Pure amnestic seizure: A clinico-intracranial EEG study.

OBJECTIVE: Enduring anterograde amnesia is caused by lesions in bilateral mesial temporal lobes. However, whether transient dysfunction of bilateral mesial temporal regions induces reversible amnesia has not been proven. We investigated this association in patients with epilepsy and analyzed the electroclinical correlation during pure amnestic seizures (PAS). PAS are defined as seizures with anterograde amnesia as the only ictal manifestation, accompanied by preserved responsiveness and other cognitive functions. METHODS: We retrospectively searched our intracranial EEG database to find PAS. Pure ictal amnesia was confirmed by immediate and comprehensive ictal examinations. RESULTS: Among 401 patients who underwent intracranial EEG recording, three patients with temporal lobe epilepsy (TLE) manifesting PAS were identified. The patients talked and behaved normally during seizure but did not remember the episodes afterwards. Ictal discharges were confined to bilateral mesial temporal regions, with no or mild involvement of surrounding structures. Spread of low-voltage fast activities to bilateral mesial temporal regions corresponded to onset of ictal anterograde amnesia. Two patients underwent unilateral mesial temporal resection and became seizure-free with improvement in cognitive functions. SIGNIFICANCE: PAS is a rare ictal semiology in TLE. Bilateral mesial temporal regions that play a critical role in memory encoding are presumably the symptomatogenic zones for PAS.

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.

Impairment of unconscious emotional processing after unilateral medial temporal structure resection.

The role of the amygdala in unconscious emotional processing remains a topic of debate. Past lesion studies have indicated that amygdala damage leads to impaired electrodermal activity in response to subliminally presented emotional stimuli. However, electrodermal activity can reflect both emotional and nonemotional processes. To provide behavioral evidence highlighting the critical role of the amygdala in unconscious emotional processing, we examined patients (n = 16) who had undergone unilateral resection of medial temporal lobe structures, including the amygdala. We utilized the subliminal affective priming paradigm in conjunction with unilateral visual presentation. Fearful or happy dynamic facial expressions were presented in unilateral visual fields for 30 ms, serving as negative or positive primes. Subsequently, neutral target faces were displayed, and participants were tasked with rating the valence of these targets. Positive primes, compared to negative ones, enhanced valence ratings of the target to a greater extent when they stimulated the intact hemisphere (i.e., were presented in the contralateral visual field of the intact hemisphere) than when they stimulated the resected hemisphere (i.e., were presented in the contralateral visual field of the resected hemisphere). These results suggest that the amygdala is causally involved in unconscious emotional processing.

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.

Status of epilepsy care delivery and referral in clinics, hospitals, and epilepsy centers in Japan: A nationwide survey.

OBJECTIVE: Collaboration among medical facilities is crucial to deliver comprehensive epilepsy care to a diverse and large population of people with epilepsy. We conducted a survey among medical facilities of various sizes throughout Japan to investigate the status of epilepsy care delivery, functioning, and referral. METHODS: With the cooperation of the Japan Neurological Society (1428 facilities), Japanese Neurosurgical Society (3489 specialists), and Epilepsy Care Network (948 facilities), a questionnaire was mailed to 5865 locations that provide epilepsy care in Japan. The facilities were classified into clinics (19 beds or less), small hospitals (SH, 20-199 beds), large hospitals (LH, 200 beds or more), and epilepsy centers (EC). The status of epilepsy care delivery, functioning, and referral was compared among the four groups. RESULTS: Responses were received from 1014 facilities (17.3% response rate). After excluding duplicate responses, 957 facilities were analyzed (394 clinics, 149 SH, 388 LH, 26 EC). EC responded "manageable" in more items of epilepsy care functions in general, especially those related to epilepsy surgery, compared to LH with similar facility size. However, EC responded being less manageable in psychiatric service (61.5%), dietary therapy (46.2%), rehabilitation (53.8%), and patient employment support (61.5%). The percentage of facilities that responded "always able to refer" was highest in clinics (67.6%) and the lowest in EC (40%). Referral difficulties were more commonly encountered in EC, and less common in clinics. In EC, the most common reason for inability to refer was patient or family refusal (64%). SIGNIFICANCE: We have clarified the epilepsy care delivery, functioning, and referral in facilities of various sizes in Japan. This study highlights the issues of downward referral and patient stagnation in EC, which have not received much attention. PLAIN LANGUAGE SUMMARY: A nationwide survey of healthcare facilities ranging in size from small clinics to large hospitals in Japan examined medical care delivery and patient referrals related to epilepsy. Compared to other facilities, epilepsy centers provided a variety of medical services to people with epilepsy but were inadequate in addressing psychiatric symptoms, providing dietary therapy, rehabilitation, and patient employment support. Referrals from epilepsy centers to other medical facilities were often refused by patients and their families. This results in patient crowding at epilepsy centers.

