Post-ictal Generalized EEG Suppression Duration Research Articles

Post-ictal Generalized EEG Suppression is reduced by Enhancing Dorsal Raphe Serotonergic Neurotransmission

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. A proposed risk marker for SUDEP is the duration of post-ictal generalized EEG suppression (PGES). The mechanisms underlying PGES are unknown. Serotonin (5-HT) has been implicated in SUDEP pathophysiology. Seizures suppress activity of 5-HT neurons in the dorsal raphe nucleus (DRN). We hypothesized that suppression of DRN 5-HT neuron activity contributes to PGES and increasing 5-HT neurotransmission or stimulating the DRN before a seizure would decrease PGES duration. Adult C57BL/6J and Pet1-Cre mice received EEG/EMG electrodes, a bipolar stimulating/recording electrode in the right basolateral amygdala, and either a microdialysis guide cannula or an injection of adeno-associated virus (AAV) allowing expression of channelrhodopsin2 plus an optic fiber into the DRN. Systemic application of the selective 5-HT reuptake inhibitor citalopram (20 mg/kg) decreased PGES duration from seizures induced during wake (n = 23) and non-rapid eye movement (NREM) sleep (n = 13) whereas fluoxetine (10 mg/kg) pretreatment decreased PGES duration following seizures induced from wake (n = 11), but not NREM sleep (n = 9). Focal chemical (n = 6) or optogenetic (n = 8) stimulation of the DRN reduced PGES duration following seizures in kindled mice induced during wake. During PGES, animals exhibited immobility and suppression of EEG activity that was reduced by citalopram pretreatment. These results suggest 5-HT and the DRN may regulate PGES.

Cross-Frequency Coupling Features of Postictal Generalized EEG Suppression State.

In patients with epilepsy, convulsive seizures are often followed by a postictal generalized EEG suppression (PGES) state characterized by reduced background activity. Recent studies found a correlation between seizure termination state and PGES duration, and suggested that PGES is the result of the cessation of neuronal activity. To test that assertion, we investigated ten seizure records obtained from intracranial EEG (iEEG) from six patients, four of which had Engel Class 1 surgical outcome. In each case expert neurologists identified the most likely seizure onset electrode. We found the iEEG equivalent of PGES and an artifact-free preictal quiescent state of the same window size. Using index of cross-frequency coupling (ICFC) we identified the degree of coupling and dominant frequency bands involved in PGES and preictal quiescent states, and quantified the areas of high ICFC. We found that there was an increase in the degree of coupling between the 0.5-1.5Hz with high gamma frequency bands in the PGES states. We found that among all of the patients, as well as in Engel Class 1 patients specifically, the change in the quantified area of high ICFC was significant (p <; 0.05) between PGES and preictal quiescent states. Furthermore, we were able to identify whether a recording was from a depth or subdural electrode, or whether it was from seizure onset zone or not using ICFC markers in PGES. This suggests that there are frequency coupling markers that successfully identify PGES and that there are underlying dynamics that occur in this seemingly quiet postictal state.

Dynamics of convulsive seizure termination and postictal generalized EEG suppression.

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.

Autonomic changes following generalized tonic clonic seizures: An analysis of adult and pediatric patients with epilepsy

ObjectiveSudden unexpected death in epilepsy (SUDEP) is the most common cause of mortality directly related to epilepsy. Its incidence is higher in adult patients and its pathophysiology remains poorly understood, but likely involves autonomic dysregulation following generalized tonic clonic seizures (GTCS). In the current study, we aimed to analyze post-ictal autonomic changes following GTCS in adult and pediatric patients. MethodsPatients admitted to the epilepsy monitoring unit were prospectively recruited, and wore an electrodermal activity (EDA) wrist sensor that continuously measured sympathetic activity while being monitored with EEG and EKG electrodes. Peri-ictal EDA parameters were assessed as a measure of sympathetic activity. Peri-ictal parasympathetic activity was determined through the high frequency component (HF) analysis of heart rate variability (HRV). The duration of post-ictal generalized EEG suppression (PGES) was also documented. ResultsTwenty patients with GTCS were included in the study on whom 30 GTCS were recorded. PGES duration strongly correlated with age (r=0.62, p=0.004) and measures of the EDA response. After controlling for PGES duration, we found pediatric patients had greater sympathetic activation measured as log rising portion of the area under the curve of the EDA response (β=+0.67, p=0.034) and a higher degree of vagal suppression measured as maximal percentage change of HF power (β=−12.65, p=0.0036). ConclusionSympathetic activity can be measured in the peri-ictal period, and directly correlates with PGES duration. Age is a significant determinant of the sympathetic and parasympathetic response following a GTCS; given the same PGES duration, pediatric patients demonstrate stronger sympathetic activation and higher vagal suppression. However, the increase in PGES duration with age and the associated autonomic dysregulation may provide clues as to why there is a variable vulnerability to SUDEP across age groups.

Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition

tonic–clonic seizures (GTCSs) and 19 out of 22 (86%) complex partial seizures (CPS) were accompanied by significant increases in EDA, more than 2 standard deviations above the preictal baseline [2]. While responses for GTCSs are usually higher than those for CPS, the size of the EDA response was not associatedwith the length of the seizure nor was it associated with the duration of the motor component in GTCSs [2]. Combining EDA data with motion data improved the accuracy of automated GTCS detection [3]. We have examined the relationship between EDA response during GTCSs and postictal generalized EEG suppression (PGES). The duration of PGES is a potential biomarker of SUDEP. Postictal generalized EEG suppression was found in all monitored cases of SUDEP in the MORTEMUS study [4]. Our studies in a pediatric population with treatment-resistant epilepsy showed that longer PGES correlates with larger EDA response during GTCSs [2]. This finding was replicated in a larger cohort, including children and adults, at another hospital [5]. Thus, EDA on the wrist provides a strong correlate to PGES duration. Altered autonomic function is considered by many to be among the mechanisms that lead to SUDEP [6]. In addition to the EDAfindings, our studies showed decreased heart rate variability associated with longer duration of PGES, which is also consistent with autonomic disruption. Respiratory arrest is inducible in humans by electrical stimulation of the amygdala during the expiratory phase of the respiratory cycle [7]. Stimulation of the amygdala in patients with epilepsy can produce a very strong ipsilateral EDA response [1]. We encourage more clinical studies to collect and examine autonomic data in epilepsy, especially since it can nowbe easily collected.