# Seizure-related biomarkers of sudden unexpected death in epilepsy (SUDEP) in drug-resistant focal epilepsy (REPO2MSE): a prospective, multicentre case-control study

Philippe Ryvlin, Margaux Huot, Luc Valton, Louis Maillard, Fabrice Bartolomei, Philippe Derambure, Edouard Hirsch, Véronique Michel, Francine Chassoux, Jérôme Petit, et al.

► To cite this version:

Philippe Ryvlin, Margaux Huot, Luc Valton, Louis Maillard, Fabrice Bartolomei, et al. Seizure-related biomarkers of sudden unexpected death in epilepsy (SUDEP) in drug-resistant focal epilepsy (REPO2MSE): a prospective, multicentre case-control study. The Lancet Neurology, 2025, 25 (1), pp.50-60. 10.1016/s1474-4422(25)00379-5. hal-05403152

HAL Id: hal-05403152

https://hcl.hal.science/hal-05403152v1

Submitted on 11 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

CrossMark

# Seizure-related biomarkers of sudden unexpected death in epilepsy (SUDEP) in drug-resistant focal epilepsy (REPO₂MSE): a prospective, multicentre case-control study

<figure><img src="image_3.png" /></figure>

Philippe Ryuvin, Margaux Huot, Luc Valton, Louis Maillard, Fabrice Bartolomei, Philippe Derambure, Edouard Hirsch, Véronique Michel, Francine Chassoux, Jérôme Petit, Arielle Crespel, Arnaud Biraben, Vincent Navarro, Philippe Kahane, Bertrand De Toffol, Pierre Thomas, Sarah Rosenberg, Adriano Bernini, Anne-Laure Charlois, Laura Craciun, Fatima Chorfa, Pauline Ducouret, Axel Ferreira, Mathilde Leclercq, Manon Marty, Blanca Mercedes Alvarez, Milena Sampaio, Antoine Spahr, Noémie Timestit-Kurland, Maylis Touya, Pascal Roy, Sylvain Rheims, on behalf of the REPO₂MSE study group

## Summary

**Background** Novel biomarkers of the risk of sudden unexpected death in epilepsy (SUDEP) are needed to better inform people with epilepsy of their individual risk and identify those at a high risk. The aim of this study was to identify such biomarkers, particularly with the exploration of seizures characteristics that have not been previously investigated, including peri-ictal peripheral oxygen saturation (SpO₂) and site of seizure onset.

**Methods** We conducted a nested case-control study of SUDEP within a dedicated nationwide prospective cohort. Eligible participants were adults with drug-resistant focal epilepsy undergoing in-hospital seizure monitoring at 16 epilepsy monitoring units in France. Clinical data, results from presurgical investigations, and raw recordings from video EEG, electrocardiogram (ECG), and SpO₂ were collected until the end of the recruitment period. The French National Directory of Natural Persons Identification was queried annually to identify deaths. SUDEP cases were adjudicated on the basis of medical records and interviews documenting the circumstances of death. Each SUDEP case was matched to four controls on the basis of study centre and date of inclusion. SUDEP risk factors were identified using LASSO-penalised conditional logistic regression.

**Findings** From May 18, 2010, to Aug 23, 2015, we enrolled a total of 1074 participants and followed their vital status until the end of 2018, yielding a total of 6828 patient-years of follow-up. 42 participants died during follow-up, including 18 cases of definite or probable SUDEP, resulting in a SUDEP rate of 2.64/1000 patient-years (95% CI 1.36–3.92). Four risk factors were significantly associated with the risk of SUDEP: an extratemporal epileptogenic zone (OR 37.8, 95% CI 3.21–446.2, p=0.0039), a BMI of 30 or higher (26.0, 2.0–339.6, p=0.013), male sex (12.6, 1.5–106.8, p=0.0201), and predominantly nocturnal seizures (6.0, 1.2–28.7, p=0.026). In contrast, the presence of peri-ictal SpO₂ of less than 80% during focal seizures, the frequency of focal-to-bilateral tonic-clonic seizures, heart rate variability, age at epilepsy onset, number of antiseizure medications, and history of depression were not significantly associated with SUDEP.

**Interpretation** Extratemporal epilepsies involving the perisylvian region or frontal lobe appear to be associated with an increased risk of SUDEP. This finding warrants confirmation in larger cohorts and underscores the need to improve the diagnosis and surgical management of extratemporal epilepsies, which might contribute to improved SUDEP risk stratification and prevention.

**Funding** French Ministry of Health (Programme Hospitalier de Recherche Clinique National 2009).

**Copyright** © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

## Introduction

Sudden unexpected death in epilepsy (SUDEP) is an important cause of premature mortality, which accounted for 23.3% of all unexplained sudden deaths in people younger than 50 years in a nationwide population-based study in Denmark.¹ SUDEP also ranks as the second neurological cause of potential years of life lost after stroke.² The majority of SUDEP cases occur at night, in bed and without witnesses.³ When observed, SUDEP is most often precipitated by a generalised tonic-clonic

seizure (GTCS) followed by a postictal fatal apnoea of uncertain origin.³,⁴ Accordingly, the primary risk factors for SUDEP include the presence, elevated frequency, and nocturnal occurrence of GTCS;⁵⁻⁷ not sharing a bedroom or household; and inadequate adherence to antiseizure medications.⁶,⁷ Further progress in the understanding, prediction, and prevention of SUDEP necessitates the identification of novel biomarkers.⁸ Features related to seizures, such as peri-ictal hypoxemia and the seizure onset zone, deserve particular attention since they could

Lancet Neurol 2025; 25: 50–60

Published Online
November 21 2025
https://doi.org/10.1016/
S1474-4422(25)00379-5

See Comment page 3
Department of Clinical
Neurosciences, University
Hospital of Lausanne and
University of Lausanne,
Lausanne, Switzerland
(Prof P Ryuvin MD, A Bernini PhD,
L Craciun MD, P Ducouret PhD,
A Ferreira MD, M Marty MSc,
A Spahr MSc, M Touya MSc);
Université Lyon 1, Lyon, France
(M Huot MSc, F Chorfa MSc,
N Timestit-Kurland MSc,
Prof P Roy MD); Équipe
Biostatistique-Santé,
Laboratoire de Biométrie et
Biologie Évolutives, CNRS UMR
5558, Villeurbanne, France
(M Huot, F Chorfa,
N Timestit-Kurland, Prof P Roy);
Service de Biostatistique-
Bioinformatique, Pôle Santé
Publique, Hospices Civils de
Lyon, Lyon, France (M Huot,
F Chorfa, N Timestit-Kurland,
Prof P Roy); Department of
Neurology, University Hospital
of Toulouse, Centre de
Recherche Cerveau et
Cognition, University of
Toulouse, Toulouse, France
(L Valton MD); Department of
Neurology, University Hospital
of Nancy, Nancy, France
(Prof L Maillard MD); Assistance
Publique Hôpitaux de
Marseille, Timone Hospital,
Department of Epileptology
and Cerebral Rhythmology,
Marseille, France
(Prof F Bartolomei MD);
Department of Clinical
Neurophysiology, Lille
University Medical Center, EA
1046, University of Lille, Lille,
France (Prof P Derambure MD);
Department of Neurology,
University Hospital of
Strasbourg, Strasbourg, France
## Research in context

### Evidence before this study

We searched PubMed for articles published between Jan 1, 1969, and Sept 1, 2025, with no language restrictions, with the filter "abstract available" and "human studies", with the terms "(SUDEP OR "sudden unexpected death in epilepsy") AND ("biomarker" [ti] OR "risk factor").". We found 573 articles. After excluding 195 reviews, 378 original articles were assessed. Clinical risk factors for sudden unexpected death in epilepsy (SUDEP) included the presence, frequency, and nocturnal occurrence of generalised tonic-clonic seizures (GTCS), sleeping or living alone, non-adherence to antiseizure medication, substance use, alcohol dependence, male sex, and an elevated BMI. Neuroimaging and genetic SUDEP risk factors have also been identified, whereas several other biomarkers show inconsistent associations across studies, including early age at epilepsy onset, altered heart rate variability, and the presence and duration of postictal generalised EEG suppression.

