GRIN2A mutations in epilepsy-aphasia spectrum disorders

Objective

Epilepsy-aphasia spectrum (EAS) are a group of epilepsy syndromes denoting an association between epilepsy, speech disorders and the EEG signature of centrotemporal spikes. Mutations in the GRIN2A gene, encoding the NMDA glutamate receptor α2 subunit were reported in focal epilepsy with speech disorder. We aimed to explore the role of GRIN2A mutations in patients with centrotemporal spikes related epileptic syndromes in a Chinese cohort.

Cognitive and behavioral problems in children with centrotemporal spikes

Atypical features in benign epilepsy of childhood with centrotemporal spikes (BECTS) are not uncommon. There are children with BECTS who do not have a benign outcome in terms of neuropsychologic functioning. BECTS have been linked with Landau-Kleffner syndrome (LKS) and continuous spikes and waves during slow sleep (CSWS). At the Medical College of Georgia from January 1988 to June 1999, 78 children, ages 2-16 years, were identified to have electroencephalogram evidence of centrotemporal spikes. Their medical records were reviewed for developmental history, behavioral problems, and school performance. Children with structural lesions/other epileptic syndromes were excluded. Fifty-six demonstrated a history of clinical seizures compatible with BECTS and 22 demonstrated centrotemporal spikes without clinical seizures. Among all children with centrotemporal spikes, 9% (n = 7) were diagnosed with mild intellectual disability (intelligence quotient < 70), 10% (n = 8) with borderline functioning, 31% (n = 24) with behavioral problems, and 17% (n = 13) with specific learning disabilities. Three children with BECTS experienced language delay and regression. Seizure control for BECTS usually is achieved without much difficulty, with excellent long-term prognosis. However, the data presented indicate that a large number of BECTS patients exhibit learning or behavior problems that require intervention. A small number may demonstrate language outcome similar to children with LKS and CSWS.     

Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes

PurposeTo establish whether the disability in benign epilepsy with centrotemporal spikes (BECTS) is the result of the number of seizures, the anti-epileptic therapy or is an inherent characteristic of the syndrome itself.MethodsThirty-six children with BECTS were tested for cognitive functions prior to commencing treatment with anti-epileptic drugs, and the findings were compared with those in 15 children with normal electroencephalograms, performed for unrelated reasons. The data in the study group were further correlated with the laterality of the epileptic focus and the number of seizures.ResultsScores for verbal functioning on neuropsychological tests were significantly lower in the study group than the control group. There was no relationship between the neuropsychological scores in the patients and either lateralization of the epileptic focus or number of seizures.DiscussionChildren with BECTS have an impaired ability to process verbal information. The deficiency is apparently a result of the pathological electrical discharges that are part of the syndrome and are not dependent on the epileptic focus laterality, the number of seizures, or the anti-epileptic treatment.     

Pathophysiology of encephalopathy related to continuous spike and waves during sleep: the contribution of neuroimaging

In the last three decades, studies on functional neuroimaging have helped us to understand pathophysiological mechanisms responsible for electro‐clinical patterns associated with epileptic encephalopathies with continuous spikes and waves during slow sleep (ECSWS). MEG and EEG source reconstruction have revealed sources of pathological brain activity associated with epileptiform discharges in the perisylvian region pointing to the significance of this brain area for ECSWS. PET studies have revealed areas of focal hypermetabolism in perisylvian, superior temporal and inferior parietal regions as well as central cortices which were related to epileptic activity. The widespread hypometabolism in regions that belong to the default network (prefrontal and posterior cingulate cortices, parahippocampal gyrus and precuneus) was interpreted as remote inhibition following epileptic activity, which could contribute to cognitive deficits in affected individuals. Note that the described metabolic changes were functional and disappeared after successful treatment and recovery of ECSWS and were found in both sleep and wakefulness which may account for cognitive deficits in patients during the day. EEG‐fMRI studies have revealed a functional fingerprint of epileptic encephalopathy: significant positive BOLD signal changes were identified in the perisylvian regions, prefrontal cortex and anterior cingulate as well as thalamus and negative BOLD signal changes in the regions of the default mode network. The pattern of activation represents a propagation of epileptic activity specific to encephalopathy, which is independent of etiology and type of seizure associated with ECSWS. In summary, methods of neuroimaging have shed light on pathogenic mechanisms of ECSWS which may account for a number of clinical phenomena associated with this condition.     

