Elsevier

Epilepsy & Behavior

Volume 9, Issue 3, November 2006, Pages 515-520
Epilepsy & Behavior

Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy

https://doi.org/10.1016/j.yebeh.2006.07.008Get rights and content

Abstract

Mutations in neuronal nicotinic acetylcholine receptors have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The beneficial effect of nicotine administration was previously reported in one single case. We investigated the influence of the tobacco habits of 22 subjects from two pedigrees with α4 mutations (776ins3 and S248F). Subjects were interviewed with respect to pattern of nicotine intake and seizures. Seizure freedom was significantly associated with tobacco use (P = 0.024). All seven nonsmokers with manifest ADNFLE had persistent seizures. Seizure fluctuations, including long remissions, corresponded to changes in tobacco habits in several patients. One patient who recently had begun treatment with transdermal nicotine experienced improvement. We conclude that tobacco appears to be an environmental factor that influences seizure susceptibility in ADNFLE. Inactivation by desensitization of the mutant receptors by nicotine may explain the beneficial effect. The efficacy and safety of transdermal nicotine in ADNFLE should be further explored.

Introduction

Mutations in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic acetylcholine receptor (nAChR) subunits (α4 and β2) have been identified [1], [2]. Electrophysiological studies performed with receptors reconstituted in frog oocytes have demonstrated that both types of mutant nAChRs have increased sensitivity to acetylcholine (gain of function) [3]. The course of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is variable and unpredictable. Penetrance of seizures is incomplete. Age at onset varies, but is usually during childhood [4]. Even with frequent seizures, remissions may occur during adolescence and adulthood without seizure recurrence after discontinuation of drug therapy [2], [5], [6], [7], [8], [9]. However, relapses may occur after many years, and ADNFLE may persist through adult life in many affected individuals [4], [10], [11], [12], [13]. The seizures often respond to standard antiepileptic therapy, especially carbamazepine, but some patients appear to be pharmacoresistant [4], [9]. Genetic or environmental factors that influence penetrance, severity, treatment response, fluctuations, and remissions are largely unknown [14]. An effect of nicotine on the seizure expression may be anticipated as the mutant nAChRs have altered properties and nicotine is a nAChR agonist. Nevertheless, there has been little focus on the relationship between seizures and nicotine consumption in this disorder to date, except for one single case report. In this patient, deterioration corresponded to cessation of smoking, and transdermal nicotine appeared to be effective when added to carbamazepine in both an open and a double-blind placebo-controlled fashion [15].

In Norway, two large families with ADNFLE and different mutations in the CHRNA4 gene coding for the nAChR α4 subunit have been identified: one with an insertion mutation (776ins3), the second with a missense mutation (S248F) [12]. A large number of individuals in both families used tobacco. The present study aimed to investigate whether nicotine consumption influences the clinical course of epilepsy in mutation carriers in these families.

Section snippets

Methods

A total of 22 adult mutation carriers belonging to the two ADNFLE families were interviewed with respect to pattern of nicotine intake and seizure activity. Ten individuals belonged to the 776ins3 pedigree (Family A), and 12 to the S248F pedigree (Family B). After informed consent was obtained, relevant medical records were collected. Data concerning the amount, mode, and temporal pattern of nicotine use during the lifetime of each individual were obtained. Information on the treatment and

Results

Demographic data, epilepsy characteristics, and nicotine habits are summarized in Table 1. All members of Family A were asymptomatic or in remission, except the two female patients A-IV2 and A-IV4. All seizure-free individuals were nicotine consumers. Patient A-IV2 (age 30) had severe epilepsy, with series of hyperkinetic seizures several times a week. She has never smoked or snuffed, but has been using nicotine transdermally during the last 6 months, at first 7 mg/day with only minor effect,

Discussion

This study of 22 subjects from two ADNFLE pedigrees with different mutations in a gene coding for a nAChR subunit supports the notion that chronic nicotine consumption may influence the course and prognosis of this disorder (Table 1). The difference with respect to tobacco use was statistically significant in individuals with and without persistent seizures (Table 2). It is striking that 10 of 14 tobacco consumers were seizure-free and that all 7 nonsmokers with manifest ADNFLE had persistent

Acknowledgment

Fabienne Picard was supported by Swiss National Foundation Grant 3100A0-104190/1.

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