Schulze‐Bonhage, Andreas

Abstract Objective Novel subcutaneous electroencephalography (sqEEG) systems enable prolonged, near‐continuous cerebral monitoring in real‐world conditions. Nevertheless, the feasibility, acceptability and overall clinical utility of these systems remain unclear. We report on the longest observational study using ultra‐long‐term sqEEG to date. Methods We conducted a 15‐month prospective, observational study including 10 adult people with treatment‐resistant epilepsy. After device implantation, patients were asked to record sqEEG, to use an electronic seizure diary, and to complete acceptability and usability questionnaires. sqEEG seizures were annotated visually, aided by automated detection. Individualized temporal patterns of seizure occurrence were assessed via circadian circular statistics and via Fano factor analysis. Results Over a median duration of 438 days, 10 patients recorded a median 18.8 h/day, totaling 71 984 h of real‐world sqEEG data. Adherence and acceptability remained high throughout the study. Although 754 sqEEG seizures were recorded across patients, more than half (52%) of these were not reported in the patient diary. Of the 140 (27%) diary reports not associated with an identifiable sqEEG seizure, the majority (68%) were reported as seizures with preserved awareness. The sqEEG to diary F1 agreement score was highly variable, ranging from .06 to .97. Patient‐specific patterns of circadian seizure occurrence and seizure clustering were found, including several relevant discrepancies between sqEEG and diary. Significance We demonstrate feasibility and high acceptability of ultra‐long‐term (months–years) sqEEG monitoring. These systems help provide real‐world, more objective seizure counting compared to patient diaries. It is possible to objectively monitor individual temporal fluctuations of seizure occurrence.

Abstract Objective Wearable nonelectroencephalographic biosignal recordings captured from the wrist offer enormous potential for seizure monitoring. However, signal quality remains a challenging factor affecting data reliability. Models trained for seizure detection depend on the quality of recordings in peri‐ictal periods in performing a feature‐based separation of ictal periods from interictal periods. Thus, this study aims to investigate the effect of epileptic seizures on signal quality, ensuring accurate and reliable monitoring. Methods This study assesses the signal quality of wearable data during peri‐ictal phases of generalized tonic–clonic and focal to bilateral tonic–clonic seizures (TCS), focal motor seizures (FMS), and focal nonmotor seizures (FNMS). We evaluated accelerometer (ACC) activity and the signal quality of electrodermal activity (EDA) and blood volume pulse (BVP) data. Additionally, we analyzed the influence of peri‐ictal movements as assessed by ACC (ACC activity) on signal quality and examined intraictal subphases of focal to bilateral TCS. Results We analyzed 386 seizures from 111 individuals in three international epilepsy monitoring units. BVP signal quality and ACC activity levels differed between all seizure types. We found the largest decrease in BVP signal quality and increase in ACC activity when comparing the ictal phase to the pre‐ and postictal phases for TCS. Additionally, ACC activity was strongly negatively correlated with BVP signal quality for TCS and FMS, and weakly for FNMS. Intraictal analysis revealed that tonic and clonic subphases have the lowest BVP signal quality and the highest ACC activity. Significance Motor elements of seizures significantly impair BVP signal quality, but do not have significant effect on EDA signal quality, as assessed by wrist‐worn wearables. The results underscore the importance of signal quality assessment methods and careful selection of robust modalities to ensure reliable seizure detection. Future research is needed to explain whether seizure detection models' decisions are based on signal responses induced by physiological processes as opposed to artifacts.

AbstractObjectiveEpilepsy management employs self‐reported seizure diaries, despite evidence of seizure underreporting. Wearable and implantable seizure detection devices are now becoming more widely available. There are no clear guidelines about what levels of accuracy are sufficient. This study aimed to simulate clinical use cases and identify the necessary level of accuracy for each.MethodsUsing a realistic seizure simulator (CHOCOLATES), a ground truth was produced, which was then sampled to generate signals from simulated seizure detectors of various capabilities. Five use cases were evaluated: (1) randomized clinical trials (RCTs), (2) medication adjustment in clinic, (3) injury prevention, (4) sudden unexpected death in epilepsy (SUDEP) prevention, and (5) treatment of seizure clusters. We considered sensitivity (0%–100%), false alarm rate (FAR; 0–2/day), and device type (external wearable vs. implant) in each scenario.ResultsThe RCT case was efficient for a wide range of wearable parameters, though implantable devices were preferred. Lower accuracy wearables resulted in subtle changes in the distribution of patients enrolled in RCTs, and therefore higher sensitivity and lower FAR values were preferred. In the clinic case, a wide range of sensitivity, FAR, and device type yielded similar results. For injury prevention, SUDEP prevention, and seizure cluster treatment, each scenario required high sensitivity and yet was minimally influenced by FAR.SignificanceThe choice of use case is paramount in determining acceptable accuracy levels for a wearable seizure detection device. We offer simulation results for determining and verifying utility for specific use case and specific wearable parameters.

