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Autosomal dominant nocturnal frontal lobe epilepsy
A rare seizure disorder characterized by intermittent dystonia and/or choreoathetoid movements that occur during sleep. The clusters of nocturnal motor seizures are often stereotyped and brief.
ORPHA:98784Classification level: Disorder
Over 100 families have been described in the literature to date. Males and females are affected equally.
The age of onset varies between 3 and 47 years (usually < 20 years, with a peak during childhood). Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is defined by different motor events of increasing complexity and duration, arising during non-rapid eye movement sleep (NREM), including short-lasting (2-4 sec) stereotyped movements involving the limbs, axial musculature, and/or the head; paroxysmal arousals characterized by sudden and brief arousals (5-10 sec) sometimes accompanied by stereotyped movements, vocalization, and fear; and major attacks (20-30 sec), featuring asymmetric tonic or dystonic posturing, or complex movements (pelvic thrusting, pedaling, choreoathetoid, and ballistic movements of the limbs). Some patients may show ictal deambulatory behaviors often associated with frightened expression. The frequency is highly variable ranging from 5 attacks per night to 5 times per year. Daytime dyskinesia, generalized seizures and auras may occur. Intellect is usually preserved or mildly reduced and psychiatric comorbidity may occur. Paroxysmal hypnogenic dyskinesia (PHD), which was previously characterized as a form of paroxysmal dyskinesia, is now considered to be ADNFLE.
ADNFLE results from malfunction in the thalamo-cortical loops. The genes involved are CHRNA4 (20q13.33), CHRNB2 (1q21.3), CHRNA2 (8p21), KCNT1 (9q34.3), DEPDC5 (22q12.3), CRH (8q13), and CABP4 (11q13.2).
Diagnosis relies principally on clinical history revealing at least one of the following four criteria: motor event duration of less than 2 minutes; unstructured vocalization during the episode; experience of an aura preceding the motor attack; history of tonic-clonic seizures during sleep. Diagnosis is also achieved by recording seizures by nocturnal video polysomnography (V-PSG) and confirmed by genetic screening.
Differential diagnoses include paroxysmal dyskinesia, familial focal epilepsy with variable foci, restless legs syndrome, periodic limb movement disorders (PLMS), REM sleep behavior disorders (RBD), nocturnal panic attacks, non-REM parasomnias, obstructive sleep apnea syndrome, and arousal disorders.
Transmission is autosomal dominant with a penetrance ranging from 60 % to 80 %. High intra-familial heterogeneity has been described. Sporadic cases may occur.
Management and treatment
The treatment of choice for ADNFLE includes use of carbamazepine (200-1,000 mg/day). Carbamazepine abolishes seizures in 20% of cases, and gives significant relief (at least 50 % seizure reduction) in another 48%. Oxcarbamazepine, topiramate and acetazolamide (as add-on therapies) may also be used. Nicotine transdermal patches may be efficient in patients who are refractory to standard antiepileptic drugs. Quinidine, a potassium channel blocker, has been reported as a potential therapeutic agent in only a few patients with KCNT1 mutation implicated in ADNFLE and epilepsy of infancy with migrating focal seizures (EIMFS). Surgical treatment may be indicated for drug-resistant patients, both for seizures and for epilepsy-related sleep disturbances. Neuropsychological testing and psychiatric assessment are advised for ADNFLE affected individuals.
ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.