Changes in Perampanel Pharmacokinetics and Cytochrome P450 3A4 Activity Before, During, and After Pregnancy.

ABSTRACT: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4ß-hydroxycholesterol (4ß-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL). Similarly, serum 4ß-OHC levels did not change during pregnancy (before pregnancy, 78.2 ng/mL; during pregnancy, 62.2-83.2 ng/mL). To compare these measurements with those in nonpregnant women, we enrolled 27 nonpregnant women with epilepsy (age range, 16-40 years). In the control patients, we found a strong negative correlation between the concentration-to-dose ratio of perampanel and the 4ß-OHC level ( r = -0.78, P < 0.001). As there was no significant change in CYP3A4 activity, we concluded that the serum perampanel concentration did not change significantly before, during, or after pregnancy. More patients need to be studied to confirm these early results.

Neuropsychological outcome after frontal surgery for pediatric-onset epilepsy with focal cortical dysplasia in adolescent and young adult.

OBJECTIVE: We investigated neuropsychological outcome in patients with pharmacoresistant pediatric-onset epilepsy caused by focal cortical dysplasia (FCD), who underwent frontal lobe resection during adolescence and young adulthood. METHODS: Twenty-seven patients were studied, comprising 15 patients who underwent language-dominant side resection (LDR) and 12 patients who had languagenondominant side resection (n-LDR). We evaluated intelligence (language function, arithmetic ability, working memory, processing speed, visuo-spatial reasoning), executive function, and memory in these patients before and two years after resection surgery. We analyzed the relationship between neuropsychological outcome and resected regions (side of language dominance and location). RESULTS: Although 75% of the patients showed improvement or no change in individual neuropsychological tests after surgical intervention, 25% showed decline. The cognitive tests that showed improvement or decline varied between LDR and n-LDR. In patients who had LDR, decline was observed in Vocabulary and Phonemic Fluency (both 5/15 patients), especially after resection of ventrolateral frontal cortex, and improvement was observed in WCST-Category (7/14 patients), Block Design (6/15 patients), Digit Symbol (4/15 patients), and Delayed Recall (3/9 patients). In patients who underwent n-LDR, improvement was observed in Vocabulary (3/12 patients), but decline was observed in Block Design (2/9 patients), and WCST-Category (2/9 patients) after resection of dorsolateral frontal cortex; and Arithmetic (3/10 patients) declined after resection of dorsolateral frontal cortex or ventrolateral frontal cortex. General Memory (3/8 patients), Visual Memory (3/8 patients), Delayed Recall (3/8 patients), Verbal Memory (2/9 patients), and Digit Symbol (3/12 patients) also declined after n-LDR. CONCLUSION: Postoperative changes in cognitive function varied depending on the location and side of the resection. For precise presurgical prediction of neuropsychological outcome after surgery, further prospective studies are needed to accumulate data of cognitive changes in relation to the resection site.

Time-Course Changes in Lamotrigine Concentration after Addition of Valproate and the Safety and Long-Term Tolerability of Lamotrigine-Valproate Combination Therapy.

The aim of this study was to evaluate the time-course changes in lamotrigine (LTG) concentration after addition of valproate (VPA) and the safety and tolerability of the combination therapy. We reviewed our therapeutic drug monitoring (TDM) database and found 345 patients on LTG who received add-on therapy with VPA. VPA had been added at least 12 weeks after patients finished stepwise LTG titration. Also, we retrospectively evaluated the LTG concentration after addition of VPA and the safety and long-term tolerability of LTG-VPA combination therapy. Plasma LTG concentration increased more than 1.5-fold within 15 d of addition of VPA and reached a peak at 30 d. The rate of increase in LTG concentration occurred in a VPA concentration-dependent manner. During the first 120 d after addition of VPA, adverse events were reported by 58 patients (16.8%), but no patient developed cutaneous reactions. Kaplan-Meier analysis showed estimated retention rates for LTG-VPA combination therapy of 74.5% at 5 years. At 5 years, the mean concentration of LTG was 11.1 µg/mL (43.3 µmol/L). Because addition of VPA leads to a marked increase in LTG concentration over a short period, TDM for LTG should be performed at the earliest from 14 d after starting VPA. At 120 d after starting VPA therapy, the higher LTG concentration due to addition of VPA is not associated with an increased risk of cutaneous reactions. Although LTG-VPA combination therapy increases LTG concentration, it is well tolerated and has a high long-term retention rate.

