Phenotype-guided etiologic workup in a prospective cohort of 144 adults with developmental and epileptic encephalopathy.

Abstract

Objectives: Adults with developmental and epileptic encephalopathies (DEEs) often enter adult neurology care without etiologic clarification because of incomplete transition from pediatric services, outdated investigations, and attenuation of childhood electro-clinical features over time. We aimed to assess the clinical utility and diagnostic yield of a structured, phenotype-guided etiologic workup in adults meeting study criteria for DEE and to explore associations between electro-clinical phenotype and etiologic category.

Methods: We prospectively enrolled consecutive adults (≥18 years) with drug-resistant epilepsy and neurodevelopmental impairment temporally related to epileptic activity, consistent with the ILAE operational definition of DEE, referred to a tertiary epilepsy center between May 2022 and December 2025. Patients underwent a 4-phase reassessment pathway including critical review of prior documentation, detailed clinical and semiologic phenotyping, prolonged video-EEG monitoring, phenotype-guided genetic testing (targeted resequencing, chromosomal microarray), high-resolution neuroimaging, and multidisciplinary case review to support etiologic clarification and treatment planning.

Results: Among 144 patients (mean age 28.4 years; 57.6% male), a confirmed etiology was identified in 91 (63.2%). Genetic causes predominated (65 patients, 45.1%), including monogenic (53, 36.8%) and chromosomal (12, 8.3%) disorders, primarily resolved via targeted resequencing gene panels and via chromosomal microarray analysis respectively, while structural-metabolic etiologies accounted for 26 cases (18.1%). Lennox-Gastaut syndrome was significantly associated with structural-metabolic and chromosomal etiologies (69.2% and 58.3% vs. 9.4% in monogenic; p < 0.0001), whereas, excluding patients with a broader Lennox-Gastaut syndrome phenotype, absence seizures occurred exclusively in monogenic cases (p = 0.024). Etiologic clarification changed clinical management in 27.1% of the cohort, including antiseizure medication optimization/precision therapies (25%) and pre-surgical referral (2.1%).

Significance: In adults with suspected DEE, the practical value of this approach lies not only in diagnostic yield, but in showing that structured adult reassessment remains clinically worthwhile. Electro-clinical phenotype can help prioritize etiologic testing, and etiologic clarification can support more informed treatment planning and counseling even long after transition from pediatric care.

Plain language summary: Adults with developmental and epileptic encephalopathy (DEE) often reach adult epilepsy services without a clear diagnosis. In this study, we used a structured approach combining clinical review, video-EEG, MRI, genetic testing, and multidisciplinary discussion in 144 adults with suspected DEE. We identified a confirmed cause in 63.2% of patients. Genetic causes were the most common, but structural and metabolic causes were also important. Some seizure patterns helped guide diagnosis: Lennox-Gastaut syndrome was more common in structural-metabolic and chromosomal cases, while absence seizures occurred only in monogenic cases. Identifying the cause also helped guide treatment decisions, including medication changes, targeted therapies, surgery referral, and genetic counseling. This study shows that adults with suspected DEE can still benefit from careful diagnostic reassessment, even years after childhood.