Adjunctive levetiracetam in the treatment of Chinese and Japanese adults with generalized tonic-clonic seizures: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To assess the efficacy, safety, and tolerability of adjunctive levetiracetam (LEV) in Chinese and Japanese adults with generalized tonic-clonic (GTC) seizures (N01159; NCT01228747). METHODS: This double-blind, randomized, placebo-controlled, multicenter phase III trial comprised: 4-week retrospective and 4-week prospective baseline, 12-week dose-adjustment, and 16-week evaluation periods. Chinese and Japanese patients ≥16 years old with idiopathic generalized, symptomatic generalized, or undetermined epilepsy with GTC seizures received a single-blind placebo during the prospective baseline, and then were randomized 1:1 to placebo or LEV 1,000 mg/day administered twice daily. Patients reporting GTC seizures up to week 8 had the LEV dosage increased to 3,000 mg/day. The primary efficacy variable was percent reduction from combined baseline in GTC seizures/week during the 28-week treatment period. RESULTS: Overall, 251 patients were randomized (208 from China; 43 from Japan); 141 (56.2%) completed the 28-week treatment period. Least-squares mean percent reduction from combined baseline in GTC seizures/week (treatment period) was placebo 12.6% versus LEV 68.8% (95% confidence interval, 44.0-68.2; p < 0.0001). GTC seizure frequency reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. The 50% responder rate (treatment period) was placebo 28.4% versus LEV 77.8%. Freedom from GTC seizures (evaluation period) was placebo 3.1% versus LEV 29.6%. Incidence of treatment-emergent adverse events (TEAEs; treatment period) was placebo 52.0% versus LEV 57.1%; most frequently nasopharyngitis, protein in urine, decreased platelet count, and pyrexia. Incidence of TEAEs leading to discontinuation was 4.8% versus 3.2%; incidence of serious TEAEs was 3.2% versus 0.8% for placebo and LEV, respectively; 3 patients taking placebo died versus none taking LEV. SIGNIFICANCE: In this trial, adjunctive LEV 1,000-3,000 mg/day was effective in reducing GTC seizure frequency in Chinese and Japanese patients ≥16 years old with GTC seizures. Seizure reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. LEV was well tolerated in this population.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Efficacy and tolerability of levetiracetam as adjunctive therapy in Japanese patients with uncontrolled partial-onset seizures.

AIMS: The aim of this study was to confirm the efficacy and safety of adjunctive levetiracetam in adult Japanese patients with uncontrolled partial-onset seizures. METHODS: In a double-blind, placebo-controlled, confirmatory trial, eligible patients were randomized to receive levetiracetam 500, 1000, 2000, or 3000 mg/day or placebo for 16 weeks. The primary end-point was percentage reduction from baseline in seizure frequency/week over a 12-week evaluation period. Tolerability assessments were also conducted. Findings of this and a previous randomized, double-blind trial were compared. RESULTS: Of 401 patients screened, 352 were randomized and 316 completed the study. Median percentage reduction in seizure frequency/week from baseline was 12.92%, 18.00%, 11.11% and 31.67% in the levetiracetam 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% in the placebo group. Unlike the previous trial, the primary efficacy analysis between the levetiracetam 1000 and 3000-mg and placebo groups did not reach statistical significance (P = 0.067). Exploratory analyses demonstrated that the difference in seizure reduction versus placebo was 14.93% (95% confidence interval, 1.98-27.64; P = 0.025) for the levetiracetam 3000-mg group. All levetiracetam doses were well tolerated. The main difference between the two trials was a high placebo response in the present trial. CONCLUSIONS: The primary efficacy analysis did not reach statistical significance, a finding that could be attributed to an unexpectedly high placebo response. Nonetheless, exploratory analysis suggests that levetiracetam at 3000 mg/day may, at least marginally, be beneficial for patients with uncontrolled partial-onset seizures.

Altered activity of the primary visual area during gaze processing in individuals with high-functioning autistic spectrum disorder: a magnetoencephalography study.

BACKGROUND: Individuals with autistic spectrum disorder (ASD) demonstrate an impaired ability to infer the mental states of others from their gaze. Thus, investigating the relationship between ASD and eye gaze processing is crucial for understanding the neural basis of social impairments seen in individuals with ASD. In addition, characteristics of ASD are observed in more comprehensive visual perception tasks. These visual characteristics of ASD have been well-explained in terms of the atypical relationship between high- and low-level gaze processing in ASD. METHOD: We studied neural activity during gaze processing in individuals with ASD using magnetoencephalography, with a focus on the relationship between high- and low-level gaze processing both temporally and spatially. Minimum Current Estimate analysis was applied to perform source analysis of magnetic responses to gaze stimuli. RESULTS: The source analysis showed that later activity in the primary visual area (V1) was affected by gaze direction only in the ASD group. Conversely, the right posterior superior temporal sulcus, which is a brain region that processes gaze as a social signal, in the typically developed group showed a tendency toward greater activation during direct compared with averted gaze processing. CONCLUSION: These results suggest that later activity in V1 relating to gaze processing is altered or possibly enhanced in high-functioning individuals with ASD, which may underpin the social cognitive impairments in these individuals.