Impact of benign childhood epilepsy with centrotemporal spikes (BECTS) on school performance

BECTS represents the vast majority of childhood focal epilepsy. Owing to the age peculiarity of children who suffer from this disease, i.e., school-going age of between 6 and 9 years, the condition is often referred to as a school disorder by parents and teachers.ObjectiveThe aim of this study was to evaluate the academic performance of children with BECTS, according to the clinical and electroencephalographic ILAE criteria, and compare the results of neuropsychological tests of language and attention to the frequency of epileptic discharges.MethodsThe performances of 40 school children with BECTS were evaluated by applying a school performance test (SBT), neuropsychological tests (WISC and Trail-Making), and language tests (Illinois Test Psycholinguistic Abilities – ITPA – and Staggered Spondaic Word – SSW). The same tests were applied in the control group.ResultsChildren with BECTS, when compared to those in the control group, showed lower scores in academic performance (SPT), digits and similarities subtests of WISC, auditory processing subtest of SSW, and ITPA – representational and automatic level. The study showed that epileptic discharges did not influence the results.ConclusionChildren with BECTS scored significantly lower scores in tests on academic performance, when compared with those in the control group probably due to executive dysfunction.     

Long term outcome of benign childhood epilepsy with centrotemporal spikes: Dutch Study of Epilepsy in Childhood

PurposeTo determine long-term outcome in a cohort of children with newly diagnosed benign childhood epilepsy with centrotemporal spikes (BECTS).Methods29 children with BECTS were included in the Dutch Study of Epilepsy in Childhood. Each child was followed for 5 years, and subsequently contacted 12–17 years after enrolment to complete a structured questionnaire. Twenty children had typical BECTS, nine had atypical BECTS (age at onset <4 years, developmental delay or learning difficulties at inclusion, other seizure types, atypical EEG abnormalities).ResultsMean age at onset of epilepsy was 8.0 years with slight male preponderance. Most common seizure-types before enrolment were generalized tonic–clonic seizures (GTCS) and simple partial seizures; in 86% of the children seizures occurred during sleep. After 12–17 years, 96% had a terminal remission (TR_F) of more than 5 years and 89% of more than 10 years. Mean duration of epilepsy was 2.7 years; mean age at reaching TR_F was 10.6 years. Many children (63%) had experienced one or more (secondary) GTCS. Antiepileptic drugs were used by 79% of the children with a mean duration of 3.0 years. None of the children seemed to have developed learning problems or an arrest of cognitive development during follow-up. No significant differences were observed in patient characteristics or outcome between children with typical BECTS and children with atypical BECTS.ConclusionsAll children in our cohort, both those with typical and atypical BECTS, had a very good prognosis with high remission rates after 12–17 years. None of the predictive factors for disease course and outcome observed in earlier studies (other seizure types, age at onset, multiple seizures at onset) were prognostic in our cohort.     

The association of epileptic focus estimated by magnetoencephalography with cognitive function in non-lesional epilepsy with continuous spikes and waves during slow wave sleep (ECSWS) children

Objective

Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau–Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau–Kleffner syndrome.

