CME
Nocturnal Frontal Epilepsies: Diagnostic and Therapeutic Challenges for Sleep Specialists
Keywords
• Nocturnal frontal lobe seizures • Paroxysmal arousal • Nocturnal paroxysmal dystonia • Epileptic nocturnal wandering • Limbic system • Video-polysomnography
Nocturnal frontal lobe epilepsy (NFLE) is a particular form of partial epilepsy in which seizures appear almost exclusively during sleep and are characterized by complex and bizarre motor behaviors. NFLE was originally described by Lugaresi and Cirignotta in 1981.1 The investigators coined the term nocturnal paroxysmal dystonia (NPD), underlying the peculiar motor pattern of these paroxysmal nocturnal events characterized by ballistic movements, bimanual-bipedal activity, rocking axial and pelvic torsion, and/or sustained dystonic posturing or tremor of the limbs.1,2 The clinical and polysomnographic (PSG) features (stereotypic motor pattern of the episodes, their short duration and good response to low doses of carbamazepine) suggested an epileptic origin of the events. However, in the absence of concomitant electroencephalographic (EEG) epileptic discharges, the investigators posed the question whether these episodes constituted hitherto unrecognized epileptic seizures or a new kind of movement sleep disorder. Subsequently, Tinuper and colleagues,3 reported two of three patients with NPD whose typical short-lasting NPD progressed to a convulsion. Subdural electrodes confirmed these were associated with ictal epileptic discharges arising from the frontal lobes. In all three patients, attacks occurred repeatedly with different intensity, representing “fragments” of the same seizure. They concluded that short-lasting attacks of NPD truly represent sleep-related frontal lobe seizures.
In subsequent years, all-night PSG recordings performed under audiovisual control documented that NFLE seizures form a wide spectrum of motor manifestations varying in complexity and duration.4–9
PAs are brief simple motor phenomena, similar to an apparent sudden awakening. During a PA, the patient displays stereotyped movements such as suddenly sitting up on the bed and raising head and trunk bringing the arms forward, with a frightened expression (Fig. 1). In other cases, the patient can present dystonic postures and/or dyskinetic movements (choreoathetosic or ballistic) of a limb, typically the arm, or rhythmic movements of the pelvis and/or limbs, sometimes with vocalization. PA lasts for less than 20 seconds, is highly stereotyped and very frequent, and occurs repetitively (up to hundreds of times) throughout the night (see Fig. 1).
Patients are usually unaware of their behaviors during the night, but if PAs are very frequent, patients may feel exhausted on awakening in the morning and could present excessive daytime sleepiness.6,10,11
Major attacks, NPD, begin like PA, with a sudden arousal associated with complex, stereotyped, often violent motor behavior, with repetitive or rhythmic trunk and limb movements, rocking (coital-like) movements of the pelvis, vocalization, and screaming. In addition, patients may emit guttural sounds, curse, or swear, or they may even whistle or spit. In other episodes, a dystonic-dyskinetic component prevails and seizures may be characterized by asymmetric bilateral tonic postures with head deviation to one side, extension of the ipsilateral limbs, and flexion of the contralateral limbs (Fig. 2). In these cases, attacks resemble supplementary motor area seizures. NPD lasts longer (30–50 seconds) than PA.
ENW is the most complex and longest NFLE seizure type, lasting up to several minutes.12,13 At the onset of the episodes, patients suddenly present dystonic posturing and dyskinetic movements. Then, they get out of bed and wander around, often maintaining dystonic postures, repeatedly jumping around and changing direction in a sort of grotesque dance.13 They can vocalize unintelligibly and scream with a terrified expression. ENW can mimic sleepwalking, the well-known arousal parasomnia, but the agitated and violent motor behavior of ENW is quite different from the calmer physiologic motor pattern in sleepwalking patients.13 ENW in patients examined by us was associated with more frequent PA and with NPD, the PA representing the initial features of the more complex long-lasting episodes. This association and the orderly complexity of the attacks suggested a progressive spread of the ictal discharge to involve wider brain regions in a graded manner.5,14 Less than 10% of patients have only PA seizures; most have different types of seizures which tend to overlap in the same patient, the briefest episodes form the initial fragment of more prolonged attacks.5,6
Clinical features
NFLE affects both sexes, with a higher prevalence in men (women:men ratio is 3:7). Seizures appear more frequently during adolescence (mean age at onset, 14 ± 10 years) but can affect any age (until 64 years) and tend to increase in frequency during life.6
Seizures are frequent, occurring every night or almost every night, usually many times per night (mean 3 ± 3 attacks nightly in our population), increasing in frequency over the years, without a spontaneous improvement.6 Secondarily generalized seizures and/or seizures during wakefulness are rare, often appearing for limited periods.
A quarter of our patients had a positive family history for epilepsy, but the same seizure type, consistent with a possible autosomal dominant pattern, was established in only a few cases. Nearly half of our patients had a positive family history for 1 or more parasomnias, and a third of our patients presented in their personal history taking, mostly in infancy, sleep disorders resembling parasomnias. This frequency is much higher than that reported for large control populations. This is not a mere coincidence because the data were confirmed in our recent prospective familial aggregation study in which statistical analysis showed that probands with NFLE had a higher lifetime prevalence of some parasomnias, namely, the arousal parasomnias and bruxism, than controls.15 The higher frequency of arousal disorders in families with NFLE suggests an intrinsic link between parasomnias and NFLE. Several, not mutually exclusive, explanations for this link are possible, and, probably, an abnormal cholinergic system and related pathways could represent a model unifying the pathogenesis of NFLE and parasomnias.16
Autosomal dominant NFLE
In 1994, Scheffer and colleagues17,18 demonstrated that NFLE can be inherited as an autosomal dominant disorder, naming the condition autosomal dominant NFLE (ADNFLE). In 1995, Phillips and colleagues19 mapped the locus responsible for ADNFLE to chromosome 20q13.2, and, subsequently, mutations in the gene encoding for the α4 subunit of the Ach neuronal receptor (CHRNA4) were demonstrated.20 Further linkage sites were later described at chromosomes 15q24,21 3p22-24, and 8q11.2-q21.1,22 and other mutations were reported in genes encoding for the α2 and β2 subunits of the Ach receptor (CHRNA2 and CHRNB2).23–25
Even though mutations in Ach nicotinic neuronal receptors remain a rare cause of ADNFLE, because most families and nearly all sporadic cases were negative for these mutations, these receptors do seem to be responsible for ADNFLE. In vitro analyses of the functional properties of nAChR disclosed a gain of function of these mutant receptors associated with ADNFLE26 that may underlie the neuronal dysfunction responsible for the epileptic seizures. In addition, a recent positron emission tomography study comparing 8 nonsmoking patients with ADNFLE with 7 controls demonstrated a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex.27
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