[Effectiveness and safety of long-term levetiracetam treatment in patients with refractory epilepsy].

OBJECTIVE: To evaluate the long-term effects and tolerability of levetiracetam (LEV) in refractory epilepsy. METHODS: LEV was administered to 76 patients whose seizures were inadequately controlled by their current medications. The patients were followed for a minimum of 18 months but less than 2 years. The efficacy of LEV treatment was assessed retrospectively as the proportion of patients who experienced at least a 50% reduction in the frequency of seizures (50% RR), and adverse events were analyzed. RESULTS: The 50% RR in all 76 patients was 42%. The 50% RRs in the 54 patients with localization-related epilepsy and in the 20 patients with generalized epilepsy were 42% and 35%, respectively. The patients who responded most remarkably to the therapy, with at least a 75% reduction in the frequency of seizures, were more often those with localization-related epilepsy. Among adverse events, irritability and hyperactivity/impulsivity were observed more frequently in this study than in previous reports. These events were observed predominantly in patients suffering from autism or attention deficit hyperactivity disorder (AD/HD) as a comorbidity. γ-GTP values were improved in 14 of 17 patients whose values prior to beginning LEV treatment were higher than the normal range. This beneficial effect presumably resulted from a dose reduction or the discontinuation of other hepatotoxic antiepileptic drugs. CONCLUSIONS: LEV was useful for the treatment of refractory epilepsy, and long-term efficacy was demonstrated. LEV also appeared to be less hepatotoxic. Behavioral changes should be monitored carefully when LEV is administered to patients with concomitant autism or AD/HD.

Nationwide survey of Arima syndrome: revised diagnostic criteria from epidemiological analysis.

AIM: We have never known any epidemiological study of Arima syndrome since it was first described in 1971. To investigate the number of Arima syndrome patients and clarify the clinical differences between Arima syndrome and Joubert syndrome, we performed the first nationwide survey of Arima syndrome, and herein report its results. Furthermore, we revised the diagnostic criteria for Arima syndrome. METHODS: As a primary survey, we sent out self-administered questionnaires to most of the Japanese hospitals with a pediatric clinic, and facilities for persons with severe motor and intellectual disabilities, inquiring as to the number of patients having symptoms of Arima syndrome, including severe psychomotor delay, agenesis or hypoplasia of cerebellar vermis, renal dysfunction, visual dysfunction and with or without ptosis-like appearance. Next, as the second survey, we sent out detailed clinical questionnaires to the institutes having patients with two or more typical symptoms. RESULTS: The response rate of the primary survey was 72.7% of hospitals with pediatric clinic, 63.5% of national hospitals and 66.7% of municipal and private facilities. The number of patients with 5 typical symptoms was 13 and that with 2-4 symptoms was 32. The response rate of the secondary survey was 52% (23 patients). After reviewing clinical features of 23 patients, we identified 7 Arima syndrome patients and 16 Joubert syndrome patients. Progressive renal dysfunction was noticed in all Arima syndrome patients, but in 33% of those with Joubert syndrome. CONCLUSION: It is sometimes difficult to distinguish Arima syndrome from Joubert syndrome. Some clinicians described a patient with Joubert syndrome and its complications of visual dysfunction and renal dysfunction, whose current diagnosis was Arima syndrome. Thus, the diagnosis of the two syndromes may be confused. Here, we revised the diagnostic criteria for Arima syndrome.

[The effect of parent training program on children with attention deficit/hyperactivity disorders and/or pervasive developmental disorders].

Mothers of 18 children with attention deficit/hyperactivity disorders (AD/HD) and 6 with pervasive developmental disorders (PDD) underwent a parent training (PT) program. After the program, the Beck Depression Inventory- II (BDI - II) score, which indicates parenting stress, significantly decreased from 15 to 8 (p=0.036). A total of 22 mothers had increased parenting self-esteem, and better parent-child relationships were noted in these cases. An analysis of children's behavior by using Achenbach's Child Behavior Checklist showed that introversion tendency, physical failure, aggressive behavior, and extroversion score improved significantly after PT (p<0.05). After PT, out-of-control behaviors improved in 19 children and continued in 5. We conclude that PT for mothers of children with AD/HD and/or high-functioning PDD is effective in improving both the parenting skills of mothers and adaptive behaviors of children.

