Gregg, Nicholas M

Abstract Deep brain stimulation and responsive neurostimulation (RNS) use high‐frequency stimulation (HFS) per the pivotal trials and manufacturer‐recommended therapy protocols. However, not all patients respond to HFS. In this retrospective case series, 10 patients implanted with the RNS System were programmed with low‐frequency stimulation (LFS) to treat their seizures; nine of these patients were previously treated with HFS (100 Hz or greater). LFS was defined as frequency < 10 Hz. Burst duration was increased to at least 1000 ms. With HFS, patients had a median seizure reduction (MSR) of 13% (interquartile range [IQR] = −67 to 54) after a median of 19 months (IQR = 8–49). In contrast, LFS was associated with a 67% MSR (IQR = 13–95) when compared to HFS and 76% MSR (IQR = 43–91) when compared to baseline prior to implantation. Charge delivered per hour and pulses per day were not significantly different between HFS and LFS, although time stimulated per day was longer for LFS (228 min) than for HFS (7 min). There were no LFS‐specific adverse effects reported by any of the patients. LFS could represent an alternative, effective method for delivering stimulation in focal drug‐resistant epilepsy patients treated with the RNS System.

AbstractTo 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.

Abstract Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioural inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behaviour and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a handheld device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from nine humans and eight canines with epilepsy, and then implemented prospectively in out-of-sample testing in two pet canines and four humans with drug-resistant epilepsy living in their natural environments. Accurate seizure diaries are needed as the primary clinical outcome measure of epilepsy therapy and to guide brain-stimulation optimization. The brain co-processor system described here enables tracking interictal epileptiform spikes, seizures and correlation with patient behavioural reports. In the future, correlation of spikes and seizures with behaviour will allow more detailed investigation of the clinical impact of spikes and seizures on patients.

AbstractThere is a paucity of data to guide anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) with brain sensing. The clinical Medtronic Percept DBS device provides constrained brain sensing power within a frequency band (power‐in‐band [PIB]), recorded in 10‐min averaged increments. Here, four patients with temporal lobe epilepsy were implanted with an investigational device providing full bandwidth chronic intracranial electroencephalogram (cEEG) from bilateral ANT and hippocampus (Hc). ANT PIB‐based seizure detection was assessed. Detection parameters were cEEG PIB center frequency, bandwidth, and epoch duration. Performance was evaluated against epileptologist‐confirmed Hc seizures, and assessed by area under the precision‐recall curve (PR‐AUC). Data included 99 days of cEEG, and 20, 278, 3, and 18 Hc seizures for Subjects 1–4. The best detector had 7‐Hz center frequency, 5‐Hz band width, and 10‐s epoch duration (group PR‐AUC = .90), with 75% sensitivity and .38 false alarms per day for Subject 1, and 100% and .0 for Subjects 3 and 4. Hc seizures in Subject 2 did not propagate to ANT. The relative change of ANT PIB was maximal ipsilateral to seizure onset for all detected seizures. Chronic ANT and Hc recordings provide direct guidance for ANT DBS with brain sensing.

Abstract Noninvasive wearable devices have great potential to aid the management of epilepsy, but these devices must have robust signal quality, and patients must be willing to wear them for long periods of time. Automated machine learning classification of wearable biosensor signals requires quantitative measures of signal quality to automatically reject poor‐quality or corrupt data segments. In this study, commercially available wearable sensors were placed on patients with epilepsy undergoing in‐hospital or in‐home electroencephalographic (EEG) monitoring, and healthy volunteers. Empatica E4 and Biovotion Everion were used to record accelerometry (ACC), photoplethysmography (PPG), and electrodermal activity (EDA). Byteflies Sensor Dots were used to record ACC and PPG, the Activinsights GENEActiv watch to record ACC, and Epitel Epilog to record EEG data. PPG and EDA signals were recorded for multiple days, then epochs of high‐quality, marginal‐quality, or poor‐quality data were visually identified by reviewers, and reviewer annotations were compared to automated signal quality measures. For ACC, the ratio of spectral power from 0.8 to 5 Hz to broadband power was used to separate good‐quality signals from noise. For EDA, the rate of amplitude change and prevalence of sharp peaks significantly differentiated between good‐quality data and noise. Spectral entropy was used to assess PPG and showed significant differences between good‐, marginal‐, and poor‐quality signals. EEG data were evaluated using methods to identify a spectral noise cutoff frequency. Patients were asked to rate the usability and comfort of each device in several categories. Patients showed a significant preference for the wrist‐worn devices, and the Empatica E4 device was preferred most often. Current wearable devices can provide high‐quality data and are acceptable for routine use, but continued development is needed to improve data quality, consistency, and management, as well as acceptability to patients.

Abstract Advances in ambulatory intracranial EEG devices have enabled objective analyses of circadian and multiday seizure periodicities, and seizure clusters in humans. This study characterizes circadian and multiday seizure periodicities, and seizure clusters in dogs with naturally occurring focal epilepsy, and considers the implications of an animal model for the study of seizure risk patterns, seizure forecasting and personalized treatment protocols. In this retrospective cohort study, 16 dogs were continuously monitored with ambulatory intracranial EEG devices designed for humans. Detailed medication records were kept for all dogs. Seizure periodicity was evaluated with circular statistics methods. Circular non-uniformity was assessed for circadian, 7-day and approximately monthly periods. The Rayleigh test was used to assess statistical significance, with correction for multiple comparisons. Seizure clusters were evaluated with Fano factor (index of dispersion) measurements, and compared to a Poisson distribution. Relationships between interseizure interval (ISI) and seizure duration were evaluated. Six dogs met the inclusion criteria of having at least 30 seizures and were monitored for an average of 65 weeks. Three dogs had seizures with circadian seizure periodicity, one dog had a 7-day periodicity, and two dogs had approximately monthly periodicity. Four dogs had seizure clusters and significantly elevated Fano factor values. There were subject-specific differences in the dynamics of ISI and seizure durations, both within and between lead and clustered seizure categories. Our findings show that seizure timing in dogs with naturally occurring epilepsy is not random, and that circadian and multiday seizure periodicities, and seizure clusters are common. Circadian, 7-day, and monthly seizure periodicities occur independent of antiseizure medication dosing, and these patterns likely reflect endogenous rhythms of seizure risk.