Pro-Ictal EEG Scheduling Improves the Yield of Epilepsy Monitoring: Validating the Use of Multiday Seizure Cycles to Optimize Video-EEG Timing.

OBJECTIVE: A significant challenge of video-electroencephalography (vEEG) in epilepsy diagnosis is timing monitoring sessions to capture epileptiform activity. In this study, we introduce and validate "pro-ictal EEG scheduling", a method to schedule vEEG monitoring to coincide with periods of increased seizure likelihood as a low-risk approach to enhance the diagnostic yield. METHODS: A database of long-term ambulatory vEEG monitoring sessions (n = 5,038) of adults and children was examined. Data from linked electronic seizure diaries were extracted (minimum 10 self-reported events) to generate cycle-based estimates of seizure risk. In adults, vEEG monitoring sessions coinciding with periods of estimated high-risk were allocated to the high-risk group (n = 305) and compared to remaining studies (baseline: n = 3,586). Test of proportions and risk-ratios (RR) were applied to index differences in proportions and likelihood of capturing outcome measures (abnormal report, confirmed seizure, and diary event) during monitoring. The impact of clinical and demographic factors (age, sex, epilepsy-type, and medication) was also explored. RESULTS: During vEEG monitoring, the high-risk group was significantly more likely to have an abnormal vEEG report (190/305:62% vs 1,790/3,586:50% [%change = 12%], RR = 1.25, 95% confidence interval [CI] = [1.137-1.370], p < 0.001), present with a confirmed seizure (56/305:18% vs 424/3,586:11% [%change = 7%], RR = 1.63, 95% CI = [1.265-2.101], p < 0.001) and report an event (153/305:50% vs 1,267/3,586:35% (%change = 15%), RR = 1.420, 95% CI = [1.259:1.602], p < 0.001). Similar effects were observed across clinical and demographic features. INTERPRETATION: This study provides the first large-scale validation of pro-ictal EEG scheduling in improving the yield of vEEG. This innovative approach offers a pragmatic and low-risk strategy to enhance the diagnostic capabilities of vEEG monitoring, significantly impacting epilepsy management. ANN NEUROL 2024.

Over- and underreporting of seizures: How big is the problem?

OBJECTIVE: Clinical decisions on managing epilepsy patients rely on patient accuracy regarding seizure reporting. Studies have noted disparities between patient-reported seizures and electroencephalographic (EEG) findings during video-EEG monitoring periods, chiefly highlighting underreporting of seizures, a well-recognized phenomenon. However, seizure overreporting is a significant problem discussed within the literature, although not in such a large cohort. Our aim is to quantify the over- and underreporting of seizures in a large cohort of ambulatory EEG patients. METHODS: We performed a retrospective data analysis on 3407 patients referred to a diagnostic service for ambulatory video-EEG between 2020 and 2022. Both patient-reported events and events discovered on review of the video-EEG were analyzed and classified as epileptic, psychogenic (typically clinical motor events, without accompanying EEG change), or noncorrelated events (NCEs; without perceivable clinical or EEG change). Events were analyzed by state of arousal and indication for referral. Subgroup analysis was performed in patients with focal and generalized epilepsies. RESULTS: A total of 21 024 events were recorded by 3407 patients. Fifty-eight percent of reported events were NCEs, whereas 27% of all events were epileptic. Sixty-four percent of epileptic seizures were not reported by the patient but discovered by the clinical service on review of the recording. NCEs were in the highest proportion in the awake and drowsy arousal states and were the most common event type for the majority of referral indications. Subgroup analysis found a significantly higher proportion of NCEs in the patients with focal epilepsy (23%) compared to generalized epilepsy (10%; p < .001, chi-squared proportion test). SIGNIFICANCE: Our results reaffirm the phenomenon of underreporting and highlight the prevalence of overreporting. Overreporting likely represents irrelevant symptoms or electrographic discharges not represented on scalp electrodes, identification of which has important clinical relevance. Future studies should analyze events by risk factors to elucidate relationships clinicians can use and investigate the etiology of NCEs.

Minimum clinical utility standards for wearable seizure detectors: A simulation study.

OBJECTIVE: Epilepsy 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. METHODS: Using 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. RESULTS: The 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. SIGNIFICANCE: The 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.

