Freestone, Dean R.

Abstract There is debate on the predictive value of multiday seizure cycles versus simple statistical baselines. Multidien seizure cyclicity is a prevalent, patient‐specific phenomenon with promise for epilepsy management. We challenge the assertion that cycle tracking is no better than a moving average, which is an inherently retrospective model that lags changes in seizure likelihood. This commentary compared a causal cyclic forecast to a prospectively applied moving average across a large seizure diary cohort ( n = 768) and two gold‐standard chronic EEG cohorts ( n = 24). For the EEG and diary cohorts, cycle tracking demonstrated significantly superior accuracy to the moving average for both hourly and daily forecasts ( p < 0.0001), using multiple performance metrics. These results confirm that event‐based cyclical models offer more accurate, simulated real‐world forecasts. Robust forecasting tools must prioritize the detection and modeling of seizure cycles to move beyond simple baseline performance and provide actionable clinical utility.

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 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.

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.

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.