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.

Mesial temporal lobe epilepsy with amygdalar hamartoma-like lesion: Is it a distinct syndrome?

INTRODUCTION: We examined the clinical, semiological, scalp electroencephalographic (EEG), and neuropsychological features of patients with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS). METHODS: This retrospective study included 9 patients with mesial temporal lobe epilepsy (MTLE) who had an amygdalar lesion on preoperative MRI; underwent mesial temporal resection; were diagnosed with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS); were followed up for at least 2 years after surgery; and had a favourable postoperative seizure outcome (Engel Class I). There were 5 women and 4 men, and age at surgery ranged from 19 to 54 (mean, 36.6) years. Clinical characteristics, auras, video-recorded seizure semiology, interictal and ictal EEG, and preoperative neuropsychological data were reviewed. Twenty patients with MTLE with HS who had favourable postoperative seizure outcomes (Engel Class I) were selected as controls. RESULTS: Age at seizure onset was significantly higher in patients with AHL without HS than in those with HS. Fear was more frequently seen in patients with AHL (44 %) than in those with HS (5 %) (P = 0.022). There were no significant differences in interictal epileptiform discharges or ictal EEG pattern. Preoperative full-scale IQ score was significantly higher in the AHL group than in the HS group (mean, 92.9 v. 74.8, P = 0.004), as was preoperative memory quotient score (mean 100.7 v. 85.1, P = 0.028). CONCLUSION: We clarified the clinical, semiological, and neuropsychological features of patients with MTLE-AHL. These findings may be useful for preoperative evaluation, especially of patients with suspected MTLE but without apparent HS on preoperative MRI.

Bilateral tonic-clonic seizure and focal cortical hyperexcitability in familial Creutzfeldt-Jakob disease with E200K mutation of the prion protein.

Convulsive epileptic seizures are rare in Creutzfeldt-Jakob disease (CJD), and their clinical and EEG features have not been reported in detail. We describe a case of familial CJD with an E200K mutation of the prion protein who presented with bilateral tonic-clonic seizures (BTCS) during long-term video-EEG monitoring. Semiologically, BTCS showed focal clinical signs such as head turning and eye deviation to the left. The ictal EEG started with generalized polyspikes. Interictal EEG showed generalized periodic discharges with right fronto-temporal predominance (larger amplitude and earlier onset compared with other regions). MRI showed high-intensity signals persistently in the right temporo-parietal region on diffusion-weighted images (DWI). Interictal single-photon emission computed tomography (SPECT) showed hyperperfusion in the same region. Brain pathology revealed typical spongiform changes in CJD without other pathological findings of rapidly progressive dementia. Our case demonstrates that CJD can cause BTCS with generalized EEG changes and focal semiological/imaging abnormalities, suggesting that diffuse and inhomogeneous cortical and subcortical epileptic networks may develop in familial CJD.

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.

Periictal water drinking revisited: Occurrence and lateralizing value in surgically confirmed patients with focal epilepsy.

OBJECTIVE: Periictal water drinking (PIWD), which is a rare seizure-related autonomic behavior, has been reported in temporal lobe epilepsy (TLE) but only rarely in extra-TLE. Additionally, the lateralizing value of PIWD is controversial. We aimed to clarify the occurrence and lateralizing value of PIWD in patients with focal epilepsy. METHODS: This retrospective study included 240 focal epilepsy patients aged >10 years with a favorable postoperative seizure outcome (Engel class I). PIWD was defined as water drinking behavior during a seizure or within 2 min in the postictal phase. The occurrence of PIWD documented on video-electroencephalogram monitoring was assessed. The lateralizing value of PIWD was analyzed among patients whose language dominant hemisphere was identified. RESULTS: Twenty-three (9.5%) patients exhibited PIWD. PIWD occurred more frequently in frontal lobe epilepsy (FLE; eight of 41 patients, 19.5%) than in TLE (15 of 188 patients, 8%). The occurrence of PIWD was significantly different between FLE and extra-FLE (P = 0.035), with a low positive predictive value (34.8%). In FLE with PIWD, all but one patient underwent resective surgery involving the medial frontal lobe. In 194 patients whose language dominant hemisphere was determined, the lateralizing value of PIWD in FLE and TLE showed no statistical significance (P = 0.69 and P = 0.27, respectively). SIGNIFICANCE: Periictal water drinking occurred more often in FLE than TLE. Thus, PIWD might not be a specific periictal symptom in TLE. There was no evidence for the lateralizing value of PIWD in FLE and TLE. These findings can provide useful clinical clues for preoperative evaluations to estimate the epileptogenic zone based on seizure semiology and allow for a better understanding of pathophysiological insights into PIWD.