Sleep and seizure risk in epilepsy: bed and wake times are more important than sleep duration.

Sleep duration, sleep deprivation and the sleep-wake cycle are thought to play an important role in the generation of epileptic activity and may also influence seizure risk. Hence, people diagnosed with epilepsy are commonly asked to maintain consistent sleep routines. However, emerging evidence paints a more nuanced picture of the relationship between seizures and sleep, with bidirectional effects between changes in sleep and seizure risk in addition to modulation by sleep stages and transitions between stages. We conducted a longitudinal study investigating sleep parameters and self-reported seizure occurrence in an ambulatory at-home setting using mobile and wearable monitoring. Sixty subjects wore a Fitbit smartwatch for at least 28 days while reporting their seizure activity in a mobile app. Multiple sleep features were investigated, including duration, oversleep and undersleep, and sleep onset and offset times. Sleep features in participants with epilepsy were compared to a large (n = 37 921) representative population of Fitbit users, each with 28 days of data. For participants with at least 10 seizure days (n = 34), sleep features were analysed for significant changes prior to seizure days. A total of 4956 reported seizures (mean = 83, standard deviation = 130) and 30 485 recorded sleep nights (mean = 508, standard deviation = 445) were included in the study. There was a trend for participants with epilepsy to sleep longer than the general population, although this difference was not significant. Just 5 of 34 participants showed a significant difference in sleep duration the night before seizure days compared to seizure-free days. However, 14 of 34 subjects showed significant differences between their sleep onset (bed) and/or offset (wake) times before seizure occurrence. In contrast to previous studies, the current study found undersleeping was associated with a marginal 2% decrease in seizure risk in the following 48 h (P < 0.01). Nocturnal seizures were associated with both significantly longer sleep durations and increased risk of a seizure occurring in the following 48 h. Overall, the presented results demonstrated that day-to-day changes in sleep duration had a minimal effect on reported seizures, while patient-specific changes in bed and wake times were more important for identifying seizure risk the following day. Nocturnal seizures were the only factor that significantly increased the risk of seizures in the following 48 h on a group level. Wearables can be used to identify these sleep-seizure relationships and guide clinical recommendations or improve seizure forecasting algorithms.

Diagnostic utility of prolonged ambulatory video-electroencephalography monitoring.

OBJECTIVES: Ambulatory video-electroencephalography (video-EEG) represents a low-cost, convenient and accessible alternative to inpatient video-EEG monitoring, however few studies have examined their diagnostic yield. In this large-scale retrospective study conducted in Australia, we evaluated the efficacy of prolonged ambulatory video-EEG recordings in capturing diagnostic events and resolving the referring question. METHODS: Sequential adult and paediatric ambulatory video-EEG reports from April 2020 to June 2021 were reviewed retrospectively. Data collection included patient demographics, clinical information, and details of events and EEG abnormalities. Clinical utility was assessed by examining i) time to first diagnostic event, and ii) ability to resolve the referring questions - seizure localisation, quantification, classification, and differentiation (differentiating seizures from non-epileptic events). RESULTS: Of the 600 reports analysed, 49 % captured at least one event, and 45 % captured interictal abnormalities (epileptiform or non-epileptiform). Seizures, probable psychogenic events (mostly non-convulsive), and other non-epileptic events occurred in 13 %, 23 % and 21 % of recordings respectively, with overlap. Unreported events were captured in 53 (9 %) recordings, and unreported seizures represented more than half of all seizures captured (51 %, 392/773). Nine percent of events were missing clinical, video or electrographic data. A diagnostic event occurred in 244 (41 %) recordings, of which 14 % were captured between the fifth and eighth day of recording. Reported event frequency ≥ 1/week was the only significant predictor of diagnostic event capture. In recordings with both seizures and psychogenic events, unrecognized seizures were frequent, and seizures may be missed if recording is terminated early. The referring question was resolved in 85 % of reports with at least one event, and 53 % of all reports. Specifically, this represented 46 % of reports (235/512) for differentiation of events, and 75 % of reports (27/36) for classification of seizures. CONCLUSION: Ambulatory video-EEG recordings are of high diagnostic value in capturing clinically relevant events and resolving the referring clinical questions.

Feasibility and acceptability of an ultra-long-term at-home EEG monitoring system (EEG@HOME) for people with epilepsy.

