常染色体显性遗传夜间额叶癫痫

常染色体显性遗传性夜间额叶癫痫（autosomal dominant nocturnal frontal epilepsy，ADNFLE）是一种常染色体显性遗传的特发性局灶性癫痫综合征，1994年首先由Scheffer等描述，夜间成串的运动症状发作为最显著的临床特征。1995年Steinlein等首先发现其致病基因，是第一个被发现由基因变异引起的特发性癫痫综合征。本文对其临床特点、遗传学及发病机制的研究进展加以综述。     

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy

PURPOSE: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. METHODS: All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here; family S has a previously reported mutation in the beta 2 subunit of CHRN. RESULTS: A total of 16 individuals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of individuals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. CONCLUSIONS: The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor.     

Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family

PURPOSE: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first described partial epilepsy syndrome known to be due to a single gene mutation. We found a first Japanese ADNFLE family with a novel mutation of the neuronal nicotinic acetylcholine receptor (nAChR) alpha4 subunit (CHRNA4) gene. The aim of this report is precisely to describe the electroclinical manifestations of ADNFLE in this family and to compare these findings with those of other families reported previously in the literature. METHODS: Three affected family members were investigated electroclinically by close clinical observation, interictal EEG, video-EEG monitoring, magnetic resonance imaging, and single-photon-emission tomography. Information about other affected family members was obtained from either the spouse or the parents. Mutations within the CHRNA4 gene were examined in seven family members. RESULTS: The clinical manifestations and diagnostic findings in the members of this family were consistent with ADNFLE. However, there were intrafamilial and interfamilial variations in clinical features. The seizures of the patients were brief tonic seizures, with hyperventilation in children and secondarily generalized tonic-clonic convulsions in adults. The onset of the children's seizures began in infancy and early childhood. The children's seizures were sometimes provoked by movement and sound stimulation, and did not respond to antiepileptic drugs. On the other hand, the adults' seizures disappeared spontaneously or were easily controlled with carbamazepine. Three children showed hyperactivity, and two children had mild mental retardation. All patients had impaired consciousness during their seizures and no auras. A novel missense mutation (c755C>T) in exon 5 of the CHRNA4 gene was found in four affected family members. CONCLUSIONS: The electroclinical pictures of a Japanese family with ADNFLE were basically the same as those of other families reported, but with slight differences. ADNFLE is probably not uncommon, and it is very likely that there are unidentified patients with this inherited disorder in Japan.     

Nocturnal frontal lobe epilepsy misdiagnosed as sleep apnea syndrome

Some clinical features as the awakenings with feeling of choking, the abnormal motor activity during sleep and the excessive daytime sleepiness are relatively common both in obstructive sleep apnea syndrome and in nocturnal frontal lobe epilepsy. In these cases, a full-night video-polysomnographic monitoring is of the utmost importance to provide a differential diagnosis between the two conditions, and to verify, in the case of the co-existence of the two disorders, which is the one responsible for sleep disruption. In the present case reports, we described 2 patients referred to our Sleep Disorders Center with the above mentioned clinical features and with a previous clinical diagnosis of obstructive sleep apnea syndrome. After the recording of them, by means of full-night video-polysomnography, they were both diagnosed as having nocturnal frontal lobe epilepsy as the main sleep disorder and then successfully treated with carbamazepine.     

Nicotine as an antiepileptic agent in ADNFLE: an N-of-one study

PURPOSE: To test nicotine patch treatment for a patient with a defined mutation for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) whose seizures were refractory to standard antiepileptic therapy. METHODS: Open and double-blind trials of nicotine patches in an "n-of-one" study. The double-blind trial comprised periods during which either placebo or nicotine patches were each used for three periods of 2 weeks, randomized in a double-blind manner. RESULTS: In an open study, nicotine patches reduced seizures from 1.65 +/- 2.36 to 0.01 +/- 0.0 seizures per day (p < 0.0001). In a double-blinded placebo-controlled phase, the average frequency of seizures on nicotine versus placebo was 0 +/- 0 versus 0.56 +/- 1.14 seizures per day (p < 0.0001). CONCLUSIONS: Nicotine patches may be of benefit to some individuals with ADNFLE.     