Localized focal cortical dysplasia type II: seizure freedom with lesionectomy guided by MRI and FDG-PET.

OBJECTIVE: The authors perform thorough, noninvasive presurgical evaluations for intractable epilepsy at their center and avoid unnecessary intracranial EEG when possible. The purpose of this study was to clarify the appropriateness of their lesion-oriented surgical strategy for localized focal cortical dysplasia (FCD) type II. METHODS: Fifty-one patients with pathologically proven localized FCD type II who were followed for at least 1 year after surgery were included. Patients with FCD type II with lobar or multilobar distribution were excluded. The results of presurgical evaluations, including thin-slice 3-T MRI, FDG-PET, and ictal SPECT, as well as surgical procedures and postoperative seizure and functional outcomes, were examined retrospectively. RESULTS: MRI was positive in 46 (90%) of 51 patients, and FDG-PET revealed localized hypo- or hypermetabolism in 47 (92%) of 51 patients. Ictal SPECT revealed concordant hyperperfusion in 37 of 42 patients examined. Intracranial EEG was used in only 13 patients (25%), including 5 with negative MRI results and 4 with subtle MRI findings. Of the 15 patients with FCD in the vicinity of eloquent (sensorimotor and language) areas, intracranial EEG was used in 4. Lesionectomy was performed in all 51 patients. Intraoperative electrocorticography (ECoG) was performed in 8 patients, but the findings were not used to tailor the extent of resection. Postoperative seizure outcomes were Engel class I in 47 patients (92%) and Ia in 45 (88%). In the 15 patients with FCD in the vicinity of eloquent areas, 13 (87%) achieved a class I outcome. Predictive factors for favorable seizure outcome were complete resection of the MRI lesion (p = 0.006) and frontal lobe surgery (p = 0.012). Postoperative neurological deficits were noted in only 4 (27%) of 15 patients with FCD in the vicinity of eloquent areas. All 5 MRI-negative patients achieved an Engel class I outcome. CONCLUSIONS: In most of the patients with localized FCD type II, MRI and/or FDG-PET detected the localized abnormality. Lesionectomy without intracranial EEG led to seizure freedom in most cases. Even when lesions were in the vicinity of eloquent areas, seizure and functional outcomes were favorable. Intraoperative ECoG may thus be unnecessary. Complete resection of the lesion is essential for favorable seizure outcome in MRI-positive patients. In MRI-negative patients, surgery with intracranial EEG guided by FDG-PET provided seizure-free outcomes.

Incidence trends and risk factors for hyponatremia in epilepsy patients: A large-scale real-world data study.

Objective: This study aimed to evaluate the annual incidence and risk factors of hyponatremia in pediatric, adult, and older adult patients with epilepsy. Methods: We enrolled 26,179 patients: 8598 pediatric patients (aged 0-15 years), 16,476 adults (aged 16-64 years), and 1105 older adults (aged ≥65 years). Patients were included if their serum sodium levels were measured between January 2006 and December 2020. Moderate-severe hyponatremia was defined as a serum sodium level of less than 130 mEq/L. Results: From 2006 to 2020, 677 patients (2.6%) developed moderate-severe hyponatremia. The incidence of hyponatremia per 1000 person-years was 3.1 in the pediatric group, 19.8 in the adult group, and 50.4 in the older adult group. The incidence increased markedly from 36.8 in 2007 to 58.5 in 2020 in the older adult group but remained unchanged in the adult group and tended to decrease in the pediatric group. In the multiple logistic regression model, use of carbamazepine, valproate, phenytoin, phenobarbital, benzodiazepines, and antipsychotics was found to be a significant risk factor for hyponatremia. In adult patients, carbamazepine, benzodiazepine, and antipsychotics induced hyponatremia in a dose-dependent manner. Concomitant use of zonisamide reduced the risk of hyponatremia. Significance: Hyponatremia will become an increasingly important concern in clinical settings because the population of epilepsy patients is aging. Serum sodium levels should be monitored carefully when patients are receiving first-generation antiseizure medications or antipsychotics or combinations of these drugs. Our findings may help to minimize the risk of hyponatremia in epilepsy patients.

Effects of low-dose titration on the tolerability and safety of perampanel.

