Epilepsy: A Comprehensive Textbook
2nd Edition

Frontal lobe epilepsies, as with other focal epilepsies, were formerly invariably considered to be the consequence of an overt or obscure brain lesion. However, this view has changed during the last 10 years, as large families comprising several individuals with non–age-related partial seizures without manifest organic cause have been identified. Today, the genetic origin of nonlesional focal epilepsies is well accepted. Several familial focal epilepsy syndromes with an autosomal dominant mode of inheritance have successively been recognized, such as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), familial temporal lobe epilepsies, and familial focal epilepsy with variable foci.⁴⁶ They are considered idiopathic, like the classical benign localization-related epilepsies of childhood, since affected individuals do not exhibit any other etiology than a presumed genetic cause.

ADNFLE constitutes a reasonably homogeneous clinical syndrome. Mutations have been identified in genes coding for subunits of the cerebral nicotinic acetylcholine receptor (nAChR) in some families, establishing a clear link between ADNFLE and this ion channel. The many cases of sporadic nonlesional nocturnal frontal lobe epilepsy (NFLE) present similar clinical and electroencephalographic features.⁶⁶ It is likely that some of them represent unrecognized familial cases or are related to de novo mutations. Yet, others possibly share similar pathophysiologic mechanisms, even if their etiology is not predominantly genetic.

In the last 30 years, several reports have described patients with sudden, brief nocturnal episodes of complex motor activity and a family history of similar attacks.^18,27,68 This clinical picture was originally thought to represent a movement disorder, so-called paroxysmal nocturnal dystonia,^32,33 but was later recognized as epilepsy.^23,37 In 1993, Vigevano and Fusco used the term partial idiopathic epilepsy of frontal lobe origin to describe otherwise healthy children presenting with nocturnal tonic postural seizures with a strong family history of epilepsy.⁷² When families with a clear mendelian inheritance later were identified by Scheffer et al. in 1994, this disorder was designated ADNFLE.⁵⁹ The first reported families originated in Australia, Canada, and the United Kingdom. In the Australian family, linkage studies revealed mapping to the long arm of chromosome 20.⁴⁴ Subsequent sequencing demonstrated a missense mutation in the gene coding for a subunit of the neuronal nAChR.⁶³ This finding was a surprise, as it was not previously known that this receptor was involved in epileptogenesis. ADNFLE was the first epileptic syndrome with a proven monogenetic origin, a finding that may be considered a milestone in epileptology. Various mutations in genes coding for subunits of nAChRs have later been demonstrated in different families with this condition (Table 1).^{4,8,14,21,24,30,34,35,36,39,42,43,44,55,56,58,59,62,63,64}

ADNFLE was first described on the basis of its familial character, but does not differ clinically from the more frequently occurring sporadic cases of nonlesional NFLE. An attempt to define the general characteristics of frontal lobe epilepsy was part of the 1989 Classification of Epilepsies and Epileptic Syndromes by the International League Against Epilepsy (ILAE)¹¹:

A list of features strongly suggestive of the diagnosis was given:

ADNFLE contains several elements from this general outline. However, the unique seizure semiology in this disorder was found to fit poorly with the 1981 ILAE seizure classification.^12,31 Hence, the concept of hypermotor seizures was introduced in the more recent proposal of a semiologic seizure classification³¹:

Finally, the term hyperkinetic seizure was included in the new glossary of descriptive terminology for ictal semiology by the ILAE Task Force on Classification and Terminology⁶:

ADNFLE follows an autosomal dominant inheritance with incomplete penetrance. The first identified families allowed the

delineation of the main clinical features,⁵⁸ which later have been refined (Table 2). Subsequently, other focal idiopathic epilepsies with an autosomal dominant transmission pattern were described: The familial temporal lobe epilepsies² and the autosomal dominant partial epilepsy with variable foci.⁶⁰ ADNFLE has together with these syndromes been included within the subgroup of “familial focal epilepsies” in the list of epilepsy syndromes recently proposed by the ILAE Task Force on Classification and Terminology.¹⁵

