CoChat
Sign Up
Cited by 43Epilepsy research and treatmentPharmacological Effects and Toxicity StudiesAttention Deficit Hyperactivity Disorder

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

Open access
Bishop, Kim I., Isquith, Peter K., Gioia, Gerard A., Knupp, Kelly G., Scheffer, Ingrid E., Nabbout, Rima, Specchio, Nicola, Sullivan, Joseph +6 more·2023·Epilepsy & Behavior
DOI 10.1016/j.yebeh.2022.108994
Open this paper in CoChat — free account

Abstract

OBJECTIVE: To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome (DS). METHODS: Children with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive Function®-Preschool (BRIEF®-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI ≥ 90% and RCI ≥ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEF®-P indexes/composite T-scores were evaluated using Somers'd; pairwise comparisons were calculated by 2-sided Fisher's Exact tests (p ≤ 0.05) and Cramér's V. RESULTS: Data were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T ≥ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in ∼33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI ≥ 90% certainty) in at least one BRIEF®-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (≥50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEF®-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05). SIGNIFICANCE: In this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14-15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.yebeh.2022.108994

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • RCTs now include parental questionnaires measuring behaviour and everyday function, which typically aid the descriptive aspects of the study rather than acting as primary or secondary end points.

    “RCTs now include parental questionnaires measuring behaviour and everyday function, which typically aid the descriptive aspects of the study rather than acting as primary or secondary end points 199 .”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [199]

    The Methods (p. 2) describe parent ratings of everyday executive function in the RCT, and the limitations (p. 9) say everyday executive function was not a primary efficacy endpoint; its analysis was post-hoc and exploratory. The paper does not establish that such questionnaires typically serve descriptive purposes across RCTs rather than acting as primary or secondary endpoints. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Subsequent studies of fenfluramine in Dravet syndrome demonstrated dose-dependent clinically meaningful effects on regulating behaviour, emotion, cognition, and everyday executive functions in preschool age and sustained efficacy and safety in children, adolescents and adults in real-world practice.

    “Subsequent studies of fenfluramine in Dravet syndrome demonstrated dosedependent clinically meaningful effects on regulating behaviour, emotion, cognition, and everyday executive functions in preschool age 199 and sustained efficacy and safety in children, adolescents and adults in real-world practice 200,201 .”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [199]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 88 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. [42][42] [Gioia GA, Espy KA, Isquith PK. BRIEF Ò -P: Behavior Rating Inventory of Executive Function Ò -Preschool Version Professional Manual. Lutz, FL: Psychological Assessment Resources, Inc.; 2003.](http://refhub.elsevier.com/S1525-5050(22)00443-7/h0210) -
  2. [49][49] [Gioia GA, Isquith PK, Guy SC, Kenworthy L. Behavior Rating Inventory of Executive Function Ò (BRIEF Ò ) Professional Manual. Lutz, FL: Psychological Assessment Resources, Inc.; 2000.](http://refhub.elsevier.com/S1525-5050(22)00443-7/h0245) -
  3. [51][51] [Cramér H. The two-dimensional case. Mathematical Methods of Statistics. Princeton, NJ: Princeton University Press; 1946. p. 282.](http://refhub.elsevier.com/S1525-5050(22)00443-7/h0255) -

Cited by

Sorted by citations

Related

Authors
Bishop, K. I., Isquith, P. K., Gioia, G. A., Knupp, K. G., Scheffer, I. E., Nabbout, R., Specchio, N., Sullivan, J., Auvin, S., Helen Cross, J., Guerrini, R., Farfel, G., Galer, B. S., & Gammaitoni, A. R.
Affiliations
  • Muncie Public Library (US)
  • Children's Hospital Colorado (US)
  • Royal Children's Hospital (AU)
  • Hôpital Necker-Enfants Malades (FR)
  • Bambino Gesù Children's Hospital (IT)
  • University of California, San Francisco (US)
  • Institut Universitaire de France (FR)
  • Meyer Children's Hospital (IT)
  • Zogenix (United States) (US)
Corresponding author
Bishop, Kim I.
ORCID
Venue
Epilepsy & Behavior
Publisher
Elsevier BV
Published
2023-01
Volume
138
Pages
108994
ISSN
1525-5050 (ISSN-L)
DOI
10.1016/j.yebeh.2022.108994
OpenAlex
W4310704042
Cited by
43
References
88
Citations by year
2026: 14 · 2025: 10 · 2024: 12 · 2023: 7
FWCI
4.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Epilepsy & Behavior (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by)
  • Florence Research (University of Florence) (submittedVersion, other-oa)
Funders
Montana Water Center, Montana State University
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Keywords
fenfluramine, Dravet syndrome, executive function, self-regulation, preschool children, BRIEF-P, inhibitory control, metacognition, flexibility, brain development, stimulant medication, stiripentol, treatment-emergent adverse events, early intervention, dose-response relationship
MeSH terms
Child, Child, Preschool, Epilepsies, Myoclonic, Fenfluramine, Humans, Parents, Seizures, Executive Function

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review