Improvement of Executive Functions in Therapy of Dravet Syndrome with Fenfluramine in Preschool Children

Executive Functions During a Key Period for Brain Development

Many children with Dravet syndrome develop a disorder of executive functions (EF) during preschool age. These are defined as the ability to self-regulate, through which we manage our behavior, emotions, and cognitive processes in everyday life. Acquiring these EFs during early development is the foundation for later cognitive, emotional, and behavioral processes.

Early disruption of EF development by epilepsy can negatively impact overall quality of life and can also lead to later impairment of adaptive functioning (the ability to cope with daily life demands and adapt to changing situations). Early intervention aimed at reducing EF deficits thus becomes an important therapeutic goal in the treatment of children with epilepsy.

Dual Mechanism of Action of Fenfluramine

Fenfluramine, which is indicated as add-on therapy for seizures associated with Dravet syndrome, has both a serotonergic effect (stimulates various subtypes of 5-HT receptors) and acts as a positive modulator of the sigma-1 receptor. Data from preclinical and clinical studies conducted in healthy volunteers suggest that this unique pharmacodynamic profile can directly influence learning processes, memory, and behavior associated with cognitive performance.

The aim of the presented study was to evaluate the effect of fenfluramine therapy on everyday EF in preschool children (under 5 years of age) with Dravet syndrome. The monitored parameter was clinically significant improvement or deterioration of everyday EF during 14-15 weeks of fenfluramine treatment compared to placebo.

Analysis Methodology

Data from a cohort of children under 5 years old who participated in one of two randomized controlled phase III clinical trials were evaluated, where participants were administered either fenfluramine at doses of 0.2, 0.4, or 0.7 mg/kg/day, or placebo, as an addition to their standard therapy. In one of the studies, patients were not allowed to use stiripentol, while in the other, all patients used stiripentol.

EFs were assessed using the Behavior Rating Inventory of Executive Function – Preschool (BRIEF-P) questionnaire. This questionnaire was specifically developed for children aged 2 to 6 years and contains 63 items divided into 5 scales. It assesses the level of impulse and behavior control, ability to fluidly transition between situations, activities, or different aspects of a problem, emotional control, short-term memory, and the ability to stay focused on a task, ability to predict future situations or consequences, and ability to use instructions or set goals to adjust behavior or accomplish a task.

The test results are summarized into 3 indices: Inhibitory Self-Control Index (ISCI) describes the ability to control impulses and emotions, Flexibility Index (FI) assesses the ability to switch between activities and emotional control, and Emergent Metacognition Index (EMI) describes the level of short-term memory and planning ability. The overall score of all questionnaire items is summarized in the Global Executive Composite (GEC) parameter.

Results

61 children (median age 3 years) were included in the analysis. A total of 39 children used fenfluramine (15 at a dose of 0.2 mg/kg/day; 10 at a dose of 0.4 mg/kg/day with stiripentol, and 14 at a dose of 0.7 mg/kg/day without stiripentol). The placebo group included 22 participants.

At the start of the study, 55-86% of patients had problems in the area of inhibitory self-control (ISCI index), early metacognition (EMI index), and overall executive composite (GEC). About one third of the children had problems in the area of flexibility (FI index).

Reliable clinically significant improvement in at least one BRIEF-P index was observed in 17 study participants (28%). Clinically significant EF improvement (> 90% in the so-called reliable change index /RCI/) was achieved by most children in the group with a daily dose of 0.7 mg/kg/day fenfluramine (9 out of 14; 64%), in the group with a dose of 0.4 mg/kg/day 3 children (30%), with a dose of 0.2 mg/kg/day also 3 children (20%), and in the placebo group 2 children (9%).

Clinically significant EF improvement did not correlate with a clinically significant reduction in the number of seizures (reduction of monthly occurrence frequency by ≤ 50%). In 7 out of 17 children (41%) who achieved clinically significant EF improvement, there was no clinically significant reduction in the number of seizures. No association was observed between the administered treatment and clinically significant EF deterioration.

Conclusion

In preschool children with Dravet syndrome and disruption of everyday EF, 14-15 weeks of fenfluramine treatment was associated with clinically significant improvement in behavior, emotion, cognition, and overall everyday executive functions regulation. The improvement was dose-dependent and did not correlate with a reduction in seizure count. It appears that fenfluramine could have a direct beneficial effect on everyday EF in children with this condition during the early years of nervous system development.

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Sources:
1. Bishop K. I., Isquith P. K., Gioia G. A. et al. Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (< 5 years) with Dravet syndrome: a critical period for early neurodevelopment. Epilepsy Behav 2023; 138: 108994, doi: 10.1016/j.yebeh.2022.
2. SPC Fintrepla. Available at: www.ema.europa.eu/en/documents/product-information/fintepla-epar-product-information_cs.pdf
3. Greene J. A., Trujilo S., Isquith P. K. et al. Enhanced interpretation of the Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) [white paper]. PAR, 2019. Available at: www.parinc.com/Products/Pkey/26