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.

Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy.

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).

Psychiatric outcome of temporal lobe epilepsy surgery: A prospective, 2-year follow-up study.

OBJECTIVE: We performed a prospective, longitudinal, 2-year follow-up study to clarify psychiatric courses and outcomes after temporal lobe epilepsy surgery. METHODS: We assessed 141 patients (68 men, 73 women) aged 16 or older with structured interviews and psychiatric rating scales before surgery and 3 months, 1 year, and 2 years afterward. RESULTS: Fifty-two patients (36.9%) had a psychiatric condition before surgery or during the follow-up period or both. The number of patients with a psychiatric condition decreased from 31 (22.0%) before surgery to 14 (9.9%) at 2 years. On the basis of our results, we defined 5 courses of psychiatric conditions: course 0, no psychopathology (n = 89, 63.1%); course 1, remission or resolution of a presurgical psychiatric condition after surgery (n = 19, 13.5%); course 2, new onset, transient psychiatric condition after surgery (n = 19, 13.5%); course 3, new onset, persistent psychiatric condition after surgery (n = 2, 1.4%); and course 4, chronic psychiatric condition before and after surgery (n = 12, 8.5%). In 14/25 (56.0%) patients with a mood or anxiety disorder before surgery, the condition remitted or resolved after surgery (course 1). Eighteen of 110 patients (16.4%) without any psychopathology before surgery developed mood or anxiety disorders afterward, including major depressive disorder in 13 patients (courses 2 and 3); in more than half of these patients, the disorder manifested within 1 year. More patients with a past history of psychiatric conditions were found in course 2 than in course 0. The duration of epilepsy was longer in course 4 than in course 0, and age at epilepsy onset was lower in course 4 than in course 0. SIGNIFICANCE: Most patients with a psychiatric condition show a favorable outcome 2 years after surgery; however, some show a transient worsening or new onset of psychiatric conditions, in particular depression.

Neuropsychological outcomes after frontal lobectomy to treat intractable epilepsy.

OBJECTIVE: Frontal lobectomy is often used as a surgical treatment for frontal lobe epilepsy, especially when a large epileptogenic zone in the frontal lobe is inferred from preoperative evaluation. The frontal lobe is important for cognitive functions such as executive functions and verbal fluency, but the neuropsychological outcome after a frontal or prefrontal lobectomy that includes both the dorsolateral prefrontal cortex and ventral prefrontal cortex has not been studied thoroughly. In the present study, we evaluated neuropsychological outcomes after patients with frontal lobe epilepsy received a frontal or prefrontal lobectomy. METHODS: We retrospectively reviewed the data of patients with frontal lobe epilepsy who underwent a frontal or prefrontal lobectomy that includes both the dorsolateral prefrontal cortex and ventral prefrontal cortex at 16 years or older from October 2004 to December 2014, with a minimum postoperative follow-up of 24 months. We analyzed and compared neuropsychological outcomes, including executive functions, verbal fluency, intelligence, and memory, before and after the operation. RESULTS: Eighteen patients were 16 years or older and underwent pre- and postoperative (2 years after the operation) neuropsychological evaluations. Patients showed significant deterioration only on the Benton Visual Retention Test. Performance on tests of frontal lobe functions, such as executive function and verbal fluency, showed no significant deterioration. CONCLUSIONS: Overall cognitive performance, including functions widely thought to depend on the frontal lobe, is stable after a frontal or prefrontal lobectomy to treat frontal lobe epilepsy.

Assessment of the long-term efficacy and safety of adjunctive perampanel in tonic-clonic seizures: Analysis of four open-label extension studies.

OBJECTIVE: This post hoc analysis evaluated long-term efficacy and safety in patients with focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who entered open-label extension (OLEx) studies to receive long-term adjunctive perampanel. METHODS: Patients aged 12 years and older who completed phase II or III randomized, double-blind, placebo-controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open-label maintenance period (32-424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. RESULTS: Baseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure-freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long-term treatment. SIGNIFICANCE: This post hoc analysis suggests long-term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.

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

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.

Seizures, accidental injuries at work, and reasons for resignation in people with epilepsy.