Neural activity in the posterior superior temporal region during eye contact perception correlates with autistic traits.

The present study investigated the relationship between neural activity associated with gaze processing and autistic traits in typically developed subjects using magnetoencephalography. Autistic traits in 24 typically developed college students with normal intelligence were assessed using the Autism Spectrum Quotient (AQ). The Minimum Current Estimates method was applied to estimate the cortical sources of magnetic responses to gaze stimuli. These stimuli consisted of apparent motion of the eyes, displaying direct or averted gaze motion. Results revealed gaze-related brain activations in the 150-250 ms time window in the right posterior superior temporal sulcus (pSTS), and in the 150-450 ms time window in medial prefrontal regions. In addition, the mean amplitude in the 150-250 ms time window in the right pSTS region was modulated by gaze direction, and its activity in response to direct gaze stimuli correlated with AQ score. pSTS activation in response to direct gaze is thought to be related to higher-order social processes. Thus, these results suggest that brain activity linking eye contact and social signals is associated with autistic traits in a typical population.

[Social resources for a patient with epilepsy].

Epilepsy is a common episodic neurological disorder and is often accompanied by mental, psychiatric, and physical disorders; therefore, a comprehensive treatment, including seizure control, is needed to treat it. Epilepsy patients need frequent seizure preventive treatment, which is likely to induce medication dependence. This paper presents a report on the social resources involved in epilepsy treatment. "Services and Support for Persons with Disabilities Acts" is applicable to epilepsy patients and provides public compensation for psychiatric outpatient treatment, enabling disabled persons to apply for disability pension to support their living and medical expenditures. The Mental Health Welfare Notebook is issued to provide welfare services for the disabled, and it plays an important role in promoting employment of disabled persons. The welfare services for the disabled are diverse, ranging from home-based services to services aiding the disabled to step out of their homes, go to day care centers, or pay for house rent. The details of the welfare services for the disabled are available on the homepage of the website for the Ministry of Health, Labour and Welfare. The roles of physicians involve maximizing social resources in coordination with psychiatric social workers, aiming for normalization of disabled persons so that they are able to live comfortably in the community.

[Titration comparative study of TOPINA Tablets in patients with localization related epilepsy: double-blind comparative study by rapid and slow titration methods].

To compare the tolerability and efficacy of two titration methods (rapid and slow titration) for TOPINA Tablets with different dosages and periods of escalation, a double-blind comparative study was conducted in patients with localization-related epilepsy. A total of 183 patients were randomized to either rapid titration (initial dosage 100 mg/day increased by 100-200 mg at weekly intervals) or to slow titration (initial dosage 50 mg/day increased in 50 mg/day increments at weekly intervals). TOPINA Tablets were administered for 12 weeks to the maximum dosage of 400 mg/day. The incident of adverse events leading to treatment interruptions or withdrawals was 18.9% in rapid titration and 14.8% in slow titration, with no statistical significance (p = 0.554). The incident of adverse events and adverse reactions of slow titration was slightly lower than that of rapid titration. The common adverse events and adverse reactions reported in the two titration methods were comparable and were well tolerated. On the other hand, the efficacy of slow titration, percent reduction in seizure rate and responder rate, was comparable with that of rapid titration. In conclusion, there were no significant differences of therapeutic response to TOPINA Tablets between the two titration methods.

False lateralization of mesial temporal lobe epilepsy by noninvasive neurophysiological examinations.

Mesial temporal lobe epilepsy (mTLE) is the most common form of symptomatic localization-related epilepsy and is surgically remediable. Lateralization of the seizure onset is particularly important to determine from a surgical perspective. A 39-year-old woman with intractable mTLE first exhibited seizure at the age of 3 years. She experienced epigastric sensation and placed her right hand on her abdomen before falling backward. Although interictal scalp electroencephalography (EEG), sphenoidal scalp ictal EEG, and magnetoencephalography showed right temporal side focus, computed tomography and magnetic resonance imaging showed atrophy of the left cerebral hemisphere. Single photon emission computed tomography with technetium-99m ethyl cysteinate dimmer and I-123 iomazenil showed obscure focus on the left side. As a discrepancy existed between the results of neurophysiological examinations and imaging, we performed subdural electrode implantation on the bilateral temporal lobe. Although a bemegride-induced seizure arose from the right side during the subdural recording, the onset of 5 habitual seizures was observed in the left hippocampus. On the basis of these results, the seizure was diagnosed as left mTLE, and left anterior temporal lobectomy and amygdalohippocampectomy were performed. The patient has been free from the seizures for more than 1.5 years of follow up. Bilateral subdural electrode measurement of habitual seizures is indispensable for clarifying the actual focus when a discrepancy exists between neuroimaging and noninvasive neurophysiological examinations.

