Association of Lamotrigine Plasma Concentrations with Efficacy and Toxicity in Patients with Epilepsy: A Retrospective Study.

BACKGROUND: There is limited evidence to support the currently suggested lamotrigine (LTG) therapeutic reference range of 2.5-15 mg/L for the treatment of seizures. The objective of this study was to evaluate the association of LTG plasma concentrations with the efficacy and toxicity of the treatment in patients with epilepsy. METHODS: Patients whose LTG plasma concentration was measured between January 2013 and February 2022 were included. Efficacy was defined as seizure freedom for at least 6 months around the time of measured LTG concentration. Toxicity was defined as any LTG-related adverse drug effect documented in each patient's health record or when the reason for measuring the LTG concentration was toxicity. In addition, the dose-concentration relationship of LTG was assessed. RESULTS: In total, 549 concentrations from 259 patients with epilepsy were included. The most common reasons for therapeutic drug monitoring were suspected inefficacy (39%) and pregnancy (21%). The LTG plasma concentration was not associated with efficacy (adjusted odds ratio = 0.94; 95% confidence interval, 0.85-1.04). The LTG plasma concentration was positively associated with the incidence of toxicity after adjusting for age, sex, and number of antiepileptic drugs (odds ratio = 1.11; 95% confidence interval, 1.04-1.19). The daily dose had a significant linear correlation with the LTG plasma concentration ( P < 0.001). CONCLUSIONS: The LTG plasma concentration was associated with toxicity, whereas no association with efficacy was found. A reference range of 2.5-10 mg/L may be considered to decrease the risk of toxicity while maintaining similar efficacy. Therapeutic drug monitoring may be useful when LTG-related toxicity is suspected and in cases of pharmacokinetic changes (eg, pregnancy and concomitant use of interacting drugs) that can influence the LTG plasma concentration.

Multimodal nocturnal seizure detection in children with epilepsy: A prospective, multicenter, long-term, in-home trial.

OBJECTIVE: There is a pressing need for reliable automated seizure detection in epilepsy care. Performance evidence on ambulatory non-electroencephalography-based seizure detection devices is low, and evidence on their effect on caregiver's stress, sleep, and quality of life (QoL) is still lacking. We aimed to determine the performance of NightWatch, a wearable nocturnal seizure detection device, in children with epilepsy in the family home setting and to assess its impact on caregiver burden. METHODS: We conducted a phase 4, multicenter, prospective, video-controlled, in-home NightWatch implementation study (NCT03909984). We included children aged 4-16 years, with ≥1 weekly nocturnal major motor seizure, living at home. We compared a 2-month baseline period with a 2-month NightWatch intervention. The primary outcome was the detection performance of NightWatch for major motor seizures (focal to bilateral or generalized tonic-clonic [TC] seizures, focal to bilateral or generalized tonic seizures lasting >30 s, hyperkinetic seizures, and a remainder category of focal to bilateral or generalized clonic seizures and "TC-like" seizures). Secondary outcomes included caregivers' stress (Caregiver Strain Index [CSI]), sleep (Pittsburgh Quality of Sleep Index), and QoL (EuroQol five-dimension five-level scale). RESULTS: We included 53 children (55% male, mean age = 9.7 ± 3.6 years, 68% learning disability) and analyzed 2310 nights (28 173 h), including 552 major motor seizures. Nineteen participants did not experience any episode of interest during the trial. The median detection sensitivity per participant was 100% (range = 46%-100%), and the median individual false alarm rate was .04 per hour (range = 0-.53). Caregiver's stress decreased significantly (mean total CSI score = 8.0 vs. 7.1, p = .032), whereas caregiver's sleep and QoL did not change significantly during the trial. SIGNIFICANCE: The NightWatch system demonstrated high sensitivity for detecting nocturnal major motor seizures in children in a family home setting and reduced caregiver stress.

DeltaScan for the Assessment of Acute Encephalopathy and Delirium in ICU and non-ICU Patients, a Prospective Cross-Sectional Multicenter Validation Study.

