Long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome receiving adjunctive rufinamide therapy: An open-label study following a randomized clinical trial.

PURPOSE: To evaluate the long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive rufinamide therapy. SUBJECTS AND METHODS: We conducted an open-label extension study following a 12-week multicenter, randomized, double-blind, placebo-controlled study of adjunctive rufinamide therapy in Japanese patients with LGS. Fifty-four patients participated in the extension study. Seizure frequency was evaluated until 52 weeks after the start of the extension study. Adverse events (AEs) were evaluated throughout both studies. KEY FINDINGS: Of the 54 patients, 41 (75.9%) completed the extension study. The median duration of exposure to rufinamide was 818.0 days in all 54 patients, and 38 patients (70.4%) received rufinamide for 2 years or more. The median percent change in the frequency of tonic-atonic seizures relative to the frequency at the start of the double-blind study was -39.3% (12 weeks), -40.6% (24 weeks), -46.8% (32 weeks), -47.6% (40 weeks), and -36.1% (52 weeks). Reduction of total seizure frequency was also maintained until 52 weeks. Frequent treatment-related AEs were somnolence (20.4%), decreased appetite (16.7%), transient seizure aggravation including status epilepticus (13.0%), vomiting (11.1%), and constipation (11.1%). Adverse events were mild or moderate, except for transient seizure aggravation in three patients. Adverse events resulting in discontinuation of rufinamide were decreased appetite, drug eruption, and worsening of underlying autism. When clinically notable weight loss was defined as a decrease ≥ 7% relative to baseline, 22 patients (40.7%) experienced weight loss at least once during long-term observation, although weight loss was reported as an AE in only three patients. SIGNIFICANCE: This study demonstrated a long-term benefit of rufinamide as adjunctive therapy for Japanese patients with LGS. Exacerbation of seizures and decreased appetite/weight loss should be monitored carefully.

Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan.

PURPOSE: To evaluate the efficacy, safety, and pharmacokinetics of rufinamide as an adjunctive therapy for patients with Lennox-Gastaut syndrome (LGS) in a randomized, double-blind, placebo-controlled trial. METHODS: We conducted a multicenter clinical trial with a 4-week baseline, a 2-week titration, a 10-week maintenance, and either a follow-up visit or entry into an open-label extension. Patients with LGS (4 to 30 years old) taking between one and three antiepileptic drugs were recruited. After the baseline period, patients were randomly assigned to rufinamide or placebo. The primary efficacy variable was the percent change in the tonic-atonic seizure frequency per 28 days. KEY FINDINGS: Of the 59 patients, 29 were randomized to the rufinamide group and 30 to the placebo group. The frequency of epileptic seizures was significantly decreased in the rufinamide group than in the placebo group; the median percent change in frequency of tonic-atonic seizures was -24.2% and -3.3%, respectively, (p=0.003) and that of total seizures was -32.9% and -3.1%, respectively (p<0.001). Subgroup analyses indicated that the efficacy of rufinamide was consistent independent of clinical background characteristics. The common treatment-related adverse events in the rufinamide group were decreased appetite (17.2%), somnolence (17.2%), and vomiting (13.8%). Transient seizure aggravations were observed in 13 (22.0%) of the 59 patients, though a causal relationship with rufinamide was suspected in only one patient. All adverse events were mild to moderate in severity. The mean plasma concentration of rufinamide between 1 and 9 within 12h after administration was 17.2 µg/mL. SIGNIFICANCE: The present results showed a favorable risk-benefit profile for rufinamide as an adjunctive therapy for patients with LGS.

A human Dravet syndrome model from patient induced pluripotent stem cells.

BACKGROUND: Dravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the α-subunit of the voltage-gated sodium channel Na(v)1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndrome's human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs. RESULTS: We generated iPSCs from a Dravet syndrome patient with a c.4933C>T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (>50%), although glutamatergic neurons were observed as a minor population (<1%). Current-clamp analyses revealed significant impairment in action potential generation when strong depolarizing currents were injected. CONCLUSIONS: Our results indicate a functional decline in Dravet neurons, especially in the GABAergic subtype, which supports previous findings in murine disease models, where loss-of-function in GABAergic inhibition appears to be a main driver in epileptogenesis. Our data indicate that patient-derived iPSCs may serve as a new and powerful research platform for genetic disorders, including the epilepsies.

Nationwide survey (incidence, clinical course, prognosis) of Rasmussen's encephalitis.

