Publications (16)27.23 Total impact
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Article: Influence of CYP2C19 Polymorphism and Concomitant Antiepileptic Drugs on Serum Clobazam and N-Desmethyl Clobazam Concentrations in Patients With Epilepsy.
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ABSTRACT: OBJECTIVE:: The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients. METHODS:: A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes. RESULTS:: The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (μg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (μg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively. CONCLUSIONS:: The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype.Therapeutic drug monitoring 05/2013; · 2.43 Impact Factor -
Article: [Sleepiness:a frequent adverse reaction of antiepileptic drugs in patients with epilepsy after encephalitis/encephalopathy].
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ABSTRACT: Patients with epilepsy after encephalitis/encephalopathy (EAE) are often on polytherapy with anti-epileptic drugs (AEDs), and are at risk of adverse reactions. We examined the adverse effects of AEDs, especially sleepiness, in these patients. In this retrospective study, the medical records of 66 patients who were diagnosed with EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 were also investigated. The mean onset age of acute encephalitis was 9 years and 1 month and the mean interval from onset of acute encephalitis to onset of epilepsy was 6.4 months. Sleepiness induced by AEDs was observed in 26 of 66 patients (39.3%). The incidence of sleepiness was high in patients treated with clorazepate (75%), lamotrigine (66.7%), and ethosuximide (40%). Comparing the AEDs used by more than 20 patients, the incidence of sleepiness was high for clonazepam (30.4%) and phenytoin (25.8%). IgG, protein, and albumin levels in cerebrospinal fluid were significantly higher in patients affected by sleepiness than in those not affected. IL-8 in cerebrospinal fluid was significantly higher in the group with sleepiness compared to that without. Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels were not different between the two groups. Long-lasting blood-brain barrier dysfunction and proliferation of immature vessels induced by IL-8 may contribute to the occurrence of sleepiness as an adverse effect of AEDs in patients with EAE. We recommend to assess for blood-brain barrier dysfunction when choosing AEDs for treating patients with intractable EAE.No to hattatsu. Brain and development 11/2012; 44(6):472-6. -
Article: Retinotomy with retinal turnover to remove subretinal membranes under direct visualization for proliferative vitreoretinopathy.
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ABSTRACT: The purpose of the study was to report the outcomes for cases of proliferative vitreoretinopathy (PVR) that received retinotomy and removal of subretinal proliferative tissue under direct visualization using retinal turnover. Nineteen eyes with posterior and/or anterior grade C1-12 PVR that had undergone retinotomy and retinal turnover were reviewed. Main outcomes included the retinal reattachment rate, final best-corrected visual acuity (BCVA), postoperative intraocular pressure, extent of retinotomy, and complications. Final retinal reattachment rates with silicone oil tamponade were 100%. The mean logarithm of the minimal angle of resolution (logMAR) BCVA was significantly improved (P = 0.001). Positive correlation was found between the extent of retinotomy and both preoperative logMAR BCVA (r = 0.663, P = 0.002) and postoperative logMAR BCVA (r = 0.619, P = 0.005). There was no correlation between the extent of retinotomy and the change in preoperative and postoperative logMAR BCVA (r = -0.267, P = 0.268). Negative correlation was found between preoperative logMAR BCVA and the change in logMAR BCVA (r = -0.587, P = 0.008). There was no correlation between the extent of retinotomy and the intraocular pressure at the final visit (r = -0.316, P = 0.188). Corneal decompensation due to silicone oil in the anterior chamber occurred in one eye. Removal of subretinal proliferative tissue with retinal turnover seems to be an effective procedure.Clinical Ophthalmology 01/2012; 6:781-8. -
Article: Self-induced seizures presumably by peri-orbital somatosensory self-stimulation: a report of two cases.
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ABSTRACT: Self-induced seizures by somatosensory stimulation are rare. We describe two epileptic patients with self-induced seizures presumably by peri-orbital somatosensory stimulation. Two infants with severely delayed psychomotor development and poor visual acuity after acute subdural hemorrhage in early infancy had been diagnosed as having West syndrome. They evolutionally became to show serial self-induced seizures preceded by rubbing eye with finger in one case and touching right eyebrow with the back of left hand in the other case. Video-electroencephalography (EEG) monitoring was useful to confirm self-induced seizure by peri-orbital self-stimulation. In patients with serial seizures preceded by peculiar behaviors, we need to consider the possibility of self-induced seizures, even if they have a history of West syndrome and severe psychomotor retardation.Brain & development 12/2011; 34(8):685-90. · 1.74 Impact Factor -
Article: Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis.
