Nocturnal Frontal lobe epilepsy (Autosomal Dominant)

Disease characteristics. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.

Clinical Diagnosis

The clinical diagnostic features of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) include the following:

• Clusters of seizures with a frontal semiology*
• Occurrence of seizures predominantly during sleep*
• Normal clinical neurologic examination
• Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidity may occur
• Normal findings on neuroimaging
• Ictal EEG that may be normal or obscured by movement artifact
• Interictal EEG that shows infrequent epileptiform discharges
• Presence of the same disorder in other family members with evidence of an autosomal dominant mode of inheritance [Tassinari & Michelucci 1997, Provini et al 1999, Combi et al 2004]

* History of clusters of brief (5 seconds to 5 minutes) nocturnal motor seizures which are often stereotyped and may include nightmares, verbalizations, sudden limb movements, or other parasomnias (undesirable phenomena that occur mainly or only during sleep). The history may be obtained from the affected individual and witnesses, and supplemented if necessary by video-electroencephalogram (EEG) monitoring.

The diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is established in individuals with the above clinical features and/or a disease-causing mutation in CHRNA4, CHRNB2, or CHRNA2.

Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8-11 Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Steinlein et al 1997, Oldani et al 1998, Provini et al 1999, Picard et al 2000]. El Helou et al [2008] suggest that seizures may be initiated by K-complexes.

Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals.

Interictal sleep EEG may show infrequent epileptiform discharges.

Note: The clinical features of ADNFLE are indistinguishable from those of nonfamilial nocturnal frontal lobe epilepsy [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000]. The term ADNFLE should only be applied if the family history is positive for other affected individuals and/or if a disease-causing mutation has been identified in either CHRNA4, CHRNB2, or CHRNA2.

Natural History

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Within a family, the manifestations of the disorder may vary considerably [Hayman et al 1997]; individuals with subtle manifestations may not present for medical attention. Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE. A high incidence of true parasomnias (undesirable phenomena that occur mainly or only during sleep) has been reported in relatives of those with ADNFLE [Provini et al 1999].

Seizures may occur in any stage of sleep [Oldani et al 1996, Steinlein et al 1997, Provini et al 1999], although typically in clusters in non-REM sleep, most commonly in stage two sleep [Oldani et al 1998, Provini et al 1999]. Theaffected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event. A minority of individuals experience daytime seizures, typically during a period of poor seizure control.

The seizures are often stereotyped and brief (5 seconds to 5 minutes) [Oldani et al 1996, Thomas et al 1998, Nakken et al 1999, Provini et al 1999, Ito et al 2000, Picard et al 2000]. They vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling movements, ballism (flinging or throwing arm movements), and pelvic thrusting movements.

Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. A sense of difficulty breathing and hyperventilation may occur, as well as vocalization, clonic features, urinary incontinence, and secondary generalization.

Some individuals experience an aura, which may be nonspecific or may consist of fear, a shiver, vertigo, or a feeling of falling or being pushed.

The three distinct sub-classifications of seizure types based on clinical features of the seizures (semiology) and their duration [Oldani et al 1998, Provini et al 1999] are “paroxysmal arousals,” “paroxysmal dystonia,” and “episodic wandering.”

ADNFLE is lifelong but not progressive. Onset ranges from infancy to adulthood. About 80% of affected individuals develop ADNFLE in the first two decades of life [Oldani et al 1998, Picard et al 2000]; mean age of onset is ten years. As an individual reaches middle age, attacks may become milder and less frequent. Seizures may vary over time; for example, tonic attacks appearing in early childhood may evolve into seizures with dystonic or hyperkinetic components in later childhood.

Clinical neurologic examination is normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]; however, in some individuals neuropsychological assessment reveals reduced intellect, cognitive deficits, or psychiatric comorbidity [Khatami et al 1998, Provini et al 1999, Picard et al 2000, Cho et al 2003, Wood et al 2010].Picard et al [2009] found below-normal general intellect in 45% of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE with nicotinic receptor mutations. It is suggested that certain nAChR mutations could be associated with an increased risk for such symptoms [Steinlein et al 2012].