Nicotine Patch Improved Autosomal Dominant Sleep-Related Hypermotor Epilepsy

Abstract

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is a genetic focal epilepsy associated with mutations in the nicotinic acetylcholine receptor. Mutations in two major nicotinic acetylcholine receptor subunit genes, CHRNA4 and CHRNB2, are commonly associated with ADSHE.1Saberi B. Tehrani B.S. Pore-forming M2 domains of CHRNA4 and CHRNB2 mutations in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) phenotype.Am J Biomed Sci Res. 2019; 1: 222-223Crossref Google Scholar In up to one-third of patients with ADSHE, seizures are refractory to antiseizure medications. Here, we report complete seizure freedom with transdermal nicotine in two pediatric patients from the same family with medically refractory ADSHE. Both patients, who are siblings, presented with exclusively nocturnal focal seizures in childhood, at ages seven years (Patient 1) and 4.5 years (Patient 2). Elelctroencephalographies (EEGs) demonstrated focal electroclinical seizures with hypermotor features and interictal epileptiform discharges in sleep (Fig A and B). Genetic testing revealed a heterozygous missense mutation in CHRNA4 (c.851C>T P.Ser284Leu), which has been described as a common pathogenic gain-of-function mutation in ADSHE. Patient 2 was also diagnosed with an autism spectrum disorder. Both patients had a high nightly seizure burden with minimal improvement on numerous antiseizure medications. A trial of low-dose (7 mg/24 hour) nicotine patch was initiated at ages 16 years (Patient 1) and 14 years (Patient 2). Clinical seizures stopped in both the first night the patch was applied. Follow-up overnight EEGs confirmed seizure freedom and showed normalization or near-normalization of their interictal EEGs (Fig C). Both patients have experienced sustained seizure freedom for over 18 months with nicotine patch 7 mg/24 hour in addition to oxcarbazepine. Transdermal nicotine has been reported to provide marked seizure improvement in a subset of patients with ADSHE.2Fox J. Thodeson D.M. Dolce A.M. Nicotine: a targeted therapy for epilepsy due to nAChR gene variants.J Child Neurol. 2020; 36: 371-377Crossref PubMed Scopus (3) Google Scholar,3Lossius K. de Saint Martin A. Myren-Svelstad S. et al.Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy.Epilepsy Behav. 2020; 105: 106944Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The siblings reported here have the same CHRNA4 mutation as a 19-year-old patient who had considerable seizure improvement, although not complete resolution, with transdermal nicotine at a higher dose of 14 mg/24 hour.2Fox J. Thodeson D.M. Dolce A.M. Nicotine: a targeted therapy for epilepsy due to nAChR gene variants.J Child Neurol. 2020; 36: 371-377Crossref PubMed Scopus (3) Google Scholar Lossius et al. described striking improvement in seizures and neuropsychological test performance in three six- to 10-year-old children with a different CHRNA4 mutation (c.839C>T P.Ser280Phe) who were treated with 3.5 to 7 mg/24 hour nicotine.3Lossius K. de Saint Martin A. Myren-Svelstad S. et al.Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy.Epilepsy Behav. 2020; 105: 106944Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar With different patient characteristics, age as well as specific mutation might contribute to the efficacy of nicotine patches in controlling seizure activity. Christensen et al. discussed how nicotine increases neuronal firing of cholinergic cells in younger animals, which in turn affects the action potential shape and afterhyperpolarization.4Christensen M.H. Ishibashi M. Nielsen M.L. Leonard C.S. Kohlmeier K.A. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction.Neuropharmacology. 2014; 85: 263-283Crossref PubMed Scopus (15) Google Scholar Nicotine has been found to cause age-dependent changes in gene expression in adolescent female rat brains.5Polesskaya O.O. Fryxell K.J. Merchant A.D. et al.Nicotine causes age-dependent changes in gene expression in the adolescent female rat brain.Neurotoxicol Teratol. 2007; 29: 126-140Crossref PubMed Scopus (33) Google Scholar In adolescence, GABAergic signaling in the prefrontal cortex, an important brain region associated with ADSHE, is still developing.6Caballero A. Tseng K.Y. GABAergic function as a limiting factor for prefrontal maturation during adolescence.Trends Neurosci. 2016; 39: 441-448Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Therefore, age might be an important factor when determining whether nicotine patch treatment may be beneficial for patients with ADSHE, with regard to both seizure improvement and neuropsychologic outcomes. A limitation of our report is that our patients are from the same family and therefore may possess unique characteristics that influenced their dramatic response to transdermal nicotine. This possibility might prevent generalization of our results to all patients with same mutation in CHRNA4. Nevertheless, the two siblings reported here add to the small number of pediatric reports documenting the successful use of nicotine patches in ADSHE. Future research is needed to establish whether the nicotine patch could become an adjunct or first-line treatment in a subset of pediatric patients with ADSHE. The authors wish to thank all the patients, family members, and staff members who participated in the study.