OBJECTIVES: To measure the diagnostic accuracy of DeltaScan: a portable real-time brain state monitor for identifying delirium, a manifestation of acute encephalopathy (AE) detectable by polymorphic delta activity (PDA) in single-channel electroencephalograms (EEGs). DESIGN: Prospective cross-sectional study. SETTING: Six Intensive Care Units (ICU's) and 17 non-ICU departments, including a psychiatric department across 10 Dutch hospitals. PARTICIPANTS: 494 patients, median age 75 (IQR:64-87), 53% male, 46% in ICUs, 29% delirious. MEASUREMENTS: DeltaScan recorded 4-minute EEGs, using an algorithm to select the first 96 seconds of artifact-free data for PDA detection. This algorithm was trained and calibrated on two independent datasets. METHODS: Initial validation of the algorithm for AE involved comparing its output with an expert EEG panel's visual inspection. The primary objective was to assess DeltaScan's accuracy in identifying delirium against a delirium expert panel's consensus. RESULTS: DeltaScan had a 99% success rate, rejecting 6 of the 494 EEG's due to artifacts. Performance showed and an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.86 (95% CI: 0.83-0.90) for AE (sensitivity: 0.75, 95%CI=0.68-0.81, specificity: 0.87 95%CI=0.83-0.91. The AUC was 0.71 for delirium (95%CI=0.66-0.75, sensitivity: 0.61 95%CI=0.52-0.69, specificity: 72, 95%CI=0.67-0.77). Our validation aim was an NPV for delirium above 0.80 which proved to be 0.82 (95%CI: 0.77-0.86). Among 84 non-delirious psychiatric patients, DeltaScan differentiated delirium from other disorders with a 94% (95%CI: 87-98%) specificity. CONCLUSIONS: DeltaScan can diagnose AE at bedside and shows a clear relationship with clinical delirium. Further research is required to explore its role in predicting delirium-related outcomes.

Timing of syncope in ictal asystole as a guide when considering pacemaker implantation.

INTRODUCTION: In patients with ictal asystole (IA) both cardioinhibition and vasodepression may contribute to syncopal loss of consciousness. We investigated the temporal relationship between onset of asystole and development of syncope in IA, to estimate the frequency with which pacemaker therapy, by preventing severe bradycardia, may diminish syncope risk. METHODS: In this retrospective cohort study, we searched video-EEG databases for individuals with focal seizures and IA (asystole ≥ 3 s preceded by heart rate deceleration) and assessed the durations of asystole and syncope and their temporal relationship. Syncope was evaluated using both video observations (loss of muscle tone) and EEG (generalized slowing/flattening). We assumed that asystole starting ≤3 s before syncope onset, or after syncope began, could not have been the dominant cause. RESULTS: We identified 38 seizures with IA from 29 individuals (17 males; median age: 41 years). Syncope occurred in 22/38 seizures with IA and was more frequent in those with longer IA duration (median duration: 20 [range: 5-32] vs. 5 [range: 3-9] s; p < .001) and those with the patient seated vs. supine (79% vs. 46%; p = .049). IA onset always preceded syncope. In 20/22 seizures (91%), IA preceded syncope by >3 s. Thus, in only two instances was vasodepression rather than cardioinhibition the dominant presumptive syncope triggering mechanism. CONCLUSIONS: In IA, cardioinhibition played an important role in most seizure-induced syncopal events, thereby favoring the potential utility of pacemaker implantation in patients with difficult to suppress IA.

Pathological responses to single-pulse electrical stimuli in epilepsy: The role of feedforward inhibition.

Delineation of epileptogenic cortex in focal epilepsy patients may profit from single-pulse electrical stimulation during intracranial EEG recordings. Single-pulse electrical stimulation evokes early and delayed responses. Early responses represent connectivity. Delayed responses are a biomarker for epileptogenic cortex, but up till now, the precise mechanism generating delayed responses remains elusive. We used a data-driven modelling approach to study early and delayed responses. We hypothesized that delayed responses represent indirect responses triggered by early response activity and investigated this for 11 patients. Using two coupled neural masses, we modelled early and delayed responses by combining simulations and bifurcation analysis. An important feature of the model is the inclusion of feedforward inhibitory connections. The waveform of early responses can be explained by feedforward inhibition. Delayed responses can be viewed as second-order responses in the early response network which appear when input to a neural mass falls below a threshold forcing it temporarily to a spiking state. The combination of the threshold with noisy background input explains the typical stochastic appearance of delayed responses. The intrinsic excitability of a neural mass and the strength of its input influence the probability at which delayed responses to occur. Our work gives a theoretical basis for the use of delayed responses as a biomarker for the epileptogenic zone, confirming earlier clinical observations. The combination of early responses revealing effective connectivity, and delayed responses showing intrinsic excitability, makes single-pulse electrical stimulation an interesting tool to obtain data for computational models of epilepsy surgery.