BACKGROUND: Recent technological advancements offer new ways to monitor and manage epilepsy. The adoption of these devices in routine clinical practice will strongly depend on patient acceptability and usability, with their perspectives being crucial. Previous studies provided feedback from patients, but few explored the experience of them using independently multiple devices independently at home. PURPOSE: The study, assessed through a mixed methods design, the direct experiences of people with epilepsy independently using a non-invasive monitoring system (EEG@HOME) for an extended duration of 6 months, at home. We aimed to investigate factors affecting engagement, gather qualitative insights, and provide recommendations for future home epilepsy monitoring systems. MATERIALS AND METHODS: Adults with epilepsy independently were trained to use a wearable dry EEG system, a wrist-worn device, and a smartphone app for seizure tracking and behaviour monitoring for 6 months at home. Monthly acceptability questionnaires (PSSUQ, SUS) and semi-structured interviews were conducted to explore participant experience. Adherence with the procedure, acceptability scores and systematic thematic analysis of the interviews, focusing on the experience with the procedure, motivation and benefits and opinion about the procedure were assessed. RESULTS: Twelve people with epilepsy took part into the study for an average of 193.8 days (range 61 to 312) with a likelihood of using the system at six months of 83 %. The e-diary and the smartwatch were highly acceptable and preferred to a wearable EEG system (PSSUQ score of 1.9, 1.9, 2.4). Participants showed an acceptable level of adherence with all solutions (Average usage of 63 %, 66 %, 92 %) reporting more difficulties using the EEG twice a day and remembering to complete the daily behavioural questionnaires. Clear information and training, continuous remote support, perceived direct and indirect benefits and the possibility to have a flexible, tailored to daily routine monitoring were defined as key factors to ensure compliance with long-term monitoring systems. CONCLUSIONS: EEG@HOME study demonstrated people with epilepsy' interest and ability in active health monitoring using new technologies. Remote training and support enable independent home use of new non-invasive technologies, but to ensure long term acceptability and usability systems will require to be integrated into patients' routines, include healthcare providers, and offer continuous support and personalized feedback.

User experience of a seizure risk forecasting app: A mixed methods investigation.

OBJECTIVE: Over recent years, there has been a growing interest in exploring the utility of seizure risk forecasting, particularly how it could improve quality of life for people living with epilepsy. This study reports on user experiences and perspectives of a seizure risk forecaster app, as well as the potential impact on mood and adjustment to epilepsy. METHODS: Active app users were asked to complete a survey (baseline and 3-month follow-up) to assess perspectives on the forecast feature as well as mood and adjustment. Post-hoc, nine neutral forecast users (neither agreed nor disagreed it was useful) completed semi-structured interviews, to gain further insight into their perspectives of epilepsy management and seizure forecasting. Non-parametric statistical tests and inductive thematic analyses were used to analyse the quantitative and qualitative data, respectively. RESULTS: Surveys were completed by 111 users. Responders consisted of "app users" (n = 58), and "app and forecast users" (n = 53). Of the "app and forecast users", 40 % believed the forecast was accurate enough to be useful in monitoring for seizure risk, and 60 % adopted it for purposes like scheduling activities and helping mental state. Feeling more in control was the most common response to both high and low risk forecasted states. In-depth interviews revealed five broad themes, of which 'frustrations with lack of direction' (regarding their current epilepsy management approach), 'benefits of increased self-knowledge' and 'current and anticipated usefulness of forecasting' were the most common. SIGNIFICANCE: Preliminary results suggest that seizure risk forecasting can be a useful tool for people with epilepsy to make lifestyle changes, such as scheduling daily events, and experience greater feelings of control. These improvements may be attributed, at least partly, to the improvements in self-knowledge experienced through forecast use.

A cross-sectional investigation of cognition and epileptiform discharges in juvenile absence epilepsy.

