Long-term safety and effectiveness of stiripentol in patients with Dravet syndrome: Interim report of a post-marketing surveillance study in Japan.

BACKGROUND: A post-marketing surveillance study is investigating the safety and effectiveness of stiripentol during real-world clinical use in Japanese patients with Dravet syndrome (DS). METHODS: The safety and effectiveness of stiripentol were prospectively investigated over 104 weeks in all patients with DS who were administered the drug from November 2012 through July 2019 in Japan. Patients administered stiripentol for the first time after its approval were defined as "new patients," and those who continued to take the drug after participating in domestic clinical studies were defined as "continuous-use patients." The responder rate was defined as the proportion of patients with a ≥50 % decrease in seizure episodes at the time of assessment of stiripentol effectiveness compared with the 4 weeks before starting stiripentol. Overall improvement was evaluated by the physician in charge based on the comprehensive assessment of the patient's condition after stiripentol treatment. RESULTS: Of 411 patients whose information was collected, 410 patients (376 new and 34 continuous-use) were included in the safety analysis set, and 409 (376 new and 33 continuous-use) were included in the effectiveness analysis set. The median age of new patients was 7 years (range: 0.5-50 years) at the time of stiripentol initiation; 99 % of patients were taking concomitant sodium valproate and 93 % clobazam. Adverse drug reactions occurred in 70 % of new patients; the most common were somnolence (39 %) and loss of appetite (25 %). No new safety concerns due to stiripentol were observed. The responder rate in new patients was 43 % (110/257 patients) for convulsive seizures (tonic-clonic and/or clonic convulsions), 55 % (58/105 patients) for focal impaired awareness seizures, and 62 % (56/90 patients) for generalized myoclonic seizures and/or generalized atypical absence seizures. Overall improvement (after 104 weeks or at the time of drug discontinuation) was rated as marked or moderate in 160/353 of new patients (45 %). CONCLUSION: Stiripentol is safe and effective during long-term use in patients with DS in routine clinical practice.

[Efficacy and Safety of Lorazepam Intravenously Administered in Subjects with Status Epilepticus or Repetitive Seizures].

We evaluated the efficacy and safety of lorazepam (LZP) 4 mg for adults (age, 16 years old or older) or 0.05mg/kg for children (age, 3 months to less than 16 years) as a slow intravenous injection in 26 Japanese patients with status epilepticus or repetitive seizures. The proportion of patients whose initial seizure stopped within 10 minutes and who continued seizure-free for at least 30 minutes after the completion of initial dose as the primary endpoint was 48.0% (12/25, 95%CI: 27.8%-68.7%). However, the proportion of patients whose seizures stopped within 10 minutes and who continued seizure-free for at least 30 minutes after the completion of either initial or second dose (in 10 to 30 minutes from the initial dose) was 64.0% (16/25, 95%CI: 42.5%-82.0%) in total, and 77.8% and 56.3% in adults and children, respectively. The most common adverse events (AEs) were somnolence (7.7%) and insomnia (7.7%), and almost all AEs were mild or moderate in severity. No patient experienced serious or severe LZP-related AEs. No one discontinued the study due to AEs.

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.

Long-term efficacy and safety of lamotrigine monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures: An open-label extension study.

PURPOSE: To investigate the efficacy and safety of long-term lamotrigine (LTG) monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. METHODS: Six Japanese patients and one South Korean patient were enrolled in the extension phase of the study after completing the 12-week maintenance phase of an open-label clinical study of LTG monotherapy. During the extension phase, patients underwent efficacy and safety evaluation every 12 weeks. RESULTS: Of the seven patients, six patients completed the extension phase. The seizure-free rate confirmed by hyperventilation (HV)-electroencephalography ranged from 71.4% to 100.0% at each visit up to Week 168 of the extension phase. Similar effects were confirmed by HV-clinical signs and seizure diaries. Although no unexpected adverse events were observed, one Japanese patient was withdrawn from the extension phase due to mild drug-related rash developed 842 days after the start of LTG. CONCLUSION: Although the number of patients is limited, long-term LTG monotherapy appeared to be effective and generally well tolerated in Japanese and South Korean pediatric patients with typical absence seizures.

Efficacy and safety of vigabatrin in Japanese patients with infantile spasms: Primary short-term study and extension study.

