Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy

ObjectiveTo study the effects of antiepileptic treatment on sleep parameters and video-polysomnography (VPSG) seizures in nocturnal frontal lobe epilepsy (NFLE).MethodsTwenty patients with a clinical and VPSG diagnosis of NFLE (baseline polysomnography [PSG]) underwent a clinical follow-up and performed a second VPSG after effective antiepileptic treatment lasting for at least 6 months. Conventional sleep measures, cyclic alternating pattern (CAP) parameters, and objective VPSG seizures were assessed in NFLE patients before and after treatment and were compared with the results of 20 age- and gender-matched control subjects.ResultsAntiepileptic treatment determined a partial reduction of objective VPSG seizures of approximately 25% compared to baseline condition. Alterations of most conventional sleep measures recovered normal values, but nonrapid eye movement (NREM) sleep instability remained pathologically enhanced (CAP rate, +26% compared to controls) and was associated with persistence of daytime sleepiness.ConclusionsResidual epileptic events and high levels of unstable NREM sleep can define a sort of objective resistance of both seizures and disturbed arousal system to the therapeutic purpose of the antiepileptic drugs in NFLE. This finding could determine the need for new therapeutic options in this particular 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.     

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.     

Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy

In 1999, Hirose et al. reported a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with a neuronal nicotinic acetylcholine receptor α4 subunit mutation (S252L). We followed the siblings of this family, and found that the elder brother had Asperger’s disorder without mental retardation (MR) and the younger brother had autistic disorder with profound MR. The clinical epileptic features of the siblings were very similar, and both had deficits in socialization, but their cognitive development differed markedly. It thus seems that epilepsy is the direct phenotype of the S252L mutation, whereas other various factors modulate the cognitive and social development. No patients with ADNFLE have previously been reported to have autism spectrum disorder or profound MR.     

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.     

Topiramate treatment for nocturnal frontal lobe epilepsy

PURPOSE: Aim of this study was to evaluate the efficacy and tolerability of the antiepileptic drug topiramate (TPM) in a sample of patients with nocturnal frontal lobe epilepsy (NFLE). METHODS: A 24 patients with video-polysomnographically confirmed NFLE received topiramate as single or add-on therapy. They all completed diaries concerning the seizures frequency and complexity and underwent to periodic follow-up visits. We classified the patients as: seizure-free, responders or non-responders. RESULTS: 15 M; 9 F; mean age 29.3+/-10.4 years. The video-polysomnographic recordings showed a wide spectrum of seizures, ranging from repeated stereotypic brief motor attacks to prolonged attacks, with complex and bizarre behaviour; the recorded episodes occurred during non-REM sleep, both stage 2 and stage 3-4. The EEG during wakefulness was normal in all the patients, while seven of them showed epileptiform abnormalities during polysomnography. TPM was administered as single or add-on therapy from 50 to 300mg daily at bedtime. The follow-up duration ranged from 6 months to 6 years. The patients were classified as: seizure-free=6 (25%); responders (reduction of at least 50% of seizures)=15 (62.5%); non-responders=3 (12.5%). The adverse events were: weight loss (6 pts, 25%); paresthesias (3 pts, 12.5%); speech dysfunction (2 pts, 8.3%). All the adverse events disappeared within 3 months. CONCLUSIONS: In our experience, TPM seems to be effective in about 90% of patients with NFLE. Few of them experienced transitory adverse events. TPM could be included in the options for patients with this form of epilepsy.     

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.     

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。     

Coupling of minor motor events and epileptiform discharges with arousal fluctuations in NFLE

Purpose: We recently demonstrated that in nocturnal frontal lobe epilepsy (NFLE) highly stereotyped minor motor events (MMEs, in the form of short‐lasting stereotyped movements involving the limbs, the axial musculature, and/or the head), could occur in either the presence or absence of an epileptiform discharge (ED). In lack of a systematic analysis, both MMEs and EDs were frequently observed to occur in association with arousal fluctuations. Hereby, in the same group of refractory NFLE subjects, we report a methodical neurophysiolgical investigation set out to investigate whether, and how, the arousal mechanism, monitored through visual scoring of the cyclic alternating pattern, modulates the expression of MMEs and EDs. Methods: The relationship of MMEs, EDs and arousal fluctuation was assessed in subjects explored using implanted electrodes. Results: The occurrence of both EDs and MMEs was associated with higher level of arousal (p < 0.0001). Multivariate logistic regression analysis shows a significant effect of interaction of EDs and MMEs during CAP sleep (p < 0.001). Conclusions: Both MMEs and EDs are associated with arousal. We suggest that recurrence of EDs in itself can induce an increase in arousal level, which in turn, through a gate effect, facilitate the occurrence of MMEs. Thus, MMEs wouldn't be a direct effect of EDs, but rather originate from an indirect effect related to loss of cortical inhibition, which is secondary to arousal. In this perspective MMEs may be regarded as the result of aspecific dishinibition, triggered by internal epileptiform stimuli, of innate motor patterns generated by central pattern generators (CPGs). The CPG system might represent, through arousal facilitation, the substrate of the heterogeneous expression of MMEs in NFLE.     

