Generalized Convulsive Seizure Type,Oxygen Administration,Postictal Generalized EEG Suppression,and SUDEP Risk: Are They Related?

Commentary

Postictal generalized EEG suppression (PGES) that occurs after a seizure in the postictal period and is characterized by generalized absence of EEG activity is a putative predictor or marker of risk for sudden and unexpected death in epilepsy (SUDEP). Its occurrence has been variably described with a higher prevalence reported in association with generalized convulsive seizures (GCS). Studies also find a strong relationship between PGES and sleep (1). Significant research efforts have been aimed at improving our understanding of PGES; by elucidating its association with seizures, cardiac variability, and respiratory dysfunction, we may better understand SUDEP. To date, findings are often contradictory. One study identified the duration of PGES as predicting the risk of SUDEP (2), whereas another did not (3). Some investigators postulate that PGES causes respiratory and cardiac dysfunction (2, 3), but this effect is not uniformly supported. Lamberts et al. (1) did not find substantial changes in measures of cardiac autonomic instability in association with PGES. The Mortality in Epilepsy Monitoring Unit Study (MORTEMUS), a retrospective study of cardiorespiratory arrests that occurred during long-term video-EEG monitoring, found that PGES occurred in all cases (4). Before we can determine whether PGES is indeed a predictor or marker of SUDEP, we need to better define the factors associated with PGES which may then explain reported contradictory findings.

Alexandre and colleagues explored clinical factors associated with PGES in GCS using data from the REPO₂MSE study, an ongoing multicenter prospective study based on the French National Research Network on SUDEP predictors. As mentioned previously, PGES is more commonly seen with GCS. Video-EEG recordings of 501 seizures in 417 patients from 8 epilepsy monitoring unit centers that used the same video-EEG acquisition system were evaluated. Among the acquired seizures, a total of 110 GCS in 72 patients were identified, and 99 seizures in 69 patients were included in the analysis, as the other seizures did not have adequate recordings. Epilepsy and seizure characteristics were collected on all patients. Importantly ictal semiology of the types of GCS were characterized according to ictal semiology (5). Prior evaluations have not distinguished among different GCS types, which may explain some of the discrepant findings when describing the relationship between GCS and PGES. The following GCS types were categorized:

Type 1: A typical GCS with bilateral and symmetric tonic extension at the onset of secondary generalization followed by bilateral and symmetric four-limb myoclonic jerks.

These categories broadly distinguish between GCS with a tonic component compared to those without (type 1 vs type 2). GCS type 3 is essentially a grab bag of seizures not included in types 1 or 2. PGES was defined as an immediate (within 30 seconds following seizure termination), generalized, and severe attenuation of scalp activity no higher 10μV in amplitude during ≥ 10 seconds, apart from muscle, movements, respiratory, and electrode artifacts. The videos and EEGs were blindly reviewed by two independent investigators with good interobserver agreement (kappa ≥ 0.79).

As a whole, PGES was seen in approximately 50% of the recorded seizures. When looking at the different GCS types, differences emerged between Types 1 and 2: PGES was seen more commonly after GCS type 1 (65%) than after type 2 (15%). In the univariate analyses, PGES was significantly associated with longer duration of the tonic phase (p = 0.042), but this association was not seen in the multivariate analysis. In the multivariate analysis, PGES was significantly associated with GCS type (p < 0.001) and early administration of oxygen (p < 0.001). When comparing the different GCS types, type 1 was significantly different from type 2 (OR 66.0, 95% CI 5.4–801.6; p < 0.001) but not type 3 (OR 3.07, 95% CI 0.75–12.6; p = 0.119). Given the strong association between PGES and GCS type 1, risk factors of PGES for this seizure type were evaluated. PGES occurrence risk was significantly increased when GCS type 1 occurred in sleep (OR 5.0, 95% CI 1.2–20.9) and similar to what was seen in the whole analyses when oxygen was not administered early (OR 13.4, 95% CI 3.2–55.9).

These findings clearly identify an association between PGES and GCS with bilateral and symmetric tonic extension at onset. Clonic GCS were not a risk factor for PGES. It is difficult to fully understand the findings in reference to type 3, as this group is essentially all other GCS. The outlined semiology descriptions are not broadly used and are referenced from a paper of mesial temporal seizures with secondary generalization (5). In addition, we do not understand whether there is a difference between secondary GCS and those that are a presentation of genetic generalized epilepsies.

As the authors discuss, these findings do not clarify the relationship between PGES and SUDEP. They do support that future analyses should include an assessment of GCS type. This is, of course, impossible without video-EEG monitoring. Video-EEG monitoring studies such as MORTEMUS and REPO₂MSE are critical to improving our understanding of the relationships among GCS type, PGES, and SUDEP. When assessing SUDEP cases retrospectively without video-EEG at the time of death, it would be helpful to have prior detailed descriptions of GCS phenomenology from previous monitoring. Generally accepted descriptions of GCS types could be included in all video-EEG reports. As a community, we need to agree on how we will define GCS types.

The finding of an association between PGES and oxygen delivery is interesting and has potential implications as to how we counsel and treat patients with GCS. The presence of oxygen reduced the risk of having PGES. Perhaps we should consider routinely providing oxygen at the time of a GCS. An improved understanding of the clinical implications of PGES and its relationship with SUDEP will guide the need for oxygen.

GCS type and whether oxygen was given at the time at the time of the GCS are both associated with the presence of PGES. What isn't known is whether these risk factors and the relationships between them and PGES are associated with SUDEP. By identifying these risk factors and including them in future studies, we may better understand the vulnerable populations, mechanisms, and potential interventions for SUDEP, the leading cause of death in people with chronic refractory epilepsy.