolved imaging technique able to detect functional regions and vascular morphology during awake resections. Here, we present for the first time fUS as a fully integrated, MRI/CT-registered imaging modality in the OR. MATERIAL AND METHODS fUS relies on high-frame-rate (HFR) ultrasound, making the technique sensitive for very small motions caused by vascular dynamics (µDoppler) and allowing measurements of changes in cerebral blood volume (CBV) with micrometer-millisecond precision. This opens up the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling and 2) visualize in-vivo vascular morphology of tumor and healthy tissue. During a range of anesthetized and awake onco-neurosurgical procedures we acquired images of brain and spinal cord using conventional linear ultrasound probes connected to an experimental acquisition unit. Building on Brainlab’s ‘Cranial Navigation’ and ‘Intra-Operative Ultrasound’ modules, we could co-register our intra-operative Power Doppler Images (PDIs) to patient-registered MRI/CT-data. Using the ‘IGTLink’ research interface, we could access and store real-time tracking data for informed volume reconstructions in post-processing. RESULTS Intra-operative fUS could be registered to MRI/CT-images in real-time, showing overlays of PDIs at imaging depths of >5 centimeters. During meningioma resections, these co-registered PDIs revealed fUS’ ability to visualize the tumor’s feeding vessels and surrounding healthy vasculature prior to durotomy, with a level of detail unprecedented by conventional MRI-sequences. Comparing post-operatively reconstructed 3D-vascular maps of pre- and post-durotomy acquisitions, further confirmed the dural dependency of the vascular network feeding the tumor. During awake resections, fUS revealed distinct functional areas as activated during motor and language tasks. CONCLUSION fUS is a new real-time, high-resolution and depth-resolved imaging technique, combining characteristics uniquely beneficial for a potential image-guided resection tool. The successful integration of fUS in the onco-neurosurgical OR demonstrated by our team, is an essential step towards clinical integration of fUS, as well as the technique’s validation against modalities such as MRI and CT.

Background Evidence suggests that smaller residual tumor volumes after initial surgery are associated with longer survival in patients with astrocytoma, IDH-mutant, grade II. For IDH-mutant glioma of higher grade but also for oligodendroglioma, IDH-mutant, and 1p/19q codeleted, the impact on survival of more residual tumor is unclear. This could be related to the limited follow-up of patients with oligodendroglioma that typically have long overall survival. We expanded a previously published series of patients increase the duration of follow-up and the spectrum of tumor grades. Material and Methods Single center observational cohort study of patients with adult-type diffuse glioma, IDH-mutant, all WHO-2021 grades, from 2003 to 2021 . Molecular characteristics were assessed by next-generation targeted sequencing. Tumor volumes were calculated by semi-automatic 3D segmentation on pre- and postoperative MRI-scans. Associations between prognostic factors and survival were assessed using univariate and multivariate Cox proportional hazards models. Results 384 patients with IDH-mutant glioma (174 oligodendroglioma, 212 astrocytoma) were followed for a median of 7 years. Median age at diagnosis was 41 years (IQR 33 - 55). Significant prognostic factors for survival were Karnofsky performance status, 1p19q-status and post-operative tumor volume. Smaller post-operative tumor volume was associated with better survival, both in astrocytoma and oligodendroglioma. Age, tumor grade and MRI-contrast enhancement were not associated with survival. Conclusion Lower residual tumor volume after first surgery is a strong prognostic factor in all IDH-mutant glioma subgroups, even in patients with very small residual tumor. Importantly, age and histological tumor grade were not significantly associated with survival. The data serves as further support for optimal initial resections of tumors suspected for IDH-mutant glioma, also in oligodendroglioma.