### Added value of this study

Our study explored previously unreported seizure-related biomarkers that might have a direct causal relationship with

SUDEP mechanisms and identified the presence of an extratemporal epileptogenic zone as a novel risk factor, independent of other known clinical predictors. In contrast, our findings suggest that peri-ictal hypoxemia is unlikely to be a strong risk factor for SUDEP. The prospective design of the study also strengthens the previously reported association between SUDEP and established clinical risk factors, including elevated BMI.

### Implications of all the available evidence

Expanding the number of independent SUDEP risk factors provides an opportunity to enhance risk stratification and to better inform people with epilepsy and their caregivers about individual risk. Further studies and data-sharing initiatives are needed to confirm these findings and integrate them into comprehensive predictive models. Emerging evidence also points to new strategies for reducing SUDEP risk in people with epilepsy, including the improved identification and surgical management of perisylvian and frontal lobe epilepsies, as well as the prevention of an overweight BMI.

have a direct causal role in SUDEP mechanisms. To investigate these hypotheses, we established a prospective cohort of participants undergoing in-depth phenotyping during in-hospital seizure monitoring and conducted a nested case-control study within this cohort.

## Methods

### Study design

This is a multicentred observational case-control study nested in a prospective cohort study (ClinicalTrials.gov NCT02572297) designed for this specific purpose. The target population included individuals with drug-resistant focal epilepsy who were scheduled for in-hospital long-term video EEG monitoring of their seizures, with the intent to assess their suitability for epilepsy surgery. Participants were recruited from all 16 epilepsy monitoring units in France that routinely performed long-term monitoring in adults (appendix p 11). Participants were recruited from May 18, 2010, to Aug 23, 2015. The study was approved by a relevant ethics committee (Comité de Protection des Personnes Sud Est II, approval number 2010-006-AM6) and competent authority (Agence Nationale de Sécurité du Médicament, approval number B100108-40). Our study complied with the Strengthening the Reporting of Observational Studies in Epidemiology statement guidelines (appendix p 9).

### Participants

Inclusion criteria in the prospective cohort were: being aged 15 years or older, drug-resistant focal epilepsy, scheduled long-term monitoring using either video scalp

EEG or intracerebral EEG recordings, a registration number in the French National Directory of Natural Persons Identification, and affiliation with the French health-care system. All participants gave written informed consent to participate in the study.

The nested case-control study defined cases as all participants from the cohort who died from definite or probable SUDEP between the study onset and Dec 31, 2018. For each SUDEP case, we selected four controls (who did not die during follow-up) from the same centre, recruited as close in time to their corresponding case as possible. This matching strategy was implemented to minimise bias arising from differences in participant profiles across epilepsy monitoring units. Some epilepsy monitoring units preferentially investigated temporal lobe or lesional epilepsies, whereas others did not, and this approach evolved over time in some epilepsy monitoring units.

The sample size calculation is detailed in the appendix (p 18) and yielded a target of 18 probable and definite SUDEP cases. The study was originally powered to test the hypothesis that participants with SUDEP would have a 3.75-times higher occurrence of peri-ictal hypoxemia of less than 80% compared with controls, across all seizure types combined. This hypothesis was based on evidence available in 2010, which suggested similar rates of peri-ictal hypoxemia in focal seizures and focal-to-bilateral tonic-clonic seizures (FBTCS).⁹ However, more recent data¹⁰,¹¹ indicate that both the pathophysiology and frequency of peri-ictal hypoxemia differ between focal seizures and FBTCS, supporting the need to analyse these seizure types separately.

(Prof E Hirsch MD); Department of Neurology, Hôpital Pellegrin, Bordeaux, France
(V Michel MD); Epilepsy Unit, Department of Neurosurgery, Hôpital Lariboisière, Assistance Publique Hôpitaux de Paris, Paris, France (F Chassoux MD); Neurophysiology and Epileptology Department, GHU Paris Psychiatry & Neurosciences, Sainte Anne, Paris, France (F Chassoux); La Teppe Epilepsy Center, Tain-l'Hermitage, France
(J Petit MD); Epilepsy Unit, Montpellier, France
(A Crespel MD); Department of Neurology, University Hospital of Rennes, Rennes, France
(A Biraben MD); Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris Brain Institute, Institut du Cerveau, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Epilepsy Unit and Reference Center for Rare Epilepsies, ERN EpiCare, Pitié-Salpêtrière Hospital, Paris, France
(Prof V Navarro MD);
Department of Neurology, Michallon Hospital, Grenoble, France (Prof P Kahane MD);
Grenoble Institut des Neurosciences, INSERM U836, Grenoble, France
(Prof P Kahane); Université Joseph Fourier, Grenoble Alpes University, Grenoble, France
(Prof P Kahane); Department of Clinical Neurophysiology, INSERM U930, University Hospital of Tours, Tours, France
(Prof B De Toffol MD);
Department of Neurology, University Hospital of Nice, Nice, France
(Prof P Thomas MD);
Department of Neurology, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
(S Rosenberg MD); Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Lyon 1 University, Lyon, France (A-L Charlois MSc, M Leclercq MSc, B Mercedes Alvarez MD, M Sampaio MD, Prof S Rheims MD); Department of Neurology, University Hospital Gregorio Marañon, Madrid, Spain
(B Mercedes Alvarez); Lyon's Neuroscience Research Center, INSERM U1028, CNRS UMR 5292,
Lyon 1 University, Lyon, France
(Prof S Rheims)

Correspondence to:
Prof Philippe Ryylin, Department
of Clinical Neurosciences,
University Hospital of Lausanne
and University of Lausanne,
Lausanne 1011, Switzerland
**philippe.ryvlin@chuv.ch**

or
Prof Sylvain Rheims, Department
of Functional Neurology and
Epileptology, Hospices
Civils de Lyon, Lyon 1 University,
Lyon 69003, France
sylvain.rheims@chu-lyon.fr

See Online for appendix

## Procedures

Participants were enrolled in the study either before or at the start of long-term monitoring, during which all available relevant information was collected into a centralised pseudonymised electronic clinical report form. Collected data included demographic factors (sex was self-reported but also checked against the social security number for each participant), medical history, comorbidities, epilepsy and seizure characteristics, previous and current antiseizure and psychiatric therapies, and findings from all epilepsy-targeting investigations and surgical treatment performed during the study. In accordance with French data protection regulations and given that race and ethnicity were not scientifically required for the study objectives, these variables were not collected.

Long-term monitoring was performed according to routine clinical practice and included recording of peripheral oxygen saturation (SpO₂) via a finger pulse oximetry (Xpod pulse oximeter, Nonin Medical, Plymouth, MI, USA), connected to the video EEG acquisition system. Respiratory belts were not used in any of the centres. All available peri-ictal raw data from video EEG or intracerebral EEG, electrocardiogram (ECG), and SpO₂ were pseudonymised and centralised for analysis.

## Outcomes

The vital status of the entire cohort was assessed annually by querying the French National Directory of Natural Persons Identification. For all recorded deaths, a detailed investigation of the circumstances and causes of death was done. All relevant medical records were obtained, including the death certificate and information from the participant's physicians. If the cause of death was uncertain, or if SUDEP was suspected, the participant's closest relatives were interviewed to gather additional details. Autopsy results were considered if available. On the basis of all collected data, two SUDEP experts (PRy and SRh) independently adjudicated the cause of death as definite, probable, or possible (appendix p 23) SUDEP or non-SUDEP according to the criteria set by Nashef and colleagues.¹² Disagreements were discussed between the two experts and resolved by consensus.

Our primary aim was to investigate potential SUDEP risk factors that had not been previously examined, including the occurrence of peri-ictal bradycardia (<50 bpm) or asystole (cardiac arrest for ≥3 sec), the occurrence of peri-ictal hypoxemia (<80% SpO₂), and the localisation of the epileptogenic zone. The threshold of an SpO₂ below 80% was chosen on the basis of evidence that neural function begins to deteriorate when oxygen saturation falls to less than 80–85%,¹³ potentially contributing to long-term postictal loss of consciousness and immobility. These factors might hinder spontaneous repositioning from the prone position and exacerbate dysfunction in brainstem respiratory centres—mechanisms believed to be involved in SUDEP pathophysiology.¹⁴

The peri-ictal period was defined as the seizure itself and the subsequent 5 min. To exclude SpO₂ artifacts, video recordings of seizures were systematically checked to ensure an appropriate placement of the finger pulse oximeter. All variables were analysed separately for focal seizures and FBTCS.

