Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a familial focal epilepsy syndrome characterized by frontal lobe seizures occurring predominantly during light sleep. Although not a common condition, it is increasingly recognized, with over 100 families reported.¹ It was first described in 1994 in families from Australia, Canada, and the United Kingdom,² and subsequently became the first human epilepsy for which an underlying genetic defect was identified. The first mutation to be discovered was in the CHRNA4 gene encoding the α4 subunit of the nicotinic acetylcholine receptor (nAChR),³ a ligand-gated ion channel. The subsequent discovery of further nAChR subunit gene mutations in ADNFLE,^4,5,6 along with ion channel gene mutations in various other familial epilepsy syndromes, led to the concept of channelopathies as the fundamental basis to many epilepsy syndromes.⁷

CLINICAL, ELECTROGRAPHIC, AND IMAGING FINDINGS IN ADNFLE

Clinical Features

Seizure onset is usually in childhood, typically between 8 and 11 years of age, although onset ranges from 1 to 52 years.^8,9 Seizures tend to occur in clusters and arise almost exclusively from sleep, with children usually having 6–8 seizures per night occurring over a few hours.⁸ Seizures most commonly occur as the individual is falling off to sleep, or in the morning toward the end of the normal sleep period. Less commonly seizures occur sporadically throughout the night. Around 25% of patients also have occasional daytime seizures during periods of poor control.^8,9

Semiology is consistent with frontal lobe seizures, with rare secondarily generalized tonic–clonic seizures in some individuals. Although seizure semiology can vary markedly between patients with ADNFLE, it is usually highly stereotyped within a given individual. Subjects are often woken by a nonspecific aura but more frequent auras include a shiver, a feeling of “breath being stuck in the throat,” or sensory phenomena in the limbs.⁸ Vocalization, which may be a grunt, moan, or a single word, is very common at onset, and may continue throughout the event.⁸ Motor features are usually prominent, and may take a variety of forms such as frenetic bipedal automatisms, rhythmic axial movements, and asymmetric tonic posturing. Tonic posturing may be severe such that some individuals have bent their bed-head when holding on to it during a seizure. Other individuals have seizures that appear like a generalized tonic–clonic seizure but awareness is preserved. The appearance of the seizure may be bizarre, and misdiagnosis is not uncommon.^8,9 Consciousness is often preserved through the seizures, or may vary in different attacks in an individual, and is usually associated with a sense of fear or panic during the seizure. Not surprisingly, frequent attacks may cause a child to become scared of falling asleep. Seizures are brief, typically less than 1 minute in duration, and are highly stereotyped. They tend to occur in clusters of, on average, around eight seizures per night, although up to 70 events per night have been recorded in some individuals.⁸ Although nocturnal frontal lobe seizures may manifest in a wide variety of ictal behaviors, in general, they can be subdivided into three broad categories for descriptive purposes based on duration.¹⁰ Paroxysmal arousals are brief, stereotyped arousals, usually lasting 20 seconds or less; paroxysmal nocturnal dystonia describes events lasting up to 2 minutes with prominent dystonic components and often other frontal lobe features; and epileptic nocturnal wanderings, where the subject leaves the bed and may walk or run around, often in an agitated fashion, performing semipurposeful behaviors, last longer. Most individuals display more than one of these patterns, including subtle, brief attacks that are simply the beginning of longer seizures if scrutinized carefully on video-EEG monitoring. Epileptic nocturnal wanderings are relatively uncommon.¹⁰

ADNFLE is usually considered to be a relatively mild disorder. However, there is significant variability both within and between families, in terms of both the severity of epilepsy,⁹ the semiology of the seizures¹¹ and the associated comorbidity. Although in some cases, seizures may be frequent and difficult to treat in childhood and adolescence, in general, they resolve or improve substantially as the individual reaches adult life.^8,9 However, more recently, families have been reported with a more severe ADNFLE phenotype,¹² with frequent refractory seizures associated with cognitive impairment and psychiatric symptoms, and in some cases with cognitive decline. Moreover, recent detailed neuropsychological studies have suggested that subtle cognitive deficits are present in many other, apparently intellectually normal, individuals with ADNFLE. Impaired cognitive flexibility appears to be the core deficit,¹³ but more widespread impairments in memory and general intellectual function may also be present.¹⁴

Ictal and Interictal EEG

Interictal EEG

The interictal EEG is usually normal in wakefulness; during sleep, interictal epileptiform abnormalities may be seen in up to 50% of cases, but even when present, are often sparse.^8,9 Nonspecific abnormalities such as frontal theta and delta slowing may occur in some patients.

