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From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy
Clinical Neurophysiology 111, Suppl. 2 (2000) S2±S8
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From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy F. Provini, G. Plazzi, E. Lugaresi* Institute of Clinical Neurology, University of Bologna, Bologna, Italy
Abstract Nocturnal paroxysmal dystonia (NPD) is the term used to describe motor attacks characterized by complex behavior, with dystonicdyskinetic or ballic movements arising from NREM sleep. NPD together with paroxysmal arousals (PA), the briefest attacks, and episodic nocturnal wanderings (ENW), the most prolonged ones, constitute nocturnal frontal lobe epilepsy (NFLE). PA are sudden awakenings associated with stereotyped dystonic-dyskinetic movements, sometimes accompanied by screaming and a frightened expression. ENW are episodes of agitated ambulation, with complex, sometimes violent, motor behavior and dystonic postures involving head, trunk and limbs. NPD, PA and ENW coexist in most patients. NFLE is predominant in males and usually begins during adolescence. A familial recurrence of parasomnias in NFLE patients is much more common than in the general population. Autosomal dominant inheritance has been documented in 6% of our cases. Few patients present personal antecedents or positive neuroradiological ®ndings. Seizures are frequent, occurring every or almost every night, many times per night. Interictal wake and sleep EEG tracings are often normal and ictal epileptic activity is recorded in a relatively small number of cases. Carbamazepine controls or signi®cantly reduces seizures in about 70% of cases; the remainder are drugresistant. Videopolysomnographic recordings, showing stereotyped abnormal movements during attacks, are mandatory to con®rm the diagnosis of NFLE. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Paroxysmal arousal; Nocturnal paroxysmal dystonia; Episodic nocturnal wandering; Frontal lobe epilepsy; Autosomal dominant nocturnal frontal lobe epilepsy; Arousal disorders
1. Introduction In 1981, we described 5 patients presenting nocturnal episodes characterized by postures localized in one limb or involving the entire trunk and all limbs associated or alternated with dyskinetic movements (Lugaresi and Cirignotta, 1981). We labelled this syndrome hypnogenic and later nocturnal paroxysmal dystonia (NPD) (Lugaresi and Cirignotta, 1981; Lugaresi et al., 1986). NPD seizures were usually very short (15±45 s) and not associated with interictal and ictal electroencephalographic (EEG) abnormalities. Attacks recurred every or almost every night, many times per night, arising from NREM sleep, and did not show a spontaneous improvement over the years. Carbamazepine treatment, often at very low dosages, was effective in all patients. The stereotypic motor pattern of the seizures, the short duration and the good response to carbamazepine suggested an epileptic origin of the episodes. However, the absence of clear-cut epileptic ictal and interictal EEG abnormalities hindering a de®nitive con®rmation of the * Corresponding author. Istituto di Clinica Neurologica, Via Ugo Foscolo 7, 40123 Bologna, Italy. Tel.: 139-051-6442129; fax: 139-051-6442165. E-mail address: [email protected] (E. Lugaresi).
epileptic nature of the attacks, and the dystonic-dyskinetic motor pattern could also suggest a new kind of movement disorder (Lugaresi and Cirignotta, 1981; Lugaresi et al., 1986). Subsequently, with the aid of zygomatic and sphenoidal leads, we provided evidence for an epileptic frontal lobe origin of the attacks in 3 new cases of NPD (Tinuper et al., 1990). Comparative studies (Meierkord et al., 1992) later con®rmed that NPD patients with negative EEG ®ndings and patients with frontal lobe epilepsy proven by EEG discharges were clinically indistinguishable. Therefore, NPD and frontal lobe seizures (Lugaresi et al., 1986; Hirsh et al., 1994) characterized by complex, bizarre motor patterns with bimanual-bipedal activity, rocking axial and pelvic torsion and sometimes ambulation (Tharp, 1972; Wada and Purves, 1984; Williamson et al., 1985; Waterman et al., 1987) are one and the same disorder (Provini et al., 1999). Nocturnal attacks characterizing NFLE vary in intensity and duration and form a wide spectrum of motor manifestations whose clinical features have been delineated by all night polysomnographic (PSG) recordings performed under audio-visual control (Montagna et al., 1990; Montagna, 1992; Provini et al., 1999).