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ABSTRACT: Patients with epilepsy after encephalitis/encephalopathy (EAE) often have refractory seizures, resulting in polytherapy with the risk of adverse reactions due to anti-epileptic drugs (AEDs). We focused on the characteristics of cutaneous adverse reaction (CAR). In this retrospective study, the medical records of 67 patients who were diagnosed as having EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1 (s-TNFR 1), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in 22 patients. CARs attributed to AEDs were observed in 16 of 67 EAE patients (23.9%) (CAR group). High CAR rates were observed with phenytoin, lamotrigine, phenobarbital, and carbamazepine. Severe CARs were found in three of 67 patients (4.5%). The frequencies of CARs were significantly higher in patients with encephalitis onset older than five years of age. CAR occurred only in patients who had onset of EAE within 6 months after encephalitis. The durations from acute encephalitis to CARs were within one year for almost all AEDs, except lamotrigine. The proportion of patients with serumregulated on activation normal T cell expressed and secreted (RANTES) levels higher than the upper limit of normal range was significantly higher in CAR group than in non-CAR group. Patients in the early stage of EAE and patients with encephalitis onset older than five years of age may be at higher risk of CARs to AEDs, especially to phenytoin, lamotrigine, phenobarbital, and carbamazepine. RANTES may be a biomarker for susceptibility to CARs in EAE patients.Brain & development 10/2011; 34(6):496-503. · 1.74 Impact Factor -
Article: Lamotrigine is favourable for startle-induced seizures.
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ABSTRACT: Falling due to startle-induced seizures (SISs) often leads to injury. The triggers of SIS are mostly unexpected auditory stimuli, which are too common to avoid in daily life. As SISs are often refractory to conventional medications, effective therapeutic options have to be established. We report a small series of six patients treated with lamotrigine (LTG) as add-on therapy. Seizure control was improved greatly in three of the six patients, resulting in less restricted daily life, but no effect was observed in two and a skin rash developed in one. Patient 1 was a 19-year-old man. His seizure comprised of a sudden tonic extension of the extremities induced by auditory or visual stimulus. He fell down due to SISs, five to ten times a day, with frequent injuries. After adding LTG to treatment with valproate (VPA) and clobazam (CLB), SISs were reduced to once a month. Patient 2 was a 51-year-old woman. Sudden tonic extension of all limbs induced by unexpected sounds frequently threw her down onto the floor. Addition of LTG to treatment with CLB, zonisamide and phenytoin reduced her SISs from several to less than once a day. Patient 3 was a seven-year-old girl with post-encephalitic epilepsy. After adjunctive treatment of LTG to VPA, the severity of SISs became milder thus avoiding injury, although seizure frequency did not decrease. LTG is potentially effective for the treatment of SISs and may prevent falling. The addition of LTG treatment dramatically improved the lives of the patients presented here and should be considered as an option for startle-induced seizures.Epileptic disorders: international epilepsy journal with videotape 09/2011; 13(3):277-83. · 1.50 Impact Factor -
Article: CDKL5 alterations lead to early epileptic encephalopathy in both genders.
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ABSTRACT: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.Epilepsia 07/2011; 52(10):1835-42. · 3.96 Impact Factor -
Article: [Remarkable effect of a modified ketogenic diet in a boy with focal seizures followed by epileptic spasms in a cluster].
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ABSTRACT: A modified ketogenic diet was demonstrated to be remarkably effective in a child with intractable symptomatic focal epilepsy with combined seizures of focal seizures and epileptic spasms (ES) in a cluster (ESC). ES started at 8 months of age and disappeared with ACTH therapy. At the age of 13 months, the child began to have intractable focal seizures that, later, were followed by ESC 10 times a day. Brain MRI showed only a non-specific diffuse cerebral atrophy. Interictal EEG showed high amplitude diffuse disorganized slow waves with prominent sharp waves predominant over the bilateral occipital region. We started a modified ketogenic diet (mKD) treatment without fasting or a water/calorie limitation. Since the 20th day of mKD, the patient has been seizure free (6 months) without adverse effects. EEG showed remarkable improvement and he has some improvement in the developmental milestones. A modified ketogenic diet is easier to start and continue compared to the classic ketogenic diet, and should be tried in intractable epilepsies that are not treatable surgically early in life from the developmental prognosis point of view.No to hattatsu. Brain and development 07/2011; 43(4):305-8. -
Article: [Symptoms and clinical course of epilepsy with myoclonic absences].