Intrinsic brain activity as a diagnostic biomarker in children with benign epilepsy with centrotemporal spikes

Benign epilepsy with centrotemporal spikes (BECTS) is often associated with neural circuit dysfunction, particularly during the transient active state characterized by interictal epileptiform discharges (IEDs). Little is known, however, about the functional neural circuit abnormalities in BECTS without IEDs, or if such abnormalities could be used to differentiate BECTS patients without IEDs from healthy controls (HCs) for early diagnosis. To this end, we conducted resting‐state functional magnetic resonance imaging (RS‐fMRI) and simultaneous Electroencephalogram (EEG) in children with BECTS (n = 43) and age‐matched HC (n = 28). The simultaneous EEG recordings distinguished BECTS with IEDs (n = 20) from without IEDs (n = 23). Intrinsic brain activity was measured in all three groups using the amplitude of low frequency fluctuation at rest. Compared to HC, BECTS patients with IEDs exhibited an intrinsic activity abnormality in the thalamus, suggesting that thalamic dysfunction could contribute to IED emergence while patients without IEDs exhibited intrinsic activity abnormalities in middle frontal gyrus and superior parietal gyrus. Using multivariate pattern classification analysis, we were able to differentiate BECTS without IEDs from HCs with 88.23% accuracy. BECTS without epileptic transients can be distinguished from HC and BECTS with IEDs by unique regional abnormalities in resting brain activity. Both transient abnormalities as reflected by IEDs and chronic abnormalities as reflected by RS‐fMRI may contribute to BECTS development and expression. Intrinsic brain activity and multivariate pattern classification techniques are promising tools to diagnose and differentiate BECTS syndromes. Hum Brain Mapp 36:3878–3889, 2015. © 2015 Wiley Periodicals, Inc.     

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes the link with autism

Purpose: The continuous spike and waves during slow‐wave sleep syndrome (CSWSS) and the Landau‐Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow‐wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10^?7). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.     

Correlation between scalp high-frequency oscillations and prognosis in patients with benign epilepsy of childhood with centrotemporal spikes

Aims

The study aimed to explore whether high-frequency oscillations (HFOs) can predict seizure risk and atypical manifestations of benign epilepsy of childhood with centrotemporal spikes (BECTS).

Methods

We recruited 60 patients and divided them into three groups: (1) seizure-free BECTS, (2) active typical BECTS, and (3) active atypical forms of BECTS. Electroencephalogram was used to record the number, location, average amplitude, and duration of spikes, and spike ripples were analyzed using time-frequency technology. Multivariable logistic regression analysis was used to investigate independent predictive factors for prognosis.

Results

The number of sleep spike ripples, rather than spikes, was an independent risk factor for the active period of the disease (odds ratio [OR] = 4.714, p = 0.003) and atypical forms of BECTS (OR = 1.455, p = 0.049); the optimal thresholds for the spike ripple rate were >0 (area under the curve [AUC] = 0.885, sensitivity = 96.15%, specificity = 73.33%) and >0.6/min (AUC = 0.936, sensitivity = 84.21%, specificity = 96.15%), respectively. Furthermore, in typical BECTS, the spike ripple rate showed significant negative correlations with time since the last seizure (ρ = −0.409, p = 0.009) and age (ρ = −0.379, p = 0.016), while the spike rate did not.

Conclusion

Spike ripple was a marker for distinguishing typical and atypical forms of BECTS and reflected the risk of seizure recurrence better than the spike alone. The present findings might assist clinicians in BECTS treatment.     

Benign childhood epilepsy with centrotemporal spikes (BECTS) and developmental co-ordination disorder

BackgroundBenign epilepsy with centro-temporal spikes (BECTS) is a common childhood epilepsy syndrome also known as Rolandic Epilepsy (RE). Neurocognitive phenotypes have been described with greater focus on attention, reading and language domains but there have been far fewer studies focusing on motor functioning. This study included measures of motor, language and cognition in order to investigate the range, degree and pattern of difficulties associated with BECTS in a case series of children, but with a particular emphasis on motor skills.MethodTwenty-one children aged between 8 and 16 years with a diagnosis of BECTS were asked to complete standardized assessments for language, cognition, motor functioning and handwriting.ResultsWhen measuring across language, cognitive and motor domains, 19 (90.48%) of the twenty-one children with a diagnosis of BECTS showed some difficulties on at least one area of functioning using standardized assessment tests. Of particular note nearly half (47.62%) of the children had some difficulties in one or more areas of motor functioning.DiscussionChildren with BECTS have a heterogeneous pattern of neurocognitive impairments. The presence of motor difficulties (DCD) should be considered in all children routinely seen in clinical settings with BECTS and included in any screening processes.     