PURPOSE: To evaluate the effects of low-dose titration on the tolerability and safety of perampanel. METHODS: We retrospectively reviewed the records of 1065 patients who started perampanel therapy and compared the incidence of adverse events after standard titration (Group A: starting dose, 2 mg/day; titration speed, 2 mg/2 weeks or longer) and low-dose titration (Group B: starting dose, < 1 mg/day; titration speed, < 1 mg/2 weeks or longer). RESULTS: Adverse events were reported in 158 patients (14.8%) within the initial first 90 days of starting perampanel (mean concentration, 331 ng/mL). At 90 days, the cumulative incidence of adverse events was significantly higher in Group A than in Group B (24.5% vs. 16.3%, respectively; log-rank test p < 0.001). A Cox proportional hazards model also showed that low-dose titration decreased the incidence risk of adverse events (adjusted hazard ratio, 0.49; 95% confidence interval, 0.35-0.69). When the groups were stratified by use of enzyme-inducing antiseizure medications (inducers), Group A patients without inducers had a significantly higher cumulative incidence of adverse events than the other three subgroups (26.7%, p < 0.001). In patients taking 2 mg of perampanel, median concentrations in patients with or without inducers were 43 ng/mL and 204 ng/mL, respectively. CONCLUSION: Perampanel is generally initiated at 2 mg, but serum perampanel concentrations show substantial interindividual variation. Our study suggests that care must be taken when setting the starting dose of perampanel. In particular, low-dose titration is recommended in patients not taking inducers.

Association between cerebrospinal fluid parameters and developmental and neurological status in glucose transporter 1 deficiency syndrome.

OBJECTIVE: In glucose transporter 1 deficiency syndrome (Glut1DS), cerebrospinal fluid glucose (CSFG) and CSFG to blood glucose ratio (CBGR) show significant differences among groups classified by phenotype or genotype. The purpose of this study was to investigate the association between these biochemical parameters and Glut1DS severity. METHODS: The medical records of 45 patients who visited Osaka University Hospital between March 2004 and December 2021 were retrospectively examined. Neurological status was determined using the developmental quotient (DQ), assessed using the Kyoto Scale of Psychological Development 2001, and the Scale for the Assessment and Rating of Ataxia (SARA). CSF parameters included CSFG, CBGR, and CSF lactate (CSFL). RESULTS: CSF was collected from 41 patients, and DQ and SARA were assessed in 24 and 27 patients, respectively. Simple regression analysis showed moderate associations between neurological status and biochemical parameters. CSFG resulted in a higher R2 than CBGR in these analyses. CSF parameters acquired during the first year of life were not comparable to those acquired later. CSFL was measured in 16 patients (DQ and SARA in 11 and 14 patients, respectively). Although simple regression analysis also showed moderate associations between neurological status and CSFG and CSFL, the multiple regression analysis for DQ and SARA resulted in strong associations through the use of a combination of CSFG and CSFL as explanatory variables. CONCLUSION: The severity of Glut1DS can be predicted from CSF parameters. Glucose and lactate are independent contributors to the developmental and neurological status in Glut1DS.

Relationship between underreporting of energy intake and blood ketone levels in Japanese women with obesity: A retrospective study.

Underreporting is a problem in dietary surveys, and data on Japanese individuals with obesity are lacking. In addition, in dietary surveys of individuals with obesity, underreporting and extreme energy restrictive practices for short periods of time have been reported, and blood total ketone levels (ketone bodies) may be able to distinguish between these factors. The present study aimed to examine the relationship between underreporting [energy intake (EI)/basal metabolic rate estimate (BMR)] and ketone bodies in obese Japanese women. The participants included 91 women with obesity aged 47±9 years with a body mass index (BMI) of 29.8±3.9 kg/m² who met the exclusion criteria out of 164 individuals who participated in an institutional cohort study baseline survey between September 2006 and September 2015. The current study defined the relationship between EI/BMR, BMI and the participants' ketone body levels. EI/BMR <1.35 and ketone body level <1.0 mmol/l was defined as underreporters, while EI/BMR <1.35 and ketone body level ≥1.0 mmol/l was defined as energy-restricted reporters based on previous research. The EI/BMR of the participants was 1.44±0.32, and 25.3% had an abnormally high level of ketone bodies. Multiple regression analysis indicated that ketone bodies were explanatory variables for EI/BMR. Analysis using EI/BMR and ketone bodies estimated that 26.4% were underreporters and 12.1% were energy-restricted reporters. There were no significant differences in reported energy intake, carbohydrate intake (g/day), and percentage carbohydrate (%) between the underreporters and energy-restricted reporters. In conclusion, low EI/BMR was associated with high ketone body levels in Japanese women with obesity. The combination of EI/BMR and ketone bodies may distinguish between or screen for underreporters and energy-restricted reporters during a dietary survey.