Vigabatrin was approved for the treatment of infantile spasms by the US Food and Drug Administration, but not in Japan at the time of initiating this clinical study because of concerns about irreversible peripheral visual field defects (VFDs). This study evaluated the efficacy and safety of vigabatrin for Japanese patients with infantile spasms. Of 15 patients (aged ≥4weeks and <2years) enrolled, with the exception of two patients who did not receive vigabatrin, 13 were treated with a titrated dosage of vigabatrin (50-150mg/kg/day; limited to 3000mg/day). Twelve out of 13 patients receiving vigabatrin had spasms that were treatment refractory; these patients were concurrently treated with at least one other antiepileptic drug. One patient received vigabatrin monotherapy. Eight of the 13 patients (61.5% [95% CI: 31.6-86.1%]) had a ≥50% reduction during the dose-adjustment phase compared with baseline in the frequency of spasms, with efficacy maintained through a 2-week maintenance phase. Spasms disappeared in six out of nine patients (66.7% [95% CI: 29.9-92.5%]) who transitioned to the maintenance phase and hypsarrhythmia on electroencephalography also resolved in four patients. Hypsarrhythmia was improved in another two patients. Six out of seven patients who continued treatment through Week 32 of an extension study reported ongoing efficacy for vigabatrin. The most common adverse events (AEs) were psychiatric disorders and nervous system disorders (n=8; 61.5%) that were generally mild in severity. No treatment-related peripheral VFDs were observed. No severe AEs or AEs resulting in discontinuation of vigabatrin therapy were reported. An abnormality in magnetic resonance images was observed in one patient during the extension period. Vigabatrin was deemed to be clinically effective and well tolerated in Japanese patients with infantile spasms.

Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy.

OBJECTIVE: Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. METHODS: Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated. RESULTS: Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations. CONCLUSION: Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.

Predicting the reading skill of Japanese children.

OBJECTIVE: To clarify cognitive processes underlining the development of reading in children speaking Japanese as their first language, we examined relationships between performances of cognitive tasks in the preschool period and later reading abilities. METHODS: Ninety-one normally developing preschoolers (41 girls and 50 boys; 5years 4months to 6years 4months, mean 5years 10months) participated as subjects. We conducted seven cognitive tasks including phonological awareness tasks, naming tasks, and working memory tasks in the preschool period. In terms of reading tasks, the hiragana naming task was administered in the preschool period; the reading times, which is a composite score of the monomoraic syllable reading task, the word and the non-word reading tasks, and the single sentence reading task, was evaluated in first and second grade; and the kanji reading task (naming task) was tested in second grade. Raven's colored progressive matrices and picture vocabulary test revised were also conducted in first grade. Correlation analyses between task scores and stepwise multiple regression analyses were implemented. RESULTS: Tasks tapping phonological awareness, lexical access, and verbal working memory showed significant correlations with reading tasks. In the multiple regression analyses the performances in the verbal working memory task played a key role in predicting character naming task scores (the hiragana naming task and the kanji reading task) while the digit naming task was an important predictor of reading times. Unexpectedly, the role of phonological (mora) awareness was modest among children speaking Japanese. CONCLUSION: Cognitive functions including phonological awareness, digit naming, and verbal working memory (especially the latter two) were involved in the development of reading skills of children speaking Japanese.

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.

Predictive factors for relapse of epileptic spasms after adrenocorticotropic hormone therapy in West syndrome.

PURPOSE: To investigate whether serial electroencephalographic (EEG) findings can predict relapse of epileptic spasms after synthetic adrenocorticotropic hormone (ACTH) therapy in patients with West syndrome (WS). SUBJECTS AND METHODS: Thirty-nine WS patients (8 cryptogenic and 31 symptomatic) were included in this study. These patients received ACTH therapy for the first time and were regularly followed up for more than three years at our hospital. Sixteen patients (41.0%) showed seizure relapse (relapse group) and 23 patients (59.0%) did not show relapse (non-relapse group). We used survival analysis to investigate the influence of etiology and presence of epileptic discharges after the ACTH therapy on seizure outcome. RESULTS: Immediately after the ACTH therapy, etiology was associated with seizure outcome (p=0.003). In the early stage (1 month after the ACTH therapy), only the presence of epileptic discharges (p=0.001) had a significant association with seizure outcome, regardless of etiology. Because all relapsed patients were in the symptomatic group, we performed the same statistical analysis on symptomatic WS patient data only. We found that the group with no epileptic discharges on EEG showed a significantly higher seizure-free rate than those with epileptic discharges in the early stage (p=0.0091). CONCLUSION: This study demonstrated that serial EEG findings after ACTH therapy are significantly related to relapse of epileptic spasms.

