Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy

doi:10.1016/j.yebeh.2006.07.008

Epilepsy & Behavior

Volume 9, Issue 3, November 2006, Pages 515-520

https://doi.org/10.1016/j.yebeh.2006.07.008 Get 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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Precision treatment with nicotine in autosomal dominant sleep-related hypermotor epilepsy (ADSHE): An observational study of clinical outcome and serum cotinine levels in 17 patients
2021, Epilepsy Research
Citation Excerpt :
All had sleep-related hyperkinetic seizures. The phenotypes of the two families have previously been reported as similar (Nakken et al., 1999, Steinlein et al., 2000; Brodtkorb and Picard, 2006). Ten patients were males; seven were females.
To report the clinical outcome of nicotine exposure in patients with autosomal dominant sleep-related hypermotor epilepsy (ADSHE), along with serum concentrations of the major nicotine metabolite cotinine.
We recruited 17 ADSHE patients with CHRNA4 mutations (12 with p.S280F and 5 with p.L291 dup). Clinical characteristics were collected from hospital records. A telephone interview was performed on the use and seizure-reducing effect of nicotine applying a six-point rating scale from “none” to very good“. Serum concentrations of cotinine were measured in 14 nicotine users.
All patients but one had ever used nicotine. Nine had used snuff; seven were current users. Eleven had used transdermal nicotine; nine were current users. Seven reported long-lasting seizure control, all used nicotine, four transdermal nicotine and three snuff. In 78% of patients using continuous transdermal nicotine, the effect was rated as good or very good. Cotinine concentrations were 453 ± 196 (mean ± SD) nmol/l in seven patients using transdermal nicotine only vs. 1241 ± 494 nmol/l in seven using other forms of nicotine. No correlation with seizure control was found. Three patients experienced improvement with transdermal delivery compared to snuff.
This is the hitherto largest observational study supporting a favorable effect of nicotine in this specific seizure disorder. Better seizure control from transdermal nicotine compared to only day-time consumption suggests benefit from exposure throughout the night. According to current clinical experience, patients with uncontrolled ADSHE harboring relevant mutations should be offered precision treatment with transdermal nicotine.
Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy
2020, Epilepsy and Behavior
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.
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.
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.
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.
Smoking prevalence and seizure control in Chinese males with epilepsy
2017, Epilepsy and Behavior
Smoking has a negative effect on most diseases, yet it is under-investigated in people with epilepsy; thus its role is not clear in the general population with epilepsy. We performed a retrospective pilot study on males with epilepsy to determine the smoking rate and its relationship with seizure control using univariate analysis to calculate odds ratios (ORs) and also used a multi-variate logistic regression model. The smoking rate in our sample of 278 individuals was 25.5%, which is lower than the general Chinese population smoking rate among males of 52.1%. We used two classifications: the first classified epilepsy as generalized, or by presumed topographic origin (temporal, frontal, parietal and occipital). The second classified the dominant seizure type of an individual as generalized tonic clonic seizure (GTCS), myoclonic seizure (MS), complex partial seizure (CPS), simple partial seizure (SPS), and secondary GTCS (sGTCS). The univariable analysis of satisfactory seizure control profile and smoking rate in both classifications showed a trend towards a beneficial effect of smoking although most were not statistically significant. Considering medication is an important confounding factor that would largely influence seizure control, we also conducted multi-variable analysis for both classifications with drug numbers and dosage. The result of our model also suggested that smoking is a protective factor. Our findings seem to suggest that smoking could have a potential role in seizure control although confounders need exploration particularly in view of the potential long term health effects. Replication in a much larger sample is needed as well as case control studies to elucidate this issue.
Distinctive effects of nicotinic receptor intracellular-loop mutations associated with nocturnal frontal lobe epilepsy
2016, Neuropharmacology
Citation Excerpt :
Thus, while the C2 NFLE mutants do indeed alter HS and LS expression ratios, they do so to favor the HS-isoform, the opposite direction to that shown for TM-domain mutants (Son et al., 2009). Nicotine has previously been shown to reduce seizure rates for carriers of NFLE mutations, and has been used as a self-medication treatment strategy (Brodtkorb and Picard, 2006; Willoughby et al., 2003). While prior investigations of the TM-domain NFLE mutations demonstrated changes in ligand potency (especially with regards to nicotine), this aspect of C2 NFLE mutant subunit effects has previously not been studied.
