Abstracts

Rationale: Autosomal-dominant, sleep-related, hypermotor epilepsy (ADSHE) is characterized by hypermotor seizures and may be caused by gain-of-function mutations affecting the nicotinic acetylcholine receptor (nAChR). The most common mutations occur in the CHRNA4 (cholinergic receptor, nicotinic, alpha polypeptide 4) gene, encoding the alpha4 subunit that interacts with various combinations of alpha and beta subunits to form functional nAChRs. Even though carbamazepine and other antiepileptic drugs (AEDs) are effective in many patients, 30 % continue to have seizures. A beneficial effect of nicotine has been reported in some adult patients with this disorder. We wished to evaluate the effect in children with uncontrolled ADSHE. Methods: Transdermal nicotine was applied to three boys from two unrelated families, two aged 10 years (7 mg/24 h) and one 6 years (3.5 mg/24 h). ADSHE was caused by the p.S280F-CHRNA4 mutation in all three patients. The children suffered from frequent, persistent nocturnal seizures and had developed educational, psychosocial, and dysexecutive problems. Seizure frequency, as well as cognitive and behavioral parameters (Wechsler Scale, Developmental Neuropsychological Assessment), were assessed before and after treatment. Results: A dramatic seizure reduction was reported within a few days after treatment onset. Hypermotor seizures disappeared; only sporadic arousals, sometimes with minor motor elements were observed. Behavioral symptoms and daily functioning improved, and cognitive problems decreased with a significant increase in Wechsler Scale scores. The effect on seizure frequency and cognition remained stable after a follow up of one to three years. Conclusions: Mutations in the nAChRs may have wider consequences than just the seizure disorder. Cognitive impairment involving executive and memory functions has been demonstrated among adult patients with ADSHE, including patients with the p.S280F-CHRNA4 mutation. The present findings cannot determine whether nicotine exposure directly ameliorates the cognitive and behavioral dysfunction, or if seizure control itself and abolished ictal sleep fragmentation are crucial factors. The treatment was well tolerated in these patients. However, long-term effects of nicotine treatment in children are obscure, and the balance between benefit and risk should be carefully weighed.Nicotine appears to be a mechanistic treatment for this specific disorder, probably due to desensitization of the mutated receptors. This mode of precision therapy should be available to more patients with uncontrolled CHRNA4-related ADSHE after a careful genetic and clinical selection. Funding: No funding