Memory for novel and familiar environments relies on the hippocampus: A case study on a patient with a right anteromesial temporal lobectomy.

While the hippocampus has been ascribed a prominent role in navigation ability, it is still a subject of debate whether it contributes to learning novel environments only or to remembering familiar environments as well. We attempt to shed light on this issue by reporting on a patient who developed complaints of severe difficulties with navigation after she underwent a right anteromesial temporal lobectomy. A standard neuropsychological assessment revealed only a visuospatial working memory deficit. Clear evidence for problems with novel environments were found on a virtual route learning test. Two real-world tests were used to investigate her ability to recall familiar environments. The first test was based on the area she grew up in (and still visits regularly) and the second test concerned her current place of residence which she never visited prior to the surgery. While her landmark recognition in general was accurate, she showed notable difficulties with indicating their locations on a map and with giving accurate route descriptions between them for both real-world environments. This pattern of findings suggests that the hippocampus is not only important for navigation in novel environments, but also for familiar environments learned long ago.

Increased gamma and decreased fast ripple connections of epileptic tissue: A high-frequency directed network approach.

OBJECTIVE: New insights into high-frequency electroencephalographic activity and network analysis provide potential tools to improve delineation of epileptic tissue and increase the chance of postoperative seizure freedom. Based on our observation of high-frequency oscillations "spreading outward" from the epileptic source, we hypothesize that measures of directed connectivity in the high-frequency range distinguish epileptic from healthy brain tissue. METHODS: We retrospectively selected refractory epilepsy patients with a malformation of cortical development or tumor World Health Organization grade I/II who underwent epilepsy surgery with intraoperative electrocorticography for tailoring the resection based on spikes. We assessed directed functional connectivity in the theta (4-8 Hz), gamma (30-80 Hz), ripple (80-250 Hz), and fast ripple (FR; 250-500 Hz) bands using the short-time direct directed transfer function, and calculated the total, incoming, and outgoing propagation strength for each electrode. We compared network measures of electrodes covering the resected and nonresected areas separately for patients with good and poor outcome, and of electrodes with and without spikes, ripples, and FRs (group level: paired t test; patient level: Mann-Whitney U test). We selected the measure that could best identify the resected area and channels with epileptic events using the area under the receiver operating characteristic curve, and calculated the positive and negative predictive value, sensitivity, and specificity. RESULTS: We found higher total and outstrength in the ripple and gamma bands in resected tissue in patients with good outcome (rippletotal : P = .01; rippleout : P = .04; gammatotal : P = .01; gammaout : P = .01). Channels with events showed lower total and instrength, and higher outstrength in the FR band, and higher total and outstrength in the ripple, gamma, and theta bands (FRtotal : P = .05; FRin : P < .01; FRout : P = .02; gammatotal : P < .01; gammain : P = .01; gammaout : P < .01; thetatotal : P = .01; thetaout : P = .01). The total strength in the gamma band was most distinctive at the channel level (positive predictive value [PPV]good  = 74%, PPVpoor  = 43%). SIGNIFICANCE: Interictally, epileptic tissue is isolated in the FR band and acts as a driver up to the (fast) ripple frequency range. The gamma band total strength seems promising to delineate epileptic tissue intraoperatively.

A Comparison of Evoked and Non-evoked Functional Networks.