[Effect of topiramate for patients with intractable epilepsy].

The effects of topiramate (TPM) were evaluated in 51 patients with intractable epilepsy. Callosotomy and hemispherotomy were performed in 16 patients and one patient before the administration of TPM, respectively. The 50% responder rate (50%RR) was recorded in 39% of the total patient population and in 58% of patients with symptomatic location-related epilepsy (SLE). TPM was most effective for frontal lobe epilepsy (FLE), and the 50%RR was recorded in 88% of those patients. TPM (50%RR) was more effective in secondary generalized seizures (in 75%) and complex partial seizures (in 67%) in comparison to that of tonic-clonic seizures (in 44%) and drop attacks (in 29%). Seventy-one percent of the patients with atypical absence seizures increased seizure frequency. The 50%RR was recorded in 22% of the patients who underwent epilepsy surgery, and 29% of those patients also showed seizure aggravation due to TPM. These results suggest the efficacy of TPM for intractable epilepsy.

[Case of drug-induced hypersensitivity syndrome due to lamotrigine: demonstration of sequential reactivation of herpesviruses].

Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe multiorgan disorder. The reactivation of human herpesvirus-6 (HHV-6) and other human herpesviruses has been reported to be associated with its pathogenesis. We herein report a case of 14-year-old female who developed DIHS during the treatment with lamotrigine, a novel antiepileptic drug. She initially presented with fever, skin rash, cervical lymphadenopathy, leukocytosis with eosinophilia and atypical lymphocytosis, liver dysfunction and hypogammaglobulinemia. Discontinuation of the drug and administration of prednisolone led to improvement;however, tapering of prednisolone and administration of midazolam and ketamine thereafter triggered clinical deterioration. She subsequently developed hyperthyroidism followed by hypothyroidism. Herpesviral loads were determined in her peripheral blood by real-time PCR during the course of the treatment, and sequential reactivation of Epstein-Barr virus (EBV), HHV-6 and cytomegalovirus was demonstrated. EBV viremia was detected throughout the course, except for a short period when HHV-6 viremia was at the peak. HHV-6 viremia developed after the secondary deterioration. Cytomegalovirus viremia appeared transiently before the hyperthyroidic state reversed and became hypothyroidic. Although this syndrome should be regarded as a systemic reaction induced by a complex interplay among herpesviruses and the immune responses against viral infections and drugs, it remains unknown how such a sequential reactivation is related to the pathogenesis of the condition.

Novel mutations in the SIL1 gene in a Japanese pedigree with the Marinesco-Sjögren syndrome.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder. Mutation in the SIL1 gene accounts for the majority of MSS cases. However, some individuals with typical MSS without SIL1 mutations have been reported. In this study, we identified two novel mutations in a Japanese pedigree with MSS, one of which was an intragenic deletion not detected using the PCR-direct sequencing protocol. This family consisted of three affected siblings, an unaffected sibling and unaffected parents. We found a homozygous 5-bp deletion, del598-602(GAAGA), in exon 6 of all affected siblings by PCR. Thus, we expected that both parents would be heterozygous for the mutation. As expected, the father was heterozygous, whereas the mother demonstrated no mutations. We then carried out array comparative genomic hybridization and quantitative PCR analyses, and identified an approximately 58 kb deletion in exon 6 in the patients and mother. As a result, the mother was hemizygous for a 58-kb deletion. The affected siblings contained two mutations, a 5-bp and a 58-kb deletion, resulting in SIL1 gene dysfunction. It is possible that some reported cases of MSS without base alterations in the SIL1 gene are caused by deletions rather than locus heterogeneity.