Clinical value of therapeutic drug monitoring for levetiracetam in pediatric patients with epilepsy.

PURPOSE: To identify pediatric patients who require therapeutic drug monitoring (TDM) of levetiracetam (LEV). METHODS: We retrospectively investigated 2413 routine therapeutic drug monitoring data on serum LEV concentration from 1398 pediatric patients (age, 0-15 years). Samples were grouped by age (infants, < 1 year; preschool children, 1-5 years; primary school children, 6-11 years; and adolescents, 12-15 years), and the LEV concentration-to-dose (CD) ratio was calculated. RESULTS: The mean CD ratio was highest in adolescents (analysis of variance, p < 0.001); 22.5 % and 15.7 % higher in adolescents than in preschool children and school children, respectively (Scheffé test, p < 0.001); and higher in infants than in preschool children. Preschool children had the lowest ratio and tended to show an increase in the ratio from age 2 to 5 years. Use of enzyme-inducing antiseizure medication reduced the CD ratio by 6.1 % in infants, 12.2 % in preschool children, 5.9 % in primary school children, and 9.4 % in adolescents. The mean CD ratio was 2.7 %, 26.9 %, and 39.3 % higher in preschool children, primary school children, and adolescents with defined chronic kidney disease (CKD) than in the respective age group of patients without CKD. The therapeutic concentration range for a long-term LEV therapy was 11 to 32 µg/mL. CONCLUSIONS: LEV pharmacokinetics are significantly different between infant and preschool children, so TDM of LEV is clinically useful in these patients. In pediatric patients at higher risk for CKD, glomerular filtration rate and LEV levels should be carefully monitored.

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

Therapeutic Drug Monitoring for Rufinamide in Japanese Patients With Epilepsy: Focus on Drug Interactions, Tolerability, and Clinical Effectiveness.

BACKGROUND: The purposes of this study were to assess drug interactions between rufinamide and concomitant antiepileptic drugs (AEDs) and to identify the therapeutic window for rufinamide. METHODS: Serum samples (n = 1531) were obtained from 178 patients (aged 2-57 years), and clinical records were retrospectively reviewed to evaluate the safety and efficacy of rufinamide (mean observation time, 1073 ± 846 days). RESULTS: Rufinamide exhibited linear pharmacokinetics at doses of up to 60 mg/kg (range, 50-3200 mg/d). Concomitant use of the enzyme-inducing AEDs such as phenytoin, carbamazepine, and phenobarbital reduced rufinamide concentrations by 43.4%, 13.2%, and 30.3%, respectively. By contrast, concomitant use of valproate significantly elevated rufinamide concentrations. Clinical response was seen in 41 patients (23.0%), with a median therapeutic concentration (interquartile range) of 20.6 mcg/mL (13.3-27.0). There was no difference in the therapeutic concentrations between seizure types, but patients with tonic/atonic seizures tended to have higher rufinamide concentrations. During the study period, adverse events were reported in 64 patients (35.8%), including somnolence, gastrointestinal disorders, dizziness, and irritability/behavior disorders. Conditional logistic regression analysis showed that patients administered a concentration greater than 20 mcg/mL had an 8.6-fold higher incidence of adverse events. CONCLUSIONS: Therapeutic drug monitoring for rufinamide is clinically useful for predicting drug interactions between rufinamide and concomitant AEDs. When a patient has tonic/atonic seizures, careful titration is required for concentrations greater than 20 mcg/mL.

Burden of seizures and comorbidities in patients with epilepsy: a survey based on the tertiary hospital-based Epilepsy Syndrome Registry in Japan.

OBJECTIVE: To examine the current medical and psychosocial status of patients with epilepsy, aiming to facilitate appropriate application of the Intractable/Rare Diseases Act of Japan. METHODS: By analysing the cross-sectional data of patients registered in the tertiary hospital-based Epilepsy Syndrome Registry of Japan, we investigated the proportion of patients who met the severity criteria as defined by the Act (seizure frequency of at least once a month, or presence of intellectual/neurological/psychiatric symptoms, or both) and whether there are candidate syndrome/diseases to be added to the existing list in the Act. RESULTS: In total, 2,209 patients were registered. After excluding self-limited/idiopathic epilepsies, 1,851 of 2,110 patients (87.7%) met the severity criteria. The patients were classified into eight main epilepsy syndromes (594 patients), 20 groups based on aetiology (1,078 patients), and three groups without known aetiology (427 patients). Most of the groups classified by syndrome or aetiology had high proportions of patients satisfying the severity criteria (>90%), but some groups had relatively low proportions (<80%) resulting from favourable outcome of surgical therapy. Several small groups with known syndrome/aetiology await detailed analysis based on a sufficiently large enough number of patients registered, some of whom may potentially be added to the list of the Act. SIGNIFICANCE: The registry provides data to examine the usefulness of the severity criteria and list of diseases that are operationally defined by the Act. Most epilepsy patients with various syndromes/diseases and aetiology groups are covered by the Act but some are not, and the list of designated syndromes/diseases should be complemented by further amendments, as suggested by future research.