OBJECTIVES: Despite the prevalence of cognitive symptoms in the idiopathic generalized epilepsies (IGEs), cognitive dysfunction in juvenile absence epilepsy (JAE), a common yet understudied IGE subtype, remains poorly understood. This descriptive study provides a novel, comprehensive characterization of cognitive functioning in a JAE sample and examines the relationship between cognition and 24-h epileptiform discharge load. METHOD: Forty-four individuals diagnosed with JAE underwent cognitive assessment using Woodcock Johnson III Test of Cognitive Abilities with concurrent 24-h ambulatory EEG monitoring. Generalized epileptiform discharges of any length, and prolonged generalized discharges ≥3 s were quantified across wakefulness and sleep. The relationship between standardized cognitive scores and epileptiform discharges was assessed through regression models. RESULTS: Cognitive performances in overall intellectual ability, acquired comprehension-knowledge, processing speed, long-term memory storage and retrieval, and executive processes were 0.63-1.07 standard deviation (SD) units lower in the JAE group compared to the population reference mean, adjusted for educational attainment. Prolonged discharges (≥3 s) were recorded in 20 patients (47.6%) from 42 available electroencephalography (EEG) studies and were largely unreported. Duration and number of prolonged discharges were associated with reduced processing speed and long-term memory storage and retrieval. SIGNIFICANCE: Cognitive dysfunction is seen in patients with JAE across various cognitive abilities, including those representing more stable processes like general intellect. During 24-h EEG, prolonged epileptiform discharges are common yet underreported in JAE despite treatment, and they show moderate effects on cognitive abilities. If epileptiform burden is a modifiable predictor of cognitive dysfunction, therapeutic interventions should consider quantitative 24-h EEG with routine neuropsychological screening. The growing recognition of the spectrum of neuropsychological comorbidities of IGE highlights the value of multidisciplinary approaches to explore the causes and consequences of cognitive deficits in epilepsy.

Perceived seizure risk in epilepsy: Chronic electronic surveys with and without concurrent electroencephalography.

OBJECTIVE: Previous studies suggested that patients with epilepsy might be able to forecast their own seizures. This study aimed to assess the relationships between premonitory symptoms, perceived seizure risk, and future and recent self-reported and electroencephalographically (EEG)-confirmed seizures in ambulatory patients with epilepsy in their natural home environments. METHODS: Long-term e-surveys were collected from patients with and without concurrent EEG recordings. Information obtained from the e-surveys included medication adherence, sleep quality, mood, stress, perceived seizure risk, and seizure occurrences preceding the survey. EEG seizures were identified. Univariate and multivariate generalized linear mixed-effect regression models were used to estimate odds ratios (ORs) for the assessment of the relationships. Results were compared with the seizure forecasting classifiers and device forecasting literature using a mathematical formula converting OR to equivalent area under the curve (AUC). RESULTS: Fifty-four subjects returned 10 269 e-survey entries, with four subjects acquiring concurrent EEG recordings. Univariate analysis revealed that increased stress (OR = 2.01, 95% confidence interval [CI] = 1.12-3.61, AUC = .61, p = .02) was associated with increased relative odds of future self-reported seizures. Multivariate analysis showed that previous self-reported seizures (OR = 5.37, 95% CI = 3.53-8.16, AUC = .76, p < .001) were most strongly associated with future self-reported seizures, and high perceived seizure risk (OR = 3.34, 95% CI = 1.87-5.95, AUC = .69, p < .001) remained significant when prior self-reported seizures were added to the model. No correlation with medication adherence was found. No significant association was found between e-survey responses and subsequent EEG seizures. SIGNIFICANCE: Our results suggest that patients may tend to self-forecast seizures that occur in sequential groupings and that low mood and increased stress may be the result of previous seizures rather than independent premonitory symptoms. Patients in the small cohort with concurrent EEG showed no ability to self-predict EEG seizures. The conversion from OR to AUC values facilitates direct comparison of performance between survey and device studies involving survey premonition and forecasting.

Seizure occurrence is linked to multiday cycles in diverse physiological signals.

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.

Deep learning for automated detection of generalized paroxysmal fast activity in Lennox-Gastaut syndrome.

