Publications by authors named "Katsumi Imai"

117 Publications

Change in the pharmacokinetics of lacosamide before, during, and after pregnancy.

Seizure 2021 Mar 15;88:12-14. Epub 2021 Mar 15.

Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Shizuoka, 420-8688, Japan; Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan.

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http://dx.doi.org/10.1016/j.seizure.2021.03.011DOI Listing
March 2021

Pharmacokinetics, tolerability, and clinical effectiveness of perampanel in Japanese patients with epilepsy.

Seizure 2020 Dec 29;83:181-186. Epub 2020 Oct 29.

Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Shizuoka, 420-8688, Japan; Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan.

Objective: We aimed to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum perampanel concentration and to correlate the concentration with clinical response and tolerability.

Methods: A total of 4224 serum samples were obtained from 763 pediatric, adolescent, and adult patients for routine therapeutic drug monitoring. We compared the extent of enzyme induction between cytochrome P450 3A4 (CYP3A4) inducer regimens and built a statistical model to estimate the serum perampanel concentration that considered use of CYP3A4 inducers and inhibitors. To assess the tolerability and clinical effectiveness of perampanel therapy, we used the nested case-control approach. The case group was matched with the control group for age, sex, epilepsy type, and perampanel exposure periods.

Results: Concomitant use of the inducers phenytoin, carbamazepine, and phenobarbital dose-dependently reduced the perampanel concentration by 51 %, 67 %, and 37 %, respectively. The estimate model showed a good correlation between the predicted and measured concentrations (r = 0.62, p < 0.001). In 206 patients, the seizure reduction from baseline was > 50 % and the median perampanel concentration was 351 ng/mL (interquartile range, 191-603 ng/mL). Adverse events, such as somnolence, dizziness, and irritability, were experienced by 185 patients. The responder odds ratio was 5.1-fold higher in patients with a serum concentration > 600 ng/mL than in those with a serum concentration < 200 ng/mL; however, the former group had a 7.9-fold higher incidence of adverse events.

Conclusion: Therapeutic drug monitoring is clinically useful to assess drug interactions between perampanel and CYP3A4 inducers and inhibitors. We recommend that the target concentration of perampanel is initially set at 200-600 ng/mL. Serum concentrations > 600 ng/mL were associated with greater anti-seizure effects but had an increased risk of adverse events.
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http://dx.doi.org/10.1016/j.seizure.2020.10.017DOI Listing
December 2020

Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6-dependent Epilepsy Than Pyridoxal 5'-Phosphate.

Pediatr Neurol 2020 12 2;113:33-41. Epub 2020 Sep 2.

Department of Child Neurology, Okayama University Hospital, Okayama, Japan; Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid.

Methods: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations.

Results: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain.

Conclusions: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.08.020DOI Listing
December 2020

Therapeutic Monitoring of Lacosamide in Japanese Patients With Epilepsy: Clinical Response, Tolerability, and Optimal Therapeutic Range.

Ther Drug Monit 2020 10;42(5):754-759

Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama.

Background: Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects.

Methods: The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records.

Results: In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. By contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 mcg/mL (26.4 μmol/L) and 8.4 mcg/mL (33.6 μmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 μmol/L) and 7.5 mcg/mL (30 μmol/L), respectively.

Conclusions: Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.
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http://dx.doi.org/10.1097/FTD.0000000000000764DOI Listing
October 2020

Food intake and dietary patterns that affect urinary sodium excretion in young women.

J Clin Hypertens (Greenwich) 2020 06 7;22(6):1090-1097. Epub 2020 Jun 7.

Health Promotion Center, Nakamura Gakuen University, Fukuoka, Japan.

We aimed to clarify food intake and dietary patterns that affect urinary sodium excretion (urinary salt excretion) among young women. We used 2012 to 2018 data from the health and nutrition testing on admission, which is a part of ongoing epidemiological studies, for students enrolling in the Faculty of Nutrition Science, Nakamura Gakuen University. Fasting urine samples were collected from the participants, and their estimated daily salt excretion was calculated using the Tanaka equation. The dietary assessment used was the semi-quantitative food frequency questionnaire, and we confirmed its validity. The participants included 2218 women aged 18 to 20 years who were classified into four groups according to urinary salt excretion (g/d) from their spot urine: Q , <5.56; Q , 5.56≤, <6.79; Q , 6.79≤, <8.12; and Q , 8.12<. The high urinary salt group had a significantly higher consumption of oil and fat, fish, meat, eggs, soybean, green and yellow vegetables, white vegetables, seaweeds, and pickled vegetables compared with the low urinary salt groups. When we compared the differences of the quartiles for urinary sodium excretion and the factor loadings for three dietary patterns by factor analysis with varimax rotation, the high urinary salt group showed a higher tendency for Japanese dietary patterns of factor 1 compared with the low urinary salt group. In conclusion, the various foods, including foods containing proteins and vegetables and Japanese dietary pattern centering on fish, vegetables, soybeans, and seaweed, affected the urinary sodium excretion in young women.
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http://dx.doi.org/10.1111/jch.13906DOI Listing
June 2020

Methylprednisolone pulse therapy in 31 patients with refractory epilepsy: A single-center retrospective analysis.