To date, the number of reported ADNFLE families exceeds 100.^{4,8,10,14,21,24,25,30,34,35,39,40,41,42,43,45,46,55,58,62} Undoubtedly, they only represent a small fraction of ADNFLE families worldwide and the prevalence of this disorder is obscure. Several known families have probably not been reported when genetic analyses have not been performed or have been inconclusive. In addition, it is likely that there still are families in which the epileptic nature of the paroxysmal nocturnal events has remained unrecognized or misdiagnosed. The reported ADNFLE families all comprise at least two affected first-degree relatives with an inheritance pattern suggestive of autosomal dominant transmission. Twenty-seven affected individuals have been reported in the largest and first described family in Australia.⁴⁴ Up until now, mutations have been found in genes encoding subunits of nAChR in 12 families and in one sporadic case (Table 1). Thus, identified mutations currently account for only a minority (10% to 12%) of published ADNFLE families. Sporadic NFLE cases are relatively common,⁵¹ and some may harbor the same mutations that have been identified in ADNFLE.⁴³

ADNFLE was the first idiopathic epilepsy for which a responsible gene was recognized.

Mutations have been identified in the CHRNA4 gene encoding the nAChR α4 subunit and in the CHRNB2 gene encoding the nAChR β2 subunit (Table 1). Up until now, four different mutations have been described in CHRNA4: (a) S248F, a missense mutation replacing serine with phenylalanine in position 248 in the amino acid sequence, observed in an Australian, a Spanish, a Norwegian, and a Scottish family^36,56,63,64; (b) 776ins3, an insertion of three nucleotides at nucleotide position 776, leading to the insertion of a leucine in the amino acid sequence, in another Norwegian family⁶²; (c) S252L, a missense mutation replacing a serine by a leucine in position 252 in the amino acid sequence in a Japanese, a Polish, and a Korean family, and in a sporadic case of Lebanese origin who subsequently had an affected son^{8,21,24,35,43,55}; and (d) T265I, another missense mutation, in a German family.³⁰ Some authors use an alternative codon numbering, which may cause nomenclature confusion.^10,55,56 Three different mutations (V287L, V287M, and I312M) are described in the CHRNB2 gene in an Italian, a Scottish, and an English family, respectively.^4,14,42

The nAChRs are pentameric ligand-gated ion channel receptors consisting of different functional subunit combinations (Fig. 1). When acetylcholine (ACh) binds to the nAChR, the ion channel opens and lets cations enter. The known ADNFLE mutations are located within the second transmembrane domain (M2) of the subunits, which constitutes the walls of the ionic pore, except for the mutation β2-I312M, which is in the third transmembrane domain. Thus, it appears that mutations with a principally direct effect on the ionic pore may cause ADNFLE. The fact that the major nAChRs in humans are made from an assembly of α4 and β2 subunits explains well that defects in both subunits are associated with the same disorder. The α4β2 nAChRs are the most abundant form and are found in the entire brain, with a predominance in the thalamus. They may have a presynaptic or a postsynaptic location. The first have a neuromodulatory role (facilitation of neurotransmitter release), whereas the latter induce a depolarization of the postsynaptic neuron. To assess the changes in the electrophysiologic properties of the mutant receptors, a system of
heterologous expression in frog (Xenopus) oocytes has been used. These cells were injected with an equivalent amount of the mutant and nonmutant allele, in addition to cDNA coding for the other normal subunit, in order to obtain mutant “heterozygous” receptors mimicking an autosomal dominant disorder. Six different mutations led to a significant increase in sensitivity to ACh of the mutant receptors.^4,5,30,38,42 The seventh mutation, the CHRNB2 V287L mutation, caused retardation of channel desensitization.¹⁴ Thus, contrary to the first conclusions obtained from the assessment of homozygous mutant receptors, the current studies suggest a gain of function of the mutant nicotinic receptor for the various mutations. In contrast, another study of five mutations proposed a reduction of the Ca²⁺ dependence of the ACh response, which could explain an increase of glutamate release during bouts of synchronous activity, as an alternative common mechanism.⁵² However, the precise cellular mechanisms leading to epileptogenesis in ADNFLE remain elusive. In particular, it is not clear how an alteration of an nAChR subtype that is present in the thalamus and in the entire cortex may cause a partial epilepsy.