OBJECTIVES: Generalized paroxysmal fast activity (GPFA) is a key electroencephalographic (EEG) feature of Lennox-Gastaut Syndrome (LGS). Automated analysis of scalp EEG has been successful in detecting more typical abnormalities. Automatic detection of GPFA has been more challenging, due to its variability from patient to patient and similarity to normal brain rhythms. In this work, a deep learning model is investigated for detection of GPFA events and estimating their overall burden from scalp EEG. METHODS: Data from 10 patients recorded during four ambulatory EEG monitoring sessions are used to generate and validate the model. All patients had confirmed LGS and were recruited into a trial for thalamic deep-brain stimulation therapy (ESTEL Trial). RESULTS: The correlation coefficient between manual and model estimates of event counts was r2 = 0.87, and for total burden was r2 = 0.91. The average GPFA detection sensitivity was 0.876, with an average false-positive rate of 3.35 per minute. There was no significant difference found between patients with early or delayed deep brain stimulation (DBS) treatment, or those with active vagal nerve stimulation (VNS). CONCLUSIONS: Overall, the deep learning model was able to accurately detect GPFA and provide accurate estimates of the overall GPFA burden and electrographic event counts, albeit with a high false-positive rate. SIGNIFICANCE: Automated GPFA detection may enable automated calculation of EEG biomarkers of burden of disease in LGS.

Seizure forecasting: Bifurcations in the long and winding road.

To date, the unpredictability of seizures remains a source of suffering for people with epilepsy, motivating decades of research into methods to forecast seizures. Originally, only few scientists and neurologists ventured into this niche endeavor, which, given the difficulty of the task, soon turned into a long and winding road. Over the past decade, however, our narrow field has seen a major acceleration, with trials of chronic electroencephalographic devices and the subsequent discovery of cyclical patterns in the occurrence of seizures. Now, a burgeoning science of seizure timing is emerging, which in turn informs best forecasting strategies for upcoming clinical trials. Although the finish line might be in view, many challenges remain to make seizure forecasting a reality. This review covers the most recent scientific, technical, and medical developments, discusses methodology in detail, and sets a number of goals for future studies.

Seizure forecasting using minimally invasive, ultra-long-term subcutaneous EEG: Generalizable cross-patient models.

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.

Ambient air pollution and epileptic seizures: A panel study in Australia.

OBJECTIVE: Emerging evidence has shown that ambient air pollution affects brain health, but little is known about its effect on epileptic seizures. This work aimed to assess the association between daily exposure to ambient air pollution and the risk of epileptic seizures. METHODS: This study used epileptic seizure data from two independent data sources (NeuroVista and Seer App seizure diary). In the NeuroVista data set, 3273 seizures were recorded using intracranial electroencephalography (iEEG) from 15 participants with refractory focal epilepsy in Australia in 2010-2012. In the seizure diary data set, 3419 self-reported seizures were collected through a mobile application from 34 participants with epilepsy in Australia in 2018-2021. Daily average concentrations of carbon monoxide (CO), nitrogen dioxide (NO2 ), ozone (O3 ), particulate matter ≤10 µm in diameter (PM10 ), and sulfur dioxide (SO2 ) were retrieved from the Environment Protection Authority (EPA) based on participants' postcodes. A patient-time-stratified case-crossover design with the conditional Poisson regression model was used to determine the associations between air pollutants and epileptic seizures. RESULTS: A significant association between CO concentrations and epileptic seizure risks was observed, with an increased seizure risk of 4% (relative risk [RR]: 1.04, 95% confidence interval [CI]: 1.01-1.07) for an interquartile range (IQR) increase of CO concentrations (0.13 parts per million), whereas no significant associations were found for the other four air pollutants in the whole study population. Female participants had a significantly increased risk of seizures when exposed to elevated CO and NO2 , with RRs of 1.05 (95% CI: 1.01-1.08) and 1.09 (95% CI: 1.01-1.16), respectively. In addition, a significant association was observed between CO and the risk of subclinical seizures (RR: 1.20, 95% CI: 1.12-1.28). SIGNIFICANCE: Daily exposure to elevated CO concentrations may be associated with an increased risk of epileptic seizures, especially for subclinical seizures.

Seizure forecasting using minimally invasive, ultra-long-term subcutaneous electroencephalography: Individualized intrapatient models.