Previously characterized nicotinic acetylcholine receptor (nAChR) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-associated mutations are found in α2, α4 and β2 subunit transmembrane (TM) domains. They predominantly increase ACh potency and, for β2-subunit mutants, increase macroscopic currents. Two recently-identified mutations, α4(R336H) and β2(V337G), located in the intracellular cytoplasmic loop (C2) have been associated with non-familial NFLE. Effects of these mutations on α4β2-nAChR function and expression were studied for the first time, using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Biased-ratio preparations elucidated the mutations' effects at alternate isoforms: high-sensitivity [HS; (α4)₂(β2)₃] or low-sensitivity [LS; (α4)₃(β2)₂] via 1:10 or 30:1 [α4:β2] cRNA injection ratios, respectively. An unbiased (1:1 [α4:β2] cRNA) injection ratio was also used to study potential shifts in isoform expression. α4(R336H)-containing receptors showed significant increases in maximal ACh-induced currents (I_max) in all preparations (140% increase compared to wild type control). β2(V337G)-containing receptors significantly increased I_max in the LS-favoring preparation (20% increase compared to control). Expression of either mutation consistently produced enrichment of HS-isoform expression in all preparations. α4β2-nAChR harboring either NFLE mutant subunit showed unchanged ACh, sazetidine-A, nicotine, cytisine and mecamylamine potency. However, both mutant subunits enhanced partial agonist efficacies in the LS-biased preparation. Using β2-subunit-specific [¹²⁵I]mAb 295 immunolabeling, nAChR cell-surface expression was determined. Antibody binding studies revealed that the β2(V337G) mutation tended to reduce cell-surface expression, and function per receptor was significantly increased by either NFLE mutant subunit in HS-favoring preparations. These findings identify both common and differing features between TM- and C2-domain AD/NFLE-associated mutations. As we discuss, the shared features may be particularly salient to AD/NFLE etiology.
Midwakh-induced seizures: Case series from UAE
2014, Epilepsy and Behavior
Drug-induced seizures are rare causes of hospital admissions (Coleman, 2004) [1]. Various classes of drugs are reported to induce seizures either directly, due to their epileptogenic potential or due to drug withdrawal effect, or indirectly, due to systemic and CNS-related side effects (Thundiyil et al., 2011) [2]. Midwakh is commonly used among young Emiratis. However, its CNS-related adverse effects are not well studied. We report seven consecutive patients with a history of seizures provoked by smoking midwakh and a negative workup for epilepsy. Six of these patients had no further seizures after they had agreed to discontinue smoking midwakh.
Tobacco smoking, epilepsy, and seizures
2014, Epilepsy and Behavior
Citation Excerpt :
Multiple smokers in both families reported increased seizure severity and frequency when they stopped smoking, but decreased seizure frequency and severity when they resumed tobacco smoking. One member, in particular, a nonsmoker in the past, had decreased seizure frequency and severity several months after she started transdermal nicotine patches [34]. What were or are the smoking habits or smoking status in the families where ADNFLE was originally found?
Tobacco smoking is considered the greatest risk factor for death caused by noncommunicable diseases. In contrast to extensive research on the association between tobacco smoking and diseases such as heart attack, stroke, and cancers, studies on the association between tobacco smoking and seizures or epilepsy are insufficient. The exact roles tobacco smoking and nicotine use play in seizures or epilepsy have not been well reviewed.
We reviewed available literature and found that 1) there are vast differences between tobacco smoke and nicotine based on their components and their effects on seizures or epilepsy; 2) the seizure risk in acute active tobacco smokers, women who smoke during pregnancy, electronic cigarette smokers, and the role of smoking in sudden unexplained/unexpected death in epilepsy remain unclear; 3) seizure risks are higher in acute secondhand smokers, chronic active smokers, and babies whose mothers smoke; 4) tobacco smoke protects against seizures in animal models whereas nicotine exerts mixed effects in animals; and 5) tobacco smoking agents can be noneffective, proconvulsant, or anticonvulsant. Finally, the opportunities for future research on this topic is discussed.

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Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgment

Am J Hum Genet

Brain Res Brain Res Rev

Lancet

Mayo Clin Proc

Neuron

A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy

Nat Genet

Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder

Brain

Autosomal dominant nocturnal frontal lobe epilepsy: an electroclinical study of a Norwegian family with ten affected members

Epilepsia

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy

Epilepsia

A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1

Neurology

Dominant partial epilepsies: a clinical, electrophysiological and genetic study of 19 European families

Brain