Ictal EEG

Seizures typically arise from stage 2 NREM sleep, but may also occur in stage 3 or 4. The ictal EEG is often difficult to interpret, frequently being obscured by muscle and motion artifact. When ictal electrographic patterns are discernable they are usually poorly localized, although typically show a frontal predominance. Ictal patterns may comprise rhythmic sharp waves or repetitive 8–11 Hz spikes, but frank recruiting rhythms are rarely seen;¹¹ more often, nonspecific patterns such as diffuse flattening or rhythmic frontal theta or delta rhythms are recorded.^8,9,10,11 In about 25% of cases, both interictal and ictal EEG are normal.⁹ Therefore, EEG alone may be of limited diagnostic value; inpatient video-EEG monitoring, with the ability to analyze the stereotypy of seizure semiology, may be required in cases of diagnostic uncertainty. video-EEG monitoring may lead to the identification of attacks of variable duration such as paroxysmal arousals and seizures of longer duration occurring in one individual. The briefest awakenings may be dismissed as simply arousals until they are directly compared with the clear-cut seizures and seen to be a fragment of the characteristic semiology.

Neuroimaging

Computerized tomography and magnetic resonance imaging (MRI) studies are normal in ADNFLE.^8,9 Interictal abnormalities of¹⁸ fludeoxyglucose (FDG) positron emission tomography (PET) have been reported showing frontal hypometabolism without a characteristic pattern.¹¹ PET studies in individuals with ADNFLE using a specific α4β2 PET ligand ([¹⁸F]-F-A-85380) showed increased binding in brainstem and epithalamus, but reduced binding in mesial frontal regions, when compared to controls.¹⁵ Ictal single photon emission computerised tomography (SPECT) studies may show frontal hyperperfusion relative to the interictal state (Fig. 27–1).

DIFFERENTIAL DIAGNOSIS

The diagnosis of ADNFLE may be difficult for two reasons. Firstly, making a correct diagnosis of nocturnal frontal lobe epilepsy (NFLE) in an individual is not always straightforward; and secondly, the familial nature of the condition may not be obvious.

By far the biggest practical problem in clinical practice is the distinction of NFLE from NREM arousal parasomnias such as night terrors and somnambulism that may occur in children and adults. However, a careful history, will usually be sufficient to distinguish these disorders. The most important historical features indicating NFLE as opposed to benign parasomnias are: the timing of events (in NFLE this is often within 30 minutes of sleep onset, whereas parasomnias typically occur after 1–2 hours of sleep); the number of events per night (in NFLE, there are often multiple events in a single night, whereas parasomnias rarely occur more than once or, at most, twice per night); the duration of events, which may be brief or prolonged in parasomnias, but in NFLE are almost invariably brief (usually less than 1 minute); and the presence of an aura (very common in at least a proportion of seizures in individuals with NFLE, but almost never a feature of parasomnias). Extensive wandering is rare in NFLE, although may occasionally occur and is nondirected, but is common in parasomnias and often partially directed (such as voiding in a drawer instead of the toilet). Conversely, lucid recall for events is common in at least a proportion of seizures in NFLE, but is very uncommon in parasomnias (although some vague recollection may be reported). If these features are explicitly discussed with the patient and witness when taking the history, a correct diagnosis will be reached in most cases, often during the initial clinical consultation.

The frontal lobe epilepsy and parasomnias (FLEP) scale, a simple validated clinical scale that addresses these aspects of the history, may be used to assist the clinician in arriving at the correct diagnosis (Table 27–1).¹⁶ In cases where diagnostic uncertainty remains despite a rigorous history, recording of events using video-EEG monitoring is usually required; however, this is not always achievable if attacks are relatively infrequent. Other sleep disorders that can sometimes cause potential confusion with NFLE and should be considered in the child with nocturnal attacks include rhythmic movement disorder of sleep, sleep-related breathing disorders, and psychogenic nonepileptic attacks.