Abstracts

This is a Late Breaking abstract

Rationale: Cardiofaciocutaneous syndrome (CFCS) is a rare genetic disorder associated with characteristic skin and craniofacial features, congenital heart disease, and neurodevelopmental disabilities. Medically refractory epilepsy is among the most frequent complications. Although recent studies have established a link between severe seizures and specific variants in the BRAF and MAP2K1 genes, the wide variability in epilepsy type, seizure frequency, and treatment response makes accurate clinical prognosis challenging. To identify efficacious anti-seizure medications (ASMs) and other treatment approaches, we collected epilepsy treatment history in a large multinational CFCS cohort.

Methods: An online caregiver-report survey was developed to investigate seizure semiology, history of antiepileptic therapies, and treatment response. Information regarding level of seizure control, adverse effects, and rationale for discontinuing medications was obtained. The survey was completed by 138 families, with 76 individuals (55%) having a history of epilepsy. A “good response” to an ASM was recorded when caregivers reported >50% decrease in seizures; a “poor response” was indicated by no improvement or worsening of seizures. A treatment efficacy score was calculated based on seizure control attained as well as adverse effects requiring discontinuation of the medication. Infrequently used ASMs ( < 10 patients) were excluded from analysis.

Results: Epilepsy characteristics and treatment approaches varied widely (Table 1). Of the eleven ASMs assessed, oxcarbazepine, a sodium channel blocker, was reported as having the best seizure control profile, with 16/21 (76%) families reporting a good response. Oxcarbazepine and zonisamide were associated with the fewest adverse effects, 5/24 (20%) and 2/11 (18%) respectively. The most commonly prescribed ASM, levetiracetam, was associated with more adverse effects 14/42 (33%) and poorer seizure control 14/38 (37%). Phenobarbital and clobazam, both GABAergic drugs, presented less robust seizure control 4/12 (36%) and 3/14 (21%) respectively along with poor tolerability. ASM efficacy remained fairly consistent for individuals with BRAF and MAP2K1 gene variants. Few patients utilized surgical or dietary interventions.

Conclusions: Epilepsy treatment in CFCS is challenging due to wide variability in presentation and severity, as well as frequent medically refractory status. Although other ASMs were prescribed more frequently, oxcarbazepine had highest efficacy in moderating seizures and less frequent adverse effects. Limitations include a lack of comprehensive information about dosing regimens and drug trial duration, along with reliance on retrospectively reported survey data. These findings can assist in the development of clinical neurological care guidelines for CFCS. Future trials of therapeutics that target the RAS/MAPK pathway may be considered to address epilepsy among patients with CFCS and related syndromes whose seizures are not responsive to traditional ASMs.

Funding: CFC International, NIH CTSA UL1TR002494