Pathophysiology Of Sudden Unexpected Death Research Articles

Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models.

Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of sudden and unexpected death in epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting the limitations of these models and the intrinsic difficulties of investigating SUDEP. The interpretation of preclinical data and their translation to diagnostic and therapeutic developments in patients thus require a high level of confidence in their relevance to model the human situation. Preclinical models of SUDEP are heterogeneous and include rodent and nonrodent species. A critical aspect is whether the animals have isolated seizures exclusively induced by a specific trigger, such as models where seizures are elicited by electrical stimulation, pharmacological intervention, or DBA mouse strains, or whether they suffer from epilepsy with spontaneous seizures, with or without spontaneous SUDEP, either of nongenetic epilepsy etiology or from genetically based developmental and epileptic encephalopathies. All these models have advantages and potential disadvantages, but it is important to be aware of these limitations to interpret data appropriately in a translational perspective. The majority of models with spontaneous seizures are of a genetic basis, whereas SUDEP cases with a genetic basis represent only a small proportion of the total number. In almost all models, cardiorespiratory arrest occurs during the course of the seizure, contrary to that in patients observed at the time of death, potentially raising the issue of whether we are studying models of SUDEP or models of periseizure death. However, some of these limitations are impossible to avoid and can in part be dependent on specific features of SUDEP, which may be difficult to model. Several preclinical tools are available to address certain gaps in SUDEP pathophysiology, which can be used to further validate current preclinical models.

Seizures Cause Prolonged Impairment of Ventilation, CO2 Chemoreception and Thermoregulation.

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1a R1407X/+ (Dravet syndrome; DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.

Diaphragmatic pacing for the prevention of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy is the leading cause of epilepsy related death. Currently, there are no reliable methods for preventing sudden unexpected death in epilepsy. The precise pathophysiology of sudden unexpected death in epilepsy is unclear; however, convergent lines of evidence suggest that seizure-induced respiratory arrest plays a central role. It is generally agreed that sudden unexpected death in epilepsy could be averted if the patient could be rapidly ventilated following the seizure. The diaphragm is a muscle in the chest which contracts to draw air into the lungs. Diaphragmatic pacing is a surgical intervention which facilitates normal ventilation in situations, such as spinal cord injury and sleep apnoea, in which endogenous respiration would be inadequate or non-existent. In diaphragmatic pacing, electrodes are implanted directly onto diaphragm or adjacent to the phrenic nerves which innervate the diaphragm. These electrodes are then rhythmically stimulated, thereby eliciting contractions of the diaphragm which emulate endogenous breathing. The goal of this study was to test the hypothesis that seizure-induced respiratory arrest and death can be prevented with diaphragmatic pacing. Our approach was to induce respiratory arrest using maximal electroshock seizures in adult, male, C57BL6 mice outfitted with EEG and diaphragmatic electrodes (n = 8 mice). In the experimental group, the diaphragm was stimulated to exogenously induce breathing. In the control group, no stimulation was applied. Breathing and cortical electrographic activity were monitored using whole body plethysmography and EEG, respectively. A majority of the animals that did not receive the diaphragmatic pacing intervention died of seizure-induced respiratory arrest. Conversely, none of the animals that received the diaphragmatic pacing intervention died. Diaphragmatic pacing improved postictal respiratory outcomes (two-way ANOVA, P < 0.001) and reduced the likelyhood of seizure-induced death (Fisher’s exact test, P = 0.026). Unexpectedly, diaphragmatic pacing did not instantly restore breathing during the postictal period, potentially indicating peripheral airway occlusion by laryngospasm. All diaphragmatically paced animals breathed at some point during the pacing stimulation. Two animals took their first breath prior to the onset of pacing and some animals had significant apnoeas after the pacing stimulation. Sudden unexpected death in epilepsy results in more years of potential life lost than any other neurological condition with the exception of stroke. By demonstrating that seizure-induced respiratory arrest can be prevented by transient diaphragmatic pacing in animal models we hope to inform the development of closed-loop systems capable of detecting and preventing sudden unexpected death in epilepsy.

SUDEP risk and autonomic dysfunction in genetic epilepsies

The underlying pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains unclear. This phenomenon is likely multifactorial, and there is considerable evidence that genetic factors play a role. There are certain genetic causes of epilepsy in which the risk of SUDEP appears to be increased relative to epilepsy overall. For individuals with pathogenic variants in genes including SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1 and DEPDC5, there are varying degrees of evidence to suggest an increased risk for sudden death. Why the risk for sudden death is higher is not completely clear; however, in many cases pathogenic variants in these genes are also associated with autonomic dysfunction, which is hypothesized as a contributing factor to SUDEP. We review the evidence for increased SUDEP risk for patients with epilepsy due to pathogenic variants in these genes, and also discuss what is known about autonomic dysfunction in these contexts.

