Dexamethasone versus Surgery for Chronic Subdural Hematoma.

BACKGROUND: The role of glucocorticoids without surgical evacuation in the treatment of chronic subdural hematoma is unclear. METHODS: In this multicenter, open-label, controlled, noninferiority trial, we randomly assigned symptomatic patients with chronic subdural hematoma in a 1:1 ratio to a 19-day tapering course of dexamethasone or to burr-hole drainage. The primary end point was the functional outcome at 3 months after randomization, as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Noninferiority was defined by a lower limit of the 95% confidence interval of the odds ratio for a better functional outcome with dexamethasone than with surgery of 0.9 or more. Secondary end points included scores on the Markwalder Grading Scale of symptom severity and on the Extended Glasgow Outcome Scale. RESULTS: From September 2016 through February 2021, we enrolled 252 patients of a planned sample size of 420; 127 were assigned to the dexamethasone group and 125 to the surgery group. The mean age of the patients was 74 years, and 77% were men. The trial was terminated early by the data and safety monitoring board owing to safety and outcome concerns in the dexamethasone group. The adjusted common odds ratio for a lower (better) score on the modified Rankin scale at 3 months with dexamethasone than with surgery was 0.55 (95% confidence interval, 0.34 to 0.90), which failed to show noninferiority of dexamethasone. The scores on the Markwalder Grading Scale and Extended Glasgow Outcome Scale were generally supportive of the results of the primary analysis. Complications occurred in 59% of the patients in the dexamethasone group and 32% of those in the surgery group, and additional surgery was performed in 55% and 6%, respectively. CONCLUSIONS: In a trial that involved patients with chronic subdural hematoma and that was stopped early, dexamethasone treatment was not found to be noninferior to burr-hole drainage with respect to functional outcomes and was associated with more complications and a greater likelihood of later surgery. (Funded by the Netherlands Organization for Health Research and Development and others; DECSA EudraCT number, 2015-001563-39.).

Morphological correlates of pyramidal cell axonal myelination in mouse and human neocortex.

The axons of neocortical pyramidal neurons are frequently myelinated. Heterogeneity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and caliber are critical local determinants of fast-spiking interneuron myelination. However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy to examine the extent to which axonal morphology is predictive of the topography of myelination along neocortical pyramidal neurons. We identified critical thresholds for axonal caliber and interbranch distance that are necessary, but not sufficient, for myelination of pyramidal cell axons in mouse primary somatosensory cortex (S1). Specifically, we found that pyramidal neuron axonal segments with a caliber < 0.24 µm or interbranch distance < 18.10 µm are rarely myelinated. Moreover, we further confirmed that these findings in mice are similar for human neocortical pyramidal cell myelination (caliber < 0.25 µm, interbranch distance < 19.00 µm), suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is a critical correlate of the topography and cell-type specificity of neocortical myelination.

Quantifying dysmorphologies of the neurocranium using artificial neural networks.

BACKGROUND: Craniosynostosis, a congenital condition characterized by the premature fusion of cranial sutures, necessitates objective methods for evaluating cranial morphology to enhance patient treatment. Current subjective assessments often lead to inconsistent outcomes. This study introduces a novel, quantitative approach to classify craniosynostosis and measure its severity. METHODS: An artificial neural network was trained to classify normocephalic, trigonocephalic, and scaphocephalic head shapes based on a publicly available dataset of synthetic 3D head models. Each 3D model was converted into a low-dimensional shape representation based on the distribution of normal vectors, which served as the input for the neural network, ensuring complete patient anonymity and invariance to geometric size and orientation. Explainable AI methods were utilized to highlight significant features when making predictions. Additionally, the Feature Prominence (FP) score was introduced, a novel metric that captures the prominence of distinct shape characteristics associated with a given class. Its relationship with clinical severity scores was examined using the Spearman Rank Correlation Coefficient. RESULTS: The final model achieved excellent test accuracy in classifying the different cranial shapes from their low-dimensional representation. Attention maps indicated that the network's attention was predominantly directed toward the parietal and temporal regions, as well as toward the region signifying vertex depression in scaphocephaly. In trigonocephaly, features around the temples were most pronounced. The FP score showed a strong positive monotonic relationship with clinical severity scores in both scaphocephalic (ρ = 0.83, p < 0.001) and trigonocephalic (ρ = 0.64, p < 0.001) models. Visual assessments further confirmed that as FP values rose, phenotypic severity became increasingly evident. CONCLUSION: This study presents an innovative and accessible AI-based method for quantifying cranial shape that mitigates the need for adjustments due to age-specific size variations or differences in the spatial orientation of the 3D images, while ensuring complete patient privacy. The proposed FP score strongly correlates with clinical severity scores and has the potential to aid in clinical decision-making and facilitate multi-center collaborations. Future work will focus on validating the model with larger patient datasets and exploring the potential of the FP score for broader applications. The publicly available source code facilitates easy implementation, aiming to advance craniofacial care and research.