The growing interest in brain networks to study the brain's function in cognition and diseases has produced an increase in methods to extract these networks. Typically, each method yields a different network. Therefore, one may ask what the resulting networks represent. To address this issue we consider electrocorticography (ECoG) data where we compare three methods. We derive networks from on-going ECoG data using two traditional methods: cross-correlation (CC) and Granger causality (GC). Next, connectivity is probed actively using single pulse electrical stimulation (SPES). We compare the overlap in connectivity between these three methods as well as their ability to reveal well-known anatomical connections in the language circuit. We find that strong connections in the CC network form more or less a subset of the SPES network. GC and SPES are related more weakly, although GC connections coincide more frequently with SPES connections compared to non-existing SPES connections. Connectivity between the two major hubs in the language circuit, Broca's and Wernicke's area, is only found in SPES networks. Our results are of interest for the use of patient-specific networks obtained from ECoG. In epilepsy research, such networks form the basis for methods that predict the effect of epilepsy surgery. For this application SPES networks are interesting as they disclose more physiological connections compared to CC and GC networks.

Evoked directional network characteristics of epileptogenic tissue derived from single pulse electrical stimulation.

We investigated effective networks constructed from single pulse electrical stimulation (SPES) in epilepsy patients who underwent intracranial electrocorticography. Using graph analysis, we compared network characteristics of tissue within and outside the epileptogenic area. In 21 patients with subdural electrode grids (1 cm interelectrode distance), we constructed a binary, directional network derived from SPES early responses (<100 ms). We calculated in-degree, out-degree, betweenness centrality, the percentage of bidirectional, receiving and activating connections, and the percentage of connections toward the (non-)epileptogenic tissue for each node in the network. We analyzed whether these network measures were significantly different in seizure onset zone (SOZ)-electrodes compared to non-SOZ electrodes, in resected area (RA)-electrodes compared to non-RA electrodes, and in seizure free compared to not seizure-free patients. Electrodes in the SOZ/RA showed significantly higher values for in-degree and out-degree, both at group level, and at patient level, and more so in seizure-free patients. These differences were not observed for betweenness centrality. There were also more bidirectional and fewer receiving connections in the SOZ/RA in seizure-free patients. It appears that the SOZ/RA is densely connected with itself, with only little input arriving from non-SOZ/non-RA electrodes. These results suggest that meso-scale effective network measures are different in epileptogenic compared to normal brain tissue. Local connections within the SOZ/RA are increased and the SOZ/RA is relatively isolated from the surrounding cortex. This offers the prospect of enhanced prediction of epilepsy-prone brain areas using SPES.

Tailoring epilepsy surgery with fast ripples in the intraoperative electrocorticogram.

OBJECTIVE: Intraoperative electrocorticography (ECoG) can be used to delineate the resection area in epilepsy surgery. High-frequency oscillations (HFOs; 80-500 Hz) seem better biomarkers for epileptogenic tissue than spikes. We studied how HFOs and spikes in combined pre- and postresection ECoG predict surgical outcome in different tailoring approaches. METHODS: We, retrospectively, marked HFOs, divided into fast ripples (FRs; 250-500 Hz) and ripples (80-250 Hz), and spikes in pre- and postresection ECoG sampled at 2,048 Hz in people with refractory focal epilepsy. We defined four groups of electroencephalography (EEG) event occurrence: pre+post- (+/-), pre+post+ (+/+), pre-post+ (-/+) and pre-post- (-/-). We subcategorized three tailoring approaches: hippocampectomy with tailoring for neocortical involvement; lesionectomy of temporal lesions with tailoring for mesiotemporal involvement; and lesionectomy with tailoring for surrounding neocortical involvement. We compared the percentage of resected pre-EEG events, time to recurrence, and the different tailoring approaches to outcome (seizure-free vs recurrence). RESULTS: We included 54 patients (median age, 15.5 years; 25 months of follow-up; 30 seizure free). The percentage of resected FRs, ripples, or spikes in pre-ECoG did not predict outcome. The occurrence of FRs in post-ECoG, given FRs in pre-ECoG (+/-, +/+), predicted outcome (hazard ratio, 3.13; confidence interval = 1.22-6.25; p = 0.01). Seven of 8 patients without spikes in pre-ECoG were seizure free. The highest predictive value for seizure recurrence was presence of FRs in post-ECoG for all tailoring approaches. INTERPRETATION: FRs that persist before and after resection predict poor postsurgical outcome. These findings hold for different tailoring approaches. FRs can thus be used for tailoring epilepsy surgery with repeated intraoperative ECoG measurements. Ann Neurol 2017;81:664-676.

