An electroclinical case-control study of sudden unexpected death in epilepsy

Lhatoo SD, Faulkner HJ, Dembny K, et al. (2010) An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol. 2010 Dec;68(6):787-96.

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Abstract: OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) accounts for approximately 1 in 5 deaths in patients with epilepsy, but its cause remains unexplained. A recorded seizure resulting in death in our center appeared to suggest that postictal generalized electroencephalographic (EEG) suppression (PGES) and apnea are implicated in SUDEP. Our objective was to determine the association between PGES, as a possible identifiable EEG marker of profound postictal cerebral dysfunction, and SUDEP. METHODS: We studied 10 adult patients from our video-telemetry database who had 30 documented epileptic seizures during video-EEG recording and who later died of SUDEP. They were compared with 30 matching live controls with 92 epileptic seizures taken from the same database. Clinical and EEG findings were analyzed. RESULTS: PGES was seen in 15/30 (50%) case and 35/92 (38%) control seizures. A Mann-Whitney U test showed that PGES was significantly longer in the generalized motor seizures of the SUDEP group (p < 0.001). After adjustment for variables, odds ratio analysis of all seizures indicated significantly elevated odds of SUDEP with PGES durations of >50 seconds (p < 0.05). Beyond 80 seconds, the odds were quadrupled (p < 0.005). After adjustment for variables, for each 1-second increase in duration of PGES, the odds of SUDEP increased by a factor of 1.7%(p < 0.005). INTERPRETATION: Prolonged PGES (>50 seconds) appears to identify refractory epilepsy patients who are at risk of SUDEP. Risk of SUDEP may be increased in direct proportion to duration of PGES. Profound postictal cerebral dysfunction, possibly leading to central apnea, may be a pathogenetic mechanism for SUDEP.

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Context

A core concept in potential mechanism of SUDEP is the concept of electro-cerebral shutdown, seen on scalp EEG as prolonged post-ictal generalized EEG suppression (PGES). PGES is usually after generalized tonic-clonic seizures and is seen on scalp EEG as diffuse “flattening” after seizure ends. PGES has been recorded in a few cases of SUDEP and has generated debate over the potential role of this phenomenon as a potential ‘biomarker’ of SUDEP risk. Some hypothesize that the electrical flattening represents an “electrocerebral shutdown”, which precipitates the terminal cardiopulmonary events. In this case-control study, Lhatoo et al report that prolonged PGES (>50 seconds) appears to identify refractory epilepsy patients who are at risk of SUDEP and risk of SUDEP may be increased in direct proportion to duration of PGES. This study seemed to be a breakthrough in SUDEP research since it identified a potential biomarker to define and target prevention strategies.

However, the evidence that PGES is a reliable risk factor for SUDEP is controversial. It has been suggested that PGES is associated with respiratory inhibition leading to SUDEP, but the relationship between PGES and respiratory depression is not known. Surges 2011 reported similar findings: PGES was significantly longer in the generalized motor seizures of the SUDEP group (p < 0.001). After adjustment for variables, odds ratio analysis of all seizures indicated significantly elevated odds of SUDEP with PGES durations of >50 seconds (p < 0.05). Beyond 80 seconds, the odds were quadrupled (p < 0.005). After adjustment for variables, for each 1-second increase in duration of PGES, the odds of SUDEP increased by a factor of 1.7%(p < 0.005). These data indicate that prolonged PGES (>50 seconds) identifies refractory epilepsy patients who are at risk of SUDEP, and risk of SUDEP may be increased in direct proportion to duration of PGES.

Generalized convulsive seizures (GCS) is a known risk factor for SUDEP. Alexandre et al 2015 reported that PGES tend to occur more frequently in patients who had especially patients with tonic-clonic seizures with bilateral and symmetric tonic arm extension during sleep (also reported by Lamberts 2013 and can be potentially prevented by early administration of oxygen. Seyal et al 2012 reported that the duration of ictal oxygen desaturation was longer, mean oxygen desaturation nadir was lower, and peak end tidal CO2 was higher in patients with generalized convulsive seizures with PGES than seizures without PGES. Wu et al 2016 reported that periictal interventions (e.g., oxygen administration, suctioning, and repositioning) significantly shorten the duration of generalized convulsive seizures when compared with those without interventions (p=0.003). They hypothesize that the interventions shorten the duration of PGES, and may, as a consequence, reduce the risk of SUDEP. However, ictal administration of oxygen did not influence the occurrence or duration of PGES. On the other hand, Peng et al 2017 did not find any difference in the duration of PGES between patients who had GCS in sleep and wakefulness. In addition, Lamberts et al 2013 reported that PGES consistency was less frequent in people with more convulsive seizures recorded, suggesting that PGES is an inconsistent finding in any one individual. That study also found that antiepileptic drug reduction appear to facilitate the occurrence of PGES. Further complicating consideration of the role of PGES as a potential biomarker for SUDEP risk, the definition of PGES is not consistent -- the majority of patients with PGES have additional brief bursts of suppression after the initial burst of suppression (Kang et al. 2017).

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