The existence of cranial bone flap displacement during brain radiotherapy.

This retrospective study examined bone flap displacement during radiotherapy in 25 post-operative brain tumour patients. Though never exceeding 2.5 mm, the sheer frequency of displacement highlights the need for future research on larger populations to validate its presence and assess the potential clinical impact on planning tumour volume margins.

DeepFLAIR: A neural network approach to mitigate signal and contrast loss in temporal lobes at 7 Tesla FLAIR images.

BACKGROUND AND PURPOSE: Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS: Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS: SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS: The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

Current state of the art of traditional and minimal invasive epilepsy surgery approaches.

Introduction: Open resective surgery remains the main treatment modality for refractory epilepsy, but is often considered a last resort option due to its invasiveness. Research question: This manuscript aims to provide an overview on traditional as well as minimally invasive surgical approaches in modern state of the art epilepsy surgery. Materials and methods: This narrative review addresses both historical and contemporary as well as minimal invasive surgical approaches in epilepsy surgery. Peer-reviewed published articles were retrieved from PubMed and Scopus. Only articles written in English were considered for this work. A range of traditional and minimally invasive surgical approaches in epilepsy surgery were examined, and their respective advantages and disadvantages have been summarized. Results: The following approaches and techniques are discussed: minimally invasive diagnostics in epilepsy surgery, anterior temporal lobectomy, functional temporal lobectomy, selective amygdalohippocampectomy through a transsylvian, transcortical, or subtemporal approach, insulo-opercular corticectomies compared to laser interstitial thermal therapy, radiofrequency thermocoagulation, stereotactic radiosurgery, neuromodulation, high intensity focused ultrasound, and disconnection surgery including callosotomy, hemispherotomy, and subpial transections. Discussion and conclusion: Understanding the benefits and disadvantages of different surgical approaches and strategies in traditional and minimal invasive epilepsy surgery might improve the surgical decision tree, as not all procedures are appropriate for all patients.

Surgical complications of vagus nerve stimulation surgery: A 14-years single-center experience.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Background: Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance. Methods: GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ. Results: WES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect. Conclusions: Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.

Hemispherotomy Revised: A complication overview and a systematic review meta-analysis.

Introduction: Hemispherectomy/hemispherotomy has been employed in the management of catastrophic epilepsy. However, initial reports on the associated mortality and morbidity raised several concerns regarding the technique's safety. Their actual, current incidence needs to be systematically examined to redefine hemispherotomy's exact role. Research question: Our current study examined their incidence and evaluated the association of the various hemispherotomy surgical techniques with the reported complications. Material & methods: A PRISMA-compliant systematic review and meta-analysis was performed. We searched PubMed, Scopus, and Web of Science until December 2022. Fixed- and random-effects models were employed. Egger's regression test was used for estimating the publication bias, while subgroup analysis was utilized for defining the role of the different hemispherotomy techniques. Results: We retrieved a total of 37 studies. The overall procedure mortality was 5%, with a reported mortality of 7% for hemispherectomy and 3% for hemispherotomy. The reported mortality has decreased over the last 30 years from 32% to 2%. Among the observed post-operative complications aseptic meningitis and/or fever occurred in 33%. Hydrocephalus requiring a shunt insertion occurred in 16%. Hematoma evacuation was necessary in 8%, while subgaleal effusion in another 8%. Infections occurred in 11%. A novel post-operative cranial nerve deficit occurred in 11%, while blood transfusion was necessary in 28% of the cases. Discussion and conclusion: Our current analysis demonstrated that the evolution from hemispherectomy to hemispherotomy along with neuroanesthesia advances, had a tremendous impact on the associated mortality and morbidity. Hemispherotomy constitutes a safe surgical procedure in the management of catastrophic epilepsies.

Successful epilepsy surgery in two cases with multiple sclerosis.