Multimodal seizure detection: A review.

A review is given on the combined use of multiple modalities in non electroencephalography (EEG)-based detection of motor seizures in children and adults. A literature search of papers was done on multimodal seizure detection with extraction of data on type of modalities, study design and algorithm, sensitivity, false detection rate, and seizure types. Evidence of superiority was sought for using multiple instead of single modalities. Seven papers were found from 2010 to 2017, mostly using contact sensors such as accelerometers (n = 5), electromyography (n = 2), heart rate (n = 2), electrodermal activity (n = 1), and oximetry (n = 1). Remote sensors included video, radar, movement, and sound. All studies but one were in-hospital, with video-EEG as a gold standard. Algorithms were based on physiology and supervised machine learning, but did not always include a separate test dataset. Sensitivity ranged from 4% to 100% and false detection rate from 0.25 to 20 per 8 hours. Tonic-clonic seizure detection performed best. False detections tended to be restricted to a minority (16%-30%) of patients. Use of multiple sensors increased sensitivity; false detections decreased in one study, but increased in another. These preliminary studies suggest that detection of tonic-clonic seizures might be feasible, but larger field studies are required under more rigorous design that precludes bias. Generic algorithms probably suffice for the majority of patients.

Intracranial Recordings of Occipital Cortex Responses to Illusory Visual Events.

UNLABELLED: Ambiguous visual stimuli elicit different perceptual interpretations over time, creating the illusion that a constant stimulus is changing. We investigate whether such spontaneous changes in visual perception involve occipital brain regions specialized for processing visual information, despite the absence of concomitant changes in stimulation. Spontaneous perceptual changes observed while viewing a binocular rivalry stimulus or an ambiguous structure-from-motion stimulus were compared with stimulus-induced perceptual changes that occurred in response to an actual stimulus change. Intracranial recordings from human occipital cortex revealed that spontaneous and stimulus-induced perceptual changes were both associated with an early transient increase in high-frequency power that was more spatially confined than a later transient decrease in low-frequency power. We suggest that the observed high-frequency and low-frequency modulations relate to initiation and maintenance of a percept, respectively. Our results are compatible with the idea that spontaneous changes in perception originate from competitive interactions within visual neural networks. SIGNIFICANCE STATEMENT: Ambiguous visual stimuli elicit different perceptual interpretations over time, creating the illusion that a constant stimulus is changing. The literature on the neural correlates of conscious visual perception remains inconclusive regarding the extent to which such spontaneous changes in perception involve sensory brain regions. In an attempt to bridge the gap between existing animal and human studies, we recorded from intracranial electrodes placed on the human occipital lobe. We compared two different kinds of ambiguous stimuli, binocular rivalry and the phenomenon of ambiguous structure-from-motion, enabling generalization of our findings across different stimuli. Our results indicate that spontaneous and stimulus-induced changes in perception (i.e., "illusory" and "real" changes in the stimulus, respectively) may involve sensory regions to a similar extent.

Ripples on rolandic spikes: A marker of epilepsy severity.

OBJECTIVE: Children with rolandic spikes may or may not have seizures, ranging from benign rolandic epilepsy to severe atypical rolandic epilepsy. We investigated whether ripples (80-250 Hz), superimposed on rolandic spikes in surface electroencephalography (EEG), can differentiate between different entities. METHODS: In this cohort study we analyzed the EEG studies of children with rolandic spikes without other EEG or magnetic resonance imaging (MRI) abnormalities. They were divided into the following three groups: (1) rolandic spikes but no epilepsy, (2) typical rolandic epilepsy, and (3) atypical and symptomatic rolandic epilepsy. Ripples superimposed on rolandic spikes were marked in 10 minutes of EEG, and compared to the number of seizures before the EEG. Receiver operating characteristic (ROC) curves were constructed to determine the predictive value of ripples and spikes for having epilepsy (groups 2 and 3) and for differentiating benign courses (groups 1 or 2) from atypical and symptomatic epilepsy (group 3). Ripples were also marked in the time frequency spectrum of averaged rolandic spikes. RESULTS: Ripples were found in 13 of 22 children. Children without epilepsy showed no ripples, except for a single child with only one ripple. The number of ripples showed a significant positive correlation with the number of seizures (ρ = 0.70, p = 0.001), whereas spikes had a borderline significant correlation (ρ = 0.43, p = 0.05). Presence of more than two ripples was a predictor for having seizures (area under the curve [AUC] 0.84), whereas spikes could not predict having seizures (AUC 0.53). More than five ripples predicted the difference between benign courses and atypical and symptomatic epilepsy (AUC 0.91, sensitivity 63%, specificity 100%). Ripples in the time frequency spectra appeared in all children and were not related to seizures. SIGNIFICANCE: Absence of ripples on top of rolandic spikes predicts a relative benign clinical entity, whereas in the presence of several ripples, the child is likely to have more seizures than classical rolandic epilepsy, and pharmacologic treatment might be needed.