Epilepsy Behav 2020 08 6;109:107116. Epub 2020 May 6.

National Epilepsy Center, NHO, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.

Purpose: We investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy.

Methods: We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum-albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥50% for three months after the first course of MP.

Results: Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01).

Conclusion: Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.
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http://dx.doi.org/10.1016/j.yebeh.2020.107116DOI Listing
August 2020

Identification of new biomarkers of pyridoxine-dependent epilepsy by GC/MS-based urine metabolomics.

Anal Biochem 2020 09 24;604:113739. Epub 2020 Apr 24.

Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.

α-Aminoadipic semialdehyde and its cyclic form (Δ-piperideine-6-carboxylate) accumulate in patients with α-aminoadipic semialdehyde dehydrogenase (AASADH; antiquitin; ALDH7A1) deficiency. Δ-Piperideine-6-carboxylate is known to react with pyridoxal 5'-phosphate (PLP) to form a Knoevenagel condensation product, resulting in pyridoxine-dependent epilepsy. Despite dramatic clinical improvement following pyridoxine supplementation, many patients still suffer some degree of intellectual disability due to delayed diagnosis. In order to expedite the diagnosis of patients with suspected AASADH deficiency and minimize the delay in treatment, we used gas chromatography-mass spectrometry-based metabolomics to search for potentially diagnostic biomarkers in urine from four patients with ALDH7A1 mutations, and identified Δ-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as candidate biomarkers. In a patient at postnatal day six, but before pyridoxine treatment, Δ-piperideine-6-carboxylate and pipecolate were present at very high concentrations, indicating that these compounds may be good biomarkers for untreated AASADH deficiency patients. On the other hand, following pyridoxine/PLP treatment, 6-oxopipecolate was shown to be greatly elevated. We suggest that noninvasive urine metabolomics screening for Δ-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate will be useful for prompt and reliable diagnosis of AASADH deficiency in patients within any age group. The most appropriate combination among Δ-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as biomarkers for AASADH deficiency patients appears to depend on the age of the patient and whether pyridoxine/PLP supplementation has been implemented. We anticipate that the present bioanalytical information will also be useful to researchers studying glutamate, proline, lysine and ornithine metabolism in mammals and other organisms.
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http://dx.doi.org/10.1016/j.ab.2020.113739DOI Listing
September 2020

Verbal function recovery in a postoperative case with epileptic encephalopathy.

Pediatr Int 2020 Mar;62(3):412-414

NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka-shi, Shizuoka, Japan.

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http://dx.doi.org/10.1111/ped.14087DOI Listing
March 2020

Prevalence and risk factors for hyponatremia in adult epilepsy patients: Large-scale cross-sectional cohort study.

Seizure 2019 Dec 23;73:26-30. Epub 2019 Oct 23.

Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan.

Purpose: To evaluate the risk factors and prevalence of hyponatremia among epilepsy patients in relation to use of antiepileptic drugs (AEDs).

Methods: We retrospectively reviewed 14,620 adult patients (aged 18-103 years) and classified them into the following 3 groups: patients without AED treatment (n = 2165, Group I), patients receiving antiepileptic drugs other than carbamazepine (n = 7442, Group II), and patients treated with carbamazepine (n = 5013, Group III). This study did not include the patients receiving oxcarbazepine or eslicarbazepine acetate because these AEDs are not marketed in Japan. Severe hyponatremia was defined as a serum sodium level < 130 mEq/L.

Results: In Groups I, II, and III, the mean sodium level was 140, 139, and 137 mEq/L, respectively. The highest frequency of severe hyponatremia was observed in Group III (7%), and it was much higher than in Group I (0.8%) or Group II (1.2%). In Groups II and III, old age, low body weight, and concomitant use of phenobarbital, benzodiazepines, or antipsychotics were risk factors for hyponatremia. In Group III, the sodium level decreased as the carbamazepine dose increased. At a carbamazepine dose exceeding 600 mg/day, there was 10.9-fold higher prevalence of hyponatremia, and the risk was potentiated by concomitant use of valproate.

Conclusion: The serum sodium level should be monitored carefully when patients are receiving AED polypharmacy combined with antipsychotics. In particular, concomitant administration of valproate enhances the risk of hyperammonemia in patients receiving carbamazepine. These findings may help clinicians to avoid hyponatremia in patients with epilepsy.
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http://dx.doi.org/10.1016/j.seizure.2019.10.013DOI Listing
December 2019

Impact of CYP2C19 Phenotypes on Clinical Efficacy of Stiripentol in Japanese Patients With Dravet Syndrome.