Occurrence of bilaterally independent epileptic spasms after a corpus callosotomy in West syndrome.

We report a patient with intractable West syndrome whose epileptic spasms (ESs) were initially bilaterally synchronous, as is typical; after a complete corpus callosotomy, however, bilaterally independent ESs originated in either hemisphere. Activity of probable cortical origin associated with ESs was detected by observing ictal gamma oscillations. Brain MRI revealed no structural abnormality before surgery. This case suggests that ESs with a hemispheric origin may appear generalized because of synchronizing effects in the corpus callosum in some patients.

Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: A multicenter, open-label study in Japan.

BACKGROUND: We have previously shown the benefits of short-term add-on stiripentol therapy for Dravet syndrome inadequately controlled by clobazam and valproate in Japanese patients. We report here the outcomes of long-term stiripentol use. METHODS: Patients with Dravet syndrome having ≥4 clonic/tonic-clonic seizures per 30 days while on clobazam and valproate (with or without bromide) received add-on stiripentol for 16 weeks. Those benefiting from stiripentol (50mg/kg/day; up to 2500mg/day) continued the therapy for additional up to 40 weeks. Responders were defined as those whose clonic/tonic-clonic seizures became ≤50% frequent as compared to baseline. RESULTS: Of 24 patients starting stiripentol, 21 received the drug for >16 weeks and 19 completed the study. At the endpoint, the responder rate was 54%, with 2 patients remaining clonic/tonic-clonic seizure-free. Twenty-two patients experienced stiripentol-related adverse events, with two having severe ones. They included somnolence (79%), loss of appetite (67%), ataxia (58%), and elevated gamma-glutamyltransferase (38%). No adverse events led to study discontinuation, but 19 patients required dose reduction for stiripentol and/or either antiepileptic drug combined. Stiripentol dose reduction was done in 9 patients, mostly due to somnolence or loss of appetite. CONCLUSIONS: During adjunctive stiripentol use with clobazam and valproate, careful monitoring for adverse events such as somnolence and loss of appetite is recommended, and dose reduction may become needed for any of the antiepileptics. Despite the need for safety precautions, the durable responses to stiripentol for up to 56 weeks suggest that the drug is effective as an adjunct to clobazam and valproate for the treatment of Dravet syndrome.

High-frequency EEG activity in epileptic encephalopathy with suppression-burst.

OBJECTIVE: We explored high-frequency activity in the suppression-burst (SB) pattern of interictal electroencephalogram (EEG) in early infantile epileptic encephalopathy including Ohtahara syndrome (OS) and early myoclonic encephalopathy (EME) to investigate the pathophysiological characteristics of SB. METHODS: Subjects included six patients with the SB EEG pattern related to OS or EME (Group SB). The results were evaluated in comparison to tracé alternant (TA) observed during the neonatal period in nine patients to rule out possible nonspecific relationships between high-frequency activity and periodic EEG patterns (Group TA). EEG was digitally recorded with a sampling rate of 500Hz and the analysis was performed in each of the particular bipolar channel-pairs. We visually selected 20 typical consecutive burst sections and 160 inter-burst sections for comparison from the sleep record of each patient and performed the time-frequency analysis. We investigated the maximum frequencies of power enhancement in each derivation in both groups. RESULTS: In Group SB, a significant increase in power at a frequency of 80-150Hz was observed in association with the bursts, particularly in the bilateral parieto-occipital derivations, in all patients. In Group TA, on the contrary, no significant increase in high-frequency power was found. The maximum frequencies of power enhancement were significantly higher in Group SB than in Group TA (p<0.001 by repeated-measures ANOVA). CONCLUSION: Interictal high frequencies of up to 150Hz were detected in the suppression-burst EEG patterns in epileptic encephalopathy in early infancy. Further studies will be necessary to identify the role of the interictal high-frequency activity in the pathophysiology of such early epileptic encephalopathy.