Spatiotemporal characteristics of electrocortical brain activity during mental calculation.

Mental calculation is a complex mental procedure involving a frontoparietal network of brain regions. Functional MRI (fMRI) studies have revealed interesting characteristics of these regions, but the precise function of some areas remains elusive. In the present study, we used electrocorticographic (ECoG) recordings to chronometrically assess the neuronal processes during mental arithmetic. A calculation task was performed during presurgical 3T fMRI scanning and subsequent ECoG monitoring. Mental calculation induced an increase in fMRI blood oxygen level dependent signal in prefrontal, parietal and lower temporo-occipital regions. The group-fMRI result was subsequently used to cluster the implanted electrodes into anatomically defined regions of interest (ROIs). We observed remarkable differences in high frequency power profiles between ROIs, some of which were closely associated with stimulus presentation and others with the response. Upon stimulus presentation, occipital areas were the first to respond, followed by parietal and frontal areas, and finally by motor areas. Notably, we demonstrate that the fMRI activation in the middle frontal gyrus/precentral gyrus is associated with two subfunctions during mental calculation. This finding reveals the significance of the temporal dynamics of neural ensembles within regions with an apparent uniform function. In conclusion, our results shed more light on the spatiotemporal aspects of brain activation during a mental calculation task, and demonstrate that the use of fMRI data to cluster ECoG electrodes is a useful approach for ECoG group analysis.

Safety of a dedicated brain MRI protocol in patients with a vagus nerve stimulator.

Although implanted metallic devices constitute a relative contraindication to magnetic resonance imaging (MRI) scanning, the safety of brain imaging in a patient with a vagus nerve stimulator (VNS) is classified as "conditional," provided that specific manufacturer guidelines are followed when a transmit and receive head coil is used at 1.5 or 3.0 Tesla. The aim of this study was to evaluate the safety of performing brain MRI scans in patients with the VNS. From September 2009 until November 2011, 101 scans were requested in 73 patients with the VNS in The Netherlands. Patients were scanned according to the manufacturer's guidelines. No patient reported any side effect, discomfort, or pain during or after the MRI scan. In one patient, a lead break was detected based on device diagnostics after the MRI-scan. However, because no system diagnostics had been performed prior to MR scanning in this patient, it is unclear whether MR scanning was responsible for the lead break. The indication for most scans was epilepsy related. Twenty-six scans (26%) were part of a (new) presurgical evaluation and could probably better have been performed prior to VNS implantation. Performing brain MRI scans in patients with an implanted VNS is safe when a modified MRI protocol is followed.

Delirium detection based on monitoring of blinks and eye movements.