Ther Drug Monit 2020 04;42(2):302-308

Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders.

Background: Stiripentol is a strong inhibitor of CYP2C19 and CYP3A4. This study compared the effect of stiripentol on the pharmacokinetics of clobazam and N-desmethyl-clobazam (NCLB; an active metabolite of clobazam) between different CYP2C19 phenotypes. We also evaluated the clinical impact of CYP2C19 phenotypes in Japanese patients with Dravet syndrome receiving a combination of valproic acid, clobazam, and stiripentol.

Methods: We retrospectively reviewed 241 blood samples from 64 patients (aged 1-40 years) and calculated the concentration/dose (CD) ratio [serum level (ng/mL) divided by dose (mg/kg)] for clobazam and NCLB. Based on their CYP2C19 genotypes, patients were classified as extensive metabolizers (EM group: CYP2C19*1/*1, *1/*2, or *1/*3) or poor metabolizers (PM group: CYP2C19*2/*2, *3/*3, or *2/*3). We also reviewed the clinical records of 56 patients who commenced stiripentol therapy and calculated the retention rate for stiripentol therapy over an observation period of 208 weeks.

Results: Concomitant administration of stiripentol led to a marked increase in the CD ratio of clobazam (1.8-fold in the EM group and 1.5-fold in the PM group). In addition, stiripentol increased the CD ratio of NCLB by 6.6-fold in the EM group, but decreased it by 0.7-fold in the PM group. The estimated retention rate with stiripentol therapy was higher, and the duration of retention was longer in the EM group than in the PM group (1378 versus 933 days, P < 0.001). In patients with the PM phenotype, the adjusted hazard ratio for ceasing stiripentol therapy was 6.7 (95% confidence interval: 1.8-24.7, P < 0.005).

Conclusions: The effect of stiripentol on the pharmacokinetics of NCLB was significantly different between patients with the EM and PM phenotypes, which could influence the clinical response of Japanese patients with Dravet syndrome receiving the combination of valproic acid, clobazam, and stiripentol.
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http://dx.doi.org/10.1097/FTD.0000000000000676DOI Listing
April 2020

Corrigendum to "Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome" [Epilepsy Res. 154 (2019) 34-38].

Epilepsy Res 2019 Oct 27;156:106158. Epub 2019 Jun 27.

NHO Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka-shi, Shizuoka 420-8688, Japan.

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http://dx.doi.org/10.1016/j.eplepsyres.2019.106158DOI Listing
October 2019

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders.

Brain Dev 2019 Oct 4;41(9):776-782. Epub 2019 Jun 4.

Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.

Background: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders.

Methods: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM).

Results: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1.

Conclusion: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.
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http://dx.doi.org/10.1016/j.braindev.2019.05.007DOI Listing
October 2019

Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome.

Epilepsy Res 2019 08 21;154:34-38. Epub 2019 Apr 21.

NHO Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka-shi, Shizuoka 420-8688, Japan.

Purpose: In the present study, we aimed to investigate the efficacy and tolerability of perampanel in patients with Dravet syndrome.

Methods: We retrospectively reviewed data regarding seizure frequency and adverse effects in 10 patients (four boys, six girls) with Dravet syndrome following treatment with perampanel. Perampanel treatment was considered effective when seizure frequency had been reduced by more than 50%.

Results: The mean age of patients at perampanel introduction was 11.5 ± 2.2 years. Seizure types were as follows: generalized tonic-clonic seizure (n = 8), unilateral clonic seizure (n = 6), myoclonic seizure (n = 3), atypical absence seizure (n = 3), and focal impaired awareness seizure (n = 1). The average number of concomitant anti-epileptic drugs (AEDs) was 3 ± 0.9. The mean duration of perampanel use was 11.1 ± 3.8 months. Seizure frequency was reduced by more than 50% in five patients (50%). The efficacy of perampanel for each seizure type was as follows: generalized tonic-clonic seizure: 50% (4/8), unilateral clonic seizure: 50% (3/6), myoclonic seizure: 33% (1/3), atypical absence seizure: 33% (1/3), and focal impaired awareness seizure: 100% (1/1). The effects of perampanel in each patient occurred between 3 and 6 months following the initiation of treatment. Seizure reduction was observed beginning at perampanel doses of 0.1 ± 0.07 mg/kg/day. Adverse events were observed in seven of 10 patients. Although somnolence was noted in 50% of patients, most events were mild.

Conclusions: The results of this retrospective observational study indicate that perampanel treatment may be promising in some patients with Dravet syndrome. Additional studies are necessary to verify the actual efficacy of perampanel for Dravet syndrome.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.02.014DOI Listing
August 2019

Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations.

Epileptic Disord 2019 Feb;21(1):48-54

National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka.