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.

[New antiepileptic drugs: characteristics and clinical applications].

New antiepileptic drugs (AEDs) that have been used in many other countries for more than 10 years have only recently became available for use in Japan. Gabapentin, topiramate, lamotrigine and levetiracetam were licensed for use in Japan between 2006 and 2010. Stiripentol for Dravet syndrome and rufinamide for Lennox-Gastaut syndrome were also approved in 2012 and 2013 as orphan drugs. Clinical trials of other new AEDs such as oxcarbazepine, vigabatrin, lacosamide, and perampanel are in progress. In this review, the general characteristics of the new AEDs are discussed with regards to their effectiveness, tolerability, drug interaction, safety and mechanisms of action. The effectiveness, of the new AEDs compared with established AEDs is also discussed. Clinical applications of the new AEDs, focusing on gabapentin, topiramate, lamotrigine and levetiracetam are also discussed based on our domestic experience as well as overseas reports.

Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence.

PURPOSE: To evaluate the efficacy and safety of stiripentol as add-on therapy in Japanese patients with Dravet syndrome treated with clobazam (CLB) and valproate (VPA). METHODS: In this open-label study, patients aged 1-30 years entered a 4-week baseline phase, followed by a 4-week stiripentol dose-adjustment and 12-week fixed-dose phase. The primary efficacy endpoint was responder rate (proportion of patients with a ≥50% reduction from baseline phase in clonic or tonic-clonic seizure frequency over the last 4 weeks of fixed-dose treatment [target phase]). Safety and pharmacokinetics were also assessed. KEY FINDINGS: Of 27 patients screened in the baseline phase, 24 patients entered the dose-adjustment phase. All patients completed the study. Responder rate was 66.7% (16/24, 95% CI: 44.7-84.4%), and four patients became free from clonic or tonic-clonic seizures. The duration of clonic or tonic-clonic seizures was also significantly reduced in the target versus baseline phase. The most frequent adverse events were somnolence, anorexia, ataxia, nasopharyngitis and γ-glutamyl transpeptidase increase, all of which were of mild-to-moderate severity. Stiripentol plasma concentration in the fixed-dose phase was 4-25 µg/mL. After adding stiripentol to CLB and VPA, the minimum plasma concentrations of CLB and N-desmethyl-CLB (NCLB) increased and that of 4'-hydroxy-N-desmethyl-CLB(OH-NCLB) decreased, while those of VPA and bromide (optionally used) were not affected. SIGNIFICANCE: Add-on stiripentol to CLB and VPA was well tolerated and significantly decreased clonic or tonic-clonic seizures in patients with Dravet syndrome.

Inhibitory function and working memory in attention deficit/hyperactivity disorder and pervasive developmental disorders: does a continuous cognitive gradient explain ADHD and PDD traits?

To clarify the relationship between attention deficit/hyperactivity disorder (AD/HD) and pervasive developmental disorders (PDD), we investigated the common features and differences of these disorders in neuropsychological profiles. The subjects were 4 groups of Japanese boys aged 6 to 15 years, categorized by diagnosis:AD/HD (n＝20), PDD with comorbid AD/HD (PDD＋:n＝16), PDD without comorbid AD/HD (PDD－:n＝8), and typically developing (n＝60). We evaluated executive function (EF) through verbal and visuospatial memory tasks, the Go/NoGo task, and the color-word matching Stroop task. We performed a categorical analysis to estimate the effects of the 3 disorders on EF and a dimensional analysis to estimate the effects of symptom scales on EF. We found that the AD/HD and PDD＋ subjects had negative effects on verbal working memory and intra-individual response variability. The severity of these impairments was positively correlated with the inattentiveness score. The subjects with a PDD＋ or PDD－ diagnosis had poorer scores on interference control;the severity of this impairment was correlated with the PDD symptom score. Impairments in visuospatial working memory were detected in the AD/HD and PDD－ groups but not in the PDD＋ group. Impairments in inhibition of the pre-potent response were noted in all 3 categories. AD/HD and PDD share neuropsychological features, though each disorder has a specific impairment pattern. Our findings partially support the idea that AD/HD and PDD are on a spectrum.

Successful treatment of early myoclonic encephalopathy using lidocaine and carbamazepine.