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1.1. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) Recently, Berkovic's group demonstrated that NFLE can be inherited as an autosomal dominant disorder (ADNFLE) (Scheffer et al., 1994, 1995). Familial cases of NFLE had been described previously but the autosomal dominant inheritance of the syndrome had not been appreciated (Lee et al., 1985; Montagna, 1992; Vigevano and Fusco, 1993). Up to now, linkage studies have localized a gene for ADNFLE to chromosome 20q 13.2 (Phillips et al., 1995), and 3 mutations were identi®ed in the neuronal nicotinic acetylcholine receptor a4 subunit, two in white families (Steinlein et al., 1995, 1997; Saenz et al., 1999) and one in a Japanese family (Hirose et al., 1999) and a new linkage to chromosome 15 has also been suggested (Phillips et al., 1998). Nevertheless, not all ADNFLE families carry the described mutations, indicating not only a clinical but probably also a genetic heterogeneity within ADNFLE (Berkovic et al., 1995; Mochi et al., 1997). 1.2. NFLE: paroxysmal motor manifestations NFLE seizures can be divided into 3 main types: paroxysmal arousals (PA), lasting less than 20 s; nocturnal paroxysmal dystonia (NPD), lasting less than 2 min; and episodic nocturnal wandering (ENW), lasting up to 3 min. Few patients presented only one type of seizure. In fact, seizures of different duration tended to overlap in the same patient, the briefest episodes being the initial fragment of more prolonged attacks (Fig. 1). This indicates that there is a continuity between the different clinical manifestations (PA, NPD and ENW) due to epileptic discharges spreading over the cortex (Sforza et al., 1993). PA, NPD and ENW are therefore 3 different aspects of the same pathophysiological condition due to an epileptic focus in the orbito-mesial frontal region (Montagna, 1992; Provini et al., 1999). 1.3. Paroxysmal arousals (PA) PA consists in an abrupt, frequently recurring, arousal from sleep associated with stereotyped movements: patients raise their heads, sit on the bed, screaming or looking around with a frightened expression. Dystonic or dyskinetic posture usually involves the upper and lower limbs. In some rare cases awakening is not so sudden and the pathological hallmark of the attacks can be con®rmed by their recurrence with the same stereotyped motor pattern, as in a patient who presented an abnormal sustained contraction of the upper limbs associated with choreo-athetoid vermicular movements of the ®ngers. 1.4. Nocturnal paroxysmal dystonia (NPD) NPD seizures begin as PA with a sudden arousal associated with a complex stereotyped, sometimes bizarre, sequence of movements, characterized by asymmetric tonic
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or dystonic postures (like seizures originating in the supplementary motor areas) of limbs, neck and head, cycling or kicking of the limbs in all directions, rhythmic twisting of the trunk and rocking of the pelvis or choreoathetoid movements (Fig. 2). Patients can whistle or utter guttural sounds or incoherent words, with a frightened expression. Clonic asymmetric jerks may also appear. A few cases are characterized by a violent ballic pattern with ¯aying of the limbs. 1.5. Episodic nocturnal wanderings (ENW) (agitated somnambulism) ENW begin with a sudden awakening associated with dystonic posture or dyskinetic movements as PA and NPD, followed by agitated somnambulism characterized by jumping out of bed, twisting around, sudden direction changes, moving around aimlessly, as in a grotesque dance. Patients can talk unintelligibly or scream with a terri®ed expression. Dystonic postures may involve the head, trunk, and limbs. The agitated and violent motor behavior may lead to severe injuries to the patient himself and is quite different from the calmer `physiological' motor pattern of walking in the sleep-walking patient. Recently we documented that agitated somnambulic episodes resembling those previously described by Pedley and Guilleminault (1977) were associated with ictal EEG epileptic discharges con®rming that ENW are ictal events (Plazzi et al., 1995). ENW are not very frequent and could not be recorded even during PSG recording. Besides, in patients who report ENW, PA and/or NPD are often recorded even if they are not reported. Due to their short duration, PA are always underestimated or even not reported, especially in patients with PA alone. These patients usually refer only poor sleep quality and tiredness during the daytime. Daytime somnolence may thus be the only symptom reported by patients with recurrent paroxysmal awakenings during the night (Peled and Lavie, 1986). In many patients PA and NPD can recur with a periodic repetition, every 30 s±2 min (Sforza et al., 1993; Provini et al., 1999), in particular during light sleep, with the same stereotyped pattern. In these cases, seizures of intermediate duration appear between the shortest attacks (a few seconds) and the more prolonged ones (1±2 min), documenting that there is a continuum between PA and NPD. A K-complex often coincides or immediately precedes the seizure onset, suggesting K complexes might trigger epileptic seizures. In fact, during light NREM sleep, in physiological conditions, K complexes recur periodically (Lugaresi et al., 1972). Periodic K complexes during sleep could thus modulate the activity of frontal lobe foci, triggering the onset of the seizures with the same periodicity. 2. NFLE: clinical and polygraphic aspects of the syndrome We described clinical, electroencephalographic (EEG)
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Fig. 1. Episodes of nocturnal frontal lobe epilepsy of varying intensity on the same night. The hypnogram (top) shows sleep stages correlated to seizures of different duration during the night: Paroxysmal arousals ( j ); Nocturnal paroxysmal dystonia (B). Paroxysmal arousal ( j ): the patient suddenly raises her head and trunk turning over with dystonic right arm posture. Nocturnal paroxysmal dystonia (B): the patient suddenly stiffens and ¯exes her right arm, raising her head and trunk with abduction of the legs and dystonic posture of her right foot.
