We report resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy. The 18.5-year-old female patient had refractory epilepsy from the age of 11. Recurrent electroencephalography (EEG) recordings showed mostly generalized activity, albeit with right frontal predominance. Almost all antiepileptic medications failed to provide benefit. She developed an encephalopathic state with cognitive decline. The nonlesional frontal lobe epilepsy and a family history of a cousin with nocturnal epilepsy with frontal origin suggested genetic etiology. Transdermal nicotine patches brought complete resolution of the seizures, normalization of the EEG, and a significant improvement in her thinking process and speech organization. Sequencing of the CHRNB2 and CHRNA4 genes did not detect a mutation. Transdermal nicotine patches should be considered in severe pharmacoresistant frontal lobe epilepsy.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by mutations in genes encoding for subunits of the nicotinic acetylcholine receptors (nAChRs) (CHRNA4 and CHRNB2) (Steinlein, 2004). Penetrance is 70%. ADNFLE is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations and sometimes clonic jerking. The epilepsy usually begins in childhood. Carbamazepine monotherapy is frequently effective (Scheffer et al., 1995). ADNFLE was initially described as a benign epilepsy, with patients having a normal intellect and normal neurologic examination. Subsequent studies have indicated that cognitive dysfunction may be an integral part of the broad phenotype. Certain nAChR mutations might be associated with an increased risk for cognitive and psychiatric deficits (Steinlein et al., 2012). It has been noticed that tobacco habits influence seizure susceptibility in ADNFLE. A beneficial effect of nicotine patch administration has previously been reported in two studies on patients with ADNFLE with known mutations in the CHRNA4 gene (Willoughby et al., 2003; Brodtkorb & Picard, 2006).
We describe resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy.
Patient and Methods
The patient, now 18.5 years old, presented at 11 years with intractable nonlesional epilepsy with frontal lobe origin. Perinatal history and early development were normal. She was reported as a “grade A” student before epilepsy commenced. She has a family history of a first cousin with nocturnal epilepsy of frontal origin with normal cognitive function.
Seizures first presented at 11 years of age as twitches of the left corner of the mouth accompanied by speech arrest. Shortly after, she developed a variety of seizures including short staring episodes, twitching of the left corner of the mouth accompanied by a right turn of the head with or without loss of tone and generalized tonic–clonic seizures. Seizures were both diurnal and nocturnal.
Recurrent electroencephalography (EEG) recordings showed mostly generalized activity albeit with frontal predominance (Fig. 1). Fifteen antiepileptic medications were administered including ketamine, as well as several trials of immunomodulatory treatments, a modified ketogenic diet, and vagus nerve stimulation, but these did not improve the seizures. Multiple magnetic resonance imaging (MRI) studies were normal. Surgical candidacy was denied.
During the years seizure frequency increased significantly. Cognitive deterioration was first suspected at the age of 13.5. At the age of 14 years her IQ score on the Wechsler Intelligence Scale for Children, Fourth Edition test was 100 with a performance IQ of 91. At the age of 15 she was diagnosed as having acquired learning disabilities. A psychiatric assessment at the age of 16 years revealed a severe thought processing disorder with indirect and tangential speech, lack of motivation, deterioration of cognitive function, and faulty social judgment. Nicotine patches were administered while the patient was on multiple drug therapy and started at a dose of 7 mg and elevated gradually to 21 mg.
Following administration of the nicotine patches, the frequency of the seizures decreased and after 1 month stopped altogether. Her EEG normalized for the first time in 7 years. There was a significant improvement in her cognitive state, thought organization, and affect. She was totally seizure free for 9 months and then had a cluster of short seizures during hyponatremia. Sequencing of the CHRNB2 and CHRNA4 genes, encoding subunits of the nAChR did not detect any mutations.
nAChRs are pentameric ligand-gated cation channels. Binding of ACh or nicotine to the receptor causes a conformational change and opening of the ion pore. Activation of the channel can cause depolarization, which results in an excitatory postsynaptic potential and can also cause the release of a variety of neurotransmitters when expressed in the presynaptic surface. NAChRs can be in a resting state with closed channels, in an activated state with open channels, or in a desensitized state with closed channels that are refractory to activation. The desensitized state is induced by prolonged or repeated exposure to a stimulus (Albuquerque et al., 2009).