Risk factors for psychiatric adverse effects associated with perampanel therapy.

PURPOSE: To identify the risk factors for psychiatric adverse effects associated with perampanel therapy. METHODS: We retrospectively evaluated the adverse effects of perampanel by reviewing clinical records from 895 Japanese patients with epilepsy (aged 1-86 years) who started perampanel therapy at National Epilepsy Center, Shizuoka, Japan, between June 2016 and December 2019. Patients were classified into 3 groups: those without adverse effects (Group I), those with psychiatric adverse effects (Group II), and those with common adverse effects (Group III). RESULTS: The number of patients assigned to each group was as follows: Group I, n = 641; Group II, n = 93; and Group III, n = 161. The mean follow-up period was 458 ±â€¯265 days (median, 511 days). Kaplan-Meier survival estimates showed that the median time to treatment failure was shorter in Group II than in Group III (294 vs. 392 days, respectively; log-rank test, p < 0.001). According to polytomous logistic regression, younger age (<16 years) was associated with a lower risk of common and psychiatric adverse effects. The risk factors for psychiatric adverse effects (Group II) were intellectual disability (adjusted odds ratio [AOR], 2.6; 95% confidence interval (CI), 1.5-4.5) and psychiatric comorbidity (AOR, 3.8; 95% CI, 2.3-6.3); in patients with intellectual disability, the occurrence of psychiatric adverse effects was concentration dependent. Patients with lamotrigine use had a 0.54-fold lower risk of psychiatric adverse effects. In Group III, concomitant use of inducers was associated with a decreased risk of common adverse effects (AOR, 0.68; 95% CI, 0.46-0.99). SIGNIFICANCE: We found clear differences in the risk factors for psychiatric adverse effects. In patients with intellectual disability, care must be taken when titrating perampanel, and therapeutic drug monitoring should be performed.

Current medico-psycho-social conditions of patients with West syndrome in Japan.

OBJECTIVE: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. METHODS: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. RESULTS: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. SIGNIFICANCE: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

Surgical strategy for refractory epilepsy secondary to porencephaly: ictal SPECT may obviate the need for intracranial electroencephalography. Patient series.

BACKGROUND: Surgical treatment of intractable epilepsy caused by porencephaly can be difficult because of poorly localizing or lateralizing electroclinical findings. The authors aimed to determine whether noninvasive evaluations are sufficient in these patients. OBSERVATIONS: Eleven patients were included in this study. The porencephalic cyst was in the left middle cerebral artery (MCA) area in 9 patients, the left posterior cerebral artery area in 1 patient, and the bilateral MCA area in 1 patient. Interictal electroencephalography (EEG) revealed multiregional, bilateral, interictal epileptiform discharges in 5 of 11 patients. In 6 of 10 patients whose seizures were recorded, the ictal EEG was nonlateralizing. Nine patients underwent ictal single-photon emission computed tomography (SPECT), which revealed lateralized hyperperfusion in 8 of 9 cases. Fluorodeoxyglucose positron emission tomography (FDG-PET) was useful for identifying the functional deficit zone. No patient had intracranial EEG. The procedure performed was hemispherotomy in 7 patients, posterior quadrant disconnection in 3 patients, and occipital disconnection in 1 patient. A favorable seizure outcome was achieved in 10 of 11 patients without the onset of new neurological deficits. LESSONS: Ictal SPECT was useful for confirming the side of seizure origin when electroclinical findings were inconclusive. Thorough noninvasive evaluations, including FDG-PET and ictal SPECT, enabled curative surgery without intracranial EEG. Seizure and functional outcomes were favorable.

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

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 (r2 = 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.

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

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.

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

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.

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

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: Q1 , <5.56; Q2 , 5.56≤, <6.79; Q3 , 6.79≤, <8.12; and Q4 , 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.