Several recent studies have reported potassium sodium-activated channel subfamily T member 1 (KCNT1) mutations in epilepsy patients on quinidine therapy. The efficacy and safety of quinidine for epilepsy treatment, however, remains controversial. We herein report the cases of four patients with KCNT1 mutations treated with quinidine. A reduction in seizures of more than 50% after quinidine treatment was observed in one patient with epilepsy of infancy with migrating focal seizures (EIMFS), whereas two patients with EIMFS and one with focal epilepsy did not achieve apparent seizure reduction. The relationship between quinidine dose and serum quinidine concentration was inconsistent, particularly at high quinidine doses. One patient with EIMFS developed ventricular tachycardia the day after an increase in quinidine dose from 114 to 126 mg/kg/day. The serum trough quinidine concentration and the corrected QT interval (QTc) before arrhythmia onset were 2.4 μg/ml and 420 ms, respectively, and peak serum quinidine concentration after arrhythmia onset was 9.4 μg/ml. Another patient with EIMFS showed aberrant intraventricular conduction with a quinidine dose of 74.5 mg/kg/day and a serum trough concentration of 3.2 μg/ml. Given that serum quinidine levels may elevate sharply after a dose increase, careful monitoring of electrocardiographs and serum concentrations is required. Based on a review of previous reports and our experience with this case, quinidine should be considered as a promising drug for patients with EIMFS harbouring KCNT1 mutations, however, its efficacy remains controversial due to the limited number of cases, and more information on optimal serum concentrations and appropriate titration methods is required.
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http://dx.doi.org/10.1684/epd.2019.1026DOI Listing
February 2019

Different types of suppression-burst patterns in patients with epilepsy of infancy with migrating focal seizures (EIMFS).

Seizure 2019 Feb 18;65:118-123. Epub 2019 Jan 18.

National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka-shi, Shizuoka, 420-8688, Japan.

Purpose: In rare cases, patients with epilepsy of infancy withmigrating focal seizures (EIMFS) exhibit suppression-burst (SB) patterns on electroencephalography (EEG), similar to the findings observed in patients with Ohtahara syndrome and early myoclonic encephalopathy. In this report, we discuss six cases of EIMFS in which patients exhibited two types of SB patterns.

Methods: We evaluated six patients with EIMFS who had been admitted to the NHO Shizuoka Institute of Epilepsy and Neurological Disorders between 2011 and 2018. We retrospectively examined clinical characteristics and EEG findings for each patient. In all patients, the first EEG was performed within 1 month after seizure onset. Afterwards, EEG examinations were performed at irregular intervals (ranging from 1 to 5 months).

Results: Age at seizure onset ranged from 2 days to 3 months. SB was first detected within 1 month of age in two patients, and within the range of 3-14 months in the remaining four patients. Among the latter four patients, SB patterns persisted at the final EEG recording in three patients (34-54 months). In all patients, SB patterns were observed during sleep only. Interhemispheric asynchrony in SB was observed in the two patients who exhibited SB within 1 month of age, while synchronous SB patterns were observed in the remaining four patients.

Conclusions: Our findings indicate that EIMFS may be associated with two types of SB patterns (early-onset and late-onset), which can be distinguished based on the stage of emergence and level of synchrony.
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http://dx.doi.org/10.1016/j.seizure.2019.01.009DOI Listing
February 2019

Phenotypic features of 1q41q42 microdeletion including WDR26 and FBXO28 are clinically recognizable: The first case from Japan.

Brain Dev 2019 May 8;41(5):452-455. Epub 2019 Jan 8.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Tokyo Women's Medical University Institute of Integrated Medical Sciences, Tokyo, Japan. Electronic address:

1q41q42 microdeletion syndrome has been established in 2007. Since then, more than 17 patients have been reported so far. The reported deletions showed random breakpoints and deletion regions are aligned as roof tiles. Patients with 1q41q42 microdeletion syndrome show intellectual disability, seizures, and distinctive features. Many genotype-phenotype correlation studies have been performed and some genes included in this region have been suggested as potential candidate genes. Recently, de novo variants in WDR26 and FBXO28 were identified in patients who showed consistent phenotypes with 1q41q42 microdeletion syndrome. Thus, both genes are now considered as the genes possibly responsible for 1q41q42 microdeletion syndrome. Here, the first case of a Japanese patient with a de novo 1q41q42 microdeletion is reported. Owing to the distinctive features, this syndrome would be clinically recognizable.
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http://dx.doi.org/10.1016/j.braindev.2018.12.006DOI Listing
May 2019

Chronic dysfunction of blood-brain barrier in patients with post-encephalitic/encephalopathic epilepsy.

Seizure 2018 Dec 13;63:85-90. Epub 2018 Nov 13.

Department of Pediatrics, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO, Shizuoka, Japan.