For FBTCS, we only considered postictal SpO₂, given the absence of reliable finger oximetry measurements during the seizure. We additionally assessed the presence and duration of apnoea that lasted 10 sec or longer during the postictal coma when the quality of the video EEG recording allowed for reliable audio and visual detection of respiratory efforts and associated artifacts on the postictal depressed EEG. We also evaluated the presence and duration of postictal generalised EEG suppression using a validated automated tool,¹⁵ with all outputs verified through visual inspection of EEG traces.

The localisation of the epileptogenic zone was classified as temporal or extratemporal, with the extratemporal category further divided into frontal, perisylvian, or posterior for post-hoc analyses. It was established independently by two epilepsy surgery experts (PRy and SRh) for all SUDEP cases and their controls, masked to the participants' group. Disagreements were resolved by consensus. The adjudication was based on the results of all available presurgical investigations, the brain region operated or proposed to be operated, and the postoperative seizure outcome, if applicable. The posterior category encompassed epileptogenic zones involving the parietal or the occipital lobe, or both, whereas the perisylvian category was distinguished by the role of the insulo-opercular complex in peri-ictal autonomic dysfunction and laryngospasm.¹⁶⁻¹⁸ Conclusions regarding the localisation of the epileptogenic zone were sent back to the corresponding recruiting centres to ensure that the experts' assessment was consistent with their own clinical conclusions.

Other potential novel SUDEP risk factors included the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ). Results for both scales were prospectively collected and used as surrogate markers of depression comorbidity and sleep apnoea syndrome, respectively. Finally, we considered several previously reported SUDEP risk factors, including sex, age at epilepsy onset, the presence and frequency of FBTCS during the last 5 years, predominantly nocturnal seizures in the last year, BMI, heart rate variability (HRV), and epilepsy surgery during follow-up (corresponding to the time elapsing from date of inclusion to the date of death in participants with SUDEP and to the same period for their corresponding controls). HRV was assessed by calculating the Root Mean Square of Successive Differences over a 5-min daytime segment of interictal ECG.

## Statistical analyses

Descriptive statistics for continuous variables were reported as the median with IQR and as numbers and
<table><thead><tr><th rowspan="2">Sex</th><th rowspan="2">Epilepsy history</th><th rowspan="2">Age at onset of tested epilepsy, medications</th><th rowspan="2">Number of tested years</th><th rowspan="2">Average seizure frequency during the previous year</th><th rowspan="2">GTCS frequency during the previous year</th><th rowspan="2">Predominantly nocturnal seizures</th><th rowspan="2">MRI findings</th><th rowspan="2">Localisation of MRI findings</th><th rowspan="2">Other available neuro-imaging data</th><th rowspan="2">Type of video EEG monitoring</th><th rowspan="2">Category of the epilepto-epileptogenic zone</th><th rowspan="2">Sides of the zone</th><th colspan="3">Death-related information</th></tr><tr><th>Age at death</th><th>Place of death</th><th>Type of SUDEP</th></tr></thead><tbody><tr><td>1</td><td>Female</td><td>14</td><td>3</td><td>≥1 per month</td><td>Yes</td><td>Yes</td><td>Focal cortical dysplasia</td><td>Left fronto-central</td><td>..</td><td>Scalp EEG</td><td>Frontal</td><td>Left</td><td>No surgery planned</td><td>22</td><td>6</td><td>Home, bed</td><td>Probable</td></tr><tr><td>2</td><td>Female</td><td>8</td><td>8</td><td>≥1 per month</td><td>Yes</td><td>Yes</td><td>Normal</td><td>..</td><td>Idal SPECT</td><td>Scalp EEG</td><td>Perisylvian</td><td>Left</td><td>No surgery planned, vagus nerve stimulation started</td><td>36</td><td>14</td><td>Home, bed</td><td>Probable</td></tr><tr><td>3</td><td>Male</td><td>13</td><td>6</td><td>Two per month</td><td>None in last 5 years</td><td>Yes</td><td>Focal cortical dysplasia</td><td>Right fronto-central</td><td>..</td><td>Scalp EEG</td><td>Frontal</td><td>Right</td><td>No surgery planned</td><td>19</td><td>1</td><td>Home, bed</td><td>Probable</td></tr><tr><td>4</td><td>Male</td><td>Perinatal insult</td><td>3</td><td>5</td><td>Seven per month</td><td>Yes</td><td>Normal</td><td>..</td><td>..</td><td>Scalp EEG</td><td>Frontal</td><td>Right</td><td>No surgery planned, vagus nerve stimulation started</td><td>24</td><td>17</td><td>Institution, bed</td><td>Probable</td></tr><tr><td>5</td><td>Male</td><td>6</td><td>2</td><td>Four per month</td><td>≥1 per month</td><td>Yes</td><td>Normal</td><td>..</td><td>..</td><td>Scalp EEG</td><td>Temporal</td><td>Right</td><td>Presurgical tests ongoing</td><td>33</td><td>4</td><td>Home, bed</td><td>Probable</td></tr><tr><td>6</td><td>Male</td><td>17</td><td>7</td><td>≥1 per month</td><td>≥1 per year to &lt;1 per month</td><td>Yes</td><td>Normal</td><td>..</td><td>["F] FDG-PET, MEG</td><td>Scalp EEG</td><td>Perisylvian</td><td>Left</td><td>No surgery planned</td><td>25</td><td>21</td><td>Home</td><td>Definite</td></tr><tr><td>7</td><td>Male</td><td>Febrile convulsion</td><td>1</td><td>6</td><td>≥1 per day</td><td>None in last 5 years</td><td>No</td><td>Encephalomalacia</td><td>Left fronto-perisylvian</td><td>["F] FDG-PET, MEG</td><td>Scalp EEG, stereo EEG</td><td>Perisylvian</td><td>Left</td><td>Left fronto-perisylvian cortectomy, no post-operative seizure (Engel class 1)</td><td>38</td><td>44</td><td>Home, bed</td><td>Probable</td></tr><tr><td>8</td><td>Male</td><td>31</td><td>3</td><td>Two per month</td><td>≥1 per month</td><td>Yes</td><td>Vascular malformation</td><td>Right perisylvian</td><td>["F] FDG-PET</td><td>Scalp EEG, stereo EEG</td><td>Perisylvian</td><td>Right</td><td>Right temporoperisylvian cortectomy, no post-operative seizure (Engel class 1)</td><td>43</td><td>43</td><td>Home, bed</td><td>Probable</td></tr><tr><td>9</td><td>Male</td><td>Epilepsy in the family</td><td>13</td><td>3</td><td>One per month</td><td>None in last 5 years</td><td>No</td><td>Normal</td><td>..</td><td>..</td><td>Stereo EEG</td><td>Perisylvian</td><td>Bilateral</td><td>No surgery planned</td><td>22</td><td>44</td><td>Home, couch</td><td>Definite</td></tr></tbody><tfoot><tr><td colspan="10" style="text-align: right;">(Table 1 continues on next page)</td><td></td><td></td><td></td><td></td></tr></tfoot></table>
<table><thead><tr><th rowspan="2">Sex</th><th rowspan="2">Epilepsy history</th><th colspan="3">Seizure characteristics</th><th colspan="5">Neuroimaging and EEG findings and surgical status</th><th colspan="4">Death-related information</th></tr><tr><th>Age at onset of tested epilepsy, medications years</th><th>Number of tested antiseizure medications</th><th>Average seizure frequency during the previous year</th><th>Predominantly nocturnal seizures</th><th>MRI findings</th><th>Localisation of MRI findings</th><th>Other available neuro-imaging data</th><th>Type of video EEG monitoring genic zone</th><th>Category of the epilepto-epileptic zone</th><th>Sides of the genic zone</th><th>Last surgical status before SUDEP</th><th>Age at death, from years</th><th>Place of death inclusion to death, months</th><th>Type of SUDEP</th></tr></thead><tbody><tr><td colspan="16">(Continued from previous page)</td></tr><tr><td>10</td><td>Female Severe traumatic brain injury</td><td>12</td><td>8</td><td>Four per month</td><td>≥1 per month</td><td>No</td><td>Post-traumatic scar</td><td>Left perisylvian</td><td>[#F] FDG-PET</td><td>Scalp EEG</td><td>Perisylvian</td><td>Left</td><td>No surgery planned</td><td>53</td><td>50</td><td>Home</td><td>Probable</td></tr><tr><td>11</td><td>Male</td><td>1</td><td>6</td><td>Two per month</td><td>≥1 per year to &lt;1 per month</td><td>No</td><td>Encephalomalacia</td><td>Left perisylvian</td><td>[#F] FDG-PET</td><td>Scalp EEG</td><td>Perisylvian</td><td>Left</td><td>No surgery planned, vagus nerve stimulation started</td><td>31</td><td>56</td><td>Home, bed</td><td>Probable</td></tr><tr><td>12</td><td>Male</td><td>44</td><td>4</td><td>Four per month</td><td>≥1 per year to &lt;1 per month</td><td>No</td><td>Normal</td><td>...</td><td>[#F] FDG-PET, ictal SPECT</td><td>Scalp EEG</td><td>Temporal</td><td>Left</td><td>No surgery planned</td><td>50</td><td>65</td><td>Hotel room</td><td>Definite</td></tr><tr><td>13</td><td>Male Operated cavernoma</td><td>31</td><td>6</td><td>Two per month</td><td>≥1 per year to &lt;1 per month</td><td>No</td><td>Post operative scar</td><td>Left fronto-perisylvian</td><td>[#F] FDG-PET</td><td>Scalp EEG, stereo EEG</td><td>Perisylvian</td><td>Left</td><td>No surgery planned</td><td>48</td><td>50</td><td>Home, bed</td><td>Probable</td></tr><tr><td>14</td><td>Male</td><td>14</td><td>8</td><td>20 per month</td><td>≥1 per month</td><td>Yes</td><td>Malformation of cortical development</td><td>Left frontal</td><td>[#F] FDG-PET, MEG</td><td>Scalp EEG, stereo EEG</td><td>Frontal</td><td>Left</td><td>Left fronto-mesial cortectomy, post-operative seizures (Engel class 3)</td><td>39</td><td>66</td><td>Home, bed</td><td>Probable</td></tr><tr><td>15</td><td>Female Tuberous sclerosis</td><td>0</td><td>5</td><td>Unknown year</td><td>&lt;1 per year</td><td>Yes</td><td>Tuber</td><td>Left precentral</td><td>[#F] FDG-PET</td><td>Scalp EEG, stereo EEG</td><td>Frontal</td><td>Left</td><td>No surgery planned</td><td>64</td><td>51</td><td>Home, bathroom†</td><td>Probable</td></tr><tr><td>16</td><td>Male</td><td>1</td><td>10</td><td>Two per month</td><td>≥1 per year to &lt;1 per month</td><td>No</td><td>Normal</td><td>...</td><td>[#F] FDG-PET</td><td>Scalp EEG</td><td>Perisylvian</td><td>Right</td><td>No surgery planned</td><td>52</td><td>48</td><td>Home, bed</td><td>Probable</td></tr><tr><td>17</td><td>Female Epilepsy in the family</td><td>10</td><td>6</td><td>Ten per month</td><td>None in last 5 years</td><td>No</td><td>Normal</td><td>...</td><td>...</td><td>Scalp EEG</td><td>Temporal</td><td>Bilateral</td><td>No surgery planned</td><td>55</td><td>94</td><td>Home, floor</td><td>Probable</td></tr><tr><td>18</td><td>Male</td><td>29</td><td>5</td><td>One per month</td><td>≥1 per year to &lt;1 per month</td><td>No</td><td>Encephalomalacia</td><td>Right fronto-perisylvian</td><td>MEG</td><td>Stereo EEG</td><td>Perisylvian</td><td>Right</td><td>Right frontal cortectomy, post-operative seizures (Engel class 3)</td><td>35</td><td>82</td><td>Home</td><td>Definite</td></tr></tbody></table>

