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.

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.

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.

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.

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

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.

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

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 × 10-6) 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.

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

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 ±â€¯SD; 5.0 ±â€¯4.2 years). Mean disease duration was 14.5 ±â€¯8.5 years. Mean age at pre-surgical DQ-IQ evaluation was 34.8 ±â€¯10.7 years. Mean DQ-IQ was 60.5 ±â€¯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 (R2 = 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.

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

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 99mTc-ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) showed hypoperfusion and ictal 99mTc-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.

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

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 99 mTc-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.

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

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.

Determination of CSF 5-methyltetrahydrofolate in children and its application for defects of folate transport and metabolism.

OBJECTIVE: To describe an assay of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) of children, to determine reference values, and to report the clinical significance of this assay in metabolic disorders affecting folate transport and metabolism. METHODS: CSF 5MTHF was determined by high-performance liquid chromatography with fluorescent detection in pediatric patients including one with FOLR1 gene mutation and one with methylenetetrahydrofolate reductase (MTHFR) deficiency. CSF total folate was measured using an automated analyzer. RESULTS: 5MTHF and total folate were determined in 188 and 93 CSF samples, respectively. CSF 5MTHF was high throughout the first six months of life and subsequently declined with age. Reference values of CSF 5MTHF and total folate were determined from 162 and 82 samples, respectively. The patient with FOLR1 gene mutation had extremely low CSF 5MTHF and total folate, though these values normalized after folinic acid supplementation. The patient with MTHFR deficiency had extremely low 5MTHF and moderately low total folate; these values were not associated and showed no significant change after folic acid supplementation. CONCLUSIONS: This 5MTHF assay is simple, rapid, sensitive, reliable, and cost-effective. It will aid in the diagnosis and therapeutic monitoring of metabolic disorders affecting folate transport and metabolism.

An analysis of epileptic negative myoclonus by magnetoencephalography.

PURPOSE: To clarify the neurophysiologic mechanism of epileptic negative myoclonus (ENM), we analyzed the magnetoencephalography (MEG) of a patient with ENM. METHODS: The 52-year-old right-handed male had frequent ENM in the right upper limb during awake and monthly seizures with sudden tonic stiffening of the right forearm during sleep. MRI demonstrated a focal cortical dysplasia in the cortex of the posterior portion of the left superior frontal sulcus. Whole-head type MEG, electroencephalography and electromyography were simultaneously recorded during ENM. Single equivalent currents dipoles (ECDs) were calculated for each spike component followed by silent period (SP) in the right deltoid muscle. These MEG spike components were averaged with respect to their peaks, and single ECD was also calculated for the averaged spike component. Furthermore, we analyzed the MEG with the silent-period-locked-averaging (SPLA) method. Twenty MEG signal data were averaged with respect to the onset of SP. Twenty epochs in each of five separate periods of recording were repeatedly averaged. ECDs were calculated for spike components observed in each averaged epoch. RESULTS: ECDs of each spike followed by SP were clustered near the cortex of the left central sulcus. In MEG spike averaging and SPLA method, ECDs at the peak of spike components were located near the right shoulder division of the primary sensorimotor cortex reproducibly. ECDs on the ascending phase before the peak were located lateral to the above ECD location in MEG spike averaging method. CONCLUSIONS: ENM was produced by an inhibitory action on the primary sensorimotor cortex corresponding to the body segment in which ENM occurs.

Developmental outcome after surgery in focal cortical dysplasia patients with early-onset epilepsy.

The purpose of this study was to investigate the developmental outcome after surgery for early-onset epilepsy in patients with focal cortical dysplasia (FCD). Among 108 patients with histopathologically confirmed FCD operated between 1985 and 2008, we selected 17 patients with epilepsy onset up to 3 years of age. Development was evaluated by the developmental quotient or intelligence quotient (DQ-IQ) and mental age was measured by the Mother-Child Counseling baby test or the Tanaka-Binet scale of intelligence. Postsurgical development outcome was evaluated by the changes in DQ-IQ and mental age as well as rate of increase in mental age (RIMA) after surgery. RIMA was calculated as the increase in mental age per chronological year (months/year; normal average rate: 12 months/year). Age at epilepsy onset of 17 patients ranged from 15 days to 36 months (mean±SD, 11.0±10.0 months). Age at surgery ranged from 18 to 145 months (75.1±32.4 months). Evaluation just before surgery showed that 13 of 17 (76.4%) patients had DQ-IQ below 70. Ten patients (58.8%) were seizure-free throughout the postsurgical follow-up period. After surgery, DQ-IQ was maintained within 10 points of the presurgical level in 13 patients (76.4%), and increased by more than 10 points in one patient (5.9%). After surgery, RIMA in patients with Engel's class I (7.5±3.8) was higher than patients with Engel's class II-IV (2.6±3.4) (unpaired t-test with Welch's correction, t=2.99, df=15, p=0.0092). RIMA was particularly low in two patients with spasm. In four patients with presurgical DQ-IQ<70, seizure-free after surgery and without spasm, DQ-IQ did not increase but RIMA improved from 3.6±2.8 before surgery to 6.9±2.5 months/year after surgery. RIMA became better from 2 years after surgery. In four patients with presurgical DQ-IQ≥70 and no spasm, two showed the same or higher RIMA than normal average after surgery. In 58.8% of FCD patients with early onset epilepsy, epilepsy surgery effectively controlled seizures, and in 82.3% of patients, epilepsy surgery preserved or improved development. Residual seizures after surgery and lower DQ-IQ before surgery might be potential risk factors for poor development after surgery. In patients of Engel's class I with lower presurgical DQ-IQ, catch-up increase in mental age was observed after two years following surgery.