We report two female infants with early myoclonic encephalopathy (EME) whose intractable focal seizures were suppressed with lidocaine and carbamazepine (CBZ). Although EME is a form of early-onset epileptic encephalopathy characterised by myoclonus and focal seizures that are highly resistant to treatment, lidocaine and CBZ may prove effective in treating this disorder. Future studies should be performed in order to determine whether there are common specific mechanisms of seizure generation related to the sodium channel in these patients.

Questionnaire-based assessment of behavioral problems in Japanese children with epilepsy.

Behavioral problems in Japanese children with epilepsy were investigated by means of a questionnaire for parents consisting of three checklists: the Child Behavior Checklist (CBCL)/4-18 Japanese Edition, the High-Functioning Autism Spectrum Screening Questionnaire (ASSQ), and the Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale-IV (ADHD-RS) for parents. The participants were the parents of 108 children aged 6-18 years with apparently normal intelligence. The CBCL indicated abnormal behavior in 10.5 to 35.6% of the children, and T scores on both the internalizing and externalizing scales had a significant positive relation with scores on the ASSQ and ADHD-RS. It was revealed through multivariate logistic regression analysis that the persistence of seizures was significantly related with abnormality on the externalizing scale of the CBCL (p=0.010, odds ratio: 3.48, 95% confidence interval: 1.34-9.02). Future studies are needed to determine whether seizure freedom improves behavior in children with epilepsy.

Cortical contribution to scalp EEG gamma rhythms associated with epileptic spasms.

The cortical contribution for the generation of gamma rhythms detected from scalp ictal EEG was studied in unique cases of epileptic spasms and a review of the related literature was conducted. Ictal scalp gamma rhythms were investigated through time-frequency analysis in two cases with a combination of focal seizures and spasms and another case with spasms associated with cortical dysplasia. In the two patients with combined seizures, the scalp distribution of ictal gamma rhythms was related to that of focal seizure activity. In the third patient, an asymmetric distribution of the ictal scalp gamma rhythms was transiently revealed in correspondence to the dysplasic cortex during hormonal treatment. Therefore, the dominant region of scalp gamma rhythms may correspond to the epileptogenic cortical area. The current findings have reinforced the possibility of the cortical generation of ictal scalp gamma rhythms associated with spasms. The detection of high frequencies through scalp EEG is a technical challenge, however, and the clinical significance of scalp gamma rhythms may not be the same as that of invasively recorded high frequencies. Further studies on the pathophysiological mechanisms related to the generation of spasms involving high frequencies are necessary in the future, and the development of animal models of spasms will play an important role in this regard.

Immunomodulatory therapy versus surgery for Rasmussen syndrome in early childhood.

We examined seizure, cognitive, and motor outcomes in patients with Rasmussen syndrome or Rasmussen encephalitis (RS), after recent initiation of immunomodulatory therapies. Among 53 patients with a diagnosis of RS referred from all over Japan, 49 patients (male 22, female 27) with symptoms and findings characteristic of RS were evaluated. Regular intravenous immunoglobulin (IVIg) therapy was administered at a dose of 100mg/kg/day, etc. Regular steroid pulse therapy was conducted with methylprednisolone at a dose of 30mg/kg/day (children) or 1000mg/day (adults) for 3days. Tacrolimus was given at an initial dose of 0.1mg/kg/day (children). Mean onset age was 8.7±10.5years. Seizure-free rate was 71% after treatment by functional hemispherectomy (FH), and response rate for seizures was 81% by regular steroid pulse therapy, 42% by tacrolimus therapy, and 23% by regular IVIg therapy. Rate of patients with IQ higher than 80 (R80) was 50% by regular steroid pulse therapy, 43% by regular IVIg therapy, 29% by tacrolimus therapy, and 0% by FH. R80 after regular steroid pulse therapy was 100% in patients without MRI lesions, and 37% in those with advanced MRI lesions. Improvement of motor function (paresis) was observed only by immunomodulatory therapy. Motor function was aggravated in 100% of patients treated by FH, 62% by regular IVIg, and 10% by regular steroid pulse therapy. We suggest a new treatment strategy for RS using early immunomodulatory therapy: initiation of regular steroid pulse therapy after early diagnosis indicated by biomarkers, then switching to tacrolimus therapy after several months.