[#F]FDG-PET=[#F]fluoroodeoxyglucose PET, GTCS=generalised tonic-clonic seizure, MEG=magnetoencephalography. SPECT=single photon emission CT, SUDEP=sudden unexpected death in epilepsy. †Notable medical history that could have contributed to the development of epilepsy. †The patient was found in the bathtub in the supine position with only 5 cm of water.

<caption>Table 1: Epilepsy and seizures characteristics, surgical status and death-related information in the 18 patients who died of a probable or definite SUDEP</caption>
<table><thead><tr><th></th><th>SUDEP group<br>(n=18)</th><th>Controls<br>(n=72)</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td></tr><tr><td>Male</td><td>13 (72%)</td><td>38 (53%)</td></tr><tr><td>Female</td><td>5 (28%)</td><td>34 (47%)</td></tr><tr><td>Median age at onset of epilepsy</td><td>12.5 (3.4-16.3)</td><td>14.8 (8.9-24.0)</td></tr><tr><td>Median age at inclusion</td><td>33.7 (24.4-44.2)</td><td>32.6 (24.4-42.5)</td></tr><tr><td>Median duration of epilepsy at inclusion</td><td>19.5 (7.1-31.9)</td><td>12.6 (6.8-22.3)</td></tr><tr><td>Past history of depression</td><td></td><td></td></tr><tr><td>No history of depression (%)</td><td>15 (83%)</td><td>51 (71%)</td></tr><tr><td>A history of depression (%)</td><td>3 (17%)</td><td>21 (29%)</td></tr><tr><td>BMI at inclusion</td><td></td><td></td></tr><tr><td>Median BMI</td><td>23.8 (22.1-28.7)</td><td>23.4 (20.4-25.4)</td></tr><tr><td>BMI &lt;30</td><td>14 (78%)</td><td>70 (97%)</td></tr><tr><td>BMI ≥30</td><td>4 (22%)</td><td>2 (3%)</td></tr><tr><td>NDDI-E score at inclusion</td><td></td><td></td></tr><tr><td>Median NDDI-E score</td><td>13.0 (10.5-14.8)</td><td>12.0 (9.0-15.0)</td></tr><tr><td>NDDI-E score &lt;15</td><td>10/14 (71%)</td><td>46/65 (71%)</td></tr><tr><td>NDDI-E score ≥15</td><td>4/14 (29%)</td><td>19/65 (29%)</td></tr><tr><td>SA-SDQ score at inclusion</td><td></td><td></td></tr><tr><td>Median SA-SDQ score in men</td><td>29.0 (20.3-39.5)</td><td>20.0 (17.0-24.0)</td></tr><tr><td>Median SA-SDQ score in women</td><td>22.0 (18.0-26.0)</td><td>19.0 (17.0-24.0)</td></tr><tr><td>SA-SDQ &lt;26 (for women) or &lt;29 (for men)</td><td>6/13 (46%)</td><td>45/58 (78%)</td></tr><tr><td>SA-SDQ ≥26 (for women) or ≥29 (for men)</td><td>7/13 (54%)</td><td>13/58 (22%)</td></tr><tr><td>Frequency of FBTCS during the last 5 years</td><td></td><td></td></tr><tr><td>None</td><td>4 (22%)</td><td>40 (56%)</td></tr><tr><td>&lt;1 per year</td><td>1 (6%)</td><td>5 (7%)</td></tr><tr><td>≥1 per year and &lt;1 per month</td><td>8 (44%)</td><td>24 (33%)</td></tr><tr><td>≥1 per month</td><td>5 (28%)</td><td>3 (4%)</td></tr><tr><td>Nocturnal seizures during the last year</td><td></td><td></td></tr><tr><td>Predominantly diurnal seizures</td><td>9 (50%)</td><td>59 (82%)</td></tr><tr><td>Predominantly nocturnal seizures</td><td>9 (50%)</td><td>13 (18%)</td></tr><tr><td>Number of concurrent antiseizure medications at inclusion</td><td></td><td></td></tr><tr><td>Monotherapy</td><td>3 (17%)</td><td>11 (15%)</td></tr><tr><td>Polytherapy</td><td>15 (83%)</td><td>61 (85%)</td></tr><tr><td>MRI findings</td><td></td><td></td></tr><tr><td>Normal MRI (%)</td><td>8 (44%)</td><td>20 (28%)</td></tr><tr><td>MRI abnormality (%)</td><td>10 (56%)</td><td>52 (72%)</td></tr></tbody><tfoot><tr><td colspan="3">(Table 2 continues in next column)</td></tr></tfoot></table>