Impact of cytochrome P450 inducers with or without inhibitors on the serum clobazam level in patients with antiepileptic polypharmacy.

PURPOSE: The aim of this study was to evaluate the effect of cytochrome P450 (CYP) inducers/inhibitors on the pharmacokinetics of clobazam (CLB) in patients receiving antiepileptic polypharmacy. METHODS: A total of 2,504 samples obtained from 1,280 patients for routine therapeutic drug monitoring were retrospectively reviewed. These samples were grouped according to the antiepileptic drug regimens or age, and then the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB was calculated for comparison. RESULTS: The mean CD ratio of CLB in adult patients using enzyme inducers (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) alone or in combination) was 60.8% lower than the ratio in patients without inducers. Among the inducers, patients using PHT had a significantly lower CD ratio than patients using PB or CBZ (p < 0.001). When PHT was combined with CBZ and/or PB, no additive or synergetic interactions was observed. The CD ratio of CLB in pediatric patients using inducers was 44.3% lower than in patients without inducers. The influence of inducers was unchanged regardless of the child's age, and the effect was stronger in adults than in pediatric patients. Other than inducers, valproic acid (VPA) additively reduced the CD ratio, whereas concomitant use of stiripentol significantly elevated the CD ratio in patients receiving VPA. In contrast, CYP3A4 substrates, such as zonisamide and topiramate, had little influence on the CD ratio of CLB. CONCLUSION: We identified an impact of CYP inducers/inhibitors on the CLB concentration. Our findings demonstrated that clinically relevant interactions occur between CLB and concomitant antiepileptic drugs.

[Dietary therapy of epilepsy].

Reappraisal of ketogenic diets (KD) were delayed in Japan compared to USA and Korea. The reasons are unknown, but possible explanations are (1) Japanese food culture prefers rice and less fat and (2) ACTH therapy is preferred for West syndrome in Japan. Since Japanese child neurologists were surprised at dramatic effects on glucose transporter 1 deficiency syndrome (Glut-1DS) in 2003, KD have been slowly accepted for treatment of epilepsy in Japan. New generation KD including modified Atkins diet (mAD) are preferred to classical KD. KD can be causal therapy in Glut-1DS and some of mitochondrial disorders, though anti-epileptic drugs are symptomatic therapy. KD can alleviate intractable seizures in epilepsies with brain malformation in addition to West syndrome and Dravet syndrome, etc. KD may work for brain tumor, cancer, neurodegenerative disorders including Alzheimer's disease. C7-8 triglycerides or fatty acid esters are under development as medicines replacing KD.

Thumb opposition in severe carpal tunnel syndrome with undetectable APB-CMAP.

Thumb opposition does not always represent the function of the median nerve due to variations in thenar muscle innervation. One hundred and thirty hands of 109 idiopathic carpal tunnel syndrome (CTS) patients with an undetectable compound muscle action potential of the abductor pollicis brevis (APB-CMAP) were classified into one of four groups; Type 1 (86.2%) had thenar muscle atrophy and could not perform thumb opposition; Type 2 (10.8%) had thenar muscle atrophy but could perform thumb opposition; Type 3 (2.3%) did not have thenar muscle atrophy and could perform thumb opposition, but needle electromyography of the APB showed neurogenic changes and Type 4 (0.8%) had no thenar muscle atrophy, could perform thumb opposition, and needle electromyography showed no neurogenic changes. Over 10% of severe CTS patients have mild or no muscle atrophy and intact thumb opposition. The purpose of this study was to investigate the variations in thenar muscle innervation in patients with severe CTS.

Immunomodulatory therapy versus surgery for Rasmussen syndrome in early childhood.

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