Currently, it is assumed that the mutant nAChRs alter the activity level of frontal thalamocortical loops, which play a major role during sleep. A positron emission tomography (PET) study using 2-[¹⁸F]-F-A-85380, a high-affinity agonist of the heteromeric (α4β2) nAChRs, has recently offered an opportunity to investigate some in vivo consequences of the molecular defect.⁴⁸ Eight ADNFLE patients with an identified mutation in nAChRs were studied. Their pattern of nAChR brain distribution was clearly different compared to healthy volunteers. A significant decrease in nAChR density in the right dorsolateral prefrontal region and a significant increase in the epithalamus, ventral mesencephalon, and cerebellum were demonstrated. The regional decrease in the nAChR density in the prefrontal cortex appears congruent with a frontal lobe epilepsy. We propose two explanations for the regional increase in the nAChR number in the mesencephalon: (a) a regional malformation of central nervous system (CNS) circuits, with an increase of synaptic density, since nAChRs may have a role in the migration of neocortical neurons and in synaptogenesis⁵³; and (b) a regional nAChR up-regulation, related to the hypersensitivity of the mutant nAChRs to ACh and the richness of local ACh release sites. A consequence of the increased nAChR density in mesencephalon could be an overactivated cholinergic pathway ascending from the brainstem. This pathway acts on postsynaptic nAChRs on thalamocortical cells and participates in “desynchronization” and interruption of the sleep physiologic oscillations at the time of the arousals.^13,28,65 Thus, the findings of the recent PET study⁴⁸ support the theory that ADNFLE seizures are due to a defective interruption and a pathologic transformation of synchronized sleep oscillations.

Other in vivo functional studies using transgenic animal models have also enhanced the understanding of ADNFLE pathogenesis. A CHRNA4 knockout mouse showed increased anxiety compared with the behavioral phenotype of the wild type, but did not exhibit spontaneous seizures.⁵⁴ CHRNB2 knockout mice showed abnormal functional organization in the dorsal lateral geniculate nucleus,¹⁹ reduced sensitivity to nicotine-induced locomotor depression,⁷⁰ and reduced fragmentation of non–rapid eye movement (REM) sleep by micro-arousals.²⁹ This last phenotypical trait is an interesting finding, as sleep microstructure analysis of NFLE and ADNFLE patients has revealed sleep fragmentation with an increase in arousals and sleep instability in all non-REM sleep stages.^67,74 Knockin mice containing a point mutation in the pore-forming M2 domain of the α4 subunit (Leu9’Ser) showed increased anxiety, increased sensitivity to induced seizures by agonists (such as nicotine, the nicotinic agonist epibatidine, but not the γ-aminobutyric acid (GABA)_A receptor blocker and proconvulsant bicuculline), but no spontaneous epileptic seizures,¹⁶ and also dopaminergic deficits.²⁶ When tested in oocytes, the α4β2 nAChRs with this specific mutation displayed an increased ACh sensitivity, as observed with the human ADNFLE mutations.^5,26 In addition to these mice models, a new transgenic rat model harboring a true ADNFLE mutation is currently under investigation.²² This model appears more interesting as it expresses spontaneous seizures resembling those of ADNFLE.