Cognition and health-related quality of life in long-term survivors of high-grade glioma: an interactive perspective from patient and caregiver.

BACKGROUND: The health-related quality of life (HRQoL) and cognition are important indicators for the quality of survival in patients with high-grade glioma (HGG). However, data on long-term survivors and their caregivers are scarce. We aim to investigate the interaction between cognition and HRQoL in long-term survivors, their caregivers' evaluations, and the effect on caregiver strain and burden. METHODS: 21 long-term HGG (8 WHO grade III and 13 WHO grade IV) survivors (survival ≥ 5 years) and 15 caregivers were included. Cognition (verbal memory, attention, executive functioning, and language), HRQoL, anxiety and depression, caregiver strain, and caregiver burden were assessed with standardized measures. Questionnaires were completed by patients and/or their caregivers. RESULTS: Mean survival was 12 years (grade III) and 8 years (grade IV). Cognition was significantly impaired with a large individual variety. Patients' general HRQoL was not impaired but all functioning scales were deviant. Patient-proxy agreement was found in most HRQoL subscales. Three patients (14%) showed indications of anxiety or depression. One-third of the caregivers reported a high caregiver strain or a high burden. Test scores for attention, executive functioning, language, and/or verbal memory were correlated with perceived global health status, cognitive functioning, and/or communication deficits. Caregiver burden was not related to cognitive deficits. CONCLUSIONS: In long-term HGG survivors maintained HRQoL seems possible even when cognition is impaired in a large variety at the individual level. A tailored approach is therefore recommended to investigate the cognitive impairments and HRQoL in patients and the need for patient and caregiver support.

3D Analysis of the Cranial and Facial Shape in Craniosynostosis Patients: A Systematic Review.

With increasing interest in 3D photogrammetry, diverse methods have been developed for craniofacial shape analysis in craniosynostosis patients. This review provides an overview of these methods and offers recommendations for future studies. A systematic literature search was used to identify publications on 3D photogrammetry analyses in craniosynostosis patients until August 2023. Inclusion criteria were original research reporting on 3D photogrammetry analyses in patients with craniosynostosis and written in English. Sixty-three publications that had reproducible methods for measuring cranial, forehead, or facial shape were included in the systematic review. Cranial shape changes were commonly assessed using heat maps and curvature analyses. Publications assessing the forehead utilized volumetric measurements, angles, ratios, and mirroring techniques. Mirroring techniques were frequently used to determine facial asymmetry. Although 3D photogrammetry shows promise, methods vary widely between standardized and less conventional measurements. A standardized protocol for the selection and documentation of landmarks, planes, and measurements across the cranium, forehead, and face is essential for consistent clinical and research applications.

Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: a first-in-human phase 1 dose escalation trial.

BACKGROUND: This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) - an inhibitory regulator of cancer stem cells (CSCs) - in recurrent glioblastoma. METHODS: In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion. RESULTS: Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4. CONCLUSION: Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs. TRIAL REGISTRATION: ClinicaTrials.gov identifier: NCT02869243.

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers.

BACKGROUND: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). METHODS: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. RESULTS: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. CONCLUSION: GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.

Efficacy and safety of peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE in 15 patients with progressive treatment-refractory meningioma.