F. Provini et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S2±S8
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Fig. 2. Episodes of nocturnal frontal lobe epilepsy. The hypnogram (top) correlates 3 nocturnal paroxysmal dystonia seizures (B) with sleep stages during the night. Photographic sequences show the semiology of the episodes characterized by violent movements of the trunk and limbs and dystonic posturing of the left hemisoma.
and videopolysomnographic data in 100 patients observed consecutively who had a diagnosis of NFLE con®rmed by videotape recordings (Provini et al., 1999). NFLE usually begins during adolescence (mean age at onset: 14 ^ 10 years) like other partial epilepsies (Hauser, 1998), but the wide range of onset (between 1 and 64 years of age) suggests that the causative mechanisms are polymorphic. Like some other sleep non-epileptic paroxysmal motor disorders (REM sleep behavior disorders), NFLE predominates in males (7:3 in our population). Neurological examination is normal in most cases. Few patients present personal antecedents (birth anoxia, febrile convulsions, head injury) or positive neuro-imaging ®ndings. These data con®rm that an acquired etiology is seldom disclosed.
A quarter of our patients had a family history positive for epilepsy, but autosomal dominant inheritance (ADNFLE) (two or more members with the same seizure type) was only established in 8 patients belonging to 6 families (Provini et al., 1999). A third of our cases (all the familial cases and other sporadic forms randomly selected) did not carry the described mutations on the CHRNA4 gene. We thus con®rm that ADNFLE is a genetically heterogeneous disorder. Nearly half of our patients had a positive family history for one or more parasomnias and a third of our patients presented in their personal history, mostly in infancy, sleep disorders resembling parasomnias. This very high frequency of `parasomnias' is much higher than that reported for large control populations in which the preva-
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lence of sleep terrors and sleepwalking ranges from 1 to 6% of the entire population (Cirignotta et al., 1983; Hublin et al., 1997). These data could be explained in two different ways: an underlying genetic or acquired mechanism favors the onset of typical arousal disorders and, later in life, the onset of epileptic seizures, or the nocturnal epileptic seizures appearing during childhood in patients and relatives were mistaken for night terrors and sleepwalking. If the latter is the case, ADNFLE, as suggested by others (Oldani et al., 1996, 1998), is more common than we believed. Seizures frequently occur every or almost every night, usually many times per night (mean 3 ^ 3 attacks nightly in our population). Stress, sleep deprivation and menstruation are often reported as triggering factors for seizures. Rare secondarily generalized seizure and/or seizures during wakefulness were referred in about a third of our patients. The association of PA and NPD is present in most patients and ENW are also recorded or reported in 40% of cases. PA alone are recorded in few patients (9%). Interictal wake and sleep EEG tracings are often normal and ictal epileptic activity (spikes and spikes and waves) is recorded in a relatively small number of cases. In some patients special electrodes are needed to detect EEG epileptic abnormalities. In nearly all patients, seizure onset is characterized by autonomic manifestations involving heart rate, breathing, vasomotor tone and sympathetic skin response. The antiepileptic drug of choice for NFLE is carbamazepine, controlling or signi®cantly reducing seizures in about 70% of the cases; the remaining patients, commonly with a high seizure frequency, are drug-resistant. The percentage of drug-resistant patients is therefore the same as that found in other frontal lobe epilepsies. The claimed benign nature of NFLE is therefore due to the limited social impact related to the nocturnal occurrence of the seizures. 3. Differential diagnosis Due to their nocturnal occurrence, it is dif®cult to obtain a semeiological description of the attacks. On the other hand, ictal and interictal EEG discharges are lacking in many cases so that diagnosis cannot be based on EEG ®ndings. Only repeated videoPSG observations demonstrating the intraindividual stereotypy of the attacks and the abnormal aspect of the seizures with dystonic-dyskinetic or ballic components can establish the ®nal diagnosis in most patients. NFLE is frequently misdiagnosed as an arousal disorder (sleep terror±sleep walking), especially in children, but disorders of arousal tend to arise earlier, in childhood, and to disappear over the years. In addition, episodes of sleep terror and sleep walking are isolated and rare (one episode every 1±4 months) (Sours et al., 1963) without the stereotypic `extrapyramidal' patterns (dystonic posturing, ballic movements, tremor, choreo-athetosis) (Table 1).
