Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures

Abstract

Objective: We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. Methods: EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. Results: In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter-and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. Significance: We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study Wendling and Nabbout contributed equally to the manuscript.

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

“…Refining the electro-clinical characteristics and the temporal sequence should help to establish the diagnosis of EIMFS. The identification of EEG markers characteristic of seizure patterns will improve further this diagnosis (Kuchenbuch et al, 2018). The poor prognosis of this DEE requires an urgent development of trials that should be used early at onset as the early control of seizures might improve the prognosis but should also be tested at later stages as epilepsy remains active in the chronic phase of this syndrome.…”

In silico model reveals the key role of GABA in KCNT1‐epilepsy in infancy with migrating focal seizures

“…We included the EEG of seven EIMFS patients with KCNT1 pathogenic variants (five seizures per patient; for details see Kuchenbuch et al 5 ). We also included a 10‐month‐old girl with a normal EEG as a control for normal activity at this age.…”

“…EIMFS is characterized by a seizure onset before the age of 6 months in a previously healthy child, followed by a stormy phase of seizures with a specific and pathognomonic ictal electroencephalographic (EEG) pattern called “migrating” seizure with drug resistance and a psychomotor regression resulting in a developmental global delay with an acquired microcephaly. We described two EEG markers of the EIMFS ictal pattern, namely, the time delay index and the phase coherence index, which were specific to EIMFS with KCNT1 pathogenic variants 5 …”

“…We described two EEG markers of the EIMFS ictal pattern, namely, the time delay index and the phase coherence index, which were specific to EIMFS with KCNT1 pathogenic variants. 5 In 2012, we identified KCNT1 as the main causative gene of this syndrome. 6 This gene encodes a sodium-activated potassium channel (known as slack or slo2.2) that is widely distributed in the brain.…”

KCNT1-Related Epilepsy: A Review

“…25 Growing evidence on a genetic etiology has been published; missense mutation in the sodium-gated potassium channel has been found in more than one-third of MMFSI patients. [26][27][28][29][30][31][32][33][34][35][36] Kuchenbuch et al 37 showed, by EEG study (with chronograms and phase coherence) of seven MMFSI patients with KCNT1 mutations, that seizures began mainly in temporal and occipital regions, and evolved with a stable frequency (4--10 Hz). In 71% of cases, interhemispheric migrating seizures spread from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures present more involvement of frontotemporal, temporal, and occipital channels.…”