Background Awake craniotomy is used to resect tumor while preserving language. However, differences between patients in post-operative speech/language outcome are observed despite careful intra-operative monitoring. Literature describes improved performance in language tasks during cognitive tests in musicians. Moreover increased white matter connectivity properties in the corpus callosum are described in musicians compared to non-musicians. We hypothesize better recovery of language in musical patients after awake glioma surgery, caused by higher connectivity properties from the corpus callosum. Material and Methods Adult patients undergoing resection for glioma with an awake resection procedure at two neurosurgical centers were prospectively included. Patients without standardized language tests at pre- and post-operative level, with a glioblastoma multiforme (WHO grade 4) or undergoing re-resection were excluded. Language was assessed with the Diagnostic Instrument for Mild Aphasia (DIMA) and corrected for age and education years from a healthy population. The patients’ musical skill was assessed through questionnaires, and divided in groups based on the Musical Expertise Criterion (MEC) which defines musicality based the duration and intensity of musical training. Volumetric measures of the corpus callosum, corrected for total brain volumes, was calculated of each included patient based on the pre-operative structural MRI. Results Forty-six patients, enrolled between June 2015 and September 2019, were followed-up (mean/SD; 240/174 days after craniotomy) and divided in: non-musician (41.3%, n = 19), amateur-musician (34.8%, n=16) and trained-musician (23.9%, n = 11). Overall a decrease in language was observed after craniotomy (mean/SD) of -0.361/0.771. Musical abilities correlated with less decrease in language (mean/SD) when comparing non-musicians (-0.543/0.683) to amateur (-0.272/0.910) and trained (-0.176/0.693) musicians. An increased but non-significant trend (p=0.28) between musicality and corpus callosum / brain ratio (mean/SD) was observed in non-musicians (0.763, 0.718;0.808), amateur musicians (0.792, 0.745;0.838) and trained musicians (0.835, 0.778;0.891). Conclusion Musicality seemed to improve language outcome after awake glioma surgery, possibly attributed due to a higher white matter connectivity in the corpus callosum. Future studies with larger sample sizes are needed to confirm our findings.

Background The standard treatment for patients with eloquent gliomas is awake craniotomy (AC) with direct electrical stimulation, which results in a larger extent of resection while maintaining language function. Intraoperative language monitoring includes different standardized tasks and spontaneous speech elicitation. Despite careful monitoring, it was found that spontaneous speech deteriorated long-term after surgery. However, intraoperative spontaneous speech has not been investigated before. Detailed analyses may reveal possible predictors for language outcome. For the first time, we present a case study in which we investigate and quantify semi-spontaneous speech before, during and after AC. Material and Methods A left-handed 50-year old male with a glioblastoma (WHO grade 4) in the left parietal lobe underwent AC. Semi-spontaneous speech was collected (audio/video recording) using the Sabadel story retelling task at: 1 day before (T1), during (T2), 2 days (T3) and 2 months (T4) after surgery. Recordings were manually transcribed and language errors were quantified. A preliminary acoustic analysis with simple automatic peak detection was performed. Comparisons between test moments were made. Results Manual transcription showed 1) notable changes in the number of paraphasias (T1: 1% - T2: 1% - T3: 9% - T4: 5%), interjections (T1: 9% - T2: 9% - T3: 15% - T4: 10%), minimal utterances (T1: 4% - T2: 4% - T3: 6% - T4: 1%), false starts (T1: 3% - T2: 5% - T3: 6% - T4: 8%), self-corrections (T1: 3% - T2: 2% - T3: 4% - T4: 7%) and 2) small changes in repetitions (T1: 1% - T2: 0% - T3: 2% - T4: 3%), hesitations (T1: 1% - T2: 0% - T3: 2% - T4: 0%), incomplete sentences (T1: 1% - T2: 0% - T3: 0% - T4: 1%), grammatical errors (T1: 2% - T2: 1% - T3: 2% - T4: 2%). The total number of words (T1: 273 - T2: 283 - T3: 249 - T4: 287) and utterances (T1: 39 - T2: 41 - T3: 36 - T4: 34) varied slightly. Acoustic analysis showed a slight increase in word length during and directly after surgery but it recovered to preoperative level on the long-term (T1: .66 s - T2: .75 s - T3: .87 s - T4: .69 s). Conclusion The semi-spontaneous speech task in this case study was sensitive to capture changes in perioperative language status. Paraphasias, interjections, minimal utterances, hesitations and word length increased directly after surgery followed by a decrease 2 months later. This is a frequently reported pattern of transient language deficits. However, other errors (false starts, repetitions, self-corrections, incomplete sentences) increased at 2 months after surgery, indicating longer term language deficits. Future exploration of both the acoustic analysis, which shows potential for real-time feedback, and the manual transcriptions, could possibly lead to a better understanding of intra- and postoperative language performance as a prognostic factor for long-term language outcome, with possible implications for language therapy.

