Dravet syndrome (DS) is an SCN1A mutation-related, infantile-onset epilepsy syndrome, characterized by a distinctive seizure history: prolonged febrile or afebrile seizures beginning in the first year of life, followed by subsequent multiple seizure types. Patients with DS experience developmental regression during early childhood, mostly because of frequent pharmaco-resistant seizures (1–3). Early diagnosis of DS is critical to avoid anticonvulsants that may aggravate seizures and increase morbidity (4).

Premature mortality is a leading cause of fear among caregivers (5–7). Up to 15% of patients with DS die during early childhood or adolescence (1), and most of them experience SUDEP (1), which is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in patients with epilepsy (8). SUDEP accounts for 7.5%–17% of all deaths of epilepsy (9, 10), but SUDEP rates are particularly high in patients with DS attributing to 20% of all deaths (11). The mean age of SUDEP is as young as 4.6 years in patients with DS (6), emphasizing the high risk of mortality.

SUDEP is a diagnosis of exclusion (12), as the definitive post-mortem signs or biomarkers of SUDEP have not yet been identified (13, 14). Indirect evidence has linked SUDEP to seizure-induced apnea, pulmonary edema, dysregulation of cerebral circulation, and cardiac arrhythmias (9, 10, 15), which may occur secondary to hormonal or metabolic changes or autonomic discharges (9, 15, 16), but the exact mechanisms remain unclear.

Electroencephalography (EEG) is a critical tool that can show the clinical status of patients, as well as ictal changes (17, 18) and age-related changes in patients with DS (19). Recently, few studies have analyzed the risk of SUDEP using EEG in patients with various epilepsies. One recent multi-center study has suggested that machine learning-driven models may be used to quantify SUDEP risk in patients with epilepsy (20). Another study used the data of a group of patients with drug-resistant epilepsy to compare the EEG and ECG data of 21 patients with definite or probable SUDEP, and it reported an increased autonomic stimulation associated with seizures in patients with SUDEP (21). However, these studies included patients with various epilepsies, and the results were largely dependent on the ECG data (20, 21).

In the present study, we performed a quantitative EEG analysis to identify the EEG features related to a high risk of SUDEP. We hypothesized that the EEG features would be different between patients with high SUDEP scores and the others with lower SUDEP scores.

A total 64 patients with DS [38 males and 26 females, aged: 128.51 ± 75.50 months (range: 23–380 months)] were included in this study. A total of 13 HCs [7 males and 6 females, aged: 95.46 ± 86.48 months (range: 13–263 months)] were included in this study.

Low-SUDEP group consisted of 14 patients [10 males and 4 females, aged: 122.73 ± 54.10 months (range: 68–238 months)], mid-SUDEP, 14 [6 males and 8 females, aged: 113.83 ± 76.73 months (range: 55–380 months)] and high-SUDEP, 31 [19 males and 12 females, aged: 138.51 ± 81.81 months (range: 23–347 months)]. Five patients were excluded because of lacking information on clinical data.

There was a difference in age between patients with DS and HCs (p = 0.021), and other demographics are no different.

Demographic data of the DS patients and the HCs are reported in Table 2.

SUDEP is a fatal condition that can occur frequently in patients with DS. However, biomarker for predicting SUDEP remains to be investigated. This study demonstrates that patients with high SUDEP-7 scores have different EEG features from those with low SUDEP-7 scores, suggesting that EEG may be used as a biomarker of SUDEP in DS.

The most significant finding of this study was the increase in the theta powers in patients with high SUDEP-7 scores. At the same time, the relative alpha powers of EEG signals decreased in the same group. In previous studies, the 1–30 Hz-frequency range and theta activity (4–7 Hz) showed a consistent relationship with epilepsy. Topographically a diffuse increase in theta activity characterizes the broad spectrum of genetic-developmental, non-lesional childhood epilepsies (23, 24), idiopathic generalized epilepsies (25), and focal epilepsies with dissimilar aetiology (26, 27) compared to the theta activity in healthy controls. Previous studies have reported a diffuse theta, and delta slowing in DS (17, 28). Modifications of theta and delta rhythms have been reported in SCN1a knock-out mice (29).

