Authors :
Presenting Author: Perrine Hugon, PharmD, PhD – Biocodex
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Health; The Florey Institute of Neuroscience and Mental Health, University of Melbourne; University of Melbourne, Royal Children’s Hospital; Murdoch Children’s Research Institute
Nicola Specchio, MD, PhD, FRCP – Bambino Gesù Children’s Hospital, IRCCS, Member of the ERN EpiCARE; University Hospitals KU
Maurizio Viri, MD – AOU Maggiore della Carità Novara
Domenica I Battaglia, MD, PhD – Fondazione Policlinico Universitario Agostino Gemelli, IRCCS
Manish Prasad, MBBS, MD Paediatrics, MRCPCH, CCT Paeds Neurology – Queens Medical Centre, Nottingham
Marina Trivisano, MD, PhD – Bambino Gesù Children's Hospital
Adrián Valls-Carbó, MD – Hospital Ruber Internacional de Madrid
Talia Allan, MSc – Austin Health & The University of Melbourne
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional de Madrid
Rationale:
Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug-resistant seizures and a wide range of non-seizure manifestations. Patients require individualized treatment, typically with a combination of antiseizure medications (ASMs). Optimizing polytherapy to maximize seizure control while minimizing adverse events (AEs) is critical. We aimed to evaluate polypharmacy management in DS individuals treated with stiripentol (STP), an approved adjunctive therapy to clobazam (CLB) in the US, and to CLB and valproate (VPA) in Europe.
Methods:
Ten patients with DS from six centres who underwent STP weaning followed by reinstitution of STP were retrospectively ascertained, and descriptive analysis performed.
Results:
STP was introduced in all patients for seizure control despite multiple prior ASM attempts (median 3 [range 1-7, n=9], most commonly VPA [88.9% patients], topiramate [55.6%], CLB [44.4%]). Initiation of STP occurred at a median age of 37 months (range 9–221), reaching a median maximal dose of 50.0 mg/kg/day (range 25.0-54.9, n=7). STP led to complete cessation of generalized tonic-clonic seizures (GTCS) in two patients, and markedly reduced the frequency or duration of hemiclonic, tonic, myoclonic or absence seizures in four. One patient reported prominent myoclonus during STP treatment. STP was tapered or discontinued after a median treatment duration of 102 months (range 17-203) for (i) AEs with add-on fenfluramine (FFA) (unsteadiness, tiredness and weight loss, myoclonic seizure cluster and moderate anorexia, severe psychiatric disorder, n=3), (ii) FFA clinical trials or dose increase (n=4), (iii) attempts to simplify polytherapy after seizure reduction with add-on FFA (n=2), cannabidiol (n=2) or ketogenic diet (n=1), or (iv) temporary shortage (n=1). Seizures —generally GTC and tonic seizures— worsened in all patients, so STP was reintroduced within a median time of 3.4 months (range 0.2-36.0, n=8). At last follow up (median 33.5 months [range 6-90, n=8] after STP reintroduction), all patients remained on STP (median dose 18.2 mg/kg/day [range 10.0-57.7, n=9]), with a median of 3.5 (range 3-5) additional therapies, most commonly CLB, VPA, and FFA (100%, 70% and 60% of patients, respectively). Seizures reduced or stabilized, and cognition and behaviour improved in one and two patients, respectively. Excessive somnolence and constipation were reported in one individual.
Conclusions:
In this case series, STP withdrawal led to seizure worsening, underscoring its key role in DS. Reintroduction typically restored seizure control back to previous levels or achieved further improvement. These cases highlight the need to taper STP with caution and support its key role as a backbone of therapy for patients with DS.
Funding:
Biocodex supported abstract submission.