OBJECTIVE: One of the most disabling aspects of living with chronic epilepsy is the unpredictability of seizures. Cumulative research in the past decades has advanced our understanding of the dynamics of seizure risk. Technological advances have recently made it possible to record pertinent biological signals, including electroencephalogram (EEG), continuously. We aimed to assess whether patient-specific seizure forecasting is possible using remote, minimally invasive ultra-long-term subcutaneous EEG. METHODS: We analyzed a two-center cohort of ultra-long-term subcutaneous EEG recordings, including six patients with drug-resistant focal epilepsy monitored for 46-230 days with median 18 h/day of recorded data, totaling >11 000 h of EEG. Total electrographic seizures identified by visual review ranged from 12 to 36 per patient. Three candidate subject-specific long short-term memory network deep learning classifiers were trained offline and pseudoprospectively on preictal (1 h before) and interictal (>1 day from seizures) EEG segments. Performance was assessed relative to a random predictor. Periodicity of the final forecasts was also investigated with autocorrelation. RESULTS: Depending on each architecture, significant forecasting performance was achieved in three to five of six patients, with overall mean area under the receiver operating characteristic curve of .65-.74. Significant forecasts showed sensitivity ranging from 64% to 80% and time in warning from 10.9% to 44.4%. Overall, the output of the forecasts closely followed patient-specific circadian patterns of seizure occurrence. SIGNIFICANCE: This study demonstrates proof-of-principle for the possibility of subject-specific seizure forecasting using a minimally invasive subcutaneous EEG device capable of ultra-long-term at-home recordings. These results are encouraging for the development of a prospective seizure forecasting trial with minimally invasive EEG.

Machine learning and wearable devices of the future.

Machine learning (ML) is increasingly recognized as a useful tool in healthcare applications, including epilepsy. One of the most important applications of ML in epilepsy is seizure detection and prediction, using wearable devices (WDs). However, not all currently available algorithms implemented in WDs are using ML. In this review, we summarize the state of the art of using WDs and ML in epilepsy, and we outline future development in these domains. There is published evidence for reliable detection of epileptic seizures using implanted electroencephalography (EEG) electrodes and wearable, non-EEG devices. Application of ML using the data recorded with WDs from a large number of patients could change radically the way we diagnose and manage patients with epilepsy.

Cycles of self-reported seizure likelihood correspond to yield of diagnostic epilepsy monitoring.

OBJECTIVE: Video-electroencephalography (vEEG) is an important component of epilepsy diagnosis and management. Nevertheless, inpatient vEEG monitoring fails to capture seizures in up to one third of patients. We hypothesized that personalized seizure forecasts could be used to optimize the timing of vEEG. METHODS: We used a database of ambulatory vEEG studies to select a cohort with linked electronic seizure diaries of more than 20 reported seizures over at least 8 weeks. The total cohort included 48 participants. Diary seizure times were used to detect individuals' multiday seizure cycles and estimate times of high seizure risk. We compared whether estimated seizure risk was significantly different between conclusive and inconclusive vEEGs, and between vEEG with and without recorded epileptic activity. vEEGs were conducted prior to self-reported seizures; hence, the study aimed to provide a retrospective proof of concept that cycles of seizure risk were correlated with vEEG outcomes. RESULTS: Estimated seizure risk was significantly higher for conclusive vEEGs and vEEGs with epileptic activity. Across all cycle strengths, the average time in high risk during vEEG was 29.1% compared with 14% for the conclusive/inconclusive groups and 32% compared to 18% for the epileptic activity/no epileptic activity groups. On average, 62.5% of the cohort showed increased time in high risk during their previous vEEG when epileptic activity was recorded (compared to 28% of the cohort where epileptic activity was not recorded). For conclusive vEEGs, 50% of the cohort had increased time in high risk, compared to 21.5% for inconclusive vEEGs. SIGNIFICANCE: Although retrospective, this study provides a proof of principle that scheduling monitoring times based on personalized seizure risk forecasts can improve the yield of vEEG. Forecasts can be developed at low cost from mobile seizure diaries. A simple scheduling tool to improve diagnostic outcomes may reduce cost and risks associated with delayed or missed diagnosis in epilepsy.

Signal quality and power spectrum analysis of remote ultra long-term subcutaneous EEG.