Delirium is a frequent occurring complication in surgical patients. Nevertheless, a scientific work-up of the clinical relevance of delirium after intracranial surgery is lacking. We conducted a systematic review (CRD42020166656) to evaluate the current diagnostic work-up, incidence, risk factors and health outcomes of delirium in this population. Five databases (Embase, Medline, Web of Science, PsycINFO, Cochrane Central) were searched from inception through March 31st, 2021. Twenty-four studies (5589 patients) were included for qualitative analysis and twenty-one studies for quantitative analysis (5083 patients). Validated delirium screening tools were used in 70% of the studies, consisting of the Confusion Assessment Method (intensive care unit) (45%), Delirium Observation Screening Scale (5%), Intensive Care Delirium Screening Checklist (10%), Neelon and Champagne Confusion Scale (5%) and Nursing Delirium Screening Scale (5%). Incidence of post-operative delirium after intracranial surgery was 19%, ranging from 12 to 26% caused by variation in clinical features and delirium assessment methods. Meta-regression for age and gender did not show a correlation with delirium. We present an overview of risk factors and health outcomes associated with the onset of delirium. Our review highlights the need of future research on delirium in neurosurgery, which should focus on optimizing diagnosis and assessing prognostic significance and management.

Awake craniotomy with electrocortical and subcortical mapping (AC) has become the mainstay of surgical treatment of supratentorial low-grade gliomas in eloquent areas, but not as much for glioblastomas. This retrospective controlled-matched study aims to determine whether AC increases gross total resections (GTR) and decreases neurological morbidity in glioblastoma patients as compared to resection under general anesthesia (GA, conventional). Thirty-seven patients with glioblastoma undergoing AC were 1:3 controlled-matched with 111 patients undergoing GA for glioblastoma resection. The two groups were matched for age, gender, preoperative Karnofsky Performance Score (KPS), preoperative tumor volume, tumor location, and type of adjuvant treatment. Primary outcomes were extent of resection and the rate of postoperative complications. The secondary outcome was overall postoperative survival. After matching, there were no significant differences in clinical variables between groups. Extent of resection was significantly higher in the AC group: mean extent of resection in the AC group was 94.89% (SD = 10.57) as compared to 70.30% (SD = 28.37) in the GA group (p = 0.0001). Furthermore, the mean rate of late minor postoperative complications in the AC group (0.03; SD = − 0.16) was significantly lower than in the GA group (0.15; SD = 0.39) (p = 0.05). No significant differences between groups were found for the other subgroups of postoperative complications. Moreover, overall postoperative survival did not differ between groups (p = 0.297). These findings suggest that resection of glioblastoma using AC is associated with significantly greater extent of resection and less late minor postoperative complications as compared with craniotomy under GA without the use of surgery adjuncts. However, due to certain limitations inherent to our study design (selection bias) and the absence of the use of surgery adjuncts in the GA group, we advocate for a prospective study to further build upon this evidence and study the use of AC in glioblastoma patients.

BACKGROUND Post-operative delirium (POD) is a frequent and severe complication after neurosurgical operations. Good prediction of POD after craniotomy in neuro-oncologic patients is important to install prophylactic measures, increase recognition and apply early treatment. Hence, we compared logistic regression with machine learning to build an accurate predictive model in a large dataset. MATERIAL AND METHODS POD was defined in case of a Delirium Observation Scale (DOS) ≥ 3 or start of antipsychotic treatment for delirium within 10 days after surgery. Adult patients undergoing a craniotomy for a neuro-oncologic disease in the Erasmus Medical Centre in Rotterdam were retrospectively included. The cohort was split into a training (75%), after three-fold cross validation, and test set (25%). Logistic regression and Lasso Elastic-Net Regularized Generalized Linear Models (GLMNet) were trained based on 19 pre- and intra-operative features and risk factors were identified based on the superior model. RESULTS We included 1025 neuro-oncologic craniotomies between June 2017 and September 2020. Overall incidence of POD was 18.6% (95%CI 17.4–19.8). Compared to logistic regression, Lasso GLMNet performed superior (AUC 0.73 vs. 0.76) based on the optimal tuning parameters (α=1, λ=0.014). Several non-modifiable risk factors such as age (OR1.01), prior delirium (OR1.04), memory problems (OR1.12), surgery duration (OR1.01) and modifiable risk factors, such as low potassium (OR0.97) levels and opioid administration (OR1.03), were identified. CONCLUSION POD is a frequent complication after craniotomy in neuro-oncologic patients. Lasso GLMNet was useful in predicting POD in this cohort. Validation in a prospective cohort of this model should be applied to further evaluate its value in diminishing POD.