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ABSTRACT: There is no comprehensive study so far in Japan on epilepsy with myoclonic absences (EMA), characterized by myoclonic absences (MA) as a specific seizure type. We retrospectively studied 9 patients (4 males and 5 females) with EMA confirmed by ictal video EEG and polygraph (EEG+EMG) recordings. The age at MA onset ranged from 18 to 92 months and the age at the last follow-up ranged from 3 to 39 years. The patients had IQ of 40 to 79. Eight patients had been free from seizures for more than one year at the last follow up. MA was controlled by valproate sodium monotherapy or combination of valproate sodium and ethosuximide with appropriate plasma levels. Generalized tonic clonic seizures and severe mental retardation were not necessarily associated with poor seizure outcome. Patients with long MA duration or MA status epilepticus were prone to be refractory to medication. EMA can be divided into two subgroups based on the seizure outcome, favorable and unfavorable. Further large-scale study is required.No to hattatsu. Brain and development 01/2011; 43(1):14-8. -
Article: HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients.
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ABSTRACT: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 with carbamazepine-induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA-B*1508, HLA-B*1511, or HLA-B*1521, which are members of the HLA-B75 type along with HLA-B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA-B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA-B*1502 carriers, four patients had HLA-B*1511. Our data suggest that HLA-B*1511, a member of HLA-B75, is a risk factor for carbamazepine-induced SJS/TEN in Japanese.Epilepsia 12/2010; 51(12):2461-5. · 3.96 Impact Factor -
Article: STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study.
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ABSTRACT: We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct-sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause.Epilepsia 12/2010; 51(12):2449-52. · 3.96 Impact Factor -
Article: [Antibodies to glutamate receptor in limbic encephalitis].
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ABSTRACT: N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR), is an important molecule, which contributes to the pathophysiological processes of various neurological diseases by various molecular mechanisms. Antibodies against NMDA-type GluR (NR) are detected by immunoblot analysis, enzyme-linked immunosorbent assay (ELISA), or immunocytochemical analysis (Dalmau's method). Immunoblot method uses whole molecules of GluRepsilon2 (NR2B), which are synthesized in NIH3T3 cells by using tetracycline system as antigens. In ELISA, synthesized peptides of each domain of GluRepsilon2 and GluRtheta1 (NR1) are used. Immunocytochemical method uses human embryonic kidney (HEK) cells transfected by expression vectors for NR1+NR2B/2A. In non-paraneoplastic, non-herpetic acute limbic encephalitis (NHALE), serum antibodies to GluRepsilon2 (NR2B) were detected in approximately 60% of the patients from acute to chronic stages further, these antibodies in the cerebrospinal fluid (CSF) were detected in 50% (acute stage), 40% (recovery stage), and 30% (chronic stage) of the patients. The antibodies against GluRepsilon2 seemed to increase in the sera after infection and infiltrate the central nervous system through the blood-brain barrier (BBB), which was damaged by cytokines, etc. The antibodies against GluRepsilon2 recognize broad regions of GluRepsilon2 as epitopes. In NHALE patients with ovarian teratoma, antibodies to NR recognize epitopes on GluRepsilon2 (NR2B) and GluRtheta1 (NR1). Pathophysiology of antibodies against NR is estimated to cause internalization of NR on surface of neurons, resulting in inhibition of NR function.Brain and nerve = Shinkei kenkyū no shinpo 08/2010; 62(8):827-37. -
Article: [Effectiveness of topiramate in eleven patients with Dravet syndrome].