PURPOSE: There is no evidence-based systemic therapy for patients with progressive meningiomas for whom surgery or external radiotherapy is no longer an option. In this study, the efficacy and safety of peptide receptor radionuclide therapy (PRRT) in patients with progressive, treatment-refractory meningiomas were evaluated. METHODS: Retrospective analysis of all meningioma patients treated with [177Lu]Lu-DOTA-TATE from 2000 to 2020 in our centre. Primary outcomes were response according to RANO bidimensional and volumetric criteria and progression-free survival (PFS). Overall survival (OS) and tumour growth rate (TGR) were secondary endpoints. TGR was calculated as the percentage change in surface or volume per month. RESULTS: Fifteen meningioma patients received [177Lu]Lu-DOTA-TATE (7.5-29.6 GBq). Prior to PRRT, all patients had received external radiotherapy, and 14 patients had undergone surgery. All WHO grades were included WHO 1 (n=3), WHO 2 (n=5), and WHO 3 (n=6). After PRRT, stable disease was observed in six (40%) patients. The median PFS was 7.8 months with a 6-month PFS rate of 60%. The median OS was 13.6 months with a 12-month OS rate of 60%. All patients had progressive disease prior to PRRT, with an average TGR of 4.6% increase in surface and 14.8% increase in volume per month. After PRRT, TGR declined to 3.1% in surface (p=0.016) and 5.0% in volume (p=0.013) per month. CONCLUSION: In this cohort of meningioma patients with exhaustion of surgical and radiotherapeutic options and progressive disease, it was shown that PRRT plays a role in controlling tumour growth.

Impact of an external ventricular shunt (EVD) handling protocol on secondary meningitis rates: a historical cohort study with propensity score matching.

BACKGROUND: External ventricular drainage (EVD) is frequently used in neurosurgical procedures for cerebrospinal fluid (CSF) drainage. It is, however, associated with high infection rates, namely secondary meningitis and ventriculitis. Based on a previous high prevalence of these infections among patients with EVDs, we have proposed and implemented a protocol in an effort to decrease the infection rate. The aim of this study was to measure the effect of hospital-wide implementation of the EVD handling protocol on secondary EVD infections. PATIENTS AND METHODS: We included 409 consecutive patients who received a new EVD for other indications than infectious pathologies from January 2000 until June 2012. Patients above 18 years of age were divided into pre- (n = 228) and post-protocol (n = 181) groups. Patient and disease demographics, as well as EVD data together with confounders for secondary meningitis were recorded in a database. Propensity score matching was then performed to create groups matched for sex, age, reason for drainage, type of shunt, time in situ and duration of surgery to place the EVD. Binomial logistic regression for confounder adjustment and regression discontinuity analyses were then performed on the matched cohort. RESULTS: Infections occurred more frequently in the pre-protocol group (23% vs 9%, p <  0.001). The incidence of infection was 33/1000 drain-days pre-protocol and 9/1000 drain-days post-protocol. Regression analysis in a propensity score-matched cohort (n = 103 in the pre- and n = 178 in the post-protocol groups) showed that the pre-protocol period was independently associated with more infections (OR 2.69; 95%-CI 1.22-5.95, p = 0.01). CONCLUSIONS: The incidence of secondary EVD infections can be reduced significantly by the implementation of a strict hospital-wide EVD handling protocol.

Localization patterns of speech and language errors during awake brain surgery: a systematic review.

Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with eloquent area gliomas. DES detects speech and language errors, which indicate functional boundaries that must be maintained to preserve quality of life. During DES, traditional object naming or other linguistic tasks such as tasks from the Dutch Linguistic Intraoperative Protocol (DuLIP) can be used. It is not fully clear which speech and language errors occur in which brain locations. To provide an overview and to update DuLIP, a systematic review was conducted in which 102 studies were included, reporting on speech and language errors and the corresponding brain locations during awake craniotomy with DES in adult glioma patients up until 6 July 2020. The current findings provide a crude overview on language localization. Even though subcortical areas are in general less often investigated intraoperatively, still 40% out of all errors was reported at the subcortical level and almost 60% at the cortical level. Rudimentary localization patterns for different error types were observed and compared to the dual-stream model of language processing and the DuLIP model. While most patterns were similar compared to the models, additional locations were identified for articulation/motor speech, phonology, reading, and writing. Based on these patterns, we propose an updated DuLIP model. This model can be applied for a more adequate "location-to-function" language task selection to assess different linguistic functions during awake craniotomy, to possibly improve intraoperative language monitoring. This could result in a better postoperative language outcome in the future.

Standardized mortality ratios for regionalized acute cardiovascular care.