Diverse Pathophysiology of Sudden Unexpected Death in Epilepsy in Children

Diverse Pathophysiology of Sudden Unexpected Death in Epilepsy in Children

Postictal generalized EEG suppression and postictal immobility: what do we know?

Despite representing the leading cause of epilepsy-related mortality, the pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains elusive. In this context, the identification of clinical markers of SUDEP assumes a great importance and has been the target of many studies aimed at stratifying patients' individual risk. Among the potentially most hazardous post-ictal phenomena observed following convulsive seizures in monitored SUDEP cases, postictal generalized EEG suppression and postictal immobility have attracted attention as potential SUDEP risk factors. In this manuscript, we review the current knowledge on postictal generalized EEG suppression and postictal immobility, aiming to identify their pathophysiological mechanisms, reported frequencies and associated clinical factors, and critically evaluate the evidence on their potential relevance as SUDEP risk markers.

Local brain activity persists during apparently generalized postictal EEG suppression.

Postictal generalized EEG suppression (PGES) frequently occurs after generalized convulsive seizures (GCS) and may be involved in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). It is usually determined using conventional scalp EEG which is likely to miss cerebral activity in deeper brain structures. Here, we examined intracranial EEG activity after GCS to unravel the pattern and extent of local brain activity during apparent PGES on scalp EEG (s-PGES). We retrospectively reviewed electroencephalographic data of people with chronic epilepsy who had GCS during presurgical video-EEG monitoring using simultaneous intracranial and scalp EEG (10-20 system) electrodes. Twenty-five GCS (20 with s-PGES) of 15 patients with an average number of 88±42 intracranial electrode contacts were included. The majority of GCS with s-PGES (18 of 20) displayed persisting or reemerging intracranial EEG activity during apparent PGES on scalp EEG. Three patterns were identified: Pattern 1 (11 GCS, 6 patients) consisted of continuous local interictal activity; Pattern 2 (5 GCS, 5 patients) displayed suppressed EEG activity at all intracranial contacts in the early phase of s-PGES, but reemerging local brain activity before s-PGES dissolved; and Pattern 3 (2 GCS, 2 patients) showed persistent local ictal activity during s-PGES. Persisting intracranial EEG activity at PGES onset on scalp EEG was present in 10±14% (range: 0 to 42%) of all intracranial contacts and mostly in the temporal lobe. Our results reveal that, during apparently generalized postictal EEG suppression, local brain activity persists or reemerges in most GCS. Possible implications of this localized neuronal activity in the context of SUDEP are discussed in the paper.

Postictal immobility and generalized EEG suppression are associated with the severity of respiratory dysfunction.

The pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains undetermined. Seizures are accompanied by respiratory dysfunction (RD). Postictal generalized electroencephalography (EEG) suppression (PGES) may follow generalized tonic-clonic seizures (GTCS). Following GTCS patients have impaired arousal and may be motionless. Patients with SUDEP are usually prone. Postictal immobility (PI) may contribute to SUDEP by not permitting repositioning of the head to allow unimpeded ventilation. To determine whether RD and/or ictal characteristics are associated with PI, we analyzed patients with GTCS in the epilepsy monitoring unit. We investigated for associations between PI duration and PGES, ictal/postictal oxygen saturation (SpO2 ), end-tidal CO2 (ETCO2 ), seizure localization, duration, and tonic and total convulsive phase duration. We investigated for linkage between PGES and these measures. Seventy patients with 181 GTCS and available SpO2 and/or ETCO2 data were studied. Simple linear regression analysis by seizures showed that PI duration was associated with peak periictal ETCO2 (p = 0.03), duration of oxygen desaturation (p = 0.005) and with SpO2 nadir (p = 0.02). PI duration was not associated with tonic, convulsive phase or total seizure duration. Analysis by patients also showed significant association of PI with RD. Duration of PI was longer following seizures with PGES (p < 0.001). PGES was not associated with the tonic, convulsive phase or total seizure duration. SpO2 nadir was lower in seizures with PGES (p = 0.046), ETCO2 peak change (p = 0.003) was higher, and duration of ETCO2 elevation (p = 0.03) was longer. Multivariable regression analysis showed that PGES and severe RD were associated with PI duration. The duration of PI and presence of PGES are associated with periictal RD. The duration of PI is also associated with the presence of PGES. Seizure duration or duration of the convulsive phase is not associated with PI or PGES. Interventions aimed at reversing impaired arousal and PI may reduce SUDEP risk.