OBJECTIVE: To investigate whether delirious patients differ from nondelirious patients with regard to blinks and eye movements to explore opportunities for delirium detection. METHODS: Using a single-center, observational study in a tertiary hospital in the Netherlands, we studied 28 delirious elderly and 28 age- and gender-matched (group level) nondelirious elderly, postoperative cardiac surgery patients. Patients were evaluated for delirium by a geriatrician, psychiatrist, or neurologist using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Blinks were automatically extracted from electro-oculograms and eye movements from electroencephalography recordings using independent component analysis. The number and duration of eye movements and blinks were compared between patients with and without delirium, based on the classification of the delirium experts described above. RESULTS: During eyes-open registrations, delirious patients showed, compared with nondelirious patients, a significant decrease in the number of blinks per minute (median: 12 [interquartile range {IQR}: 5-18] versus 18 [IQR: 8-25], respectively; p = 0.02) and number of vertical eye movements per minute (median: 1 [IQR: 0-13] versus 15 [IQR: 2-54], respectively; p = 0.01) as well as an increase in the average duration of blinks (median: 0.5 [IQR: 0.36-0.95] seconds versus 0.34 [IQR: 0.23-0.53] seconds, respectively; p <0.01). During eyes-closed registrations, the average duration of horizontal eye movements was significantly increased in delirious patients compared with patients without delirium (median: 0.41 [IQR: 0.15-0.75] seconds versus 0.08 [IQR: 0.06-0.22] seconds, respectively; p <0.01). CONCLUSION: Spontaneous eye movements and particularly blinks appear to be affected in delirious patients, which holds promise for delirium detection.

Prognosis and therapy of tumor-related versus non-tumor-related status epilepticus: a systematic review and meta-analysis.

BACKGROUND: Status epilepticus (SE) is a medical emergency with high mortality rates. Of all SE's, 7% are caused by a brain tumor. Clinical guidelines on the management of SE do not make a distinction between tumor-related SE and SE due to other causes. However, pathophysiological research points towards specific mechanisms of epilepsy in brain tumors. We investigated whether clinical features support a distinct profile of tumor-related SE by looking at measures of severity and response to treatment. METHODS: Systematic review of the literature and meta-analysis of studies on adult SE that report separate data for tumor-related SE and non-tumor-related SE on the following outcomes: short-term mortality, long-term morbidity, duration of SE, and efficacy of anticonvulsant intervention. RESULTS: Fourteen studies on outcome of SE were included. Tumor-related SE was associated with higher mortality than non-tumor-related SE (17.2% versus 11.2%, RR 1.53, 95%-CI 1.24-1.90). After exclusion of patients with hypoxic-ischemic encephalopathy (a group with a known poor prognosis) from the non-tumor-group, the difference in mortality increased (17.2% versus 6.6%; RR 2.78, 95%-CI 2.21 - 3.47). Regarding long-term morbidity and duration of SE there were insufficient data. We did not find studies that systematically compared effects of therapy for SE between tumor- and non-tumor-related SE. CONCLUSIONS: Based on - mostly retrospective - available studies, short-term mortality seems higher in tumor-related SE than in SE due to other causes. Further studies on the outcome and efficacy of different therapeutic regimens in tumor-related SE are needed, to clarify whether tumor-related SE should be regarded as a distinct clinical entity.

ER-detect: a pipeline for robust detection of early evoked responses in BIDS-iEEG electrical stimulation data.

Human brain connectivity can be measured in different ways. Intracranial EEG (iEEG) measurements during single pulse electrical stimulation provide a unique way to assess the spread of electrical information with millisecond precision. To provide a robust workflow to process these cortico-cortical evoked potential (CCEP) data and detect early evoked responses in a fully automated and reproducible fashion, we developed Early Response (ER)-detect. ER-detect is an open-source Python package and Docker application to preprocess BIDS structured iEEG data and detect early evoked CCEP responses. ER-detect can use three response detection methods, which were validated against 14-manually annotated CCEP datasets from two different sites by four independent raters. Results showed that ER-detect's automated detection performed on par with the inter-rater reliability (Cohen's Kappa of ~0.6). Moreover, ER-detect was optimized for processing large CCEP datasets, to be used in conjunction with other connectomic investigations. ER-detect provides a highly efficient standardized workflow such that iEEG-BIDS data can be processed in a consistent manner and enhance the reproducibility of CCEP based connectivity results.

Corticosteroids versus clobazam for treatment of children with epileptic encephalopathy with spike-wave activation in sleep (RESCUE ESES): a multicentre randomised controlled trial.