Distinctive polysomnographic traits in nocturnal frontal lobe epilepsy

Purpose: To describe the polysomnographic features and distribution of epileptic motor events, in relation to conventional sleep measures and cyclic alternating pattern (CAP) parameters, in 40 untreated patients with nocturnal frontal lobe epilepsy (NFLE). Methods: We analyzed the basal polysomnographic recordings of 40 patients (20 male and 20 female; mean age: 31 ± 10 years) with a diagnosis of nocturnal frontal lobe epilepsy. Conventional sleep measures and CAP parameters were assessed. Polysomnographic recordings were subdivided in sleep cycles. The distribution of the epileptic motor events (including minor motor events, paroxysmal arousals, tonic‐dystonic, or hyperkinetic seizures and epileptic nocturnal wandering) was analyzed throughout: total sleep time, non–rapid eye movement (NREM) and REM sleep, light sleep (S1 + S2), slow wave sleep (SWS), each sleep cycle, CAP or non‐CAP sleep, phase A and phase B of CAP. Only clear epileptic motor events supported by video–polysomnographic evidence were taken into consideration. Polysomnographic findings of patients with NFLE were compared with those of 24 age‐ and gender‐balanced healthy subjects without sleep complaints. Key Findings: Compared to controls, patients with NFLE showed a significant increase in wake after sleep onset, SWS duration, and REM latency, whereas REM sleep duration was significantly lower in NFLE patients. The patients with NFLE showed a significant increase of CAP time, CAP rate (72% vs. 32% in control group), CAP cycles, and mean duration of a CAP sequence. These findings were associated with a significant enhancement of all subtypes of the A phases of CAP (mainly subtype A1). A total of 139 epileptic motor events supported by video‐polysomnographic evidence were counted: 98% of all seizures occurred in NREM sleep and 72% of NREM seizures emerged from SWS, the latter being particularly collected in the first sleep cycles and decreasing in frequency together with the progressive decline of deep sleep. Ninety percent of total NREM seizures occurred during a CAP sequence, and CAP‐related seizures occurred in association with a phase A. Significance: Significant polysomnographic alterations seem to emerge in patients with NFLE (increased REM latency, epileptic fragmentation of SWS, and increase of CAP rate). The analysis of seizure distribution showed that most epileptic events occurred in SWS, with predominance in the first sleep cycle and decreasing in frequency together with the homeostatic decline of SWS across the night. Within the NREM sleep, CAP is a manifestation of unstable sleep and represents a powerful predisposing condition for the occurrence of nocturnal motor seizures, which arise in concomitance with a phase A.     

Autosomal dominant nocturnal frontal lobe epilepsy

Abstract. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic–dyskinetic seizures. Video–polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (4 and 2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype–phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy.     

Sleep-related minor motor events in nocturnal frontal lobe epilepsy

PURPOSE: Nocturnal frontal lobe epilepsy (NFLE) is characterized by a wide spectrum of sleep-related motor manifestations of increasing complexity, ranging from major episodes to brief motor events (minor motor events, MMEs). NFLE patients may exhibit a large quantity of MMEs in the form of short-lasting stereotyped movements. Whereas major episodes are considered epileptiform manifestations, it remains unclear whether the MMEs are related to epileptiform discharges (EDs). METHODS: To study the relation between EDs and the occurrence of MMEs, we report a detailed neurophysiolgical evaluation in NFLE subjects explored by using implanted electrodes. RESULTS: The median value of ED-related movements was 71.8%. Motor expression in relation to epileptiform discharge was surprisingly variable; no peculiar expression of MMEs could be attributed to the presence of EDs. CONCLUSIONS: Our data suggest that ED-associated MMEs are extremely polymorphous, and no univocal relation to EDs can be identified. We hypothesize that MMEs are not a direct effect of epileptiform discharge (i.e., not epileptic in origin), but the result of aspecific disinhibition of innate motor patterns. We warn clinicians that the epileptic nature of minimal motor phenomena in NFLE cannot be established on the clinical phenomenology of the event.     