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].     

A study of the relationship between the seizure focus and 1H-MRS in temporal lobe epilepsy and frontal lobe epilepsy

Several studies of temporal lobe epilepsy (TLE) patients have investigated the relationship between the seizure focus and 1H magnetic resonance spectroscopy (1H-MRS). There have also been a few reports in other types of partial epilepsy. We examined the relationship between the seizure focus and the reduction in N-acetylaspartate: creatine (NAA : Cr) ratio using 1H-MRS in both TLE and frontal lobe epilepsy (FLE) patients. We studied 21 patients with unilateral TLE and seven patients with unilateral FLE. We used a 1.5 Tesla magnetic resonance unit (Signa Horizon; General Electric). Approximately 15 x 15 x 20 mm3 voxel of interest (VOI) was placed over the anterior portion of the bilateral hippocampus in the TLE patients, and the anterodorsal position of bilateral frontal lobe in the FLE patients. The seizure focus was identified by interictal scalp electro-encephalogram (EEG). In the TLE patients the NAA : Cr ratios were reduced in the seizure focus, while in the FLE patients they were not always reduced in the seizure focus. In the TLE patients the coincidence rate between the seizure focus and the reduction in the NAA:Cr ratio was 90% (19 of 21 patients), while in the FLE patients the coincidence rate was only 57% (four of seven patients).     

Diagnostic accuracy of a structured interview for nocturnal frontal lobe epilepsy (SINFLE): a proposal for developing diagnostic criteria

Objectives

To measure the accuracy of anamnestic features collected during clinical history for the diagnosis of nocturnal frontal lobe epilepsy (NFLE).

Methods

A case-control diagnostic study. Participants included a case group of people with ascertained target disease (NFLE group) and a control group of people with sleep disorders potentially confounding for NFLS (NOT-NFLE group), defined by means of a consensus procedure among experts (panel diagnosis as reference standard). Two major clinical patterns defining the semeiology of the epileptic event (i.e. dystonic, DP, and/or hyperkinetic pattern, HP), and 13 additional minor features were identified, formulated as questions, and telephonically administered to NFLE and NOT-NFLE groups by a trained doctor blinded to the final diagnosis. The diagnostic accuracy of each characteristic was tested against the reference standard.

Results

Out of 262 selected subjects, 101 were recruited; 42 were NFLE and 59 NOT-NFLE. A positive history of DP or HP had a sensitivity of 59.5% and a specificity of 91.5%, irrespective of the other minor anamnestic features. The anamnestic model improved, with a sensitivity of 59.5% and specificity of 96.6%, if at least one of the following four minor anamnestic features was added: (a) duration less than two minutes, (b) unstructured vocalization during the episode, (c) experience of an aura preceding the motor attack, and (d) a history of tonic-clonic seizures during sleep.

Conclusions

The present study disclosed two major anamnestic patterns and four minor features that we called SINFLE, with unsatisfactory sensitivity but high specificity. These patterns could be the basis for developing future NFLE diagnostic criteria and to quantify the diagnostic accuracy of elements usually collected in the clinical history.     

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.     

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.     

Differentiating frontal lobe epilepsy from psychogenic nonepileptic seizures

Patients with psychogenic nonepileptic seizures (PNES) remain one of the most challenging patient populations. The misdiagnosis of PNES is costly to patients, the health care system, and to society. The first step in treatment is proper diagnosis. Video electroencephalography remains the gold standard for PNES diagnosis. Differentiating frontal lobe epilepsy (FLE) from PNES can be difficult; however, clinical findings and laboratory advances are emerging that more clearly establish the diagnosis of PNES. This article provides clues to differentiating FLE from PNES so that neurologists and mental health providers are better equipped to offer treatments for PNES.     

夜发性额叶癫痫三家系临床和遗传学特征

目的 分析夜发性额叶癫痫3个家系的临床、脑电图和遗传学特征.方法 在3个夜发性额叶癫痫家系患者及部分亲属中收集临床、脑电图及神经影像学等资料,并采用测序方法筛查烟碱型乙酰胆碱受体(nAChR)α4、β2和α2亚单位编码基因(CHRNA4、CHRNB2和CHRNA2).结果 3个家系中有6例患者(其中男5例),平均年龄(20.5±11.5)岁,平均发病年龄(7.3±5.5)岁,临床表现为夜发性额叶发作,具体发作类型包括姿势性发作2例,躯体自动症发作4例,最多每夜发作6次.发作间期、发作期视频脑电图2例患者表现为正常或动作伪差,2例表现为前部导联慢波节律,3例出现前部导联棘波、棘慢波及尖波.神经系统及神经影像检查未见异常.抗癫痫药物治疗反应良好.CHRNA4、CHRNB2和CHRNA2部分序列(包含跨膜区1～3)筛查未见突变.结论 夜发性额叶癫痫是一种遗传异质性癫痫综合征.