<table><thead><tr><th></th><th>SUDEP group<br>(n=18)</th><th>Controls<br>(n=72)</th></tr></thead><tbody><tr><td>(Continued from previous column)</td><td></td><td></td></tr><tr><td>Heart rate variability</td><td></td><td></td></tr><tr><td>Median short-term interictal<br>root mean square of successive<br>differences</td><td>28.7 (19.5-40.3)</td><td>29.3 (23.0-42.6)</td></tr><tr><td>Epileptogenic zone*</td><td></td><td></td></tr><tr><td>Temporal epileptogenic zone</td><td>3 (17%)</td><td>48 (67%)</td></tr><tr><td>Extratemporal epileptogenic<br>zone</td><td>15 (83%)</td><td>24 (33%)</td></tr><tr><td>Frontal</td><td>5 (28%)</td><td>10 (14%)</td></tr><tr><td>Perisylvian</td><td>10 (56%)</td><td>7 (10%)</td></tr><tr><td>Posterior</td><td>0</td><td>7 (10%)</td></tr><tr><td>Epilepsy surgery during follow-up†</td><td></td><td></td></tr><tr><td>Not operated on during<br>follow-up</td><td>14 (78%)</td><td>54 (75%)</td></tr><tr><td>Operated on during follow-up</td><td>4 (22%)</td><td>18 (25%)</td></tr><tr><td>Operated on patients with a<br>temporal epileptogenic zone</td><td>0/3</td><td>13/48 (27%)</td></tr><tr><td>Operated on patients with an<br>extratemporal epileptogenic<br>zone</td><td>4/15 (27%)</td><td>7/24 (29%)</td></tr><tr><td>Proportion of patients at Engel class 1 at 12 months after surgery</td><td></td><td></td></tr><tr><td>All operated on patients</td><td>2/4 (50%)</td><td>14/20 (70%)</td></tr><tr><td>Operated on patients with a<br>temporal epileptogenic zone</td><td>..</td><td>11/13 (85%)</td></tr><tr><td>Operated on patients with an<br>extratemporal epileptogenic<br>zone</td><td>2/4 (50%)</td><td>3/7 (43%)</td></tr></tbody><tfoot><tr><td colspan="3">Data are n (%), n/N (%), or median (IQR). FBTCS=focal-to-bilateral tonic-clonic seizure. NDDI-E=Neurological Disorders Depression Inventory for Epilepsy. SA-SDQ=Sleep Apnea Scale of the Sleep Disorders Questionnaire. SUDEP=sudden unexpected death in epilepsy. *The localisation of the epileptogenic zone was based on the following information and investigations when available: past history of potential epilepsy cause, ictal semiology, interictal and ictal scalp-EEG, MRI, [¹⁹F]fluorodeoxyglucose PET, ictal single photon emission CT, and invasive EEG. †In the SUDEP group, duration of follow-up corresponded to the time elapsing between inclusion and death. In the control group, duration of follow-up was the same as that of their corresponding participant in the SUDEP group.</td></tr></tfoot></table>

regularisation for variable selection. For each imputed dataset, a value for the LASSO penalty variable (lambda) was estimated by cross-validation. In addition to sex, which was included a priori, only variables selected in more than 50% of the imputed datasets were retained for further analyses. Given that LASSO is not a statistically conservative method, we further refined the model by sequentially removing the least associated covariates fitting unpenalised conditional regression models and comparing submodels using Wald tests, with Rubin's rules applied to the imputed datasets. Odds ratios (ORs) and 95% CIs were estimated from each imputed dataset and then combined using Rubin's rules for models that included variables with imputed data; otherwise, estimates were derived from the complete dataset. All statistical tests (two-sided) were done to fix

percentages for categorical variables. Missing data were handled using multivariate imputation by chained equations, generating 100 imputed datasets. Stratification was taken into account in the imputation design by introducing the variable defining the strata (each case with its own controls) as a factor in the imputation model. Given the matched study design, analyses were done using conditional logistic regression models. We first used a penalised multivariable conditional logistic regression model with Least Absolute Shrinkage and Selection Operator (LASSO)
<table><thead><tr><th></th><th colspan="2">SUDEP group (n=18)</th><th colspan="2">Controls (n=72)</th></tr><tr><th></th><th>Total</th><th>With SpO<sub>2</sub></th><th>Total</th><th>With SpO<sub>2</sub></th></tr></thead><tbody><tr><td colspan="5"><strong>Number of patients with recorded seizure data available</strong></td></tr><tr><td>Strictly focal seizures</td><td>15 (83%)</td><td>13 (72%)</td><td>59 (82%)</td><td>49 (68%)</td></tr><tr><td>FBTCS</td><td>8 (44%)</td><td>3 (17%)</td><td>12 (17%)</td><td>6 (8%)</td></tr><tr><td colspan="5"><strong>Number of recorded seizures</strong></td></tr><tr><td>Strictly focal seizures</td><td>49</td><td>37</td><td>207</td><td>134</td></tr><tr><td>FBTCS</td><td>15</td><td>4</td><td>20</td><td>6</td></tr><tr><td colspan="5"><strong>Number of recorded seizures per patient with at least one recorded seizure</strong></td></tr><tr><td>Strictly focal seizures</td><td>3.3±5.3 (1.0)</td><td>2.8±5.1 (1.0)</td><td>3.5±3.9 (2.0)</td><td>2.7±3.6 (2.0)</td></tr><tr><td>FBTCS</td><td>1.9±1.7 (1.0)</td><td>1.3±0.8 (1.0)</td><td>1.7±0.9 (1.5)</td><td>1.0±0.0 (1.0)</td></tr><tr><td colspan="5"><strong>Proportion of seizures with peri-ictal SpO<sub>2</sub> &lt;80%</strong></td></tr><tr><td>Strictly focal seizures</td><td>2/37 (5%)</td><td></td><td>8/134 (6%)</td><td></td></tr><tr><td>FBTCS</td><td>3/4 (75%)</td><td></td><td>2/6 (33%)</td><td></td></tr><tr><td colspan="5"><strong>Proportion of patients with peri-ictal SpO<sub>2</sub> &lt;80%*</strong></td></tr><tr><td>Strictly focal seizures</td><td>2/13 (15%)</td><td></td><td>7/49 (14%)</td><td></td></tr><tr><td>FBTCS</td><td>3/3 (100%)</td><td></td><td>2/6 (33%)</td><td></td></tr></tbody></table>

Data are n (%), n/N (%), or mean ±SD (median). FBTCS=focal-to-bilateral tonic-clonic seizure. SUDEP=sudden unexpected death in epilepsy. *For patients with multiple seizures recorded, only that with the lowest SpO₂ value was considered.

<caption>**Table 3: Availability of recorded seizures and peri-ictal hypoxemia by group**</caption>

the type 1 error rate at 5%, and were done using R software version 4.4.1.

## Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

## Results

We included a total of 1084 participants in our prospective cohort from May 18, 2010, to Aug 23, 2015. After excluding six duplicate entries and four participants who withdrew their consent, our final cohort comprised 1074 people with epilepsy. During a follow-up period totalling 6828 patient-years, 42 of the 1074 eligible participants (4%) died, resulting in a crude death rate of 6.15/1000 patient-years (95% CI 3.92–8.05; appendix p 6). Of these 42 deaths, 18 (43%) were adjudicated as probable (14) or definite (4) SUDEP, one as possible SUDEP (2%), and 23 (55%) as non-SUDEP (appendix p 2).

None of the participants who died of SUDEP suffered from known comorbidities that could have contributed to their death, particularly cardiovascular conditions. All 18 probable and definite SUDEP occurred without witnesses. Participants were found in their bed in 11 cases, outside their bed in three, and without further details in the other four. The rate of probable and definite SUDEP was 2.64/1000 patient-years (95% CI 1.36–3.92). Detailed information regarding the 18 definite and probable SUDEP is provided in table 1.

For each of the 18 participants who died of probable or definite SUDEP, four matched controls were selected from

the full cohort. In total, 90 participants (18 SUDEP cases and 72 controls) were included in the case-control study.

Demographics and clinical data are presented in table 2 and the appendix (p 3). Four of the 11 tested covariates had missing data, affecting the following number of the 90 participants: 24 for peri-ictal hypoxemia (27%), 19 for SA-SDQ (21%), 14 for HRV (16%), and 11 for NDDI-E (12%; appendix pp 7, 8). Compared with the controls, participants who died of SUDEP were younger at epilepsy onset, had a longer epilepsy duration, were more likely to be male, more likely to have obesity, had elevated SA-SDQ scores, had a higher frequency of FBTCS in the past 5 years, and had predominantly nocturnal seizures, normal MRI findings, and extratemporal epileptogenic zones, including perisylvian and frontal epileptogenic zones. In contrast, age at inclusion, NDDI-E score, number and types of antiseizure medications, HRV, and proportion of operated participants during follow-up were similar between the groups.

