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.     

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.     

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.     

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.     

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。     

Connectivity of the supplementary motor area in juvenile myoclonic epilepsy and frontal lobe epilepsy

Purpose: Subtle structural abnormalities of frontal lobe gray and white matter have been described in cryptogenic frontal lobe and idiopathic generalized epilepsies. The supplementary motor area (SMA) has a role in motor control, and its involvement during frontal lobe epileptic seizures is characterized by a typical asymmetric tonic posturing. Moreover, motor networks are dysfunctional in juvenile myoclonic epilepsy (JME). We tested the hypothesis that SMA structural connectivity is altered in focal frontal lobe epilepsy (FLE) and JME compared to healthy controls. Methods: Diffusion tensor imaging (DTI) and probabilistic tractography were used to map the structural connectivity of the SMA, defined by motor functional magnetic resonance imaging (MRI), in 15 patients with JME, 36 patients with FLE, and 18 healthy controls. Key Findings: Structural connectivity of the SMA was significantly reduced in JME compared to controls (reduced fractional anisotropy and increased mean diffusivity). In FLE there was no significant difference compared to controls, and in all groups there was stronger connectivity in the left hemisphere (higher fractional anisotropy) compared to the right. There was no difference in SMA connectivity between patients with medial or lateral frontal lobe epileptic foci. Significance: Reduced white matter connectivity is the structural correlate of functional frontal lobe abnormalities in JME. In FLE, the structural connectivity of the SMA was preserved, suggesting a robust motor network that is not compromised by longstanding epilepsy involving the medial frontal lobes.     

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).     

Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures

BACKGROUND: Nocturnal frontal lobe seizures (NFLS) show one or all of the following semeiological patterns: (1) paroxysmal arousals (PA: brief and sudden recurrent motor paroxysmal behavior); (2) hyperkinetic seizures (HS: motor attacks with complex dyskinetic features); (3) asymmetric bilateral tonic seizures (ATS: motor attacks with dystonic features); (4) epileptic nocturnal wanderings (ENW: stereotyped, prolonged ambulatory behavior). OBJECTIVE: To estimate the interobserver reliability (IR) of video-recording diagnosis in patients with suspected NFLS among sleep medicine experts, epileptologists, and trainees in sleep medicine. METHODS: Sixty-six patients with suspected NFLS were included. All underwent nocturnal video-polysomnographic recording. Six doctors (three experts and three trainees) independently classified each case as "NFLS ascertained" (according to the above specified subtypes: PA, HS, ATS, ENW) or "NFLS excluded". IR was calculated by means of Kappa statistics, and interpreted according to the standard classification (0.0-0.20 = slight agreement; 0.21-0.40 = fair; 0.41-0.60 = moderate; 0.61-0.80 = substantial; 0.81-1.00 = almost perfect). RESULTS: The observed raw agreement ranged from 63% to 79% between each pair of raters; the IR ranged from "moderate" (kappa = 0.50) to "substantial" (kappa = 0.72). A major source of variance was the disagreement in distinguishing between PA and nonepileptic arousals, without differences in the level of agreement between experts and trainees. CONCLUSIONS: Among sleep experts and trainees, IR of diagnosis of NFLS, based on videotaped observation of sleep phenomena, is not satisfactory. Explicit video-polysomnographic criteria for the classification of paroxysmal sleep motor phenomena are needed.     

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.     

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.     

Sleep-related hypermotor seizures in aspartylglucosaminuria: A case report

From the age of 24 years a young man with a definitive diagnosis of aspartylglucosaminuria (AGU) presented short-lasting sleep-related paroxysmal events characterized by sudden awakening with a frightened look, hyperventilation, and complex bilateral motor activity. Nocturnal video-polysomnography recorded several events consistent with a diagnosis of hypermotor epileptic seizures. This pattern of sleep-related epileptic seizures has been reported in rare familial cases, more often in cryptogenic and symptomatic patients in the spectrum of nocturnal frontal lobe epilepsy. Epilepsy and sleep-related nonepileptic problems are common in patients with AGU, but no case of hyperkinetic nocturnal frontal lobe seizures has been reported to date. Differential diagnosis of abnormal paroxysmal motor events in sleep is frequently a challenge for the clinician: Video-polysomnographic recordings might serve to identify the possible epileptic origin of some of the excessive motor activities during sleep referred in patients with AGU.     

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.