Magnetoencephalography in patients with tuberous sclerosis and localization-related epilepsy.

PURPOSE: To clarify the usefulness of magnetoencephalography (MEG) for diagnosis of the spatial relations between spike foci and suspicious epileptogenic tubers on MRI in patients with tuberous sclerosis (TS) and to compare MEG spike foci with single-photon emission computed tomography (SPECT) findings. METHODS: We analyzed magnetic fields of epileptic spike discharges in 15 patients with TS and localization-related epilepsy (LRE) by using MEG (a whole-head 204-channel magnetometer system). We investigated the spatial relation between the equivalent current dipoles (ECDs) of interictal spike discharges and visible cortical tubers on MRI. We also compared results of MEG and MRI with SPECT findings. RESULTS: MEG detected a cluster of ECDs around one cortical tuber in six of 15 patients and clusters of ECDs around two cortical tubers in five patients. Interictal SPECT was disappointing in detection of epileptic foci in TS. However, MEG spike foci showed spatial consistency with ictal hyperperfusion areas in two patients. Three patients with single ECD clusters underwent surgical treatment: two have been seizure free, and one has obtained seizure reduction of >90%. CONCLUSIONS: ECDs were located around visible tuber nodules. MEG enabled precise localization of the epileptic foci and provided crucial information for surgical treatment in patients with TS and partial epilepsy. TS patients showing a single ECD cluster on MEG may be appropriate candidates for surgical treatment.

Single and multiple clusters of magnetoencephalographic dipoles in neocortical epilepsy: significance in characterizing the epileptogenic zone.

PURPOSE: To characterize the epileptogenic zone in neocortical epilepsy (NE) by using magnetoencephalography (MEG). METHODS: We defined and compared locations of single and multiple clusters of equivalent current dipoles (ECDs) for interictal spikes with MRI findings, ictal-onset zones (IOZs) from subdural electroencephalography (SDEEG), resected areas, and postsurgical outcomes of 20 patients who underwent cortical resection for medically intractable NE. RESULTS: Fourteen patients had single clusters; six had multiple clusters. Overlap of clusters and IOZs defined group A (nine patients), in which a single cluster coincided with the IOZ; group B1 (four patients), in which a single cluster was within or partially overlapped the IOZ; group B2 (five patients), in which multiple-cluster sections overlapped IOZs; group C (two patients; one single; one multiple), in which no overlap was seen. More single clusters (nine of 14) than multiple clusters (none of six) coincided with the IOZ (p = 0.014). More patients with single clusters (10 of 14) than patients with multiple clusters (one of six) had seizure-free outcomes (p = 0.049). Eight of nine patients in group A, versus three of 11 in groups B1, B2, and C, achieved seizure-free outcomes (p = 0.0098). Correlations between MRI findings and postsurgical outcomes were not statistically significant; eight of 13 patients with single lesions, one of four with no lesions, and two of three with multifocal lesions had seizure-free outcomes. CONCLUSIONS: In neocortical epilepsy, MEG ECD clusters correlated with SDEEG IOZs. Single clusters indicated discrete epileptogenic zones that required complete resection for seizure-free outcome. Multiple clusters necessitated that the multiple or extensive epileptogenic zones be completely identified and delineated by SDEEG.

Multi-institutional study on the correlation between chromosomal abnormalities and epilepsy.

While there is an abundance of literature describing the association of chromosome aberrations with epilepsy, only a few refer to the detailed features of epilepsy. It is important to investigate the associations between specific chromosome abnormalities and features of epilepsy to identify genes involved in epilepsy and treat them more effectively. We investigated the correlation between specific chromosome aberrations and epilepsy by sending questionnaires to the members of Kyoto Multi-institutional Study Group of Pediatric Neurology. Seventy-six patients were collected from 10 institutions. Chromosome abnormalities included: Down syndrome (n = 19); Angelman syndrome (n = 8); Prader-Willi syndrome (n = 4); 4p- syndrome (n = 3); 1q- syndrome (n = 2); 5p- syndrome (n = 2); Miller-Dieker syndrome (n = 2); 18q- syndrome; (n = 2); Klinefelter syndrome; (n = 2); and 32 other individual chromosomal aberrations. Overall, the severity of mental retardation correlated with the severity of epilepsy. We could abstract characteristic features of epilepsy in some syndromes. In Angelman and Prader-Willi syndromes, febrile seizures occurred frequently, the onset of epilepsy was in early childhood and seizure phenotype was multiple. Paroxysmal discharge of the occipital region and diffuse high voltage slow wave on electroencephalography were characteristic in Angelman syndrome. In Down syndrome, West syndrome and focal epilepsy were common and the prognosis of epilepsy in West syndrome with Down syndrome was good. In 4p- syndrome, febrile seizures were often seen, and unilateral or generalized clonic or tonic-clonic status epilepticus were characteristic. For the other chromosomal aberrations investigated here, the patient numbers were too small to abstract common features of epilepsy.