OBJECTIVE: Few studies have examined seizures, accidental injuries at work, and reasons for resignation in people with epilepsy (PWE). We performed a questionnaire survey of PWE to identify the risk of injury at work, its relationship to different seizure characteristics, and reasons for resignation. METHODS: We distributed a questionnaire survey in the outpatient clinic of a single epilepsy center. Medical information was obtained retrospectively from medical records. RESULTS: Of 200 patients who received the questionnaire, 172 responded. Two-fifths of PWE had experienced seizures at work, but the risk of accidental injuries due to epileptic seizures was only 0.01 person/year (1.0%) and 0.018 injuries/year, whereas the risk of accidental injuries not related to seizures was 0.039 person/year (3.9%) and 0.083 injuries/year. All accidental injuries due to seizures at work were caused by seizures characterized by a fall and inappropriate behavior with impaired awareness. Most accidental injuries due to seizures at work were caused by seizures that occurred at least once a year. The types of injuries reported were bruising, abrasion, laceration, fracture, burn, and submersion injuries. A quarter of PWE had left previous jobs because of epilepsy, of these, about four-fifths reported that seizures at the workplace had interfered with their own or others' tasks. SIGNIFICANCE: The risk of seizure-related injury is not high compared to the risk of injury not related to seizures, and most injuries due to seizures are not severe. The features of seizures with a fall, impaired awareness, and inappropriate behavior, as well as seizure frequency, should be considered when evaluating the risks associated with seizures in the workplace. Most PWE who had left their previous job because of epilepsy had experienced seizures at the workplace interfering with their own or others' tasks.

Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes.

BACKGROUND: Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. METHODS: To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. RESULTS: The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. CONCLUSIONS: Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.

A post hoc analysis of the long-term safety and efficacy of perampanel in Asian patients with epilepsy.

This post hoc analysis assessed the long-term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic-clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long-term extension phase of 3 phase-3 perampanel trials (study 307) or the 10-week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double-blind phase-3 trials and 669 had previously received perampanel 2-12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre-perampanel baseline for all focal seizures was -28.1%, and -51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre-perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long-term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase-3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.

Is additional mesial temporal resection necessary for intractable epilepsy with cavernous malformations in the temporal neocortex?

PURPOSE: Cavernous malformation (CM) in the temporal neocortex causes intractable epilepsy. Whether to resect additional mesial temporal structures in addition to the lesionectomy is a still controversial issue. To clarify the need for the procedure, we retrospectively analyzed pre- and postoperative clinical data of patients with surgically removed CM. SUBJECTS AND METHODS: We included data from 18 patients with CM in the temporal neocortex who presented with intractable epilepsy. Eleven patients of our early series were treated with extended resection, i.e., lesionectomy and the resection of additional mesial temporal structures. Seven patients underwent lesionectomy, i.e., removal of the CM and of hemosiderin-stained surrounding brain tissue. Pathological assessments of the resected hippocampus were performed. Chronic intracranial electroencephalography (EEG) recordings were obtained in 6 patients. We performed perioperative neuropsychological assessments in all patients. RESULTS: The seizure outcome was recorded as Engel class I in 17 patients (94.4%); Ia = 12 (66.7%) Ib = 2 (11.1%), Ic = 1 (5.6%), Id = 2 (11.1%), and class IIb in one patient (5.6%). Adding resection of the mesial temporal structures to lesionectomy did not alter the seizure outcome. Pathology of hippocampus revealed limited neuronal loss in CA4. Ictal onsets in the ipsilateral lateral cortex were detected in all 6 patients who underwent intracranial EEG. In 4 patients each, we also detected ictal onsets from the ipsilateral mesial temporal structures and from the contralateral temporal lobe. Postoperatively, in the patients where their CM was located in the language-dominant hemisphere (n = 10), the full-scale intelligence quotient (IQ) and the performance IQ increased (p < 0.05), whereas the verbal memory (WMS-R) deteriorated in two of 5 patients. CONCLUSION: Excellent seizure outcomes were obtained even the lesionectomy alone. To confirm appropriate surgical strategy for lateral temporal CM with intractable epilepsy, further studies in large sample size are needed.