Purpose: This study aimed to elucidate the characteristics and effects of chronic blood-brain barrier (BBB) dysfunction in patients with post-encephalitic/encephalopathic epilepsy (PEE), using brain images and the cerebral spinal fluid (CSF)/serum albumin ratio (albumin quotient, QAlb) as a marker of BBB function.

Methods: We examined the albumin levels in CSF and serum samples from 312 patients with refractory epilepsy in our center between 2004 and 2015. Sixty samples from patients with PEE and 97 samples from age- and sex-matched disease controls (DC) were evaluated. We classified PEE patients into a widespread lesion group and a focal lesion group by severity on brain magnetic resonance images in the chronic phase after acute encephalitis/encephalopathy.

Results: Median QAlb was higher in PEE than in DC [median (range) ×10: PEE 3.6 (1.0-10.3) versus DC 2.7 (1.0-6.7), p = 0.007]. In a linear regression analysis of the relationship between QAlb and patient's age at CSF examination or duration of epilepsy, the slope of the regression line was greater in PEE than in DC. Furthermore, in patients under ten years of age, linear regression analysis of QAlb versus seizure frequency showed a weak but positive correlation. Among PEE patients, seizure frequency was higher in the widespread lesion group than in the focal lesion group [300 (4-3000) versus 30 (1-1500) seizures/month, p <  0.001].

Conclusion: Our study suggests that patients with PEE have more severe BBB dysfunction, and that the BBB dysfunction is associated with refractory epilepsy.
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http://dx.doi.org/10.1016/j.seizure.2018.11.005DOI Listing
December 2018

Influence of Inflammation on the Pharmacokinetics of Perampanel.

Ther Drug Monit 2018 12;40(6):725-729

Department of Clinical Research, National Epilepsy Center, NHO, Shizuoka Institute of Epilepsy and Neurological Disorders.

Background: It is well-known that the pharmacokinetics of various drugs are influenced by inflammation. This study evaluated the relationship between C-reactive protein (CRP; an inflammation marker) and the pharmacokinetics of perampanel.

Methods: Among 111 patients who underwent measurement of both CRP and perampanel, 23 patients had a serum CRP level exceeding 1.5 mg/dL (CRP-positive). We compared the concentration/dose ratio (CD ratio) of perampanel in these 23 patients between the times when they were CRP-positive and CRP-negative. To evaluate the effect of CRP on the CD ratio, multiple regression analysis was performed with the following covariates: CRP-positive status, body weight, and use of phenytoin, carbamazepine, or phenobarbital, and combinations of these drugs.

Results: In 10 patients using enzyme-inducing antiepileptic drugs (AEDs), the mean CD ratio increased by 53.5% [from 1389 to 2132 (ng/mL)/(mg/kg)] when they were CRP-positive. In 13 patients without enzyme-inducing AEDs, the mean CD ratio increased by 100.8% [from 3826 ng/mL to 7683 (ng/mL)/(mg/kg)] when they were CRP-positive. By multiple regression analysis, the CRP level was a significant independent determinant of the CD ratio of perampanel. Despite a marked increase of the CD ratio, no adverse events were reported.

Conclusions: Irrespective of concomitant administration of enzyme-inducing AEDs, the serum perampanel concentration showed a marked increase in patients with inflammation. However, this increase was not associated with central nervous system toxicity. Although it is unknown whether the concentration of free and/or bound perampanel was increased, it seems likely that dose reduction is unnecessary for elevation of the serum perampanel level in patients with inflammation.
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http://dx.doi.org/10.1097/FTD.0000000000000556DOI Listing
December 2018

Independent occurrence of de novo and variants in brothers with different neurological disorders - leukodystrophy and autism.

Hum Genome Var 2018 19;5:18. Epub 2018 Jul 19.

4Department of Genetics, Yokohama City University, Yokohama, Japan.

Consecutive occurrence of de novo variants in the same family is an extremely rare phenomenon. Two siblings, a younger brother with hypomyelinating leukodystrophy and an elder brother with severe intellectual disability and autistic features, had independent de novo variants of c.139T > G (p.Leu47Val) and c.1393G > A (p.Glu465Lys), respectively. These novel variants were predicted to be pathogenic. Both patients also had a known variant, c.499C > T (p.Arg167Trp).
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http://dx.doi.org/10.1038/s41439-018-0020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053359PMC
July 2018

Risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia.

Brain Dev 2019 Jan 31;41(1):77-84. Epub 2018 Jul 31.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, NHO, Shizuoka, Japan.

Objective: The purpose of this study was to identify the risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia (FCD).

Methods: 77 patients with histopathologically confirmed FCD were studied. The statistical relationship between cognition levels and clinical factors at presurgical evaluation was analyzed. Cognitive function was evaluated by development quotient or intelligence quotient (DQ-IQ).