Notably, the alpha band powers decreased in DS patients with high SUDEP scores. Alpha-band oscillations play an important role in information processing. Alpha band rhythm increases attention by inhibiting task-irrelevant processes (30–33). In epilepsy, a slower alpha rhythm is associated with poorer seizure control (34). These findings suggest that the dysregulation of alpha activities, which represent cognitive activities, is related to a high SUDEP risk score. Intellectual disability has been suggested as a factor associated with a high SUDEP risk, but data about this hypothesis is still limited (35). Our findings correlate with these previous findings, and demonstrate that alpha is decreased in high-SUDEP group using a quantitative EEG analysis. Our findings suggest that an increased theta and alpha activity may be used to predict an increased risk of SUDEP.

In this study, we also compared the EEG findings of patients with DS to those of HCs. This study showed that absolute beta activities increased diffusely in patients with DS, in which occipital delta activities decreased in patients with DS. The relative alpha and gamma powers of EEG signals decreased in the same group. An increase in diffuse beta activity might be associated with anti-seizure drugs. Sedative benzodiazepines increase beta activity (36). Clobazam, an oral 1,5-benzodiazepine, is the first-line treatment drug for DS (37).

Delta is usually considered the slowest EEG frequency band (38). Delta oscillations are frequently observed in pathologic conditions, including coma (39–41) and Lennox-Gastaut syndrome (42). Increased delta activity can be observed as an ictal (43) or postictal activity (28). However, we found a decrease in delta activity in DS that might be correlated with their age. It is known that the rate of slowing increases with age in DS, suggesting that delta activity increases with the duration of epilepsy (17). Previous findings showed that SUDEP risk is increased in correlation with the duration of epilepsy (44).

In contrast to delta oscillations which usually represent pathologic conditions, gamma waves are the fastest brain waves which mainly occur when brain is highly alert and conscious. Gamma activity represents the finely-tuned inhibitory inter-neuron network (45), specifically γ-aminobutyric acid type A (GABAA) receptor-induced inhibitory postsynaptic currents (46–49). As the functional connectivity of the brain is modulated by the inhibitory inter-neuron network, dysregulation and reduction of gamma activity are observed in pathological conditions such as Alzheimer’s disease (50). A normal gamma frequency represents cognitive functions including sensory processing (51, 52), recognition, and memory (53). Modifications of gamma oscillations have been reported in mouse models of Alzheimer’s disease (in which NaV1.1 expression is reduced, leading to epileptiform activities) (54).

This study had some limitations. As our center was a tertiary referral epilepsy center, only patients with severely drug-resistant epilepsy were included. This could have caused a selection bias. In addition, we used a SUDEP-7 inventory score in our investigation instead of the actual event because SUDEP is not a condition that can be confirmed. However, we still think this study is valuable because this seven-item weighted inventory derived from a prospective SUDEP study (22, 55) is a validated, well-known tool which has been used frequently to identify risk factors for SUDEP (55–57). Also, a broad range of age (2–31 years old) was considered. In future research, it may be beneficial to compare subpopulations within different age ranges to highlight potential differences during specific life stages. This could help use this data for early intervention strategies before clinical deterioration and seizures occur.

Here, we identified the quantitative EEG findings that correlate with a high SUDEP-7 score. Patients with high theta band powers, and the low relative alpha band powers warrant high-level supervision.

The datasets presented in this article are not readily available because participants and guardians have not given consent for data sharing. Requests to access the datasets should be directed to SK, seheekim@yuhs.ac.

The studies involving humans were approved by the Institutional Review Board of Severance Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The Ethics Committee/Institutional Review Board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because this study is retrospective nature of the study.

J-YK contributed to analyzing data and wrote the paper. JS collected the data. SK wrote sections of the manuscript. LK and SK supervised the study process and manuscript writing. All authors contributed to the article and approved the submitted version.

This study was supported by the Seokcheon grant from the Korean Pediatric Society, a faculty research grant of Yonsei University College of Medicine (6-2018-0057), and the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean government (MSIT) (grant number 2017-0-00432) for the development of a noninvasive integrated BCI SW platform to control home appliances and external devices through an AR/VR interface.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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