The suggested mechanism by which nicotine decreases seizure frequency in ADNFLE is related to the pathophysiology of the disorder. According to in vitro electrophysiologic studies, mutant nAChRs display increased ACh sensitivity, causing a gain of function with an overactive receptor. The beneficial effect of nicotine is most likely achieved by desensitization of an overactive mutant receptor, turning the receptor into its closed state refractory to activation. Chronic exposure to nicotine is known to desensitize nAChRs, and in typical smokers, virtually all nAChRs are desensitized, especially α4β2 receptors (Bertrand et al., 2002; Marini & Guerrini, 2007; Hoda et al., 2008).
Carbamazepine has a few modes of action in epilepsy, one of which is interaction with nAChR by entering the ionic pore and blocking it. The mutated nAChRs show a threefold increase in sensitivity toward carbamazepine (Picard et al., 1999).
Our patient’s epilepsy resembles ADNFLE because of the family history, the nonlesional frontal lobe origin, the age of onset, the semiology of the seizures, and even the cognitive deterioration, but it differs from classic ADNFLE with respect to the diurnal occurrence of seizures and the intractability. The cousin’s epilepsy is more consistent with NFLE. We have not yet found a mutation in nAChR in our patient but further genetic investigations are underway.
There is a possibility that our patient’s seizures are not directly related to nAChR subunits and that the effect of nicotine is an indirect effect of nicotine receptor activation through its influence on other neurotransmitters.
Only minor short-term side effects have been described due to nicotine treatment. Hyponatremia has been described in one patient that was treated for smoking cessation with a suspected causality (Finch et al., 2004). The hyponatremia in our patient is probably attributed to the combination of oxcarbazepine and nicotine treatment.
The long-term consequences of transdermal nicotine treatment are not well known. Cardiovascular complications are considered much lower from pure transdermal nicotine compared to cigarette smoking. Nicotine enhances cognitive performance in humans in the short-term period including learning, memory, and attention processes. Nevertheless adolescent smoking strongly correlates with cognitive and behavioral impairments during later life, and in rodents, even a short exposure to nicotine during this period can induce a cascade of intracellular signaling, gene expression profiles, and structural changes that last into adulthood and may induce permanent deficiencies (Poorthuis et al., 2009).
There are only two articles on the relationship between ADNFLE and nicotine consumption. Willoughby et al. (2003) described a woman with refractory ADNFLE who initially responded to carbamazepine treatment but deteriorated following cessation of smoking. Application of transdermal nicotine controlled her seizures. Brodtkorb and Picard (2006) investigated the influence of tobacco habits of 22 subjects from two pedigrees with ADNFLE and found that tobacco habits influenced seizure susceptibility. A patient with severe refractory epilepsy was treated with transdermal nicotine and reported fewer awakenings and less overt motor seizures.
Our report is the first to describe complete cessation of seizures with resolution of an encephalopathic state by nicotine transdermal treatment. We suggest that transdermal nicotine should be considered in pharmacoresistant cases of frontal lobe epilepsy even without known mutations in nAChRs. The disruptive effect on quality of life of uncontrolled seizures must be weighed against the potential chronic long-term side effects of nicotine for each individual. This treatment option should be further explored for its consequences, and prospective studies should be performed.
We thank Dr. Marcio Sotero De Menezes for suggesting the nicotine patch treatment in our patient following resolution of epilepsy in his patient with a similar presentation.
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All coauthors have been substantially involved in the study and/or the preparation of the manuscript; and no undisclosed groups or persons have had a primary role in the study and/or in manuscript preparation and all coauthors have seen and approved the submitted version of the paper and accept responsibility for its content.