Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study
Willoughby JO, Pope KJ and Eaton V;
Commented by , 27 Oct 2003
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare disorder caused in many families by one of several mutations affecting the neuronal nicotinic acid acetylcholine receptor alpha 4 subunit (CHRNA4) (1). A 29-year-old woman with ADNFL showed exacerbation of seizure frequency during a stressful life period, shortly after stopping smoking. This observation led her physicians to a trial of nicotine therapy.
To assess the influence of transdermal administration of nicotine on seizure frequency in a patient with ADNFLE.
Initially, open-label prospective assessment of the effect of transdermal nicotine (Nicoderm CQ 7 mg/24 hr) on seizure counts.
Thereafter, comparison of transdermal nicotine versus placebo according to a n-of-1 randomized double-blind cross-over design. Placebo or nicotine were administered daily each for 3 periods of two weeks.
Throughout the trial the patient continued to receive carbamazepine at an unchanged dosage.
During the open phase, seizure frequency averaged 0.01 seizures per day during 9 months of continuous nicotine treatment compared with 1.65 seizures per day during a 3 month baseline.
In the double-blind phase, total number of seizures were 0 on active drug (42 days) compared with 29 on placebo (42 days) (p<0.0001).
I only exceptionally select case reports to comment as “paper of the month”. This, however, is of special interest:
- It shows the value of coupling clinical observation with pathophysiological knowledge and good research skills: thus, a serendipitous observation paved the way to the discovery of a potential new therapy.
- It highlights that well controlled randomized trials can be conducted in a single patient. Of course, there can be ethical concerns in alternating placebo and an efficacious treatment in the same patient: in this case, it was justified by the brief and relatively benign semiology of the seizures.
- It may provide a rare example of a mechanistic approach to antiepileptic drug treatment, even though the consequences of the ADNFLE-associated mutations remain incompletely understood. As oocyte expression studies suggest that the CHRN4 mutations in ADNFLE lead to gain of function (2), the authors speculate that therapeutic benefit from nicotine may result from desensitization of the mutated receptor. Other explanations are, however, possible.
- These findings may have broader implications in epilepsy research. In fact, recent evidence suggests that the nicotinic acetylcholine receptor plays a role in regulating epileptiform activity in the hippocampus (3). Moreover, the CHRNA4 gene or a closely linked gene may be one of the susceptibility factors for febrile convulsions (4) and idiopathic generalized epilepsies (5).
- At the current state of knowledge, evidence on the efficacy on nicotine in ADNFLE should be regarded as preliminary, and further studies in larger series are needed. Interestingly, the authors mention that a sibling of their patient has severe ADNFLE unresponsive to anticholinesterase or anticholinergic agents, but a nicotine trial was apparently not attempted in that person.
- Steinlein O, Mulley JC, Propping P, et al, A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genetics 1995; 11; 201-203
- Bertrand D, Picard F, Le Hellard S, et al. How mutations in the nAchRs can cause ADNFLE epilepsy. Epilepsia 2002; 43 (Suppl 5);112-122
- Roshan-Milani S, Ferrigan L, Khoshnood MJ, et al.. Regulation of epileptiform activity in hippocampus by nicotinic acetylcholine receptor activation. Epilepsy Research 2003; 56; 51-65
- Chou I-C, Lee C-C, Huang C-C, et al. Association of the neuronal nicotinic acetylcholine receptor subunit alpha 4 polymorphisms with febrile convulsions. Epilepsia 2003; 44; 1089-93
- Steinlein O, Sander T, Stoodt J, et al. Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit alpha4 with common idiopathic generalized epilepsies. American Journal of Medical Genetics 1997; 74; 445-449