Background Intraoperative stimulation mapping (ISM) using electrocortical mapping (awake craniotomy, AC) or evoked potentials has become a solid option for the resection of supratentorial low-grade gliomas in eloquent areas, but not as much for high-grade gliomas. This meta-analysis aims to determine whether the surgeon, when using ISM and AC, is able to achieve improved overall survival and decreased neurological morbidity in patients with high-grade glioma as compared to resection under general anesthesia (GA). Methods A systematic search was performed to identify relevant studies. Adult patients were included who had undergone craniotomy for high-grade glioma (WHO grade III or IV) using ISM (among which AC) or GA. Primary outcomes were rate of postoperative complications, overall postoperative survival, and percentage of gross total resections (GTR). Secondary outcomes were extent of resection and percentage of eloquent areas. Results Review of 2049 articles led to the inclusion of 53 studies in the analysis, including 9102 patients. The overall postoperative median survival in the AC group was significantly longer (16.87 versus 12.04 months; p

Doublecortin (DCX) is a microtubule-associated protein expressed by migrating neuroblasts and is considered to be a reliable marker of neurogenesis. DCX has been used to study the relation between neurogenesis in adult human brain and neurological and neurodegenerative disease processes in the search for putative therapeutic strategies. Using autopsy and surgically resected tissue from a total of 60 patients, we present evidence that DCX is present in several cellular compartments of differentiated astrocytes in the adult human neocortex. One of these compartments consisted of peripheral processes forming punctate envelopes around mature neuronal cell bodies. Markers of glial activation, such as GFAP and HLA, were not associated with DCX immunoreactivity, however, the presence of cytoarchitectural alterations tended to correlate with reduced DCX staining of astrocytic somata. Interestingly, local Alzheimer pathology that showed no relation with cytoarchitectural abnormalities appeared to correlate negatively with the expression of DCX in the astrocytic somata. In combination with the literature our data support the view that DCX in the adult human neocortex may have a function in glia-to-neuron communication. Furthermore, our results indicate that in the adult human neocortex DCX is neither a reliable nor a selective marker of neurogenesis.

Multicellular tumor spheroids are used as a model to assess the efficacy of replicating oncolytic adenoviruses. As most assays used to assess cellular viability are unsuitable for oncolytic viruses because of ongoing viral replication, we have used positron emission tomography (PET) to sequentially determine the incorporation of 18F-labeled deoxyglucose (18F-DG) as a measure of viability and compared the results to more commonly used assays for measuring the effect of oncolytic therapy. Glioma monolayer cultures and spheroids were infected with wild-type replicating adenovirus and viability was measured by 18F-DG incorporation, WST-1 assay, crystal violet assay, and spheroid volume 2 to 10 days following infection. Results show that volume measurements in adenovirus-infected spheroids are confounded by the cytopathic effect occurring in infected cells. 18F-DG PET provides a useful method to assess small differences in cell number and viability following oncolytic viral therapy in glioma monolayer cultures and spheroids without the need for disintegration of these cultures. Moreover, using 18F-DG PET, repeated sequential measurements of spheroid viability can be made, decreasing the required number of spheroids per experiment. This is a valuable feature when using spheroids derived from limited amounts of patient material.

We describe the case - to our knowledge unique - of an 8-year-old boy who presented with acute onset of lower cranial nerve palsy and tetraparesis caused by a hematoma in a dorsal exophytic pilocytic astrocytoma of the medulla oblongata. The boy showed near-complete recovery after neurosurgical management in two stages: first, emergency evacuation of the hematoma with tumor biopsy, and second, complete tumor removal 5 months after the initial event. Intraoperative electrophysiological monitoring techniques for the lower cranial nerves are of value in preserving their functional integrity. Ultrasonography is helpful in assessing the extent of tumor removal. Although the pathological diagnosis of a pilocytic astrocytoma would not justify radiotherapy, local field radiotherapy was added mainly because of the unexpectedly rapid tumor progression during the interval between the two surgical procedures. The literature on brainstem and tumor hematoma in children is reviewed.