Seizure-related findings are detailed in table 3. Focal seizures with interpretable peri-ictal SpO₂ and lack of oxygen administration were recorded in 13 (72%) of 18 participants with SUDEP and 49 (68%) of 72 controls. The proportion of focal seizures with peri-ictal SpO₂ of less than 80% was two of 37 (5.4%, 95% CI 1.0–20.5%) in participants who died of SUDEP and eight of 134 (6.0%, 2.8–11.9%) in controls. Only two participants, both controls, showed inconsistent SpO₂ findings across several focal seizures. There were two participants of 13 (15.4%, 2.7–46.4%) with at least one recorded focal seizure with peri-ictal SpO₂ of less than 80% in the SUDEP group and seven of 49 (14.3%, 6.6–28.4%) in the control group (table 3).

FBTCS were recorded in eight participants who died of SUDEP (44%) and 12 controls (17%), with less than half of those providing interpretable peri-ictal SpO₂ (three participants with SUDEP and six controls). These small sample sizes precluded any comparison between groups for FBTCS characteristics, and only descriptive statistics were performed on these data, showing a numerically higher rate of post-ictal SpO₂ of less than 80% but a lower rate of post-ictal apnoea in participants with SUDEP compared with controls (appendix p 3). No episode of bradycardia or asystole were observed in either participants who died of SUDEP or controls, leading to the exclusion of these covariates from statistical analyses.

The LASSO-penalised conditional logistic regression model identified eight covariates that were selected in more than 50% of the 100 imputed datasets and were therefore included in subsequent analyses: sex, localisation of the epileptogenic zone, age at epilepsy onset, frequency of FBTCS, predominantly nocturnal seizures, HRV, SA-SDQ score, and BMI (appendix p 4). Six covariates were selected in less than 50% of the 100 imputed datasets and were therefore excluded during this step: peri-ictal SpO₂ of less than 80% during focal seizures, epilepsy surgery during follow-up, history of
depression, NDDI-E score, presence of an MRI lesion, and number of antiseizure medications. To refine the model, non-penalised nested conditional logistic regression models were compared using the Wald test, starting from the eight-variable model. Four covariates were sequentially removed due to non-significance: HRV (p=0.854), SA-SDQ score (p=0.501), age at epilepsy onset (p=0.428), and frequency of FBTCS (p=0.118; appendix p 5). The final model retained sex and three covariates significantly associated with SUDEP, for which there were no missing data. Compared with controls, participants who died of SUDEP had a higher likelihood of presenting with an extratemporal epileptogenic zone (OR 37.8, 95% CI 3.2-446.2; p=0.0039), BMI of 30 or higher (26.0, 2.0-339.6; p=0.013), male sex (12.6, 1.5-106.8; p=0.0201), and predominantly nocturnal seizures with the frequency of FBTCS. This analysis suggested that an extratemporal epileptogenic zone (33.0, 3.2-339.2; p=0.0033) and a BMI of 30 or higher (42.6, 1.3-1402.6; p=0.035) were associated with SUDEP, whereas male sex (p=0.056) and FBTCS frequency (p=0.067) were not significant (appendix p 5).

Based on numerical values, the association between an extratemporal epileptogenic zone and SUDEP risk appears to be primarily driven by a higher proportion of perisylvian epileptogenic zones in participants who died of SUDEP (ten [56%] of 18) compared with controls (seven [10%] of 72); and, to a lesser extent, by a more frequent frontal localisation in participants who died of SUDEP (five [28%] of 18) than in controls (ten [14%] of 72). In contrast, posterior epileptogenic zones were not observed in the SUDEP group and were present in only seven (10%) of the 72 controls.

## Discussion

The primary objective of this case-control study, nested in a dedicated prospective cohort of participants undergoing in-hospital seizure recording, was to delineate novel SUDEP risk factors that might help to improve individual risk assessment and facilitate future clinical trials targeting SUDEP prevention.⁵,¹⁹ The study identified the presence of an extratemporal epileptogenic zone as a clinically relevant novel SUDEP risk factor, particularly when affecting the perisylvian region or the frontal lobe, and did not observe a significant association between peri-ictal hypoxemia of less than 80% during focal seizures and SUDEP.

Our study benefited from a highly reliable assessment of vital status and robust documentation of the circumstances and causes of death in all deceased participants. As a result, adjudication of the cause of death as either non-SUDEP or probable or definite SUDEP was achieved in 98% of cases. This high level

of diagnostic certainty lends confidence to our estimated incidence of probable or definite SUDEP (2.64/1000 patient-years), despite being lower than that typically reported in drug-resistant epilepsy (4.5/1000 patient-years).²⁰ Another epilepsy monitoring unit-based prospective series in the USA reported a SUDEP rate of 4.76/1000 patient-years, and 3.26/1000 patient-years for probable or definite SUDEP.⁷ Several factors might account for the lower incidence observed in our cohort. First, a 7% annual decrease in SUDEP incidence was reported to occur during the longitudinal assessment of epilepsy cohorts, for reasons that are unclear.²¹ This decline in SUDEP incidence over time is expected to be more pronounced in our cohort, which was followed up for an average of 6.4 years, compared to the US cohort, which was followed for an average of 3.2 years.²¹ Second, approximately a third of our cohort underwent epilepsy surgery during follow-up—a procedure associated with a threefold reduction in SUDEP risk,²² and a postoperative SUDEP incidence of 0.84/1000 patient-years.²³

Our main finding is the association between SUDEP and the localisation of the epileptogenic zone, with a higher risk of SUDEP in people with extratemporal epilepsy, particularly those affecting the perisylvian region or the frontal lobe. Notably, the localisation of the epileptogenic zone is an enduring biomarker that can be modified by epilepsy surgery. A single-centre retrospective study has previously reported more frequent extratemporal lobe lesion in participants who died from SUDEP than in the control group of people with epilepsy.²⁴ However, the absence of information regarding the rate of SUDEP per time unit limits the conclusions that can be drawn from these findings. Several factors might explain a higher risk of SUDEP in people with extratemporal epilepsies, including more frequent FBTCS in frontal lobe epilepsy and a greater likelihood of nocturnal seizures in frontal and perisylvian epilepsies.¹⁷,²⁵ Additionally, some of the brain regions underlying these epilepsies participate in central cardiorespiratory functions, particularly the insula, which is a core component of the central autonomic network,¹⁶ and the frontocentral and opercular regions, which directly control the motor activity of the respiratory tract. Participants with insulo-opercular seizures frequently

<table><caption>Table 4: Final non-penalised conditional logistic regression model</caption><thead><tr><th></th><th>Odds ratio (95% CI)</th><th>p value*</th></tr></thead><tbody><tr><td>Sex (male or female)</td><td>12.61 (1.49-106.83)</td><td>0.0201</td></tr><tr><td>Epileptogenic zone (temporal or extratemporal)</td><td>37.84 (3.21-446.15)</td><td>0.0039</td></tr><tr><td>Predominantly nocturnal seizure (yes or no)</td><td>5.95 (1.23-28.74)</td><td>0.0265</td></tr><tr><td>BMI ≥30 (yes or no)</td><td>25.97 (1.99-339.56)</td><td>0.0130</td></tr></tbody><tfoot><tr><td colspan="3">*Two-tailed p-values (Wald test).</td></tr></tfoot></table>
report respiratory distress and sensations of suffocation,¹⁷ sometimes culminating into laryngospasm.¹⁸ A few case reports of SUDEP and near-SUDEP (people who almost died of a SUDEP but were rescucitated) in participants with epilepsies or surgical damage involving the insula also support the hypothesis of an insular dysfunction contributing to SUDEP pathophysiology.⁴,²⁶,²⁷

All our other findings are in line with previous reports,⁵⁻⁷ including the higher risk of SUDEP in boys and men,⁵,⁶ in people with epilepsy with predominantly nocturnal seizures,⁵,⁶ and in those with an elevated BMI.²⁸⁻³⁰ A high BMI could increase the risk of SUDEP through various mechanisms, including a more severe respiratory effect of a postictal prone position, greater difficulty repositioning from such a position, and a higher incidence of cardiac pathology and obstructive sleep apnoea syndrome. Obstructive sleep apnoea syndrome has been proposed as a potential risk factor for SUDEP,³¹ a hypothesis that we could not confirm using SA-SDQ as a surrogate marker for this syndrome.

