Other sleep-related paroxysmal events were identified as epileptic as well. Peled and Lavie (1986) described 14 patients with hypersomnia secondary to recurrent nocturnal arousals, which were shown to be associated with paroxysmal epileptiform discharges occurring exclusively during stage 2 or 3 of NREM sleep; three patients showed dramatic improvement after treatment with anticonvulsants. Montagna et al. (1990) made similar observations, concluding that, even though epileptic in nature, paroxysmal arousals constituted a clinical entity distinct from nocturnal paroxysmal dystonia characterized by attacks of even shorter duration. However, the same authors, in a subsequent review (Montagna, 1992) and strengthened by additional videopolygraphic recordings in three patients (Sforza et al., 1993), pointed out again that stereotyped episodes of increasing complexity and duration could coexist in the same patient and therefore probably represented clinical variants of the same disorder. In addition, they stressed the peculiar periodic recurrence of these paroxysmal motor events at 20-60-s intervals throughout lighter stages of NREM sleep, similar to the periodic oscillations of other physiological phenomena observed by Lugaresi et al. (1972). Based on studies by Terzano et al. (1985), who found that EEG activity during NREM sleep could be divided into 40-s periodic sequences of greater and lesser arousal that they termed cyclic alternating pattern, the authors concluded that periodic fluctuations in cortical-subcortical excitability could exert a modulating influence on the nocturnal motor attacks, thus explaining their tendency to occur in the vicinity of a K-complex. The argument was picked up by Terzano and colleagues (1997), who confirmed this hypothesis in six patients with a diagnosis of nocturnal paroxysmal dystonia (without epileptiform EEG features). Additional evidence for the epileptic nature of some instances of episodic nocturnal wanderings and paroxysmal arousals, respectively, was subsequently presented by Plazzi et al. (1995) and Zucconi et al. (1997).
nocturnal frontal lobe epilepsy
Finally, an overview of the clinical and EEG features of 100 consecutive cases of presumed nocturnal frontal lobe epilepsy was published by Provini et al. (1999). Although the authors propose that all patients are affected by the same disorder, namely, nocturnal frontal lobe epilepsy, they again emphasize the usefulness of a clinical distinction of their patients' multifaceted nocturnal motor manifestations into three subgroups, maintaining the previously introduced terminology. Paroxysmal arousals would constitute brief (<20 s) episodes characterized by sudden eye opening, head raising or sitting up in bed, often with a frightened expression and sometimes vocalization; nocturnal paroxysmal dystonia would describe episodes of intermediate duration (20 s-2 min) and include more complex behavior with wide, often ballistic movements, dystonic posturing or choreoathetoid movements of head, trunk, and limbs and vocalization; and the term episodic nocturnal wandering would be applied to the episodes of longest duration (1-3 min), characterized by stereotyped, paroxysmal ambulation, often agitated and accompanied by screaming and bizarre, dystonic movements, which set them apart from classical sleepwalking episodes.
Although some of the patients, as previously reported, present all three types of seizures, the distinction into the three groups is corroborated also by other statistically significant clinical associations. These involve the presence of an unremarkable personal history and absence of daytime or secondary generalization of seizures in patients with paroxysmal arousals, a family history of epilepsy and a higher overall frequency of seizures including secondary generalization of seizures in patients with nocturnal paroxysmal dystonia, and a family history positive for parasomnias and a personal history of sleepwalking in patients with episodic nocturnal wanderings. In about half of the cases, no interictal or ictal epileptiform EEG abnormalities were seen, but the authors are confident in making a diagnosis of frontal lobe epilepsy based on the stereotypy and the mode of occurrence of the nocturnal attacks, as well as the response to antiepileptic medication in several of the patients.
autosomal dominant frontal lobe epilepsy
The first familial cases of nocturnal paroxysmal dystonia were reported by Lee et al. (1985). The authors described a family with five affected members in three generations, suggesting an autosomal dominant inheritance pattern. However, given the absence of EEG abnormalities in three family members studied in detail, an epileptic origin of their motor manifestations was thought to be unlikely. The existence of an idiopathic frontal lobe epilepsy syndrome with onset in childhood and benign course was proposed by Vigevano and Fusco (1993) based on observations in 10 children; familial occurrence of seizures was noted but no specific inheritance pattern was identified.