A Machine Learning Approach to First Pass Reperfusion in Mechanical Thrombectomy: Prediction and Feature Analysis

IntroductionNovel machine learning (ML) methods are being investigated across medicine for their predictive capabilities while boasting increased adaptability and generalizability. In our study, we compare logistic regression with machine learning for feature importance analysis and prediction in first-pass reperfusion.MethodsWe retrospectively identified cases of ischemic stroke treated with mechanical thrombectomy (MT) at our institution from 2012–2018. Significant variables used in predictive modeling were demographic characteristics, medical history, admission NIHSS, and stroke characteristics. Outcome was binarized TICI on first pass (0-2a vs 2b-3). Shapley feature importance plots were used to identify variables that strongly affected outcomes.ResultsAccuracy for the Random Forest and SVM models were 67.1% compared to 65.8% for the logistic regression model. Brier score was lower for the Random Forest model (0.329 vs 0.342) indicating better predictive capability. Other supervised learning models performed worse than the logistic regression model, with accuracy of 56.2% for Naïve Bayes and 61.6% for XGBoost. Shapley plots for the Random Forest model showed use of aspiration, hyperlipidemia, hypertension, use of stent retriever, and time between symptom onset and catheterization as the top five predictors of first pass reperfusion.ConclusionUse of machine learning models, such as Random Forest, for the study of MT outcomes, is more accurate than logistic regression for our dataset, and identifies new factors that contribute to achieving first pass reperfusion. The benefits of machine learning, such as improved predictive capabilities, integration of new data, and generalizability, establish ML as the preferred model for studying outcomes in stroke.     

Epidemiological study of Landau–Kleffner syndrome (LKS) in Japan

Objective: We aimed to determine the incidence and prevalence of LKS in Japanese children. Methods: A questionnaire was sent to all 3004 Japanese hospitals that have a department of pediatrics. The questionnaire asked for the number of first-visit LKS patients and LKS patients who were followed up at or visited their clinic during the past one year Vital statistics of the same year (2008) published by Ministry of Health, Labor and Welfare, Japan were referenced to calculate the estimated incidence and prevalence of LKS among Japanese children. Results: Chiefs of 1562 pediatric departments answered our inquiry (51.9% of returns). Six chiefs had one new LKS patient, aged 6–14 years. Thirty two patients with LKS were followed in the same period. The number of children with LKS less than 20 years of age who needed medical care was at least 23 and at most 31. Vital statistics of Japan 2009 revealed that the population of children aged 5–14 years was 11,861,464 and that aged 5–19 years was 18,007,968. Discussion: The number of the first-visit LKS patients was 6 in a year. We estimated the incidence of LKS in the 5- to 14-years-old Japanese population as about 1 in 978,000. The number of LKS patients aged 5–19 was estimated to range from 44.2 to 59.6 among a population of 18,007,968. This means the prevalence of LKS under medical care is roughly one in 302,147–407,420 children aged 5–19. This study is the first epidemiological estimation of the incidence and prevalence of children with LKS in Japan or, for that matter, in any other area. Conclusion: (1) Incidence of children with LKS aged 5–14 years was about 1 in a million in Japan. (2) Prevalence of children with LKS aged 5–19 and under medical care was one in about 300,000–410,000 in Japan. (3) This study constitutes the first epidemiological estimation of LKS in Japan.     