Brain surgery is the only curative treatment for people with focal epilepsy, but it is unclear whether this induces active disease in multiple sclerosis (MS). This creates a barrier to evaluate MS patients for epilepsy surgery. We present two cases of successful epilepsy surgery in patients with pharmacoresistant epilepsy and stable MS and give an overview of the existing literature. (1) a 28-year-old woman with seizures arising from a right basal temporo-occipital ganglioglioma was seizure-free after surgery, without MS relapse but with one new MS lesion postsurgically. (2) a 46-year-old woman with seizures arising from a natalizumab-associated progressive multifocal leukoencephalopathy (PML) lesion in the right frontal lobe was seizure-free after surgery preceded by extraoperative subdural electrocorticography, with new subclinical MS lesions. We are the first to report brain surgery in a PML survivor. Both patients stabilized radiologically after initiating second-line therapies. Successful epilepsy surgery can substantially increase the quality of life in patients with pharmacoresistant epilepsy and MS. With increasing survival rates of brain tumors and PML, the risk-benefit ratio of epilepsy surgery compared to a potential MS relapse after surgery becomes critically important. Shared decision-making is valuable for balancing the risks related to both diseases.

Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery-protocol for a multicentre, prospective cohort study.

INTRODUCTION: Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. METHODS AND ANALYSIS: A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. ETHICS AND DISSEMINATION: The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019-1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. TRIAL REGISTRATION: NL8278; Pre-results.

QUality of life and Economic evaluation after neuroSTimulation for Epilepsy (QUESTE) in adolescents and adults with drug-resistant epilepsy: protocol for a multicentre, prospective observational cohort study in The Netherlands.

INTRODUCTION: Epilepsy is one of the most common chronic neurological disorders. Antiseizure medication (ASM) is the first choice of treatment, however, 30% of epilepsy patients are drug-resistant. For these patients, neuromodulation can be an option, especially when epilepsy surgery is not possible or did not lead to seizure freedom. Epilepsy is associated with reduced quality of life (QoL), which heavily depends on seizure control.The most recent Cochrane reviews have shown that vagus nerve stimulation and deep brain stimulation of the anterior nucleus of the thalamus, lead to a responder rate OR of, respectively, 1.93 and 1.20. The question arises if neuromodulation for drug-resistant epilepsy (DRE) will be more cost-effective than sole treatment with ASM. The current study aims to determine the change in QoL after neuromodulation. Secondarily, we will aim to study the cost-effectiveness of these treatments. METHODS AND ANALYSIS: This prospective cohort study aims at including 100 patients aged 16 or above who will be referred for neuromodulation, from January 2021 to January 2026. After informed consent, QoL and other relevant parameters will be assessed at baseline, 6 months, 1, 2 and 5 years after surgery. Data on seizure frequency will be derived from patient charts. We expect that DRE patients will report better QoL after neuromodulation. Even if they would still report seizures, the treatment can be seen as useful. This is especially true when patients can participate in society again to a greater extent than before treatment. ETHICS AND DISSEMINATION: The board of directors of participating centres all gave permission for this study to commence. The medical ethics committees decided that this study does not fall under the Medical Research Involving Human Subjects Act (WMO). The findings of this study will be presented at (inter)national conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9033.

Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions.

By clearing GABA from the synaptic cleft, GABA transporters (GATs) play an essential role in inhibitory neurotransmission. Consequently, in vivo visualization of GATs can be a valuable diagnostic tool and biomarker for various psychiatric and neurological disorders. Not surprisingly, in recent years several research attempts to develop a radioligand have been conducted, but so far none have led to suitable radioligands that allow imaging of GATs. Here, we provide an overview of the radioligands that were developed with a focus on GAT1, since this is the most abundant transporter and most of the research concerns this GAT subtype. Initially, we focus on the field of GAT1 inhibitors, after which we discuss the development of GAT1 radioligands based on these inhibitors. We hypothesize that the radioligands developed so far have been unsuccessful due to the zwitterionic nature of their nipecotic acid moiety. To overcome this problem, the use of non-classical GAT inhibitors as basis for GAT1 radioligands or the use of carboxylic acid bioisosteres may be considered. As the latter structural modification has already been used in the field of GAT1 inhibitors, this option seems particularly viable and could lead to the development of more successful GAT1 radioligands in the future.