BACKGROUND: Standardized Mortality Ratios (SMRs) are case-mix adjusted mortality rates per hospital and are used to evaluate quality of care. However, acute care is increasingly organized on a regional level, with more severe patients admitted to specialized hospitals. We hypothesize that the current case-mix adjustment insufficiently captures differences in case-mix between non-specialized and specialized hospitals. We aim to improve the SMR by adding proxies of disease severity to the model and by calculating a regional SMR (RSMR) for acute cerebrovascular disease (CVD) and myocardial infarction (MI). METHODS: We used data from the Dutch National Basic Registration of Hospital Care. We selected all admissions from 2016 to 2018. SMRs and RSMRs were calculated by dividing the observed in-hospital mortality by the expected in-hospital mortality. The expected in-hospital mortality was calculated using logistic regression with adjustment for age, sex, socioeconomic status, severity of main diagnosis, urgency of admission, Charlson comorbidity index, place of residence before admission, month/year of admission, and in-hospital mortality as outcome. RESULTS: The IQR of hospital SMRs of CVD was 0.85-1.10, median 0.94, with higher SMRs for specialized hospitals (median 1.12, IQR 1.00-1.28, 71%-SMR > 1) than for non-specialized hospitals (median 0.92, IQR 0.82-1.07, 32%-SMR > 1). The IQR of RSMRs was 0.92-1.09, median 1.00. The IQR of hospital SMRs of MI was 0.76-1.14, median 0.98, with higher SMRs for specialized hospitals (median 1.00, IQR 0.89-1.25, 50%-SMR > 1 versus median 0.94, IQR 0.74-1.11, 44%-SMR > 1). The IQR of RSMRs was 0.90-1.08, median 1.00. Adjustment for proxies of disease severity mostly led to lower SMRs of specialized hospitals. CONCLUSION: SMRs of acute regionally organized diseases do not only measure differences in quality of care between hospitals, but merely measure differences in case-mix between hospitals. Although the addition of proxies of disease severity improves the model to calculate SMRs, real disease severity scores would be preferred. However, such scores are not available in administrative data. As a consequence, the usefulness of the current SMR as quality indicator is very limited. RSMRs are potentially more useful, since they fit regional organization and might be a more valid representation of quality of care.

Reliability and Agreement of Automated Head Measurements From 3-Dimensional Photogrammetry in Young Children.

This study aimed to assess the reliability and agreement of automated head measurements using 3-dimensional (3D) photogrammetry in young children. Specifically, the study evaluated the agreement between manual and automated occipitofrontal circumference (OFC) measurements (n = 264) obtained from 3D images of 188 patients diagnosed with sagittal synostosis using a novel automated method proposed in this study. In addition, the study aimed to determine the interrater and intrarater reliability of the automatically extracted OFC, cephalic index, and volume. The results of the study showed that the automated OFC measurements had an excellent agreement with manual measurements, with a very strong regression score ( R2 = 0.969) and a small mean difference of -0.1 cm (-0.2%). The limits of agreement ranged from -0.93 to 0.74 cm, falling within the reported limits of agreement for manual OFC measurements. High interrater and intrarater reliability of OFC, cephalic index, and volume measurements were also demonstrated. The proposed method for automated OFC measurements was found to be a reliable alternative to manual measurements, which may be particularly beneficial in young children who undergo 3D imaging in craniofacial centers as part of their treatment protocol and in research settings that require a reproducible and transparent pipeline for anthropometric measurements. The method has been incorporated into CraniumPy, an open-source tool for 3D image visualization, registration, and optimization, which is publicly available on GitHub ( https://github.com/T-AbdelAlim/CraniumPy ).

Health-related Quality of Life in Children and Adolescents With Sagittal Synostosis.

BACKGROUND: This study evaluated the health-related quality of life (HR-QoL) in patients with sagittal synostosis (SS), and the influence of frequent headaches and surgical techniques on the HR-QoL. METHOD: Patients with SS aged 8 to 18 years were invited to participate between June 2016 and February 2017. The Child Health Questionnaire was used to assess the HR-QoL. A detailed questionnaire was used to assess the severity of headache symptoms. The control group consisted of 353 school children aged 5 to 14 years. RESULTS: In all, 95 parents of patients with SS were invited to participate, of whom 68 (71.6%) parents completed the CHQ-PF50. The mean age of the participating patients was 12.4 years (10.8 to 14.2). The Psychosocial- and Physical summary of the patients with SS was similar to the general population. In the distinct CHQ scales, "Family cohesion" ( P =0.02) was higher, and "Mental health" ( P =0.05) was lower compared with the general population. The type and timing of surgery did not affect the HR-QoL. Thirty-two patients (47.1%) reported having headache complaints at least once a month. The CHQ scores of SS patients with frequent headaches had a significantly lower score of mild to large effect than those without headaches. CONCLUSION: Patients with SS have a slightly lower to similar HR-QoL compared with the general population. In all, 47.1% of SS patients have frequent headaches, resulting in lower average HR-QoL. The type and timing of surgery did not affect the results. Clinicians should be aware of lower HR-QoL in some subgroups of patients with SS.