Table 1 Diagnostic guidelines NFLE is much more likely than sleep arousal disorder if: B Attacks recur several times during the same night B Attacks occur in a stereotyped fashion B Attacks arise or persist into adulthood B Tremor, dystonia, ballism or abnormal movements are present during the attack
REM sleep behaviour disorder. A REM sleep-related parasomnia, (Schenck et al., 1986) can be readily differentiated from NFLE on the basis of later onset (around 60 years of age) and polymorphic behavior with a dream associated with the typical polygraphic ®nding of REM sleep without atonia. Nocturnal panic attacks are also characterized by a sudden awakening from sleep with dramatic autonomic activation and a sensation of imminent death. The episodes, usually arising in adolescence (15±19 years) or middle age, often recur only once per night and are prolonged (24 min as a mean) (Craske and Barlow, 1989; Dantendorfer et al., 1996; Plazzi et al., 1998). Differential diagnosis of NFLE must also include attacks described under the terms NPD of intermediate and long duration (Lugaresi and Cirignotta, 1984; Montagna et al., 1992). NPD with intermediate duration (3±5 min), triggered by arousal during sleep and by protracted exercise during wakefulness, differ from NFLE in their duration, due to the triggering effect of exercise and, above all, the peculiar motor pattern, characterized by asynchronous jerks of the head, trunk and limbs making the patient look like a puppet on strings. NPD with long-lasting (2±50 min) dystonicdyskinetic attacks, arising from light sleep, recurring several times per night and resistant to AED were observed in two patients. One of them developed Huntington's disease 20 years after onset of the nocturnal attacks. The long duration of the attacks, the inef®cacy of anticonvulsants and the link with Huntington's disease in one patient suggest a basal ganglia involvement. 4. NFLE: a hypothesis of the underlying mechanisms The clinical and EEG features of NFLE and the positive neuroradiological ®ndings offer some evidence that the epileptogenic focus is located in the mesio-orbital frontal cortex. This cortical region represents the highest integrative level of the limbic circuits. The limbic cortex has close links with the ventrostriatopallidal system, which acts as a motor control system in parallel with the better known neocortical system (Groenewegen et al., 1990), the visceral thalamus, which plays a strategic role in sleep-wake regulation, and with basal forebrain, hypothalamus and brainstem, which control body homeostasis (Lugaresi et al., 1998). Thus, epileptic discharges which originate in the mesio-orbital frontal cortex, impinging on the limbic
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subcortical structures mentioned above, may lead to a sudden change in sleep, motor and autonomic behavior. The clinical consequences are an abrupt arousal, complex abnormal movements, respiratory, cardiocirculatory and sympathetic skin modi®cations. Deep cortical hyperpolarization-depolarization sequence characterizing K complexes probably trigger the epileptic discharges originating in the mesio-orbital frontal cortex. This hypothesis is also supported by the fact that the seizures tend to recur with the same periodicity as that of K complexes in physiological conditions (see above). 5. Conclusion NFLE is a more common epileptic syndrome than is currently believed, accounting for 13% of PSG recordings for nocturnal motor disorders run in our laboratory. The apparent rarity of NFLE may be due to the fact that diagnosis is seldom made without audiovisual recording. VideoPSG recordings, showing a stereotyped, abnormal motor pattern during attacks, are mandatory to con®rm the diagnosis. NFLE should always be suspected when paroxysmal nocturnal motor events arise or persist into adulthood and recur several times during the same night. NFLE is only apparently benign, many patients being resistant to AED therapy, but the social impact of seizures is limited since they are con®ned to sleep. ADNFLE is a genetic variant of NFLE, in itself both clinically and biologically heterogeneous. Acknowledgements We thank Stefano Vandi, Filomena Miele and Nino Bertozzi for their contribution to the statistical analysis, Carlo Grassi for photographic assistance, Alessandra Laf® for technical assistance in preparing the manuscript. Supported by MURST grant 40% 1997. References Berkovic SF, Phillips HA, Sheffer IE, Lopes-Cendes I, Bhatia KP, Fish DR, et al. Genetic heterogeneity in autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia 1995;36(Suppl 4):147. Cirignotta F, Zucconi M, Mondini S, Lenzi PL, Lugaresi E. Enuresis, sleepwalking, and nightmares: an epidemiological survey in the Republic of San Marino. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology, and long-term evolution, New York: Raven Press, 1983. pp. 237±241. Craske MG, Barlow DH. Nocturnal panic. J Nerv Ment Dis 1989;177:160± 167. Dantendorfer K, Frey R, Maierhofer D, Saletu B. Sudden arousals from slow wave sleep and panic disorders: successful treatment with anticonvulsants-a case report. Sleep 1996;19:744±746. Groenewegen HK, Berendse HW, Wolters JG, Lohman AHM. The anatomical relationship of the prefrontal cortex with the striatopallidal