Cerebrovascular glycocalyx damage and microcirculation impairment in patients with temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is increasingly associated with blood-brain barrier dysfunction and microvascular alterations, yet the pathophysiological link is missing. An important barrier function is exerted by the glycocalyx, a gel-like layer coating the endothelium. To explore such associations, we used intraoperative videomicroscopy to quantify glycocalyx and microcirculation properties of the neocortex and hippocampus of 15 patients undergoing resective brain surgery as treatment for drug-resistant TLE, and 15 non-epileptic controls. Fluorescent lectin staining of neocortex and hippocampal tissue was used for blood vessel surface area quantification. Neocortical perfused boundary region, the thickness of the glycocalyx' impaired layer, was higher in patients (2.64 ± 0.52 µm) compared to controls (1.31 ± 0.29 µm), P < 0.01, indicative of reduced glycocalyx integrity in patients. Moreover, erythrocyte flow velocity analysis revealed an impaired ability of TLE patients to (de-)recruit capillaries in response to changing metabolic demands (R2 = 0.75, P < 0.01), indicating failure of neurovascular coupling mechanisms. Blood vessel quantification comparison between intraoperative measurements and resected tissue showed strong correlation (R2 = 0.94, P < 0.01). This is the first report on in vivo assessment of glycocalyx and microcirculation properties in TLE patients, confirming the pivotal role of cerebrovascular changes. Further assessment of the cerebral microcirculation in relation to epileptogenesis might open avenues for new therapeutic targets for drug-resistant epilepsy.

Advances in Image Processing for Epileptogenic Zone Detection with MRI.

Focal epilepsy is a common and severe neurologic disorder. Neuroimaging aims to identify the epileptogenic zone (EZ), preferably as a macroscopic structural lesion. For approximately a third of patients with chronic drug-resistant focal epilepsy, the EZ cannot be precisely identified using standard 3.0-T MRI. This may be due to either the EZ being undetectable at imaging or the seizure activity being caused by a physiologic abnormality rather than a structural lesion. Computational image processing has recently been shown to aid radiologic assessments and increase the success rate of uncovering suspicious regions by enhancing their visual conspicuity. While structural image analysis is at the forefront of EZ detection, physiologic image analysis has also been shown to provide valuable information about EZ location. This narrative review summarizes and explains the current state-of-the-art computational approaches for image analysis and presents their potential for EZ detection. Current limitations of the methods and possible future directions to augment EZ detection are discussed.

Neurocognition in adults with intracranial tumors: does location really matter?

OBJECTIVE: As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. METHODS: This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p < .001 and p < .05 for voxel- and cluster-level, resp.). RESULTS: A cohort of 179 intracranial tumor patients was included [aged 19-85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20-30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. INTERPRETATION: Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

From a dysembryoplastic neuroepithelial tumor to a glioblastoma multiforme: Pitfalls of initial diagnosis on biopsy material, a case report.

BACKGROUND: Ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNET) belong to the group of low-grade epilepsy-associated tumors (LEAT) and are the most prevalent tumor types found in patients undergoing epilepsy surgery. Histopathological differentiation between GG and DNET can be difficult on biopsies due to limited tumor tissue. CASE DESCRIPTION: Here, we present a rare case where a low-grade tumor was initially classified as DNET, based on biopsy findings and unfortunately dedifferentiated within 10 years into a glioblastoma multiforme. After gross total resection, the initial tumor was reclassified as GG. CONCLUSION: This case illustrates the diagnostic challenges of LEAT, especially on biopsy material. Therefore, we advocate to counsel for complete resection and histopathological diagnosis utilizing tumor markers to confirm the nature of the tumor and to advice type of follow-up and eventual concurrent treatment.

Nerve fiber density differences in the temporal dura mater: An explanation for headache after temporal lobectomy? An anatomical study.