P97. The pathophysiology of sudden unexpected death in epilepsy (SUDEP)

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in people suffering from chronic refractory epilepsy. The underlying pathophysiological mechanisms that are critically involved in SUDEP are still not well understood. Cardiac arrhythmia, depressed autonomic function after seizure activity and also seizure-related respiratory failure have been discussed to be part of the final cascade leading to SUDEP. This final cascade is thought to be triggered by the seizure activity resulting in dramatically elevated levels of epinephrine, norepinephrine as well as other regulatory hormones and neurotransmitters. However, not all cases of SUDEP are directly linked to a seizure suggesting that SUDEP is not an unitary event and most likely caused by multiple factors. We therefore analysed the respiratory patterns, heartbeat and arousals of patients in the epilepsy video-eeg monitoring unit (EMU), before and after the withdrawal of antiepileptic (AED). The frequency, variability of the breathing and heartbeat in correlation with the sleep-stages were analysed. Moreover, the respiratory pattern peri-ictal (before and following generalized tonic–clonic and complex partial seizures) were analyzed, since this period has been identified as the crucial time window for SUDEP.

Seizure-related autonomic changes in children.

Although sudden unexpected death in epilepsy is encountered less frequently in children versus adults, it is still an important direct epilepsy-related cause of death in this population. Just as in adults, the pathophysiology of sudden unexpected death in epilepsy in children is believed to involve seizure-related autonomic dysfunction. Seizures that develop during the pediatric period can be marked by some of the most dramatic alterations in autonomic functions seen at any age. This article reviews such seizure-related autonomic changes, including ictal nausea/emesis, hypersalivation, hypoxemia, apnea, tachycardia, bradycardia, cardiac repolarization anomalies, reduced heart rate variability, and postictal generalized EEG suppression. Understanding age-related changes in the autonomic effects of seizures and how they relate to risk of sudden death may help us to one day better elucidate the pathophysiology of sudden unexpected death in epilepsy. Given the high rate of sudden unexpected death in epilepsy in certain pediatric populations (such as those with Dravet syndrome), this knowledge is desperately needed.

High‐grade Atrioventricular Block Triggered by Spontaneous and Stimulation‐induced Epileptic Activity in the Left Temporal Lobe

Cardiac bradyarrhythmias may play a pivotal role in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). We describe a patient with left temporal lobe epilepsy in whom high-grade atrioventricular conduction blocks were triggered by both spontaneous and stimulation-induced epileptic activity in the left temporal lobe. Electrophysiological data obtained by surface and intracranial electrodes point to a cerebral cardioarrhythmogenesis in the left amygdala and anterior hippocampus.

Epilepsy and Activity of the Autonomic Nervous System.

Decrease of Sympathetic Cardiovascular Modulation after Temporal Lobe Epilepsy Surgery Hilz MJ, Devinsky O, Doyle W, Mauerer A, Dutsch M. Brain 2002;125(Pt 5):985–995 In temporal lobe epilepsy (TLE), there is evidence of ictal and interictal autonomic dysregulation, predominantly with sympathetic overactivity. The effects of TLE surgery on autonomic cardiovascular control and on baroreflex sensitivity (BRS) have not been studied. To evaluate such effects, we monitored heart rate (HR), systolic blood pressure [BP(sys)], and respiration in 18 TLE patients 3–4 months before and after TLE surgery. We used Blackman-Tukey spectral analysis to assess sympathetic and parasympathetic modulation as powers of HR and BP(sys) oscillations in the low-frequency (LF, 0.04–0.15 Hz) and high-frequency (HF, 0.15–0.5 Hz) bands. BRS was determined as the LF transfer function gain between BP and HR. After surgery, HR, BP(sys), respiration, and HF powers remained unchanged, whereas LF powers of HR [1.57 ± 1.54 beats/min( 2 )] and BP(sys) [2.19 ± 1.34 mm Hg( 2 )] and BRS (0.68 ± 0.31 beats/min/mm Hg) were smaller than presurgical LF powers of HR [3.87 ± 3.26 beats/min( 2 )] and BP(sys) [4.80 ± 3.84 mm Hg( 2 )] and BRS (1.12 ± 0.39 beasts/min/mm Hg; P &lt; 0.05). After TLE surgery, there is a reduction of sympathetic cardiovascular modulation and BRS that might result from decreased influences of interictal epileptogenic discharges on brain areas involved in cardiovascular autonomic control. TLE surgery seems to stabilize the cardiovascular control in epilepsy patients by reducing the risk of sympathetically mediated tachyarrhythmias and excessive brady-cardiac counterregulation, both of which might be relevant for the pathophysiology of sudden unexpected death in epilepsy patients (SUDEP). Thus TLE surgery might contribute to reducing the risk of SUDEP.