For a long period of time, no other genes than those coding for nAChR subunits were reported to be responsible for this condition. Just recently, mutations have been identified in the promoter of the corticotropin-releasing hormone (CRH) gene.⁹ The first mutation, a polymorphism present in 3% of the general population, was detected in three families and in two sporadic cases. The second, not present in 115 healthy subjects, was detected in one ADNFLE proband. However, in vitro the first mutation caused an increase in the protein level, whereas the second resulted in a decrease.⁹ Although the nAChRs are known to activate CRH release,^7,57 the pathophysiologic link between CRH and nAChRs in ADNFLE is still obscure.

The main clinical features are listed in Table 1. Mean age of onset of ADNFLE varies between 8 and 11.5 years, according to clinical studies. It starts below 20 years in 85% of cases. Onset ages as low as 2 months and as high as 56 years have been reported.^46,58 The penetrance appears to be up to 80%. Males and females are equally affected.¹⁰ Seizures arise from sleep. They are more or less stereotyped in each patient over the years. It is remarkable that sudden arousals are characteristic for ADNFLE^4,39,56,64 in contrast to the reduced consciousness that typically occurs in seizures with medial temporal lobe onset. Some patients describe an aura. They are nonspecific and include a broad variety of phenomena: Somatosensory (shivering/tingling, either diffusely or localized, mostly in the head, sometimes in the limbs; and also epigastric discomfort), special sensory (e.g., sensations of light, auditory hallucinations, vertigo), psychic (fear, malaise, déjà vu, dreaming activity), and autonomic (breathing difficulty).^58,64

The motor manifestations are characterized by a wide range of clinical features, which in part can be regarded as a release of subcortical activity. Extrapyramidal features are often prominent. Behavior and autonomic elements may reflect limbic overactivity. The mildest form consists only of a sudden awakening with an elevation of head and trunk, often associated with the expression of fear. Abrupt and rapidly changing movements of the limbs and the trunk may occur, leading to a bizarre sequence of various brief dystonic postures, reminiscent of a mechanic puppet. Hyperkinetic activity (frantic movements with bipedal activity, pelvic thrashing) or tonic stiffening are common features. During the seizure, a breathless sensation is reported by many patients.^{36,42,43,46,56,58} Seizures usually last less than 1 minute, with a mean duration of 30 seconds,^46,58 but some seizures are prolonged and may take the form of nocturnal wanderings. Postictal symptoms are absent or very brief. Rare secondarily generalized seizures are observed in about half of the patients, but the unusual semiologic pattern may cause classification difficulties. Some patients report that awareness is partly retained even during apparent generalized convulsions, a phenomenon that may wrongly raise the suspicion of psychogenic seizures.

Seizures frequently occur in clusters, predominantly during the first few hours after falling asleep or early in the morning. Some patients have attacks every night, while others report mild and rare symptoms. Periods with high seizure frequency may alternate with seizure-free intervals. In one study, the mean seizure frequency was around eight episodes per night.⁵⁸
Diurnal seizures, apart from during naps, are very rare, but may be observed in the most severe cases, particularly during periods of poor seizure control.^40,46,64 Some patients may also experience status epilepticus. Stress, sleep deprivation, and menstruation may increase seizure frequency. Sensory stimulation during sleep (e.g., shaking the body of the patient or a sudden sound) may sometimes provoke seizures.^24,43,55 On the background of a video-polysomnographic study of a large number of patients, the attacks were classified into four categories according to duration, semiology, and complexity of motor behavior (minimal, minor, major, and prolonged episodes).^40,41 The mildest form is described as paroxysmal arousals, consisting of a sudden awakening with dystonic posturing of upper or lower limbs.^49,50,69 They can recur with a periodic repetition, every 30 seconds to 2 minutes during light sleep. Paroxysmal arousals are probably the most frequent type of seizures, but, due to their short duration, many patients remain unaware of them. The information from relatives about apparently unaffected individuals is thus hampered with a high degree of uncertainty. Structured interviews of all pedigree members and their proxies, particularly their bed partners, are thus necessary to recognize the true penetrance of this disorder. The clinical observation is the major diagnostic tool in NFLE, particularly since even ictal electroencephalograms (EEGs) may be inconclusive. Nocturnal video recordings, preferably with polysomnographic parameters, may be necessary for the clinical diagnosis.