OBJECTIVE: Patients who undergo a temporal lobectomy for drug-resistant epilepsy more frequently complain about postoperative headache compared to patients who undergo a craniotomy in any other region. The pathophysiological mechanism is not well understood. It is hypothesized that a relatively high density of sensory nerve fibers in the temporomesial dura underlies a higher sensitivity to pain upon stimulation. The objective of this study was to address this hypothesis by comparing the nerve fiber density in the temporomesial dura to that in the temporolateral dura. METHODS: Temporomesial (n = 6) and temporolateral (n = 6) dura mater samples (2.5 × 2 cm) were dissected from the middle cranial fossa of 5 formalin fixed human cadavers. Paraffin embedded specimens were cut in a sagittal direction into 5 µm sections (temporomesial group n = 106, temporolateral group n = 113), and immunohistochemically stained for S100 as a marker of myelinated nerve fibers. The number of S100-immunoreactive nerve fiber bundles was counted in an anterior-posterior direction by a blinded observer, expressed as mean ± standard error of the mean per cm for each group, and statistically analyzed by a linear mixed-effects model. To assess potential observer bias, a randomized subset of the sections (n = 28) was evaluated by a second blinded observer and statistically analyzed by intraclass correlation coefficient (ICC). RESULTS: The temporomesial dura expressed 4.1 ± 2.1 and the temporolateral dura displayed 1.0 ± 0.7 nerve fiber bundles per cm (ß = 3.2, SE= 0.30, 95% CI [2.6, 3.8], p < 0.001). There is a significant decrease in nerve fiber bundle density in the mesial to lateral direction (mean difference -0.1, SE= 0.0, 95% CI [-0.1, -0.2], p < 0.001). The ICC was 0.69. CONCLUSIONS: The density of myelinated nerve fiber bundles is about 4 times higher in the temporomesial dura, than in the temporolateral dura. Assuming that dural innervation primarily consists of sensory trigeminal fibers, this observation suggests that a summation of stimuli to surpass the threshold to convey pain is reached sooner in the temporomesial than in the temporolateral dura mater.

Assessment of need for hemostatic evaluation in patients taking valproic acid: A retrospective cross-sectional study.

INTRODUCTION: Valproic acid (VPA) is a frequently prescribed anti-epileptic drug. Since its introduction side effects on hemostasis are reported. However, studies show conflicting results, and the clinical relevance is questioned. We aimed to determine the coagulopathies induced by VPA in patients who undergo high-risk surgery. The study results warrant attention to this issue, which might contribute to reducing bleeding complications in future patients. METHODS: Between January 2012 and August 2020, 73 consecutive patients using VPA were retrospectively included. Extensive laboratory hemostatic assessment (including platelet function tests) was performed before elective high-risk surgery. Patient characteristics, details of VPA treatment, and laboratory results were extracted from medical records. RESULTS: 46.6% of the patients using VPA (n = 73) showed coagulopathy. Mainly, platelet function disorder was found (36.4%). Thrombocytopenia was seen in 9.6% of the patients. Data suggested that the incidence of coagulopathies was almost twice as high in children as compared to adults and hypofibrinogenemia was only demonstrated in children. No association was found between the incidence of coagulopathies and VPA dosage (mg/kg/day). CONCLUSION: A considerable number of patients using VPA were diagnosed with coagulopathy, especially platelet function disorder. Further prospective studies are needed to confirm the need for comprehensive laboratory testing before elective high-risk surgery in these patients.

Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry.

Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298).

On the Threshold of Scientific Medicine: Gerard van Swieten and His Perception of the Pathophysiology in Traumatic Brain Injury.

Gerard van Swieten (1700-1772), famous pupil of Professor Herman Boerhaave (1668-1738) of Leiden University and personal physician of Austrian Habsburg Empress Maria Theresa (1717-1780). Herman Boerhaave was a renowned Dutch physician inside and outside Europe in the 18th century. He was not only appointed professor in medicine, chemistry, and botany but also a chancellor of the Leiden University in 1714 and published his well-known Aphorismi de cognoscendis et curandis morbis in 1709. Gerard van Swieten commented upon Boerhaave's aphorisms and demonstrated actual knowledge, less well-known among the medical community, about the pathophysiology of traumatic brain injury which half a century later (19th century) became known as the Monro-Kellie doctrine. Using the original commentaries upon Boerhaave's aphorisms by van Swieten himself, we explored his way of formulating the pathophysiological concept of traumatic brain injury, which still is valid today.