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From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy F. Provini, G. Plazzi, E. Lugaresi* Institute of Clinical Neurology, University of Bologna, Bologna, Italy
Abstract Nocturnal paroxysmal dystonia (NPD) is the term used to describe motor attacks characterized by complex behavior, with dystonicdyskinetic or ballic movements arising from NREM sleep. NPD together with paroxysmal arousals (PA), the briefest attacks, and episodic nocturnal wanderings (ENW), the most prolonged ones, constitute nocturnal frontal lobe epilepsy (NFLE). PA are sudden awakenings associated with stereotyped dystonic-dyskinetic movements, sometimes accompanied by screaming and a frightened expression. ENW are episodes of agitated ambulation, with complex, sometimes violent, motor behavior and dystonic postures involving head, trunk and limbs. NPD, PA and ENW coexist in most patients. NFLE is predominant in males and usually begins during adolescence. A familial recurrence of parasomnias in NFLE patients is much more common than in the general population. Autosomal dominant inheritance has been documented in 6% of our cases. Few patients present personal antecedents or positive neuroradiological ®ndings. Seizures are frequent, occurring every or almost every night, many times per night. Interictal wake and sleep EEG tracings are often normal and ictal epileptic activity is recorded in a relatively small number of cases. Carbamazepine controls or signi®cantly reduces seizures in about 70% of cases; the remainder are drugresistant. Videopolysomnographic recordings, showing stereotyped abnormal movements during attacks, are mandatory to con®rm the diagnosis of NFLE. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Paroxysmal arousal; Nocturnal paroxysmal dystonia; Episodic nocturnal wandering; Frontal lobe epilepsy; Autosomal dominant nocturnal frontal lobe epilepsy; Arousal disorders
1. Introduction In 1981, we described 5 patients presenting nocturnal episodes characterized by postures localized in one limb or involving the entire trunk and all limbs associated or alternated with dyskinetic movements (Lugaresi and Cirignotta, 1981). We labelled this syndrome hypnogenic and later nocturnal paroxysmal dystonia (NPD) (Lugaresi and Cirignotta, 1981; Lugaresi et al., 1986). NPD seizures were usually very short (15±45 s) and not associated with interictal and ictal electroencephalographic (EEG) abnormalities. Attacks recurred every or almost every night, many times per night, arising from NREM sleep, and did not show a spontaneous improvement over the years. Carbamazepine treatment, often at very low dosages, was effective in all patients. The stereotypic motor pattern of the seizures, the short duration and the good response to carbamazepine suggested an epileptic origin of the episodes. However, the absence of clear-cut epileptic ictal and interictal EEG abnormalities hindering a de®nitive con®rmation of the * Corresponding author. Istituto di Clinica Neurologica, Via Ugo Foscolo 7, 40123 Bologna, Italy. Tel.: 139-051-6442129; fax: 139-051-6442165. E-mail address: [email protected] (E. Lugaresi).
epileptic nature of the attacks, and the dystonic-dyskinetic motor pattern could also suggest a new kind of movement disorder (Lugaresi and Cirignotta, 1981; Lugaresi et al., 1986). Subsequently, with the aid of zygomatic and sphenoidal leads, we provided evidence for an epileptic frontal lobe origin of the attacks in 3 new cases of NPD (Tinuper et al., 1990). Comparative studies (Meierkord et al., 1992) later con®rmed that NPD patients with negative EEG ®ndings and patients with frontal lobe epilepsy proven by EEG discharges were clinically indistinguishable. Therefore, NPD and frontal lobe seizures (Lugaresi et al., 1986; Hirsh et al., 1994) characterized by complex, bizarre motor patterns with bimanual-bipedal activity, rocking axial and pelvic torsion and sometimes ambulation (Tharp, 1972; Wada and Purves, 1984; Williamson et al., 1985; Waterman et al., 1987) are one and the same disorder (Provini et al., 1999). Nocturnal attacks characterizing NFLE vary in intensity and duration and form a wide spectrum of motor manifestations whose clinical features have been delineated by all night polysomnographic (PSG) recordings performed under audio-visual control (Montagna et al., 1990; Montagna, 1992; Provini et al., 1999).
