Aileen Mcgonigal

Patrick Marquis

Samuel Medina

Fabrice Bartolomei

Sylvain Rheims

Christophe Bernard

Christian G Bénar

Postictal stereo-EEG changes following bilateral tonic-clonic seizures

teaching and research institutions in France or abroad, or from public or private research centers.

We read with interest Bateman et al's study 1 on postictal electroclinical changes following bilateral tonic-clonic seizures using subdural grids, depth electrodes or both. They observed post-ictal gamma band activity in the majority of 31 seizures, while other frequencies were suppressed. This calls into question whether post-ictal generalized electroencephalographic (EEG) suppression (PGES) is characterized by absence of activity, as previously suggested. Gamma activity was hypothesized by the authors as possibly representing persistent brainstem activity.

We recently studied post-ictal electrical activity in 100 bilateral tonic-clonic seizures using stereoelectroencephalography (SEEG) [START_REF] Marchi | Postictal electroencephalographic (EEG) suppression: A stereo-EEG study of 100 focal to bilateral tonic-clonic seizures[END_REF] . Different patterns were described: PGES (all electrodes involved), regional suppression (RS) (subset of electrodes), or no suppression. We used a 70Hz high frequency filter; therefore, observed absence of activity in PGES and RS was within the 0-70Hz range.

Our definitions used different EEG criteria, notably higher sensitivity, to increase detection of low amplitude changes (<20V/mm in our study versus a fixed 50V/mm cut-off in Bateman et al.). This may help explain higher prevalence of "post-ictal attenuation" (24/31 seizures, 84%) in Bateman et al.'s series, compared to prevalence of PGES in our study (27/100 seizures, 27%). We acknowledge that the term "generalized" in PGES must be used with caution in the context of intracranial recording since the whole brain is not sampled, as previously discussed [START_REF] Marchi | Postictal electroencephalographic (EEG) suppression: A stereo-EEG study of 100 focal to bilateral tonic-clonic seizures[END_REF] . We also highlight that in Marchi et al., we reported on 52 patients explored with SEEG, whereas Bateman et al. report 16 patients of whom 3 had stereotactically implanted depth electrodes and the remainder subdural recording. To investigate whether high gamma band activity was present in our cases, we randomly selected 3 previously described SEEG cases with PGES 2 , all post-ictally unresponsive and immobile with no obvious muscle contraction. We studied unfiltered monopolar and bipolar recordings, sampled at 512Hz, using time-frequency analysis. This detected marked increase in gamma activity (20-120Hz) in both monopolar and bipolar recordings during PGES (Fig 1A) in all 3. We noticed an anatomical gradient, whereby gamma activity was seen in the most external electrode contacts, that is, closest to skull entry point. Indeed, some contacts displaying gamma activity were extra-cortical, within CSF space (Fig 1B). This raises the question of a non-cerebral cause. Previously, high gamma band power increases observed in SEEG electrodes close to periorbital regions were demonstrated to be contamination from ocular saccades [START_REF] Jerbi | Saccade related gamma-band activity in intracerebral EEG: dissociating neural from ocular muscle activity[END_REF] .

Association between tonic electromyographic (EMG) activity in frontalis muscles and presence of PGES was recently highlighted using surface EEG [START_REF] Park | Tonic electromyographic activity following bilateral tonic-clonic seizures is associated with periictal respiratory dysfunction and postictal generalized EEG suppression[END_REF] , interpreted as possibly relating to seizure-induced hypoxemia as observed in rat models [START_REF] Lee | Hypoxia-induced short-term potentiation of respiratorymodulated facial motor output in the[END_REF] . Authors excluded large EMG fluctuations associated with visible movements. Might it therefore be possible that some of the gamma activity observed by Bateman et al. is related to facial/scalp muscular contraction? They observed "rigid immobility" postictally in around 1/3 of cases; it would be interesting to look at association with gamma band activity and, most importantly, evaluate anatomical distribution of gamma.

In the light of these observations, we prospectively tested a single patient interictally, comparing SEEG signal with electromyography (EMG) of frontalis muscle. This showed gamma activity in external contacts of frontal SEEG electrode during voluntary facial contraction (Fig 1C and1D), confirming muscle activity as a possible confounding factor.

Animal models of SUDEP show a large post-ictal DC shift in brainstem, likely reflecting depolarization block, which can underlie spreading depression [START_REF] Bernard | Spreading depression: Epilepsy's wave of death[END_REF] . This could explain both cardiorespiratory shutdown and PGES, observed in clinical cases of SUDEP [START_REF] Ryvlin | Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study[END_REF] . However, widespread depolarization block would be expected to produce absence of broadband activity. Thus, further investigation is crucial to confirm whether observed gamma activity is of cerebral origin or not.

Lyon' s

 s Neuroscience Research Center (INSERM U1028, CNRS 5292), Lyon, France Corresponding author : Dr Aileen McGonigal, Service de Neurophysiologie Clinique, CHU Timone, AP-HM, Marseille, France Email : aileen.mcgonigal@univ-amu.fr Tel: 00 33 491384995 Fax: 00 33 491385826 To the Editors:

Acknowledgements

This work has been carried out within the Federation Hospitalo-Universitaire (FHU) EPINEXT thanks to the support of the A*MIDEX project (ANR-11-IDEX-0001-02) funded by the "Investissements d'Avenir" French Government program managed by the French National Research Agency (ANR).

Conflicts of Interest

None of the authors has any conflict of interest to disclose.

Ethical Publication Statement

We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.