Autosomal dominant frontal lobe epilepsy was first described by Scheffer et al. (1994), who collected six families with 39 affected individuals in Australia, the United Kingdom, and Canada, and were able to demonstrate monogenic inheritance with an autosomal dominant transmission pattern. A more extensive description of the clinical characteristics of five of these families, which proved to be quite homogeneous, was published the following year (Scheffer et al., 1995). Their seizures were characterized by daily clusters of brief nocturnal motor attacks thought to be typical for frontal lobe seizures, often preceded by an aura that could include virtually all kinds of sensory or psychic phenomena. Onset of seizures was in the first two decades of life in most cases, and there was considerable intrafamilial variation in the severity of the seizure disorder. Seizure frequency overall tended to decrease over time and only a few individuals over 50 years of age still reported recurrent attacks. Diagnosis was made mostly on the basis of clinical symptoms, because most patients did not have interictal epileptiform EEG abnormalities and only 3 out of 10 patients studied with video EEG showed ictal changes compatible with epilepsy. However, as in previously reported patients with similar symptomatology, treatment with carbamazepine was often effective. The first gene found to be responsible for this new syndrome was identified only shortly thereafter by Phillips et al. (1995) in a large Australian kindred and mapped to chromosome 20ql3.2-ql3.3; Steinlein et al. (1995) discovered a corresponding missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4), resulting in a substitution of serine with phenylalanine. More families, mostly of Caucasian descent, were described in the literature (Oldani et al., 1996, 1998; Nakken et al., 1999), and all affected individuals shared overall similar clinical characteristics. The attacks were highly stereotyped intraindividually, but intrafamilial variation of symptoms was again emphasized. Hayman et al. (1997) were able to study two patients from unrelated families with ictal single photon emission computed tomography (SPECT) and demonstrated focal frontal seizure onset, yet in different locations. Evidence for genetic heterogeneity emerged as well: Steinlein et al. (1997) reported a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family, consisting of the insertion of an extra leucine into the amino acid chain. Both CHRNA4 mutations are thought to produce a decrease in receptor function (Steinlein et al., 1997), and the authors propose that varying proportions of defective acetylcholine receptors could account for clinical variations between individuals. More mutations were discovered in the following years. Phillips et al. (1998) found evidence of another acetylcholine receptor defect with linkage to chromosome 15q24 in an English family and excluded the presence of the hitherto known mutations in an additional six families. Hirose et al. (1999) reported on a new CHRNA4 mutation, and the first mutation discovered in an Asian (Japanese) family, resulting in the replacement of serine 252 in the M2 domain of CHRNA4 with a leucine. Nevertheless, in most of the approximately 40 families reported to date the genetic defect has not yet been identified, and additional discoveries are likely to occur.
Paroxysmal nocturnal motor events characterized by complex, often stereotyped dystonic or choreic movements with sudden onset and variable duration often defy precise classification. Over the years, different hypotheses regarding their origin have been advanced, and they have been variably diagnosed as sleep disorder, movement disorder or epilepsy. More recently, evidence has been mounting that many of these motor manifestations indeed represent seizures originating from the frontal lobe, although epileptiform EEG abnormalities are often lacking. Autosomal dominant transmission has been described in several families, and different mutations affecting the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) have been discovered.
However, it should be borne in mind that "not everything that shakes is epilepsy," and that a diagnosis of epilepsy on clinical grounds alone leaves room for the doubt that the paroxysmal motor events displayed by some of the reported patients might actually have a different etiology. There is certainly strong evidence for a genetic basis of the symptomatology in many of the patients diagnosed as having nocturnal frontal lobe epilepsy, but an autosomal dominant inheritance pattern has been demonstrated also in many patients with paroxysmal dyskinesias. The discovery of a channelopathy in patients with frontal lobe epilepsy may provide a future link between epilepsy and some paroxysmal movement disorders, and perhaps NREM parasomnias as well.
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