[Basic Principles of Electroencephalogram].

Electroencephalogram(EEG)signals are mainly generated by postsynaptic potentials(EPSP)in the apical dendrites of pyramidal cells in the cortex. The mechanism of generation of interictal epileptiform discharges(IED)is paroxysmal depolarization shift(PDS). IEDs are negative towards the cortical surface and positive towards the white matter. To interpret EEG, readers should know normal EEG waveforms of wakefulness and sleep, normal variants such as wicket spikes or small sharp spikes, and artifacts such as eye movements or electromyography. Overinterpretation of EEG is a major cause of misdiagnosis; therefore, the accurate identification of IED is essential. The International Federation of Clinical Neurophysiology has proposed a criteria for the identification of IED. Long-term video-EEG is useful for correct diagnosis and localization of the epileptogenic zone in the setting of presurgical evaluation of intractable epilepsy and is also useful for the differential diagnosis of epileptic seizures and non-epileptic events. Clinical history and symptomatology are of utmost importance for correct diagnosis. Diagnosis should not be made using only EEG findings.

A Single-center Analysis of Three Japanese Patients with Mahjong-related Seizures.

Mahjong is one of the most popular Chinese tile games played in Japan. Mahjong-related seizures (MRS) are rare praxis-induced seizures. We identified three patients with MRS from February 2000 to February 2021. All cases were men, with a middle-age onset, generalized convulsive seizures, and lack of non-provoked, myoclonic, and absence seizures. All patients had no or non-specific neuroimaging or electroencephalogram abnormalities. They did not have features linked to idiopathic generalized epilepsy. All patients were seizure-free after behavioral adjustments, although one patient required anti-seizure medication and avoided long duration games. These changes may help other patients with MRS continue playing Mahjong.

Ictal direct current shifts contribute to defining the core ictal focus in epilepsy surgery.

Identifying the minimal and optimal epileptogenic area to resect and cure is the goal of epilepsy surgery. To achieve this, EEG analysis is recognized as the most direct way to detect epileptogenic lesions from spatiotemporal perspectives. Although ictal direct-current shifts (below 1 Hz) and ictal high-frequency oscillations (above 80 Hz) have received increasing attention as good indicators that can add more specific information to the conventionally defined seizure-onset zone, large cohort studies on postoperative outcomes are still lacking. This work aimed to clarify whether this additional information, particularly ictal direct-current shifts which is assumed to reflect extracellular potassium concentration, really improve postoperative outcomes. To assess the usefulness in epilepsy surgery, we collected unique EEG data sets recorded with a longer time constant of 10 s using an alternate current amplifier. Sixty-one patients (15 with mesial temporal lobe epilepsy and 46 with neocortical epilepsy) who had undergone invasive presurgical evaluation for medically refractory seizures at five institutes in Japan were retrospectively enrolled in this study. Among intracranially implanted electrodes, the two core electrodes of both ictal direct-current shifts and ictal high-frequency oscillations were independently identified by board-certified clinicians based on unified methods. The occurrence patterns, such as their onset time, duration, and amplitude (power) were evaluated to extract the features of both ictal direct-current shifts and ictal high-frequency oscillations. Additionally, we examined whether the resection ratio of the core electrodes of ictal direct-current shifts and ictal high-frequency oscillations independently correlated with favourable outcomes. A total of 53 patients with 327 seizures were analyzed for wide-band EEG analysis, and 49 patients were analyzed for outcome analysis. Ictal direct-current shifts were detected in the seizure-onset zone more frequently than ictal high-frequency oscillations among both patients (92% versus 71%) and seizures (86% versus 62%). Additionally, ictal direct-current shifts significantly preceded ictal high-frequency oscillations in patients exhibiting both biomarkers, and ictal direct-current shifts occurred more frequently in neocortical epilepsy patients than in mesial temporal lobe epilepsy patients. Finally, although a low corresponding rate was observed for ictal direct-current shifts and ictal high-frequency oscillations (39%) at the electrode level, complete resection of the core area of ictal direct-current shifts significantly correlated with favourable outcomes, similar to ictal high-frequency oscillation outcomes. Our results provide a proof of concept that the independent significance of ictal direct-current shifts from ictal high-frequency oscillations should be considered as reliable biomarkers to achieve favourable outcomes in epilepsy surgery. Moreover, the different distribution of the core areas of ictal direct-current shifts and ictal high-frequency oscillations may provide new insights into the underlying mechanisms of epilepsy, in which not only neurons but also glial cells may be actively involved via extracellular potassium levels.

