Seizures, Epilepsy, and SUDEP: A Change of Heart?

Abstract

CommentarySudden unexpected death in epilepsy (SUDEP) is defined by the sudden, unexplainable death of an individual with epilepsy and accounts for approximately 17% of epilepsy-related deaths. Patients with longstanding epilepsy characterized by frequent generalized tonic-clonic seizures that are relatively poorly controlled appear to be at highest risk. Physiological factors that may contribute to SUDEP include peri-ictal, centrally-originating autonomic irregularities leading to cardiac and respiratory arrest. Electrocardiographic abnormalities characterized mainly by rhythm and repolarization changes, including prolonged QT interval, are also associated with the occurrence of generalized seizures in patients with epilepsy and may contribute to SUDEP, especially when it occurs postictally (1). Similar to clinical reports, arrhythmias associated with altered cardiac Na + channel function have been demonstrated in rodent epilepsy models, including the kainate-induced status epilepticus model of temporal lobe epilepsy (TLE) (2), but the mechanisms supporting these changes were previously undescribed. Biet and colleagues investigated epilepsy-related changes in several Na + currents that underlie action potential repolarization and timing in cardiomyocytes as they relate to cardiac conduction and excitability. Significant functional and molecular cardiac channel remodeling was detected in conjunction with development of spontaneous seizures in the TLE model, consistent with epilepsy-induced overexpression of a neuronal Na + channel isoform in cardiomyocytes, which predispose to an increase in QT interval.Normally, cardiomyocyte action potential generation and inactivation are tightly regulated in order to maintain appropriate cardiac contraction rhythms. As in central neurons, cardiac action potentials are mediated by Na + currents, although neuronal and cardiomyocyte Na + currents differ in their kinetics and are composed of different channel isoforms. Cardiac Na + currents are mediated mainly by a relatively tetrodotoxin (TTX)-insensitive Na + channel isoform, Na V 1.5, encoded by the SCNA5 gene, which imparts relatively fast activation and inactivation kinetics. Normally, Na + currents and action potentials in neurons are mediated by a TTX-sensitive Na + channel isoform, Na V 1.1, which has somewhat slower kinetics and is encoded by the SCNA1 gene. Using electrophysiological recordings in vitro, the authors found that action potential duration was increased in cardiomyocytes from epileptic rats, and TTX was more potent in reducing action potential duration and peak Na + current amplitude in epileptic rats than in controls. Activation threshold was also hyperpolarized relative to controls. Interestingly, these changes were very similar to Na + current increases reported in hippocampal neurons from spontaneously epileptic rats (3). Increased activation of a late Na + (Na L ) current tends to increase cardiac action potential duration, which can result physiologically in increased QT interval that can lead to lon...

Perampanel: Does it have broad‐spectrum potential?

“…Drug‐resistant epilepsy can lead to increased morbidity and mortality, as well as social disability . Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy‐related cause of death, accounting for approximately 17% of epilepsy‐related mortality . The primary risk factor for SUDEP is recurrent generalized tonic–clonic (GTC) seizures, with odds ratios of 2.94 for 1‐2 seizures/year, 8.28 for 3‐12 seizures/year, 9.06 for 13‐50 seizures/year, and 14.51 for >50 seizures/year .…”

“…[24][25][26] Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death, 18 accounting for approximately 17% of epilepsy-related mortality. 27 The primary risk factor for SUDEP is recurrent generalized tonicclonic (GTC) seizures, with odds ratios of 2.94 for 1-2 seizures/year, 8.28 for 3-12 seizures/year, 9.06 for seizures/year, and 14.51 for >50 seizures/year. 28 Other risk factors include long duration of epilepsy, young age at onset, nocturnal seizures, lack of seizure control, and polytherapy.…”

The Association of Nocturnal Seizures and Interictal Cardiac/Central Autonomic Function in Frontal Lobe Epilepsy: Heart Rate Variability and Central Autonomic Network Analysis

“…The autonomic nervous system modulates cardiorespiratory function, and its dysfunctions are associated with sudden death in cardiac disease. [5][6][7] Repetitive seizures in people with epilepsy may promote cardiorespiratory dysregulation and subsequent fatal cardiac arrhythmia and respiratory failure. 8 The cardiac autonomic nervous system is modulated by the central autonomic network (CAN), which integrates afferent cardiac autonomic information.…”

Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

“…Considering the diverse patient population affected, SUDEP is likely influenced by multiple factors; however, in all cases the final event that causes death is likely to be cardiac and/or respiratory failure. Cardiac dysfunction has long been considered a likely cause of death, as arrhythmias are the cause of many other forms of sudden death (Huikuri et al, 2001;Srinivasan and Schilling, 2018), cardiac rhythm disturbances are often associated with seizures (Schraeder and Lathers, 1989;Nashef et al, 1996;Langan et al, 2000;So et al, 2000), and some long QT gene mutations have been linked to SUDEP (Johnson et al, 2009;Tiron et al, 2015;Auerbach et al, 2016;Smith, 2016).…”