Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome

• Published in: Epilepsy & behavior 2021-08, Vol.121 (Pt A), p.108024, Article 108024
• Main Authors: Bishop, Kim I., Isquith, Peter K., Gioia, Gerard A., Gammaitoni, Arnold R., Farfel, Gail, Galer, Bradley S., Nabbout, Rima, Wirrell, Elaine C., Polster, Tilman, Sullivan, Joseph
• Format: Article
• Language: English
• Subjects: Adolescent; Anticonvulsants - therapeutic use; Behavior Rating Inventory of Executive Function, 2nd edition (BRIEF®2); Child; Dravet syndrome; Epilepsies, Myoclonic - drug therapy; Executive Function; Fenfluramine; Fenfluramine - therapeutic use; Humans; Seizure frequency; Seizures - drug therapy; Young Adult
• ISSN: 1525-5050; 1525-5069
• DOI: 10.1016/j.yebeh.2021.108024

After 1 year of fenfluramine in children and young adults with Dravet syndrome:•78% of patients achieved ≥50% reduction in convulsive seizure frequency.•50% of patients achieved ≥75% reduction in convulsive seizure frequency.•Sustained ≥50% reductions were associated with improved everyday executive function. Individuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use. Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year. This is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5–18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF®) parent form, a questionnaire capturing parents’/caregivers’ perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF® were mapped to the current edition, the BRIEF®2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF®2 T-scores from baseline in the core study to Year 1 of the OL