Results: Ages at seizure onset were younger than 15 years (mean ± SD; 5.0 ± 4.2 years). Mean disease duration was 14.5 ± 8.5 years. Mean age at pre-surgical DQ-IQ evaluation was 34.8 ± 10.7 years. Mean DQ-IQ was 60.5 ± 20.5, and 41 of 77 (53.2%) patients had mental retardation (DQ-IQ < 70). Younger seizure onset and seizure clustering were significantly associated with lower DQ-IQ (p < 0.001). A multiple regression study identified higher seizure frequency pattern, a history of epileptic spasm and status epilepticus as aggravating factors of DQ-IQ decline (R = 0.63, p < 0.001). On the other hand, the risk was decreased in patients with habitual focal aware seizure and transient seizure-free periods up to 6 months in the course of epilepsy. FCD location (FCD site, extent of radiological lesion and laterality) and histopathology of FCD did not affect DQ-IQ.

Conclusions: Our study suggests that seizure characteristics including higher seizure frequency pattern, a history of epileptic spasm, status epilepticus, seizure clustering and early onset of seizure are risk factors of cognitive impairment in FCD patients.
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http://dx.doi.org/10.1016/j.braindev.2018.07.014DOI Listing
January 2019

Successful hemispherotomy in two refractory epilepsy patients with cerebral hemiatrophy and contralateral EEG abnormalities.

Brain Dev 2018 Aug 15;40(7):601-606. Epub 2018 Mar 15.

Department of Psychiatry, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.

We describe two cases of refractory epilepsy with cerebral hemiatrophy and contralateral electroencephalographic (EEG) abnormalities, in which hemispherotomy of the atrophic hemisphere effectively controlled seizures. Case 1 was a 5-year-1-month-old girl with refractory bilateral asymmetrical tonic posturing seizures predominantly in the right arm. Magnetic resonance imaging showed left porencephaly corresponding to a left middle cerebral artery infarction. Case 2 was a 3-year-8-month-old boy with refractory bilateral asymmetrical tonic posturing seizures predominantly in the right arm due to atrophy of the left cerebral hemisphere after septic meningitis. Both patients had right hemiparesis and was incapable of pinching by the right hand. Contralateral interictal and ictal EEG abnormalities were observed. Interictal Tc-ethyl cysteinate dimer (Tc-ECD) single photon emission computed tomography (SPECT) showed hypoperfusion and ictal Tc-ECD-SPECT showed hyperperfusion within the left cerebral hemisphere. Left hemispherotomy was performed. Cases 1 and 2 remained seizure-free at the last follow-up 18 months and 15 months, respectively, after surgery, and contralateral interictal EEG abnormalities disappeared. In patients with cerebral hemiatrophy and contralateral EEG abnormalities, epilepsy surgery may be considered when the laterality of seizure semiology, functional imaging findings and motor deficits were concordant with the atrophic side. Ictal SPECT is effective to confirm the epileptogenic hemisphere.
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http://dx.doi.org/10.1016/j.braindev.2018.02.014DOI Listing
August 2018

Relationship between plasma protein S levels and apolipoprotein C-II in Japanese middle-aged obese women and young nonobese women.

Blood Coagul Fibrinolysis 2018 Jan;29(1):39-47

Graduate School of Health and Nutrition Sciences, Nakamura Gakuen University.

: Protein S, a nonenzymatic cofactor to activated protein C, presents in two forms in plasma, free form and in a complex with C4b-binding protein. The aim of this study was to determine the association of plasma protein S levels with the variables related to cardiovascular disease risk. The relationships between plasma protein S levels with lipids, inflammation markers, and adiposity were first examined on middle-aged obese women (n = 62), then on young nonobese women (n = 160) to verify the findings in the obese women. Total and free protein S antigen levels in middle-aged obese women, approximately half being in a postmenopausal state and suffered from dyslipidemia, correlated negatively with estradiol and positively with triglycerides, total cholesterol, LDL cholesterol, apoA-II, apoB, apoC-II, apoC-III, apoE, hemoglobin A1c, and protein C, whereas there was no correlation with HDL cholesterol, apoA-I, BMI, visceral fat area, blood pressure, or factor VII activity. Multiple linear regression analyses revealed that protein C, apoC-II, and fibrinogen were significant predictors of total protein S antigen levels, accounting for 51.9% of variance, and apoC-II as a singular significant predictor for free protein S antigen levels (12.3% of variance). In young nonobese women, most being normolipidemic, apoC-II was also selected as a significant predictor of total protein S antigen levels, but not of free protein S antigen levels. The positive relationship between plasma protein S levels and apoC-II, a key regulator of triglycerides hydrolysis, may contribute to the pathogenesis of increased concentrations of plasma protein S.
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http://dx.doi.org/10.1097/MBC.0000000000000662DOI Listing
January 2018

Ketogenic diet using a Japanese ketogenic milk for patients with epilepsy: A multi-institutional study.