PRRT2 mutation in a Japanese woman: Adult-onset focal epilepsy coexisting with movement disorders and cerebellar atrophy.

Proline-rich transmembrane protein 2 (PRRT2) was confirmed as the causative gene of paroxysmal kinesigenic dyskinesia (PKD) as shown by genome-wide linkage analyses. PRRT2 mutations are also associated with benign familial infantile seizures, infantile convulsions and choreoathetosis, and childhood absence epilepsy, but few reports have investigated adult-onset epilepsy. We describe here a rare presentation of adult-onset focal epilepsy with a PRRT2 mutation in a 31-year-old woman who showed cerebellar atrophy, familial paroxysmal kinesigenic dyskinesia, and paroxysmal non-kinesigenic dystonia. Video-electroencephalography (EEG) demonstrated focal impaired awareness seizures, in which ictal EEG changes showed left temporal onset with rhythmic theta activity over the left temporal region. Magnetic resonance imaging showed mild cerebellar atrophy. The administration of lamotrigine 50 mg/day resulted in freedom from her seizures and lamotrigine 150 mg/day reduced paroxysmal non-kinesigenic dystonia. Furthermore, she had a rare frameshift mutation, c.604_607del, p.Ser202fs of which the pathogenicity has been reported in ClinVar, but it has not been reported in Japan. Mutation of the PRRT2 gene can cause adult-onset epilepsy, paroxysmal non-kinesigenic movement disorder, and cerebellar atrophy, suggesting an expanding clinical phenotypic spectrum associated with PRRT2 mutations.

Localizing and Lateralizing Value of Seizure Onset Pattern on Surface EEG in FCD Type II.

BACKGROUND: Surface ictal electroencephalographic (EEG) monitoring has an important role in the presurgical evaluation of patients with focal cortical dysplasia (FCD). This study aimed to examine the characteristics of seizure onset pattern (SOP) on surface ictal EEG. This information will be useful for invasive monitoring planning. METHODS: We reviewed 290 seizures from 31 patients with intractable seizures related to FCD type II (6 patients with FCD IIa and 25 patients with FCD IIb). We categorized the SOPs into five patterns and evaluated the relationships between the SOPs and the location and pathology of the FCD II subtype. RESULTS: The most common SOP was no apparent change (39.0%), followed by rhythmic slow wave and repetitive spikes/sharp waves. The SOP of rhythmic slow wave was associated with FCD II in the temporal lobe (P < 0.001), and the SOP of no apparent change was associated with FCD II in the occipital lobe (P = 0.012). The SOPs of rhythmic slow waves and fast activity were most common in FCD IIa, P < 0.001 and 0.031, respectively. The repetitive spikes/sharp waves SOP was the most common pattern in FCD IIb (P < 0.001). The surface SOPs provided correct localization and lateralization of epileptic foci in FCD in 62.1% and 62.7%, respectively. In 61.3% of the patients, over 50% of the SOPs in each patient indicated accurate localization. CONCLUSIONS: SOPs in surface EEG monitoring are beneficial for presurgical evaluation and lead to localization of epileptic foci and pathologic subtypes of FCD.

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.

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.

Impairment of emotional expression detection after unilateral medial temporal structure resection.

Detecting emotional facial expressions is an initial and indispensable component of face-to-face communication. Neuropsychological studies on the neural substrates of this process have shown that bilateral amygdala lesions impaired the detection of emotional facial expressions. However, the findings were inconsistent, possibly due to the limited number of patients examined. Furthermore, whether this processing is based on emotional or visual factors of facial expressions remains unknown. To investigate this issue, we tested a group of patients (n = 23) with unilateral resection of medial temporal lobe structures, including the amygdala, and compared their performance under resected- and intact-hemisphere stimulation conditions. The participants were asked to detect normal facial expressions of anger and happiness, and artificially created anti-expressions, among a crowd with neutral expressions. Reaction times for the detection of normal expressions versus anti-expressions were shorter when the target faces were presented to the visual field contralateral to the intact hemisphere (i.e., stimulation of the intact hemisphere; e.g., right visual field for patients with right hemispheric resection) compared with the visual field contralateral to the resected hemisphere (i.e., stimulation of the resected hemisphere). Our findings imply that the medial temporal lobe structures, including the amygdala, play an essential role in the detection of emotional facial expressions, according to the emotional significance of the expressions.