Effect of awake craniotomy in glioblastoma in eloquent areas (GLIOMAP): a propensity score-matched analysis of an international, multicentre, cohort study.

BACKGROUND: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). METHODS: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18-90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (<70 years vs ≥70 years), preoperative National Institute of Health Stroke Scale (NIHSS) score (score of 0-1 vs ≥2), and preoperative KPS (90-100 vs ≤80). We used Cox proportional hazard regressions to analyse the effect of awake mapping on the primary outcomes including postoperative neurological deficits (measured by deterioration in NIHSS score at 6 week, 3 months, and 6 months postoperatively), overall survival, and progression-free survival. We used logistic regression to analyse the predictive value of awake mapping and other perioperative factors on postoperative outcomes. FINDINGS: Between Jan 1, 2010, and Oct 31, 2020, 3919 patients were recruited, of whom 1047 with tumour resection for primary eloquent glioblastoma were included in analyses as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised 536 patients, of whom 134 had awake craniotomies and 402 had asleep resection. In the overall matched cohort, awake craniotomy versus asleep resection resulted in fewer neurological deficits at 3 months (26 [22%] of 120 vs 107 [33%] of 323; p=0·019) and 6 months (30 [26%] of 115 vs 125 [41%] of 305; p=0·0048) postoperatively, longer overall survival (median 17·0 months [95% CI 15·0-24·0] vs 14·0 months [13·0-16·0]; p=0·00054), and longer progression-free survival (median 9·0 months [8·0-11·0] vs 7·3 months [6·0-8·8]; p=0·0060). In subgroup analyses, fewer postoperative neurological deficits occurred at 3 months and at 6 months with awake craniotomy versus asleep resection in patients younger than 70 years (3 months: 22 [21%] of 103 vs 93 [34%] of 272; p=0·016; 6 months: 24 [24%] of 101 vs 108 [42%] of 258; p=0·0014), those with an NIHSS score of 0-1 (3 months: 22 [23%] of 96 vs 97 [38%] of 254; p=0·0071; 6 months: 27 [28%] of 95 vs 115 [48%] of 239; p=0·0010), and those with a KPS of 90-100 (3 months: 17 [19%] of 88 vs 74 [35%] of 237; p=0·034; 6 months: 24 [28%] of 87 vs 101 [45%] of 223, p=0·0043). Additionally, fewer postoperative neurological deficits were seen in the awake group versus the asleep group at 3 months in patients aged 70 years and older (two [13%] of 16 vs 15 [43%] of 35; p=0·033; no difference seen at 6 months), with a NIHSS score of 2 or higher (3 months: three [13%] of 23 vs 21 [36%] of 58; p=0·040) and at 6 months in those with a KPS of 80 or lower (five [18%] of 28 vs 34 [39%] of 88; p=0·043; no difference seen at 3 months). Median overall survival was longer for the awake group than the asleep group in the subgroups younger than 70 years (19·5 months [95% CI 16·0-31·0] vs 15·0 months [13·0-17·0]; p<0·0001), an NIHSS score of 0-1 (18·0 months [16·0-31·0] vs 14·0 months [13·0-16·5]; p=0·00047), and KPS of 90-100 (19·0 months [16·0-31·0] vs 14·5 months [13·0-16·5]; p=0·00058). Median progression-free survival was also longer in the awake group than in the asleep group in patients younger than 70 years (9·3 months [95% CI 8·0-12·0] vs 7·5 months [6·5-9·0]; p=0·0061), in those with an NIHSS score of 0-1 (9·5 months [9·0-12·0] vs 8·0 months [6·5-9·0]; p=0·0035), and in those with a KPS of 90-100 (10·0 months [9·0-13·0] vs 8·0 months [7·0-9·0]; p=0·0010). No difference was seen in overall survival or progression-free survival between the awake group and the asleep group for those aged 70 years and older, with NIHSS scores of 2 or higher, or with a KPS of 80 or lower. INTERPRETATION: These data might aid neurosurgeons with the assessment of their surgical strategy in individual glioblastoma patients. These findings will be validated and further explored in the SAFE trial (NCT03861299) and the PROGRAM study (NCT04708171). FUNDING: None.