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1.1. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) Recently, Berkovic's group demonstrated that NFLE can be inherited as an autosomal dominant disorder (ADNFLE) (Scheffer et al., 1994, 1995). Familial cases of NFLE had been described previously but the autosomal dominant inheritance of the syndrome had not been appreciated (Lee et al., 1985; Montagna, 1992; Vigevano and Fusco, 1993). Up to now, linkage studies have localized a gene for ADNFLE to chromosome 20q 13.2 (Phillips et al., 1995), and 3 mutations were identi®ed in the neuronal nicotinic acetylcholine receptor a4 subunit, two in white families (Steinlein et al., 1995, 1997; Saenz et al., 1999) and one in a Japanese family (Hirose et al., 1999) and a new linkage to chromosome 15 has also been suggested (Phillips et al., 1998). Nevertheless, not all ADNFLE families carry the described mutations, indicating not only a clinical but probably also a genetic heterogeneity within ADNFLE (Berkovic et al., 1995; Mochi et al., 1997). 1.2. NFLE: paroxysmal motor manifestations NFLE seizures can be divided into 3 main types: paroxysmal arousals (PA), lasting less than 20 s; nocturnal paroxysmal dystonia (NPD), lasting less than 2 min; and episodic nocturnal wandering (ENW), lasting up to 3 min. Few patients presented only one type of seizure. In fact, seizures of different duration tended to overlap in the same patient, the briefest episodes being the initial fragment of more prolonged attacks (Fig. 1). This indicates that there is a continuity between the different clinical manifestations (PA, NPD and ENW) due to epileptic discharges spreading over the cortex (Sforza et al., 1993). PA, NPD and ENW are therefore 3 different aspects of the same pathophysiological condition due to an epileptic focus in the orbito-mesial frontal region (Montagna, 1992; Provini et al., 1999). 1.3. Paroxysmal arousals (PA) PA consists in an abrupt, frequently recurring, arousal from sleep associated with stereotyped movements: patients raise their heads, sit on the bed, screaming or looking around with a frightened expression. Dystonic or dyskinetic posture usually involves the upper and lower limbs. In some rare cases awakening is not so sudden and the pathological hallmark of the attacks can be con®rmed by their recurrence with the same stereotyped motor pattern, as in a patient who presented an abnormal sustained contraction of the upper limbs associated with choreo-athetoid vermicular movements of the ®ngers. 1.4. Nocturnal paroxysmal dystonia (NPD) NPD seizures begin as PA with a sudden arousal associated with a complex stereotyped, sometimes bizarre, sequence of movements, characterized by asymmetric tonic
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or dystonic postures (like seizures originating in the supplementary motor areas) of limbs, neck and head, cycling or kicking of the limbs in all directions, rhythmic twisting of the trunk and rocking of the pelvis or choreoathetoid movements (Fig. 2). Patients can whistle or utter guttural sounds or incoherent words, with a frightened expression. Clonic asymmetric jerks may also appear. A few cases are characterized by a violent ballic pattern with ¯aying of the limbs. 1.5. Episodic nocturnal wanderings (ENW) (agitated somnambulism) ENW begin with a sudden awakening associated with dystonic posture or dyskinetic movements as PA and NPD, followed by agitated somnambulism characterized by jumping out of bed, twisting around, sudden direction changes, moving around aimlessly, as in a grotesque dance. Patients can talk unintelligibly or scream with a terri®ed expression. Dystonic postures may involve the head, trunk, and limbs. The agitated and violent motor behavior may lead to severe injuries to the patient himself and is quite different from the calmer `physiological' motor pattern of walking in the sleep-walking patient. Recently we documented that agitated somnambulic episodes resembling those previously described by Pedley and Guilleminault (1977) were associated with ictal EEG epileptic discharges con®rming that ENW are ictal events (Plazzi et al., 1995). ENW are not very frequent and could not be recorded even during PSG recording. Besides, in patients who report ENW, PA and/or NPD are often recorded even if they are not reported. Due to their short duration, PA are always underestimated or even not reported, especially in patients with PA alone. These patients usually refer only poor sleep quality and tiredness during the daytime. Daytime somnolence may thus be the only symptom reported by patients with recurrent paroxysmal awakenings during the night (Peled and Lavie, 1986). In many patients PA and NPD can recur with a periodic repetition, every 30 s±2 min (Sforza et al., 1993; Provini et al., 1999), in particular during light sleep, with the same stereotyped pattern. In these cases, seizures of intermediate duration appear between the shortest attacks (a few seconds) and the more prolonged ones (1±2 min), documenting that there is a continuum between PA and NPD. A K-complex often coincides or immediately precedes the seizure onset, suggesting K complexes might trigger epileptic seizures. In fact, during light NREM sleep, in physiological conditions, K complexes recur periodically (Lugaresi et al., 1972). Periodic K complexes during sleep could thus modulate the activity of frontal lobe foci, triggering the onset of the seizures with the same periodicity. 2. NFLE: clinical and polygraphic aspects of the syndrome We described clinical, electroencephalographic (EEG)
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Fig. 1. Episodes of nocturnal frontal lobe epilepsy of varying intensity on the same night. The hypnogram (top) shows sleep stages correlated to seizures of different duration during the night: Paroxysmal arousals ( j ); Nocturnal paroxysmal dystonia (B). Paroxysmal arousal ( j ): the patient suddenly raises her head and trunk turning over with dystonic right arm posture. Nocturnal paroxysmal dystonia (B): the patient suddenly stiffens and ¯exes her right arm, raising her head and trunk with abduction of the legs and dystonic posture of her right foot.