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ABSTRACT: Dravet syndrome is a rare, but highly refractory epilepsy syndrome. As conventional drugs are not effective, introduction of new effective drugs in clinical use will benefit patients with this disease. We assessed the effectiveness of topiramate (TPM) as adjunctive therapy in 11 patients with Dravet syndrome. TPM was started at doses ranging from 10 to 50 mg/day (0.57 to 2.0 mg/kg/day), and the dosage was increased gradually up to the maximum dose (9 mg/kg/day) depending on efficacy and tolerability. The frequencies of convulsive seizures (generalized tonic-clonic seizures, unilateral seizures, partial onset generalized tonic-clonic seizures) during two months before starting TPM, two months after starting TPM, and the fifth and sixth months after starting TPM were determined. The mean dose (mean +/- SD) of TPM at the second month was 2.7 +/- 1.5 mg/kg/day (1.0-5.7 mg/kg/day, n= 11), and that at the sixth month was 4.5 +/- 2.2 mg/kg/day (1.0-7.3 mg/kg/day, n=10). Evaluation at the second month revealed that one of 11 patients (9%) became seizure-free, six patients (54%) showed greater than 50% seizure reduction, three patients (27%) showed less than 50% seizure reduction, and one patient (9%) had aggravation of convulsive seizures resulting in discontinuation of TPM at the first month. Evaluation at the sixth month revealed that one of 10 patients (10%) was seizure-free, seven patients (70%) had greater than 50% seizure reduction, two patients (20%) had less than 50% seizure reduction, and no patient (0%) had aggravation. Adverse effects were observed in five patients; dizziness in three patients, sleepiness in three patients, and oligohidrosis in one patient. In the present study, TPM was useful as an adjunctive therapy to reduce the frequency of convulsive seizures in patients with Dravet syndrome. A large-scale efficacy study of TPM for Dravet syndrome is warranted.No to hattatsu. Brain and development 07/2010; 42(4):273-6. -
Article: HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions.
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ABSTRACT: Carbamazepine (CBZ) is frequently used for treating epilepsy, but this drug causes cutaneous adverse drug reactions (cADRs) that may range from mild to severe. It is reported recently that the human leukocyte antigen HLA-B*1502 is associated with Stevens-Johnson syndrome (SJS) induced by CBZ in Han Chinese. We examined HLA class I in 15 Japanese patients who fulfilled the diagnostic criteria for CBZ-induced cADRs (mild in 10 and severe = SJS in 5). HLA-B*1518, HLA-B*5901 and HLA-C*0704 alleles showed higher relative risks (above 10.0) for severe cADRs. The haplotype (HLA-A*2402-B*5901-C*0102) had high relative risk (16.09) for severe cADRs. In patients with severe cADRs, frequencies of HLA-A*1101, HLA-A*3303, HLA-B*1501, HLA-B*4403, HLA-B*5101, HLA-B*5201, HLA-C*0702, and HLA-C*1202 alleles are relatively lower than in the Japanese population. These data may suggest that HLA-B*5901 is one of the candidate markers for CBZ-induced SJS in Japanese.Epilepsia 09/2009; 51(2):297-300. · 3.96 Impact Factor -
Article: HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis.
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ABSTRACT: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 and HLA-B*5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B*1502 and HLA-B*5801 in Japanese SJS/TEN patients. HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan. There were no HLA-B*1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B*5801 carriers, which included four allopurinol-related SJS/TEN patients. While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.Pharmacogenomics 12/2008; 9(11):1617-22. · 3.97 Impact Factor -
Article: [Autoantibodies against glutamate receptors in patients with encephalitis].
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ABSTRACT: We examined autoantibodies against GluRepsilon2 in patients with acute encephalitis, who were categorized into localized encephalitis and widespread encephalitis. Patients with localized encephalitis are defined as patients showing psychic symptoms (illusions, anxiety and distraction etc.), solitary seizures and/or very mild impairment of consciousness in the initial stage. Patients with widespread encephalitis are defined as patients showing a profound loss of consciousness and or convulsive status in the initial stage. In 24 patients with localized encephalitis, immunoglobulin (Ig) M autoantibodies against GluRepsilon2 tended to appear in CSF in the acute stage (0-20 days after onset of neurological symptoms) or recovery stage (21-60 days after onset of neurological symptoms) of encephalitis. In 22 patients with widespread encephalitis, IgM autoantibodies against GluRepsilon2 in CSF tended to appear in the recovery stage (21-60 days after onset of neurological symptoms) or chronic stage (>60 days after onset of neurological symptoms) of encephalitis. All patients with localized encephalitis had autoantibodies to the extracellular N epitope. However, no patients with widespread encephalitis had autoantibodies to the extracellular N epitope in acute stages. These data may suggest that GluR autoimmunity contributes to the onset of localized encephalitis.Rinsho shinkeigaku = Clinical neurology 12/2007; 47(11):848-51.
Top co-authors
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Institutions
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2012
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Osaka Medical Center and Research Institute for Maternal and Child Health
Izumi, Osaka-fu, Japan
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2007–2011
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National Epilepsy Center
Shizuoka-shi, Shizuoka-ken, Japan
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