Brain Dev 2018 Mar 26;40(3):188-195. Epub 2017 Nov 26.

Department of Pediatrics, Tokyo Women's Medical University, Japan.

Background: In Japan, Meiji 817-B (M817-B), a powdered ketogenic milk, has been available since the ketogenic diet was introduced to infants and tube-fed children with medication-resistant epilepsy in the 1980s.

Methods: We retrospectively evaluated the efficacy, tolerability, and side effects of the ketogenic diet using M817-B as the main source of daily food intake for patients with epilepsy by sending questionnaires to the members of a subcommittee of the Japan Epilepsy Society that focuses on the proper use of M817-B.

Results: A total of 42 patients were enrolled. Age at the initiation of the diet therapy ranged from 3 to 244 months (median, 32.5 months). Thirty-four patients were fed via tube, and the remaining 8 were fed orally. About 93% of patients were able to continue the diet for 1 month, 74% for 3 months, and 64% for 6 months. The median period of continuation was 16 months. One patient was able to continue as long as 7 years. The ketogenic ratio was maintained at about 3.0. The seizure-free rate and responder (>50% seizure reduction) rate were about 10% and 30-40%, respectively during the 12 months on the diet. Mean serum beta-hydroxybutyrate increased to almost 4 mM at 1 month and was maintained during the diet period. Side effects, which required discontinuation of the diet therapy, occurred in 11 of 42 patients and included hypertonia, weight loss, vomiting, hypoglycemia, metabolic acidosis, and hypokalemia.

Conclusion: M817-B could be used long-term with demonstrated efficacy in seizure reduction, although there are some side effects that may require cessation of the diet therapy.
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http://dx.doi.org/10.1016/j.braindev.2017.11.003DOI Listing
March 2018

Influence of Renal Function on Pharmacokinetics of Antiepileptic Drugs Metabolized by CYP3A4 in a Patient With Renal Impairment.

Ther Drug Monit 2018 02;40(1):144-147

Department of Clinical Research, National Epilepsy Center, NHO, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

Background: Several studies have demonstrated that renal impairment not only decreases renal clearance but also hepatic clearance of medications that are CYP3A4 substrates. We evaluated the influence of renal function on the pharmacokinetics of antiepileptic drugs metabolized by CYP3A4.

Methods: We retrospectively calculated the concentration/dose ratio (CD ratio) for topiramate and clobazam in an epilepsy patient with renal impairment. In addition, we determined the CD ratio of perampanel in 17 patients with normal renal function and compared it with that in the patient with renal impairment.

Results: A patient with frontal lobe epilepsy and mild renal impairment [creatinine clearance (CCr): 67.7 mL/min] was taking phenytoin and 3 CYP3A4 substrates (topiramate, clobazam, and perampanel). With progression of renal impairment (CCr: 28.1 mL/min), the CD ratios of topiramate and clobazam increased by about 2-fold. The mean CD ratio of perampanel was 1740 ± 966 ng·mL·mg·kg in the 17 patients with normal renal function using phenytoin. By contrast, the CD ratio of perampanel was markedly higher (range: 5327-9113 ng·mL·mg·kg) in the patient with renal impairment (CCr: <20 mL/min).

Conclusions: These findings suggest that dose adjustment based on therapeutic drug monitoring is probably necessary when topiramate, clobazam, or perampanel is prescribed for patients with moderate-to-severe renal impairment.
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http://dx.doi.org/10.1097/FTD.0000000000000461DOI Listing
February 2018

Ictal single photon emission computed tomographic study of myoclonic absence seizures.

Brain Dev 2018 Feb 17;40(2):126-129. Epub 2017 Aug 17.

Epilepsy Centre, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.

Background: Epilepsy with myoclonic absences (EMAs) is a rare epileptic disorder characterized by a predominant type of seizures, myoclonic absences (MAs). The pathophysiology of MAs in patients with EMAs remains unknown. Here, we report the first characterization of the ictal phase of MAs by single photon emission computed tomography (SPECT).

Methods: We evaluated 1 male (Patient 1) and 1 female (Patient 2) patient with EMAs, aged 8 and 4years at first SPECT investigation, respectively. We performed ictal and interictal Tc-ethyl cysteinate dimer (ECD) SPECT. We then generated images of subtraction ictal SPECT co-registered to MRI (SISCOM) from the interictal and ictal data to evaluate topographic changes in cerebral blood flow (CBF) during MAs as compared to the interictal state.

Results: In Patient 1, the CBF increased in the perirolandic areas, thalamus, caudate nucleus, and precuneus, and decreased in the middle frontal gyrus and bilateral orbitofrontal regions. In Patient 2, CBF increased in the thalamus, putamen, and globus pallidus. In contrast to the CBF in Patient 1, CBF was decreased in the precuneus.