Clinical neurologic examination is normal. A normal intelligence was one of the ADNFLE features originally described.⁵⁸ Nevertheless, subsequent descriptions reported neuropsychological deficits in some patients. In four families with typical ADNFLE, most patients also suffered from mild to moderate intellectual disability.^4,8,24,25 Two of these families had an α4-S252L mutation, one the β2-I312M mutation and one no identified mutation. The patient with the de novo α4-S252L mutation was reported to be of low average intellect.⁴³ Several of the cognitively affected patients had pronounced memory deficits. A neuropsychological study of two other patients from ADNFLE families without identified mutations showed specific frontal lobe neuropsychological disturbances.⁴⁶ Currently, it is unknown whether the observed neuropsychological deficits are a consequence of the seizure disorder or a behavioral phenotype primarily associated with the genetic defect. In addition, in some families psychiatric disturbances have been reported in up to half of the patients during the active phase of their epilepsy.^{4,24,35,36,46} Behavioral disorders with hyperactivity, irritability, aggressiveness, and impulsive behavior are the most frequent findings, but psychosis have also been reported in some patients.³⁵ The psychiatric impact may contribute to the diagnostic confusion, which still may occur in this disorder.

No obvious clinical elements seem to differentiate mutation-positive from mutation-negative families.

Diagnostic difficulties have been recurrent problems in many families with ADNFLE. Nocturnal seizures often occur without eyewitnesses, and if present, the beginning of even dramatic episodes is often not seen. Darkness and covers frequently restrict the detailed observation by bedroom partners. Even ictal EEG recordings may be inconclusive. Previously, many patients with NFLE were considered to suffer from a primary movement disorder termed paroxysmal nocturnal dystonia^32,33 (see Historical Perspectives). Misdiagnoses as parasomnias, in the form of night terrors, nightmares, and somnambulism, have been common. Based on the history alone, the differential diagnosis
from benign parasomnias may be difficult in children. Attack frequency differs and symptoms usually occur as single or isolated recurrent episodes in the parasomnias in contrast to the frequent clustering of nocturnal frontal lobe seizures. Due to pronounced autonomic and emotional symptoms with arousal and fear, psychiatric disorders such as panic attacks and hysteria may also be suspected. REM behavior disorder is characterized by agitated, sometimes violent movements occurring during REM sleep. The majority is males above age 60 and other neurologic disorders such as Parkinson disease or multisystem atrophy are common.^{1,10,24,50,58,69} Other members within the same family can certainly be afflicted with these disorders, but hardly with a distinct autosomal dominant transmission pattern. Besides hypnagogic myoclonias, short nocturnal movements resembling mild seizures can be present in healthy subjects. However, in NFLE the episodes are more stereotypical and include sudden movements with dyskinetic or dystonic components. When characteristic hyperkinetic seizures during sleep are video-recorded, the diagnosis of NFLE is usually readily made.

A careful pedigree analysis confirms the familial occurrence of the disorder and differentiates ADNFLE from the more common sporadic forms of NFLE. Other autosomal dominant focal epilepsies (e.g., from the temporal lobe) may also manifest themselves with nocturnal seizures, but have otherwise different ictal semiologies. However, families with autosomal dominant partial epilepsy with variable foci may contain patients with a seizure pattern similar to NFLE. They can thus wrongly be considered as ADNFLE families before the phenotypic variability is appreciated. In this syndrome, seizures arise from different cortical regions in different family members and a predominance of seizures while awake may be observed in some individuals.³