Predicting poor school performance in children suspected for sleep-disordered breathing

ObjectiveHabitually snoring children are at a greater risk of poor school performance (PSP). We investigated the ability of conventional sleep-disordered breathing (SDB) measures for predicting PSP in habitually snoring children.MethodsThe dataset of Hannover Study on Sleep Apnea in Childhood (HASSAC), a large community-based study in primary school children, was retrospectively analyzed. All habitual snorers were included. Based on their grades, children were grouped into good and poor school performers. SDB measures obtained by a parental questionnaire, a home pulse oximetry, and a home polysomnography were evaluated for their accuracy in predicting poor school performance by calculating receiver operating characteristic curves and area under this curve (AUC). The most predictive single factors were identified and entered into a prediction model.ResultsOf 114 habitual snorers (mean age 9.6 years, 51 boys), 59 had PSP. All investigated SDB measures showed low accuracy (ie, AUC <0.8). The highest AUC observed was 0.686 for a questionnaire score, 0.565 for an oximetry factor, and 0.624 for a polysomnography factor. Of 20 single significant predictors for PSP, five were selected for inclusion into a prediction model. The model reached an unadjusted AUC of 0.826 and an adjusted AUC of 0.851.ConclusionsConventional SDB measures obtained with questionnaire, oximetry, or polysomnography may not be sufficiently predictive of PSP in children suspected for SDB. However, combining factors in a clinical prediction model may improve prediction. Results of such a model may be used to assess the risk of developing neurocognitive impairment and to decide whether a child suspected for SDB might benefit from treatment.     

Evaluation of levetiracetam and valproic acid as low-dose monotherapies for children with typical benign childhood epilepsy with centrotemporal spikes (BECTS)

PurposeThis study aimed to compare the monotherapeutic efficacies of levetiracetam (LEV) and valproic acid (VPA) in a cohort of newly diagnosed children with typical benign childhood epilepsy with centrotemporal spikes (BECTS).MethodsA total of 56 children with typical BECTS were retrospectively reviewed in the analyses. Thirty-three children received LEV and 23 received VPA as initial monotherapy, and the treatments lasted for at least 18 months.ResultsThe average dosage of LEV was 22.7 ± 4.7 mg/kg/day, and that of VPA was 18.7 ± 5.7 mg/kg/day. The seizure-freedom rates were not significantly different between the two groups at 6 (57.5% vs. 60.9%), 12 (81.8% vs. 73.9%) or 18 months (100% vs. 100%). However, a greater number of the children taking VPA achieved Electroencephalography (EEG) normalization compared to those taking LEV both at 12 (78.3% vs. 45.5%) and 18 months (95.7% vs. 72.7%; p < 0.05). No children discontinued therapy due to adverse effects during the follow-up. Only one child (4.7%) in the VPA group exhibited mild weight gain (BMI increase of 2 at the end of follow-up) but did not withdraw from treatment.ConclusionLow-dosage VPA and LEV monotherapies are equally effective in controlling seizures, but VPA exhibited better efficacy than LEV in improving the electrophysiological abnormalities of children with BECTS. None of the patients discontinued therapy, which was likely due to the administration of low dosages.     

Intellectual functioning in children with epilepsy: Frontal lobe epilepsy,childhood absence epilepsy and benign epilepsy with centro-temporal spikes

PurposeThe purpose of our study is to describe intellectual functioning in three common childhood epilepsy syndromes – frontal lobe epilepsy (FLE), childhood absence epilepsy (CAE) and benign epilepsy with centro-temporal spikes (BECTS). And also to determine the influence of epilepsy related variables, type of epilepsy, age at epilepsy onset, duration and frequency of epilepsy, and treatment on the scores.MethodsIntellectual functioning was examined in a group of 90 children with epilepsy (30 FLE, 30 CAE, 30 BECTS), aged 6–15 years, and compared with a control group (30). All subjects obtained a Full Scale IQ ≥ 70 and they were receiving no more than two antiepileptic medications. Participants completed the Wechsler Intelligence Scale for Children – Third Edition. The impact of epilepsy related variables (type of epilepsy, age at epilepsy onset, duration of epilepsy, seizure frequency and anti-epileptic drugs) on intellectual functioning was examined.ResultsChildren with FLE scored significantly worse than controls on WISC-III Verbal IQ, Full Scale IQ and Processing Speed Index. There was a trend for children with FLE to have lower intelligence scores than CAE and BECTS groups. Linear regression analysis showed no effect for age at onset, frequency of seizures and treatment. Type of epilepsy and duration of epilepsy were the best indicators of intellectual functioning.ConclusionIt is crucial that children with FLE and those with a longer active duration of epilepsy are closely monitored to allow the early identification and evaluation of cognitive problems, in order to establish adequate and timely school intervention plans.     

