Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy

Kristine Lossius; Anne de Saint Martin; Sverre Myren-Svelstad; Marit Bjørnvold; Guro Minken; Caroline Seegmuller; Maria Paola Valenti Hirsch; Jamel Chelly; Ortrud Steinlein; Fabienne Picard; Eylert Brodtkorb

doi:10.1016/j.yebeh.2020.106944

Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy

Epilepsy Behav. 2020 Apr:105:106944. doi: 10.1016/j.yebeh.2020.106944. Epub 2020 Feb 22.

Affiliations

¹ National Centre for Epilepsy, Division for Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
² Pediatric Neurology, Reference Center for Rare Epilepsies, Strasbourg University Hospital, France.
³ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olav University Hospital, Trondheim, Norway. Electronic address: s@myren-svelstad.no.
⁴ Pediatric Neurology, Reference Center for Rare Epilepsies, Strasbourg University Hospital, France; Neurology Department, Reference Center for Rare Epilepsies, Strasbourg University Hospital, France.
⁵ Neurology Department, Reference Center for Rare Epilepsies, Strasbourg University Hospital, France.
⁶ Genetic Department, Strasbourg University, Hospital, IGBMC, INSERM, CNRS, Strasbourg University, France.
⁷ Institute of Human Genetics, University Hospital, Ludwig Maximillian University of Munich, Munich, Germany.
⁸ EEG and Epilepsy Unit, Department of Neurology, University Hospitals and Medical School of Geneva, Geneva, Switzerland.
⁹ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olav University Hospital, Trondheim, Norway.

PMID: 32097883
DOI: 10.1016/j.yebeh.2020.106944

Abstract

Objective: 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). Benefit from nicotine consumption has been reported in adult patients with this disorder. For the first time, the effect of transdermal nicotine is evaluated in children.

Methods: Transdermal nicotine was applied to three boys, two aged 10 years (7 mg/24 h) and one six years (3.5 mg/24 h). Autosomal dominant sleep-related hypermotor epilepsy was caused by the p.S280F-CHRNA4 (cholinergic receptor, nicotinic, alpha polypeptide 4) mutation. The children suffered from frequent, persistent nocturnal seizures and had developed educational and psychosocial problems. Seizure frequency and cognitive and behavioral parameters were assessed before and after treatment.

Results: A striking seizure reduction was reported soon after treatment onset. Hypermotor seizures disappeared; only sporadic arousals, sometimes with minor motor elements, were observed. Psychometric testing documented improvement in cognitive domains such as visuospatial ability, processing speed, memory, and some areas of executive functions.

Significance: Nicotine appears to be a mechanistic treatment for this specific disorder, probably because of desensitization of the mutated receptors. It may control seizures resistant to conventional drugs for epilepsy and impact socioeducational function in children. This mode of precision therapy should receive more attention and should be available to more patients with uncontrolled CHRNA4-related ADSHE across the age span.

Keywords: Autosomal dominant sleep-related hypermotor epilepsy (ADSHE); Nicotine; Nicotinic acetylcholine receptor; Precision therapy; p.S280F-CHRNA4.

Publication types

Case Reports

MeSH terms

Adolescent
Child
Epilepsy, Reflex / diagnosis
Epilepsy, Reflex / drug therapy*
Epilepsy, Reflex / genetics*
Humans
Male
Mutation / genetics
Nicotine / administration & dosage*
Receptors, Nicotinic / genetics*
Sleep / drug effects
Sleep / genetics*
Tobacco Use Cessation Devices*
Treatment Outcome

Substances

Receptors, Nicotinic
nicotinic acetylcholine receptor alpha4 subunit
Nicotine