Burst-Suppression EEG in Early Infantile Developmental and Epileptic Encephalopathies: Phenotype, Genotype, and Outcome.

Abstract (English)

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 <i>KCNQ2</i>, <i>STXBP1</i>, and <i>SCN2A</i> 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: <i>KCNQ2</i>, <i>STXBP1</i>, "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. <i>KCNQ2</i> (n = 24) and <i>STXBP1</i> (n = 16) accounted for one-third of diagnoses, whereas <i>SCN2A</i> (n = 3) and <i>KCNT1</i> (n = 2) were less frequent. In <i>KCNQ2</i> cases, seizures and BS onset occurred earlier than in <i>STXBP1</i> 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 <i>KCNQ2</i> and <i>STXBP1</i> variants. Novel associations were found with <i>DPM1</i>, <i>GRIN2A</i>, <i>KCNT2</i>, <i>PIGO</i>, <i>PURA</i>, <i>WWOX</i>, and candidate genes (<i>KMT2E</i>, <i>SNAP25</i>, and <i>SYT1</i>). 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. <i>KCNQ2</i>, <i>STXBP1</i>, and <i>SCN2A</i> 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.