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Fig. 2. Episodes of nocturnal frontal lobe epilepsy. The hypnogram (top) correlates 3 nocturnal paroxysmal dystonia seizures (B) with sleep stages during the night. Photographic sequences show the semiology of the episodes characterized by violent movements of the trunk and limbs and dystonic posturing of the left hemisoma.
and videopolysomnographic data in 100 patients observed consecutively who had a diagnosis of NFLE con®rmed by videotape recordings (Provini et al., 1999). NFLE usually begins during adolescence (mean age at onset: 14 ^ 10 years) like other partial epilepsies (Hauser, 1998), but the wide range of onset (between 1 and 64 years of age) suggests that the causative mechanisms are polymorphic. Like some other sleep non-epileptic paroxysmal motor disorders (REM sleep behavior disorders), NFLE predominates in males (7:3 in our population). Neurological examination is normal in most cases. Few patients present personal antecedents (birth anoxia, febrile convulsions, head injury) or positive neuro-imaging ®ndings. These data con®rm that an acquired etiology is seldom disclosed.
A quarter of our patients had a family history positive for epilepsy, but autosomal dominant inheritance (ADNFLE) (two or more members with the same seizure type) was only established in 8 patients belonging to 6 families (Provini et al., 1999). A third of our cases (all the familial cases and other sporadic forms randomly selected) did not carry the described mutations on the CHRNA4 gene. We thus con®rm that ADNFLE is a genetically heterogeneous disorder. Nearly half of our patients had a positive family history for one or more parasomnias and a third of our patients presented in their personal history, mostly in infancy, sleep disorders resembling parasomnias. This very high frequency of `parasomnias' is much higher than that reported for large control populations in which the preva-
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lence of sleep terrors and sleepwalking ranges from 1 to 6% of the entire population (Cirignotta et al., 1983; Hublin et al., 1997). These data could be explained in two different ways: an underlying genetic or acquired mechanism favors the onset of typical arousal disorders and, later in life, the onset of epileptic seizures, or the nocturnal epileptic seizures appearing during childhood in patients and relatives were mistaken for night terrors and sleepwalking. If the latter is the case, ADNFLE, as suggested by others (Oldani et al., 1996, 1998), is more common than we believed. Seizures frequently occur every or almost every night, usually many times per night (mean 3 ^ 3 attacks nightly in our population). Stress, sleep deprivation and menstruation are often reported as triggering factors for seizures. Rare secondarily generalized seizure and/or seizures during wakefulness were referred in about a third of our patients. The association of PA and NPD is present in most patients and ENW are also recorded or reported in 40% of cases. PA alone are recorded in few patients (9%). Interictal wake and sleep EEG tracings are often normal and ictal epileptic activity (spikes and spikes and waves) is recorded in a relatively small number of cases. In some patients special electrodes are needed to detect EEG epileptic abnormalities. In nearly all patients, seizure onset is characterized by autonomic manifestations involving heart rate, breathing, vasomotor tone and sympathetic skin response. The antiepileptic drug of choice for NFLE is carbamazepine, controlling or signi®cantly reducing seizures in about 70% of the cases; the remaining patients, commonly with a high seizure frequency, are drug-resistant. The percentage of drug-resistant patients is therefore the same as that found in other frontal lobe epilepsies. The claimed benign nature of NFLE is therefore due to the limited social impact related to the nocturnal occurrence of the seizures. 3. Differential diagnosis Due to their nocturnal occurrence, it is dif®cult to obtain a semeiological description of the attacks. On the other hand, ictal and interictal EEG discharges are lacking in many cases so that diagnosis cannot be based on EEG ®ndings. Only repeated videoPSG observations demonstrating the intraindividual stereotypy of the attacks and the abnormal aspect of the seizures with dystonic-dyskinetic or ballic components can establish the ®nal diagnosis in most patients. NFLE is frequently misdiagnosed as an arousal disorder (sleep terror±sleep walking), especially in children, but disorders of arousal tend to arise earlier, in childhood, and to disappear over the years. In addition, episodes of sleep terror and sleep walking are isolated and rare (one episode every 1±4 months) (Sours et al., 1963) without the stereotypic `extrapyramidal' patterns (dystonic posturing, ballic movements, tremor, choreo-athetosis) (Table 1).