OBJECTIVE: Ultra long-term subcutaneous electroencephalography (sqEEG) monitoring is a new modality with great potential for both health and disease, including epileptic seizure detection and forecasting. However, little is known about the long-term quality and consistency of the sqEEG signal, which is the objective of this study. METHODS: The largest multicenter cohort of sqEEG was analyzed, including 14 patients with epilepsy and 12 healthy subjects, implanted with a sqEEG device (24/7 EEG™ SubQ), and recorded from 23 to 230 days (median 42 days), with a median data capture rate of 75% (17.9 hours/day). Median power spectral density plots of each subject were examined for physiological peaks, including at diurnal and nocturnal periods. Long-term temporal trends in signal impedance and power spectral features were investigated with subject-specific linear regression models and group-level linear mixed-effects models. RESULTS: sqEEG spectrograms showed an approximate 1/f power distribution. Diurnal peaks in the alpha range (8-13Hz) and nocturnal peaks in the sigma range (12-16Hz) were seen in the majority of subjects. Signal impedances remained low, and frequency band powers were highly stable throughout the recording periods. SIGNIFICANCE: The spectral characteristics of minimally invasive, ultra long-term sqEEG are similar to scalp EEG, whereas the signal is highly stationary. Our findings reinforce the suitability of this system for chronic implantation on diverse clinical applications, from seizure detection and forecasting to brain-computer interfaces.

Computer-assisted EEG diagnostic review for idiopathic generalized epilepsy.

Epilepsy diagnosis can be costly, time-consuming, and not uncommonly inaccurate. The reference standard diagnostic monitoring is continuous video-electroencephalography (EEG) monitoring, ideally capturing all events or concordant interictal discharges. Automating EEG data review would save time and resources, thus enabling more people to receive reference standard monitoring and also potentially heralding a more quantitative approach to therapeutic outcomes. There is substantial research into the automated detection of seizures and epileptic activity from EEG. However, automated detection software is not widely used in the clinic, and despite numerous published algorithms, few methods have regulatory approval for detecting epileptic activity from EEG. This study reports on a deep learning algorithm for computer-assisted EEG review. Deep convolutional neural networks were trained to detect epileptic discharges using a preexisting dataset of over 6000 labelled events in a cohort of 103 patients with idiopathic generalized epilepsy (IGE). Patients underwent 24-hour ambulatory outpatient EEG, and all data were curated and confirmed independently by two epilepsy specialists (Seneviratne et al., 2016). The resulting automated detection algorithm was then used to review diagnostic scalp EEG for seven patients (four with IGE and three with events mimicking seizures) to validate performance in a clinical setting. The automated detection algorithm showed state-of-the-art performance for detecting epileptic activity from clinical EEG, with mean sensitivity of >95% and corresponding mean false positive rate of 1 detection per minute. Importantly, diagnostic case studies showed that the automated detection algorithm reduced human review time by 80%-99%, without compromising event detection or diagnostic accuracy. The presented results demonstrate that computer-assisted review can increase the speed and accuracy of EEG assessment and has the potential to greatly improve therapeutic outcomes. This article is part of the Special Issue "NEWroscience 2018".

Forecasting cycles of seizure likelihood.

OBJECTIVE: Seizure unpredictability is rated as one of the most challenging aspects of living with epilepsy. Seizure likelihood can be influenced by a range of environmental and physiological factors that are difficult to measure and quantify. However, some generalizable patterns have been demonstrated in seizure onset. A majority of people with epilepsy exhibit circadian rhythms in their seizure times, and many also show slower, multiday patterns. Seizure cycles can be measured using a range of recording modalities, including self-reported electronic seizure diaries. This study aimed to develop personalized forecasts from a mobile seizure diary app. METHODS: Forecasts based on circadian and multiday seizure cycles were tested pseudoprospectively using data from 50 app users (mean of 109 seizures per subject). Individuals' strongest cycles were estimated from their reported seizure times and used to derive the likelihood of future seizures. The forecasting approach was validated using self-reported events and electrographic seizures from the Neurovista dataset, an existing database of long-term electroencephalography that has been widely used to develop forecasting algorithms. RESULTS: The validation dataset showed that forecasts of seizure likelihood based on self-reported cycles were predictive of electrographic seizures for approximately half the cohort. Forecasts using only mobile app diaries allowed users to spend an average of 67.1% of their time in a low-risk state, with 14.8% of their time in a high-risk warning state. On average, 69.1% of seizures occurred during high-risk states and 10.5% of seizures occurred in low-risk states. SIGNIFICANCE: Seizure diary apps can provide personalized forecasts of seizure likelihood that are accurate and clinically relevant for electrographic seizures. These results have immediate potential for translation to a prospective seizure forecasting trial using a mobile diary app. It is our hope that seizure forecasting apps will one day give people with epilepsy greater confidence in managing their daily activities.