Carbamazepine has been postulated to be the drug of choice in ADNFLE. It has been reported to be more effective than valproate and appears to suppress seizures completely in about two thirds of patients with this syndrome.^46,58 Low doses of carbamazepine (around 600 mg/day in adults) are often sufficient. The detection of an association between nAChR mutations and ADNFLE gave the opportunity to compare the effect of carbamazepine on mutated and wild-type receptors in vitro. Studies in Xenopus oocytes demonstrated that carbamazepine most probably acts as an open channel blocker and generally inhibits α4β2 nAChRs, but that most mutants display a higher sensitivity to this effect.^5,47 Carbamazepine may shut down the mutant receptors, whereas remaining wild-type receptors are less affected.^47,64 Pharmacoresistance to carbamazepine and other antiepileptic drugs has nevertheless been observed in one third of patients. Most reported families have at least had one pharmacoresistant individual, whereas other affected family members have had a good therapeutic response.¹⁰ There is indeed considerable interfamilial and intrafamilial clinical variability concerning epilepsy severity and effect of antiepileptic therapy in this condition.

Acetazolamide was reported to reduce or control seizures in one family without evidence for nAChR mutations.⁷¹ In one single patient with uncontrolled seizures from the original Australian family, transdermal nicotine appeared to be very effective when added to carbamazepine in both an open and a double-blind placebo-controlled fashion.⁷³ These preliminary data encourage attempts to treat patients who prove to be refractory to standard antiepileptic therapy with these agents.

The effect of surgical treatment has not been reported in ADNFLE in spite of its localization-related clinical manifestations. A priori, resective surgery does not appear to be an appropriate option in disorders caused by mutations affecting receptors with widespread distribution in the brain. Prudence should also be exercised in sporadic NFLE.

The phenotypic expression of this condition spans from a persistent, severe disability to only a mild intermittent sleep disruption, not recognized as an epileptic manifestation by either the affected individuals or their proxies. Even with frequent seizures, remissions can occur during adolescence and adulthood, without seizure recurrence after discontinuation of drug therapy.^{17,34,36,39,42,46,64} However, relapses may occur after many years, and in some families, ADNFLE persists through adult life in many of the affected individuals.^58,62,64,66 Genetic or environmental factors that determine penetrance or remission are not yet identified. The reported efficacy of nicotine administration⁷³ is interesting in this respect, and to date it is not known to what extent chronic consumption of nicotine could influence the course and prognosis of this disorder. The fact that the attacks are exclusively sleep related in most patients and usually do not change their chronodependency is important when assessing these patients for motor vehicle driving.

ADNFLE was the first idiopathic epilepsy for which a distinct genetic basis was identified. Mutations in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (α4 and β2) have been identified. ADNFLE is characterized by nocturnal attacks that tend to cluster and can recur several times during one night. Seizures have prominent motor features and mainly occur during non-REM sleep, particularly shortly after falling asleep, before waking up in the morning, and during daytime naps. Onset age varies, but is usually within the two first decades of life. Currently, it is hypothesized that the pathogenetic mechanism is linked to overactivity in ascending cholinergic circuits that control arousal, leading to an imbalance of function in the frontal lobes. The ictal symptoms are thought to represent a paroxysmal disinhibition of subcortical activity in the form of automatic motor and limbic activity. The hyperkinetic sleep-related seizure is the clinical hallmark of the disorder. Interictal cognitive and psychiatric symptoms have been described in some families, but it is uncertain whether these features are true phenotypic traits. Most patients respond to antiepileptic therapy, especially carbamazepine, but one third of patients are pharmacoresistant. Some patients report long seizure-free periods. Unknown factors influence penetrance, treatment response, severity, and remission. Further studies, clinical as well as on the molecular level, are needed for a more complete understanding of ADNFLE. Nevertheless, the recent discoveries in ADNFLE have suggested new neurobiologic mechanisms for familial epilepsy and throw new light on the pathogenesis of epilepsy in general.