Influence of Inflammation on the Pharmacokinetics of Perampanel.

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.

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

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.

Bidirectional electric communication between the inferior occipital gyrus and the amygdala during face processing.

Faces contain multifaceted information that is important for human communication. Neuroimaging studies have revealed face-specific activation in multiple brain regions, including the inferior occipital gyrus (IOG) and amygdala; it is often assumed that these regions constitute the neural network responsible for the processing of faces. However, it remains unknown whether and how these brain regions transmit information during face processing. This study investigated these questions by applying dynamic causal modeling of induced responses to human intracranial electroencephalography data recorded from the IOG and amygdala during the observation of faces, mosaics, and houses in upright and inverted orientations. Model comparisons assessing the experimental effects of upright faces versus upright houses and upright faces versus upright mosaics consistently indicated that the model having face-specific bidirectional modulatory effects between the IOG and amygdala was the most probable. The experimental effect between upright versus inverted faces also favored the model with bidirectional modulatory effects between the IOG and amygdala. The spectral profiles of modulatory effects revealed both same-frequency (e.g., gamma-gamma) and cross-frequency (e.g., theta-gamma) couplings. These results suggest that the IOG and amygdala communicate rapidly with each other using various types of oscillations for the efficient processing of faces. Hum Brain Mapp 38:4511-4524, 2017. © 2017 Wiley Periodicals, Inc.

Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring.

BACKGROUND: This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy. METHODS: A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan-Meier method. RESULTS: Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 µmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days; P = 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P = 0.002). CONCLUSIONS: Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.

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

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.

Significance of Very-High-Frequency Oscillations (Over 1,000Hz) in Epilepsy.

OBJECTIVE: We previously reported ictal very-high-frequency oscillations (VHFO) of 1,000 to 2,500Hz recorded by subdural macroelectrodes using a 10-kHz sampling rate. The purpose of this study was to clarify the clinical significance of ictal VHFO in neocortical epilepsy. METHODS: This study included 13 patients with neocortical epilepsy who underwent subdural electrode implantation and had at least 1 seizure recorded at a 10-kHz sampling rate and were followed for more than 2 years postoperatively. Extent of resection was determined considering the seizure onset zone (SOZ) and irritative zone, structural lesion, and functional areas. Areas showing VHFO and those with HFO were not taken into consideration. The presence or absence of VHFO (>1,000 Hz), HFO (200-1,000Hz) and SOZ, and completeness of resection of these areas were compared with postoperative seizure outcome. RESULTS: Seven patients had favorable (Engel class Ia) and 6 had unfavorable outcomes (other classes). VHFO was recorded in 6 of 7 patients with a favorable outcome. On the contrary, VHFO was recorded in only 1 of 6 patients with unfavorable outcome. The presence of VHFO was significantly associated with favorable outcome. VHFO was recorded on a limited number of electrodes, and VHFO-generating areas were resected completely, whereas HFO-generating areas and/or SOZ were not always resected completely in both favorable and unfavorable outcome groups. INTERPRETATION: The presence of ictal VHFO may be predictive of favorable outcome. Ictal VHFO may be a more specific marker than ictal HFO or SOZ for identifying the core of epileptogenic zone.

Seizures with tonic posturing: Semiologic difference between supplementary sensorimotor area (SSMA) origin and extra-SSMA origin.

In seizures with tonic posturing, differentiation of seizures originating in SSMA from seizures originating in cortices other than SSMA and spreading to SSMA has not been previously attempted. Twenty-two patients were studied with intractable focal epilepsy with tonic limb posturing as the most prominent semiology, who underwent resective surgery and obtained favorable postoperative seizure outcomes. These 22 patients were divided into an SSMA group (N = 12) and an extra-SSMA group (N = 10), according to the location of resection. Resection area in the extra-SSMA group was located in the dorsolateral frontal or prefrontal area in four patients, the frontal operculum (insula) in two, the parietal cortex in three, and the temporoparietal cortex in one patient. Video-recorded seizures were carefully reviewed. Tonic posturing characteristics and the presence or absence of accompanying symptoms were compared between groups. Incidence of preservation of consciousness was significantly higher in the SSMA group (p < 0.001). Patients in the SSMA group demonstrated a propensity for having unilateral or bilateral asymmetrical tonic limb posturing. In contrast, patients in the extra-SSMA group had a statistically significantly higher incidence of bilateral symmetrical tonic limb posturing (p < 0.05). These findings may be helpful in identifying seizure origin.

Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy.

PURPOSE: Lamotrigine (LTG) is used to treat epilepsy. The variability of LTG pharmacokinetics among individuals may be attributed to polymorphisms in the genes of uridine diphosphate glucuronosyltransferases (UGTs) 1A4 and UGT2B7 and/or combination with other drugs. In this study, we evaluated the association between LTG concentrations and patient characteristics such as genetic polymorphisms and the co-administration of antiepileptic drugs. METHODS: We recruited 122 patients with epilepsy. LTG concentrations were measured in blood samples from each patient under steady-state condition. We assessed the influence of multiple factors on LTG concentrations and derived a formula for predicting LTG concentrations using multiple linear regression analysis. RESULTS: We derived a formula to predict LTG concentrations that considers the daily dose of LTG, body weight, valproic acid concentration, phenytoin co-administration, and the co-administration of phenobarbital and/or carbamazepine as well as UGT1A4 142T>G and UGT2B7 -161C>T polymorphisms (adjusted coefficients of determination R (2) = 0.734). Furthermore, we used this formula to reveal a strong positive correlation between measured and predicted LTG concentrations (r (2) = 0.76, p < 0.001). CONCLUSION: We derived a formula that will be useful in clinical practice for predicting LTG concentrations in patients with epilepsy.

Individualized phenytoin therapy for Japanese pediatric patients with epilepsy based on CYP2C9 and CYP2C19 genotypes.

BACKGROUND: The aims of this study were to identify the target dose of phenytoin (PHT) and to compare the treatment continuation rate between patients receiving conventional therapy and patients receiving individualized therapy based on genotyping of the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles. The operational definition for the target dose of PHT used in this study was the dose that yielded a steady-state PHT concentration within the range of 15-20 mcg/mL without dose-related adverse effects. METHODS: We investigated 394 samples from 170 Japanese pediatric patients aged 9 months to 15 years to identify factors that influenced the target dose of PHT. We also analyzed the clinical records of 156 patients who commenced PHT therapy at our hospital and retrospectively assessed the time to treatment failure within 1 year after starting PHT therapy. During the study period, 17 patients underwent genotyping at the start of PHT therapy. If the patients had the CYP2C9*3, CYP2C19*2, or CYP2C19*3 alleles, the initial dose of PHT was reduced by 10%-50% according to previous reports. The other 139 patients received conventional PHT therapy. RESULTS: According to multiple regression analysis, the body weight, concomitant use of sulthiame, and the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles influenced the target dose of PHT. Our model explained 74% of the interindividual variability of the target dose of PHT. The total withdrawal rate in the individualized therapy group and the conventional therapy group was 23.5% and 33.1%, respectively. The adjusted hazard ratio for withdrawal of PHT therapy in the individualized therapy group was 0.37 (95% confidence interval; 0.12-1.10, P = 0.074). CONCLUSIONS: These findings suggest that genotyping can help to estimate the optimum target dose of PHT and may contribute to avoid intoxication and concentration-dependent adverse effects.

Preservation of absolute pitch after right amygdalohippocampectomy for a pianist with TLE.

Absolute pitch (AP) ability is a rare musical phenomenon. In the literature, it has been suggested that the relative specialization for pitch processing is in the right temporal lobe in the non-AP population. Since the anatomic basis for absolute pitch is not fully understood and cases of temporal lobe epilepsy of AP possessors are extremely rare, applicability of resection as a treatment of epilepsy in this particular area should be evaluated with caution. In the present study, we examined an AP possessor who suffered from medically refractory temporal lobe epilepsy and underwent right selective amygdalohippocampectomy (SAH). The SAH procedure clearly avoided disturbing important structures for AP, inasmuch as postsurgically she preserved her AP ability and was seizure-free. She did well post-operatively in the test of pure sine wave tones with short reaction time, which could be identified as "true" absolute pitch.