Factors Associated with Drug-resistant Epilepsy in Patients with Pediatric-onset Genetic Epilepsy
AUTHORS
John Schreiber, MD; Julie Ziobro, MD/PhD; Nadee Dayananda, MBBS, MSc; Sonal Bhatia, MBBS, MD; Senyene E. Hunter, MD, PhD; Cynthia Keator, MD; Cemal Karakas, MD; Anthony Fine, MD; Debopam Samanta, MD; Katherine Xiong, MD; Julie Sturza, MPH; Jason Coryell, MD
ABSTRACT
Rationale: Our ability to identify a genetic etiology in epilepsy has grown substantially over the past decade. The current yield of positive results from epilepsy gene panels or whole exome/genome sequencing (WES/WGS) is approximately 30-50% in patients with drug-resistant epilepsy (DRE) of unknown cause. However, while our diagnostic capabilities have flourished, our ability to use this diagnostic information to inform counseling and treatment has lagged. We aimed to examine factors associated with pediatric DRE with genetic etiologies to aid in prognostication.
Methods: We leveraged a multicenter database, created in 2021 by the Pediatric Epilepsy Research Consortium Genetics special interest group, recording clinician-derived data on genetic testing and seizure/epilepsy characteristics in pediatric patients with seizures and a pathogenic, likely pathogenic, or potentially causative variant of uncertain significance (VUS) identified on genetic testing. For this analysis, seven centers had contributed patient data. Statistical analysis was performed using SAS software.
Results: This analysis included 288 patients. Positive genetic tests included 176 gene panels, 55 WES, 34 chromosome microarrays, 10 single gene tests, 4 karyotypes, 7 FISH, 3 WGS, and 21 others. Seventeen had both positive WES and gene panel. A total of 130 patients had DRE; 115 did not. The remainder were not classified. Patients with DRE had younger age of seizure onset (median 0.5 years, IQR 0.5-3.5 vs 2.5 years, IQR 0.5-4.5) (p=0.003), higher prevalence of a developmental delay (DD)/intellectual disability (ID) and/or autism (95/130, 73% vs 53/115, 46%) (p < 0.05) and longer epilepsy duration (median 77 months, IQR 44-114) than those without DRE (median 50 months, IQR 32-99) (p < 0.05). Younger age of seizure onset was also associated with DD/ ID (median 0.5 years, IQR 0.5-3.5 vs 2.5 years, IQR 1.5-6.5 years). Finally, we found no difference in the proportion of DRE in patients with a positive gene panel (77/151 = 51%), positive WES (17/33 = 52%), or both positive gene panel and WES (11/17 = 65%) (p=0.6).