High-frequency oscillations in a spectrum of pediatric epilepsies characterized by sleep-activated spikes in scalp EEG

ObjectiveWe studied ripple-band (80–200 Hz) high-frequency oscillations in scalp electroencephalogram (EEG) in various pediatric epilepsies featuring sleep-activated spikes, such as epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) and investigated their characteristics.MethodsThe subjects were 94 children with epileptic disorders including idiopathic and non-idiopathic CSWS, benign epilepsy with centrotemporal spikes (BECTS), Panayiotopoulos syndrome, other types of focal epilepsies (oFE), and focal spikes without clinical seizures (Latent). We detected ripple oscillations using a semi-automatic detection tool based on localized power increase.ResultsIn the idiopathic CSWS Group, the median ratio of ripples per spike in the initial EEG was 5.73, which was significantly higher than those in the BECTS, Panayiotopoulos syndrome, oFE, and Latent Groups (0.39, 0.02, 0.35, 0, respectively, all with p < 0.01). Ripples were particularly frequent at younger ages.ConclusionsThis paper is the first to confirm a high ratio of ripples per spike in CSWS in the largest number of patients to date.SignificanceThe dense generation of ripples, which occurs through a combination of heavy loading of individual spikes with ripples and large numbers of spikes during sleep, characterizes CSWS and might be closely related to the pathophysiology of this epileptic encephalopathy.     

Disengagement and inhibition of visual-spatial attention are differently impaired in children with rolandic epilepsy and Panayiotopoulos syndrome

We assessed voluntary orientation and reorientation of visuospatial attention in 313 healthy 6- to 22-year-old participants, 30 children suffering from benign epilepsy with centrotemporal spikes (BECTS) and 13 children with Panayiotopoulos syndrome (PS). The developmental section highlights the late development of reorienting skills. Only children with BECTS-R showed a strong tendency toward a rightward bias in attentional orientation. Additionally, a unilateral deficit of disengagement characterizes the patients with BECTS-R and comorbid ADHD. Right rolandic spikes seem to aggravate subclinical reorienting difficulties. Finally, children with PS failed to diffuse inhibition, except in the nearest area outside the attentional focus. This deficit could be attributed to the typical occipital-to-frontal spreading of the spikes in PS. By showing distinct attentional deficiencies according to the epileptic syndrome and the epileptic focus lateralization in BECTS, the results provide new evidence for alterations of attentional mechanisms by interictal epileptic activity, which probably contribute to learning difficulties.     

Efficacy and safety of add-on levetiracetam in refractory childhood epilepsy

Purpose: The purpose of the present study was to evaluate the efficacy and safety of levetiracetam (LEV) in refractory epileptic children. Methods: The study group included 61 outpatients (7 generalized, 48 localization-related, 3 undetermined, 3 unclassified) aged between 16 months and 18 years. LEV was given twice daily at a total dose of 10 mg/kg/day. The final mean dose was 50.7 mg/kg/day. The mean number of prior anti-epileptic drugs was 5.2. The entire treatment period was more than 6 months after LEV administration. Results: Fifteen children (24.6%) became seizure-free for 6 months after starting LEV, and 18 (29.5%) had a seizure reduction of more than 50% for the entire 6 months. The response rate was 33/61 (54.1%). Responders included 2/3 of patients (66.7%) with epilepsy with continuous spikes and waves during slow sleep and 13/19 (68.4%) with frontal lobe epilepsy. The effective dosage of LEV in the responders demonstrated a wide range (mean, 46.1 mg/kg/day; range, 19.4–59.1 mg/kg/day), and showed bimodal distribution. Adverse events occurred in only two patients who did not require LEV discontinuation. Conclusion: LEV represents an important addition to the treatments available for refractory epileptic children.