There was an absence of a significant trend toward an association between SUDEP and frequency of FBTCS, a notable negative finding given the well established association between GTCS and SUDEP.⁵ Our small sample size might partly explain this negative finding. Additionally, although previous studies assessed GTCS frequency during the year preceding SUDEP,⁶ we evaluated FBTCS frequency at study inclusion, with a median delay of 3·6 years between inclusion and SUDEP. Non accounted changes in FBTCS frequency during this interval might have further attenuated the association.

The incidence of peri-ictal oxygen desaturation (SpO₂ <80%) during focal seizures, as well as the proportion of participants with at least one such event, was identical in both the SUDEP and control groups. This is despite participants in the SUDEP group having a higher mean number of recorded focal seizures, which would theoretically increase the likelihood of detecting hypoxemia in this group. These negative findings align with those of a US prospective study published in 2025 by Ochoa-Urrea and colleagues,⁷ further suggesting that peri-ictal hypoxemia is unlikely to be a reliable SUDEP risk factor. In contrast, the duration of both ictal and postictal central apnoea was found to predict SUDEP risk in this US study,⁷ an association we were unable to evaluate because we have not collected respiratory data in our study. The small number of recorded FBTCS also prevented us from assessing associations between SUDEP postictal generalised EEG suppression.

The absence of peri-ictal bradycardia and asystole among our 72 controls is unsurprising, given the reported incidence of such arrhythmias ranges from 0·27% to 0·4% in people with epilepsy undergoing long-term monitoring.¹²,³³ The absence of these cardiac abnormalities in our SUDEP group suggests that they are unlikely to be common SUDEP risk factors. The 2025 US prospective study, which assessed a broader

range of peri-ictal arrhythmias, did not find an association between these arrhythmias and SUDEP, except in the subgroup of drug-resistant people with epilepsy.⁷ Short-term interictal HRV was not associated with SUDEP in either the US study or our study.⁷ Retrospective studies with HRV data have reported mixed results, probably reflecting differences in populations and methods.³⁴⁻³⁷

Epilepsy surgery performed during follow-up was not associated with a reduced risk of SUDEP, in contrast to the findings of a recent meta-analysis.²⁰ The small proportion of participants who underwent an operation in our case-control cohort (24% overall), combined with the study's small sample size, likely explains this negative finding. Moreover, SUDEP occurred in two individuals who were presumed to have been successfully treated with epilepsy surgery. Several hypotheses can explain this observation: some participants might have been misclassified as seizure-free due to unrecognised seizures or reluctance to report recurrence; SUDEP might have been triggered by a first postoperative breakthrough seizure, particularly in the context of antiseizure medication withdrawal; SUDEP can, in some cases, occur in the absence of a documented triggering seizure. Furthermore, the surgical management of perisylvian and frontal lobe epilepsies, which we found to carry a higher risk of SUDEP, poses notable functional and safety challenges—particularly when the epileptogenic zone includes the motor cortex, language areas, or the insula.¹⁷,³⁸ Neuromodulation offers an alternative therapeutic option for these clinical situations,³⁹ with some studies suggesting that vagus nerve stimulation might confer a protective effect against SUDEP.⁶,⁴⁰

A key limitation of our study is the small sample size of our case-control cohort, with only 18 definite or probable SUDEP cases. This limitation contributes to the wide confidence intervals observed for the identified risk factors and warrants caution when interpreting the odds ratios, which might overestimate the true underlying relative risks. Similarly, the null findings for specific covariates might reflect insufficient statistical power and should also be interpreted with caution.

Another limitation of our study is its generalisability, because our cohort only included people with drug-resistant focal epilepsy, excluding those with other types of epilepsy. However, the largest nationwide population-based SUDEP cohort, in Sweden, indicates that 73% of participants with SUDEP had focal epilepsy,⁶ suggesting that our findings are relevant to most participants with SUDEP. Investigating seizure-related biomarkers in other types of epilepsy would still be valuable, because it could uncover risk factors not observed in focal epilepsy.

This prospective study identified the seizure onset zone as a novel SUDEP risk factor, independent of previously reported biomarkers, opening new avenues for advancing the understanding, prediction, and prevention of SUDEP. Investigating how perisylvian and frontal lobe epileptogenic zones—and their specific
subregions—increase SUDEP risk might help elucidate the mechanisms underlying generalised convulsive seizure-triggered fatal apnoea. Accordingly, research studies of the autonomic and respiratory networks in people with epilepsy undergoing intracerebral EEG investigations should be encouraged. The development of comprehensive predictive models incorporating all available biomarkers, including the epileptogenic zone when available, is essential to improve SUDEP risk stratification. Achieving this goal will require international collaborative efforts to share existing datasets and prospectively collect high-quality clinical data. The association between specific seizure-onset zones and SUDEP risk also has direct clinical implications. This finding supports the need for more systematic, timely, and optimised diagnostic evaluations in people with drug-resistant focal epilepsies, to better identify those at higher risk and to expand their therapeutic options, including surgery and neuromodulation where appropriate. Finally, our confirmation of an increased risk of SUDEP in overweight individuals with epilepsy underscores the importance of recognising, managing, and preventing this modifiable comorbidity.

### Contributors

PRy and SRh designed and coordinated the study. PRy wrote the first draft of the manuscript. PRo designed and coordinated the statistical plan and analyses. MH wrote the statistical plan, performed the statistical analyses, and provided the statistical report. FCho and NT-K participated in the statistical analyses. PRy, SR, LV, LM, FB, PD, EH, VM, FCha, JP, AC, AB, VN, PK, BDT, PT, and SRo coordinated participant recruitment and data collection in their respective centres. A-LC, LC, ML, MM, BMA, and MS collected and curated data.

PD managed storage and access to raw data. AB and AF assessed the duration of focal-to-bilateral tonic-clonic seizures, postictal immobility, and apnoea. AS assessed postictal generalised EEG suppression. MT assessed heart rate variability. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The two leading authors (PR and SRh) had access to and verified the data.

### Declaration of interests

BMA has received speaker fees from Angelini-Pharma, Bial, Eisai, Jazz Pharmaceuticals, Kern Pharma, Nutricia, and UCB Pharma; and consultant fees from Angelini-Pharma, Bial, Eisai, Jazz Pharmaceuticals, Kern Pharma, Nutricia, and UCB Pharma. FB has received consultant fees from Angelini Pharma, Jazz Pharmaceuticals, Livanova, UCB Pharma, and Neuraxpharm; and speaker fees from Angelini Pharma, Bial, Eisai, GW, Jazz Pharmaceuticals, Livanova, Medtronic, UCB Pharma, Zogenix, and Neuraxpharm. AB has received consultant fees from Angelini Pharma, B3TSI, Jazz Pharmaceuticals, Livanova, Neuraxpharm, UCB Pharma; and speaker fees from Angelini Pharma, Bial, Eisai, GW, Jazz Pharmaceuticals, Livanova, and UCB Pharma. AC has received speaker and consultant fees from Angelini Pharma, Eisai. PD has received consultant fees from Angelini Pharma, UCB Pharma, and Neuraxpharm; and speaker fees from Angelini Pharma and UCB Pharma. EH has received consultant fees from Angelini Pharma and UCB Pharma; speaker fees from Angelini Pharma, UCB Pharma, and Jazz Pharmaceutical; and support for attending meetings and travel from Angelini Pharma, UCB Pharma, and Eisai. PK has received consultant fees from Angelini Pharma and Jazz Pharmaceutical; speaker fees from Dixi Medical; and support for attending meetings and travel from Angelini Pharma. LM has received consultant fees from Angelini Pharma, Bioserenity, Eisai, GW, Jazz Pharmaceuticals, and UCB Pharma; and speaker fees from Angelini Pharma, Bioserenity, Eisai, GW, Jazz Pharmaceuticals, and UCB Pharma.