The feasibility and added value of mapping music during awake craniotomy: A systematic review.

The value of mapping musical function during awake craniotomy is unclear. Hence, this systematic review was conducted to examine the feasibility and added value of music mapping in patients undergoing awake craniotomy. An extensive search, on 26 March 2021, in four electronic databases (Medline, Embase, Web of Science and Cochrane CENTRAL register of trials), using synonyms of the words "Awake Craniotomy" and "Music Performance," was conducted. Patients performing music while undergoing awake craniotomy were independently included by two reviewers. This search resulted in 10 studies and 14 patients. Intra-operative mapping of musical function was successful in 13 out of 14 patients. Isolated music disruption, defined as disruption during music tasks with intact language/speech and/or motor functions, was identified in two patients in the right superior temporal gyrus, one patient in the right and one patient in the left middle frontal gyrus and one patient in the left medial temporal gyrus. Pre-operative functional MRI confirmed these localizations in three patients. Assessment of post-operative musical function, only conducted in seven patients by means of standardized (57%) and non-standardized (43%) tools, report no loss of musical function. With these results, we conclude that mapping music is feasible during awake craniotomy. Moreover, we identified certain brain regions relevant for music production and detected no decline during follow-up, suggesting an added value of mapping musicality during awake craniotomy. A systematic approach to map musicality should be implemented, to improve current knowledge on the added value of mapping musicality during awake craniotomy.

Comparative effectiveness of intracranial hypertension management guided by ventricular versus intraparenchymal pressure monitoring: a CENTER-TBI study.

OBJECTIVE: To compare outcomes between patients with primary external ventricular device (EVD)-driven treatment of intracranial hypertension and those with primary intraparenchymal monitor (IP)-driven treatment. METHODS: The CENTER-TBI study is a prospective, multicenter, longitudinal observational cohort study that enrolled patients of all TBI severities from 62 participating centers (mainly level I trauma centers) across Europe between 2015 and 2017. Functional outcome was assessed at 6 months and a year. We used multivariable adjusted instrumental variable (IV) analysis with "center" as instrument and logistic regression with covariate adjustment to determine the effect estimate of EVD on 6-month functional outcome. RESULTS: A total of 878 patients of all TBI severities with an indication for intracranial pressure (ICP) monitoring were included in the present study, of whom 739 (84%) patients had an IP monitor and 139 (16%) an EVD. Patients included were predominantly male (74% in the IP monitor and 76% in the EVD group), with a median age of 46 years in the IP group and 48 in the EVD group. Six-month GOS-E was similar between IP and EVD patients (adjusted odds ratio (aOR) and 95% confidence interval [CI] OR 0.74 and 95% CI [0.36-1.52], adjusted IV analysis). The length of intensive care unit stay was greater in the EVD group than in the IP group (adjusted rate ratio [95% CI] 1.70 [1.34-2.12], IV analysis). One hundred eighty-seven of the 739 patients in the IP group (25%) required an EVD due to refractory ICPs. CONCLUSION: We found no major differences in outcomes of patients with TBI when comparing EVD-guided and IP monitor-guided ICP management. In our cohort, a quarter of patients that initially received an IP monitor required an EVD later for ICP control. The prevalence of complications was higher in the EVD group. PROTOCOL: The core study is registered with ClinicalTrials.gov , number NCT02210221, and the Resource Identification Portal (RRID: SCR_015582).

eHealth cognitive rehabilitation for brain tumor patients: results of a randomized controlled trial.

