Burst-Suppression EEG in Early Infantile Developmental and Epileptic Encephalopathies

Florence Riccardi, Béatrice Desnous, Emilie Borloz, Anne Lepine, Caroline Lacoste, Cécile Mignon-Ravix, Pierre Cacciagli, Chantal Missirian, Florence Molinari, Jérémie Mortreux, Alexandra Afenjar, Cécilia Altuzarra, Stéphane Auvin, Claire Bar, Magalie Barth, Stéphanie Biscaye, Emilie Bourel-Ponchel, Sébastien Cabasson, Claude Cances, Pierre Castelnau, Isabelle Caubel, Maryline Carneiro, Brigitte Chabrol, Alexandra Chadie, Annabelle Chaussenot, Emmanuel Cheuret, Mondher Chouchane, Benjamin Cogné, Estelle Colin, Florence Demurger, Vincent Desportes, Anne Dieux-Coeslier, Diane Doummar, Cyril Goizet, Alice Goldenberg, Jamal Ghoumid, Anne-Marie Guerrot, Yvan Herenger, Delphine Heron, Gabriella Horvath, Serge Ilunga, Bertrand Isidor, Médéric Jeanne, Sophie Julia, Anna Kaminska, Emmanuelle Lagrue, Laetitia Lambert, Anne-Sophie Lebre, Jérémie Lefranc, Gaëtan Lesca, Virginie Levrat, Hicham Mansour, Isabelle Marey, Stéphane Marret, Hélène Maurey, Julia Metreau, Cyril Mignot, Sophie Naudion, Julien Neveu, Olivier Patat, Laurent Pasquier, Julie Boeswillwald Perrier, Florence Petit, Anne-Lise Poulat, Chloé Quélin, Christian Richelme, Paul Rollier, Stéphane Rondeau, Agathe Roubertie, Elise Schaefer, Anne De Saint-Martin, Christel Thauvin, Stéphanie Torre, Annick Toutain, Rudy Van Coster, Dorothée M. Ville, Nathalie Villeneuve, Laurent Villard, Mathieu Milh
Neurology. 2026-06-23; 106(12):
DOI: 10.1212/wnl.0000000000218013

Riccardi F(1)(2), Desnous B(3), Borloz E(1), Lepine A(3), Lacoste C(4),
Mignon-Ravix C(1), Cacciagli P(4), Missirian C(4), Molinari F(1), Mortreux
J(1)(4), Afenjar A(5), Altuzarra C(6), Auvin S(7), Bar C(8), Barth M(9), Biscaye
S(10), Bourel-Ponchel E(11), Cabasson S(12), Cances C(13), Castelnau P(14),
Caubel I(15), Carneiro M(16), Chabrol B(3), Chadie A(17), Chaussenot A(18),
Cheuret E(13), Chouchane M(19), Cogné B(20), Colin E(9), Demurger F(21),
Desportes V(16), Dieux-Coeslier A(22), Doummar D(23), Goizet C(24), Goldenberg
A(25), Ghoumid J(22), Guerrot AM(25), Herenger Y(26), Heron D(27), Horvath
G(28), Ilunga S(29), Isidor B(20), Jeanne M(26), Julia S(30), Kaminska A(31),
Lagrue E(14), Lambert L(32), Lebre AS(33), Lefranc J(34), Lesca G(35), Levrat
V(36), Mansour H(37), Marey I(27), Marret S(17), Maurey H(38), Metreau J(38),
Mignot C(27), Naudion S(24), Neveu J(39), Patat O(30), Pasquier L(40), Perrier
JB(41), Petit F(22), Poulat AL(16), Quélin C(40), Richelme C(39), Rollier P(40),
Rondeau S(17), Roubertie A(42), Schaefer E(43), De Saint-Martin A(44), Thauvin
C(45)(46), Torre S(17), Toutain A(26), Van Coster R(47), Ville DM(16),
Villeneuve N(3), Villard L(1)(4), Milh M(48).