Topiramate in frontal lobe epilepsy

BACKGROUND: Frontal lobe epilepsy (FLE) is a type of epilepsy that is difficult to treat and there are few studies about the use of topiramate (TPM). AIM OF THE STUDY: To evaluate the efficacy and tolerability of TPM monotherapy in FLE. METHODS: The study group consisted of 55 (33 male; 22 female) patients. TPM was administered as a first drug (n = 16) or converted after previous treatment (n = 39). All patients were followed every 3 months for at least 1 year. The patients were subdivided into two groups: 'newly diagnosed' patients and 'difficult-to-treat' patients. RESULTS: Overall, all patients completed the 1-year study. At the end of follow-up, 10 patients showed disappearance of seizures and 33 patients showed improvement in seizure frequency. In particular, among the newly diagnosed patients 6/16 patients showed complete cessation of seizures and 5/16 patients showed very good response; in the other group, 4/39 patients showed complete cessation and 4/39 patients showed a very good response. No patients of both groups had worsening of seizures. No treatment-limiting adverse events associated with TPM were reported. CONCLUSIONS: TPM is effective in newly diagnosed patients with FLE; TPM can be considered for the treatment of FLE.     

Evidence for a fourth locus for autosomal dominant nocturnal frontal lobe epilepsy

Mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy have been identified in two members of the neuronal nicotinic acetylcholine receptor gene family: CHRNA4(ENFL1 locus) and CHRNB2 (ENFL3 locus) coding for alpha4 and beta2 subunit, respectively. However, mutations in these genes account for only a minority (less than 10%) of cases. For a third ADNFLE locus (ENFL2) on chromosome 15q24 the gene was not identified. The involvement of the three loci in the pathogenesis of ADNFLE was investigated in 12 unrelated Italian families, selected on the basis of anamnestic and video-polysomnographic data. Compliant family members were typed for polymorphic markers spanning the analyzed chromosome regions. Linkage analyses excluded association of all chromosome regions with ADNFLE in 72% of cases. In two, four and one families it was impossible to ascertain or exclude association with ENFL1, ENFL2, or ENFL3, respectively, however, no mutations have been detected in the nicotinic receptor genes located in these regions. These data strongly suggest that ENFL1, ENFL2 and ENFL3 are minor loci for the disease and point to the existence of at least a fourth locus for ADNFLE.     

Ictal kissing in a patient with right frontal lobe epilepsy

When performing pre‐surgical evaluation of patients with refractory epilepsy, the analysis of seizure semiology is one of the key elements used to generate a hypothesis about the location of the epileptogenic zone. Ictal kissing is a very rarely observed ictal automatism described in patients with temporal lobe epilepsy. We present a 62‐year‐old man who was referred to our epilepsy centre for comprehensive evaluation. During prolonged video‐EEG monitoring, six focal‐onset hyperkinetic seizures were registered. In five seizures, the patient repeatedly produced sonorous kisses “into the air”. Initial ictal EEG pattern consisted of rhythmic theta or alpha activity at the right fronto‐polar and fronto‐medial electrodes. MRI depicted focal cortical dysplasia located in the right prefrontal medial cortex. This case suggests that ictal kissing can also occur in the setting of right frontal lobe epilepsy; we therefore believe that this observation expands the anatomo‐clinical correlation for this rare ictal automatism. [Published with video sequences].     

Resolution of epileptic encephalopathy following treatment with transdermal nicotine

We report resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy. The 18.5‐year‐old female patient had refractory epilepsy from the age of 11. Recurrent electroencephalography (EEG) recordings showed mostly generalized activity, albeit with right frontal predominance. Almost all antiepileptic medications failed to provide benefit. She developed an encephalopathic state with cognitive decline. The nonlesional frontal lobe epilepsy and a family history of a cousin with nocturnal epilepsy with frontal origin suggested genetic etiology. Transdermal nicotine patches brought complete resolution of the seizures, normalization of the EEG, and a significant improvement in her thinking process and speech organization. Sequencing of the CHRNB2 and CHRNA4 genes did not detect a mutation. Transdermal nicotine patches should be considered in severe pharmacoresistant frontal lobe epilepsy.     

Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy

Mutations in neuronal nicotinic acetylcholine receptors have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The beneficial effect of nicotine administration was previously reported in one single case. We investigated the influence of the tobacco habits of 22 subjects from two pedigrees with alpha4 mutations (776ins3 and S248F). Subjects were interviewed with respect to pattern of nicotine intake and seizures. Seizure freedom was significantly associated with tobacco use (P=0.024). All seven nonsmokers with manifest ADNFLE had persistent seizures. Seizure fluctuations, including long remissions, corresponded to changes in tobacco habits in several patients. One patient who recently had begun treatment with transdermal nicotine experienced improvement. We conclude that tobacco appears to be an environmental factor that influences seizure susceptibility in ADNFLE. Inactivation by desensitization of the mutant receptors by nicotine may explain the beneficial effect. The efficacy and safety of transdermal nicotine in ADNFLE should be further explored.     

Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected individuals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two individuals. No mutations were identified in alpha4, alpha2, or beta2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non-nAChR-related mechanisms.     

114例特发性夜间额叶癫痫的临床及脑电图研究

目的 分析114例特发性夜间额叶癫痫(NFLE)患者的临床特征、脑电图和神经影像学表现、治疗效果及预后.方法 回顾性分析解放军总医院癫痫门诊自1999年6月至2007年1月收治的114例NFLE患者的临床资料.结果 NFLE以夜间成串的偏转性、姿势性强直及过度运动发作为最显著的临床特征;本组22.9%清醒发作间期常规脑电图及28%清醒发作间期动态脑电图可见额叶癫痫样放电,38%睡眠发作间期动态脑电图可见额叶癫痫样放电,66.7%发作期脑电图可见额叶癫痫样放电;79.8%药物治疗有效,其中29.7%可完全控制.结论 NTLE具有特征性的临床发作特点,发作期及发作间期脑电图改变阳性率不高,临床上应注意鉴别.额叶癫痫容易在夜间发作,睡眠腩电图对NFLE具有重要的诊断价值.     

Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor

Certain paroxysmal nocturnal behaviors have been established as features of nocturnal frontal lobe epilepsy (NFLE). Despite insight into its genetics, the majority of patients with NFLE are not linked to a known mutation and clinical diagnosis remains a challenge. We describe a family presenting with stereotyped nocturnal arousals from non-rapid eye movement sleep, bilateral hand posturing, and pelvic thrusting in the mother, but subtle motor activity in the daughter, and minimal or no epileptiform EEG discharges. Despite normal IQ, there were moderate and severe verbal memory deficits in the mother and daughter, respectively. Genetic testing revealed the CHRNB2 mutation I312M in transmembrane region 3 (M3) of the neuronal nicotinic acetylcholine receptor. Phenotypic similarities in unrelated families suggest the determining role of this mutation in NFLE, whereas different inter- and intrafamilial cognitive profiles point to other factors. The absence of clear motor features of NFLE in the daughter emphasizes the shortcomings of current clinical criteria and the potential for genetic testing to further guide clinical diagnostic criteria.     

Increased expression of urokinase‐type plasminogen activator receptor in the frontal cortex of patients with intractable frontal lobe epilepsy

Urokinase‐type plasminogen activator receptor (uPAR) is a glycosyl phosphatidylinositol‐anchored protein involved in cell adhesion, proliferation, differentiation, migration, invasion, and tissue repair and remodeling. Our aim was to investigate uPAR expression in the frontal cortex of patients with intractable frontal lobe epilepsy and to explore the possible role of uPAR in intractable epilepsy. Tissue samples were obtained from the frontal cortex of 25 patients who had undergone surgery for intractable epilepsy and 15 histologically normal frontal cortex tissues from patients with orbital frontal lobe severe contusion (the control group). The frontal cortex expression of uPAR was studied by Western blot and immnohistochemistry. Double immunofluorescence was used to determine the expression of uPAR in astrocytes, microglia, and neurons. The normal frontal cortex uPAR protein level was shown to be low. In the brain tissue of patients with intractable epilepsy, the expression of uPAR protein increased dramatically. Based on the results of double immunofluorescence, many uPAR‐positive cells are colocalized with the cell soma of NeuN‐positive neurons, whereas only a few GFAP‐ and CD11b‐positive cells colocalized with uPAR staining. These findings provide new information pertaining to the epileptogenesis of intractable epilepsy and suggest that increased expression of uPAR in human brain may be associated with human intractable epilepsy. © 2010 Wiley‐Liss, Inc.