PURPOSE: Rasmussen's encephalitis (RE) is a progressive and catastrophic epileptic disorder caused by chronic localized encephalitis. We performed a nationwide survey of RE to assess the clinical picture, treatment effect, and prognosis of Japanese RE patients. SUBJECTS & METHODS: The subjects were 27 patients (male:12; female:15) from 13 medical facilities. All of them satisfied the clinical and neuroimaging criteria for RE, including 14 pathologically proven cases. RESULTS: They were divided into the childhood-onset rapidly progressive type (CORP, n=19), and late-onset slowly progressive type (LOSP, n=8). The mean age at epilepsy onset was 4 years and 4 months in CORP, and 16 years in LOSP. The mean period between the onset age of epilepsy and development of frequent seizures was 1 year and 4 months in the former, and 3 years and 4 months in the latter. The immunomodulatory treatment including high-dose steroid (n=14) and high-dose intravenous immunoglobulin therapies (IVIgG, n=12) achieved more than a 50% reduction in the seizure frequency in 5 (36%) and 4 (33%) patients, respectively. Eight and seven patients underwent focal cortical resection and functional hemispherectomy, leading to significant improvement in 5 of the 8 patients and excellent seizure control in all 7 patients, respectively. CONCLUSION: Although the high-dose steroid and IVIG therapies may have alleviated the exacerbation of seizures in those with RE, they could not halt the disease progression. Functional hemispherectomy is still the only curative therapy for RE, despite the fact that the early introduction of this procedure remains controversial.

Microchromosomal deletions involving SCN1A and adjacent genes in severe myoclonic epilepsy in infancy.

PURPOSE: Genetic abnormalities of the gene encoding alpha1 subunit of the sodium channel (SCN1A), which can be detected by direct sequencing, are present in more than 60% of patients with severe myoclonic epilepsy in infancy (SMEI) or its borderline phenotype (SMEB). Microchromosomal deletions have been recently reported as additional causes of SMEI. This study examines whether such microdeletions are associated with SMEI as well as with SMEB. METHODS: We recruited patients with SMEI (n = 35) and SMEB (n = 34), who were confirmed previously to have no mutations of SCN1A by direct sequencing. Microdeletions were sought by multiplex ligation-dependent probe amplification (MLPA), and then confirmed and characterized by fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH), respectively. RESULTS: Heterozygous multiple exonic deletions were identified in 7/35 SMEI patients (20%) and 0/34 SMEB patients (0%), with a net frequency of 10.1% (7/69 patients). Deletions were confirmed by FISH and aCGH analysis. The concomitant deletions of adjacent genes were revealed by aCGH. None of the parents who agreed to undergo the analysis had such deletions suggesting that the deletions were de novo. The phenotypes of patients with the deletions were indistinguishable from those of SMEI resulting from point mutations. DISCUSSION: Our findings indicate that microchromosomal deletion, often involving not only SCN1A but also several adjacent genes, is associated with core SMEI. As microchromosomal deletion cannot be anticipated by the phenotypes or detected by conventional methods, genetic abnormalities in SMEI should be carefully sought by techniques that can detect microdeletions.

Causes of childhood epilepsy in Vietnam: cases in Bach Mai Hospital.

BACKGROUND: Little is known about childhood epilepsy in Vietnam, and because the causes of symptomatic epilepsy could be the result of both rapid economic development and traditional Vietnamese lifestyle, the purpose of the present paper was to clarify the nature of childhood epilepsy in Vietnam. METHOD: A classification of epilepsy using International League Against Epilepsy classification was made and an investigation of causes was carried out. RESULTS: Of those 162 new patients diagnosed as having epilepsy in Bach Mai Hospital, Hanoi, Vietnam, from February 2002 to February 2004 (male 84, female 78), there were 58 cases of generalized epilepsy: 22 symptomatic and 36 idiopathic or cryptogenic. A total of 90 patients were diagnosed as having localization-related epilepsy: 53 as symptomatic and 37 as idiopathic or cryptogenic. A total of 14 cases were also considered as not epileptic after strict review of both the history and the examination data. CONCLUSION: Concerning the causes, the following were noted: (i) the rate of infectious diseases and trauma as causes of epilepsy was considerably higher in Vietnam than in developed countries; (ii) certain infectious diseases could be prevented if vaccinations and public health knowledge were improved; and (iii) the number of trauma cases, mainly due to traffic accidents, would likely be reduced if the traffic system was improved.

Three Japanese patients with glucose transporter type 1 deficiency syndrome.

We report three Japanese patients with glucose transporter type 1 deficiency syndrome (Glut1DS). Two patients had a normal erythrocyte 3-O-methylglucose (3OMG) uptake, one with a previously reported T295M substitution and the other with a novel 12-bp insertion at nt 1034-1035, ins CAGCAGCTGTCT. The third patient, with deficient 3OMG uptake, had a previously reported hot-spot mutation, R333W. All three patients responded to a ketogenic diet. All patients showed a significant improvement in ataxia, with blood beta-hydroxybutyrate (BOHB) levels ranging from 0.1 to 3mM. BOHB levels of at least 3mM were necessary to control seizures, and higher ketone levels are recommended to meet brain energy needs during development. FDG-PET scan, performed before and after a ketogenic diet in the R333W patient, did not change despite a clinical improvement. This clinical condition is treatable and early diagnosis is important.