Author information:
(1)Aix-Marseille Univ, MMG, Inserm, Marseille, France.
(2)Medical Genetics Department, Sainte Musse Hospital, CHITS, Toulon, France.
(3)Pediatric Neurology Department, La Timone Children Hospital, APHM, Marseille,
France.
(4)Medical Genetics, La Timone Hospital, APHM, Marseille, France.
(5)APHP, Sorbonne Université, Centre de Référence Malformations et Maladies
Congénitales du Cervelet et Déficiences Intellectuelles de Causes Rares, UF de
Génétique Clinique, Hôpital Trousseau, France.
(6)Service de Pédiatrie, Hôpital Jean Minjoz, CHRU de Besançon, France.
(7)Service de Neuropédiatrie et d’Epilepsie, Hôpital Robert-Debré, CHU de Paris,
France.
(8)Department of Pediatric Neurology, Reference Center for Rare Epilepsies, CHU
Bordeaux; CNRS, INCIA, UMR 5287, NRGen Team, Univ. Bordeaux, France.
(9)Service de Génétique Médicale, CHU d’Angers, France.
(10)Service de Pédiatrie Néonatale et Réanimation, CHU de Montpellier, France.
(11)Service de Pédiatrie, CHU d’Amiens, France.
(12)Service de Neuropédiatre, CH de Pau, France.
(13)Service de Pédiatrie, Hôpital des Enfants, CHU de Toulouse, France.
(14)Service de Neuropédiatrie, Hôpital Clocheville, CHRU de Tours, France.
(15)Service de Pédiatrie, CH de Lorient, France.
(16)Service de Neuropédiatrie, Hôpital Femme Mère Enfant, Bron, CHU de Lyon,
France.
(17)Service de Pédiatrie Néonatale et Réanimation – Neuropédiatrie, CHU de
Rouen, France.
(18)Service de Génétique, UCA, CHU de Nice, France.
(19)Service de Pédiatrie, CHU de Dijon, France.
(20)Service de Génétique Médicale, Hôtel Dieu, CHU de Nantes, France.
(21)Service de Génétique Clinique, CHBA de Vannes, France.
(22)Univ. Lille, CHU Lille, France.
(23)APHP Sorbonne Université, Service de Neuropédiatrie, et Centre de Référence
Neurogénétique, Maladies Rares du Système Nerveux Central, Hôpital d’Enfants
Armand-Trousseau, Paris, France.
(24)Service de Génétique Médicale, GH Pellegrin, CHU de Bordeaux, France.
(25)Département de Génétique, CHU de Rouen, Centre Normand de Génomique et de
Médecine Personnalisée, France.
(26)Service de Génétique, Hôpital Bretonneau, CHRU de Tours, France.
(27)APHP, Département de Génétique, GH Pitié-Salpêtrière, France.
(28)Division of Biochemical Genetics, Department of Pediatrics, University of
British Columbia, BC Children’s Hospital, Vancouver, Canada.
(29)Service de Pédiatrie Néonatale, CHU de Nimes, France.
(30)Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, France.
(31)Service de Neurologie Pediatrique, Hôpital Necker Enfants Malades, APHP,
Paris, France.
(32)Service de Neurologie Pédiatrique, CHRU de Nancy, France.
(33)CHU Reims, Université de Reims Champagne-Ardenne and Université Paris Cité,
Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, [Krebs
team], France.
(34)Service de Neuropédiatrie, Hôpital Morvan, CHU de Brest, France.
(35)Service de Génétique Moléculaire et Médicale, GH Edouard Herriot, CHU de
Lyon, France.
(36)Service de Pédiatrie, CH d’Annecy-Genevois, France.
(37)Saint George Hospital University Medical Center, Beyrouth, Lebanon.
(38)Service de Neuropédiatrie, Hôpital Bicêtre, CHU de Paris, France.
(39)Service Neuropédiatrie, Hôpital Pédiatrique Universitaire Lenval, Nice,
France.
(40)Service de Génétique Clinique, Hôpital Sud, CHU de Rennes, France.
(41)Service de Pédiatrie, Hôpital Femme-Enfant-Adolescent, CHU de Nantes,
France.
(42)Service de Neuropédiatrie, Hôpital Gui de Chauliac, CHRU Montpellier,
France.
(43)Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace,
Hôpitaux Universitaires de Strasbourg, France.
(44)Department of Pediatrics – Centre de Référence des Épilepsies Rares,
University Hospital of Strasbourg, Strasbourg, France.
(45)Service de Génétique Médicale, CHU de Dijon, France.
(46)UMR 1231 GAD Genetics of Developmental Disorders, University of Bourgogne,
France.
(47)Pediatric Neurology and Metabolism, Ghent University Hospital, Belgium; and.
(48)Aix-Marseille Univ, APHM, Child Neurology Unit, Timone Children Hospital,
Marseille, France.

BACKGROUND AND OBJECTIVES: Developmental and epileptic encephalopathies (DEEs)
with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal
epileptic syndromes, typically presenting in the first months of life with
refractory seizures and profound neurodevelopmental impairment. Although
variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes,
the full genetic spectrum remains uncertain. We aimed to delineate the
electroclinical characteristics, genetic etiologies, and long-term outcomes in a
large MRI-negative EIDEE-BS cohort.
METHODS: We retrospectively analyzed 110 patients with BS EEG enrolled from a
database of 1,540 individuals with suspected genetic epilepsies (2008-2023).
Clinical, EEG, and genetic data were systematically collected. Patients were
stratified into 4 groups: KCNQ2, STXBP1, « other pathogenic variants, » and
« without a genetic diagnosis. » EEG traces were reviewed independently, and
outcomes were assessed through long-term follow-up.
RESULTS: Pathogenic or likely pathogenic variants were identified in 62.7% of
patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24)
and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3)
and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset
occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3
days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than
suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel
associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and
candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo
heterozygous; however, recessive and X-linked inheritance patterns were also
observed. Mortality was high (25%), primarily from status epilepticus and
complications of severe disability. Most patients (72.5%) had persistent
seizures at follow-up (a mean of 6.5 years), as well as profound intellectual
disabilities, irrespective of genotype.
DISCUSSION: This large series highlights the strong monogenic basis of EIDEE-BS.
KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG
features, particularly BS timing and morphology, can help anticipate the
underlying genotype and guide precision therapy, including the early use of
sodium channel blockers in selected cases. These findings support recent ILAE
reclassification efforts and underscore the importance of comprehensive genomic
testing for improved diagnosis and counseling.