Abstract Objective The factors that influence seizure timing are poorly understood, and seizure unpredictability remains a major cause of disability. Work in chronobiology has shown that cyclical physiological phenomena are ubiquitous, with daily and multiday cycles evident in immune, endocrine, metabolic, neurological, and cardiovascular function. Additionally, work with chronic brain recordings has identified that seizure risk is linked to daily and multiday cycles in brain activity. Here, we provide the first characterization of the relationships between the cyclical modulation of a diverse set of physiological signals, brain activity, and seizure timing. Methods In this cohort study, 14 subjects underwent chronic ambulatory monitoring with a multimodal wrist‐worn sensor (recording heart rate, accelerometry, electrodermal activity, and temperature) and an implanted responsive neurostimulation system (recording interictal epileptiform abnormalities and electrographic seizures). Wavelet and filter–Hilbert spectral analyses characterized circadian and multiday cycles in brain and wearable recordings. Circular statistics assessed electrographic seizure timing and cycles in physiology. Results Ten subjects met inclusion criteria. The mean recording duration was 232 days. Seven subjects had reliable electroencephalographic seizure detections (mean = 76 seizures). Multiday cycles were present in all wearable device signals across all subjects. Seizure timing was phase locked to multiday cycles in five (temperature), four (heart rate, phasic electrodermal activity), and three (accelerometry, heart rate variability, tonic electrodermal activity) subjects. Notably, after regression of behavioral covariates from heart rate, six of seven subjects had seizure phase locking to the residual heart rate signal. Significance Seizure timing is associated with daily and multiday cycles in multiple physiological processes. Chronic multimodal wearable device recordings can situate rare paroxysmal events, like seizures, within a broader chronobiology context of the individual. Wearable devices may advance the understanding of factors that influence seizure risk and enable personalized time‐varying approaches to epilepsy care.

AbstractFocal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD.We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization.FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques.Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Abstract Neuromodulation is a key therapeutic tool for clinicians managing patients with drug‐resistant epilepsy. Multiple devices are available with long‐term follow‐up and real‐world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS‐ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow‐up for all modalities, albeit in uncontrolled follow‐up or retrospective studies. A significant number of patients experience seizure‐free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved—DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Abstract This study describes a generalized cross‐patient seizure‐forecasting approach using recurrent neural networks with ultra‐long‐term subcutaneous EEG (sqEEG) recordings. Data from six patients diagnosed with refractory epilepsy and monitored with an sqEEG device were used to develop a generalized algorithm for seizure forecasting using long short‐term memory (LSTM) deep‐learning classifiers. Electrographic seizures were identified by a board‐certified epileptologist. One‐minute data segments were labeled as preictal or interictal based on their relationship to confirmed seizures. Data were separated into training and testing data sets, and to compensate for the unbalanced data ratio in training, noise‐added copies of preictal data segments were generated to expand the training data set. The mean and standard deviation (SD) of the training data were used to normalize all data, preserving the pseudo‐prospective nature of the analysis. Different architecture classifiers were trained and tested using a leave‐one‐patient‐out cross‐validation method, and the area under the receiver‐operating characteristic (ROC) curve (AUC) was used to evaluate the performance classifiers. The importance of each input signal was evaluated using a leave‐one‐signal‐out method with repeated training and testing for each classifier. Cross‐patient classifiers achieved performance significantly better than chance in four of the six patients and an overall mean AUC of 0.602 ± 0.126 (mean ± SD). A time in warning of 37.386% ± 5.006% (mean ± std) and sensitivity of 0.691 ± 0.068 (mean ± std) were observed for patients with better than chance results. Analysis of input channels showed a significant contribution ( p < .05) by the Fourier transform of signals channels to overall classifier performance. The relative contribution of input signals varied among patients and architectures, suggesting that the inclusion of all signals contributes to robustness in a cross‐patient classifier. These early results show that it is possible to forecast seizures training with data from different patients using two‐channel ultra‐long‐term sqEEG.