BACKGROUND: Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is a rare syndrome associated with cognitive and behavioural regression. On the basis of mostly small observational and retrospective studies, corticosteroids and clobazam are often considered the most effective treatments for this syndrome. We aimed to compare cognitive outcomes of children with EE-SWAS 6 months after starting treatment with either corticosteroids or clobazam. METHODS: We did a multicentre, randomised controlled trial at eight tertiary referral centres for rare epilepsies in seven European countries. Children were eligible to participate if they were aged 2-12 years, were diagnosed with EE-SWAS within 6 months before inclusion, and had not been treated with corticosteroids or clobazam previously. Participants were randomly assigned (1:1) to treatment with corticosteroids (either continuous treatment with 1-2 mg/kg per day of prednisolone orally or pulse treatment with 20 mg/kg per day of methylprednisolone intravenously for 3 days every 4 weeks) or clobazam (0·5-1·2 mg/kg per day orally). The primary outcome was cognitive functioning after 6 months of treatment, which was assessed by either the intelligence quotient (IQ) responder rate (defined as improvement of ≥11·25 IQ points) or the cognitive sum score responder rate (defined as improvement of ≥0·75 points). Safety was assessed by number of adverse events and serious adverse events. Data were analysed in the intention-to-treat population, which included all children as randomised who had primary outcome data available at 6 months. The trial is registered with the Dutch Trial Register, Toetsingonline, NL43510.041.13, and the ISRCTN registry, ISRCTN42686094. The trial was terminated prematurely because enrolment of the predefined number of 130 participants was deemed not feasible. FINDINGS: Between July 22, 2014, and Sept 3, 2022, 45 children were randomly assigned to either corticosteroids (n=22) or clobazam (n=23); two children assigned clobazam dropped out before 6 months and were excluded from the intention-to-treat analysis. At the 6-month assessment, an improvement of 11·25 IQ points or greater was reported for five (25%) of 20 children assigned corticosteroids versus zero (0%) of 18 assigned clobazam (risk ratio [RR] 10·0, 95% CI 1·2-1310·4; p=0·025). An improvement of 0·75 points or more in the cognitive sum score was recorded for one (5%) of 22 children assigned corticosteroids versus one (5%) of 21 children assigned clobazam (RR 1·0, 95% CI 0·1-11·7, p=0·97). Adverse events occurred in ten (45%) of 22 children who received corticosteroids, most frequently weight gain, and in 11 (52%) of 21 children who received clobazam, most often fatigue and behavioural disturbances. Occurrence of adverse events did not differ between groups (RR 0·8, 95% CI 0·4-1·4; p=0·65). Serious adverse events occurred in one child in the corticosteroid group (hospitalisation due to laryngitis) and in two children in the clobazam group (hospitalisation due to seizure aggravation, and respiratory tract infection). No deaths were reported. INTERPRETATION: The trial was terminated prematurely, and the target sample size was not met, so our findings must be interpreted with caution. Our data indicated an improvement in IQ outcomes with corticosteroids compared with clobazam treatment, but no difference was seen in cognitive sum score. Our findings strengthen those from previous uncontrolled studies that support the early use of corticosteroids for children with EE-SWAS. FUNDING: EpilepsieNL, WKZ fund, European Clinical Research Infrastructure Network, and Ming fund.

Dissociation between neuronal activity in sensorimotor cortex and hand movement revealed as a function of movement rate.

It is often assumed that similar behavior is generated by the same brain activity. However, this does not take into account the brain state or recent behavioral history and movement initiation or continuation may not be similarly generated in the brain. To study whether similar movements are generated by the same brain activity, we measured neuronal population activity during repeated movements. Three human subjects performed a motor repetition task in which they moved their hand at four different rates (0.3, 0.5, 1, and 2 Hz). From high-resolution electrocorticography arrays implanted on motor and sensory cortex, high-frequency power (65-95 Hz) was extracted as a measure of neuronal population activity. During the two faster movement rates, high-frequency power was significantly suppressed, whereas movement parameters remained highly similar. This suppression was nonlinear: after the initial movement, neuronal population activity was reduced most strongly, and the data fit a model in which a fast decline rapidly converged to saturation. The amplitude of the beta-band suppression did not change with different rates. However, at the faster rates, beta power did not return to baseline between movements but remained suppressed. We take these findings to indicate that the extended beta suppression at the faster rates, which may suggest a release of inhibition in motor cortex, facilitates movement initiation. These results show that the relationship between behavior and neuronal activity is not consistent: recent movement influences the state of motor cortex and facilitates next movements by reducing the required level of neuronal activity.