Monday, November 16, 2015

Postictal generalized EEG suppression and SUDEP

Alexandre V, Mercedes B, Valton L, Maillard L, Bartolomei F, Szurhaj W, Hirsch
E, Marchal C, Chassoux F, Petit J, Crespel A, Nica A, Navarro V, Kahane P, De
Toffol B, Thomas P, Rosenberg S, Denuelle M, Jonas J, Ryvlin P, Rheims S;
REPO2MSE study group. Risk factors of postictal generalized EEG suppression in
generalized convulsive seizures. Neurology. 2015 Nov 3;85(18):1598-603.



To identify the clinical determinants of occurrence of postictal generalized EEG suppression (PGES) after generalized convulsive seizures (GCS).


We reviewed the video-EEG recordings of 417 patients included in the REPO2MSE study, a multicenter prospective cohort study of patients with drug-resistant focal epilepsy. According to ictal semiology, we classified GCS into 3 types: tonic-clonic GCS with bilateral and symmetric tonic arm extension (type 1), clonic GCS without tonic arm extension or flexion (type 2), and GCS with unilateral or asymmetric tonic arm extension or flexion (type 3). Association between PGES and person-specific or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures.


A total of 99 GCS in 69 patients were included. Occurrence of PGES was independently associated with GCS type (p < 0.001) and lack of early administration of oxygen (p < 0.001). Odds ratio (OR) for GCS type 1 in comparison with GCS type 2 was 66.0 (95% confidence interval [CI 5.4-801.6]). In GCS type 1, risk of PGES was significantly increased when the seizure occurred during sleep (OR 5.0, 95% CI 1.2-20.9) and when oxygen was not administered early (OR 13.4, 95% CI 3.2-55.9).


The risk of PGES dramatically varied as a function of GCS semiologic characteristics. Whatever the type of GCS, occurrence of PGES was prevented by early administration of oxygen.

The study by Alexandre et al. advances our understanding of potential mechanisms underlying SUDEP, albeit indirectly, and offers a tool to prevention. The study found the risk of postictal EEG generalized suppression (PGES) varied with semiologic characteristics of GCS and was less likely with early administration of oxygen.
PGES was first described by Bird et al. (1997) in an unsupervised but monitored SUDEP case undergoing intracranial video-EEG. The case-control study by Lhatoo et al. supported the role of PGES in SUDEP. PGES was longer in 30 seizures in 10 patients who later died from SUDEP, compared to 92 seizures in 30 patients who did not. The longer the duration of PGES, the greater the risk. Analysis per patient was not reported, potentially biasing results. Nevertheless, the logic for PGES as a SUDEP biomarker was compelling and indeed all 10 analyzed SUDEP cases in MORTEMUS showed PGES concurrent with terminal cardiorespiratory dysfunction. PGES is associated with autonomic dysregulation and few spontaneous movements; there are more bedside interventions in patients with PGES by nurses, even though unaware of EEG findings. PGES is also associated with more severe oxygen desaturation duration and peak end-tidal CO2 elevation. With brain shutdown, breathing, arousal, and autonomic regulation are gravely impaired. Add to that the common setting for SUDEP, an unobserved nocturnal seizure that may leave the person prone with the airway partially or fully obstructed, in deep postictal coma, unable to correct his or her position despite hypercapnia and hypoxia. A perfect storm, the recipe for death in epilepsy. The case for PGES appears closed with a logical mechanism and converging evidence.
But the case is not closed. In the one replication study, neither the presence nor duration of PGES differed between SUDEPs and controls. The variable consistency of PGES within individuals raises doubt over its usefulness as a predictive tool. But it may still be a marker for SUDEP risk in a given seizure, although not the initiating event in a terminal cascade.  As Alexandre and coauthors state, PGES might be a marker of postictal hypoxemia rather than a precipitating factor. The variation in PGES with semiologic characteristics of GCS is another potential difference between studies. Tonic-clonic GCS with bilateral and symmetric tonic arm extension (GCS type 1) carry the highest risk of PGES and clonic GCS without a tonic phase a lower risk. A prolonged tonic phase of a seizure was previously associated with PGES. Of interest is the suggestion of a greater level of drug withdrawal in GCS with PGES...

Two theories may explain why SUDEP victims are most often found dead in bed: lack of supervision, as supported by the MORTEMUS study, and different pathophysiology in sleep-related seizures. That PGES was more common with nocturnal GCS type 1 appears to support the latter; however, the study gives no indication of response times to seizures at night compared to the day. Thus, the increased risk of PGES with nocturnal seizures may reflect hypoxia due to delayed intervention. A limitation noted by Surges et al. in their study was that “…people were usually administered oxygen via a face mask and position was often changed…,” an intervention possibly contributing to the lack of association between PGES and SUDEP...

This study may provide another clue about the nature of interventions; namely, that the earlier the oxygen is administered, the less likely PGES will occur. But what could not be controlled for is whether oxygen was key, or the accompanying actions such as repositioning, suctioning, or stimulation. The lower SUDEP rates in the community with supervision in sleep suggest that oxygen may not be the critical intervention...

Paradoxically, in many hospitals, nurses routinely give oxygen after a GCS. But when professionals are asked if oxygen should be administered at home, the typical answer is that there is no evidence it does anything. That answer may no longer be correct but, for the reasons outlined above, the evidence does not at this stage support adoption of its widespread use in the community. Indirect evidence suggests that interventions can reduce SUDEP risk, despite some cases occurring in medical settings with prompt resuscitation. While family members should not blame themselves for not being there to prevent SUDEP, patients with epilepsy need the opportunity to make informed choices regarding supervision and living independently.

Devinsky O, Nashef L. SUDEP: The death of nihilism. Neurology. 2015 Nov

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