Table 1 Diagnostic guidelines NFLE is much more likely than sleep arousal disorder if: B Attacks recur several times during the same night B Attacks occur in a stereotyped fashion B Attacks arise or persist into adulthood B Tremor, dystonia, ballism or abnormal movements are present during the attack
REM sleep behaviour disorder. A REM sleep-related parasomnia, (Schenck et al., 1986) can be readily differentiated from NFLE on the basis of later onset (around 60 years of age) and polymorphic behavior with a dream associated with the typical polygraphic ®nding of REM sleep without atonia. Nocturnal panic attacks are also characterized by a sudden awakening from sleep with dramatic autonomic activation and a sensation of imminent death. The episodes, usually arising in adolescence (15±19 years) or middle age, often recur only once per night and are prolonged (24 min as a mean) (Craske and Barlow, 1989; Dantendorfer et al., 1996; Plazzi et al., 1998). Differential diagnosis of NFLE must also include attacks described under the terms NPD of intermediate and long duration (Lugaresi and Cirignotta, 1984; Montagna et al., 1992). NPD with intermediate duration (3±5 min), triggered by arousal during sleep and by protracted exercise during wakefulness, differ from NFLE in their duration, due to the triggering effect of exercise and, above all, the peculiar motor pattern, characterized by asynchronous jerks of the head, trunk and limbs making the patient look like a puppet on strings. NPD with long-lasting (2±50 min) dystonicdyskinetic attacks, arising from light sleep, recurring several times per night and resistant to AED were observed in two patients. One of them developed Huntington's disease 20 years after onset of the nocturnal attacks. The long duration of the attacks, the inef®cacy of anticonvulsants and the link with Huntington's disease in one patient suggest a basal ganglia involvement. 4. NFLE: a hypothesis of the underlying mechanisms The clinical and EEG features of NFLE and the positive neuroradiological ®ndings offer some evidence that the epileptogenic focus is located in the mesio-orbital frontal cortex. This cortical region represents the highest integrative level of the limbic circuits. The limbic cortex has close links with the ventrostriatopallidal system, which acts as a motor control system in parallel with the better known neocortical system (Groenewegen et al., 1990), the visceral thalamus, which plays a strategic role in sleep-wake regulation, and with basal forebrain, hypothalamus and brainstem, which control body homeostasis (Lugaresi et al., 1998). Thus, epileptic discharges which originate in the mesio-orbital frontal cortex, impinging on the limbic
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subcortical structures mentioned above, may lead to a sudden change in sleep, motor and autonomic behavior. The clinical consequences are an abrupt arousal, complex abnormal movements, respiratory, cardiocirculatory and sympathetic skin modi®cations. Deep cortical hyperpolarization-depolarization sequence characterizing K complexes probably trigger the epileptic discharges originating in the mesio-orbital frontal cortex. This hypothesis is also supported by the fact that the seizures tend to recur with the same periodicity as that of K complexes in physiological conditions (see above). 5. Conclusion NFLE is a more common epileptic syndrome than is currently believed, accounting for 13% of PSG recordings for nocturnal motor disorders run in our laboratory. The apparent rarity of NFLE may be due to the fact that diagnosis is seldom made without audiovisual recording. VideoPSG recordings, showing a stereotyped, abnormal motor pattern during attacks, are mandatory to con®rm the diagnosis. NFLE should always be suspected when paroxysmal nocturnal motor events arise or persist into adulthood and recur several times during the same night. NFLE is only apparently benign, many patients being resistant to AED therapy, but the social impact of seizures is limited since they are con®ned to sleep. ADNFLE is a genetic variant of NFLE, in itself both clinically and biologically heterogeneous. Acknowledgements We thank Stefano Vandi, Filomena Miele and Nino Bertozzi for their contribution to the statistical analysis, Carlo Grassi for photographic assistance, Alessandra Laf® for technical assistance in preparing the manuscript. Supported by MURST grant 40% 1997. References Berkovic SF, Phillips HA, Sheffer IE, Lopes-Cendes I, Bhatia KP, Fish DR, et al. Genetic heterogeneity in autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia 1995;36(Suppl 4):147. Cirignotta F, Zucconi M, Mondini S, Lenzi PL, Lugaresi E. Enuresis, sleepwalking, and nightmares: an epidemiological survey in the Republic of San Marino. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology, and long-term evolution, New York: Raven Press, 1983. pp. 237±241. Craske MG, Barlow DH. Nocturnal panic. J Nerv Ment Dis 1989;177:160± 167. Dantendorfer K, Frey R, Maierhofer D, Saletu B. Sudden arousals from slow wave sleep and panic disorders: successful treatment with anticonvulsants-a case report. Sleep 1996;19:744±746. Groenewegen HK, Berendse HW, Wolters JG, Lohman AHM. The anatomical relationship of the prefrontal cortex with the striatopallidal
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