VN has received consultant fees from Angelini Pharma, Jazz Pharmaceutical, Neuraxpharm, and UCB Pharma; and speaker fees from Angelini Pharma, Eisai, Jazz Pharmaceutical, and UCB Pharma. JP has received speaker fees from Eisai, Livanova, and UCB Pharma. SRh has received consultant fees from Angelini Pharma, Jazz Pharmaceuticals, Neuraxpharm, and UCB Pharma; and speaker fees from Angelini Pharma, Jazz Pharmaceuticals, Livanova, and UCB Pharma. LV has received consultant fees from Angelini Pharma, Jazz Pharmaceutical, Livanova, Neuraxpharm, and UCB Pharma; and speaker fees from Angelini Pharma, Eisai, Jazz Pharmaceutical, Livanova, and UCB Pharma.

### Data sharing

De-identified data supporting the findings of this study are available from the corresponding authors upon reasonable request, which should be sent to philippe.ryvlin@chuv.ch and sylvain.rheims@chu-lyon.fr.

### Acknowledgments

The REPO-MSE study was supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique National 2009). We thank all study participants and the staff at the recruiting centres for their contributions and are especially grateful to the bereaved families of participants who died during the study for generously providing invaluable information. PRy, SRh, FB, PD, and EH are members of the European Reference Network EpiCare.

### References

1. Kløvgård M, Lynge TH, Tsiropoulos I, et al. Sudden unexpected death in epilepsy in persons younger than 50 years: a retrospective nationwide cohort study in Denmark. *Epilepsia* 2021; **62**: 2405-15.

2. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: assessing the public health burden. *Epilepsia* 2014; **55**: 1479-85.

3. Sveinsson O, Andersson T, Carlsson S, Tomson T. Circumstances of SUDEP: a nationwide population-based case series. *Epilepsia* 2018; **59**: 1074-82.

4. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. *Lancet Neurol* 2013; **12**: 966-977.

5. Harden C, Tomson T, Gloss D, et al. Practice guideline summary: sudden unexpected death in epilepsy incidence rates and risk factors: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. *Neurology* 2017; **88**: 1674-80.

6. Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Clinical risk factors in SUDEP: a nationwide population-based case-control study. *Neurology* 2020; **94**: e419-29.

7. Ochoa-Urrea M, Luo X, Vilella L, et al. Risk markers for sudden unexpected death in epilepsy: an observational, prospective, multicentre cohort study. *Lancet* 2025; **406**: 1497-507.

8. Ryvlin P, Rheims S, Lhatoo SD. Risks and predictive biomarkers of sudden unexpected death in epilepsy patient. *Curr Opin Neurol* 2019; **32**: 205-12.

9. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. *Brain* 2008; **131**: 3239-45.

10. Rheims S, Alvarez BM, Alexandre V, et al. Hypoxemia following generalized convulsive seizures: risk factors and effect of oxygen therapy. *Neurology* 2018; **92**: e183-93.

11. Lacuey N, Zonjy B, Hampson JP, et al. The incidence and significance of periictal apnea in epileptic seizures. *Epilepsia* 2018; **59**: 573-82.

12. Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. *Epilepsia* 2012; **53**: 227-33.

13. Hafen BB, Sharma S. Oxygen saturation. StatPearls. Treasure Island, FL: StatPearls Publishing, 2024.

14. Devinsky O. Sudden, unexpected death in epilepsy. *N Engl J Med* 2011; **365**: 1801-11.

15. Theeranaew W, McDonald J, Zonjy B, et al. Automated detection of postictal generalized EEG suppression. *IEEE Trans Biomed Eng* 2018; **65**: 371-77.
16 Thijs RD, Ryvlin P, Surges R. Autonomic manifestations of epilepsy: emerging pathways to sudden death? *Nat Rev Neurol* 2021; **17**: 774–88.

17 Ryvlin P, Nguyen DK. Insular seizures and epilepsies: ictal semiology and minimal invasive surgery. *Curr Opin Neurol* 2021; **34**: 153–65.

18 Murray RC, Powell D, Curry JM, Sperling MR, Evans JJ, Spiegel JR. Epileptic laryngospasm presenting as a primary sleep disturbance. *Arch Otolaryngol Head Neck Surg* 2010; **136**: 1025–27.

19 Ryvlin P, Nashef L, Tomson T. Prevention of sudden unexpected death in epilepsy: a realistic goal? *Epilepsia* 2013; **54** (suppl 2): 23–28.

20 Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. *Lancet Neurol* 2008; **7**: 1021–31.

21 Tomson T, Sveinsson O, Carlsson S, Andersson T. Evolution over time of SUDEP incidence: a nationwide population-based cohort study. *Epilepsia* 2018; **59**: e120–124.

22 Rheims S, Sperling MR, Ryvlin P. Drug-resistant epilepsy and mortality-why and when do neuromodulation and epilepsy surgery reduce overall mortality. *Epilepsia* 2022; **63**: 3020–36.

23 Fiore G, de Tisi J, O'Keeffe A, et al. Long-term survival after adult epilepsy surgery: mortality and predictors in a large cohort. *Epilepsia* 2025; published online July 25. https://doi.org/10.1111/epi.18564.

24 Almeida AG, Nunes ML, Palmini AL, Costa JC. Incidence of SUDEP in a cohort of patients with refractory epilepsy: the role of surgery and lesion localization. *Arq Neuropsiquiatr* 2010; **68**: 898–902.

25 Crespel A, Baldy-Moulinier M, Coubes P. The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. *Epilepsia* 1998; **39**: 150–57.

26 Ryvlin P. Avoid falling into the depths of the insular trap. *Epileptic Disord* 2006; **8** (suppl 2): S37–56.

27 Lacuey N, Zonjy B, Theerannaew W, et al. Left-insular damage, autonomic instability, and sudden unexpected death in epilepsy. *Epilepsy Behav* 2016; **55**: 170–73.

28 Eslami V, Kimberley Molina D, Ákos Szabó C. Definite SUDEP population in Bexar County, Texas: a 36-year data registry. *Epilepsy Behav* 2021; **121**: 108005.

29 Liu Q, Tan B, Zhang J, et al. Derivation and validation of a new prediction model for sudden unexpected death in epilepsy based on a longitudinal prospective population-based cohort. *Epilepsy Behav* 2023; **147**: 109446.

30 Li R, Zhao D, Hu B, Li N, Li J, Lin W. Incidence and risk factors of sudden unexpected death in epilepsy in rural Northeast China. *Seizure* 2025; **126**: 99–105.

31 McCarter AR, Timm PC, Shepard PW, et al. Obstructive sleep apnea in refractory epilepsy: a pilot study investigating frequency, clinical features, and association with risk of sudden unexpected death in epilepsy. *Epilepsia* 2018; **59**: 1973–81.

32 Schuele SU, Bermeo AC, Alexopoulos AV, et al. Video-electrographic and clinical features in patients with ictal asystole. *Neurology* 2007; **69**: 434–41.

33 Rocamura R, Kurthen M, Lickfett L, Von Oertzen J, Elger CE. Cardiac asystole in epilepsy: clinical and neurophysiologic features. *Epilepsia* 2003; **44**: 179–85.

34 Surges R, Henneberger C, Adjei P, Scott CA, Sander JW, Walker MC. Do alterations in inter-ictal heart rate variability predict sudden unexpected death in epilepsy? *Epilepsy Res* 2009; **87**: 277–80.

35 Sivathamboo S, Friedman D, Laze J, et al. Association of short-term heart rate variability and sudden unexpected death in epilepsy. *Neurology* 2021; **97**: e2357–67.

36 Myers KA, Bello-Espinosa LE, Symonds JD, et al. Heart rate variability in epilepsy: a potential biomarker of sudden unexpected death in epilepsy risk. *Epilepsia* 2018; **59**: 1372–80.

37 Evangelista G, Dono F, Consoli S, et al. Heart rate variability modification as a predictive factor of sudden unexpected death in epilepsy: how far are we? A systematic review and meta-analysis. *Eur J Neurol* 2023; **30**: 2122–31.

38 Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. *Lancet Neurol* 2014; **13**: 1114–26.

39 Ryvlin P, Rheims S, Hirsch LJ, Sokolov A, Jehi L. Neuromodulation in epilepsy: state-of-the-art approved therapies. *Lancet Neurol* 2021; **20**: 1038–47.

40 Ryvlin P, So EL, Gordon CM, et al. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. *Epilepsia* 2018; **59**: 562–72.