Seizure phenotypes of a family with missense mutations in SCN2A.

The seizure phenotypes of a Japanese family with missense mutations in SCN2A are described. The proband of the family had partial epilepsy after febrile seizures plus. He had three missense mutations of SCN2A (R19K, R188W, and R524Q). The R188W mutation was suggested by electrophysiologic studies to be the main disease mutation. However, it is suggested that the penetrance rate of this pedigree is extremely low, or that other genes may have modified the phenotype of the proband.

Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB).

PURPOSE: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes. METHODS: We examined 96 healthy volunteers and 58 unrelated individuals whose clinical features were consistent with either core SMEI (n = 31) or SMEB (n = 27). We screened for genetic abnormalities within exons and their flanking introns of the genes encoding major subunits of the Na+ channels (SCN1A, SCN2A, SCN1B, and SCN2B) by using a direct sequencing method. RESULTS: In both core SMEI and SMEB, various mutations of SCN1A including nonsense and missense mutations were identified, whereas no mutations of SCN2A, SCN1B, and SCN2B were found within the regions examined. All mutations were heterozygous and not found in 192 control chromosomes. Mutations were identified in 26 (44.8%) of the 58 individuals and were more frequent (p < 0.05) in core SMEI (19 of 31) than in SMEB (seven of 27), as assessed by the continuity-adjusted chi2 test. Mutations resulting in a molecular truncation were found only in core SMEI. Among the mutations, two missense mutations were found in both core SMEI and SMEB. CONCLUSIONS: Our findings confirm that SMEB is part of the SMEI spectrum and may expand the recognition of SMEI and suggest other responsible or modifying genes.

Lack of neuronal damage in atypical absence status epilepticus.

PURPOSE: Whether status epilepticus of nonconvulsive epileptic seizures is harmful still remains controversial. To investigate this, the presence and/or extent of neuronal damage in patients with absence status epilepticus (ASE) and patients with complex partial status epilepticus (CPSE) was examined and compared. METHODS: Neuron-specific enolase (NSE) in CSF was examined in the patients with ASE and compared with that of the patients having CPSE. Clinical aspects of these patients also were investigated. RESULTS: CSF NSE levels in ASE patients were lower than those of CPSE patients and were considered as the normal values. No clinical symptoms indicated neuronal damage in the ASE patients. CONCLUSIONS: This study suggests that ASE does not induce neuronal damage. Serum NSE is not always correlated to CSF NSE, and determination of serum NSE levels may be an inappropriate method of estimating neuronal damage in some cases of ASE.

Short-term plasticity of hippocampal neuropeptides and neuronal circuitry in experimental status epilepticus.

PURPOSE: We used a model of self-staining status epilepticus (SSSE), induced by brief intermittent stimulation of the perforant path in unanesthetized rats, to study the mechanism of initiation and of maintenance of SSSE and the role of neuropeptides in those processes. METHODS: The perforant path was stimulated intermittently for 7 min (ineffective stimulation) or 30 min (generating SSSE). Peptides and their agonists and antagonists were delivered either intraperitoneally, or directly into the hippocampus through a implanted cannula. Behavior and electroencephalogram (EEG) were recorded through a videotape-telemetry system with automatic spike and seizures detection programs, which were supplemented by manual review of the records to confirm the diagnosis. Immunocytochemistry and enzyme-linked immunosorbent assay followed published methods. RESULTS: Initiation of SSSE was blocked by many agonists of inhibitory neurotransmitters or neuromodulators, and by many antagonists of excitatory synapses, and was facilitated by agents with the opposite action, suggesting the activation of a complex circuit with multiple potential entry points. Once SSSE was established, however, only N-methyl-d-aspartate (NMDA)-receptor ligands and a few neuropeptides had major effects on its maintenance. Galanin and dynorphin had powerful anticonvulsant roles in the maintenance phase of SSSE, whereas somatostatin and neuropeptide Y suppressed seizures only transiently. SSSE seemed to induce maladaptive changes in neuropeptides: it depleted the hippocampus of the galanin- and dynorphin-immunoreactive (IR) fibers, which normally function as endogenous anticonvulsants; whereas it induced overexpression of the proconvulsant neuropeptides substance P and neurokinin B; however, late in the course of SSSE, galanin-IR interneurons appeared in the dentate hilus. CONCLUSIONS: Initiation of SSSE seems to involve a circuit with many points of entry, and blockage of any point along this circuit inhibits the development of SSSE. Far fewer agents alter the maintenance phase of SSSE. Galanin, dynorphin, somatostatin, and neuropeptide Y have anticonvulsant roles, matching the previous described convulsant role of substance P and neurokinin B. Galanin and dynorphin seem to undergo maladaptive changes, which appear to play an important role of the maintenance phase of SSSE. Later, the de novo expression of inhibitory neuropeptides in novel cells in hippocampus coincides with the waning of seizures and may play a role in their termination.