BACKGROUND: Evidence-based cognitive rehabilitation programs for brain tumor patients are not widely available, despite the high need. We aimed to evaluate the effects of a tablet-based cognitive rehabilitation program on cognitive performance, cognitive complaints, fatigue, and psychological distress in primary brain tumor patients following neurosurgery. Also, attrition, adherence and patient satisfaction with the program were evaluated. METHODS: Adults with presumed low-grade glioma and meningioma were recruited before surgery. Three months thereafter, participants were allocated to the intervention group or waiting-list control group using minimization. The 10-week eHealth app ReMind, based on the effective face-to-face intervention, consisted of psychoeducation, strategy-training and attention retraining. Performance-based cognitive outcomes and patient-reported outcomes were assessed before surgery and 3, 6 and 12 months thereafter. Mean scores, percentages of cognitively impaired individuals and reliable change indices (RCIs) were compared between groups. RESULTS: Sixty-two out of 183 eligible patients were randomized. Of the people who declined, 56% reported that participation would to be too burdensome. All participants found a tablet-app suitable for delivery of cognitive rehabilitation and 90% rated the program as "good" or "excellent". Performance-based cognitive outcomes and patient-reported outcomes did not significantly differ in group means over time nor RCIs between the intervention (final n = 20) and control group (final n = 25). CONCLUSIONS: Recruitment at this early stage was difficult, resulting in limited statistical power. No significant effects were demonstrated, while adherence and satisfaction with the eHealth program were good. In clinical practice, ReMind may be helpful, if timing would be adapted to patients' needs.

Traumatic axonal injury (TAI): definitions, pathophysiology and imaging-a narrative review.

INTRODUCTION: Traumatic axonal injury (TAI) is a condition defined as multiple, scattered, small hemorrhagic, and/or non-hemorrhagic lesions, alongside brain swelling, in a more confined white matter distribution on imaging studies, together with impaired axoplasmic transport, axonal swelling, and disconnection after traumatic brain injury (TBI). Ever since its description in the 1980s and the grading system by Adams et al., our understanding of the processes behind this entity has increased. METHODS: We performed a scoping systematic, narrative review by interrogating Ovid MEDLINE, Embase, and Google Scholar on the pathophysiology, biomarkers, and diagnostic tools of TAI patients until July 2020. RESULTS: We underline the misuse of the Adams classification on MRI without proper validation studies, and highlight the hiatus in the scientific literature and areas needing more research. In the past, the theory behind the pathophysiology relied on the inertial force exerted on the brain matter after severe TBI inducing a primary axotomy. This theory has now been partially abandoned in favor of a more refined theory involving biochemical processes such as protein cleavage and DNA breakdown, ultimately leading to an inflammation cascade and cell apoptosis, a process now described as secondary axotomy. CONCLUSION: The difference in TAI definitions makes the comparison of studies that report outcomes, treatments, and prognostic factors a daunting task. An even more difficult task is isolating the outcomes of isolated TAI from the outcomes of severe TBI in general. Targeted bench-to-bedside studies are required in order to uncover further pathways involved in the pathophysiology of TAI and, ideally, new treatments.

Three-Dimensional Stereophotogrammetry in the Evaluation of Craniosynostosis: Current and Potential Use Cases.

ABSTRACT: Three-dimensional (3D) stereophotogrammetry is a novel imaging technique that has gained popularity in the medical field as a reliable, non-invasive, and radiation-free imaging modality. It uses optical sensors to acquire multiple 2D images from different angles which are reconstructed into a 3D digital model of the subject's surface. The technique proved to be especially useful in craniofacial applications, where it serves as a tool to overcome the limitations imposed by conventional imaging modalities and subjective evaluation methods. The capability to acquire high-dimensional data in a quick and safe manner and archive them for retrospective longitudinal analyses, provides the field with a methodology to increase the understanding of the morphological development of the cranium, its growth patterns and the effect of different treatments over time.This review describes the role of 3D stereophotogrammetry in the evaluation of craniosynostosis, including reliability studies, current and potential clinical use cases, and practical challenges. Finally, developments within the research field are analyzed by means of bibliometric networks, depicting prominent research topics, authors, and institutions, to stimulate new ideas and collaborations in the field of craniofacial 3D stereophotogrammetry.We anticipate that utilization of this modality's full potential requires a global effort in terms of collaborations, data sharing, standardization, and harmonization. Such developments can facilitate larger studies and novel deep learning methods that can aid in reaching an objective consensus regarding the most effective treatments for patients with craniosynostosis and other craniofacial anomalies, and to increase our understanding of these complex dysmorphologies and associated phenotypes.

Characterisation of vasodilatory responses in the presence of the CGRP receptor antibody erenumab in human isolated arteries.

BACKGROUND: Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine. METHODS: We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 µM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab. RESULTS: Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab. CONCLUSION: Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.