Seizures, Cerebral Shutdown, and SUDEP

Abstract

In Clinical ResearchThere is strong evidence to suggest that sudden unexpected death in epilepsy (SUDEP) is a seizure-related phenomenon (1-5). The agonal pathophysiological processes in SUDEP are likely to begin during, or in the immediate aftermath of, a seizure. However, potential mechanisms are speculative. Epidemiological studies have consistently pointed to the generalized tonic-clonic seizure as the seizure type most commonly associated with SUDEP (6, 7), and almost all SUDEP reports of deaths during monitoring have occurred after generalized tonic-clonic seizures, (8-11) and often during sleep (3,12). This seizure type is associated with more severe obtundation of sensorium in the postictal period and can be associated with cardiorespiratory dysfunction during this time. Several questions arise: How do seizures terminate, and how do termination mechanisms relate to postictal arousal? Is the extent of obtundation and subsequent postictal arousal different in the frequent generalized tonic-clonic seizures of patients with chronic intractable epilepsy at high risk of SUDEP? Does postictal arousal differ according to the sleep-wake state at the time of seizure onset? Is postictal failure of arousal the same as the "cerebral shutdown" phenomenon seen on EEG? These questions remain unanswered. Seizure Termination and the Postictal StateThe generalized tonic-clonic seizure is usually characterized by generalized tonic posturing, a phase of tremulousness or "vibration" followed by a generalized clonic phase and, usually, seizure termination within the first 2 minutes of the clinical onset of generalization (13). In some genetic generalized epilepsies (e.g., juvenile myoclonic epilepsy), there may be generalized myoclonic jerking before the tonic phase; in secondarily generalized seizures, there may be a pretonic phase where version or "figure 4" posturing occurs. However, given this relative stereotypy, there is considerable clinical as well as electrographic heterogeneity in the postictal period (14, 15). Some patients recover quickly, while others have varying periods of postictal stupor. Some have brief periods of focal or generalized EEG slowing, while others have prolonged postictal generalized EEG suppression (PGES) and recovery to baseline can sometimes take many hours. Whether this postictal electroclinical heterogeneity aids SUDEP risk-stratification is debated (9, 16). Undoubtedly, there are a number of potential influences, including those of medication effects, but none have been systematically studied. Postictal Generalized EEG Suppression and "Cerebral Shutdown"PGES occurs in between 8% of pediatric seizure patients (17) to 65% or more of adult patients with generalized motor seizures (9) and has been reported in several monitored SUDEP/near SUDEP cases (8-11, 18, 19) where some authors have used the term "cerebral shutdown" (19). Prolonged PGES may be an independent risk factor for SUDEP, but whether it is a surrogate marker or a direct index of cerebral and brainstem dysregulation is unclear. It...

SUDEP in the North American SUDEP Registry

“…For some, a perfect storm of sleep state, altered reduced sympathetic activity, serotonin circadian cycling, and more prolonged postictal generalized EEG suppression leading to cerebral shutdown may combine to impair autonomic function, arousal, and respiration, making SUDEP more likely with seizures during sleep. 35,36…”

Serotonin neurones have anti‐convulsant effects and reduce seizure‐induced mortality

“…In addition to cardiac and respiratory aetiologies for SUDEP, PGES has been proposed to play a role in causing death (Bozorgi & Lhatoo, ). The exact mechanisms of PGES are not known, but there are several possibilities.…”

Decreased heart rate and enhanced sinus arrhythmia during interictal sleep demonstrate autonomic imbalance in generalized epilepsy

“…The closure of this critical gap in understanding has been suggested by researchers (Kothare and Singh 2014) as essential to obtaining a complete picture of autonomic regulation in epilepsy. This, in turn, would better inform us on the physiological mechanisms of sudden unexpected death in epilepsy (SUDEP) (Bozorgi and Lhatoo 2013;Lhatoo et al 2015;Moghimi and Lhatoo 2013) and improve the efficacy of risk factors used to provide clinical prognoses for both epilepsy and SUDEP (Lhatoo et al 2015;Varon et al 2015b).…”