Conclusions: Using SPECT, we showed that, in addition to the thalamus and basal ganglia, the perirolandic cortical motor area is involved in MAs. We hypothesize that in MAs the blood perfusion in the perirolandic cortical motor area might have changed under the influence of the cortico-thalamic network oscillation features. The CBF properties observed by means of our SPECT procedure may represent key features of the pathophysiological mechanisms underlying MAs.
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http://dx.doi.org/10.1016/j.braindev.2017.07.013DOI Listing
February 2018

Therapeutic Drug Monitoring for Perampanel in Japanese Epilepsy Patients: Influence of Concomitant Antiepileptic Drugs.

Ther Drug Monit 2017 08;39(4):446-449

*Department of Clinical Research, National Epilepsy Center, NHO, Shizuoka Institute of Epilepsy and Neurological Disorders;†Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka; and‡Laboratory of Clinical Pharmacokinetics and Drug Safety, Shizuoka General Hospital, Shizuoka, Japan.

Background: Perampanel is a new antiepileptic drug (AED) that acts as a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist and is mainly metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the influence of concomitant AEDs on the serum concentration profile of perampanel.

Methods: A total of 215 serum samples obtained from 76 patients aged 12 years or older were analyzed for routine therapeutic drug monitoring, and the concentration-to-dose ratio (CD ratio) of perampanel was compared among patients on various AED regimens.

Results: In patients not taking concomitant enzyme-inducing AEDs, the mean CD ratio was 3963 ng·mL·mg·kg (range: 1793-13,299). By contrast, the mean CD ratio was lower in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473-1853) ng·mL·mg·kg in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P < 0.001). Twenty-one patients responded with ≥50% reduction of seizure frequency from baseline, and their mean serum perampanel concentration was 450 ng/mL (range: 85-1500).

Conclusions: There is a large interindividual variation in CD ratio of perampanel because its metabolism is highly susceptible to interactions with enzyme-inducing AEDs. Therapeutic drug monitoring could be clinically useful for determining the influence of AED CYP3A4 inducers on perampanel concentrations.
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http://dx.doi.org/10.1097/FTD.0000000000000416DOI Listing
August 2017

Interannual study of spot urine-evaluated sodium excretion in young Japanese women.

J Clin Hypertens (Greenwich) 2017 Jul 23;19(7):653-660. Epub 2017 May 23.

Health Promotion Center, Nakamura Gakuen University, Fukuoka, Japan.

The authors investigated interannual differences in the sodium excretion levels of young healthy Japanese women as estimated from spot urine analysis at Nakamura Gakuen University from 1995 to 2015. Participants included 4931 women aged 18 to 20 years who were classified into three time periods according to year of health check: first (1995-2001), second (2002-2007), and third (2008-2015). Estimated daily urinary sodium and potassium excretion levels and the sodium to potassium ratio were 120.6±31.9 mmol, 35.2±8.1 mmol, and 3.5±0.9, respectively. Adjusted for body weight, sodium excretion, and potassium excretion significantly decreased in the second and third period compared with the first period (P<.001). Systolic blood pressure also decreased in the same way between time periods (P<.001). Estimated urinary excretion levels of sodium and potassium in young Japanese women have decreased over the past 20 years independently of body weight.
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http://dx.doi.org/10.1111/jch.13025DOI Listing
July 2017

Sodium and potassium urinary excretion levels of preschool children: Individual, daily, and seasonal differences.

J Clin Hypertens (Greenwich) 2017 Jun 27;19(6):577-583. Epub 2017 Jan 27.

Hypertension Center, Steel Memorial Yawata Hospital, Kitakyushu, Japan.

In this study, the authors measured sodium and potassium concentrations in spot urine samples of preschool children on multiple days, and evaluated individual, daily, and seasonal effects. A total of 104 healthy preschool children aged 4 to 5 years were studied. Urine samples were collected from the first urine of the day after waking for three consecutive days (Monday-Wednesday) four times a year (spring, summer, autumn, winter). The authors estimated the daily urine volume as 500 mL and daily creatinine excretion as 300 mg, and used these to calculate daily sodium and potassium excretion levels. Daily sodium and potassium excretion levels and sodium to potassium ratios were highly variable. The coefficient variant in the children's excretion levels were also high within and between individuals. Sodium excretion levels and sodium to potassium ratios were higher on Monday (weekend sodium intakes) than Tuesday. Season had no effect on sodium or potassium excretion levels, but the sodium to potassium ratio was higher in summer than in winter. In conclusion, levels of urinary sodium excretion are comparatively high and those of potassium are low in preschool students, with high variability within and between individuals.
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http://dx.doi.org/10.1111/jch.12966DOI Listing
June 2017

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

Epilepsy Res 2017 02 26;130:7-12. Epub 2016 Dec 26.

Department of Child Neurology, Asahigawaso Rehabilitation and Medical Center, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.12.014DOI Listing
February 2017